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`HIGH CONCENTRATION OLOPATADINE
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`OPHTHALMIC COMPOSITION
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`Cross-Reference to Related Application
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`The present application claims priority based on US. Provisional Patent
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`Application Serial No. 61/487,789 filed May 19, 2011 and US. Provisional Patent.
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`Application Serial No. 61/548,957 filed October 19, 2011.
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`Technical Field of the Invention
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`The present
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`invention relates to an ophthalmic composition containing a
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`relatively high concentration of olopatadine. More particularly,
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`the present
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`invention relates to an ophthalmic aqueous solution containing a relatively high
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`concentration of solubilized olopatadine wherein the solution is capable of
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`providing enhanced relief from symptoms of ocular allergic disorders (e.g.,
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`conjunctivitis) in the early phase, the late phase or preferably both phases.
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`Background of the Invention
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`Individuals suffering from allergic conjunctivitis experience symptoms such
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`as ocular irritation, itchiness, redness and the like.
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`It has been found that these
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`symptoms are significantly reduced using topical ophthalmic solutions containing
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`olopatadine.
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`Such solutions are sold under the tradenames PATANOL® and
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`PATADAY®, which are both commercially available from Alcon Laboratories,
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`Inc., Fort Worth, TX.
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`These marketed solutions were generally believed to be the most efficacious
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`products known for addressing symptoms of allergic conjunctivitis. Surprisingly,
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`and as discussed further below,
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`it has been discovered that
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`relatively high
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`concentration solutions of olopatadine provide significantly improved reduction of
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`late phase ocular allergic conjunctivitis symptoms in addition to relief from early
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`phase symptoms. Even more surprising,
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`it has been discovered that such high
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`concentrations of olopatadine also provide significantly improved reduction of
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`redness in the early phase. Further,
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`it has been discovered that enhanced relief
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`from these early and late phase symptoms can be achieved through once a day
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`dosing of relatively high concentration olopatadine solution as opposed to greater
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`dosing frequencies.
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`The discovery of improved reduction of early and late phase symptoms is
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`quite significant and desirable for individuals suffering from allergic conjunctivitis.
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`Generally, these discoveries can provide patients greater relief from itching and
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`provide better aesthetic appearance to the eye. Further, avoiding more frequent
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`dosing is more convenient for patients and helps assure better compliance. Further
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`yet, improved early prevention and/or reduction of redness is particularly desirable
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`since patients generally have a desire to keep as much redness out of their eyes as
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`possible.
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`The discovery that relatively high concentration solutions of olopatadine can
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`relieve late phase ocular allergic conjunctivitis symptoms provides hope to
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`sufferers of ocular allergic conjunctivitis that a single dose of olopatadine per day
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`could provide a substantial degree of full day relief from their symptoms.
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`However, the development of a multi-dose ophthalmic solution that includes high
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`concentrations of olopatadine necessary to achieve desired levels of efficacy is
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`extremely difficult and complex.
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`Solubilizing high concentrations of olopatadine in a stable manner has
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`proven difficult by itself. Olopatadine, by itself, is only soluble in water (pH about
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`7.0) at room temperature up to a concentration of about 0.18 w/v%. However, it is
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`desirable to achieve solubilization of much higher concentrations of olopatadine in
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`an effort to treat late phase allergic conjunctivitis.
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`Solubilizing such higher concentrations of olopatadine has proven difficult.
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`As one example, exeipients
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`such as polyethylene glycol
`
`(PEG) 400 and
`
`polyvinylpyrrolidone (PVP), when used at reasonably desirable concentrations,
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`have proven incapable, alone or
`
`in combination, of solubizing sufficient
`
`concentrations of olopatadine in compositions having approximately neutral pH.
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`Thus, innovation is required to solubilize a sufficient concentration of olopatadine.
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`In the process of such innovation,
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`is has been discovered that higher
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`35 molecular weight PEGs such as PEG 6000 can significantly enhance solubility of
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`olopatadine. However, such PEGs cause risk of discomfort when administered to
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`humans.
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`It has also been discovered that cyclodextrins, such as hydroxypropyl-y-
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`cyclodextrin, hydroxypropyl-B—cyclodextrin and sulfoalkyl ether~B~cyclodextrin,
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`have the ability to solubilize significantly higher concentrations of olopatadine.
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`However, use of undesirably high concentrations of cyclodextrins has been found
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`to reduce olopatadine efficacy and/or preservation efficacy of solutions. As such,
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`still further innovation was needed to create a desirable olopatadine formulation
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`that not only solubilized sufficient amounts of olopatadine, but also allowed the
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`formulation to achieve other desirable pharmaceutical characteristics.
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`Thus, the present invention is directed at an ophthalmic composition that can
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`provide high concentrations of olopatadine topically to the eye. Further, the present
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`invention is directed to such a composition wherein the olopatadine is solubilized in
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`solution in a stable manner, the composition exhibits consistent efficacy against late
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`phase symptoms of allergic conjunctivitis,
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`the composition exhibits sufficient
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`antimicrobial activity to provide desired levels of preservation efficacy or any
`combination thereof.
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`Summary of the Invention
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`The present invention is directed to an ophthalmic composition for treatment
`
`of allergic conjunctivitis.
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`The composition will
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`include a relatively high
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`concentration ofolopatadine, preferably at least 0.67 w/v % olopatadine, preferably
`
`dissolved in solution. The composition will typically include a cyclodextrin, and
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`more particularly, a y—cyclodextrin derivative and/or a B-cyclodextrin derivative to
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`aid in solubilizing the olopatadine. The cyclodextrin derivative is preferably
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`hydroxypropyl—y-cyclodextrin (HP—y-CD), hydroxypropyl— B—cyclodextrin (HP- B—
`
`CD),
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`sulfoalkyl ether B—cyclodextrin (SAE~ B-CD)(e.g.,
`
`sulfobutyl ether
`
`[3-
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`cyclodextrin (SBE—B-CD)), or a combination thereof.
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`The composition will
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`typically include a lactam polymer (e.g., polyvinylpyrrolidone (PVP)) to aid in the
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`solubilization of the olopatadine. The composition will also typically include a
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`polyether (e.g., polyethylene glycol (PEG)) for enhancing solubility and/or aiding
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`in achieving the desired tonicity.
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`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,
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`to have a viscosity of 10 to 200 cps or any combination thereof. The
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`composition will also typically include a preservative to allow the composition to
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`achieve United States and/or European Pharmacopeia preservation standards.
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`Preferred preservatives include a polymeric quaternary ammonium compound, such
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`as polyquaternium-l, and benzalkonium chloride. The composition also typically
`
`includes boratc and/or polyol to aid in achieving desired preservation.
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`The present invention also contemplates a method of treating ocular allergy
`
`symptoms. The method will include topically applying a composition having a
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`defined combination of the characteristics described above to an eye of a human.
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`This step of topically applying the composition preferably includes dispensing an
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`eyedrop from an eyedropper.
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`Brief Description of the Drawings
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`FIG. 1 is a graph of mean conjunctiva! redness determined by a conjunctival
`
`allergen challenge (CAC) at 27 minutes.
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`FIG. 2 is a graph of mean conjunctival redness determined by a conjunctiva]
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`allergen challenge (CAC) atl6 hours.
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`FIG. 3 is a graph of mean total redness determined by a conjunctival
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`allergen challenge (CAC) at 24 hours.
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`FIG. 4 is a graph of mean ocular itching determined by a conjunctival
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`allergen challenge (CAC) at 24 hours.
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`FIG. 5 is a graph of mean conjunctival redness determine by a conjunctival
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`allergen challenge (CAC) at 24 hours.
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`Detailed Description of the Invention
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`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
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`composition also includes a unique set of excipients for solubilizing the olopatadine
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`while maintaining comfort of the composition and/or efficacy of the composition in
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`treating symptoms associate with allergic conjunctivitis, particularly symptoms
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`associated with late phase allergic conjunctivitis.
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`Preferably,
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`the composition
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`exhibits improved late phase efficacy in reducing ocular itching, ocular redness or
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`both. The composition also preferably exhibits improved early phase efficacy in
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`reducing ocular redness relative to vehicle and/or relative to lower concentrations
`
`of olopatadine.
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`In a preferred embodiment, the ophthalmic composition is a multi-
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`dose ophthalmic composition that also exhibits a required degree of preservation
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`efficacy.
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`Unless indicated otherwise, all component amounts (i.e., concentrations) are
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`presented on a weight volume percent
`
`(w/v%) basis and all
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`references to
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`concentrations of olopatadine are to olopatadine free base.
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`Olopatadine is a known compound that can be obtained by the methods
`
`disclosed in US. Pat. No. 5,116,863,
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`the entire contents of which are hereby
`
`incorporated by reference in the present specification for all purposes.
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`The
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`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
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`0.68%, still more typically at least 0.7%, possibly at least 0.75% and even possibly
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`at least 0.85% but typically no greater than 1.5% more typically no greater than
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`1.0%, still more typically no greater than 0.8%, possibly no greater than 0.75% and
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`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
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`concentrations of olopatadine are particularly important since it has been found that
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`efficacy of olopatadine in aqueous ophthalmic solutions in reducing late phase
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`allergy symptoms and enhanced reduction of early phase redness begins to show
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`improvement at concentrations greater than 0.5 w/v% of olopatadine and begins to
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`show statistically significant
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`improvements
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`in reducing late phase allergy
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`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
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`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
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`phosphate; organic acid salts such as acetate, maleate, fumarate, tartrate and citrate;
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`alkali metal saits such as sodium salt and potassium salt; alkaline earth metal salts
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`such as magnesium salt and calcium salt; metal salts such as aluminum salt and
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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.
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`The most preferred form of olopatadine for use in the solution compositions of the
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`present
`
`invention
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`is
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`the
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`hydrochloride
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`salt
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`of
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`(Z)—1 1 —(3—
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`dimethylaminopropylidene)-6,11—dihydro—dibenz—[b,e joxepin-2-acetic acid. When
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`olopatadine is added to the compositions of the present invention in this salt form,
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`0.77% olopatadine hydrochloride is equivalent
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`to 0.7% olopatadine free base,
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`0.88% olopatadinc hydrochloride is equivalent to 0.8% olopatadine free base, and
`0.99% olopatadine hydrochloride is equivalent to 0.9% olopatadine free base.
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`Generally,
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`it
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`is preferred that the entire concentration of olopatadine is
`
`dissolved in the composition as a water based or aqueous solution. However, it is
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`contemplated that olopatadine could be only partially dissolved. For example, a
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`portion of the oiopatadine could be in solution with the remainder being in
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`suspension.
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`The composition of
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`the present
`
`invention also preferably includes
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`cyclodextrin
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`derivative
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`and more
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`preferably B-cyclodextrin
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`derivative,
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`“ii—cyclodextrin derivative or both to aid in solubilizing the olopatadine (i.e., as a
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`solubilizer).
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`The B—cyclodextrin
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`derivative,
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`y—cyelodextrin
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`derivative
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`or
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`combination thereof is typically present in the composition at a concentration that is
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`at least 0.5% w/v, more typically at least 1.0% w/v and even possibly at least 1.3%
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`w/v, but is typically no greater than 4.0% w/v, typically no greater than 3.2% w/v
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`and even possibly no greater than 2.8% w/v. Preferably, the total concentration of
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`cyclodextrin is from 0.9 w/v% to 3.2 w/V%.
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`The specific amount of B—cyelodextrin derivative, y~cyclodextrin derivative
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`or combination thereof in a particular composition will typically depend upon the
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`type or combination of types of derivatives used. One particularly desirable
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`B~cyclodextrin derivative is a hydroxy alkyl-B-cyclodextrin such as hydroxypropyl—
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`B—cyclodextrin (HP-B-CD). One particularly desirable y—eyclodextrin derivative is a
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`hydroxy alkyl—y-eyclodextrin such as hydroxypropyl—y—cyelodextrin (HP—y-CD).
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`Another particularly desirable fi-cyclodextrin derivative is sulfoalkyl ether-B-
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`cyclodextrin (SAE-B—CD), particularly sulfobutyl ether—B-cyclodextrin (SBE—B—
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`CD).
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`It
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`is contemplated that a combination of hydroxypropyl‘B—cyclodextrin,
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`hydroxypropyl— y -eyclodextrin and/or sulfoalkyl ether-B-eyclodextrin derivative
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`may be employed in a single composition, but it is typically desirable to use only
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`one of the three as the sole or substantially the sole (i.e., at least 90% by weight of
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`the cyclodextrin component) cyclodcxtrin derivative.
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`When HP-B—CD is employed as the sole or substantially sole B—cyclodextrin
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`derivative,
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`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%
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`w/v and is typically no greater than 1.7% w/v. When HP-y-CD is employed as the
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`sole or substantially sole y-cyclodextrin derivative,
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`it is typically present in the
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`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
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`3.0% w/v, typically no greater than 2.2% w/v and is typically no greater than 1.7%
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`w/v. When SAE-B—CD is employed as the sole or substantially sole B—cyclodextrin
`
`derivative,
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`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
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`0.9% w/v, but is typically no greater than 2.4% w/v, typically no greater than 1.5%
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`w/v and is typically no greater than 1.1% w/v.
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`HP-B—CD is a commodity product and pharmaceutical grades of HP-B—CD
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`can be purchased from a variety of sources, for example, from SIGMA ALDRICH,
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`which has
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`its corporate headquarters in St. Louis, Missouri or ASHLAND
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`SPECIALTY INGREDIENTS, headquartered in Wayne, New Jersey. HP—y—CD is
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`a commodity product and pharmaceutical grades of HP~y~CD can be purchased
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`from. a variety of sources, for example, from SIGMA ALDRICH, which has its
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`corporate headquarters
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`in St. Louis, Missouri or ASHLAND SPECIALTY
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`INGREDIENTS, headquartered in Wayne, New Jersey. SAE-B-CD can be formed
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`based upon the teachings of US. Patent Nos. 5,134,127 and 5,376,645, which are
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`incorporated herein by reference for all purposes.
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`It
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`is generally preferred,
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`however, to use purified SAE—B—CD. Purified SAE—fi—CD is preferably formed in
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`accordance with the teachings of U.S. Patent Nos. 6,153,746 and 7,635,773.
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`Purified SAE—B—CD is commercially available under the tradename CAPTISOL®
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`from CyDcx Pharmaceuticals, Inc., Lenexa, KS.
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`With regard to y—cyclodextrin derivative and B-cyclodextrin derivative in the
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`composition of the present
`
`invention,
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`it has been found that undesirably high
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`concentrations of y~cyclodextrin derivative and/or B-cyclodextrin derivative can
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`significantly interfere with preservation efficacy of the compositions, particularly
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`when benzalkonium chloride and/or polymeric quaternary ammonium compound
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`are employed as preservation agents. Thus, lower concentrations of y-eyclodextrin
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`derivative
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`and/or
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`B-cyelodextrin
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`derivative
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`are
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`typically
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`preferred.
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`Advantageously,
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`it has also been found, however,
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`that
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`the ability of the y-
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`cyclodextrin derivative and B-cyclodextrin derivatives in solubilizing olopatadine is
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`very strong and relatively low concentrations of y-cyclodextrin derivative and/or B—
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`cyclodextrin derivative can solubilize significant concentrations of olopatadine in
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`aqueous solution. As such, more desirable and reasonable concentrations of
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`additional solubilizing agent can be used to aid in solubilizing the desired amounts
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`of olopatadine.
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`Further, it has been found that a composition formed using a combination of
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`solubilizing agents such as polyvinylpyrrolidone, tyloxapol, polyethylene glycol
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`and others to solubilize relatively high concentrations of olopatadine in the absence
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`of y-cyclodextrin derivative and/or B—cyclodextrin derivative will typically lack
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`long term stability or shelf life.
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`It has been found that such a composition will
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`typically begin to precipitate after undesirably short periods of time. Thus,
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`it is
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`important to employ the y-eyelodextrin derivative and/or B-cyclodextrin derivative
`in combination with one or more additional solubilizers.
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`As such, the ophthalmic composition of the present invention includes at
`
`least one solubilizing agent (i.e., solubilizer), but possibly two or more solubilizing
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`agents, in addition to eyelodextrin. The additional solubilizing agents can include
`
`surfactants such as eastor oil, polysorbate or others. Preferably, the additional
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`solubilizing agent[s] includes one or more polymers. One preferred polymer for
`
`aiding in solubilizing the olopatadine is
`
`lactam polymer. Another preferred
`
`polymer for aiding in solubilizing the olopatadine is polyether.
`
`As used herein, the phrase “lactam polymer” refers to any polymer formed
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`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 0/0 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
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`4.3% w/v. Polyvinylpyrrolidone (PVP) is the most preferred lactam polymer and
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`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
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`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
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`still more typically no greater than 62,000. One preferred PVP is sold under the
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`tradenames PLASDONE® K29/32 or K30, which have an average molecular
`
`weight of approximately 50,000 and are commercially available from ASHLAND
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`SPECIALTY INGREDIENTS, headquartered in Wayne, NJ, USA.
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`The polyether can aid in the solubility of olopatadine in the composition
`
`and/or can provide tonieity to the composition (i.e., act as a tonicity agent). The
`
`polyether is typically present in the composition at a concentration that is at ieast
`
`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.
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`In a preferred embodiment, the
`
`ophthalmic
`
`composition
`
`includes
`
`hydroxyethyl
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`cellulose
`
`(HEC),
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`hydroxylpropylmethyl cellulose (HPMC) or both. One preferred HEC is sold under
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`the tradename NASTROSOL® ZSOHX, which is commercially available from
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`llereules Incorporated, Aqualon Division, Argyle, TX. One preferred HPMC is
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`sold under the tradename E4M 2910 and is commercially available from Dow
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`Chemical, Midland, MI.
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`The amounts and molecular weights of HPMC and/or HEC used in the
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`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
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`Brookfield viscometer (LVDVl-t, CP-42, 12 RPM and a temperature of 25 0C). 1n
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`a preferred embodiment, the viscosity of the composition is at least 2.0 centipoise
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`(cps), more typically at least 15 cps, even more typically at least 21 cps and even
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`possibly at least 27 cps, but is typically no greater than 65 cps, typically no greater
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`than 40 cps, more typically nor greater than 33 cps and even possibly no greater
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`than 30 cps. Advantageously, and as further discussed below, viscosity within
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`these ranges has been discovered to be more desirable for producing desired droplet
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`sizes when the composition of the present invention is topically delivered from an
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`eye dropper.
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`The preferred average molecular weight of HEC, when used, is typically in
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`the range of 90,000 to 1,300,000 (e.g., approximately 1,000,000). The preferred
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`average molecular weight of HPMC is typically in the range of 10,000 to 1,500,000
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`and more typically in the range of 189,000 to 688,000).
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`When HPMC is used alone,
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`it
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`is typically present
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`in composition at a
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`concentration that is at least 0.15% w/V, more typically at least 0.3% w/v and even
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`more typically at
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`least 0.5% w/v, but
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`is typically no greater than 1.5% w/v,
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`typically no greater than 1.0% w/v and is typically no greater than 0.7% w/v.
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`When HEC is used alone,
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`it
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`is
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`typically present
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`in the composition at a
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`concentration that is at least 0.1% w/v, more typically at least 0.25% w/v and even
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`more typically at least 0.45% w/v, but
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`is typically no greater than 1.4% w/v,
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`typically no greater than 0.9% w/v and is typically no greater than 0.65% w/v.
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`Advantageously, when l’lPMC and lilEC are used to together, they may produce a.
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`synergistic viscosity effect which allows the use of low concentrations of these
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`cxcipients to produce the desired viscosity of the compositions. When HPMC and
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`HEC are used in combination, HPMC is typically present in composition at a
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`concentration that is at least 0.05% w/v, more typically at least 0.1% w/v and even
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`more typically at
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`least 0.2% w/v, but
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`is typically no greater than 1.0% w/v,
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`typically no greater than 0.55% w/v and is typically no greater than 0.4% w/v.
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`When l-lPMC and IIEC are used in combination, NBC is typically present
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`in
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`composition at a concentration that is at least 0.02% w/v, more typically at least
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`0.06% w/v and even more typically at least 0.09% w/v, but is typically no greater
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`than 0.6% w/v, typically no greater than 0.3% w/v and is typically no greater than
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`0.17% w/v. Notably,
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`in at least some embodiments of the present
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`invention,
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`HPMC is a preferred viscosity enhancing agent since, as the data present below
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`shows, it can also aid in solubilizing the olopatadine.
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`The composition can also include buffering agents and/or tonieity agents.
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`Suitable tonicity—adjusting agents and/or buffering agents include, but are not
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`limited to, mannitol, sodium chloride, glycerin, sorbitol, phosphates, borates,
`acetates and the like.
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`Borate is a highly preferred buffering agent and will typically be included in
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`the composition of the present invention. As used herein, the term "borate" shall
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`refer to boric acid, salts of boric acid, borate derivatives and other pharmaceutically
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`acceptable borates, or combinations thereof. Most suitable are: boric acid, sodium
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`borate, potassium borate, calcium borate, magnesium borate, manganese borate,
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`and other such borate salts. Typically, when used, the borate is at least about 0.05
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`w/v %, more typically at least about 0.18 w/v % and even possibly at least about
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`0.27 w/v % of the ophthalmic composition and is typically less than about 1.0 w/v
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`%, more typically less than about 0.75 w/v % and still more typically less than
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`about 0.4 w/v %, and even possibly less than about 0.35 w/v % of the ophthalmic
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`composition.
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`The composition of the present invention can also include polyol. As used
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`herein, the term “polyol” includes any compound having at least one hydroxyl
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`group on each of two adjacent carbon atoms that are not in trans configuration
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`relative to each other.
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`The polyol can be linear or cyclic, substituted or
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`unsubstituted, or mixtures thereof, so long as the resultant complex is water soluble
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`and pharmaceutically acceptable. Examples of such compounds include:
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`sugars,
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`sugar alcohols, sugar acids and uronic acids. Preferred polyols are sugars, sugar
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`alcohols and sugar acids, including, but not limited to: mannitol, glycerin, xylitol,
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`sorbitol and propylene glycol.
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`It is contemplated that the polyol may be comprised
`
`of two or more different polyols.
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`When both borate and polyol are present in the composition, borate typically
`
`interacts with polyol, such as glycerol, propylene glycol, sorbitol and mannitol, or
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`any combination thereof to form borate polyol complexes. The type and ratio of
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`such complexes depends on the number of OH groups of a polyol on adjacent
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`carbon atoms that are not in trans configuration relative to each other.
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`It shall be
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`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
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`borate and polyol can act as buffers and/or tonicity agents and can also aid in
`
`enhancing preservation efficacy of the composition.
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`In a preferred embodiment of the invention,
`
`the composition includes
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`propylene glycol, glycerine or both.
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`It has been found that y—cyclodextrin
`
`derivatives and/or B-cyclodextrin derivatives tend to inhibit preservation efficacy
`
`within the formulations of the present invention, however, propylene glycol in the
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`prcscnce of borate appears to significantly limit this inhibition. Moreover, it has
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`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
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`w/V% but is typically no greater than 5.0 w/v%, more typically no greater than 2.2
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`w/v% and even more typically no greater than 1.7 w/V%.
`
`In a same or alternative preferred embodiment of the invention,
`
`the
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`composition includes mannitol,
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`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. When used, mannitol,
`
`sorbitol or a combination thereof is typically present
`
`in the composition at a
`
`concentration that is at least 0.05 w/v%, more typically at least 0.2 w/v% and even
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`possibly at least 0.4 w/v% but is typically no greater than 3.0w/v%, more typically
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`no greater than 1.0 w/v% and even more typically no greater than 0.5 w/v%.
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`The composition of the present invention typically includes a preservative.
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`Potential
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`preservatives
`
`include, without
`
`limitation,
`
`hydrogen
`
`peroxide,
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`benzalkonium chloride (BAK), polymeric quaternary ammonium compound
`
`(PQAM),
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`biquanides,
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`sorbic
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`acid,
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`chlorohexidine or others.
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`Of
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`these,
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`benzalkonium chloride and polymeric quaternary ammonium compound such as
`
`polyquaternium—l have proven quite desirable.
`
`The polymeric quaternary ammonium compounds useful in the compositions
`
`of the present invention are those which have an antimicrobial effect and which are
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`ophthalmically acceptable. Preferred compounds of this type are described in US.
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`Pat. Nos. 3,931,319; 4,027,020; 4,407,791; 4,525,346; 4,836,986; 5,037,647 and
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`5,300,287; and. PCT application WO 91/09523 (Dziabo et al.). The most preferred
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`polymeric ammonium compound is polyquaternium-l , otherwise known as
`
`POLYQUAD® with a number average molecular weight between 2,000 to 30,000.
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`Preferably, the number average molecular weight is between 3,000 to 14,000.
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`When used, the polymeric quaternary ammonium compound is generally
`
`used in the composition of the present invention in an amount that is greater than
`
`about 0.00001 w/v %, more typically greater than about 0.0003 w/v % and even
`
`more typically greater than about 0.0007 w/V % of the ophthalmic composition.
`
`Moreover, the polymeric quaternary ammonium compound is generally used in the
`
`composition of the present invention in an amount that is less than about 0.01 w/v
`
`%, more typically less than. about 0.007 w/v %, even more typically less than 0.003
`
`w/v%, still more typically less than 0.0022 w/v% and even possibly less than about
`
`0.0015 w/v % ofthe ophthalmic composition.
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`BAK is generally used in the composition of the present invention in an
`
`amount that is greater than about 0.001 w/v %, more typically greater than about
`
`0.003 w