`NUMBER
`61/548,957
`
`FILING or
`37l(c)DATE
`10/19/2011
`
`GRPART
`UNIT
`
`FIL FEE REC'D
`250
`
`26356
`ALCON
`IP LEGAL, TB4-8
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`
`Ul\TfED STATES DEPA RTME'IT OF COMMERCE
`United States Patent and Trademark Office
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`\VVi\V.USpto.gov
`
`ATTY.DOCKET.NO
`3988 US Prl
`
`TOT CLAIMS IND CLAIMS
`
`CONFIRMATION NO. 8822
`FILING RECEIPT
`111111111111111111111111]~!l]~~1~~1~~H~~1~1~11111111111111111111111111111
`
`Date Mailed: 11/04/2011
`
`Receipt is acknowledged of this provisional patent application. It will not be examined for patentability and will
`become abandoned not later than twelve months after its filing date. Any correspondence concerning the application
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`
`Applicant( s)
`
`Daniel A. Gamache, Arlington, TX;
`Laman Alani, Fort Worth, TX;
`Malay Ghosh, Fort Worth, TX;
`Francisco Javier Galan, Teia, SPAIN;
`Nuria Carreras Perdiguer, Caldes de Montbui, SPAIN;
`Onkar N. Singh, Arlington, TX;
`Power of Attorney:
`Scott Chapple--46287
`
`If Required, Foreign Filing License Granted: 11/02/2011
`The country code and number of your priority application, to be used for filing abroad under the Paris Convention,
`is US 61 /548,957
`Projected Publication Date: None, application is not eligible for pre-grant publication
`Non-Publication Request: No
`Early Publication Request: No
`Title
`
`High Concentration Olopatadine Ophthalmic Compositions
`
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`APOTEX EX1011
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`Page 1
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`page 3 of 3
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`Page 3
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`
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`Atty. Docket No.: 3988 US Prl
`
`HIGH CONCENTRATION OLOPATADINE
`OPHTHALMIC COMPOSITION
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`Technical Field of the Invention
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`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 conjunctivitis in the
`early phase, the late phase or preferably both phases.
`
`Background of the Invention
`
`from ocular allergic conjunctivitis experience
`Individuals suffering
`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
`PA TANOL® and PA TADA Y®, which are both commercially available from
`Alcon Research Ltd., Fort Worth, TX.
`
`Recently, 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. Such discovery is significant since
`relief from such late phase symptoms is particularly desirable for individual
`suffering from ocular allergic conjunctivitis. Further, it has been discovered that
`relief from these late phase symptoms can be achieved through once a day dosing
`of relatively high concentration olopatadine solution as opposed to greater dosing
`frequencies. A voiding more frequent dosing is more convenient for patients and
`helps assure better compliance with a simpler dosing regimen.
`
`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
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`Atty. Docket No.: 3988 US Prl
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`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 up to a
`concentration of about 0.18 w/v% in water at a pH of about 7 .0 and at about room
`temperature. However, it is desirable to achieve solubilization of much higher
`concentrations of olopatadine in an effort to treat late phase ocular 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 to be insufficient, alone or in combination, to solubilize sufficient
`concentrations of olopatadine. 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(cid:173)
`cyclodextrin, hydroxypropyl-J3-cyclodextrin and sulfoalkyl ether-f3-cyclodextrin
`have the ability to solubilize significantly higher concentrations of olopatadine,
`however, use of undesirably high concentrations of these cyclodextrins has been
`found to reduce olopatadine efficacy and/or preservation efficacy of solutions
`including the undesirably high concentrations of cyclodextrin. 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 desired 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 ocular allergic conjunctivitis,
`the composition exhibits
`sufficient antimicrobial activity to provide desired levels of preservation efficacy or
`any combination thereof.
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`Atty. Docket No.: 3988 US Prl
`
`Summary of the Invention
`
`The present invention is directed to an ophthalmic composition for treatment
`of ocular allergic conjunctivitis. The composition will include a relatively high
`concentration of olopatadine, preferably at least 0.67 w/v % olopatadine, dissolved
`in solution. The composition will typically include a cyclodextrin, and more
`particularly, a y-cyclodextrin derivative and/or a 13-cyclodextrin derivative to aid in
`the solubility of the olopatadine. The cyclodextrin derivative is preferably
`hydroxypropyl-y-cyclodextrin (HP-y-CD), hydroxypropyl- 13-cyclodextrin (HP- f3-
`CD), sulfoalkyl ether 13-cyclodextrin (SAE-
`f3-CD)(e.g., sulfobutyl ether 13-
`cyclodextrin (SBE-13-CD)), a combination thereof or the like. The composition will
`typically include a lactam polymer (e.g., polyvinylpyrrolidone (PVP)) to aid in the
`solubility 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
`isotonic, be disposed in an eyedropper, have a pH of 5.5 to 8.0, to have an
`osmolality of 200 to 450 or any combination thereof. The composition will also
`typically includes a preservative to allow the composition to achieve United States
`and/or European Pharmacopeia preservation standards. Preferred preservatives
`include a polymeric quaternary ammonium compound 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
`eye drop from an eyedropper.
`
`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
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`Atty. Docket No.: 3988 US Prl
`
`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
`late phase ocular allergic
`treating ocular allergic conjunctivitis, particularly
`conjunctivitis. 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 are presented on a %
`(w/v) basis and all references to 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 solution
`formulation of the present invention contains 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 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%).
`
`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
`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
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`Atty. Docket No.: 3988 US Prl
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`(Z)-11-(3-
`of
`salt
`hydrochloride
`the
`is
`invention
`present
`dimethylaminopropylidene )-6, 11-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.
`
`includes
`invention also preferably
`The composition of the present
`cyclodextrin
`derivative
`and more
`preferably
`f3-cyclodextrin
`derivative,
`y-cyclodextrin derivative or both to aid in solubilizing the olopatadine (i.e., as a
`solubilizer).
`The
`f3-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.
`
`The specific amount of f3-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
`f3-cyclodextrin derivative is a hydroxy alkyl-f3-cyclodextrin such as hydroxypropyl(cid:173)
`f3-cyclodextrin (HP-f3-CD). One particularly desirable y-cyclodextrin derivative is a
`hydroxy alkyl-y-cyclodextrin such as hydroxypropyl-y-cyclodextrin (HP-y-CD).
`Another particularly desirable f3-cyclodextrin derivative is sulfoalkyl ether-f3-
`cyclodextrin (SAE-f3-CD), particularly sulfobutyl ether-f3-cyclodextrin (SBE-f3-
`CD).
`It is contemplated that a combination of hydroxypropyl-f3-cyclodextrin,
`hydroxypropyl- y -cyclodextrin and/or sulfoalkyl ether-j3-cyclodextrin derivative
`may be employed in a single composition, but it is typically desirable to use only
`one of the three as the sole or substantially the sole (i.e., at least 90% by weight of
`the cyclodextrin component) cyclodextrin derivative.
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`When HP-f3-CD is employed as the sole or substantially sole f3-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%
`35 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
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`Atty. Docket No.: 3988 US PrJ
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`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-f3-CD is employed as the sole or substantially sole f3-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 t~an 1.1 % w/v.
`
`HP-f3-CD is a commodity product and pharmaceutical grades of HP-f3-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-f3-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-f3-CD. Purified SAE-f3-CD is preferably formed in
`accordance with the teachings of U.S. Patent Nos. 6,153,746 and 7,635,773.
`Purified SAE-f3-CD is commercially available under the tradename CAPTISOL®
`from CyDex Pharmaceuticals, Inc., Lenexa, KS.
`
`With regard to y-cyclodextrin derivative and f3-cyclodextrin derivative in the
`composition of the present invention, it has been found that undesirably high
`concentrations of y-cyclodextrin derivative and/or f3-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 concentrations of y-cyclodextrin
`derivative
`and/or
`f3-cyclodextrin
`derivative
`are
`typically
`preferred.
`Advantageously, it has also been found, however, that the ability of the y(cid:173)
`cyclodextrin derivative and f3-cyclodextrin derivatives in solubilizing olopatadine is
`very strong and relatively low concentrations of y-cyclodextrin derivative and/or 13-
`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.
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`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 f:3-cyclodextrin derivative will typically lack
`It has been found that such a composition will
`long term stability or shelf life.
`typically begin to precipitate after undesirably short periods of time. Thus, it is
`important to employ the y-cyclodextrin derivative and/or f:3-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 solubilizing agents can include surfactants
`such as castor oil, polysorbate or others. Preferably, the 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
`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
`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
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`Atty. Docket No.: 3988 US Prl
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`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 polyethe1: 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 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 preferred embodiment, the
`ophthalmic
`composition
`includes
`hydroxyethyl
`cellulose
`(HEC),
`hydroxylpropylmethyl cellulose (HPMC) or both. One preferred HEC is sold under
`the tradename NASTROSOL® 250HX, 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 HEC used in the
`composition will depend upon the viscosity, osmolality and other attributes to be
`achieved for the composition. As used herein, viscosity is measured by a
`Brookfield viscometer (L VDVI+, CP-42, 12 RPM and a temperature of 25 °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.
`
`s
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
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`Atty. Docket No.: 3988 US Prl
`
`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).
`
`5
`
`10
`
`15
`
`When HPMC is used alone, it is typically present m 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
`20 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 leq.st
`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,
`HPMC is a preferred viscosity enhancing agent since, as the data present below
`shows, it can also aid in solubilizing the olopatadine.
`
`2s
`
`30
`
`35
`
`The composition can also include buffering agents and/or tonicity agents.
`Suitable tonicity-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 pharmaceutically
`
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`Atty. Docket No.: 3988 US Prl
`
`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 pharmaceutically acceptable. Examples of such compounds include: sugars,
`sugar alcohols, sugar acids and uronic acids. Preferred polyols are sugars, sugar
`alcohols and sugar acids, including, but not limited to: mannitol, glycerin, xylitol,
`sorbitol and