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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`
`APPLICATION
`NUMBER
`
`FILING or
`371(0) DATE
`
`GRP ART
`UNIT
`
`
`
`
`
`F
`
`61/548,957
`
`10/19/2011
`
`FEE REC'D
`
`250
`
`ATTY.DOCKET.NO
`
`3988 US Prl
`
`TOT CLAHVIS IND CLAIMS
`
`26356
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`CONFIRMATION NO. 8822
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`FILING RECEIPT
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`lllllllllllllllllIllllIIIIIIIIIIIIIllllllllllllllIllllllllllllllIllllllllllllllIllllllllllll
`00000005075695
`
`Date Mailed: 11/04/2011
`
`It will not be examined for patentability and will
`Receipt is acknowledged of this provisional patent application.
`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;
`Nuna 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
`
`PROTECTING YOUR INVENTION OUTSIDE THE UNITED STATES
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`Since the rights granted by a US. patent extend only throughout the territory of the United States and have no
`effect in a foreign country, an inventor who wishes patent protection in another country must apply for a patent
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`application under the Patent Cooperation Treaty (PCT). An international (PCT) application generally has the same
`effect as a regular national patent application in each PCT-member country. The PCT process simplifies the filing
`of patent applications on the same invention in member countries, but does not result in a grant of "an international
`patent" and does not eliminate the need of applicants to file additional documents and fees in countries where patent
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`

`security or the export of technical data. Licensees should apprise themselves of current regulations especially with
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`

`

`Atty. Docket No.: 3988 US l’rl
`
`HIGH CONCENTRATION OLOPATADINE
`
`OPHTHALMIC COMPOSITION
`
`Technical Field of the Invention
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`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 solubilizcd 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
`
`Individuals
`
`suffering from ocular
`
`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 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. Avoiding 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 Pr]
`
`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
`
`5
`
`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.
`
`10
`
`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
`
`15
`
`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
`
`20
`
`olopatadine. However, such PEGs cause risk of discomfort when administered to
`
`humans.
`
`It has also been discovered that cyclodextrins such as hydroxypropyl—y-
`
`cyclodextrin, hydroxypropyl—B—cyclodextrin and sulfoalkyl
`
`ether—B—cyclodextrin
`
`have the ability to solubilize significantly higher concentrations of olopatadine,
`
`however, use of undesirably high concentrations of these cyclodextrins has been
`
`25
`
`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.
`
`30
`
`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
`
`35
`
`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 Pr]
`
`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 B—cyclodextrin derivative to aid in
`
`the solubility of the olopatadine.
`
`The cyclodextrin derivative is preferably
`
`hydroxypropyi—y—cyclodextrin (HP-y—CD), hydroxypropyl— B—cyclodextrin (HP— [3—
`
`CD),
`
`sulfoalkyl ether B-cyclodextrin (SAE-
`
`[3-CD)(e.g.,
`
`sulfobutyl ether
`
`[3-
`
`cyclodextrin (SBE—B—CD», a combination thereof or the like. The composition will
`
`typically include a lactam polymer (e.g., polyvinylpyrrolidonc (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
`
`eyedrop 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
`
`-3-
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`Atty. Docket No.: 3988 US Pr]
`
`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 ocular allergic conjunctivitis, particularly late phase ocular allergic
`
`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 US. 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 ieast
`
`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
`
`10
`
`15
`
`20
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`25
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`30
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`Atty. Docket No.: 3988 US l’rl
`
`present
`
`invention
`
`is
`
`the
`
`hydrochloride
`
`salt
`
`of
`
`(Z)—1 l-(3-
`
`dimethylaminopropylidene)—6,l i-dihyd1‘o-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.
`
`The
`
`composition of
`
`the present
`
`invention also preferably includes
`
`eyelodextrin
`
`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.
`
`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—eyclodextrin such as hydroxypropyl—
`
`B—cyelodextrin (HP—B—CD). One particularly desirable y-cyclodextrin derivative is a
`
`hydroxy alkyl—y—cyclodextrin such as hydroxypropyl-y—cyclodextrin (llP—y—CD).
`
`Another particularly desirable B-cyclodextrin derivative is sulfoalkyl
`
`ether-B—
`
`cyclodextrin (SAE-B~CD), particularly sulfobutyl ether—B—cyelodextrin (SBE-B—
`
`CD).
`
`It
`
`is contemplated that a combination of hydroxypropyl-B—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
`
`one of the three as the sole or substantially the sole (i.e., at least 90% by weight of
`
`the cyclodextrin component) eyelodextrin 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—eyclodextrin derivative,
`
`it
`
`is typically present in the
`
`composition at a concentration that is at least 0.5% W/v, more typically at least
`
`10
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`
`20
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`25
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`30
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`Atty. Docket No.: 3988 US Pr]
`
`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% WW 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 US. 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—B—CD is preferably formed in
`
`accordance with the teachings of US. 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
`
`when benzalkonium chloride and/or polymeric quaternary ammonium compound
`
`are employed as preservation agents. Thus, lower concentrations ofy-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—cyclodextrin derivative and/or B~
`
`cyclodextrin derivative can solubilize significant concentrations of olopatadine in
`
`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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`Atty. Docket N0.: 3988 US Pr]
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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 B-cyclodextrin derivative will
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`typically lack
`
`long term stability or shelf life.
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`It has been found that such a composition will
`
`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-cyclodextrin derivative and/or B-cyclodextrin derivative
`in combination with one or more additional solubilizcrs.
`
`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.
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`Preferably,
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`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.
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`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
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`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
`
`least 20,000, more typically at least 46,000 and even more typically at least 54,000
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`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
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`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
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`and/or can provide tonicity to the composition (i.e., act as a tonicity agent). The
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`polycther is typically present in the composition at a concentration that is at least
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`_7_
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`Atty. Docket No.: 3988 US Pr]
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`1.0% w/v, more typically at least 3.0% w/v and even more typically at least 3.7 %
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`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.
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`5
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`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
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`the particular solubility and particular tonicity desired for the composition.
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`In a
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`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
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`at least 380 but is typically no greater than 800, more typically no greater than 580
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`and still more typically no greater than 420. One preferred PEG is PEG400.
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`It may also be desirable for the ophthalmic composition of the present
`
`invention to include viscosity enhancing agent in order to enhance residence time
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`15
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`of the composition upon the cornea when the composition is topically administered.
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`Examples of potentially suitable viscosity enhancing agent
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`include, without
`
`limitation, carboxyvinyl polymer, galactomannan, hyaluronic acid, cellulosic
`
`polymer, any combination thereof or the like.
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`In a preferred embodiment,
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`the
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`ophthalmic
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`composition
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`includes
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`hydroxyethyl
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`cellulose
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`(HEC),
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`20
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`hydroxylpropylmethyl cellulose (HPMC) or both. One preferred HEC is sold under
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`the tradename NASTROSOL® 250HX, which is commercially available from
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`Hercules Incorporated, Aqualon Division, Argyle, TX. One preferred I-IPMC 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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`25
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`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 (LVDVH, CP—42, 12 RPM and a temperature of 25 0C).
`
`In
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`30
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`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
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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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`35
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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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`Atty. Docket No.: 3988 US Prl
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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
`
`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
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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.
`
`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
`
`exeipients 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
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`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
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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,
`
`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.
`
`The composition can also include buffering agents and/or tonieity 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 borie acid, salts of boric acid, borate derivatives and other pharmaceutically
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`-9-
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`Atty. Docket No.2 3988 US Pr]
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`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
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`5
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`0.27 w/V % of the ophtha