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`UNITED STATES PATENT AND TRADEMARK OFFIGE
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`
`APPLICATION
`NUMBER
`
`FILING or
`371(c) DATE
`
`GRP ART
`UNIT
`
`
`
`
`
`FIL
`
`61/548,957
`
`10/19/2011
`
`FEE REC'D
`
`250
`
`ATTY.DOCKET.NO
`
`3988 US Prl
`
`ITOT CLAIMSJIND CLAIMS
`
`26356
`ALCON
`
`IP LEGAL, TB4-8
`
`6201 SOUTH FREEWAY
`FORT WORTH, TX 76134
`
`CONFIRMATION NO. 8822
`
`FILING RECEIPT
`
`AC000000050 75695
`
`Date Mailed: 11/04/2011
`
`It will not be examined for patentability and will
`Receipt is acknowledged of this provisional patent application.
`become abandonednotlater than twelve monthsafter its filing date. Any correspondence concerning the application
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`any corrections to this Filing Receipt with your reply to the Notice. When the USPTO processesthe reply
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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;
`Powerof Attorney:
`Scott Chapple--46287
`
`If Required, Foreign Filing License Granted: 11/02/2011
`The country code and number of your priority application, to be usedfor 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 U.S. patent extend only throughoutthe 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
`in a specific country or in regional patent offices. Applicants may wish to consider the filing of an international
`page 1 of 3
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`IPR2018-01020 and IPR2018-01021, Exhibit 1010, Page 1
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`IPR2018-01020 and IPR2018-01021, Exhibit 1010, Page 1
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`
`
`application under the Patent Cooperation Treaty (PCT). An international (PCT) application generally has the same
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`GRANTED
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`if the phrase "IF REQUIRED, FOREIGN FILING
`The applicant has been granted a license under 35 U.S.C. 184,
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`page 2 of 3
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`IPR2018-01020 and IPR2018-01021, Exhibit 1010, Page 2
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`IPR2018-01020 and IPR2018-01021, Exhibit 1010, Page 2
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`
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`security or the export of technical data. Licensees should apprise themselvesof current regulations especially with
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`page 3 of 3
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`IPR2018-01020 and IPR2018-01021, Exhibit 1010, Page 3
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`IPR2018-01020 and IPR2018-01021, Exhibit 1010, Page 3
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`Atty. Docket No.: 3988 US Pr1
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`HIGH CONCENTRATION OLOPATADINE
`
`OPHTHALMIC COMPOSITION
`
`Technical Field of the Invention
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`invention relates to an ophthalmic composition containing a
`The present
`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
`
`experience
`conjunctivitis
`allergic
`suffering from ocular
`Individuals
`It has been
`symptoms such as ocular irritation, itchiness, redness and the like.
`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.
`
`it has been discovered that
`Recently, and as discussed further below,
`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 Pri
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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.
`
`is has been discovered that higher
`In the process of such innovation,
`molecular weight PEGs such as PEG 6000 can significantly enhance solubility of
`olopatadine. However, such PEGs cause risk of discomfort when administered to
`humans.
`It has also been discovered that cyclodextrins such as hydroxypropyl-y-
`cyclodextrin, hydroxypropyl-B-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
`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
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`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
`hydroxypropyl-y-cyclodextrin (HP-y-CD), hydroxypropyl- B-cyclodextrin (HP- B-
`CD),
`sulfoalkyl ether B-cyclodextrin (SAE- B-CD)(e.g.,
`sulfobutyl ether p-
`cyclodextrin (SBE-B-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
`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 compositionis
`preferably an aqueous solution. The ophthalmic composition includesa relatively
`high concentration of olopatadine solubilized in aqueous solution. The ophthalmic
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`Atty. Docket No.: 3988 US Pr1
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`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 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%, moretypically 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 showstatistically significant improvements in reducing late phase allergy
`symptomsat concentrations of about 0.7 w/v% olopatadine and above(e.g., at least
`0.65 w/v%,at least 0.67 w/v% orat 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 aluminumsalt and
`zine 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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`IPR2018-01020 and IPR2018-01021, Exhibit 1010, Page 7
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`Atty. Docket No.: 3988 US Pri
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`(Z)-11-(-
`of
`salt
`hydrochloride
`the
`is
`invention
`present
`dimethylaminopropylidene)-6, 1 1-dihydro-dibenz-[b,e Joxepin-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 frec base.
`
`invention also preferably includes
`the present
`composition of
`The
`derivative
`and more
`preferably
`f-cyclodextrin
`derivative,
`cyclodextrin
`y-cyclodextrin derivative or both to aid in solubilizing the olopatadine (i.e., as a
`solubilizer).
`The
`f-cyclodextrin derivative,
`y-cyclodextrin
`derivative
`or
`combination thereof is typically present in the composition at a concentration thatis
`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--cyclodextrin such as hydroxypropyl-
`B-cyclodextrin (HP-B-CD). One particularly desirable y-cyclodextrin derivative is a
`hydroxy alkyl-y-cyclodextrin such as hydroxypropyl-y-cyclodextrin (HP-y-CD).
`Another particularly desirable B-cyclodextrin derivative is sulfoalkyl ether-B-
`cyclodextrin (SAE-B-CD), particularly sulfobutyl ether-B-cyclodextrin (SBE-f-
`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) cyclodextrin derivative.
`
`When HP-B-CD is employed as the sole or substantially sole B-cyclodextrin
`derivative,
`it is typically present in the composition at a concentration that is at
`least 0.5% w/v, more typically at least 1.0% w/v and even more typically at least
`1.3% w/v, but is typically no greater than 3.0% w/v, typically no greater than 2.2%
`w/v and is typically no greater than 1.7% w/v. When HP-y-CD is employed as the
`sole or substantially sole y-cyclodextrin derivative,
`it
`is typically present in the
`composition at a concentration that is at least 0.5% w/v, more typically at least
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`Atty. Docket No.: 3988 US Prt
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`1.0% w/v and even moretypically at least 1.3% w/v, but is typically no greater than
`3.0% w/v, typically no greater than 2.2% w/v andis typically no greater than 1.7%
`w/v. When SAE-B-CD is employed as the sole or substantially sole B-cyclodextrin
`derivative,
`it is typically present in the composition at a concentration that is at
`least 0.3% w/v, more typically at least 0.7% w/v and even more typically at least
`0.9% w/v, but is typically no greater than 2.4% w/v, typically no greater than 1.5%
`w/v andis 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 hasits
`corporate headquarters
`in St. Louis, Missouri or ASHLAND SPECIALTY
`INGREDIENTS, headquartered in Wayne, New Jersey. SAE-B-CD can be formed
`based upon the teachings of U.S. Patent Nos. 5,134,127 and 5,376,645, which are
`incorporated herein by reference for all purposes.
`It
`is generally preferred,
`however, to use purified SAE-B-CD. Purified SAE-B-CD is preferably formed in
`accordance with the teachings of U.S. Patent Nos. 6,153,746 and 7,635,773.
`Purified SAE-B-CD is commercially available under the tradename CAPTISOL®
`from CyDex Pharmaccuticals, 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 of y-cyclodextrin
`derivative
`and/or
` -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 olopatadineis
`very strong and relatively low concentrations of y-cyclodextrin derivative and/or pB-
`cyclodextrin derivative can solubilize significant concentrations of olopatadine in
`aqueous solution. As such, more desirable and reasonable concentrations of
`additional solubilizing agent can be usedto aid in solubilizing the desired amounts
`of olopatadine.
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`Atty. Docket No.: 3988 US Prl
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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
`typically lack
`long term stability or shelf life.
`It has been found that such a composition will
`typically begin to precipitate after undesirably short periods of time.
`‘Thus,
`it is
`important to employ the y-cyclodextrin derivative and/or B-cyclodextrin derivative
`in combination with one or more additional solubilizers.
`
`As such, the ophthalmic composition of the present invention includes at
`least one solubilizing agent (1.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 polymeris 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 andis 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 whenit 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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`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 (PIG) 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 moretypically
`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 (LVDVI+, 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.
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`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 ofHPMCis typically in the range of 10,000 to 1,500,000
`and more typically in the range of 189,000 to 688,000).
`
`in composition at a
`is typically present
`it
`When HPMCis used alone,
`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 HECare 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 Icast 0.05% w/v, more typically at least 0.1% w/v and even
`more typically at
`least 0.2% w/v, but
`is typically no greater than 1.0% w/v,
`typically no greater than 0.55% w/v andis typically no greater than 0.4% w/v.
`When HPMC and HEC are used in combination, HEC is typically present
`in
`composition at a concentration that is at least 0.02% w/v, more typically at least
`0.06% w/v and even more typically at least 0.09% w/v, but is typically no greater
`than 0.6% w/v,typically no greater than 0.3% w/v and is typically no greater than
`0.17% w/v. Notably,
`in at
`least some embodiments of the present
`invention,
`HPMCis 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 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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`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 andis typically less than about 1.0 w/v
`%, more typically less than about 0.75 w/v % andstill 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
`the term “polyol” includes any compound having at least one hydroxyl
`herein,
`group on each of two adjacent