`
`HIGH CONCENTRATION OLOPATADINE
`
`OPHTHALMIC COMPOSITION
`
`Cross-Reference to Related Application
`
`The present application claims priority based on U.S. Provisional Patent
`Application Serial No. 61/487,789 filed May 19, 2011 and U.S. Provisional Patent
`Application Serial No. 61/548,957 filed October 19, 2011.
`
`Technical Field of the Invention
`
`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 disorders (e.g.,
`conjunctivitis) in the early phase, the late phase or preferably both phases.
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`Backgroundof the Invention
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`Individuals suffering from allergic conjunctivitis experience symptoms such
`as ocular irritation, itchiness, redness and the like.
`It has been found that these
`symptoms are significantly reduced using topical ophthalmic solutions containing
`olopatadine.
`Such solutions are sold under the tradenames PATANOL® and
`PATADAY®, which are both commercially available from Alcon Laboratories,
`Inc., Fort Worth, TX.
`
`These marketed solutions were generally believed to be the most efficacious
`products known for addressing symptoms ofallergic conjunctivitis. Surprisingly,
`and as discussed further below,
`it has been discovered that
`relatively high
`concentration solutions of olopatadine provide significantly improved reduction of
`late phase ocular allergic conjunctivitis symptoms in addition to relief from early
`phase symptoms. Even more surprising,
`it has been discovered that such high
`concentrations of olopatadine also provide significantly improved reduction of
`redness in the early phase. Further,
`it has been discovered that enhanced relief
`from these early and late phase symptoms can be achieved through once a day
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`dosing of relatively high concentration olopatadine solution as opposed to greater
`dosing frequencies.
`
`The discovery of improved reduction of early and late phase symptomsis
`quite significant and desirable for individuals suffering from allergic conjunctivitis.
`Generally, these discoveries can provide patients greater relief from itching and
`provide better aesthetic appearance to the eye. Further, avoiding more frequent
`dosing is more convenient for patients and helps assure better compliance. Further
`yet, improved early prevention and/or reduction of redness is particularly desirable
`since patients generally have a desire to keep as much rednessout of their eyes as
`possible.
`
`The discovery that relatively high concentration solutions of olopatadine can
`relieve late phase ocular allergic conjunctivitis symptoms provides hope to
`sufferers of ocular allergic conjunctivitis that a single dose of olopatadine per day
`could provide a substantial degree of full day relief from their symptoms.
`However, the development of a multi-dose ophthalmic solution that includes high
`concentrations of olopatadine necessary to achieve desired levels of efficacy is
`extremely difficult and complex.
`
`Solubilizing high concentrations of olopatadine in a stable manner has
`provendifficult by itself. Olopatadine, by itself, is only soluble in water (pH about
`7.0) at room temperature up to a concentration of about 0.18 w/v%. However,it is
`desirable to achieve solubilization of much higher concentrations of olopatadine in
`an effort to treat late phase allergic conjunctivitis.
`
`Solubilizing such higher concentrations of olopatadine has proven difficult.
`As one example, excipients
`such as polyethylene glycol
`(PEG) 400 and
`polyvinylpyrrolidone (PVP), when used at reasonably desirable concentrations,
`have proven incapable, alone or
`in combination, of solubizing sufficient
`concentrations of olopatadine in compositions having approximately neutral pH.
`Thus, innovation is required to solubilize a sufficient concentration of olopatadine.
`
`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-
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`cyclodextrin, hydroxypropyl-B-cyclodextrin and sulfoalkyl ether-B-cyclodextrin,
`have the ability to solubilize significantly higher concentrations of olopatadine.
`However, use of undesirably high concentrations of cyclodextrins has been found
`to reduce olopatadine efficacy and/or preservation efficacy of solutions. As such,
`still further innovation was needed to create a desirable olopatadine formulation
`that not only solubilized sufficient amounts of olopatadine, but also allowed the
`formulation to achieve other desirable pharmaceutical characteristics.
`
`Thus, the present invention is directed at an ophthalmic composition that can
`provide high concentrations of olopatadine topically to the eye. Further, the present
`invention is directed to such a composition wherein the olopatadine is solubilized in
`solution in a stable manner, the composition exhibits consistent efficacy against late
`phase symptoms of allergic conjunctivitis,
`the composition exhibits sufficient
`antimicrobial activity to provide desired levels of preservation efficacy or any
`combination thereof.
`
`Summaryofthe Invention
`
`The present inventionis directed to an ophthalmic composition for treatment
`of allergic conjunctivitis.
`The composition will
`include a relatively high
`concentration of olopatadine, preferably at least 0.67 w/v % olopatadine, preferably
`dissolved in solution. The composition will typically include a cyclodextrin, and
`more particularly, a y-cyclodextrin derivative and/or a B-cyclodextrin derivative to
`aid in solubilizing the olopatadine. The cyclodextrin derivative is preferably
`hydroxypropyl-y-cyclodextrin (HP-y-CD), hydroxypropyl- B-cyclodextrin (HP- B-
`CD),
`sulfoalkyl ether B-cyclodextrin (SAE- B-CD)(e.g.,
`sulfobutyl ether B-
`cyclodextrin (SBE-B-CD)), or a combination thereof.
`The composition will
`typically include a lactam polymer(e.g., polyvinylpyrrolidone (PVP)) to aid in the
`solubilization of the olopatadine. The composition will also typically include a
`polyether (e.g., polyethylene glycol (PEG)) for enhancing solubility and/or aiding
`in achieving the desired tonicity.
`It is generally desirable for the composition to be
`disposed in an eyedropper, have a pH of 5.5 to 8.0, to have an osmolality of 200 to
`450,
`to have a viscosity of 10 to 200 cps or any combination thereof. The
`composition will also typically include a preservative to allow the composition to
`achieve United States and/or European Pharmacopeia preservation standards.
`Preferred preservatives include a polymeric quaternary ammonium compound, such
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`as polyquaternium-1, and benzalkonium chloride. The composition also typically
`includes borate and/or polyol to aid in achieving desired preservation.
`
`The present invention also contemplates a method of treating ocular allergy
`symptoms. The method will include topically applying a composition having a
`defined combination of the characteristics described above to an eye of a human.
`This step of topically applying the composition preferably includes dispensing an
`eyedrop from an eyedropper.
`
`Brief Description of the Drawings
`
`FIG. 1 is a graph of mean conjunctival redness determined by a conjunctival
`allergen challenge (CAC) at 27 minutes.
`
`FIG. 2 is a graph of mean conjunctival redness determined by a conjunctival
`allergen challenge (CAC) at16 hours.
`
`FIG. 3 is a graph of mean total redness determined by a conjunctival
`allergen challenge (CAC) at 24 hours.
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`FIG. 4 is a graph of mean ocular itching determined by a conjunctival
`allergen challenge (CAC) at 24 hours.
`
`FIG. 5 is a graph of mean conjunctival redness determine by a conjunctival
`allergen challenge (CAC) at 24 hours.
`
`Detailed Description of the Invention
`
`The present invention is predicated upon the provision of an ophthalmic
`composition for treatment of allergic conjunctivitis. The ophthalmic composition is
`preferably an aqueous solution. The ophthalmic composition includes a relatively
`high concentration of olopatadine solubilized in aqueous solution. The ophthalmic
`composition also includes a unique set of excipients for solubilizing the olopatadine
`while maintaining comfort of the composition and/or efficacy of the composition 1n
`treating symptoms associate with allergic conjunctivitis, particularly symptoms
`associated with late phase allergic conjunctivitis.
`Preferably,
`the composition
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`exhibits improved late phase efficacy in reducing ocular itching, ocular redness or
`both. The composition also preferably exhibits improved early phase efficacy in
`reducing ocular redness relative to vehicle and/or relative to lower concentrations
`of olopatadine.
`In a preferred embodiment, the ophthalmic composition is a multi-
`dose ophthalmic composition that also exhibits a required degree of preservation
`efficacy.
`
`Unless indicated otherwise, all component amounts (i.e., concentrations) are
`presented on a weight volume percent
`(w/v%) basis and all
`references to
`concentrations of olopatadine are to olopatadinefree base.
`
`Olopatadine is a known compound that can be obtained by the methods
`disclosed in U.S. Pat. No. 5,116,863,
`the entire contents of which are hereby
`incorporated by reference in the present specification for all purposes.
`‘The
`formulation of the present invention contains at least 0.50%, more typically at least
`0.55%, 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 and enhanced reduction of early phase redness begins to show
`improvement at concentrations greater than 0.5 w/v% ofolopatadine and begins to
`show statistically 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% or at
`least 0.68 w/v%). Most preferably,
`the
`concentration of the olopatadine in the composition is 0.7 w/v%.
`
`Generally, olopatadine will be added in the form of a pharmaceutically
`acceptable salt. Examples of the pharmaceutically acceptable salts of olopatadine
`include inorganic acid salts such as hydrochloride, hydrobromide, sulfate and
`phosphate; organic acid salts such as acetate, maleate, fumarate, tartrate and citrate;
`alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts
`such as magnesium salt and calcium salt; metal salts such as aluminum salt and
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`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
`present
`invention
`is
`the
`hydrochloride
`salt
`of
`(Z)-11-G-
`dimethylaminopropylidene)-6,11-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 free base.
`
`is preferred that the entire concentration of olopatadine is
`it
`Generally,
`dissolved in the composition as a water based or aqueous solution. However,it is
`contemplated that olopatadine could be only partially dissolved. For example, a
`portion of the olopatadine could be in solution with the remainder being in
`suspension.
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`invention also preferably includes
`the present
`The composition of
`cyclodextrin
`derivative
`and more
`preferably B-cyclodextrin
`derivative,
`y-cyclodextrin derivative or both to aid in solubilizing the olopatadine (i.e., as a
`solubilizer).
`The
`-cyclodextrin derivative,
`y-cyclodextrin
`derivative
`or
`combination thereofis typically present in the composition at a concentration that is
`at least 0.5% w/v, more typically at least 1.0% w/v and even possibly at least 1.3%
`w/v, but is typically no greater than 4.0% w/v, typically no greater than 3.2% w/v
`and even possibly no greater than 2.8% w/v. Preferably, the total concentration of
`cyclodextrin is from 0.9 w/v% to 3.2 w/v%.
`
`The specific amount of B-cyclodextrin derivative, y-cyclodextrin derivative
`or combination thereof in a particular composition will typically depend upon the
`type or combination of types of derivatives used. One particularly desirable
`B-cyclodextrin derivative is a hydroxy alkyl-B-cyclodextrin such as hydroxypropyl-
`B-cyclodextrin (HP-B-CD). Oneparticularly 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-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 1s 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
`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 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 and is typically no greater than 1.7% w/v. When HP-y-CD is employed as the
`sole or substantially sole y-cyclodextrin derivative,
`it is typically present in the
`composition at a concentration that is at least 0.5% w/v, more typically at least
`1.0% w/v and even 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 and is typically no greater than 1.7%
`w/v. When SAE-B-CD is employed as the sole or substantially sole B-cyclodextrin
`derivative, it is typically present in the composition at a concentration that is at
`least 0.3% w/v, more typically at least 0.7% w/v and even moretypically 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.
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`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 Pharmaceuticals, Inc., Lenexa, KS.
`
`With regard to y-cyclodextrin derivative and B-cyclodextrin derivative in the
`composition of the present
`invention,
`it has been found that undesirably high
`concentrations of y-cyclodextrin derivative and/or B-cyclodextrin derivative can
`significantly interfere with preservation efficacy of the compositions, particularly
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`when benzalkonium chloride and/or polymeric quaternary ammonium compound
`are employed as preservation agents. Thus, lower concentrations of y-cyclodextrin
`derivative
`and/or
` f-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 B-
`cyclodextrin derivative can solubilize significant concentrations of olopatadine in
`aqueous solution. As such, more desirable and reasonable concentrations of
`additional solubilizing agent can be used to aid in solubilizing the desired amounts
`of olopatadine.
`
`Further, it has been found that a composition formed using a combination of
`solubilizing agents such as polyvinylpyrrolidone, tyloxapol, polyethylene glycol
`and others to solubilize relatively high concentrations of olopatadine in the absence
`of y-cyclodextrin derivative and/or B-cyclodextrin derivative will typically lack
`long term stability or shelf life.
`It has been found that such a composition will
`typically begin to precipitate after undesirably short periods of time. Thus,
`it is
`important to employ the y-cyclodextrin derivative and/or B-cyclodextrin derivative
`in combination with one or more additional solubilizers.
`
`As such, the ophthalmic composition of the present invention includes at
`least one solubilizing agent (i.e., solubilizer), but possibly two or more solubilizing
`agents, in addition to cyclodextrin. The additional solubilizing agents can include
`surfactants such as castor oil, polysorbate or others. Preferably, the additional
`solubilizing agent[s] includes one or more polymers. One preferred polymer for
`aiding in solubilizing the olopatadine is
`lactam polymer. Another preferred
`polymerfor 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 and is typically no greater than
`4.3% w/v. Polyvinylpyrrolidone (PVP) is the most preferred lactam polymer and
`can be the only or substantially the only lactam polymer. Thus,
`in a preferred
`embodiment, the lactam polymer consists or consists essentially of only PVP. The
`average molecular weight of the lactam polymer, particularly when it is PVP, is at
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`least 20,000, more typically at least 46,000 and even moretypically 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.c., act as a tonicity agent). The
`polyether is typically present in the composition at a concentration that is at least
`1.0% w/v, more typically at least 3.0% w/v and even more typically at least 3.7 %
`w/v, but is typically no greater than 8.0% w/v,typically no greater than 5.0% w/v
`and is typically no greater than 4.3% w/v. Polyethylene glycol (PEG) is the most
`preferred polyether and can be the only or substantially the only polyether polymer.
`Thus in a preferred embodiment, the polyether consists or consist essentially of
`only PEG. The average molecular weight of the PEG will typically depend upon
`the particular solubility and particular tonicity desired for the composition.
`In a
`preferred embodiment, the average molecular weight of the polyether, particularly
`whenit is PEG, is at least 200, more typically at least 320 and even more typically
`at least 380 but is typically no greater than 800, more typically no greater than 580
`and still more typically no greater than 420. One preferred PEG is PEG400.
`
`It may also be desirable for the ophthalmic composition of the present
`invention to include a viscosity enhancing agent in order to enhance residence time
`of the composition upon the cornea when the composition is topically administered.
`Examples of potentially suitable viscosity enhancing agent
`include, without
`limitation, carboxyvinyl polymer, galactomannan, hyaluronic acid, cellulosic
`polymer, any combination thereof or the like.
`In a preferred embodiment, the
`ophthalmic
`composition
`includes
`hydroxyethy!
`cellulose
`(HEC),
`hydroxylpropylmethy] cellulose (HPMC) or both. One preferred HECis 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
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`achieved for the composition. As used herein, viscosity is measured by a
`Brookfield viscometer (LVDVI+, CP-42, 12 RPM and a temperature 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.
`
`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 HPMCis 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/vand 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 1s
`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 TIPMC and HEC are used to together, they may produce a
`synergistic viscosity effect which allows the use of low concentrations of these
`excipients to produce the desired viscosity of the compositions. When HPMC and
`HEC are used in combination, HPMC is typically present in composition at a
`concentration that is at least 0.05% w/v, more typically at least 0.1% w/v and even
`more typically at
`least 0.2% w/v, but
`is typically no greater than 1.0% w/v,
`typically no greater than 0.55% w/v andis typically no greater than 0.4% w/v.
`When ITIPMC and HEC are used in combination, IIEC 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 andis typically no greater than
`0.17% w/v. Notably,
`in at least some embodiments of the present
`invention,
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`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 thelike.
`
`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
`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 % ofthe 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
`herein, the term “polyol” includes any compound having at least one hydroxyl
`group on each of two adjacent carbon atoms that are not in frans 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 propylene glycol.
`It is contemplated that the polyol may be comprised
`of two or more different polyols.
`
`Whenboth borate and polyol are present in the composition, borate typically
`interacts with polyol, such as glycerol, propylene glycol, sorbitol and mannitol, or
`any combination thereof to form borate polyol complexes. The type and ratio of
`such complexes depends on the number of OH groups of a polyol on adjacent
`carbon atomsthat are not in trans configuration relative to each other.
`It shall be
`understood that weight/volume percentages of the ingredients polyol and borate
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`include those amounts whether as part of a complex or not. Advantageously, the
`borate and polyol can act as buffers and/or tonicity agents and can also aid in
`enhancing preservation efficacy of the composition.
`
`the composition includes
`In a preferred embodiment of the invention,
`propylene glycol, glycerine or both.
`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
`presence of borate appears to significantly limit this inhibition. Moreover, it has
`been found that glycerine often acts in a manner very similar to propylene glycol
`when used for aiding preservation. When used, propylene glycol, glycerine or a
`combination thereofis typically present in the composition at a concentration that is
`at least 0.4 w/v%, more typically at least 0.65 w/v% and even possibly at least 0.85
`w/v% but is typically no greater than 5.0 w/v%, more typically no greater than 2.2
`w/v% and even more typically no greater than 1.7 w/v%.
`
`the
`In a same or alternative preferred embodiment of the invention,
`composition includes mannitol,
`sorbitol or both. Mannitol may also aid
`preservation of the composition of the present invention when used in the presence
`of borate. Moreover, it has been found that sorbitol often acts in a manner very
`similar to mannitol when used for aiding preservation. 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
`possibly at least 0.4 w/v% but is typically no greater than 3.0w/v%, more typically
`no greater than 1.0 w/v% and even moretypically no greater than 0.5 w/v%.
`
`The composition of the present invention typically includes a preservative.
`Potential
`preservatives
`include, without
`limitation,
`hydrogen
`peroxide,
`benzalkonium chloride (BAK), polymeric quaternary ammonium compound
`(PQAM),
`biquanides,
`sorbic
`acid,
`chlorohexidine or others.
`Of
`these,
`benzalkonium chloride and polymeric quaternary ammonium compound such as
`polyquaternium-! 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
`ophthalmically acceptable. Preferred compoundsof this type are described in U.S.
`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 (Dziaboet al.). The most preferred
`polymeric ammonium compound is polyquaternium-1, otherwise known as
`POLYQUAD® with a number average molecular weight between 2,000 to 30,000.
`Preferably, the number average molecular weight is between 3,000 to 14,000.
`
`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 compoundis 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 moretypically 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 % of the ophthalmic composition.
`
`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/v % and even more typically greater than about 0.007 w/v % of the
`ophthalmic composition. Moreover, BAK is generally used in the composition of
`the present invention in an amountthat is less than about 0.1 w/v %, more typically
`less than about 0.03 w/v % and even more typically less than about0.020 or 0.015
`w/v % of the ophthalmic composition.
`
`It is also contemplated that the composition of the present invention may
`benefit from the use of two different po