`US008791154B2
`
`c12) United States Patent
`Gamache et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,791,154 B2
`Jul. 29, 2014
`
`(54)
`
`HIGH CONCENTRATION OLOPATADINE
`OPHTHALMIC COMPOSITION
`
`(75)
`
`Inventors: Daniel A. Gamache, Arlington, TX
`(US); Laman Alani, Fort Worth, TX
`(US); Malay Ghosh, Fort Worth, TX
`(US); Francisco Javier Galan,
`Barcelona (ES); Nuria Carreras
`Perdiguer, Barcelona (ES); Onkar N.
`Singh, Arlington, TX (US)
`
`(73)
`
`Assignee: Alcon Research, Ltd., Fort Worth, TX
`(US)
`
`( *)
`
`Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 1 day.
`
`(21)
`
`Appl. No.: 13/475,607
`
`(22)
`
`Filed:
`
`May 18, 2012
`
`(65)
`
`Prior Publication Data
`
`US 2012/0295967 Al
`
`Nov. 22, 2012
`
`(60)
`
`(51)
`
`(52)
`
`(58)
`
`(56)
`
`Related U.S. Application Data
`
`Provisional application No. 61/487,789, filed on May
`19, 2011, provisional application No. 61/548,957,
`filed on Oct. 19, 2011.
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 311335
`A61K 47/4B
`COBB 37116
`COBL5/16
`A61K9/0B
`A61K9/00
`A61K 47132
`U.S. Cl.
`CPC ......... A61K 311335 (2013.01); A61K 47/4B969
`(2013.01); COBB 3710015 (2013.01); COBL 5116
`(2013.01); A61K 47132 (2013.01); A61K 9/0B
`(2013.01); A61K 9/004B (2013.01)
`USPC ........................................... 514/450; 514/449
`Field of Classification Search
`USPC .................................................. 514/449, 450
`See application file for complete search history.
`
`References Cited
`
`U.S. PATENT DOCUMENTS
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`912005 Gruening et al.
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`CA
`EP
`
`5/2001
`2 391 076
`1 004 309
`512000
`(Continued)
`
`OTHER PUBLICATIONS
`
`Chigbu, "The management of allergic eye disease in primary eye
`care", Contact Lens & Anterior Eye, 32, pp. 260-272, 2009.
`Chigbu, "The pathophysiology of ocular allergy: A review", Contact
`Lens & Anterior Eye, 32, pp. 3-15, 2009.
`Ciprandi et al., "Cetirizine reduces inflammatory cell recruitment and
`ICAM-1 (or CD54) expression on conjunctiva! epithelium in both
`early- and late-phase reactions after allergen-specific challenge", J
`Allergy Clin Immunol, vol. 95, No. 2, pp. 612-621, Feb. 1995.
`Du Buske, "Clinical comparison ofhistarnine Hl-receptor antagonist
`drugs", JAllergyClinlmmunol, vol. 98, No. 6,part3,pp. S307-S318,
`Dec. 1996.
`
`(Continued)
`
`Primary Examiner - My-Chau T Tran
`(74) Attorney, Agent, or Firm - Scott A. Chapple
`
`ABSTRACT
`(57)
`The present invention is an ophthalmic composition contain(cid:173)
`ing a relatively high concentration of olopatadine. The com(cid:173)
`position is typically an ophthalmic aqueous solution contain(cid:173)
`ing relatively high concentrations of olopatadine solubilized
`within the solution. The composition is preferably capable of
`providing enhanced relief from symptoms of ocular allergic
`conjunctivitis, particularly late phase symptoms of ocular
`allergic conjunctivitis.
`
`27 Claims, 5 Drawing Sheets
`
`ARGENTUM PHARM. 1001
`
`000001
`
`ARGENTUM PHARM. 1001
`
`
`
`US 8, 791,154 B2
`Page 2
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`2005/0244472 Al
`2006/0210645 Al
`2007 /0020336 Al
`2008/0132444 Al
`200910118262 Al
`2009/0232763 Al
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`201110082145 Al*
`2012/0015953 Al*
`
`1112005 Hughes et al.
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`112007 Loftsson et al.
`6/2008 Li et al.
`512009 Rohrs et al.
`912009 Kabra et al.
`912009 Trach et al.
`9/2010 Abelson et al.
`9/2010 Matsumura et al.
`12/2010 Kabra
`412011 Schneider et al.
`112012 Beauregard et al.
`
`FOREIGN PATENT DOCUMENTS
`
`514/235.2
`514/250
`
`EP
`EP
`EP
`EP
`GB
`JP
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`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`0862414
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`2169508
`2001-1587 50
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`
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`212007
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`1111988
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`7 /1991
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`212003
`212006
`2/2008
`12/2008
`9/2010
`
`OTHER PUBLICATIONS
`Fukuda et al., "Critical role oflgE-dependent mast cell activiation in
`a murine model of allergic conjunctivitis", J Allergy Clin Immunol,
`vol. 124, No. 4, 827-833.e2, Oct. 2009.
`International Search Report for corresponding PCT /US2012/038663
`with mailing date Jul. 25, 2012.
`International Written Opinion for corresponding PCT/US2012/
`038663 with mailing date Jul. 25, 2012.
`Izushi et al., "The role of histamine Hl receptors in late-phase reac(cid:173)
`tion of allergic conjunctivitis", European Journal of Pharmacology,
`440:79-82, 2002.
`Leonardi and Abelson, "Double-Masked, Randomized, Placebo(cid:173)
`Controlled Clinical Study of the Mast Cell-Stabilizing Effects of
`Treatment with Olopatadine in the Conjunctiva! Allergen Challenge
`Model in Humans", Clinical Therapeutics, vol. 25, No. 10, pp. 2539-
`2552, 2003.
`Ozaki et al., "Mast-cell activation augments the late phase reaction in
`experimental immune-mediated blepharoconjunctivitis", Graefe's
`Arch Clin Exp Ophthalmol, 241:394-402, 2003.
`U eta et al., letter to editor, "Development ofeosinophilic conjunctiva!
`inflammation at late-phase reaction in mst cell-deficient mice", J
`Allergy Clin Immunol, pp. 476-478, Aug. 2007.
`Vogelson et al., "Preclinical and Clinical Antiallergic Effect of
`Olopatadine 0.2% Solution 24 Hours after Topical Ocular Adminis(cid:173)
`tration", Allergy and Asthma Proc., vol. 25, No. 1, pp. 69-75, Jan.(cid:173)
`Feb. 2004.
`Yanni et al., "The In Vitro and In Vivo Ocular Pharmacology of
`Olopatadine (AL-4943A), an Effective Anti-Allegic/ Antihistaminic
`Agent", Journal of Ocular Pharmacology and Therapeutics, vol. 12,
`No. 4, 1996.
`International Preliminary Report on Patentability for corresponding
`PCT/US2012/038663 with mailing date Nov. 28, 2013.
`* cited by examiner
`
`000002
`
`
`
`U.S. Patent
`
`Jul. 29, 2014
`
`Sheet 1of5
`
`US 8,791,154 B2
`
`40.r.========;--------------1
`t+t Olopatadine 0.77%
`35 *--+--* Olopatadine 0.2%
`e- G-o Vehicle
`
`( l - - - -
`
`~ 0
`
`-------------~----------~
`---------~ -- - - -~-*
`
`_____ __,....
`
`~
`ill
`~ 3.0
`ill
`~
`"; ~j
`.>
`:):j
`u
`§
`''='I
`
`----
`"'"--
`
`----------- -
`
`--------~--
`.------
`
`--------·
`
`0 15
`i::
`u
`:::
`~ 1.0
`~
`
`05
`
`7
`
`s
`
`9
`
`10
`
`11
`
`13
`
`14
`
`c
`Post·CAC Thne (Minutes)
`
`1s
`
`FIG. 1
`
`•
`
`16 n
`
`18
`
`19
`
`~o
`
`000003
`
`
`
`U.S. Patent
`
`Jul. 29, 2014
`
`Sheet 2 of 5
`
`US 8,791,154 B2
`
`4.o.r.=======::::;----------------,
`H-t Olopatadine 0.77%
`3.5 *--+-* Olopatadine 0.2%
`e- e-o Veltlcle
`
`1.5
`
`1.0
`
`05
`
`00
`
`,,,. ---------- -
`
`t- .-
`
`------
`
`:
`
`;
`
`I
`
`7
`
`I
`
`8
`
`I
`
`9
`
`I
`
`10
`
`I
`
`11
`
`I
`
`I
`
`I
`
`I
`
`1~
`
`14
`13
`15
`Post·CAC Time (Minutes)
`
`I
`
`16
`
`I
`
`17
`
`I
`
`18
`
`I
`
`19
`
`I
`
`~o
`
`FIG. 2
`
`000004
`
`
`
`U.S. Patent
`
`Jul. 29, 2014
`
`Sheet 3 of 5
`
`US 8,791,154 B2
`
`10.r;:::::=====::::::;-----------------i
`H-t Olopatadine 0. 77%
`9 t-++ Olopatadine 0.2%
`8 e- e-o Veltlcle
`
`------~----------~
`---*
`
`7
`
`s
`
`9
`
`10
`
`11
`
`l~
`
`13
`
`14
`
`15
`
`16 n
`
`18
`
`19
`
`~o
`
`Post·CAC Time (Minutes)
`
`FIG. 3
`
`000005
`
`
`
`U.S. Patent
`
`Jul. 29, 2014
`
`Sheet 4 of 5
`
`US 8,791,154 B2
`
`4.o-rr=======:::;----------------,
`t-t-t Olopatadine 0. 77%
`15 *-+-*' Olopatadine 0.2%
`e- e-o Vehicle
`
`on 30
`,..
`]
`~ ~s (l- -
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`e- -
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-e
`
`~ 0
`
`... co -;:
`....
`()
`0
`= 1.5
`+-
`co
`Ill
`~ 1.0 t-
`
`-~---~------'1----------~--;1:
`
`0 5
`
`00
`
`I
`
`3
`
`4
`
`Post·CAC Tune (rvlinutes)
`
`6
`
`I
`
`7
`
`FIG. 4
`
`000006
`
`
`
`U.S. Patent
`
`Jul. 29, 2014
`
`Sheet 5 of 5
`
`US 8,791,154 B2
`
`40.r.=======~----------------,
`
`t-t-t Olopatadine 0.77%
`35 *--+--* Olopatadine 0.2%
`e- e-oveltlcle
`
`~
`Q)
`~ 3.0
`
`Q)
`
`!)--
`
`-
`
`-
`
`-
`
`,...
`
`-
`
`-
`
`-
`
`-
`
`~ ~5
`~
`E (J
`------~----------~
`- ~~ __,..._.,----- - -~-'f.-- - - - -
`~ 0 *" ____,~~ - - - ·
`s ·si
`0 u
`
`1.5 ----~~,....--~
`
`- -
`
`;
`
`05
`
`7
`
`s
`
`9
`
`1 o 11
`
`1 s
`12
`13
`14
`Post·CAC Time (Minutes)
`
`16 n 1 s
`
`19
`
`~o
`
`FIG. 5
`
`000007
`
`
`
`US 8,791,154 B2
`
`1
`HIGH CONCENTRATION OLOPATADINE
`OPHTHALMIC COMPOSITION
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`The present application claims priority based on U.S. Pro(cid:173)
`visional Patent Application Ser. No. 61/ 487, 789 filed May 19,
`2011 and U.S. Provisional Patent Application Ser. No.
`61/548,957 filed Oct. 19, 2011.
`
`TECHNICAL FIELD OF THE INVENTION
`
`The present invention relates to an ophthalmic composition
`containing a relatively high concentration of olopatadine.
`More particularly, the present invention relates to an oph(cid:173)
`thalmic aqueous solution containing a relatively high concen(cid:173)
`tration of solubilized olopatadine wherein the solution is
`capable of providing enhanced relief from symptoms of ocu-
`lar allergic disorders (e.g., conjunctivitis) in the early phase, 20
`the late phase or preferably both phases.
`
`BACKGROUND OF THE INVENTION
`
`2
`only soluble in water (pH about 7 .0) at room temperature up
`to a concentration of about 0.18 w/v %. However, it is desir(cid:173)
`able to achieve solubilization of much higher concentrations
`of olopatadine in an effort to treat late phase allergic conjunc(cid:173)
`tivitis.
`Solubilizing such higher concentrations of olopatadine has
`proven difficult. As one example, excipients such as polyeth(cid:173)
`ylene glycol (PEG) 400 and polyvinylpyrrolidone (PVP),
`when used at reasonably desirable concentrations, have
`10 proven incapable, alone or in combination, of solubizing suf(cid:173)
`ficient concentrations of olopatadine in compositions having
`approximately neutral pH. Thus, innovation is required to
`solubilize a sufficient concentration of olopatadine.
`In the process of such innovation, is has been discovered
`15 that higher molecular weight PEGs such as PEG 6000 can
`significantly enhance solubility of olopatadine. However,
`such PEGs cause risk of discomfort when administered to
`humans. It has also been discovered that cyclodextrins, such
`as hydroxypropyl-y-cyclodextrin, hydroxypropyl-~-cyclo
`dextrin and sulfoalkyl ether-~-cyclodextrin, have the ability
`to solubilize significantly higher concentrations of olopata-
`dine. 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
`25 innovation was needed to create a desirable olopatadine for(cid:173)
`mulation that not only solubilized sufficient amounts of olo(cid:173)
`patadine, but also allowed the formulation to achieve other
`desirable pharmaceutical characteristics.
`Thus, the present invention is directed at an ophthalmic
`30 composition that can provide high concentrations of olopata(cid:173)
`dine 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
`35 allergic conjunctivitis, the composition exhibits sufficient
`antimicrobial activity to provide desired levels of preserva(cid:173)
`tion efficacy or any combination thereof.
`
`Individuals suffering from allergic conjunctivitis experi(cid:173)
`ence symptoms such as ocular irritation, itchiness, redness
`and the like. It has been found that these symptoms are sig(cid:173)
`nificantly reduced using topical ophthalmic solutions con(cid:173)
`taining olopatadine. Such solutions are sold under the trade(cid:173)
`names PATANOL® and PATADAY®, which are both
`commercially available from Alcon Laboratories, Inc., Fort
`Worth, Tex.
`These marketed solutions were generally believed to be the
`most efficacious products known for addressing symptoms of
`allergic conjunctivitis. Surprisingly, and as discussed further
`below, it has been discovered that relatively high concentra(cid:173)
`tion solutions of olopatadine provide significantly improved
`reduction of late phase ocular allergic conjunctivitis symp(cid:173)
`toms in addition to relief from early phase symptoms. Even
`more surprising, it has been discovered that such high con- 40
`centrations 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
`dosing of relatively high concentration olopatadine solution 45
`as opposed to greater dosing frequencies.
`The discovery of improved reduction of early and late
`phase symptoms is quite significant and desirable for indi(cid:173)
`viduals suffering from allergic conjunctivitis. Generally,
`these discoveries can provide patients greater relief from 50
`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 55
`keep as much redness out of their eyes as possible.
`The discovery that relatively high concentration solutions
`of olopatadine can relieve late phase ocular allergic conjunc(cid:173)
`tivitis symptoms provides hope to sufferers of ocular allergic
`conjunctivitis that a single dose of olopatadine per day could 60
`provide a substantial degree of full day relief from their
`symptoms. However, the development of a multi-dose oph(cid:173)
`thalmic solution that includes high concentrations of olopata(cid:173)
`dine 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
`
`SUMMARY OF THE INVENTION
`
`The present invention is directed to an ophthalmic compo(cid:173)
`sition for treatment of allergic conjunctivitis. The composi(cid:173)
`tion will include a relatively high concentration of olopata(cid:173)
`dine, 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 deriva-
`tive and/or a ~-cyclodextrin derivative to aid in solubilizing
`the olopatadine. The cyclodextrin derivative is preferably
`hydroxypropyl-y-cyclodextrin (HP-y-CD), hydroxypropyl(cid:173)
`~-cyclodextrin (HP-~-CD), sulfoalkyl ether ~-cyclodextrin
`(SAE-~-CD)( e.g., sulfobutyl ether ~-cyclodextrin (SBE-~-
`CD)), or a combination thereof. The composition will typi(cid:173)
`cally 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 desir(cid:173)
`able forthe composition to be disposed in an eyedropper, have
`a pH of 5.5 to 8.0, to have an osmolality of200 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 preserva(cid:173)
`tives include a polymeric quaternary animonium compound,
`65 such as polyquaternium-1, and benzalkonium chloride. The
`composition also typically includes borate and/or polyol to
`aid in achieving desired preservation.
`
`000008
`
`
`
`US 8,791,154 B2
`
`3
`The present invention also contemplates a method of treat(cid:173)
`ing ocular allergy symptoms. The method will include topi(cid:173)
`cally 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 5
`includes dispensing an eyedrop from an eyedropper.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a graph of mean conjunctiva! redness determined
`by a conjunctiva! allergen challenge (CAC) at 27 minutes.
`FIG. 2 is a graph of mean conjunctiva! redness determined
`by a conjunctiva! allergen challenge (CAC) at 16 hours.
`FIG. 3 is a graph of mean total redness determined by a
`conjunctiva! allergen challenge (CAC) at 24 hours.
`FIG. 4 is a graph of mean ocular itching determined by a
`conjunctiva! allergen challenge (CAC) at 24 hours.
`FIG. 5 is a graph of mean conjunctiva! redness determine
`by a conjunctiva! allergen challenge (CAC) at 24 hours.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`4
`% 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 phar(cid:173)
`maceutically acceptable salt. Examples of the pharmaceuti(cid:173)
`cally acceptable salts of olopatadine include inorganic acid
`salts such as hydrochloride, hydro bromide, sulfate and phos-
`phate; 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
`10 salt and calcium salt; metal salts such as aluminum salt and
`zinc salt; and organic amine addition salts such as triethy(cid:173)
`lamine addition salt (also known as tromethamine ), morpho(cid:173)
`line addition salt and piperidine addition salt. The most pre(cid:173)
`in the solution
`ferred form of olopatadine for use
`15 compositions of the present invention is the hydrochloride
`salt of (Z)-11-~-dimethylaminopropylidene )-6, 11-dihydro(cid:173)
`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% olo-
`20 patadine free base, 0.88% olopatadine hydrochloride is
`equivalent to 0.8% olopatadine free base, and 0.99% olopata(cid:173)
`dine hydrochloride is equivalent to 0.9% olopatadine free
`base.
`Generally, it is preferred that the entire concentration of
`olopatadine is dissolved in the composition as a water based
`or aqueous solution. However, it is contemplated that olopata(cid:173)
`dine could be only partially dissolved. For example, a portion
`of the olopatadine could be in solution with the remainder
`being in suspension.
`The composition of the present invention also preferably
`includes cyclodextrin derivative and more preferably ~-cy
`clodextrin derivative, y-cyclodextrin derivative or both to aid
`in solubilizing the olopatadine (i.e., as a solubilizer). The
`~-cyclodextrin derivative, y-cyclodextrin derivative or com(cid:173)
`bination 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 greaterthan 4.0% w/v, typically no greaterthan 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 ~-cyclodextrin derivative, y-cyclo-
`dextrin derivative or combination thereofin a particular com(cid:173)
`position will typically depend upon the type or combination
`of types of derivatives used. One particularly desirable ~-cy
`clodextrin derivative is a hydroxy alkyl-~-cyclodextrin such
`as hydroxypropyl-~-cyclodextrin (HP-~-CD). One particu(cid:173)
`larly desirable y-cyclodextrin derivative is a hydroxy alkyl-y(cid:173)
`cyclodextrin such as hydroxypropyl-y-cyclodextrin (HP-y(cid:173)
`CD). Another particularly desirable ~-cyclodextrin derivative
`is sulfoalkyl ether-~-cyclodextrin (SAE-~-CD), particularly
`sulfobutyl ether-~-cyclodextrin (SBE-~-CD). It is contem(cid:173)
`plated that a combination of hydroxypropyl-~-cyclodextrin,
`hydroxypropyl-y-cyclodextrin and/or sulfoalkyl ether-~-cy
`clodextrin derivative may be employed in a single composi(cid:173)
`tion, 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-~-CD is employed as the sole or substantially
`sole ~-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 greaterthan2.2% w/v and is typically no greaterthan 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
`
`The present invention is predicated upon the provision of
`an ophthalmic composition for treatment of allergic conjunc(cid:173)
`tivitis. The ophthalmic composition is preferably an aqueous 25
`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 main(cid:173)
`taining comfort of the composition and/or efficacy of the 30
`composition in treating symptoms associate with allergic
`conjunctivitis, particularly symptoms associated with late
`phase allergic conjunctivitis. Preferably, the composition
`exhibits improved late phase efficacy in reducing ocular itch(cid:173)
`ing, ocular redness or both. The composition also preferably 35
`exhibits improved early phase efficacy in reducing ocular
`redness relative to vehicle and/or relative to lower concentra(cid:173)
`tions of olopatadine. In a preferred embodiment, the oph(cid:173)
`thalmic composition is a multi-dose ophthalmic composition
`that also exhibits a required degree of preservation efficacy. 40
`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 olopata(cid:173)
`dine are to olopatadine free base.
`Olopatadine is a known compound that can be obtained by 45
`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%, more typically at least 0.6% or0.65%, even more 50
`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 55
`than 0.72% of olopatadine where concentrations of olopata(cid:173)
`dine typically represent concentrations of olopatadine in free
`base form ifthe 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 60
`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 % of olopatadine and begins to show
`statistically significant improvements in reducing late phase 65
`allergy symptoms at concentrations of about 0.7 w/v % olo(cid:173)
`patadine and above (e.g., at least 0.65 w/v %, at least 0.67 w/v
`
`000009
`
`
`
`US 8,791,154 B2
`
`10
`
`5
`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 greaterthan2.2% w/v and is typically no greaterthan 1.7%
`w/v. When SAE-~-CD is employed as the sole or substan(cid:173)
`tially sole ~-cyclodextrin derivative, it is typically present in 5
`the composition at a concentration that is at least 0.3% w/v,
`more typically at least 0.7% w/v and even more typically at
`least 0.9% w/v, but is typically no greater than 2.4% w/v,
`typically no greater than 1.5% w/v and is typically no greater
`than 1.1 % w/v.
`HP-~-CD is a commodity product and pharmaceutical
`grades of HP-~-CD can be purchased from a variety of
`sources, for example, from SIGMAALDRICH, which has its
`corporate headquarters in St. Louis, Mo. or ASHLAND SPE(cid:173)
`CIALTY INGREDIENTS, headquartered in Wayne, N.J. HP(cid:173)
`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, Mo. or ASHLAND SPECIALTY
`INGREDIENTS, headquartered in Wayne, N.J. SAE-~-CD
`can be formed based upon the teachings of U.S. Pat. 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-~-CD. Purified SAE-~-CD is preferably 25
`formed in accordance with the teachings of U.S. Pat. Nos.
`6,153,746 and 7,635,773. Purified SAE-~-CD is commer(cid:173)
`cially available under the tradename CAPTISOL® from
`CyDex Pharmaceuticals, Inc., Lenexa, Kans.
`With regard to y-cyclodextrin derivative and ~-cyclodex- 30
`trin derivative in the composition of the present invention, it
`has been found that undesirably high concentrations ofy-cy(cid:173)
`clodextrin derivative and/or ~-cyclodextrin derivative can
`significantly interfere with preservation efficacy of the com(cid:173)
`positions, particularly when benzalkonium chloride and/or 35
`polymeric quaternary ammonium compound are employed as
`preservation agents. Thus, lower concentrations of y-cyclo(cid:173)
`dextrin derivative and/or ~-cyclodextrin derivative are typi(cid:173)
`cally preferred. Advantageously, it has also been found, how(cid:173)
`ever, that the ability of the y-cyclodextrin derivative and 40
`~-cyclodextrin derivatives in solubilizing olopatadine is very
`strong and relatively low concentrations of y-cyclodextrin
`derivative and/or ~-cyclodextrin derivative can solubilize sig(cid:173)
`nificant concentrations of olopatadine in aqueous solution. As
`such, more desirable and reasonable concentrations of addi- 45
`tional 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 polyvinylpyr(cid:173)
`rolidone, tyloxapol, polyethylene glycol and others to solu- 50
`bilize relatively high concentrations of olopatadine in the
`absence of y-cyclodextrin derivative and/or ~-cyclodextrin
`derivative will typically lack long term stability or shelflife.
`It has been found that such a composition will typically begin
`to precipitate after undesirably short periods of time. Thus, it 55
`is important to employ the y-cyclodextrin derivative and/or
`~-cyclodextrin derivative in combination with one or more
`additional solubilizers.
`As such, the ophthalmic composition of the present inven(cid:173)
`tion 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. Prefer(cid:173)
`ably, the additional solubilizing agent[ s] includes one or more
`polymers. One preferred polymer for aiding in solubilizing
`the olopatadine is lactam polymer. Another preferred poly(cid:173)
`mer for aiding in solubilizing the olopatadine is polyether.
`
`6
`As used herein, the phrase "lactam polymer" refers to any
`polymer formed from more than one lactam monomer. The
`lactam polymer is typically present in the composition at a
`concentration that is at least 1.0% w/v, more typically at least
`3.0% w/v and even more typically at least 3.7% w/v, but is
`typically no greater than 8.0% w/v, typically no greater than
`5.0% w/v and is typically no greater than 4.3% w/v. Polyvi(cid:173)
`nylpyrrolidone (PVP) is the most preferred lactam polymer
`and can be the only or substantially the only lactam polymer.
`Thus, in a preferred embodiment, the lactam polymer consists
`or consists essentially of only PVP. The average molecular
`weight of the lactam polymer, particularly when it is PVP, is
`at least 20,000, more typically at least 46,000 and even more
`typically at least 54,000 but is typically no greater than
`15 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 SPE-
`20 CIALTY INGREDIENTS, headquartered in Wayne, N.J.,
`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 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 greaterthan 5.0% w/v and is typically no greater
`than 4.3% w/v. Polyethylene glycol (PEG) is the most pre(cid:173)
`ferred polyether and can be the only or substantially the only
`polyether polymer. Thus in a preferred embodiment, the poly-
`ether consists or consist essentially of only PEG. The average
`molecular weight of the PEG will typically depend upon the
`particular solubility and particular tonicity desired for the
`composition. In a preferred embodiment, the average
`molecular weight of the polyether, particularly when it is
`PEG, is at least 200, more typically at least 320 and even more
`typically at least 3 80 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, galacto-
`mannan, hyaluronic acid, cellulosic polymer, any combina(cid:173)
`tion thereof or the like. In a preferred embodiment, the oph(cid:173)
`thalmic composition includes hydroxyethyl cellulose (HEC),
`hydroxylpropylmethyl cellulose (HPMC) or both. One pre(cid:173)
`ferred HEC is sold under the tradename NASTROSOL®
`250HX, which is commercially available from Hercules
`Incorporated, Aqualon Division, Argyle, Tex. One preferred
`HPMC is sold under the tradename E4M 2910 and is com-
`mercially available from Dow Chemical, Midland, Mich.
`The amounts and molecular weights ofHPMC and/or HEC
`used in the composition will depend upon the viscosity,
`osmolality and other attributes to be achieved for the compo(cid:173)
`sition. As used herein, viscosity is measured by a Brookfield
`60 viscometer (LVDVI+, CP-42, 12 RPM and a temperature of
`25° C.). In a preferred embodiment, the viscosity of the com(cid:173)
`