(12) Unlted States Patent
`(10) Patent No.:
`US 8,791,154 B2
`
`Gamache et al.
`(45) Date of Patent:
`Jul. 29, 2014
`
`USOO8791154B2
`
`(75)
`
`(54) HIGH CONCENTRATION OLOPATADINE
`OPHTHALMIC COMPOSITION
`Inventors: Daniel A. Gamache, Arlington, TX
`(US); Laman Alani, Fort Worth, TX
`.
`(3:)? glam]. thsh’.FOg\Y,Onh’ TX
`(
`), ”muse" *fo“
`a an:
`Barcelona (ES); Nur1a Carreras
`Perdiguer, Barcelona (ES); Onkar N.
`'
`'
`smgh’ Arhngton’ TX (Us)
`(73) Assignee: Alcon Research, Ltd., Fort Worth, TX
`(US)
`
`:1:
`
`.
`~
`) Not1ce.
`
`(
`
`~
`~
`~
`~
`Subject. to any disclaimer, the term ofthls
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 1 day.
`
`21,332,232 2
`5
`a
`5,037,647 A
`5,068,225 A
`5,116,863 A
`5,134,127 A
`5,141,961 A
`5,300,287 A
`5,376,645 A
`5,472,954 A
`gaggéaggg :
`a
`a
`5,624,962 A
`5,641,805 A *
`5,874,414 A
`5,874,418 A *
`5,888,493 A
`6,153,746 A
`6,280,745 B1
`6,407,079 B1
`6,511,949 B1
`6,828,356 B2
`
`$1333 flgufifiiyi et 3L
`10 a OS
`8/1991 Chowhan et a1.
`11/1991 P
`11
`t
`1.
`5/1992 06351113123th1.
`7/1992 Stella et a1.
`8/1992 Coapman
`4/1994 Park
`12/1994 Stella et a1.
`12/1995 Loftsson
`1/1337 gileQKSki it 31~
`ejIll eta .
`4/1997 Takeuchi et a1.
`6/1997 H ak
`t
`2/1999 szeloi‘fvgtif
`2/1999 Stella et a1.
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`3/1999 Sawaya
`11/2000 Shah et a1.
`8/2001 Flore et a1.
`6/2002 Muller et 31.
`1/2003 Nitta et a1.
`12/2004 Su et a1.
`
`........... 514/450
`
`1.
`
`(21) Appl. No.: 13/475 607
`3
`.
`Flledi
`
`May 18, 2012
`
`(22)
`
`(65)
`
`Prior Publication Data
`
`US 2012/0295967 A1
`
`Nov. 22, 2012
`
`_
`_
`Related U.S. Appllcatlon Data
`
`(60) Provisional application No. 61/487,789, filed on May
`19, 2011, provisional application No. 61/548,957,
`filed on Oct. 19,2011.
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int Cl
`A61K 31/335
`A61K 47/48
`C083 37/16
`C08L 5/16
`A61K 9/08
`A61K 9/00
`A61K 47/32
`(52) U S Cl
`.
`'
`'
`'
`CPC ””””” A61K 31/335 (2013’01)’ A61K 47/48969
`(201301); C083 37/0015 (201301); C08L 5”"
`(2013 ~01); A61K 47/32 (2013 ~01); A61K 9/08
`(2013.01); A61K 9/0048 (2013.01)
`USPC ........................................... 514/450; 514/449
`
`2/2006 Castillo et a1.
`6,995,186 B2 *
`7/2006 Avila et a1.
`7,074,424 B2
`12/2006 Hamano et a1.
`7,147,844 B2
`9/2008 Trach et a1.
`7,429,602 B2
`12/2009 Antle
`7,635,773 B2
`1/2002 Curatolo et a1.
`2002/0006443 A1
`10/2002 Vandecruys
`2002/0150616 A1
`9/2003 Babcock et a1.
`2003/0170309 A1
`2004/0198828 A1* 10/2004 Abelson et a1.
`2005/0004074 A1
`1/2005 Lyons et a1.
`2005/0191270 A1
`9/2005 Gruening et a1.
`.
`(Cont1nued)
`
`................ 514/450
`
`............... 514/571
`
`CA
`
`EP
`
`FOREIGN PATENT DOCUMENTS
`2 391 076
`5/2001
`
`1004 309
`
`5/2000
`(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 & Anterlor Eye, 32, pp. 3-15, 2009.
`Ciprandieta1.,“Cetirizinereducesinflammatorycellrecruitmentand
`ICAM-l (or CD54) expression on conjunctival epithelium in both
`early- and late-phase reactions after allergen-specific challenge”, J
`Allergy Clin Immunol, v01. 95, N0. 2, pp. 612-621, Feb. 1995.
`Du Buske, “Clinical comparison ofhistamine Hl-receptor antagonist
`drugs”, JAllergyClin Immunol, v01. 98, N0. 6, part3, pp. S307-S318,
`Dec. 1996.
`
`(58) Field of Classification Search
`USPC .................................................. 514/449, 450
`See application file for complete search history.
`References Cited
`
`(56)
`
`d
`C t'
`( on “me )
`Primary Examiner 7 My-Chau T Tran
`(74) Attorney, Agent, or Firm 7 Scott A. Chapple
`
`U.S. PATENT DOCUMENTS
`_
`18/137431 gagglafloski et al
`”/1974 Rankin
`1/1976 Green et a1.
`3/ 1976 Rankin
`5;1977 Greenleta1.1
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`10/1983 Stark
`9/1984 Wolfet a1.
`6/1985 Stark
`
`3,5353; :
`3:856:919 A
`3,931,319 A
`3,947,573 A
`4,027,020 A
`j’gg’ggg :
`4:407:791 A
`4,470,965 A
`4,525,346 A
`
`'
`
`ABSTRACT
`(57)
`The present invention is an ophthalmic composition contain-
`ing a relatively high concentration of olopatadine. The com-
`position is typically an ophthalmic aqueous solution contain-
`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
`|PR2018-01020 and |PR2018-01021, Exhibit 1001, Page 1
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1001, Page 1
`
`

`

`US 8,791,154 B2
`
`Page 2
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`2005/0244472 A1
`2006/0210645 A1
`2007/0020336 A1
`2008/0132444 A1
`2009/0118262 A1
`2009/0232763 A1
`2009/0239842 A1
`2010/0240625 A1
`2010/0249062 A1
`2010/0324031 A1
`2011/0082145 A1*
`2012/0015953 A1*
`
`11/2005
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`
`Hughes et al.
`Du Mee et al.
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`Li et al.
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`Kabra et al.
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`Matsumura et al.
`Kabra
`Schneider et al.
`Beauregard et al.
`
`......... 514/235.2
`.......... 514/250
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`FOREIGN PATENT DOCUMENTS
`
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`EP
`EP
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`WO
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`
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`2001-158750
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`2008/015695
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`
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`
`OTHER PUBLICATIONS
`Fukuda et al., “Critical role of IgE-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/US2012/03 8663
`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 H1 receptors in late-phase reac-
`tion of allergic conjunctivitis”, European Journal of Pharmacology,
`440:79-82, 2002.
`Leonardi and Abelson, “Double-Masked, Randomized, Placebo-
`Controlled Clinical Study of the Mast Cell-Stabilizing Effects of
`Treatment with Olopatadine in the Conjunctival 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.
`Ueta et al., letter to editor, “Development ofeo sinophilic conjunctival
`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-
`tration”, Allergy and Asthma Proc., vol. 25, No. 1, pp. 69-75, Jan.-
`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
`
`|PR2018-01020 and |PR2018-01021, Exhibit 1001, Page 2
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1001, Page 2
`
`

`

`US. Patent
`
`Jul. 29, 2014
`
`Sheet 1 of5
`
`US 8,791,154 B2
`
`
`
`
`
`IVIeanConjunctivalRedness
`
`' m010patadine0.77%
`',
`*HOIOpatadmeO.2%
`9 HVehicle
`
`
`
`
`Post-CAC Time (Minutes)
`
`FIG. 1
`
`|PR2018—01020 and |PR2018-01021, Exhibit 1001, Page 3
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1001, Page 3
`
`

`

`US. Patent
`
`Jul. 29, 2014
`
`Sheet 2 of5
`
`US 8,791,154 B2
`
`
`
`
`
`MeanConjunctivalRedness
`
`4.0
`
`*‘H Olopatadine 0.77%
`35 *‘H Olopatadine 0.2%
`9 9‘0 Vehicle
`
`
`
`
`Post-CAC Time (Minutes)
`
`FIG. 2
`
`|PR2018—01020 and |PR2018-01021, Exhibit 1001, Page 4
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1001, Page 4
`
`

`

`U.S. Patent
`
`Jul. 29, 2014
`
`Sheet 3 of5
`
`US 8,791,154 B2
`
`
`
`J m Olopatadine 0.77%
`*‘H Olopatadine 0.2%
`{9“ HVehicle
`71
`
`6 G— """"" H .. —
`__..._«~—~—-‘”"“"
`
`*‘”'“‘
`5 Mrfiww—fi'
`4 M"
`
`3!
`31
`
`1..
`
`
`
`,,,,,,
`
`__________..__——rfir—'
`
`"
`
`_________ ,
`
`MM
`
`3“
`
`
`
`
`
`MeanTotalRedness
`
`Post-CAC Time (Minutes)
`
`FIG. 3
`
`|PR2018—01020 and |PR2018-01021, Exhibit 1001, Page 5
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1001, Page 5
`
`

`

`US. Patent
`
`Jul. 29, 2014
`
`Sheet 4 of5
`
`US 8,791,154 B2
`
`4.0
`
`H“ Olopatadine 0.77%
`35 *‘H Olopatadmeo.2%
`990Vehicle
`
`‘5 o— —- ———————————— e— ___________ __ ._ —e
`
`3.0
`
`‘0
`
`15
`
`10
`
`9.0
`
`E§
`
`E
`’3
`
`0 O a
`
`0 2
`
`
`”Hm—fl.
`
`_-_....--——————+
`
`~W-____
`
`Post-CAC Time (Minutes)
`
`FIG. 4
`
`|PR2018—01020 and |PR2018-01021, Exhibit 1001, Page 6
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1001, Page 6
`
`

`

`US. Patent
`
`Jul. 29, 2014
`
`Sheet 5 of5
`
`US 8,791,154 B2
`
`4.0
`H" Olopatadine 0.77%
`3.5 *‘H Olopatadine 0.2%
`9 9'0 Vehicle
`
`l) O
`
`
`
`
`
`MeanConjunctivalRedness
`
`| 'I
`
`
`
`
`
`
`IIIIIIIII11rfi-Ir11'lr1mr-1mlr-ler-r1IIIIIIITITTT-rrrrfi—n—r
`
`7
`
`8
`
`9
`
`10
`
`11
`
`13
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`’30
`
`Post-CAC Time (Minutes)
`
`FIG. 5
`
`|PR2018—01020 and |PR2018-01021, Exhibit 1001, Page 7
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1001, Page 7
`
`

`

`US 8,791,154 B2
`
`1
`HIGH CONCENTRATION OLOPATADINE
`OPHTHALMIC COMPOSITION
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`The present application claims priority based on US. Pro-
`visional Patent Application Ser. No. 61/487,789 filed May 19,
`2011 and US. 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-
`thalmic aqueous solution containing a relatively high concen-
`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,
`the late phase or preferably both phases.
`
`BACKGROUND OF THE INVENTION
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`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-
`able to achieve solubilization of much higher concentrations
`of olopatadine in an effort to treat late phase allergic conjunc-
`tivitis.
`
`Solubilizing such higher concentrations of olopatadine has
`proven difficult. As one example, excipients such as polyeth-
`ylene glycol (PEG) 400 and polyvinylpyrrolidone (PVP),
`when used at reasonably desirable concentrations, have
`proven incapable, alone or in combination, of solubizing suf-
`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
`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-B-cyclo-
`dextrin and sulfoalkyl ether-B-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 efiicacy
`and/or preservation efficacy of solutions. As such, still further
`innovation was needed to create a desirable olopatadine for-
`mulation that not only solubilized sufficient amounts of olo-
`patadine, 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 olopata-
`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
`allergic conjunctivitis, the composition exhibits sufficient
`antimicrobial activity to provide desired levels of preserva-
`tion efficacy or any combination thereof.
`
`SUMMARY OF THE INVENTION
`
`Individuals suffering from allergic conjunctivitis experi-
`ence symptoms such as ocular irritation, itchiness, redness
`and the like. It has been found that these symptoms are sig-
`nificantly reduced using topical ophthalmic solutions con-
`taining olopatadine. Such solutions are sold under the trade-
`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-
`tion solutions of olopatadine provide significantly improved
`reduction of late phase ocular allergic conjunctivitis symp-
`toms in addition to relief from early phase symptoms. Even
`more surprising, it has been discovered that such high con-
`The present invention is directed to an ophthalmic compo-
`centrations of olopatadine
`also provide
`significantly
`sition for treatment of allergic conjunctivitis. The composi-
`improved reduction of redness in the early phase. Further, it
`tion will include a relatively high concentration of olopata-
`has been discovered that enhanced relief from these early and
`dine, preferably at least 0.67 w/v % olopatadine, preferably
`late phase symptoms can be achieved through once a day
`dissolved in solution. The composition will typically include
`dosing of relatively high concentration olopatadine solution
`a cyclodextrin, and more particularly, a y-cyclodextrin deriva-
`as opposed to greater dosing frequencies.
`tive and/or a B-cyclodextrin derivative to aid in solubilizing
`The discovery of improved reduction of early and late
`the olopatadine. The cyclodextrin derivative is preferably
`phase symptoms is quite significant and desirable for indi-
`hydroxypropyl-y-cyclodextrin (HP-y-CD), hydroxypropyl-
`viduals suffering from allergic conjunctivitis. Generally,
`B-cyclodextrin (HP-B-CD), sulfoalkyl ether B-cyclodextrin
`these discoveries can provide patients greater relief from
`(SAE-B-CD)(e.g., sulfobutyl ether B-cyclodextrin (SEE-[3-
`itching and provide better aesthetic appearance to the eye.
`CD)), or a combination thereof. The composition will typi-
`Further, avoiding more frequent dosing is more convenient
`cally include a lactam polymer (e.g., polyvinylpyrrolidone
`for patients and helps assure better compliance. Further yet,
`(PVP)) to aid in the solubilization of the olopatadine. The
`improved early prevention and/or reduction of redness is
`composition will also typically include a polyether (e.g.,
`particularly desirable since patients generally have a desire to
`polyethylene glycol (PEG)) for enhancing solubility and/or
`keep as much redness out of their eyes as possible.
`aiding in achieving the desired tonicity. It is generally desir-
`The discovery that relatively high concentration solutions
`able for the composition to be disposed in an eyedropper, have
`of olopatadine can relieve late phase ocular allergic conjunc-
`a pH of5.5 to 8.0, to have an osmolality of200 to 450, to have
`tivitis symptoms provides hope to sufferers of ocular allergic
`a viscosity of 10 to 200 cps or any combination thereof. The
`conjunctivitis that a single dose of olopatadine per day could
`composition will also typically include a preservative to allow
`provide a substantial degree of full day relief from their
`the composition to achieve United States and/or European
`symptoms. However, the development of a multi-dose oph-
`Pharmacopeia preservation standards. Preferred preserva-
`thalmic solution that includes high concentrations of olopata-
`tives include a polymeric quaternary ammonium compound,
`dine necessary to achieve desired levels of efficacy is
`such as polyquaternium-l, and benzalkonium chloride. The
`extremely difficult and complex.
`composition also typically includes borate and/or polyol to
`Solubilizing high concentrations of olopatadine in a stable
`aid in achieving desired preservation.
`manner has proven difficult by itself. Olopatadine, by itself, is
`|PR2018-01020 and |PR2018-01021, Exhibit 1001, Page 8
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1001, Page 8
`
`

`

`US 8,791,154 B2
`
`3
`The present invention also contemplates a method oftreat-
`ing ocular allergy symptoms. The method will include topi-
`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
`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) at 16 hours.
`FIG. 3 is a graph of mean total redness determined by a
`conjunctival allergen challenge (CAC) at 24 hours.
`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 conjunc-
`tivitis. 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 main-
`taining comfort of the composition and/or efficacy of the
`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-
`ing, 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 concentra-
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`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-
`maceutically acceptable salt. Examples of the pharmaceuti-
`cally acceptable salts of olopatadine include inorganic acid
`salts such as hydrochloride, hydrobromide, 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
`salt and calcium salt; metal salts such as aluminum salt and
`zinc salt; and organic amine addition salts such as triethy-
`lamine addition salt (also known as tromethamine), morpho-
`line addition salt and piperidine addition salt. The most pre-
`ferred form of olopatadine for use in the
`solution
`compositions of the present invention is the hydrochloride
`salt of (Z)-1 1-[3-dimethylaminopropylidene)-6,11-dihydro-
`dibenZ-[b,e]oxepin-2-acetic acid. When olopatadine is added
`to the compositions of the present invention in this salt form,
`0.77% olopatadine hydrochloride is equivalent to 0.7% olo-
`patadine free base, 0.88% olopatadine hydrochloride is
`equivalent to 0.8% olopatadine free base, and 0.99% olopata-
`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-
`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 B-cy-
`clodextrin derivative, y-cyclodextrin derivative or both to aid
`in solubilizing the olopatadine (i.e., as a solubilizer). The
`B-cyclodextrin derivative, y-cyclodextrin derivative or com-
`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 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 %.
`
`tions of olopatadine. In a preferred embodiment, the oph-
`thalmic composition is a multi-dose ophthalmic composition
`that also exhibits a required degree of preservation efficacy.
`Unless indicated otherwise, all component amounts (i.e.,
`The specific amount of B-cyclodextrin derivative, y-cyclo-
`concentrations) are presented on a weight volume percent
`dextrin derivative or combination thereof in a particular com-
`(w/v %) basis and all references to concentrations of olopata-
`position will typically depend upon the type or combination
`dine are to olopatadine free base.
`of types of derivatives used. One particularly desirable B-cy-
`Olopatadine is a known compound that can be obtained by
`the methods disclosed in US. Pat. No. 5,116,863, the entire
`clodextrin derivative is a hydroxy alkyl-B-cyclodextrin such
`as hydroxypropyl-B-cyclodextrin (HP-B-CD). One particu-
`contents ofwhich are hereby incorporated by reference in the
`larly desirable y-cyclodextrin derivative is a hydroxy alkyl-y-
`present specification for all purposes. The formulation of the
`cyclodextrin such as hydroxypropyl-y-cyclodextrin (HP-y-
`present invention contains at least 0.50%, more typically at
`CD). Another particularly desirable B-cyclodextrin derivative
`least 0.55%, more typically at least 0.6% or 0.65%, even more
`is sulfoalkyl ether-B-cyclodextrin (SAE-B-CD), particularly
`typically at least 0.67% or 0.68%, still more typically at least
`sulfobutyl ether-B-cyclodextrin (SBE-B-CD). It is contem-
`0.7%, possibly at least 0.75% and even possibly at least
`plated that a combination of hydroxypropyl-B-cyclodextrin,
`0.85% but typically no greater than 1.5% more typically no
`hydroxypropyl-y-cyclodextrin and/or sulfoalkyl ether-B-cy-
`greater than 1.0%, still more typically no greater than 0.8%,
`clodextrin derivative may be employed in a single composi-
`possibly no greater than 0.75% and even possibly no greater
`tion, but it is typically desirable to use only one of the three as
`than 0.72% of olopatadine where concentrations of olopata-
`the sole or substantially the sole (i.e., at least 90% by weight
`dine typically represent concentrations of olopatadine in free
`of the cyclodextrin component) cyclodextrin derivative.
`base form if the olopatadine is added to the composition as a
`When HP-B-CD is employed as the sole or substantially
`salt. These lower limits of concentrations of olopatadine are
`sole B-cyclodextrin derivative, it is typically present in the
`particularly important since it has been found that efficacy of
`composition at a concentration that is at least 0.5% w/v, more
`olopatadine in aqueous ophthalmic solutions in reducing late
`typically at least 1.0% w/v and even more typically at least
`phase allergy symptoms and enhanced reduction of early
`1 .3% w/v, but is typically no greater than 3.0% w/v, typically
`phase redness begins to show improvement at concentrations
`no greater than 2.2% w/v and is typically no greater than 1 .7%
`greater than 0.5 w/v % of olopatadine and begins to show
`w/v. When HP-y-CD is employed as the sole or substantially
`statistically significant improvements in reducing late phase
`sole y-cyclodextrin derivative, it is typically present in the
`allergy symptoms at concentrations of about 0.7 w/v % olo-
`composition at a concentration that is at least 0.5% w/v, more
`patadine and above (e.g., at least 0.65 w/v %, at least 0.67 w/v
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`US 8,791,154 B2
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`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 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 substan-
`tially 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 and is typically no greater
`than 1.1% w/v.
`
`HP-B-CD is a commodity product and pharmaceutical
`grades of HP-B-CD can be purchased from a variety of
`sources, for example, from SIGMA ALDRICH, which has its
`corporate headquarters in St. Louis, Mo. or ASHLAND SPE-
`CIALTY INGREDIENTS, headquartered in Wayne, N.J . HP-
`y-CD is a commodity product and pharmaceutical grades of
`HP-y-CD can be purchased from a variety of sources, for
`example, from SIGMA ALDRICH, which has its corporate
`headquarters in St. Louis, Mo. or ASHLAND SPECIALTY
`INGREDIENTS, headquartered in Wayne, N.J. SAE-B-CD
`can be formed based upon the teachings of US. 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-B-CD. Purified SAE-B-CD is preferably
`formed in accordance with the teachings of US. Pat. Nos.
`6,153,746 and 7,635,773. Purified SAE-B-CD is commer-
`cially available under the tradename CAPTISOL® from
`CyDex Pharmaceuticals, Inc., Lenexa, Kans.
`With regard to y-cyclodextrin derivative and B-cyclodex-
`trin derivative in the composition of the present invention, it
`has been found that undesirably high concentrations of y-cy-
`clodextrin derivative and/or B-cyclodextrin derivative can
`significantly interfere with preservation efficacy of the com-
`positions, particularly when benzalkonium chloride and/or
`polymeric quaternary ammonium compound are employed as
`preservation agents. Thus, lower concentrations of y-cyclo-
`dextrin derivative and/or B-cyclodextrin derivative are typi-
`cally preferred. Advantageously, it has also been found, how-
`ever, that the ability of the y-cyclodextrin derivative and
`B-cyclodextrin derivatives in solubilizing olopatadine is very
`strong and relatively low concentrations of y-cyclodextrin
`derivative and/or B-cyclodextrin derivative can solubilize sig-
`nificant concentrations ofolopatadine in aqueous solution. As
`such, more desirable and reasonable concentrations of addi-
`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-
`rolidone, tyloxapol, polyethylene glycol and others to solu-
`bilize 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.
`
`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-
`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
`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-
`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 greater than 5 .0% w/v and is typically no greater
`than 4.3% w/v. Polyethylene glycol (PEG) is the most pre-
`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 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, galacto-
`mannan, hyaluronic acid, cellulosic polymer, any combina-
`tion thereof or the like. In a preferred embodiment, the oph-
`thalmic composition includes hydroxyethyl cellulose (HEC),
`hydroxylpropylmethyl cellulose (HPMC) or both. One pre-
`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-
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`mercially available from Dow Chemical, Midland, Mich.
`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 compo-
`sition. As used herein, viscosity is measured by a Brookfield
`As such, the ophthalmic composition of the present inven-
`viscometer (LVDVI+, CP-42, 12 RPM and a temperature of
`tion includes at least one solubilizing agent (i.e., solubilizer),
`25° C.). In a preferred embodiment, the viscosity of the com-
`but possibly two or more solubilizing agents, in addition to
`position is at least 2.0 centipoise (cps), more typically at least
`cyclodextrin. The additional solubilizing agents can include
`15 cps, even more typically at least 21 cps and even possibly
`surfactants such as castor oil, polysorbate or others. Prefer-
`at least 27 cps, but is typically no greater than 65 cps, typically
`ably, the additional solubilizing agent[s] includes one or more
`no greater than 40 cps, more typically nor greater than 33 cps
`polymers. One preferred polymer for aiding in solubilizing
`and even possibly no greater than 30 cps. Advantageously,
`the olopatadine is lactam polymer. Another preferred poly-
`and as further discussed below, viscosity within these ranges
`mer for aiding in solubilizing the olopatadine is polyether.
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`US 8,791,154 B2
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`8
`pylene glycol. It is contemplated that the polyol may be
`comprised of two or more different polyols.
`When both borate and polyol are present in the composi-
`tion, borate typically interacts with polyol, such as glycerol,
`propylene glycol, sorbitol and mannitol, or any combination
`thereofto form borate polyol complexes. The type and ratio of
`such complexes depends on the number of OH groups of a
`polyol on adjacent carbon atoms that are not in trans configu-
`ration relative to each other. It shall be understood that
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`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