(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`
`(19) World Intellectual Property Organization { A
`
`International Bureau
`
`(43) International Publication Date
`7 February 2008 (07.02.2008)
`
` fe) TANIA UME TACT UTTAU
`
`(10) International Publication Number
`WO 2008/015695 A2
`
`(51) International Patent Classification:
`A6OLK 47/40 (2006.01)
`A6I1K 31/335 (2006.01)
`
`(21) International Application Number:
`PCT/IN2007/000199
`
`(22) International Filing Date:
`
`15 May 2007 (15.05.2007)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`(30) Priority Data:
`748/MUM/2006
`
`English
`
`English
`
`15 May 2006 (15.05.2006)
`
`IN
`
`(71) Applicant (for all designated States except US): SUN
`PHARMACEUTICAL
`INDUSTRIES
`LIMITED
`
`[IN/IN]; Acme Plaza, Andheri-Kurla Road, Andheri (e),
`Mumbai400 059 (IN).
`
`(72)
`(75)
`
`Inventors; and
`Inventors/Applicants (for US only): BHOWMICK,
`Subhas, Balaram [IN/IN]; Sun Pharma Advanced Re-
`search Centre, Nima Compound, Near Pratham Enclave,
`Tandalja Road, Baroda 390 020 (IN). LADDHA,Ritu,
`Nitin [IN/IN]; Sun Pharma Advanced Research Centre,
`Nima Compound, Near Pratham Enclave, Tandalja Road,
`Baroda 390 020 (IN). KHOPADE,Surekha [IN/IN]; Sun
`Pharma Advanced Research Centre, Nima Compound,
`Near Pratham Enclave, Tandalja Road, Baroda 390 020
`(IN).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BH, BR, BW,BY, BZ, CA, CH,
`CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES,
`FI, GB, GD, GE, GH, GM, GT, HN, HR, HU,ID,IL, IN,
`IS, JP, KE, KG, KM,KN,KP, KR, KZ, LA, LC, LK, LR,
`LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, Mx,
`MY, MZ, NA, NG, NI, NO, NZ, OM,PG,PH, PL, PT, RO,
`RS, RU, SC, SD, SE, SG, SK, SL, SM,SV, SY, TJ, TM,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM,ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM,KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU,TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK,EE,ES, FI,
`FR, GB, GR,HU,IE,IS, IT, LT, LU, LV, MC, MT, NL,PL,
`PT, RO,SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM,
`GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Declarations under Rule 4.17:
`
`as to the identity of the inventor (Rule 4.17(i))
`as to applicant’s entitlement to apply for and be granted a
`patent (Rule 4.17/(ii))
`as to the applicant’s entitlement to claim the priority of the
`earlier application (Rule 4.17(iii))
`of inventorship (Rule 4.17(iv))
`
`Published:
`
`without international search report and to be republished
`upon receipt of that report
`
`(54) Title: INCLUSION COMPLEX
`
`
`
`08/015695A2INITIOMNDTACATCAIOTIAAA
`
`© (57) Abstract: The invention relates to an inclusion complex of olopatadine or its pharmaceutically acceptable salt and hydrox-
`yalkyl-B-cylcodextrin, preferably hydroxypropyl-B-cylcodextrin. The present invention also relates to an aqueous topical solution
`comprising a therapeutically effective amount of olopatadine or its pharmaceutically acceptable salt; hydroxyalkyl-8-cylcodextrin,
`preferably hydroxypropyl-8-cylcodextrin and hydroxypropyl methylcellulose in an amountsufficient to enhance the physicalstabil-
`
`S ity of the solution.
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page1
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`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page1
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`

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`WO2008/015695
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`PCT/IN2007/000199
`
`INCLUSION COMPLEX
`
`FIELD OF THE INVENTION
`
`10
`
`way
`
`The presentinvention relates to inclusion complex of olopatadine in cyclodextrin and to aqueous
`solutions of olopatadine or its pharmaceutically acceptable salt for topical administration and
`process for preparation thereof.:
`
`BACKGROUNDOF THE INVENTION
`
`Olopatadine hydrochloride is a carboxylic acid derivative of doxepin, chemically describedas
`(Z)-1 1-[3-(Dimethylamino) propylidene]-6,| 1-dihydrodibenz [b,eJoxepin-2-acetic acid
`hydrochloride [C2jH2; NO3 .HCIJ, as disclosed in U.S. Pat Nos.4,871,865 and 4.923,892, buth
`assigned to Burroughs Wellcome. Olopatadine has antihistaminic and antiasthmatic activity.
`
`Qlopatadine hydrochloride is commercially available in the U.S as U.1% and 0.2%sterile
`ophthalmic solutions under the brand names PATANOL"and PATADAY*™respectively, both
`marketed by Alcon. PATANOL®is indicated for the treatment of signs and symptomsofallergic
`conjunctivitis and the approved ophthalmic solution contains olopatadine hydrochloride
`equivalent to 0.1% olopatadine, 0.01% benzalkonium chloride as preservative, dibasic sodium
`phosphate, sodium chloride, hydrochloric acid and / or sodium hydroxide (to adjust the pH) and
`purified water. It has a pH of about 7, and osmolality of about 300mOsm/kg. PATADAY™is
`indicated for the treatment of ocular itching associated with allergic conjunctivitis and the
`approved ophthalmic
`solution contains olopatadine hydrochloride
`equivalent
`to
`0.2%
`olopatadine, 0.01% benzalkoniumchloride as preservative, povidone, dibasic sodium phosphate,
`sodium chloride, edetate disodium, hydrochloric acid and / or sodium hydroxide (to adjust the
`pH) andpurified water. It has a pHof about 7, and osmolality ol about 300mOsin/kg.
`
`One obstacle for preparing olopatadine hydrochloride aqueous sulutions for topical delivery Is
`the stability of the aqueous solutions of olopatadine hydrochloride over the storage period.
`Ulopatadine aqueous solutions having a concentrations of 0.17%ow/vor higher were found to be
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page2
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`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page2
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`WO2008/015695
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`PCT/IN2007/000199
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`unstable over extended storage periods. The olopatadine hydrochloride precipitates or
`crystallizes out of the solution when used in concentrations higherthan 0.17%w/v. Hence, there
`is a needfor preparing aqueoussolutions of olopatadine hydrochloride containing olopatadine in
`concentrations of about 0.17%w/v orgreater, which are stable whenstored overthe shelf life of
`
`the product.
`
`10
`
`the ‘186 patent) discloses topically
`United States Patent No.6,995,186 (Alcon Inc., 2006,
`administrable solution compositionfortreating allergic or inflammatory disorders of the eye and
`nose comprising olopatadine and a polymeric ingredient, where the polymeric ingredient is a
`polymeric physical stability enhancing ingredient consisting essentially of polyvinylpyrrolidone
`or polystyrene sulfonic acid in an amount sufficient to enhance the physical stability of the
`solution, and wherein the composition does not contain polyvinyl alcohol, polyvinyl acrylic
`acid, hydroxypropy! methyl cellulose, sodium carboxymethyl cellulose, xanthan gum. Polyvinyl
`alcohol, polyviny! acrylic acid, hydroxypropyl methylcellulose, sodiumcarboxy methyl cellulose
`and xanthan gum have been disclosed in the *186 patent
`to cause physical
`instability of
`
`olopatadine solutions.
`
`In order to overcome the physical stability problems associated with olopatadine aqueous
`solutions, we have tried various
`ingredients selected from hydroxypropyl-f-cyclodextrin
`(HPBCD), polysorbate 20, polysorbate 80, propylene glycol, hydroxypropyl methylcellulose
`2910
`(HPMC E4M_
`premium),
`polyvinylpyrrolidone K-30,
`xanthan
`gum,
`sodium
`carboxymethylcellulose (Sodium CMC), carbopol 934P, polyviny! alcohol and mixtures thereof.
`
`to ta
`
`solutions of olopatadine
`topical
`stable aqueous
`We have now surprisingly found that
`hydrochloride can be prepared by forming an inclusion complex with a hydroxyalkyl clodextrin,
`preferably hydroxypropyl-B-cyclodextrin (HPBCD). Optionally, hydroxypropyl methylcellulose
`(HPMC) maybe used to stabilize the inclusion complexin the pharmaceutical eumposition,
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page3
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`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page3
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`PCT/IN2007/000199
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`SUMMARYOF THE INVENTION
`
`In one aspect of the invention, there is provided an inclusion complex of olopatadine orits
`pharmaceutically acceptable salt and a hydroxyalkyl cyclodextrin, preferably hydroxypropyl-B-
`cyclodextrin.
`
`In another aspect of the invention, there is provided an aqueous topical solution comprising a
`therapeutically effective amount of olopatadine or
`its pharmaceutically acceptable salt:
`hydroxyalkyl B-cylcodextrin,
`preferably hydroxypropy! 8-cylcodextrin and hydroxypropy!
`methy! cellulose in amountsufficient to enhancethe physical stability of the solution.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`thn
`
`invention provides an inclusion complex of olopatadine or its pharmaceutically
`The present
`acceptable salt and hydroxyalkyl-B-cyclodextrin, particularly hydroxypropyl-f-cyclodextrin. ‘The
`present
`invention also provides an aqueous topical solution, comprising a
`therapeutically
`effective amount of olopatadine or
`its pharmaceutically acceptable salt, hydroxyalkyl-B-
`cyclodextrin, particularly hydroxypropyl-B-cyclodextrin and hydroxypropyl methylcellulose in
`an amount sufficient to enhance the physical stability of the solution.
`
`Unless indicated otherwise, all component concentrations are presented on a %(w/v) basis andall
`
`reference to olopatadine are to olopatadine free base.
`
`The lerm “in an amount sufficient to enhance the physical stability of the solution”, as used
`herein means that the amount of—hydroxyalkyl-B-cyclodextrin. particularly hydroxypropyl-B-
`cyclodextrin is sufficient to form a complex with olopatadine orits pharmaceutically acceptable
`salt and thus keep it in solution, i.e. Preventits precipitation orcrystallization.
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page4
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`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page4
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`ms
`
`10
`
`tO Ln
`
`invention, the aqueous topical solution contains
`According to one embodiment of the present
`olopatadine or
`its pharmaceutically acceptable salts. 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 vilrate:
`alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as
`magnesium salt and calciumsalt; metal salts such as aluminumsalt and zine salt; and organic
`amine addition salts
`such as
`triethylamine addition salt
`(also known as
`tromethamine),
`morpholine addition salt andpiperidine addition salt. In a preferred embodimentof the present
`invention, the olopatadine for use in the aqueoustopical solution is a hydrochloride salt.
`In a
`most preferred embodiment of the present invention, the olopatadine hydrochloride salt may be
`used in concentrations such that it is equivalent to the olopatadine free base in amountranging
`Hom about 0.17% to about 0.62%. Preferably, the solution formulations intendedfor use in the
`eye contain about 0.17%to about 0.25%olopatadine and the solution formulations intended tor
`use in the nose contain about 0.35% to about 0.62% olopatadine,
`
`According to one embodimentof the present invention, the aqueous topical solution comprises
`cyclodextrin to enhance the physical stability of the solution. Cyclodentrins are a group of
`structurally related saccharides which are formed by enzymatic cyclization of stareh by a group
`of amylases termed glycosyltransferases. Cyclodextrins are cyclic oligosaccharides, consisting of
`(alpha-1,4)-linked alpha-D-glucopyranose units, with a lipophilic central cavity and a hydrophilic
`outer surface.
`In aqueous solutions, cyclodextrins form inclusion complexes with many drugs
`through a process in which the water molecules located in the central cavity are replaced by
`either the whole drug molecule, or more frequently, by some lipophilic portion of the drug
`structure. Once included in the cyclodextrin cavity,
`the drug molecules may be dissociated
`through complex dilution, by réplacementof the included drug by some othersuitable molecule
`or, the drug may be transferred to the matrix for whichit has the highest affinity. Importantly,
`since nv covalent bonds are formed or broken during the drug-cyelodextrin complex formation,
`the complexes are in dynamic equilibrium with free drug and cyclodextrin molecules. In solution,
`the complexes are usually prepared by addition of an excess amount of the drug tu an aqueous
`cyclodextrin solution. The most common naturally occurring cyclodextrins
`are
`alpha-
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page5
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`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page5
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`WO2008/015695
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`PCT/IN2007/000199
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`cyclodextrin, B-cyclodextrin and gamma-cyclodextrin consisting of 6, 7 and 8 glucopyranose
`units,
`respectively and their. derivatives. B-cyclodextrin appears
`to be
`the most useful
`pharmaceutical complexing agent due to its cavity size, availability and low cost. Examples of
`cyclodextrin derivatives that may be used in the pharmaceutical compositions of present
`invention include the hydroxypropyl derivatives of alpha-, beta- and gamma-cyclodentrin,
`sulfoalkylether cyclodextrins such as sulfobutylether beta-cyclodextrin, alkylated cyclodextrins
`such as the randomly methylated beta-cyclodextrin, and various branched cyclodextrins such as
`ulucosyl- and maltosy! beta-cyclodextrin, andthe like, and mixtures thereof.
`
`15
`
`The preferred cyclodextrins for use in the present invention include alky! cyclodextrins, hydroxy
`alkyl cyclodextrin, such as hydroxy propyl beta-cyclodextrin, carboxy alkyl cyclodextrins and
`sulfoatkyl ether cyclodextrin, such as sulfo butyl ether beta-cyclodextrin. Examples ofsuitable
`cyclodextrins for use in the present invention non-exclusively include alpha-cyclodextrin;, beta-
`eyclodextrin; gamma-cyclodextrin, methy! alpha-cyclodextrin; methyl beta-cyclodextrin, methyl!
`yamma-cyclodextrin; ethyl beta-cyclodextrin; butyl! alpha-cycfodextrin; butyl beta-cyclodextrin:
`butyl
`gamma-cyclodextrin,
`pentyl
`gamma-cyclodextrin.
`hydroxyethyl
`beta-cyclodextrin;
`hydroxyethyl gamma-cyclodextrin, 2-hydroxypropyl alpha-cyclodextrin; 2-hydroxypropyl beta-
`cyclodextrin; 2-hydroxypropyl gamma-cyclodextrin; 2-hydroxybutyl beta-cyclodextrin; acetyl!
`
`alpha-cyclodextrin; propionyl—beta-acetyl beta-cyclodextrin: acetyl gamma-cyclodextrin;
`
`
`cyclodextrin; butyryl beta-cyclodextrin, succinyl! alpha-cyclodextrin: succinyl! beta-cyclodextrin:
`
`
`
`succinyl benzoyl—beta-cyclodextrin:gamma-eyclodextrin; palmity! beta-cyclodextrin;
`
`toluenesulfonyl
`beta-cyclodextrin;
`acetyl methyl
`beta-cyclodextrin,
`acetyl
`butyl —beta-
`cyclodextrin,
`glucosyl
`alpha-eyclodextrin;
`glucosyl
`beta-cyclodextrin:
`glucosyl
`gammua-
`eyclodextrin; maltosy!
`alpha-cyclodextrin; maltosy!
`beta-cyclodextrin; maltosyl
`yamma-
`cyclodextrin: alpha-cyclodextrin carboxymethylether; beta-cyclodextrin carboxymethylether;
`gamma-cyclodextrin carboxymethylether, earboxymethylethy! beta-cyclodextrin, phosphate ester
`alpha-cyclodextrin; phosphate ester beta-cyclodextrin; phosphate ester gamma-cyclodextrin: 3-
`trimethylammonium-2-hydroxypropyl beta-cyclodextrin;
`sulfobuty]
`ether beta-cyclodextrin;
`carboxymethyl alpha-cyclodextrin; carboxymethyl! beta-cyclodextrin; carboxymethyl gamma-
`cyclodextrin, and combinations thereof. The most preferred cyclodextrin for use
`in the
`
`12 Ay
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`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page6
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`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page6
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`WO2008/015695
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`PCT/IN2007/000199
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`In a
`pharmaceutical composition of the present invention is hydroxy propyl beta-cyclodextrin.
`preferred embodiment ofthe present invention, hydroxypropyl beta-cyclodextrin may be usedin
`concentrations ranging from about 0.1% to about 20%w/v of the composition, and more
`preferably used in concentrations ranging from about 1.0% to about 10% w/v of the composition.
`Generally,
`for solutions meant
`for ophthalmic administration preferable concentration of
`hydroxypropyl beta-cyclodextrin is in the range from about 1.0% to about 5%:
`lor solutions
`meant for nasal administration, the concentration of hydroxypropyl! beta-vyclodextrin is in the
`
`Ws
`
`range from about 1.0% to about 10%.
`
`Olopatadine orits pharmaceutically acceptable salt, according to the present invention, forms an
`10
`
`
`
`inclusion cyclodextrins,—particularlycomplex with hydroxyalkyl-B-cyclodextrin, more
`particularly hydroxypropy!-B-cyclodextrin . The term “inclusion complex” as used herein refers
`to a combination of olopatadine orits pharmaceutically acceptable salt as defined above and a
`ceyclodexirin wherein the olopatadine orits pharmaceutically acceptable salt or a portion thereol’
`is associated with the cyclodextrin. Typically, the olopatadine orits pharmaceutically acceptable
`salt or guest molecule,
`is included within the cavity of the cyclodextrin, or the host molecule,
`wherein the cavity of the cyclodextrin is the space created by the eyclodextrin torous and the
`cyclodextrin substituents. The ratio of olopatadine or its pharmaceutically acceplable salt
`to
`hydroxypropyl B-cyleodestrin in the inclusion complex is from about
`|:1.05 to about 1:50 by
`weight. The amount of hydroxypropyl f-cylvodextrin
`present
`in the inclusion complex is
`sufficient to enhance the physicalstability of the olopatadine solution.
`
`I sn
`
`includes
`the composition further
`invention,
`According to one embodiment of the present
`hydroxypropy! methylcellulose (HPMC). The hydroxypropy! methylcellulose (HPMC) usedin
`the composition acts as a stabilizer for the inclusion complex of hydroxypropyl! beta-cyclodextrin
`and olopatadine or
`its pharmaceutically acceptable salt. Various yrades of hydroxypropy!
`methylvellulose (available from Dow Chemical, U.S.A under the METHOCEL trademark) may
`be used in the present invention. The grades commercially available are categorized depending
`upon the chemical substitution and hydrationrates, and may be usedin the compositions olthe
`present
`invention. Hydroxypropyl methylcellulose having a methoxy content of 19-24 % and
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page7
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`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page7
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`PCT/IN2007/000199
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`at
`
`relative rate of hydration is available
`hydroxypropyl content of 7-12 % with a fastest
`commercially under the brand name of Methocel Grade K. Hydroxypropy! methylcellulose with
`28-30 % methoxy content and.7-12 % ofhydroxypropyl content with a faster relative hydration
`rate as comparedto the above grade is available commercially under the brand name of Methovel
`Grade E. Hydroxypropyl methylcellulose with 27-30 % methoxy content and 4.0 - 7.5 % of
`hydroxypropyl content with a slow relative hydration rate is available as Methocel F grade and
`that with 27.5-31.5 % methoxy content and 0 % hydroxypropyl content and with slowest rate of
`hydration is available as Methocel Grade A.In a preferred embodimentof the present invention,
`hydroxypropyl methylcellulose, a 2%w/v aqueous solution of which has a viscosity of 4000 cps
`at 20°C. and which is commercially available as METHOCEL E4M, is used.
`In preferred
`embodiments of
`the
`present
`invention,
`hydroxypropyl methylcellulose may
`be
`used
`concentrations ranging from about 0.001% to about 5%, and more preferably in concentrations
`ranging from about 0.01% to about | % wy.
`
`The aqueous topical solution of the present invention may include an effective amount of an
`antimicrobial preservative. Examples of pharmaceutically acceptable preservatives that may be
`used in
`the present
`invention include, but are not
`limited to. benzethonium chloride,
`butylparaben, methy! paraben, ethyl paraben, propyl paraben, benzalkunium chloride, cetyl
`pyridinium chloride, thimerosal, chlorobutanol, phenylethy! alcohol. benzyl alcohol, potassium
`sorbate, sodium benzoate, sorbic acid and the like and mixtures thereof, The preferred
`preservative for the aqueoustopical solution of the present invention is benzalkonium chloride.
`It may be used in an amount ranging from about 0.005% to about | %w/v.
`
`IO wn
`
`invention may include an effective amount ofa
`The aqueous topical solution of the present
`chelating agent. Chelating agents remove trace amounts of metal ions such as iron, copper and
`lead and act as antioxidants, as otherwise these heavy metals catalyze oxidation reactions.
`Presently preferred chelating agents include different salts of edetic acid, These non-exclusively
`include edetate disodium, edetate calcium disodium, edetate tetrasodium, edetate trisodium, and
`the like and mixtures thereof. The preferred chelating agent for the aqueous topical solution of
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page8
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`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page8
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`the present invention is disodium edetate. It may be presentin the concentrations ranging from
`about 0.005% to about 0.1% w/v.
`
`wa
`
`The aqueous topical solution ofthe present invention may further include an effective amount of
`a tonicity agent. Examples oftonicity agents that may be usedin the aqueous topical solution of
`the present invention include all pharmaceutically acceptable and pharmacologically inert water-
`soluble compoundsreferred to in the pharmacopoeias such as UnitedStates Pharmacopoeia, as
`well as in Remington: The Science and Practice of Pharmacy; edition 19; Mack Publishing
`Company, Easton, Pennsylvania (1995). Preferred tonicity agent is sodiumchloride, which may
`be added in an amount which renders the solution isoosmotic. The aqueous topical solution is
`intended to be administered as nasal solution or eye drops. The osmolality may be adjusted
`preferably between 150 to 450 mOsm,and morepreferably between 250 to 350 mOsm.
`
`|
`invention may include an effective amount of
`The aqueous topical solution-of the present
`buffering agent. The buffering agents are included to minimize any change in pH during shelf
`life of the aqueous topical solution. Examples of buffering agents include, but are not limitedto,
`lactic avid, vitric acid, tartaric acid, phosphoric acid, avetic acid, hydrochloric acid. nitric acid,
`tromethamine, sodium or potassium metaphosphate, sodium or potassium phusphate, dibasic
`sodium phosphate dodecahydrate,
`sodium or potassiumacetate, ammonia. sodium varbonate,
`sodium or potassium hydroxide, dibasic sodium phosphate, sodium borate, and the like and
`mixtures thereof. Strong mineral acids like hydrochloric acid or strong bases such as,sodium
`hydroxide may be used for adjusting pH. The aqueous topical solution intended for ophthalmic
`administration has a pH4 to 8, preferably pH of 6.5 to 7.5, and most preferably a pHof6.8 to
`7.2. The aqueous topical solution intended for nasal administration has a pHof3.0 to 6.0. and
`most preferably a pH of 3.5 to 5.0.
`
`bo A
`
`invention may optionally include an effective
`The aqueous topical solution of the present
`amount of an antioxidant. The antioxidant may be one or more antioxidants, reducing agents and
`antioxidant synergist, and may be selected from acety! cysteine, alpha tocophero! acetate, d-
`alpha tocopherol. dl-alpha tocopherol, ascorby! palmitate, butylated hydroxyanisole (BHA),
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page9
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`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page9
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`butylated hydroxytoluene (BHT), cysteine, cysteine hydrochloride, propyl gallate, ascorbic acid,
`valcium ascorbate, calcium bisulphate, calcium sulphite, ascorbic acid,
`isoascorbic acid,
`potassium metabisulfite, sodium ascorbate, sodium bisulphate, sodium metabisulphite, sodium
`sulphite. sodium thiosulphate,
`thioglycerol, citric acid . edetic avid(EDTA) and its: salts,
`hydroxyquinoline sulphate, phosphoric acid, sodiumcitrate and tartaric acid. ‘The antioxidants
`may be used in amounts conventional to the pharmaceutical art.
`
`invention may optionally include an effective
`The aqueous topical solution of the present
`amount of viscosity enhancer. An increase in viscosity of topical solutions will result in a longer
`residence time in eye ornose,providing a longertime for drug absorption and effect. The list of
`viscosity enhancers that are conventionally used for
`topical
`solutions are given in
`the
`pharmacopoeias such as United States Pharmacopoeia, as well as in Remington: The Science
`and Practice of Pharmacy; edition 19; Mack Publishing Company, Easton, Pennsylvania (1995).
`The viscosity enhancers may be used in concentrations conventional to the pharmaceuticalart.
`
`The aqueous topical solution of the present invention is chemically stable. The term “chemically
`stable” as used herein means that the aqueous topical solution whenstored on the shelf lor up lo
`two years has less than 2% total degradation products as determined by the area normalization
`method, The chemical stability may be assessed by accelerated stability testing. The aqueous
`topical solution of the present. invention may be stored in a closed container at 30°C / 65%
`relative humidity or 40°C / 75%relative humidity or 2-8"C (refrigeration condition) and analyzed
`at one month duration for up to three months or six months,
`It
`is generally accepted that a
`product is stable on the shelf over a period of two years, if the product is stable for three months
`at an acceleratedstability test condition of 40°C / 75% relative humidity.
`
`lo a
`
`The lerm “physical stability” as used herein. means that when aqueous topical solution ofthe
`present invention are stored in a closed containercrystals of olopatadine do not appear.
`
`The chemical stability is assessed by evaluating the percent total degradation of olopatadine
`aqueous topical solutions that are subjected to accelerated stability test conditions and ambient
`
`9
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page10
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page10
`
`

`

`WO2008/015695
`
`PCT/IN2007/000199
`
`conditions using high performance liquid chromatography (HPLC). The chromatographic
`conditions for analyzing the degradation of olopatadine and the procedure for calculating the
`
`percent total degradation products in olopatadine aqueous topical solution is given below:
`
`Column
`
`Flowrate
`
`Temperature
`
`Detection
`
`: Hypersi] BDS Cx (250 X 4.6)
`
`: 1.0 ml/min
`
`: Ambient
`
`> 210nm
`
`Concentration
`
`: 50/65 ppm
`
`Injection volume
`
`» 20h]
`
`Run time
`
`> 40 min
`
`Mobile Phase
`
`: Buffer : Acetonitrile (720 : 280)
`
`Buffer : 6.8 gm ICH2PO,
`
`is dissolved in 1000m1 of water andthe solutionis
`
`adjusted to a pH of 4.5 with orthophosphoric acid.
`
`Retention time
`
`: 10.5 min
`
`Diluent
`
`: Mobile phase
`
`Standard preparation : 50/65 mg olopatadine HC] is dissolved in 100 ml with mobile phase.
`
`A sample of 5 ml is diluted to 50 ml with mobile phase
`
`Test preparation
`
`: 2 ml of the olopatadine HC] solution is diluted with 200 ml of mobile
`
`phase
`
`‘The percent total degradation products in the olopatadine aqueous topical solution is calculated
`
`by area normalization method (excluding peaks from placebo and diluent,
`
`if any) trom the
`
`chromatogram obtained by
`
`injecting 201 of
`
`test preparation as described above
`
`in
`
`chromatographic conditions
`for analyzing degradation of olopatadine. The
`formula
`for
`calculating the percent total degradation products in olopatadine aqueous topical solution is
`
`i) in
`
`given below:
`
`“ Individual degradation product =
`
`----------saeeeseennnneeeeneeeeeeennen X 100
`
`Peak area of individual degradation product
`
`Total area ofall the peaks
`
`10
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page11
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page11
`
`

`

`WO2008/015695
`
`PCT/IN2007/000199
`
`% Total degradation products
`
`=
`
`Sumofall % individual degradation products
`
`For Finished dosage forms (for example - solutions) the value of percent individual degradation
`product should not be more than 1% andthe percent total degradation products should not be
`
`an
`
`more than 2%. A value of percent total degradation products lesser than 2% in the aqueous
`
`topical solution ofthe present invention is consideredto be acceptable.
`
`According to one embodiment of the present
`
`invention,
`
`the aqueous tupical solution may be
`
`prepared by the following process:
`
`a, Dissolving hydroxypropyl-B-cyclodextrin(HPBCD) in water for injectiontill clear solution
`
`is formed.
`
`b. Dissolving tonicity agent, buffering agent, chelating agent and antimicrobial preservative in
`
`the bulk solution of step (a) and stirring to get clear solution.
`
`WN
`
`ve. Dissolving olopatadine hydrochloride in water for injection and adding to the solution of
`
`step (a).
`
`d. Adjusting pH ofthe solution between 3.5-5.0 for nasal solution, and between 6.8-7.2 for
`
`ophthalmic solution with 0.1N hydrochloric acid and 0.1N sodium hydroxide.
`
`Final adjustment of volume with waterfor injection and measuring pH.
`
`Filtering of the solution through 2tmprefilter and then through U.2um nylon 66 membrane
`
`e,
`
`fr,
`
`lilter, and transferring the solutions to sterile containers.
`
`The aqueous topical solution of the present invention may be lormulated to be dispensed in
`
`suitable containers as drops, sprays, metered sprays, aerosols and metered aerosols. The aqueous
`
`tL Ww
`
`ltupical solution to be delivered as nasal spray may be filled in containers fitted with a spray
`
`pump with or without a metering valve. The aqueous topical solution to be delivered as aerosol
`maybe filled into canisters suitable for delivering pharmaceutical aerosols. Canisters generally
`comprise a container capable of withstanding the vapour pressure of the propellant used suchas
`a plastic or plastic-coated glass bottle, or preferably a metal can, for example an aluminium can
`
`which may optionally be anodized,
`
`lacquer-coated and / or plastic-coated, which containeris
`
`11
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page12
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page12
`
`

`

`WO2008/015695
`
`PCT/IN2007/000199
`
`closed with a metering valve. The metering valves are designedto delivera metered amount of
`the aqueous solution per actuation, and have a gasket to prevent leakage of propellant through
`the valve. In a preferred embodiment of the present invention, the aqueous topical solution is
`packed in opaque plastic or glass containers.
`In a more preferred embodiment of the present
`invention, the container for an ophthalmic solution is an opaque, white low-density polyethylene
`container that has beensterilized using ethylene oxide like lupolen bottle. In another preferred
`embodiment of the present invention, the containerfor a nasal solution is a U.S.P type | amber
`color glass container equipped with a suitable nasal spray pump.
`
`it will be understood by thoseofskill in the art that numerous and various modifications can be
`made without departing from the spirit of the present invention. Therefore, it should be clearly
`understood that the following examples are illustrative only and are not intended to limit the
`
`scope of-the present invention.
`
`in
`
`ho7
`
`wn
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page13
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page13
`
`

`

`Tabie 1
`
`
`Comparative Examples A-H
`
`C
`D
`E
`A
`Ingredients
`B
`F
`G
`H
`Concentration (“%wiy)
`_|
`
`
`
`Olopatadine 0627| 0.527|0.527|0.527|0.527 0.527| 0.665
`
`hydrochloride
`
`
`Polysorbate 20
`
`Polysorbate 80
`
`
`
`Propyleneglycol|0.05 0.05
`
`Hydroxypropy
`methylcellulose
`(2910 EAM
`-
`-
`-
`-
`-
`0.10
`0.25
`0.10
`premium)
`|
`|
`
`Polyvinyl
`|
`|
`-
`pyrrolidone K~
`-
`-
`-
`-
`-
`-
`2.00
`:
`|
`30
`|_|
`
`
`Sodium chloride|- 0.60 = - - 0.60 0.80 0.30
`
`
`
`Benzalkonium | 5
`5
`44
`5
`5
`5
`5
`
`
`chloride (50% ) 0.02|9.02 0.02 - 0.02 0.02 pe 0.02
`
`
`
`Disudium
`_
`v0
`;
`r
`;
`_
`;
`;
`edetate
`_|
`|
`—_
`
`Dibasic sodium
`t
`+r
`|
`Q.15
`0.25
`0.25
`0.50
`0.20
`phosphate
`0.06
` 0.10|lodecahydrate L LL |
`0.50
`
`
`
`
`pH4.s|p45|pH4.5|pH4.5|pH4.5|pH 4.5 pH|pH3.s |
`-5.0
`-5.0 4" -5.0
`-5.0
`-5.0
`2)
`-5.0
`
`q.sl00|q.sl00|q.s!00|q.s100 qs100_ | 4100 q.slO|q.sl00
`
`ml
`ml,
`ml
`0 ml
`ml
`
`
`|
`
`
`
`WO2008/015695
`
`PCT/IN2007/000199
`
`COMPARATIVE EXAMPLES A-M
`The compositions shown in table | and table 2 below were prepared and subjected to stability
`studies
`for evaluating the physical stability. The vials were studied for stability at
`two
`temperature conditions: one at room temperature (25° + 2°C) and the other at refrigeration
`temperature (2-8°C) condition.
`
`5
`
`5
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`NaOH/HC|
`
`Waterfor
`Injection
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page14
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page14
`
`

`

`WO2008/015695
`
`PCT/IN2007/000199
`
`5
`
`
`
`Comparative Examples I-M
`M
`L
`J
`K
`I
`Ingredients
`
`Concentration (“w/y)
`
`Olopatadine
`0.527
`0.527
`0.527
`0.527
`0.527
`hydrochioricde
`
`-
`-
`-
`Xantham gum
`0.10
`-
`
`Sodium CMC
`-
`0.10
`-
`-
`
`
`
`
`
`
`
`
`
`
`
`
`Table 2
`
`-
`0.10
`-
`-
`- 4
`2.00 a”
`To - TT -
`-
`0.20
`0.60
`0.80
`0.80
`0.80
`0,02
`|
`0.02 i 0.02
`0.02 7 0.02
`L
`|
`-
`0.15
`0.15
`0.15
`0.15
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page15
`
` |
`
`t
`+
`
`|
`
`Carbopol 934P
`Polyvinyl alcohol
`Sodium chloride
`Benzalkonium
`chloride(50%)
`Dibasiv sodium
`phosphate
`anhydrous
`
`NaOH/HC! pH3.5-5.0|pH3.5 =5.0| pH 3.5—T pH 3.5 pH