(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization _
`International Bureau
`
`(43) International Publication Date
`
`7 February 2008 (07.02.2008)
`
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`(10) International Publication Number
`
`WO 2008/015695 A2
`
`(51) International Patent Classification:
`A61K 47/40 (2006.01)
`A61K 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
`
`[TN/IN]; Acme Plaza, Andheri—Kurla Road, Andheri (e),
`Mumbai 400 059 (IN).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): BHOWMICK,
`Subhas, Balaram [TN/IN]; Sun Pharma Advanced Re—
`search Centre, Nima Compound, Near Pratham Enclave,
`Tandalja Road, Baroda 390 020 (IN). LADDHA, Ritu,
`Nitin [TN/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 4.1 7(i))
`as to applicant’s entitlement to apply for and be granted a
`patent (Rule 4.1 7(ii))
`as to the applicant’s entitlement to claim the priority of the
`earlier application (Rule 4.1 7(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
`
`
`
`08/015695A2|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`6 (57) Abstract: The invention relates to an inclusion complex of olopatadine or its pharmaceutically acceptable salt and hydrox—
`N yalkyl—B—cylcodextr‘in, preferably hydroxypropyl—B—cylcodextr‘in. The present invention also relates to an aqueous topical solution
`comprising a therapeutically effective amount of olopatadine or its pharmaceutically acceptable salt; hydroxyalkyl—B—cylcodextrin,
`preferably hydroxypropyl—B—cy1codextrin and hydroxypropyl methylcellulose in an amount sufficient to enhance the physical stabil—
`
`W0 ity of the solution.
`
`|PR2018—01020 and |PR2018-01021, Exhibit 1003 page1
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`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page1
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`

`

`WO 2008/015695
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`PCT/IN2007/000199
`
`INCLUSION COMPLEX
`
`FIELD OF THE INVENTION
`
`The present invention 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. =
`
`10
`
`BACKGROUND OF THE INVENTION
`
`Olopatadine hydrochloride is a carboxyl'ic acid derivative ofdoxepin. chemically described as
`
`(Z)-l l-[3-(Dimethylamino) propylidene]-6,l l—dihydrodibenz [b.e]oxepin—2—acetic acid
`
`hydrochloride [Cgli’133 NO;
`
`.HCl], as disclosed in US. Pat Nos.~‘l.87l.8()5 and 4.923.892. both
`
`assigned to Burroughs Wellcome. Olopatadine has antihistaminic and antiasthinatic activity.
`
`Olopatadine hydrochloride is commercially available in the US as 0.1% and 0.2% sterile
`
`ophthalmic solutions under the brand names PATANOL‘“’ and PATADAY" respectively, both
`marketed by Alcon. PATANOLM’ is indicated for the treatment ol"signs and symptoms ol’allergic
`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.
`
`lt has a pH ol’ 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 OIOpatadine hydrochloride
`
`equivalent
`
`to
`
`0.2%
`
`olopatadine, 0.01% benzalkonium chloride as preservative, povidone, dibasic sodium phosphate,
`
`sodium chloride, edetate disodium. hydrochloric acid and / or sodium hydroxide (to adjust the
`
`pH) and purilied water. lt has a pH 01" about 7. and osmolality ol'about 300mOsm/hg.
`
`One obstacle l’or preparing olopatadine hydrochloride aqueous solutions lor topical deliver)
`
`is
`
`the stability 01‘ the aqueous solutions ol’ olopatadine hydrochloride over the storage period.
`
`Olopatadine aqueous solutions having a concentrations 01’ 0. l 7%w/v or higher were l’ound to be
`
`|PR2018—01020 and |PR2018-01021, Exhibit 1003 page2
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`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page2
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`WO 2008/015695
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`PCT/IN2007/000199
`
`unstable over extended storage periods. The olopatadine hydrochloride precipitates or
`
`crystallizes out ofthe solution when used in concentrations higher than 0. l 7%w/v. Hence, there
`
`is a need for preparing aqueous solutions ofolopatadine hydrochloride containing olopatadine in
`
`concentrations of about 0.17%w/v or greater, which are stable when stored over the shelf life of
`
`the product.
`
`United States Patent No.6,995,186 (Alcon inc., 2006,
`
`the “186 patent) discloses topically
`
`administrable solution composition for treating allergic or inflammatory disorders ofthe 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 oi“ the
`
`solution, and wherein the composition does not contain polyvinyl alcohol, polyvinyl acrylic
`
`acid, hydroxypmpyl methyl cellulose, sodium carboxymethyl cellulose, xanthan gum. Polyvinyl
`
`alcohol, polyvinyl acrylic acid, hydroxypropyl methylcellulose, sodium carboxy methyl cellulose
`
`‘J‘I
`
`and xanthan gum have been disclosed in the ”186 patent
`
`to cause physical
`
`instability ol‘
`
`olopatadine solutions.
`
`in order to overcome the physical stability problems associated with olopatadine aqueous
`
`solutions, we have tried various
`
`ingredients selected from hydroxypropyl—B-cyclodextrin
`
`(HPBCD), polysorbate 20, polysorbate 80, propylene glycol, hydroxypropyl methylcellulose
`
`29H)
`
`(HPMC E4M premium),
`
`polyvinylpyrrolidone
`
`K—30,
`
`xanthan
`
`gum,
`
`sodium
`
`, cartmxyrnethylcellulose (Sodium CMC), car-bopol 934P, polyvinyl alcohol and mixtures tlrereol’.
`
`We have now surprisingly found that
`
`stable aqueous
`
`topical
`
`solutions ol’ olopatadine
`
`ix)
`
`hydrochloride can be prepared by forming an inclusion complex with a hydroxyalkyl clodextrin,
`
`preferably hydroxypropyl—B—cyclodextrin (HPBCD). Optionally, hydroxypropyl methylcellulose
`
`(HPMC‘) may be used to stabilize the inclusion complex in the plrarrrraCeutical composition.
`
`[\3
`
`|PR2018—01020 and |PR201 8-01 021, Exhibit 1003 page3
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`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page3
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`

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`WO 2008/015695
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`PCT/IN2007/000199
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`SUMMARY OF THE INVENTION
`
`In one aspect of the invention, there is provided an inclusion complex of olopatadine or its
`
`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:
`
`hyclroxyalkyl B~cylcodextrin,
`
`preferably hydroxypropyl B—cylcodextrin and hydroxypropyl
`
`methyl cellulose in amount sufficient to enhance the physical stability of the solution.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The present
`
`invention provides an inclusion complex of olopatadine or its plnirinaceutically
`
`acceptable salt and hydroxyall<yl—[3~cyclodextrin, particularly hydroxyprtnayl—|5—cycloclextrin. The
`
`therapeutically
`invention also provides an aqueous topical solution, comprising> a
`present
`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 and all
`
`reference to olopatacline are to olopatadine free base.
`
`The term “in an amount sufficient to enhance the physical stability of the solution“, as used
`
`herein means that the amount of
`
`hydroxyalkyl—[fi-cyclodextrin. particularly hydroxypropyl-B—
`
`cyclodextrin is sufficient to form a complex with olopatadine or its pharmaceutically acceptable
`
`salt and thus keep it in solution, i.e. Prevent its precipitation or crystallization.
`
`|PR2018—01020 and |PR2018-01021, Exhibit 1003 page4
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`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page4
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`

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`WO 2008/015695
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`PCT/IN2007/000199
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`According to one embodiment ol’ the present
`
`invention, the aqueous topical solution contains
`.
`
`olopatadine or
`
`its pharmaceutically acceptable salts. Examples
`
`01“
`
`the pharmaceutically
`
`acceptable salts ol’olopatadine include inorganic acid salts such as hydrochloride, hydrobromide.
`sull‘ate and phosphate; organic acid salts such as acetate, maleate. l’umarate, tartrate and citrate:
`
`U1
`
`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
`
`triethylamine addition salt
`
`(also known as
`
`tromethamine),
`
`morpholine addition salt and piperidine addition salt. In a preferred embodiment of the present
`
`invention, the olopatadine for use in the aqueous topical solution is a hydrochloride salt.
`
`in a
`
`1
`
`0
`
`most preferred embodiment of the present invention, the olopatadine hydrochloride salt may be
`
`used in concentrations such that it is equivalent to the blopatadine free base in amount ranging
`
`From about 0.17% to about 0.62%. Preferably, the solution Formulations intended For use in the
`
`eye contain about 0.17% to about 0.25% olopatadine and the solution Formulations intended for
`
`use in the nose contain about 0.35% to about 0.62% olopatadine.
`
`According to one embodiment of the present invention, the aqueous topical solution comprises
`
`cyclodextrin to enhance the physical stability of the solution. Cyclodextrins are a group ol‘
`
`structurally related saccharides which are l‘ormed by enzymatic cyclization of starch by a group
`
`ol‘amylases termed glycosyltransl’erases. Cyclodextrins are cyclic oligosacchz-u‘ides, consisting ol‘
`
`(eilplia—l,¢l)-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
`
`ls) (J1
`
`through complex dilution, by replacement of the included drug by some other suitable molecule
`
`or, the drug may be transferred to the matrix for which it has the highest al’l’inity. lmportantly,
`
`since no covalent bonds are l‘ormed or broken during the drug—cyclodextrin complex Formation,
`
`the complexes are in dynamic equilibrium with tree drug and cyclodextrin molecules. In solution.
`
`the complexes are usually prepared by addition ol’ an excess amount ol' the drug to an aqueous
`
`cyclodextrin solution. The most common naturally occurring cyclodextrins
`
`are
`
`alpha-
`
`|PR2018—01020 and |PR201 8-01 021, Exhibit 1003 page5
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`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page5
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`WO 2008/015695
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`PCT/IN2007/000199
`
`cyclodextrin, B-cyclodextrin and gamma—cyclodextrin consisting ol’ 6, 7 and 8 glucopyranose
`
`units.
`
`respectively and their r. derivatives. B-cyclodextrin appears
`
`to be
`
`the most usel’ul
`
`pharmaceutical complexing agent due to its cavity size, availability and low cost. Examples 01"
`
`cyclodextrin derivatives that may be used in the pharmaceutical compositions of present
`
`U1
`
`invention include the hydroxypropyl derivatives of alpha-, beta» and gamma-cyclodextrin,
`
`sull’oalkylether cyclodextrins such as sulfobutylether beta-cyclodextrin, alkylated cyclodextrins
`
`such as the randomly methylated beta—cyclodextrin, and various branched cyclodextrins such as
`
`glucosyl- and maltosyl beta—cyclodextrin, and the like, and mixtures thereol‘.
`
`The prel‘erred cyclodextrins For use in the present invention include alkyl cyclodextrins, hyclroxy
`alkyl cyclodext‘rin. such as hydroxy propyl beta-cyclod'extrin, carboxy allx’yl cyclodextrins and
`sullioalkyl ether cyclodextrim such as sull‘b butyl ether beta~cyclodextrin Examples ol' suitable
`
`cyclodextrins l‘or use in the present invention non—exclusively include alpha—eyclodextrin; betu~
`cyclotlextrin; gamma-cyclodextrin; methyl alpha—cyclodextrin; methyl beta—cyclodextrin; methyl
`gamma—eyelodextrin; ethyl beta—cyclodextrin; butyl alpha—cyclodextrin; 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 gainma—cyclodextrin; 2—hydroxybutyl beta—cyclodextrin; acetyl
`
`beta—
`propionyl
`gamma—eyelodextrin;
`acetyl
`acetyl beta-cyclodextrin;
`alpha—cyclodextrin;
`eyclodextrin; butyryl beta—cyclodextrin; succinyl alpha-cyclodextrin: succinyl beta-cyclodextrin;
`
`suecinyl
`
`gamma—eyelodextrin;
`
`benzoyl
`
`beta—cyclodextrin;
`
`palmityl
`
`beta—cyclodextrin;
`
`toluenesull‘onyl
`
`beta—cyclodextrin;
`
`acetyl methyl
`
`beta-cyclodextrin;
`
`acetyl
`
`butyl
`
`beta—
`
`cyclodextrin;
`
`glucosyl
`
`alpha—cycloclextrin;
`
`glucosyl
`
`beta—cyclodextrin:
`
`glucosyl
`
`gamma-
`
`cyclodextrin; maltosyl
`
`alpha—cyclodextrin; maltosyl
`
`beta—cyclodextrin; maltosyl
`
`gamma—
`
`IQ U1
`
`cycltit‘lextrin; alpha—cyclodextrin carboxymethylether; beta—cyclodextrin carboxymetliylether;
`
`gamma-eyelodextrin carboxymethylether; carboxymethylethyl beta—cyclodcxtrin; phosphate ester
`
`alplut—cyclodextrin; phosphate ester beta—cyclodextrin; phosphate ester gainma—cyclodextrin; 3—
`
`trimet‘hylammoniurn—Z—hydroxypropyl
`
`beta~cyclodextrin;
`
`sull’obutyl
`
`ether
`
`beta—cyclodextrin;
`
`carboxymethyl alpha—cyclodextrin; carboxymethyl beta—cyclodextrin; carboxymethyl gamma—
`
`cyclodextrin, and combinations thereof. The most preferred cyclodextrin for use
`
`in the
`
`|PR2018—01020 and |PR201 8-01 021, Exhibit 1003 page6
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`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page6
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`WO 2008/015695
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`PCT/IN2007/000199
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`pharmaceutical composition 01’ the present invention is hydroxy propyl beta-cyclodextrin.
`
`In a
`
`prel’erred embodiment of the present invention, hydroxypropyl beta-cyclodextrin may be used in
`
`concentrations ranging from about 0.1% to about 20%w/v ol" the composition, and more
`
`prel‘erably used in concentrations ranging from about 1.0% to about 10% w/v ol‘ the composition.
`
`‘J1
`
`Generally,
`
`l‘or solutions meant
`
`l’or ophthalmic administration prel’erable concentration 01‘
`
`l'or solutions
`hydroxypropyl beta—cyclodextrin is in the range from about 1.0% to about 5%;
`meant 1"or nasal administration, the concentration 01" hydroxypropyl beta—cyclodextrin is in the
`
`range from about 1.0% to about 10%.
`
`10
`
`Olopatadine or its pharmaceutically acceptable salt, according to the present invention, forms an
`inclusion
`complex with
`cyclodextrins,
`particularly
`hydroxyalkyl-B—cyclodextrin, more
`particularly hydroxypropyl—B-cyclodextrin . The term “inclusion complex” as used herein rel’ers
`to a combination of olopatadine or its pharmaceutically acceptable salt as defined above and a
`
`cyclodextrin wherein the olopatadine or its pharmaceutically acceptable salt or a portion thereol'
`is associated with the cyclodextrin. Typically, the olopatadine or its pharmaceutically acceptable
`
`Ux
`
`is included within the cavity of the cyclodextrin, or the host molecule,
`salt or guest molecule.
`wherein the cavity 01’ the cyclodextrin is the space created by the cyclodextrin torous and the
`
`to
`cyclodextrin substituents. The ratio 01" olopatadine or its pharmaceutically acceptable salt
`hydroxypropyl [3—cylcodextrin in the inclusion complex is l'rom about 1:1.05 to about 1:50 by
`weight. The amount 01’ hydroxypropyl
`[fi—cylcodextrin
`present
`in the inclusion complex is
`
`sufficient to enhance the physical stability ol’the olopatadine solution.
`
`According to one embodiment of the present
`invention,
`the composition further
`includes
`hydroxypropyl methylcellulose (HPMC). The hydroxypropyl methylcellulose (HPMC) used in
`the composition acts as a stabilizer for the inclusion complex 01’ hydroxypropyl beta—cyclodextrin
`and olopatadine or
`its pharmaceutically acceptable salt. Various grades 01’ hydroxypropyl
`
`[\3
`
`methylcellulose (available From Dow Chemical, U.S.A under the METHOCEL trademarlx') may
`be used in the present invention. The grades commercially available are categorized depending
`upon the chemical substitution and hydration rates. and may be used in the compositions ol' the
`present
`invention.
`l-lydroxypropyl methylcellulose having a methoxy content ol‘ 19—24 % and
`
`|PR2018—01020 and |PR2018-01021, Exhibit 1003 page7
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`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page7
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`WO 2008/015695
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`PCT/IN2007/000199
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`hydroxypropyl content of 7-l2 % with a fastest
`
`relative rate of hydration is available
`
`commercially under the brand name of Methocel Gracie K. l-lydroxypropyl methylcellulose with
`28—30 "/0 methoxy content andA7—12 % ol' hydroxypropyl content with a faster relative hydration
`
`rate as compared to the above grade is available commercially under the brand name of Mcthocel
`
`'Ji
`
`Gracie E.
`
`l-lydroxypropyl methylcellulose with 27-30 % methoxy content and 4.0 - 7.5 ”/0 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 embodiment of 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 l % w/v.
`
`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. belt/:ethonium chloride.
`butylparaben, methyl paraben. ethyl paraben. propyl paraben. benzalltonium chloride. cetyl
`pyridinium chloride, thimerosal, chlorobutanol. phenylethyl alcohol. benzyl alcohol‘ potassium
`sorbate, sodium benzoate, sorbic acid and the like and mixtures thereof. The preferred
`
`preservative for the aqueous topical solution of the present invention is benzalkonium chloride.
`
`It may be used in an amount ranging from about 0,005% to about l%w/v.
`
`[\3
`
`invention may include an effective amount of a
`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
`
`|PR2018—01020 and |PR201 8-01 021, Exhibit 1003 page8
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`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page8
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`WO 2008/015695
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`PCT/IN2007/000199
`
`the present invention is disodium edetate. It may be present in the concentrations ranging from
`
`about 0.005% to about 0.1% w/v.
`
`The aqueous topical solution of the present invention may further include an effective amount ol‘
`
`U1
`
`a tonicity agent. Examples of tonicity agents that may be used in the aqueous topical solution ol‘
`
`the present invention include all pharmaceutically acceptable and pharmacologically inert water—
`
`soluble compounds referred to 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 U995). Preferred tonicity agent is sodium chloride, 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 more preferably between 250 to 350 mOsm.
`
`l
`
`The aqueous topical solution-of the present
`
`invention may include an effective amount of
`
`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 limited to.
`
`lactic acid, citric acid, tartaric acid. phosphoric acid, acetic acid, hydrochloric acid. nitric acid.
`
`tromethamine, sodium or potassium metaphosphate, sodium or potassium phosphate. dibasic
`
`sodium phosphate dodecahydrate,
`sodium or potassium acetate, ammonia. sodium carbonate.
`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 assodium
`
`hydroxide may be used for adjusting pH. The aqueous topical solution intended for ophthalmic
`
`administration has a pH 4 to 8, preferably pH of 6.5 to 7.5, and most preferably a pH of 6.8 to
`
`7.2. The aqueous topical solution intended for nasal administration has a pH ol‘3.0 to 6.0. and
`
`Ix) (J1
`
`most preferably a pH of3.5 to 5.0.
`
`The aqueous topical solution of the present
`
`invention may optionally include an effective
`
`amount ofan antioxidant. The antioxidant may be one or more antioxidants. reducing agents and
`
`antioxidant synergist, and may be selected from acetyl cysteine, alpha tocopherol acetate.
`
`d—
`
`alpha tocopherol, dl—alpha tocopherol, ascorbyl palmitate, butylated hydroxyanisole (BHA),
`
`|PR2018—01020 and |PR201 8-01 021, Exhibit 1003 page9
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page9
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`

`

`WO 2008/015695
`
`PCT/IN2007/000199
`
`butylated hydroxytoluene (BHT), cysteine, cysteine hydrochloride, propyl gallate, ascorbic acid,
`
`calcium ascorbate. calcium bisulphate, calcium sulphite, ascorbic acid,
`
`isoascorbic acid.
`
`potassium metabisultite, sodium ascorbate, sodium bisulphate, sodium metabisulphite. sodium
`
`sulphitc. sodium thiosulphate.
`
`thioglycerol, citric acid , edetic acidtlz‘DTA) and its salts.
`
`U1
`
`liytlroxyquinoline sulphate, phosphoric acid, sodium citrate and tartaric acid. The antioxidants
`
`may be used in amounts conventional to the pharmaceutical art.
`
`The aqueous topical solution of the present
`
`invention may optionally include an effective
`
`amount ol‘viscosity enhancer. An increase in viscosity ol’ topical solutions will result in a longer
`
`10
`
`residence time in eye or nose, providing a longer time for drug absorption and effect. The list 01“
`
`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 pharmaceutical art.
`
`The aqueous topical solution oFthe present invention is chemically stable. The term “chemically
`
`stable“ as used herein means that the aqueous topical solution when stored on the shell" Tor up to
`
`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 aqtrcous
`
`topical solution ol~ the present. invention may be stored in a closed container at 30%" / 05%
`relative humidity or 400C / 75% relative humidity or 2—8”C (refrigeration condition) and analyzed
`
`at one month duration for tip to three months or six months.
`
`it
`
`is generally accepted that a
`
`product is stable on the shell“ over a period ol’ two years, il“ the product is stable l’or three months
`
`at an accelerated stability test condition ol’ 40“C / 75% relative humidity.
`
`[Q 'J}
`
`The term “physical stability” as used herein means that when aqueous topical solution ol" the
`
`present invention are stored in a closed container crystals ofolopatadine do not appear.
`
`The chemical stability is assessed by evaluating the percent total degradation ol‘ olopatadine
`
`aqueous topical solutions that are subjected to accelerated stability test conditions and ambient
`
`C)
`
`|PR2018—01020 and |PR2018-01021, Exhibit 1003 page10
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`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page10
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`

`

`WO 2008/015695
`
`PCT/IN2007/000199
`
`conditions using high performance liquid chromatography (I-IPLC). 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:
`
`(‘olumn
`
`U1
`
`Flow rate
`
`Temperature
`
`Detection
`
`: l-lypersil BDS Cs (250 X 4.6)
`
`: 1.0 ml/min
`
`: Ambient
`
`: 210 nm
`
`Concentration
`
`: 50/65 ppm
`
`Injection volume
`
`: 20p]
`
`10
`
`Run time
`
`: 40 min
`
`Mobile Phase
`
`: Buffer: Acetonitrile (720 : 280)
`
`Buffer : 6.8 gm KI—lgPO4 is dissolved in lOOOml of water and the solution is
`
`adjusted to a pH of 4.5 with orthophosphoric acid.
`
`Retention time
`
`: 10.5 min
`
`Diluent
`
`: Mobile phase
`
`Standard preparation : 50/65 mg olopatadine HCl is dissolved in lOO ml with mobile phase.
`
`A sample ofS ml is diluted to 50 ml with mobile phase
`
`Test preparation
`
`: 2 ml 01‘ the olopatadine HCI solution is diluted with 200 ml oi~ 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,
`
`il“ any) from the
`
`chromatogram obtained by
`
`injecting 20p] of
`
`test preparation as described above
`
`in
`
`chromatographic conditions
`
`for analyzing degradation of olopatadine. The
`
`formula
`
`tor
`
`calculating the percent total degradation products in olopatadine aqueous topical solution is
`
`given below:
`
`"/0 individual degradation product =
`
`-------------------------------------------------------------- X 100
`
`Peak area of individual degradation product
`
`Total area ol’all the peaks
`
`10
`
`IO U1
`
`10
`
`|PR2018—01020 and |PR2018-01021, Exhibit 1003 page11
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`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page11
`
`

`

`WO 2008/015695
`
`PCT/IN2007/000199
`
`U1
`
`10
`
`% Total degradation products
`
`“
`
`Sum of all % individual degradation products
`
`For l'inished dosage forms (For example - solutions) the value of“ percent individual degradation
`
`product should not be more than 1% and the percent total degradation products should not be
`
`more than 2%. A value of percent total degradation products lesser than 2% in the aqueous
`
`topical solution ot‘the present invention is considered to be acceptable.
`
`According to one embodiment ol’ the present
`
`invention.
`
`the aqueous topical solution may be
`
`prepared by the following process:
`
`a. Dissolving hydroxypropyl-B—cyclodextrin(HPl3CD) in water For injection till clear solution
`
`is Formed.
`
`b. Dissolving tonicity agent, buffering agent, chelating agent and antimicrobial preservative in
`
`the bulk solution ol'istep (a) and stirring to get clear solution.
`
`c. Dissolving olopatadine hydrochloride in water for injection and adding to the solution ol
`
`step (a).
`
`d. Adjusting pH of the solution between 3.5-5.0 for nasal solution. and between 6.8—7.2 tor
`
`e.
`
`l“.
`
`Ophthalmic solution with O.IN hydrochloric acid and (MN sodium hydroxide.
`
`Final adjustment ot‘volume with water for injection and measuring pH.
`
`Filtering ol’ the solution through 2pm prefllter and then through 0.2th nylon 66 membrane
`
`filter; and transl‘erring the solutions to sterile containers.
`
`The aqueous topical solution ol‘ the present invention may be lormulated to be diSpensed in
`
`suitable containers as drops, sprays, metered sprays, aerosols and metered aerosols. The aqueous
`
`[Q U1
`
`topical solution to be delivered as nasal spray may be filled in containers titted with a spray
`
`pump with or without a metering valve. The aqueous topical solution to be delivered as aerosol
`
`may be filled into canisters suitable for delivering pharmaceutical aerosols. Canisters generally
`comprise a container capable of withstanding the vapour pressure of the propellant used such as
`
`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 container is
`
`11
`
`|PR2018—01020 and |PR2018-01021, Exhibit 1003 page12
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`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page12
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`

`

`WO 2008/015695
`
`PCT/IN2007/000199
`
`closed with a metering valve. The metering valves are designed to deliver a metered amount ol‘
`the atlueous solution per actuation, and have a gasket to prevent leakage ol’ propellant through
`
`the valve. In a prel’erred embodiment oFthe present invention, the aqueous topical solution is
`
`packed in opaque plastic or glass containers.
`
`In a more preferred embodiment ol’ the present
`
`inventiorL the container For an ophthalmic solution is an opaque, white low-density polyethylene
`
`container that has been sterilized using ethylene oxide like lupolen bottle. In another prel‘errcd
`
`embodiment ol‘ the present invention, the container For a nasal solution is a U.S.P type I amber
`
`color glass container equipped with a suitable nasal spray pump.
`
`l0
`
`it will be understood by those of skill
`
`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.
`
`
`
`Ix.)‘
`
`Ln
`
`|PR2018—01020 and |PR2018-01021, Exhibit 1003 page13
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1003 page13
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`

`

`WO 2008/015695
`
`PCT/IN2007/000199
`
`COMPARATIVE EXAMPLES A-M
`
`The compositions shown in table 1 and table 2 below were prepared and subjected to stability
`
`studies
`
`l’or evaluating the physical stability. The vials were studied l’or stability at
`
`two
`
`5
`
`temperature conditions: one at room temperature (250 i
`
`2°C) and the other at refrigeration
`
`temperature (2~8”C) condition.
`
`_|
`
`
`
`0.527
`
`0.527
`
`0.527
`
`0. 527
`
`-
`
`methylcellulose
`
`_
`
`_
`
`-
`
`_
`
`—
`
`
`premium)
`
`—l
`
`
`
`.
`
`O 10
`
`,,
`.x.
`
`5
`
`O
`
`.
`0. 0
`
`l
`
`
`
`Table 1
`
`
`Com arative Examples A-H
`
`Ingredients
`C
`D
`E
`A
`B
`F
`(J
`H
`Concentration (%w/v)
`
`Olo J'ttadine
`~- —I
`j—
`—|
`l‘
`.
`0.527
`27 0.665
`hydrochloride
`-
`Polysorbate 20
`Polysorbate 80
`.
`‘
`.
`
`Pr_pyleneJLUlycol
`0.05
`
`
`l-lydroxypropyl—l
`(29l0 E4M
`J_
`Polyvinyl
`2.00
`pyrrolidone K—
`30
`0.30
`Sodium chloride
`0
`q
`Benzalkonium —'
`'0“
`O 0
`chloride (50% )
`_
`0 0|
`_
`Disodium
`L_'
`|_
`cdetate
`_‘_
`
`_l_
`Dibasic sodium
`l—_
`phosphate
`0.06
`0.50
`0.20
`__l
`lindecahydrate L
`_l_
`pH 3.5 —l
`31;
`pH 4.5
`pH 4.5
`pl—l 4.5
`pH 4.5
`N-Oll /llCl
`pH 4.5
`pH 4.5
`—5.0
`_5'0
`-5.0
`—5.0
`—5.0
`N“
`~5.0
`i—so +6.0
`l—Water lor
`q.leO q.leO q.le0
`q.leO q.leO q.s100
`q.310
`qsIOO
`
`ml
`ml.
`ml
`0 ml
`ml
`lnjection
`
`
`
`0.50
`
`0.25
`
`0.25
`
`0. l 5
`
`0.10
`
`10
`
`13
`
`|PR2018—01020 and |PR2018-01021, Exhibit 1003 page14
`
`
`
`
`
`
`
`
`
`
`
`
`-