(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll 111111111111111111111111111111111
`
`( 43) International Publication Date
`7 February 2008 (07.02.2008)
`
`PCT
`
`(10) International Publication Number
`WO 2008/015695 A2
`(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,
`Fl, 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, Fl,
`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
`
`(51) International Patent Classification:
`A61K 47140 (2006.01)
`A61K 311335 (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:
`7 48/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),
`Mumbai 400 059 (IN).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): BHOWMICK,
`Subhas, Balaram [IN/IN]; Sun Pharma Advanced Re(cid:173)
`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).
`
`-iiiiiiiiiiii
`
`iiiiiiiiiiii
`
`iiiiiiiiiiii --iiiiiiiiiiii -iiiiiiiiiiii ----
`----iiiiiiiiiiii
`iiiiiiiiiiii ----
`
`l()
`
`°" \0
`l()
`,....i
`Q ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
`Qo (54) Title: INCLUSION COMPLEX
`Q
`0
`(57) Abstract: The invention relates to an inclusion complex of olopatadine or its pharmaceutically acceptable salt and hydrox(cid:173)
`M yalkyl-B-cylcodextrin, preferably hydroxypropyl-B-cylcodextrin. The present invention also relates to an aqueous topical solution
`0 comprising a therapeutically effective amount of olopatadine or its pharmaceutically acceptable salt; hydroxyalkyl-B-cylcodextrin,
`> preferably hydroxypropyl-B-cylcodextrin and hydroxypropyl methylcellulose in an amount sufficient to enhance the physical stabil(cid:173)
`
`~ ity of the solution.
`
`000001
`
`ARGENTUM PHARM. 1004
`
`

`
`WO 2008/015695
`
`PCT /IN2007 /000199
`
`INCLUSION COMPLEX
`
`FIELD OF THE INVENTION
`
`5 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.·
`
`BACKGROUND OF THE INVENTION
`
`Olopatacline hydrochloride is a carboxylic acid derivative of doxepin, chemically described as
`
`lZ )-1 l-[3-( Dimethy !amino) propy lidene ]-6, 11-clihydrocl ibenz [b,e ]oxepin-2-acetic acid
`
`hydrochloride [C2il-b NOJ .HCI], as disclosed in U.S. Pat Nos.4,871,865 and 4.9:?.3,89:?., bulh
`
`assigned to Burroughs Wellcorne. Olopatacline has antihistarninic and antiusthmatic activity.
`
`IO
`
`15
`
`Olopalacline hydrochloride is commercially available in the U.S as U. l % and U.:?.17o sterik·
`
`l)phthalrnic solutions under the brand names PATANOL'~' and PATADAY'" respectively, both
`
`marketed by Alcon. PATANOL !lIJ is indicated for the treatment of signs and symptoms of allergic
`
`conjunctivitis and
`
`the approved ophthalmic solution contains olopatadine hydrochloride
`
`:20
`
`equivalent to 0.1% olopatacline, 0.01% benzalkonium chloride as preservative, dibasic sodium
`
`phosphate, sodium chloride, hydrochloric acid and I or sodium hydroxide (to adjust the pH) and
`
`purified water. lt has a pH of about 7, and osmolality of about 300rn0sm/kg. PAT ADAY'" is
`
`indicated !'or the treatment of ocular itching associated with allergic conjunctivitis and the
`
`approved ophthalmic solution contains olopatadine hydrochloride equivalent
`
`to U.2%
`
`:25
`
`olopatadine, 0.01 % benzalkonium chloride as preservative, poviclone, di basic sodium phosphate,
`sod iu111 chloride, ecletate cl isod ium. hydrochloric acid and I or sod i urn hydroxide t to adjust the
`pl-I) w1d puriried water. It has a pH of about 7, and osrnolality ul'about 3UOm0srn/kg.
`
`30
`
`Une ubstacle !or preparing olojxlladine hydrochloride aqueous ;,ulmiuns !'or lupical delht:r) i~
`the stability or the aqueous soluliuns ol' olopatadine hydrochloride uver the stm~1ge period.
`Ulopatadine aqueous solutions having bt concentrations of O. I 7%w/v or higher wen; found to be
`
`000002
`
`

`
`WO 2008/015695
`
`PCT/IN2007 /000199
`
`unstable over extended storage periods. The olopatadine hydrochloride precipitates ur
`
`crystallizes out of the solution when used in concentrations higher than O. I 7%w/v. Hence, there
`
`is a need for preparing aqueous solutions of olopatadine hydrochloride containing olopatacline in
`
`concentrations of about O. l 7%w/v or greater, which are stable when stored over the shelf life of
`
`5
`
`the product.
`
`United States Patent No.6,995, 186 (Alcon Inc., 2006, the '186 patent) discloses topically
`
`adrn in istrable solution composition for treating allergic or inflammatory cl isorders of the eye and
`
`nose comprising olopatadine and a polymeric ingredient, where the polymeric ingredient is a
`
`10
`
`polyrneric physical stability enhancing ingredient consisting essentially of polyvinylpyrroliclone
`
`or polystyrene sulfonic acid in an amount sufficient to enhance the physical stability of the
`
`so,lution, and wherein
`
`the con;position does not contain polyvinyl alcohol, polyvinyl acrylic
`
`acid, hyclroxypropyl methyl cellulose, sodiurn carboxymethyl cellulose, xanthan gum. Polyvinyl
`
`alcohol, polyvinyl acrylic acid, hyclroxypropyl methylcellulose, sodium carboxy methyl cellulose
`
`15
`
`and xanthan gum have been clisclose'cl in the ·I 86 patent lo cause physical instability ol'
`
`olopatadine solutions.
`
`In order to overcome the physical stability problems associated with olopatacline aqueous
`
`solutions, we have
`
`tried various
`
`ingredients selected from hydroxypropyl-~-cyclodextrin
`
`20
`
`(HPf:lCD), polysorbate 20, polysorbate 80, propylene glycol, hydroxypropyl methylcellulose
`
`'.29 l 0
`
`(HPMC E4M
`
`premium),
`
`polyvinylpyrrolidone K-30,
`
`xanthan gurn,
`
`sodium
`
`carboxymethylcellulose (Sodium CMC), carbopol 934P, polyvinyl alcohol and mixtures thereof.
`
`We have now surprisingly found
`
`that stable aqueous topical solutions of olopatacline
`
`15
`
`hydrochloride can be prepared by forming an inclusion complex with a hyciro.valkyl cloclextrin,
`
`prel"erably hyclroxypropyl-f:l-cycloclextrin (HPf:lCD). Optionally, hydroxypropyl methylcellulose
`
`(1-lPMCJ may be used to stabilize ihe inclusion complex in the pharnwc~utical l'Ulllposition.
`
`30
`
`2
`
`000003
`
`

`
`WO 2008/015695
`
`PCT/IN2007 /000199
`
`SUMMARY OF THE INVENTION
`
`In one aspect ol' the invention, there is provided an inclusion complex of olopatadine or its
`
`5
`
`pharmaceutically acceptable salt and a hydroxyalkyl cyclodextrin, preferably hyclroxypropyl-~­
`
`cycloclextrin.
`
`ln another aspect of the invention, there is provided an aqueous topical solution comprising a
`
`therapeutically effective amount of olopatadine or
`
`its pharmaceutically acceptable salt:
`
`10
`
`hyclroxyalkyl ~-cylcodextrin,
`
`preferably hydroxypropyl ~-cylcoclextrin and hyclroxypropyl
`
`methyl cellulose in amount sufficient to enhance the physical stability of the solution.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`15
`
`The present invention provides an inclusion complex or olopatadine ur its plrnrnHH.:eutiL:ally
`
`ctcceptable salt and hydroxyalkyl-~-cyclodextrin, particularly hyclruxyprupyl-f:l-cycloclextri11. The
`
`present invention also provides an aqueous topical solution, comprising R therapeutically
`
`effective amount of olopatacline or its pharmaceutically acceptable salt; hyclroxyalkyl-r:l(cid:173)
`
`cycloclextrin, particularly hydroxypropyl-~-cycloclextrin and hyclroxypropyl methylcellulose in
`
`20
`
`an amount sufficient to enhance the physical stability of the solution.
`
`Unless indicated otherwise, all component concentrations are presented on a o/o(w/v) basis and all
`'
`
`reference to olopatacline are to olopatadine free base.
`
`25 Thl: term "in an amount sufficient to enhance the physical stability or the solution", as used
`
`herein means that the amount of hyclroxyalkyl-r:l-cyclodextrin. particularly hydroxypropyl-f:l(cid:173)
`
`cycludextrin .is sufficient to form a complex with olopatacline or its plrnrrnaccutically acceptnbk
`
`salt and thus keep it in solution. i.e. Prevent its precipitation or crystallizatiun.
`
`3
`
`000004
`
`

`
`WO 2008/015695
`
`PCT/IN2007 /000199
`
`Accurcling to one e111bodi111ent of the present invention, the aqueous topical solution contains
`
`olopalacline or
`
`its phar111aceutically acceptable salts. Examples ol' the pharmaceuticully
`
`acceptable salts of olopatacline include inorganic acid salts such as hydrochloride. hydrobromicle.
`
`sulfate and phosphate; organic acid salts such as acetate, maleate. l'umarate. tartrate and citrate:
`
`5
`
`alkali metal salts such as sodium salt and potassiu111 salt; alkaline earth metal salts such as
`
`magnesium salt and calcium salt; metal salts such as alu111inu111 salt and zinc salt; and organic
`
`a111ine addition salts such as triethylamine addition salt (also known as trometha111ine).
`
`morpholine addition salt and p!peridine 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
`
`10 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 amount ranging
`
`from about 0.17% to about 0.62%. Preferably, the solution for111ulations intended for use in the
`
`eye contain about 0.17% to about 0.25% olopatadine and the solution formulations intended !or
`
`use in the nose contain about 0.35% to about 0.62% olopatadine.
`
`15
`
`According lo one e111bodi111ent of the present invention, the aqueous topical solution comprises
`
`cyclodextrin to enhance the physical stability of the solution. Cyclodextrins are a group ul'
`
`strncturally related saccharides which are formed by enzymatic cyclization of starch by a grnup
`
`ul' rnnylases ter111ecl glycosyltransFerases. Cyclodextrins are cyclic oligosaccharides, consisting ol'
`
`'.20
`
`(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
`
`7~ _)
`
`through complex dilution, by re.placement of the included drug by some other suitable molecule
`
`or. the drug may be transferred to the matrix for which it has the highest affinity. Importantly.
`
`since no covalent bonds are formed ur broken during the clrug-cyclodextrin complex formation,
`
`the complexes are in dynamic equilibrium with free drug and cyclodextrin molecules. In solution.
`
`the complexes nre usually prepared by addition of an excess amount ul' the drug tu an aqueous
`
`JU
`
`cyclodextrin solution. The most common naturally occurring cycloclextrins are alpha-
`
`4
`
`000005
`
`

`
`WO 2008/015695
`
`PCT/IN2007 /000199
`
`cyclodextrin, ~-cyclodextrin and gamma-cycloclextrin consisting of 6, 7 and 8 glucopyranose
`
`units, respectively and
`
`their .. derivatives. ~-cycloclextrin appears
`
`to be
`
`the most useful
`
`pharmaceutical complexing agent clue to its cavity size, availability and low cost. Examples of
`
`cyclodextrin derivatives that may be used
`
`in the pharmaceutical compositions of present
`
`5
`
`invention include the hyclroxypropyl derivatives of alpha-, beta- and gamma-cyclodextrin,
`
`sulfoalkylether cyclodextrins such as sulfobutylether beta-cyclodextrin, alkylated cyclodexlrins
`
`such as the randomly methylated beta-cyclodextrin, and various branched cycloclextrins such as
`
`glucusyl- and rnaltosyl beta-cyclodextrin, and the like, and mixtures thereol'.
`
`10 The prelerrecl cycloclextrins for use in the present invention include alkyl cyclodextrins, hyclruxy
`
`alkyl cyclodextrin, such as hydroxy propyl beta-cyclodextrin, carboxy alkyl cyclodextrins aml
`
`sulfoalkyl ether cyclodextrin, such as sulfo butyl ether beta-cycloclextrin. Examples or suitable
`
`cyclodextrins !'or use in the present invention non-exclusively include alphn-cycloclextrin; beta(cid:173)
`
`cyclodextrin; gamma-cyclodextrin; methyl alpha-cyclodextrin; methyl beta-cycloclextrin; methyl
`
`15
`
`ga111111a-cycloclextrin; ethyl beta-cycloclextrin; butyl alpha-cycfoclextrin; butyl beta-cyclodextrin;
`
`butyl gamrna-cycloclextrin; pentyl ga111111a-cyclodextrin; hydroxyethy I beta-cycloclextrin;
`
`hyclroxyethyl gamma-cycloclextrin; 2-hydroxypropyl alpha-cyclodextrin; 2-hyclroxypropyl beta(cid:173)
`
`cyclodextrin; 2-hydroxypropyl gamma-cycloclextrin; 2-hydroxybutyl beta-cyclodextrin; acetyl
`
`alpha-cycloclextrin; acetyl beta-cycloclextrin; acetyl gamma-cyclodextrin; propionyl beta-
`
`20
`
`cycloclextrin; butyryl beta-cycloclextrin; succinyl alpha-cyclodextrin: succinyl beta-cyclodextrin;
`
`succinyl
`
`gamma-eye loclextri n;
`
`benzoyl
`
`beta-eye loclextri n;
`
`palm ityl
`
`beta-cyclodextri n;
`
`to! uenesu I !Onyl beta-cyclodextrin; acetyl methyl beta-cyclodextri n;
`
`acety I butyl beta-
`
`cycloclcxtrin; glucosyl alpha-cyclodextrin; glucosyl beta-eye lodextrin: glucosyl gamnrn-
`
`cycloclextrin; maltosyl a I pha-cyclodextrin;
`
`rnaltosyl beta-cyclodextrin; maltosyl gamma-
`
`2 5
`
`eye lodextri n: a I pha-cyc lodextrin carboxymethy !ether; beta-cyclodextrin carboxyrnetl1y I ether;
`
`gu!llrna-cycloclextrin carboxymethylether; carboxyrnethylethyl beta-cyclodi:xtrin; phosphate l'.:-iter
`
`ulpha-cycloclextrin; phosphate ester beta-cyclodextrin; phosphate ester garnma-cyclodextril!; 3-
`
`tri me thy lam rnon i um-2-hydroxypropy I beta-cycloclextrin; su I fobuty I ether beta-cyclodextri 11;
`
`carboxymethyl alpha-cycloclextrin; carboxymethyl beta-cyclodextrin; carboxymethyl gamma-
`
`30
`
`cyclodextrin, and combinations thereof. The most preferred cyclodextrin for use
`
`in
`
`the
`
`5
`
`5
`
`000006
`
`

`
`WO 2008/015695
`
`PCT/IN2007 /000199
`
`plwrmm:eutical composition of the present invention is hydroxy propyl beta-cyclodextrin. In a
`
`preferred embodiment of the present invention, hydroxypropyl beta-cyclodextrin may be used in
`
`concentrations ranging from about 0.1 % to about 20%w/v of the composition, and more
`
`prel'erably used in concentrations ranging from about 1.0% to about I 0% w/v of the composition.
`
`5 Generally,
`
`l'or solutions meant for ophthalmic administration preferable concentration or
`
`hyclrnxypropyl beta-cycloclextrin is in the range from about 1.0% tl! about 5~/o: !'or solutions
`
`meant for nasal administration, the concentration of hydroxypropyl beta-cycloclextrin is in the
`
`range from about 1.0% to about I 0%.
`
`10 Olopatadine or its pharmaceutically acceptable salt, according to the present invention, forms an
`
`inclusion
`
`complex with
`
`cyclodextrins, particularly
`
`hyclroxyalkyl-~-cycloclextrin, more
`
`particularly hydroxypropyl-~-cyclodextrin . The term "inclusion complex" as used herein refers
`
`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'
`
`15
`
`is associated with the cyclodextrin. Typically, the olopatadine or its pharmaceutically acceptable
`
`salt ur 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 cycloclextrin torous and the
`
`cyclodextrin substituents. The ratio of olopatacline or its pharmaceutically acceptable salt to
`
`hydruxypropyl f:kylcuclextrin in the inclusion complex is l'rom ubuut I:\ .b5 tu about I :50 b)
`
`20 weight. The amount l)f hyclroxypropyl IJ-cylcoclextrin
`
`present in the inclu:-,ion curnple:-.. is
`
`sufficient to enhance the physical stability of the olopatadine solution.
`
`According to one embodiment of the present invention, the composition further includes
`
`hydroxypropyl methylcellulose (HPMC). The hydroxypropyl methylcellulose (HPMC) used in
`
`25
`
`the composition acts as a stabilizer for the inclusion complex of hydroxypropyl beta-cyclodextrin
`
`a11d olopatadine or its pharmaceutically acceptable salt. Various grades of hydroxypropyl
`
`methylcellulose (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 hydration rates, and may be used in the compositions or the
`
`30
`
`present invention. Hydroxypropyl methylcellulose having a methoxy conte11t uf I 9-24 % uncl
`
`6
`
`000007
`
`

`
`WO 2008/015695
`
`PCT/IN2007 /000199
`
`hydroxypropyl content of 7-12 % \'Vith a fastest relative rate of hydration
`
`is available
`
`commercially under the brand 1~ame of Methocel Gracie K. 1-lyclroxypropyl methylcellulose with
`
`28-30 % methoxy content and 7-12 % of' hydroxypropyl content with a !'aster relative hydration
`rate as compared to the above grade is available commercially under thl' brund name or ML'thocel
`5 Gracie E. Hyclroxypropyl methylcellulose with 27-30 % methoxy content and 4.0 - 7.5 % or
`
`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 % hyclroxypropyl content and with slowest rate of
`
`hydration is avai,lable 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
`
`10
`
`at 20°C and which is commercially available as METHOCEL E4M, is used. In preferred
`
`embodiments of
`
`the present
`
`invention, hyclroxypropyl methylcellulose may be used
`
`concentrations ranging from about 0.00 I% to about 5%, and more preferably in concentrations
`
`ranging from about 0.01 % to about 1 % w/v.
`
`15
`
`The aqueous topical solution or the present invention may include an el'fective amount of an
`
`antimicrobial preservative. Examples of pharmaceutically acceptable preservatives that may be
`
`used
`
`in
`
`the present
`
`invention
`
`include, but are not
`
`limited
`
`tu. bi:1w;:thu11iu111 chlurick,
`
`butylparaben, methyl paraben, ethyl paraben, propyl parabe11, be11znlku11iu111 chluricle. ci:."lyl
`
`pyridinium chloride, thimerosaL chlorobutanol, phenylethyl alcohol, benzyl alcohol, putussiu1n
`
`20
`
`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 1 %w/v.
`
`The aqueous topical solution of the present invention may include an effective amount of a
`
`r _)
`
`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 ecletic acid. These non-exclusively
`
`include ecletate clisodium, edetate calcium clisodium, edetate tetrasodium, edetate trisocliurn. and
`the like and mixtures thereoi'. The preferred chelating agent for tile aqueous topical solution ur
`
`7
`
`000008
`
`

`
`WO 2008/015695
`
`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.
`
`5
`
`The aqueous topical solution l)l'the present invention may l'urther include an effective arnount ol'
`a tonicity agent. Examples ol'tonicity agents that may be used in the aqueous topical solution ur
`the present invention include all pharmaceutically acceptable and pharmacologically inert water(cid:173)
`
`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 ( 1995). Preferred tonicity agent is sodium chloride, which may
`
`10
`
`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
`
`prelerably between 150 to 450 mOsm, and more preferably between 250 lo 350 mOsrn.
`
`I
`The aqueous topical solution. of the present invention may include an effective amount or
`
`15
`
`bulfering agent. The buffering agents are included to minimize any change in pH during shell'
`
`li!'e uf the aqueuus topical solution. Examples of buffering agents include. but are not limited to.
`
`lactic acid, citric acid. tartaric acid, phosphoric acid, acetic acid. hydruchluric acid. 11itric <H:id.
`
`L1'll111etlrn111ine. sodium or potassium metaphosphate, sodium ur putassiu111 phusphate. diba~ic
`
`20
`
`sodium phosphate clodecahyclrate, sodium or potassium acetate, nrnmonia. sodium carbo11att:.
`sodium or potassium hydroxi~le, dibasic sodium phosphate, sodium borate. and the like: rn1d
`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 pH 4 to 8, preferably pH of 6.5 to 7.5, and most preferably a pH of 6.8 to
`
`7.?.. The aqueous topical solution intended for nasal administration has a pH ol' 3.0 to 6.0. and
`
`25 most preferably a pH of 3.5 to 5.0.
`
`The aqueous topical solution of the present invention may optionally include an effective
`
`amount of an antioxidant. The antioxidant may be one or more antioxidants. reducing agents and
`
`u11tiux.idant synergist, and may be selected from acetyl cysteine, alpha tocopherol acetate. cl-
`
`30
`
`alpha t(lcopheroL di-alpha toc\.)pherol, ascorbyl palmitate, butylated hyclruxyanisole tBHA),
`
`8
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`000009
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`WO 2008/015695
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`PCT/IN2007 /000199
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`butylaled hydroxytoluene (BI-IT), cysteine, cysteine hydrochloride, propyl gallate, ascorbic acid,
`
`cnlciu111 ascorbate, calcium bisulphate, calcium sulphite, ascorbic acid,
`
`isoascorbic acid,
`
`potassium rnetabisulfite, sodium ascorbate, sodium bisulphate, sodium 111etabisulphite, sodium
`
`sulphite, sodium Lh iosu I phate, thioglycerol, citric acid , ecletic m: id( EDT/\) ancl
`
`its sa I Is,
`
`5
`
`hydroxyquinoline sulphate, phosphoric acid, sodium citrat~ ancl tartaric ncid. The n11tiuxidrn1ls
`
`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 of topical solutions will result in a longer
`'
`residence time in eye or nose, providing a longer time for drug absorption and effect. The list of
`
`I 0
`
`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, Pennsylvariia ( 1995 ).
`
`The viscosity enhancers may be used in concentrations conventional to the pharmaceutical art.
`
`15
`
`The aqueous topical solution of the present invention is chemically stable. The term "chemically
`
`stable" as used herein means that the aqueous topical solution when stored on the shelf lbr up tu
`
`two years has less than 2% total degradati~n products as determirn:cl by the area 11onnali1aliu11
`
`method. The chemical stability may be assessed by accelerated stability testing. The aqu'-·ous
`
`20
`
`topical solution or the present invention may be stored in a closed c:ontainer al JO"C I 65%
`
`relative humidity or 40°C I 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
`
`prncluct is stable on the she If over a period of two years, if the product is stable for three months
`
`al an accelerated stability test condition of 40uC I 75% relative humidity.
`
`The term "'physical stability" as used herein means that when aqueous topical solution or the
`
`present invention are stored in a closed container crystals of olopatadine do not appear.
`
`The chemical stabi I ity is assessed by evaluating the percent total degradation or o Iopa tad ine
`
`30
`
`aqueous topical solutions that are subjected to accelerated stability test conditions and ambient
`
`9
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`000010
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`WO 2008/015695
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`conditions using high perfor111ance liquid chro111atography (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:
`
`Culumn
`
`: HypersiJ BOS Cs (250 X 4.6)
`
`5
`
`Flow rule
`
`: 1.0 ml/min
`
`Tempera tu re
`
`Detection
`
`: Ambient
`
`: 210 nm
`
`Concentration
`
`: 50/65 ppm
`
`Injection volurne
`
`I 0 Run time
`
`: 20~Li
`: 40 rnin
`
`Mobile Phase
`
`: Buffer: Acetonitrile (720 : 280)
`
`Buffer: 6.8 gm KI-bP04 is dissolved in I OOOml of water and the solution is
`
`adjusted to a pH of 4.5 with orthophosphoric acid.
`
`Retention tirne
`
`: I 0.5 min
`
`15 Diluent
`
`: Mobile phase
`
`Standard preparation : 50165 mg olopatadine I-IC! is dissolved in I 00 ml with rnobile phase.
`
`A sample of 5 rnl is diluted to 50 ml with mobile phase
`
`Test preparation
`
`: 2 ml or the olopatadine I-ICl solution is clilutecl with 200 ml o!' mubile
`
`phase
`
`'.20
`
`The percent total degradation products in the olopatadine aqueous topical solutiun is calculalecl
`
`by area normalization method (excluding peaks from placebo and diluent, if any) frorn the
`
`chromatogram obtained by
`
`injecting 20~tl of test preparation as described above
`
`Ill
`
`chromatographic con cl itions
`
`for analyzing degradation of o lopatad ine. The formula
`
`fur
`
`'.25
`
`calculating the percent total degradation products in olopatadine aqueous topical solution is
`
`given belovv:
`
`% Individual degradation product
`
`-------------------------------------------------------------- X I 0 0
`
`Peak area of individual degradation product
`
`30
`
`10
`
`Total area of all the peaks
`
`10
`
`000011
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`WO 2008/015695
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`PCT/IN2007 /000199
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`% Total degradation products
`
`Sum of all % individual degradation products
`
`For finished dosage forms (for example - solutions) the value of percent individual degradation
`
`5
`
`product should not be more than l % 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 ol'the present invention is considered to be acceptable.
`
`/\ccording to one embodiment of' the present invention, the aqueous topicnl solution may be
`
`I U
`
`prepared by the following process:
`
`a. Dissolving hydroxypropyl-p-cyclodextrin(HPPCD) in water for injection till clear solutiun
`
`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.
`
`15
`
`c. Dissolving olopatacline hydrochloride in water for injection and adding to the solution of
`
`step (a).
`
`cl. Adjusting pH of the solution between 3.5-5.0 for nasal solution, and between 6.8-7.2 !Or
`
`ophthalmic solution with 0.1 N hydrochloric acid and 0.1 N sodium hydroxide.
`
`e. Final adjustment of volume with water for injection and measuring pH.
`
`20
`
`f. Filtering of the solution through 2~tm prefilter and then through O.?.~un nylon 66 membrane
`
`l'ilter, and translerring the solutions to sterile containers.
`
`Thl' aqueous topical solution or the present invention may be l'orrnulaled to be dispensecl in
`
`suitable containers as drops, sprays, metered sprays, aerosols and metered aerosols. The aqueous
`
`25
`
`topical 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 cleliverecl 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
`
`30
`
`which may optionally be anodizecl, lacquer-coated and I or plastic-coated, which container is
`
`1 1
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`000012
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`WO 2008/015695
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`
`closed with a metering valve. The metering valves are designed to deliver a metered amount or
`
`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
`
`5
`
`invention, 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'ernxl
`
`elllbodimenl ol' the present invention, the container for a nasal solution is u U.S.P type I amber
`
`color glass container equipped with a suitable nasal spray pump.
`
`I 0
`
`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.
`
`I 5
`
`25
`
`30
`
`12
`
`000013
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`COMPARATIVE EXAMPLES A-M
`
`The t.:ompositions shown in table I and table 2 below were prepared and subjected to stability
`
`5
`
`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.
`
`I ngredien.ts
`
`A
`
`B
`
`Table 1
`
`Comparative Examples A-H
`c
`D
`F
`E
`Concentration CY<iw/v)
`
`G
`
`H
`
`0.527
`
`-
`
`-
`
`Olopatacline
`hyclrochloricle
`0.005
`Polysorbate 20
`Polysorbate 80
`-
`Propylene glycol 0.05
`Hydroxypropyl
`rnethy Ice! I u lose
`(::!910 E4M
`premium)
`Polyvinyl
`pyrroliclone K-
`30
`Sodium chloride
`Benznlkonium
`chloride \50%J
`Disuclium
`cdetatc
`Dibasic sodium
`phosphate
`dodecahydrate
`
`-
`0.02
`
`-
`
`0.20
`
`o.527
`-
`0.005
`-
`
`0.527
`-
`'0.0 l
`0.05
`
`0.527
`-
`-
`1.50
`
`0.527
`-
`-
`0.05
`
`0.527
`-
`-
`-
`
`0.527
`-
`-
`-
`
`0.665
`-
`-
`-
`
`-
`
`-
`
`0.60
`
`0.02
`
`-
`
`-
`
`-
`
`0.02
`
`-
`
`-
`
`-
`
`-
`
`-
`-
`
`-
`
`-
`
`-
`
`-
`0.02
`
`-
`
`0.10
`
`0.25
`
`0.10
`
`-
`
`0.60
`
`0.02
`
`-
`
`-
`
`0.80
`
`0.02
`
`-
`
`2.00
`
`0.30
`
`0.02
`
`0.0 I
`
`0.06
`
`0.50
`
`0.50
`
`0.25
`
`0.25
`
`0.15
`
`U. I 0
`
`NaOH /HCI
`
`Water for
`Injection
`
`pH 4.5
`-5.0
`
`q.s I 00
`111 I
`
`pH 4.5
`-5.0
`
`q.s I 00
`111 L
`
`pH 4.5
`-5.0
`
`q.sl 00
`111 I
`
`p!-1 4.5
`-5.0
`
`q.sl 00
`111 I
`
`pH 4.5
`-5.0
`
`q.sl 00
`m I
`
`pH 4.5
`-5.0
`
`pH
`3.5
`-5.0
`q.sl 00 q.s I 0
`m I
`0 111 I
`
`pH 3.5
`-5.0
`
`q.s I 00
`111 I
`
`IU
`
`13
`
`000014
`
`

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`WO 2008/015695