(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`2 August 2001 (02.08.2001)
`
`(I0) International Publication Number
`
`WO 01/54687 A1
`
`(51) International Patent Classificationlz
`31/551, A61P 27/14
`
`A61K 31/335,
`
`[US/US], 2821 Donnybrook Drive, Burleson, TX 76028
`(US).
`
`(2 1) International Application N umber:
`
`PCT/US01/02418
`
`(74) Agents: RYAN, Patrick, M. et 211.; R & D Counsel Q—148,
`6201 South Freeway, Fort Worth, TX 76134-2099 (US).
`
`(22) International Filing Date: 24 January 2001 (24.01.2001)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/177,804
`
`25 January 2000 (25.01.2000)
`
`US
`
`(71) Applicant for all designated States except US): ALCON
`UNIVERSAL LTD. [CH/CH]; Bosch 69, PO. Box 62,
`CH-6331 Hunenberg (CH).
`
`(81) Designated States (national): AU, BR, CA, CN, JP, MX,
`PL, US, ZA.
`
`(84) Designated States (regional): European patent (AT, BE,
`CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC,
`NL, PT, SE, TR).
`
`Published:
`
`with international search report
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): YANNI, John, M.
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes andAbbreviations " appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`WO01/54687A1
`
`(54) Title: OPHTHALMIC ANTI-ALLERGY COMPOSITIONS SUITABLE FOR USE WITH CONTACT LENSES
`
`(57) Abstract: Topically administrable anti-allergy compositions comprising olopatadine and a polymeric quaternary ammonium
`preservative are suitable for use by patients wearing contact lenses.
`
`APOTEX EX1021
`
`Page 1
`
`

`
`WO 01/54687
`
`PCT/US01/02418
`
`OPHTHALMIC ANTI-ALLERGY COMPOSITIONS SUITABLE FOR USE
`
`WITH CONTACT LENSES
`
`BACKGROUND OF THE INVENTION
`
`The present invention relates generally to ophthalmic anti-allergy
`
`compositions.
`
`In particular, the present invention relates to topical anti-allergy
`
`compositions that can be safely applied by a patient wearing contact lenses.
`
`Ophthalmic formulations generally contain one or more active
`compounds along with excipients such as surfactants, comforting agents,
`
`complexing agents, stabilizers, buffering systems, chelating agents, viscosity
`
`agents or gelling polymers and anti-oxidants. Ophthalmic“formulations which
`
`are intended for multidose use require a preservative. Benzalkonium chloride
`
`("BAC") is the most widely used ophthalmic preservative.
`
`Topically administrable multidose ophthalmic products are generally
`
`not suitable for use with contact lenses because the active or the preservative
`
`may bind to or accumulate in the contact lenses, causing irritation or toxic
`
`effects.
`
`Olopatadine is a known anti-allergy drug. See U.S. Patent No.
`
`5,641,805 (Yanni, et al.). PATANOL® brand of olopatadine hydrochloride
`
`ophthalmic solution is marketed as a topical anti-allergy composition.
`
`Emedastine is a known anti-histamine drug. EMAD|NE® brand of emedastine
`
`difumarate solution is marketed as a topical anti-allergy composition. Like
`
`other topically administrable anti-allergy products, these compositions are
`
`preserved with BAC. BAC is known to bind to or accumulate in contact
`
`lenses. Thus, like other topically administrable ophthalmic pharmaceutical
`
`products containing BAC, PATANOL® brand of olopatadine hydrochloride
`
`ophthalmic solution and EMADlNE® brand of emedastine difumarate
`
`ophthalmic solution contain in their labelling information precautionary
`
`Page 2
`
`

`
`WO 01/54687
`
`PCT/US01/02418
`
`instructions to remove contact lenses before use and to wait ten minutes after
`
`administering the product before replacing the lenses. The dosing regimen
`
`for anti-allergy products typically calls for two to four applications a day,
`
`making it inconvenient for contact lens wearers to treat ophthalmic allergy
`
`symptoms.
`
`Polyquaternium-1, which is used under the trade name Po|yquad®, is
`
`one preservative known to be compatible with contact lenses.
`
`Polyquaternium-1 and other polymeric quaternary ammonium compounds are
`
`used as disinfectants and preservatives in contact lens care and artificial tear
`
`solutions. See, for example, U.S. Patent Nos. 5,037,647; 4,525,346; and
`
`4,407, 791. The currently marketed Opti-Free® brand of contact lens care
`
`products, including multi—purpose solutions and cleaning solutions, contains
`
`polyquaternium-1 as a disinfectant and preservative.
`
`In addition to contact lens care products, polyquaternium-1 can also be
`
`used as a preservative in certain topically administrable ophthalmic drug
`
`products. U.S. Patent No. 5,603,929 discloses the use of polyquaternium-1 in
`
`combination with boric acid to preserve topically administrable ophthalmic
`
`compositions of acidic drugs, such as non-steroidal anti-inflammatory drugs.
`
`Although the '929 patent defines suitable ophthalmic drug compounds for use
`
`with the polyquaternium-1 and boric acid preservative system to include
`
`ophthalmically acceptable salts, amides, esters and prodrugs of the many
`
`types of acidic drugs, it does not mention anti- allergy drugs or olopatadine in
`
`particular. See Col. 3, lines 12 -30 of the '929 patent.
`
`Page 3
`
`

`
`WO 01/54687
`
`PCT/US01/02418
`
`SUMMARY OF THE INVENTION
`
`It has now been discovered that compositions of olopatadine and
`
`emedastine that comprise polyquaternium-1 as a preservative are suitable for
`
`use with contact lenses. The present invention relates to mu|ti—dose, topically
`
`administrable compositions of olopatadine and emedastine containing a
`
`polymeric quaternary ammonium compound, such as polyquaternium-1, as a
`
`preservative. The compositions of the present invention do not contain BAC.
`
`The present invention also relates to a method for treating or
`controlling ocular allergies in patients wearing contact lenses which comprises
`
`topically administering a composition comprising olopatadine or emedastine
`
`and a polymeric quaternary ammonium compound as a preservative, where
`
`the composition is applied without removing the contact lenses.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Olopatadine is (Z)-11-(3—dimethy|aminopropylidene)-6,11-
`
`dihydrodibenz[b,e]— oxepin-2-acetic acid. Olopatadine can be made using the
`
`methods disclosed in U.S. Patent No. 5, 116,863, the entire contents of which
`
`are hereby incorporated by reference. The concentration of olopatadine in the
`
`compositions of the present invention will range from about 0.0001 to 5
`
`%(w/v), preferably from about 0.001 to 0.25 %(w/v), and most preferably from
`
`about 0.1 to 0.25 %(w/v), based on the sterilized purified water. The
`
`olopatadine ingredient may be present in the form of a pharmaceutically
`acceptable salt. Unless indicated otherwise, "o|opatadine" as used herein
`
`refers to both olopatadine and its pharmaceutically acceptable salts. The
`
`most preferred form of olopatadine is olopatadine hydrochloride. The most
`
`preferred concentration of olopatadine hydrochloride is from about 0.111 to
`
`0.222 %(w/v), which is equivalent to 0.1 to 0.2 %(w/v) olopatadine.
`
`Emedastine's chemical name is 1—(2-ethoxyethyl)-2-(4-methyl—1—
`
`homopiper-azinyl)-benzimidazole. The ophthalmic use of emedastine is
`
`3
`
`Page 4
`
`

`
`WO 01/54687
`
`PCT/US01/02418
`
`disclosed in U.S. Patent No. 5,441,958. Emedastine can be made using the
`
`methods disclosed in U.S. Patent No. 4,430,343, the entire contents of which
`
`are hereby incorporated by reference. The concentration of emedastine in the
`
`compositions of the present invention will range from about 0.0001 to 1
`
`%(w/v), preferably from about 0.005 to 0.1 %(w/v), and most preferably about
`
`0.05 %(w/v). The emedastine ingredient may be present in the form of a
`
`pharmaceutically acceptable salt. Unless indicated othen/vise, "emedastine"
`
`as used herein refers to both emedastine and its pharmaceutically acceptable
`
`salts. The most preferred form of emedastine is emedastine difumarate. The
`
`most preferred concentration of emedastine difumarate is about 0.0884
`
`%(w/v), which is equivalent to 0.05 %(w/v) emedastine.
`
`In addition to olopatadine or emedastine, or a pharmaceutically
`
`acceptable salt thereof, the compositions of the present invention contain a
`
`polymeric quaternary ammonium compound as a preservative. The polymeric
`
`quaternary ammonium compounds useful in the compositions of the present
`
`invention are those which have an antimicrobial effect and which are
`
`ophthalmically acceptable. Preferred compounds of this type are described in
`
`US Patents Nos. 3,931,319; 4,027,020; 4,407,791; 4,525,346; 4,836,986;
`
`5,037,647 and 5,300,287; and PCT application WO 91/09523 (Dziabo et al.).
`
`The most preferred polymeric ammonium compound is polyquaternium-1 ,
`
`othen/vise known as Polyquad® or Onamer M®, with a number average
`
`molecular weight between 2,000 to 30,000. Preferably, the number average
`
`molecular weight is between 3,000 to 14,000.
`
`The polymeric quaternary ammonium compounds are generally used in
`
`the compositions of the present invention in an amount from about 0.00001 to
`
`about 3 %(w/v), preferably from about 0.001 to about 0.1 %(w/v). Most
`
`preferably, the compositions of the present invention contain from about 0.001
`
`to about 0.05 %(w/v) of polymeric quaternary ammonium compounds.
`
`It may be necessary or desirable to add boric acid to the compositions
`
`to achieve desired levels of preservative efficacy. See U.S. Patent No.
`
`4
`
`Page 5
`
`

`
`WO 01/54687
`
`PCT/US01/02418
`
`5,603,929, the entire contents of which are hereby incorporated by reference.
`
`The boric acid suitable for use in the compositions of the present invention
`
`includes not only boric acid, but also its ophthalmically acceptable acid
`
`addition salts, as well as borate-polyol complexes of the type described in US
`
`Patent No. 5,342,620 (Chowhan). If present, the amount of boric acid will
`
`generally range from about 0.3 to about 5.0 %(w/v).
`
`The compositions of the present invention should have an
`
`ophthalmically acceptable tonicity, such as 260- 320 mOsm/kg, and an
`
`ophthalmically acceptable pH, such as pH 5 -8, and preferably pH 6.8 -7.6.
`
`The topically administrable, multi-dose compositions of the present invention
`
`optionally comprise other excipients, such as tonicity adjusting agents,
`
`buffering agents, chelating agents, and pH adjusting agents. For example,
`
`sodium chloride, mannitol, or the like may be used as the isotonic agent;
`
`sodium hydrogenphosphate, sodium dihydrogenphosphate, p-hydroxybenzoic
`
`acid ester, boric acid orthe like as the buffering agent; sodium edetate or the
`
`like as the chelating agent or stabilizer; and sodium hydroxide, hydrochloric
`
`acid or the like as the pH adjusting agent.
`
`The compositions of the present invention may also include viscosity
`
`modifying agents such as: cellulosic ethers, such as, hydroxypropyl methyl
`
`cellulose (HPMC), hydroxyethyl cellulose (HEC), ethyl hydroxyethyl cellulose,
`
`hydroxypropyl cellulose, methyl cellulose, and carboxymethyl cellulose;
`
`carbomers (e.g. Carbopo|®; polyvinyl alcohol; polyvinyl pyrrolidone; alginates;
`
`carrageenans; and guar, karaya, agarose, locust bean, and xanthan gums.
`
`The following examples are presented to illustrate further various
`
`aspects of the present invention, but are not intended to limit the scope of the
`
`invention in any respect.
`
`Page 6
`
`

`
`WO 01/54687
`
`PCT/US01/02418
`
`EXAMPLE 1
`
`Formulation
`
`ln 0 redient
`Olopatadine
`H drochloride
`
`NaC|
`
`Pol eth Iene Gl col 400
`Pol uaternium-1
`Dibasic sodium
`hoshate anh drous
`HCI/NEIOH
`Purified Water
`
`0.111 or 0.222
`
`0.111 or 0.222
`
`q.s. to 260 — 320
`mOsm/k
`2.0
`0.001-0.15
`. 0.5
`
`0.3
`
`2.0
`0.005
`0.5
`
`.S. to H 6.8 - 7.2
`.s. to 100%
`
`.S. to H 7
`.s. to 100%
`
`EXAMPLE‘2
`
`— Formulation %w/v
`
`Emedastine difumarate
`
`Hydroxypropyl
`meth lcellulose 2910
`
`Polyquaternium-1
`Dibasic Sodium
`Phoshate Anh drous
`
`HCI/NaOH
`
`0 0884
`.s. to 260L320 mOsm/k
`0 25
`
`0.001 — 0.15
`M
`0.5
`
`.s. to H 7.4
`.s.to100%
`
`The invention has been described by reference to certain preferred
`
`embodiments; however, it should be understood that it may be embodied in
`
`other specific forms or variations thereof without departing from its spirit or
`
`essential characteristics. The embodiments described above are therefore
`
`considered to be illustrative in all respects and not restrictive, the scope of the
`
`invention being indicated by the appended claims rather than by the foregoing
`
`description.
`
`Page 7
`
`

`
`WO 01/54687
`
`PCT/US01/02418
`
`WHAT IS CLAIMED IS:
`
`1.
`
`A topically administrable, multi-dose anti-allergy composition suitable
`
`for use by patients wearing contact lenses, wherein the composition
`
`comprising an anti-allergy effective amount of a drug selected from the group
`
`consisting of olopatadine and emedastine; and an ophthalmically acceptable
`
`polymeric quaternary ammonium compound as a preservative, provided that
`
`the composition does not contain benzalkonium chloride.
`
`2.
`
`The composition of Claim 1 wherein the drug is olopatadine and the
`
`anti-allergy effective amount of olopatadine is from about 0.0001 to 5 %(w/v).
`
`3.
`
`The composition of Claim 2 wherein the anti-allergy effective amount of
`
`olopatadine is from about 0.001 to 0.25 %(w/v).
`
`4.
`
`The composition of Claim 3 wherein the olopatadine is olopatadine
`
`hydrochloride and the anti-allergy effective amount of olopatadine is from
`
`about 0.1 — 0.25 %(w/v).
`
`5.
`
`The composition of Claim 1 wherein the drug is emedastine and the
`
`anti-allergy effective amount of emedastine is from about 0.0001 to 1 %(w/v).
`
`6.
`
`The composition of Claim 5 wherein the anti-allergy effective amount of
`
`emedastine is from about 0.005 to 0.1 %(w/v).
`
`7.
`
`The composition of Claim 5 wherein the emedastine is emedastine
`
`difumarate and the anti-allergy effective amount of emedastine is about
`
`0.0884 %(w/v).
`
`8.
`
`The composition of Claim 1 wherein the polymeric quaternary
`
`ammonium compound is polyquaternium-1.
`
`Page 8
`
`

`
`WO 01/54687
`
`PCT/US01/02418
`
`9. >
`
`The composition of Claim 8 wherein the polymeric quaternary
`
`ammonium compound is present in an amount from about 0.00001 to about 3
`
`%(w/v).
`
`10.
`
`The composition of Claim 9 wherein the polymeric quaternary
`
`ammonium compound is present in an amount from about 0.001 to about 0.1
`
`%(w/v).
`
`’ 11.
`
`The composition of Claim 1 wherein the composition further comprises
`
`one or more ingredients selected from the group consisting of tonicity
`
`adjusting agents; buffering agents; chelating agents; pH adjusting agents; and
`
`viscosity modifying agents.
`
`12.
`
`A method for treating or controlling ocular allergies in patients wearing
`
`contact lenses which comprises topically administering a composition
`
`comprising an anti-allergy effective amount of a drug selected from the group
`
`consisting of olopatadine and emedastine; and a polymeric quaternary
`
`ammonium compound as a preservative, wherein the composition is applied
`
`without removing the contact lenses and the composition does not contain
`
`benzalkonium chloride.
`
`13.
`
`The method of Claim 12 wherein the drug is olopatadine and the anti-
`
`allergy effective amount of olopatadine is from about 0.0001 to 5 %(w/v).
`
`14.
`
`The method of Claim 13 wherein the olopatadine is olopatadine
`
`hydrochloride and the anti-allergy effective amount of olopatadine is from
`
`about 0.1 to 0.25 %(w/v).
`
`15.
`
`The method of Claim 12 wherein the drug is emedastine and the anti-
`
`allergy effective amount of emedastine is from about 0.005 to 0.1 %(w/v).
`
`Page 9
`
`

`
`WO 01/54687
`
`PCT/US01/02418
`
`16.
`
`The method of Claim 15 wherein the emedastine is emedastine
`
`difumarate and the anti-allergy effective amount of emedastine is about
`
`0.0884 %(w/v).
`
`17.
`
`The method of Claim 12 wherein the polymeric quaternary ammonium
`
`compound is po|yquaternium—1.
`
`18.
`
`The method of Claim 17 wherein the polymeric quaternary ammonium
`
`compound is present in an amount from about 0.00001 to about 3 %(w/v).
`
`19.
`
`The method of Claim 12 wherein the composition further comprises
`
`one or more ingredients selected from the group consisting of tonicity
`
`adjusting agents; buffering agents; chelating agents; pH adjusting agents; and
`
`' viscosity modifying agents.
`
`Page 10
`
`

`
`interna
`
`Application No
`
`PCT/US O1/02418
`
`INTERNATIONAL SEARCH REPORT
`
`A. CLASSIFICATION OF S BJECT MATTER
`IPC 7
`A61K31 335
`A61K31/551
`
`A61P27/14
`
`According to international Patent Classification (IPC) orto both national classification and IPC
`B. FIELDS SEARCHED
`Minimum documentation searched (classification system followed by classification symbols)
`IPC 7
`A61K
`
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
`
`Electronic data base consulted during the international search (name of data base and, where practical, search terms used)
`
`WPI Data, EPO-Internal, PAJ, CHEM ABS Data, BIOSIS, MEDLINE, EMBASE
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Category °
`
`Citation of document, with indication. where appropriate. of the relevant passages
`
`Relevant to claim No.
`
`US 5 192 780 A (ALCON LABORATORIES,
`9 March 1993 (1993-03-09)
`column 2,
`line 9 - line 19
`column 3,
`line 5 - line 6
`column 4,
`line 12
`claims 1-4
`
`INC.)
`
`1-19
`
`US 5 037 647 A (ALCON_1ABORATORIES,
`6 August 1991 (1991-08-06)
`cited in the application
`column 1,
`line 64 —column 2,
`
`line 34
`
`INC.)
`
`US 4 525 346 A (ALCON LABORATORIES,
`25 June 1985 (1985-06-25)
`cited in the application
`column 1,
`line 33 — line 48
`column 2,
`line 30 —column 3,
`examples 5,6,14-23
`
`line 21
`
`INC.)
`
`Further documents are listed in the continuation of box 0.
`° Special categories of cited documents 2
`
`'A' document defining the general state of the art which is not
`considered to be of particular relevance
`'E' earlier document but published on or afierthe international
`filing date
`'L' document which may throw doubts on priority claim(s) or
`which is cited to establish the publication date of another
`citation or other special reason (as specified)
`'0' document referring to an oral disclosure, use, exhibition or
`other means
`'P' document published priorto the international filing date but
`laterthan the priority date claimed
`Date of the actual completion of the international search
`
`25 May 2001
`
`Name and mailing address of the ISA
`European Patent Office, P.B. 5818 Patenilaan 2
`NL — 2280 HV Flijswijk
`Tel. (4-31-70) 340-2040, TX‘ 31 651 epo ni,
`Fax: (+31—70) 340-3016
`
`Form PCT/ISA/210 (second sheet) (July 1992)
`
`_/_._
`
`Patent family members are listed in annex.
`
`‘T’
`
`later document published after the international filing date
`or pnorlty date and not in conflict with the application but
`inven ion
`cited to understand the principle or theory underlying the
`'X' document of particular relevance; the claimed invention
`cannot be considered novel or cannot be considered to
`involve an Inventive step when the document is taken alone
`'Y' document of particular relevance‘, the claimed invention
`cannot be considered to involve an inventive step when the
`document is combined with one or more other such docu-
`in he a .
`ments. such combination being obvious to a person skilled
`'&' document member of the same patent family
`
`Date of mailing of the international search report
`
`06/O6/2001
`Authorized officer
`
`Economou, D
`
`Page 11
`
`

`
`INTERNATIONAL SEARCH REPORT
`C.(contInuation) DOCUMENTS CONSIDERED TO BE RELEVANT
`
`lnternat
`
`Application No
`
`PCT/Us 01/02413
`
`Calegory °
`
`Citalion of document, with indication,where appropriate, of the relevant passages
`
`Relevant to claim No.
`
`US 5 603 929 A (ALCON LABORATORIES,
`18 February 1997 (1997-02-18)
`cited in the app11cat1on
`co1umn 2,
`line 18 — 11ne 30
`co1umn 2, 1ine 61 -co1umn 3, 11ne 30
`c1a1ms 1-20
`
`INC.)
`
`Form PCT/ISA/210 (continuaiion ol second sheet) (July 1992)
`
`Page 12
`
`

`
`INTERNATIONAL SEARCH REPORT
`lrlflfnation on patent family members
`
`,me,,,a
`
`l Application No
`
`PCT/US 01/02418
`
`Patent document
`cited in search report
`
`Publication
`date
`
`Patent family
`member(s)
`
`US 5192780
`
`A
`
`09-03-1993
`
`US 5037647
`
`A
`
`06-08-1991
`
`US 4525346
`
`25-06-1985
`
`US 5603929
`
`A
`
`18-02-1997
`
`Form PCT/ISA/210 (patenliamily annex) (July 1992)
`
`636685
`6774090
`2031593
`0433766
`4009339
`9009941
`
`182081
`625099
`4311389
`1334573
`68929031
`68929031
`115690
`0359574
`2136055
`105321
`3031328
`1011941
`6049060
`2502733
`168660
`230663
`26017
`9002555
`8907060
`
`4407791
`46441
`557817
`9050382
`1194421
`3279945
`223883
`0076136
`831770
`77661
`55742
`2054804
`58501515
`160782
`201967
`19376
`8301003
`8206966
`
`686917
`4162296
`2180554
`0739197
`2954356
`9503791
`9614829
`5653972
`
`Publication
`date
`
`06-05-1993
`20-06-1991
`19-06-1991
`26-06-1991
`14-01-1992
`30-10-1991
`
`15-07-1999
`02-07-1992
`02-04-1990
`28-02-1995
`19-08-1999
`11-11-1999
`09-05-1990
`21-03-1990
`16-11-1999
`31-07-2000
`31-12-1999
`20-04-2000
`29-06-1994
`30-08-1990
`02-06-1993
`28-05-1991
`29-01-1992
`22-03-1990
`29-05-1991
`
`04-10-1983
`15-10-1989
`08-01-1987
`08-04-1983
`01-10-1985
`26-10-1989
`19-05-1983
`06-04-1983
`19-05-1983
`25-09-1984
`02-01-1991
`22-11-1990
`08-09-1983
`16-05-1990
`20-03-1985
`02-04-1986
`31-03-1983
`27-07-1983
`
`12-02-1998
`06-06-1996
`23-05-1996
`30-10-1996
`27-09-1999
`15-04-1997
`23-05-1996
`05-08-1997
`
`Page 13