WORLD lN'I'ELLECTUAL_ PROPERTY ORGANIZATION
`International Bureau
`
`
`
`INTERNAT'IONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 5 =
`A6lK 31/19 9/00 47/18
`’
`’
`
`
`
`(11) International Publication Number:
`
`WO 94/15597
`
`(43) International Publication Date:
`
`21 July 1994 (21.07.94)
`
`(21) International Application Number:
`
`PCT/US94/00188
`
`(22) International Filing Date:
`
`6 January 1994 (06.01.94)
`
`(81) Designated States: AU, CA, JP, European patent (AT, BE,
`CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT,
`SE).
`
`(30) Priority Data:
`08/003,107
`
`11 January 1993 (11.01.93)
`
`US
`
`Published
`With intemational search report.
`
`(71) Applicant: ALLERGAN, INC. [US/US]; 2525 Dupont Drive,
`PO. Box 19534, Irvine, CA 92713-9534 (US).
`
`(72) Inventor: WONG, Michelle, R; 15662 Myrtle Avenue, Tustin,
`CA 92680 (US).
`
`(74) Agents: BARAN, Robert, J. et al.; Allergan, Inc., 2525 Dupont
`Drive, P.O. Box 19534, Irvine, CA 92713-9534 (US).
`
`(54) Title: OPHTHALMIC COMPOSITIONS COMPRISING BENZYLLAURYLDIMETI-IYLAMMONIUM CHLORIDE
`
`(57) Abstract
`
`An ophthalmic solution generally includes an ophthalmologically acceptable drug formulation incompatible with benzalkonium
`chloride and lauralkonium chloride present in an anti-microbially effective amount. The incompatibility of the ophthalmologically acceptable
`drug manifests itself by forming insoluble ion pairs with the benzalkonium chloride. It has been found that lauralkonium chloride which
`is the C12 homolog of benzalkonium chloride is effective as a preservative without apparent interaction with the acidic ophthalmologically
`acceptable drug and formulations maintain their antimicrobial efficiency over periods of up to one year or more.
`
`
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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PC!‘ on the front pages of pamphlets publishing international
`applications under the PCT.
`
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cote d'Ivoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`
`§§3EEEQ892988Q9E
`
`United Kingdom
`Georgia
`Guinea
`
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Lieditenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaeo
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`
`
`§E§§§EEE5E§:s:==sasaaa
`
`Mauritania
`Malawi
`Nigu
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Fedaation
`Sudan
`Sweden
`Slovenia
`Slovakia
`Senegal
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`United States of Amaica
`Uzbekistan
`Viet Nam
`
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`WO 94115597
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`'
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`PCT/US94/00188
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`OPHTHALMIC COMPOSITIONS COMPRISING BENZYLLAURYLDIMETHYLAMMONIUM CHLORIDE
`
`The present invention generally relates to improved ophthalmic
`
`formulations and solutions and more particularly to improved preservative
`
`systems for ophthalmologically acceptable drug formulations which have
`
`,10
`
`an incompatibility with benzalkonium chloride. More specifically, the
`
`present invention pertains to the preservative for an anti-inflammatory
`
`drug such as sodium flurbiprofen (Ocufenil).
`
`Ophthalmologically acceptable drug formulations generally contain
`
`15
`
`effective compounds and a number of ophthalmologically acceptable excip-
`
`ients.
`
`Such excipients generally include solutions, ointments, and
`
`suspensions, etc. More specifically, such excipients include stabilizing
`
`agents, surfactants, buffering systems, chelating systems, viscosity agents,
`
`and, importantly, a preservative.
`
`20
`
`Ophthalmic formulations, understandably, must be sterile and if a
`
`multi-doseregime is intended, the formulation must be preserved with an
`
`effective antimicrobial agent. I
`
`25
`
`As discussed in U.S. Patent No. 5,110,493, organo-mercurials have
`
`been used extensively as the preservatives in ophthalmic solutions. As
`
`reported in this reference,
`
`these compounds pose difficulties due to
`
`potential mercury toxicity as well as poor chemical stability.
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`Therefore, benzalkonium chloride, which is a quaternary ammonium
`
`compound, has been widely used in ophthalmic solutions. It is also well-
`
`known, however, that benzalkonium chloride is considered incompatible
`
`with anionic drugs, forming insoluble compounds which cause the solution
`
`5
`
`to turn cloudy.
`
`This is because of the fact that many acidic drug entities carry a
`
`negative charge at physiological pH.
`
`In fact, all acidic drug entities will
`
`carry a negative charge at all pH above their pKa.
`
`10
`
`In the case of benzalkonium chloride, which is a positively charged
`
`preservative, ion pairs can be
`
`formed with negatively charged drug
`
`compounds, forming an insoluble ion pair which causes the drug to
`
`precipitate out of solution. Concomitant with the removal of the drug
`
`15
`
`from solution is the removal of benzalkonium chloride, thereby rendering
`
`this quaternary gerrnicide incapable of performing its function as an
`
`antimicrobial agent.
`
`Benzalkonium chloride is a mixture of a1kyldimethylbenzyl-
`
`20
`
`ammonium chloride of the general formula as shown below in which R
`
`represents a mixture of the alkyls from C8H17 to C181-I37
`
`As hereinbefore noted, it is well-known that benzalkonium chloride is
`
`generally incompatible with anionic detergents or anionic drug compounds.
`
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`WO 94/15597
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`PCT/US94/00188
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`See U.S. Patent No. 5,110,493, and The Merck Index, llth Edition, Merck
`
`& Co., Inc., 1989.
`
`The present invention specifically relates to the discovery that a
`
`5
`
`particular member of a group of compounds, generally known as
`
`benzalkonium chloride, exhibits properties totally different from other
`
`members of the group and different from the gross properties of the
`
`mixture known as benzalkonium chloride.
`
`10
`
`This discovery by the applicant must be taken in the context that all
`
`compositions are made of the same substances, retaining their fixed
`
`chemical properties.
`
`The elements are capable of an infinity of
`
`permutations, and selection of that group or element of a group which
`
`proves serviceable to a given need requires a high degree of originality.
`
`15
`
`This general premise relates to the invention at hand. The applicant has
`
`discovered that lauralkonium chloride, which is the C12 homolog of
`
`benzalkonium chloride,
`
`is compatible with acidic drug entities with
`
`apparently no insoluble ion pairs being formed therewith. This is contrary
`
`to the properties of the mixture of alkyldimethylbenzylammonium chloride,
`
`20
`
`known as benzalkonium chloride, which includes a mixture of the alkyls
`
`SUMMARY OF THE INVENTION
`
`25
`
`An ophthalmic solution, in accordance with the present invention,
`
`generally includes an ophthalmologically acceptable drug formulation
`
`incompatible with benzalkonium chloride and lauralkonium chloride
`
`present
`
`in an antimicrobially effective amount. More specifically,
`
`flurbiprofen is an example of an acidic drug that forms an insoluble ion-
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`pair with benzalkonium chloride.
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`However, when combined with
`
`lauralkonium chloride, no apparent insoluble ion pairs are formed.
`
`More particularly, in accordance with the present invention, the
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`5
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`ophthalmic solution may further include citric acid monohydrate, sodium
`
`citrate dihydrate, polyvinyl alcohol, edetate disodium dihydrate, sodium
`
`chloride, potassium chloride and water.
`
`The amount of lauralkonium chloride is any antimicrobially
`
`10
`
`effective amount and preferably may be up to about 0.005% by weight per
`
`volume of the solution, and the amount of sodium flurbiprofen may be
`
`present in any effective amount and preferably about 0.03% by weight per
`
`volume.
`
`15
`
`The combination of lauralkonium chloride is further emphasized in
`that it can be combined with an acidic ophthalmologically acceptable drug
`
`formulation having a negative charge at physiological pH, and further the
`
`fact that the acidic ophthalmologically acceptable drug is capable of
`
`forming an insoluble ion-pair with benzalkonium chloride, no apparent
`
`20
`
`insoluable ion-pairs are produced when the drug is in combination with
`
`lauralkonium chloride, taken itself.
`
`Further, the invention includes a method for preserving an acidic
`
`ophthalmologically acceptable drug solution, comprising adding to the
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`25
`
`ophthalmologically acceptable drug solution an antimicrobially effective
`
`amount of lauralkonium chloride.
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`DETAILED DESCRIPTION
`
`Flurbiprofen is a classic example of an acidic drug that forms an
`
`insoluble ion-pair with benzalkonium chloride. It has been discovered that
`
`5
`
`this interaction (insoluble ion-pair
`
`formation) can be overcome by
`
`formulating the flurbiprofen with the C12 homolog of benzalkonium
`
`chloride and lauralkonium chloride.
`
`The lauralkonium chloride utilized will comprise at least 95% and
`
`10
`
`preferably about 97.8% of the C12 homolog, 1.5% of the C14 homolog,
`
`and 0.7% of the C16 homolog.
`
`The following examples,
`
`illustrating the utility of lauralkonium
`
`chloride as opposed to benzalkonium chloride, include the preparation or
`
`15
`
`compounding of flurbiprofen formulations as follows.
`
`Compounding occurs in two parts:
`
`l’a1_rt1_: Disperse polyvinyl alcohol in rapidly stirring purified water
`
`20
`
`and heat to 85°C. Maintain temperature and stirring for one hour to
`
`dissolve the polyvinyl alcohol.
`
`_RLZ While mixing a bulk of purified water of at least 50% of
`
`the final lot volume, add edetate disodium, benzalkonium chloride or
`
`25
`
`lauralkonium chloride, potassium chloride, sodium chloride, sodium citrate
`
`and citric acid allowing each to dissolve or mix well before adding the
`
`next. Adjust the pH to 6.4-6.6 with dilute sodium hydroxide and/or
`
`hydrochloric acid. Add sodium flurbiprofen to the bulk and mix well.
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`While mixing Part 2, add Part 1 and mix thoroughly. Adjust the pH
`
`to 6.4-6.6 with dilute sodium hydroxide and/or hydrochloric acid. Sterilize
`
`the lot by filtration (0.22u) and aseptically fill units into pre-sterilized
`
`containers.
`
`The benzalkonium chloride and the lauralkonium chloride utilized
`
`in the present examples were obtained from E.M. Industries, Inc. of
`
`Hawthorne, NY and Triple Crown Ammerica, Inc. of Perkasie, PA,
`
`respectively.
`
`10
`
`Example
`
`Table 1 shows the ingredients for Examples A and B, with the
`
`formulations being identical, except that Example A utilizes benzalkonium
`
`15
`
`chloride and Example B utilizes lauralkonium chloride in the same
`
`amounts, i.e., 0.005%, by weight per volume.
`
`20
`
`25
`
`30
`
`
`
`
`
`
`
`
`TABLE 1
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`OCULENG’ FORMULATIONS
`
`Ingredient
`
`
`
`Example A
`
`Example B
`
`
`
`
`
`
`
`
`——
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`
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`~ 0-65
`0.075
`
`qsto mo
`
`pH6.4 to 6.6
`
`PM4 to 6.6
`
`
`
`
`
`
`
`
`
`
`
`
`Example A results in a cloudy solution with precipitate and loss of
`
`antimicrobial efficacy while Example B remains as a solution and the
`
`10
`
`solution maintains its antimicrobial efficacy. Example A failed to pass the
`
`preservative effectiveness test as described in the British Pharrnacopeia
`
`while Example B passes
`
`the British Pharmacopieia preservative
`
`effectiveness test.
`
`15
`
`In addition, the ability of lauralkonium chloride to stay in solution
`
`and to maintain its antimicrobial effectiveness as a function of time was
`
`also monitored. Table 2 shows the concentration of lauralkonium chloride
`
`in the formulation described in Example B. Table 3 shows the ability of
`
`lauralkonium chloride to maintain its antimicrobial efficacy over a period
`
`20
`
`of up to one year or more.
`
`TABLE 2
`
`
`
`No. of Days
`
`
`
`Lauralkonium
`
`chloride - ppm
`
`
`
`46.0
`
`46.0
`
`45.8
`
`45.0
`
`
`
`25
`
`13
`
`32
`
`75
`
`1 15
`
`
`
`192
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`PCT/US94/00188
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`370
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`48.2
`
`TABLE 3
`
`No. of Days
`
`Pass BP-as Pass BP-88
`
`Microbiology Results
`
`10
`
`Although there has been hereinabove described a specific
`
`ophthalmic solution and method in accordance with the present invention,
`
`for the purpose of illustrating the manner in which the invention may be
`
`used to advantage, it should be appreciated that the invention is not
`
`15
`
`limited thereto. Accordingly, any and all modifications, variations, or
`
`equivalent arrangements which may occur to those skilled in the art,
`
`should be considered to be within the scope of the present invention as
`
`defined in the appended claims.
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`WHAT
`
`IS CLAIMED IS:
`
`‘
`
`1.
`
`An ophthalmic solution comprising:
`
`an ophthalmologically acceptable drug formulation
`
`incompatible with benzalkonium chloride; and
`
`a preservative consisting essentially of lauralkonium
`
`chloride and present in an antirnicrobially effective amount.
`
`2.
`
`The ophthalmic solution according to Claim 1 wherein said
`
`ophthalmologically acceptable drug formulation comprises
`
`sodium
`
`flurbiprofen.
`
`3.
`
`The ophthalmic solution according to claim 2 further
`
`comprising citric acid monohydrate, sodium citrate dihydrate, polyvinyl
`
`alcohol, edetate disodium dihydrate, sodium chloride, potassium chloride,
`
`and water.
`
`4.
`
`The ophthalmic solution according to Claims 1, 2 or 3
`
`wherein said lauralkonium chloride is present in an amount up to about
`
`0.005% by weight per volume of the solution.
`
`5.
`
`The ophthalmic solution according to claim 2 or 3 wherein
`
`the sodium flurbiprofen is present in an amount up to about 0.03% by
`
`weight per volume of the solution and the lauralkonium chloride is present
`
`in an amount up to about 0.005 % by volume of the solution.
`
`6.
`
`An ophthalmic solution comprising:
`
`an
`
`acidic
`
`ophthalmologically
`
`acceptable
`
`drug
`
`formulation having a negative charge at physiological pH;
`
`and
`
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`PCT/US94/00188
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`-10-
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`a preservative consisting essentially of lauralkonium
`
`chloride and present in an antimicrobially effective amount.
`
`7.
`
`The ophthalmic solution according to Claim 6 wherein said
`
`ophthalmologically acceptable drug formulation comprises
`
`sodium
`
`flurbiprofen.
`
`8.
`
`The ophthalmic solution according to Claim 7 further
`
`comprising citric acid monohydrate, sodium citrate dihydrate, polyvinyl
`
`alcohol, edetate disodium dihydrate, sodium chloride, potassium chloride,
`
`and water.
`
`9.
`
`The ophthalmic solution according to Claims 6, 7 or 8
`
`wherein said lauralkonium chloride is present in an amount up to about
`
`0.005% by weight per volume of the solution.
`
`10.
`
`The ophthalmic solution according to Claim 7 or 8 wherein
`
`the sodium flurbiprofen is present in an amount up to about 0.03% by
`
`weight per volume of the solution and the lauralkonium chloride is present
`
`in an amount up to about 0.005% by volume of the solution.
`
`11.
`
`A method for preserving an acidic ophthalmically acceptable
`
`drug solution comprising adding to said ophthalrnically acceptable drug
`
`solution an antirnicrobially effective amount of lauralkonium chloride.
`
`12.
`
`An ophthalmic solution comprising:
`
`an acidic ophthalmologically acceptable drug capable
`
`of forming an insoluble ion-pair with benzalkonium chloride;
`
`and
`
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`
`WO 94115597
`
`PCT/US94/00188
`
`-11-
`
`5
`
`a preservative consisting essentially of lauralkonium
`
`chloride and present in an antimicrobially effective amount.
`
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`INTERNATIONAL SEARCH REPORT
`
`
`[mm Ml Appmauon No
`PCT/US 94/00188
`
`
`
`
`
`
`A61K47/18
`
`. CL
`ASSIFICATION OF SUBJECT MATTER
`
`C
`P
`5
`A61K31/19
`A61K9/00
`
`
`A I
`
`
`
`According to lntnnational Patent Classification (IPC) or to both national classification and [PC
`B. FIELDS SEARCHED
`Minimum documentation searched (classification system followed by classification symbols)
`IPC 5
`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)
`
`
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Citation ofdocument, with indication, where appropriate, ofthe relevantpassages
`
`
`Relevantto claim No.
`
`CHEMICAL ABSTRACTS, vol. 112, no. 16,
`16 April 1990, Columbus, Ohio, US;
`abstract no. 145590h,
`see abstract
`& JP,A,01 246 227 (SANTEN PHARMACEUTICAL
`C0.,LTD.) 2 October 1989
`
`DATABASE WPI
`Week 8231,
`Derwent Publications Ltd., London, GB;
`AN 82-64749E (31)
`see abstract
`& JP,A,57 102 817 (KAKENYAKU KAKO KK) 26
`June 1982
`
`
`
`
`
`X
`
`A
`
`m Patent family members are listed in annex.
`
`
`
`D Further documents are listed in the continuation of box C.
`' 5
`‘a1
`te
`'
`f ‘ted d
`:
`‘T’ later document published alter the intemational filing date
`pea
`ca zones 0 cl
`ocumcms
`or priority date and not in conflict with the application but
`‘tI_<:(r”t‘ir1derstand the principle or theory underlying the
`A ddgwjélg r‘:fe“:a‘;lt;§‘° 3" wmch is mt
`-x- document of puficula, rdevmcc; the claimed invention
`‘E’ earlier document but published on or alter the international
`cannot be considered novel or cannot be considered to
`filing date
`involve an inventive step when the document is taken alone
`"L' document which may throw doubts on priority clairn(s) or
`-y- document 01-pamcma, mevanoe. the claimed mwnu-on
`which is cited to establish the publication date of another
`cannot be considered to involve an inventive step when the
`°mu°“ °' °‘h°" ‘P°°‘31 "35°“ (35 ”P°°if'°d)
`document is combined with one or more other such docu-
`'0' document referring to an oral disclosure, use, exhibition or
`merits, such combination being obvious to a person skilled
`other means
`m thc 3”‘
`‘P’ document published prior to the international filing date but
`'&' document member of the same patent family
`later than the priority date clairned
` Date of the actual completion of the international Search
`Date of mailing of the international search report
`
`
`
`11 April 1994
`
`Authorized officcr
`
`Name and mailing address of the ISA
`
`European Patent Office, P.B. 5818 Patentlaan 2
`N1. - 2280 HV Rijswijk
`Tel. (+ 31-70) 340-2040, Tx. 3! 651 epo nl,
`Fax: (+ 31-70) 340-3016
`
`
`
`
` Scarponi, U
`
`Form PCT/ISA/210 (second sheet) (July 1992)
`
`Metrics EX1020, Page 14
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`"INTERNATIONAL SEARCH REPORT
`'
`lnformauon on patnnt family members
`
`
`Inter.
`nal Application No
`PCT/US 94/00188
`
`
`Publication
`date
`
`Patent family
`member(s)
`
`
`cited in search report
`
`JP-A-
`JP-B-
`US-A-
`
`50058310
`59016038
`4091167
`
`
`
`
`21-05-75
`12-04-84
`23-05-78
`
`Paxent. document
`
`Publication
`date
`
`21-05-75
`
`
`
`
`
`Form PCT/ISA/210 (patent fnmily annex) (July 1992)
`
`Metrics EX1020, Page 15
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