`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`Cl
`CM
`CN
`cs
`cz
`DE
`DK
`ES
`Fl
`FR
`GA
`
`Austria
`Australia
`Barbados
`Belgium
`Burldna Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`~d'Ivoire
`Cameroon
`Oiioa
`Czechoslovakia
`Czech Republic
`Germany
`Denmark
`Spain
`Finland
`France
`Gabon
`
`GB
`GE
`GN
`GR
`HU
`IE
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`u
`LK
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`ofKo=
`Republic of Ko=
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`Mauritania
`MR
`MW Malawi
`NE
`Niger
`NL
`Nctbcrlands
`Norway
`NO
`New Zealand
`NZ
`PL
`Poland
`PT
`Portugal
`RO
`Romania
`Russian Federation
`RU
`Sudan
`SD
`Sweden
`SE
`Slovenia
`SI
`Slovakia
`SK
`Senegal
`SN
`TD
`Cbad
`Togo
`TG
`Tajikistan
`TJ
`TT
`Trinidad and Tobago
`Ukraine
`UA
`us
`United States of America
`uz
`Uzbekistan
`VN
`VietNam
`
`..
`
`..
`
`Page 2 of 15
`
`

`

`wo 94/15597
`
`PCT IUS94/00188
`
`-1-
`
`OPHTHALMIC COMPOSITIONS COMPRISING BENZYLLAURYLDIMETHYLAMMONIUM CHLORIDE
`
`5
`
`JO
`
`15
`
`20
`
`25
`
`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
`
`an incompatibility with benzalkonium chloride. More specifically, the
`present invention pertains to the preservative for an anti-inflammatory
`drug such as sodium flurbiprofen (Ocufe~).
`
`Ophthalmologically acceptable drug formulations generally contain
`effective compounds and a number of ophthalmologically acceptable excip(cid:173)
`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.
`
`Ophthalmic formulations, understandably, must be sterile and if a
`multi-dose·regime is intended, the formulation must be preserved with an
`effective antimicrobial agent.
`
`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.
`
`Page 3 of 15
`
`

`

`wo 94/15597
`
`PCT /US94/00188
`
`-2-
`
`Therefore, benzalkonium chloride, which is a qua\emary ammonium
`compound, has been widely used in ophthalmic solutions. It is also well(cid:173)
`known, however, that benzalkonium chloride is considered incompatible
`with anionic drugs, forming insoluble compounds which cause the solution
`to tum 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.
`
`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
`from solution is the removal of benzalkonium chloride, thereby rendering
`this quaternary germicide incapable of performing its function as an
`antimicrobial agent.
`
`Benzalkonium chloride is a mixture of alkyldimethylbenzyl-
`ammonium chloride of the general formula as shown below in which R
`represents a mixture of the alkyls from CsH17 to c18~7
`
`5
`
`10
`
`15
`
`20
`
`As hereinbefore noted, it is well-known that benzalkonium chloride is
`generally incompatible with anionic detergents or anionic drug compounds.
`
`Page 4 of 15
`
`

`

`wo 94/15597
`
`PCT /US94/00188
`
`-3-
`
`See U.S. Patent No. 5,110,493, and The Merck Inde~ 11th 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
`
`from CsH17 to C1sH37·
`
`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-
`
`Page 5 of 15
`
`

`

`wo 94/15597
`
`PCT /US94/00188
`
`-4-
`
`pair with benzalkonium chloride. However, when combined with
`lauralkonium chloride, no apparent insoluble ion pairs are formed.
`
`.
`
`More particularly, in accordance with the present invention, the
`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
`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.
`
`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
`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
`ophthalmologically acceptable drug solution an antimicrobially effective
`amount of lauralkonium chloride.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`Page 6 of 15
`
`

`

`wo 94/15597
`
`PCT IUS94/00188
`
`-5-
`
`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
`this interaction (insoluble ion-pair formation) can be overcome by
`
`5
`
`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.
`
`15
`
`20
`
`25
`
`The following examples, illustrating the utility of lauralkonium
`chloride as opposed to benzalkonium chloride, include the preparation or
`compounding of flurbiprofen formulations as follows.
`
`Compounding occurs in two parts:
`
`Part 1: Disperse polyvinyl alcohol in rapidly stirring purified water
`and heat to 8SOC. Maintain temperature and stirring for one hour to
`dissolve the polyvinyl alcohol.
`
`Part 2: While mixing a bulk of purified water of at least 50% of
`the final lot volume, add edetate disodium, benzalkonium chloride or
`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.
`
`Page 7 of 15
`
`

`

`wo 94/15597
`
`PCT /US94/00188
`
`-6-
`
`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 (0.22/J) 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, P A,
`
`respectively.
`
`Example
`
`Table 1 shows the ingredients for Examples A and B, with the
`
`formulations being identical, except that Example A utilizes benzalkonium
`chloride and Example B utilizes lauralkonium chloride in the same
`
`amounts, i.e., 0.005%, by weight per volume.
`
`TABLE 1
`
`OCULEN® FORMULATIONS
`
`5
`
`10
`
`15
`
`20
`
`Ingredient
`
`Sodium flurbiprofen
`
`25
`
`Benzalkonium chloride
`
`Lauralkonium chloride
`
`Citric acid monohydrate USP
`
`Sodium citrate dihydrate USP
`
`Polyvinyl alcohol 20-90 Grade
`
`Example A
`
`Example B
`
`% wjv
`
`% w/v
`
`0.03
`
`0.005
`-
`0.05
`
`0.45
`
`1.4
`
`0.03
`-
`.005
`
`0.05
`
`0.45
`
`1.4
`
`30
`
`Edetate disodium dihydrate USP
`
`0.0127
`
`0.0127
`
`Page 8 of 15
`
`

`

`wo 94/15597
`
`PCT JUS94/00 188
`
`-7-
`
`Sodium chloride USP
`
`Potassium chloride USP
`
`0.65
`
`0.075
`
`.
`
`0.65
`
`0.075
`
`Purified water USP
`
`qs to 100
`
`qs to 100
`
`Sodium hydroxide NF
`
`pH 6.4 to 6.6
`
`pH 6.4 to 6.6
`
`5
`
`Hydrochloric acid NF
`
`pH 6.4 to 6.6
`
`pH 6.4 to 6.6
`
`10
`
`15
`
`20
`
`25
`
`Example A results in a cloudy solution with precipitate and loss of
`
`antimicrobial efficacy while Example B remains as a solution and the
`solution maintains its antimicrobial efficacy. Example A failed to pass the
`preservative effectiveness test as described in the British Pharmacopeia
`while Example B passes
`the British Pharmacopieia preservative
`effectiveness test.
`
`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
`of up to one year or more.
`
`TABLE2
`
`No. of Days
`
`Lauralkonium
`chloride - ppm
`
`13
`32
`
`75
`
`115
`192
`
`46.0
`
`46.0
`
`45.8
`
`45.0
`
`47.7
`
`Page 9 of 15
`
`

`

`wo 94/15597
`
`PCT /US94/00 188
`
`-8-
`
`5
`
`10
`
`15
`
`II
`
`370
`
`48.2
`
`~I
`
`TABLE 3
`
`No. of Days
`
`Microbiology Results
`
`13
`
`370
`
`Pass BP-88
`
`Pass BP-88
`
`there has been hereinabove described a specific
`Although
`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
`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.
`
`Page 10 of 15
`
`

`

`wo 94/15597
`
`PCT /US94/00188
`
`-9-
`
`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 antimicrobially effective amount.
`
`5
`
`2.
`
`The ophthalmic solution according to Claim 1 wherein said
`
`ophthalmologically acceptable drug formulation comprises sodium
`flurbiprofen.
`
`The ophthalmic solution according to claim 2 further
`3.
`comprising citric acid monohydrate, sodium citrate dihydrate, polyvinyl
`alcohol, edetate disodium dihydrate, sodium chloride, potassium chloride,
`and water.
`
`The ophthalmic solution according to Claims 1, 2 or 3
`4.
`wherein said lauralkonium chloride is present in an amount up to about
`0.005% by weight per volume of the solution.
`
`The ophthalmic solution according tu claim 2 or 3 wherein
`5.
`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
`
`Page 11 of 15
`
`

`

`wo 94/15597
`
`PCT /US94/00188
`
`-10-
`
`5
`
`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.
`
`The ophthalmic solution according to Claim 7 or 8 wherein
`10.
`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 ophthalmically acceptable drug
`solution an antimicrobially 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
`
`Page 12 of 15
`
`

`

`wo 94/15597
`
`PCT /US94/00188
`
`-11-
`
`5
`
`J
`
`a preservative consisting essentiaJly of lauralkonium
`chloride and present in an antimicrobially effective amount.
`
`Page 13 of 15
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`-lnten.
`.'Ia! Application No
`PCT/US 94/00188
`
`A. CLA::.SIFICAliON OF SUWECf MATIER
`IPC 5 A61K31/19
`A61K9/00
`
`A61K47/18
`
`According to ln111:mational Patent Classification (IPC) or to both national classification and IPC
`
`B. FIELDS SEARCHED
`Mimmum documCIIWlon searched (classification system followed by classification symbols)
`IPC 5 A61K
`
`•
`
`.
`
`Documentation seardlcd other lban rmnimum 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
`
`Category • Citation of document, with indication, where appropriate, of the relevant passages
`
`Relevant to claim No.
`
`X
`
`A
`
`CHEMICAL ABSTRACTS, vol. 112, no. 16,
`16 Apri 1 1990, Columbus, Ohio, US;
`abstract no. 145590h,
`see abstract
`& JP,A,01 246 227 (SANTEN PHARMACEUTICAL
`CO. ,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
`-----
`
`1,3,4,6,
`8,9,11,
`12
`
`2,5,7,10
`
`D Further documents arc listed in the continuation of box C.
`
`• Special categories of cited documents :
`
`• 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 after the international
`ftling date
`•L• document which may throw doubts on priority claim(s) or
`which is ated to establish the publication date of another
`citation or other special reason (as specified)
`·o· document referring to an oral disclosure, use, exhibition or
`other means
`•p• document published prior to the international filing date but
`later than the priority date claimed
`
`D Patent family members arc listed in annex.
`·r later document published after the international filing date
`or priority date and not in conflict with the application but
`cited to understand the principle or theory underlying the
`mvention
`·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.
`ments, such combination being obvious to a person skilled
`in the art.
`·&· document member of the same patent family
`
`1
`
`Date of the actual completion of the international search
`
`Date of mailing of the international search report
`
`11 April 1994
`
`r-:-... t}lt:, •. • .
`
`Name and mailing address of the ISA
`European Patent Office, P .B. 5818 Patentlaan 2
`NL • 2280 HV Rijswijk
`Tel. (+31-70) 340-2040, Tx. 31 651 epo nl,
`Fax: ( + 31-70) 340-3016
`
`Authorized officer
`
`Scarponi, u
`
`Fonn PCT/lSN210 (second sheet) (July 1992)
`
`Page 14 of 15
`
`

`

`Patent family
`member(s)
`JP-A-
`21-05-75
`50058310
`JP-8-
`12-04-84
`59016038
`US-A-
`23-05-78
`4091167
`.
`----------------------------------------------------------------------
`JP-A-57102817
`26-06-82
`NONE
`
`r - - - '
`Inter.
`nal Application No
`PCT/US 94/00188
`
`I Publication
`
`date
`
`INTERNATIONAL SEARCH REPORT
`
`Infonnallon on patent family members
`
`Patent document
`cited in seBrCh report
`J'P-A-01246227
`
`I Publication
`
`date
`21-05-75
`
`I
`
`•
`
`Fonn PCT/ISA,IJIO (patent family annex) (July 19!/J)
`
`Page 15 of 15
`
`