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`WORLD lNTEL.LBCI'lJAl, PROPERTY ORGANIZATION
`lntemanonal Bureau
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`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
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`51) I“i°‘-''"3fi°1“‘1 Pawn‘ Ciassmci“-i0“ 6 i
`W0 99/24542
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`C11D 3/43, 3/32, 3/37, A61L 2/00 ll
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`20 May 1999 (2005.99)
`C111) 1/722
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`(21) International Application Number:
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`(22) International Filing Date:
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`PC‘.T.I'US98/23818
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`10 November 1993 (10.1 1.98)
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`(30) Priority Data;
`60/065.50]
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`12 November I997 (12.1 1.97)
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`(11) International Publication Number:
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`(43) International Publication Date:
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`(31) Designated States: AL, AU, BA, BB, BG, BR, CA, CN, CU,
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`CZ, EE. ES, FI, GB, GE, HR, HU, ID, IL, IS, JP, KE, KG,
`L
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`KP, KR, LC, LK, R, LT, LV, MD, MG, MK, MN, MW,
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`MX, NO, NZ, PL, PT. RO, RU, SE, SG, SI, SK, SL, TJ,
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`TR, 'I'l‘, UA, UZ, VN, YU, ARIPO patent (GH, GM, KE,
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`LS, MW, SD, SZ. UG, ZW), European in-1te11t(AT, BE, CH,
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`CY, DE, DK, ES, Fl, FR, GB‘. GR, IE, IT, LU, MC, NL,
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`PT, SE), OAPI patent (BF, BJ, CF, CG. CI, CM, GA, GN,
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`GW, ML, MR, NE, SN, TD, TG).
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`US
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`(71) Applicant: BAUSCH & LOMB INCORPORATED [US/US]:
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`One Bausch & Lomb Place, Rochester, NY 14604-2701
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`(US).
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`(72) Inventors: HEILER, David, J.; 173 Wadsworth Avenue, Avon,
`NY 14414 (US). XIA, Eming; 93 Cliippeniiam Drive,
`Penfieltl, NY 14-526 (US). SIMPSON, Lisa, C3,
`'73 Raton
`Avenue, Rochester. NY 14626 (US). MARSH. David, A.;
`Apartment 2065, 5505 Cross Creek Lane, Fort Worth, TX
`76109 (US).
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`(74) Agents: KONKOL, Chris, 1'. et ai.; Bausch & Lomb In-
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`corporated, One Bausch & Lomb Place, Rochester, NY
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`t4604—27Dl (US).
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`Published
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`With irtrerrzatfonal search report.
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`(54) Title: DISINFECTING CONTACT LENSES WI'l"H BlS(BIGUANlDES) AND POLYMERIC BIGUANIDES
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`(57) Abstract
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`The present invention is directed to an ophthalmically safe disinfecting solution for Contact lenses comprising a biguanide polymer
`in combination with a bis(biguanide), and a method of using the composition,
`in the form of an aqueous solution, for disinfecting andfor
`preserving contact lenses. especially soft contact lenses. The invention can be used to formulate products having greater convenience ancllor
`benefits compared to traditional disinfecting products for contact lenses and can provide a broader, more potent and faster antimicrobial
`activity overall.
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`SENJU-MITSUBISHI 2079
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`FDR THE PURPOSES OF INFORMATION ONLY
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`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
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`LS
`Lesotho
`LT
`Lilhtlrmia
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`LU
`Luxembourg
`LV
`Latvia
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`MC
`Monaco
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`MD
`Republic of Moldova
`MG
`Maulagasczrr
`MK
`The forrner Yugoslav
`Republic of Macedonia
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`Mali
`Mongolia
`Mauritrlnia
`Malawi
`Mexico
`Niger
`Netherlands
`Nmway
`New Zealanrl
`Poland
`Pnrtugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
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`ML
`MN
`MR
`MW
`MK
`NE
`NL
`NO
`NZ
`PL
`PT
`R0
`RU
`SI)
`SE
`SC.‘
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`ES
`Fl
`FR
`GA
`Gil
`GE
`GH
`GN
`GR
`I-[U
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`IL
`IS
`[T
`.11‘
`K12‘.
`KG
`KP
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`KR
`KZ
`LC
`LI
`LK
`LR
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`Spain
`Finland
`France
`Gabnn
`United Kingdom
`Gcergia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechlernttcin
`Sri Lanka
`Liberia
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`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`1}?
`BG
`HJ
`BR
`BY
`‘CA
`CF
`CG
`CH
`CI
`CM
`CN
`CU
`CZ
`DE
`DK
`EE
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`Albniiia
`An-nenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Darbrtdos
`Belgiurrl
`Burkina liaso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Conga
`Switzerland
`Cert d‘Ivnire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Eslnnirr
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`51
`SIC
`SN
`52.
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`US
`UZ
`VN
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`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Triniclarl rind Tobago
`Ukraine
`Uganda
`United States of Americrt
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
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`, wo 99/24542
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`PCTfUS98I23818
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`DISINFECTING CONTACT LENSES WITH BIS(BIGUANIDES) AND POLYMERIC BIGUANIDES
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`Field of the Invention
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`This invention relates to new and improved solutions for the treatment of contact
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`lenses and to methods for treating contact lenses with such solutions. In particular, the
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`present invention is directed to disinfecting systems comprising the novel combination of
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`two disinfecting agents, namely a bis(biguanidc) and a polymeric biguanide.
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`Background of the Invention
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`Generally, contact lenses in wide use fall into three categories:
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`(1) hard lenses
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`formed from materials prepared by polymerization of acrylic esters, such as polymethyl
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`methacrylate (PMMA), (2) rigid gas permeable (RGP) lenses formed from silicone
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`acrylates and fluorosilicone methacrylates, and (3) gel, hydrogel or soft type lenses made
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`of polymerized hydrophilic or hydrophobic monomers, such as 2-hydroxyethyl
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`methacrylate (I-IEMA). The hard acrylic type contact lenses are characterized by low
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`water vapor diffusion constants, resistance to the effects of light, oxygen and hydrolysis,
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`and absorb only minor amounts of aqueous fluids. Because of the durability of hard
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`contact lenses, coupled with their tendency not to absorb appreciable amounts of water,
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`the selection of suitable disinfecting agents, cleaning agents or other lens care
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`compounds is relatively non-critical.
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`However, unlike hard lenses, soft-type contact lenses have a tendency to bind and
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`concentrate significantly more fluids, environmental pollutants, water impurities, as well
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`as antimicrobial agents and other active ingredients commonly found in lens—care
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`solutions. In most instances, the low levels of the ingredients in lens—care solutions do
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`not lead to eye tissue irritation when used properly. Nevertheless, especially due to the
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`inherent binding action of protein deposits to soft-lens materials, some disinfecting
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`agents and preservatives tend to build up on lens surfaces and may become concentrated
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`to potentially hazardous levels, such that when released could cause corneal
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`inflammation and other eye tissue irritation.
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`‘ wo 99/24542
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`PCT/US98/23818
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`Certain antibacterial agents were found to be more compatible with contact lenses
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`and exhibit less binding on lens surfaces.
`In one case, it was found that chlorhexidine, a
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`biguanide, binds to soft lens material seven times less than benzalkonium chloride. The
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`presence ofproteinaceous oily tear-film deposits on a lens, however, can double the
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`amount of chlorhexidine absorbed on the lens compared to a clean lens. U.S. patent
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`4,354,952 discloses very dilute disinfecting and cleaning solutions containing
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`chlorhexidine or its salt in combination with certain atnphoteric and non-ionic
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`surfactants. These solutions were‘ found to reduce the amount of binding of
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`chlorhexidine on hydrophilic soft contact lenses. Notwithstanding the reduction in
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`binding achieved by this invention, the use of chlorhexidine did result in certain
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`tradeoffs. The antimicrobial activity of the chlorhexidine may be diminished when used
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`with certain amphoteric surfactants. Furthermore, it was reported that if not used in
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`proper ratio, the surfactant and disinfectant will precipitate unless a non-ionic type
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`surfactant is also employed.
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`British Patent 1,432,345 discloses contact lens disinfecting compositions
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`containing a polymeric biguanide and a mixed phosphate buffer. Compositions as
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`disclosed by this patent, however, have corneal staining values of 17% or more, far
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`above that which is desirable for patient acceptability.
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`U.S. Patent 4,758,595 to Ogunbiyi et al. disclosed that a contact-lens solution
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`containing a polyaminopropyl biguanide (PAPB), also known as polyhexamethylene
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`biguanide (PHMB), has enhanced efficacy when combined with a borate buffer. These
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`disinfecting and preservative solutions are especially noteworthy for their broad
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`spectrum of bactericidal and fungicidal activity at low concentrations coupled with very
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`low toxicity when used with soft~type contact lenses.
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`U.S. Patent No. 5,453,435 to Raheja et al., disclosed a preservative system that
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`comprises a combination of chlorhexidine and polyhexarnethylene biguanide. This
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`preservative system, used in commercial products for rigid—gas-permeable lenses, was
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`found to exhibit an improved combination of efficacy and low eye irritation.
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`Compositions containing PHMB and borate have been commercialized in various
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`products, but at levels of about 1 ppm or less for use with soft contact lenses. It is
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`generally desirable to provide the lowest level of a bactericide possible, while
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`-2-
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`_ WO 99124542
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`maintaining the desirable level of disinfection efficacy, in order to provide a generous
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`margin for safety and comfort.
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`PCT!US98/23818
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`Some of the most popular products for disinfecting lenses are multipurpose
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`solutions that can be used to clean, disinfect and wet contact lenses, followed by direct
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`insertion (placement on the eye) without rinsing. Obviously, the ability to use a single
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`solution for contact-lens care is an advantage. Such a solution, however, must be
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`particularly gentle to the eye, since, as indicated above, some of the solution will be on
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`the lens when inserted and will come into contact with the eye.
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`With conventional contact-lens cleaners or disinfectants, including multi-purpose
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`solutions, lens wearers typically need to digitally or manually rub the contact lenses
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`(typically between a finger and palm or between fingers) during treatment of the contact
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`lenses. The necessity for the daily “rubbing" of contact lenses adds to the time and effort
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`involved in the daily care of contact lenses. Many contact-lens wearers dislike having to
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`perform such a regimen or consider it to be an inconvenience. Some wearers may be
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`negligent in the proper “rubbing" regimen, which may result in contact-lens discomfort
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`and other problems. Sometimes rubbing, if performed too rigorously, which is
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`particularly apt to occur with beginning lens wearers, may damage the lenses. This can
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`be problematic when a replacement lens is not immediately available.
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`Contact lens solutions that qualify as a “Chemical Disinfecting Solution” do not
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`require rubbing to meet biocidal performance criteria (for destroying representative
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`bacteria and fungi) set by the US Food and Drug Administration (FDA) under the
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`PrernarketNotif1cation (5l0k) Guidance Document For Contact Lens Care Products,
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`In contrast, a contact-lens solution, referred to as a “Chemical
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`May 1, 1997.
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`Disinfecting System,” that does not qualify as a Chemical Disinfecting Solution, requires
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`a rubbing regimen to pass biocidal performance criteria. Traditionally, rnulti-purpose
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`solutions (used for disinfecting and wetting or for disinfecting, cleaning, and wetting)
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`have qualified as a Chemical Disinfecting System, but not as a Chemical Disinfecting
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`Solution.
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`A Chemical Disinfecting Solution would generally require a more efficacious or
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`stronger disinfectant than a Chemical Disinfecting System. The stronger the biocidal
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`_ W0 99f24542
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`PCTIUS98/23818
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`effect of a solution, however, the more likely that it may exhibit toxic effects or
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`adversely effect lens—wearer comfort. For example, many very efficacious bactericides
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`used in other contexts, such as mcuthwashes, cosmetics, or shampoos, while being
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`sufficiently safe for use in such products, would be too toxic for ophthalmic use,
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`especially for use with soft lenses because of the abovementioned tendency of soft
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`lenses to bind chemicals and the sensitivity of eye tissues. Similarly, the concentrations
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`of certain bactericidcs may need to be within lower limits in solutions for use with soft
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`contact lenses than in other products or in solutions for other types of lenses, especially
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`when such solutions are not rinsed from the contact lens before placing the lens in the
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`eye.
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`It would be desirable to obtain a contact-lens solution that would simultaneously
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`provide both (I) an increased level and/or broader spectrum of biocidal activity, and (2) a
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`low order of toxicity to eye tissue, such that the solution can be used to treat a contact
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`lens such that the lens can subsequently be placed on the eye without rinsing the solution
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`from the lens. While challenging to develop, it would be especially desirable to obtain a
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`Chemical Disinfecting Solution that could be used for soft contact lenses and that would
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`allow direct placement of a contact lens on an eye following soaking in the solution
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`andfor rinsing and rewetting with the solution. Such a product may provide increased
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`efficacy, resulting in greater protection to the lens wearer against infection caused by
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`microorganisms, while providing maxiinum convenience. Finally, it would be desirable
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`for the biocidal efficacy of the disinfecting solution to be sufficiently high to achieve
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`efficacious disinfection, or at least not inherently inefficacious disinfection, of a contact
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`lens with respect to bacteria and fungi in the event, for whatever reason, that the contact
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`lens wearer does not carry out a regimen involving mechanical rubbing or the like using
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`the contact-lens solution.
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`PCT/US98I23818
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`_WO 99124542
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`Brief Description of the Invention
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`The present invention is directed to an ophthalmicaily safe disinfecting solution
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`(a)
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`for contact lenses comprising:
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`about 0.10 to about 4.0 ppm of a bis(biguanide) in the form of a
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`dihydrochloride salt, or a corresponding concentration of the same bis(bigua:1ide) in the
`form of the free base or a different water-soluble salt, which_bis(biguanide)'has the
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`following general formula:
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`R‘-NH--(“S-NI-I—fiI—-NH-(CH2)fi-Ni-I—fi—NH-fi—NH—-—R2
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`NH
`NH
`NH
`NH
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`(1)
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`or their water-soluble salt form, wherein R‘ and R2 are independently selected from the
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`group consisting of branched or unbranched alkyl, alkoxyalkyl or alkylsulfide radical,
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`and n is 4 to 16; and
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`about 0.1 to about 3.0 ppm of a polymeric biguanide having the formula:
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`(b)
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`T1
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`X‘-E-Z--NH——(”I—-NI-I~—-(H3--NH}Z—X2
`NH
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`wherein Z is an organic divalent bridging group which may be the same or different
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`throughout the polymer, n on average is at least 3, and X’ and X3 are
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`independently selected from the groups -NH; and —NH - |(I3 — NH — CN.
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`NH
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`(II)
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`(c)
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`(d)
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`an effective amount of a buffering agent; and
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`water in an amount of at least about 80% by weight.
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`Preferably, the compositions of the present invention also include one or more
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`surfactants. In one embodiment of the invention, the surfactant is a neutral or non-ionic
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`surfactant.
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`The invention is also directed to a method of disinfecting, or cleaning and
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`disinfecting, a contact lens comprising soaking the lens for a given period of time in the
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`aqueous solution described above, and subsequently directly placing the treated lens on
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`_ W0 99/24542
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`PCTIUS98.’2.38l8
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`an eye of the wearer. In one embodiment of this method, a contact lens does not require
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`rubbing with the solution to achieve the necessary disinfection.
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`Brief Description of the Drawings
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`FIG. 1 is a bar graph showing the biocidal efficacy, after 15 minutes, of a
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`solution containing the combination of two disinfecting age_n_ts, namely a bis(biguaiiide)
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`and a biguanide polymer, versus the theoretical sum of the biocidal efficacy of separate
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`solutions of each disinfecting agent. The increased efficacy of the combination
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`compared to the theoretical sum is a measure of the synergy of the combination. I n
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`1 shows the theoretical log reduction compared to the actual log reduction
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`for alexidine and PHMB, with respect to C. albicans microorganisms, after 15 minutes
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`particular, Fig.
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`exposure.
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`FIG. 2 is a bar graph showing the biocidal efficacy, after 30 minutes, of a
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`solution containing the combination of a bis(biguanide) and a biguanide polymer versus
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`the theoretical sum of the biocidal efficacy of separate solutions of each disinfecting
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`agent. In particular, Fig. 2. shows the theoretical log reduction compared to the actual
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`log reduction for alexidine and PHMB, with respect to C. ai'bz'cczns microorganisms, after
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`30 minutes exposure.
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`Detailed Description ofthe Invention
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`As indicated above, the present invention is directed to a composition involving
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`the combined used of a biguanide polymer and a bis(biguanide), and a method of using
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`the composition, in the form of an aqueous solution, for disinfecting and/or preserving
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`contact lenses, especially soft contact ienses. This synergistic combination offers
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`maximum convenience while providing increased efficacy and hence better protection
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`against microorganisms compared to traditional disinfecting products for contact lenses.
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`The solution according to the present invention provides a broader, more potent and
`faster antimicrobial activity overall, when considering the entire range of
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`microorganisms, based on representative bacteria and fungi commonly tested. In
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`particular, the disinfecting solutions of the present invention are effective at low
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`PCTlUS98!23818
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`_ WO 99124542
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`concentrations against a wide spectrum of microorganisms, including but not limited to
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`Staphylococcus aureus, Pseudomonns aeruginosa, Serratia marcescens, Candida
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`albicans, and Fusnrium salami ’
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`A disinfecting solution is generally defined as a contact-lens care product
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`containing one or more active ingredients (for example, anti-microbial agents and/or
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`preservatives) in sufficient concentrations to destroy harmful microorganisms on the
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`surface of alcontact lens within the recommended minimum soaking time. The
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`recommended minimum soaking time is included in the package instructions for use of
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`the disinfecting solution. The term “disinfecting solution” does not exclude the
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`possibility that the solution may also be useful as a preserving solution, or that the
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`disinfecting solution may also be useful for other purposes such as daily cleaning, rinsing
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`and storage of contact lenses, depending on the particular formulation. The present
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`solution, in combination with its container or bottle and packaging, including instructions
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`for use in accordance with a specified regimen, may be considered a novel and improved
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`kit, package, or system for the care of contact lenses.
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`By the term “soft lens” is meant a lens having a proportion of hydrophilic repeat
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`units such that the water content of the lens during use is at least 20% by weight. The
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`term "soft contact lens" as used herein generally refers to those contact lenses which
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`readily flex under small amounts of force. Typically, soft contact lenses are formulated
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`from polymers having a certain proportion of repeat units derived from hyclroxyethyl
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`methacrylate and/or other hydrophilic monomers, typically crosslinked with a
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`crosslinking agent. However, newer soft lenses, are being made from hi gh-Dk silicone-
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`containing materials.
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`By the term “ophthalmically safe” with respect to a contact-lens solution is meant
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`that a contact lens treated with the solution is safe for direct placement on the eye
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`without rinsing, that is, the solution is safe and comfortable for daily contact with the eye
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`via a contact lens that has been wetted with the solution. An ophthalmically safe
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`solution has a tonicity and pH that is compatible with the eye and comprises materials,
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`and amounts thereof, that are non—cytotoxic according to ISO standards and U.S. FDA
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`(Food & Drug Administration) regulations.
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`

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`. WO 99124542
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`-
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`PCTlUS98f23818
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`A solution that is useful for cleaning, chemical disinfection, storing, and rinsing a
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`soft contact lens is referred to herein as a “multipurpose solution.” Multi-purpose
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`solutions do not exclude the possibility that some wearers, for example, wearers
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`particularly sensitive to chemical disinfectants or other chemical agents, may prefer to
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`rinse or wet a contact lens with another solution, for example, a sterile saline solution
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`prior to insertion of the lens. The term “rnulti-purpose solution" also does not exclude
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`the possibility of periodic cleaners not used on a daily basis or supplemental cleaners for
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`removing proteins, for example enzyme cleaners, which are typically used on a weekly
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`basis. By the term “cleaning” is meant that the solution contains one or more cleaning
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`agents in sufficient concentrations to loosen and remove loosely held lens deposits and
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`other contaminants on the surface of a contact lens, especially if used in conjunction with
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`digital manipulation (for example, manual rubbing of the lens with a solution) or with an
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`accessory device that agitates the solution in contact with the lens, for example, a
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`mechanical cleaning aid. The critical micelle concentration of a surfactant—containing
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`solution is one way to evaluate its cleaning effectiveness.
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`The term “effective multi-purpose solution” analogously refers to a solution
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`useful for daily chemical disinfection, storing, and rinsing a contact lens, which solution
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`does not claim to clean a Contact lens, but which solution still obviates the need for any
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`other solution for daily cleaning, that is, no other solution must necessarily be used in
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`conjunction or combination with the solution on a daily basis. Although such solutions
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`may comprise a surfactant or other agent that may inherently loosen or preventing lens
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`deposits to some extent, such solutions are not necessarily capable of cleaning a contact
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`lens. Effective mnlti—pur-pose solutions are therefore only applicable for lenses used for
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`limited period of time,’ either disposable or frequent replacement lenses.
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`Traditionally, rnulti-purpose solutions on the market require a regimen involving
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`mechanical rubbing of the contact lens with the multi—pnrpose solution, in order to
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`provide the required disinfection. That is, such a regimen is required under
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`governmental regulatory authorities (for example, the FDA or Food & Drug
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`Administration in the USA) for a Chemical Disinfection System that does not qualify as
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`a Chemical Disinfecting Solution. The invention according to the present invention has
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`the advantage that it is possible to formulate a product that, on the one hand, is gentle
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`-3-
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`PCT/US98/23818
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`_ WO 99124542
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`enough to be used as both a disinfecting solution and a wetting agent and, on the other
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`_ hand, is able to meet the biocidal performance disinfection for a Chemical Disinfecting
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`Solution under criteria established by the US FDA for Contact Lens Care Products (May
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`1’, 1997) that does not require a regimen involving rubbing of the lenses (even though
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`rubbing of the lens may provide further removal of microorganisms). In other words, the
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`compositions according to the present invention may optionally be fonnulated to meet
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`the requirements of the FDA or ISO Stand—Alone Procedure for contact lens disinfecting
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`products. Accordingly, it is possible to make formulations that offer higher patient
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`compliance and greater universal appeal than traditional disinfecting or disinfecting and
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`cleaning products.
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`It is noted that the combination of the biguanide polymer and the bis(biguanide)
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`provides enhanced efficacy while not causing imitation or discomfort to the eyes, always
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`an important and challenging concem in the art of contact-lens care. Thus, increased
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`amounts of the bignanide polymer, by itself, to achieve the same efficacy as the
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`combination would result in greater eye irritation. Specifically, it has been found that
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`increased amounts of the biguanide polymer, by itself to achieve the necessary
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`disinfection for a Chemical Disinfecting Solution would result in unacceptable eye
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`irritation. Even if a rubbing regimen is recommended when using solutions of the
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`present invention, the enhanced biocidal activity may provide greater protection against
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`infection, especially if the rubbing by the contact-lens wearer is inadequate or omitted
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`through negligence or disregard of the product instructions.
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`According to the present invention, the bis(biguanide) germicides employed in
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`the present solutions include compounds, and their water~soluble salts, having following
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`formula:
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`R1—NH——<“:—-NH—E-—NH—(cH2)rNH—E—NH—fif~—NH—a2
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`NH
`NH
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`NH
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`(1)
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`wherein R‘ and R2 are independently selected (i.e., the same or different) from the group
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`consisting of branched or unbranched alkyl having 4~l2, preferably 6~l 0, carbon atoms,
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`alkoxyalkyl (i.e., ether) or alkylsulfide (thioether or cliaikylsulfide) radical having 4-12,
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`preferably 6-10, carbon atoms, or cycloalkyl or cycloalkyl-alkyl radical having 5-12,
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`-9-
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