EP1030902A1 - Desinfektion von kontaktlinsen mit bis-biguaniden und polymerbiguaniden - Google Patents

Desinfektion von kontaktlinsen mit bis-biguaniden und polymerbiguaniden

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Publication number
EP1030902A1
EP1030902A1 EP98957702A EP98957702A EP1030902A1 EP 1030902 A1 EP1030902 A1 EP 1030902A1 EP 98957702 A EP98957702 A EP 98957702A EP 98957702 A EP98957702 A EP 98957702A EP 1030902 A1 EP1030902 A1 EP 1030902A1
Authority
EP
European Patent Office
Prior art keywords
solution
lens
biguanide
disinfecting
bis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98957702A
Other languages
English (en)
French (fr)
Inventor
David J. Heiler
Susan P. Spooner
Lisa C. Simpson
David A. Marsh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bausch and Lomb Inc
Original Assignee
Bausch and Lomb Inc
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Filing date
Publication date
Application filed by Bausch and Lomb Inc filed Critical Bausch and Lomb Inc
Publication of EP1030902A1 publication Critical patent/EP1030902A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/48—Medical, disinfecting agents, disinfecting, antibacterial, germicidal or antimicrobial compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L12/00—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor
    • A61L12/08—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor using chemical substances
    • A61L12/14—Organic compounds not covered by groups A61L12/10 or A61L12/12
    • A61L12/141—Biguanides, e.g. chlorhexidine
    • A61L12/142—Polymeric biguanides
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D1/00—Detergent compositions based essentially on surface-active compounds; Use of these compounds as a detergent
    • C11D1/66—Non-ionic compounds
    • C11D1/722—Ethers of polyoxyalkylene glycols having mixed oxyalkylene groups; Polyalkoxylated fatty alcohols or polyalkoxylated alkylaryl alcohols with mixed oxyalkylele groups
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/0005—Other compounding ingredients characterised by their effect
    • C11D3/0078—Compositions for cleaning contact lenses, spectacles or lenses
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/16—Organic compounds
    • C11D3/26—Organic compounds containing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/16—Organic compounds
    • C11D3/26—Organic compounds containing nitrogen
    • C11D3/32—Amides; Substituted amides
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/16—Organic compounds
    • C11D3/37—Polymers
    • C11D3/3703—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • C11D3/3719—Polyamides or polyimides
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/16—Organic compounds
    • C11D3/37—Polymers
    • C11D3/3746—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • C11D3/3769—(Co)polymerised monomers containing nitrogen, e.g. carbonamides, nitriles or amines
    • C11D3/3773—(Co)polymerised monomers containing nitrogen, e.g. carbonamides, nitriles or amines in liquid compositions
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D1/00—Detergent compositions based essentially on surface-active compounds; Use of these compounds as a detergent
    • C11D1/008—Polymeric surface-active agents
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D2111/00—Cleaning compositions characterised by the objects to be cleaned; Cleaning compositions characterised by non-standard cleaning or washing processes
    • C11D2111/40—Specific cleaning or washing processes

Definitions

  • This invention relates to new and improved solutions for the treatment of contact lenses and to methods for treating contact lenses with such solutions.
  • the present invention is directed to disinfecting systems comprising the novel combination of two disinfecting agents, namely a bis(biguanide) and a polymeric biguanide.
  • contact lenses in wide use fall into three categories: (1) hard lenses formed from materials prepared by polymerization of acrylic esters, such as polymethyl methacrylate (PMMA), (2) rigid gas permeable (RGP) lenses formed from silicone acrylates and fluorosilicone methacrylates, and (3) gel, hydrogel or soft type lenses made of polymerized hydrophilic or hydrophobic monomers, such as 2-hydroxyethyl methacrylate (HEMA).
  • PMMA polymethyl methacrylate
  • RGP rigid gas permeable lenses formed from silicone acrylates and fluorosilicone methacrylates
  • gel, hydrogel or soft type lenses made of polymerized hydrophilic or hydrophobic monomers, such as 2-hydroxyethyl methacrylate (HEMA).
  • HEMA 2-hydroxyethyl methacrylate
  • the hard acrylic type contact lenses are characterized by low water vapor diffusion constants, resistance to the effects of light, oxygen and hydrolysis, and absorb only minor amounts of aqueous fluids. Because of the durability of hard contact lenses,
  • soft-type contact lenses have a tendency to bind and concentrate significantly more fluids, environmental pollutants, water impurities, as well as antimicrobial agents and other active ingredients commonly found in lens-care solutions.
  • the low levels of the ingredients in lens-care solutions do not lead to eye tissue irritation when used properly.
  • some disinfecting agents and preservatives tend to build up on lens surfaces and may become concentrated to potentially hazardous levels, such that when released could cause comeal inflammation and other eye tissue irritation.
  • Certain antibacterial agents were found to be more compatible with contact lenses and exhibit less binding on lens surfaces.
  • chlorhexidine a biguanide
  • benzalkonium chloride binds to soft lens material seven times less than benzalkonium chloride.
  • the presence of proteinaceous oily tear-film deposits on a lens can double the amount of chlorhexidine absorbed on the lens compared to a clean lens.
  • U.S. patent 4,354,952 discloses very dilute disinfecting and cleaning solutions containing chlorhexidine or its salt in combination with certain amphoteric and non-ionic surfactants. These solutions were found to reduce the amount of binding of chlorhexidine on hydrophilic soft contact lenses. Notwithstanding the reduction in binding achieved by this invention, the use of chlorhexidine did result in certain tradeoffs.
  • the antimicrobial activity of the chlorhexidine may be diminished when used with certain amphoteric surfactants. Furthermore, it was reported that if not used in proper ratio, the surfactant and disinfectant will precipitate unless a non-ionic type surfactant is also employed.
  • British Patent 1,432,345 discloses contact lens disinfecting compositions containing a polymeric biguanide and a mixed phosphate buffer. Compositions as disclosed by this patent, however, have corneal staining values of 17% or more, far above that which is desirable for patient acceptability.
  • U.S. Patent 4,758,595 to Ogunbiyi et al. disclosed that a contact-lens solution containing a polyaminopropyl biguanide (PAPB), also known as polyhexamethylene biguanide (PHMB), has enhanced efficacy when combined with a borate buffer.
  • PAPB polyaminopropyl biguanide
  • PHMB polyhexamethylene biguanide
  • U.S. Patent No. 5,453,435 to Raheja et al. disclosed a preservative system that comprises a combination of chlorhexidine and polyhexamethylene biguanide. This preservative system, used in commercial products for rigid-gas-permeable lenses, was found to exhibit an improved combination of efficacy and low eye irritation.
  • compositions containing PHMB and borate have been commercialized in various products, but at levels of about 1 ppm or less for use with soft contact lenses. It is generally desirable to provide the lowest level of a bactericide possible, while maintaining the desirable level of disinfection efficacy, in order to provide a generous margin for safety and comfort.
  • Some of the most popular products for disinfecting lenses are multipurpose solutions that can be used to clean, disinfect and wet contact lenses, followed by direct insertion (placement on the eye) without rinsing. Obviously, the ability to use a single solution for contact-lens care is an advantage. Such a solution, however, must be particularly gentle to the eye, since, as indicated above, some of the solution will be on the lens when inserted and will come into contact with the eye.
  • lens wearers typically need to digitally or manually rub the contact lenses (typically between a finger and palm or between fingers) during treatment of the contact lenses.
  • the necessity for the daily "rubbing" of contact lenses adds to the time and effort involved in the daily care of contact lenses.
  • Some wearers may be negligent in the proper "rubbing" regimen, which may result in contact-lens discomfort and other problems.
  • a Chemical Disinfecting Solution would generally require a more efficacious or stronger disinfectant than a Chemical Disinfecting System.
  • the stronger the biocidal effect of a solution however, the more likely that it may exhibit toxic effects or adversely effect lens-wearer comfort.
  • many very efficacious bactericides used in other contexts, such as mouthwashes, cosmetics, or shampoos, while being sufficiently safe for use in such products would be too toxic for ophthalmic use, especially for use with soft lenses because of the above-mentioned tendency of soft lenses to bind chemicals and the sensitivity of eye tissues.
  • the concentrations of certain bactericides may need to be within lower limits in solutions for use with soft contact lenses than in other products or in solutions for other types of lenses, especially when such solutions are not rinsed from the contact lens before placing the lens in the eye.
  • a contact-lens solution that would simultaneously provide both (1) an increased level and/or broader spectrum of biocidal activity, and (2) a low order of toxicity to eye tissue, such that the solution can be used to treat a contact lens such that the lens can subsequently be placed on the eye without rinsing the solution from the lens.
  • a Chemical Disinfecting Solution that could be used for soft contact lenses and that would allow direct placement of a contact lens on an eye following soaking in the solution and/or rinsing and rewetting with the solution.
  • Such a product may provide increased efficacy, resulting in greater protection to the lens wearer against infection caused by microorganisms, while providing maximum convenience.
  • biocidal efficacy of the disinfecting solution it would be desirable for the biocidal efficacy of the disinfecting solution to be sufficiently high to achieve efficacious disinfection, or at least not inherently inefficacious disinfection, of a contact lens with respect to bacteria and fungi in the event, for whatever reason, that the contact lens wearer does not carry out a regimen involving mechanical rubbing or the like using the contact-lens solution.
  • the present invention is directed to an ophthalmically safe disinfecting solution for contact lenses comprising:
  • R 1 and R 2 are independently selected from the group consisting of branched or unbranched alkyl, alkoxyalkyl or alkylsulfide radical, and n is 4 to 16;
  • Z is an organic divalent bridging group which may be the same or different throughout the polymer, n on average is at least 3, and X 1 and X 2 are independently selected from the groups -NH 2 and -NH - C - NH - CN.
  • compositions of the present invention also include one or more surfactants.
  • the surfactant is a neutral or non-ionic surfactant.
  • the invention is also directed to a method of disinfecting, or cleaning and disinfecting, a contact lens comprising soaking the lens for a given period of time in the aqueous solution described above, and subsequently directly placing the treated lens on an eye of the wearer.
  • a contact lens does not require rubbing with the solution to achieve the necessary disinfection.
  • FIG. 1 is a bar graph showing the biocidal efficacy, after 15 minutes, of a solution containing the combination of two disinfecting agents, namely a bis(biguanide) and a biguanide polymer, versus the theoretical sum of the biocidal efficacy of separate solutions of each disinfecting agent.
  • the increased efficacy of the combination compared to the theoretical sum is a measure of the synergy of the combination.
  • Fig. 1 shows the theoretical log reduction compared to the actual log reduction for alexidine and PHMB, with respect to C. albicans microorganisms, after 15 minutes exposure.
  • FIG. 2 is a bar graph showing the biocidal efficacy, after 30 minutes, of a solution containing the combination of a bis(biguanide) and a biguanide polymer versus the theoretical sum of the biocidal efficacy of separate solutions of each disinfecting agent.
  • Fig. 2. shows the theoretical log reduction compared to the actual log reduction for alexidine and PHMB, with respect to C. albicans microorganisms, after 30 minutes exposure.
  • the present invention is directed to a composition involving the combined used of a biguanide polymer and a bis(biguanide), and a method of using the composition, in the form of an aqueous solution, for disinfecting and/or preserving contact lenses, especially soft contact lenses.
  • This synergistic combination offers maximum convenience while providing increased efficacy and hence better protection against microorganisms compared to traditional disinfecting products for contact lenses.
  • the solution according to the present invention provides a broader, more potent and faster antimicrobial activity overall, when considering the entire range of microorganisms, based on representative bacteria and fungi commonly tested.
  • the disinfecting solutions of the present invention are effective at low concentrations against a wide spectrum of microorganisms, including but not limited to Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Candida albicans, and Fusarium solani.
  • a disinfecting solution is generally defined as a contact-lens care product containing one or more active ingredients (for example, anti-microbial agents and/or preservatives) in sufficient concentrations to destroy harmful microorganisms on the surface of a contact lens within the recommended minimum soaking time.
  • the recommended minimum soaking time is included in the package instructions for use of the disinfecting solution.
  • the term "disinfecting solution” does not exclude the possibility that the solution may also be useful as a preserving solution, or that the disinfecting solution may also be useful for other purposes such as daily cleaning, rinsing and storage of contact lenses, depending on the particular formulation.
  • the present solution, in combination with its container or bottle and packaging, including instructions for use in accordance with a specified regimen, may be considered a novel and improved kit, package, or system for the care of contact lenses.
  • soft lens is meant a lens having a proportion of hydrophilic repeat units such that the water content of the lens during use is at least 20% by weight.
  • soft contact lens generally refers to those contact lenses which readily flex under small amounts of force.
  • soft contact lenses are formulated from polymers having a certain proportion of repeat units derived from hydroxyethyl methacrylate and/or other hydrophilic monomers, typically crosslinked with a crosslinking agent.
  • newer soft lenses are being made from high-Dk silicone- containing materials.
  • ophthalmically safe with respect to a contact-lens solution is meant that a contact lens treated with the solution is safe for direct placement on the eye without rinsing, that is, the solution is safe and comfortable for daily contact with the eye via a contact lens that has been wetted with the solution.
  • An ophthalmically safe solution has a tonicity and pH that is compatible with the eye and comprises materials, and amounts thereof, that are non-cyto toxic according to ISO standards and U.S. FDA (Food & Drug Administration) regulations.
  • Multi-purpose solutions do not exclude the possibility that some wearers, for example, wearers particularly sensitive to chemical disinfectants or other chemical agents, may prefer to rinse or wet a contact lens with another solution, for example, a sterile saline solution prior to insertion of the lens.
  • the term "multi-purpose solution” also does not exclude the possibility of periodic cleaners not used on a daily basis or supplemental cleaners for removing proteins, for example enzyme cleaners, which are typically used on a weekly basis.
  • cleaning is meant that the solution contains one or more cleaning agents in sufficient concentrations to loosen and remove loosely held lens deposits and other contaminants on the surface of a contact lens, especially if used in conjunction with digital manipulation (for example, manual rubbing of the lens with a solution) or with an accessory device that agitates the solution in contact with the lens, for example, a mechanical cleaning aid.
  • digital manipulation for example, manual rubbing of the lens with a solution
  • accessory device that agitates the solution in contact with the lens, for example, a mechanical cleaning aid.
  • the critical micelle concentration of a surfactant-containing solution is one way to evaluate its cleaning effectiveness.
  • effective multi-purpose solution analogously refers to a solution useful for daily chemical disinfection, storing, and rinsing a contact lens, which solution does not claim to clean a contact lens, but which solution still obviates the need for any other solution for daily cleaning, that is. no other solution must necessarily be used in conjunction or combination with the solution on a daily basis.
  • solutions may comprise a surfactant or other agent that may inherently loosen or preventing lens deposits to some extent, such solutions are not necessarily capable of cleaning a contact lens. Effective multi-purpose solutions are therefore only applicable for lenses used for limited period of time, either disposable or frequent replacement lenses.
  • the invention according to the present invention has the advantage that it is possible to formulate a product that, on the one hand, is gentle enough to be used as both a disinfecting solution and a wetting agent and, on the other hand, is able to meet the biocidal performance disinfection for a Chemical Disinfecting Solution under criteria established by the US FDA for Contact Lens Care Products (May 1, 1997) that does not require a regimen involving rubbing of the lenses (even though rubbing of the lens may provide further removal of microorganisms).
  • the compositions according to the present invention may optionally be formulated to meet the requirements of the FDA or ISO Stand- Alone Procedure for contact lens disinfecting products. Accordingly, it is possible to make formulations that offer higher patient compliance and greater universal appeal than traditional disinfecting or disinfecting and cleaning products.
  • the combination of the biguanide polymer and the bis(biguanide) provides enhanced efficacy while not causing irritation or discomfort to the eyes, always an important and challenging concern in the art of contact-lens care.
  • increased amounts of the biguanide polymer, by itself, to achieve the same efficacy as the combination would result in greater eye irritation.
  • increased amounts of the biguanide polymer, by itself, to achieve the necessary disinfection for a Chemical Disinfecting Solution would result in unacceptable eye irritation.
  • the enhanced biocidal activity may provide greater protection against infection, especially if the rubbing by the contact-lens wearer is inadequate or omitted through negligence or disregard of the product instructions.
  • the bis(biguanide) germicides employed in the present solutions include compounds, and their water-soluble salts, having following formula:
  • R 1 and R 2 are independently selected (i.e., the same or different) from the group consisting of branched or unbranched alkyl having 4-12, preferably 6-10, carbon atoms, alkoxyalkyl (i.e., ether) or alkylsulfide (thioether or dialkylsulfide) radical having 4-12, preferably 6-10, carbon atoms, or cycloalkyl or cycloalkyl-alkyl radical having 5-12, preferably 7-10, carbon atoms; and n is 4 to 16, preferably 6 to 10.
  • cycloalkyl either in cycloalkyl or cycloalkyl-alkyl, is meant unsubstituted or substituted cycloalkyl, where the substituents are one or more alkyl, alkoxy (-OR) , or alkylthio (-SR) groups having 1-6 carbon atoms.
  • the biguanides of Formula (I) are suitably used in the total amount of 0.1 to 4.0 ppm, preferably 1.0 to 3.0 ppm based on the total aqueous solution. More preferably, the bis(biguanides) are used in the amount of 1.5 to 2.5, most preferably about 2.0 ppm.
  • the concentration of the bis(biguanide) in solution is directly related to its bactericidal efficacy.
  • ppm refers to "parts per million” and 1.0 ppm corresponds to 0.0001 percent by weight. It is based on the total weight of the composition or, in this case, the total weight of the aqueous disinfecting solution.
  • the amount of the bis(biguanide) or other components in a solution according to the present invention refers to the amount formulated and introduced into the solution at the time the solution is made. Over time (for example, over a storage period of 18 months), the assayed amount of a bis(biguanide) in solution may decrease somewhat.
  • the bis(biguanide) compounds have the above Formula (I) wherein R and R 2 are independently selected from the group consisting of branched or unbranched alkyl, alkoxyalkyl (i.e., ether) or alkylsulfide (thioether) radical, and n is 5 to 7.
  • R 1 and R 2 in Formulas (I) above may be, for example, an n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, octyl, 2-ethylhexyl, dodecyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentylmethyl or cyclohexylmethyl radical.
  • 2-ethylhexyl (alexidine), 1,5-dimethylhexyl, 1-methylhexyl, 1,3- dimethylpentyl, 1 ,4-dimethylpentyl, cyclohexylmethyl, 2-norbornyl, propyloxyoctyl, and propyloxybutyl.
  • the acid-addition salts of the invention may be derived from an inorganic or organic acid. In most circumstances it is preferable that the salts be derived from an acid which is readily water soluble and which affords an anion which is suitable for human usage, for example a pharmaceutically-acceptable anion.
  • acids are hydrochloric, hydrobromic, phosphoric, sulphuric, acetic, D-gluconic, 2-pyrrolidino-5- carboxylic, methanesulphonic, carbonic, lactic and glutamic acids.
  • the hydrochloride salt is preferred.
  • the bis(biguanides) of Formula (I) have relatively hydrophobic end groups.
  • the Log P of the compounds is 5 to 10, more preferably 6 to 8, wherein P is the partition coefficient of the free base, using the following equation, wherein C is the molar concentration of the bis(biguanide) in each phase and ⁇ is the degree ⁇ f ionization of the bis(biguanide):
  • the compound is partitioned between a 0.05 M phosphate buffer (pH 11) saturated with octanol and octanol saturated with phosphate buffer after gentle shaking at room temperature (26 °C).
  • the volume ratio of these two phases and the amount of sample are chosen so that the absorbence of the sample from the buffered layer after partitioning has a value between 0.2 and 0.9, using a 1 -cm cell and buffer solution as a blank.
  • Particularly preferred bis(biguanide) compounds of this invention are 2- (decylthiomethyl)-pentane-l,5-bis(5-isopropylbiguanide), 2-(decylthio-methyl)pentane- l,5-bis(5,5-diethylbiguanide), and hexane-l,6-bis(2-ethylhexylbiguanide), the latter also known as alexidine or l, -hexamethylenebis(5-(2-ethylhexyl)-biguanide) dihydrochloride.
  • bis(biguanides) include 1 , 1 '-hexamethylenebis(5- heptyl-biguanide) dihydrochloride, 1,1 '-hexamethylenebis(5-octyl-biguanide) dihydrochloride, and l,l'-hexamethylenebis(5-hexyl-biguanide) dihydrochloride.
  • the biguanide compounds of Formula (I) may be made by reacting a bis- cyanoguanidine of the formula: NC— NH— C— NH— A-NH— C— NH— CN II II
  • the reactants are heated together until the reaction is complete.
  • the reaction proceeds fastest at higher temperatures, but if thermal stability is a problem, the reaction should be carried out at lower temperature for a longer period.
  • the reactants are most conveniently melted together in the absence of a solvent, but if desired an inert solvent such as DMSO, 2-methoxyethanol, 2-ethoxyethanol, nitrobenzene, sulpholane, isopropanol, n-butanol, ethylene glycol dimethyl ether or water, or a mixture of such solvents, may be used.
  • the bis-cyanoguanidine of the Formula (VI) may be manufactured from known starting materials such as hexamethylenedinitrile which is reduced, for example, with hydrogen and Raney nickel or with borane in dimethyl sulphide to the corresponding diamine (VIII), and the diamine in the form of an acid-addition salt, conveniently the dihydrochloride, is reacted with sodium dicyanamide or other suitable salt to form the required starting material (VI), as depicted below.
  • known starting materials such as hexamethylenedinitrile which is reduced, for example, with hydrogen and Raney nickel or with borane in dimethyl sulphide to the corresponding diamine (VIII), and the diamine in the form of an acid-addition salt, conveniently the dihydrochloride, is reacted with sodium dicyanamide or other suitable salt to form the required starting material (VI), as depicted below.
  • M is a sodium, potassium, zinc or other suitable salt.
  • the sodium salt is commercially available.
  • the compounds of the present invention can also be made by reacting a diamine of the Formula (VIII) in the form of an acid addition salt, with a cyanoguanidine of the formula:
  • a suitable salt of the diamine is, for example, the dihydrochloride.
  • the reactants are heated together until the reaction is complete. The reaction proceeds fastest at higher temperature, but if thermal stability is a problem, the reaction should be carried out at lower temperature over a longer period. If a melt can be formed at those temperatures the reactants are conveniently melted together in the absence of a solvent. If not, or alternatively, the reactants are heated together in a suitable inert solvent, for example those mentioned above.
  • the acid-addition salts of the invention are obtained by conventional means.
  • the cyanoguanidines of the Formulae (IX) and (X), which may be used as starting materials in the above process, may be obtained by reacting sodium dicyanamide with an appropriate amine R'N ⁇ 2 or R 2 NH 2 , in the form of an acid-addition salt, conveniently the dihydrochloride, in a suitable inert solvent.
  • the bis(biguanide) known as alexidine is produced from the following sequence of reactions.
  • Compound (XI) is hexamethvlenediamine dihydrochloride (MW 189), Compound (XII) is sodium dicyanamide, Compound XIII is HMBDA, hexamethylene bis(cyanoguanido), Compound (XIV) is 2-ethyl-hexylamine hydrochloride (MW 165.7), and Compound (XV) is alexidine dihydrochloride a.k.a. [l,6-bis-(2-ethylhexylbiguanido]hexane dihydrochloride a.k.a. hexane-l,6-bis(2-ethylhexyl biguanide) dihydrochloride.
  • This compound has a molecular weight in g/mole (MW) of 581.7 and empirical formula C_6H 56 N ⁇ o-2HCl.
  • the Compound (XV) is commercially available from various sources, including Sigma Chemical Co. (St. Louis. Missouri).
  • the methods for synthesized compounds of the present invention are also disclosed in European Patent Application Publication No. 0 125 092 (published 14.11.84); Rose, F.L. .and Swain, G., "Bisdiguanide Having Antibacterial Activity," J. Chem. Soc, p. 4422-4425 (1956); and Warner, Victor D.
  • the bis(biguanides) of the present invention may be used in combination with one or more polymeric biguanides, and water-soluble salts thereof, having the following formula:
  • Z is an organic divalent bridging group which may be the same or different throughout the polymer, n is on average at least 3, preferably on average 5 to 20, and X 1 and X 2 are independently selected from the groups -NH 2 and -NH - C - NH - CN.
  • water-soluble polymeric biguanides will have number average molecular weights of at least 1,000 and more preferably will have number average molecular weights from 1,000 to 50,000.
  • Suitable water-soluble salts of the free bases include, but are not limited to hydrochloride, borate, acetate, gluconate, sulfonate, tartrate and citrate salts.
  • the polymeric biguanides, in combination with the bisbiguanides of the present invention, are effective in concentrations as low as 0.00001 weight percent (0.1 ppm). It has also been found that the bactericidal activity of the solutions may be enhanced or the spectrum of activity broadened through the use of a combination of such polymeric biguanides with the compounds of Formula (I) above.
  • the effective amount of the polymeric biguanides (irrespective of the particular salt form or whether the free base is used ) may in total be as low as about 0.000010 weight percent (0.10 ppm) and up to about 0.00030 weight percent (3.0 ppm) in the present invention, whether in the form of a water-soluble salt or the free base.
  • the total amount of polymeric biguanide, in combination with the total amount of compounds of Formula (I) above is about 0.3 to 2.0 ppm, more preferably about 0.4 to 1.0, most preferably about 0.5 to 0.8 ppm.
  • polystyrene foam Most preferred are the polymeric hexamethylene biguanides, commercially available, for example, as the hydrochloride salt from Zeneca (Wilmington, DE) under the trademark CosmocilTM CQ. Such polymers and water-soluble salts are referred to as polyhexamethylene (PHMB) or polyaminopropyl biguanide (PAPB).
  • PHMB or PAPB polyaminopropyl biguanide
  • the predominant compound falling within the above formula may have different X 1 and X 2 groups or the same groups, with lesser amounts of other compounds within the formula.
  • Such compounds are known and are disclosed in US Patent No. 4,758,595 and British Patent 1,432,345, which patents are hereby incorporated herein by reference.
  • the water-soluble salts are compounds where n has an average value of 2 to 15, most preferably 3 to 12.
  • Optional additional disinfectant/germicide components may be employed in the present invention to further potentiate, compliment or broaden the spectrum of microbiocidal activity of the invention.
  • Suitable complementary germicidal agents include, but are not limited to thimerosol, sorbic acid, alkyl triethanolamines, phenylmercuric salts, quaternary ammonium compounds, and polyquatemium copolymers, and mixtures thereof.
  • Suitable salts are soluble in water at ambient temperature to the extent of at least 0.5 weight percent.
  • salts include the gluconate, isethionate, (2-hydroxyethanesulfonate), formate, acetate, glutamate, succinanate, monodiglycollate, methanesulfonate, lactate, isobutyrate and glucoheptonate.
  • Representative examples of the quaternary ammonium compounds are compositions comprised of balanced mixtures of n-alkyl dimethyl benzyl ammonium chlorides.
  • An example of a polyquatemium polymer used in ophthalmic applications include Polyquatemium 1® (chemical registry number 75345-27-6) available from Onyx corporation.
  • the present solution optionally comprises at least one surfactant.
  • Suitable surfactants can be either amphoteric, cationic, anionic, or nonionic which may be present (individually or in combination) in amounts up to 15 percent, preferably up to 5 percent by weight of the composition or solution.
  • Preferred surfactants are amphoteric or nonionic surfactants, which when used impart cleaning and conditioning properties.
  • the surfactant should be soluble in the lens care solution and non-irritating to eye tissues.
  • Many nonionic surfactants comprise one or more chains or polymeric components having oxyalkylene (-O-R-) repeats units wherein R has 2 to 6 carbon atoms.
  • Preferred non-ionic surfactants comprise block polymers of two or more different kinds of oxyalkylene repeat units, which ratio of different repeat units determines the HLB of the surfactant.
  • Satisfactory non-ionic surfactants include polyethylene glycol esters of fatty acids, e.g. coconut, polysorbate, polyoxyethylene or polyoxypropylene ethers of higher alkanes ( ⁇ -C J S). Examples of the preferred class include polysorbate 20 (available under the trademark Tween® 20), polyoxyethylene (23) lauryl ether (Brij® 35), polyoxyethyene (40) stearate (Myrj® 52), polyoxyethylene (25) propylene glycol stearate (Atlas® G 2612).
  • Non-ionic surfactant in particular consisting of a poly(oxypropylene)-poly(oxyethylene) adduct of ethylene diamine having a molecular weight from about 7,500 to about 27,000 wherein at least 40 weight percent of said adduct is poly(oxyethylene) has been found to be particularly advantageous for use in cleaning and conditioning both soft and hard contact lenses when used in amounts from about 0.01 to about 15 weight percent.
  • CTFA Cosmetic Ingredient Dictionary's adopted name for this group of surfactants is poloxamine. Such surfactants are available from BASF Wyandotte Corp., Wyandotte, Michigan, under the registered trademark "Tetronic".
  • An analogous of series of surfactants, suitable for use in the present invention is the poloxamer series which is a poly(oxy ethylene) poly(oxypropylene) block polymers available under the trademark "Pluronic" (commercially available form BASF).
  • Amphoteric surfactants suitable for use in a composition according to the present invention include materials of the type are offered commercially under the trade name "Miranol.” Another useful class of amphoteric surfactants is exemplified by cocoamidopropyl betaine, commercially available from various sources.
  • surfactants when employed with a buffer enhancer will generally be present in an amount from 0.01 to 5.0 percent (w/w), preferably 0.1 to 5.0 percent
  • the aqueous solutions of the present invention for treating contact lenses are also adjusted with tonicity agents, to approximate the osmotic pressure of normal lacrimal fluids which is equivalent to a 0.9 percent solution of sodium chloride or 2.5 percent of glycerol solution.
  • the solutions are made substantially isotonic with physiological saline used alone or in combination, otherwise if simply blended with sterile water and made hypotonic or made hypertonic the lenses will lose their desirable optical parameters.
  • excess saline may result in the formation of a hypertonic solution which will cause stinging and eye irritation.
  • the pH of the present solutions should be maintained within the range of 5.0 to 8.0, more preferably about 6.0 to 8.0, most preferably about 6.5 to 7.8, suitable buffers may be added, such as boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of Na 2 HPO 4 , NaH 2 PO 4 and KH 2 PO 4 ) and mixtures thereof.
  • suitable buffers may be added, such as boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of Na 2 HPO 4 , NaH 2 PO 4 and KH 2 PO 4 ) and mixtures thereof.
  • Borate buffers are preferred, particularly for enhancing the efficacy of biguanides.
  • buffers will be used in amounts ranging from about 0.05 to 2.5 percent by weight, and preferably, from 0.1 to 1.5 percent.
  • the disinfecting/preserving solutions of this invention preferably contain a borate buffer
  • Ethylene- diaminetetraacetic acid (EDTA) and its salts (disodium) are preferred examples. They are usually added in amounts ranging from about 0.01 to about 0.2 weight percent.
  • Other suitable sequestering agents include gluconic acid, citric acid, tartaric acid and their salts, e.g. sodium salts.
  • Preferred sequestering agents, which are also effective for removing protein deposits, are the phosphonate compounds disclosed in WO 97/31659.
  • aqueous solutions of the present invention are especially useful for soft contact lenses, with or without further additives. Nevertheless, the solutions of the present invention may be formulated into specific contact lens care products, such as wetting solutions, soaking solutions, cleaning and conditioning solutions, as well as multi-purpose type lens care solutions, etc. and mixtures thereof. Finally, such solutions can be applied to the lenses outside the eye or while on the eye, for example, in the form of droplets.
  • water-soluble viscosity builders in the solutions of the present invention. Because of their demulcent effect, viscosity builders have a tendency to enhance the lens wearer's comfort by means of a film on the lens surface cushioning impact against the eye. Included among the water-soluble viscosity builders are the cellulose polymers like hydroxyethyl or hydroxypropyl cellulose, carboxymethyl cellulose, povidone, polyvinyl alcohol, and the like. Such viscosity builders may be employed in amounts ranging from about 0.01 to about 4.0 weight percent or less.
  • the present solutions may also include optional demulcents.
  • the aqueous solutions according to the present invention can be effectively used in disinfecting contact lenses by any of the well recognized methods.
  • the lenses may be treated by the "cold" soaking method at room temperature for a period ranging from about 5 minutes to about 12 hours.
  • the lenses are then removed from the solution, rinsed with the same or a different solution, for example a preserved isotonic saline solution and then replaced on the eye.
  • contact-lens wearers are commonly required to digitally or manually b the contact lenses (typically between a finger and palm or between fingers) during daily cleaning and/or disinfecting of contact lenses.
  • a method is provided in which rubbing is not required during treatment with the claimed specified solution, between removal from the eye and replacement of the lens following lens care.
  • a soft lens is disinfected or both disinfected and cleaned with a multipurpose solution or an effective multipurpose solution that is the only daily solution needed for treating the lens outside the eye.
  • the described solution is used to treat a contact lens without rubbing, by a method comprising:
  • step (a) may involve immersing the contact lens in the solution. Soaking may optionally comprise shaking or similarly agitating a container of the solution by manual means. Preferably, step (a) involves a period of soaking the contact lens in a container wherein the contact lens is completely immersed in the solution.
  • direct placement is herein meant that the solution is not diluted or rinsed off the lens with a different contact-lens solution prior to "insertion" or placement on the eye.
  • the method uses a product that is formulated as a multi-purpose or effective multi-purpose solution, wherein no other solution or product is required for daily cleaning of the lens, with the possible exception of an enzyme cleaner.
  • the claimed solution is used to clean a frequent replacement lens (FRL) that is planned for replacement after not more than about three months of use in the eye, or that is planned for replacement after not more than about 30 days of use in the eye, or that is planned for replacement after not more than about two weeks in the eye.
  • the lens is made from a polymer comprising about 0.0 to 5 mole percent repeat units derived from methacrylic acid (MAA), 10 to 99 mole percent of repeat units derived from hydroxyethyl methacrylate, and about 0.5 to 5 mole percent of cross-linking repeat units.
  • Cross-linking repeat units may be derived, for example, from such monomers as ethyleneglycol dimethacrylate, divinylbenzene, and trimethylpropane trimethacrylate.
  • This Example illustrates the preparation of 1 ,6 bis(cyanoguanidino) hexane, used as a starting material for bis(biguanides) of the present invention.
  • sodium dicyanamide NaC N 3
  • 1-butanol aqueous hydrochloric acid
  • a milky white precipitate appeared immediately which was probably the amine hydrochloride.
  • the mixture was then refluxed for 3.5 hr. The suspension was then cooled to room temperature and filtered.
  • This Example illustrates the preparation of the bis(biguanide) known as alexidine for use in the present invention.
  • Hexamethylene bis(cyanoguanido) in the amount of 1.003g (0.004498 moles) was placed into a flask.
  • 1.474 mL (1.163g; 0.008996 moles) of 2-ethylhexylamine was added.
  • 0.74 mL (0.008996 moles) of concentrated HC1 was added.
  • the mixture was heated in a flask to boil away the H 2 O. After the H 2 O was gone, the temperature of the melt had risen to 195°C.
  • the temperature was decreased to 150-160°C and maintained for 1 hour.
  • the material was cooled to room temperature. The solid can be dissolved in hot water and allowed to crystallize.
  • This Example illustrates the preparation of poly(hexamethylene biguanide), also referred to as PAPB or PHMB, for use in combination with bis(biguanides) in the present invention.
  • PAPB poly(hexamethylene biguanide)
  • PHMB poly(hexamethylene biguanide)
  • This example illustrates the preparation of an aqueous disinfecting solution according to the present invention comprising a combination of alexidine and polyhexamtheylene biguanide (also referred to as PHMB).
  • PHMB polyhexamtheylene biguanide
  • the solution is prepared by gradually heating 80 percent of the water to 80°C while dissolving the disodium EDTA therein.
  • the boric acid and sodium borate are added to the heated solution of disodium EDTA and dissolved.
  • the sodium chloride is then added to the solution and dissolved, followed by the addition of the surfactant.
  • the solution is sterilized by autoclaving to 120°C for 45 minute. After the solution is cooled to room temperature, the alexidine bis(biguanide) and the PHMB are added as a solution through a sterile filter, followed by the balance of distilled water.
  • the solution is packaged in sterilized plastic containers.
  • This Example illustrates the improved antimicrobial efficacy of the combination of alexidine with polyhexamethylene biguanide (PHMB) in an aqueous disinfecting solution for contact lenses.
  • the antimicrobial efficacy of each of various compositions for the chemical disinfection of contact lenses was evaluated.
  • Microbial challenge inoculums were prepared using Pseudomonas aeruginosa (ATCC 9027), Staphylococcus aureus (ATCC 6538), Serratia marcescens (ATCC 13880), Candida albicans (ATCC 10231), and Fusarium solani (ATCC 36031).
  • the test organisms were cultured on appropriate agar and the cultures were harvested using sterile DPBST (Dulbecco's Phosphate Buffered Saline plus 0.05% w/v polysorbate 80) or a suitable diluent and transferred to a suitable vessel. Spore suspensions were filtered through sterile glass wool to remove hyphal fragments.
  • Serraiia marcescens was filtered (eg., through a 1.2 ⁇ filter) to clarify the suspension. After harvesting, the suspension was centrifuged at no more than 5000 x g for a maximum of 30 minutes at 20-25°C. The supernatant was poured off and resuspended in DPBST or other suitable diluent. The suspension was centrifuged a second time, and resuspended in DPBST or other suitable diluent. All challenge bacterial and fungal cell suspensions were adjusted with DPBST or other suitable diluent to 1 x 10 -10 8 cfu/rnL.
  • the appropriate cell concentration may be estimated by measuring the turbidity of the suspension, for example using a spectrophotometer at a preselected wavelength, for example 490 nm.
  • One tube was prepared containing a minimum of 10 mL of test solution per challenge organism.
  • Each tube of the solution to be tested was inoculated with a suspension of the test organism sufficient to provide a final count of 1.0 x l ⁇ ⁇ 6 cfu/mL, the volume of the inoculum not exceeding 1% of the sample volume. Dispersion of the inoculum was ensured by vortexing the sample for at least 15 seconds.
  • the inoculated product was stored at 10-25°C.
  • the viable count of organisms was determined in appropriate dilutions by preparation of triplicate plates of trypticase soy (TSA) agar for bacteria and Sabouraud dextrose agar (SDA) for mold and yeast.
  • TSA trypticase soy
  • SDA Sabouraud dextrose agar
  • the bacterial recovery plates were incubated at 30-35°C for 2-4 days.
  • the yeast was incubated at 20-30°C for 2-4 days and mold recovery plates at 20-25 °C for 3-7 days.
  • the average number of colony forming units was determined on countable plates.
  • Countable plates refer to 30-300 cfu/plates for bacteria and yeast, and 8 to 80 cfu/plate for mold except when colonies are observed only for the 10° or 10 " ' dilution plates.
  • the microbial reduction was then calculated at the specified time points.
  • inoculum controls were made by dispersing an identical aliquot of the inoculum into a suitable diluent, for example DPBST, using the same volume of diluent used to suspend the organism as listed above. Following inoculation in a validated neutralizing broth and incubation for an appropriate period of time, the inoculum control must be between 1.0 x 10 5 - 1.0 x 10 6 cfu/mL
  • the solutions were evaluated based on the performance requirement referred to as the "Stand- Alone Procedure for Disinfecting Products" (hereafter the “stand-alone test") and is based on the Disinfection Efficacy Testing for contact lens care products under the Premarket Notification (510(k)) Guidance Document For Contact Lens Care Products dated May 1, 1997, prepared by the U.S. Food and Drug Administration, Division of Ophthalmic Devices. This performance requirement is comparable to current ISO standards for disinfection of contact lenses (revised 1995).
  • the stand-alone test challenges a disinfecting product with a standard inoculum of a representative range of microorganisms and establishes the extent of viability loss at pre-determined time intervals comparable with those during which the product may be used.
  • the primary criteria for a given disinfection period (corresponding to a potential minimum recommended disinfection period) is that the number of bacteria recovered per mL must be reduced by a mean value of not less than 3.0 logs within the given disinfection period.
  • the number of mold and yeast recovered per mL must be reduced by a mean value of not less than 1.0 log within the minimum recommended disinfection time with no increase at four times the minimum recommended disinfection time.
  • This Example illustrates the microbiocidal efficacy of solutions according to the present invention.
  • the above testing procedures were used for evaluating the antimicrobial efficacy against C. albicans of disinfecting solutions such as prepared in Example 4, but which contain the bis(biguanide) alexidine at various concentrations extending from 1 ppm to 4 ppm and the biguanide polymer at various concentrations extending from 0.3 to 1.5 ppm.
  • the results are shown in Table 2 after a 5 minute soak, Table 3 after a 15 minute soak, Table 4 after a 30 minute soak, and Table 5 after a 45 minute soak.
  • Tables 6 to 9, corresponding respectively to Tables 2 to 5, compares the theoretical kill, based on the sum of individual disinfecting agents versus actual kill using the combination of disinfecting agents.
  • Figure 2 shows the biocidal efficacy against C. albicans of the test solutions after a period of 30 minutes compared to the theoretical efficacy.

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EP98957702A 1997-11-12 1998-11-10 Desinfektion von kontaktlinsen mit bis-biguaniden und polymerbiguaniden Withdrawn EP1030902A1 (de)

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US6309596B1 (en) * 1998-12-15 2001-10-30 Bausch & Lomb Incorporated Treatment of contact lenses with aqueous solution comprising a biguanide disinfectant stabilized by a poloxamine
JP2001242428A (ja) * 1999-12-20 2001-09-07 Tomey Corp コンタクトレンズ用液剤およびソフトコンタクトレンズの洗浄、消毒、保存方法
MY128134A (en) * 2000-09-28 2007-01-31 Novartis Ag Compositions and methods for cleaning contact lenses
WO2004112848A1 (en) * 2003-06-16 2004-12-29 Bausch & Lomb Incorporated Lens care solutions for hydrogel contact lenses
JP2007502883A (ja) * 2003-08-18 2007-02-15 エスケー ケミカルズ カンパニー リミテッド ポリアルキレンバイグアニジン塩の製造方法
US20060292105A1 (en) * 2005-06-28 2006-12-28 Lever O W Jr Topical preservative compositions
CN102993056A (zh) * 2012-12-04 2013-03-27 甘肃省化工研究院 一种双氯苯双胍己烷化合物的制备方法
CN102993057B (zh) * 2012-12-04 2014-09-17 甘肃省化工研究院 1,6-双氰基胍基己烷的合成方法
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