KR20010031986A - Disinfecting contact lenses with bis(biguanides) and polymeric biguanides - Google Patents

Abstract

The present invention relates to a disinfecting solution for ophthalmic contact lenses comprising an acetylated polymer in combination with bis (bicyanide) and a method of using a composition in the form of an aqueous solution for sterilizing and / or preserving contact lenses, in particular soft contact lenses . The present invention can be used to formulate products that are more convenient and / or advantageous than conventional disinfecting products for contact lenses, and can provide antimicrobial activity as a whole broader, stronger and faster.

Description

DISINFECTING CONTACT LENSES WITH BIS (BIGUANIDES) AND POLYMERIC BIGUANIDES <br> <br> <br> Patents - stay tuned to the technology DISINFECTING CONTACT LENSES WITH BIS (BIGUANIDES) AND POLYMERIC BIGUANIDES

In general, commonly used contact lenses are divided into three categories: (1) hard lenses formed from materials produced by polymerization of acrylic esters, such as polymethyl methacrylate (PMMA), (2) silicone acrylates, and fluoro A rigid gas permeable (RGP) lens formed from silicon methacrylate, and (3) a gel made from hydrophilic or hydrophobic monomers polymerized as 2-hydroxyethyl methacrylate (HEMA), hydrogel or soft Type lens. Hard acrylic type contact lenses feature light, oxygen, resistance to hydrolytic effects and low water vapor diffusion constants, absorbing only a small amount of aqueous fluid. Due to the durability of the hard contact lens combined with the property of not absorbing a significant amount of water, the selection of suitable disinfectants, cleaners, or other lens management compounds is relatively unimportant.

However, unlike a hard lens, a soft-type contact lens is a combination of a large amount of fluid, environmental contaminants, water impurities as well as other active ingredients commonly found in antimicrobials and lens care solutions, And has the property of concentrating. In most cases, when used properly, low level components in the lens management solution do not cause inflammation of the eye tissue. However, due to the inherent binding action of the protein precipitate, especially to the soft lens material, some disinfectants and preservatives can be loaded on the lens surface and concentrated to potentially dangerous levels, which, when released, (Eye) tissue inflammation.

Any antimicrobial agent is known to be more compatible with contact lenses and less binding on the lens surface. In some cases, chlorhexidine, biguanide has been found to bind to soft lens material seven times less than benzalkonium chloride. However, the presence of a proteinaceous oil tear-film precipitate on the lens can double the amount of chlorhexidine adsorbed on the lens compared to a clean lens. U.S. Patent No. 4,354,952 discloses a highly diluted disinfection and washing solution comprising chlorhexidine or a salt thereof in combination with any amphoteric and nonionic surfactant. This solution has been found to reduce the amount of chlorhexidine binding on hydrophilic soft contact lenses. Despite the reduction of binding made by the above invention, the use of chlorhexidine caused some problems. The antimicrobial activity of the chlorohexidine can be reduced when used with certain amphoteric surfactants. Furthermore, it has been reported that, unless used in proper proportions, surfactants and disinfectants will precipitate unless a non-ionic type surfactant is used.

British Patent 1,432,345 discloses a contact lens disinfecting composition comprising a polymeric bean anion and a mixed phosphate buffer. However, the composition disclosed by this patent has a corneal staining value of 17% or more, which is a preferable value in patient acceptability.

U.S. Pat. No. 4,758,595 to Ogunbiyi et al. Discloses a contact lens-solution containing polyaminopropyl bevuanide (PAPB), known as polyhexamethylenebiguanide (PHMB), in combination with a borate buffer solution. . This disinfection and preservation solution is particularly noteworthy for its broad bactericidal activity against bacteria and fungi at low concentrations of very low toxicity when used with soft type contact lenses.

U.S. Patent No. 5,453,435 to Raheja et al. Discloses a preservation system comprising a combination of chlorhexidine and polyhexamethylene beguinide. This retention system, which is used in commercial products for solid-gas-permeable lenses, is known to exhibit improved combination of efficiency and low ocular inflammation.

Compositions containing PHMB and borate salts have been commercialized into various products, but have been commercialized at levels of only about 1 ppm or less for use with soft contact lenses. It is generally desirable to provide the lowest level of possible sterilizing agent, in order to provide a wide range of safety and comfort while maintaining the desired level of disinfecting efficacy.

Some of the most popular lens disinfection products are multipurpose solutions that can be inserted (attached to the eye) directly without washing, disinfecting, and rinsing the contact lens after cleaning. Obviously, it is an advantage to be able to use a single solution for contact lens management. However, such a solution should be particularly gentle on the eye, as indicated above, since some solution may be present on the lens upon insertion and contact with the eye.

It is typically necessary to rub the contact lens with the fingers or by hand (typically between the fingers and palms or between the fingers) with a conventional contact-lens cleaner or disinfectant containing a multipurpose solution while the lens wearer handles the contact lens Do. In addition to the time and effort involved in the daily management of contact lenses, it is necessary to &quot; rubbing &quot; the contact lens daily. Many contact lens wearers are reluctant to perform these management practices, or think this is uncomfortable. Some wearers may be subject to appropriate &quot; rubbing &quot; care, which can cause discomfort and other problems with contact lenses. Occasionally, rubbing can damage the lens if done too strongly, which is particularly easy for beginners wearing lenses. This can be a problem when there are no readily available interchangeable lenses.

The contact lens solution specified as the "Chemical Disinfecting Solution" is a premarket notification instruction (510k) guidance document for contact lens management products (May 1, 1997) Does not require rubbing to meet biocidal performance criteria set by the US Food and Drug Administration (FDA). Conversely, contact lens solutions, which are not defined as chemical disinfection solutions and are considered "chemical disinfecting systems", require rubbing management methods to pass the biocide performance criteria. Traditionally, multipurpose solutions (for disinfection and wetting or disinfection, cleaning and wetting) are defined as chemical disinfection systems, but not as chemical disinfection solutions.

Chemical disinfection solutions will generally require more effective or stronger disinfectants than chemical disinfection systems. However, the stronger the biocidal effect of the solution, the more likely it is to exhibit the adverse effects against the toxic effect and the wearing comfort of the lens wearer. For example, many highly effective fungicides used in other ingredients such as mouthwash, cosmetics, or shampoos are safe enough for use in such products, while the properties of the soft lens that binds to the above-mentioned chemicals, Because of the sensitivity of the lens to ophthalmic use, especially for use with soft lenses will be too toxic. Similarly, the concentration of any disinfectant may be required to a lower limit in solutions for use with soft contact lenses than in solutions for other types of lenses or other products. Especially if this solution is not rinsed in contact lenses before putting the lenses in the eye.

It would be desirable to obtain a contact lens solution that can simultaneously provide both (1) an increase in biocidal activity levels and / or an extended range, and (2) a low degree of toxicity to eye tissue, The solution can be used to treat the contact lens so that the lens can be worn on the eye without rinsing the solution on the lens. In particular, it is desirable to obtain a chemical disinfectant solution that can be used in soft contact lenses, soak the contact lenses and / or rinse and rewet with the solution, then allow direct attachment of the contact lenses to the eye something to do. These products, while providing maximum convenience, can increase the efficacy to better protect the wearer of the lens against infections caused by microorganisms. As a result, it is desirable that the biocidal efficacy of the disinfectant solution is high enough, or at least essentially ineffective, to disinfect the contact lens effectively for bacteria and fungi, and for some reason the contact lens wearer may need to use a contact lens solution It would be desirable to not use a control method involving mechanical rubbing or the like.

The present invention relates to a new and improved contact lens treatment solution and a method of treating contact lenses with such a solution. In particular, the present invention relates to a disinfection system consisting of a novel composition of two disinfectants, namely bis (biguanide) and polymeric bean anions.

Figure 1 is a bar graph showing the theoretical sum of the antimicrobial efficacy of a solution comprising two disinfectants, namely a combination of bis (bicyanide) and a bicyanide polymer, versus the antimicrobial efficacy of each disinfectant solution after 15 minutes. The increased efficacy of the combination over the theoretical sum is a measure of the synergism of the combination. In particular, Figure 1 shows the theoretical log reduction of actual log reduction of Alexine and PHMB after 15 min exposure to Candida albicans microorganisms.

FIG. 2 is a bar graph showing the theoretical sum of the antimicrobial efficacy of solutions containing a combination of bis (biguanide) and a biguanide polymer after 30 minutes versus the antimicrobial efficacy of individual solutions of each disinfectant. In particular, Figure 2 shows the theoretical log reduction of actual log reduction of Alexine and PHMB after 30 min exposure to Candida albicans microorganisms.

Summary of the Invention

The present invention relates to an ophthalmically safe disinfectant solution for contact lenses comprising:

(a) from about 0.10 to about 4.0 ppm of a bis (anhydride) in the form of a dihydrochloride salt having the general formula: or a corresponding concentration of the corresponding bis (anhydride) in free base or other water-soluble salt form:

Or a water soluble salt form thereof, wherein R ¹ and R ² are independently selected from the group consisting of a branched or unbranched alkyl, alkoxyalkyl or alkylsulfide radical and n is 4 to 16; And

(b) from about 0.1 to about 3.0 ppm of a polymeric beanoid having the formula:

Wherein Z is an organic divalent bridging group which may be the same or different in the whole polymer, n is an average of 3 or more, X ¹ and X ² are -NH ₂ groups and Lt; / RTI &gt;

(c) an effective amount of a buffering agent; And

(d) at least about 80% water by weight.

Preferably, the compositions of the present invention also comprise one or more surfactants. In one embodiment of the invention, the surfactant is a neutral or nonionic surfactant.

The present invention also relates to a method of disinfecting or cleaning and disinfecting contact lenses, comprising immersing the lens in the aqueous solution for a given period of time and directly inserting the treated lens into the wearer's eye. In one embodiment of the method of the present invention, the contact lens does not require rubbing with the solution to make the necessary disinfection.

DETAILED DESCRIPTION OF THE INVENTION

As described above, the present invention relates to a composition comprising a combination of an acetylated polymer and bis (anhydride), and a composition comprising said composition in the form of an aqueous solution for disinfecting and / or preserving contact lenses, in particular soft contact lenses &Lt; / RTI &gt; These synergistic combinations provide maximum convenience while providing increased efficacy, thus providing better protection against microorganisms as compared to traditional disinfecting products for contact lenses. Considering the overall range of microorganisms on the basis of typical bacteria and fungi normally tested, the solutions according to the present invention provide broader, more potent and faster antimicrobial activity as a whole. Particularly, the disinfecting solution of the present invention can be used at a low concentration, such as Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Candida albicans, Is effective against a wide range of microorganisms including, but not limited to, Fusarium solani.

The disinfecting solution is contact-lens managed (e.g., containing one or more active ingredients (e.g., anti-microbial agents and / or preservatives) at a concentration sufficient to eradicate harmful microorganisms on the surface of the contact lens within the recommended minimum immersion time It is generally defined as a product. The recommended minimum immersion time is included in the packaging instructions for use of the disinfectant solution. The term &quot; disinfecting solution &quot; does not exclude the possibility that the solution may also be useful as a preservation solution, or that the disinfecting solution may be useful for other purposes such as daily cleaning, rinsing and storage of contact lenses, depending on the particular formulation . This solution can be thought of as a new and improved kit, package or system for the management of contact lenses, together with containers, bottles and packaging, including instructions for use according to a particular method.

The term &quot; soft lens &quot; refers to a lens having a proportion of hydrophilic repeating units having a moisture content of at least 20 wt% when the lens is worn. As used herein, the term &quot; soft contact lens &quot; refers to a contact lens that is generally flexible, even with small force. Typically, soft contact lenses are formulated in polymers with a certain proportion of repeating units derived from hydroxyethyl methacrylate crosslinked with a crosslinking agent and / or other hydrophilic monomers. However, the more recent soft lenses are made of materials containing high Dk silicon.

The term &quot; anesthetically stable &quot; in the contact lens solution means that it is safe to wear the contact lens directly on the eye without rinsing the solution treated contact lens, that is to say the solution in contact with the eye through the wet contact lens This means that it is safe and comfortable. The scientifically safe solution has an appropriate tonicity and pH for the eye and includes substances and amounts that are not cytotoxic according to the ISO standard and the US Food and Drug Administration (FDA) regulations.

Solutions useful for cleaning, chemical disinfection, storing and rinsing soft contact lenses are referred to herein as &quot; versatile solutions &quot;. Multipurpose solutions exclude the possibility that a wearer who is sensitive to, for example, any wearer, especially a chemical disinfectant or other chemical agent, may prefer to rinse or wet the contact lens with another solution such as a sterile saline solution before inserting the lens I never do that. Also, the term &quot; multipurpose solution &quot; does not exclude the possibility of periodic or complementary cleansers, such as enzyme cleansers, which are usually used weekly, which are not used daily to remove proteins. The term &quot; cleaning &quot; means that when the solution is used together with a peripheral device which stirs the solution in contact with a contact lens, such as a mechanical cleaning aid, with a particularly hand operation (e.g. rubbing the lens with the solution by hand) Is meant to include one or more detergents at a concentration sufficient to remove and remove the lens deposit and other contaminants on the surface of the contact lens. The critical micelle concentration of a solution containing a surfactant is one method of assessing its cleaning efficacy.

The term &quot; effective multi-purpose solution &quot; similarly refers to a solution useful for the daily chemical disinfection, storage, and rinsing of contact lenses. The solution does not require cleaning of the contact lens, but it eliminates the need for any other routine cleaning solution, i.e. the other solution does not necessarily have to be used with or in combination with the routine solution. Such a solution will consist of a surfactant, or essentially any other agent that reduces or prevents lens deposits, but such a solution is not necessarily capable of cleaning contact lenses. Thus, an effective multi-purpose solution can only be used for lenses that are used for a limited period of time, i.e., lenses that need to be disposable or frequently exchanged.

Typically, a multipurpose solution in the market requires a control method that involves mechanically rubbing the contact lens into a multi-purpose solution to provide the required disinfection. That is, this management method is required under government regulatory authorities (eg, the US FDA or Food Sanitation) for chemical disinfection systems that are not certified as chemical disinfection solutions. The invention according to the invention has the advantage that on the one hand it is possible to produce a soft product sufficiently to be used both as a disinfectant solution and a wetting agent and on the other hand it is advantageous for the lens (even if rubbing the lens to remove microorganisms better) (May 1, 1997) established by the US FDA for contact lens management products that do not require management practices, including rubbing a chemical disinfection solution. That is, the composition according to the present invention can be selectively manufactured to meet the requirements of the FDA or ISO stand-alone procedure for contact lens disinfection products. Thus, formulations can be made that provide a higher degree of patient compliance and a more universal need than traditional disinfectants or disinfectants and cleaners.

It is known that the combination of BIGUANIDE polymer and bis (BIGUANIDE) provides improved efficacy without causing irritation or discomfort to the eyes, which is always a significant and challenging problem in the field of contact lens management. Thus, in order to achieve the same efficacy as the combination, increasing the amount of the acetaminopolymer itself will stimulate the eye. Specifically, it has been found that increasing the amount of the acetaminopolymer itself to achieve the necessary disinfection in chemical disinfection solutions results in irritation to the unacceptable eye. Even when using the solution of the present invention, rubbing management is recommended, but even when the contact lens wearer ignores or neglects the product description and omits or insufficiently scours it, the improved antibacterial activity provides greater protection against infection .

According to the present invention, the bis (acetonide) bactericides used in the present invention include the following compounds and water-soluble salts thereof:

Here, R^OneAnd R²Branched or unbranched alkyl having from 4 to 12, preferably from 6 to 10, carbon atoms independently, (i. E. The same or different), from 4 to 12, preferably from 6 to 10 Alkoxyalkyl (i.e., ether) or alkylsulfide (thioether or dialkylsulfide) radical having from 1 to 12 carbon atoms, or a cycloalkyl or cycloalkyl-alkyl radical having from 5 to 12, preferably 7 to 10 carbon atoms, Alkyl radicals; And n is 4 to 16, preferably 6 to 10. Cycloalkyl &quot; means an unsubstituted or substituted cycloalkyl, by the term &quot; cycloalkyl &quot; in cycloalkyl or cycloalkyl-alkyl. Wherein the substituents are one or more alkyl, alkoxy (-OR), or alkylthio (-SR) groups having 1 to 6 carbons.

In this disinfecting solution, the bean-anion of formula (I) is suitably used in an amount of from 0.1 to 4.0 ppm, preferably from 1.0 to 3.0 ppm, based on the total aqueous solution. More preferably, bis (biguanide) is used in an amount of 1.5 to 2.5, most preferably about 2.0 ppm. The concentration of bis (biguanide) in solution is directly related to sterilization efficacy. The term &quot; ppm &quot; means &quot; part per million &quot; and 1.0 ppm corresponds to 0.0001 wt%. Based on the total weight of the composition or, in this case, the total weight of the aqueous disinfecting solution.

In the present invention, the amount of bis (biguanide) or other ingredients in the solution according to the present invention means the amount of solution formulated into the solution at the time of manufacture. As time elapses (e.g., after a storage period of 18 months), the analyzed amount of bis (acetyl) in the solution will be somewhat reduced.

Preferably, the bis (biguanide) compound has the above formula (I). Wherein R ¹ and R ² are independently selected from the group consisting of branched or unbranched alkyl, alkoxyalkyl (ie, ether) or alkyl sulfide (thioether) radicals, and n is from 5 to 7.

In the above formula (I), each of R ¹ and R ² is, for example, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, octyl, Butyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentylmethyl, or cyclohexylmethyl radical. But are not limited to, 2-ethylhexyl (alexidine), 1,5-dimethylhexyl, 1-methylhexyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, cyclohexylmethyl, Oxybutyl is preferred.

The acid-addition salts of the present invention may be derived from inorganic or organic acids. In most situations, the salts are preferably those which are soluble in water and which are derived from acids which are suitable for use in humans, for example, which can provide pharmaceutically acceptable anions. Examples of such acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, D-gluconic acid, 2-pyrrolidino-5-carboxylic acid, methane sulfuric acid, carbonic acid, lactic acid and glutamic acid. Hydrochloric acid is preferred.

The bis (anhydride) of formula (I) has a relatively hydrophobic end group. The Log P of the compound is preferably 5 to 10, more preferably 6 to 8. Where P is the partition coefficient of the free base, C is the molar concentration of bis (acetonide) at each phase and? Is the ionization degree of bis (acetonide)

After gentle stirring at room temperature (26 DEG C), the compound is partitioned between octanol saturated with 0.05M phosphate buffer (pH 11) and saturated with phosphate buffer to obtain partition coefficient of bis . Using a buffer and 1-cm cell as the blank, the volume ratio of these two phases and the amount of sample are selected so that the absorbance of the sample from the buffered layer after dispensing has a value of 0.2 to 0.9. By operating at a fixed pH and recognizing or calculating the pKa, the P value can be measured using the above formula. See, for example, &quot; Quantative Structure-Activity Relationship for Biguanides, Carbamidates and Bisbiguanides as Inhibitors of Streptococcus mutants. 6715 &quot;, Warner, V. and Lynch, D., J. Med. Chem., 1979, Vol. 22, no. 4 at 359, 365; and Albert, and Serjeant, E., "Determination of Ionization and Stability Constants," Butler and Tanner Ltd., London, England, 1962.

Particularly preferred bis (acetyl) compounds of the present invention are 2- (decylthiomethyl) -pentane-1,5-bis (5-isopropylbiguanide), 2- (decylthio- Bis (5,5-diethylbiguanide) and hexane-1,6-bis (2-ethylhexylguanidide) or 1,1'-hexamethylenebis (5- Ethylhexyl) -biguanid &lt; / RTI &gt; dihydrochloride. Other preferred bis (bicyandiides) include 1,1'-hexamethylene bis (5-heptyl-biguanide) dihydrochloride, 1,1'-hexamethylene bis (5-octyl-biguanide) dihydrochloride , And 1,1'-hexamethylene bis (5-hexyl-biguanide) dihydrochloride.

Biguanide compounds of formula (I) to be prepared by bis-dicyano guanidine this acid addition salt form of the amine R ¹ NH _2, or two different amines R ¹ NH ₂ and R ² NH ₂ and the reaction of the formula have:

In the above, R ¹ and R ² have the above-described meanings at a temperature of 100 ° C to 170 ° C, and A is an alkylene group having a necessary number of carbon atoms. A preferred amine salt is the hydrochloride salt. Most diamines are available in a variety of sources.

The reactants are heated together until the reaction is complete. The reaction proceeds faster at higher temperatures, but if thermal stability is a problem, the reaction must be carried out at lower temperatures over a longer period of time. The reactants are most conveniently dissolved together in the absence of solvent, but they may be dissolved in a suitable solvent such as DMSO, 2-methoxyethanol, 2-ethoxyethanol, nitrobenzene, sulfolane, isopropanol, n-butanol, ethylene glycol dimethylether or water or a mixture of such solvents May be used.

Bis-cyano guanidines of formula (VI) can be prepared from known starting materials, such as hexamethylene dinitrile, reduced to hydrogen and Raney nickel or reduced to borane in dimethyl sulfide, corresponding to diamines (VIII) And the diamine, conveniently in the form of an acid-addition salt, is reacted with sodium dicyanide or other suitable salt to form the required starting material (VI) as illustrated below.

In the above, M is sodium, potassium, zinc or other suitable salts. Sodium salts are commercially available.

The compounds of the present invention may also be prepared by reacting a diamine of formula (VIII) in the form of an acid addition salt with cyanoguanidine of the formula: or cyanoguanidine of the formula (IX) and cyanoguanidine of the formula:

In the above, R ¹ and R ² have the meanings described above at a temperature of 100 ° C to 170 ° C.

A suitable salt of the diamine is, for example, dihydrochloride. The reactants are heated together until the reaction is complete. The reaction is faster at higher temperatures, but if thermal stability is a problem, the reaction must be carried out at low temperatures over a long period of time. If a melt can form at this temperature, the reactants will conveniently melt together in the absence of the solvent. Otherwise, alternatively, the reactants are heated together, for example, in a suitable inert solvent as described above. The acid-addition salts of the present invention are obtained by conventional means.

The cyano guanidines of formulas (IX) and (X) which can be used as starting materials for the process can be obtained by reacting sodium dicyanamide with the appropriate amine R ¹ NH ₂ or R ² NH ₂ in a suitable inert solvent.

For example, bis (bicyanide), known as alexidine, is produced according to the following reaction sequence.

(XIV) is hexamethylene diamine dihydrochloride (molecular weight 189), compound (XII) is sodium dicyanamide, compound (XIII) is HMBDA, hexamethylene bis (cyanoguanido) Hexylamine hydrochloride (molecular weight 165.7), compound (XV) is known as [1,6-bis- (2-ethylhexylamide)] hexane dihydrochloride and hexane- Is alexidine dihydrochloride known as bis (2-ethylhexylbiguanide) dihydrochloride. This compound has a molecular weight (MW) of 581.7 g / mol and is the empirical formula C ₂₆ H ₅₆ N ₁₀ -2HCl. Compound (XV) is commercially available from a variety of companies, including Sigma Chemical Co. (St. Louis, Mo.).

Methods for the synthesized compounds of the present invention are also disclosed in European Patent Application Publication No. 0 125 092 (published November 14, 1984); Rose, F. L. and Swain, G., &quot; Bisbiguanide Having Antibacterial Activity, &quot; J. Chem. Soc., P. 4422-4425 (1956); And Warner, Victor D. and Lynch, Donald, &quot; Quantitative Structure-Activity Relationships of Biguanide, Carbamimidates, and Bisdiguanides as Inhibitors of Streptococcus Mutans No. &quot; 6715. &quot; J. Med. Chem., Vol. 22, No. 6, pp. 359-366 (1979).

The bis (anhydride) of the present invention (Formula I) can be used in admixture with one or more polymeric bean anions having the following formula, and water soluble salts thereof:

Z is an organic divalent bridging group which may be the same or different from each other through the polymer, n is an average of 3 or more, preferably an average of 5 to 20, X ¹ and X ² are each an -NH ₂ group .

One preferred group of water-soluble polymeric beanoids will have an average molecular weight of 1,000 or more, more preferably an average molecular weight of 1,000 to 50,000. Suitable water-soluble salts of the free base include, but are not limited to, hydrochloride, borate, acetate, gluconate, sulfonate, tartrate and citrate salts.

The above-described acetonide and preparation methods are described in the literature. For example, U.S. Patent No. 3,428,576 discloses the preparation of polymeric bean anions and salts thereof and diamine salts of dicyanimides in diamines.

Polymeric bean ions mixed with the bis bisguanides of the present invention are effective at low concentrations such as 0.00001 wt% (0.1 ppm). It has also been found that the sterilizing activity of a solution can be enhanced or the range of bactericidal activity can be extended through the use of a combination of such a polymeric asanide with a compound of formula (I) above. An effective amount of a polymeric beanoid, whether in the form of a water-soluble salt or free base, whether or not a particular salt form or free base is used, is present in the present invention in a total amount of about 0.000010% by weight (0.10 ppm) ppm). The total amount of the compound of formula (I) above is preferably about 0.3 to 2.0 ppm, more preferably about 0.4 to 1.0, and most preferably about 0.5 to 0.8 ppm, in total amount of the polymeric bean anion.

For example, the course carry ^TM security space (Cosmocil CQ ^TM) under the trademark Zeneca (Zeneca) No (Wilmington, Delaware), the hydrochloride of the non-polymeric hexamethylene available from Degas is most preferred. Such polymers and water-soluble salts are referred to as polyhexamethylene (PHMB) or polyaminopropylbiguanide (PAPB). The term PHMB or PAPB, as used herein, is considered to include one or more than one bifunctional having the following formula:

Wherein X ¹ and X ² are defined above, and n is 1 to 500.

Depending on the manner in which the biguanide is made, the majority of compounds belonging to the above formula will have other X ¹ and X ² groups or the same group and will have a smaller amount of other chemicals belonging to the above formula. Such compounds are known and are disclosed in U.S. Patent No. 4,758,595 and British Patent No. 1,432,345, the patents incorporated herein by reference. Water-soluble salts are compounds in which n has an average value of from 2 to 15, most preferably from 3 to 12.

Additional disinfecting / germicidal compounds that are optional for further enhancing, extending or increasing the range of antimicrobial activity of the present invention may be used in the present invention. Depending on the particular disinfecting agent known to those skilled in the art, at a concentration ranging from about 0.000001 to about 0.5% by weight, this includes an antimicrobially effective amount of a disinfectant that is compatible with the solution and does not settle out in solution. Suitable supplemental bactericides include, but are not limited to, thimerosol, sorbic acid, alkyltriethanolamine, phenylmercuric salts, quaternary ammonium compounds and polyquaternium copolymers and mixtures thereof. Suitable salts are water-soluble to an extent of at least 0.5% by weight at ambient temperature. Such salts include gluconate, isethionate, (2-hydroxyethanesulfonate), formate, acetate, glutamate, succinate, monodiglycolate, methanesulfonate, lactate, isobutyrate, and glucoheptonate do. A representative example of quaternary ammonium is a composition consisting of an equilibrium mixture of n-alkyldimethylbenzylammonium chloride. An example of a polyquaternium polymer used ophthalmically is Polyquaternium 1 available from Onyx corporation (Chemical Registration No. 75345-27-6).

The solution optionally comprises at least one surfactant. Suitable surfactants may be amphoteric, cationic, anionic, or nonionic, which may be present (individually or combined) in the composition or solution up to 15% by weight, preferably up to 5% by weight. Preferred surfactants are amphoteric or nonionic surfactants which, when used, provide washability and controllability. Surfactants should be soluble in the lens care solution and should not irritate the eye tissue. Many non-ionic surfactants consist of one or more polymers or polymer compounds having an oxyalkylene (-OR-) repeating unit wherein R has from 2 to 6 carbon atoms. A preferred nonionic surfactant comprises a block polymer of oxyalkylene repeat units and the ratio of the other repeat units above determines the HLB of the surfactant. Satisfactory non-ionic surfactants include polyethylene glycol esters, polysorbates, polyoxyethylene or polyoxypropylene ethers of fatty acids such as higher alkanes (C ₁₂ -C ₁₈ ) coconut. An example of a preferred class is polysorbate 20 (Tween) 20), polyoxyethylene (23) lauryl ether (Brij) 35), polyoxyethylene (40) stearate (Myrj) 52), polyoxyethylene (25) propylene glycol stearate (Atlas) G 2612). One nonionic surfactant specifically composed of a poly (oxypropylene) -poly (oxyethylene) adduct of ethylenediamine having a molecular weight of from about 7,500 to about 27,000 wherein at least 40% by weight of the adduct is poly (oxyethylene) &Lt; / RTI &gt; to about 15% by weight, based on the total weight of the composition, for cleaning and conditioning both soft contact lenses and hard contact lenses. CTFA Cosmetic Ingredients This group of surfactants used in the dictionary is the name poloxamine. Such surfactants are commercially available under the trademark &quot; Tetronic &quot; from BASF Wyandott Corp., Michigan. A similar series of surfactants suitable for use in the present invention is the Poloxamer series, a poly (oxyethylene) poly (oxypropylene) block polymer commercially available under the trade name &quot; Pluronic &quot;

In view of the foregoing description, various other ions as well as amphoteric and anionic surfactants suitable for the present invention are described in McCutcheon's Detergents amd Emulsifiers, North American Edition, McCutcheon Division, MC Publishing Co., Glen Rock, NJ 07452 and the CTFA International Cosmetic Ingredient Handbook, published by The Cosmetic, Toiletry, and Fragrance Association, Washington, DC.

Suitable amphoteric surfactants for use in compositions according to the present invention include materials of the type sold commercially under the trademark &quot; Miranol &quot;. Another useful class of amphoteric surfactants is exemplified by cocoamidopropyl betaine, which is commercially available from a variety of sources.

When used with a buffer enhancer, such surfactants will generally be present in an amount of 0.01 to 5.0% (W / W), preferably 0.1 to 5.0%.

Typically, the aqueous solution of the present invention for contact lens treatment is adjusted with a tonicity agent to approximate the osmotic pressure of a normal tear fluid that emerges with a 0.9% solution of sodium chloride or 2.5% of the glycerol solution. The solution is prepared as a substantially isotonic solution with physiological saline solution used alone or in combination with it, and if it is merely mixed with sterile water to become hypotonic or hyperosmotic, the lens will lose its desirable optical parameters. Thus, excess saline can form a fluid that causes pain and eye irritation in the eye.

The pH of the solution should be maintained in the range of 5.0 to 8.0, very preferably in the range of about 6.0 to 8.0, and most preferably in the range of about 6.5 to 7.8, A suitable buffer such as sodium bicarbonate, TRIS, various mixed phosphate buffers (including Na ₂ HPO ₄ , NaH ₂ PO _4, and KH ₂ PO ₄ ), and mixtures thereof, may be added. Borate buffers are particularly preferred for enhancing the efficacy of the biguanides. Generally, the buffer will be used in an amount ranging from about 0.05 to 2.5 wt%, preferably 0.1 to 1.5 wt%. The disinfecting / preserving solution of the present invention preferably comprises a borate buffer system comprising boric acid, sodium borate, potassium tetraborate, potassium metaborate or mixtures thereof.

In addition to the buffering agent, in some cases it may be desirable to include a sequestering agent in the present solution, in order to react with the lens and / or the protein precipitate and with the metal ions that can collect on the lens. Ethylenediaminetetraacetic acid (EDTA) and salts thereof (disodium salt) are preferred examples. It is usually added in an amount ranging from about 0.01 to about 0.2 weight percent. Other suitable sequestering agents include gluconic acid, citric acid, tartaric acid and salts thereof, such as sodium salts. Also preferred is a phosphonate compound disclosed in WO97 / 31659, which is effective for removing protein precipitates.

The aqueous solution of the present invention is particularly useful for soft lenses regardless of the additional additives. However, 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 multipurpose type lens care solutions and the like, and mixtures thereof. Ultimately, such a solution can be used in the form of a droplet, for example, outside the eye or in the eye.

It may also be desirable to include a viscosity builder in the solution of the present invention. Due to the mitigating effect of this, the viscous agent has the tendency to relax the impact on the eyes in the form of a film on the surface of the lens to improve the fit of the wearer. Water-soluble viscosifiers include cellulose polymers such as hydroxyethyl or hydroxypropyl cellulose, carboxymethyl cellulose, povidone, polyvinyl alcohol, and the like. Such viscosifiers may be used in amounts ranging from about 0.01 to about 4.0 weight percent. The solution may also contain any emollient.

The aqueous solution according to the present invention can be effectively used for disinfecting contact lenses by any widely accepted method. During a period of from about 5 minutes to about 12 hours at room temperature, the lens may be treated by a &quot; cold &quot; soaking method. Remove the lens from solution and wash it with the same or different solution, for example preserved isotonic saline, and rewarm it into the eye.

As indicated above, contact lens wearers are usually required to manually or manually rub contact lenses (typically between fingers and palms, or between fingers) during routine cleaning and / or disinfection of contact lenses. In one embodiment of the present invention, there is provided a method of requiring rubbing during treatment with a particular solution as claimed between the removal from the eye and the reattaching of the lens after lens management. In a preferred embodiment of this method, the soft lens is disinfected or disinfected and cleaned with an effective multi-purpose solution that is a multipurpose solution or a daily solution needed only to treat the lens out of the eye. Thus, in one embodiment of the method according to the invention, the solution described by the method constituted below is used to treat contact lenses without rubbing:

(a) immersing a non-rubbing contact lens in a solution for a certain period of time, and

(b) directly wearing the treated contact lens on the wearer's eye.

Typically, step (a) may comprise immersing the contact lens in a solution. The soaking may optionally involve arbitrarily shaking or similarly stirring the vessel of the solution. Preferably, step (a) comprises immersing the contact lens in a container of contact lenses fully immersed in solution for a period of time. The term &quot; directly worn &quot; as used herein means that the solution is diluted with another contact-lens solution or the lens is not cleaned before &quot; inserted &quot; In a particularly preferred embodiment, the method uses a product which is formulated as a multipurpose or effective multi-purpose solution, in which no other solution or product is required for routine cleaning of the lens except for possible enzyme cleansing agents.

In another embodiment of the method according to the invention, the claimed solution is intended to be replaced after about 3 months of use in the eye, or intended to be replaced after about 30 days or less use in the eye, (FRL), which is designed to be replaced after a long period of time. Preferably, the lens comprises about 0.0 to about 5 mole percent of recurring units derived from methacrylic acid (MAA), from about 10 to about 99 mole percent of recurring units derived from hydroxyethyl methacrylate, and from about 0.5 To 5 mol% of the polymer. The crosslinked repeating units may be derived from, for example, monomers such as ethylene glycol dimethacrylate, divinylbenzene, and trimethylpropane trimethacrylate.

The following examples illustrate compositions and methods of the present invention.

Example 1

This example illustrates the preparation of 1,6 bis (cyanoguanidino) hexane which is used as starting material for the bis (bicyanide) of the present invention. 35.80 g (0.402 mol) of sodium dicyanamide (NaC ₂ N ₃ ) is suspended in 400 ml of 1-butanol. Then, 23.60 g (0.204 mol) of 1,6-hexanediamine was added with 33.0 ml of concentrated hydrochloric acid aqueous solution (0.400 mol). A milky white precipitate appeared immediately like amine hydrochloride. The mixture was refluxed for 3.5 hours. The suspension was then cooled to room temperature and filtered. The white solid was washed well with distilled water before drying under vacuum. Yield 46.38 g; 93.1%. C ₁₀ H ₁₈ N ₈ theoretical value; C 48.0%; H7.20%; N44.80%; Found: C 47.7%; H7.40%; N45.12%. 300 MHz ¹ H NMR (d ⁶ -DMSO) 6.60 ppm ( ⁶ p, br m); 2.93 ppm (4p, m); 1.34 ppm (4p, br s); 1.15 ppm (4p, br s). IR (KBr pellet, cm ^-1 ) 3142 (m); 2943; 2912; 2862 (w); 2179 (s); 1658; 1609 (s).

Example 2

This example illustrates the preparation of bis (viguanidine) known to be an Alexine used in the present invention. 1.003 g (0.004498 mol) of hexamethylenebis (cyanoguanido) were placed in a flask. To this was added 1.474 ml (1.163 g; 0.008996 moles) of 2-ethylhexylamine. Then 0.74 mL (0.008996 moles) of saturated HCl was added. The mixture was heated in a flask and boiled and evaporated H ₂ O. After the H ₂ O was evaporated, the temperature of the melt rose to 195 ° C. The temperature was lowered to 150-160 &lt; 0 &gt; C and held for 1 hour. The material was cooled at room temperature. The solids can be dissolved in hot water and allowed to crystallize.

Example 3

This example illustrates the preparation of poly (hexamethylene beguinide) also referred to as PAPB or PHMB for use in combination with bis (biguanides) in the present invention. 25.08 g (0.100 mole) of 1,6-bis (cyanoguanidino) hexane and 18.99 g (0.100 mole) of 1,6-hexanediamine dihydrochloride were suspended in 500 ml of distilled water. The pH of this mixture was lowered to 6.8 by dilute hydrochloric acid. The water was then removed by distillation under reduced pressure. The white solid was then transferred to a three-necked flask equipped with a mechanical stirrer and a heating mantle. The original mixture of solids was then placed under nitrogen and the temperature of the mixture was raised to 150-55 占 폚. The molten reaction mixture had a viscosity of honey. Before cooling at room temperature, the mixture was stirred at 150-55 [deg.] C for 1-1.5 hours. The obtained poly (hexamethylenebiguanide) is obtained as a glassy solid. The yield is almost quantitative. Melting temperature 105-125 ℃. 300 MHz ¹ H NMR (D ₂ O) 3.13 ppm (21.1 p, brt); 2.93 ppm (2p, t); 1.49 ppm (21.1 p, br s); 1.28 ppm (21.1 p, br s). IR (KBr pellet, cm ^-1 ) 3325; 3201 (s); 2931; 2858 (m); 2175 (MH @ +); 1631; 1589; 1550 (s).

Example 4

This example illustrates the preparation of an aqueous disinfecting solution according to the present invention comprising a combination of alexidine and polyhexamethylene bengillan (also referred to as PHMB). The following ingredients are used in the indicated weight percentages per total volume of solution:

% (W / V) PHMB 0.00008 Alexidine &lt; / RTI &gt; 0.0002 Poloxamine 1107 ** 1.0 Na ₂ EDTA 0.11 Boric acid 0.66 Sodium borate 0.10 Sodium chloride 0.54 Distilled water (qs) 100.0

** Molecular weight 14,500, Tetronic 1107, a poly (oxypropylene) poly (oxyethylene) block copolymer adduct of ethylenediamine, commercially available under the trademark BASF Yuan Dot Corporation from Yuan Dot, Michigan

The solution is prepared by progressively heating 80% of water at 80 ° C while dissolving the EDTA disodium salt. Boric acid and sodium borate were added to the heated EDTA disodium salt and dissolved. Sodium chloride is then added to the solution and dissolved, followed by the addition of a surfactant. The solution is sterilized by autoclave at 120 ° C for 5 minutes. After the solution is cooled to room temperature, alexidine bis (biquinide) and PHMB are added as a solution through a sterilizing filter and equilibrated with distilled water. Place the solution in a sterile plastic container.

Example 5

This example illustrates the improved antimicrobial efficacy of polyhexamethylenebiguanide (PHMB) and alexidine combination in disinfecting aqueous solutions of contact lenses. The antimicrobial efficacy of each of the various compositions for the chemical disinfection of contact lenses was evaluated.

The microbial inoculum may be selected from the group consisting of Pseudomonas aeruginosa (ATCC 9027), Staphylococcus aureus (ATCC 6538), Serratia marcescens (ATCC 13880), Candida albicans Candida albicans (ATCC 10231), and Fusarium solani (ATCC 36031). The test organism is cultured on a suitable agar and the culture is harvested using sterile DPBST (Dulbecco's Phosphate Buffered saline and 0.05% w / v polysorbate 80) or a suitable diluent and placed in an appropriate container . The spore suspension was filtered through a sterile glass wool to remove mycelial fragments. The supernatant masses were filtered (eg via a 1.2μ filter) by appropriate filtration to purify the suspension. After collection, the suspension was centrifuged at only 5000 x g for a maximum of 30 minutes at 20-25 ° C. The supernatant was removed and resuspended in DPBST or other suitable diluent. The suspension was centrifuged a second time and resuspended in DPBST or other suitable diluent. All aggressive bacterial cells or fungal cell suspensions were adjusted to 1 × 10 ⁷ -10 ⁸ cfu / mL with DBPST or other appropriate diluent. Appropriate cell concentration can be assessed by measuring the turbidity of the suspension, e.g., using a spectrophotometer at a predetermined wavelength (e.g., 490 nm). One tube was prepared to contain at least 10 mL of test solution per attack organism. Each tube of the solution to be tested is 1.0 × 10 ⁵ -10 ⁶ were inoculated with a suspension of the test organism sufficient to provide the inoculum volume of water does not exceed 1% of the final volume of the sample and the number of cfu / mL. Samples were shaken for more than 15 seconds to ensure that the inoculum was dispersed. The inoculated product was stored at 10-25 ° C. A 1.0 mL aliquot of the inoculated product was taken to determine the viable count after a certain time after disinfection. When the proposed control immersion time is 4 hours, the measurement points for bacteria are, for example, 1, 2, 3, and 4 hours. Yeast and mold were tested at an additional point in time of 16 hours (four times the maintenance time) or more. The suspension was vigorously shaken for at least 5 seconds and mixed well. A 1.0 mL aliquot collected at specific time intervals was made into a series of 10-fold dilutions suitable for the identified neutral medium. The suspension was vigorously mixed and incubated for an appropriate period of time allowing the microbial agent to neutralize. Survival counts of organisms were determined by preparing a triple plate of trypticase soy agar (TSA) for bacteria and Sabouraud dextrose agar (SDA) for fungi and yeast in a suitable diluent . The bacterial recovery plate was incubated at 30-35 ° C for 2-4 days. The yeast was incubated at 20-30 ° C for 2-4 days, and the mold recovery plate was incubated at 20-25 ° C for 3-7 days. The average number of colonies forming monoliths was measured on countable plates. A countable plate means 30-300 cfu / plate for bacteria and yeast, and 8-80 cfu / plate for mold, unless the colonies are only observed for 10 ⁰ or 10 ^-1 dilution plates. And, microbial reduction was calculated at a specific point in time. In order to demonstrate the suitability of the medium used for growth of the test organism and to determine the initial inoculum concentration, the same volume of diluent used to suspend the organisms listed above was used, And dispersed in a diluent, for example, DPBST, to prepare an inoculum control. The inoculum control should be between 1.0 × 10 ⁵ -1.0 × 10 ⁶ cfu / ml, which is inoculated into the identified neutral broth and incubated for an appropriate period of time.

The solution was evaluated on the basis of the performance referred to as the "Stand-Alone Procedure for Disinfecting Product" (hereinafter referred to as the "Certification Procedure") and was prepared by the US Food and Drug Administration, Was measured based on disinfection efficacy tests for contact lens care products under the premarket commercial (520 (k)) guidance document for contact lens care products of May 1. This performance requirement is comparable to current ISO standards for disinfection of contact lenses. The certification test involves antigen administration to a disinfecting article with a standard range of standard inoculum of microorganisms and determines the degree of survival reduction at a predetermined time interval that can be compared to that while the article can be used. The primary criterion for a given disinfection period is that the number of bacteria recovered per mL should be reduced by a median of at least 3.0 logs within a given disinfection period. The number of fungi and yeast recovered per mL should not be increased by four times the proposed minimum disinfection time and should be reduced by an average of at least 1.0 log within the proposed maximum disinfection time.

The test procedure described above was followed to determine if it would pass the main performance criteria at intervals of 5 minutes, 15 minutes, 30 minutes, and 4 hours. In this test group, the concentration of Alexinidine was mixed with 0.0 or 0.8 ppm of PAPB in an amount ranging from 0.0 to 4.0 ppm, and a PAPB amount of 0.8 ppm was used in a multi-purpose solution commercially available for soft contact lenses . The results are shown in Table 1 below.

Alexidine * 2HCL (ppm) PAPB (ppm) Immersion time Log Reduction S. Mathesense Log Reduction C. Albikans 0.5 0.8 5 minutes 15 minutes 30 minutes 60 minutes -2.03.24.3 0.61.11.83.5 1.0 0.8 5 minutes 15 minutes 30 minutes 60 minutes -2.63.7> 4.3 0.51.12.24.2 2.6 0.8 5 minutes 15 minutes 30 minutes 60 minutes -2.7> 4.3> 4.3 0.72.23.3> 4.2 4.0 0.8 5 minutes 15 minutes 30 minutes 60 minutes -> 4.3> 4.3> 4.3 1.13.0> 4.2> 4.2 0.5 0.0 5 minutes 15 minutes 30 minutes 60 minutes -0.61.62.5 0.31.0-0.2-0.1 2.6 0.0 5 minutes 15 minutes 30 minutes 60 minutes -2.2> 4.3> 4.3 0.40.50.51.4 0.0 0.8 5 minutes 15 minutes 30 minutes 60 minutes -1.32.03.1 0.60.81.42.9

The results show that the addition of alexidine to polyhexamethylenebiguanide improves antimicrobial efficacy and has an enhanced efficacy that can be used for practical use at about 4.0 ppm so that any enhanced antimicrobial efficacy can be achieved at a high concentration The possibility of an increase in toxicity in an antimicrobial agent of the present invention may not be justified. For C. albicans, the combination of 2.6 ppm of Alexine with 0.8 ppm of PAPB showed better efficacy than the sum of 2.6 ppm of Alexine itself and 0.8 ppm of PAPB itself, resulting in a synergistic effect at 15 minutes and 30 minutes .

Example 6

This example illustrates the biocidal efficacy of a solution according to the present invention. The test procedure described above was used to evaluate the antimicrobial efficacy of the disinfectant solution as prepared in Example 4 against C. albicans, but the solution contained varying concentrations of bis (bicyclonide) alecidines ranging from 1 ppm to 4 ppm and And various concentrations of acetone polymers ranging from 0.3 to 1.5 ppm. The results after immersion for 5 minutes are shown in Table 2, the results after immersion for 15 minutes are shown in Table 3, the results after immersion for 30 minutes are shown in Table 4, and the results after immersion for 45 minutes are shown in Table 5. [ Tables 6 to 9, corresponding to Tables 2 to 5, respectively, compare the theoretical and actual deaths, based on the sum of the respective disinfectants, using combinations of disinfectants. The following equation was used for this calculation: log10 (exp10 (PHMB) + exp10 (Alexin)). In other words, to calculate the theoretical log kill, the log reduction anchovy for each separate disinfectant was converted to the number of killed organisms and this value was added, resulting in a new log value for the sum.

(5 minutes) PHMB 0 ppm 0.3 ppm 0.8 ppm 1.5 ppm Alexidine 0 ppm 0.4 0.4 0.7 1.0 1 ppm 0.5 0.6 0.9 1.1 2 ppm 0.7 0.8 0.9 1.5 3 ppm 0.8 1.1 1.6 2.6 4 ppm 1.1 1.8 2.8 3.4

(15 minutes) PHMB 0 ppm 0.3 ppm 0.8 ppm 1.5 ppm Alexidine 0 ppm 0.4 0.7 1.5 1.9 1 ppm 0.4 1.1 2.2 2.9 2 ppm 0.8 1.7 2.8 3.5 3 ppm 1.6 2.7 3.7 4.5 4 ppm 2.6 3.8 4.8 > 4.8

(30 minutes) PHMB 0 ppm 0.3 ppm 0.8 ppm 1.5 ppm Alexidine 0 ppm 0.4 1.0 2.1 3.1 1 ppm 0.5 1.8 3.3 4.4 2 ppm 1.2 2.1 3.7 4.5 3 ppm 1.9 3.5 4.8 > 4.8 4 ppm 3.4 > 4.8 > 4.8 > 4.8

(45 minutes) PHMB 0 ppm 0.3 ppm 0.8 ppm 1.5 ppm Alexidine 0 ppm 0.4 1.1 3.0 4.1 1 ppm 0.4 2.1 3.7 > 4.8 2 ppm 0.9 2.6 4.5 > 4.8 3 ppm 2.1 4.5 > 4.8 > 4.8 4 ppm 3.7 4.8 > 4.8 > 4.8

(5 minutes) log killing Formulation Theoretical value Found 1 ppm alexidine /0.3 ppm PHMB 0.8 0.6 2 ppm alexidine /0.3 ppm PHMB 0.9 0.8 3 ppm alexidine /0.3 ppm PHMB 0.9 1.1 4 ppm Alexine / 0.3 ppm PHMB 1.2 1.8 1 ppm Alexine / 0.8 ppm PHMB 0.9 0.9 2 ppm Alexine / 0.8 ppn PHMB 1.0 0.9 3 ppm allcidin / 0.8 ppm PHMB 1.1 1.6 4 ppm Alexine / 0.8 ppm PHMB 1.2 2.8 1 ppm alexidine / 1.5 ppm PHMB 1.1 1.1 2 ppm alexidine / 1.5 ppm PHMB 1.2 1.5 3 ppm alexidine / 1.5 ppm PHMB 1.2 2.6 4 ppm alexidine / 1.5 ppm PHMB 1.4 3.4

(15 minutes) Log kill Formulation Theoretical value Found 1 ppm alexidine /0.3 ppm PHMB 0.9 1.1 2 ppm alexidine /0.3 ppm PHMB 1.1 1.7 3 ppm alexidine /0.3 ppm PHMB 1.7 2.7 4 ppm Alexine / 0.3 ppm PHMB 2.6 3.8 1 ppm Alexine / 0.8 ppm PHMB 1.5 2.2 2 ppm Alexine / 0.8 ppm PHMB 1.6 2.8 3 ppm alexidine / 0.8 ppm pHMB 1.9 3.7 4 ppm Alexine / 0.8 ppm PHMB 2.6 4.8 1 ppm alexidine / 1.5 ppm PHMB 1.9 2.9 2 ppm alexidine / 1.5 ppm PHMB 1.9 3.5 3 ppm alexidine / 1.5 ppm PHMB 2.1 4.5 4 ppm alexidine / 1.5 ppm PHMB 2.7 4.8

(30 minutes) Log kill Formulation Theoretical value Found 1 ppm alexidine /0.3 ppm PHMB 1.1 1.8 2 ppm alexidine /0.3 ppm PHMB 1.4 2.1 3 ppm alexidine /0.3 ppm PHMB 2.0 3.5 4 ppm Alexine / 0.3 ppm PHMB 3.4 4.8 1 ppm Alexine / 0.8 ppm PHMB 2.1 3.3 2 ppm Alexine / 0.8 ppm PHMB 2.2 3.7 3 ppm alexidine / 0.8 ppm pHMB 2.3 4.8 4 ppm Alexine / 0.8 ppm PHMB 3.4 4.8 1 ppm alexidine / 1.5 ppm PHMB 3.1 4.4 2 ppm alexidine / 1.5 ppm PHMB 3.1 4.5 3 ppm alexidine / 1.5 ppm PHMB 3.1 4.8 4 ppm alexidine / 1.5 ppm PHMB 3.6 4.8

(45 minutes) Log kill Formulation Theoretical value Found 1 ppm alexidine /0.3 ppm PHMB 1.2 2.1 2 ppm alexidine /0.3 ppm PHMB 1.3 2.6 3 ppm alexidine /0.3 ppm PHMB 2.1 4.5 4 ppm Alexine / 0.3 ppm PHMB 3.7 4.8 1 ppm Alexine / 0.8 ppm PHMB 3.0 3.7 2 ppm Alexine / 0.8 ppm PHMB 3.0 4.5 3 ppm alexidine / 0.8 ppm pHMB 3.1 4.8 4ppn alexidine /0.8ppmPHMB 38 4.8 1 ppm alexidine / 1.5 ppm PHMB 4.1 4.8 2 ppm alexidine / 1.5 ppm PHMB 4.1 4.8 3 ppm allcidine / 1.5 ppm PHMB 4.1 4.8 4 ppm alexidine / 1.5 ppm PHMB 4.2 4.8

The above results show synergistic microbial effects on C. albicans. In the case of the above excellent ratio, the log kill in the combination of Alexin and PHMB is higher than the sum of the individual disinfectants, and its synergistic effect is evident from the results after 15 minutes. After 45 minutes, when a higher percentage of microorganisms have already died, this synergistic effect will become less obvious. Based on the above data, FIG. 1 shows the effect of C. albicans on the theoretical efficacy of a test solution containing a combination of Alexine and PHMB after 15 minutes, based on the sum of individual solutions containing Alexine alone and PHMB alone, respectively. It shows the biocidal efficacy against albinans. Figure 2 shows the biocidal efficacy of the test solution against C. albicans after 30 minutes compared to the theoretical efficacy.

The invention is described in conjunction with specific embodiments thereof, but is for illustrative purposes only. Accordingly, many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, all such alternatives, modifications, and variations are intended to be within the scope of the appended claims and their full scope.

Claims (15)

An ophthalmically safe disinfectant solution for contact lenses comprising an aqueous solution containing the following components: (a) a microbiologically effective amount of a water-soluble salt or free base type bis (biguanide) having the following formula: about 0.10 to about 4.0 ppm: (I) Wherein R ¹ and R ² are selected from the group consisting of branched or unbranched alkyl having from 4 to 12 carbon atoms, alkoxyalkylether or alkylsulfide radical having from 4 to 12 carbon atoms, or from 5 to 12 carbon atoms &Lt; / RTI &gt; cycloalkyl or cycloalkyl-alkyl radical, and n is 4 to 16; (b) about 0.10 to about 3.0 ppm of a polymeric bean anion having the general formula: Z is an organic divalent bridging group which may be the same or different through the polymer, n is an average of 3 or more, X ¹ and X ² are -NH ₂ and Lt; / RTI &gt; (c) an effective amount of a buffering agent; And (d) at least about 80% water by weight. The method according to claim 1, Wherein R ¹ and R ² are independently selected from the group consisting of branched or unbranched alkyl, alkoxyalkyl ether or alkyl sulfide thioether radicals having 6 to 10 carbon atoms and n is 4 to 10, Disinfectant solution for safe contact lenses. The method according to claim 1, An optically safe disinfectant solution for contact lenses comprising a polymeric bean-ion which is a mixture of molecules having the general formula: (Wherein X ¹ and X ² are as defined above and n is an average of 5 to 20) The method according to claim 1, 0.0 &gt;% &lt; / RTI &gt; to 5.0% of a surfactant. 5. The method of claim 4, Wherein the surfactant is a neutral or nonionic surfactant having a plurality of poly (oxyalkylene) chains, each poly (oxyalkylene) comprises (-OR) repeat units, wherein R is independently 2 An unscientific safe disinfectant solution for contact lenses which is an alkylene having 6 carbon atoms. 5. The method of claim 4, Wherein said surfactant is a neutral or nonionic surfactant comprising a block copolymer of poly (ethylene oxide) and poly (propylene oxide) segments. The method of claim 1, An unscientific safe disinfectant solution for contact lenses wherein the amount of bis (bigninoides) is from 1.0 to 3.0 ppm. The method according to claim 1, An optically safe disinfectant solution for contact lenses wherein the amount of polymeric guanidone is from 0.1 to 2.0 ppm. A method of disinfecting, or cleaning and disinfecting a soft contact lens with a multipurpose solution or an effective multi-purpose solution, comprising the steps of: (a) soaking the lens in the solution to allow disinfection of the contact lens with a solution containing the following ingredients in the formulation: (i) a biocidal effective amount of a water-soluble salt or free base type bis (beguinid) having the general formula: about 0.1 to about 4.0 ppm: (I) Wherein R ¹ and R ² are selected from the group consisting of branched or unbranched alkyl having from 4 to 12 carbon atoms, alkoxyalkylether or alkylsulfide radical having from 4 to 12 carbon atoms or from 5 to 12 carbon atoms &Lt; / RTI &gt; cycloalkyl or cycloalkyl-alkyl radical, and n is 4 to 16; (ii) from about 0.10 to about 3.0 ppm of a polymeric beanoid having the general formula: Z is an organic divalent bridging group which may be the same or different through the polymer, n is an average of 3 or more, X ¹ and X ² are -NH ₂ and Lt; / RTI &gt; And (Iii) an effective amount of a buffering agent; And (b) directly positioning the treated lens in the wearer &apos; s eye, comprising the steps of: (i) eliminating the need to rinse with another solution prior to rewinding to the eye, (ii) requiring a different solution for routine handling of the lens Do not step. 10. The method of claim 9, Wherein the method does not include rubbing the lens with the solution, as is not required in the product use instructions. 11. The method according to claim 9 or 10, Wherein R &lt; ¹ &gt; and R &lt; ² &gt; are independently selected from the group consisting of branched or unbranched alkyl, alkoxyalkyl ether and alkyl sulfide thioether radicals and n is from 4 to 10; 12. The method of claim 11, Wherein the polymeric bean-anion is a mixture of polymeric &lt; RTI ID = 0.0 &gt; (Wherein X ¹ and X ² are as defined above and n is an average of 5 to 20) 11. The method according to claim 9 or 10, Wherein said solution is set to be replaced after wearing for a period of up to about 30 days or used to clean the projected lens. 14. The method of claim 13, Wherein the lens is set or planned to be worn for up to about 14 days after wearing. 11. The method according to claim 9 or 10, Wherein the solution comprises from about 0.0 to 5 mole% of recurring units derived from methacrylic acid (MAA), from 10 to 99 mole% of recurring units derived from hydroxyethyl methacrylate and from about 0.5 to 5 mole% of crosslinkable repeat units &Lt; / RTI &gt; is used to clean a lens made from a polymer that is &lt; RTI ID = 0.0 &gt;