MXPA00004566A - Disinfecting contact lenses with polyquaterniums and polymeric biguanides - Google Patents

Abstract

The present invention is directed to an ophthalmically safe disinfecting solution for contact lenses comprising the combination of a polymeric biguanide and a polyquaternium polymer of a substituted or unsubstituted vinylimidazole or its vinylimidazolium salt, which copolymer has a weight average molecular weight of 5,000 to 5,000,000. The invention is also directed to an improved method of disinfecting a contact lens.

Description

DISINFECTION OF CONTACT LENSES WITH POLYMETHANS AND POLYMERIC BIGUANIDES Field of the Invention This invention relates to new and improved solutions for the treatment of contact lenses and methods for the treatment of contact lenses with said solutions. Specifically, the present invention is directed to disinfectant solutions consisting of the combination of a biguanide polymer and a substituted or unsubstituted vinylimidazole poly-quaternimide copolymer or its vinylimidazolium salt.

BACKGROUND OF THE INVENTION In general, contact lenses that have wide use fall into three categories: (1) hard lenses formed with materials prepared by polymerization of acrylic esters, such as polymethyl methacrylate (MAPM); (2) rigid gas-permeable (RPG) lenses formed with silicone acrylates and fluorosilicone methacrylates, and (3) gel, hydrogel or soft type lenses made with hydrophilic or hydrophobic polymerized monomers, such as 2-hydroxyethyl methacrylate (MAHE). Acrylic-type hard lenses are characterized by low water vapor diffusion constants and resistance to the effects of light, oxygen and hydrolysis and absorb only minor amounts of aqueous fluids. Due to the durability of hard contact lenses, together with their tendency not to absorb appreciable amounts of water, the selection of disinfectants, cleaning agents or other suitable lens care compounds is relatively non-critical.

However, unlike hard lenses, soft-type contact lenses tend to bind and significantly concentrate more fluids, environmental contaminants and water impurities, as well as antimicrobial agents and other active components commonly found in water solutions. care of the lenses. In most cases, the low levels of the components in the lens care solutions do not lead to eye tissue irritation when used properly. However, especially due to the inherent binding action of protein deposits on soft lens materials, some disinfectants and preservatives tend to accumulate on lens surfaces and may concentrate at potentially dangerous levels, such as way that, when they are released, they can cause corneal inflammation and irritation of other ocular tissues. It was found that certain antibacterial agents were compatible with contact lenses and exhibited less binding to the lens surfaces. In one case, it was found that the exidine chlorine, a biguanide, binds to the soft lens material seven times less than the benzal-conium chloride. The presence of oily and protein deposits of the tear film on a lens, however, can double the amount of chlorhexidine absorbed on the lens compared to a clean lens. U.S. Pat. No. 4,354,952 discloses very dilute disinfectant and cleansing solutions containing chlorhexidine or its salt in combination with certain amphoteric and nonionic surfactants. These solutions resulted in reducing the amount of chlorhexidine binding on the soft hydrophilic contact lenses. Notwithstanding the reduction in binding achieved by this invention, the use of chlorhexidine did give rise to some market problems. The antimicrobial activity of chlorhexidine may be diminished when used with certain amphoteric surfactants. Moreover, it was said that if they are not used in the proper proportion, the surfactant and the disinfectant will precipitate, unless a non-ionic type surfactant is also used. The use of certain ionic polymers in solutions for cleaning and preservation of contact lenses is also known. For example, U.S. Pat. No. 5,096,607 and WO 94/13774 describe the use of certain polyquaternials as antimicrobial agents, typically in amounts less than 100 parts per million (ppm) in actual business practice. U.S. Pat. No. 4,443,429 to Smith et al. describes the use in a disinfecting solution for contact lenses of a homopolymer of dimethyldiallylammonium chloride known as Merquat® 100, having a molecular weight of from about 10,000 to about 1,000,000. Polyquaternium polymers in general are a well-known class of polymers, of which many varieties are commercially available. The International Dictionary of Cosmetic Ingredients CTFA includes polyquaternials called Polyquaternium-1 to Polyquaternium-44 and new polyquaterniums are continuously being developed. British Patent 1,432,345 discloses disinfecting compositions for contact lenses containing a polymeric biguanide and a mixed phosphate buffer. The compositions described in this patent, however, have values of corneal coloration of 17% or more, much greater than desirable for patient acceptance. U.S. Pat. 4,758,595 to Ogunbiyi et al. described that a solution for contact lenses containing polyaminopropylbiguanide (PAPB), also known as po-lihexametilehbiguanide (PHMB), has a higher efficiency when combined with a borate buffer. These disinfectant and preservative solutions are especially notorious for their broad spectrum of bactericidal and fungicidal activity at low concentrations, together with very low toxicity when used with soft type contact lenses. U.S. Pat. No. 5,453,435 to Raheja et al., Described a preservative system which consisted of a combination of chlorhexidine and polyhexamethylenebiguanide. It was found that this preservative system, used in commercial products for rigid gas-permeable lenses, exhibited a better combination of efficacy and low ocular irritation. Compositions containing PHMB and borate have been commercialized in various products, but at levels of about 1 ppm or less, for use in soft contact lenses. In general, it is desirable to have the lowest possible level of a bactericide, while maintaining the desirable level of disinfection efficiency, in order to obtain a generous margin of safety and comfort. Some of the most popular products for lens disinfection are solutions for multiple purposes, which can be used to clean, disinfect and moisten contact lenses, followed by direct insertion (eye placement) without rinsing. Obviously, the ability to use a single solution for the care of contact lenses is an advantage. Said solution, however, must be particularly gentle for the eye, since, as indicated above, part of the solution will be in the lens when it is inserted and will come into contact with the eye. With conventional contact lens cleaners or disinfectants, including multi-purpose solutions, lens wearers typically need to digitally or manually rub contact lenses (typically between a finger and the palm of the hand or between the fingers) during the treatment of the contact lenses. The need for daily "rubbing" of contact lenses adds to the time and effort involved in the daily care of contact lenses. Many contact lens wearers do not like having to perform such a regimen or consider it as an inconvenience. Some users may be negligent in the proper "rub" regime, which can lead to discomfort of contact lenses and other problems. Sometimes, rubbing, if carried out too rigorously, which is particularly likely to occur with users who start contact lenses, can damage the lens. This can be a problem when a spare lens is not immediately available. Solutions for contact lenses qualified as "Chemical Disinfection Solution" do not require rubbing to meet the performance criteria bioci-da (to destroy representative bacteria and fungi) established by the US Food and Drug Administration (FDA). . under the Premarket Notification (510k) Guidance Document For Contact Lens Care Products, May 1, 1997. On the contrary, a solution for contact lenses, referred to as a "Disinfection System" Chemistry ", which is not qualified as a Chemical Disinfection Solution, requires a rub rate to meet biocidal performance criteria Traditionally, multi-use solutions (used to disinfect and moisten or to disinfect, clean and moisten) have been qualified as a chemical disinfection system, but not as a chemical disinfection solution, a chemical disinfection solution would require, in general, a disinfectant more effective or stronger than a chemical disinfection system.The greater the biocidal effect of a solution, however, it is more likely that it may exhibit toxic effects or adversely affect the user's comfort of the lens, for example, many highly effective bactericides used in other contexts, such as mouthwashes, cosmetics or shampoos, being safe enough for use. in such products, they would be too toxic for ophthalmic use, especially for use in soft lenses Thus, due to the aforementioned tendency of soft lenses to bind chemical products and the sensitivity of ocular tissues. Similarly, the concentrations of certain bactericides may need to be within lower limits in solutions for use in soft contact lenses than in other products or in solutions for other types of lenses, especially when such solutions are not clear from the contact lens before placing the lens in the eye. It would be desirable to obtain a solution for contact lenses that will simultaneously provide (1) a higher level and / or a broader spectrum of biocidal activity and (2) a low level of toxicity to ocular tissue, so that the solution can to be used to treat a contact lens, so that the lens can then be placed in the eye without rinsing the lens solution. In addition to being interesting to develop, it would be especially desirable to obtain a Chemical Disinfection Solution that could be used for soft contact lenses and that would allow the direct placement of a contact lens in an eye after wetting in the solution and / or clarify and rewet with the solution. Said product can provide a greater efficiency, giving rise to a greater protection for the user of the lens against the infection caused by microorganisms, while giving maximum convenience. Finally, it would be desirable for the biocidal efficacy of the disinfectant solution to be high enough to achieve effective disinfection, or at least a non-inherently ineffective disinfection, of a contact lens with respect to bacteria and fungi in the event that, for For any reason, the user of the contact lens does not carry out a regime involving mechanical rubbing or the like using the solution for contact lenses.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to an ophthalmically safe disinfecting solution for contact lenses, consisting of: (a) between about 0.10 and about 3.0 ppm (between 0.00001 and 0.0003 per weight percent) of a polymeric biguanide, or water-soluble salt thereof, having the following formula: • X1- [-Z-NH-C-NH-C-NH-] nZ-X2 (IV) NH NH where Z is an organic divalent bridge group which may be the same or different along the polymer, n is 1 to 500 and X1 and X2 are independently selected from the groups -NH2 and -NH-C-NH-CN, and II NH b) between about 10 and about 400 ppm active component (between 0.0010 and 0.04 weight percent) of at least one polyquaternium, consisting of 10 to 45 mole percent of repeating units derived from substituted or unsubstituted vinylimidazoles or their vinylimidazolium salts, which copolymer has a weight average molecular weight of 5,000 to 5,000,000.

DETAILED DESCRIPTION OF THE INVENTION The combined use of the biguanide polymer and the polyquaternium polymer described herein offers a greater advantage and / or protection for lens wearers against microorganisms compared to traditional contact lens disinfectants. This combination of disinfectant agents provides more potent and faster antimicrobial activity across the entire range of microorganisms, as demonstrated by representative bacteria and fungi commonly studied. Biguanide polymers such as PHMB have been shown to be effective biocide agents. PHMB, however, is less effective against fungi than against bacteria. The Applicants have seen that the class of the polyquaternium polymers described herein, on the other hand, is relatively effective against fungi and less effective against bacteria, so that the biocidal spectrum of the polyquaternium described herein has turned out to be advantageous and unexpectedly complementary to the spectrum biocide of biguanide polymers such as PHMB.

Specifically, the solutions according to the present invention provide a broader, more potent and faster overall antimicrobial activity when considering the entire range of microorganisms, based on commonly tested representative bacteria and fungi. In particular, the disinfectant solutions of the present invention are effective at low concentrations against a broad spectrum of microorganisms, including, but not limited to, Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Candida albicans and Fusarium solani. A disinfectant solution is defined, in general, as a contact lens care product that contains one or more active components (e.g., antimicrobial agents and / or preservatives) in concentrations sufficient to destroy the deleterious microorganisms on the surface of a contact lens within the minimum recommended soaking time. The recommended minimum soaking time is included in the instructions for use of the disinfectant solution. The term "disinfectant solution" does not exclude the possibility that the solution may also be useful as a preservative solution, or that the disinfectant solution may also be useful for other purposes, such as daily cleaning, rinsing and storing contact lenses, depending on the particular formulation. The present solution, together with its container or bottle and packaging, which includes instructions for use according to a specified regime, can be considered as a new and improved kit, package or system for the care of contact lenses. By the term "soft lens" reference is made to a lens having a proportion of hydrophilic repeating units such that the water content of the lens during use is at least 20% by weight. The term "soft contact lens", as used herein, refers, in general, to those contact lenses that easily bend under small amounts of force. Typically, soft contact lenses are formulated from polymers having a certain proportion of repeating units derived from hydroxyethyl methacrylate and / or other hydrophilic monomers, typically crosslinked with a crosslinking agent. However, more modern contact lenses are being made from materials containing high Dk silicone. By the term "ophthalmically safe" with respect to a solution for contact lenses it is meant that a contact lens treated with the solution is safe for direct placement in the eye without rinsing, ie, that the solution is safe and comfortable for daily contact with the eye through a contact lens that has been moistened with the solution. An ophthalmically safe solution has a tonicity and a pH that are compa-tibies with the eye and contains materials, and quantities thereof, that are non-cytotoxic according to ISO standards and the FDA (Food &Drug Administration) guidelines of the USA Reference is here made to a solution which is useful for the cleaning, chemical disinfection, storage and rinsing of a soft contact lens as a "multi-use solution". The multipurpose solutions do not exclude the possibility that some users, for example users 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, before insertion of the lens. The term "multi-use solution" also does not exclude the possibility of periodic cleaners not used on a daily basis or supplemental cleaners to remove proteins, for example enzymatic cleaners, which are typically used on a weekly basis. By the term "cleaning" is meant that the solution contains one or more cleaning agents in sufficient concentrations to release and remove poorly bound 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. The critical micelle concentration of a surfactant-containing solution is one way to evaluate its cleaning efficiency. The term "effective multipurpose solution" refers, in an analogous way, to a useful solution for daily chemical disinfection, storage and rinsing of a contact lens, whose solution is not intended to clean a contact lens, but whose solution is still It obviates the need for any other solution for daily cleaning, that is, that no other solution must necessarily be used together with the solution, or in combination with it, on a daily basis. Although such solutions may contain a surfactant or other agent that can inherently release or prevent deposits of the lens to some extent, such solutions are not necessarily capable of cleaning a contact lens. Effective multipurpose solutions are, therefore, only applicable to lenses used for a limited period of time, either for disposable or frequent replacement lenses. Traditionally, the multipurpose solutions of the market require a regime that involves the mechanical rubbing of the contact lens with the multipurpose solution, in order to obtain the required disinfection. That is, such a regime is necessary according to the governmental regulatory authorities (for example, the FDA or Food &; US Drug Administration) for a Chemical Disinfection System that is not qualified as a Chemical Disinfection Solution. The invention according to the present invention has the advantage that it is possible to formulate a product that, on the one hand, is soft enough to be used as a disinfectant solution and as a wetting agent at the same time and, on the other hand, is capable of achieving a biocidal performance disinfection for a Chemical Disinfection Solution according to the criteria established by the US FDA. for Products for the Care of Contact Lenses (May 1, 1997) that does not require a regime that involves the rubbing of the lenses (even though the rubbing of the lens may offer a greater elimination of microorganisms). In other words, the compositions according to the present invention can be optionally formulated to meet the requirements of the FDA or the ISO Independent Procedure for contact lens disinfection products. Consequently, it is possible to make formulations that offer greater compliance on the part of the patient and a greater universal appeal than traditional products for disinfection or for disinfection and cleaning. It is pointed out that the combination of the biguanide polymer and the polyquaternium according to the present invention provides greater efficacy, while not causing irritation or discomfort in the eye, this being an important and provocative concern in the technique of contact lens care. Therefore, greater amounts of the biguanide polymer, by itself, to achieve the same efficacy as the combination would result in greater eye irritation. Specifically, it has been seen that larger amounts of the biguanide polymer, by itself, to achieve the disinfection necessary for a Chemical Disinfection Solution would result in unacceptable ocular irritation. Even if a rub rate is recommended when using the solutions of the present invention, the higher biocidal activity can provide greater protection against infection, especially if the rubbing by the contact lens wearer is unsuitable or Ignore due to negligence or for ignoring product instructions. As indicated above, the combination of a biguanide polymer and a polyquaternium polymer has resulted in strong antimicrobial activity throughout the range of microorganisms typically associated with ophthalmic preservation and disinfection. Other advantages of the present disinfection system have been found. It has been found that the polyquaternium polymer used in the present invention inhibits the deposition of proteins on hydrophilic contact lenses and it has been found that the polymer stabilizes the biguanide polymer known as PHMB throughout the shelf life of the product. The polyquaternium polymer used in the present invention consists of 10 to 45 mole percent of a repeating unit with quaternary amine functionality which is the product of the copolymerization reaction of one or more comonomers selected from the group consisting of substituted vinylimidazoles or unsubstituted or their vinylimidazolium salts and their mixtures. By the term "repeating unit with quaternary amine functionality" it is meant here that the repeating unit consists of a quaternary amine group in which a positively charged nitrogen atom is covalently bound to four radicals (not hydrogen atom) ) and ionically bound to a negatively charged counter ion, such as chloride. The polyquaternium polymers of the present invention suitably have a weight average molecular weight Mp of about 5,000 to 5,000,000, preferably about 10,000 to 500,000, more preferably about 20,000 to 200,000. Polyquaternium polymers useful in the present invention may include, but without limitation, copolymers in which the repeating units with quaternary amine functionality are derived from 1-vinyl- and 3-methyl-1-vinylimidazole, 1-vinyl- and 3-methyl-1-vinylimidazole, their halides or other salt forms, their derivatives and mixtures of the above. Preferably, the polyquaternium polymer consists of 10 to 45 mole percent of reuppetitive units derived from a vinylimidazole or vi-nilimidazolium comonomer and 90 to 55 mole percent of repeating units derived from one or more neutral comonomers, such as vinylpyrrolidone. The polyquaternium polymer suitably includes an organic or inorganic anionic counter-ion of suitably suitable. A preferred counterion is chloride. It is possible to copolymerize up to 90%, preferably from 40% to 90%, molar of comonomers compatible in terms of copolymerization which have a quaternary amine functionality with the comonomers with quaternary amine functionality. Suitable comonomers include, but are not limited to, vinylpyrrolidone, acrylamide, acrylic acid, alkyl methacrylate, tertiary amines such as N, N-dialkylaminoalkyl acrylate and methacrylate, and mixtures compatible with copolymerization thereof. A preferred alkyl group has from 1 to 6 carbon atoms. More preferably, the alkyl groups are methyl, ethyl and / or butyl. Up to 25 mol%, preferably from 0% to 10 mol%, of the copolymerization-compatible comonomers having quaternary amine functionality, apart from the quaternary amine functionality monomers described above, can be copolymerized. Examples include the dimethyldiallyl salt. The polymerization techniques for the preparation of the polyquaternials used in the present invention are well known to those skilled in the art and there are many variations of such techniques practiced in a similar manner in commerce. There is a continuous commercial development of new variations of polyquaternium polymers that comply with the present invention; for example, various polymers having different combinations of the same or similar repeating units, different relative proportions of comonomers and / or different molecular weights are continuously being developed commercially. A particularly preferred polyquaternium copolymer is the "Luviquat® FC370 polymer (designation from the CTFA International Cosmetic Ingredient Dictionary, Polyquaternium-16, marketed by BASF, Ludwigshafen, Germany), which is the polymerization product of a comonomer mixture of which 70% is vinylpyrrolidone and 30% is vinylimidazolium metachloride, marketed as a composition with a solids content of approximately "40% by weight in water.

In the present composition, the polyquaternium copolymer is suitably present in an amount of less than 400 ppm active component, between about 10 and 400 ppm (between 0.001 and 0.04 weight percent of the composition), preferably between 25 and 300 ppm (between 0.0025 and 0.03 weight percent) in aqueous solution, more preferably between about 50 ppm and about 200 ppm (between 0.005 and 0.02 weight percent), more preferably about 100 ppm (0.01 weight percent). In a particular embodiment of the invention, the amount of copolymer is less than 100 ppm, between about 10 and 100 ppm or between 10 and 99 ppm (between 0.001 and 0.0099 weight percent). All ppm of the copolymer used herein are with respect to the amount of active component and the quantities of commercially available aqueous solutions of a copolymer that are used in the preparation of solutions according to the present invention must be adjusted accordingly. The solution for contact lenses contains from 80 to 99% by weight, preferably from 93 to 99% by weight, of water. The second component of the preservative / disinfectant system of the present invention is a polymeric biguanide (one or more) and water-soluble salts thereof, having the following formula: X 1 - [-Z-NH-C-NH-C-NH-] nZ-X2 (IV) NH NH where Z is an organic divalent bridging group which may be the same or different along the polymer, n is on average at least 3, preferably 5 to 20, and X1 and X2 are independently selected from among the NH2 and -NH-C-NH-CN groups. NH NH A preferred group of water-soluble polymeric biguanides will have number average molecular weights of at least 1,000 and, more preferably, will have number average molecular weights of 1,000 to 50,000. Suitable water-soluble salts of the free bases include, but are not limited to, the hydrochloride, borate, acetate, gluconate, sulfonate, tartrate and citrate salts. The biguanides described above and the methods of preparation are described in the literature. For example, U.S. Pat. No. 3,428,576 describes the preparation of polymeric biguanides from a diamine and its salts and a diamine salt of dicyanimide. The polymeric biguanides, together with the polyquaternium of the present invention, are effective at concentrations as low as 0.00001 percent by weight (0.1 ppm). The total concentration of a polymeric biguanide of Formula (IV) or (V) (independently of the particular salt form or of whether the free base is used) can be, in total, only about 0.000010 weight percent (0.10 ppm) and up to about 0.00030 weight percent- (3.0 ppm) in the present invention, either in the form of a water-soluble salt or as a free base. More preferred are polymeric hexamethylene biguanides (marketed as the hydrochloride salt by Zeneca, Wilmington, DE, under the trademark Cosmocil ™ CQ). Reference is also made to said polymers and their water-soluble salts such as polyaminopropylbiguanide (PAPB). The term "poly examethylenebiguanide" (PHMB), as used herein, is intended to encompass one or more biguanides having the following formula: X 1 - (CH 2) 3- [- (CH 2) 3 -NH-C-NH-C-NH- (CH2) 3-] n- (CH2) 3-X2 (V) NH NH where X1 and X2 are as defined above and n is from 1 to 500. Depending on the form in which the biguanides are prepared, the predominant compound which falls within the above formula may have different groups X1 and X2 or the same groups, with smaller amounts of other compounds in the formula. Such compounds are known and are described in US Pat. No. 4,758,595 and British Patent 1,432,345, the patents of which are hereby incorporated by reference. Preferably, water-soluble salts are compounds in which n has a mean value of 2 to 15, more preferably 3 to 12. The disinfectant solutions used in this invention may optionally contain other antimicrobial agents that are compatible. As used here, antimicrobial agents are defined as non-oxidative organic chemical agents that derive their antimicrobial activity through a chemical or physicochemical interaction with microbial organisms. Suitable antimicrobial agents are the polymeric quaternary ammonium salts used in ophthalmic applications, such as poly [dimethylamine-2-butene-1,4-diyl] chloride, [4-tris (2-hydroxyethyl) ammonium dichloride. [-2-butenyl-w- [tris (2-hydroxyethyl) ammonium] (chemical registration number 75345-27-6), generally available as Polyquaternium 1®, from ONYX Corporation, benzalkonium halides and bis (biguanides), such as salts of alexidine, free base of alexidine and salts of chlorhexidine. The antimicrobial agents used herein are preferably employed in the absence of mercury-containing compounds, such as thimerosal. The salts of alexidine and chlorhexidine may be organic or inorganic and are typically gluconates, nitrates, acetates, phosphates, sulfates, halides and the like. Typically, said agents can be used in concentrations of 0.00001% (w / v) or higher. The solutions of the present invention can be formulated in specific products for the care of contact lenses, such as wetting solutions, soaking solutions, cleaning and conditioning solutions, as well as solutions for multi-purpose contact lenses, etc. and its mixtures. When used in a cleaner, neutral (non-ionic) surfactants can impart additional cleaning and conditioning properties and are normally present in amounts of up to 15 weight percent. Suitable surfactants may be amphoteric, cationic, anionic to nonionic, which may be present (individually or in combination) in amounts of up to 15 percent, preferably up to 5 percent by weight of the composition or solution. The preferred surfactants are amphoteric or non-ionic surfactants, which, when used, impart cleaning and conditioning properties. The surfactant must be soluble in the solution for the care of the lens and non-irritating to the ocular tissues. Many nonionic surfactants consist of one or more chains or polymeric components having repeating oxyalkylene units (-0-R-), where R has from 2 to 6 carbon atoms. Preferred nonionic surfactants consist of block polymers of two or more different types of repeating oxyalkylene units, whose ratio of different repeating units determines the EHL of the surfactant. Suitable nonionic surfactants include the polyethylene glycol esters and fatty acids, for example, coconut, polysorbate, polyoxyethylene or polyoxypropylene ethers of higher alkanes (C 12 -C 8). Examples of the preferred class include polysorbate 20 (available under the trademark Tween® 20), polyoxyethylene (23) lauryl ether (Brij® 35), polyoxyethylene stearate (40) (Myrj® 52), polyoxyethylene stearate (25). ) propylene glycol (Atlas® G 2612). A particular non-ionic surfactant, consisting of a poly (oxypropylene) -poly (oxyethylene) adduct of ethylenediamine having a molecular weight of 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 the cleaning and conditioning of both soft and hard contact lenses when used in amounts of about 0.01 to about 15 weight percent. The name adopted by the CTFA Cosmetic Ingredient Dictionary for this group of surfactants is poloxamine. Said surfactants can be purchased from BASF Wyandotte Corp., Wyandotte, Michigan, under the trademark "Tetronic". An analogous series of surfactants, suitable for use in the present invention, is the series of poloxamers, which are block polymers of poly (oxyethylene) and poly (oxypropylene), available under the brand name "Pluronic" (marketed by BASF). Various other ionic, as well as amphoteric and anionic surfactants, suitable for the invention can be easily determined, in view of the above description, by McCutcheon's Detergents and Emulsifiers, North American Edition, McCutcheon Division, MC Publishing Co., Glen Rock, NJ 07452 , and the CTFA International Cosmetic In-gredient Handbook, published by The Cosmetic, Toiletry and Fragrance Association, Washington, DC Suitable amphoteric surfactants for use in a composition according to the present invention include materials of the type commercially available under the trade designation "Miranol". Another useful class of amphoteric surfactants is exemplified by cocoamidopropyl betaine, marketed by various sources. The above surfactants, when employed with a buffer enhancer, will generally be present in an amount of 0.01 to 5.0 percent (w / w), preferably 0.1 to 5.0 percent. Typically, the aqueous solutions of the present invention for the treatment of 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 a 2.5 percent solution of glycerol. Solutions are made to be substantially isotonic with physiological saline alone or in combination; otherwise, if they are simply mixed with sterile water and become hypotonic or hypertonic, the lenses will lose their desirable optical parameters. Correspondingly, excess saline can result in the formation of a hypertonic solution, which will produce stinging and eye irritation. The pH of the present solutions should be maintained in the range of 5.0 to 8.0, more preferably of about 6.0 to 8.0, more preferably of 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 Na2HP04, NaH2P04 and KH2P04) and mixtures thereof. Borate buffers are preferred, particularly to increase the effectiveness of the biguanides. In general, buffers will be used in amounts ranging from about 0.05 to 2.5 percent by weight and, preferably, between 0.1 and 1.5 percent. The disinfectant / preservative solutions of this invention preferably contain a borate buffer system, which contains one or more of boric acid, sodium borate, potassium tetraborate, potassium metaborate or mixtures thereof. In addition to buffering agents, in some cases it may be desirable to include sequestering agents in the present solutions in order to bind metal ions that might otherwise react with the lens and / or protein deposits and accumulate in the lens. Ethylenediaminetetraacetic 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 its salts, for example sodium salts. Still other more potent sequestering agents can be used to further inhibit the deposition of proteins on the lenses, for example the phosphonates described in WO 97/31659. The solutions of the present invention can be formulated in specific products for the care of contact lenses, such as wetting solutions, soaking solutions, cleaning and conditioning solutions, as well as lens care solutions of multipurpose type, etc. . and its mixtures. Said solutions can also be formulated for application to a contact lens while still in the eye, for example in the form of droplets. It may also be desirable to include water-soluble viscosity builders in the solutions of the present invention. Due to its demulcent effect, viscosity increasers tend to increase comfort for the wearer of the lens by means of a film on the surface of the lens that dampens the impact against the eye. Water-soluble viscosity increasing agents include cellulose polymers such as hydroxyethyl- or hydroxypropylcellulose, carboxymethylcellulose, povidone, polyvinyl alcohol and the like. Said viscosity increasers can be employed in amounts in the range of about 0.01 to about 4.0 weight percent or less. The present solutions may also include eventual demulcents. The aqueous solutions according to the present invention can be used effectively in the disinfection of contact lenses by any of the well-recognized methods. The lenses can 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 re-placed in the eye. As indicated above, contact lens wearers usually need to rub contact or contact lenses with their fingers (typically, between a finger and the palm or between the fingers) during the daily cleaning and / or disinfection of contact lenses. In one embodiment of the present invention, there is provided a method in which no rubbing is required during treatment with the claimed specified solution, between removal of the eye and repositioning of the lens after care of the lens. In a preferred embodiment of said method, a soft lens is disinfected, or disinfected and cleaned, with a multipurpose solution or an effective multipurpose solution, which is the only daily solution necessary to treat the lens outside the eye. Thus, in one embodiment of a method according to the invention, the described solution is used to treat a contact lens without rubbing, by a method consisting of: (a) soaking the contact lens that has not been rubbed with the solution for a specified period of time and (b) directly placing the treated contact lens in the user's eye. Typically, step (a) may involve immersing the contact lens in the solution. The soaking may eventually consist of shaking or similarly stirring a container of the solution by manual means. Preferably, step (a) involves a period of soaking the contact lens in a container in which the contact lens is completely submerged in the solution. By the term "direct placement" it is meant here to say that the solution is not diluted or rinsed from the lens with a different solution for contact lenses before the "insertion" or placement in the eye. In a particularly preferred embodiment, the method utilizes a multi-use solution that does not need rubbing or effective multipurpose solution, where no other solution or product is required for daily cleaning of the lens, with the possible exception of an enzymatic cleaner. In yet another embodiment of a method according to the present invention, the claimed solution is used to clean a soft lens which is a frequent replacement lens (FRF), planned to be replaced after no more than about three months of use in the eye , or planned to be replaced after no more than approximately 30 days of use in the eye, or planned to be replaced after no more than approximately two weeks in the eye. Preferably, the lens is made of a polymer consisting of about 0.0 to 5 mole percent of repeating units derived from methacrylic acid (AMA), 10 to 99 mole percent of repeating units of methacrylate derivatives hydroxyethyl and about 0.5 to 5 mole percent of crosslinking repeating units. The crosslinking repeating units can derive, for example, from monomers such as ethylene glycol dimethacrylate, divinylbenzene and trimethylolpropane trimetacrylate. The following Examples illustrate the compositions and methods of the present invention. EXAMPLE 1 This example illustrates an embodiment of the present invention for the treatment of contact lenses. The components of the composition are the following: TABLE 1 * A trademark of BASF, Ludwigshafen, Germany.

** Molecular Weight 14,500, Tetronic® 1107, an adduct of poly (oxypropylene) -poly (oxyethylene) block copolymer of ethylenediamine, a trademark of BASF Wyandotte Corp., Wyandotte, MI. Purified water is added to a stainless steel container up to approximately 85% of the total weight of the batch. The container is then placed on a hot plate equipped with a mixer and the solution is heated to about 60 ° C with mixing. The buffer and other salts are added one at a time, making sure that each one has dissolved before adding the next salt. The heat is then deactivated and Poloxamine 1107 is added with constant mixing. Luviquat® FC 370 polymer is added and mixed to dissolve it. The solution is allowed to cool, after an eventual autoclaving, and the PHMB solution is added through a sterile filter and water in sufficient quantity for the desired weight. The pH and osmolality of the formulation are measured and adjusted to a pH of 7.2 ± 0.1, if necessary. EXAMPLE 2 This Example illustrates the preparation of an aqueous disinfectant solution for contact lenses according to the present invention. TABLE 2 * A brand of BASF, Ludwigshafen, Germany. ** Molecular Weight 14,500, Tetronic® 1107, an adduct of poly (oxypropylene) -poly (oxyethylene) block copolymer of ethylenediamine, a trademark of BASF Wyandotte Corp., Wyandotte, MI. *** A brand of Monsanto Co., St. Louis, MI Purified water is added to a stainless steel container up to approximately 85% of the total weight of the batch. The container is then placed on a hot plate equipped with a mixer and the solution is heated to about 60 ° C with mixing. The buffer and other salts are added one at a time, making sure that each one has dissolved before adding the next salt. The heat is then deactivated and Poloxamine 1107 is added with constant mixing. Luviquat® FC 370 polymer is added and mixed to dissolve it. The solution is allowed to cool, after an eventual autoclaving, and the PHMB solution is added through a sterile filter and water in sufficient quantity for the desired weight. The pH and osmolality of the formulation are measured and adjusted to a pH of 7.2 ± 0.1, if necessary. COMPARATIVE EXAMPLE 3 This Comparative Example illustrates the preparation of an aqueous disinfectant solution for contact lenses without the polyquaternium polymer.

TABLE 3 * Molecular Weight 14,500, Tetronic® 1107, an adduct of poly (oxypropylene) -poly (oxyethylene) block copolymer of ethylenediamine, a trademark of BASF Wyandotte Corp., Wyandotte, MI. The solution can be prepared by gradually heating 80 percent of the water to 80 ° C, while disodium EDTA dissolves therein. The boric acid and sodium borate buffers are added to the heated disodium EDTA solution and dissolved. The sodium chloride is then added to the solution and dissolved, followed by the addition of the poloxamine surfactant. Hydrochloric acid and sodium hydroxide are added as necessary to obtain a pH of 7.2. The osmolality is 280-320 mOsm / kg. The solution is sterilized by autoclaving at 120 ° C for 45 minutes. After cooling the solution to room temperature, the biguanide polymer is added through a sterile filter, followed by the remainder of distilled water.

EXAMPLE 4 This Example illustrates the microbicidal efficacy of a solution according to the present invention. The antimicrobial efficacy was evaluated as follows. Microbial inocula 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 the appropriate agar and the cultures were harvested using "DPBST" (Dulbecco Phosphate Buffered Saline plus a 0.05% w / v Polysorbate 80) sterile or a suitable diluent and transferred to a vessel. suitable. Spore suspensions were filtered through sterile glass wool to remove the hypha fragments. Serratia marcescens filtrate, as appropriate (for example, through a 1.2 μ filter) to clarify the suspension. After collection, the suspension was centrifuged at no more than 5,000 x g for a maximum of 30 minutes at 20-25 ° C. The supernatant was poured and resuspended in DPBST or other suitable diluent. The suspension was centrifuged a second time and resuspended in DPBST or other suitable diluent. All inoculum suspensions of bacterial and fungal cells were adjusted with DPBST or other suitable diluent at 1 x 107-108 cfu / ml. The appropriate cell concentration can be estimated by measuring the turbidity of the suspension, for example using a spectrophotometer at a preselected wavelength, for example 490 nm. A tube containing a minimum of 10 ml of test solution per inoculum organism was prepared. Each tube of the test solution was inoculated with a suspension of the test organism sufficient to give a final count of 1.0 x 10 -10 cfu / ml, the volume of the inoculum not exceeding 1% of the volume of the sample. The dispersion of the inoculum was assured by vortexing the sample for at least 15 seconds. The inoculated product was stored at 10-25 ° C. Aliquots were taken in the amount of 1.0 ml of the inoculated product for the determination of the viable counts after certain periods of time of disinfection. The time points for the bacteria were, for example, 1, 2, 3 and 4 hours when the soaking time of the proposed regimen was 4 hours. Yeasts and molds were studied at an additional time point of _ >16 hours (4 times the time of the regime). The suspension was mixed well by vigorous vortexing for at least 5 seconds. The 1.0 ml aliquots removed at the specified time intervals were subjected to an appropriate series of decimal dilutions in validated neutralizing media. The suspensions were mixed vigorously and incubated for a suitable period of time to allow neutralization of the microbial agent. The viable count of organisms was determined in appropriate dilutions by preparing triplicate plates of agar "trypticase soy" (TSA) for bacteria and Sabouraud dextrose agar ("SDA") for molds and yeasts. Bacterial recovery plates were incubated at 30-35 ° C for 2-4 days. The yeasts were incubated at 20-30 ° C for 2-4 days and the mold recovery plates at 20-25 ° C for 3-7 days. The average number of colony forming units in the countable plates was determined. Reciptable plates refer to 30-300 ufe / plate for bacteria and yeast and 8 to 80 ufe / plate for molds, except when the colonies are observed only for the plates of the 10 ° or 10"1 dilution. microbial reduction at specified time points In order to demonstrate the suitability of the medium used for the growth of the test organisms and to obtain an estimate of the initial inoculum concentration, inoculum controls were made by dispersing an identical aliquot of the inoculum in a suitable diluent, for example DPBST, using the same volume of diluent used to suspend the organism as indicated above.After inoculation in a suitable neutralizing broth and incubation for an appropriate period of time, the inoculum control should be of 1.0 x 105 - 1.0 x 106 cfu / ml The solutions were evaluated based on the performance requirement referred to as "Procedure Independent for Disinfecting Products "(hereinafter referred to as the" independent test ") and based on the Disinfection Efficacy Test 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 US Food and Drug Administration, Division of Ophthalmic Devices. This performance requirement is comparable to current ISO standards for contact lens disinfection (reviewed in 1995). The independent test inoculates a disinfectant product with a standard inoculum from a representative range of microorganisms and establishes the degree of viability loss at predetermined time intervals comparable to those during which the product can be used. There is a primary performance criterion and a secondary performance criterion. The primary criterion for a given disinfection period (corresponding to a minimum potential recommended disinfection period) is that the number of bacteria recovered per ml must be reduced by an average value of not less than 3.0 logs within the given disinfection period . The number of molds and yeasts recovered per ml should be reduced by an average value of not less than 1.0 log within the minimum recommended disinfection time without an increase to four times the recommended minimum disinfection time. This Example shows the comparable antimicrobial efficacy of the solution of Example 2 above compared to the comparative solution of Comparative Example 3 above, using the test procedures described above, at time intervals of 1 hour, 2 hours, 3 hours and 4 hours for bacteria and 1 hour, 2 hours, 3 hours, 4 hours and 24 hours for fungi (yeasts and molds). The results are shown in Table 4 below.

TABLE 4 The results of the Independent ISO / CEN test indicate that the presence of Polyquaternium-16 increased the biocidal efficacy of the formulation against Candida albicans and Fusarium solani. Moreover, the composition according to the present invention (biguanide polymer and polyquaternium) is capable of meeting the requirements of the ISO Stand-Alone Procedure for Contact Lens Disinfecting Products at 4 o'clock. Comparatively, the comparative example (biguanide polymer alone) did not pass the independent test at 1 hour and 2 hours and only passed the test very accurately at 3 hours and 4 hours, indicating that the product would not disinfect from a reliably a contact lens against the standard test bacteria and fungi without a rubbing regime, especially in view of the fact that the amount of biguanide polymer in a product may decrease somewhat throughout its shelf life. Having described the invention together with specific examples thereof, this is illustrative only. Accordingly, many alternatives, modifications and variations will be apparent to those skilled in the art in light of the foregoing description and it is intended, therefore, to cover all such alternatives, modifications and variations insofar as they fall within the spirit and scope of the appended claims.

Claims (23)

Claims

1. An ophthalmologically safe solution for treating contact lenses, consisting of an aqueous solution constituted, before mixing, by the following components: (a) between about 10 and 400 ppm of a polyquaternium polymer consisting of 10 to 45 molar percent a repeating unit with quaternary amine functionality that is "the product of the copolymerization reaction of one or more comonomers selected from the group consisting of substituted or unsubstituted vinylimidazoles or their vinylimidazolium salts and mixtures thereof, which polymer has a weight average molecular weight from 5,000 to 5,000,000, and (b) a polymeric biguanide, in a total amount of between about 0.10 and about 3.0 ppm, having the formula: X 1 - [-Z-NH-C-NH-C -NH-] nZ-X2 II NH NH where Z is an organic divalent bridging group that can be the same or different along the polymer, n is on average at least 3 and X1 and X2 are independently selected from the groups -NH2 and -NH-C-NH-CN; II NH (c) an effective amount of a buffering agent; and (d) water in an amount of at least about 80% by weight.

2. The solution for contact lenses of claim 1, wherein said polyquaternium polymer is present in an amount of between 50 and 300 ppm.

3. The solution for contact lenses of claim 1, wherein said polyquaternium copolymer contains 20 to 40 percent molar of said repeating unit.

4. The solution for contact lenses of claim 1, wherein the polyquaternium copolymer is a copolymer of up to 90 mole percent of repeating units which are the reaction product of one or more comonomers selected from the group consisting of vinylpyrrolidone, acrylamide, Acrylic acid, methyl methacrylate and mixtures of these compatible in terms of copolymerization.

5. The solution for contact lenses of claim 1, wherein the polymer biguanide is a mixture of molecules with the formula: X 1 - (CH 2) 3 - t - (CH 2) 3 - NH - C - NH - C - NH - (CH 2) ) 3-] n- (CH2) 3-X2 II II NH NH where X1 and X2 are as defined above and n is on average from 5 to 20.

6. The contact lens solution of claim 1, further containing a neutral or non-ionic surfactant in an amount of 0.01 to 5.0 percent.

7. The contact lens solution of claim 6, wherein the surfactant is a neutral or non-ionic surfactant having a plurality of poly (oxyalkylene) chains, each of which poly (oxyalkylenes) contains repeating units (-0R) , where R is independently an alkylene having 2 to 6 carbon atoms.

8. The solution for contact lenses of claim 6, wherein the surfactant is a neutral or non-ionic surfactant containing a block copolymer of poly (ethylene oxide) and poly (propylene oxide) segments.

9. The solution for contact lenses of claim 1, wherein the amount of biguanide polymer is 0.2 to 2.0 ppm.

10. The contact lens solution of claim 9, wherein the amount of biguanide polymer is from about 0.5 ppm to about 1.5 ppm.

11. The solution for contact lenses of claim 1, wherein the buffering agent is a borate buffer system.

12. A method of treatment of a soft contact lens with a solution, whose method consists of: (a) wetting the lens in a solution, in such a way that an acceptable disinfection of the contact lens with the solution is obtained, whose solution consists of , in its formulation, in the following components: (i) a polyquaternium polymer, in a total amount between about 10 and 400 ppm, whose polyquaternium polymer consists of 10 to 45 mole percent of a repeating unit with amine functionality quaternary which is the product of the copolymerization reaction of one or more comonomers selected from the group consisting of substituted or unsubstituted vinylimidazoles or their vinylimidazolium salts and mixtures thereof, and whose polymer has a weight-average molecular weight of 5,000 to 5,000,000; (ii) a polymeric biguanide, in a total amount of between about 0.10 and about 3.0 ppm, having the following general formula: X1- [-Z-NH-C-NH-C-NH-] nZ- X2 ?? NH NH where Z is an organic divalent bridging group that can be the same or different along the polymer, n is on average at least 3 and X1 and X2 are independently selected from the groups -NH2 and -NH-C-NH-CN , and NH (iii) an effective amount of a buffering agent, and (b) directly placing the treated lens in the eye of the user, where (i) it is not required to rinse with a different solution before repositioning in the eye and ( ii) no other solution is required for daily disinfection of the lens.

13. The method of claim 12, wherein the method of treating the contact lens does not include rubbing the lens with the solution, as it is not required by the instructions for use of the solution.

14. The method of claim 12, wherein the solution is a disinfectant solution.

15. The method of claim 12, wherein the solution is a multi-purpose solution or effective multipurpose solution.

16. The method of claim 12, wherein said polyquaternium polymer is present in an amount of between 50 and 300 ppm.

17. The method of claim 12, wherein said polyquaternium copolymer contains 20 to 40 mole percent of said repeating unit with quaternary amine functionality.

18. The method of claim 12, wherein the polyquaternium copolymer is a copolymer of up to 90 mole percent of a repeating unit which is the reaction product of one or more comonomers selected from the group consisting of vinylpyrrolidone, acrylamide, acrylic acid, methyl methacrylate and mixtures of these compatible in terms of copolymerization.

19. The method of claim 12, wherein the polymeric biguanide is a mixture of polymeric biguanides having the following formula: X 1 - (CH 2) 3- ["(CH 2) 3-NH-C-NH-C-NH- ( CH2) 3-] n- (CH2) 3-X2 NH NH where X1 and X2 are as defined above and n is on average from 5 to 20.

20. The method of claim 12, wherein the solution is used to treat a lens that is made or planned to be replaced after no more than about 30 days of use.

21. The method of claim 12, wherein the lens is planned or made for replacement after no more than about 14 days of use.

22. The method of claim 12, wherein the solution is used to treat a lens that is made of a polymer consisting of about 0.0 to 5 mole percent of repeating units derived from methacrylic acid (AMA), a to 99 mole percent of repeating units derived from hydroxyethyl methacrylate and about 0.5 to 5 mole percent of crosslinking repeating units.

23. A kit for use by a user of contact lenses for disinfecting or disinfecting and cleaning a contact lens, which kit consists of: (a) a container with the ophthalmically safe disinfectant solution according to claim 1 and (b) instructions for use, which include indications for the user of the contact lens to carry out the method according to claim 12.