Contact lens treatment solution

Abstract

The present invention provides a contact lens treatment solution comprising (a) one or more of tris (hydroxymethyl) aminomethane, bis (2-hydroxyethyl) amino-tris (hydroxymethyl) methane, and salts thereof; and (b) one or more antimicrobial agents comprising one or more polyquaternium polymers.

Description

[0001] Priority

[0002] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 419,468, filed on October 26, 2022, entitled "Contact Lens Treating Solution", the content of which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION

[0003] An increasing number of people use contact lenses as a means of correcting vision and / or compensating for eye abnormalities. However, contact lenses typically must be worn and removed daily, and cleaned and disinfected between each wearing, which requires sterile solutions and containers.

[0004] During the wearing and normal handling of contact lenses, microorganisms as well as biomolecules such as lipids, proteins, etc. may adhere to the contact lenses and contaminate the solution and / or storage container. In addition, a tear film containing proteins, lipids and even microorganisms may cover the surface of the eye. Any of these components found in the tear film, on the outer surface of the eye or on the surrounding skin may be carried into the solution and / or storage container for the contact lenses. Then, the microorganisms that multiply in the solution and / or storage container can be transferred to the eye via the contact lenses and become pathogens that may cause eye infections, resulting in impaired vision and blindness. Various schemes have been developed to clean these deposits and disinfect the microorganisms. SUMMARY OF THE INVENTION

[0005] According to an illustrative embodiment, a contact lens treating solution comprises (a) one or more of tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane, and salts thereof; and (b) one or more antimicrobial agents comprising one or more polyquaternary ammonium polymers.

[0006] The contact lens treating solution of the illustrative embodiment advantageously exhibits a significantly improved disinfection efficacy against each of bacterial and fungal species after autoclaving. In addition, the contact lens treating solution of the illustrative embodiment is an improved contact lens treating solution, whereby polyquaternary ammonium polymers (such as polyquaternium-1) maintain their disinfection and preservative efficacy when subjected to elevated temperatures.

[0007] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraph, the contact lens treating solution contains tris(hydroxymethyl)aminomethane or a salt thereof as component (a).

[0008] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution contains bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane as component (a).

[0009] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution comprises (a) one or more of tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane, and its salts, in an amount of about 0.05 wt.% to about 2.0 wt.%, based on the total weight of the contact lens treatment solution; and (b) one or more antimicrobial agents comprising one or more polyquaternary ammonium polymers, in an amount of about 0.00001 wt.% to about 0.0010 wt.%, based on the total weight of the contact lens treatment solution.

[0010] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution comprises (a) one or more of tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane, and its salts, in an amount of about 0.1 wt.% to about 1.0 wt.%, based on the total weight of the contact lens treatment solution; and (b) one or more antimicrobial agents comprising one or more polyquaternary ammonium polymers, in an amount of about 0.00002 wt.% to about 0.0003 wt.%, based on the total weight of the contact lens treatment solution.

[0011] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the one or more polyquaternary ammonium polymers comprise from about 30 to about 50,000 quaternary amine functional repeating units.

[0012] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the one or more polyquaternary ammonium polymers have a weight average molecular weight Mw of from about 3,000 to about 5,000,000.

[0013] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the one or more polyquaternary ammonium polymers have a weight average molecular weight Mw of from about 5,000 to about 40,000.

[0014] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the one or more polyquaternary ammonium polymers are cationic.

[0015] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the one or more polyquaternary ammonium polymers comprise polyquaternium-1.

[0016] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution further comprises one or more surfactants.

[0017] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the one or more surfactants are selected from the group consisting of poloxamers, poloxamines, and mixtures thereof.

[0018] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the poloxamer is at least one of poloxamer di(meth)acrylate and reverse poloxamer di(meth)acrylate, and the poloxamine is at least one of poloxamine di(meth)acrylate and reverse poloxamine di(meth)acrylate.

[0019] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, based on the total weight of the contact lens treatment solution, the poloxamer is present in the contact lens treatment solution in an amount in the range of from about 0.001 wt.% to about 5.0 wt.%, and based on the total weight of the contact lens treatment solution, the poloxamine is present in the contact lens treatment solution in an amount in the range of from about 0.001 wt.% to about 5.0 wt.%.

[0020] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution further comprises one or more additional antimicrobial agents.

[0021] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the one or more additional antimicrobial agents are selected from the group consisting of polymeric biguanides or salts or free bases thereof, terpene compounds, branched-chain glycerol monoalkyl ethers, branched-chain glycerol monoalkylamines, branched-chain glycerol monoalkyl sulfides, fatty acid monoesters, amidoamine compounds, and combinations thereof, wherein the fatty acid monoesters comprise an aliphatic fatty acid moiety having six to fourteen carbon atoms and an aliphatic hydroxy moiety.

[0022] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution further comprises one or more comfort agents.

[0023] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the one or more comfort agents are selected from the group consisting of polyols, antioxidants, and complex carbohydrates.

[0024] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the polyol is one or more of glycerol and erythritol.

[0025] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution further comprises one or more polysaccharides.

[0026] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the one or more polysaccharides comprise one or more of an anionic polysaccharide and a nonionic polysaccharide.

[0027] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the one or more polysaccharides comprise one or more of the following: hyaluronic acid or its salts, chondroitin sulfate, chitosan, aloe vera, carboxymethyl cellulose, hemicellulose, hydroxypropyl methylcellulose, methylcellulose, and ethylcellulose.

[0028] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution further comprises one or more of the following: a chelating agent, a tonicity regulator, a buffer, a pH regulator, a viscosity regulator, and a emollient.

[0029] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution contains a borate buffer in an amount less than 0.3 wt.%.

[0030] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution does not contain a borate buffer.

[0031] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution is in the form of an eye care or contact lens care product selected from the group consisting of: eye drops, preserved contact lens solutions, contact lens cleaning solutions, and contact lens multi-purpose solutions.

[0032] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution is in the form of a multi-purpose solution or a lubricant eye drop.

[0033] According to another illustrative embodiment, a method of cleaning and disinfecting a contact lens comprises soaking the contact lens in a contact lens treatment solution for a period of time sufficient to clean and disinfect the contact lens, the contact lens treatment solution comprising (a) one or more of tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane, and its salts; and (b) one or more antimicrobial agents comprising one or more polyquaternary ammonium polymers.

[0034] According to yet another illustrative embodiment, a method for inhibiting bacterial adhesion to the surface of a contact lens includes contacting the surface of the contact lens with a contact lens treatment solution that includes (a) one or more of tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane, and salts thereof; and (b) one or more antimicrobial agents that include one or more polyquaternary ammonium polymers. DETAILED DESCRIPTION

[0035] The illustrative embodiments described herein relate to contact lens treatment solutions for cleaning, rinsing, storing, and / or disinfecting contact lenses. For example, "daily cleaners" containing various surfactants and disinfectants are recommended for daily use to remove most deposits and debris from contact lenses. In methods for preventing protein deposition, contact lens treatment solutions containing chemical reagents such as cationic polymers have been developed to prevent protein adhesion to the contact lens surfaces of rigid gas permeable (RGP) and soft contact lenses. In addition, for both types of rigid and soft contact lenses, a solution for wetting the lenses prior to insertion into the eye is typically required, although the formulation of the solution often varies based on their different properties. After a contact lens has been inserted into the eye, an ophthalmic solution for rewetting, lubricating, and / or enhancing the comfort of the contact lens wearer can be applied to the eye with the aid of a dropper dispenser. Hypotonic and isotonic solutions for improving the comfort of wearing soft contact lenses by direct addition to the contact lens in the eye typically contain a viscosity enhancer, a lubricant, a surfactant, a buffer, a preservative, and a salt.

[0036] Multi-purpose solutions are popular because of the convenience of using a single solution for cleaning, disinfecting, and conditioning contact lenses prior to insertion into the eye. Multi-purpose solutions are also designed to function as wetting agents without the need for rinsing, which means that for eye contact, the solution must be ophthalmically safe. This limits to some extent the types and concentrations of both the cleaning agents and the fungicides that can be used as preservatives or disinfectants in the solution, as they tend to irritate the eyes. In addition, the surfactant must not inhibit the wetting or conditioning function of the solution.

[0037] Polyquaternium-1 is a known disinfectant / antimicrobial agent and preservative used in various lens care solutions. Currently commercially available lens care products utilize combinations of polyquaternium-1 with borate, borate / citrate, borate / citrate-glycylglycine, and citrate buffer systems. However, when these buffer systems containing polyquaternium-1 are subjected to elevated temperatures, polyquaternium-1 may degrade, thereby reducing its disinfecting and preserving efficacy.

[0038] Accordingly, the non-limiting illustrative embodiments described herein overcome the foregoing problems by providing an improved contact lens treatment solution, whereby a polyquaternary ammonium polymer (such as polyquaternium-1) retains its disinfecting and preservative efficacy when subjected to elevated temperatures.

[0039] A contact lens treatment solution according to a non-limiting illustrative embodiment comprises at least (a) one or more of tris(hydroxymethyl)aminomethane (TRIS), bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane (bis-tris), and salts thereof; and (b) one or more antimicrobial agents comprising one or more polyquaternary ammonium polymers.

[0040] Tris(hydroxymethyl)aminomethane (2-amino-2-(hydroxymethyl)propane-1,3-diol) or a salt thereof is also known as tromethamine and is commonly referred to as tris, tris buffer, or tris base. In one non-limiting illustrative embodiment, the tris component is tris(hydroxymethyl)aminomethane in the base form. Bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane or a salt thereof is also commonly referred to as bis-tris.

[0041] In an illustrative embodiment, one or more of tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane, and salts thereof are present in the contact lens treatment solution in an amount in the range of about 0.05 wt.% to about 2.0 wt.%, based on the total weight of the contact lens treatment solution. In another embodiment, one or more of tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane, and salts thereof are present in the contact lens treatment solution in an amount in the range of about 0.1 wt.% to about 1.0 wt.%, based on the total weight of the contact lens treatment solution.

[0042] The contact lens treatment solution further contains one or more antimicrobial agents, the one or more antimicrobial agents comprising one or more polyquaternary ammonium polymers or salts or free bases thereof. In an illustrative embodiment, the one or more polyquaternary ammonium polymers may have quaternary amine functional repeating units in the range of about 30 units to about 50,000 units. In one exemplary embodiment, at least one polyquaternary ammonium polymer may have quaternary amine functional repeating units in the range of about 50 units to about 2,000 units. "Quaternary amine functional repeating unit" is understood herein to mean a repeating unit that contains a quaternary amine group, where the positively charged nitrogen atom is covalently bonded to four groups (no hydrogen atoms) and ionically bonded to a negatively charged counterion (such as chloride ion).

[0043] One or more polyquaternium polymers may have a weight average molecular weight Mw of from about 3,000 to about 5,000,000. In one exemplary embodiment, at least one polyquaternium polymer may have a weight average molecular weight Mw of from about 5,000 to about 500,000. In one exemplary embodiment, one or more polyquaternium polymers may have a weight average molecular weight Mw of from about 5,000 to about 200,000. In one exemplary embodiment, one or more polyquaternium polymers may have a weight average molecular weight Mw of from about 5,000 to about 50,000. In one exemplary embodiment, one or more polyquaternium polymers may have a weight average molecular weight Mw of from about 5,000 to about 30,000.

[0044] In non-limiting illustrative embodiments, polyquaternium polymers useful herein may include copolymers in which the quaternary amine functional repeating units are derived from one or more of the following types of monomers: N,N-dimethyl-N-ethyl-aminoethyl acrylate and methacrylate, 2-methacryloyloxyethyl trimethylammonium, N-(3-methacrylamidopropyl)-N,N,N-trimethylammonium, 1-vinyl and 3-methyl-1-vinylimidazole, N-(3-acrylamido-3-methylbutyl)-N,N,N-trimethylammonium, N-(3-methacryloyloxy-2-hydroxypropyl)-N,N,N-trimethylammonium, their halide or other salt forms, and their derivatives, such as those involving substitution, addition, or removal of alkyl groups (such as alkyl groups having 1 to 6 carbon atoms). The quaternary amine functional repeating units may also be obtained as a reaction product of two or more compounds, for example, by using a strong alkylating agent such as 1,4-dichloro-2-butene, which may react, for example, with 1,4-bis[dimethylamino]-2-butene and triethanolamine to produce a polymeric polyquaternary compound. The quaternary amine functional repeating units may also be prepared from other polymers, such as by reacting a trimethylammonium-substituted epoxide with the hydroxyl groups of hydroxyethyl cellulose. Suitable quaternary amine functional repeating units also include those found in polyionicenes formed by polycondensation reactions; in such repeating units, the nitrogen of the quaternary amine is integral with the polymer backbone and is located between alkylene, oxyalkylene, or other segments.

[0045] In an illustrative embodiment, the nitrogen in the quaternary amine functional repeating unit is part of a saturated or unsaturated heterocycle, such as a five - or six - membered ring. In one embodiment, the polyquaternary ammonium polymer is a copolymer of a vinyl imidazolium salt or a dimethyldiallylammonium salt. In one embodiment, up to about 90 mole % (e.g., from about 40 mole % to about 90 mole %) of a comonomer that is copolymerizable and compatible and does not have a quaternary amine functional group can be copolymerized with the quaternary amine functional comonomer. Suitable comonomers include, for example, vinyl pyrrolidone, acrylic acid, alkyl methacrylates, amides, and amines (such as acrylamide and N,N - dialkylaminoalkyl acrylates and methacrylates), hydroxyethyl cellulose, and their copolymerizable and compatible mixtures. In one embodiment, the alkyl group has 1 to 6 carbon atoms.

[0046] The polyquaternary ammonium polymers so defined are a well - known class of polymers, and many variants thereof are commercially available. For example, the current CTFA International Cosmetic Ingredient Dictionary includes polyquaternary ammoniums designated as polyquaternium - 1 to polyquaternium - 68, many of which can be used in the illustrative embodiments disclosed herein based on this teaching. The polymerization techniques for preparing such materials are also well - known to those skilled in the art, and many variants of such techniques are also similar in commercial practice. New variants of such polyquaternary ammonium polymers are constantly being commercially developed. For example, various polymers with different combinations of the same or similar repeating units, different relative proportions of comonomers, and / or different molecular weights are constantly being commercially developed.

[0047] In an illustrative embodiment, at least one of the one or more polyquaternary ammonium polymers is polyquaternium - 1. Polyquaternium - 1 can be obtained commercially under the trade name M from suppliers such as Stepan Inc., or can be synthesized by well - known methods, see for example U.S. Patent No. 4,027,020, the content of which is incorporated herein by reference. If desired, the polymer can have alternative end groups, such as hydroxyallyl end groups, aminoallyl end groups, and diene end groups, see for example U.S. Patent No. 7,705,112, the content of which is incorporated herein by reference.

[0048] The one or more polyquaternary ammonium polymers suitably include anionic organic or inorganic counterions suitable for ophthalmic use. In an illustrative embodiment, the preferred counterion is chloride.

[0049] In certain embodiments, the cationic oligomer or polymer is characterized by a charge density that can be determined by methods known in the art, such as colloid titration. In an illustrative embodiment, the charge density of the cationic oligomer or polymer is at least about 0.1 meq / g, in another embodiment at least about 2.5 meq / g, and in yet another embodiment at least about 5 meq / g.

[0050] In illustrative embodiments, one or more polyquaternary ammonium polymers are present in the contact lens treatment solution in an amount in the range of from about 0.00001 wt.% to about 0.001 wt.%, based on the total weight of the contact lens treatment solution. In illustrative embodiments, one or more polyquaternary ammonium polymers are present in the contact lens treatment solution in an amount in the range of from about 0.00001 wt.% to about 0.0005 wt.%, based on the total weight of the contact lens treatment solution. In another embodiment, one or more polyquaternary ammonium polymers are present in the contact lens treatment solution in an amount in the range of from about 0.00002 wt.% to about 0.0003 wt.%, based on the total weight of the contact lens treatment solution.

[0051] The contact lens treatment solution disclosed herein further contains one or more additional additives. In non-limiting illustrative embodiments, the contact lens treatment solution may further comprise one or more surfactants. Suitable surfactants include, for example, one or more poloxamers and / or poloxamines. Representative examples of suitable poloxamers are poloxamer block copolymers. A specific class of poloxamer block copolymers are those available under the trade name Pluronic (BASF Wyandotte Corp., Wyandotte, Mich.). Poloxamers include Pluronics and reverse Pluronics. Pluronics are a series of ABA block copolymers composed of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) blocks, generally as shown in Formula I:

[0052] HO(C 2 H 4 O) a (C 3 H 6 O) b (C 2 H 4 O) a H(I)

[0053] wherein a is independently at least 1, and b is at least 1.

[0054] Reverse Pluronics are a series of BAB block copolymers composed of poly(propylene oxide)-poly(ethylene oxide)-poly(propylene oxide) blocks, respectively, and are generally shown as Formula II:

[0055] HO(C 3 H 6 O) b (C 2 H 4 O) a (C 3 H 6 O) b H(II)

[0056] wherein a is at least 1, and b is independently at least 1. The poly(ethylene oxide) (PEO) block is hydrophilic, while the poly(propylene oxide) (PPO) block is hydrophobic in nature. The Pluronics in each series have different ratios of PEO and PPO, which ultimately determine the hydrophilic-lipophilic balance (HLB) of the material, i.e., changing the HLB value is based on changing the values of a and b, where a represents the number of hydrophilic poly(ethylene oxide) units (PEO) present in the molecule, and b represents the number of hydrophobic poly(propylene oxide) units (PPO) present in the molecule. In an illustrative embodiment, the Pluronics will have an HLB in the range of about 5 to about 24. In another embodiment, the Pluronics will have an HLB in the range of about 1 to about 5.

[0057] Pluronics and reverse Pluronics have terminal hydroxyl groups that can be end-functionalized. Examples of end-functionalized Pluronics as discussed herein are Pluronic dimethacrylates such as those disclosed in U.S. Patent Application Publication No. 2003 / 0044468 and U.S. Patent No. 9,309,357 (e.g., F127 dimethacrylate), the contents of these patents are incorporated herein by reference. Other examples include glycidyl-terminated copolymers of polyethylene glycol and polypropylene glycol disclosed in U.S. Patent No. 6,517,933, the content of this patent is incorporated herein by reference.

[0058] Functionalized Pluronics provide the desired reactivity at the ends of the molecule. The functional groups can be varied and are determined based on the intended use of the functionalized PEO- and PPO-containing block copolymer. That is, the PEO- and PPO-containing block copolymer is reacted to provide end-functional groups that are complementary to the monomer mixture for the intended formation of the device. The term block copolymer as used herein should be understood to mean that the Pluronics have two or more blocks in their polymer backbone.

[0059] In one embodiment, based on the total weight of the contact lens treatment solution, one or more poloxamines are present in the contact lens treatment solution in an amount in the range of from about 0.001 wt.% to about 5.0 wt.%. In another illustrative embodiment, based on the total weight of the contact lens treatment solution, one or more poloxamines are present in the contact lens treatment solution in an amount in the range of from about 0.005 wt.% to about 1.0 wt.%.

[0060] While poloxamers and reverse poloxamers are considered bifunctional molecules (based on the terminal hydroxyl groups), poloxamines are in a tetrafunctional form, i.e., molecules are tetrafunctional block copolymers terminated with primary hydroxyl groups and linked by a central diamine. Specific classes of poloxamine block copolymers are those available under the trade name Tetronic (BASF). Poloxamines include Tetronics and reverse Tetronics. Poloxamines have the general structure of Formula III below:

[0061]

[0062] wherein a is independently at least 1, and b is independently at least 1.

[0063] Functionalized poloxamines provide the desired reactivity at the termini of the molecule. The functional groups can vary and are determined based on the intended use of the functionalized PEO- and PPO-containing block copolymer. That is, the PEO- and PPO-containing block copolymer is reacted to provide terminal functional groups complementary to the monomer mixture from which the device is intended to be formed. The term block copolymer as used herein is understood to mean that the poloxamine has two or more blocks in its polymer backbone.

[0064] In one embodiment, based on the total weight of the contact lens treatment solution, one or more poloxamines are present in the contact lens treatment solution in an amount in the range of from about 0.001 wt.% to about 5.0 wt.%. In another illustrative embodiment, based on the total weight of the contact lens treatment solution, one or more poloxamines are present in the contact lens treatment solution in an amount in the range of from about 0.1 wt.% to about 1.2 wt.%.

[0065] In a non-limiting illustrative embodiment, the contact lens treatment solution may further comprise one or more additional antimicrobial agents. Suitable ophthalmically acceptable antimicrobial agents include, for example, polymeric biguanides or their salts or free bases, terpenes or their derivatives, branched-chain glycerol monoalkyl ethers, branched-chain glycerol monoalkyl amines, branched-chain glycerol monoalkyl sulfides, fatty acid monoesters, wherein the fatty acid monoesters comprise an aliphatic fatty acid moiety having from six to fourteen carbon atoms and an aliphatic hydroxy moiety, amidoamine compounds, etc. and combinations thereof. Antimicrobial agents suitable for use herein include chemicals that obtain their antimicrobial activity through chemical or physicochemical interactions with microbial organisms. These agents can be used alone or in combination.

[0066] Suitable polymeric biguanide antimicrobial agents include, for example, polymeric hexamethylene biguanide (PHMB) (commercially available from Zeneca, Wilmington, Del.), their polymers, and water-soluble salts. In an illustrative embodiment, the water-soluble polymeric biguanide for use herein may have a number average molecular weight of at least about 1,000 or a number average molecular weight of from about 1,000 to about 50,000. Suitable water-soluble salts of the free base include, for example, hydrochloride, borate, acetate, gluconate, sulfonate, tartrate, and citrate. Generally, the hexamethylene biguanide polymer (also known as polyaminopropyl biguanide (PAPB)) has a number average molecular weight of up to about 100,000. Such compounds are known and are disclosed in U.S. Patent No. 4,758,595, which is incorporated herein by reference.

[0067] PHMB is preferably described as a polymeric biguanide composition comprising at least three and preferably at least six biguanide polymers, which we refer to as PHMB-A, PHMB-CG, and PHMB-CGA, and whose general chemical structures are shown below.

[0068]

[0069] For each of these polymers, "n" represents the average number of repeating groups. In fact, for each of the polymers shown, there will be a distribution of polymer lengths. Previous synthetic routes for PHMB provided a polymeric biguanide composition having approximately 50% by weight of the polymeric composition as PHMB-CGA, i.e., capped with a cyanoguanidyl group at one end and an amine at the other end, approximately 25% by weight of PHMB-A, and approximately 25% by weight of PHMB-CG. Given this approximate weight ratio of the three main PHMB polymers described above, the percentage of cyanoguanidyl-capped ends is also approximately 50% of the total number of end groups. In the present application, we refer to this conventional polymeric biguanide composition as poly(hexamethylene biguanide) or PHMB.

[0070] May also be used as by 13Polymeric biguanide compositions for CNMR measurement that include less than about 18 mole % terminal amine groups. The polymeric biguanide compositions may also be characterized by a relative increase in the molar concentration of terminal guanidine groups or terminal cyanoguanidyl groups. For example, in one embodiment, the biguanide composition includes less than about 18 mole % terminal amine groups and about 40 mole % or more terminal guanidine groups. In another embodiment, the biguanide composition includes less than about 18 mole % terminal amine groups and about 55 mole % or more terminal guanidine groups.

[0071] This biguanide composition is designated PHMB-CG*. Polymeric biguanide compositions are also generally referred to as "hexamethylene biguanide", and those of ordinary skill in the art will recognize that it includes PHMB as well as PHMB-CG*.

[0072] Suitable terpene antimicrobial agents include, for example, any monoterpene, sesquiterpene, and / or diterpene or derivatives thereof. Acyclic, monocyclic, and / or bicyclic monoterpenes, sesquiterpenes, and / or diterpenes can be used, as well as those with a greater number of rings. As used herein, "derivatives" of terpenes are to be understood to mean terpene hydrocarbons having one or more functional groups, such as terpene alcohols, terpene ethers, terpene esters, terpene aldehydes, terpene ketones, etc., and combinations thereof. In this context, both trans and cis isomers are suitable. In one embodiment, the terpene and the terpene moiety in the derivatives can contain from 6 to about 100 carbon atoms or from about 10 to about 25 carbon atoms.

[0073] Representative examples of suitable terpene alcohol antimicrobial agents include verbenol, trans-piperitol, cis-2-pinanol, nopol, isoborneol, carbinol, piperitol, thymol, α-terpineol, terpinene-4-ol, menthol, 1,8-terpin, dihydro-terpineol, nerol, geraniol, linalool, citronellol, hydroxycitronellol, 3,7-dimethyloctanol, dihydro-myrcenol, tetrahydro-isocitronellol, perillyl alcohol, falcarindiol, etc., and mixtures thereof.

[0074] Representative examples of suitable terpene ether and terpene ester antimicrobial agents include 1,8-cineole, 1,4-cineole, isobornyl methyl ether, rose pyran, α-terpinyl methyl ether, menthofuran, trans-anethole, methyl chavicol, allo-ocimene diepoxide, limonene monoepoxide, isobornyl acetate, nonyl acetate, α-terpinyl acetate, linalyl acetate, geranyl acetate, citronellyl acetate, dihydro-terpinyl acetate, neryl acetate, etc., and mixtures thereof.

[0075] Representative examples of terpenic aldehydes and terpenic ketones antimicrobial agents include myrtenal, campholenal, perillaldehyde, citronellal, citral, hydroxycitronellal, camphor, verbenone, carvone, dihydrocarvone, carvone, piperitone, menthone, geranylacetone, pseudoisophorone, α-ionone, iso-pseudo-methylionone, n-pseudo-methylionone, iso-methylionone, n-methylionone, etc. and mixtures thereof. Any other terpene olefin having functional groups known in the art can be used herein in the compositions of the present invention.

[0076] In illustrative embodiments, suitable terpenes or their derivatives as antimicrobial agents include, but are not limited to, tricyclene, α-pinene, terpinolene, carveol, pentanol, nerol, β-santalol, citral, pinene, nerol, b-ionone, caryophyllene (from cloves), guaiacol, anisaldehyde, cedrol, linalool, d-limonene (orange oil, lemon oil), longifolene, anisyl alcohol, patchouli alcohol, α-cadinene, 1,8-cineole, ρ-cymene, 3-carene, ρ-8-methane, trans-menthone, borneol, α-fenchol, isoamyl acetate, terpin, cinnamaldehyde, ionone, geraniol (from roses and other flowers), myrcene (from bayberry wax, bay oil and verbena), nerol, citronellol, carvacrol, eugenol, carvone, α-terpineol, anethole, camphor, menthol, limonene, nerolidol, farnesol, phytol, carotene (vitamin A 1 )), squalene, thymol, tocotrienol, perilla alcohol, borneol, selinene, carene, terpene, linalool, 1-terpene-4-ol, zingiberene (from ginger), etc. and mixtures thereof.

[0077] In illustrative embodiments, a suitable branched-chain glycerol monoalkyl ether antimicrobial agent is 3-[(2-ethylhexyl)oxy]-1,2-propanediol (EHOPD). In another embodiment, a suitable branched-chain glycerol monoalkylamine antimicrobial agent is 3-[(2-ethylhexyl)amino]-1,2-propanediol (EHAPD). In another embodiment, a suitable branched-chain glycerol monoalkyl sulfide antimicrobial agent is 3-[(2-ethylhexyl)thio]-1,2-propanediol (EHSPD). In yet another embodiment, the ophthalmic composition comprises any mixture of EHOPD, EHAPD, and EHSPD antimicrobial agents. The chemical structures of EHOPD, EHAPD, and EHSPD are provided below.

[0078]

[0079] EHOPD is also known as octoxyglycerin and is sold under the trade name For sale: SC50 (Schülke & Mayr). EHOPD is a branched glycerol monoalkyl ether, which is known to be mild to the skin and exhibits antibacterial activity against a variety of Gram-positive bacteria such as Micrococcus luteus, Corynebacterium aquaticum, Corynebacterium flavescens, Corynebacterium callunae, and Corynebacterium nephredi. Therefore, EHOPD is used in various skin deodorant preparations at a concentration of about 0.2% to 3% by weight. EHAPD can be prepared from 2-ethylhexylamine and 2,3-epoxy-1-propanediol using chemistry well-known to those of ordinary skill in the art. EHSPD can be prepared from 2-ethylhexyl mercaptan and 2,3-epoxy-1-propanediol using chemistry well-known to those of ordinary skill in the art.

[0080] Suitable fatty acid monoester antimicrobials include, for example, those fatty acid monoesters comprising an aliphatic fatty acid moiety having from six to fourteen carbon atoms and an aliphatic hydroxy moiety. The term "aliphatic" refers to a straight-chain or branched-chain, saturated or unsaturated hydrocarbon having from six to fourteen carbon atoms. In illustrative embodiments, the aliphatic fatty acid moiety is a straight-chain, saturated or unsaturated hydrocarbon having from eight to ten carbons. In another embodiment, the aliphatic fatty acid moiety is a branched-chain, saturated or unsaturated hydrocarbon having from eight to ten carbons.

[0081] The aliphatic hydroxy moiety of the fatty acid monoester can be any aliphatic compound having at least one hydroxy group. Additionally, the aliphatic hydroxy moiety can have from three to nine carbons. The aliphatic hydroxy moiety can include, but is not limited to, propylene glycol, glycerol, polyalkylene glycols such as polyethylene glycol or polypropylene glycol, cyclic polyols such as sorbitol, glucose, mannose, sucrose, fructose, fucose, and inositol and their derivatives, and linear polyols such as mannitol and sorbitol and their derivatives, etc., and mixtures thereof.

[0082] Suitable amidoamine antimicrobials include, for example, those amidoamines having the following general formula:

[0083] R 15 -(OCH 2 CH 2 ) m -X-(CH 2 ) n -Y

[0084] wherein R 15 is C 6 -C 30Saturated or unsaturated hydrocarbons, including, for example, straight-chain or branched, substituted or unsubstituted alkyl, alkylaryl or alkoxyaryl groups; m is from zero to 16; n is from 2 to 16; X is –C(O)-NR 16 - or –R 16 N-C(O)-; Y is –N(R 17 ) 2 , where R 16 and R 17 are each independently hydrogen, C 1 -C 8 saturated or unsaturated alkyl or hydroxyalkyl, or a pharmaceutically acceptable salt thereof.

[0085] As will be readily appreciated by those skilled in the art, some of the amidoamines used in the contact lens treatment solutions disclosed herein are commercially available. For example, myristamidopropyl dimethylamine is available under the trade name from Alcon Inc. (Fort Worth, Tx.); lauramidopropyl dimethylamine is available under the trade name L-13 from Inolex Chemical Company (Philadelphia, Pa.); stearamidopropyl dimethylamine is also available as S-13 from Inolex Chemical Company. The above amidoamines can be synthesized according to known techniques, including those described in U.S. Patent No. 5,573,726, the content of which is incorporated herein by reference.

[0086] In one non-limiting illustrative embodiment, one or more of the foregoing antimicrobial agents can be used in an amount that will at least partially reduce the microbial population in the contact lens treatment solution employed. If desired, one or more antimicrobial agents can be used in a disinfecting amount, which will reduce the microbial bioburden by at least two log orders in, for example, four hours and / or by one log order in one hour. In one non-limiting illustrative embodiment, the disinfecting amount is the amount that will eliminate the microbial burden on the contact lens when used in a recommended soak time protocol (FDA Chemical Disinfection Efficacy Test - Contact Lens Solution Draft Guidelines, July 1985).

[0087] In one embodiment, based on the total weight of the contact lens treatment solution, one or more additional antimicrobial agents are present in the contact lens treatment solution in an amount in the range of from about 0.00005 wt.% to about 0.15 wt.%. In another illustrative embodiment, based on the total weight of the contact lens treatment solution, one or more antimicrobial agents are present in the contact lens treatment solution in an amount in the range of from about 0.0001 wt.% to about 0.001 wt.%.

[0088] In one non-limiting illustrative embodiment, the contact lens treatment solution disclosed herein may further comprise one or more polysaccharides. In illustrative embodiments, the polysaccharide comprises an anionic polysaccharide. Suitable anionic polysaccharides include, for example, hyaluronic acid or its salts, such as sodium hyaluronate or potassium hyaluronate, chondroitin sulfate, chitosan, aloe vera, and carboxymethyl cellulose. In illustrative embodiments, the polysaccharide comprises a non-ionic polysaccharide. Suitable non-ionic polysaccharides include, for example, hemicellulose, hydroxypropyl methylcellulose, methylcellulose, and ethylcellulose.

[0089] In illustrative embodiments, based on the total weight of the contact lens treatment solution, one or more polysaccharides are present in the contact lens treatment solution in an amount in the range of from about 0.01 wt.% to about 0.02 wt.%.

[0090] In one non-limiting illustrative embodiment, the contact lens treatment solution may further comprise one or more comfort agents. Suitable comfort agents include, for example, polyols, antioxidants, and complex carbohydrates. Suitable polyols include, for example, glucose, mannitol, erythritol, sorbitol, polyvinyl alcohol, maltose, glycerol, and trehalose. Suitable antioxidants include, for example, α-tocopherol and other water-soluble vitamin E moieties, ascorbic acid, ascorbyl glucoside, cysteine, carnosol, carnitine, epicatechin, gallic acid, resveratrol, ellagic acid, pycnogenol, lycopene, astaxanthin, coenzyme Q10, caffeic acid, hydroquinone monomethyl ether, and butylated hydroxytoluene. Suitable complex carbohydrates include, for example, tremella polysaccharide and carboxymethyl cellulose.

[0091] In one embodiment, based on the total weight of the contact lens treatment solution, one or more comfort agents are present in the contact lens treatment solution in an amount in the range of from about 0.1 wt.% to about 2.0 wt.%. In another illustrative embodiment, based on the total weight of the contact lens treatment solution, one or more comfort agents are present in the contact lens treatment solution in an amount in the range of from about 0.2 wt.% to about 1.5 wt.%.

[0092] The contact lens treatment solution disclosed herein may further contain one or more other components that are commonly present in contact lens treatment solutions. In non-limiting illustrative embodiments, the contact lens treatment solution disclosed herein may further contain, for example, chelating agents; tonicity regulators; buffers; pH regulators, viscosity regulators, emollients, etc., and these components help to make the contact lens treatment solution more comfortable for the user and / or more effective for its intended use.

[0093] In one illustrative embodiment, one or more suitable chelating components may be employed to assist in removing lipid and protein deposits from the lens surface after daily use. Typically, the contact lens treatment solution will include a relatively low amount, such as about 0.005% to about 0.20 (w / v) of ethylenediaminetetraacetic acid (EDTA) or its corresponding metal salts, such as the disodium salt Na 2 EDTA.

[0094] Suitable tonicity regulators include, for example, glucose, calcium chloride, and magnesium chloride, etc. and mixtures thereof. These tonicity regulators are typically used alone in an amount of about 0.01% w / v to about 2.5% w / v. In one embodiment, the tonicity regulator is used in an amount in the range of about 0.2% w / v to about 1.5% w / v. The tonicity regulator may be used in an amount that provides a final effective tonicity value of at least about 150 mOsm / kg. In one illustrative embodiment, the tonicity regulator is used in an amount that provides a final effective tonicity value of about 150 mOsm / kg to about 420 mOsm / kg. In one illustrative embodiment, the tonicity regulator is used in an amount that provides a final effective tonicity value of about 150 mOsm / kg to about 350 mOsm / kg. In one illustrative embodiment, the tonicity regulator is used in an amount that provides a final effective tonicity value of about 160 mOsm / kg to about 320 mOsm / kg.

[0095] In non-limiting illustrative embodiments, the contact lens treatment solution disclosed herein contains an amount of borate buffer that is less than 0.3 wt.%. In one non-limiting illustrative embodiment, the contact lens treatment solution disclosed herein does not contain borate buffer. In another non-limiting illustrative embodiment, the contact lens treatment solution disclosed herein does not contain sodium salt buffer (e.g., NaCl). In another non-limiting illustrative embodiment, the contact lens treatment solution disclosed herein contains an amount of borate buffer that is less than 0.3 wt.%, and does not contain sodium salt buffer (e.g., NaCl). In another non-limiting illustrative embodiment, the contact lens treatment solution disclosed herein does not contain borate buffer and sodium salt buffer (e.g., NaCl).

[0096] In non-limiting illustrative embodiments, the contact lens treatment solutions disclosed herein can be formulated for direct instillation into the eye, including, for example, eye drop solutions and eye lubricants for rewetting contact lenses during wear and those that are also eligible as multi-purpose solutions. In non-limiting illustrative embodiments, the contact lens treatment solutions disclosed herein can be formulated as compositions for indirect instillation into the eye, such as contact lens treatment solutions for treating contact lenses prior to placing the lenses in the eye or packaging solutions for storing the lenses.

[0097] The contact lens treatment solutions of the illustrative embodiments are physiologically compatible. Specifically, the contact lens treatment solutions should be "ophthalmically safe" for use with contact lenses, which means that contact lenses treated with the contact lens treatment solutions are generally suitable and safe to be placed directly on the eye without rinsing, that is, the contact lens treatment solutions are safe and comfortable for daily contact with the eye via the contact lenses that have been wetted with the solution. According to ISO (International Organization for Standardization) standards and U.S. Food and Drug Administration (FDA) regulations, ophthalmically safe compositions have an osmolarity and pH that are compatible with the eye and contain non-cytotoxic materials and amounts thereof. The composition should be sterile because the absence of microbial contaminants in the product prior to release must be statistically proven to the extent required for such products.

[0098] In illustrative embodiments, the pH of the contact lens treatment solutions disclosed herein can be a pH maintained within the range of from about 4.0 to about 9.0, or from about 5.0 to about 8.0, or from about 6.0 to about 8.0, or from about 6.5 to about 7.8. In another illustrative embodiment, the pH of the contact lens treatment solutions disclosed herein can be a pH greater than or equal to about 7.

[0099] In an illustrative embodiment, the tonicity of the contact lens treatment solution disclosed herein can be a tonicity in the range of at least about 150 mOsm / kg, or at least about 200 mOsmol / kg and up to about 420 mOsmol / kg. In another illustrative embodiment, the tonicity of the contact lens treatment solution disclosed herein can be a tonicity of about 150 mOsm / kg to about 420 mOsm / kg. In another illustrative embodiment, the tonicity of the contact lens treatment solution disclosed herein can be a tonicity of about 150 mOsm / kg to about 350 mOsm / kg. In another illustrative embodiment, the tonicity of the contact lens treatment solution disclosed herein can be a tonicity of about 160 mOsm / kg to about 320 mOsm / kg. In an illustrative embodiment, the tonicity of the contact lens treatment solution disclosed herein can be a tonicity of about 300 mOsm / kg to about 400 mOsm / kg. In another illustrative embodiment, the tonicity of the contact lens treatment solution disclosed herein can be a tonicity of about 350 mOsm / kg to about 400 mOsm / kg. The contact lens treatment solution is substantially isotonic or hypertonic (e.g., slightly hypertonic) and is ophthalmically acceptable.

[0100] In a non-limiting illustrative embodiment, the contact lens treatment solution disclosed herein can be formulated as a "multi-purpose solution". The multi-purpose solution can be used for cleaning, disinfecting, storing, and rinsing the lenses, especially soft contact lenses. The multi-purpose solution does not preclude the possibility that some wearers (e.g., wearers who are particularly sensitive to chemical disinfectants or other chemical agents) may prefer to rinse or moisten the contact lenses with another solution (e.g., a sterile saline solution) before inserting the lenses. The term "multi-purpose solution" also does not preclude the possibility of periodic cleaners that are not used daily or supplementary cleaners for further removal of proteins, such as enzyme cleaners, which are typically used once a week. The term "clean" means that the solution contains one or more agents at a concentration sufficient to loosen and remove lens deposits and other contaminants that are loosely held on the surface of the contact lens, which can be used in combination with digital manipulation (e.g., manually rubbing the lens with the solution) or an auxiliary device that agitates the solution in contact with the lens, such as a mechanical cleaning aid.

[0101] Traditionally, multi-purpose solutions on the market have required a protocol involving mechanically rubbing the lens with the multi-purpose solution in order to provide the required disinfection and cleaning. Government regulatory agencies (e.g., the FDA) require such protocols for chemical disinfection systems that do not meet the criteria for chemical disinfection solutions. In an illustrative embodiment, a cleaning and disinfection solution can be formulated that is capable of providing improved cleaning and disinfection on the one hand and is mild enough to be used as a wetting agent, such as for use as eye drops, on the other hand. In another illustrative embodiment, the contact lens treatment solution disclosed herein is formulated to meet the requirements of the FDA or ISO independent procedures for contact lens disinfection products.

[0102] Thus, in a non-limiting illustrative embodiment, a method of cleaning and disinfecting contact lenses includes soaking the contact lenses in a contact lens treatment solution disclosed herein for a period of time sufficient to clean and disinfect the contact lenses. Suitable periods of time can include, for example, at least about 30 seconds, or from about 2 to about 12 hours, or from about 2 to about 4 hours.

[0103] In an illustrative embodiment, a rubbing protocol can be used, which will include, for example, adding a few drops of the contact lens treatment solution disclosed herein to each side of the lens and then gently rubbing the surface between the fingers for about 3 to about 10 seconds. The lens can then optionally be rinsed and subsequently immersed in the contact lens treatment solution in a lens storage case for a suitable period of time, such as a few minutes or hours, such as at least two hours. The lens is removed from the lens storage case and repositioned on the eye.

[0104] The type of contact lens in contact with the contact lens treatment solution disclosed herein is not critical and any contact lens is contemplated. Representative examples of such lenses include, but are not limited to, soft contact lenses, such as soft hydrogel lenses; soft non-hydrogel lenses, etc., hard contact lenses (such as rigid gas permeable lens materials), etc., rigid gas permeable (RGP) lenses, intraocular lenses, overlay lenses, etc. As understood by those skilled in the art, a lens is considered "soft" if it can be folded back onto itself without breaking. Any material known for use in the production of contact lenses can be used herein. For example, the contact lens treatment solution can be used with (1) a hard lens formed from a material prepared by acrylate polymerization, such as poly(methyl methacrylate) (PMMA), (2) an RGP lens formed from silicone acrylate and fluorosilicone methacrylate, and (3) a soft hydrogel contact lens made from a hydrogel polymeric material (such as silicone hydrogel), where a hydrogel is defined as a crosslinked polymer system containing water in an equilibrium state.

[0105] Typically, hydrogels exhibit excellent biocompatibility properties, i.e., properties that are biologically or biochemically compatible by not producing toxicity, damage, or immune responses in living tissues. Representative conventional hydrogel contact lens materials are prepared by polymerizing a monomer mixture comprising at least one hydrophilic monomer (e.g., (meth)acrylic acid, 2-hydroxyethyl methacrylate (HEMA), glycerol methacrylate, N,N-dimethylacrylamide, and N-vinylpyrrolidone (NVP)). In the case of silicone hydrogels, in addition to the hydrophilic monomers, the monomer mixture from which the copolymer is prepared further comprises a silicone-containing monomer. Typically, the monomer mixture will also include a crosslinking monomer, such as ethylene glycol dimethacrylate, tetraethylene glycol dimethacrylate, and methacryloyloxyethyl vinyl carbonate. Alternatively, a silicone-containing monomer or a hydrophilic monomer can be used as a crosslinking agent.

[0106] The following examples are provided to enable those skilled in the art to practice the invention and are illustrative only. The examples should not be construed as limiting the scope of the illustrative embodiments as defined in the claims. In the examples, the following abbreviations were used.

[0107] TRIS: Tromethamine buffer.

[0108] Bis-Tris: Bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane.

[0109] Na 2 EDTA: Disodium ethylenediaminetetraacetate.

[0110] AMP-95: Aqueous solution of 95% 2-amino-2-methyl-1-propanol.

[0111] PAPB: Polyaminopropyl biguanide.

[0112] Polyquaternium-1: A polyquaternium polymer represented by the following structure:

[0113]

[0114] Examples 1 to 4 and Comparative Examples A to E

[0115] Contact lens treatment solutions were prepared by mixing the following components listed in Table 1.

[0116] Table 1

[0117]

[0118] Comparative Examples A to E

[0119] Contact lens treatment solutions were prepared by mixing the following components listed in Table 2.

[0120] Table 2

[0121]

[0122] Test

[0123] The degradation of PQ-1 was evaluated by comparing the disinfection efficacy of an autoclaved aqueous solution and a non-autoclaved aqueous solution. Autoclaving was performed at 121 °C for 30 minutes. The contact lens treatment solutions of Examples 1 to 4 and Comparative Examples A to E were tested in a modified ISO 14729 test with a 4-hour disinfection time to determine their efficacy against three bacterial species (Staphylococcus aureus, S.a., Pseudomonas aeruginosa, P.a., and Serratia marcescens, S.m.) and one fungal species (Fusarium solani, F.s.) with 10% organic soil.

[0124] The independent biocidal tests were conducted as follows. Microbial challenge inocula were prepared using Staphylococcus aureus (ATCC 6538), Pseudomonas aeruginosa (ATCC 9027), Serratia marcescens (ATCC 13880), and Fusarium solani (ATCC 36031). The challenge microorganisms were transferred to the recommended agar and incubated for an appropriate duration and temperature. Cultures were harvested using sterile Dulbecco's phosphate buffered saline plus 0.05% w / v polysorbate 80 (DPBST) or a suitable diluent and transferred to a suitable container. The spore suspension was filtered through sterile glass wool to remove hyphal fragments. Serratia marcescens (where appropriate) was filtered through a 1.2 μm filter to clarify the suspension. After harvesting, the suspension was centrifuged at a temperature of 20 - 25 °C at no more than 5000 x g for up to 30 minutes. The supernatant was decanted and the pellet was resuspended in DPBST or other suitable diluent to a concentration of 1X10 7 to 1X10 8 cfu / ml.

[0125] The appropriate microbial concentration can be estimated by measuring the turbidity of the suspension, for example, using a spectrophotometer at a preselected wavelength (e.g., 490 nm). Prepare a test tube that contains at least 10 mL of the test solution for each challenge microorganism. An inoculum control (IC) was prepared by dispersing an equal aliquot of the inoculum into a suitable diluent (DPBST) using the same volume as in the test sample. At the start of the test (T = 0), the IC of each challenge microorganism was serially diluted and inoculated onto a suitable agar. Each test solution tube to be tested was inoculated with an amount sufficient to provide 1x10 5 to 1x106 The test microbial suspension with a final count of cfu / mL, and the volume of the inoculum does not exceed 1% of the sample volume. Ensure the dispersion of the inoculum by thoroughly mixing the sample (e.g., by vortexing each test tube for at least 5 seconds). Store the inoculated product at 20 °C to 25 °C. After a certain period of disinfection, take a 1.0 mL aliquot of the inoculated product for determining the viable count.

[0126] Thoroughly mix the suspension by vortexing vigorously for at least 5 seconds. A 1.0 mL aliquot taken at the specified time intervals is subjected to a series of appropriate ten-fold dilutions in a validated neutralizing medium. Vigorously mix the suspension and incubate for an appropriate period (at least 10 minutes and not more than 1 hour before plating) to allow the neutralization of the microbial agent. Determine the viable count of the microorganisms at the appropriate dilution by preparing two plates of tryptic soy agar (TSA) for bacteria and sabouraud dextrose agar (SDA) for molds and yeasts. Incubate the bacterial recovery plates at 30 °C to 35 °C for two to four days. Incubate the yeast recovery plates at 20 °C to 25 °C or 30 °C to 35 °C for three to five days. Incubate the mold recovery plates at 20 °C to 25 °C for four to seven days. Determine the average number of colony-forming units (cfu) on the countable plates. Countable plates refer to 30 to 300 cfu / plate for bacteria and yeasts, and 8 to 80 cfu / plate for molds, unless colonies are observed only on the plates at the 10° or 10 1 dilution. Then calculate the microbial reduction at the specified time points. To demonstrate the suitability of the medium for testing the growth of microorganisms and to provide an estimate of the initial inoculum concentration, prepare an inoculum control by dispersing the same aliquot of the inoculum into a suitable diluent for suspending the above microorganisms. After inoculating and incubating in a validated neutralizing broth for an appropriate period, the inoculum control must be between 1.0x10 5 and 1.0x10 6 cfu / mL.

[0127] The log reduction values for the 4-hour disinfection efficacy test of the contact lens treatment solutions of Examples 1 to 4 and Comparative Examples A to D are shown in Table 3 below.

[0128] Table 3

[0129] S.a. P.a. S.m. F.s. Example 1, not autoclaved 3.5 >4.6 4.8 3.2 Example 1, autoclaved 3.4 3.6 2.8 2.8 Example 2, not autoclaved 3.2 4.6 3.6 2.5 Example 2, autoclaved 2.3 4.4 3.3 2.2 Example 3, not autoclaved 2.3 <1.1 <1.3 <1.7 Example 3, autoclaved 2.0 <1.1 <1.3 <1.7 Example 4, not autoclaved 3.7 >4.6 4.8 4.2 Example 4, autoclaved 2.2 3.1 3.3 2.5 Comparative Example A, not autoclaved 2.8 3.0 3.5 2.9 Comparative Example A, autoclaved <1.0 <1.1 <1.3 <1.4 Comparative Example B, not autoclaved 3.5 >4.6 2.5 3.8 Comparative Example B, autoclaved <1.1 <1.1 <1.3 <1.4 Comparative Example C, not autoclaved 3.9 4.3 4.5 <1.7 Comparative Example C, autoclaved <1.2 <1.1 <1.3 <1.7 Comparative Example D, not autoclaved 4.1 4.4 4.3 <1.7 Comparative Example D, autoclaved <1.2 <1.1 <1.3 <1.7 Comparative Example E, not autoclaved 3.0 4.6 2.2 <1.7 Comparative Example E, autoclaved <1.2 <1.1 <1.3 <1.7

[0130] Compared with the contact lens treatment solutions of Comparative Examples A to E, the contact lens treatment solutions of Examples 1 to 4 showed significantly improved disinfection efficacy against each of the bacterial and fungal species after autoclaving. In addition, Examples 3 and 4 showed that a sufficient amount of one or more of tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane and its salts and each of one or more polyquaternary ammonium polymers needs to be added to the contact lens treatment solution to achieve the desired antimicrobial efficacy.

[0131] Examples 5 and 6

[0132] A contact lens treatment solution was prepared by mixing the following components listed in Table 4.

[0133] Table 4

[0134]

[0135] Comparative Examples F and G

[0136] A contact lens treatment solution was prepared by mixing the following components listed in Table 5.

[0137] Table 5

[0138] Ingredient (% w / w) Comparative Example F Comparative Example G Glycylglycine 0.30 - Dipotassium hydrogen phosphate 0.76 - Boric acid - 0.60 Sodium citrate - 0.60 <![CDATA[Sodium 2 EDTA]]> 0.10 0.05 Sodium chloride - 0.10 Potassium chloride 0.55 - Sorbitol - 1.20 AMP-95 - 0.45 Poloxamer 1304 - 0.05 Polyquaternium-1 1 ppm 1 ppm Purified water, q.s. to 100 - - pH 7.5 7.9 Tonicity (mOsm / kg) 240 220

[0139] Test

[0140] The degradation of PQ-1 was evaluated by comparing the disinfection efficacy of both the non-autoclaved aqueous solution and the autoclaved aqueous solution. Autoclaving was carried out at 121 °C for 30 minutes. The contact lens treatment solutions of Examples 5 and 6 and Comparative Examples F and G were tested in the 4-hour disinfection efficacy test as described above, and the 4-hour disinfection time was evaluated to determine their efficacy against three bacterial species (Staphylococcus aureus (S.a.), Pseudomonas aeruginosa (P.a.) and Serratia marcescens (S.m.)) and one fungal species (Fusarium solani (F.s.)) with 10% organic soil. The results of the disinfection efficacy screening are shown in Table 6 below.

[0141] Table 6

[0142] S.a. P.a. S.m. F.s. Example 5, not autoclaved 4.2 >4.6 4.7 >4.3 Example 5, autoclaved 3.6 >4.6 4.0 3.0 Example 6, not autoclaved 4.1 >4.6 4.3 4.3 Example 6, autoclaved 3.2 >4.6 3.3 2.1 Comparative Example F, not autoclaved 4.2 >4.6 >4.7 >4.3 Comparative Example F, autoclaved 1.6 <1.1 <1.2 <1.3 Comparative Example G, not autoclaved 3.9 >4.6 3.6 >4.3 Comparative Example G, autoclaved <1.2 <1.1 <1.2 <1.3

[0143] Compared with the contact lens treatment solutions of Comparative Examples F and G, the contact lens treatment solutions of Examples 5 and 6 showed significantly improved disinfection efficacy against each of the bacterial and fungal species after autoclaving.

[0144] According to one aspect of the present invention, a contact lens treatment solution comprises (a) one or more of tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane, and salts thereof; and (b) one or more antimicrobial agents comprising one or more polyquaternary ammonium polymers.

[0145] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution contains tris(hydroxymethyl)aminomethane or a salt thereof as component (a).

[0146] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution contains bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane as component (a).

[0147] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution comprises (a) one or more of tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane, and salts thereof in an amount of about 0.05 wt.% to about 2.0 wt.%, based on the total weight of the contact lens treatment solution; and (b) one or more antimicrobial agents comprising one or more polyquaternary ammonium polymers in an amount of about 0.00001 wt.% to about 0.0010 wt.%, based on the total weight of the contact lens treatment solution.

[0148] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution comprises (a) one or more of tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane, and salts thereof in an amount of about 0.1 wt.% to about 1.0 wt.%, based on the total weight of the contact lens treatment solution; and (b) one or more antimicrobial agents comprising one or more polyquaternary ammonium polymers in an amount of about 0.00002 wt.% to about 0.0003 wt.%, based on the total weight of the contact lens treatment solution.

[0149] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the one or more polyquaternary ammonium polymers comprise from about 30 to about 50,000 quaternary amine functional repeating units.

[0150] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the one or more polyquaternary ammonium polymers have a weight average molecular weight Mw of about 3,000 to about 5,000,000.

[0151] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the one or more polyquaternary ammonium polymers have a weight average molecular weight Mw of about 5,000 to about 40,000.

[0152] In one or more additional illustrative embodiments, such as may be combined with the foregoing paragraphs, the one or more polyquaternium polymers are cationic.

[0153] In one or more additional illustrative embodiments, such as may be combined with the foregoing paragraphs, the one or more polyquaternium polymers comprise polyquaternium-1.

[0154] In one or more additional illustrative embodiments, such as may be combined with the foregoing paragraphs, the contact lens treatment solution further comprises one or more surfactants.

[0155] In one or more additional illustrative embodiments, such as may be combined with the foregoing paragraphs, the one or more surfactants are selected from the group consisting of poloxamers, poloxamines, and mixtures thereof.

[0156] In one or more additional illustrative embodiments, such as may be combined with the foregoing paragraphs, the poloxamer is at least one of poloxamer di(meth)acrylate and reverse poloxamer di(meth)acrylate, and the poloxamine is at least one of poloxamine di(meth)acrylate and reverse poloxamine di(meth)acrylate.

[0157] In one or more additional illustrative embodiments, such as may be combined with the foregoing paragraphs, based on the total weight of the contact lens treatment solution, the poloxamer is present in the contact lens treatment solution in an amount in the range of about 0.001 wt.% to about 5.0 wt.%, and based on the total weight of the contact lens treatment solution, the poloxamine is present in the contact lens treatment solution in an amount in the range of about 0.001 wt.% to about 5.0 wt.%.

[0158] In one or more additional illustrative embodiments, such as may be combined with the foregoing paragraphs, the contact lens treatment solution further comprises one or more additional antimicrobial agents.

[0159] In one or more additional illustrative embodiments, such as may be combined with the foregoing paragraphs, the one or more additional antimicrobial agents are selected from the group consisting of polymeric biguanides or salts or free bases thereof, terpene compounds, branched-chain glycerol monoalkyl ethers, branched-chain glycerol monoalkylamines, branched-chain glycerol monoalkyl sulfides, fatty acid monoesters, amidoamine compounds, and combinations thereof, wherein the fatty acid monoesters comprise an aliphatic fatty acid moiety having six to fourteen carbon atoms and an aliphatic hydroxy moiety.

[0160] In one or more additional illustrative embodiments, such as may be combined with the foregoing paragraphs, the contact lens treatment solution further comprises one or more comfort agents.

[0161] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the one or more comfort agents are selected from the group consisting of polyols, antioxidants, and complex carbohydrates.

[0162] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the polyol is one or more of glycerol and erythritol.

[0163] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution further comprises one or more polysaccharides.

[0164] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the one or more polysaccharides comprise one or more of anionic polysaccharides and nonionic polysaccharides.

[0165] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the one or more polysaccharides comprise one or more of the following: hyaluronic acid or its salts, chondroitin sulfate, chitosan, aloe vera, carboxymethyl cellulose, hemicellulose, hydroxypropyl methyl cellulose, methyl cellulose, and ethyl cellulose.

[0166] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution further comprises one or more of the following: chelating agents, tonicity regulators, buffers, pH regulators, viscosity regulators, and emollients.

[0167] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution contains a borate buffer in an amount less than 0.3 wt.%.

[0168] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution does not contain a borate buffer.

[0169] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution is in the form of an eye care or contact lens care product selected from the group consisting of: eye drops, preserved contact lens solutions, contact lens cleaning solutions, and contact lens multipurpose solutions.

[0170] In one or more additional illustrative embodiments, as may be combined with the foregoing paragraphs, the contact lens treatment solution is in the form of a multipurpose solution or a lubricant eye drop.

[0171] According to another aspect of the present invention, a method of cleaning and disinfecting a contact lens includes soaking the contact lens in a contact lens treatment solution according to one or more illustrative embodiments (such as may be combined with the foregoing paragraphs), the contact lens treatment solution comprising (a) one or more of tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane, and salts thereof; and (b) one or more antimicrobial agents comprising one or more polyquaternary ammonium polymers for a period of time sufficient to clean and disinfect the contact lens.

[0172] According to yet another illustrative embodiment, a method of inhibiting bacterial adhesion to the surface of a contact lens includes contacting the surface of the contact lens with a contact lens treatment solution according to one or more illustrative embodiments (such as may be combined with the foregoing paragraphs), the contact lens treatment solution comprising (a) one or more of tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane, and salts thereof; and (b) one or more antimicrobial agents comprising one or more polyquaternary ammonium polymers.

[0173] Although the compositions and methods are described in terms of "comprising" various components or steps, the compositions and methods may also "consist essentially of" or "consist of" the various components or steps, unless otherwise specified.

[0174] The terms "a," "an," and "the" are intended to include plural alternatives, e.g., at least one. Unless otherwise specified, the terms "comprising," "having," and "including," as used herein, are defined to be inclusive (i.e., open-ended language).

[0175] Various numerical ranges are disclosed herein. When the applicant discloses or claims any type of range, the applicant intends to disclose or claim separately each possible number that the range could reasonably encompass, including the endpoints of the range and any sub-ranges and combinations of sub-ranges encompassed, unless otherwise specified. For example, all numerical endpoints of the ranges disclosed herein are approximate, unless excluded by the accompanying conditions.

[0176] A numerical value or range may be expressed herein as “about” from “about” a particular value, and / or to “about” another particular value. When expressing such a numerical value or range, other embodiments disclosed include the recited specific values, from a particular value and / or to another particular value. Similarly, when a value is expressed as an approximation by use of the antecedent “about”, it should be understood that the particular value forms another embodiment. It should also be understood that many numerical values are disclosed herein, and each numerical value is also disclosed herein as “about” a particular value other than the numerical value itself. In another aspect, the use of the term “about” means ±20% of the value, ±15% of the value, ±10% of the value, ±5% of the value, ±3% of the value, or ±1% of the value.

[0177] If, for any reason, the applicant chooses to claim less than the full extent of the present disclosure, e.g., in view of references that the applicant may not have been aware of at the time of filing the application, the applicant reserves the right to limit or exclude any single member of any such group of values or ranges, including any sub-range or combination of sub-ranges within the group, which may be claimed according to ranges or in any similar manner. Further, the applicant reserves the right to exclude or except any member of the claimed group by way of proviso.

[0178] For the sake of brevity, the various features of the compositions are described in the context of a single embodiment, but may also be provided separately or in any suitable sub-combination. All combinations of the embodiments are specifically covered by the illustrative embodiments disclosed herein as if each combination were separately and expressly disclosed. Additionally, all sub-combinations listed in the embodiments describing such variables are also expressly covered by the compositions of the present invention and are disclosed herein as if each such sub-combination were separately and expressly disclosed herein.

[0179] It will be understood that various modifications may be made to the embodiments disclosed herein. Accordingly, the above description should not be construed as restrictive, but merely as illustrative of the preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustrative purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of the present invention. Additionally, other modifications will be conceived by those skilled in the art within the scope and spirit of the appended features and advantages.

Claims

1. A contact lens treatment solution, comprising: (a) one or more of tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane, and salts thereof; and (b) one or more antimicrobial agents comprising one or more polyquaternary ammonium polymers.

2. The contact lens treatment solution according to claim 1, wherein component (a) is tris(hydroxymethyl)aminomethane or a salt thereof.

3. The contact lens treatment solution according to claim 1 or 2, comprising: (a) based on the total weight of the contact lens treatment solution, about 0.05 wt.% to about 2.0 wt.% of the one or more of tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane, and salts thereof; and (b) based on the total weight of the contact lens treatment solution, about 0.00001 wt.% to about 0.0010 wt.% of the one or more antimicrobial agents comprising one or more polyquaternary ammonium polymers.

4. The contact lens treatment solution according to claim 1 or 2, comprising: (a) based on the total weight of the contact lens treatment solution, about 0.1 wt.% to about 1.0 wt.% of the one or more of tris(hydroxymethyl)aminomethane, bis(2-hydroxyethyl)amino-tris(hydroxymethyl)methane, and salts thereof; and (b) based on the total weight of the contact lens treatment solution, about 0.00002 wt.% to about 0.0003 wt.% of the one or more antimicrobial agents comprising one or more polyquaternary ammonium polymers.

5. The contact lens treatment solution according to any one of claims 1 to 4, wherein the one or more polyquaternary ammonium polymers comprise from about 30 to about 50,000 quaternary amine functional repeating units.

6. The contact lens treatment solution according to any one of claims 1 to 5, wherein the one or more polyquaternary ammonium polymers have a weight average molecular weight Mw of from about 3,000 to about 5,000,000.

7. The contact lens treatment solution according to any one of claims 1 to 5, wherein the one or more polyquaternary ammonium polymers have a weight average molecular weight Mw of from about 5,000 to about 40,000.

8. The contact lens treatment solution according to any one of claims 1 to 7, wherein the one or more polyquaternary ammonium polymers are cationic.

9. The contact lens treatment solution according to any one of claims 1 to 8, wherein the one or more polyquaternary ammonium polymers comprise polyquaternium-1.

10. The contact lens treatment solution according to any one of claims 1 to 9, further comprising one or more surfactants.

11. The contact lens treatment solution according to claim 10, wherein the one or more surfactants are selected from the group consisting of poloxamers, poloxamines, and mixtures thereof.

12. The contact lens treatment solution according to claim 11, wherein, based on the total weight of the contact lens treatment solution, the poloxamer is present in the contact lens treatment solution in an amount in the range of from about 0.001 wt.% to about 5.0 wt.%, and based on the total weight of the contact lens treatment solution, the poloxamine is present in the contact lens treatment solution in an amount in the range of from about 0.001 wt.% to about 5.0 wt.%.

13. The contact lens treatment solution according to any one of claims 1 to 12, further comprising one or more additional antimicrobial agents.

14. The contact lens treatment solution according to claim 13, wherein the one or more additional antimicrobial agents are selected from the group consisting of polymeric biguanides or salts or free bases thereof, terpene compounds, branched-chain glycerol monoalkyl ethers, branched-chain glycerol monoalkylamines, branched-chain glycerol monoalkyl sulfides, fatty acid monoesters, amidoamine compounds, and combinations thereof, wherein the fatty acid monoesters comprise an aliphatic fatty acid moiety having from six to fourteen carbon atoms and an aliphatic hydroxy moiety.

15. The contact lens treatment solution according to any one of claims 1 to 14, further comprising one or more comfort agents.

16. The contact lens treatment solution according to claim 15, wherein the one or more comfort agents are selected from the group consisting of polyols, antioxidants, and complex carbohydrates.

17. The contact lens treatment solution according to claim 16, wherein the polyol is one or more of glycerol and erythritol.

18. The contact lens treatment solution according to any one of claims 1 to 17, further comprising one or more polysaccharides.

19. The contact lens treatment solution according to claim 18, wherein the one or more polysaccharides comprise one or more of anionic polysaccharides and nonionic polysaccharides.

20. The contact lens treatment solution according to claim 19, wherein the one or more polysaccharides comprise one or more of the following: hyaluronic acid or a salt thereof, chondroitin sulfate, chitosan, aloe vera, carboxymethyl cellulose, hemicellulose, hydroxypropyl methyl cellulose, methyl cellulose, and ethyl cellulose.

21. The contact lens treatment solution according to any one of claims 1 to 20, further comprising one or more of the following: chelating agents, tonicity regulators, buffers, pH regulators, viscosity regulators, and emollients.

22. The contact lens treatment solution according to any one of claims 1 to 21, wherein the contact lens treatment solution contains less than 0.3 wt.% of a borate buffer.

23. The contact lens treatment solution according to any one of claims 1 to 22, wherein the contact lens treatment solution does not contain a borate buffer.

24. The contact lens treatment solution according to any one of claims 1 to 23, which is in the form of an eye care or contact lens care product, the eye care or contact lens care product being selected from the group consisting of: eye drops, preserved contact lens solution, contact lens cleaning solution, and contact lens multipurpose solution.

25. The contact lens treatment solution according to any one of claims 1 to 23, which is in the form of a multipurpose solution or a lubricating eye drop.

26. A method of cleaning and disinfecting a contact lens, the method comprising immersing the contact lens in the contact lens treatment solution according to any one of claims 1 to 25 for a period of time sufficient to clean and disinfect the contact lens.

27. A method for inhibiting bacterial adhesion to the surface of a contact lens, the method comprising contacting the surface of the contact lens with the contact lens treatment solution according to any one of claims 1 to 25.

28. Use of the contact lens treatment solution according to any one of claims 1 to 25 for cleaning and disinfecting a contact lens.

29. Use of the contact lens treatment solution according to any one of claims 1 to 25 for inhibiting bacterial adhesion to the surface of a contact lens.

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