KR20000053221A - Compositions and methods in which bis(biguanides) provide enhanced antimicrobial efficacy for disinfecting contact lenses - Google Patents

Abstract

PURPOSE: An ophthalmically safe disinfecting solution for contact lenses comprising a bis(biguanide) having formula (I), is provided, wherein the biguanides may be combined with a polymeric biguanide for complementary or synergistic biocidal efficacy. CONSTITUTION: An ophthalmically safe disinfecting solution for contact lenses comprising a bis(biguanide) having formula (I), is provided, wherein R1 and R4 are independently selected from the group consisting of branched or unbranched alkyl having 4-12 carbon atoms, ether or thioether radical having 4-12 carbon atoms, or cycloalkyl or cycloalkyl-alkyl radical having 5-12 carbon atoms; R2 and R3 are independently selected from the group consisting of hydrogen, alkyl having 1-12 carbon atoms, alkoxyalkyl having 1-12 carbon atoms, or cycloalkyl or cycloalkyl-alkyl having 5-12 carbon atoms; R6 and R7 are independently selected from the group consisting of hydrogen and alkyl radical having 1-6 carbon atoms, and A in the following formula is selected from the divalent radical having 4-16 carbon atoms consisting of a divalent alkyl, alkyloxyalkyl, alkylsulfide, or a polymethylene interrupted with a cyclic divalent radical.

Description

Compositions and Methods In Which Bis (Biguanides) Provide Enhanced Antimicrobial Efficacy For Disinfecting Contact Lenses}

In general, contact lenses fall into three categories: (1) hard lenses made of a material produced by polymerization of acrylic esters such as polymethylmethacrylate (PMMA), and (2) silicone acrylates. And gels, hydrogels or soft type lenses of polymers of hydrophilic or hydrophobic monomers such as hard gas permeable (RGP) lenses of fluorosilicone methacrylate, and (3) 2-hydroxyethyl methacrylate (HEMA). . The characteristics of the hard acrylic type contact lenses are low water vapor diffusion constants, resistance to the effects of light, oxygen and hydrolysis, and absorption of small amounts of aqueous fluids. Since hard contact lenses are durable with the ability to absorb water only undetectably, it is relatively unimportant to choose an appropriate disinfectant, cleaner or other lens care compound.

However, unlike hard lenses, soft lenses and some new hard gas permeable contact lenses combine and concentrate significant amounts of fluids, environmental contaminants, impurities in water, as well as other active ingredients commonly found in antimicrobials and lens care solutions. There is a tendency. In most cases, low concentrations of these components in the lens care solution do not cause eye tissue irritation when used properly. However, due to the inherent binding activity of protein deposits to soft lens materials, some disinfectants and preservatives tend to form on the lens surface and can be concentrated at harmful concentrations, which can cause corneal inflammation and other eye tissue irritation when released. Can be.

Efforts to solve the problem of disinfecting and preservatives binding and concentrating on contact lens surfaces and reducing the possibility of eye tissue irritation have been performed in the past, but have not been satisfactory. For example, even with low levels of toxicity, not all disinfectants can be used for all types of contact lenses. Although disinfectants are effective antimicrobials, their use can lead to loss of hydrophilic properties, solution instability, or even lack of suitability for some types of hard lenses (eg, high silicon content).

Some antimicrobials have been found that are more compatible with contact lenses and less likely to bind to the lens surface. For example, biguanide chlorohexidine binds to soft lens material seven times less than benzalkonium chloride, but the presence of protein-based oily tear film deposits on the lens, compared to clean lenses, It has been found that the seedin can be absorbed in twice the amount. US Pat. No. 4,354,952 discloses a high dilution disinfectant and wash solution comprising some amphoteric and nonionic surfactants with chlorohexidine or salts thereof. These solutions have been found to reduce the amount of binding of chlorohexidine to hydrophilic soft contact lenses. Despite the reduction in binding obtained by this patent invention, there are points to consider when using chlorohexidine. That is, the antimicrobial activity of chlorohexidine may be reduced when used with some amphoteric surfactants. Moreover, if not used in an appropriate proportion, surfactants and disinfectants will precipitate if nonionic surfactants are not used.

US Pat. No. 4,361,548 discloses contact lens disinfectants and preservatives comprising a dilute aqueous solution of a polymer, ie, polydimethyldiallylammonium chloride (DMDAAC), having a molecular weight of about 10,000 to 1,000,000. DMDAAC homopolymers can be used in small amounts, such as 0.00001% by weight, when used with an enhancer such as chimerosal, sorbic acid or phenyl mercury salt. Although the use of DMDAAC reduces the amount of binding to the lens and thus reduces eye tissue irritation, it has been found that the clinical concentration is desirable only in some users.

British Patent No. 1,432,345 discloses a contact lens disinfection composition containing a phosphate buffer mixed with a polymeric biguanide. The product under this patent was found to be less consumer preferred. Corneal contamination is an indicator of patient preference and the contamination of the composition as disclosed in this patent is at least 17%, much more than the patient prefers.

Several efforts to reduce or eliminate the binding of disinfectants to contact lenses have led to the use of antibinding agents or antidote agents such as polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA). However, in most cases, the use of these polymers alone has been found to be ineffective in reducing lens binding and ocular tissue irritation.

U.S. Patent No. 4,758,595 (Ogunbiyi et al.) States that the effect is enhanced when contact lens solutions comprising polyaminopropyl biguanide (PAPB) are mixed with borate buffer. This solution is suitable for both non-soft lenses and soft lenses, and is suitable for use with any commonly known disinfection technique and high temperature disinfection methods, including ″ low temperature ″ dipping under room temperature conditions. Disinfectants and preservatives have very low toxicity when used in soft type contact lenses and are particularly good at a wide range of bactericidal and fungicidal activities at low concentrations. Ogunbiyi et al. Reported that biguanide polymers with high molecular weight ranges exhibit lower toxicity levels than those with lower molecular weights.

Compositions comprising PAPB and borate or other non-phosphate buffers are commercially available in a variety of products, but their concentration is less than about 1 ppm when used in soft lenses. It is advisable to use the disinfectant at the lowest possible concentration to provide the benefits of stability and comfort while maintaining the desired concentration that provides the disinfection effect.

Some of the most popular products for lens disinfection are multipurpose solutions used for contact lens cleaning, disinfection and hydration that are then inserted directly into the eye without being rinsed. It is clear that it is advantageous to use a single solution for contact lens care. However, this solution should not be particularly poisonous to the eye as it will be on the lens when the lens is in contact with the eye as described above.

When using contact lens cleaners or disinfectants, including conventional multipurpose solutions, the lens wearer rubs the contact lens with fingers or manually (usually between fingers and palms or between fingers) during daily cleaning and / or disinfection of contact lenses. There is a need. Often ″ rubbing ″ contact lenses requires a lot of time and effort to manage the contact lenses every day. Many contact lens wearers hate or feel uncomfortable with performing ″ rubbing ″ care every day. Some wearers may ignore proper ″ rubbing ″ care practices, causing contact lens discomfort and other problems. Sometimes rubbing too hard can cause lens damage, especially for beginners wearing lenses. If a replacement lens is not available right away, it can be problematic or inconvenient.

In general, contact lens solutions that do not need to be rubbed need a more effective and stronger disinfectant than those that need to be rubbed. However, the stronger the sterilizing effect of the solution, the more adverse effects or toxic effects may appear on the comfort of the lens wearer. Indeed, many highly effective fungicides used in other applications, such as mouthwashes, cosmetics or shampoos, are safe enough for use in such products but too toxic for ophthalmic applications, especially soft lenses, as described above. This is because a chemical agent tends to bind to the soft lens. Similarly, the lower limit of the concentration of certain fungicides in solutions used with contact lenses than in other products or other types of lens solutions should be lower, especially when the solution is used in the eye.

Although the disinfectant tends to bind on the lens surface, it obtains a contact lens solution that simultaneously provides both (1) an increase in the level of antimicrobial activity, and (2) low toxicity to the eye tissue, so that the contact lens is not rinsed using this solution. It is good to handle. While continuing to develop further, it is particularly desirable to obtain a disinfectant that can be used as a versatile solution for soft contact lenses and that can be used directly in the eye after immersing the contact lens in solution and / or cleaning and rehydrating with the solution. Do. Finally, it is desirable to obtain a disinfectant solution that is sufficiently large in antibacterial effect that does not require rubbing to effectively and completely disinfect the contact lens.

The present invention relates to a novel and improved solution for treating contact lenses and a method of treatment using the solution. In particular, the present invention relates to the use of disinfectants in disinfectants comprising certain bis (biguanides) and in improved care methods for contact lens treatment.

Brief description of the invention

The present invention provides an ophthalmology comprising a corresponding concentration of about 2.0 ppm to about 8.0 ppm of bis (biguanide) present in the form of dihydrochloride salt, or the same bis (biguanide) present in the form of free base or different water soluble salts. The present invention relates to a disinfectant solution for a contact lens which is safe for use, wherein the bis (biguanide) is represented by the following general formula (I).

Wherein R ¹ and R ⁴ are C ₄ -C ₁₂ branched or unbranched alkyl, C ₄ -C ₁₂ alkoxyalkyl or alkylsulfide radical, or C ₅ -C ₁₂ cycloalkyl or cycloalkyl- Each selected from the group consisting of alkyl radicals (that may be the same or different); R ² and R ³ are each selected from the group consisting of hydrogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxyalkyl or C ₅ -C ₁₂ cycloalkyl or cycloalkyl-alkyl; R ⁶ and R ⁷ are each selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl radicals; A is a divalent group of C ₄ -C ₁₆ and is selected from the group consisting of alkylene, alkyloxyalkyl and alkyl sulfide radicals, wherein the alkyloxyalkyl or alkylsulfide radicals described above are at least one oxygen and / or sulfur A polymethylene chain having an atom inserted or a polymethylene chain substituted with an alkoxy (-OR ⁸ ) or alkylthio (-SR ⁹ ) group, wherein R ⁸ and R ⁹ are alkyl of C ₁ -C ₁₂ , C ₅ -C ₁₂ Are each selected from the group consisting of cycloalkyl or cycloalkyl-alkyl, or A is a C ₈ -C ₁₆ divalent polymethylene group having a divalent radical cyclohexane or 1,4-diazacyclohexane.

The solution of the invention also comprises at least one effective amount of a buffer, preferably about 0.01% to 5% by weight of the composition (solution), at least one surfactant effective amount, preferably about 0.01% to 5% by weight, and water At least about 90% by weight. In one aspect of the invention, the surfactant is a neutral or nonionic surfactant.

Furthermore, the present invention relates to bis (biguanide) represented by the formula (I) in the form of a hydrochloride salt of about 2.0 to 8.0 ppm, preferably of 2.0 to 6.0 ppm (or of a free base or salt other than hydrogen chloride Contact comprising directly immersing the lens in the wearer's eye after immersing the lens for a specified time in an aqueous solution comprising a bactericidal effective amount, an effective amount of a buffer, and an effective amount of a surfactant in the same bis (biguanide) form) A method of cleaning and / or disinfecting a lens is provided. In a preferred embodiment of the present invention there is no need to rub the lens with a solution to disinfect the contact lens.

In another embodiment of the present invention, using 0.1 to 4.0 ppm of bis (biguanide) represented by the formula (I) together with 0.1 to 3.0 ppm of polymerizable biguanide seems to provide a synergistic effect.

Detailed description of the invention

As mentioned above, the present invention relates to a composition in the form of an aqueous solution containing the compound represented by the above formula (I), and to a method for disinfecting and / or preserving contact lenses, in particular soft contact lenses, using the solution. will be. The disinfectant solution of the present invention is a wide range of microorganisms, including but not limited to Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Candida albicans It is also effective at low concentrations for) and Fusarium solani. Disinfectant solutions generally refer to contact lens care articles that include one or more active ingredients (eg, antimicrobials and / or preservatives) at a concentration sufficient to destroy harmful microorganisms on the surface of the contact lens within the recommended minimum immersion time. The recommended minimum immersion time is given in the instructions on the packaging for disinfectant use. In addition to packaging and bottles or containers containing instructions for use according to a particular care method, the solution of the present invention should take into account new and improved kits, packages or systems for contact lens care.

By "soft lens" is meant a lens having a proportion of hydrophilic repeat units such that, when in use, the water content of the lens is at least 20% by weight. In general, as used herein, "soft contact lens" means a contact lens that bends easily even with a small force. Typically, soft contact lenses are formulated with a polymer containing a proportion of repeating units derived from hydroxyethyl methacrylate and / or other hydrophilic monomers and crosslinked with a crosslinking agent. In contrast, a ″ hard contact lens ″ covers only the corneal part of the eye, usually consisting of poly (methyl methacrylate) crosslinked with ethylene glycol dimethacrylate or the like, and conventional rigid gas permeable lenses (RGPs) Silicone-containing monomers that form materials with higher oxygen permeability.

″ Disinfectant ″ is a solution containing one or more bactericidal compounds, which reduces or substantially reduces the microorganisms present on the contact lens to be tested by administering the microorganisms to the contact lens or solution contained in the solution containing the inoculation of the microorganisms described above. It is effective to remove. The term ″ disinfectant ″ includes the possibility that this solution may also be useful as a preservative, depending on the particular formulation, and that the disinfectant may be useful for other uses, such as daily cleaning, rinsing, and storage of contact lenses.

Useful solutions that are all used to clean, chemically disinfect, store and rinse contact lenses are referred to as "multipurpose solutions". This solution may be part of a ″ multipurpose solution system ″ or ″ multipurpose solution packaging ″. The process for using a versatile solution, system, or package is called a "multifunctional disinfection control method". Multipurpose solutions include other solutions, such as sterile saline, used when some wearers, particularly those who are sensitive to chemical disinfectants or other chemical agents, prefer to rinse or hydrate contact lenses before inserting the lenses. ″ Multipurpose solution ″ is also used as a periodic cleaner, such as an enzyme cleaner, to remove cyclic cleaners or proteins that are not used daily, and are usually used on a weekly basis. A ″ cleaning liquid ″ is a lens that is loosely attached to the surface of a contact lens, especially when used with hand manipulation (such as manually rubbing a lens with a solution) or with an auxiliary device such as a mechanical cleaning aid that stirs the solution into contact with the lens. By a solution comprising at least one detergent in a concentration sufficient to drop or remove deposits and other contaminants. Critical micelle concentrations of the surfactant containing solution are one method of evaluating the cleaning effect.

″ Effective multi-purpose solution ″, ″ Efficient multi-purpose solution system ″, ″ Effective multi-purpose solution packaging ″ and ″ Effective multi-function disinfection management method ”all similarly refer to solutions useful for daily chemical disinfection, storage and rinsing of contact lenses, rubbed and cleaned Means a solution that does not need to be and does not need other solutions for daily cleaning. In other words, you only need to use a multi-purpose solution for daily contact lens care with no other solution. This solution may include surfactants or other agents that prevent or mitigate lens deposition to some extent. Such solutions do not require similar manual or mechanical means (means to provide pressure and friction along the lens surface) to provide rubbing or rubbing action to remove deposits from the lens. Such care methods that do not require rubbing can be used in particular for replacement lenses, which lenses are recommended to be replaced for a limited time in the wearer's eye, for example within about 30 days of wearing, preferably within about 14 days. .

″ Ophthalmologically safe ″ for a contact lens solution means that the contact lens is safe to put directly into the eye without being rinsed when treated with this solution. That is, it is safe and comfortable to make contact lenses wet with the solution every day. Safe solutions for ophthalmic use have suitable pH and isotonicity for the eyes and have ISO standard and U.S. Contains ingredients and quantities that are non-toxic in accordance with FDA.

Bis (biguanide) fungicides used in the solution of the present invention include a compound represented by the following formula (I) and a water-soluble salt thereof.

Formula I

Wherein R ¹ and R ⁴ are C ₄ -C ₁₂ , preferably C ₆ -C ₁₀ branched or unbranched alkyl, C ₄ -C ₁₂ , preferably C ₆ -C ₁₀ alkoxyalkyl ( Ie ether) or alkylsulfide (thioether or dialkylsulfide) radicals, or C ₅ -C ₁₂ , preferably C ₇ -C ₁₀ cycloalkyl or cycloalkyl-alkyl radicals, respectively; (Ie can be the same or different); R ² and R ³ are hydrogen, C ₁ -C ₁₂ , preferably alkyl of C ₁ -C ₆ , C ₁ -C ₁₂ , preferably alkoxyalkyl of C ₁ -C ₆ or C ₅ -C ₁₂ , preferably Preferably selected from the group consisting of C ₆ -C ₁₀ cycloalkyl or cycloalkylalkyl; R ⁶ and R ⁷ are each selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl radicals; A is a divalent group of C ₄ -C ₁₆ , preferably C ₆ -C ₁₀ and is selected from the group consisting of alkylene (divalent radical of aliphatic hydrocarbon), alkyloxyalkyl and alkylsulfide radicals [where alkyl The oxyalkyl or alkylsulfide radical is a polymethylene chain with one or more oxygen and / or sulfur atoms inserted or a polymethylene chain substituted with an alkoxy (-OR ⁸ ) or alkylthio (-SR ⁹ ) group, wherein R ⁸ and R ⁹ is each selected from the group consisting of C ₁ -C ₁₂ alkyl, C ₅ -C ₁₂ cycloalkyl or cycloalkyl-alkyl], or A is a divalent cyclohexane or diazacyclohexane ring (a nitrogen atom the piperazine or 1,4-poly-1,4-diaza ring attached to the methylene cyclohexane and the like) is inserted into the C ₈ -C _16, preferably through is a divalent C ₈ -C ₁₆ polymethylene group. In cycloalkyl or cycloalkylalkyl, "cycloalkyl" means unsubstituted or substituted cycloalkyl, wherein the substituent is one or more alkyl, alkoxy (-OR) or alkylthio (-SR) of C ₁ -C ₆ .

In one embodiment of the present invention, the biguanides represented by the formula (I) have a total amount of 2.0 to 8.0 ppm, preferably 2.5 to 6.0 ppm, based on the total aqueous solution (based on the weight of the hydrogen chloride salt, Containing hydrogen chloride). Bis (biguanides) are more preferably used at 3.0 to 5.0 ppm, most preferably 3.5 to 4.5 ppm, based on the corresponding molar amount of the hydrogen chloride salt, another salt or free base thereof. The bis (biguanides) used in the present invention may be present in the form of salts or free bases other than hydrogen chloride, in which the above ppm ranges are molar amounts and when the bis (biguanide) hydrogen chloride salt is used. Adjust to equal to get the corresponding ppm range. The bis (biguanide) concentration in the solution is directly related to the bactericidal effect. Equimolar or equal concentrations of the corresponding weights of different salt forms of bis (biguanide) can be easily calculated and used to determine the appropriate amount of the component. ″ Ppm ″ is ″ parts per million ″ and 1.0 ppm corresponds to 0.0001% by weight. This is based on the total weight of the composition or, in the case of the present invention, the total weight of the disinfecting aqueous solution.

The amount of bis (biguanide) or other compound in the solution of the present invention means the amount introduced or formulated into the solution when the solution is prepared. After a period of time (such as after 18 months of storage), analyzing the amount of bis (biguanide) in the solution may be somewhat reduced.

The bis (biguanide) compound is preferably a compound represented by the following formula (II) or a water-soluble salt thereof.

Wherein R ¹ and R ⁴ are each selected from the group consisting of branched or unbranched alkyl, alkoxyalkyl (ie ether) or alkylsulphide (eg thioether) radicals, and n is 5-7.

In formula (I) or formula (II) each R ¹ and R ⁴ is, for example, n-butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, neopentyl, octyl, 2-ethylhexyl, dodecyl, cyclobutyl, cyclopentyl , Cyclohexyl, cycloheptyl, cyclopentylmethyl or cyclohexylmethyl radicals. 2-ethylhexyl (alexidine), 1,5-dimethylhexyl, 1-methylhexyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, cyclohexylmethyl, 2-norbornyl, propyloxyoctyl and propyloxy Butyl is good.

Each of R ² and R ³ in formula (I) is for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, neopentyl, octyl, 2-ethylhexyl, Dodecyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentylmethyl or cyclohexylmethyl radicals. When at least one of R ² and R ³ is an alkoxyalkyl radical, R ² or R ³ may be for example 2-methoxyethyl.

Each R ⁶ and R ⁷ in formula (I) may be, for example, a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, pentyl or neopentyl radicals.

Preferred group A in formula (I) includes hexamethylene and divalent derivatives derived from N, N- (2-aminoethyl) -1,4-piperadine and the like in which each nitrogen atom is bonded to a polymethylene group of C ₁ -C ₄ . And divalent hexamethylene with radicals inserted.

Acid addition salts of the invention can be derived from inorganic or organic acids. In most cases, salts derived from acids which are readily soluble in water and which provide suitable anions for human use, such as pharmaceutically acceptable anions, are preferred. Examples of such acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, D-gluconic acid, 2-pyrrolidino-5-carboxylic acid, methanesulfonic acid, carboxylic acid, lactic acid and glutamic acid. Hydrochloric acid salts are good.

The terminal group of bis (biguanide) represented by the formula (I) is preferably relatively hydrophobic. The LogP of the chemical is preferably 5 to 10, preferably 6 to 8, where P is the partition coefficient of the free base and is calculated using the following equation.

P = C _Octanol / C _Buffer (1-α)

Where α is the degree of ionization.

To obtain the partition constant of bis (biguanide), the compound is partitioned between 0.05 M phosphate buffer (pH11) saturated with octanol and octanol saturated with phosphate after gentle shaking at room temperature. The volume ratio of these two phases and the amount of sample are chosen such that the absorbance of the sample from the buffered layer after dispensing with buffer as 1 cm cell and blank is between 0.2 and 0.9. Working at a fixed pH and known pK _α or calculated pK _α , the above equation can be used to determine the P value.

References cited herein by reference [Quantitative Structure-Activity Relationships for Biguanides, Carbamidates, and Bisbiguanides as Inhibitors of Streptococcus mutans NO. 6715 ″, and Warner V. And Lynch D. J. Med. Chem. 1979, Vol. 22, no. 4, 359, 365 and Albert and Surgeon E., ″ Determination of Ionization and Stability Constants ″, Butler and Tanner Limited, London, UK, 1962.

Examples of preferred bis (biguanide) compounds of the present invention are 2- (decylthiomethyl) pentane-1,5-bis (5-isopropylbiguanide), 2- (decylthiomethyl) pentane-1,5 -Bis (5,5-diethylbiguanide) and hexane-1,6-bis (2-ethylhexylbiguanide) (known as alexidine) or 1,1'-hexamethylenebis (5- ( 2-ethylhexyl) biguanide) dihydrochloride. Examples of other preferred bis (biguanides) include 1,1'-hexamethylenebis (5-heptylbiguanide) dihydrochloride, 1,1'-hexamethylenebis (5-octyl biguanide) dihydrochloride and 1,1'-hexamethylenebis (5-hexyl biguanide) dihydrochloride, etc. are mentioned.

R ⁶ and R ⁷ each is a biguanide compound is bis (VI) of formula I wherein the hydrogen-cyanoguanidine an amine R ¹ R ² NH or two different amine R ¹ R ² NH and R ³ R ⁴ NH And the form of acid addition salts thereof can be prepared by reacting at a temperature of 100 ° C to 170 ° C (A, R ¹ , R ² , R ³ and R ⁴ as described above). Preferred amine salts are hydrochlorides. Most diamines are commercially available from various sources.

The reactants are heated together until the reaction is complete. The reaction proceeds rapidly at high temperatures, but when thermal stability is a problem, the reaction must be carried out at low temperatures for a long time. The reactants are most readily melted together in the absence of solvent, but if necessary inert solvents such as DMSO, 2-methoxyethanol, 2-ethoxyethanol, nitrobenzene, sulfolane, isopropanol, n-butanol, ethylene glycol dimethyl ether Or water or a mixture of these solvents.

Bis-cyanoguanidine of formula (VI) can be prepared from known starting materials such as hexamethylenedinitrile, for example, reduced to the corresponding diamine of formula (VIII) using hydrogen and Raney nickel or using borane in dimethyl sulfide. The diamine of acid addition salt form, often dihydrochloride, can be reacted with sodium dicyanamide or other suitable salt to form the desired starting material of Formula VI, as shown in Scheme 1 below.

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

The compounds of the present invention are reacted with a diamine of formula (VIII) in acid addition salt form with cyanoguanidine of formula (IX) or with cyanoguanidine of formula (IX) and with cyanoguanidine of formula (X) Can be prepared by reaction.

Wherein A, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and R ⁷ are as described above.

An example of a suitable salt of diamine is dihydrochloride. The reactions were heated together until the reaction was complete. The reaction proceeds rapidly at high temperatures, but when thermal stability is a problem, the reaction must be carried out at low temperatures for a long time. If a melt can be formed at this temperature, the reactants readily melt together in the absence of solvent. Otherwise, the reactants are heated together in a suitable inert solvent as described above. The acid addition salt of the present invention is obtained by a conventional method.

The cyanoguanidines of formula IX and formula X, wherein R ⁶ and R ⁷ are hydrogen, which can be used as starting materials in the process, are prepared by the addition of sodium dicyanamide in acid addition salt form, Obtained by reaction with a suitable amine R ¹ R ² NH or R ³ R ⁴ NH in a suitable inert solvent.

The cyanoguanidines of Formula IX and Formula X, wherein R ⁶ and R ⁷ are other than hydrogen, which may be used as starting materials in the process, are dialkyl (cyanoimido) dithio-carbo Nates, for example dimethyl (cyanoimido) dithio-carbonate, can be obtained by reacting with appropriate amines R ¹ R ² NH or R ⁶ NH ₂ or R ³ R ⁴ NH and R ⁷ NH ₂ .

For example, bis (biguanide), also known as alexidine, is produced by the following sequence of reactions.

The compound of formula XI is hexamethylenediamine dihydrochloride (molecular weight 189), the compound of formula XII is sodium dicyanamide, the compound of formula XIII is HMBDA, hexamethylene bis (cyanoguanido), and the compound of formula XIV is 2-Ethyl-hexylamine dihydrochloride (molecular weight 165.7), the compound of formula XV is Alexidine dihydrochloride aka [1,6-bis (2-ethylhexylbiguanido] hexane dihydrochloride aka hexane-1,6- Bis (2-ethylhexylbiguanide) dihydrochloride This compound has a molecular weight (molecular weight g / mol) of 581.7 and an empirical formula of C ₂₆ H ₅₆ N ₁₀ .2HCl The compound of formula XV is a Sigma Chemical Corporation (US Available from a variety of sources, including St. Louis, Missouri.

Various compounds can be prepared by suitable starting materials in which ″ A ″ in the above formula (I) is alkoxy or thioalkyl substituted alkylene, wherein the compound according to formula (VII) is represented by R ⁵ YH wherein Y is a sulfur atom or oxygen source as a strong base Ximine) to make hexendinite from. Various compounds of formula (I) wherein R ² and R ³ are H can be readily obtained as N derivatives of 1,6-bisbiguanidohexane.

In addition, the preparation of the synthetic compounds of the present invention is described in European Patent Application Publication No. 0,125,092 issued November 14, 1984; Rose F. L. And Suwain G. ″ Bisdiguanide Having Antibacterial Activity ″, J. Chem. Soc. p 4422-4425 (1956); Warner Victor D. And Lynch, Donald, ″ Quantitative Structure-Activity Relationships of Biguanide, Carbaminidates, and Bisdiguanides as Inhibitors of Streptococcus Mutans No. 6715 ″, J. Med. Chem., Vol. 22, no. 6, p 359-366 (1979).

Secondary disinfectants / sterilizers can be used as preservatives, but they can enhance, complement or widen the range of bactericidal activity of formula (I). The sterilizing effective amount of the fungicide which does not precipitate in the solution and can be used together is a concentration in the range of about 0.00001 to about 0.5% by weight, preferably about 0.0001 to about 0.1% by weight. Non-limiting examples of suitable complementary fungicides include chimerosal, sorbic acid, alkyl triethanolamine, phenylmercury salts such as nitrates, borates, acetates, chlorides and mixtures thereof. Suitable salts are soluble in water at about 0.5% by weight at room temperature. Examples of such salts include gluconate, isethionate, (2-hydroxyethanesulfonate), formate, acetate, glutamate, succinate, monodiglycolate, methanesulfonate, lactate, isobutyrate and glucoheptonate. have.

Further embodiments of reinforcing or complementary disinfectants for use in the present invention generally include certain quaternary ammonium compounds having a wide range of bactericidal activity and hydration properties and the like. Representative examples of quaternary ammonium compounds include balanced mixtures of n-alkyl dimethylbenzyl ammonium chloride. Other examples include polymeric quaternary ammonium salts used for ophthalmology such as the trademark Polyquaterium 1 (Chemical Registration No. 75345-27-6) available from Onyx Corporation.

In other embodiments of the present invention, bis (biguanides) as described above may be used in admixture with small amounts of other bis (biguanides) such as chlorhexidine. Such compounds are described in detail in British Patent No. 705,838.

Finally, the bis (biguanide) of the present invention (formula I or formula II) can be used with one or more polymeric biguanides. In particular, one aspect of the present invention relates to an ophthalmically safe disinfectant for contact lenses comprising from about 0.10 to about 4.0 ppm of bis (biguanide) as described above together with 0.10 to 3.0 ppm of polymeric biguanide. This bisbiguanide is represented by the above formula (II) wherein R ¹ and R ⁴ are C ₄ -C ₁₂ , preferably C ₆ -C ₁₀ branched or unbranched alkyl, C ₄ -C ₁₂ , preferably Are each selected from the group consisting of C ₆ -C ₁₀ alkoxyalkyl or alkylsulfide radicals, or C ₅ -C ₁₂ , preferably C ₇ -C ₁₀ cycloalkyl or cycloalkyl-alkyl radicals; n is 4 to 16, preferably 4 to 10.

In one embodiment, when bis (biguanide) is used in combination with polymeric biguanide to give a synergistic effect, the bis (biguanide) of formula I is 0.1 to 4.0 ppm, preferably based on total aqueous solution Is suitably used in an amount of 1.0 to 3.0 ppm (comprising two hydrogen chlorides, often as in alexidine, by weight of hydrochloride). Bis (biguanides) may be used with respect to hydrochloride preferably in the range of 1.5 to 2.5 ppm, more preferably about 2.0 ppm, or the corresponding ppm range of other salts or free bases thereof. When bis (biguanide) used in the present invention is present in the form of salts or free bases other than hydrochloride, the ppm range is adjusted to be equal to the molar ratio of bis (biguanide) to the hydrochloride salt. To get the ppm range.

In this embodiment, 0.10 to 4.0 ppm of the bis (biguanide) of the present invention can be used as a combination of one or more polymeric biguanides of formula (IV) and water soluble salts thereof.

Wherein Z is an organic divalent bridging group which may be the same or different throughout the polymer, n is at least 3 on average, preferably 5 to 20 and X ¹ and X ² are each -NH ₂ and Is selected from. One preferred group of water-soluble polymer biguanides has a number average molecular weight of at least 1,000, more preferably 1,000 to 50,000. Non-limiting examples of suitable water soluble salts of free base include hydrochloride, borate, acetate, gluconate, sulfonate, tartarate and citrate salts and the like.

The aforementioned biguanides and methods for their preparation are described in the literature. For example, US Pat. No. 3,428,576 describes a process for preparing polymer biguanides from diamines and salts thereof and diamine salts of dicyanide.

Polymer biguanides in combination with bisbiguanides of the present invention are effective at concentrations as low as 0.00001% by weight (0.1 ppm). It has also been found that the bactericidal activity of the solution can be broadened in the range of activity or the solution can be improved through the use of such polymeric biguanides and compounds of formula (I). The effective amount of polymeric biguanide (regardless of salt form or with or without free base) is low at about 0.000010% by weight (0.10 ppm) in the form of a water-soluble salt or free base, up to about 0.00030% by weight (3.0 ppm). ) Can be. The total amount of polymeric biguanides, together with the total amount of the compound of formula I, is preferably about 0.3 to 2.0 ppm, more preferably 0.4 to 1.0 ppm, most preferably 0.5 to 0.8 ppm.

Most preferred is polymer hexamethylene biguanide (commercially available as hydrochloride under the trade name Cosmocil ^™ CQ from Genca, Wilmington, Delaware, USA). Polymers and water soluble salts are called PHMB or polyaminopropyl biguanides (PAPBs). The term polyhexamethylene biguanide as used herein is meant to include one or more biguanides of the formula (V):

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

Depending on the method of making the biguanide, the main compound included within the scope of the above formula may include various X ¹ and X ² groups or the same group, and includes small amounts of other compounds included in the above formula. Such compounds are known and described in US Pat. No. 4,758,595 and British Pat. No. 1,432,345, which are incorporated herein by reference. The water-soluble salt is preferably a compound having an average value of n of 2 to 15, most preferably 3 to 12.

The solution used in the present invention may comprise one or more surfactants. Examples of suitable surfactants may be amphoteric, cationic, anionic or nonionic (alone or in combination) which may be present in an amount of up to 15% by weight, preferably up to 5.0% by weight of the composition or solution. . Examples of preferred surfactants when used to impart cleaning and conditioning properties are amphoteric or nonionic surfactants. The surfactant should be soluble in the lens care solution and should not irritate eye tissue. Many nonionic surfactants include one or more chain or polymer components with oxyalkylene (—OR—) repeat units, wherein R is C ₂ -C ₆ . Preferred nonionic surfactants comprise block copolymers of two or more different types of oxyalkylene repeat units, wherein the ratio of the various repeat units is determined by the HLB of the surfactant. Examples of satisfactory nonionic surfactants include polyethylene glycol esters of fatty acids such as coconut, polysorbate, polyoxyethylene or polyoxypropylene of higher alkanes (C ₁₂ -C ₁₈ ), and the like. Examples of preferred types include polysorbate 20 (available under the trade name Tween 20), polyoxyethylene (23) lauryl ether (registered Brij 35), polyoxyethylene (40) stearate (registered trademark Myrj 52), poly Oxyethylene (25) propylene glycol stearate (registered trademark Atlas G 2612) and the like. Nonionic surfactants, in particular those comprised of poly (oxypropylene) -poly (oxyethylene) adducts of ethylene diamine having a molecular weight of about 7,500 to about 27,000 and at least 40 wt% of adducts are poly (oxyethylene) It has been found to be particularly useful for use in cleaning and conditioning of both soft and hard contact lenses when used in an amount of about 15% by weight. For this group of surfactants, the CTFA Cosmetic Ingredient Dictionary calls it poloxamine. Such surfactants are commercially available under the tradename " Tetronic " from BASF Wyndott Corporation, Wynndot, Michigan. Suitable analogs of the surfactant family suitable for use in the present invention include the poloxamer family, which is a poly (oxyethylene) poly (oxypropylene) block polymer available from BASF under the tradename ″ Pluronic ″.

In addition to amphoteric and anionic surfactants suitable for the present invention, a variety of other ionic surfactants are described in McCutcheon's Detergents and Emulsifiers, North American Edition, McCurney Division, MC Public Company, 07452 Glen, NJ, USA And is published in the CTFA International Cosmetic Ingredient Handbook, Cosmetics, Toy Recreation and Fragrance Assistance, Washington, D.C., USA.

Examples of amphoteric surfactants suitable for use in the present invention include materials of the type sold under the tradename ″ Miranol ″ and the like. Another useful class of amphoteric surfactants is cocoamidopropyl betaine, available from various sources.

When used with a buffer enhancer, the above-mentioned surfactants are generally present in amounts of 0.01 to 5.0% (w / w), preferably 1.0 to 5.0% (w / w).

Typically, the aqueous solution used in the present invention to treat contact lenses is adjusted to an osmotic pressure of normal tears corresponding to approximately 0.9% sodium chloride solution or 2.5% glycerol solution using isotonic agents. The solution is made almost isotonic, either alone or in combination, with physiological saline, and if necessary simply mixed with sterile water to make it hypotonic or hypertonic, the lens will lose its desirable optical parameters. Therefore, excess brine will form a hypertonic solution that will sting and irritate the eyes.

The pH of the solution used in the present invention is maintained in the range of 5.0 to 8.0, more preferably about 6.0 to 8.0, most preferably about 6.5 to 7.8, and boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS And various mixed phosphate buffers (including combinations of Na ₂ HPO ₄ , NaH ₂ PO ₄ and KH ₂ PO ₄ ) and mixtures thereof, and the like. Borate buffer is preferred because it enhances the efficiency of biguanides. The buffer is used in an amount in the range of about 0.05 to 2.5% by weight, preferably 0.1 to 1.5% by weight. The disinfection / preservation solution of the present invention preferably comprises a borate or mixed phosphate buffer comprising at least one boric acid, sodium borate, potassium tetraborate, potassium metaborate or mixtures thereof. In addition to the buffer, in some cases it is desirable to include metal ions in the solution that contain an isolating agent that can react with and collect on the lens and / or protein deposits. Ethylene-diaminetetraacetic acid (EDTA) and its salts (disodium) are preferred examples. They are typically added in amounts ranging from about 0.01 to about 0.2 weight percent. Examples of other suitable sequestrants include gluconic acid, citric acid, tartaric acid and salts thereof, such as sodium salts.

Isotonic aqueous solutions of bis (biguanides) of formula I, optionally containing fungicides, are particularly useful for soft contact lenses with or without additional additives. Nevertheless, the solutions of the present invention may be formulated with specific contact lens care products such as hydration solutions, immersion solutions, cleaning solutions and conditioning solutions, as well as multipurpose lens care solutions and the like and mixtures thereof. Such additives can be used to give the wearer a better fit. However, the additive must be nontoxic and be usable with contact lenses.

It may also be desirable to add a water soluble viscosity enhancer to the solution of the present invention. Due to this viscous effect, viscosity enhancers tend to enhance the wearer's fit by films on the lens surface that mitigate the impact on the eye. Among the water soluble viscosity enhancers are cellulose polymers such as hydroxyethyl or hydroxypropyl cellulose, carboxymethyl cellulose and the like. Such viscosity enhancers can be used in amounts ranging from about 0.01% to about 4.0% by weight. Such solutions may include any viscous agents.

The aqueous solution according to the present invention can be effectively used for disinfecting contact lenses by any known method. The lens can be treated by ″ low temperature ″ dipping at room temperature for about 20 minutes to about 12 hours. The lens is then removed from the solution, rinsed with a solution equal to or different from preserved isotonic saline and placed in the eye.

As mentioned above, contact lens wearers need to rub the contact lens with their fingers or manually (usually between fingers and palms or between fingers) during cleaning and / or disinfection of contact lenses daily. In one aspect of the invention, there is provided a method that does not require rubbing in the process of removing the lens from the eye and then subjecting the lens to the eye after lens care and with the particular solution claimed. In a preferred embodiment of this method, the soft lens is sterilized or simultaneously disinfected and cleaned with a multipurpose solution or an effective multipurpose solution which is a daily use solution for treating the lens outside the eye. Thus, in one aspect of the invention the solution described above is used to treat contact lenses without rubbing, the method comprising steps (a) and (b).

(a) immersing a contact lens that has not been rubbed with a solution for a specified time, and

(b) placing the treatment contact lens directly into the wearer's eye.

Typically, step (a) involves immersing the contact lens in solution. Immersion may optionally include shaking or stirring the container of the solution by manual means. Step (a) preferably includes a period during which the contact lens is immersed in the container completely immersed in solution. ″ Direct Insertion ″ means not rinsing or diluting the lens with different contact lens solutions prior to eye contact or ″ insertion ″. In particularly preferred embodiments, non-rubbing multipurpose or effective multipurpose solutions are used. This solution eliminates the need for other solutions or products to clean the lens daily, and the enzyme cleaner can be used separately.

Since the solution of the present invention increases the bactericidal effect, it is possible to treat the lens without rubbing with the solution, and this management method includes a immersion time of less than 4 hours. Sufficient disinfection can be achieved, for example, in about 20 minutes to about 90 minutes, with a recommended minimum soak time of about 20 minutes to about 90 minutes. The solution is preferably formulated to provide the required disinfecting power without immersing the lens in the solution for a given time in about 50 minutes to about 70 minutes, preferably about 60 minutes, corresponding to the minimum dipping time. The minimum immersion time is from about 50 minutes to about 70, preferably about 60 minutes.

In another method of the invention, the claimed solution is intended to be replaced within about 3 months of use in the eye, or to be replaced within about 30 days of use in the eye, or to be replaced within about 2 weeks of use in the eye. It is used to clean a frequently replaced lens (FRL), which is a planned lens. The lens is a polymer comprising about 0.0-5 mol% of repeating units derived from methacrylic acid (MAA), 10-99 mol% of repeating units derived from hydroxyethyl methacrylate and 0.5-5 mol% of crosslinked repeating units. Are manufactured. Crosslinking repeating units can be derived from monomers such as, for example, ethylene glycol dimethacrylate, divinylbenzene and trimethylpropane trimethylacrylate.

This example illustrates the compositions and methods of the present invention.

Example 1

This example illustrates the preparation of 1,6-bis (cyanoguanidino) used as starting material for bis (biguanide) of the present invention. Sodium dicyanamide (NaC ₂ N ₃ ) was suspended in 400 ml of 1-butanol at a content of 35.80 g (0.402 mol). Then 23.60 g (0.204 mol) of 1,6-hexanediamine and 33.0 mL (0.400 mol) of concentrated hydrochloric acid solution were added. A milky white precipitate was produced immediately, presumably an amine hydrochloride. The mixture was refluxed for 3.5 hours. The suspension was cooled to room temperature and it was filtered. The white solid was washed with distilled water and dried under vacuum.

Yield 46.38 g, 93.1%

Elemental Analysis for C ₁₀ H ₁₈ N ₈

Theory C 48.0%; H 7.20%; N 44.80%

Found C 47.7%; H 7.40%; N 45.12%

6.60 ppm (6p, br m) 300 MHz ¹ NMR (d ⁶ DMSO); 2.93 ppm (4p, m); 1.34 (4p, broad singlet); 1.15 ppm (4p, br s)

IR (KBr pellet, cm ⁻¹ ) 3142 (m); 2943; 2912; 2862 (w); 2179 (s); 1658; 1609 (s).

Example 2

This example illustrates a method for preparing alexidine for use in the present invention. Compound hexamethylene bis (cyanoguanidino) was added to the flask in an amount of 1.003 g (0.004498 mol). To this was added 1.474 mL (1.163 g, 0.008996 mol) of 2-ethylhexylamine. 0.74 mL (0.008996 mol) of concentrated HCl was then added. The mixture was heated in a flask to evaporate off H ₂ O. After H ₂ O was removed, the temperature of the melt was raised to 195 ° C. The temperature was reduced to 150-160 ° C. and maintained for 1 hour. This material was cooled to room temperature. The solid was dissolved in hot water and crystals were allowed to form.

Example 3

This example illustrates the preparation of poly (hexamethylene guanide) (also referred to as PAPB or PHMB) for use in mixing with bis (biguanide) in the present invention. In 500 ml of distilled water, 25.08 g (0.100 mol) of 1,6-bis (cyanoguanidino) hexane and 18.99 g (0.100 mol) of 1,6-hexadiamine dihydrochloride were suspended. Dilute hydrochloric acid was used to lower the pH of this mixture to 6.8. Water was removed by evaporation under reduced pressure. A white solid was placed in a three neck flask equipped with a mechanical stirrer and heating mantle. The mixture of solids was placed under nitrogen and the temperature of the mixture was raised to 150-155 ° C. The molten reaction mixture has a consistency like honey. The mixture was stirred at 150 ° C.-155 ° C. for 1-1.5 hours and then cooled to room temperature. The resulting poly (hexamethylene biguanide) was obtained as a glassy solid. The yield was almost quantitative. Melting Point: 105 ℃ ~ 125 ℃

300 MHz ¹ H NMR (D ₂ O) 3.13 ppm (21.1 p, br t); 2.93 ppm (2p, t); 1.49 ppm (21.1 p, br s), 1.28 ppm (21.1 p, br s)

IR (KBr pellet, cm ⁻¹ ) 3325; 3201 (s); 2931; 2858 (m); 2175 (mw); 1631; 1589; 1550 (s).

Example 4

This example illustrates the preparation of a contact lens disinfecting aqueous solution for use in the present invention.

% (w / v) Alexidine 2HCl 0.0004 Poloxamine 1107 ^** 1.0 Na ₂ EDTA 0.11 Boric acid 0.66 Sodium borate 0.10 Sodium chloride 0.54 Distilled water 100.0 ^** Molecular weight 14,500, 70% (w / v) Trademark Tetronic 1107, poly (oxypropylene) poly (oxyethylene) block copolymer adduct of ethylene diamine, BASF Corporation, Wynn Dot, Mich. Trademark

A solution was prepared by dissolving disodium EDTA in it while gradually heating 80% water to 80 ° C. Boric acid and sodium borate were added and dissolved in a heated solution of disodium EDTA. Sodium chloride was added to the solution, which was dissolved, followed by the addition of surfactant. The solution was sterilized by autoclave at 120 ° C. for 45 minutes. After the solution was cooled to room temperature, bis (biguanide) was added through a sterile filter and the rest was filled with distilled water. The solution was packaged in sterile plastic containers.

Example 5

This example illustrates the bactericidal effect of the solution according to the invention. The antimicrobial effects on each of the various compositions for chemical disinfection of contact lenses were evaluated. Microbe attack inoculations include Pseudomonas aeruginosa (ATCC 9027), Staphylococcus aureus (ATCC 6538), Serratia marcescens (ATCC 13880), Candida albi Preparation was made using Candida albicans (ATCC 10231) and Fusarium solani (ATCC 36031). The test microorganisms were incubated on appropriate agar and cultures were collected using sterile DPBST (Dulbecco Phosphate Buffered Saline + 0.05% w / v Polysorbate 80) or appropriate dilution and transferred to the appropriate containers. The spore suspension was filtered through sterile glass wool to remove mycelial segments. The Serratia marcesense was filtered appropriately (eg, through a 1.2 μ filter) to clear the suspension. After collection, the suspension was centrifuged up to 5,000 × g at 20 ° C.-25 ° C. for up to 30 minutes. The supernatant was discarded and resuspended in DPBST or other appropriate dilution. The suspension was second centrifuged and resuspended in DPBST or other appropriate dilution. All challenge bacterial and fungal cell suspensions were adjusted to 1 × 10 ^{7-10 8} cfu / ml using DPBST or other appropriate dilution. Appropriate cell concentrations were assessed, for example, by measuring the turbidity of the suspension using a spectrometer at a preselected wavelength (eg 490 nm). Test tubes containing at least 10 ml of test solution were prepared for each challenge microorganism. Each solution test tube to be tested is inoculated with a suspension of test microorganisms sufficient to provide a final count of 1.0 × 10 ⁵ -10 ⁶ cfu / mL and the volume of inoculum not exceed 1% of the sample volume. It was. The inoculum was then dispersed by vortexing the sample for at least 15 seconds. Inoculated products were stored at 10 ° C.-25 ° C. After sterilization for a period of time, 1.0 ml aliquots of the inoculated product were taken to determine viability. Bacteria were examined at 1, 2, 3 and 4 hours if the proposed management soak time was 4 hours. Yeast and mold were also examined at additional time points ≧ 16 hours (4 times the administration time). The suspension was mixed well by vortexing vigorously for at least 5 seconds. 1.0 ml aliquots separated at specific time intervals were subjected to an appropriate series of 10-fold dilutions in certified neutralizing media. The suspension was mixed vigorously and incubated for a suitable period of time to neutralize the microbial preparation. The viable microbial counts were determined in appropriate dilutions by preparing triple plates of glucose agar medium (SDA) and bacterial trypticase soy agar medium (TSA) with fungi and yeast. Bacteria recovery plates were incubated at 30 ° C.-35 ° C. for 2-4 days. Yeast recovery plates were incubated at 20 ° C.-30 ° C. for 2-4 days, and mold recovery plates were incubated at 20 ° C.-25 ° C. for 3-7 days. The average number of colony forming units was measured on countable plates. By countable plate is meant 30 to 300 cfu for bacteria and yeast per plate and 8 to 80 cfu for mold, except when colonies are only observed in 10 ⁰ or 10 ⁻¹ diluted plates. Subsequently, the reduction in the number of microorganisms at a certain time point was calculated. To confirm the suitability of the medium used for propagation of the test microorganisms and to evaluate the initial inoculation concentration, the same aliquots of the inoculum are dispersed into an appropriate dilution, such as DPBST, using the same volume of diluent used to suspend the microorganisms described above. To obtain an inoculation control. After inoculation in certified neutral gravy and incubated for an appropriate period of time, the inoculation control was 1.0 × 10 ⁵ to 1.0 × 10 ⁶ cfu / ml.

Disinfection Efficacy Testing and ″ Independence for Disinfection Products ”of Contact Lens Care Products as Draft Premarket Notification (510 (k)) Guidance Document For Contact Lens Care Products, dated April 1, 1996, by the Department of Ophthalmology, Department of Ophthalmic Devices, US Food and Drug Administration. The solution was evaluated based on performance requirements, also called the Stand-Alone procedure ″ (hereinafter referred to as ″ independent test ″). This performance requirement is comparable to the current ISO standards for contact lens disinfection (revised in 1995). Independent tests were administered to a disinfectant product a standard inoculum of a representative range of microorganisms and compared the degree of survival reduction of the microorganisms at predetermined time intervals while the product was in use. There are primary and secondary performance criteria. The primary criterion for a given disinfection period (corresponding to the minimum recommended disinfection period) is whether the number of bacteria recovered per ml can be lowered to an average log reduction of 3.0 or more within a given disinfection period. Is it possible to reduce the number of molds and yeasts recovered per milliliter so that the log reduction is averaged above 1.0 within the minimum recommended disinfection time, and there should be no increase for four times the minimum recommended disinfection time? Failure to meet these primary performance criteria is described in the Draft Premarket Notification (510 (k)) Guidance Document For Contact Lens Care Products dated April 1, 1996 by the US Food and Drug Administration or similarly ISO / CEN-managed test. There is a second performance criterion for quality testing of the solution to determine whether it passes the “control test process” described in the process. Under secondary performance criteria, the combined log reduction for all three bacteria should average above 5.0 within the recommended disinfection period. The minimum allowable mean log reduction value for any single bacterial type is 1.0. Stationary conditions for yeast and mold should be observed during the recommended disinfection period. If the secondary performance criteria are passed (also referred to as minimal antimicrobial activity in the independent process), the control test performs the proposed disinfection control (usually rubbing) as a standard inoculum of a representative range of microorganisms. The inoculum in step is preliminarily applied to the contact lens.

The test procedure is the same as that prepared in Example 4 but is used to evaluate the antimicrobial effect of the disinfectant solution containing bis (biguanide) alexidine at various concentrations from 1 ppm to 5 ppm over a one hour test period. The results are shown in Table 2 below.

microbe Alexidine and 2HCl concentration (ppm) Log Decrease Value After 1 Hour s. Aureus One 1.6 s. Aureus 2 4.3 s. Aureus 3 〉 4.8 s. Aureus 4 〉 4.8 s. Aureus 5 〉 4.8 blood. Aeruzinosa One 〉 5.0 blood. Aeruzinosa 2 〉 5.0 blood. Aeruzinosa 3 〉 5.0 blood. Aeruzinosa 4 〉 5.0 blood. Aeruzinosa 5 〉 5.0 s. Marsessen One 3.5 s. Marsessen 2 〉 4.8 s. Marsessen 3 〉 4.8 s. Marsessen 4 〉 4.8 s. Marsessen 5 〉 4.8

The results show that the bis (biguanide) alexidine solution passes the 1 hour independent test for bacteria at 2.0 ppm since the log reduction of all three bacteria must be 3 within a given disinfection time. From 1.0 ppm alexidine does not pass the 1 hour independent test for bacteria (for Serratia marsessense). To determine whether the 1 hour independent test passed, fungi should also be tested, which was performed in the following examples.

Example 6

This example used the test procedure described in Example 5 above, but formulated at a concentration of 4.0 ppm of alexidine and 15 minutes of 25%, 50%, 75% and 100% of the 1 hour minimum recommended disinfection time, The antimicrobial effects of the solutions described in Example 4 of the present invention were presented at time intervals of 30 minutes, 45 minutes and 60 minutes. The solution was aged at 25 ° C. for 19 months. The results are shown in Table 3 below.

microbe Immersion time Log reduction Staphylococcus aureus 15 minutes 30 minutes 45 minutes 60 minutes 2.54.4〉 4.9〉 4.9 Pseudomonas Aeruzinosa 15 minutes 30 minutes 45 minutes 60 minutes 4.0〉 4.8〉 4.8〉 4.8 Serratia Marsessense 15 minutes 30 minutes 45 minutes 60 minutes 3.2> 4.7> 4.7> 4.7 Cantida Albicans 15 minutes 30 minutes 45 minutes 60 minutes 4 hours 1.92.52.72.83.4 Fusarium Solani 15 minutes 30 minutes 45 minutes 60 minutes 4 hours 3.44.34.44.2〉 4.4

Based on the same criteria as disclosed in Example 5, the Alexidine solution formulated at 4.0 ppm can pass an independent test (no rubbing or washing) at 30, 45 and 60 minutes. In the case of Staphylococcus aureus, the test did not pass because the desired range of values was not obtained at 15 minutes.

Example 7

This example presented the antimicrobial effect of an embodiment of the present invention using the test procedure described in Example 5 above. This test is similar to Example 6 but using different lots aged for only 18 months. Alexidine concentrations were formulated at 4.0 ppm and tested at time intervals of 15 minutes, 30 minutes, 45 minutes and 60 minutes. The results are shown in Table 4 below.

microbe Immersion time Log reduction Staphylococcus aureus 15 minutes 30 minutes 45 minutes 60 minutes 3.74.7〉 4.8〉 4.8 Pseudomonas Aeruzinosa 15 minutes 30 minutes 45 minutes 60 minutes 4.2〉 4.8〉 4.8〉 4.8 Serratia Marsessense 15 minutes 30 minutes 45 minutes 60 minutes 3.04.7〉 4.8〉 4.8 Cantida Albicans 15 minutes 30 minutes 45 minutes 60 minutes 4 hours 1.01.71.92.13.1 Fusarium Solani 15 minutes 30 minutes 45 minutes 60 minutes 4 hours 2.4〉 4.5〉 4.5〉 4.5〉 4.5

In this test, alexidine passed independent tests at 30, 45 and 60 minutes and only 15 minutes at Serratia Marsessense and Candida albicans. The 30-minute, 45-minute, and 1-hour independent testing clearly demonstrates increased disinfection and passes acceptance criteria.

Example 8

This example presented the antimicrobial effect of the solution of the present invention using the test procedure described in Example 5 above. At the end of time, these tests were similar to Example 6 except that different batches were used. Alexidine concentrations were formulated at 4.0 ppm and tested at time intervals of 15 minutes, 30 minutes, 45 minutes and 60 minutes, 25%, 50%, 75% and 100% of the 1 hour minimum recommended disinfection time. The solution was aged at 25 ° C. for 19 months. The results are shown in Table 5 below.

microbe Immersion time Log reduction Staphylococcus aureus 15 minutes 30 minutes 45 minutes 60 minutes 3.5〉 4.9〉 4.9〉 4.9 Pseudomonas Aeruzinosa 15 minutes 30 minutes 45 minutes 60 minutes 3.3> 4.8> 4.8> 4.8 Serratia Marsessense 15 minutes 30 minutes 45 minutes 60 minutes 2.54.6〉 4.7〉 4.7 Cantida Albicans 15 minutes 30 minutes 45 minutes 60 minutes 4 hours 0.91.71.81.92.6 Fusarium Solani 15 minutes 30 minutes 45 minutes 60 minutes 4 hours 3.6〉 4.6〉 4.6〉 4.6〉 4.6

In this test, the Alexidine solution passed independent tests at 30, 45 and 60 minutes, but at 15 minutes the log reduction for Serratia marcessens was less than 3 and the log reduction for yeast Candida albicans. The test did not pass because the value was less than 1. The results presented in Tables 3, 4, and 5 above may result in some deviations due to testing different lots of solutions disclosed in Example 4 above, but the 4.0 ppm alexidine solution is at least approximately to pass the independent test without rubbing. You can see that it takes 30 minutes.

Comparative Example 9

This example compared the antimicrobial effect of a similar solution containing only PHMB as a fungicide and the solution of the present invention. Both solutions were borate buffered to enhance the efficacy of biguanides. The test procedure used to evaluate the antimicrobial effect of the disinfectant solution was the same as that described in Example 5 above. The results are shown in Table 6 below.

Test microorganism Test time 1.0 ppm PHMB 4.0 ppm Alexidine 2HCl Staphylococcus aureus 1 hour 2 hours 3 hours 4 hours 3.53.9〉 4.9〉 4.9 〉 4.9〉 4.9〉 4.9〉 4.9 Pseudomonas Aeruzinosa 1 hour 2 hours 3 hours 4 hours 3.54.04.1> 4.8 〉 4.8〉 4.8〉 4.8〉 4.8 Serratia Marsessense 1 hour 2 hours 3 hours 4 hours 3.24.2〉 4.7〉 4.7 3.7〉 4.7〉 4.7〉 4.7 Canditta albicans 1 hour 2 hours 3 hours 4 hours 24 hours 2.93.03.43.44.3 2.94.3> 4.73.94.6 Fusarium Solani 1 hour 2 hours 3 hours 4 hours 24 hours 0.40.50.40.41.3 3.14.14.54.6

As shown in Example 5, the acceptance criterion is that the number of bacteria recovered per ml is 99.9% (recommended in the instructions inserted in the label, package and / or package) for 99.9% (log reduction of 3 or more). The number of molds and yeasts recovered per milliliter can be as low as 90% (log reduction of 1 or more) within the minimum recommended disinfection time and increased over four times the minimum recommended time. It should not be. The above results show that 1.0 ppm PHMB did not pass the 1 hour independent test. This is because the fungus Fusarium Solani has not been sufficiently reduced. In contrast, the 4.0 ppm alexidine solution of the present invention passed a 1 hour independent test. After 1 hour the number of molds was reduced to 3.1 log values. Currently, PHMB is used at about 1.0 ppm in commercial solutions for soft lens disinfection. Clinical investigations have shown that increasing the PHMB concentration to 3.0 ppm may be less safe than desirable for use in soft contact lenses. In contrast, as shown in the following examples, based on a rabbit study, it was found that the Alexidine 4.0 ppm solution can be used in humans very safely for soft lens disinfection.

Example 10

This example was prepared as described in Example 4, but confirmed the toxicity of the alexidine present in the solution prepared at various concentrations of bis (biguanide) to the eye. The amount of alexidine is 4 ppm (test 1), 6 ppm (test 2), 8 ppm (test 3), 10 ppm (test 4), 12 ppm (test 5), 15 ppm (test 6), and 18 ppm (test), respectively. A series of formulations were prepared at 7), 22 ppm (test 8), 27 ppm (test 9), 33 ppm (test 10), 40 ppm (test 11) and 50 ppm (test 12). Alexidine's test solution was used to immerse the trademark J & J SureVue (Etafilcon A) lens in 2.5 ml of solution for at least one week to obtain maximum alexidine uptake.

An ocular stimulation screening study was performed in rabbits to determine the threshold of ocular stimulation. Eyes treated with treatment lenses were compared to the opposite control eye. The treated lens was placed in the rabbit's right eye, and the control lens was placed in the left eye. Any lens placed in the eye while wearing the lens was reinserted after washing with 0.9% sodium chloride USP solution (SC). Before the lens was placed, eyes were examined under a direct light source 50 to 70 minutes, 7 to 8 hours, 23 to 24 hours and 30 to 32 hours after the lens was placed. Draize grading system [Draise J. H., G. Woodward and H. O. Calberry, 1994. A study on the toxicity and irritation of substances used locally on skin and mucous membranes. J. Pharmacol. Exp. Ther. 82: 377-390, and the visual observations were recorded according to the criteria. The maximum total grade is the sum of all grades obtained for the cornea, iris and conjunctiva. The total possible maximum grade is 110 in one eye, 80 for the cornea, 10 for the iris and 20 for the conjunctiva.

The visual inspection of each animal for each eye is shown in Table 7 below (all gross measurements).

After using the lens Test number Alexidine 2HCl (ppm) Before using lens 50-70 minutes 7-8 hours 23 to 24 hours 30-32 hours R L R L R L R L R L One 4 0 0 2 2 2 0 2 0 2 2 2 4 0 0 2 2 2 2 2 2 2 2 3 4 0 0 2 2 2 2 2 2 2 2 4 6 2 0 2 2 2 0 2 0 2 0 5 6 2 2 2 2 2 2 2 2 2 2 6 6 2 2 2 2 2 0 2 0 2 0 7 8 0 0 2 0 2 0 2 2 2 2 8 8 2 2 2 2 2 2 2 0 2 2 9 8 2 2 2 2 2 2 2 2 2 2 10 10 2 0 2 0 4 0 2 0 2 0 11 10 2 2 2 0 2 0 2 2 2 2 12 10 0 0 2 0 4 2 0 0 0 0 13 12 2 0 2 2 2 2 2 2 2 2 14 12 2 2 2 2 2 2 2 2 2 2 15 12 2 2 2 2 2 2 2 2 2 2 16 15 0 0 2 2 4 0 2 0 2 0 17 15 2 2 4 2 4 0 2 2 2 2 18 15 0 0 2 0 4 0 0 0 2 0 19 18 2 0 2 2 6 2 2 0 2 0 20 18 2 2 2 2 6 2 2 2 2 2 21 18 2 2 2 2 6 2 2 2 2 2 22 22 2 0 2 2 11 0 2 0 2 2 23 22 2 2 2 2 11 0 2 0 2 2 24 22 0 0 2 0 11 0 2 0 2 0 25 27 2 0 2 2 13 2 2 2 2 0 26 27 2 0 2 2 11 2 2 2 2 0 27 27 2 2 2 2 6 2 2 2 2 0 28 27 2 0 2 2 11 2 7 2 7 2 29 27 2 0 2 2 11 2 7 2 7 2 30 27 2 0 2 2 9 0 2 0 2 0 R = right (test) eye; L = Left (Control) Eye

In rabbits, lenses immersed in 10 ppm alexidine showed first symptoms due to increased ocular toxicity, and conjunctival reactions were observed 7-8 hours after lens wearing. This sporadic conjunctival reaction is evident when the amount of alexidine in the solution is 15 ppm, and continues to increase as the amount used increases. Iris invasion was observed at 22 ppm and corneal opacity was observed at 27 ppm. Conjunctival hyperemia, conjunctival edema and hepatitis developed on the basis of only drape observations in lenses of 22 ppm to 27 ppm (Test Nos. 8 and 9). In addition to the above observations, iris infections were observed in lenses 8 and 9. The above results show that formulations with alexidine greater than 10 ppm cannot be used to disinfect soft contact lenses. A preferred formulation is a formulation with 4 ppm of alexidine, which represents a 2.5-fold safer advantage for abnormally initiating eye health in rabbits.

Example 11

This example illustrates a method of making an antiseptic aqueous solution of a method comprising a combination of alexidine and polyhexamethylene biguanide (also referred to as PAPB or PHMB). The following components were used as the indicated component (% by weight) per total volume of the solution.

% (w / v) PHMBHCl 0.00008 Alexidine 2HCl 0.0002 Poloxamine 1107 ^** 1.0 Na ₂ EDTA 0.11 Boric acid 0.66 Sodium borate 0.10 Sodium chloride 0.54 Distilled water 100.0 ^** Molecular Weight 14,500, 70% (w / v) Trademark Tetronic 1107, Poly (oxypropylene) poly (oxyethylene) block copolymer adduct of ethylene diamine, BASF WY-DOT CORP. Brand Name of

A solution was prepared by dissolving disodium EDTA in it while gradually heating 80% by weight of water to 80 ° C. Boric acid and sodium borate were added and dissolved in a heated solution of disodium EDTA. Sodium chloride was added to the solution, which was dissolved, followed by the addition of surfactant. The solution was sterilized by autoclave at 120 ° C. for 45 minutes. After the solution was cooled to room temperature, bis (biguanide) and PAPB were added through a sterile filter and the remainder was filled with distilled water. The solution was packaged in sterile plastic containers.

Example 12

This example illustrates the improved antibacterial effect of a combination of alexidine and polyhexamethylene biguanide (PAPB) in a disinfecting aqueous solution for contact lenses. It was determined whether the primary performance criteria were passed at 5, 15, 30 and 4 hours according to the test procedure described in Example 5 above. Alexidine concentrations in these tests were formulated in combination with 0.0 ppm (control) or 0.8 ppm PAPB in the range of 0.0 ppm to 4.0 ppm, the latter being present in commercially available multipurpose solutions for soft contact lenses. It is used. The results are shown in Table 8 below.

Alexidine 2HCl PAPBHCl (ppm) Immersion time Log reduction value Marsessen Log reduction value. Albicans 0.5 0.8 5 minutes - 0.6 15 mins 2.0 1.1 30 minutes 3.2 1.8 60 mins 4.3 3.5 1.0 0.8 5 minutes - 0.5 15 mins 2.6 1.1 30 minutes 3.7 2.2 60 mins 〉 4.3 4.2 2.6 0.8 5 minutes - 0.7 15 mins 2.7 2.2 30 minutes 〉 4.3 3.3 60 mins 〉 4.3 〉 4.2 4.0 0.8 5 minutes - 1.1 15 mins 〉 4.3 3.0 30 minutes 〉 4.3 〉 4.2 60 mins 〉 4.3 〉 4.2 0.5 0.0 5 minutes - 0.3 15 mins 0.6 1.0 30 minutes 1.6 -0.2 60 mins 2.5 -0.1 2.6 0.0 5 minutes - 0.4 15 mins 2.2 0.5 30 minutes 〉 4.3 0.5 60 mins 〉 4.3 1.4 0.0 0.8 15 mins - 0.6 30 minutes 1.3 0.8 45 mins 2.0 1.4 60 mins 3.1 2.9

From the above results, the addition of alexidine to polyhexamethylene biguanide greatly improved the antibacterial effect. When several parameters were compromised for practical use, the improved effect was obtained at about 4.0 ppm. This is because the use of higher concentrations of antimicrobials may increase the toxicity and therefore cannot be used even if the antimicrobial effect is improved. Seed. Albicans appears to have a synergistic effect at times of 15 minutes and 30 minutes and is more potent than the sum of alexidine 2.6 ppm itself and PAPB 0.8 ppm itself in combination with 2.6 ppm of alexidine and 0.8 ppm of PAPB. appear.

Example 13

This example illustrates a method for preparing the disinfecting aqueous solution of the present invention comprising a combination of alexidine and polyhexamethylene biguanide (also referred to as PHMB). The following components were used as the indicated component (% by weight) per total volume of the solution.

% (w / v) PHMB 0.0008 Alexidine 2HCl 0.0002 Poloxamine 1107 ^** 1.0 Na ₂ EDTA 0.11 Boric acid 0.66 Sodium borate 0.10 Sodium chloride 0.54 Distilled water 100.0 ^** Molecular Weight 14,500, 70% (w / v) Trademark Tetronic 1107, Poly (oxypropylene) poly (oxyethylene) block copolymer adduct of ethylene diamine, BASF WY-DOT CORP. Brand Name of

A solution was prepared by dissolving disodium EDTA in it while gradually heating 80% by weight of water to 80 ° C. Boric acid and sodium borate were added and dissolved in a heated solution of disodium EDTA. Sodium chloride was added to the solution, which was dissolved, followed by the addition of surfactant. The solution was sterilized by autoclave at 120 ° C. for 45 minutes. After the solution was cooled to room temperature, alexidine bis (biguanide) and PHMB were added through a sterile filter and the remainder was filled with distilled water. The solution was packaged in sterile plastic containers.

Example 14

This example illustrates the bactericidal effect of the solution of the present invention. Prepared in the same manner as in Example 13 using the above test procedure, but containing only 1 ppm to 4 ppm of bis (biguanide) alexidine at various concentrations and 0.3 ppm to 1.5 ppm of various concentrations of biguanide polymer. Antimicrobial efficacy was evaluated for C. albicans using a disinfectant solution. The results after soaking for 5 minutes are shown in Table 10, the results after soaking for 10 minutes are shown in Table 11, the results after soaking for 30 minutes are shown in Table 12, and the results after soaking for 45 minutes are shown in Table 13. Tables 14-17, which correspond to Tables 10-13, respectively, compare the theoretical lethality based on the actual number of dead microorganisms relative to the sum of the individual disinfectants using a mixture of disinfectants.

8 minutes later PHMB 0 ppm 0.3 ppm 0.8 ppm 1.5 ppm Alexandrid 0 ppm 0.4 0.4 0.7 1.0 1 ppm 0.5 0.6 0.9 1.1 2 ppm 0.7 0.8 0.9 1.5 3 ppm 0.8 1.1 1.6 2.6 4 ppm 1.1 1.8 2.8 3.4

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

30 minutes later PHMB 0 ppm 0.3 ppm 0.8 ppm 1.5 ppm Alexandrid 0 ppm 0.4 1.0 2.1 3.1 1 ppm 0.5 1.8 3.3 4.4 2 ppm 1.2 2.1 3.7 4.5 3 ppm 1.9 3.5 4.8 〉 4.8 4 ppm 3.4 〉 4.8 〉 4.8 〉 4.8

45 minutes later PHMB 0 ppm 0.3 ppm 0.8 ppm 1.5 ppm Alexandrid 0 ppm 0.4 1.1 3.0 4.1 1 ppm 0.4 2.1 3.7 〉 4.8 2 ppm 0.9 2.6 4.5 〉 4.8 3 ppm 2.1 4.5 〉 4.8 〉 4.8 4 ppm 3.7 4.8 〉 4.8 〉 4.8

5 minutes later Log Lethal Microbial Count Formulation Theory real 1 ppm alexidine / 0.3 ppm PHMB 0.9 0.6 2 ppm alexidine / 0.3 ppm PHMB 1.1 0.8 3 ppm alexidine / 0.3 ppm PHMB 1.2 1.1 4 ppm alexidine / 0.3 ppm PHMB 1.5 1.8 1 ppm alexidine / 0.8 ppm PHMB 1.2 0.9 2 ppm alexidine / 0.8 ppm PHMB 1.4 0.9 3 ppm alexidine / 0.8 ppm PHMB 1.5 1.6 4 ppm alexidine / 0.8 ppm PHMB 1.8 2.8 1 ppm alexidine / 1.5 ppm PHMB 1.5 1.1 2 ppm alexidine / 1.5 ppm PHMB 1.7 1.5 3 ppm alexidine / 1.5 ppm PHMB 1.8 2.6 4 ppm alexidine / 1.5 ppm PHMB 2.1 3.4

15 minutes later Log Lethal Microbial Count Formulation Theory real 1 ppm alexidine / 0.3 ppm PHMB 1.1 1.1 2 ppm alexidine / 0.3 ppm PHMB 1.5 1.7 3 ppm alexidine / 0.3 ppm PHMB 2.3 2.7 4 ppm alexidine / 0.3 ppm PHMB 3.3 3.8 1 ppm alexidine / 0.8 ppm PHMB 1.9 2.2 2 ppm alexidine / 0.8 ppm PHMB 2.3 2.8 3 ppm alexidine / 0.8 ppm PHMB 3.1 3.7 4 ppm alexidine / 0.8 ppm PHMB 4.1 4.8 1 ppm alexidine / 1.5 ppm PHMB 2.3 2.9 2 ppm alexidine / 1.5 ppm PHMB 2.7 3.5 3 ppm alexidine / 1.5 ppm PHMB 3.5 4.5 4 ppm alexidine / 1.5 ppm PHMB 4.5 4.8

30 minutes later Log Lethal Microbial Count Formulation Theory real 1 ppm alexidine / 0.3 ppm PHMB 1.5 1.8 2 ppm alexidine / 0.3 ppm PHMB 2.2 2.1 3 ppm alexidine / 0.3 ppm PHMB 2.9 3.5 4 ppm alexidine / 0.3 ppm PHMB 4.4 4.8 1 ppm alexidine / 0.8 ppm PHMB 2.6 3.3 2 ppm alexidine / 0.8 ppm PHMB 3.3 3.7 3 ppm alexidine / 0.8 ppm PHMB 4.0 4.8 4 ppm alexidine / 0.8 ppm PHMB 4.8 4.8 1 ppm alexidine / 1.5 ppm PHMB 3.6 4.4 2 ppm alexidine / 1.5 ppm PHMB 4.3 4.5 3 ppm alexidine / 1.5 ppm PHMB 4.8 4.8 4 ppm alexidine / 1.5 ppm PHMB 4.8 4.8

45 minutes later Log Lethal Microbial Count Formulation Theory real 1 ppm alexidine / 0.3 ppm PHMB 1.5 2.1 2 ppm alexidine / 0.3 ppm PHMB 2.0 2.6 3 ppm alexidine / 0.3 ppm PHMB 3.2 4.5 4 ppm alexidine / 0.3 ppm PHMB 4.8 4.8 1 ppm alexidine / 0.8 ppm PHMB 3.4 3.7 2 ppm alexidine / 0.8 ppm PHMB 3.9 4.5 3 ppm alexidine / 0.8 ppm PHMB 4.8 4.8 4 ppm alexidine / 0.8 ppm PHMB 4.8 4.8 1 ppm alexidine / 1.5 ppm PHMB 4.5 4.8 2 ppm alexidine / 1.5 ppm PHMB 4.8 4.8 3 ppm alexidine / 1.5 ppm PHMB 4.8 4.8 4 ppm alexidine / 1.5 ppm PHMB 4.8 4.8

The results indicate that the combination of Alexidine and PHMB in a good ratio is higher than the number of log lethal microorganisms combined with the results of the individual disinfectants, and the synergistic effect is evident and results begin to appear after 15 minutes. At 45 minutes, the synergistic effect is somewhat lower since most of the microorganisms have already been killed.

Although the present invention has been described in connection with specific embodiments, it is for illustrative purposes only. Accordingly, various alternatives, modifications, and variations will be apparent to those skilled in the art in view of the foregoing specification, and all alternatives, modifications, and variations are within the scope and spirit of the appended claims.

Claims (31)

(a) a bactericidal effective amount of bis (biguanide) represented by the following formula (I) in an amount of about 2.0 to about 8.0 ppm or other water-soluble salt of the corresponding molar content or bis (biguanide) in free base form thereof, (b) an effective amount of buffer, (c) an effective amount of surfactant, and (d) An ophthalmic safe contact lens disinfectant solution containing an aqueous solution comprising at least about 90% by weight of water in the formulation. Formula I Wherein R ¹ and R ⁴ are each C ₄ -C ₁₂ branched or unbranched alkyl, C ₄ -C ₁₂ alkoxyalkyl ether or alkylsulfide radical, or C ₅ -C ₁₂ cycloalkyl or cycloalkyl-alkyl Selected from the group consisting of radicals, R ² and R ³ are each selected from the group consisting of hydrogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxyalkyl, C ₅ -C ₁₂ cycloalkyl or cycloalkyl-alkyl, R ⁶ and R ⁷ are each selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl radicals, A is a divalent group of C ₄ -C ₁₆ and is selected from the group consisting of alkylene, alkyloxyalkyl and alkylsulfide radicals wherein the alkyloxyalkyl or alkylsulfide radicals described above are at least one oxygen and / or sulfur A polymethylene chain with an atom inserted or a polymethylene chain substituted with an alkoxy (-OR ⁸ ) or alkylthio (-SR ⁹ ) group, wherein R ⁸ and R ⁹ are each C ₁ -C ₁₂ alkyl, C ₅ -C ₁₂ Selected from the group consisting of cycloalkyl or cycloalkyl-alkyl; or A is a C ₈ -C ₁₆ divalent polymethylene group having a divalent radical of cyclohexane or diaza-cyclohexane inserted. The disinfectant for contact lenses safe for ophthalmic use according to claim 1, wherein bis (biguanide) is a compound represented by the following general formula (II). Formula II Wherein R ¹ and R ⁴ are each selected from the group consisting of C ₆ -C ₁₀ branched or unbranched alkyl, C ₆ -C ₁₀ alkoxyalkyl ether or alkylsulfide thioether radicals, n is 5 to 7 to be. The disinfectant solution for contact lenses safe for ophthalmic use according to claim 2, wherein R ¹ and R ⁴ are C ₆ -C ₁₀ branched or unbranched alkyl. The disinfectant solution for contact ophthalmic safety according to claim 1, wherein the surfactant is a neutral or nonionic surfactant present in an amount of 0.01% to 5.0%. 2. The surfactant of claim 1, wherein the surfactant is a neutral or nonionic surfactant having a plurality of poly (oxyalkylene) chains, each poly (oxyalkylene) comprising a (—OR) repeat unit, wherein R A disinfectant solution for contact lenses that is safe for ophthalmic where each is C ₂ -C ₆ alkylene. 6. The disinfectant solution for an ophthalmic safe contact lens according to claim 5, wherein the surfactant is a neutral or nonionic surfactant comprising a block copolymer of poly (ethylene oxide) and poly (propylene oxide) segments. The disinfectant solution for contact ophthalmic safety according to claim 1, wherein the amount of bis (biguanide) is 2.5 ppm to 6.0 ppm. The disinfectant solution for contact ophthalmic safety according to claim 1, wherein the amount of bis (biguanide) is 3.0 ppm to 5.0 ppm. (a) (i) Bis (biguanide) hydrochloride represented by the following formula (I) in an amount of about 2.0 to about 8.0 ppm or other water-soluble salt of corresponding molar content or bis (biguanide) in free base form thereof ), (ii) an effective amount of buffer, (iii) immersing the lens to obtain an acceptable contact lens disinfection within the minimum recommended immersion period comprising an effective amount of surfactant in the formulation, (b) placing the treatment lens directly into the wearer's eye, and (i) eliminating the need for rinsing with other solutions prior to eye contact and (ii) eliminating the need for other solutions to clean the lens daily A method of cleaning and disinfecting or disinfecting soft contact lenses with a versatile solution. Formula I Wherein R ¹ and R ⁴ are each C ₄ -C ₁₂ branched or unbranched alkyl, C ₄ -C ₁₂ alkoxyalkyl or alkylsulfide radical, or C ₅ -C ₁₂ cycloalkyl or cycloalkyl-alkyl radical Is selected from the group consisting of R ² and R ³ are each selected from the group consisting of hydrogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxyalkyl, C ₅ -C ₁₂ cycloalkyl or cycloalkyl-alkyl, R ⁶ and R ⁷ are each selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl radicals, A is a divalent group of C ₄ -C ₁₆ and is selected from the group consisting of alkylene, alkyloxyalkyl and alkylsulfide radicals wherein the alkyloxyalkyl or alkylsulfide radicals described above are at least one oxygen and / or sulfur A polymethylene chain with an atom inserted or a polymethylene chain substituted with an alkoxy (-OR ⁸ ) or alkylthio (-SR ⁹ ) group, wherein R ⁸ and R ⁹ are each C ₁ -C ₁₂ alkyl, C ₅ -C ₁₂ Selected from the group consisting of cycloalkyl or cycloalkyl-alkyl; or A is a C ₈ -C ₁₆ divalent polymethylene group having a divalent radical of cyclohexane or diaza-cyclohexane inserted. (a) (i) a bactericidal effective amount of bis (biguanide) represented by the following formula (I) in an amount of about 2.0 to about 8.0 ppm, or other water-soluble salt of the corresponding molar content, or bis (biguani) in free base form thereof: De), (ii) an effective amount of buffer, (iii) immersing the lens in solution so as to obtain acceptable contact lens disinfection without rubbing the lens with a solution comprising an effective amount of surfactant in the formulation, (b) placing the treatment lens directly into the wearer's eye, and (i) removing the lens from the eye and disinfecting it with a solution and then rubbing the lens with the same or different solution in the middle of putting the lens in the eye, (ii) it does not need to be cleaned with other solutions prior to eye contact. (iii) A method of cleaning and disinfecting or disinfecting a soft contact lens with a multipurpose solution or an effective multipurpose solution that does not involve rubbing, in which no other solution is required to clean the lens daily. Formula I Wherein R ¹ and R ⁴ are each C ₄ -C ₁₂ branched or unbranched alkyl, C ₄ -C ₁₂ alkoxyalkyl or alkylsulfide radical, or C ₅ -C ₁₂ , preferably C ₇ -C Selected from the group consisting of ₁₀ cycloalkyl or cycloalkyl-alkyl radicals, R ² and R ³ are each selected from the group consisting of hydrogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxyalkyl, C ₅ -C ₁₂ cycloalkyl or cycloalkyl-alkyl, R ⁶ and R ⁷ are each selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl radicals, A is a divalent group of C ₄ -C ₁₆ and is selected from the group consisting of alkylene, alkyloxyalkyl and alkylsulfide radicals wherein the alkyloxyalkyl or alkylsulfide radicals described above are at least one oxygen and / or sulfur A polymethylene chain with an atom inserted or a polymethylene chain substituted with an alkoxy (-OR ⁸ ) or alkylthio (-SR ⁹ ) group, wherein R ⁸ and R ⁹ are each C ₁ -C ₁₂ alkyl, C ₅ -C ₁₂ Selected from the group consisting of cycloalkyl or cycloalkyl-alkyl; or A is a C ₈ -C ₁₆ divalent polymethylene group having a divalent radical of cyclohexane or diaza-cyclohexane inserted. The method of claim 9 or 10, wherein the soft contact lens is cleaned and disinfected or disinfected with a multipurpose solution or an effective multipurpose solution, which is used to clean a lens set or planned to be replaced within about 90 days of wearing the solution. Way. The method of claim 11, wherein the solution comprises about 0.0-5 mol% of repeating units derived from methacrylic acid (MAA), 10-99 mol% of repeating units derived from hydroxyethyl methacrylate and about 0.5-5 percent of crosslinked repeating units. A method of cleaning and disinfecting or disinfecting a soft contact lens with a multipurpose solution or an effective multipurpose solution, wherein the lens is made of a polymer comprising mole percent and the lens is set or planned to be replaced within about 14 days of wearing. A method according to claim 9 or 10, wherein the lens wearer has a minimum dipping time required for lens care of 4 hours or less to clean and disinfect or disinfect the soft contact lens with a multipurpose solution or an effective multipurpose solution. The method of claim 9, wherein the bis (biguanide) is a compound represented by the following formula (II) or a water-soluble salt thereof: A method for cleaning and disinfecting or disinfecting a soft contact lens with an multipurpose solution or an effective multipurpose solution. Formula II Wherein R ¹ and R ⁴ are each selected from the group consisting of branched or unbranched alkyl, alkoxyalkyl ether or alkylsulfide thioether radicals, n is 5-7. (a) a bactericidal effective amount of bis (biguanide) represented by the following formula (I) in an amount of about 0.10 to about 4.0 ppm or other water-soluble salt of the corresponding molar content or bis (biguanide) in free base form thereof, (b) at least one polymer biguanide represented by the following formula (IV) in a total amount of 0.10 to about 3.0 ppm, (c) an effective amount of buffer, (d) an effective amount of surfactant, and (e) Ophthalmically safe disinfectant contact lenses containing an aqueous solution comprising at least about 90% by weight of water before mixing. Formula I Formula IV Wherein R ¹ and R ⁴ are each C ₄ -C ₁₂ branched or unbranched alkyl, C ₄ -C ₁₂ alkoxyalkyl ether or alkylsulfide radical, or C ₅ -C ₁₂ cycloalkyl or cycloalkyl-alkyl Selected from the group consisting of radicals, R ² and R ³ are each selected from the group consisting of hydrogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxyalkyl, C ₅ -C ₁₂ cycloalkyl or cycloalkyl-alkyl, R ⁶ and R ⁷ are each selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl radicals, A is a divalent group of C ₄ -C ₁₆ and is selected from the group consisting of alkylene, alkyloxyalkyl and alkylsulfide radicals, wherein the alkyloxyalkyl or alkylsulfide radicals described above have at least one oxygen and / or sulfur valence An inserted polymethylene chain or a polymethylene chain substituted with an alkoxy (-OR ⁸ ) or alkylthio (-SR ⁹ ) group, wherein R ⁸ and R ⁹ are each C ₁ -C ₁₂ alkyl, C ₅ -C ₁₂ cyclo Selected from the group consisting of alkyl or cycloalkyl-alkyl, or A is a divalent polymethylene group of C ₈ -C _{16 to which} a divalent radical of cyclohexane or 1,4-diaza-cyclohexane is inserted, Z is an organic divalent bridging group which may be the same or different throughout the polymer, n is on average 3 or more, X ¹ and X ² are -NH ₂ and Is selected from. The disinfectant solution for an ophthalmicly safe contact lens according to claim 14, wherein the bis (biguanide) of (a) is represented by the following general formula (I). Formula I Wherein R ¹ and R ⁴ are each selected from the group consisting of C ₆ -C ₁₀ straight or branched chain alkyl, C ₆ -C ₁₀ alkoxyalkyl ether or alkylsulfide thioether radicals, and A is C ₄ -C ₁₂ Is a bivalent saturated chain. 15. The disinfectant solution for an ophthalmicly safe contact lens according to claim 14, comprising a polymer biguanide which is a polymer mixture represented by the following formula (V). Formula V Wherein X ¹ and X ² are as described above. 15. The disinfectant solution for contact ophthalmic safety according to claim 14, wherein the surfactant is a neutral or nonionic surfactant present in an amount of 0.01% to 5.0%. 15. The surfactant of claim 14, wherein the surfactant is a neutral or nonionic surfactant having a plurality of poly (oxyalkylene) chains, each poly (oxyalkylene) comprising a (-OR) repeat unit, wherein R A disinfectant solution for contact lenses that is safe for ophthalmic where each is C ₂ -C ₆ alkylene. 15. The disinfectant solution of an ophthalmic safe contact lens according to claim 14, wherein the surfactant is a neutral or nonionic surfactant comprising a block copolymer of poly (ethylene oxide) and poly (propylene oxide) segments. 15. The disinfectant solution for contact lenses safe according to claim 14, wherein the amount of bis (biguanide) is 1.0 ppm to 3.0 ppm. 15. The disinfectant solution of an ophthalmic safe contact lens according to claim 14, wherein the amount of polymer biguanide is 0.1 ppm to 2.0 ppm. (a) (i) a bactericidal effective amount of bis (biguanide) represented by the following formula (I) in an amount of about 0.1 to about 4.0 ppm, or other water-soluble salt of the corresponding molar content, or bis (biguanian) in free base form thereof: De), (ii) at least about 0.10 to about 3.0 ppm of at least one polymer biguanide represented by Formula IV, (iii) an effective amount of buffer, (iii) immersing the lens in the solution to obtain an acceptable disinfection of the contact lens with a solution comprising an effective amount of a surfactant in the formulation, (b) placing the treatment lens directly into the wearer's eye, and (i) eliminating the need for rinsing with other solutions prior to eye contact and (ii) eliminating the need for other solutions to clean the lens daily A method of cleaning and disinfecting or disinfecting soft contact lenses with a versatile solution. Formula I Formula IV Wherein R ¹ and R ⁴ are each C ₄ -C ₁₂ branched or unbranched alkyl, C ₄ -C ₁₂ alkoxyalkyl ether or alkylsulfide radical, or C ₅ -C ₁₂ cycloalkyl or cycloalkyl-alkyl Selected from the group consisting of radicals, R ² and R ³ are each selected from the group consisting of hydrogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxyalkyl, C ₅ -C ₁₂ cycloalkyl or cycloalkyl-alkyl, R ⁶ and R ⁷ are each selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl radicals, A is a divalent group of C ₄ -C ₁₆ and is selected from the group consisting of alkylene, alkyloxyalkyl and alkylsulfide radicals, wherein the alkyloxyalkyl or alkylsulfide radicals described above have at least one oxygen and / or sulfur valence An inserted polymethylene chain or a polymethylene chain substituted with an alkoxy (-OR ⁸ ) or alkylthio (-SR ⁹ ) group, wherein R ⁸ and R ⁹ are each C ₁ -C ₁₂ alkyl, C ₅ -C ₁₂ cyclo Selected from the group consisting of alkyl or cycloalkyl-alkyl, or A is a divalent polymethylene group of C ₈ -C _{16 to which} a divalent radical of cyclohexane or 1,4-diaza-cyclohexane is inserted, Z is an organic divalent bridging group which may be the same or different throughout the polymer, n is 3 or more, X ¹ and X ² are -NH ₂ and Is selected from. (a) (i) a bactericidal effective amount of bis (biguanide) represented by the following formula (I) in an amount of about 0.10 to about 4.0 ppm, or other water-soluble salt of the corresponding molar content, or bis (biguani) in free base form thereof: De), (ii) at least one polymer biguanide represented by the following formula (IV) in an amount of about 0.10 to about 3.0 ppm, (iii) an effective amount of buffer, (iv) immersing the lens in solution so that an acceptable contact lens disinfection is obtained without rubbing the lens with a solution comprising an effective amount of surfactant in the formulation prior to mixing, (b) inserting the treatment lens directly into the wearer's eye, wherein (i) removing the lens from the eye and disinfecting it with a solution and then rubbing the lens with the same or different solution in between (ii) cleaning soft contact lenses with an all-purpose solution or an effective multi-purpose solution that does not require a rinse with another solution before it gets into the eye, and (iii) does not require a rubbing step to clean the lens daily And how to disinfect or disinfect. Formula I Formula IV Wherein R ¹ and R ⁴ are each C ₄ -C ₁₂ branched or unbranched alkyl, C ₄ -C ₁₂ alkoxyalkyl ether or alkylsulfide thioether radical, or C ₅ -C ₁₂ cycloalkyl or cycloalkyl Is selected from the group consisting of alkyl radicals, R ² and R ³ are each selected from the group consisting of hydrogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxyalkyl, C ₅ -C ₁₂ cycloalkyl or cycloalkyl-alkyl, R ⁶ and R ⁷ are each selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl radicals, A is a divalent group of C ₄ -C ₁₆ and is selected from the group consisting of alkylene, alkyloxyalkyl and alkylsulfide radicals wherein the alkyloxyalkyl or alkylsulfide radicals described above are at least one oxygen and / or sulfur A polymethylene chain with an atom inserted or a polymethylene chain substituted with an alkoxy (-OR ⁸ ) or alkylthio (-SR ⁹ ) group, wherein R ⁸ and R ⁹ are each C ₁ -C ₁₂ alkyl, C ₅ -C ₁₂ Selected from the group consisting of cycloalkyl or cycloalkyl-alkyl, or A is a divalent polymethylene group of C ₈ -C _{16 to which} a divalent radical of cyclohexane or 1,4-diaza-cyclohexane is inserted, Z is an organic divalent bridging group which may be the same or different throughout the polymer, n is 3 or more, X ¹ and X ² are -NH ₂ and Is selected from. The method of claim 22, wherein the bis (biguanide) is a compound represented by the following formula (II): A method for cleaning and disinfecting or disinfecting a soft contact lens with a multipurpose solution or an effective multipurpose solution. Formula II Wherein R ¹ and R ⁴ are each selected from the group consisting of branched or unbranched alkyl, alkoxyalkyl ether or alkylsulfide thioether radicals, n is 5-7. 23. The method of claim 22, wherein the polymer biguanide is a mixture of polymer biguanides of Formula (V) wherein the soft contact lens is cleaned and disinfected or sterilized with an effective multipurpose solution. Formula V Wherein X ¹ and X ² are as described above and n is on average 5 to 20. The method of claim 22, wherein the solution is used to clean a lens set or planned to be replaced within about 30 days of wearing. A method of cleaning and disinfecting or disinfecting a soft contact lens with a multipurpose solution or an effective multipurpose solution. The method of claim 27, wherein the soft contact lens is cleaned and disinfected or sterilized with a multipurpose solution or an effective multipurpose solution that is planned or set to be replaced within about 14 days of wearing. 23. The method of claim 22, wherein the solution comprises about 0.0-5 mol% of repeat units derived from methacrylic acid (MAA), 10-99 mol% of repeat units derived from hydroxyethyl methacrylate and 0.5-5 mol of crosslinked repeat units. A method of cleaning and disinfecting or disinfecting a soft contact lens with a multipurpose solution or an effective multipurpose solution which is made of a polymer comprising%. (a) a container comprising an ophthalmically safe disinfectant according to claim 1, and (b) A kit for use by a contact lens wearer for disinfecting and cleaning or disinfecting the contact lens, including packaging instructions describing how to use the contact lens wearer to perform the method of claim 10. (a) a container comprising an ophthalmically safe disinfectant according to claim 14, and (b) A kit for use by a contact lens wearer for disinfecting and cleaning or disinfecting the contact lens, including packaging instructions describing how to use the contact lens wearer to perform the method of claim 23.