JP2001522672A - Disinfection of contact lenses using bis (biguanides) and polymerized biguanides - Google Patents

Abstract

  (57) [Summary] The present invention relates to an eye-safe disinfecting solution for contact lenses, comprising a biguanide polymer in combination with a bis (biguanide), and in the form of an aqueous solution for disinfecting and / or preserving contact lenses, especially soft contact lenses. , Methods of using the composition. The present invention can be used to formulate products that have greater convenience and / or advantages as compared to traditional disinfecting products for contact lenses, and, overall, are broader, more powerful And it can provide faster antimicrobial activity.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION The present invention relates to new and improved solutions for treating contact lenses, and to methods for treating contact lenses using such solutions. In particular, the present invention relates to a disinfection system comprising a novel combination of two disinfectants, a bis (biguanide) and a polymerized biguanide.

BACKGROUND OF THE INVENTION Generally, widely used contact lenses fall into three categories: (1) acrylates (eg, polymethyl methacrylate (PMM)
A) a hard lens formed from a material prepared by polymerization of (a)), (2) a gas permeable rigid (RGP) lens formed from silicone acrylate and fluorosilicone methacrylate, and (3) a polymerized Gels, hydrogels or soft type lenses made from hydrophilic or hydrophobic monomers such as 2-hydroxyethyl methacrylate (HEMA). Hard acrylic acid type contact lenses are characterized by a low water vapor diffusion constant, resistance to the effects of light, oxygen and hydrolysis, and absorb only small amounts of aqueous fluids. The choice of an appropriate disinfectant, cleaning agent or other lens care compound is relatively unimportant, as hard contact lenses are durable, along with their tendency to absorb less water.

However, unlike hard lenses, soft type contact lenses bind significantly more fluids, environmental contaminants, water impurities, and other active ingredients commonly found in antimicrobial agents and lens care solutions, And it has a tendency to concentrate. In most cases, low levels of components in the lens care solution will not irritate ocular tissue when used properly. Nevertheless, some disinfectants and preservatives tend to accumulate on the lens surface, especially due to the inherent binding action of protein deposits to the soft lens material, and potentially dangerous levels And, when released, can cause corneal inflammation and irritation to other ocular tissues.

Certain antibacterial agents have been found to be more compatible with contact lenses and exhibit less binding to the lens surface. In one case, the biguanide chlorhexidine was found to bind 7 times less to the soft lens material than benzalkonium chloride. However, the presence of a proteinaceous oily tear film deposit on the lens can double the amount of chlorhexidine absorbed by the lens as compared to a clean lens. U.S. Pat. No. 4,354,952 discloses a very dilute disinfecting and cleaning solution containing chlorhexidine or a salt thereof in combination with certain amphoteric and non-ionic surfactants. These solutions have been found to reduce the amount of chlorhexidine bound on hydrophilic soft contact lenses. Despite the reduction in binding achieved by the present invention, the use of chlorhexidine did not result in any particular exchange conditions. The antimicrobial activity of chlorhexidine may be reduced if certain amphoteric surfactants are used. In addition, surfactants and disinfectants were reported to precipitate if not used in the proper ratios, unless non-ionic surfactants were also used.

[0005] GB 1,432,345 discloses a composition for contact lens disinfection comprising a polymerized biguanide and a mixed phosphate buffer. However, the composition disclosed by this patent has a corneal staining value of 17% or more, well above the value desired for patient acceptability.

US Pat. No. 4,758,595 to Ogunbiyi et al. Discloses polyaminopropyl biguanide (PAPB) (polyhexamethylene biguanide (PHMB)
(Also known as a contact lens solution) have enhanced potency when combined with a borate buffer. These disinfection and storage solutions are particularly noteworthy for their broad spectrum of bactericidal and fungicidal activity at low concentrations, coupled with very low toxicity when used with soft-type contact lenses.

[0007] US Pat. No. 5,453,435 to Raheja et al. Disclosed a storage system comprising a combination of chlorhexidine and polyhexamethylene biguanide. This storage system has been used in commercial products for gas permeable rigid lenses and has been found to exhibit an improved combination of efficacy and low eye irritation.

[0008] Compositions containing PHMB and borate have been commercialized in various products,
At levels below about 1 ppm for use on soft contact lenses. In general, it is desirable to provide the lowest level of bactericide potential possible, while maintaining the desired level of disinfecting efficacy to provide sufficient margin for safety and comfort.

[0009] Some of the most common products for disinfecting lenses are for cleaning, disinfecting and moistening contact lenses, followed by direct insertion without rinsing (placed in the eye). A versatile solution that can be used. Clearly, the ability to use a single solution for contact lens care is an advantage. However, such solutions must be particularly eye-friendly. Because, as described above, some of the solution is on the lens and comes into contact with the eye when inserted.

For conventional contact lens cleaners or disinfectants (including multi-purpose solutions), the lens wearer typically wears the contact lens with his or her fingers (typically, while treating the contact lens). Rubbing between fingers and palms or between fingers). The need to "rub" contact lenses daily adds to the time and effort involved in contact lens daily care. Many contact lens wearers do not like or find it inconvenient to perform such a regime. Some wearers may neglect a proper "rubbing" regime, which can cause contact lens discomfort and other problems. Occasionally, rubbing (especially likely to occur to novice lens wearers) can damage the lens if done too strictly. This can be a problem if interchangeable lenses are not readily available.

Contact lens solutions that are approved as “chemical disinfecting solutions” are the pre-market notification (510k) guidance document for contact lens care products (May 1997).
Rubbing is necessary to meet the biocidal performance criteria (typically for destroying bacteria and fungi) set by the U.S. Food and Drug Administration (FDA) is not. In contrast, contact lens solutions (referred to as "chemical disinfection systems"), which are not approved as chemical disinfection solutions, require a rubbing regime to pass the biocidal performance standard. Traditionally, multipurpose solutions (used for disinfecting and moistening or for disinfecting, cleaning, and moistening) have been approved as chemical disinfection systems, but not as chemical disinfecting solutions.

Chemical disinfecting solutions generally require more effective or more powerful disinfectants than chemical disinfecting systems. However, as the biocidal effect of the solution becomes more potent, it is more likely that it may exhibit toxic effects or adverse effects on the comfort of the lens wearer. For example, many highly effective bactericides used in other situations (eg, gargles, cosmetics, or shampoos) are sufficiently safe for the use of such products while the eye Are too toxic for use in soft lenses, especially because of the above-mentioned tendency of soft lenses to bind chemicals and the sensitivity of ocular tissue. Similarly, the concentration of a particular bactericide may be increased in solutions for use in soft contact lenses, especially when such solutions are not rinsed from the lens prior to placing the contact lens in the eye. It may need to be within lower limits than in other products or in solutions for other types of lenses.

(1) increased levels and / or a wide range of biocidal activity, and (
2) A contact lens solution that simultaneously provides both low order toxicity to ocular tissues, so that the solution can be used to treat contact lenses, and then the solution is removed from the lens It is desirable to have a contact lens solution that allows the lens to be placed in the eye without rinsing. Attempts have been made to develop a chemical, which can be used for soft contact lenses and which can be placed directly on the eye after immersion in a solution and / or rinsing and re-wetting with the solution. It is particularly desirable to have a disinfecting solution. Such products may provide increased efficacy, which will provide greater protection for the lens wearer against infections caused by microorganisms, while providing maximum simplicity. Finally, the bactericidal efficacy of the disinfecting solution with respect to bacteria and fungi, for any reason, if the contact lens wearer does not perform a regimen, including mechanical rubbing with the contact lens solution. Is high enough to achieve effective disinfection of contact lenses, or at least not an essentially ineffective disinfection.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to an eye safe disinfecting solution for contact lenses, comprising: (a) about 0.10 to about 4.0 ppm dihydrochloride A bis (biguanide) in the form of the same bis (biguanide) in the form of a free base or a different water-soluble salt at a corresponding concentration, wherein the bis (biguanide) has the following general formula or a water-soluble salt thereof: Has the form:

[0015]

Embedded image Wherein R ¹ and R ² are independently selected from the group consisting of branched or unbranched, alkyl, alkoxyalkyl, or alkyl sulfide;
Is from 4 to 16, a bisbiguanide; and (b) from about 0.1 to about 3.0 ppm of a polymeric biguanide, wherein the polymeric biguanide has the following formula:

[0016]

Embedded image Wherein Z is an organic divalent bridging group which may be the same or different throughout the polymer, n is on average at least 3, and X ¹ and X ² are-
NH ₂ group and

[0017]

Embedded image A polymeric biguanide independently selected from the group; (c) an effective amount of a buffer; and (d) water in an amount of at least about 80% by weight.

[0018] Preferably, the compositions of the present invention also include one or more surfactants. In one embodiment of the present invention, the surfactant is a neutral or non-ionic surfactant.

The present invention also relates to a method of disinfecting or cleaning and disinfecting contact lenses, the method comprising immersing the lens in the above aqueous solution for a predetermined time, and subsequently mounting the treated lens. Placing directly on the eyes of the subject. In one embodiment of the method, the contact lens does not require rubbing with this solution to achieve the required disinfection.

DETAILED DESCRIPTION OF THE INVENTION As mentioned above, the present invention relates to a composition for the combined use of a biguanide polymer and a bis (biguanide) for disinfecting and / or preserving contact lenses, especially soft contact lenses. And a method of using the composition in the form of an aqueous solution. This synergistic combination provides increased efficacy and, therefore, better protection against microorganisms compared to traditional disinfecting products for contact lenses, while providing maximum convenience. The solutions according to the invention generally provide a broader, more potent and faster antimicrobial activity when considering the full spectrum of microorganisms, based on the representative bacteria and fungi that are generally tested.
In particular, the disinfecting solution of the present invention is effective at a low concentration against a wide range of microorganisms,
Such microorganisms include Staphylococcus aureus, Pseu
domonas aeruginosa, Serratia marcesce
ns, Candida albicans, and Fusarium sola
ni, but not limited thereto.

The disinfecting solution is generally one or more active ingredients (eg, an antimicrobial and / or antimicrobial agent) at a concentration sufficient to destroy harmful microorganisms on the surface of the contact lens within the recommended minimum immersion time. Or preservatives). The recommended minimum immersion time is specified in the package instructions for use of the disinfectant solution (
package instruction). The term "disinfecting solution"
Depending on the particular formulation, the solution may be useful as a storage solution, or the disinfecting solution may be useful for other purposes such as daily cleaning, rinsing and storage of contact lenses. Does not exclude sex. Combined with the container or bottle and package containing instructions for use according to the particular regimen,
The solution of the present invention is a new and improved kit for contact lens care,
It can be considered a package, or system.

The term “soft lens” refers to a lens having a proportion of hydrophilic repeating units such that the water content of the lens in use is at least 20% by weight. The term “soft contact lens” as used herein generally refers to a contact lens that flexes easily under small forces. Typically, soft contact lenses are formulated from polymers having a certain percentage of repeating units, derived from hydroxyethyl methacrylate and / or other hydrophilic monomers, typically crosslinked with a crosslinking agent. . However, newer soft lenses are made from high Dk silicone-containing materials.

With respect to contact lens solutions, the term “eye safe” means that contact lenses treated with this solution are safe to place directly on the eye without rinsing, ie, this It means that the solution is safe and comfortable for daily contact with the eye through contact lenses moistened with this solution. An ophthalmically safe solution is one that has tonicity and pH compatible with the eye and
SO standards and U.S.A. S. Contains non-cytotoxic materials and amounts according to FDA (US Food and Drug Administration) regulations.

Solutions useful for cleaning, chemically disinfecting, storing, and rinsing soft contact lenses are referred to herein as "multi-purpose solutions." The multi-purpose solution allows some wearers (e.g., wearers who are particularly sensitive to chemical disinfectants or other chemicals) to remove the lens prior to inserting the contact lens into another solution (e.g., sterile physiological solution). Saline)
It does not exclude the possibility of choosing to rinse or moisten. The term "multi-purpose solution" also refers to periodic detergents that are typically used on a weekly basis and are not used on a daily basis, or supplemental detergents to remove proteins (eg, enzyme detergents). Does not exclude the possibility. The term “cleaning” is used when the solution is used in particular in combination with finger manipulation (eg, rubbing the lens with a finger using the solution) or an attached device that agitates the solution in contact with the lens When used in combination with (e.g., a mechanical cleaning aid), the solution is one of sufficient concentration to release and remove lens deposits and other contaminants loosely retained on the surface of the contact lens. It is meant to include the above cleaning agents. The critical micelle concentration of a surfactant-containing solution is one way to evaluate its cleaning effectiveness.

The term “effective multi-purpose solution” likewise chemically disinfects contact lenses daily,
A solution useful for storing and rinsing, which does not require cleaning contact lenses, but which further obviates the need for any other solution for daily cleaning ( That is, other solutions need not be used with or in combination with day-based solutions). Such solutions may include surfactants or other agents that may essentially release or prevent lens deposits to some extent, but such solutions may not necessarily clean contact lenses. Therefore, an effective multi-purpose solution is only applicable to lenses used for a limited time (either disposable or frequently changed lenses).

Traditionally, multipurpose solutions on the market require a regime that involves mechanically rubbing the contact lens with the multipurpose solution to provide the necessary disinfection. That is, such a regime is required under government regulatory agencies for chemical disinfection systems that are not approved as chemical disinfecting solutions (eg, FDA or US Food and Drug Administration). The invention according to the invention is gentle enough on the one hand to be used as both a disinfecting solution and a humectant, and on the other hand (although rubbing the lens can provide further removal of microorganisms). A product capable of meeting biocidal performance disinfection for chemical disinfecting solutions under the standards established by the US FDA (May 1, 1997) for contact lens care products that do not require a regimen that includes Has the advantage that it is possible to formulate In other words, compositions according to the present invention can be formulated as needed to meet the requirements of FDA or ISO independent procedures for contact lens disinfection products. Thus, it is possible to produce formulations that provide higher patient compliance and greater versatility appeal than traditional disinfection or disinfection and cleaning products.

The combination of biguanide polymer and bis (biguanide) provides enhanced efficacy, but does not cause irritation or discomfort to the eye, which is always a significant and intriguing interest in the field of contact lens care Is noted.
Thus, increasing the amount of the biguanide polymer to achieve the same efficacy as the combination with the biguanide polymer alone results in greater eye irritation. For details,
It has been found that increasing the amount of biguanide polymer alone to achieve the required disinfection for the chemical disinfecting solution with the biguanide polymer results in unacceptable eye irritation. Even where a rubbing regime is recommended when using the solution of the present invention, enhanced biocidal activity is improperly or omitted by rubbing or ignoring product instructions, especially by contact lens wearers. May provide greater protection against infection.

According to the present invention, the bis (biguanide) fungicide used in the solution of the present invention comprises a compound having the formula: and the water-soluble salts thereof:

[0029]

Embedded image Here, R ¹ and R ² are branched or unbranched, 4 to 12, preferably 6
An alkyl having 10 to 10 carbon atoms, an alkoxyalkyl (i.e. ether) or alkyl sulfide (thioether or dialkyl sulfide) radical having 4 to 12, preferably 6 to 10 carbon atoms, or
Is independently selected from the group consisting of cycloalkyl or cycloalkyl-alkyl radicals having 12, preferably 7 to 10 carbon atoms (ie, the same or different); and n is 4 to 16, preferably 6 10 to 10. The term "cycloalkyl" in either cycloalkyl or cycloalkyl-alkyl means unsubstituted or substituted cycloalkyl. Here, the substituent is
One or more alkyl, alkoxy (-OR), or alkylthio (-SR) groups having from 1 to 6 carbon atoms.

In the disinfecting solution of the present invention, the biguanide of the formula (I) is suitably used in a total amount of 0.1 to 4.0 ppm, preferably 1.0 to 3.0 ppm, based on the total aqueous solution. More preferably, bis (biguanide) is used in an amount of 1.5-2.5 ppm, most preferably 2.0 ppm. The concentration of bis (biguanide) in solution is directly related to its bactericidal efficacy. The term “ppm” refers to “parts per million”,
1.0 ppm corresponds to 0.0001% by weight. This is based on the total weight of the composition, ie in this case the total weight of the aqueous disinfecting solution.

In the present application, the amount of bis (biguanide) or other component in a solution according to the present invention refers to the amount formulated and introduced into the solution when the solution is made. Over time (eg, beyond the 18 month storage period), the assayed amount of bis (biguanide) in solution may decrease somewhat.

Preferably, the bis (biguanide) compound has the above formula (I), wherein R ¹ And R^TwoIs a branched or unbranched alkyl or alkoxyalkyl
From ether) or alkyl sulfide (thioether) radicals.
And n is 5-7.

Each of R ¹ and R ^{2 in} the above formula (I) is, for example, n-butyl, isobutyl, s
It can be an ec-butyl, tert-butyl, pentyl, neopentyl, octyl, 2-ethylhexyl, dodecyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentylmethyl, or cyclohexylmethyl radical. Preferably, 2-ethylhexyl (alexidine), 1,5-dimethylhexyl, 1-methylhexyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, cyclohexylmethyl, 2-norbornyl, propyloxyoctyl, and propyloxy Butyl.

The acid addition salts of the present invention can be derived from inorganic or organic acids. In most cases, it is preferable to derive the salt from an acid, which provides an anion that is readily soluble in water and that is suitable for human use (eg, a pharmaceutically acceptable anion). Examples of such acids are hydrochloric, hydrobromic, phosphoric, sulfuric, acetic, D-gluconic, 2-pyrrolidino-5-carboxylic, methanesulfonic, carbonic, lactic and glutamic acids. Hydrochloride is preferred.

The bis (biguanides) of the formula (I) have relatively hydrophobic end groups. Preferably, the compound has a Log P of 5-10, more preferably 6-8. here,
P is the following formula:

[0036]

Embedded image Where C is the molar concentration of bis (biguanide) in each phase and α is the degree of ionization of bis (biguanide). In order to obtain the partition coefficient of bis (biguanide), the compound was shaken gently at room temperature (26 ° C.) followed by 0.05M phosphate buffer (pH 11) saturated with octanol.
And octanol saturated with phosphate buffer. The volume ratio of these two phases and the amount of sample are such that the absorbance of the sample from the buffered layer after partitioning has a value between 0.2 and 0.9 (1 cm cell and buffer as blank). (Using a solution). The fixed pH, by or to calculate knowing the pK _a, P values can be determined using the above equation. "Quantitat
live Structure-Activity Relationships
for Biguanides, Carbamidates, and B
isbiguanides as Inhibitors of Strept
ococcus mutans No. 6715 ", Warner, V. et al. And Lynch, D.A. , J. et al. Med. Chem, 1979, Vol. 22, No. 4, 359, 365; and Albert and Serjeant, E. et al.
, "Determination of Ionization and St.
availability Constants ", Butler and Tanner
Ltd. , London, England, 1962 (both references are incorporated herein by reference).

Particularly preferred bis (biguanide) compounds of the present invention are 2- (decylthiomethyl) -pentane-1,5-bis (5-isopropylbiguanide), 2- (decylthio-methyl) pentane-1,5- Bis (5,5-diethylbiguanide) and hexane-1,6-bis (2-ethylhexylbiguanide), the latter also being alexidine or 1,1'-hexamethylenebis (5- (2-ethylhexyl) -biguanide. ) Also known as dihydrochloride. Other preferred bis (biguanides) are 1,1'-hexamethylenebis (5-heptyl-biguanide) dihydrochloride, 1,1'-hexamethylenebis (5-octyl-biguanide)
Dihydrochloride, and 1,1′-hexamethylenebis (5-hexyl-biguanide) dihydrochloride.

The biguanide compound of formula (I) is a bis-cyanoguanidine of the following formula:

[0039]

Embedded image And the amine R ¹ NH ₂ or two different amines R ¹ NH ₂ and R ² NH ₂ in the form of their acid addition salts. Here, R ¹ and R ² have the above-mentioned meaning at a temperature of 100 ° C. to 170 ° C., and A is an alkylene group having a required number of carbon atoms. A preferred amine salt is hydrochloride. Most diamines are commercially available from various sources.

The reactants are heated together until the reaction is complete. The reaction proceeds fastest at higher temperatures, but if thermal stability is an issue, the reaction should be performed for a longer time at lower temperatures. The reactants are most conveniently melted together in the absence of a solvent, but if desired, an inert solvent such as DMSO, 2-methoxyethanol, 2-ethoxyethanol, nitrobenzene, sulfolane, isopropanol, n-butanol, ethylene glycol dimethyl ether or water, or a mixture of such solvents).

The bis-cyanoguanidine of the formula (VI) can be converted to a corresponding starting material, such as, for example, hydrogen and Raney nickel or with borane in dimethyl sulfide to the corresponding diamine of the formula (VIII) , Hexamethylene dinitrile)
Can be manufactured from The acid addition salt, diamine, conveniently in the form of dihydrochloride, then reacts with sodium dicyanamide or other suitable salt to form the required starting material of formula (VI) as shown below.

[0042]

Embedded image Where M is sodium, potassium, zinc, or other suitable salt. Sodium salts are commercially available.

The compounds of the present invention also include a diamine of formula (VIII) in the form of an acid addition salt having the formula:

[0044]

Embedded image Or a cyanoguanidine of formula (IX) and the following formula:

[0045]

Embedded image By reacting with cyanoguanidine. Here, R ¹ and R ² have the above meaning at a temperature of 100 ° C. to 170 ° C.

A suitable salt of a diamine is, for example, dihydrochloride. The reactants are heated together until the reaction is complete. The reaction proceeds fastest at higher temperatures,
If thermal stability is an issue, the reaction should be performed at a lower temperature for a longer time. If a melt can be formed at these temperatures, the reactants are conveniently melted together in the absence of a solvent. If not, or alternatively, the reaction is heated with a suitable inert solvent (eg, as described above). The acid addition salts of the present invention are obtained by conventional means.

Formulas (IX) and (X) which can be used as starting materials in the above process
Is the reaction of sodium dicyanamide with the appropriate amine R ¹ NH ₂ or R ² NH _{2 in} the form of an acid addition salt (conveniently dihydrochloride) in a suitable inert solvent. Can be obtained.

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

[0049]

Embedded image Compound (XI) is hexamethylenediamine dihydrochloride (MW 189
). Compound (XII) is sodium dicyanamide. Compound XI
II is HMBDA, hexamethylene bis (cyanoguanide). Compound(
XIV) is 2-ethyl-hexylamine hydrochloride (MW 165.7)
It is. Compound (XV) is alexidine dihydrochloride, also known as [1,
6-bis- (2-ethylhexylbiguanide) hexanedihydrochloride, also known as
Hexane-1,6-bis- (2-ethylhexylbiguanide) dihydrochloride
It is. This compound has (MW) molecular weight g / mol 581.7 and empirical formula C₂₆H ₅₆ N_Ten-2HCl. Compound (XV) was obtained from Sigma Chemical
 Co. (St. Louis, Missouri)
It is commercially available.

The process for the synthesized compounds of the present invention is also described in EP-A-0125.
No. 092 (issued November 14, 1984); L. And Swai
n, G. , "Bisdiguanide Haveing Antibacter
ial Activity ", J. Am. Chem. Soc. , 4422-442
5 (1956); and Warner, Victor D. et al. And Lync
h, Donald, "Quantitative Structure-Ac
activity Relationships of Biguanide, Ca
rbamimidates, and Bisdiguanides as I
nhibitors of Streptococcus Mutans No
. 6715 "J. Med. Chem. 22, Vol. 6, No. 6, pp. 359-366 (1979).

The bis (biguanides) of the invention (Formula I) can be used in combination with one or more polymerized biguanides having the following formula, and water-soluble salts thereof:

[0052]

Embedded image Here, Z is an organic divalent crosslinking group which may be the same or different throughout the polymer, and n is at least 3 on average, preferably 5 to 2 on average.
And X ¹ and X ² are independently -NH ₂ groups, and

[0053]

Embedded image Selected from the group One preferred group of water-soluble polymerized biguanides has a number average molecular weight of at least 1,000, and more preferably has a number average molecular weight of 1,000 to 50,000. Suitable water-soluble salts of the free base include, but are not limited to, hydrochloride, borate, acetate, gluconate, sulfonate, tartrate, and citrate.

The biguanides and methods of preparation disclosed above have been described in the literature. For example, U.S. Pat. No. 3,428,576 describes the preparation of polymeric biguanides from diamines and their salts and diamine salts of dicyanimide.

The polymerized biguanides in combination with the 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 combined use of such a polymerized biguanide and a compound of formula (I) above can enhance the bactericidal activity or broaden the spectrum of activity of the solution. The effective concentration of the polymerized biguanide (regardless of whether a particular salt form or free base is used) is in the present invention about 0.000010% by weight in total (0.10 pp
m) and can be up to about 0.00030% by weight (3.0 ppm). Here, it is either a water-soluble salt form or a free base. Preferably, the total amount of polymerized biguanide in combination with the total amount of the compound of formula (I) above is about 0.3-2.0 ppm, more preferably about 0.4-1.0, and most preferably about 0-1.0. 0.5 to 0.8 ppm.

Most preferred are polymerized hexamethylene biguanides, such as the hydrochloride salt from Zeneca (Wilmington, DE) under the trademark Cosm
It is commercially available as ocil ^™ CQ. Such polymers and water-soluble salts are preferred and are called polyhexamethylene (PHMB) or polyaminopropyl biguanide (PAPB). The term PHMB or PAPB as used herein is meant to include one or more biguanides having the following formula:

[0057]

Embedded image Where X ¹ and X ² are as defined above, and n is 1 to 500.

Depending on the manner in which the biguanides are prepared, the predominant compounds included in the above formula will have different X ¹ and X ² groups, along with smaller amounts of other compounds in the formula. Or may have the same groups. Such compounds are known and are disclosed in U.S. Pat. No. 4,758,595 and British Patent 1,432,345. These patents are incorporated herein by reference. Preferably,
A water-soluble salt is a compound wherein n has an average value of 2 to 15, most preferably 3 to 12.

[0059] Any additional disinfectant / bactericide components can be used in the present invention to further enhance, improve or broaden the spectrum of microbial bactericidal activity of the present invention. It contains a microbicidally effective amount of a bactericide, which is compatible in solution and does not precipitate, at a concentration ranging from about 0.000001 to about 0.5% by weight. This concentration depends on the particular disinfectant, as will be appreciated by those skilled in the art. Suitable complementary fungicides include thimerosal, sorbic acid, alkyl triethanolamine, phenyl mercuric acid salt, quaternary ammonium compounds and polyquaternium.
Including, but not limited to, copolymers, and mixtures thereof. Suitable salts are soluble in water at ambient temperature in the range of at least 0.5% by weight. These salts include gluconate, isothionate, (2-hydroxyethanesulfonate), formate, acetate, glutamate, succinate, monodiglycolate,
Methane sulfonate, lactate, isobutyrate, and glucoheptonate. A representative example of a quaternary ammonium compound is a composition consisting of a stable mixture of n-alkyldimethylbenzylammonium chloride. Examples of polyquaternium polymers used in ophthalmic applications include Onyx
Polyquaternium 1 sold by the corporation
(Registered trademark) chemical registration number
r) 75345-27-6.

The solution of the present invention optionally contains at least one surfactant. Suitable surfactants may be either amphoteric, cationic, anionic, or non-ionic, and may comprise up to 15%, preferably 5%, by weight of the composition or solution.
(Individually or in combination). Preferred surfactants are amphoteric or nonionic surfactants, which, when used, provide cleaning and conditioning properties. Surfactants should be soluble in the lens care solution and non-irritating to ocular tissues. Many nonionic surfactants comprise one or more chains or polymerizable components, having oxyalkylene (-OR-) repeat units, where R has 2 to 6 carbon atoms. . Preferred nonionic surfactants comprise a block polymer of two or more different types of oxyalkylene repeating units, wherein the ratio of the different repeating units depends on the HL of the surfactant.
Determine B. Satisfactory nonionic surfactants include polyethylene glycol esters of fatty acids such as coconut, polysorbate, higher alkanes (
Polyoxyethylene or polyoxypropylene ethers of C ₁₂ -C ₁₈₎ and the like. An example of a preferred class is polysorbate 20 (Tween brand name).
(Registered trademark) 20), polyoxyethylene (23) lauryl ether (Brij® 35), polyoxyethylene (40) stearate (M
yrj (registered trademark) 52) and polyoxyethylene (25) propylene glycol stearate (Atlas (registered trademark) G2612). In particular, about 7
A nonionic surfactant consisting of a poly (oxypropylene) poly (oxyethylene) adduct of ethylenediamine having a molecular weight of from about 500 to about 27,000, wherein at least 40% by weight of the adduct comprises (Which is (oxyethylene)) can be particularly advantageous for use in cleaning and conditioning both soft and hard contact lenses when used in amounts of about 0.01 to about 15% by weight. Have been found. CTFA of this group of surfactants
The name of Cosmetic Ingredient Dictionary is
It is poloxamine. Such surfactants include BA
SF Wyandotte Corp. , Wyandotte, Michi
It is available from gan under the registered trademark "Tetronic". A similar series of surfactants (suitable for use in the present invention) is poloxamer (polo)
xamer) series, which is a poly (oxyethylene) poly (oxypropylene) block polymer available under the trademark "Pluronic" (commercially available from BASF).

[0061] Various other ionic and amphoteric and anionic surfactants suitable for the present invention are disclosed in McCutcheon's Detergents in light of the foregoing description.
and Emulsifiers, North American Edi
, McCutcheon Division, MC Publis
ing Co. , Glen Rock, NJ07452 and the C
TFA International Cosmetic Ingredien
t Handbook, (The Cosmetic, Toiletry,
and Fragrance Association, Washingto
n, D. C. Publication).

Suitable amphoteric surfactants for use in the compositions according to the present invention include the trade names “
"Miranol". Another useful class of amphoteric surfactants is exemplified by cocoamidopropyl betaine, which is commercially available from various sources.

The surfactants described above, when used with a buffer enhancer, are generally 0.1.
It is present in an amount of 01-5.0% (w / w), preferably 0.1-5.0%.

Typically, the aqueous solution of the present invention for treating contact lenses also has 0.9
It is adjusted with a tonicity agent to approximate the normal osmolarity of normal tears equivalent to a 2.5% sodium chloride solution or a 2.5% glycerol solution. The solution is made substantially isotonic with saline, used alone or in combination. Otherwise, if simply blended with sterile water to make them hypotonic or hypertonic, the lenses lose their desired optical parameters. Similarly, excess saline can be used for stinging.
) May form a hypertonic solution that causes irritation and eye irritation.

The pH of the solution of the present invention is between 5.0 and 8.0, more preferably between about 6.0 and 8.0,
Most preferably it should be maintained in the range of about 6.5 to 7.8 and a suitable buffer (
For example, boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate
Ium, TRIS and various mixed phosphate buffers (Na_TwoHPO_Four, NaH _Two PO_Four, And KH_TwoPO_Four) And their mixtures)
Can be done. Borate buffers are preferred, especially for enhancing the efficiency of biguanides
. Generally, the buffer will comprise about 0.05-2.5% by weight, and preferably 0.1%.
Used in amounts ranging from .about.1.5% by weight. The disinfection / preservation solution of the present invention is preferably
Contains a borate buffer system that contains boric acid, sodium borate, potassium tetraborate.
Or one or more of potassium metaborate or mixtures thereof.

In addition to buffers, sequestration in solutions of the invention to bind metal ions that may otherwise react with the lens and / or protein deposits and collect on the lens It may be desirable to include an agent. Ethylene-
Diaminetetraacetic acid (EDTA) and its salt (disodium) are preferred examples. They are usually added in amounts ranging from about 0.01 to about 0.2% by weight. Other suitable sequestering agents include gluconic acid, citric acid, tartaric acid and their salts (eg, sodium salt). Preferred sequestering agents that are also effective for removing protein attachment are the phosphonate compounds disclosed in WO 97/31659.

The aqueous solutions of the present invention are particularly useful for soft contact lenses, with or without additional additives. Nevertheless, the solutions of the present invention can be formulated into certain contact lens care products, such as wetting solutions, impregnating solutions, cleaning and conditioning solutions, and multipurpose types of lens care solutions, and the like, and mixtures thereof. Eventually, such a solution is applied to the lens outside or on the eye,
For example, it can be applied in the form of drops.

It may also be desirable to include a water-soluble viscosity builder in the solution of the present invention. Because of their viscous effects, viscosity builders tend to enhance the comfort of the lens wearer with a film on the lens surface that absorbs shock to the eye. Water soluble viscosity builders include cellulose polymers such as hydroxyethyl or hydroxypropyl cellulose, carboxymethyl cellulose, povidone, polyvinyl alcohol, and the like. Such a viscosity builder may have a viscosity of about 0.01 to
It may be used in amounts ranging up to about 4.0% by weight. The solution of the present invention may also contain any demulcent.

The aqueous solutions of the present invention can be efficiently used to disinfect contact lenses by any well-recognized method. The lens is "cold" around room temperature.
By the dipping method, it can be treated for a period ranging from about 5 minutes to about 12 hours. The lens can then be removed from the solution and rinsed with the same or a different solution (eg, a stored isotonic saline solution) and then repositioned on the eye.

As indicated above, the contact lens wearer typically rubs the contact lens with a finger or hand (typically with a finger) during daily cleaning and / or disinfection of the contact lens. Between the palms or between fingers).
In one embodiment of the present invention, a method is provided that does not require rubbing during treatment with the solution of the present invention between removal of the lens from the eye and repositioning after care of the lens. In a preferred embodiment of such a method, the soft lenses are disinfected or both disinfected and cleaned using a multipurpose solution or an effective multipurpose solution. Such a solution is merely a daily solution required for the treatment of the lens outside the eye. Thus, in one embodiment of the method of the present invention, the described solution is used to treat a contact lens without rubbing by a method comprising the following steps: (a) during a specific time Dipping the contact lens that has not been rubbed with the solution, and (b) placing the treated contact lens directly on the wearer's eye.

Typically, step (a) may include immersing the contact lens in a solution. Immersion involves shaking or similarly shaking the solution container with the hand, if necessary. Preferably, step (a) comprises immersing the contact lens in a container, wherein the contact lens is completely immersed in the solution.
The term `` place directly '' as used herein means that the solution is not diluted or the lens is not soluted with a different contact lens solution prior to `` insertion '' or placement on the eye. means. In a particularly preferred embodiment, the method comprises:
Use the product formulated as a multi-purpose solution or an effective multi-purpose solution. Here, with the possible exception of an enzyme cleaner, no other solution or product is needed for daily cleaning of the lens.

In yet another embodiment of the method of the present invention, the solution of the present invention is designed for repositioning after use in the eye for about 3 months or less, or for about 30 days or less in the eye. Rinse Frequent replacement lenses (FRL), which is planned to be repositioned after use, or after about 2 weeks of use in the eye, after use Used for Preferably, the lens has from about 0.0 to 5 mole% repeating units from methacrylic acid (MAA), from 10 to 99 mole% repeating units from hydroxyethyl methacrylate and from about 0.5 to 5 moles. It is made from a polymer containing cross-linking repeat units. Crosslinking repeat units can be derived from monomers such as, for example, ethylene glycol dimethacrylate, divinylbenzene, and trimethylpropane trimethacrylate.

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

Example 1 This example illustrates the use of 1,6 used as starting material for the bis (biguanide) of the present invention.
-Illustrates the preparation of bis (cyanoguanidino) hexane. 35.80 g (0
. 402 mol) of sodium dicyanamide (NaC ₂ N ₃ ) in an amount of 400 mL.
In 1-butanol. Then, 23.60 g (0.204 mol) of 1
, 6-hexanediamine and 33.0 mL of concentrated aqueous hydrochloric acid (0.400 mol) were added. A milky white precipitate, presumed to be the amine hydrochloride, was seen immediately after addition. The mixture was then refluxed for 3.5 hours. Then the suspension was cooled to room temperature and filtered. The white solid was then thoroughly washed with distilled water before drying under reduced pressure. The yield is 46.38 g; 93.1%, the calculated value of C ₁₀ H ₁₈ N ₈ is C: 48.0%, H: 7.20%, N: 44.80%, and the actual value is C 47.7;
%, H; 7.40%, N: 45.12%. For ¹ H NMR (d ⁶ -DMSO) at 300 MHz, 6.60 ppm (6p, brm), 2.93 ppm (4p, m), 1.34 ppm (4p, brs), 1.15 ppm
(4p, brs). In IR (potassium bromide tablets, cm ^-1 ), 3142
(M); 2943; 2912; 2862 (w); 2179 (s);
658; 1609 (s).

Example 2 This example illustrates the preparation of a bis (biguanide) known as alexidine for use in the present invention. Hexamethylene bis (cyanoguanide) in an amount of 1.003 g (0.004498 mol) was placed in the flask. This is 1.474 m
L (1.163 g; 0.008996 mol) of 2-ethylhexylamine was added. Then 0.74 mL (0.008996 mol) of concentrated HCl was added. The mixture was heated in a flask to evaporate H ₂ O. After removing the H ₂ O, the melting temperature rose to 195 ° C. Reduce the temperature to 150-160 ° C and
Left for hours. This material was cooled to room temperature. This solid could be dissolved in hot water and crystallized.

Example 3 This example illustrates the preparation of poly (hexamethylene biguanide) (abbreviated as PAPB or PHMB) for use in combination with the bis (biguanide) of the present invention. 25.08 g (0.100 mol) of 1,6-bis (cyanoguanidino) hexane and 18.99 g (0.100 mol) of 1,6-hexanediaminedihydrochloride were suspended in 500 mL of distilled water. It became cloudy. The pH of the mixture was then reduced to 6.8 with dilute hydrochloric acid. Next, water was removed by distillation under reduced pressure. The white solid was then transferred to a three-necked flask equipped with a stirrer and heating mantle. The solid intimate mixture was then placed under nitrogen and the temperature of the mixture was raised to 150-55 ° C. The dissolved reaction mixture had a honey-like consistency. Allow the mixture to cool to room temperature for
Stirred at ~ 55 ° C. The resulting poly (hexamethylene biguanide) is obtained as a glassy solid. The yield is essentially quantitative. Melting temperature range: 105-125
° C. For 300 MHz ¹ H NMR (D ₂ O), 3.13 ppm (21.1 p
, Brt), 2.93 ppm (2p, t), 1.49 ppm (21.
1p, br s) and 1.28 ppm (21.1 p, br s). IR
(Potassium bromide tablets, cm ^-1 ): 3325; 3201 (s); 2931;
2858 (m); 2175 (m-w); 1631; 1589; 155
0 (s).

Example 4 This example illustrates the preparation of an aqueous disinfectant solution of the present invention comprising a combination of alexidine and polyhexamethylene biguanide (also called PHMB). Use the following ingredients (indicated by weight per total volume of solution):

[0078]

(1) (p23) This solution is prepared by dissolving disodium EDTA in this solution and gradually heating to 80 ° C. until an 80% aqueous solution is obtained.
Boric acid and sodium borate are added to the heated disodium EDTA solution and dissolved. Then, sodium chloride is added to the solution and heated to dissolve.
Thereafter, a surfactant is added. The solution is sterilized by autoclaving at 120 ° C. for 45 minutes. After cooling the solution to room temperature, bis (biguanide) and PHM
B while passing through a sterile filter and then balanced with distilled water
ce). This solution is packaged in a sterile plastic container.

Example 5 This example illustrates the improved antimicrobial efficacy of a combination of alexidine and polyhexamethylene biguanide (PHMB) in a water-soluble disinfectant for contact lenses. The antimicrobial efficacy of each of the various components for chemically disinfecting contact lenses was evaluated.

The microorganism challenge strain was identified as Pseudomonas aeruginosa (
ATCC 9027), Staphylococcus aureus (ATC
C 6538), Serratia marcescens (ATCC 138)
80), Candida albicans (ATCC 10231) and F
usarium solani (ATCC 36031). The test organism is cultured on an appropriate agar medium and the culture is sterilized with DPST (0.05% w
/ V polysorbate80 added Dulbecco's phosphate buffered saline) or appropriate diluent and collected in appropriate containers. The spore suspension was filtered through sterile glass wool to remove mycelium debris. Serrati
In a marcescens, appropriate filtration (eg, through a 1.2 μ filter) was performed to clarify the suspension. After collection, the suspension is
Centrifuged at <RTIgt; Pour this supernatant,
Resuspended in DPST or another suitable diluent. This suspension was also centrifuged a second time and resuspended in DPBST or another suitable diluent. All challenged bacterial and fungal cell suspensions were plated at 1 × with DPBST or another appropriate dilution.
It was adjusted to 10 ⁷ ~10 ⁸ cfu / mL. The appropriate cell concentration can be estimated by measuring the turbidity of the suspension using a spectrophotometer at a preselected measurement wavelength (eg, 490 nm). Minimum of 10 per challenge organism per test tube
Prepared to contain mL of test solution. Each test tube of the solution to be tested was inoculated with a sufficient suspension of the test organism so that the final cell count was 1.0 × 10 ⁵ to 10 ⁶ cfu / mL. However, the inoculation volume must not exceed 1% of the sample volume. The inoculum suspension was dispersed by vortexing the sample for at least 15 seconds. The inoculum product was stored at 10-25 ° C. After a certain sterilization time, a 1.0 mL aliquot of the inoculum product was taken to determine the viable cell count. Bacteria collection time, when the proposed regimen immersion time is 4 hours, for example,
1, 2, 3, and 4 hours. Yeast and mold were tested with an additional measurement time of 16 hours or more (four times in regimen). The suspension was mixed well by vigorous vortexing for at least 5 seconds. 1. Collected every designated time
An aliquot of 0 mL was subjected to an appropriate 10-fold dilution series in validated neutral medium. The suspension was mixed vigorously and incubated for an appropriate period to allow neutralization of the bacterial reagent. The number of viable organisms is tryptica for bacteria.
se soy (TSA) agar, and Sabouraud text for mold and yeast
Rose agar (SDA) was prepared in triplicate plates and measured at the appropriate dilution. Bacterial harvest plates were incubated at 30-35 ° C for 2-4 days. The yeast was kept at 20-30 ° C for 2-4 days, and the mold recovery plate was
Incubated at 3 ° C for 3-7 days. The average number of colony forming units was counted on the counting plate. Unless 10 ⁰ or 10 ^-1 times colonies only at a dilution plate was observed, measurement plate refers to 30 to 300 cfu / plates for bacteria and yeast, refers to 8-80 cfu / plates in molds. The bacterial reduction was then calculated at the indicated measurement time points. The same volume of diluent used to suspend the organisms listed above to demonstrate the suitability of the medium used to grow the test organism and to provide an estimate of the initial inoculum concentration Was used to create a bacterial species control by dispersing the same aliquot of the inoculum in a suitable diluent, such as DPST. After culturing in a suitable period inoculated into broth inspected neutral species controls must be in the range of ^{1.0 × 10 5 ~1.0 × 10 6} cfu / mL.

These solutions were evaluated based on the rules of practice referring to “Stand-alone method for disinfecting products” (hereinafter abbreviated as “stand-alone test”). This method is based on the pre-market notification of contact lens care products (510 (k)) prepared by the U.S. Food and Drug Administration, the Department of Ophthalmology, and the disinfection effect test of contact lens care products by the guidance document (May 1, 1997) Based on law. This code of practice may comply with the latest ISO standards for contact lens disinfection (revised 1995). The stand-alone test challenges a disinfection product with a standard range of microbial representative species and sets the extent of viable cell count loss at defined time intervals equivalent to the period during which the product can be used. Primary criteria for a given disinfection period (corresponding to the minimum possible disinfection period possible)
Means that the average number of bacteria recovered per mL was 3.0 within a predetermined disinfection time.
That is, it must be reduced to more than log. The number of molds and yeasts recovered per mL must decrease by an average of 1.0 log or more at the minimum recommended disinfection time without increasing in 4 times the minimum recommended disinfection time.

The test procedure described above was used to determine if the primary performance criteria passed at the 5 minute, 15 minute, 30 minute and 4 hour time intervals. The concentration of alexidine in this set of tests was formulated in amounts ranging from 0.0 to 4.0 ppm in combination with 0.0 or 0.8 ppm of PAPB. The latter amount of PAPB is currently used in commercial multipurpose solutions for soft contact lenses.
The results are shown in Table 1 below.

[0083]

[Table 1] The above results show that the addition of alexidine to polyhexamethylene biguanide improved antibacterial efficacy at about 4.0 ppm, with improved efficacy reaching exchange conditions (for substantial purposes). And, consequently, any improvement in antibacterial efficacy,
It shows that it is unlikely that it would be evidenced by an increased toxicity potential at high concentrations of antibacterial agent. C. 15 min and 3 for Albicans
At 0 minutes, it appears to be a synergistic effect. That is, the combination of 2.6 ppm alexidine and 0.8 ppm PAPB shows a greater effect than the sum of 2.6 ppm alexidine itself and 0.8 ppm PAPB itself.

Example 6 This example illustrates the antibacterial efficacy of a solution of the invention. The test procedure described above was followed for the disinfection solution as prepared in Example 4 using C.I. albicans was used to evaluate the antibacterial effect. However, this solution contains bis (biguanide) alexidine at various concentrations ranging from 1 ppm to 4 ppm, and 0.3 ppm to 1.5 pp.
It contains biguanide polymer at various concentrations in the range of m. The results are shown in Table 2 (after immersion for 5 minutes), Table 3 (after immersion for 15 minutes), Table 4 (after immersion for 30 minutes), and Table 5 (after immersion for 45 minutes). Tables 6-9, which correspond to Tables 2-5, respectively, compare theoretical killing based on the sum of the individual disinfectants with actual killing using a combination of disinfectants. The following equation was used for this calculation: log10 (exp1
0 (PHMB) + exp10 (alexidine)). In other words, the log reduction in kill for each different disinfectant was converted to the number of killed organisms to calculate the theoretical log of kill (log). These values were then added and a new logarithm was determined from the sum.

[0085]

[Table 2]

[0086]

[Table 3]

[0087]

[Table 4]

[0088]

[Table 5]

[0089]

[Table 6]

[0090]

[Table 7]

[0091]

[Table 8]

[0092]

[Table 9] The above results indicate that C.I. 1 shows a synergistic antibacterial effect on Albicans. Here, the log killing from the combination of alexidine and PHMB (for a good percentage) is greater than the sum of the individual disinfectants, and this synergy is evident and begins with the results after 15 minutes. At 45 minutes, if most of the microorganisms have already been killed, these synergistic effects can become insignificant. Based on the above data, FIG. 1 shows the C.I. of the test solution containing the combination of alexidine and PHMB as compared to the theoretical efficacy based on the sum of the individual solutions containing alexidine alone and PHMB alone, respectively. 15 shows the bactericidal efficacy after 15 minutes against Albicans. FIG. 2 shows the C.E. 3 against Albicans
Shows the bactericidal efficacy after 0 minutes.

Although the invention has been described in conjunction with specific embodiments thereof, this is by way of example only. Accordingly, many alternatives, modifications and variations will be apparent to those skilled in the art in light of the foregoing description. It is therefore intended that all such alternatives, modifications and changes be within the spirit and scope of the appended claims.

[Brief description of the drawings]

FIG. 1 shows the theoretical sum of the biocidal efficacy of the separate solutions of each disinfectant, 15 minutes after the solution containing the combination of the two disinfectants (ie, bis (biguanide) and biguanide polymer). It is a bar graph which shows a biocidal effect. The increased potency of the combination relative to the theoretical sum is a measure of the synergistic effect of the combination. In particular,
FIG. 1 shows C.I. after 15 minutes of exposure. FIG. 4 shows the theoretical log reduction compared to the actual log reduction for alexidine and PHMB for Albicans microorganisms.

FIG. 2 shows bis () versus the theoretical sum of the biocidal efficacy of separate solutions of each disinfectant.
4 is a bar graph showing the biocidal efficacy of a solution containing a combination of (biguanide) and a biguanide polymer after 30 minutes. In particular, FIG. 2 shows that C.I. a
Figure 4 shows the theoretical log reduction compared to the actual log reduction for alexidine and PHMB for the lbicans microorganism.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C11D 3/37 C11D 3/37 3/48 3/48 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), AL, AU, BA, BB, BG, BR, CA, CN, CU, CZ, EE, ES, FI, GB, GE, HR, HU, ID, IL, IS, JP, KE, KG, KP, KR, LC, LK, LR, LT, LV, M D, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SE, SG, SI, SK, SL, TJ, TR, TT, UA, UZ, VN, YU (72 ) Inventors Spooner, Susan P. New York, USA 14526, Penfield, Saybroke Drive 22 (72) Inventor Simpson, Lisa See. United States New York 14626, Rochester, Raton Avenue 73 (72) Inventor Marsh, David A. United States Texas 76109, Fort Worth, Cross Creek Lane 5505, Apartment 2065 F-term (reference) 2H006 DA08 DA09 4C058 AA09 BB07 CC06 JJ08 4H003 AC13 AC23 AE09 BA12 DA16 EA18 EA19 EB12 EB16 EB30 EB38 ED02 FA02 FA01 FA04 BB11 BC18 BC19 DA13 DD07 DH03

Claims (15)

[Claims] 1. An eye safe disinfecting solution for contact lenses, comprising: (a) an amount of about 0.10 to about 4.0 ppm, in the form of a water-soluble salt or free base, An amount of bis (biguanide) effective for disinfecting microorganisms, said bis (biguanide)
Has the following general formula: Here, R ¹ and R ² are branched or unbranched alkyl having 4 to 12 carbon atoms, alkoxyalkyl ether or alkyl sulfide radical having 4 to 12 carbon atoms, or 5 to A bis (biguanide), independently selected from the group consisting of cycloalkyl or cycloalkyl-alkyl radicals having 12 carbon atoms; and n is 4-16; (b) about 0.10 to about 3. 0 ppm total amount of polymerized biguanide, which has the following general formula: Wherein Z is an organic divalent bridging group, which may be the same or different throughout the polymer, n is on average at least 3, and X ¹ and X ² are -N
H ₂ group and An eye safe disinfecting solution comprising an aqueous solution comprising: a polymeric biguanide, independently selected from groups; (c) an effective amount of a buffering agent; and (d) water in an amount of at least about 80% by weight. 2. R ¹ and R ² are independently selected from the group consisting of branched or unbranched alkyl, alkoxyalkyl ether or alkyl sulfide thioether radicals having 6 to 10 carbon atoms, and n is 4 to 10
The eye-safe disinfecting solution of claim 1, wherein 3. The following general formula: Includes mixtures in which the polymerization biguanide molecules having, where X ¹ and X ² are as defined above, and n is 5-20 on average, safe to the eye according to claim 1 Disinfecting solution. 4. The eye-safe disinfecting solution according to claim 1, further comprising a surfactant in an amount of 0.01 to 5.0%. 5. The surfactant according to claim 1, wherein the surfactant is a neutral or nonionic surfactant having a plurality of poly (oxyalkylene) chains.
Comprises the (-OR) repeating unit, wherein R is independently alkylene having 2 to 6 carbon atoms. 6. The surfactant is a neutral or non-ionic surfactant,
5. The eye safe disinfectant solution of claim 4, wherein the surfactant comprises a block copolymer of poly (ethylene oxide) and poly (propylene oxide) segments. 7. The eye-safe disinfecting solution according to claim 1, wherein the amount of the bis (biguanide) is 1.0 to 3.0 ppm. 8. The eye-safe disinfecting solution according to claim 1, wherein the amount of the polymerized biguanide is 0.1 to 2.0 ppm. 9. A method of disinfecting or cleaning and disinfecting a soft contact lens using a multi-purpose solution or an effective multi-purpose solution, comprising: (a) disposing the lens in a solution; Dipping, so that an acceptable disinfection of the contact lens is obtained with the solution, the solution comprising, in the formulation, the following components: (i) about 0.1 to about 4 A microbicidally effective amount of bis (biguanide) in the form of a water-soluble salt or free base in an amount of 0.0 ppm, wherein the bis (biguanide) has the following general formula: Here, R ¹ and R ² are branched or unbranched alkyl having 4 to 12 carbon atoms, alkoxyalkyl ether or alkyl sulfide radical having 4 to 12 carbon atoms, or 5 to A bis (biguanide), independently selected from the group consisting of cycloalkyl or cycloalkyl-alkyl radicals having 12 carbon atoms; and n is 4-16; (ii) about 0.10 to about 3. A polymerized biguanide in an amount of 0 ppm, wherein the polymerized biguanide has the following general formula: Wherein Z is an organic divalent bridging group, which may be the same or different throughout the polymer, n is on average at least 3, and X ¹ and X ² are -N
H ₂ group and A polymerized biguanide, independently selected from the group; and (iii) a step comprising an effective amount of a buffering agent; and (b) placing the treated lens directly in the wearer's eye, so(
i) not requiring a rinsing step with a different solution before repositioning in the eye, and (ii) no other solution is required for daily processing of the lens. 10. The method of claim 9, wherein the method does not include rubbing the lens with the solution so as not required by instructions for use of the product. 11. The method of claim 11, wherein R ¹ and R ² are independently selected from the group consisting of branched or unbranched alkyl, alkoxyalkyl ether, and alkylsulfide thioether radicals, and n is 4-10. The method according to 9 or 10. 12. The polymerized biguanide is a mixture of a polymerized biguanide having the formula: embedded image Where X ¹ and X ² are as defined above, and n is on average 5-20
The method of claim 11, wherein 13. The solution of claim 9 or 1, wherein the solution is used to clean lenses that are set or planned to be repositioned after being worn for about 30 days or less.
The method according to 0. 14. The method of claim 13, wherein the lens is planned or set to reposition after being worn for about 14 days or less. 15. The method according to claim 1, wherein said solution is derived from methacrylic acid (MAA).
. Cleans lenses made from polymers containing 0-5 mole percent repeating units, 10-99 mole percent repeating units derived from hydroxyethyl methacrylate, and about 0.0-5 mole percent cross-linked repeating units. 11. The method according to claim 9 or 10 used for: