1. Field of the Invention
The present invention relates to compositions and methods for contact lens care, and more particularly to contact lens disinfection using polyquaternium-1 and high molecular-weight poly(hexamethylene biguanide) antimicrobials for disinfection of contact lenses.
2. Description of Related Art
Contact lenses must be disinfected and cleaned to kill harmful microorganisms that may be present or grow on the lenses, and to remove any buildup that may have accumulated on the lenses. However, adverse changes in ocular tissues during contact lens wear may arise due to exposure of ocular tissues to preservatives, disinfecting agents, cleaning agents and other components in the contact lens care solutions. This can occur through tissue contact with solutions which may directly contact ocular tissues during application or tissue contact with solutions which may adsorb or absorb to the contact lens during treatment of the contact lens by the solution, and subsequently desorb into the eye from the contact lens during wear.
Generally, contact lenses in wide use fall into three categories: (1) hard lenses formed from materials prepared by polymerization of acrylic esters, such as polymethyl methacrylate (PMMA), (2) rigid gas permeable (RGP) lenses formed from silicone acrylates and fluorosilicone methacrylates, and (3) gel, hydrogel or soft type lenses. The hard and rigid-type lenses, because they are characterized by low vapor diffusion and absorb only minor amounts of aqueous fluids, have a lower tendency to bind ingredients used in contact-lens care solutions. On the other hand, soft lenses have a greater tendency to bind active ingredients in contact-lens solutions and, therefore, it is especially challenging to develop solutions designed for the treatment of soft-type lenses, whether made from the more traditional copolymers of 2-hydroxyethyl methacrylate (HEMA) or from the newer silicon-containing hydrogel materials. Silicon-containing hydrogel materials (silicone hydrogels), such as the Focus® NIGHT & DAY™ lens from CIBA Vision (Atlanta, Ga.) or the PUREVISION™ lens, comprised of the material balafilcon® A, from Bausch & Lomb, Incorporated (Rochester, N.Y.) are believed to have great potential in the contact lens market, due to their high rate of oxygen transmission and extended-wear capability.
After wear, contact lenses must be disinfected to kill harmful microorganisms that may be present or grow on the lenses. Some of the most popular products for disinfecting lenses are multi-purpose solutions that can be used to clean, disinfect and wet contact lenses, followed by direct insertion (placement on the eye) without rinsing. The ability to use a single solution for contact lens care is an advantage to many users. Such a solution must be strong enough to kill harmful microorganisms that may be present or grow on the lenses. It must also be particularly gentle to the eye, since at least some of the solution will be on the lens when inserted and will come into contact with the eye. Such a solution must also be compatible with all contact lens materials, particularly the silicone hydrogel materials, which represent the state-of-the-art contact lens materials. Contact lens compatibility is measured in several ways. Contact lens discoloration, physical parameter change, fragility and uptake and release of solution components, particularly antimicrobial agents, are all important. One important measure of clinical acceptance of the in-vitro uptake and release of antimicrobial agents is corneal epithelial punctate fluorescein staining. This measure of clinical acceptance is determined by instilling a small amount of a fluorescent dye, fluorescein, into the eye after removing a contact lens. Fluorescein binds only to damaged or dead corneal epithelial cells, which then can be detected with a suitable excitation light source to stimulate the fluorescence of the cell-bound fluorescein. Damaged or dead cells show up as bright fluorescent green points or bright or diffuse areas. Generally, a contact lens care solution, such as a multi-purpose solution (MPS), is considered to be compatible with a particular contact lens material, according to this measure of acceptance, when fluorescein staining is superficial, has a low ocular surface area and has a patient incidence of less than 10%.
U.S. Pat. No. 4,758,595 to Ogunbiyi et al. disclosed that a contact-lens solution containing a polyaminopropyl biguanide (PAPB), also known as poly(hexamethylene) biguanide (PHMB), has advantageous properties for a multi-purpose solution, especially in the presence of a borate buffer. These disinfecting and preservative solutions are especially 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. Compositions containing PHMB and borate have been commercialized by Bausch & Lomb, Incorporated (Rochester, N.Y.) in various products including a multi-purpose solution, ReNu® MultiPlus®, at relatively low levels of about 1 ppm, for use with soft contact lenses. However, ReNu® MultiPlus® has been shown to produce an unacceptable incidence of 37% significant staining among PUREVISION™ (Bausch & Lomb Incorporated, Rochester, N.Y.) contact lens wearers by independent clinical investigators (Jones et al., Asymptomatic Corneal Staining Associated with the Use of Balafilcon Silicone-Hydrogel Contact Lenses Disinfected with a Polyaminopropyl Biguanide-Preserved Care Regimen, Optometry and Vision Science, Vol. 79, No. 12, December 2002).
Graham et al., in U.S. patent application Ser. No. 10/299,038 (Pub. No. US-2003-0129083-A1) disclose a multi-purpose solution comprising a poly(hexamethylene) biguanide (PHMB) disinfectant at 1 ppm in combination with the ophthalmic demulcents hydroxypropylmethylcellulose (HPMC) and propylene glycol, a poloxamer surfactant, a phosphate buffer and tonicity agent for disinfecting, cleaning and rewetting contact lenses. A composition of the invention has been marketed as Complete® Moisture Plus™ by Advanced Medical Optics, Incorporated (Santa Ana, Calif.). However, Complete® Moisture Plus™ has also been shown to produce a certain amount of staining among PUREVISION™ contact lens wearers by the same independent clinical investigators who evaluated ReNu®.
Asgharian, in U.S. Pat. No. 6,319,464, was able to achieve compatibility with silicone hydrogel contact lenses, Particularly PUREVISION® lenses from Bausch & Lomb, with a composition of the invention marketed as OPTI-FREE® EXPRESS® by Alcon, Incorporated in Fort Worth, Tex. A very low incidence of only 2% superficial fluorescein staining was observed (Jones et al., Asymptomatic Corneal Staining Associated with the Use of Balafilcon Silicone-Hydrogel Contact Lenses Disinfected with a Polyaminopropyl Biguanide-Preserved Care Regimen, Optometry and Vision Science, Vol. 79, No. 12, December 2002). However, this composition comprises five antimicrobial agents or adjuvants at concentrations well above 1 ppm each (Polyquaternium-1 (10 ppm), boric acid-sorbitol (600 ppm boric acid), disodium edetate (500 ppm), AMP-95 (4500 ppm) and myristamidopropyldimethylamine (MAPDA, at 5 ppm)). Together, these high concentrations of antimicrobial agents are very cytotoxic to mammalian cells (Mowrey-Mckee M, Sills A, Wright A. Comparative cytotoxicity potential of soft contact lens care regimens, The CLAO Journal 2002; 28 (3): 160-164). This level of cytotoxicity potentially can manifest itself in corneal tissue barrier function compromise and ocular discomfort, even in the absence of observable corneal epithelial punctate fluorescein staining.
A significant challenge to improving the disinfecting efficacy of a multi-purpose solution is to simultaneously improve or maintain its contact lens material compatibility and comfort. The addition of more effective disinfecting agents usually has the effect of reducing the material compatibility and comfort of the solution, in particular with silicone and non-silicone soft contact lenses and direct in-eye use. One way to achieve additional material compatibility and comfort is to lower the concentration of a disinfecting agent. However, this heretofore universally has resulted in lower antimicrobial efficacy. Also, it is known that polymeric biguanides, though chemically stable, can become partially depleted in solution over time due to sorption by the container walls, hence requiring a limited shelf life when used at relatively low concentrations that are preferred for comfort reasons.
Multi-purpose solutions that do not require digital rubbing of the contact lens with the solution as part of its regimen of use require more efficacious disinfection. Conventional contact-lens cleaners or disinfectants, including multi-purpose solutions, typically call for lens wearers to digitally or manually rub the contact lenses (typically between a finger and palm or between fingers) during treatment of the contact lenses. The necessity for the daily “rubbing” of contact lenses adds to the time and effort involved in the daily care of contact lenses. Many contact-lens wearers dislike having to perform such a regimen or consider it to be inconvenient. Additionally, some wearers are negligent in the proper “rubbing” regimen. This may result in contact-lens discomfort and other problems. Furthermore rubbing, if performed too rigorously, which is particularly apt to occur with beginning lens wearers, may damage the lenses. This can be especially problematic when a replacement lens is not immediately available.
Contact lens solutions that qualify as a “Chemical Disinfecting Solution” do not require rubbing to meet biocidal performance criteria (for destroying representative bacteria and fungi) set by the U.S. Food and Drug Administration (FDA) under the Premarket Notification (510 k) Guidance Document For Contact Lens Care Products, Appendix B, Apr. 1, 1997 and ISO/FDIS 14729: Ophthalmic optics—Contact lens care products—Microbiological requirements and test methods for products and regimens for hygienic management of contact lenses, January 2001. These aforementioned criteria are also known as the “stand-alone” disinfection standard. In contrast, a contact-lens solution, referred to as a “Chemical Disinfecting System,” not qualifying as a Chemical Disinfecting Solution, requires a rubbing regimen to pass biocidal performance criteria. These criteria are known as the regimen standard.
FDA and ISO guidelines for disinfection efficacy standards follow:
Stand-Alone Disinfectant (Primary) Criteria:
OrganismAverage log reduction at labeled soak timeS. marcescens, ATCC 138803.0 logsS. aureus, ATCC 65383.0 logsP. aeruginosa, ATCC 90273.0 logsC. albicans, ATCC 102311.0 log F. solani, ATCC 360311.0 log 
Regimen-Dependent Disinfectant (Secondary) Criteria:
OrganismAverage log reduction at labeled soak timeS. marcescens, ATCC 13880Minimum of 1.0 log per bacterium,S. aureus, ATCC 6538sum of all three bacteria log-dropsP. aeruginosa, ATCC 9027must be greater than or equal to 5.0 logC. albicans, ATCC 10231StasisF. solani, ATCC 36031Stasis
Traditionally, multi-purpose solutions (used for disinfecting and wetting or for disinfecting, cleaning, and wetting) have qualified as Chemical Disinfecting Systems, but not as Chemical Disinfecting Solutions. ReNu® MultiPlus® achieves the stand-alone disinfection standard, whereas Complete® Moisture Plus™ and other PHMB-containing multi-purpose solutions sold in the U.S. currently do not. OPTI-FREE® EXPRESS® also is marketed as a Chemical Disinfecting Solution, having passed the stand-alone standard.
Several investigators have explored the antimicrobial activity of different molecular weights of PHMB and other cationic polymers, in an attempt to optimize antimicrobial performance.
Broxton et al., in “Binding of some polyhexamethylene biguanides to the cell envelope of Escherichia coli ATCC 8739”, Microbios, 41, 15-22, 1984, found that a 15 ppm solution of a high molecular weight fraction of PHMB with an n≧10 (corresponding to an unspecified molecular weight of ≧2436) showed greater than twice the antimicrobial activity against Escherichia coli ATCC 8739, as a 10 ppm solution of PHMB having a mean n=5.5 (corresponding to a molecular weight of 1446). In this study, however, E. coli cultures were prepared with centrifugation and washing. This same centrifugation and washing technique was proven in subsequent studies by the same research group to sensitize the cells towards higher molecular weights.
Gilbert et al., in “Barrier properties of the Gram-negative cell envelope towards high molecular weight polyhexamethylene biguanides”, Journal of Applied Bacteriology, 69, 585-592, 1990, found that the antimicrobial activity of PHMB polymers against E. coli strains increased with polymer size within a series of polymers with polymerization numbers (n) of 4, 16, 30 and 35, corresponding to molecular weights of 1116, 3756, 6836 and 7936. More specifically, 1.8 ppm of the 7936 molecular weight material gave the same 1.0 log reduction in 1 minute against E. coli ATCC 8739 as 10.0 ppm of the 1116 molecular weight material, a 5.6-fold improvement. However, the same authors later reported that these results were obtained because the method of preparation of the cell suspensions employing both centrifugation and washing, leading to osmotic shock and losses of envelope lipopolysaccharide (LPS), sensitized the cells towards higher molecular weights (Gilbert et al., Synergism within polyhexamethylene biguanide biocide formulations, Journal of Applied Bacteriology, 69, 593-598, 1990). The latter study reported that the lower molecular weight fractions (e.g., n=4) of PHMB were the most active against uncentrifuged, non-osmotically stressed cell suspensions of E. coli at in-use concentrations of 2.0 ppm or greater. Thus, attempts to optimize the antimicrobial activity of PHMB have failed.
Ikeda et al., in Polycationic Biocides with Pendant Active Groups: Molecular Weight Dependence of Antibacterial Activity (Antimicrobial Agents and Chemotherapy, July, Vol. 30, No. 1, 132-136, 1986), studied two cationic antimicrobial polymers: polymethylmethacrylate containing pendant biguanide units and poly(vinylbenzyl ammonium chloride). They found that antibacterial activity of the biguanide-containing polymer against S. aureus was optimal at an intermediate molecular weight range, about 5×10e4 to 10×10e4 g/mole, with lower and higher molecular weight polymers exhibiting lower activity. However, the activity of an antimicrobial agent against one organism such as S. aureus cannot be used to predict activity against other organisms. Furthermore, cationic polymer stability in aqueous solution is not a predictable phenomemon, especially with changing molecular weight.
Kirschner, et al., in U.S. Pat. No. 5,942,218, disclose an intravenously administratable anti-infection solution comprising PHMB wherein the weight proportion of the polymer containing 5 or less units per chain is less than 2% based on entire polymer weight. Particularly preferred PHMB materials are disclosed with mean molecular weights in the region of 3,200 to 5,000. Antimicrobial activity against S. aureus and P. aeruginosa of 5 ppm solutions of PHMB of mean molecular weights 3500 and 2610 are disclosed, wherein the higher molecular weight PHMB had higher activity. Surprisingly, 2.5× lower hemolytic activity against erythrocytes was also found with one of the higher molecular weight PHMB polymers. Use of these high molecular weight PHMB polymers with contact lenses was disclosed. However, no antimicrobial activity data with high molecular weight PHMB solutions containing concentrations suitable for contact lens use at concentrations about 1 ppm were presented. In fact, this reference teaches that suitable concentrations of PHMB lie in the range of between 0.001 through 0.05 wet. % (10-500 ppm), a concentration far beyond the acceptable range for contact lens applications. The reference also does not present any data on toxicity or cytotoxicity (which is very important when placing a solution in the eye) or on any specific American Type Culture Collection (ATCC)—designated microorganisms from the FDA contact lens disinfection panel. It is well known that different ATCC sub-species of the same organism can exhibit enormous differences in antimicrobial resistance. An example of this is the well known differences in the resistances of Serratia Marcescens, ATCC numbers 14041 and 16880. ATCC 14041 is very resistant to PHMB and other antimicrobials, whereas ATCC 19880 is much less so. ATCC 14041 was formerly on the FDA Soft Contact Lens Disinfection Panel of microorganisms, against which all manufacturers of disinfecting/multi-purpose solutions had to demonstrate activity. The 14041 organism was so resistant, however, that the contact lens solution manufacturers successfully lobbied the FDA to replace this organism with the less resistant 13880 organism, which is used today.
None of the aforementioned approaches to improving PHMB or other polymers has been successfully applied to either regimen or stand-alone contact lens disinfection, nor to achieving compatibility with silicone hydrogel contact lenses.
Thus, it would be desirable to obtain a multi-purpose contact-lens solution that would provide increased disinfecting and cleaning efficacy, particularly over time. Further, it would be desirable to increase the biocidal efficacy of the product without adversely affecting material compatibility, ocular comfort or safety in terms of the level of toxicity to eye tissue. Silicone hydrogel compatibility has therefore heretofore not been accomplished without utilizing high concentrations of antimicrobial agents and significantly contributing to solution cytotoxicity or in-eye discomfort. Thus, there is a need for a simple solution comprising a limited number of antimicrobial agents, at low concentrations, which can achieve silicone hydrogel compatibility without substantially increasing mammalian cell cytotoxicity and in-eye discomfort.
USPTO Backgrounds
USPTO Backgrounds