MULTIPURPOSE DISINFECTION SOLUTIONS WITH HIGH HYALURONATE FOR OPHTHALMIC APPLICATIONS

Abstract

The present invention relates to ophthalmic formulations in which a synergistic combination of three different classes of disinfectants (a multimeric biguanide compound, a quaternary ammonium compound, and an antifungal / anti-acanthamoeba compound, in particular a combination of polyhexamethylene biguanide, polyquaternium-1, and myristamidopropyl dimethylamine) allows the use of high concentrations of hyaluronate to provide greater comfort and support for corneal health without compromising antimicrobial efficacy. The novel ophthalmic formulations support the use of hyaluronate concentrations more than 7.5 times higher than those present in currently marketed multipurpose disinfectant solutions.

Description

MULTIPURPOSE DISINFECTION SOLUTIONS WITH HIGH HYALURONATE FOR OPHTHALMIC APPLICATIONS Field of Invention The invention relates to multipurpose disinfection solutions for ophthalmic uses. Background of the Invention Multipurpose solutions for cleaning and disinfecting contact lenses, known as multipurpose disinfecting solutions (MPDS), are convenient because they allow lenses to be cleaned in a single step: neutralization of the cleaning solution is not required, and the lenses do not need to be rinsed as is necessary with, for example, hydrogen peroxide-based products. An MPDS should thoroughly clean and effectively disinfect a contact lens. Furthermore, it should provide comfort during contact lens wear. Recently, comfort has gained particular attention due to changes in the work environment; for example, the considerable use of screens and smartphones, exposure to air conditioning, etc., have led to an increasing number of dry and irritated eye problems. These symptoms are often exacerbated for contact lens wearers.This condition is known as Dry Eye. Ref. 333552 When used in conjunction with contact lenses, it can cause patients to discontinue contact lens use (Brafman and Eiden. Review of Cornea & Contact Lenses, Jan / Feb 2012, pp. 18-21). Hyaluronic acid (HA) is frequently used as a soothing and moisturizing agent in ophthalmic formulations and compositions. HA is a naturally occurring polymer composed of glucuronic acid and repeating units of N-acetyl-D-glucosamine. Hyaluronic acid (HA) usually has a high molecular weight (up to millions of Daltons) in mammals and is present in the extracellular matrix, epithelial, neural, and connective tissue, as well as in the vitreous humor of the eye (Stern et al. Eur. J. Cell Biol (2006) 85: 699-715, Saranraj et al. Int. J. Pharma. Biol. Sci. Arch. (2013) 4: 853-859). In recent decades, several positive aspects of HA supplementation in cosmetic and, in particular, ophthalmic products have been discovered. This is due to its high water-absorbing capacity (Holban & Grumezescu).Elsevier (2016). ISBN: 9780323477222), HA increases the wettability and lubrication capacity of the corneal surface and positively influences the stability of the tear film, resulting in a reduced rate of tear film evaporation and an increased tear breakup time (Zheng et al. Cornea. (2013) 32:1260-1264; Invest. Ophthalmol. Vis. Sci. (2014) 55: 3454-60; Saeed et al. Pak. J. Med. Sci. (2013) 29: 1055-1058, You et al. Hidden Pharmacol. Th. (2018) 34: 557-564, Oh et al. J. Ocul. Pharmacol. Th. (2014) 30: 533-542) These aspects are predominantly responsible for a feeling of comfort and a reduction in dry eye-like conditions. Furthermore, HA can function as a free radical scavenger and prevents damage caused by reactive oxygen species (ROS). HA is known to promote corneal cell migration and corneal re-epithelialization and is active in various wound healing processes. In addition, the polymer has been reported to protect corneal epithelial cells against damage from detergents such as sodium lauryl sulfate and surfactants such as benzalkonium chloride (Wu et al. J. Ophthalmol. (2017) Article ID 3678586; Nishida et al. (1991) Exp. Eye Res. 53: 753-758; Saranraj et al. (2013) Int. J. Pharm. Biol. Sci. Arch. 4: 853-859; Carlson et al. (2018) J. Ocul. Pharmacol. Th 34: 360-364).However, some of the physicochemical properties responsible for these latter positive effects also interfere with the use of HA in MPDS. While high effective concentrations of HA can be used, for example, in preservative-free artificial tear solutions, these same concentrations will inhibit the antimicrobial effects of commonly used disinfectants, such as quaternary ammonium compounds, in MPDS. This inhibition occurs because HA is an anionic polymer that can form complexes with cationic disinfectants, resulting in their aggregation and inactivation (U.S. Patent Nos. 8,119,1125,858,346 and 5,559,104). In principle, the inhibitory effects of HA can be compensated for by increasing disinfectant concentrations. However, such compensation may not be easily achieved since disinfectants are cytotoxic at high concentrations. (Pellinen et al. Curr. Eye Res. (2012) 37: 145-154; Paimela et al. Molecular Vision (2012) 18: 1189-1196). Therefore, it is not surprising that the HA concentration in commercially available MPDS typically does not exceed approximately 0.01% (w / v). Because comfort effects are expected to increase with concentration, the development of ophthalmic solutions containing higher concentrations of HA should be an important objective (You et al. J. Ocul. Pharmacol. Th. (2018) 34: 557-564). The concept that higher concentrations of HA would be beneficial is further supported by the studies of Torretta et al. (Int. J. Immunopathol. Pharmacol. (2016) 29: 438-442) and Romano et al. (J. Bone Jt. Infect. (2017) 2: 63-72). Recent studies have provided evidence that biofilm formation by certain bacterial strains does not occur at high HA concentrations. It should be noted that U.S. Patents Nos. 8,119,112 and 8,664,180 propose that HA concentrations greater than 0.01% w / v may be contained in MPDS. However, U.S. Patent No. 8,664,180 does not explicitly describe such compositions, and U.S. Patent No. 8,119,112, while describing MPDS with high HA concentrations, only provides experimental evidence of adequate antimicrobial activity for a composition containing 0.01% w / v HA. This description relates to MPDS that allow higher concentrations of HA than those present in commercially available MPDS, without compromising antimicrobial activity or cleaning efficacy. Summary of the Invention The present invention relates to ophthalmic formulations in which a synergistic combination of three different classes of disinfectants (a multimeric biguanide compound, a quaternary ammonium compound, and an antifungal / anti-acanthamoeba compound), in particular a combination of polyhexamethylene biguanide, polyquaternium-1, and myristamidopropyl dimethylamine, allows the use of high concentrations of hyaluronic acid to provide improved comfort and support for corneal health without compromising antimicrobial efficacy. The novel ophthalmic formulations described herein support the use of hyaluronic acid concentrations more than 7.5 times higher than those present in currently marketed MPDSs. The solutions of the present invention may preferably also be referred to as ophthalmic formulations of the present invention, or multipurpose disinfection solutions (MPDS) of the present invention. Therefore, this description refers to MPDS for ophthalmic use comprising a multimeric biguanide compound, a quaternary ammonium compound, an antifungal / anti-acanthamoeba agent, and hyaluronic acid or a hyaluronic acid salt. The multimeric biguanide compound may be present in an amount from approximately 0.00005 to approximately 0.0005% w / v, the quaternary ammonium compound in an amount from approximately 0.00005 to approximately 0.0025% w / v, and the antifungal / anti-acanthamoeba agent in an amount from approximately 0.00005 to approximately 0.0025% w / v. The antifungal / anti-acanthamoeba agent may be an amidoamine compound such as myristamidopropyl dimethylamine (MAPD) ​​or chlorhexidine sulfonate. MAPD is preferred. Hyaluronic acid or hyaluronate is present in an amount exceeding 0.01% w / v but less than approximately 0.1% w / v.The preferred concentrations of the MPDS components described herein are in the range from approximately 0.000075 to approximately 0.00025% w / v for the biguanide multimeric compound, from approximately 0.00005 to approximately 0.002% w / v for the quaternary ammonium compound, from approximately 0.00005 to approximately 0.002% w / v for the antifungal / anti-acanthamoeba agent, and from approximately 0.0151% w / v to approximately 0.09% w / v for hyaluronic acid or hyaluronate. The most preferred concentrations are from approximately 0.0001 to approximately 0.0002, from approximately 0.000075 to approximately 0.001, from approximately 0.0001 to approximately 0.0018, and from approximately 0.025 to approximately 0.085% w / v for the multimeric biguanide compound, the quaternary ammonium compound, the antifungal / anti-acanthamoeba agent, and HA, respectively. The most preferred concentrations are from 0.00012 to 0.00016, 0.000085 to 0.00012, 0.0006 to 0.0014 and 0.04 to 0.08 % w / v, respectively. The amido-amine compound, as understood herein, is preferably defined as an amide of a fatty acid and a diamine compound, formed from a fatty acid molecule and a diamine molecule. The amido-amine compounds of the present invention preferably contain an amide group -C(O)NH- and an amino group -NR2, wherein each R is independently a hydrogen or an optionally substituted hydrocarbon. The fatty acid, as understood herein, preferably refers to an alkanoic acid, optionally containing one or more C=C bonds, and optionally substituted, in particular with an -OH group. Preferably, the fatty acid has from 2 to 30 carbon atoms. More preferably, the fatty acid has from 4 to 28 carbon atoms. The diamine molecule, as defined herein, preferably contains two amino groups, one of which may optionally be substituted with one or more C1-C4 alkyls, and an alkylene residue with 1 to 10 carbon atoms.The multimeric biguanide compound is selected from the group consisting of polyhexamethylene biguanide (PHMB), polyaminopropyl biguanide (PAPB) and 1,1'-hexamethylene-bis (5-[2ethylhexyl]biguanide), and the quaternary ammonium compound is selected from the group consisting of Polyquaternium-1 (PQ-1), Polyquaternium-10 (PQ-10), Polyquaternium-42, Ndocecyl{4,4'-(2,4,8,10-tetraoxaspiro[5.5]undecan3,9diyl)}dipyridinium dibromide, 3,3'-[l,4phenylenebis(oxy)]bis(1-dodecylpyridinium) dibromide, 3—(3 — hydroxy-2-(hydroxymethyl)-2-{[(l-dodecylpyridinium-3yl)oxy]methyl[propoxy]-1-dodecylpyridinium, 5,50[2,20-(tetramethylenedicarbonyldioxy)diethyl]bis(3-alkyl-4-methylthiazolium) iodide and [4,40-(1,6-hexamethylenedithio)bis(1-octylpyridinium iodide). The most preferred biguanide compound is PHMB and the most preferred quaternary ammonium compound is PQ-1. Preferably, polyhexamethylene biguanide (PHMB) may also be referred to as poly(hexamethylene biguanide).More preferably, each compound as described herein is understood to mean either the compound itself or a pharmaceutically acceptable salt thereof. Thus, for example, the term polyhexamethylene biguanide (PHMB) is preferably understood herein to mean either polyhexamethylene biguanide (PHMB) or a pharmaceutically acceptable salt thereof. The multimeric biguanide compound, as understood herein, is preferably defined as a compound containing more than one biguanide moiety -NH-C(=NH)-NH-C(=NH)-NH-, more preferably defined as a compound comprising a repeating unit comprising a biguanide moiety NH-C(=NH)-NH-C(=NH)-NH-. The multimeric biguanide compound as defined herein may also refer to a pharmaceutically acceptable salt of a compound, as defined herein. Preferably, any compound described herein may also be present as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts are preferably defined as derivatives of the compounds described herein, where the parent compound is modified by making acidic or basic salts of itself. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of mineral or organic acids from basic residues such as amines; alkali or organic salts from acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include conventional nontoxic salts or quaternary ammonium salts of the parent compound formed, for example, from nontoxic inorganic or organic acids.For example, such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and similar acids; and salts prepared from organic acids such as, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and similar acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods.Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate acid or base in water or an organic solvent, or a mixture of the two. Organic solvents include, but are not limited to, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. ινΐΛ / a / zuzz / uuoz 1i Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, the description of which is incorporated herein by reference. The MPDS described herein comprises one or more, more typically most or all of the following additional components: a chelating agent at a concentration of approximately 0.01-0.06% w / v, a buffer solution or buffering agent at a concentration of approximately 0.01-1% w / v, a viscosity modifier at a concentration of approximately 0.01-0.25% w / v, a surfactant compound at a concentration of approximately 0.01-1% w / v, a tonicity agent at a concentration of approximately 0.001-1% w / v, and a calcium and / or magnesium salt, for example, MgCl2 and / or CaSO4, each at a concentration of approximately 0.001-0.015% w / v. Preferably, the MPDS of the present description comprises one or more, more typically most or all of the following additional components: a chelating agent at a concentration of approximately 0.01-0.06% w / v, a buffer solution or buffering agent at a concentration of approximately 0.01-1% w / v, a viscosity modifier at a concentration of approximately 0.01-0.25% w / v, a surfactant compound at a concentration of approximately 0.01-1% w / v, a tonicity agent at a concentration of approximately 0.001-1% w / v, and optionally, a calcium and / or magnesium salt, for example, MgCl2 and / or CaSO4, each at a concentration of approximately 0.001-0.015% w / v.The most preferred are, as a chelating agent, ethylenediaminetetraacetic acid (EDTA), as a buffering agent, a borate buffer solution, as a viscosity modifier, hydroxypropyl methylcellulose (HPMC) (additional preferred compounds are carboxymethylcellulose (CMC) and hydroxyethylcellulose), as a surfactant, a poloxamine, and as a tonicity agent, sodium chloride or a combination of sodium chloride and potassium chloride. Preferably, the multipurpose disinfectant solution of the present invention may further comprise one or more of a chelating agent in an amount ranging from approximately 0.01% w / v to approximately 0.06% w / v, a buffer solution in an amount ranging from approximately 0.01% w / v to approximately 1% w / v, a viscosity modifier in an amount ranging from approximately 0.01% w / v to approximately 0.25% w / v, a surfactant compound in an amount ranging from approximately 0.01% w / v to approximately 1% w / v, a tonicity agent in an amount ranging from approximately 0.001% w / v to approximately 1% w / v, a calcium salt in an amount ranging from approximately 0.001% w / v to approximately 0.015% w / v, and a magnesium salt in an amount ranging from approximately 0.001% w / v to approximately 0.015% w / v. p / v. Detailed Description of the Invention The present invention relates to a novel multipurpose disinfecting solution (MPDS) that can be used for cleaning, disinfecting, and storing contact lenses. The applicant discovered that in an MPDS containing disinfectants of the two classes typically used in MPDS—in this case, multimeric biguanide compounds and quaternary ammonium compounds—the concentration of hyaluronate (HA), which is included as a wetting, lubricating, and corneal support agent, cannot be significantly increased beyond 0.01% w / v without loss of effective antimicrobial activity. It is further noted that Biotrue from Bausch & Lomb, a typical MPDS of this type, contains HA at 0.01% w / v. Presumably, a higher concentration of HA in such an MPDS is not tolerated due to the concentration-dependent inactivation of the cationic disinfectants by HA. Surprisingly, the inventor found that adding a third-class disinfectant—in this case, an antifungal / anti-acanthamoeba agent—effectively counteracts the negative effect of HA on the antimicrobial activity of MPDS. Adequate antimicrobial activity is maintained at HA concentrations 7.5 times higher than those used in commercially available MPDS. Therefore, the MPDS formulations described herein comprise three types of disinfectants: a multimeric biguanide compound, a quaternary ammonium compound, and an antifungal / anti-acanthamoeba agent. The multimeric biguanide compound may be, but is not limited to, polyhexamethylene biguanide (PHMB), polyaminopropyl biguanide (PAPE), or 1,1'-hexamethylene-bis(5[2-ethylhexyl]biguanide) (alexidine dihydrochloride). A preferred multimeric biguanide compound is PHMB. A typical concentration range for the multimeric biguanide compound (or a suitable salt thereof) is approximately 0.00005–0.0005% (w / v). Preferably, the compound is present at a concentration of approximately 0.000075–0.00025% (w / v). A more preferable range is approximately 0.0001-0.0002% (w / v) and most preferable is approximately 0.00012-0.00016% (w / v).Ideally, the compound is present at a concentration of approximately 0.00015% (w / v). Suitable quaternary ammonium compounds include, but are not limited to, polyquaternium-1 (PQ-1; also known as Polyquad (Alcon)), polyquaternium-10 (PQ-10), and polyquaternium-42 (PQ-42). These compounds may also be referred to as preferred quaternary ammonium compounds. Additional suitable quaternary ammonium compounds are N-dodecyl{4,4'-(2,4,8,10-tetraoxaspiro[5,5]undecan-3,9-diyl)}dipyridinium dibromide (4TOSU-12), 3,3'-[1,4-phenylenebis(oxy)]bis(1-dodecylpyridinium) dibromide (3PHBO-12); 3-(3-hydroxy-2-(hydroxymethyl)-2-{[(1-dodecylpyridinium-3-yl)oxy]methylpropoxy)-1-dodecylpyridinium (3HHDMP-12), 5,50-[2,20(tetramethylenedicarbonyldioxy)diethyl]bis(3-alkyl4-methylthiazolium iodide) (5DEBT-4,8) and [4,40-(1,6-hexamethylenedithio)bis(1-octylpyridinium iodide)] (4DTBP-6,8) (Yamamoto et al. Biocontrol Science (2016) 21: 231-241; Ohkura et al. Bioorganic & Medicinal Chemistry (2005) 13: 2579-2587). Polyquaternium compounds are described, for example, in Iwata et al. Springer Science & Business Media. 2012-10-02. ISBN 9784431540618. For the quaternary ammonium compound (QAC) (or a suitable salt thereof), the typical range is approximately 0.00005-0.0025% (w / v). Preferably, the concentration is from approximately 0.00005 to approximately 0.0020% (w / v), more preferably from approximately 0.000075 to approximately 0.001% (w / v), and most preferably from approximately 0.000085 to approximately 0.00012% (w / v). Even more preferably, the concentration is approximately 0.00010% (w / v). Due to their lower cytotoxicity and allergenic potential, multimeric QACs, which have several repeating units of a quaternary ammonium group, are preferred over monomeric QACs. Of this subclass, the most preferred multimeric QAC is polyquaternium-1 (PQ-1).In some formulations, so-called bis-QACs such as (4TOSU-12), which have two quaternary ammonium groups in the same entity, can be used because they have higher activities and better biocompatibilities than conventional monomeric QACs. Mixtures of a bis-QAC and PQ-1 may also be suitable for the ophthalmic formulations described herein. Preferably, polyquaternium-1 is understood herein to be a compound according to CAS number 75345-27-6. Polyquaternium-1 as defined herein is commercially available in Biosynth Carbosynth (FP163582). Preferably, polyquaternium-10 is understood herein to mean a compound or composition in accordance with CAS number 68610-92-4. Polyquaternium-10 as defined herein is commercially available from Merck KGaA (525944). Preferably, polyquaternium-42 is understood herein to be a compound or composition in accordance with CAS number 31512-74-0. Polyquaternium-42 as defined herein is commercially available from Biosynth Carbosynth (FP59606). A suitable antifungal / anti-acanthamoeba agent is myristamidopropyl dimethylamine (MAPD; also known as Aldox (Alcon)) or another amidoamine compound, or chlorhexidine gluconate. MAPD / Aldox is the most preferred. The antifungal / anti-acanthamoeba agent is typically included in an MPDS of the present description at a concentration of approximately 0.00005 to approximately 0.0025% (w / v). Preferably, concentrations are in the range of 0.00005 to approximately 0.0020% (w / v), more preferably from 0.0001 to 0.0018% (w / v), and most preferably from approximately 0.0006 to approximately 0.0014% (w / v). Even more preferably, a concentration of 0.00120% (w / v) is preferred. The HA (as the free acid or an acceptable salt thereof) used in the ophthalmic formulations described herein usually has a molecular weight of approximately 50,000 to approximately 2 million Daltons (2 MDa), preferably from approximately 0.4 to approximately 1.8 MDa and most preferably from approximately 1.2 to approximately 1.8 MDa. As understood herein, the molecular weight of the HA preferably refers to a weight-average molecular weight, determined as discussed below. The molecular weight of HA was determined using gel permeation chromatography (GPC) with a pullulan standard according to the following protocol. A 3 mg / mL stock solution of hyaluronic acid was prepared in elution buffer (deionized water containing 0.05% (w / v) NaN3). Subsequently, 0.4 mL of the stock solution was injected into the port of a tempered GPC device (1260 Infinity LC-System, Agilent, Santa Clara, CA). Chromatography was performed at a constant flow rate of 1.0 mL / min in elution buffer. Hyaluronic acid samples were separated on a Suprema two-column system (pre-column, linear XL; 5 µm particle size; PSS, Mainz, Germany) placed in an external column oven at 55°C. Copolymers were analyzed using RI (refractive index) and UV detectors.A calibration curve (10 points) was established using a pullulan standard obtained from PSS (Mainz, Germany), including the following 10 polymers (Mw, Mn and PDI are provided): (1) Mw: 342 / Mn: 342, PDI 1.0; (2) Mw: 1320 / Mn: 1080, PDI 1.23; (3) Mw: 6200 / Mn: 5900, PDI 1.05; (4) Mw: 10000 / Mn: 9200, PDI 1.09; (5) Mw: 21700 / Mn: 20000, PDI 1.09; (6) Mw: 48800 / Mn: 45500, PDI 1.07; (7) Mw: 113000 / Mn: 100000, PDI 1.13; (8) Mw: 210000 / Mn 189000, PDI 1.11; (9) Mw: 366000 / Mn. 318000, PDI 1.15; (10) Mw: 805000 / Mn: 636000, PDI: 1.27. The molecular weights of the characterized copolymers were estimated with reference to this standard. For this purpose, the weight-average molecular weight of the polymer (Mw), number-average molecular weight of the polymer (Mn), and its PDI were determined based on GPC measurements using the PSS WinGPC Unichrom V:8.1 Build 2827 computer program (PSS; https: / / www.pss-polymer.com / ). The HA concentration is typically greater than 0.01% w / v and less than 0.1% w / v. Preferably, it is from approximately 0.0151 to 0.09% (w / v), more preferably from approximately 0.025 to 0.085% (w / v), and most preferably from approximately 0.04 to approximately 0.08% (w / v). In order to maximize the safety of the ophthalmic formulation, the HA is preferably derived from a biotechnological process, for example, produced by fermentation with bacteria or in a cell-free system using suitable enzymes. Currently, HA is produced on an industrial scale either by extraction from animal tissues, primarily rooster combs, or by large-scale fermentation using genetically modified bacterial strains (Liu et al. Microb. Cell Fact. (2011) 10: 99). Both processes have their advantages, but from a safety perspective, biotechnological methods are preferred for producing HA used in medical devices such as lens care solutions. Animal tissue extraction requires harsh conditions (milling, acid treatment, use of organic solvents, etc.) and leads to partial degradation of the HA, increasing the polymer's polydispersity index (PDI). Consequently, batch-to-batch variability can be high (Boeriu et al. Int. J. Carbohydr. Chem. (2013) vol. 2013, Article ID 624967).Furthermore, HA from an animal source may still be bound to animal proteins and, depending on the source, may also contain nucleic acids, prions, and viruses, with the consequent risk of immune reactions or disease transmission (Shiedlin et al. (2004) Biomacromolecules 5: 21222-2127). HA derived from biotechnological processes may be less likely to be contaminated. The presence of endotoxins can be avoided by using endotoxin-free strains such as B. subtilis. In addition, HA produced by biotechnology has a lower PDI compared to HA extracted from tissues, provided that culture conditions are carefully monitored and controlled. To date, HA with molecular weights up to 2 MDa can be produced by fermentation. Cell-free systems using isolated enzymes produce HA with molecular weights up to 1-2 MDa.The latter molecular weight ranges are quite suitable for ophthalmic formulations because high molecular weight HAs have a great capacity to absorb water and, due to their high viscosities, remain longer on the contact lens / eye surface than HAs of smaller molecular sizes (Sze et al. Biotech (2016) 6: 67 and the references cited therein). The MPDS described herein typically also includes a buffer solution component. The type and amount of buffer solution are selected so that the MPDS composition meets the required performance criteria, such as physicochemical attributes and shelf-life stability, antimicrobial efficacy, buffering capacity, and similar factors. The buffer solution is also selected to provide a pH compatible with the target tissue of the eye, as well as with any contact lens with which the composition is intended to be used. Suitable buffer solutions may include borate, citrate, histidine, tris, tris / glycine, or bis-tris, and combinations thereof. Phosphate may also be suitable. Preferably, the buffer solution is borate, phosphate, citrate, histidine, tris, tris / glycine, bis-tris, or combinations thereof.In general, for an ophthalmic formulation, a pH close to that of human tears, such as approximately 7.5, is very useful, although pH values ​​in the range from approximately 6.0 to approximately 8.0 are also acceptable, more preferably from approximately 6.2 to approximately 7.8, and even more preferably from approximately 7.0 to approximately 7.7. Buffer solution substances are usually present in concentrations between approximately 0.01% w / v and approximately 1% w / v. The ophthalmic formulations described here, which are intended to effectively clean contact lenses, typically comprise one or more surfactants. Useful surfactants include, but are not limited to, poloxamers (nonionic triblock copolymers composed of a central hydrophobic chain of polypropylene oxide (PPO) flanked by two hydrophilic chains of polyethylene oxide (PEO)), poloxamines (nonionic copolymers having an ethylenediamine core whose amino groups are substituted by PPO / PEO chains of varying lengths and compositions), or polysorbate-type substances (oily liquids derived from ethoxylated sorbitan (a sorbitol derivative) esterified with various fatty acids). The inclusion of such surfactants results in effective lens cleaning during lens treatment without substantially affecting the antimicrobial activity of the MPDS compositions. The concentration of surfactants in the formulations typically ranges from approximately 0.01% w / v to approximately 1% w / v. Poloxamines are preferred. Examples of poloxamines are Tetronic 90R4, Tetronic 701, Tetronic 1304, and Tetronic 1107. The cleaning characteristics of poloxamines vary depending on the PEO / PPO ratio and molecular weight, respectively. Tetronic 90R4 is preferably defined as a compound or composition according to CAS number 26316-40-5, which is available from Sigma Aldrich under catalog number 435546. Preferably, the number-average molecular weight of Tetronic 90R4 is 7200 Da. Tetronic 701 is preferably defined as a compound or composition according to CAS number 26316-40-5, which is available from Sigma Aldrich under catalog number 435511. Preferably, the number-average molecular weight of Tetronic 701 is 3600 Da. Tetronic 1304 is preferably defined as a compound or composition according to CAS number 26316-34-5. Preferably, the number-average molecular weight of Tetronic 1304 is 10500 Da. Tetronic 1107 is preferably defined as a compound or composition according to CAS number 26316-40-5. Preferably, the number-average molecular weight of Tetronic 1107 is 15000 Da.Currently described MPDS formulations typically comprise a chelating agent or a mixture of chelating agents. Such chelating agents must be able to interact with calcium and magnesium ions, as well as with residual heavy metal ions sometimes present in contact lenses. They must also be compatible with ophthalmic or medical applications. Suitable chelating agents include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), tetrasodium N,Nbis(carboxymethyl)-L-glutamate (GLDA), tetrasodium iminodisuccinate, trisodium N-(I-carboxylateethyl)iminodiacetate (MGDA), (1,4,7,10-tetraazacyclododecane-I,4,7,10-tetraacetic acid) (DOTA), diethylenetriaminepentaacetic acid (DTPA), triethylenetetramine-N,N,N',N'',N''',N'''-hexaacetic acid (TTHA), and citrate. EDTA and GLDA are preferred because they are excellent chelating agents and have good water solubility. GLDA is readily biodegradable.The concentration of chelating agents in formulations typically ranges from approximately 0.01% w / v to approximately 0.06% w / v. It is observed that commercially available MPDSs, such as Bausch & Lomb's Biotrue, contain higher levels of chelating agent. The MPDSs described herein may also include low concentrations of calcium and / or magnesium salts, ranging from approximately 0.001% w / v to approximately 0.015% w / v, whereby the combined molar amounts of the added divalent cations are lower than the chelating agent used in the same formulation. The osmolarity of the ophthalmic formulations described above can be adjusted with tonic agents. Examples of suitable tonic agents include, but are not limited to, sodium, potassium, calcium, and magnesium chloride salts, dextrose, glycerol, propylene glycol, sugars such as sorbitol and mannitol, amino acids such as glycine, and mixtures of these agents. The preferred tonic agents are sodium chloride or combinations of sodium chloride and potassium chloride, which can be combined with mannitol, sorbitol, or glycine to increase buffering or free radical scavenging capacity. Tonic agents are typically used in amounts ranging from approximately 0.001% w / v to approximately 1% w / v.Preferably, a tonicity agent(s) shall be employed in an amount that results in a final osmotic value of between approximately 220 and 380 mOsm / kg, more preferably between approximately 240 and 320 mOsm / kg and most preferably between approximately 280 and 310 mOsm / kg. Viscosity-modifying agents that may be included in the formulations described herein include cellulose polymers (including hydroxypropyl methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, and carboxymethylcellulose), glycerol, carbomers, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, poly(acryloyl-lysine), or copolymers containing acrylated side-chain amino acids, alginates, carrageenans, galactomannan (guar) polysaccharides, karaya, agarose, locust bean, tragacanth, and xanthan gum. Viscosity-modifying agents are employed in an amount effective to provide the desired lubricating effect. The concentration of these agents will typically be between approximately 0.01 and 0.25% w / v. The preferred viscosity-modifying agents are hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), and hydroxyethylcellulose (HEC).The most preferred is HPMC, which is also an excellent wetting agent. HPMC is sold, for example, by The Dow Chemical Company (Dow) under the brand name METHOCEL. Multiple types are available, differing in their degree of functionalization with methoxyl / hydroxypropyl groups, as well as in their molecular weight. An appropriate type of HPMC (or other viscosity modifier) ​​can be selected to achieve the desired viscosity, which is typically between approximately 0.5 and approximately 4 millipascal-seconds (mPa-s), preferably between approximately 1.0 and approximately 3.5 mPa-s, more preferably between approximately 1.25 and approximately 3.25 mPa-s, and most preferably between approximately 2.0 and approximately 2.8 mPa-s. The viscosity determination referred to here was performed using a spindle viscometer. For this purpose, 300 mL of the sample solution were poured into a 500 mL glass beaker and quenched in a water bath at 23 °C for 30 minutes. The viscosity was determined using a Brookfield viscometer (DV-II, 60 rpm, spindle 1, 23 °C). Typical MPDS formulations according to the present description are described in Tables 1 and 2. As is known to persons skilled in the art, the formulations of the present invention can preferably be obtained by mixing and diluting aqueous stock solutions of each of the components. Persons skilled in the art know that, in the case of hydrophobic agents, for example, Aldox, it is preferable to prepare an ethanol stock solution to which the hydrophobic agent can be added to the aqueous formulation. Table 1: Exemplary formulations of borate-based buffer solution systems Component Component concentrations (% w / v) Ex. 1 Ex.2 Ex. 3 Ex.4 Ex. 5 Ex. 6 PHMB 0.0001 0.0002 - 0.00015 0.00015 0.00015 PAPB - - 0.0002 - - - PQ-1 0.001 0.000075 0.0001 - 0.0001 0.0001 PQ-10 - - 0.0001 - - MAPD 0.0018 0.0001 0.0012 0.0012 0.0012 0.0012 HA 0.025 0.085 0.075 0.075 0.075 0.075 EDTA 0.01 0.06 - 0.04 - 0.03 GLDA - - 0.06 - 0.04 - HPMC 0.01 0.25 - 0.075 0.1 - CMC - - 0.25 - - 0.075 Tetronic 90R4 or 701 0.05 1 - 0.1 - 0.1 Tetronic 1304 - - 0.1 - 0.1 - MgCl2 0.001 0.015 0.0015 0.0015 0.003 - CaCl2 0.001 - 0.0015 0.0015 - - Borate buffer solution 0.05 1 0.4 0.4 0.4 0.4 NaCl / KCl 0.52 Table 2: Exemplary formulations of phosphate-based buffer solution systems Component Component concentrations (% w / v) Ex.7 Ex.8 Ex.9 Ex.10 Ex.11 Ex.12 PHMB 0.0001 0.0002 - 0.00015 0.00015 0.00015 PAPB - - 0.0002 - - - PQ-1 0.001 0.000075 0.0001 - 0.0001 0.0001 PQ-10 - - 0.0001 - - MAPD 0.0018 0.0001 0.0012 0.0012 0.0012 0.0012 HA 0.03 0.05 0.05 0.035 0.06 0.075 EDTA 0.01 0.06 - 0.04 - 0.03 GLDA - - 0.06 - 0.04 - HPMC 0.01 0.25 - 0.075 0.1 - CMC - - 0.25 - - 0.075 Tetronic90R4o 701 0.05 1 - 0.1 - 0.1 Tetronic 1304 - - 0.1 - 0.1 - Sodium phosphate (dibasic / monobasic) 0.4 / 0.14 0.4 / 0.14 0.4 / 0.14 0.2 / 0.07 0.3 / 0.05 0.4 / 0.14 NaCI / KCI 0.48 The present invention, as generally described, will be more easily understood with reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention. Examples Example 1: Antimicrobial Preservation Efficacy according to ISO 14729 In an effort to obtain a more convenient MPDS for patients, formulations A and B were prepared. These formulations are based on the same multimeric biguanide and quaternary ammonium compounds used in commercially available MPDSs but contain HA at a 50% higher concentration (Table 3). The ability of these formulations to inactivate microbial growth was tested according to an ISO 14729 test protocol using Biotrue MPDS, which contains 0.01% (w / v) HA, as a positive control. It should be noted that a spiral plate method was used for cell counting. Table 3 Tested formulations: Formulation Disinfectants HA (% w / v) A* PHMB 0.00015 % w / v; PQ-1 0.001 % w / v 0.0151 B* PHMB 0.00015 % w / v; Alexidine dihydrochloride 0.00017 % w / v 0.0151 C* PHMB 0.00015 % w / v; PQ-1 0.001 % w / v; MAPD 0.0012 % w / v 0.0151 D* PHMB 0.00015 % w / v, PQ-1 0.0001 % w / v; MAPD 0.0012 % w / v 0.0151 E* PHMB 0.00015 % w / v, PQ-1 0.0001 % w / v; MAPD 0.0012 % w / v 0.0750 F** PHMB 0.00015 % w / v, PQ-1 0.0001 % w / v; MAPD 0.0012 % w / v 0.0300 Biotrue PHMB 0.00012 % w / v, PQ-1 0.0001 % w / v 0.0100 *The AE formulations also comprise boric acid (0.1% w / v), disodium tetraborate decahydrate (0.3% w / v), HPMC (0.08% w / v), Tetronic 90R4 (0.1% w / v), EDTA (sodium salt dihydrate - 0.04% w / v), potassium chloride (0.04% w / v), sodium chloride (0.5% w / v), calcium chloride dihydrate (0.002% w / v) and magnesium sulfate heptahydrate (0.002% w / v); pH 7.5 (adjusted by the addition of 32% w / w of an aqueous solution of HCl). **Formulation F further comprises monobasic sodium phosphate (monohydrate, a final concentration of 0.1% w / v), dibasic sodium phosphate (heptahydrate, final concentration of 0.4% w / v), HPMC (0.08% w / v), Tetronic 90R4 (0.1% w / v), EDTA (sodium salt dihydrate - 0.04% w / v), potassium chloride (0.04% w / v), sodium chloride (0.5% w / v); pH 7.5 (adjusted by the addition of 20% w / w of an aqueous NaOH solution). These latter components are present at the concentrations indicated in parentheses, which are within the ranges described above. Test solutions containing at least 10 mL of a formulation per challenge organism are inoculated with a sufficient number of challenge organisms to provide a final count of between 1.0 x 10⁵ and 1.0 x 10⁶ CFU / mL and subsequently incubated at 20–25°C for up to 32 h. At 2, 4, 6, and 8 h, a 1 mL aliquot of the solution is extracted and analyzed for residual live microbial content using a spiral plate method. This method has a detection limit of 10² microbes (in this case, if the microbial count at inoculation is 10⁶, the maximum detectable log reduction will be 4.0). For yeast and fungal challenges (C. albicans and F. solani), an additional sample is taken after 32 h. Typical test results are shown in Table 4. The symbol > in Table 4 indicates that no colony-forming units (CEUs) were observed. The determination of viable organism count and the determination of the logarithmic reduction were performed according to ISO 14729 (first edition 2001-04-15) with the exception of a spiral plate method (Gilchrist et al. Appl Microbiol. 1973 Feb; 25(2):244-52) for the recovery of the challenge organism. Colony-forming units (Cfu) were recorded only on count plates. As defined here, count plates refer to plates with 30 to 300 Cfu / plate for bacteria and yeasts, and 8 to 80 Cfu / plate for molds. The average number of (cfu) on count plates (triplets) was recorded and the microbial reduction at specified time points [2, 4, 6, 8 h (bacteria) or 2, 4, 6, 8, 32 h (yeast, molds)] was calculated by assignment with the inoculation value for the respective challenge organism. Table 4: Antimicrobial activities of the formulations Incubation time [2h] [4h] [6h] [8h] [32h] Test organism Formulation Log Reduction Log Reduction Log Reduction Log Reduction Log Reduction n Log Staphylococcus aureus ATCC 6538 A >3.51 >3.51 >3.51 >3.51 B 1.56 2.20 C 3.26 >3.26 >3.26 >3.26 D >3.18 >3.18 >3.18 >3.18 E 2.18 >3.18 >3.18 >3.18 F Pseudomonas aeruginosa ATCC 9027 A 1.24 2.3 3.34 >3.34 B 0.44 0.64 0.72 1.00 C >3.15 >3.15 >3.15 >3.15 D >3.34 >3.34 >3.34 >3.34 > E3.3.3. >3.34 F 2.93 >3.23 >3.23 >3.23 Biotrue >3.34 >3.34 >3.34 >3.34 Serrada marescens ATCC 13880 A >3.42 >3.42 >3.42 >3.42 B 0.07 0.07 0.07 C >3.50. >3.56 >3.56 D 3.18 >3.48 >3.48 >3.48 E 3.00 >3.48 >3.48 >3.48 F 2.93 >3.23 >3.23 >3.23 Biotrue >3.41 >3.41 >3.41 >3.41 >3.41 Candida ATCC A 0.19 0.27 0.27 0.42 1.42 B 0.04 0.06 0.14 0.15 0.21 C 2.76 >3.72 >3.72 >3.72 >3.72 D 2.21 2.91 >3.69 >3.6 3.6 3.6 E. 3.69 3.69 >3.69 F 0.38 0.40 0.46 1.14 2.19 Biotrue >3.57 >3.57 >3.57 >3.57 >3.57 Fusarium sotaní ATCC 36031 A 0.54 0.9 0.94 1.37 2.24 B -0.05 -0.01 -0.05 -0.01 -0-01 C >2.20 >2.20 >2.20 >2.20 >2.20 D 2.8 3.41 >3.41 >3.41 >3.41 E 1.7 2.93 3.11 3.11 >3.41 F 1.01 1.29 1.50 1.89 >3.70 Biotrue 2.54 >2.54 >2.54 >2.54 >2.54. The data in this table represent averages from three independent experiments. The experiments were conducted in the same laboratory and by the same examiner. Neither formulation A nor formulation B met the main criteria of the ISO test procedure (3.0 log reduction for bacteria, 1.0 log reduction for yeasts and molds within the recommended wetting time) (Table 4). Therefore, a combination of PHMB and PQ-1, even when used at higher concentrations than in the Biotrue positive control formulation, is unable to provide adequate antimicrobial activity when the HA concentration is significantly increased. Antifungal activity is particularly impaired. Replacing PQ-1 with a second biguanide compound resulted in even lower antimicrobial activity. Both antibacterial and antifungal activities were low.In summary, the test results showed that the presence of only two disinfectants (of two different classes or of the same class) is insufficient to provide adequate antimicrobial activity in an MDS that has a significantly increased HA concentration compared to the commercially available MPDS. The applicant then experimented to determine whether adding a third disinfectant could remedy the deficiencies of formulations A and B. Excellent results were obtained with MAPD / Aldox was used as the third disinfectant (see Table 3 for a description of formulation C and Table 4 for the data). The effect of MAPD was strong enough to allow a reduction in the PQ-1 level to that present in the positive control formulation, the commercially available Biotrue MPDS (see Table 3 for a description of formulation D and Table 4 for the data). Assuming that comfort increases with concentration, the HA concentration was further increased in formulation E (see Table 2) to a level 7.5 times higher than that present in the commercially available MPDS (e.g., Biotrue). As revealed by the data in Table 4, the bactericidal and fungicidal activities of formulation E readily met the main criteria of the ISO test procedure at 4 h and all subsequent time points.Therefore, formulation E, comprising disinfectants from three classes—in this case, a biguanide compound, a quaternary ammonium compound, and an amidoamine compound—appears to provide an optimal combination of patient comfort (due to the presence of a high HA level) and antimicrobial activity. The slightly lower antimicrobial activity of formulation E at 2 hours compared to formulations comprising lower HA concentrations (e.g., formulations C and D) is not practically relevant, as contact lens wearers typically incubate their lenses overnight in MPDS (6–8 hours). Furthermore, formulation F, based on a phosphate buffer system, was tested under the same regime according to ISO 14729. The main criteria were as follows: a reduction of >3.0 log for three test organisms (bacteria) was achieved after 4 h, and a reduction of >1.0 log for the two fungal strains was to be achieved after 6–8 h. These results indicate that the described synergistic effects of the three disinfectant classes are functional in various buffer systems. Example 2: Long-term efficacy of antimicrobial preservation according to ISO 14730 To evaluate the long-term efficacy of the MPDS described herein, formulation E was inoculated with five standard test organisms and subsequently stored at 20–25°C for up to 28 days. Aliquots were withdrawn from the test solutions and evaluated for surviving organisms immediately after microbe addition (T 0 h) and after 7, 14, 21, and 28 days of storage according to ISO 14730 test procedures. Immediately after withdrawing the 14-day aliquots, the test solutions were reinoculated with 1 x 10⁴ to 1 x 10⁵ CFU / ml of the same microorganism. Logarithmic reductions in the levels of the test organisms were calculated for each time point. The results are presented in Table 6. Table 6: Long-term antimicrobial preservation by formulation E Incubation time [TOh] [7 Days] [14 Days] [21 Days] [28 Days] Test organism Reduction Log Reduction Log Reduction Log Reduction Log Reduction Aspergillus brasiliensis 0.02 1.92 2.35 2.35 2.13 Candida albicans 1.46 >4.51 >4.51 >4.54 >4.54 Escherichia coli 0.80 >4.58 >4.58 >4.62 >4.62 Staphylococcus aureus 0.90 >4.56 >4.56 >4.61 >4.61 Pseudomonas aeruginosa >4.03 >4.03 >4.03 >4.14 >4.15 Inoculum control Test titer at T 0 h [CFU / ml] 14-day challenge titer [CFU / ml] Cumulative challenge titer [CFU / ml] A brasiliensis 6.1 x105 3.4 x104 6.4x105 C. albicans 6.4x105 5.8 x104 7.0x105 E. coli 7.6x105 7.7 x 104 8.4x105 S. aureus 7.2x105 8.7 x104 8.1 x 105 P. aeruginosa 2.1 x ΙΟ5 6.0x104 2.7x105 Suitability Data Control Test Formulation E Control percentage [%] A brasiliensis 40 43 108 C. albicans 63 74 117 E. coli 58 64 110 S. aureus 52 57 110 P. aeruginosa 25 27 104 The greater than symbol (>) is used where no colonies were observed on the plates, taking into account the sensitivity of the assay (for details, see Example 1). Test method acceptance criteria: Positive controls are positive for the growth of the indicator organism. Negative controls are negative for the growth of the indicator organism. The suitability control must show >50% recovery of organisms in the reported test formulation solution. Test criteria according to the United States Pharmacopeia (USP) for a category 1 product (injectables, other parenterals include emulsions, otic products, sterile nasal products and ophthalmic products made with aqueous bases or vehicles): Bacteria: Reduction not less than 1.0 log from the initial count calculated at 7 days, reduction not less than 3.0 log from the initial count at 14 days, and no increase from the 14-day count to 28 days. Yeasts and molds: no increase in the initial count calculated at 7, 14 and 28 days Formulation E met all test criteria. Especially with regard to the difficult-to-treat fungus Aspergillus brasiliensis, the performance of Formulation E was excellent, with a log reduction of 2.35 on day 14 and >2 on days 21 and 28, in this case, after reinoculation with the fungus at 14 days. This indicates that the synergistic effect of the three classes of disinfectants used in this MPDS was potent and long-lasting, despite containing an HA concentration 7.5 times higher than commercially available products. Example 3: Biocompatibility of the MPDS E formulation according to ISO 10993-5 The biocompatibility of formulation E, which has a high hyaluronic acid content (0.075% w / v), was evaluated for potential cytotoxic effects using an in vitro mammalian cell culture model. Biotrue's MPDS served as a comparator. This study was conducted in accordance with the guidelines of ISO 10993-5, Biological evaluation of medical devices - Part 5: In vitro cytotoxicity testing. In short, sample solutions of Formula E or Biotrue were mixed with double-strength Minimal Essential Medium (MEM 2x) at a concentration of 50% for the test (test solutions). Controls (negative control, reagent control, and positive control) were extracted in single-strength Minimal Essential Medium (MEM 1x) at 37°C for 24 hours. Monolayers of L929 mouse fibroblast cells were coated in triplicate with test solutions or control extracts and incubated for 48 hours at 37°C in the presence of 5% CO2. After incubation, the monolayers were examined microscopically for abnormal cell morphology and cell degeneration using the scoring system in Table 5. No pH changes (color change in the medium) were observed. Negative control: High-density polyethylene (HDPE), Extraction ratio of 3 cm2: 1 mL; total extraction area 31.5 cm2; extraction with 10 mL of extraction vehicle at 37°C for 24 hours. Reagent control: Single strength Minimum Essential Medium (92% Gibco MEM with Earle salts) supplemented with 5% fetal bovine serum, 2% antibiotics (100 units / mL penicillin, 100 pg / mL streptomycin and 2.5 pg / mL amphotericin B) and 1% (2 mM) L-glutamine. Positive control: Powder-free latex gloves (Composition: natural rubber latex, zinc carbamate accelerators, zinc oxide and titanium dioxide), Extraction ratio 6 cm2: 1 mL; total extraction area 60 cm2; Extraction with 10 mL of extraction vehicle at 37°C for 24 h. Diluent vehicle: Double strength Minimum Essential Medium supplemented with 10% fetal bovine serum, 4% antibiotics (200 units / mL of penicillin, 200 pg / mL of streptomycin and 5.0 pg / mL of amphotericin B) and 2% (4 mM) of L-glutamine (2x MEM). Control Extraction Vehicle: Ix MEM (Minimum Essential Medium). The results of the experiment are shown in Table 8. Both formulation E and Biotrue showed slight cytotoxicity (grade 1) and met the ISO 10993-5 acceptance criteria for medical devices, as the grade was less than or equal to grade 2 (mild cytotoxicity). Reagent, negative, and positive controls were performed as anticipated. Formulation E showed better biocompatibility than Biotrue: cell lysis was 10% for formulation E and 20% for Biotrue. This result indicates that formulation E, which contains an HA concentration 7.5 times higher than Biotrue, has a significantly reduced cytotoxic potential (50%) compared to Biotrue. Table 7: Scoring System Grade Reactivity Conditions of all cultures 0 None Discrete intracytoplasmic granules. No lysis, no reduction in growth. 1 Slight No more than 20% of cells are round, loosely attached, and without intracytoplasmic granules, or show changes in morphology; occasional Spent cells are present; only slight inhibition of growth is observed. 2 Mild No more than 50% of cell layers contain round cells or cells devoid of intracytoplasmic granules; no extensive cell lysis; no more than 50% inhibition of growth can be observed. 3 Moderate No more than 70% of cell layers contain round cells or Spent cells; the cell layer was not completely destroyed, but growth inhibition greater than 50% was observed. 4 Severe Near complete destruction of the cell layer. Table 8: Biocompatibility test results Pozili Rounded Cells [%] Cells without intracytoplasmic granules [%] Cell lysis [%] Resulting Grade Resulting Reactivity Formulation E (1) 10 10 10 1 Slight Formulation E (2) 10 10 10 1 Slight Formulation E (3) 10 10 10 1 Slight Biotrue MPDS (1) 20 20 20 1 Slight Biotrue MPDS (2) 20 20 20 1 Slight Biotrue MPDS (3) 20 20 20 1 None Negative Control (1) 0 0 0 0 None Negative Control (2) 0 0 0 0 None Negative Control (3) 0 0 0 0 None Reagent Control (1) 0 0 0 0 None Reagent Control (2) 0 0 0 0 None Reagent Control (3) 0 0 0 0 None Positive Control (1) Not Applicable Not Applicable 100 4 Severe Positive Control (2) Not Applicable Not Applicable 100 4 Severe Positive Control (3) Not Applicable Not Applicable 100 4 Severe A large-scale batch (100 liters) of formulation E was evaluated in greater detail using an XTT test in accordance with ISO 10993, published by the International Organization for Standardization: Evaluation Biological Medical Devices, Part 1: Evaluation and testing within the risk management process, 2018, Part 5: In vitro cytotoxicity testing, 2009, using an evaluated method from ICCRRoBdorf GmbH (Germany) and a Xenometrix test kit. The XTT assay colorimetrically determines cell proliferation and viability, as well as mitochondrial metabolic competence, after treatment with a test element. The XTT assay is based on the cleavage of the yellow tetrazolium salt XTT [= (hydrated sodium 3'-(1-phenylaminocarbonyl)-(3,4-tetrazolium)-bis-(4-methoxy-6-nitro)-benzenesulfonic acid)] to form a water-soluble orange formazan dye via dehydrogenase activity in active mitochondria. This method was first described in 1988 by Scudiero et al. In short, the potential cytotoxic effect was evaluated with a series of dilutions of formulation E in Complete Medium [RPMI 1640 medium (including glutamax), supplemented with 10% FCS, 1 mM sodium pyruvate and 100 units / mL of penicillin, and 100 pg / mL of streptomycin] resulting in the following final concentrations 39.1 pg / mL, 78.1 pg / mL, 156 pg / mL, 313 pg / mL, 625 pg / mL, 1250 pg / mL, 2500 pg / mL, 5000 pg / mL. Subsequently, the effect of the solution was examined after 24 ± 1 h of treatment time in the pre-prepared L929 mouse cell line (supplied by DSMZ, 38124 Braunschweig, Germany). In parallel, several controls were also tested: Medium control = Complete medium; Solvent control = Complete medium; Positive control = Sodium dodecyl sulfate (SDS; purity: b 99%); Solvent = Deionized water, diluted with the complete medium in a 1:10 (v / v) ratio. The positive control was tested at 8 concentrations in a range from 3.1–250 pg / mL. Solvent control for the positive control = Complete medium and 10% (v / v) deionized water. At the end of the incubation period, 50 pL of the XTT labeling mixture (Xenometrix, Allschwil, Switzerland) were added to each well. The cells were incubated and subsequently transferred to a microplate reader, and absorbance values ​​were determined (Versamax® Molecular Devices, SoftMax Pro Enterprise software (version 4.7.1)) at 450 nm (reference wavelength 690 nm). A decrease in the number of live cells results in a decrease in the overall activity of mitochondrial dehydrogenases in the sample. This decrease correlates directly with the amount of orange formazan formed, as monitored by absorbance. The relative absorbance (= viability) compared to the solvent control is calculated using this formula: , , . [(ili.'urbiiurlu im illa,,1, (ιΙιλο / ίηκ κι rtlahra = 1 ()()τ :—- ------:¡:::lili t / lll, ,mt,,, / ,:, 11 CI <1bl To calculate the concentration of the toxicant needed to reduce the relative absorbance to 50% of the solvent control (XTT50), the following formula is used: .___ .. > 1% - -53Ί -LV' = c íVV. ----------------------------:- And j a) Conc. >50 = maximum measured concentration with solvent control % >50% b) Conc. <50 = measured concentration min. with % solvent control <50% c) % >50 = relative absorbance in a) in % d) % <50 = relative absorbance in b) in % The lower the XTT50 value, the greater the cytotoxic potential of the test item. A test item is considered to have a cytotoxic effect if the cell viability of at least one concentration is <70% compared to the solvent control. Table 9: Results of the XTT cytotoxicity assay (formulation E) Photometric Evaluation Cone Test Group. [pg / mL] Average Absorbance* SD Chemical Blank Average Absorbance Less Chemical Blank Viability [%]** Solvent Control (Test Item) - 0.884 0.022 0.104 0.781 100.00 Test Item = Formulation E 39.1 0.969 0.025 0.110 0.859 110.05 78.1 0.965 0.008 0.109 0.856 109.70 156 0.978 0.009 0.110 0.869 111.27 313 0.948 0.011 0.109 0.839 107.43 625 0.976 0.013 0.113 0.863 110.55 1250 0.956 0.015 0.113 0.843 107.92 2500 0.955 0.014 0.113 0.842 107.85 5000 0.900 0.029 0.112 0.787 100.85 Medium Control - 0.943 0.019 0.108 0.835 110.58 Solvent Control (Positive C) - 0.855 0.021 0.100 0.755 100.00 SDS 3.1 0.833 0.012 0.101 0.732 96.94 6.3 0.835 0.017 0.101 0.734 97.25 12.5 0.863 0.019 0.109 0.754 99.88 25.0 0.794 0.032 0.101 0.693 91.73 50.0 0.744 0.021 0.102 0.642 84.99 100 0.143 0.004 0.100 0.044 5.80 125 0.116 0.002 0.104 0.012 1.63 250 0.087 0.005 0.086 0.001 0.16 The test groups shaded in gray indicated cytotoxic effects in the photometric evaluation. * Average (absolute) absorbance of 7 pocilia ** Relative absorbance [rounded values] XTTso-The value of formulation E could not be determined as the viability did not fall below 50%; XTTso-Positive control value: 72.09 pg / mL Solvent control (positive control) / medium control ratio: 90.44%. In this XTT assay, formulation E showed no negative effects on the cell growth of mouse L929 fibroblast cells. The results are consistent with previous morphological evaluations and confirm the high biocompatibility of the solution. Example 4: Long-term HA elution from silicone hydrogel contact lenses It is known from the literature that silicone hydrogel contact lenses can absorb hyaluronic acid (HA) from lens care solutions during incubation, forming a type of HA deposit on the contact lenses. From this deposit, HA is slowly released during lens wear, improving surface wettability and comfort (Scheuer et al. Clin. Ophthalmol., 2016, pp. 1945-1952). Since the ophthalmic formulations described here contain HA concentrations 1.5 to 7.5 times higher than commercially available formulations such as Biotrue, a better deposition effect on silicone hydrogel lenses is expected for the formulations described herein. To verify this prediction, a direct comparison of formulation E and Biotrue was performed. In the experiment, HA release was evaluated using four types of commercial contact lenses: Comfilcon A (Biofinity), Fanfilcon A (Avaira Vitality), Lotrafilcon B (Air Optix Agua), and Senofilcon A (Acuvue Oasys). Multiple lenses of each lens type were removed from their packaging and equilibrated for 7 h in phosphate-buffered saline (PBS) at room temperature with agitation (in a 24-well plate; 2 lenses per well). The lenses were then soaked for 16 h under overnight storage conditions (room temperature, no agitation) in 3 mL of either the E formulation or Biotrue. After lens care storage, the lenses were gently transferred onto laboratory tissue to remove excess solution and then transferred to 24-well plates containing 500 pL of PBS / well. Next, the plates are incubated at room temperature for 24 h.100 pL aliquots were drawn from the wells at 1, 3, 5, 7, and 24 hours and stored at 40°C until analysis. Fresh PBS (100 pL) was added to the wells after each withdrawal. The aliquots were diluted 1:200 and HA was quantified by ELISA according to the manufacturer's instructions (Hyaluronan ELISA kit, R&D Systems, Minneapolis, MN). The results are shown in Table 10. The data indicate that greater amounts of HA were released at each time point (except at the 1-hour time point for Avaira Vitality lenses) from lenses that had been soaked with formulation E than from lenses that had been incubated with Biotrue. Table 10: HA release from silicone hydrogel contact lenses (ng per lens). Acuvue Oasis Biofinity AirOptix Aqua Avaira Vitality MPDS Lenses Biotrue Formulation E Biotrue Formulation E Biotrue Formulation E Biotrue Formulation E 1 hour 1784 (±128) 2751 (±309) 1344 (±198) 1766 (±835) 1569 (±71) 1953 (±383) 1634 (±68) 1110 (±89) 3 hours 1554 (±214) 2400 (±166) 1525 (±156) 1885 (±311) 1208 (±187) 1715 (±71) 1425 (±72) 2365 (±104) 5 hours 942 (±22) 1674 (±57) 1052 (±76) 1203 (±269) 721 (±22) 1407 (±82) 700 (±36) 1774 (±5) 1 hour 455 (±31) 860 (±163) 652 (±17) 946 (±90) 454 (±49) 989 (±111) 443 (±8) 861 (±23) 24 hours 148 (±8) 523 (±72) 673 (±226) 1188 (±82) 160 (±37) 634 (±142) 194 (±87) 584 (±68) Standard deviations in parentheses Example 5: Long-term HA elution from silicone hydrogel contact lenses in synthetic tear fluid A similar experiment to that discussed in Example 4 can be conducted to evaluate the release of HA from lenses incubated in different MPDS into the tear fluid. Since human tears differ in composition between individuals, for example in pH, salt content, and osmolarity, and the results may be influenced by the behavior of the study participants, a standardized in vitro test procedure is used for such a comparison. In the experiment, two types of commercial silicone hydrogel contact lenses (Biofinity, Comfilcon A Cooper Vision and Acuvue Oasys, Senofilcon A J&J) are placed in wells of a 24-well cell culture plate (unmodified plate; Eppendorf AG, Hamburg, Germany). Aliquots of 1.8 mL of the MPDS formulations to be tested (formulation E; Biotrue by B&L; Hycare by Cooper Vision) are added to the wells and the plate is incubated for 8 h at room temperature (4 contact lenses per MPDS formulation). Subsequently, the soaked contact lenses are lightly rinsed with a 0.9% NaCl solution to remove residual MPDS from the surface and carefully transferred to wells of a fresh 24-well plate containing 1.8 mL / well of a complex synthetic tear fluid (prepared according to Lorentz et al. Al. Mol. Vis. (2011) 17: 3392-3405).To evaluate HA release from contact lenses into synthetic tear fluid, 40 μL aliquots are extracted at 0 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h. (The extracted volumes are replaced with fresh synthetic tear fluid to simulate tear fluid turnover (approximately 1.2 pL / min according to Wilson, Cambridge University Press, 2004, ISBN: 9780521841580). The aliquots are stored at 4°C until HA concentration is analyzed using an Enzyme-Linked Immunosorbent Assay for Hyaluronan (ELISA HA, Echelon Biosciences, USA). This experiment is expected to reveal that greater amounts of HA are released into the tear fluid at each time point of lenses incubated with formulation E compared to lenses incubated with the other formulations. The mention of value ranges here is intended simply as a shorthand method for referring individually to each separate value within the range, unless otherwise stated here, and each separate value is incorporated into the description as if it were mentioned here individually. Unless otherwise stated, all exact values ​​provided here are representative of corresponding approximate values ​​and vice versa (for example, all exact example values ​​provided with respect to a particular factor or measurement may be considered as also providing a corresponding approximate measurement, modified by approximately, where appropriate, and vice versa). The terms a, an, the and similar terms should be interpreted to cover both singular and plural unless otherwise indicated or clearly contradicted by the context. The present description of any aspect or embodiment of the invention that uses terms such as a reference to an element or elements is intended to lend support to a similar aspect or embodiment of the invention that consists of, essentially consists of, or substantially comprises that particular element or elements, unless otherwise indicated or clearly contradicted by the context (e.g., a composition herein described comprising a particular element should be understood to also describe a composition consisting of that element, unless otherwise indicated or clearly contradicted by the context). Preferably, as understood here, the term weight-to-volume ratio, referred to herein as w / v, or (w / v), which may also be expressed as a percentage (%), refers to the ratio of the weight of the dissolved substance expressed in grams (g), to the volume of the solution expressed in milliliters (mL). This invention includes all modifications and equivalences of the subject matter mentioned in the aspects or claims presented herein to the maximum extent permitted by applicable law. All references cited in this application, including publications, patents and patent applications, shall be deemed to be incorporated in their entirety. The embodiments of the invention are described in the following numbered points: 1. A multipurpose disinfectant solution for ophthalmic applications comprising a multimeric biguanide compound in an amount ranging from approximately 0.00005 to approximately 0.0005% w / v, a quaternary ammonium compound in an amount ranging from approximately 0.00005 to approximately 0.0025% w / v, an antifungal / anti-acanthamoeba agent in an amount ranging from approximately 0.00005 to approximately 0.0025% w / v, and hyaluronic acid or a salt thereof in an amount ranging from approximately 0.015 to approximately 0.1% w / v. 2. The multi-purpose disinfection solution of point 1, wherein the antifungal / anti-acanthamoeba agent is an amido-amine compound. 3. The multipurpose disinfection solution of point 2, wherein the multimeric biguanide compound is present in an amount ranging from approximately 0.0001 to approximately 0.0002% w / v, the quaternary ammonium compound is present in an amount ranging from approximately 0.000075 to approximately 0.001% w / v, and the amido-amine compound is present in an amount ranging from approximately 0.0001 to approximately 0.0018% w / v. 4. The multipurpose disinfection solution of point 2, wherein the multimeric biguanide compound is present in an amount ranging from approximately 0.00012 to approximately 0.00016% w / v, the quaternary ammonium compound is present in an amount ranging from approximately 0.000085 to approximately 0.00012% w / v, and the amido-amine compound is present in an amount ranging from approximately 0.0006 to approximately 0.0014% w / v. 5. The multipurpose disinfection solution of any of points 1-4, wherein hyaluronic acid or a salt thereof is present in an amount ranging from approximately 0.025% w / v to approximately 0.085% w / v. 6. The multipurpose disinfection solution of any of points 1-4, wherein hyaluronic acid or a salt thereof is present in an amount in a range from approximately 0.04% w / v to approximately 0.08% w / v. 7. The multipurpose disinfection solution of any of points 1 to 6, wherein the multimeric biguanide compound is selected from the group consisting of polyhexamethylene biguanide, polyaminopropyl biguanide and 1,1'hexamethylene-bis(5-[2-ethylhexyl]biguanide), the quaternary ammonium compound is selected from the group consisting of polyquaternium-1, polyquaternium-10, polyquaternium-42, N-dodecyl{4,4'-(2,4,8,10tetraoxaspiro[5,5]undecan-3,9-diyl)}dipyridinium dibromide, 3,3'-[l,4-phenylenebis(oxy)]bis(1-dodecylpyridinium) dibromide; 3-(3-hydroxy-2-(hydroxymethyl)-2-{[(l-dodecylpyridinium-3yl)oxy]methylpropoxy)-1-dodecylpyridinium dibromide, 5,50-(2,20(tetramethylenedicarbonyldioxy)diethyl]bis(3-alkyl-4-methylthiazolium iodide) and [4,40-(1,6-hexamethylenedithio)bis(1-octylpyridinium iodide)], and the amido-amine compound is myristamidopropyl dimethylamine. 8. The multi-purpose disinfection solution of point 7, wherein the multimeric biguanide compound is polyhexamethylene biguanide and the quaternary ammonium compound is polyquaternium-1. 9. The multipurpose disinfectant solution of any of points 1 to 8 further comprising one or more chelating agents in an amount ranging from approximately 0.01% w / v to approximately 0.06% w / v, a buffer solution in an amount ranging from approximately 0.01% w / v to approximately 1% w / v, a viscosity modifier in an amount ranging from approximately 0.01% w / v to approximately 0.25% w / v, a surfactant compound in an amount ranging from approximately 0.01% w / v to approximately 1% w / v, a tonicity agent in an amount ranging from approximately 0.001% w / v to approximately 1% w / v, a calcium salt in an amount ranging from approximately 0.001% w / v to approximately 0.015% w / v, and a magnesium salt in an amount ranging from approximately 0.001% w / v to approximately 0.015% w / v. % w / v. 10. The multi-purpose disinfection solution of point 9, wherein the chelating agent is ethylenediaminetetraacetic acid. 11. The multi-purpose disinfection solution of point 9, wherein the buffer solution is a borate buffer solution. 12. The multi-purpose disinfection solution of point 9, wherein the viscosity modifier agent is selected from the group consisting of hydroxypropyl methylcellulose, carboxymethylcellulose, and hydroxyethylcellulose. 13. The multi-purpose disinfection solution of point 12, wherein the viscosity modifier is 5 hydroxypropyl methylcellulose. 14. The multi-purpose disinfection solution of point 9, wherein the surfactant compound is a poloxamine. 15. The multi-purpose disinfection solution 10 of point 9, wherein the tonicity agent is sodium chloride or a combination of sodium chloride and potassium chloride. It is noted that with regard to this date, the best method known to the applicant to put into practice the aforementioned invention is the one that is clear from the present description of the invention.

Claims

1. A solution, characterized in that it comprises a multimeric biguanide compound in an amount ranging from approximately 0.00005 to approximately 0.0005% w / v, a quaternary ammonium compound in an amount ranging from approximately 0.00005 to approximately 0.0025% w / v, an antifungal / anti-acanthamoeba agent in an amount ranging from 0.00005 to approximately 0.0025% w / v, and hyaluronic acid or a salt thereof in an amount ranging from approximately 0.015 to approximately 0.1% w / v.

2. The solution according to claim 1, characterized in that the antifungal / anti-acanthamoeba agent is an amido-amine compound.

3. The solution according to claim 2, characterized in that the multimeric biguanide compound is present in an amount ranging from approximately 0.0001 to approximately 0.0002% w / v, the quaternary ammonium compound is present in an amount ranging from approximately 0.000075 to approximately 0.001% w / v, and the amidoamine compound is present in an amount ranging from approximately 0.0001 to approximately 0.0018% w / v.

4. The solution according to claim 2, characterized in that the multimeric biguanide compound is present in an amount ranging from approximately 0.00012 to approximately 0.00016% w / v, the quaternary ammonium compound is present in an amount ranging from approximately 0.000085 to approximately 0.00012% w / v, and the amidoamine compound is present in an amount ranging from approximately 0.0006 to approximately 0.0014% w / v.

5. The solution according to any of claims 1-4, characterized in that hyaluronic acid or a salt thereof is present in an amount in a range from approximately 0.025% w / v to approximately 0.085% w / v.

6. The solution according to any of claims 1-4, characterized in that hyaluronic acid or a salt thereof is present in an amount in a range from approximately 0.04% w / v to approximately 0.08% w / v.

7. The solution according to any of claims 1-6, characterized in that the multimeric biguanide compound is selected from the group consisting of polyhexamethylene biguanide, polyaminopropyl biguanide and 1,1'hexamethylene-bis(5-[2-ethylhexyl]biguanide), the quaternary ammonium compound is selected from the group consisting of polyquaternium-1, polyquaternium-10, polyquaternium-42, N-dodecyl{4,4 / '-(2,4,8,10tetraoxaspiro[5,5]undecan-3,9-diyl)}dipyridinium dibromide, 3,3'-[1,4-phenylenebis(oxy)]bis(1-dodecylpyridinium) dibromide; 3-(3-hydroxy-2-(hydroxymethyl)-2-{[(l-dodecylpyridinium-3yl)oxy]methyl}propoxy)-1-dodecylpyridinium dibromide, 5,50-[2,20(tetramethylenedicarbonyldioxy)diethyl]bis(3-alkyl-4-methylthiazolium iodide) and [4,40-(1,6-hexamethylenedithio)bis(1-octylpyridinium iodide)], and the amido-amine compound is myristamidopropyl dimethylamine.

8. The solution according to claim 7, characterized in that the quaternary ammonium compound is 3,3'-[1,4-phenylenebis(oxy)]bis(1-dodecylpyridinium) dibromide.

9. The solution according to any of claims 1 to 7, characterized in that the quaternary ammonium compound is N-dodecyl{4,4'-(2,4,8,10tetraoxaspiro[5,5]undecan-3,9-diyl)}dipyridinium dibromide.

10. The solution according to claim 7, characterized in that the multimeric biguanide compound is poly(hexamethylene biguanide) and the quaternary ammonium compound is polyquaternium-1.

11. The solution according to any one of claims 1-10, characterized in that it further comprises one or more of a gelling agent in an amount ranging from approximately 0.01% w / v to approximately 0.06% w / v, and / or a buffer solution in an amount ranging from approximately 0.01% w / v to approximately 1% w / v, and / or a viscosity-modifying agent in an amount ranging from approximately 0.01% w / v to approximately 0.25% w / v, and / or a surfactant compound in an amount ranging from approximately 0.01% w / v to approximately 1% w / v, and / or a tonicity agent in an amount ranging from approximately 0.001% w / v to approximately 1% w / v, and / or optionally a calcium salt in an amount ranging from approximately 0.001% w / v to approximately 0.015% w / v and / or optionally a salt of magnesium in an amount in a range from approximately 0.001% w / v to approximately 0.015 % w / v.

12. The solution according to claim 11, characterized in that the chelating agent is ethylenediaminetetraacetic acid or tetrasodium N,N-bis(carboxymethyl)-L-glutamate.

13. The solution according to claim 11, characterized in that the buffer solution is a borate buffer solution or a phosphate buffer solution.

14. The solution according to claim 11, characterized in that the viscosity modifying agent is selected from the group consisting of hydroxypropyl methylcellulose, carboxymethylcellulose and hydroxyethylcellulose.

15. The solution according to claim 14, characterized in that the viscosity modifying agent is hydroxypropyl methylcellulose.

16. The solution according to claim 11, characterized in that the viscosity modifying agent is poly(acryloyl-lysine) or copolymers containing acrylated side-chain amino acids.

17. The solution according to claim 11, characterized in that the surfactant compound is a poloxamine.

18. The solution according to claim 11, characterized in that the tonicity agent is sodium chloride or a combination of sodium chloride and potassium chloride, which agents can be combined with mannitol.

19. The solution according to any of claims 1 to 18, characterized in that the solution is a multi-purpose disinfection solution.

20. The solution according to any of claims 1 to 19, for use in therapy.

21. The solution according to any of claims 1 to 19, for use in disinfection, particularly in an ophthalmic application.

22. The non-therapeutic use of the solution according to any one of claims 1 to 19, in infection, in particular of contact lenses.