TWI331535B - Antimicrobial lenses displaying extended efficacy, processes to prepare them and methods of their use - Google Patents

Description

1331535 V. INSTRUCTIONS (1) RELATED APPLICATIONS This patent application claims the priority of US Patent No. 6〇/428 62() in the 2002 "month 22曰 application. The request is also 2, December. 2〇曰Applicable United States: Part of the follow-up case of 5 1〇/〇28,400. Presently 10 15 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printing 20 25 FIELD OF THE INVENTION The present invention relates to contact lenses that provide controlled release of silver ions and methods of making and using same. BACKGROUND OF THE INVENTION Contact lenses have been commercially used to improve vision since the 1950s. The first generation of contact lenses were made of hard materials. It is worn and removed by the patient during beta waking for cleaning. Current developments in this area have resulted in the number of sustainable wearable lenses that can be worn without the need to remove soft contact lenses for cleaning. Although many patients prefer these lenses due to increased comfort, these lenses may cause some adverse effects on the user. Prolonged use of these lenses may encourage bacteria or other microorganisms, especially Pseudomonas aeruginosa CPieMt/owonai iierw ζ'ηοία, to grow on the surface of soft invisible lenses. Bacterial and other microbial growth can cause adverse side effects, such as contact lenses, acute red eye, and the like. Although bacteria and other microorganisms are most often associated with extended use of soft contact lenses, bacterial and other microbial growth problems have also arisen for hard contact lens users. U.S. Patent No. 5,820,918 discloses a process for the manufacture of a water-absorbent polymer 1331535 A7 ____ B7_____ V. Inventive Note (2): Medical material (a medical compound having a low solubility in an aqueous solution, such as an antibacterial or radiopaque compound) Device. However, the procedures disclosed in the examples produce radiopaque devices that are not suitable for use with eye devices, such as invisible lenses. 5 Therefore, it is necessary to manufacture invisible lenses that inhibit the growth of bacteria or other microorganisms and/or bacteria or other microorganisms that adhere to the surface of contact lenses. Furthermore, it is necessary to manufacture contact lenses that do not promote adhesion of bacteria or other microorganisms and/or grow on the surface of contact lenses. Furthermore, it is also necessary to manufacture contact lenses that inhibit unfavorable 10 responses associated with the growth of bacteria or other microorganisms. This need is met by the invention described below. Brief description of the diagram 5 11 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 20 5 2 Figure 1 is a graph showing the silver content as a function of time from the release of contact lenses containing Agl. Figure 2 is a graph showing the silver content as a function of time from the release of a contact lens containing AgCi. Figure 3 is a graph showing the silver content as a function of time from the release of a contact lens containing AgI. Figure 4 is a graph showing the silver content as a function of time from release of a contact lens containing Ag-imidazole. Fig. 5 is a graph showing the silver content as a function of time from the release of the stealth mirror # containing silver 2-methyl thiomercaptan, silver 2-aminothiophenol and silver thiosalicylate. -4- 1331535 Α7 Β7 V. INSTRUCTION DESCRIPTION (3) DETAILED DESCRIPTION OF THE INVENTION The present invention comprises a substantially smog-free antimicrobial lens comprising, substantially comprising or comprising a polymer and at least one silver-releasing compound A contact lens wherein the silver is released from the device of the eye 5 during use, having a rate constant (calculated using a first order kinetic equation) of at most about 1 day -1 and an initial concentration of at least about 10 ppm. The term "antimicrobial lens" as used herein refers to a lens exhibiting one or more of the following properties: inhibiting the adhesion of bacteria or other microorganisms to the lens, inhibiting the growth of bacteria or other microorganisms on the lens and killing it on the surface of the mirror 10 or Bacteria or other microorganisms in the vicinity of the lens. For the purposes of the present invention, bacteria or other microorganisms adhere to the lens. 'Bacteria or other microorganisms grow on the lens and bacteria or other microorganisms present on the surface of the lens are collectively referred to as "microbial migration." The lenses of the present invention preferably exhibit a reduction in viable bacteria or other microorganisms of at least about > 〇 _25 log (more preferably about > 0.5 log, optimal 15 is about 1. 〇l〇g (290% inhibition)) the amount'. These bacteria or other microorganisms include (but are not limited to) organic thoughts found in the eye 'especially A. sinensis (PseMc/owowfl·?, Aksana Amoeba, Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative, printing golden yellow grapes) Cocci (iSVa/^y/occwi.oTMreMs), Escherichia coli (5. 20 co/i), Staphylococcus epidermidis (Sfap/zy/occM·?· ep/d/ermfi/h) and wilting The extended release lens for prolonging the release of silver ions. The term "extended release" as used herein refers to an extended period (e.g., 2 曰 ' is preferably 7 曰, more preferably 14 曰, and in some cases may be 25 to more 30)) to release 'silver 5-A7' in an amount sufficient to inhibit microbial growth

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative, Printed 11331535

A ion. Thus, the present invention enables the manufacture of an eye device that provides antimicrobial growth throughout the entire wear process of the eye device. It has been found that the duration of silver ions can be adjusted by carefully selecting the amount and type of silver release compound incorporated into the eye device. 5 The first-order release of silver ions from the lens can be described using an anti-study dynamic model known to those skilled in the art. These patterns are disclosed, for example, in Physical Chemistry, 4th edition, F. Daniels and R. Aiberty, John Wiley & Sons, Inc., New

York ‘300 to 346. For example, the rate of silver release can be matched to the first order kinetics. In the first order release mode, the silver release rate is proportional to the total silver content remaining at any particular time. This can be explained by the equation: ~d[Ag]/dt = k[Ag] where -d[Ag]/dt is the rate of change of the silver content in the lens (expressed in units of concentration/time 15)' [Ag] Is the silver concentration at any given time, and k is the first order rate constant. This equation can be rewritten as: [Ag] = [Ag]0ekt where [Ag]. The concentration of priming silver in the lens (when the lens is placed in the eye, in contact with tears or in contact with the artificial tear model), and t is the residence time of the lens on the eye 20 (contact with tears or contact with the artificial tear model). The rate constant k is measured using a test method. The release of silver from the lens can be measured in artificial tears by placing a series of lenses of the same composition and formed by the same method. The lenses were placed in fresh artificial tears, or removed daily from tears, and analyzed by instrumental neutron activation analysis (inaa) 25 or similar methods to determine their silver content. Use data with soft 'body

V. INSTRUCTIONS INSTRUCTIONS (5) 5 10 15 The Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative prints 20 25 (for example, SigmaPUn 8.0) and plots the average silver exposure time for each time interval. The index trend line is combined with the data S. Preferably, the R value of the trend line is relatively high, such as greater than about 〇8, and preferably greater than about 〇9. The exponential matching provides a rate constant k value (with unit time -1) β. The other precision factor used to calculate the k value is the standard deviation of the k value (also calculated by the data with the software). When using the above power mode to express the release properties of silver self-contact lenses, it was found that some lenses have a significantly fixed amount of silver that is not released and released very slowly (even after 30 days) or may release the silver under different conditions. It is called "unreleased silver". Since the silver is not released during the period of the lens to be worn, the silver is not subtracted from the silver constant of the lens at each time interval. In this case, the first rate mode can be used to match the release of the remaining silver (in this case). It is called "releasable silver". Therefore, the data conforms to the following equation: [Ag] = [Ag]NR + [Ag]0e'k, where [Ag] is the total silver content in the lens at any given time, [Ag]NR is not released in the lens Silver concentration, and [Ag]. In order to release the initial content of silver. The ophthalmic device of the present invention exhibits a k value of at most about 1 day -!, preferably between about 0.001 and about 0.5 day, more preferably between about 〇 〇〇 1 and about 0.3 day -1 . Eye devices intended for longer wear (such as 2 or 4 weeks of disposable or continuous wear lenses) will be smaller than those intended to be worn with each eye. k value. Furthermore, the therapeutic lens (representing the source of infection that can kill the presence) may have an initial k value above the stated range (but the "maintenance" k value is set in the above range ««托托 1331535 A7 B7 , Description of the Invention (6) - This can be achieved by using a mixture of a single silver-releasing compound or a silver-releasing compound. The initial concentration of silver will depend on the amount of silver ions to be released and the haze of the resulting eye device. The concentration of the eye device is based on a dry concentration of at least about 10 ppm (preferably between about 10 and 1 〇, 〇〇〇 ppm, more preferably between about 25 and 5,000 ppm, and most preferably between about 5 ppm). Ag between 50 and 3,000 ppm) was found to control (a) the solubility of the silver-releasing compound, (b) the electron density of the atom bound to the silver ion, and (c) the initial 10 silver concentration incorporated in the eye device, The silver ion can be adjusted to be released from the eye device. In terms of solubility, the silver release compound suitable for use in the eye device of the present invention comprises a molar solubility of about 2.0 X 10_3 Gm/m in silver water at about 25 ° C in pure water. Raise to about 2 moles per liter. In terms of solubility, preferred The silver-releasing compound is a silver-releasing compound in which the silver ion has a molar solubility of more than 2.0 15 X 10_17 mol/liter. Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

The term "pure" as used herein refers to the use of water qualities as defined by the CRC Handbook of Chemistry and Physics, 74th Edition (CRC Press, Boca Raton Florida, 1993). The term "mole solubility" refers to the number of moles of metal dissolved per liter of water or separated from anion. This number is derived from the solubility product constant (Ksp) measured in pure water at 25 °C. (See Skoog, DA et al., FUNDAMENTALS OF ANALYTICAL CHEMISTRY, 5th ed., Saunders College Publishing, New York, 1988, see also CRC 25 Handbook of Chemistry and Physics, 74th ed. (CRC 1331535 Α 7 ^_ Β7 5, invention description (7)

Press, Boca Raton Florida, 1993). For example, if the metal salt is silver carbonate (Ag2C〇3), Ksp is expressed by the following equation: 5 Ag2C03(s)->2Ag+(aq) + C032 (aq) ο 5 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative Printing 20 5 2 ICsp is calculated as follows: Ksp = [Ag+] 2 [C〇32-] When the silver carbonate is dissolved, 'for every two silver cations, there is a carbonate anion in the solution, [C(V -] = l/2[Ag+], and the solubility product constant formula can be reformed to solve the dissolved silver concentration as follows: KsP = [Ag+]2(l/2[Ag+])=l/2[Ag+]3 [ Ag+]=(2KSPV/3 Ksp can be used to calculate the molar solubility of any metal salt as follows for AgX: [M]=(Ksp)1/2 For Ag2X: [M]=(2fCsp)l/3 In the case of Ag3X: [M] = (3Ksp) 1/4 are found in silver-release compounds (where the metal ion has a molar solubility of more than about 2xl 〇 · 3. Mohr / liter to less than about 2 〇 Mo / liter (when When measured under 25)), the metal is continuously released from the lens for up to or longer than 30 days. A preferred type of silver-releasing compound is a silver salt in which the molar solubility of silver ions is greater than or equal to about 2 〇. 〇xl〇-"Mole/L. Better The molar solubility is greater than or equal to about 9 〇〇χ 1 〇 9 m / liter ‘small -9-

1331535 A7 B7 V. Description of invention (o. at or equal to l.OxlO·5 mol/liter (when measured at 25〇c). The term “silver release compound J” used herein refers to any type of bonded silver. And a compound capable of releasing silver according to the rate described herein. Suitable silver-releasing compounds comprise P〇4-3, ci.i, Br·1, Γ1, S·2, Ο·25 and the like. The term silver-release compound used does not include the zeolite disclosed in WO 03/1 1351. Examples of silver salts include, but are not limited to, silver sulfate, silver iodate, silver carbonate, silver phosphate, silver sulfide, silver vapor, and cracking. Silver and silver oxide. Preferred silver salts are silver iodide and silver vapor. In order to produce lenses having sharpness suitable for eye purposes, it is preferred that when the silver release compound is added to the lens formulation in the form of microparticles. The silver-releasing compound has a diameter of less than about 1 〇 micrometer (10 μm), more preferably less than about 5 micrometers, and most preferably equal to or less than about 200 nanometers. The particle size may also affect the k value such that when the silver-releasing compound Microparticle form should be carefully controlled when added to the lens formulation or precipitated in the lens 15 degrees. The printed silver compound of the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs may also contain silver complexes (as long as the k value is within the above range). The term "silver complex" represents any type of inclusion. A molecule or compound having a bond to a non-bonded electron of silver or a group capable of forming a covalent bond to a silver. Preferably, the pair is a pair of non-bonded electrons or groups capable of forming a chelate 20 structure with silver ions. Examples of silver complexes include anthracene compounds such as meso-tetraphenylphosphonium, vinylpyridine, EDTA, thiols, crown ethers, mixtures thereof of thio crown ethers, and the like. In the case of a compound, the k value can be lowered by increasing the electron density at or near the atom of the silver. Conversely, by decreasing the electron density at or near the atom of 25 silver, the value of k can be increased. • 10-11331535 A7 B7 V. INSTRUCTIONS (9). Sub-donor groups (such as alkyl groups, amine groups, alkyl oxides, alkoxy groups, alcohols, and the like) can improve bonding. The electron density at or near the atom of silver. Similarly 'By adding an electron withdrawing group (such as carboxylic acid, sulfonate, decylamine, ammonium, nitro, cyano, acryloyl and halogen 5 groups and the like) can reduce the binding to or near the atom of silver The electron density of the lens. The silver content of the lens is also important for the amount of metal to be released. For a silver compound with a low k value, a higher content of silver can be used. Thus, for example, it has a k value. It is convenient to add a silver-supplemented compound having a concentration of at least about 100 ppm of the initial silver concentration of less than about 〇.2. It will be understood that it is tolerable for a metal compound having a low solubility. Higher levels of metal in the lens will be slower due to release. Conversely, when using a silver compound with high solubility, less metal content will be used. With respect to the addition of the silver-releasing compound, the molecular weight of the silver-releasing compound determines the conversion (% by weight) of the metal ion to the silver-releasing compound. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives. References to silver release compounds are available throughout the specification. However, those skilled in the art will appreciate that the teachings of the present invention are applicable to antimicrobial metals other than silver, and other suitable antimicrobial metals include 20 Mg+2, Zn+2, Cu+I, Cu+. 2 ' Au+2, Au', Au+, Pd+2

Pd+4, Pt+2 'Pt+4, mixtures thereof and the like. Suitable counterions, k values and solubilities can be readily determined using the teachings of the present invention. Preferred eye devices comprise a soft contact lens. Soft contact lens is a self-tanning elastomer or hydrogel comprising, but not limited to, anthrone 25 hydrogel and fluorohydrogel. The lens of the present invention is preferably optically transparent, and its 113-132535 economy Ministry of Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (10) · Medium optical clarity similar to such as etafilcon A, genfilcon A, lenefilcon A), polymacon, acquafilcon A, balafilcon A, galyfilcon A, sinofilcon A ) and Latfacon A (lotrafilcon A). The antimicrobial lenses of the present invention also have substantially no undesirable haze. In particular, the lenses of the present invention have a haze percentage of less than about 200%, preferably less than about 150%, more preferably less than about 100%. The haze percentage was measured using the following method. Place the hydrated test lens (in a transparent 20 x 40 x 10 mm glass unit borate buffered saline at 10 ambient temperature) over a flat black background (at an angle of 66° perpendicular to the lens unit) From the bottom with a fiber optic lamp (Titan Tool Supply Co. fiber optic light with 0.5 inch diameter guide, magnification set to 4 to 5.4)) and a 14 15 mm camera placed above the lens platform (with Navitar) TV Zoom 7000 Zoom Lens DVC 1300C: 19130 RGB Camera) The haze is measured from above when the lens image is taken perpendicular to the lens unit. Using the EPIX XCAP V 1.0 software, subtract the background scatter value from the lens scatter value by subtracting the image of the blank cell. CSI Thin Len® (CSI Flexible Wear (crotofilcon A lot number ML 62900207, magnification -1.0) quantified by a central millimeter integral of the lens and then optionally arbitrarily set to a haze value of 100 Analyze the subtracted scattered light image. Analyze the four lenses and average the results to produce a haze value as a percentage of the haze of the standard CSI lens. 25 Depending on the silver release compound selected, it can be added in many ways - 12-

11331535 A7 B7 V. INSTRUCTIONS (11) ·- Silver release compounds. Some silver-release compounds (before ripening) can be added to soft contact lens formulations. Suitable examples include those disclosed in U.S. Patent No. 5,710,302, WO 9421698, European Patent 406 406161, Japan. Patent JP 2000016905, U.S. Patent No. 5,998,498, U.S. Patent Application Serial No. 09/532,943, U.S. Patent No. 6,087,415, U.S. Patent No. 5,760,100, U.S. Patent No. 5,776,999, U.S. Patent No. 5,789,461, U.S. Patent No. 5, 849, 811 and U.S. Patent No. 5,965,631. Further, the silver-releasing compound of the present invention can be added to a formulation of a commercially available soft contact lens. Examples of soft hidden 10 lens formulations include, but are not limited to, etafilcon A, genfilcon A, lenefilcon A, polymacon, ak Acquafilcon A, ba丨afilcon A, lotrafilcon A, galyfilcon A, sinofilcon A) and analog formulations. Preferred contact lens formulations are part of the succession (applied on August 30, 2000), U.S. Patent No. 5,998,498, U.S. Patent No. 09/532,943, U.S. Patent Application Serial No. 9/532,943, U.S. Patent No. 6, 232, 415, U.S. Patent No. 5,760,100, U.S. Patent No. 5,776,999, U.S. Patent No. 5,789,461, U.S. Patent No. 5,849,81, and U.S. Patent No. 5,965,631. A (etafilcon A), balafilcon A 'acquafilcon A', latfucon A, senofilcon A, calvert Kang 25 A (galyfilcon A) and Meng Mingshui win. -13- 1331535 A7 B7 V. INSTRUCTIONS (12).. Hard contact lenses are made from polymers. These polymers include, but are not limited to, poly(methyl)methyl acrylate, bismuth acrylate. , a polymer of anthrone, fluoroacrylate, fluoroether, polyacetylene and polyimine, and a representative example thereof can be found in the patent JP 5 200010055, Japanese patent JP 6123860 and the US patent. No. 4,330,383. The intraocular lens of the present invention can be formed using known materials. For example, the lens can be made from a hard material including, but not limited to, polymethyl methacrylate, polystyrene, polycarbonate, or the like, and combinations thereof. Additionally, flexible materials can be used including, but not limited to, 10 hydrogels, anthrone materials, acrylic materials, carbon fluoride materials, and the like, or combinations thereof. A typical intraocular lens is disclosed in WO 0026698, WO 0022460 'WO 9929750 'WO 9927978 'WO 0022459 and Japanese Patent JP 2000107277, US Patent No. 4,301,012 ' 4,872,876 ' 4,863,464 ' 4,725,277 ' 15 4,73 1,079. The silver release compound can be added to the rigid contact lens formulation and the intraocular lens formulation in the same manner as the soft contact lens (before aging). Ministry of Economic Affairs, Intellectual Property Office, Employees, Consumers, Cooperation, Printing, Printing, Polymers used to make eye devices also affect the k value of silver-release compounds. For example, the value of k can be increased with increasing the equilibrium water content of the aqueous polymer (e.g., hydrogel). With respect to the lens polymer and its components, the solubility and/or affinity of the silver-releasing compound may also affect the k-value. The silver-releasing compound is preferably added to the hydrophobic gel formulation or the contact lens made therefrom. The hard ketone-containing component is a Dj§i containing at least one [-Si-0-Si] group in a monomer, a macromolecule or a 25 prepolymer, and a combined 〇-14-1332535 Α7 Β7 5. Description of the invention ( 13) Preferably, it is present in the fluorenone-containing component in an amount of 20% by weight (and more preferably more than 30% by weight) based on the total molecular weight of the fluorenone-containing component. The effective anthrone-containing component preferably has a polymerizable functional group such as acrylate, methacrylate, acrylamide, methacrylamide, N-vinyl pentamamine, N-vinylamine and Stupid vinyl functional group. Examples of the rhodium component which may be included in the anthrone hydrogel formulation include, but are not limited to, anthrone macromolecules, prepolymers, and monomers. Examples of fluorenone macromolecules include, but are not limited to, methacrylated polydimethyl siloxanes which are suspended by a hydrophilic group, as disclosed in U.S. Patent Nos. 4,259,467, 4,260,725 and 10,261,875. Polydimethyl methoxy alkane macromolecules having a polymerizable functional group, as disclosed in U.S. Patent Nos. 4,136,250, 4,153,641, 4,189,546, 4,182,822, 4,343,927, 4,254,248, 4,355,147, 4,276,402, 4,327,203, 4,341,889, 4, 486, 577, 4, 605, 712, 4, 543, 398, 15 4, 611, 575, 4, 703, 097, 4, 837, 289 ' 4,954, 586 ' 4,954, 587 ' 5,346, 946, 5, 358, 995 ' 5, 387, 632, 5, 451, 617 ' 5, 486, 579 ' 5, 962, 458 ' 5, 981, 615 'Ministry of Commerce, Intellectual Property Office, Staff Cooperatives, 5,981,675 and 6,039,913 Polymeric macromolecules incorporating a hydrophilic monomer, as disclosed in U.S. Patent Nos. 5,010,141, 20 5,057,578, 5,314,960, 5,371,147 and 5,336,797; containing polydimethyloxane blocks and polyethers; Blocks of macromolecules, such as those disclosed in U.S. Patent Nos. 4,871,785 and 5,034,461; analog. All patents mentioned herein are incorporated herein by reference. 25 The crepe-containing and/or fluorine-containing macromolecules disclosed in U.S. Patent Nos. 5,760,100' ' -15- 1331535 A7 B7 V, Inventions (14) ^ 5,776,999, 5,789,461, 5,807,944, 5,965,631 and 5,958,440 can also be used. Suitable anthrone monomers include tris(tridecyldecyloxy)decyl propyl methacrylate, hydroxy-functional fluorenone-containing macromolecules, such as 3-mercaptopropenyloxy-2-(hydroxypropion-5-yl) And propyl bis(tridecyl decyloxy) methyl decane, and disclosed in WO 03/22321, and disclosed in U.S. Patent Nos. 4,148,57, 4,139,692 ' 4,463,149 ' 4,450,264 ' 4,525,563 - 5,998,498, 3,808,178, 4,139,513 , 5,070,215, 5'710,302, 5,714,557 and 5,908,900 containing mPDMS or 10 oxoxane monomers. Other suitable oxetane-containing monomers include the guanamine analogs of TRIS disclosed in U.S. Patent No. 4,711,943, the vinyl amino phthalate or carbonate analogs disclosed in U.S. Patent No. 5,070,215, and in the United States. Monomer of the patent US 6,020,445, monomethacryloxypropyl 15-terminated polydidecyloxane, polydimethyloxane, 3-methylpropoxypropylbis(trimethyldecane) Oxy)methyl decane, decyl propylene oxy pentamethyl pentoxide and combinations thereof. Printed by the Ministry of Economic Affairs, the Intellectual Property Office, and the Consumer Cooperatives. The lenses are usually coated to improve their compatibility with living tissue. Thus, the lenses of the present invention can be coated with a plurality of agents for coating lenses. 20 For example, coating procedures, compositions and methods of WO 03/1 1551 'U.S. Patents U s 6,087,415, 5,779,943, 5,275,838, 4,973,493 ' 5,135,297, 6'193,369, 6,213,604, 6,200,626 and 5,760,100 can be used, and such The application and patents are incorporated in this case for reference. However, the benefit of the present invention is 25 to obtain the desired release characteristics without the use of a coating device to slow the moment; Release 16-1332535A7 V. Description of Invention (15) 5 10 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed System 20 25 release. Still further, the present invention encompasses a method of reducing adverse conditions associated with microbial migration on a lens in a mammalian ocular region, which comprises, comprises or consists essentially of placing antimicrobial properties comprising a metalloid compound The lens is on the eye of a mammal. The lenses are preferably worn at least 2 days per lap or continuously. Terms such as lenses, antimicrobial lenses, and metalloid compounds have their above meanings and preferred ranges. The term "adverse conditions associated with microbial migration" includes (but is not limited to) contact eye inflammation, contact lens-related peripheral ulcers, red lenses associated with contact lenses, osmotic keratitis or microbial keratitis and A similar situation. The term mammal refers to any kind of warm-blooded higher vertebrates, and the better mammals are humans. Still furthermore, the invention encompasses a method of making an antimicrobial lens comprising, including or substantially comprising a silver-releasing compound, wherein the method comprises, comprises or consists essentially of mixing a silver-release compound and a lens formulation prior to curing. . Terms such as antimicrobial lenses and silver-released compounds have their above meanings and preferred ranges. The term "formulation" refers to any component or combination of components used to make an antimicrobial lens such as monomers, prepolymers, copolymers, macroinitiators, pigments, dyes, and the like. Examples of such components are known in the art and some of these components are disclosed in the eye lens patents and patent applications cited earlier in this application. The lenses of the present invention can be made by a number of methods, for example, comprising, including or substantially including the following steps: (a) mixing a pre-salt medium, a silver-releasing compound, or a combination thereof with a lens

Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative 1331535 A7 B7 V. INSTRUCTIONS (16) Compounding; (b) Forming a lens; and (c) When using a salt precursor, the lens is treated with a metal agent. The above-mentioned meanings and preferred ranges are all used in five languages, such as antimicrobial lenses, silver-releasing compounds, and lens formulations. The term "salt precursor" means any compound or composition (including an aqueous solution) containing a cation which can be substituted with a metal ion. The salt precursor is preferably dissolved in the lens formulation at about 1 microgram per milliliter (or greater). The term salt precursor is free of sea stones (as disclosed in WO 03/1 1351) and solid silver (as described in w〇 10 02/62402). Preferably, the salt precursor in the lens is present in an amount of from about 0.00001 to about 5% by weight, more preferably from about 0.0001 to about 1% by weight, most preferably about 〇〇〇1, based on the total weight of the monomer composition. To about 〇j by weight%. Examples of salt precursors include, but are not limited to, inorganic molecules such as sodium carbonate, sodium iodide, sodium bromide, lithium vapor, lithium sulfide, sulfurized 15 nanometers, sulfurized bells, sodium tetrasodium hydride, and the like. Examples of the organic molecule include, but are not limited to, tetraalkylammonium lactate 'tetraalkylammonium sulfate, quaternary ammonium amide, such as vaporized tetraalkylammonium, tetraalkylammonium bromide or tetraalkylammonium iodide. A preferred salt precursor is sodium iodide. The phrase "formation j" represents any of a number of methods for forming a lens, including, but not limited to, light or heat curing. The lens formulations of the present invention can be formed by any of the methods known to those skilled in the art. (eg, shaking or stirring) and can be used to form a polymeric member or device by known methods. For example, by mixing a reactive component and any diluent with a 25 polymerization initiator and aging by appropriate conditions, Forming the connection -18-

1331535 Α7 Β7 V. DESCRIPTION OF THE INVENTION (17): The eye device of the present invention can be obtained by molding into a product of a suitable shape (by lathe processing, cutting, and the like). Alternatively, the reaction mixture can be placed in a mold' and then matured into suitable articles. For the manufacture of contact lenses, a number of methods are known for processing mirror-finished formulations, including spin casting and electrostatic casting. The preferred method for making the contact lens of the present invention is molding, as disclosed in U.S. Patent Nos. 4,113,224 and 4,197,266. For this method, the lens formulation is placed in a mold having the final desired shape, and the lens formulation is subjected to conditions whereby the components are polymerized to form the lens. These lenses can be treated with a solvent to remove the diluent and ultimately replace the solvent with water. This method is further disclosed in U.S. Patent Nos. 4'495' 313, 4, 680, 336, 4, 889, 664, and 5, 039, 459, incorporated herein by reference. Visible light. I--Τ Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives The term “silver agent” stands for any composition containing silver ions (aqueous solution). Examples of such compositions include, but are not limited to, aqueous or organic solutions of silver nitrate, silver triflate, or silver acetate, wherein the concentration of the silver agent in the solution is about 1 microgram/ml (or greater). Preferably, the silver agent 2 is aqueous silver nitrate, wherein the concentration of silver nitrate in the solution is greater than or equal to about 0.0001 to about 30% by weight, more preferably about 〇〇〇1 to about 1% by weight (based on the total weight of the solution). Preferably, from about 〇〇〇1 to about 0.03% by weight based on the total weight of the solution. The term "Γ" refers to any method of contacting a silver agent with a lens, and it is preferred that the lens is impregnated into a solution of the silver agent. The treatment may include heating the silver agent -19 ΙΙ 331535 Α 7 Β 7 5. The invention (18) the lens in the liquid 'but it is preferably treated under ambient conditions. The time to treat the lens with a silver agent will depend on the concentration of the silver agent in the solution and the desired concentration of the primary silver in the eye unit. Still further, the invention encompasses a method of preparing an antimicrobial lens comprising, comprising or substantially comprising a silver release compound, wherein the method comprises, comprises or comprises the following steps: (a) salt precursor Treating the cured lens; (b) treating the lens of step (a) with a silver agent. The words “antimicrobial lenses, salt precursors, silver agents and treatments” all have their above meanings and preferred ranges. The Ministry of Economic Affairs, Intellectual Property Bureau, Consumers, and Co., Ltd. All of the above methods can be combined by a single mechanical device or a combination of mechanical devices. get on. For example, if a silver-releasing compound is added to the cured mirror, all of the steps of adding the silver-releasing compound can be carried out in a hydration machine which performs the following functions. The cured lens (non-hydrated, partially hydrated 15 or fully hydrated lens) can be placed in a single plastic package. A solution of the salt precursor is added to the package and allowed to stand for a period of time sufficient to incorporate the desired amount of salt precursor into the lens (but insufficient to create unwanted haze). This time will depend on the solubility and concentration of the salt as well as the temperature. Suitable times (at ambient temperature) comprise up to about 30 minutes, and preferably 20 lines are between about 30 seconds and 5 minutes, more preferably about 2 minutes. Next, the salt precursor solution is removed, and a metal agent solution is added to the package. The soaking time β of the metal agent can be selected using the solubility, concentration and temperature. Then, the metal agent solution is removed and the lens is washed with several portions of deionized water, followed by sterilization. It should be understood that any of the above methods may include additional steps, such as cleaning the lens, autoclaving, and the like. -20- Ministry of Economic Affairs Intellectual Property Office Employees Consumption Cooperative Printed A7 _________B7 V. INSTRUCTION DESCRIPTION----- Even further, the present invention encompasses the preparation of an antimicrobial comprising, including or substantially comprising a silver-releasing compound The method of the lens comprises, comprises or substantially comprises the steps of: (a) treating the cured lens with a silver agent; 5 (b) treating the lens of step (a) with a salt precursor. ▲Antimicrobial lenses, salt precursors, metal agents and treatments all have their above meanings and preferred gardens. The following examples are included to illustrate the invention. These examples are not intended to limit the invention. It means that only one method of carrying out the invention is suggested. Other methods of practicing the invention may be found by those skilled in the art of contact lenses and the like. However, such methods are considered to be within the scope of the invention. Example 15 The silver release profile was determined as follows: 1 liter was prepared containing 8.80 g of sodium carbonate, 0.46 g of sodium dihydrogen phosphate, 4.40 g of disodium arsenate phosphate, 12 g of bovine plasma-globulin, and 1.20 g of egg white protein. And 标准 2 gram of chicken protein lysozyme in water as a standard protein donor solution. The ingredients were weighed and placed in a 1000 ml Erlenmeyer followed by a deionized 20 Torr. This solution was stored in a refrigerator in the whole process to prevent denaturation. In order to obtain a release profile, the non-hydrated lens was placed in an individual plastic bottle with 2.2 ml of standard protein donor solution (replaced every 24 hours)* in. The bottles were held in trays on a plate vibrator throughout the test (at room temperature). During the entire 30-day test period 25, three replicate samples were taken from different cockroaches, dried and passed by 'by -21-

1kίrrκJQ\^ 1331535 A7 B7 V. INSTRUCTIONS (20) INAA analyzes the remaining silver content. In terms of prolonging the antimicrobial benefits, the lenses were cultured as follows: by artificial tears (made from 8.30 g of gasified sodium, 0.46 g of diazonanate, 4.40 g of dihydrogen phosphate, uoke bovine plasma globulin, 〇 2 〇 5 g of egg white protein and 1.2 gram of chicken lysozyme diluted to 1 liter in water) A microtiter plate for lens culture was prepared in each well of a 24-well microtiter plate. The test lenses were rinsed three times with 3 ml of glycerate buffered saline and transferred aseptically into individual wells of each set of microtiter plates. The microtiter plate will be placed on the orbital blue shaker 10 and allowed to incubate for 24 hours at room temperature. After incubation, the lens was transferred to a well containing a new microtiter plate containing 500 microliters of artificial tears or removed and tested for antibacterial benefits as described below. The antibacterial efficacy of the original and cultured lenses was determined as follows: Culture of Pseudomonas aeruginosa aerwg/wosa) 15 ATCC#15442 (American Type Culture Collection, Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperatives

Rockville, MD) grew in trypsin soy medium overnight. The culture was washed three times with phosphate buffered saline (PBS, ρΗ = 7.4 +/- 0.2) and the bacterial pellet was resuspended in 1 mL of PBS. . A bacterial inoculum was prepared to produce a final concentration of about 1 x 1 〇 6 colony forming unit 20 yuan / ml (cfu / ml). Three contact lenses were rinsed with 30 ml of phosphate buffered saline (PBS'pH = 7.4 +/- 0.2) three times, and the remaining solution was removed. Each rinsed contact lens was placed in a sterile glass vial with 2 ml of the bacterial inoculum, and the bottle was then rotated (丨〇〇 rpm) for 2 hours at 37 +/- 2 °C. Remove each 25 lenses from the glass vial and rinse three times with three replacement PBSs to remove the loose 'knot -22- 1331535 Α7 Β7 5, invention instructions (21) combined cells 'put it into 1 ml PBS In the individual wells of the 24 well microtiter plates, and at 3 7 +/- 2 C, rotate in the vibrating-cultivator for an additional 22 hours. Rinse each lens five times with three replacement PBSs again to remove loosely bound cells, place them in 1 mL of PBS containing 5 0.05% (w/v) TweenTM 80, and vortex for 3 minutes at 2000 rpm. (Using centrifugal force to disintegrate the adhesion of the remaining bacteria to the lens) ° Calculate the viable bacteria of the supernatant produced, and average the detectable viable bacteria adhering to the 3 lenses, and compare this data with the control 10 log reduction of the inoculum of the group (made from the lens of the Table 1 formulation without adding silver)" The following abbreviations are used in the examples.

Blue HEMA = Reactive Blue No. 4 (blue number 4) and HEMA 15 as described in Example 4 or U.S. Patent No. 5,944,853. Reaction product CGI 1850 = 1 -hydroxycyclohexyl stupyl and bis (2,6- Dimoxybenzyl hydrazino)-2,4,4-trimethylpentyl phosphine oxide ι:ι (weight/weight) blends Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed DMA=N,N- Dimethyl acrylamide 20 DPM = propylene glycol monodecyl ether HEMA = methyl hydroxy succinic acid 2-hydroxyethyl ester IPA = isopropanol mPDMS = monomethyl propyloxy propyl terminated poly Methyloxo-oxygen (MW 800 to 1000) 25 Norbl〇c=2-(2'-hydroxy-5-methacryloxyethylphenyl)·2Η-$ and -23- 丨1331535 A7 B7 V. DESCRIPTION OF THE INVENTION (22) ·- Triazole ppm = parts per million milligrams of sample per gram of dry lens PVP = polyvinylpyrrolidone (K 90) TRIS = 3-methacryloxypropyl three (trimethyl hydrazine) The oxy) decane 5 TEGDMA = triethylene glycol dimercapto acrylate lens formulation and ripening monomer mixed formulation series are shown in Table 1. In addition to the reaction of TMI catalyzed by triethylamine, the process of macromolecules is disclosed in 10 W02002062402A1 (macromolecule B, in Example 5). Table 1 wt% macropolymer 17.98 TRIS 14.00 DMA 26.00 MPDMS 28.00 TEGDMA 1.00 HEMA 5.00 PVP (K-90) 5.00 NORBLOC 2.00 Blue HEMA 0.02 CGI 1850 1.00 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed unless otherwise specified , 7-dimethyl-3-octanol as a 15 diluent (component to diluent ratio (weight) is 80: 20). Unless otherwise indicated, a visible light fluorescent bulb (Philips TL'03) is used by placing a monomer mixture in a contact lens mold and in an N2 environment of about 45 ° C. -24-1331535 A7 ____________ B7 V. Description of invention (23)

The lens was formed by aging for 30 minutes. Use 6〇: 4〇IPA : H20 as release solution and use 1〇〇〇/0 IPA, 80/20 IPA: H2〇, 60/40 IPA : H2〇^ 40/60 IPA : H2〇^ 20 /80 IPA : H20 A 1001⁄4 Sapporo, so that the lens is hydrated. The lens 5 is then rinsed with deionized water for more than two times and stored in deionized water. Examples 1-4 A hydrogel 10 blend was prepared from the monomer mixtures listed in Table 1 above, except that 30:70 by weight of dipropylene glycol: DPMA was used as the diluent. Together with gasification silver and silver iodide (available from Aldrich Chemical Company) 'This blend is shipped to a commercially available salt mill. The Ministry of Economic Affairs, the Intellectual Property Bureau, the staff, the consumer cooperation, the printing system, the commercially available grinding machine, and the silver salt is ground to an average particle size distribution. To be equal to or less than 10 microns, a blend of monomer mixture with varying amounts of ground silver chloride (Examples 6-9) or silver iodide (Example ι-4) was prepared. When 15 is received, the resulting mixture is rotated at 50 revolutions per minute until further use. The mixture is loaded into an eight-cavity lens mold of the type described in U.S. Patent No. 4,640,489. The polymerization occurred under nitrogen purge and was photoinduced with visible light generated by 4 Philips TL 03 fluorescent bulbs (4 inches above the mold) for more than 30 minutes (at a temperature of 20 5 (TC). After curing) 'Open the mold and hydrate and leaching by placing it successively in 40/60, 0/100, 40/60 '60/40 and 100/0 by weight water and IPA solution. The minimum number of three lenses in the group was dried in a vacuum oven at 80 ° C for 3 to 4 hours (at a maximum pressure of 5 inches Hg) and sent to an independent laboratory for measurement of residuals by instrumental 25 activation analysis (INAA). Silver content. ' -25- 11331535 A7 B7 V. INSTRUCTIONS (24) The silver release profiles of these lenses are as described above and are shown in Table 2 below. In all tables, the content of Ag is in brackets. The number is the standard deviation of the reported values. The numbers in parentheses after the k and [Ag]NR values are the standard deviations calculated by the data matching software. Interval (曰) fAglCppm) Example 1 Example 2 Example 3 Implementation Example 4 0 1213(71) 619(15) 322(11) 272(9) 1 1094(117) 548(1) 270(6) 242( 9) 2 1069(95) 512(15) 247(3) 216(19) 5 949(56) 448(8) 207(6) 185(12) 10 873(127) 349(23) 133(4) 106 (23) 15 628(52) 280(5) 85(9) 96(7) 20 585(53) 225(38) 58(4) 69(7) 25 608(110) 147(22) 4〇(5 58(8) 30 501(175) 120(2) 32(1) 73(13) One-step k value for each lens was determined and is shown in Table 3. Figure 1 shows a graph of residual silver concentration as a function of time for the lenses of Example 1. Example 1 Example 2 Example 3 Example 4 rAgWppm) 425(103) 0(63) 12(12) 58(9) R2 0.97 0.99 0.99 0.99 k 0.070(0.02) 0.052(0.01) 0.09(0.01) 0.13( 0.02) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Example 5 Except for the initial silver concentration of 377 ppm, according to Example 1-4', -26- 1331535 Α7 5. Inventive Note (25) ·- Preparation lens. Test the continuous benefits using the test methods described above. The results are shown in Table 4 below. Table 4 Defects in the number of bacteria in the protein solution (log) 1 6.5 2 4.8 10 4.0 15 4.0 18 3.6 25 3.4 30 3.6 Therefore, this example shows that the lens in which Agl is dispersed is exposed to artificial tears (over the entire During the 30-day test) the total number of bacteria was greatly reduced. 10 Example 6-9 Ministry of Economic Affairs Intellectual Property Office Employee Consumption Cooperative Printing In addition to the use of AgCl as a silver-release compound, the mirror month and the analysis of silver content were prepared according to the procedure of Example Ια. The results are shown in Table 5. The residual silver concentration of the lens of Example 6 is plotted against time intervals and is shown in Figure 2. a fAgKppm) Example 6 Example 7 Example 8 Example 9 0 1462(118) 699(31) 373(14) 155(25) 1 1413(43) 553(136) 382(69) 159(14) - 27- 1331535 A7 B7 V. INSTRUCTIONS (26) 2 1136(207) 396(18) 324(50) 105(16) 5 823(43) 416(34) 184(37) 81(20) 10 602(16 ) 274(44) 141(24) 96(45) 15 513(104) 223(31) 105(23) 54(16) 20 320(39) 163(47) 129(45) 43(5) 25 388( 94) 169(59) 136(27) 38(7) 30 296(103) 190(49) 79(24) 37(16) lAsW (ppm) 321(47) 182(34) 105(17) 35(17 R2 0.99 0.93 0.95 0.89 k 0.15 (0.02) 0.19 (0.06) 020 (0.06) 0.12 (0.06) Example 10 A lens was prepared according to Examples 6-9 except that the initial silver concentration was 80 ppm. Test the continuous benefits using the test methods described above. The results are shown in Table 6 below. Table 6 Time interval (曰) Bacterial reduction (log) 1 6.5 2 2.4 10 2.1 15 13 18 12 25 0.7 30 0.6 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing Therefore, this example shows the lens with AgCl dispersed therein When 10 was exposed to artificial tears (during the entire 30-day test period), the total number of bacteria was greatly reduced. Further, Examples 5 and 10 show that the amount of microbial growth reduction is at least about 2 展现 and is at least about 2 〇 after about 2 and 1 day after the -28-1331535 A7 B7 5 and the invention description (27). A lens of about 5 1〇g. In other embodiments, lenses exhibiting a microbial growth reduction of at least about 1 log after about 2 and 10 days can be made. 5 Examples 11-14 Sodium hydride (0.38 g, Aldrich Lot #18014BI) was dissolved in 12.25 g of DMA (58.9 g of the mixture). An appropriate amount of the component is added to the mixture to form a monomer mixture of the surface. The mixture was allowed to stand at 10 40 mm Hg (at a temperature of 55. Degassing for a total of 3 minutes. Use

Zeonor (Zeon, grade 1060R) front curve and polypropylene (Fina, grade EOD 00-11) back curve' were prepared using a monomer mixture. The mold has been pre-rotated coated with poly(HEMA)' to provide mold transfer to the lens (using the method disclosed in WO 03/11551). Under visible light (Philips TLDK-visible-01 bulb in nitrogen gas pressure (0.5% 02)), the lens is matured for 12 to 15 minutes (@70±5. 〇. Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives The cooked lens was demolded and immersed in a solution of ~1 〇〇ppm silver nitrate in DI water for 2 hours. The hydration tray was then transferred to 60:40 IPA: DI water for 1.5 hours to self-mold (back surface) Remove the mirror 2 septum. Then apply the lens to the IPA-containing jar. Spray the lens on the jar cylinder and replace the IPA four times so that each replacement is 2 hours. The lens is reduced from pure IPA to DI water for replacement: a) 10% IPA for DI water; b) 20% solution for DI water; c) 30% solution for DI water; d) 40% solution for DI water; e) 50% dissolved 25 liquid for DI water; f) 75% solution for DI water; g) l〇〇% solution for -29-1332535 A7 B7 V. Invention description (28) -- DI water; h) 100% solution for DI water; i) 100% solution for DI water. Replace at 20 minute intervals. The lenses were autoclaved in 3 ml of borate buffered saline. The lens was found to contain 3 53 ± 22 ppm of silver (measured by INAA). 5 Use the above method to obtain the amount of silver released. The results are shown in Table 7. The remaining silver concentration of the lens of Example 11 is plotted against time intervals and is shown in FIG. - Packing_ except for mold transfer coating and using the appropriate salt (Nal, tetrabutylammonium hydride (TBAC1) or tetrabutylammonium bromide 10 (TBABr)) as shown in Table 7 below to add about 15 grams. Except for the monomer mixture of Table 1, Examples 12-14 were similarly carried out. Order.· Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed Table 7 Example 11 (Ag〇 Example 12 (Ag〇 Example 13 (AgBr) Example 11 (AgCD Na Salt Nal Nal ΊΒΑΒγ TBAC1 [Na Salt] (g ) 038 0.0073 0.0345 0.0176 曰 [Ag] (standard deviation) ppm 0 370 (27) 526 (21) 1165 (51) 584 (19) 1 297 (17) 426 (7) 156 (117) 96 (49) 2 NM NM 115(111) 50(18) 3 210(41) 297(15) NM NM 5 NM NM 28(3) 19(0.2) 7 82(24) 229(26) NM NM 10 NM NM 21(4) 19(2) 14 52(14) 86(11) NM NM 15 NM NM 15(5) 14(1) 21 57(22) 61(11) NM NM -30-

1331535 A7 B7 V. INSTRUCTIONS (29) 30 38(18) NM NM NM IAsInr (ppm) 43 51(35) 37(21) 37(6) R2 0.99 —0.98 0.995 0.998 k 026(0.03) 1 0.17(0.04 2.1(0.3) 2.0(02) NM=not measured via the k value (0.99) of Comparative Example 11 and the k value of Example 1-4 (k range is 0.05 to 0.13), it is found that the combined silver release compound The method affects the k value. This can also be found by comparing the k value (2.0) of Example 14 with the k value (0.89 to 0.99) of Example 6.9. In both cases, the mixed silver release compound provides a lower 1c value in the lens formulation. Example 15 10 1-vinylimidazole (4.0 g) was dissolved in 10 ml of deionized water. 3.61 g of AgN〇3 (in 10 ml of water) was added, and the resulting mixture was vigorously searched overnight. The organic layer was dissolved in acetone and dried over Naj. Remove acetone. The resulting solid product (with ethyl acetate) was ground and filtered, and then washed with ethyl acetate (followed by hexane) and printed by the Ministry of Commerce, Intellectual Property Office, Staff Consumer Cooperative. The solid product was dried on a glass frit to give 2.95 g of an off-white product. 20 This silver ethoxylate-based complex (〇. 2 g) was dissolved in 20.0 g of the monomer mixture formulation as described in Table 1. The mixture was filled into a contact lens mold using a positive curved surface and a base curved surface. The 'release and hydrated lenses are reduced under the usual curing conditions as described above. The amount of silver released from the tablets was measured as described above. The knot (4) is reported in Table 8 /k *31* 1331535 A7 B7 5. The invention description (30) has a value of 0.20 ± 0.06 and R2 is 0.96. Table 8 曰ίΜΙ 0 281(26) 1 218(22) 3 206(43) 7 169(32) 14 127(7) 21 131(3) 28 119(16) fAgUCppm) 123(11) 5 Example 16 Economy The Ministry of Intellectual Property's employee consumption cooperative printed the addition of 0.20% by weight of N,N'-bis(acrylamidino)cystamine (CYST) to the monomer mixture of Table 1. The resulting blend was mixed for a minimum of 15 minutes to ensure that the CYST was evenly distributed throughout the monomer mixture. The reaction mixture is degassed by evacuation and subsequent nitrogen purge, 10 and loaded into an eight-cavity lens mold of the type described in U.S. Patent No. 4,640,489, which is incorporated herein by reference. Said poly(2-hydroxyethyl methacrylate)). The mold was pre-cooked for 30 ± 2 seconds and then cured under visible light (Philips TL20W/03T fluorescent bulb) for 12 to 15 minutes (@70 ± 5 ° C). After aging, the mold was opened and the lens was released in a blend of 4:96 vol/vol DPM and DI water, followed by leaching in DPM/DI water to remove residual monomer and diluent. The lens was placed in a bottle containing 3 ml of borate buffered saline (0.00315 mg/ml of AgN03 was added thereto). Next, dense -32- U331535 A7 B7 V. Inventive Note (31) The bottle was sealed and heat-pressed at 121 ° C for 150 minutes. The amount of silver released was measured using the above method. The results are shown in Table 9. The data from Table 9 produced a release profile, and [Ag]NR was calculated to be 57(2) ppm, the k value was 0.20 (0.09) 曰·', and R2 was 0.86.

Table 9 曰fAeirppm'i 0 71(2) 1 67(1) 2 65(3) ~~ 3 64(5) 5 65(6) 7 60(5) — 14 28 _jm_I Example 17 Formulation of Table 1 (99.67 wt%) Consolidation of 0.33% Chelex® Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative printed 10 1 〇〇 resin (crosslinked polystyrene functionalized with sodium salt of iminodiacetic acid group). The mixture is loaded into a lens mold. The lenses are formed using the ripening and hydration conditions described in the above formulations and maturation section. The hydrated lenses were placed in a 3.0 ml/lens AgN〇3 solution (containing 13.3 ppm by weight of Ag in deionized water) and hot pressed at m〇c for 15 30 minutes. The lenses were rinsed 6 times in deionized water (about 7 ml per lens) for 30 minutes each rinse. The silver release of these lenses was measured as described above. The results are reported in Table 1 below. -33-

1331535 A7 B7 V. INSTRUCTIONS (32) 5 10 Example 18 A lens was prepared from the formulation of Table 1 using 4-vinylpyridine as described above, except that 0.23% by weight of 4-vinylpyridine was used. Silver was measured as described above. The release results are reported in Table 10. Example 19 5 ml of poly(asparagine) (0.4029 g) was combined with 0.3714 g of AgN03. This mixture was filtered and dried in vacuo (at 80 ° C) to form Ag-pASP. Lenses were prepared from 99.75% by weight of the reactive monomer mixture described in the Formulations section and 0.25% Ag-pASP blend. The amount of silver released from these lenses was measured as described above. The results are reported in Table 10. 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 25 Example 20 A lens was prepared from a mixture of 99.75 wt% of the reactive mono-branched mixture described in the Formulations section and a blend of 0.25% poly-L-lysine. The mesh mixture is loaded into the lens mold and the lens is aged and hydrated as tested in the Ripening section of the above formulation. The hydrated lenses were placed in a 3 liter milliliter/lens AgN 〇 3 solution (13 3 ppm (J amount) Ag in deionized water) and hot pressed at I21t for 3 Torr. The lenses were rinsed 5 times in ionic water (about 7 ml per lens) for each rinse in minutes. The amount of silver released from these lenses was measured as described above. The results are reported in Table 10. Table 10-34- 11331535 A7 B7 V. Description of Invention (33) Example 17 18 19 20 Chemical ^^7 Chelex 4-VP p-ASP p-LYS 曰 (Agl(ppm) 0 161(38) 4〇(5 ) 660(66) 52(10) 1 64(41) 12(7) 559(87) 8(5) 2 31(13) 10(2) 429(25) 7(1) 5 27(14) 2( 2) 372(46) 3(2) 10 11(6) 6(2) 306(50) 4(2) [AgU(ppm) 18(6) 4.8(1.9) 311(30) 4.3(1) R2 0.99 0.98 0.98 0.997 k 1.1( 0.2) 1.4(0.4) 0.42(0.12) 2.4(0.4) Example 24-27 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 100 ml of 10% by weight AgN03 in 50 ml of methanol (containing about 0.02 mol of mercaptans) In a solution of the mixture, the heterogeneous mixture was stirred for 5 minutes. The mixture was filtered, and a yellow precipitate (silver thiol) was collected, thoroughly rinsed with MeOH, then rinsed with DI-water and dried at 30 ° C in vacuo. Approximately 96 hours. Silver phenyl mercaptan (15 mg) was added to 15 g of the monomer mixture of Table 1. The mixture was sonicated for about 1 hour and then degassed at 40 mm Hg for a total of about 30 minutes. The mixed formulation is filled in an eight-cavity lens mold of the type described in U.S. Patent No. 4,640,489 The temperature was aged at 50 ± 5 ° C for 20 to 45 minutes. The polymerization was carried out under nitrogen purge and photoinitiated with visible light generated by a Philips TL 20 W/03T fluorescent bulb. The lens was similarly prepared and used. 2-nonyl thiol silver, 2-amine 15-thiophenol silver and thiosalicylate test lenses. Silver 2-methylbenzenethiol, silver 2-aminothiophenol and silver thiosalicylate All of them were prepared in the same manner as in the preparation of phenylsulfonium-silver-35-1331535 A7 B7. The invention was carried out in the same manner as that of 0.02 mM 2-mercaptothiol silver, 2-amino group. Silver thiophenol and silver thiosalicylate were substituted for 0.02 mol thiol mercaptan. The silver release of all lenses was tested. The results are shown in Table 11. Example 21 22 23 24 alcohol '2-mercaptobenzenethiol· 2-Amino-grade Chelate a [Ag] (ppm) 0 389 (31) 539 (4) 346 (16) 217 (13) 1 396 (25) 536 (6) 360 (27) 152 (44 ) 2 361(21) 534(9) 384(64) 121(35) 3 364(6) 548(14) 329(12) 85(13) 4 380(13) 538(17) 353(21) 101( 24) 5 377(13) 558(9) 353(15) 93(13) [A&1nr (ppm) 372 1150 340 88 R2 0.33 0.45 0.01 0.97 k 0.81 0.00 54 0.067 0.75 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed The release curves of Examples 21-24 are shown in Figure 5, which clearly shows that Examples 21-23 have a slow release profile. It is also easy to find that the silver concentration of the day-to-day variation of the lenses of Examples 21-23 generally does not vary by more than the standard deviation. Since the measured silver concentration change is too small and variable, R2 is extremely low, and in the case of Example 22, the value calculated for [Ag]NRm has no meaning. However, the release profile clearly shows that Examples 21-23 are within the scope 15 of the present invention. For very low release materials, such as Examples 21-23, at least '30 -36- Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1331535 A7 B7 V. Invention Description (35) ·- 曰 (preferably 45 or Measuring silver concentration during the 60th period will provide a reasonable estimate of k. The lenses of Examples 21 to 24 were tested for initial benefit. The results are shown in Table 12 below. Implementation Life]# Bacterial reduction 0〇g) 21 1.66 22 1.84 23 1.72 24 1.91 Example 25 From 99.9 wt% of the formulation of Table I combined with 0.1% Ag(II) internal elimination 10 rotation - four stupid bases (Frontier The blend of Scientific) is made by lens. The amount of silver released from these lenses was measured as described above. The results are reported in Table 13.

Table 13 Examples Example 28 Time a 0 109 1 97 2 147 3 96 4 104 5 123 1331535 A7 B7 V. Description of the Invention (36) ·- Example 26 100 parts of the ingredients shown in Table 1 will be contained and the contents are as shown in the table. The reactive monomer mixture shown in 14 was mixed with 23 parts of 3,7-dimethyl-3-octanol (D30). The reaction mixture was stirred vigorously (or until the solution appeared clear and 5 was homogeneously mixed), followed by degassing in vacuo. Table 14 Ingredient Weight % Norbloc 2.00 CGI 1850 0.48 mPDMS 1000 31.00 DMA 24.00 HEMA 6.00 TEGDMA 1.50 SiMAA2 28.00 Blue HEMA 0.02 K-90 7.00 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed and placed the reaction mixture in the thermoplastic contact lens mold 10 And irradiated with a fluorescent bulb under nitrogen pressure (at 45 ° C) for about 15 minutes. The lenses were demolded using the procedure described above and stored in jars containing DI-water with 50 ppm thiol cellulose. The lenses were placed in jars containing 1% by weight aqueous solution of silver acetate (CH3C02Ag, 3 ml/lens). Rotate the lens for 60 minutes. The CH3C02Ag was decanted and an aqueous solution of 30% by weight of calcium carbonate (CaCl2 · 2H20, 3 ml / lens) was added. Rotate the lens for 1 hour. The CaCl 2 · 2H20 solution was decanted and DI-water (3 ml/lens) was added. Turn the lens for 1 hour. Repeat DI-water cleaning. The lenses were individually transferred to -38-1331535 A7 B7. V. INSTRUCTION (37) In a bottle containing 3 ml of borate buffer packaging solution (without sodium carbonate), and heat-pressed at 121 ° C for 30 minutes. . Silver content analysis, mechanical property testing, water content, wettability and haze analysis of the test lenses. The results are shown in Table 14 below. 5 Transfer the control lens ί individually to a bottle containing 3 ml of borate buffer solution (without sodium carbonate) and heat-treat at 121 °C for 30 minutes. The lens was subjected to mechanical property testing, water content, wettability and haze analysis. The results are shown in Table 15 below. 10 Table 15 Properties Control Lens Example 26 Water Content (%) 39.06 (03) 40.5 (0.5) Modulus (psi) 94 (8) 80 (8) Elongation (%) 291 (32) 216 (104) Stretching Strength (psi) 147(24) 90(50) Toughness (4) 189(40) 106(88) Contact angle (n=5 before packaging) 44(9) 52(17) Haze (%CS1I lens) 14( 1) 484(35) Silver Contains #(ppm) N/A > 1500 The results of the Example 26 printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs show that the processing conditions cannot provide an eye with a useful nature (especially haze) Department device. 15 Examples 27-29 Lenses were made as in Example 26 and processed as follows. The lens was placed in a jar containing aqueous CH3C02Ag solution (0.50, 0.25 or 0.1% by weight solution, 3 ml/lens) and the lens was rotated for 60 minutes. Analysis -39- 11331535 A7 B7 V. Inventive Note (38) ·. CH3C02Ag solution, and add 30% by weight aqueous CaCl2 · 2H20 solution (3 ml / lens). Rotate the lens for 1 hour. The CaCl 2 · 2H20 solution was decanted and DI-water (3 ml/lens) was added. Rotate the lens for 1 hour. Repeat DI-water cleaning. The lenses were individually transferred to a vial containing 3 ml of 5 borate buffered solution (without sodium carbonate) and heat treated at 121 °C for 30 minutes. Silver content analysis, mechanical property testing, water content, wettability and haze analysis of the test lenses. The results are shown in Table 16 below. Table 16 Properties Example 27 Example 28 Example 29 «/oCH^CC^Ag 0.5 ¢4% 0.25 wt% 0.1 43⁄4% Water content (%) 40.7 (0.9) 39.1 (0.5) 40.0 (0.8) Modulus (psi) 87(11) 87(9) 84(5) Elongation (%) 258(53) 301(28) 275(50) Tensile strength (psi) 115(30) 140(26) 119(28) Toughness (iv) 140(53) 186(42) 150(48) Contact angle (n=5 before packaging) 44(12) 39(8) 31(8) Haze (%CSI lens) 232(26) 49(13) 15(8 Silver Content (ppm) 830 (80) 187 (70) 4.0 (0.6) 10 The results of the Examples 27-29 printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative show that the fog metric can be controlled by controlling the concentration of the salt precursor. Example 1 〇 shows that lenses made by in-situ precipitation of gasified silver exhibit a benefit of more than 30 days, even at concentrations of up to 80 ppm of primary silver. -40- /n^KJc\ 535 A7 B7 1. Description of the Invention (39) Brief Description Figure 1 is a graph showing the silver content as a function of time from the release of a contact lens containing Agl. Figure 2 is a graph showing the silver content as a function of time 5 released from a contact lens containing AgCl. Figure 3 is a graph showing the silver content as a function of time from the release of a contact lens containing AgI. Figure 4 is a graph showing the silver content as a function of time from release of a contact lens containing Ag-imidazole. 10 Figure 5 is a graph showing the silver content as a function of time from the release of contact lenses containing silver 2-methylbenzenethiolate, 2-aminothiolane and silver thiosalicylate. Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives Printed -41-

Claims (1)

1331535 A8 B8 C8 D8 Patent application scope 10 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 25 • 悝R ° ,, containing ionic silver with an initial concentration of at least about u Ppm, of the eye The skirt is provided with a haze of less than about entanglement and the silver is released from the ocular device at a rate constant of at most about 1 曰-1 during use. The rate constant is calculated using a first order kinetic equation. . 2. The number of eye devices in the first paragraph of the patent application range is between 0.001 and approximately 〇, 5 days·1. 3. The number of eye devices in the first paragraph of the patent application range is between about 0.01 and about 0.3 days-1. 4. The number of eye devices in the first paragraph of the patent application range is between approximately 0,001 and approximately 〇, 2 days-1. 5. The eye unit of claim 1 is between about 10 and about 10,000 ppm. 6. The eye unit of claim 1 is between about 25 and about 5,000 ppm. 7. The eye unit of claim 1 is between about 50 and about 3,000 ppm. 8. The initial silver concentration and rate constant are sufficient to provide at least a 50% reduction in microbial activity during use of the eye device of claim 1 of the patent garden. 9. The eye device of claim 3, wherein the eye piece is a contact lens. 10. The contact lens of claim 9, wherein the initial silver level and the rate constant are maintained below an amount that causes silver poisoning. 11. The contact lens of claim 9, wherein in the 〆 -42 - wherein the rate is $ wherein the rate is the rate of the primary silver, wherein the primary silver, the primary silver, wherein the primary silver is in the exhibition 1331535 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A8 B8 C8 D8 VI. After applying for the patent scope, the silver system is released from the eye device at a rate constant of at most about 丨曰·1 during use. The constants are calculated using the _ level kinetic equation. 12. If the contact lens of claim 9 is applied, it is not visible on the Da Zhao. 13. If the contact lens of claim No. 9 of the Patent Park is applied, it has a haze of less than ι5〇%. 14. The contact lens of claim 9 which has a haze of less than 10%. 10. The eye device of claim 1, wherein the polymer further comprises a ligand that the silver releasably binds. 16. The eye device of claim 1, wherein the eye device is a contact lens, and the initial silver concentration and rate constant are sufficient to provide at least about 50% reduction in microbial activity during use of the device. 15 # 〇 17. A contact lens as claimed in claim 9 wherein the use is at least 14 inches for a success. 18. The contact lens of claim 9 wherein the use is at least 30 inches of continuous wear. The contact lens of claim 9, wherein the silver is released from the contact lens during use at a level sufficient to provide at least a 70% reduction in microbial activity during the period of use. 20. The contact lens of claim 9, wherein the silver is released from the contact lens during use at a level sufficient to provide at least 90% reduction in microbial activity during the period of use. ' -43 - 1331535 A8B8C8D8 Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Consumers' Cooperatives. VI. Application for patents 21. For the eye device of the scope of the patent application, the silver release compound has a silver ion in about 25 tons of pure water. The solubility is about 2·0 X 1〇'3〇 mol/liter to about 2 mol/l. 22. The eye device of claim 3, wherein the silver halide has a molar solubility of greater than 2.0 X ΗΗ7 mol/liter in silver. 23. The contact lens of claim 9, wherein the polymer comprises a magenta hydrogel. 24. The contact lens of claim 9, wherein the ketone water 10 gel is selected from the group consisting of senofilcon A, galyfil C0n A, and latfucon A i〇trafilCOn a) and a group of balafilcon A. 25. The eye unit of claim 1 wherein the polymer is formed from a reaction mixture comprising at least one anthrone-containing component. 26. The eye device of claim 1, wherein the reaction mixture further comprises at least one hydrophilic component. 27. The eye device of claim 1, wherein the eye device is coated. 28. The contact lens of claim 9, wherein the polymer is formed from a reaction mixture comprising at least one anthrone-containing component. 29. The contact lens of claim 9, wherein the reaction mixture further comprises at least one hydrophilic component. 25 3〇 ο, • Contact lens according to item 9 of the patent application ‘where the eye-load ) 1331535 ! A8 ' Β 8 C8 I-----------D8______ VI. Scope of application for patents. 31. The contact lens of claim 9, wherein the lens exhibits a microbial growth reduction of at least about 2 log after 2 days. 32. The contact lens of claim 9, wherein the lens exhibits a microbial growth reduction of at least about 1 log after 52 days. 33. The contact lens of claim 9, wherein the lens exhibits a microbial growth reduction of at least about 2 log after the 〇曰. 34. The contact lens of claim 9, wherein the lens exhibits a microbial reduction in growth of at least about 1 log in the future. 10 35. The contact lens of claim 9 wherein the lens exhibits a microbial reduction of at least about 0.5 log after 3 days. 0 Ministry of Economy, Intellectual Property Office, Staff Consumer Cooperative Printed -45 -