CN100408106C - Antimicrobial lenses displaying extended efficacy - Google Patents
Antimicrobial lenses displaying extended efficacy Download PDFInfo
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- CN100408106C CN100408106C CNB2003801091493A CN200380109149A CN100408106C CN 100408106 C CN100408106 C CN 100408106C CN B2003801091493 A CNB2003801091493 A CN B2003801091493A CN 200380109149 A CN200380109149 A CN 200380109149A CN 100408106 C CN100408106 C CN 100408106C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L12/00—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor
- A61L12/08—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor using chemical substances
- A61L12/088—Heavy metals
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- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B1/00—Optical elements characterised by the material of which they are made; Optical coatings for optical elements
- G02B1/04—Optical elements characterised by the material of which they are made; Optical coatings for optical elements made of organic materials, e.g. plastics
- G02B1/041—Lenses
- G02B1/043—Contact lenses
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- G—PHYSICS
- G02—OPTICS
- G02C—SPECTACLES; SUNGLASSES OR GOGGLES INSOFAR AS THEY HAVE THE SAME FEATURES AS SPECTACLES; CONTACT LENSES
- G02C7/00—Optical parts
- G02C7/02—Lenses; Lens systems ; Methods of designing lenses
- G02C7/024—Methods of designing ophthalmic lenses
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Abstract
This invention relates to antimicrobial ophthalmic devices containing silver releasing compounds and methods for their production. The antimicrobial lenses of the present invention have percent haze of less than about 200% and have a release rate constant, calculated using a first order kinetics equation of up to about 1 days-1 and an initial silver concentration of at least about 10 ppm.
Description
Related application
Present patent application requires the provisional application U.S.60/428 of submission on November 22nd, 2002,620 priority.
Technical field
The present invention relates to contact lens, this contact lens can provide the silver ion of control to discharge, with and production method and purposes.
Background technology
Since nineteen fifties, contact lens has been widely used in improving vision.Initial contact lens is made by hard material.They are used by the patient in one's waking hours the patient, and are removed for purification.Present development has caused soft contact lens in this field, and it can be worn continuously with several days or more days, and need not be removed for purification.Though many patients have a preference for these lens, because it has the comfortableness of raising, these lens may cause some adverse reaction to user.The prolongation of lens is used and may be impelled antibacterial or other microorganisms, especially Pseudomonas aeruginosa to accumulate on soft contact lens surfaces.The accumulation of antibacterial and other microorganisms may cause adverse side effect, for example acute pink eye disease of contact lens or the like.Though it is relevant that the prolongation of the contact lens that the problem of antibacterial and other microorganisms is common with the softest is used, the accumulation of antibacterial and other microorganisms takes place too for the user of hard contact lens.
US 5,820, and 918 disclose the medical device of being made by the polymeric material that can absorb water, and this polymeric material contains the pharmaceutical compound that has low solubility in aqueous solution, for example antiseptic or radiopaque chemical compound.Yet disclosed process produces opaque device among the embodiment, and it is not suitable for device for eyes, for example contact lens.
Therefore, need to produce a kind of like this contact lens, it can suppress antibacterial or other microbial growths, and/or suppresses antibacterial or other microorganisms are adhered on the surface of contact lens.In addition, need to produce a kind of like this contact lens, it does not promote antibacterial or other microorganisms adhesion and/or the growth on contact lens surfaces.Also need to produce a kind of like this contact lens, it can the inhibition disadvantageous reaction relevant with antibacterial or other microbial growths.These needs have been satisfied by the present invention as described below.
Description of drawings
Fig. 1 is the figure that shows the silver amount that discharges as time function from the contact lens that comprises AgI.
Fig. 2 is the figure that shows the silver amount that discharges as time function from the contact lens that comprises AgCl.
Fig. 3 is the figure that shows the silver amount that discharges as time function from the contact lens that comprises AgI.
Fig. 4 is the figure that shows the silver amount that discharges as time function from the contact lens that comprises the Ag-imidazoles.
Fig. 5 is the figure that shows the silver amount that discharges as time function from the contact lens that comprises following material: 2-methylbenzene mercaptan silver, the amino thiophenols silver of 2-and thiosalicylic acid silver.
The specific embodiment
The present invention includes antimicrobial lens, it does not have blushing basically, these lens comprise contact lens, are made up of contact lens basically or are made up of contact lens, this contact lens comprises the chemical compound of polymer and at least a release silver, wherein silver is released from described contact lens during use, the speed constant that is had uses first _ order kinetics equation to calculate, and is about 1 day of maximum
-1, and initial silver concentration is about at least 10ppm.
Term " antimicrobial lens " lens that refer to have one or more following performances as used herein: suppress antibacterial or other microorganisms adhesion to lens, suppress antibacterial or other microorganisms grow on the lens and surface at lens on or in killing bacteria or other microorganisms in the zone of lens.For purpose of the present invention, antibacterial or other microorganisms exist antibacterial or other microorganisms to adhesion, antibacterial or other microorganisms of lens on growth on the lens and the surface at lens, be generically and collectively referred to as " microorganism cluster ".
Preferably, lens of the present invention have at least approximately＞0.25, more preferably approximately＞0.5, most preferably reduce (〉=90% inhibition) greater than about 1.0 the antibacterial alives or the logarithm of other microorganisms.This bacterioid or other microorganisms include but are not limited to, those organisms, the especially Pseudomonas aeruginosa that exists in eye, Acanthamoeba kind, staphylococcus aureus, escherichia coli, staphylococcus epidermidis and serratia marcescens.
The present invention relates to have the contact lens that the silver ion of prolongation discharges.As used herein " release of prolongation " be meant that in the time that prolongs silver ion discharges with the amount that is enough to suppress the microorganism cluster, the time of described prolongation is for example two days, preferred seven days, more preferably 14 days and in some cases nearly or more than 30 days.Therefore, the present invention allows to make device for eyes, and this device whole provides the antimicrobial sociability for this device for eyes in wearing with process at it.Have been found that the amount and the type that are introduced in the chemical compound of the release silver in the device for eyes by careful selection, can adjust the time that discharges silver ion.
Chemical reaction kinetic model well known by persons skilled in the art can be used for describing the one-level of silver ion from lens and discharge.In these models some is described in for example " physical chemistry " of F.Daniels and R.Albert, the 4th edition, John Wiley ﹠amp; Sons, Inc., New York, 300-346 page or leaf.For example, the speed of silver release can fit to first order kinetics.Discharge in the model in one-level, down, speed and remaining silver-colored total amount that silver discharges change pro rata at any given time.This can describe in order to following equation:
-d[Ag]/dt＝k[Ag]
Wherein ,-d[Ag]/dt is the rate of change of silver content in the lens, with the unit representation of concentration/time, [Ag] is that the concentration and the k of silver are first order rate constants down at any given time.This equation can be rewritten as:
[Ag]＝[Ag]
0e
-kt
Wherein, [Ag]
0Be to be placed in the eye when lens, contact with tear fluids, when perhaps contacting with synthetical tear fluids model, the initial concentration of the silver in the lens, and t be lens in eye, contact with tear fluids, perhaps the retention time that contacts with synthetical tear fluids model.
Speed constant, k, the service test method is measured.The release of silver from lens can be placed in the synthetical tear solution and measures by will be a series of having same composition and the lens by identical method formation.Put into fresh synthetical tear solution or every day with lens and remove from tear solution every day, and analyze by instrumental neutron activation analysis (INAA) or similar method, to measure its silver content.Use data fitting software, for example SigmaPlot 8.0, and the average silver under each interval was mapped to open-assembly time.Data are carried out the match of exponential trend line.For this Trendline, preferred R
2Value is higher, for example greater than about 0.80, and is preferably greater than about 0.90.Exponential fitting provides the rate constants k value, and it has the time
-1Unit.Another metric that calculates the accuracy of k value is the standard error of k value, and it also uses the data fitting computed in software.
Stating kinetic model in the use describes in the release behavior of silver from contact lens, have been found that, some lens has a kind of so apparent constant basis of silver, itself in addition after 30 days, do not discharge yet, very slow discharge or may only under different conditions, discharge.This silver is called " non-release silver " at this.Because this silver is not released during wearing with the cycle in lens predetermined, therefore under each interval, non-release silver is deducted from lens silver steady state value.In the case, the first-rate model can be used for the release of (being called " can discharge silver " at this) of remaining silver of match.Therefore data fitting is become following equation:
[Ag]＝[Ag]
NR+[Ag]
0e
-kt
Wherein, [Ag] is the total amount of the silver in the lens under the t at any time, [Ag]
NRBe the concentration of non-release silver in the lens, and [Ag]
0It is the primary quantity that can discharge silver.
The k value that device for eyes of the present invention has is for the highest about 1 day
-1, preferably about 0.001 by about 0.5 day
-1Between, and more preferably at about 0.001 to about 0.3 day
-1Between.Be intended for the device for eyes of long wearing time (for example fortnight or four stars phase disposable or wear continuously and use lens), compare, will preferably have lower k value with the disposable device for eyes of wearing usefulness that is intended for every day.Simultaneously, the treatment lens, it refers to eliminate the infection of existence, can have the initial k value of the scope that is higher than above regulation, still " keeps " in the scope that k value is in above regulation.This can realize by the mixture that uses single silver to discharge chemical compound or silver release chemical compound.
The initial concentration of silver will depend on the mist degree of amount of wishing d/d silver ion and the device for eyes that obtains.The concentration that is fit to comprises at least approximately 10ppm, preferably about 10 and 10, between the 000ppm, more preferably about 25 and 5, between the 000ppm and most preferably about 50 and 3, between the 000ppmAg, based on the dry weight of device for eyes.
Have been found that silver ion can adjust by controlling following factor from the release of device for eyes: (a) silver discharges the dissolubility of chemical compound, (b) be keyed to silver ion atom electron density and (c) introduce the initial concentration of the silver of device for eyes.
About dissolubility, the silver that is suitable for device for eyes of the present invention discharges chemical compound and comprises such chemical compound, the molar solubility of its silver ion that has in pure water under about 25 ℃ greater than about 2.0 * 10
-30Mol arrives approximately less than about 2 mol.About dissolubility, it is that wherein silver ion has greater than about 2.0 * 10 that preferred silver discharges chemical compound
-17The silver of the molar solubility of mol discharges chemical compound.
Term " pure " refers to as CRC chemistry and physics handbook as used herein, the 74th edition, and CRCPress, Boca Raton Florida, the quality of the water that defines in 1993.Term " molar solubility " refer in every premium on currency dissolved or with the molal quantity of the dissociative metal of anion.This value is by obtaining 25 ℃ of dissolubility-constant product (Ksp) of measuring down in pure water.(with reference to Skoog, D.A. etc., analytical chemistry basis, the 5th edition, Saunders CollegePublishing, New York, 1988, also with reference to CRC chemistry and physics handbook, the 74th edition, CRCPress, Boca Raton Florida, disclosed value in 1993) for example, be Disilver carbonate (Ag if silver discharges chemical compound
2CO
3), Ksp is by following The Representation Equation
Ag
2CO
3(s)→2Ag
+(aq)+CO
3 2-(aq)
Ksp is calculated as follows
Ksp＝[Ag
+]
2[CO
3 -2]
When Disilver carbonate dissolves,, in solution, there are a carbonate anion, [CO for per two silver-colored cationes
3 2-]=1/2[Ag
+], and dissolubility-constant product equation can be adjusted to following form, to obtain dissolved silver concentration:
Ksp＝[Ag
+]
2(1/2[Ag
+])＝1/2[Ag
+]
3
[Ag
+]＝(2Ksp)
1/3
Ksp can be used for calculating the molar solubility that any silver discharges chemical compound, as shown below:
For AgX:[M]=(Ksp)
1/2
For Ag
2X:[M]=(2Ksp)
1/3
For Ag
3X:[M]=(3Ksp)
1/4
Have been found that wherein metal ion mensuration under 25 ℃ has approximately greater than about 2.00 * 10
-30Mol to less than the molar solubility of about 2 mol the time, silver discharge chemical compound will from least one day at most or from lens, discharge silver in more than a period of time of 30 day time continuously.The classification that preferred silver discharges chemical compound is a silver salt, and wherein the molar solubility of silver ion is more than or equal to about 2.00 * 10
-17Mol.Preferred molar solubility is when measuring down for 25 ℃, for more than or equal to about 9.00 * 10
-9Mol is to being less than or equal to 1.0 * 10
-5Mol.
Term " silver discharge chemical compound " refers to anyly have combination and to discharge the chemical compound of the ability of silver in the speed of this regulation as used herein.The silver that is fit to discharges chemical compound and comprises silver salt, and wherein the anion of Shi Heing includes but are not limited to, PO
4 -3, Cl
-1, Br
-1, I
-1, S
-2, O
-2Or the like.Term silver release chemical compound does not comprise zeolite as used herein, for example those disclosed among the WO 03/11351.The example of silver salt includes but are not limited to, silver sulfate, silver iodate, silver phosphate, Argentous sulfide., silver chloride, silver iodide and silver oxide.Preferred silver salt is silver iodide and silver chloride.
Be suitable for the lens of eye in order to produce to have with the transparency of purpose, preferably when silver discharges chemical compound and adds lens formulation as granule, the diameter that silver discharges chemical compound less than about ten microns (10 μ m), be more preferably less than about 5 microns, most preferably be equal to or less than about 200 nanometers.Particle size also may influence k value, therefore when silver discharges chemical compound as granule adding lens formulation, when perhaps being deposited in the lens, should note controlling particle size.
Silver discharges chemical compound can also comprise silver complex, as long as k value is within above-mentioned scope.Term " silver complex " refers to any molecule or chemical compound, and it comprises the non-bonding electrons that can form the coordinate bond that is connected to silver, perhaps can form the group of the covalent bond that is connected to silver.Preferably have a plurality of non-bonding electrons to or can form those of group of chelate structure with silver ion.The example of silver complex comprises porphyrin compound, for example in-tetraphenylporphyrin, vinylpyridine, EDTA, mercaptan, crown ether, sulfo-crown ether, its mixture, or the like.
When using silver complex, k value can be keyed to the atom place of silver or near electron density reduces by raising.On the contrary, k value can by reduction be keyed to silver the atom place or near electron density improve.Can improve the atom place that is keyed to silver or near electron density by adding electron donating group, described electron donating group for example is alkyl group, amino group, trialkylphosphine oxide, alkoxy base, alcohol or the like.Similarly, the electron density that is keyed to the atom of silver can reduce by adding electron withdraw group, and described electron withdraw group for example is carboxylic acid, sulfonate, amide, ammonium, nitro, cyano group, acyloxy and halogen group or the like.Should be appreciated that electron donating group and electron withdraw group also can be in other positions in the silver complex, to obtain desirable influence to the electron density that is connected in silver-colored atom.
The amount of silver also is critical for the amount with d/d metal in the lens.Discharge chemical compound for silver, can use higher silver amount with low k value.Therefore, for example, discharge chemical compound less than about 0.2 silver, wish to discharge chemical compound to be enough to provide at least approximately the amount of the initial silver concentration of 100ppm to add silver for k value.Should be appreciated that for the metallic compound with low solubility, allow to contain the metal of high level in lens, will be slowly because discharge.On the contrary, when use has the silver release chemical compound of high-dissolvability, will use less amount of metal.With regard to adding silver release chemical compound, the molecular weight that silver discharges chemical compound has determined the weight percent of metal ion to count to the conversion that silver discharges chemical compound.
In description, mentioned silver-colored release chemical compound.Yet, it will be appreciated by those skilled in the art that instruction of the present invention can be applied to desilver antimicrobial metal in addition.Other antimicrobial metals that are fit to are drawn together: Mg
+ 2, Zn
+ 2, Cu
+ 1, Cu
+ 2, Au
+ 2, Au
+ 3, Au
+ 1, Pd
+ 2, Pd
+ 4, Pt
+ 2, Pt
+ 4, its mixture or the like.The equilibrium ion that is fit to or part, k value and dissolubility can easily use instruction of the present invention to determine.
Preferred device for eyes comprises soft contact lens.Soft contact lens is included but are not limited to by elastomer silicone or hydrogel manufacturing, silicone hydrogel and fluorinated water gel (fluorohydrogels).Preferably, lens of the present invention are transparent on the optics, have can with the optical clarity of comparing by the lens of following material manufacture: etafilcon A, genfilcon A, lenefilcon A, polymacon, acquafilcon A, balafilconA, galyfilcon A, senofilcon A and lotrafilcon A.
Antimicrobial lenses of the present invention does not also have undesirable mist degree basically.Especially, lens of the present invention have less than about 200%, preferably less than about 150% be more preferably less than about 100% percent haze.Percent haze uses following method to measure.Mist degree passes through following process measurement: in 20 * 40 * 10 millimeters transparent glass cells, this glass cell is on the black background of plane, at ambient temperature the test lens of hydration are put into BBS, use optical fiber lamp (the optical fiber lamp of Titan Tool Supply Co., have 0.5 " photoconduction of diameter; be set in the energy setting of 4-5.4) to become 66 ° of angles of cut from following irradiation with lens examination pond; and use video camera (DVC 1300C:19130 RGB video camera; have Navitar TV Zoom 7000 zoom lens) perpendicular to the image of lens examination pond from top seizure lens, this video camera is placed on 14 millimeters places more than the lens platform.Use EPIX XCAP V1.0 software, by deducting the image in blank examination pond, subtracting background scattering from the scattering of lens.By 10 millimeters upper integrals of central authorities, then with CSI Thin Lens at lens
The above-mentioned scattered light image that deducts is analyzed in (CSI FlexibleWear (crotofilcon A) lot ML 62900207 Power-1.0, it at random is set at 100 haze value) contrast quantitatively.Analyze four lens, the result is average, produce haze value as the percentage ratio of standard C SI lens.
Silver discharges chemical compound and can add in many ways, and this silver that depends on selection discharges chemical compound.Some silver discharges chemical compound can add (before solidifying) soft contact lens preparation.The example that is fit to comprises and is described in the following patent those: US 5,710, and 302, WO9421698, EP406161, JP2000016905, U.S.5,998,498, US patent application 09/532,943, U.S.6,087,415, U.S.5,760,100, U.S.5,776,999, U.S.5,789,461, U.S.5,849,811 and U.S.5,965,631.In addition, silver release chemical compound of the present invention can add in the preparation of the soft contact lens of commodity.Soft contact lens examples of formulations comprises, but be not limited to etafilcon A, genfilcon A, lenefilcon A, polymacon, acquafilcon A, balafilcon A and lotrafilcon A, galyfilcon A, senofilcon A or the like.Preferred contact lens preparation is etafilcon A, balafilconA, acquafilcon A, lotrafilcon A, senofilcon A, galyfilcon A and silicone hydrogel, as preparing in following patent: U.S.5,998,498, the US patent application 09/532,943, the partial continuous application of US patent application 09/532,943, on August 30th, 2000 submitted to, WO 03/022321, U.S.6,087,415, U.S.5,760,100, U.S.5,776,999, U.S.5,789,461, U.S.5,849,811 and U.S.5,965,631.
Hard contact lens is by the polymer manufacturing, this polymer comprises, but be not limited to, poly-(methyl) methacrylate, silicone acrylates, silicone acrylates, fluorinated acrylic ester, fluoro-ether, polyacetylene and polyimides, wherein the preparation of representational example can see JP 200010055, JP 6123860 and U.S.4,330,383.Intraocular lens of the present invention can use known material to form.For example, lens can comprise by rigid material, without limitation, and polymethyl methacrylate, polystyrene, Merlon or the like and its mixture.In addition, can use flexible material, comprise, without limitation, hydrogel, silicone materials, acrylic acid series material, fluoro carbon materials or the like or its mixture.Typical intraocular lens is described in WO 0026698, WO 0022460, WO 9929750, WO 9927978, WO 0022459 and JP 2000107277, U.S.4,301,012; 4,872,876; 4,863,464; 4,725,277; 4,731,079.Silver discharges chemical compound can add hard contact lens preparation and intraocular lens preparation in the same ground with the situation in soft contact lens (before solidifying).
The polymer that is used to make device for eyes also influences the k value that silver discharges chemical compound.For example, k value can with the bag aqueous polymer for example the raising of the equilibrium moisture content of hydrogel increase.Dissolubility and/or affinity that silver for lens polymerization thing and its component discharges chemical compound also may influence k value.
Preferred silver discharges chemical compound and is added in siloxanes aquogel preparation or the contact lens by its manufacturing.The component that comprises siloxanes is the component that comprises at least one [Si-O-Si] group in monomer, macromonomer or prepolymer.Preferably, Si and the O that is connected with the total molecular weight that accounts for the component that comprises siloxanes for being present in the component that comprises siloxanes greater than 20 percetages by weight with more preferably greater than the amount of 30 percetages by weight.The useful component that comprises siloxanes preferably comprises polymerizable functional group, for example acrylate, methacrylate, acrylamide, Methacrylamide, N-vinyl lactam, N-vinylamide and styryl functional group.The example that can be included in the silicone components in the siloxanes aquogel preparation includes but are not limited to, siloxane macromer, prepolymer and monomer.The example of siloxane macromer comprises, without limitation, uses the polydimethylsiloxane of pendant hydrophilic group metering system acidify, as U.S. Patent number 4,259,467; 4,260,725 and 4,261, described in 875; Be described in the polydimethylsiloxanemacromer macromer with polymerizable functional group of following document: United States Patent (USP) 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; 4,661,575; 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; 5,962,548; 5,981,615; 5,981,675; With 6,039,913; Introduce the polysiloxanes macromonomer of hydrophilic monomer, for example be described in those of following patent: United States Patent (USP) 5,010,141; 5,057,578; 5,314,960; 5,371,147 and 5,336797; The macromonomer that comprises polydimethylsiloxane block and polyether block for example is described in those of following patent: United States Patent (USP) 4,871,785 and 5,034,461, its mixture or the like.All are incorporated herein its full content as a reference in this patent of enumerating.
Be described in United States Patent (USP) 5,760,100; 5,776,999; 5,789,461; 5,807,944; 5,965,631 and 5,958,440 the macromonomer that comprises siloxanes and/or fluorine also can use.The siloxanyl monomers that is fit to comprises three (trimethylsiloxy group) silylpropyl methacrylate, comprises the monomer of hydroxyl-functional siloxanes, for example 3-methacryloxy-2-hydroxyl propoxyl group) two (trimethylsiloxy group) methyl-monosilanes of propyl group, and in WO 03/22321 those disclosed and be described in following patent comprise mPDMS's or siloxanyl monomers: United States Patent (USP) 4,120,570,4,139,692,4,463,149,4,450,264,4,525,563; 5,998,498; 3,808,178; 4,139,513; 5,070,215; 5,710,302; 5,714,557 and 5,908,906.
The additional suitable monomer that comprises siloxanes comprises, be described in U.S.4,711, the amide analogue of TRIS in 943, be described in U.S.5,070, vinyl carbamate in 215 or carbonate analog, with be included in U.S.6,020, monomer in 445, the end capped polydimethylsiloxane of monomethyl acryloxy propyl group, polydimethylsiloxane, two (trimethylsiloxy group) methyl-monosilanes of 3-methacryloxypropyl, methacryloxypropyl pentamethyl disiloxane and its mixture.
Usually, lens are applied, to improve itself and the living tissue compatibility.Therefore, lens of the present invention can apply with many reagent that are used for coated lens.For example, can use the coating process, compositions and the method that are described in following patent: WO 03/11551, 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, and these applications and patent are incorporated herein by the reference of these processes, compositions and method.Yet benefit of the present invention is the release characteristics that can obtain to wish, and do not use the coating means slow down silver release.
In addition, the present invention includes the method that reduces the adverse effect relevant with the cluster of microorganism on lens, described lens are placed into mammiferous eye, this method may further comprise the steps, be made up of following steps, perhaps be made up of following steps basically: the antimicrobial lenses that will comprise metal release chemical compound is placed on the mammiferous eyes.Preferred these lens worn every day with or wore usefulness continuously at least 2 days.Term lens, antimicrobial lenses and metal discharge chemical compound and all have its above-mentioned implication and preferred range.Word " adverse effect relevant with the microorganism cluster " includes but are not limited to, contact eyes inflammation, the periphery ulcer relevant with contact lens, the pink eye disease of being correlated with contact lens, permeability keratitis, microorganism keratitis or the like.Term mammal refers to any warm blooded higher level vertebrate animals, and preferred mammal is the people.
In addition, the present invention includes the method for producing antimicrobial lenses, these lens comprise that silver discharges chemical compound, basically discharging chemical compound by silver forms, perhaps discharging chemical compound by silver forms, wherein this method may further comprise the steps, and is made up of following steps basically, perhaps is made up of following steps: silver is discharged chemical compound mixed before solidifying with lens formulation.Term antimicrobial lenses and silver discharge chemical compound and have its above-mentioned implication and preferred range.Terms " formulation " refers to be used to make any composition or the constituents mixt of antimicrobial lenses, for example monomer, prepolymer, copolymerization-polymer, macromonomer initiator, pigment, dyestuff or the like.The example of this constituents is well known in the art, and in these compositions some is disclosed in the glasses patent and patent application that the application's book is enumerated previously.
Lens of the present invention can be by a lot of method manufacturings, the method that for example may further comprise the steps, is made up of following steps basically or be made up of following steps:
(a) salt precursor, silver release chemical compound or its mixture are mixed with lens formulation;
(b) form lens; With
(c) when using the salt precursor, handle lens with argentum reagent.
Term antimicrobial lenses, silver discharge chemical compound and lens formulation all has its above-mentioned implication and preferred range.Term " salt precursor " refers to any chemical compound or compositions (comprising aqueous solution), and it comprises can use the displaced cation of silver ion.The preferred salt precursor can about 1 mcg/ml or bigger concentration be dissolved in lens formulation.This term does not comprise as the zeolite described in the WO 03/11351, as the solid silver described in the WO 02/62402.The preferred amount of salt precursor in lens is about 0.00001 to about 10.0 percetages by weight, more preferably about 0.0001 to about 1.0 percetages by weight, most preferably about 0.001 to about 0.1 percetage by weight, based on the gross weight of monomer composition.The example of salt precursor includes but are not limited to, inorganic molecule, for example sodium chloride, sodium iodide, sodium bromide, lithium chloride, lithium sulfide, sodium sulfide, Potassium monosulfide., sodium tetrachloro argentate or the like.The example of organic molecule includes but are not limited to, lactic acid tetra-allkylammonium, sulphuric acid tetra-allkylammonium, for example chlorination of quaternary ammonium halides, bromination or iodate tetra-allkylammonium.Preferred precursor salt is a sodium iodide.
Term " formation " refers to be used to form big metering method any of lens, includes, but are not limited to use up or heat cure.Lens formulation of the present invention can form by any method known to those skilled in the art, for example shakes or stirs, and be used to form polymer product or device by known method.
For example, device for eyes of the present invention can prepare by following steps: reactive component and any diluent are mixed with polymerization initiator, and solidify by suitable condition, to form product, this product can be configured as suitable shape by turning, cutting or the like subsequently.Selectively, reactant mixture can be placed in the mould, and is solidified into suitable goods subsequently.
In producing contact lens, the whole bag of tricks that is used to process lens formulation is known, comprises rotational casting and static casting.The rotational casting method is disclosed in U.S.3, and 408,429 and 3,660,545, and static casting method is disclosed in U.S.4,113,224 and 4,197,266.The preferable methods that is used for production contact lens of the present invention is a molding methods.For this method, lens formulation is put into mould, this mould has the shape of the lens of final hope, and this lens formulation is stood certain condition, makes the component polymerization whereby, to produce lens.Lens can be used solvent processing, removing diluent, and final water displacement diluent.This method also is described in U.S. patent 4,495,313; 4,680,336; 4,889,664; With 5,039,459, be hereby incorporated by.Preferred curing is to use radiation, preferred ultraviolet or visible light, and most preferably uses visible light.
Term " argentum reagent " refers to any compositions (comprising aqueous solution) that comprises silver ion.The example of this based composition includes but are not limited to, the moisture or organic solution of silver nitrate, silver trifluoromethanesulfonate or silver acetate, and wherein the concentration of argentum reagent in solution is about 1 mcg/ml or bigger.Preferred argentum reagent is a silver nitrate aqueous solution, wherein in solution the concentration of silver nitrate be more than or equal to about 0.0001 to about 30 percetages by weight, more preferably approximately greater than 0.001 to about 1 percetage by weight, gross weight based on solution, and most preferably arrive about 0.03 percetage by weight, based on the gross weight of solution greater than about 0.001.Term " processing " refers to any method that argentum reagent is contacted with lens, and wherein preferable methods is that lens are immersed in the solution of argentum reagent.Processing can comprise heats lens in the solution of argentum reagent, but preferred process is carried out at ambient temperature.Lens depend on concentration and desirable silver the initial concentration in device for eyes of argentum reagent in solution with the time that argentum reagent is handled.
In addition, the present invention includes the method for preparing antimicrobial lenses, this antimicrobial lenses comprises silver and discharges chemical compound, is made up of silver release chemical compound basically or is made up of silver release chemical compound, and wherein said method may further comprise the steps, is made up of following steps basically or is made up of following steps:
(a) handle solidified lens with the salt precursor;
(b) lens of usefulness argentum reagent treatment step (a).
Term antimicrobial lenses, salt precursor, argentum reagent and processing all have its above-mentioned implication and preferred range.
All above-mentioned methods can be carried out by means of the combination of single machinery or machinery.For example, be added into solidified lens if silver discharges chemical compound, all add the step of these silver release chemical compounds can carry out on hydration machine, and the effect of this hydration machine is as follows.Solidified lens (lens non-hydrated, partially hydrated or complete hydration) can be placed in the single blister package.The solution of salt precursor is added this packing, place time enough,, but be not enough to produce undesirable mist degree so that the salt precursor of desirable amount adds lens.Time will be depended on dissolubility and the concentration and the temperature of salt.The time (at ambient temperature) that is fit to comprises about 30 minutes at most, and preferably between about 30 seconds to 5 minutes, and more preferably about two minutes.Subsequently, remove the solution of the precursor that desalts, and the solution of metal reagent is added described packing.Remove metal reagent solution subsequently, and, sterilize then with several parts of described lens of deionized water wash.Should be appreciated that any said method can comprise additional step, for example wash lens, HIGH PRESSURE TREATMENT or the like.
In addition, the present invention includes the method for preparing antimicrobial lenses, this antimicrobial lenses comprises silver and discharges chemical compound, is made up of silver release chemical compound basically or is made up of silver release chemical compound, and wherein said method may further comprise the steps, is made up of following steps basically or is made up of following steps:
(a) handle lens with argentum reagent.
(b) lens of usefulness salt precursor treatment step (a).
Term antimicrobial lenses, salt precursor, metal reagent and processing all have its above-mentioned implication and preferred range.
In order to demonstrate the invention, following examples are provided.These embodiment do not limit the present invention.They only advise implementing method of the present invention.In the contact lens field and other technical professionals can find to implement additive method of the present invention.Yet these methods are deemed to be within the scope of the present invention.
Embodiment
The silver releasing pattern is measured as follows: prepare the accurate protein of a raising of indices and give liquid solution, it comprises 8.80g sodium chloride, 0.46g sodium dihydrogen phosphate, 4.40g sodium hydrogen phosphate, 1.20g Ox blood plasma-globulin, 1.20g egg albumin and 1.20g egg albumen lysozyme in deionized water.Weigh up described composition, and put into 1000mL Erlenmeyer, it is filled with deionized water then.Between the operating period of this solution, it is kept in the refrigerator under 4 ℃, to prevent degeneration.In order to obtain releasing pattern, the lens of non-hydrated to be put into fill the individual plastic bottle that 2.2 milliliters of standard proteins are given liquid solution, this solution was changed in per 24 hours.In experiment, bottle is remained in the pallet on the oscillator plate, this at room temperature carries out.In 30 days test periods, take out triplicate lens specimen in the time of different number of days, carry out drying, and analyze remaining silver content by INAA.
In order to measure the antimicrobial efficacy of prolongation, lens are cultivated according to following: the artificial tear solution of 500 microlitres (8.30g sodium chloride, 0.46g potassium dihydrogen phosphate, 4.40g sodium hydrogen phosphate, 1.20g Ox blood plasma gamma globulin, 1.20g egg albumin and 1.20g egg albumen lysozyme are diluted to one liter in water make) is placed on prepares to be used for the microwell plate that lens are cultivated in each hole of 24-hole microwell plate.With the rinsing in 30 milliliters of phosphate buffered saline (PBS)s of three replacings of test lens, and sterilely transfer in the single hole of every cover microwell plate.Then microwell plate is placed on the orbital shaker, and allowed at room temperature to cultivate 24 hours.After cultivating, lens are transferred in the hole of the new microwell plate that comprises the artificial tear solution of 500 microlitres, perhaps remove, and according to test antibiotic effect as described below.
The antibiotic effects of and lens that cultivate initial according to following mensuration: in the tryptic soy medium with Pseudomonas aeruginosa, ATCC# 15442 (American Type Culture Collection (American Type Culture Collection), Rockville, MD) grow overnight.In phosphate buffered saline (PBS) (PBS, pH=7.4+/-0.2), culture is washed three times, and bacteria particles is resuspended among 10 milliliters of PBS.Prepare the microbionation body, produce about 1 * 10
6The final concentration of colony-forming units/milliliter (cfu/mL).With the rinsing in 30 milliliters of phosphate buffered saline (PBS)s (PBS, pH=7.4+/-0.2) of three replacings of three contact lenses, to remove residual solution.The lens of each rinsing are put into aseptic cuvette with 2 milliliters of microbionation bodies, then with its rotation (100rpm) two hours in agitator-incubator under 37+/-2 ℃.Each lens is removed from cuvette, rinsing is five times in the PBS of three replacings, removing the bonded cell of loosely, to put into the single hole of the 24-hole microwell plate that comprises 1 milliliter of PBS, and ℃ down other 22 hours of the rotation in 37+/-2 in agitator-incubator.Once more with the rinsing five times in the PBS that changes for three times of each lens, to remove the bonded cell of loosely, put into 10 milliliters of PBS that comprise 0.05% (w/v) Tween 80, and under 2000rpm vortex 3 minutes, use centrifugal force to make of the adhesion fracture of remaining antibacterial to lens.The antibacterial alive of the supernatant that counts to get, and it is average to be attached to the result of detectable antibacterial alive of 3 lens, and these data reduce to provide with the logarithm with the correlated inoculum of tester (lens by table 1 preparation is made add silver).
Used following abbreviation among the embodiment
Blue HEMA=such as embodiment 4 or U.S. patent 5,944, reactive blue numbering 4 described in 853 and the product of HEMA
CGI 1850=1-hydroxy-cyclohexyl benzophenone and two (2,6-dimethoxy benzoyl)-2,1: 1 (w/w) blend of 4-4-tri-methyl-amyl phosphine oxide
DMA=N, the N-DMAA
The DPM=dipropylene glycol monomethyl ether
HEMA=methacrylic acid 2-hydroxyl ethyl ester
The IPA=isopropyl alcohol
The end capped polydimethylsiloxane of mPDMS=monomethyl acryloxy propyl group (MW800-1000)
Norbloc=2-(2 '-hydroxy-5-methyl base acryloxy ethylphenyl)-2H-benzotriazole
Ppm=part/1,000,000 part, microgram sample/every gram dry lens
PVP=polyvinylpyrrolidone (K90)
TRIS=3-methacryloxypropyl three (trimethylsiloxy group) silane
The TEGDMA=tetraethylene glycol dimethacrylate
Lens formulation and curing
The monomer mixing formula is listed in the table 1.The preparation of macromonomer is described in WO2002062402A1 (the macromonomer B among the embodiment 5), except using the reaction of triethylamine catalysis TMI.
Table 1
| Weight % | |
| Macromonomer | 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 |
Unless otherwise mentioned, add 3 as diluent, 7-dimethyl-3-capryl alcohol, component and diluent ratio (weight) they are 80: 20.Unless otherwise mentioned, by monomer mixture being put into the contact lens mould, and at N
2Use visible fluorescence lamp (PhilipsTL03) to solidify down 30 minutes at about 45 ℃ in the environment, form lens.Use 60: 40 IPA: H
2O is as discharging solution with the lens hydration, and uses 100%IPA, 80/20 IPA: H
2O, 60/40 IPA: H
2O, 40/60IPA: H
2O, 20/80 IPA: H
2O and 100%H
2O is hydration progressively.Then that lens rinsing in deionized water is other twice, and be kept in the deionized water.
Embodiment 1-4
Make hydrogel blend by the monomer mixture that is listed in the above table 1, except using 30: 70 (weight) dipropylene glycol: DPMA is as diluent.This blend is sent into industrial mill with silver chloride and the silver iodide bought from Aldrich chemical company.This industrial mill is ground to the average particle size distribution that is equal to or less than 10 microns with silver salt, and the silver chloride (embodiment 6-9) of the grinding of preparation monomer mixture and variable quantity or the blend of silver iodide (embodiment 1-4).After the reception, the mixture that obtains is rolled under 50rpm, up to further use.Mixture is added in United States Patent (USP) 4,640, in the eight chamber lens dies of the type of describing in 489.Under 50 ℃ temperature, polyase 13 is 0 minute under nitrogen purging, and this polymerization uses the visible light that produces from four PhilipsTL03 fluorescent lamps (on mould 4 inches) to carry out light-initiated.After solidifying, mould is opened, and with the lens hydration, and the water by they being put into continuously 40/60,0/100,40/60,60/40 and 100/0 (weight) and the solution of IPA carry out lixiviate.Will from minimum three lens of each group in vacuum drying oven under 80 ℃, under the maximum pressure of five inches Hg dry three to four hours, and deliver to independently laboratory, (INAA) measures remaining silver content by instrumental neutron activation analysis.
Measured the silver-colored releasing pattern of these lens as mentioned above, and be shown in the following table 2.In all tables, the value in the bracket after the Ag content is the standard deviation of the value of report.K and [Ag]
NRValue in the bracket after the value is the standard error by the data fitting computed in software.
Table 2
The one-level k value of each lens of measuring is shown in table 3.Fig. 1 has shown the lens for embodiment 1, as the figure of the remaining silver concentration of time function.
Table 3
| |
|
Ex 3 | Ex 4 | |
| [Ag] NRppm | 425(103) | 0(63) | 12(12) | 58(9) |
| R square | 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) |
Lens have been made according to embodiment 1-4, except initial silver content is 377ppm.Use aforesaid test, tested the lasting effect of these lens.The results are shown in following table 4.
Table 4
| Natural law in protein solution | Antibacterial reduces (log) |
| 1 | 6.5 |
| 2 | 4.8 |
| 10 | 4.0 |
| 15 | 4.0 |
| 18 | 3.6 |
| 25 | 3.4 |
| 30 | 3.6 |
Therefore, this embodiment shows, when being exposed to artificial tear solution, in whole 30 days test period, the lens that are dispersed with AgI therein can reduce count of bacteria in fact.
Embodiment 6-9
Made lens and analyzed silver content according to the process of embodiment 1-4, discharged chemical compound as silver except using AgCl.The results are shown in table 5.The remaining silver concentration of the lens of embodiment 6 is mapped to interval, and be shown among Fig. 2.
Table 5
Lens have been made according to embodiment 6-9, except initial silver content is 80ppm.Use aforesaid test, tested the lasting effect of these lens.The results are shown in following table 6.
Table 6
| Interval (my god) | Antibacterial reduces (log) |
| 1 | 6.5 |
| 2 | 2.4 |
| 10 | 2.1 |
| 15 | 1.3 |
| 18 | 1.2 |
| 25 | 0.7 |
| 30 | 0.6 |
Therefore, this embodiment shows, when being exposed to artificial tear solution, in whole 30 days test period, the lens that are dispersed with AgCl therein can reduce count of bacteria in fact.In addition, embodiment 5 and 10 shows, can produce a kind of like this lens, and these lens had the reduction of about at least 2 logarithmic microorganism clusters after about 2 and 10 days, and after 30 days, has about at least 0.5 logarithmic reduction.In other embodiments, can produce the lens that after about 2 and 10 days, have the reduction of about at least 1 logarithmic microorganism cluster.
Embodiment 11-14
(0.38g, Aldrich lot# 18014BI) is dissolved in 12.25g DMA (58.9g monomer mixture) with sodium iodide.The component that adds suitable amount in this mixture is to form the monomer mixture of table 1.Under 55 ℃ of temperature, this monomer mixture was outgased under 40 millimetress of mercury 30 minutes altogether.Use antecurvature and polypropylene (Fina, the grade EOD00-11) palintrope of Zeonor (Zeon, grade 1060R), described monomer mixture is used to prepare lens.Mould rotates-has applied poly-(HEMA) in advance, so that for lens provide mould transfer coated, wherein used disclosed method among the WO03/11551.At blanket of nitrogen (＜0.5O
2) in, under 70 ± 5 ℃, lens were solidified 12-15 minute down at visible light (Philips TLDK-visible light-01 lamp).
With solidified lens release, and be dipped in～solution of silver nitrate in DI water of 100ppm in 2 hours.Then the hydration pallet is transferred to 60: 40 IPA: in the DI water, continue 1.5 hours, from mould (palintrope) so that lens spin off.Then lens are cleaned in comprising the wide mouthed bottle of IPA.Lens are rolled on the wide mouthed bottle roller, and IPA is changed four times, between changing, kept 2 hours.Then by exchanging out: a) 10% IPA changes DI water into; B) 20% solution changes DI water into; C) 30% solution changes DI water into; D) 40% solution changes DI water into; E) 50% solution changes DI water into; F) 75% solution changes DI water into; G) 100% solution changes DI water into; H) 100% solution changes DI water into; I) 100% solution changes DI water into,, to DI water lens is progressively handled from purified IPA.Exchange was carried out at interval with 20-minute.Lens are carried out HIGH PRESSURE TREATMENT in 3 milliliters of borate-buffer saline.Measure by INAA, described lens comprise 353 ± 22ppm silver.
Using aforesaid method to measure silver discharges.The results are shown in table 7.The remaining silver concentration of the lens of embodiment 11 is mapped to interval, and be shown among Fig. 3.
Carried out embodiment 12-14 similarly, except not carrying out the mould transfer coated, and the suitable salt (NaI, tetrabutylammonium chloride (TBACl) or Tetrabutylammonium bromide (TBABr)) that will be shown in the amount in the following table 7 adds the monomer mixture of the tables 1 of about 15 grams.
Table 7
NM=does not measure
By the k value (0.99) of comparing embodiment 11 and the k value of embodiment 1-4 (k value is 0.05 to 0.13), can find out that the method for introducing silver release chemical compound can influence k value.By the k value (2.0) of comparing embodiment 14 and the k value (0.89-0.99) of embodiment 6-9, also can see this point.In both cases, silver is discharged chemical compound add lens formulation, lower k value is provided.
1-vinyl imidazole (4.0 gram) is dissolved in 10 ml deionized water.Add 3.61 gram AgNO
3Solution in 10 ml waters, and the mixture that obtains stirred tempestuously spend the night.Organic layer is dissolved in acetone, and at Na
2SO
4Last dry.Remove acetone.The solid product that obtains is ground and filters with ethyl acetate, with the ethyl acetate washing, use hexane wash then then.On glass dust,, provide 2.95 gram canescence products with the solid product drying.
Silver-colored vinyl imidazole coordination compound (0.2 gram) is dissolved in the monomer mixture preparation in the table 1 of being described in of 20.0 grams.Mixture is added the contact lens mould, and this mould uses the antecurvature and end of being made by Topas curved.With lens curing under general condition of cure, release and hydration, as described above.The silver of measuring these lens as mentioned above discharges.The result reports in table 8.K value be 0.20 ± 0.06 and R2 be 0.96.
Table 8
| My god | [Ag] |
| 0 | 281(26) |
| 1 | 218(22) |
| 3 | 208(43) |
| 7 | 169(32) |
| 14 | 127(7) |
| 21 | 131(3) |
| 28 | 119(16) |
| [Ag] NRppm | 123(11) |
Embodiment 16
By the N with 0.20 percetage by weight, N '-two (acryloyl group) cystamine (CYST) adds the monomer mixture of table 1, makes contact lens.The blend that obtains was mixed 15 minutes at least, to guarantee CYST uniform distribution in monomer mixture.By finding time, carry out nitrogen purging then, the reactive monomeric mixture is outgased, and be added in United States Patent (USP) 4,640, the lens die of the type of describing in 489, this mould applies with poly-(methacrylic acid 2-hydroxyl ethyl ester), and is disclosed among the embodiment 14 as WO03/11551.With mould precuring 30 ± 2 seconds, then, under 70 ± 5 ℃, under visible light (Philips TL20W/03T fluorescent lamp), solidified 12-15 minute.After solidifying, to open mould, and in the DPM of 4: 96 volume/volume and DI-water blend, lens are broken away from, lixiviate in DPM/DI-water then is to remove any residual monomer and diluent.Lens are put into the bottle that comprises 3 milliliters of borate-buffer saline, add the 0.0.0315 mg/ml AgNO of 50 microlitres
3Solution.Then with bottle sealing, and 121 ℃ of following HIGH PRESSURE TREATMENT 150 minutes.
Using aforesaid method to measure silver discharges.The results are shown in table 9.Produced release profiles by the data in the table 9, and [Ag] that calculate
NRBe 57 (2) ppm, k value is 0.20 (0.09) day
-1, and R
2Be 0.86.
Table 9
| My god | [Ag](ppm) |
| 0 | 71(2) |
| 1 | 67(1) |
| 2 | 65(3) |
| 3 | 64(5) |
| 5 | 65(6) |
| 7 | 60(5) |
| 14 | 54(8) |
| 28 | 59(2) |
Embodiment 17
Preparation (99.67 weight %) and 0.33%Chelex with table 1
100 resins (with the functionalized crosslinked polystyrene of iminodiacetic acid sodium salt group) mix.Mixture is added lens die.Curing and hydrating condition that use is described in above preparation and cured portion form lens.Comprise the AgNO of 13.3ppm (weight) Ag with what these hydrated lens were put into the 3.0ml/ lens at deionized water
3Solution, and 121 ℃ of following HIGH PRESSURE TREATMENT 30 minutes.With lens rinsing six times in deionized water (about 7 milliliters of each lens), each rinsing 30 minutes.The silver of measuring these lens as mentioned above discharges.The result is reported in the following table 10.
Embodiment 18
Use 4-vinylpridine, as mentioned above, the preparation from table 1 is made lens, except using 0.23% (weight) 4-vinylpridine.Measure silver as mentioned above.Release the results are shown in table 10.
Embodiment 19
Poly-(aspartic acid) (0.4029 gram) in 5 ml waters restrained AgNO with 0.3714
3Mix.Mixture is filtered, and dry under 80 ℃ in a vacuum, form Ag-pASP.Make lens by the reactive monomer mixture of in the preparation part, describing of 99.75% (weight) and 0.25% Ag-pASP.The silver of measuring these lens as mentioned above discharges.The result is reported in table 10.
Make lens by the reactive monomer mixture of in the preparation part, describing of 99.75% (weight) and 0.25% poly-L-Lysine.Monomer mixture is put into the contact lens mould, solidify and hydration, described in above preparation cured portion.Comprise the AgNO of 13.3ppm (weight) Ag with what these hydrated lens were put into the 3.0ml/ lens at deionized water
3Solution, and 121 ℃ of following HIGH PRESSURE TREATMENT 30 minutes.With lens rinsing five times in deionized water (the about 7ml of each lens), each rinsing 30 minutes.The silver of measuring these lens as mentioned above discharges.The result is reported in table 10.
Table 10
Embodiment 24-27
10% (weight) AgNO that in comprising 50 ml methanol solution of about 0.02 mole of phenylmercaptan., adds 100 milliliters
3This multiphase mixture was stirred 30 minutes.This mixture is filtered, and the yellow mercury oxide of collecting with the thorough rinsing of methanol, phenylmercaptan. silver is used the DI-water rinse then, and under vacuum 30 ℃ dry about 96 hours down.The monomer mixture that phenylmercaptan. silver (15 milligrams) is added the table 1 of 15 grams.With about one hour of this mixture sonication, about altogether 30 minutes of the degassing under 40mmHg then.The monomer mixture preparation is added in the eight chamber lens dies of the type of describing in the United States Patent (USP) 4,640,489, and under 50 ± 5 ℃ temperature, solidified 20 to 45 minutes.Be aggregated under the nitrogen purging and carry out, and use the visible light that produces by Philips TL20W/03T fluorescent lamp to carry out light-initiated.
Use 2-methylbenzene thiophenol silver, 2-aminothiophenol silver and thiosalicylic acid silver to prepare similarly and tested lens.All prepare 2-methylbenzene thiophenol silver, 2-aminothiophenol silver and thiosalicylic acid silver, wherein substitute about 0.02 mole phenylmercaptan. with about 0.02 mole 2-methylbenzene thiophenol, 2-aminothiophenol and thiosalicylic acid respectively in the mode identical with preparation phenylmercaptan. silver.All lens carry out the test that silver discharges.The results are shown in table 11.
Table 11
The release profiles of embodiment 21-24 is shown in Fig. 5, and it clearly illustrates that embodiment 21-23 has releasing pattern very slowly.Also can easily see this point from the following fact: the lens of embodiment 21-23, the variation of the silver concentration of every day is not usually with the quantitative changeization of the deviation that is above standard.Because the variation of the silver concentration of measuring is so little and is variable that R2 is very low, and under the situation of embodiment 22, [Ag]
NRValue of calculation nonsensical.Yet releasing pattern clearly illustrates that embodiment 21-23 is within the scope of the invention.For the material of very slow release, for example embodiment 21-23 measures silver concentration rational k estimated value will be provided at least 30 days time and in the preferred 45 or 60 days time.
Lens to embodiment 21 to 24 have been tested initial effect.
The results are shown in following table 12.
Table 12
| Ex# | Antibacterial reduces (log) |
| 21 | 1.66 |
| 22 | 1.84 |
| 23 | 1.72 |
| 24 | 1.91 |
In the preparation and 0.1% Ag (II) by the table 1 of 99.9% (weight)-blend of tetraphenylporphyrin (Frontier Scientific) makes lens.The silver of measuring these lens as mentioned above discharges.The result is reported in table 13.
Table 13
| Embodiment | Embodiment 28 |
| Time | |
| My god | |
| 0 | 109 |
| 1 | 97 |
| 2 | 147 |
| 3 | 96 |
| 4 | 104 |
| 5 | 123 |
Embodiment 26
The reactive monomeric mixture comprises 100 parts the component that is shown in Table 1, and the amount to be shown in Table 14, have 23 parts 3,7-dimethyl-3-capryl alcohol (D
3O).Reactant mixture is mixed tempestuously (perhaps get transparent and mixed equably), under fine vacuum, outgas then up to solution becomes.
Table 14
| Component | Weight % |
| Norbloc | 2.00 |
| CGI 1850 | 0.48 |
| |
31.00 |
| DMA | 24.00 |
| HEMA | 6.00 |
| TEGDMA | 1.50 |
| SiMAA2 | 28.00 |
| Blue HEMA | 0.02 |
| K90 | 7.00 |
Then reactant mixture is put into thermoplasticity contact lens mould, and used fluorescent lamp, under blanket of nitrogen, keeping about 15 minutes under 45 ℃.Use aforesaid process with lens release, and be kept in the wide mouthed bottle of the DI-water that comprises methylcellulose with 50ppm.
Lens are put into comprise 1 weight % silver acetate aqueous solution (CH
3CO
2Ag, 3mL/ lens) wide mouthed bottle.Lens were rolled 60 minutes.With CH
3CO
2Ag solution decant, and add 30 weight % calcium chloride water (CaCl
22H
2O, the 3mL/ lens).Lens were rolled one hour.With CaCl
22H
2O solution decant, and add DI-water (3mL/ lens).Lens were rolled one hour.Repeat washing.Lens are transferred in the bottle that comprises 3 milliliters of borate buffering package solution (not comprising sodium chloride) individually, and 121 ℃ of following HIGH PRESSURE TREATMENT 30 minutes.Lens are tested, analyzed silver content, carry out mechanical test, test water content, wettability and carry out the mist degree analysis.The results are shown in following table 14.
To contrast lens and transfer to individually in the bottle that comprises 3 milliliters of borate buffering package solution (not comprising sodium chloride), and 121 ℃ of following HIGH PRESSURE TREATMENT 30 minutes.Lens are carried out mechanical test, water content, wettability and mist degree analysis.The results are shown in following table 15.
Table 15
| Performance | The contrast lens | Embodiment 26 |
| Water content (%) | 39.6(0.3) | 40.5(0.5) |
| Modulus (psi) | 94(8) | 80(8) |
| Percentage elongation (%) | 291(32) | 216(104) |
| Hot strength (psi) | 147(24) | 90(50) |
| Toughness (psi) | 189(40) | 106(88) |
| (adv. is in packing, n=5) for contact angle | 44(9) | 52(7) |
| Mist degree (%CSI lens) | 14(1) | 484(35) |
| Silver content (ppm) | N/A | ＞1500 |
The result of embodiment 26 shows that these treatment conditions can not provide the device for eyes with performance, especially mist degree of share.
Embodiment 27-29
With the embodiment 26 the same lens of making, and handle according to following.Lens are put into comprise CH
3CO
2The wide mouthed bottle of Ag aqueous solution (0.50,0.25 or 0.10 weight % solution, 3 milliliters/lens).Lens were rolled 60 minutes.With CH
3CO
2Ag solution decant, and add 30 weight %CaCl
22H
2O aqueous solution (3mL/ lens).Lens were rolled one hour.This CaCl of decant
22H
2O solution and adding DI-water (3mL/ lens).Lens were rolled one hour.Repeat the DI-washing.Lens are transferred in the bottle that comprises 3 milliliters of borate buffering package solution (not comprising sodium chloride) individually, and 121 ℃ of following HIGH PRESSURE TREATMENT 30 minutes.Lens are tested, analyzed silver content, carry out mechanical test, test water content, wettability and carry out the mist degree analysis.The results are shown in following table 16.
Table 16
| Performance | Embodiment 27 | Embodiment 28 | Embodiment 29 |
| ％CH 3CO 2Ag | 0.5wt％ | 0.25wt％ | 0.1wt％ |
| Water content (%) | 40.7(0.9) | 39.1(0.5) | 40.0(0.8) |
| Modulus (psi) | 87(11) | 87(9) | 84(5) |
| Percentage elongation (%) | 258(53) | 301(28) | 275(50) |
| Hot strength (psi) | 115(30) | 140(26) | 119(28) |
| Toughness (psi) | 140(53) | 186(42) | 150(48) |
| (adv. is in packing, n=5) for contact angle | 44(12) | 39(8) | 31(8) |
| Mist degree (%CSI lens) | 232(26) | 49(13) | 15(8) |
| Silver content (ppm) | 830(80) | 187(70) | 4.0(6.0) |
The result of embodiment 27-29 shows that the value of mist degree can be controlled by the concentration of the silver-colored precursor of control.Embodiment 10 shows, the lens of making by the silver chloride in situ precipitation show and surpass 30 days effect, in addition initial silver concentration is low also can be like this to 80ppm.
Claims (35)
1. device for eyes, it comprises polymer and at least a silver discharges chemical compound, wherein the initial concentration of ionized silver is 10ppm at least, the diameter that wherein said silver discharges chemical compound is less than or equal to 10 microns, and described during use silver discharges with given pace from described device for eyes, its speed constant uses first _ order kinetics equation to calculate, for the highest 1 day
-1
2. the device for eyes of claim 1, wherein said speed constant was at 0.001 and 0.5 day
-1Between.
3. the device for eyes of claim 1, wherein said speed constant was at 0.01 and 0.3 day
-1Between.
4. the device for eyes of claim 1, wherein said speed constant was at 0.001 and 0.2 day
-1Between.
5. the device for eyes of claim 1, wherein said initial silver concentration is 10 and 10, between the 000ppm.
6. the device for eyes of claim 1, wherein said initial silver concentration is 25 and 5, between the 000ppm.
7. the device for eyes of claim 1, wherein said initial silver concentration is 50 and 3, between the 000ppm.
8. the device for eyes of claim 1, wherein in the use of described device, described initial silver concentration and speed constant are enough to provide the reduction of at least 50% microbial activity.
9. the device for eyes of claim 1, wherein said device for eyes is a contact lens.
10. the device for eyes of claim 9, wherein said initial silver concentration and speed constant are maintained at the amount that causes argyrism that is lower than.
11. the device for eyes of claim 9, wherein after one day, during use, silver discharges from described device for eyes with certain speed, and wherein speed constant uses first _ order kinetics equation to calculate, for the highest 1 day
-1
12. the device for eyes of claim 9, it does not have visible blushing in fact.
13. the device for eyes of claim 9, it has the mist degree less than 150%.
14. the device for eyes of claim 9, it has the mist degree less than 100%.
15. the device for eyes of claim 1, wherein said polymer also comprises part, and described silver can combine with this part releasedly.
16. the device for eyes of claim 1, wherein said device for eyes is a contact lens, and described initial silver concentration and speed constant are enough to provide the reduction of at least 50% microbial activity in the use of described device.
17. the device for eyes of claim 9, wherein said use are to wear continuously with at least 14 days.
18. the device for eyes of claim 9, wherein said use are to wear continuously with at least 30 days.
19. the device for eyes of claim 9, wherein during use, described silver discharges from described contact lens with the amount of the reduction that is enough to be provided in the described use 70% bacterial activity at least.
20. the device for eyes of claim 9, wherein during use, described silver discharges from described contact lens with the amount of the reduction that is enough to be provided in the described use 90% bacterial activity at least.
21. the device for eyes of claim 1, the molar solubility of the silver ion that wherein said silver release chemical compound is had in 25 ℃ pure water is 2.0 * 10
-30Mol is to 2 mol.
22. the device for eyes of claim 1, the molar solubility of the silver ion that wherein said silver release chemical compound has in pure water is greater than 2.0 * 10
-17Mole/L.
23. the device for eyes of claim 9, wherein said polymer comprises siloxanes aquogel.
24. the device for eyes of claim 9, wherein said siloxanes aquogel are selected from senofilcon A, galyfilcon A, lotrafilcon A and balafilcon A.
25. the device for eyes of claim 1, wherein said polymer forms by comprising at least a reactant mixture that contains the component of siloxanes.
26. the device for eyes of claim 1, wherein said reactant mixture also comprises at least a hydrophilic component.
27. the device for eyes of claim 1, wherein said device for eyes is coated.
28. the device for eyes of claim 9, wherein said polymer forms by comprising at least a reactant mixture that contains the component of siloxanes.
29. the device for eyes of claim 9, wherein said reactant mixture also comprises at least a hydrophilic component.
30. the device for eyes of claim 9, wherein said device for eyes is coated.
31. the device for eyes of claim 9, wherein said lens showed the minimizing of at least 2 logarithmic microorganism clusters after two days.
32. the device for eyes of claim 9, wherein said lens showed the minimizing of at least 1 logarithmic microorganism cluster after two days.
33. the device for eyes of claim 9, wherein said lens showed the minimizing of at least 2 logarithmic microorganism clusters after 10 days.
34. the device for eyes of claim 9, wherein said lens showed the minimizing of at least 1 logarithmic microorganism cluster after 10 days.
35. the device for eyes of claim 9, wherein said lens showed the minimizing of at least 0.5 logarithmic microorganism cluster after 30 days.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US42862002P | 2002-11-22 | 2002-11-22 | |
| US60/428,620 | 2002-11-22 | ||
| US10/715,745 | 2003-11-18 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1741823A CN1741823A (en) | 2006-03-01 |
| CN100408106C true CN100408106C (en) | 2008-08-06 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2003801091493A Expired - Fee Related CN100408106C (en) | 2002-11-22 | 2003-11-21 | Antimicrobial lenses displaying extended efficacy |
Country Status (5)
| Country | Link |
|---|---|
| KR (1) | KR20060039391A (en) |
| CN (1) | CN100408106C (en) |
| AR (3) | AR042122A1 (en) |
| TW (2) | TWI341405B (en) |
| WO (1) | WO2004047878A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030044447A1 (en) * | 2000-12-21 | 2003-03-06 | Diana Zanini | Antimicrobial contact lenses and methods for their production |
| US8425926B2 (en) * | 2003-07-16 | 2013-04-23 | Yongxing Qiu | Antimicrobial medical devices |
| US7335613B2 (en) * | 2004-04-08 | 2008-02-26 | Rohm And Haas Company | Fiber substrate with antibacterial finish and methods of making and using the same |
| US7390774B2 (en) * | 2004-04-08 | 2008-06-24 | Rohm And Haas Company | Antibacterial composition and methods of making and using the same |
| US20060142525A1 (en) * | 2004-12-29 | 2006-06-29 | Bausch & Lomb Incorporated | Hydrogel copolymers for biomedical devices |
| AU2006222708A1 (en) * | 2005-10-07 | 2007-04-26 | Rohm And Haas Company | Method for disinfecting or sanitizing a surface |
| US20080102095A1 (en) * | 2006-10-31 | 2008-05-01 | Kent Young | Acidic processes to prepare antimicrobial contact lenses |
| AU2012261717B2 (en) * | 2006-10-31 | 2014-09-04 | Johnson & Johnson Vision Care, Inc. | Antimicrobial polymeric articles, processes to prepare them and methods of their use |
| KR20090101894A (en) * | 2006-10-31 | 2009-09-29 | 존슨 앤드 존슨 비젼 케어, 인코포레이티드 | Processes to prepare antimicrobial contact lenses |
| US20080100797A1 (en) * | 2006-10-31 | 2008-05-01 | Nayiby Alvarez-Carrigan | Antimicrobial contact lenses with reduced haze and preparation thereof |
| US20080102122A1 (en) * | 2006-10-31 | 2008-05-01 | Shivkumar Mahadevan | Antimicrobial polymeric articles, processes to prepare them and methods of their use |
| AU2014210607B2 (en) * | 2006-10-31 | 2015-04-30 | Johnson & Johnson Vision Care, Inc. | Antimicrobial polymeric articles, processes to prepare them and methods of their use |
| US20080241225A1 (en) * | 2007-03-31 | 2008-10-02 | Hill Gregory A | Basic processes to prepare antimicrobial contact lenses |
| US20090092538A1 (en) * | 2007-10-08 | 2009-04-09 | Amit Khanolkar | Methods for forming stabilized metal salt particles |
| RU2621301C1 (en) * | 2016-03-24 | 2017-06-01 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Волгоградский государственный технический университет" (ВолгГТУ) | Method of obtaining highly-dispersed stabilized particles of sodium iodide in water solutions |
| DE102018126842B4 (en) * | 2018-10-26 | 2020-10-15 | Carl Zeiss Meditec Ag | Ophthalmic implant, method for producing an ophthalmic implant and use of a ligand for producing an ophthalmic implant |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10024363A1 (en) * | 2000-05-17 | 2001-11-29 | Woehlk Contact Linsen Gmbh | Silver impregnated contact lens comprises body formed of matrix with silver with sulfide, halogenide and oxide, with silver precipitated and diffused |
| WO2002049683A2 (en) * | 2000-12-21 | 2002-06-27 | Johnson & Johnson Vision Care, Inc. | Antimicrobial contact lenses and methods for their production |
-
2003
- 2003-11-21 WO PCT/US2003/037368 patent/WO2004047878A1/en not_active Application Discontinuation
- 2003-11-21 AR ARP030104316 patent/AR042122A1/en unknown
- 2003-11-21 KR KR1020057009221A patent/KR20060039391A/en not_active Application Discontinuation
- 2003-11-21 CN CNB2003801091493A patent/CN100408106C/en not_active Expired - Fee Related
- 2003-11-24 TW TW092132888A patent/TWI341405B/en not_active IP Right Cessation
- 2003-11-24 TW TW92132886A patent/TWI331535B/en not_active IP Right Cessation
-
2009
- 2009-06-08 AR ARP090102057 patent/AR072076A2/en unknown
- 2009-06-08 AR ARP090102056 patent/AR072075A2/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10024363A1 (en) * | 2000-05-17 | 2001-11-29 | Woehlk Contact Linsen Gmbh | Silver impregnated contact lens comprises body formed of matrix with silver with sulfide, halogenide and oxide, with silver precipitated and diffused |
| WO2002049683A2 (en) * | 2000-12-21 | 2002-06-27 | Johnson & Johnson Vision Care, Inc. | Antimicrobial contact lenses and methods for their production |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1741823A (en) | 2006-03-01 |
| KR20060039391A (en) | 2006-05-08 |
| TWI331535B (en) | 2010-10-11 |
| AR042122A1 (en) | 2005-06-08 |
| TWI341405B (en) | 2011-05-01 |
| WO2004047878A1 (en) | 2004-06-10 |
| TW200505510A (en) | 2005-02-16 |
| AR072075A2 (en) | 2010-08-04 |
| TW200504402A (en) | 2005-02-01 |
| AR072076A2 (en) | 2010-08-04 |
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