Antimicrobial medical devices

Abstract

The present invention provides methods for making an antimicrobial medical device, preferably an antimicrobial ophthalmic device, more preferably an antimicrobial extended-wear contact lens, which contains silver nano-particles distributed uniformly therein. The antimicrobial medical device can exhibit antimicrobial activity over an extended period of time.

1 - 13 . (canceled) 
     
     
         14 . A method for making an antimicrobial medical device, comprising the steps of: obtaining a polymerizable fluid composition comprising a siloxane-containing macromer and a soluble silver salt; adding into the fluid composition at least one biocompatible reducing agent to form a mixture, wherein the amount of the biocompatible reducing agent added in the mixture is sufficient to reduce the silver salt into silver nanoparticles; mixing thoroughly the mixture for a period of time sufficient to reduce at least 40% of the silver salt into silver nanoparticles so as to form a polymerizable dispersion; introducing an amount of the polymerizable dispersion in a mold for making a medical device; and polymerizing the mixture in the mold to form the antimicrobial medical device containing silver nanoparticles. 
     
     
         15 . The method of  claim 14 , wherein the medical device is an ophthalmic device. 
     
     
         16 . The method of  claim 15 , wherein the polymerizable fluid composition is obtained by dissolving a desired amount of the silver salt in a formulation selected from the group consisting of formulations of lotrafilcon A, lotrafilcon B, etafilcon A, genfilcon A, lenefilcon A, polymacon, acquafilcon A, and balafilcon. 
     
     
         17 . The method of  claim 15 , wherein the siloxane-containing macromer is selected from the group consisting of Macromer A, Macromer B, Macromer C, and Macromer D,
 wherein Macromer A is a polysiloxane macromer having a number-average molecular weight of 2000 to 10,000 and the segment of the formula:
   CP-PAO-DU-ALK-PDMS-ALK-DU-PAO-CP 
   where PDMS is a divalent poly(disubstituted siloxane), ALK is an alkylene or alkylenoxy group having at least 3 carbon atoms, DU is a diurethane-containing group, PAO is a divalent polyoxyalkylene, and CP is selected from acrylates and methacrylates,   wherein Macromer B is a polysiloxane-comprising perfluoroalkyl ether and has the formula:
   P 1 —(Y) m -(L-X 1 ) p -Q-(X 1 -L) p -(Y) m —P 1  
 
   where each P 1 , independently of the others, is a free-radical-polymerizable group; each Y, independently of the others, is —CONHCOO—, —CONHCONH—, —OCONHCO—, —NHCONHCO—, —NHCO—, —CONH—, —NHCONH—, —COO—, —OCO—, —NHCOO— or —OCONH—; m and p, independently of one another, are 0 or 1; each L, independently of the others, is a divalent radical of an organic compound having up to 20 carbon atoms; each X 1 , independently of the others, is —NHCO—, —CONH—, —NHCONH—, —COO—, —OCO—, —NHCOO— or —OCONH—; and Q is a bivalent polymer fragment consisting of the segments:
 (a) -(E) k -Z—CF 2 —(OCF 2 ) x —(OCF 2 CF 2 ) y —OCF 2 —Z-(E) k -,
 where x+y is a number in the range of from 10 to 30;
 each Z, independently of the others, is a divalent radical having up to 12 carbon atoms or Z is a bond; 
 each E, independently of the others, is —(OCH 2 CH 2 ) q —, where q has a value of from 0 to 2, and where the link —Z-E- represents the sequence —Z—(OCH 2 CH 2 ) q —; and 
  k is 0 or 1; 
 
 
 (b) 
   
       
         
           
           
               
               
           
         
         
           
             wherein is an integer from 5 to 100; Alk is alkylene having up to 20 carbon atoms; 80-100% of the radicals R 1 , R 2 , R 3  and R 4 , independently of one another, are alkyl and 0-20% of the radicals R 1 , R 2 , R 3  and R 4 , independently of one another, are alkenyl, aryl or cyanoalkyl; and 
           
           (c) X 2 —R—X 2 , where R is a divalent organic radical having up to 20 carbon atoms, and each X 2 , independently of the others, is —NHCO—, —CONH—, —NHCONH—, —COO—, —OCO—, —NHCOO— or OCONH—;
 with the provisos that there must be at least one of each segment (a), (b), and (c) in Q, that each segment (a) or (b) has a segment (c) attached to it, and that each segment (c) has a segment (a) or (b) attached to it; 
 
           wherein Macromer C has an average molecular weight of from about 300 to about 30,000 and comprises at least one segment of the formula (I), (IV), (V), (VI) or (VII): 
         
       
       
         
           
           
               
               
           
         
         
           in which (a) is a polysiloxane segment; (b) is a polyol segment which contains at least 4 carbon atoms; Z is a segment (c) or a group X 1 ; (c) is defined as X 2 —R—X 2 , wherein R is a bivalent radical of an organic compound having up to 20 carbon atoms and each X 2  independently of the other is a bivalent radical which contains at least one carbonyl group; X 1  is defined as X 2 ; x is 0, 1 or 2; q has an average numerical value of 1-20; and (d) is a radical of the formula (II):
   X 3 -L-(Y) k —P 1   (II)
 
 
           in which P 1  is alkenyl, alkenylaryl or alkenylarylenealkyl having up to 20 carbon atoms; Y and X 3  independently of one another are a bivalent radical which contains at least one carbonyl group; k is 0 or 1; and L is a bond or a divalent radical having up to 20 carbon atoms of an organic compound, 
           wherein the polysiloxane segment (a) is derived from a compound of the formula (III): 
         
       
       
         
           
           
               
               
           
         
         
           in which n is an integer from 5 to 500; 99.8-25% of the radicals R 1 , R 2 , R 3 , R 4 , R 5  and R 6  independently of one another are alkyl and 0.2-75% of the radicals R 1 , R 2 , R 3 , R 4 , R 5  and R 6  independently of one another are partly fluorinated alkyl, aminoalkyl, alkenyl, aryl, cyanoalkyl, alk-NH-alk-NH 2  or alk-(OCH 2 ) m —(OCH 2 )p-OR 7 , R 7  is hydrogen or lower alkyl, alk is alkylene, and m and p independently of one another are an integer from 0 to 10, one molecule containing at least one primary amino or hydroxyl group, 
           wherein the alkylenoxy groups —(OCH 2 CH 2 ) m  and —(OCH 2 ) p  in formula (III) are either distributed randomly in a ligand alk-(OCH 2 CH 2 ) m —(OCH 2 ) p —OR 7  or are distributed as blocks in a chain, 
           wherein the polysiloxane segment (a) in formula (I) is linked a total of 1-50 times, via a group Z with the segment (b) or another segment (a), Z in an a-Z-a sequence always being a segment (c), 
           wherein the segments (b) in Macromer C according to the formula (VI) are linked in total (per molecule) with up to 20 with up to 6 polymerizable segments (d), 
           wherein the average number of segments (d) per molecule of the formula (VII) is in the range from 2 to 5, and very preferably is in the range from 3 to 4, 
           wherein macromer D has the formula:
   ACRYLATE-LINK-ALK-O-ALK-PDAS-ALK-O-ALK-LINK-ACRYLATE 
 
           in which the ACRYLATE is selected from acrylates and methacrylates; LINK is selected from urethanes and dirurethane linkages; ALK-O-ALK is R 1 —O—R 2  or R 3 —O—R 4 , R 1 , R 2 , R 3 , and R 4 , independently of one another, are lower alkylene; and PDAS is a poly(dialkylsiloxane) having a segment of the formula: 
         
       
       
         
           
           
               
               
           
         
         
           in which n is an integer from about 5 to about 500; and R 5 , R 6 , R 7 , and R 8  are independently of one another, are lower alkyl. 
         
       
     
     
         18 . The method of  claim 14 , wherein the polymerizable fluid composition comprises a siloxane-containing monomer and/or a hydrophilic monomer. 
     
     
         19 . The method of  claim 18 , wherein the polymerizable fluid composition comprises: (a) about 20 to 40 weight percent of a siloxane-containing macromer, (b) about 5 to 30 weight percent of a siloxane-containing monomer, and (c) about 10 to 35 weight percent of a hydrophilic monomer. 
     
     
         20 . The method of  claim 19 , wherein the siloxane-containing monomer is selected from the group consisting of methacryloxyalkylsiloxanes, tristrimethylsilyloxysilylpropyl methacrylate (TRIS), 3-methacryloxy propylpentamethyldisiloxane and bis(methacryloxypropyl)tetramethyldisiloxane, and mixtures thereof, wherein the hydrophilic monomer is selected from the group consisting of N,N-dimethylacrylamide (DMA), 2-hydroxyethylmethacrylate (HEMA), hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxypropyl methacrylate (HPMA), trimethylammonium 2-hydroxy propylmethacrylate hydrochloride, dimethylaminoethyl methacrylate (DMAEMA), dimethylaminoethylmethacrylamide, acrylamide, methacrylamide, allyl alcohol, vinylpyridine, glycerol methacrylate, N-(1,1 dimethyl-3-oxobutyl)acrylamide, N-vinyl-2-pyrrolidone (NVP), acrylic acid, methacrylic acid and mixtures thereof. 
     
     
         21 . The method of  claim 14 , wherein the polymerizable fluid composition further comprises a stabilizer for stabilizing silver nano-particles. 
     
     
         22 . The method of  claim 21 , wherein the stabilizer is a polyacrylic acid (PAA), a poly(ethyleneimine) (PEI), a PVP, or a polyionic material having amino groups and/or sulfur-containing groups. 
     
     
         23 . The method of  claim 14 , wherein a stabilizer is added into the polymerizable fluid composition together with the biocompatible reducing agent, wherein the stabilizer is a polyacrylic acid (PAA), a poly(ethyleneimine) (PEI), a PVP, or a polyionic material having amino groups and/or sulfur-containing groups. 
     
     
         24 . A method for making an antimicrobial medical device, comprising the steps of: obtaining lyophilized stabilized-silver nano-particles; directly dispersing a desired amount of the lyophilized stabilized-silver nano-particles in a polymerizable fluid composition comprising a siloxane-containing macromer to form a polymerizable dispersion; introducing an amount of the polymerizable dispersion in a mold for making a medical device; and polymerizing the polymerizable dispersion in the mold to form the antimicrobial medical device containing silver nanoparticles. 
     
     
         25 . The method of  claim 24 , wherein the medical device is an ophthalmic device. 
     
     
         26 . The method of  claim 24 , wherein the stabilized-silver nano-particles are obtained by reducing silver ions or silver salts in a solution in the presence of a stabilizer by means of a reducing agent or of heating or UV irradiation. 
     
     
         27 . The method of  claim 26 , wherein the stabilizer is a polyacrylic acid (PAA), a poly(ethyleneimine) (PEI), a PVP, or a polyionic material having amino groups and/or sulfur-containing groups. 
     
     
         28 . The method of  claim 25 , wherein the polymerizable fluid composition is selected from the group consisting of formulations of lotrafilcon A, lotrafilcon B, etafilcon A, genfilcon A, lenefilcon A, polymacon, acquafilcon A, and balafilcon. 
     
     
         29 . The method of  claim 25 , wherein the siloxane-containing macromer is selected from the group consisting of Macromer A, Macromer B, Macromer C, and Macromer D,
 wherein Macromer A is a polysiloxane macromer having a number-average molecular weight of 2000 to 10,000 and the segment of the formula:
   CP-PAO-DU-ALK-PDMS-ALK-DU-PAO-CP 
   where PDMS is a divalent poly(disubstituted siloxane), ALK is an alkylene or alkylenoxy group having at least 3 carbon atoms, DU is a diurethane-containing group, PAO is a divalent polyoxyalkylene, and CP is selected from acrylates and methacrylates,   wherein Macromer B is a polysiloxane-comprising perfluoroalkyl ether and has the formula:
   P 1 —(Y) m -(L-X 1 ) p -Q-(X 1 -L) p -(Y) m —P 1  
 
   where each P 1 , independently of the others, is a free-radical-polymerizable group; each Y, independently of the others, is —CONHCOO—, —CONHCONH—, —OCONHCO—, —NHCONHCO—, —NHCO—, —CONH—, —NHCONH—, —COO—, —OCO—, —NHCOO— or —OCONH—; m and p, independently of one another, are 0 or 1; each L, independently of the others, is a divalent radical of an organic compound having up to 20 carbon atoms; each X 1 , independently of the others, is —NHCO—, —CONH—, —NHCONH—, —COO—, —OCO—, —NHCOO— or —OCONH—; and Q is a bivalent polymer fragment consisting of the segments:
 (a) -(E) k -Z—CF 2 —(OCF 2 ) x —(OCF 2 CF 2 ) y —OCF 2 —Z-(E) k -,
 where
 x+y is a number in the range of from 10 to 30; 
 each Z, independently of the others, is a divalent radical having up to 12 carbon atoms or Z is a bond; 
 each E, independently of the others, is —(OCH 2 CH 2 ) q —, where q has a value of from 0 to 2, and where the link —Z-E- represents the sequence —Z—(OCH 2 CH 2 ) q —; and 
  k is 0 or 1; 
 
 
 (b) 
   
       
         
           
           
               
               
           
         
         
           
             wherein is an integer from 5 to 100; Alk is alkylene having up to 20 carbon atoms; 80-100% of the radicals R 1 , R 2 , R 3  and R 4 , independently of one another, are alkyl and 0-20% of the radicals R 1 , R 2 , R 3  and R 4 , independently of one another, are alkenyl, aryl or cyanoalkyl; and 
           
           (c) X 2 —R—X 2 , where R is a divalent organic radical having up to 20 carbon atoms, and each X 2 , independently of the others, is —NHCO—, —CONH—, —NHCONH—, —COO—, —OCO—, —NHCOO— or OCONH—;
 with the provisos that there must be at least one of each segment (a), (b), and (c) in Q, that each segment (a) or (b) has a segment (c) attached to it, and that each segment (c) has a segment (a) or (b) attached to it; 
 
           wherein Macromer C has an average molecular weight of from about 300 to about 30,000 and comprises at least one segment of the formula (I), (IV), (V), (VI) or (VII): 
         
       
       
         
           
           
               
               
           
         
         
           in which (a) is a polysiloxane segment; (b) is a polyol segment which contains at least 4 carbon atoms; Z is a segment (c) or a group X 1 ; (c) is defined as X 2 —R—X 2 , wherein R is a bivalent radical of an organic compound having up to 20 carbon atoms and each X 2  independently of the other is a bivalent radical which contains at least one carbonyl group; X 1  is defined as X 2 ; x is 0, 1 or 2; q has an average numerical value of 1-20; and (d) is a radical of the formula (II):
   X 3 -L-(Y) k —P 1   (II)
 
 
           in which P 1  is alkenyl, alkenylaryl or alkenylarylenealkyl having up to 20 carbon atoms; Y and X 3  independently of one another are a bivalent radical which contains at least one carbonyl group; k is 0 or 1; and L is a bond or a divalent radical having up to 20 carbon atoms of an organic compound, 
           wherein the polysiloxane segment (a) is derived from a compound of the formula (III): 
         
       
       
         
           
           
               
               
           
         
         
           in which n is an integer from 5 to 500; 99.8-25% of the radicals R 1 , R 2 , R 3 , R 4 , R 5  and R 6  independently of one another are alkyl and 0.2-75% of the radicals R 1 , R 2 , R 3 , R 4 , R 5  and R 6  independently of one another are partly fluorinated alkyl, aminoalkyl, alkenyl, aryl, cyanoalkyl, alk-NH-alk-NH 2  or alk-(OCH 2 ) m —(OCH 2 )p-OR 7 , R 7  is hydrogen or lower alkyl, alk is alkylene, and m and p independently of one another are an integer from 0 to 10, one molecule containing at least one primary amino or hydroxyl group, 
           wherein the alkylenoxy groups —(OCH 2 CH 2 ) m  and —(OCH 2 ) p  in formula (III) are either distributed randomly in a ligand alk-(OCH 2 CH 2 ) m —(OCH 2 ) p —OR 7  or are distributed as blocks in a chain, 
           wherein the polysiloxane segment (a) in formula (I) is linked a total of 1-50 times, via a group Z with the segment (b) or another segment (a), Z in an a-Z-a sequence always being a segment (c), 
           wherein the segments (b) in Macromer C according to the formula (VI) are linked in total (per molecule) with up to 20 with up to 6 polymerizable segments (d), 
           wherein the average number of segments (d) per molecule of the formula (VII) is in the range from 2 to 5, and very preferably is in the range from 3 to 4, 
           wherein macromer D has the formula:
   ACRYLATE-LINK-ALK-O-ALK-PDAS-ALK-O-ALK-LINK-ACRYLATE 
 
           in which the ACRYLATE is selected from acrylates and methacrylates; LINK is selected from urethanes and dirurethane linkages; ALK-O-ALK is R 1 —O—R 2  or R 3 —O—R 4 , R 1 , R 2 , R 3 , and R 4 , independently of one another, are lower alkylene; and PDAS is a poly(dialkylsiloxane) having a segment of the formula: 
         
       
       
         
           
           
               
               
           
         
         
           in which n is an integer from about 5 to about 500; and R 5 , R 6 , R 7 , and R 8  are, independently of one another, are lower alkyl. 
         
       
     
     
         30 . The method of  claim 25 , wherein the polymerizable fluid composition comprises a siloxane-containing monomer and/or a hydrophilic monomer. 
     
     
         31 . The method of  claim 30 , wherein the polymerizable fluid composition comprises: (a) about 20 to 40 weight percent of a siloxane-containing macromer, (b) about 5 to 30 weight percent of a siloxane-containing monomer, and (c) about 10 to 35 weight percent of a hydrophilic monomer. 
     
     
         32 . The method of  claim 31 , wherein the siloxane-containing monomer is selected from the group consisting of methacryloxyalkylsiloxanes, tristrimethylsilyloxysilylpropyl methacrylate (TRIS), 3-methacryloxy propylpentamethyldisiloxane and bis(methacryloxypropyl)tetramethyldisiloxane, and mixtures thereof, wherein the hydrophilic monomer is selected from the group consisting of N,N-dimethylacrylamide (DMA), 2-hydroxyethylmethacrylate (HEMA), hydroxyethyl acrylate, hydroxypropyl acrylate, hydroxypropyl methacrylate (HPMA), trimethylammonium 2-hydroxy propylmethacrylate hydrochloride, dimethylaminoethyl methacrylate (DMAEMA), dimethylaminoethylmethacrylamide, acrylamide, methacrylamide, allyl alcohol, vinylpyridine, glycerol methacrylate, N-(1,1 dimethyl-3-oxobutyl)acrylamide, N-vinyl-2-pyrrolidone (NVP), acrylic acid, methacrylic acid and mixtures thereof. 
     
     
         33 - 43 . (canceled)