Antimicrobial medical devices including silver nanoparticles

• US 20080181931A1
• Filed: 01/29/2008
• Published: 07/31/2008
• Est. Priority Date: 01/31/2007
• Status: Abandoned Application

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Qian, Xinming, Qiu, Yongxing
• Application Number:
  US12/011,652
• Publication Number:
  US 20080181931A1
• Time in Patent Office: Days
• US Class Current: 424/429
• CPC Class Codes: A61L 12/088 Heavy metals
• CPC Class Codes: A61L 2300/104 Silver, e.g. silver sulfadiazine
• CPC Class Codes: A61L 2300/404 Biocides, antimicrobial agents, antiseptic agents
• CPC Class Codes: A61L 2300/624 Nanocapsules
• CPC Class Codes: A61L 2400/12 Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: C08L 43/04 Homopolymers or copolymers of monomers containing silicon
• CPC Class Codes: C08L 83/04 Polysiloxanes
• CPC Class Codes: G02B 1/043 Contact lenses

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 chloride-treated silver nanoparticles distributed uniformly therein. The antimicrobial medical device can exhibit antimicrobial activity over an extended period of time but is substantially free of the characteristic yellowish color of the untreated silver nanoparticles.

Claims

1. A method for making an antimicrobial medical device, comprises the steps of:

obtaining a polymerizable dispersion comprising in-situ formed Ag-nanoparticles and a silicone-containing monomer or macromer or prepolymer;

treating the Ag-nanoparticles-containing polymerizable dispersion with chloride;

introducing an amount of the chloride-treated 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 Ag-nanoparticles.

2. The method of claim 1, wherein in-situ formation of Ag-nanoparticles is performed according to either process A or process B or combination thereof,

wherein the process A comprises the steps of:

(1) adding a desired amount of a soluble silver salt into a polymerizable fluid composition comprising a monomer capable of reducing silver cations and a silicone-containing monomer or macromer or prepolymer so as to form a mixture; and

(2) mixing thoroughly the mixture for a period of time long enough to reduce at least 20% of the added amount of the silver salt into silver nanoparticles so as to form a polymerizable dispersion, and

wherein the process B comprises the steps of;

(1) adding into a polymerizable fluid composition comprising a silicone-containing monomer or macromer or prepolymer 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 at least 20% of the silver salt into Ag-nanoparticles; and

(2) mixing thoroughly the mixture for a period of time sufficient to reduce at least 20% of the silver salt into Ag-nanoparticles so as to form a polymerizable dispersion.

3. The method of claim 1, wherein the step of treating the Ag-nanoparticles-containing polymerizable dispersion with chloride is performed according to either procedure A or procedure B or combination thereof,

wherein the procedure A comprises:

(1) adding chloride salt, such as NaCl in solid form, directly into the dispersion;

(2) mixing thoroughly resultant mixture for a period of time long enough to substantially reduce yellowish color of Ag-nanoparticles in the dispersion; and

(3) removing remaining solid chloride salt,

wherein the procedure B comprises;

(1) adding a NaCl or hydrochloride solution into the dispersion and (2) mixing thoroughly resultant mixture for a period of time long enough to substantially reduce yellowish color of Ag-nanoparticles in the dispersion.

4. The method of claim 1, wherein the silicone-containing prepolymer is at least one member selected from the group consisting of a prepolymer with at least one ethylenically unsaturated group, a prepolymer with two or more thiol groups, a prepolymer with at least one ene-group;

wherein the silicone-containing macromer is at least one member selected from the group consisting of a macromer with at least one ethylenically unsaturated group, a macromer with two or more thiol groups, a macromer with at least one ene-group;

wherein the silicone-containing monomer is at least one member selected from the group consisting of a monomer with one ethylenically unsaturated group, a monomer with two thiol groups, a monomer with one ene-group;

wherein the ene-group is defined by any one of formula (I)-(III)

5. A method for making an antimicrobial medical device, comprising the steps of:

a. reducing silver ions in a solution in the presence of a stabilizer to obtain Ag-nanoparticles stabilized by the stabilizer to form a Ag-nanoparticle dispersion;

b. treating the Ag-nanoparticle dispersion with chloride;

c. lyophilizing the chloride-treated Ag-nanoparticle dispersion to obtain lyophilized Ag-nanoparticles;

d. directly dispersing a desired amount of the lyophilized Ag-nanoparticles in a polymerizable fluid composition comprising a silicone-containing monomer or macromer or prepolymer to form a polymerizable dispersion;

e. introducing an amount of the polymerizable dispersion in a mold for making a medical device; and

f. polymerizing the polymerizable dispersion in the mold to form the antimicrobial medical device containing silver nanoparticles.

6. The method of claim 5, wherein the step b is performed according to either procedure A or procedure B or combination thereof,

wherein the procedure A comprises:

(1) adding chloride salt, such as NaCl in solid form, directly into the Ag-nanoparticle dispersion;

(2) mixing thoroughly the mixture for a period of time long enough to substantially reduce yellowish color of Ag-nanoparticles in the dispersion; and

(3) removing remaining solid chloride salt, and

wherein the procedure B comprises;

(1) adding a concentrated NaCl solution or concentrated hydrochloride solution into the Ag-nanoparticle dispersion and (2) mixing thoroughly the mixture for a period of time long enough to substantially reduce yellowish color of Ag-nanoparticles in the dispersion.

7. The method of claim 5, wherein the silicone-containing prepolymer is at least one member selected from the group consisting of a prepolymer with at least one ethylenically unsaturated group, a prepolymer with two or more thiol groups, a prepolymer with at least one ene-group;

wherein the silicone-containing macromer is at least one member selected from the group consisting of a macromer with at least one ethylenically unsaturated group, a macromer with two or more thiol groups,.a macromer with at least one ene-group;

wherein the silicone-containing monomer is at least one member selected from the group consisting of a monomer with one ethylenically unsaturated group, a monomer with two thiol groups, a monomer with one ene-group;

wherein the ene-group is defined by any one of formula (I)-(III)

8. The method of claim 5, wherein the stabilizer is a polyionic material, a polyvinylpyrrolidone, a copolymer of n-vinylpyrrolidone with one ore more vinylic monomers, or mixture thereof.

9. The method of claim 5, wherein the stabilizer is an acrylic acid, polyacrylic acid, poly(ethyleneimine), polyvinylpyrrolidone of a molecular weight of up to 1,500,000, a copolymer of a molecular weight of up to 1,500,000 of vinylpyrrolidone with one or more vinylic monomer, a polyionic material having amino groups and/or sulfur-containing groups or mixture thereof.

10. A antimicrobial ophthalmic device, comprising:

a polymer matrix, wherein the polymer matrix includes a polysiloxane unit;

chloride-treated Ag-nanoparticles distributed therein; and

a dye or pigment distributed therein, provided that the medical device is substantially free of the yellowish color of Ag-nanoparticles,

wherein the ophthalmic device has a oxygen permeability (D_k) of greater than about 40 barrers, an ion permeability characterized by an ionoflux diffusion coefficient of great than about 1.0×

10⁴ mm²/min, and a water content of at least 15 weight percent when fully hydrated,

wherein the antimicrobial medical device exhibit at least a 5-fold reduction (≧

80% inhibition) of viable microorganisms.

11. The antimicrobial ophthalmic device of claim 10, wherein the polymer matrix is a polymerization product of a polymerizable composition including the chloride-treated Ag-nanoparticles and a silicone-containing monomer or macromer or prepolymer.

12. The antimicrobial ophthalmic device of claim 11, wherein the silicone-containing prepolymer is at least one member selected from the group consisting of a prepolymer with at least one ethylenically unsaturated group, a prepolymer with two or more thiol groups, a prepolymer with at least one ene-group;

wherein the silicone-containing macromer is at least one member selected from the group consisting of a macromer with at least one ethylenically unsaturated group, a macromer with two or more thiol groups, a macromer with at least one ene-group;

wherein the silicone-containing monomer is at least one member selected from the group consisting of a monomer with one ethylenically unsaturated group, a monomer with two thiol groups, a monomer with one ene-group;

wherein the ene-group is defined by any one of formula (I)-(III)

13. The ophthalmic device of claim 11, wherein the polymerizable composition comprises a vinylic monomer capable of reducing silver cations, wherein the vinylic monomer is selected from the group consisting of acrylamide, methacrylamide, di(lower alkyl)acrylamides, di(lower alkyl)methacrylamides, (lower allyl)acrylamides, (lower allyl)methacrylamides, hydroxyl-substituted (lower alkyl)acrylamides, hydroxyl-substituted (lower alkyl)methacrylamides, and N-vinyl lactams.

14. The ophthalmic device of claim 13, wherein the vinylic monomer is N,N-dimethylacrylamide (DMA) or N-vinyl-2-pyrrolidone (NVP).