U.S. patent application number 13/847164 was filed with the patent office on 2013-08-29 for antimicrobial medical devices.
The applicant listed for this patent is NOVARTIS AG. Invention is credited to Manal M. Gabriel, John Martin Lally, Xinming Qian, Yongxing Qiu.
Application Number | 20130224309 13/847164 |
Document ID | / |
Family ID | 34135082 |
Filed Date | 2013-08-29 |
United States Patent
Application |
20130224309 |
Kind Code |
A1 |
Qiu; Yongxing ; et
al. |
August 29, 2013 |
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.
Inventors: |
Qiu; Yongxing; (Duluth,
GA) ; Lally; John Martin; (Bendbrook, TX) ;
Gabriel; Manal M.; (Marietta, GA) ; Qian;
Xinming; (Alpharetta, GA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NOVARTIS AG; |
|
|
US |
|
|
Family ID: |
34135082 |
Appl. No.: |
13/847164 |
Filed: |
March 19, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10891407 |
Jul 14, 2004 |
8425926 |
|
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13847164 |
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60487780 |
Jul 16, 2003 |
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Current U.S.
Class: |
424/618 |
Current CPC
Class: |
A61L 2300/442 20130101;
B29D 11/00038 20130101; A61L 2300/104 20130101; A61L 2300/404
20130101; A61L 27/54 20130101; A61L 2300/624 20130101; B82Y 30/00
20130101; A01N 59/16 20130101; G02B 1/043 20130101; A61L 12/088
20130101 |
Class at
Publication: |
424/618 |
International
Class: |
G02B 1/04 20060101
G02B001/04; A01N 59/16 20060101 A01N059/16 |
Claims
1-32. (canceled)
33. An antimicrobial ophthalmic device, comprising: a polymer
matrix, silver-nanoparticles distributed therein and at least one
dye and/or pigment distributed therein, wherein the polymer matrix
includes a polysiloxane unit, has a high oxygen permeability
characterized by a D.sub.k greater than 60 barrers and a high ion
permeability characterized by an ionoflux diffusion coefficient of
great than 6.0.times.10.sup.-4 mm.sup.2/min, and comprises a water
content of at least 15 weight percent when fully hydrated, wherein
the antimicrobial medical device exhibit at least a 5-fold
reduction (.gtoreq.80% inhibition) of viable microorganisms, and
wherein the dye and/or pigment, in combination with the color of
the silver nano-particle, provides a desired color.
34. The antimicrobial ophthalmic device of claim 33, wherein the
polymer matrix is a polymerization product of a polymerizable
composition including a siloxane-containing macromer, a
siloxane-containing monomer, and a hydrophilic monomer.
35. The antimicrobial ophthalmic device of claim 34, 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:
Pi
--(Y).sub.m-(L-X.sub.1).sub.p-Q-(X.sub.1-L).sub.p-(Y).sub.m--P.sub.1
where each P.sub.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.sub.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).sub.k-Z-CF.sub.2--(OCF.sub.2).sub.x--(OCF.sub.2CF.sub.2).sub.y--OCF.-
sub.2--Z-(E).sub.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.sub.2CH.sub.2).sub.q--, where q has a
value of from 0 to 2, and where the link --Z-E- represents the
sequence --Z--(OCH.sub.2CH.sub.2).sub.q--; and k is 0 or 1; (b)
##STR00011## wherein is an integer from 5 to 100; Alk is alkylene
having up to 20 carbon atoms; 80-100% of the radicals R.sub.1,
R.sub.2, R.sub.3 and R.sub.4, independently of one another, are
alkyl and 0-20% of the radicals R.sub.1, R.sub.2, R.sub.3 and
R.sub.4, independently of one another, are alkenyl, aryl or
cyanoalkyl; and (c) X.sub.2--R--X.sub.2, where R is a divalent
organic radical having up to 20 carbon atoms, and each X.sub.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): ##STR00012## 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.sub.1; (c) is
defined as X.sub.2--R--X.sub.2, wherein R is a bivalent radical of
an organic compound having up to 20 carbon atoms and each X.sub.2
independently of the other is a bivalent radical which contains at
least one carbonyl group; X.sub.1 is defined as X.sub.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.sub.3-L-(Y).sub.k--P.sub.1 (II) in
which P.sub.1 is alkenyl, alkenylaryl or alkenylarylenealkyl having
up to 20 carbon atoms; Y and X.sub.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):
##STR00013## in which n is an integer from 5 to 500; 99.8-25% of
the radicals R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and
R.sub.6 independently of one another are alkyl and 0.2-75% of the
radicals R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6
independently of one another are partly fluorinated alkyl,
aminoalkyl, alkenyl, aryl, cyanoalkyl, alk-NH-alk-NH.sub.2 or
alk-(OCH.sub.2).sub.m--(OCH.sub.2).sub.p--OR.sub.7, R.sub.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.sub.2CH.sub.2).sub.m and
--(OCH.sub.2).sub.p in formula (III) are either distributed
randomly in a ligand
alk-(OCH.sub.2CH.sub.2).sub.m--(OCH.sub.2).sub.p--OR.sub.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.sub.1--O--R.sub.2 or R.sub.3--O--R.sub.4, R.sub.1, R.sub.2,
R.sub.3, and R.sub.4, independently of one another, are lower
alkylene; and PDAS is a poly(dialkylsiloxane) having a segment of
the formula: ##STR00014## in which n is an integer from about 5 to
about 500; and R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are,
independently of one another, are lower alkyl.
36. The ophthalmic device of claim 34, wherein the concentration of
the siloxane-containing macromer is about 20 to 40 weight percent,
wherein the concentration of the siloxane-containing monomer is
about 5 to 30 weight percent, and wherein the concentration of the
hydrophilic monomer is about 10 to 35 weight percent.
37. The ophthalmic device of claim 36, 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.
38. The ophthalmic device of claim 34, 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.
39. The ophthalmic device of claim 38, wherein the vinylic monomer
is N,N-dimethylacrylamide (DMA) or N-vinyl-2-pyrrolidone (NVP).
40. The ophthalmic device of claim 34, wherein the polymerizable
composition comprises a stabilizer for stabilizing silver
nano-particles.
41. The ophthalmic device of claim 40, 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.
42. The ophthalmic device of claim 34, wherein the polymerizable
composition comprises a pigment.
43. The ophthalmic device of claim 42, wherein the pigment is
phthalocyanine blue, cobalt blue, Toner cyan BG, Permajet blue B2G,
phthalocyanine green, chromium sesquioxide; various iron oxides,
and carbazole violet.
Description
[0001] This application claims the benefit under 35 USC .sctn.119
(e) of U.S. provisional application No. 60/487,780 filed Jul. 16,
2003, incorporated by reference in its entirety.
[0002] The present invention generally relates to methods for
making an antimicrobial medical device having silver nano-particles
distributed therein and to an antimicrobial medical device made
therefrom.
BACKGROUND
[0003] Contact lenses are often exposed to one or more
microorganisms during wear, storage and handling. They can provide
surfaces onto which the microorganisms can adhere and then
proliferate to form a colony. Microbial adherence to and
colonization of contact lenses may enable microorganisms to
proliferate and to be retained on the ocular surface for prolonged
periods and thereby may cause infection or other deleterious
effects on the ocular health of the eye in which the lens is used.
Therefore, it is desirous to make various efforts to minimize
and/or eliminate the potential for microorganism adhesion to and
colonization of contact lenses.
[0004] Many attempts have been made to develop antimicrobial
medical devices. Two approaches have been proposed. One approach is
to incorporate antimicrobial compounds into a polymeric composition
for molding a contact lens. For example, Chalkley et al. in Am. J.
Ophthalmology 1966, 61:866-869, disclosed that germicidal agents
were incorporated into contact lenses. U.S. Pat. No. 4,472,327
discloses that antimicrobial agents may be added to the monomer
before polymerization and locked into the polymeric structure of
the lens. U.S. Pat. Nos. 5,358,688 and 5,536,861 disclose that
contact lenses having antimicrobial properties may be made from
quaternary ammonium group containing organosilicone polymers.
European patent application EP0604369 discloses that
deposit-resistant contact lenses can be prepared from hydrophilic
copolymers that are based on 2-hydroxyethyl methacrylate and
comonomers containing a quaternary ammonium moiety. Another example
is an ocular lens material, disclosed in European patent
application EP0947856A2, which comprises a quaternary phosphonium
group-containing polymer. A further example is U.S. Pat. No.
5,515,117 which discloses contact lenses and contact lens cases
made from materials which comprise polymeric materials and
effective antimicrobial components. A still further example is U.S.
Pat. No. 5,213,801 which discloses contact lenses made from
materials comprising a hydrogel and an antimicrobial ceramic
containing at least one metal selected from Ag, Cu and Zn.
[0005] The other approach for making antimicrobial medical devices
is to form antimicrobial coatings, containing leachable or
covalently attached antimicrobial agents, on medical devices.
Antimicrobial coatings containing leachable antimicrobial agents
may not be able to provide antimicrobial activity over the period
of time when used in the area of the human body. In contrast,
antimicrobial coating containing covalently bound antimicrobial
agents can provide antimicrobial activity over a relatively longer
period of time. However, antimicrobial compounds in such coatings
may exhibit diminished activity when comparing the activity of the
unbound corresponding antimicrobial compounds in solution, unless
assisted by hydrolytic breakdown of either the bound antimicrobial
compounds or the coating itself. Like the above-described approach,
the antimicrobial coating may not be able to provide desired
surface properties such as hydrophilicity and/or lubricity and also
may have adverse effects on the desired bulk properties of a
medical device (for example, the oxygen permeability of a contact
lens).
[0006] Currently, a wide variety of antimicrobial agents have been
proposed to be used as coatings for contact lenses (see, for
example, U.S. Pat. No. 5,328,954). Prior known antimicrobial
coatings include antibiotics, lactoferrin, metal chelating agents,
substituted and unsubstituted polyhydric phenols, amino phenols,
alcohols, acid and amine derivatives, and quaternary ammonium
group-containing compounds. However, such antimicrobial coatings
have disadvantages and are unsatisfactory. The overuse of
antibiotics can lead to proliferation of antibiotic-resistant
microorganisms. Other coatings may not have broad spectrum
antimicrobial activity, may produce ocular toxicity or allergic
reactions, or may adversely affect lens properties required for
ensuring corneal health and for providing the patient with good
vision and comfort.
[0007] In spite of the forgoing efforts, there is no commercially
viable contact lenses, especially extended-wear contact lenses,
which exhibit antimicrobial activities over a long period of time.
Therefore, there is still a need for the development of new contact
lenses which have high bactericidal efficacy, a broad spectrum of
antimicrobial activities, and minimal adverse effects on the
wearer's ocular health and comfort. There is also a need for
contact lenses which have high bactericidal efficacy, a broad
spectrum of antimicrobial activities, and minimal adverse effects
on the wearer's ocular health and comfort over a relatively long
period of wearing time. Such contact lenses may have increased
safety as extended-wear contact lenses which could provide comfort,
convenience, and safety.
[0008] One object of the invention is to provide a method for
making an antimicrobial ophthalmic device which has a relatively
high antimicrobial activity over a long period of time when being
used, coupled with high oxygen permeability and ion
permeability.
[0009] Another object of the invention is to provide a
cost-effective and efficient process for making an antimicrobial
ophthalmic device which has a relatively high antimicrobial
activity over a long period of time when being used, coupled with
high oxygen permeability and ion permeability.
[0010] A further object of the invention is to provide a
cost-effective and efficient process for forming an antimicrobial
coating on a medical device. an antimicrobial ophthalmic device
which has a relatively high antimicrobial activity over a long
period of time when being used, a high oxygen permeability and a
high ion permeability.
SUMMARY OF THE INVENTION
[0011] These and other objects of the invention are met by the
various aspects of the invention described herein.
[0012] The invention, in one aspect, provides a method for making
an antimicrobial medical device, preferably an antimicrobial
ophthalmic device, more preferably an antimicrobial contact lens,
even more preferably an antimicrobial extended wear lens. The
method comprises the steps of: obtaining a polymerizable fluid
composition comprising a siloxane-containing macromer and a vinylic
monomer capable of reducing silver cations; forming a polymerizable
dispersion comprising silver nanoparticles and having a stability
of at least about 60 minutes, wherein the silver nanoparticles are
obtained by adding a desired amount of a soluble silver salt into
the fluid composition; 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.
[0013] The invention, in another aspect, provides a method for
making an antimicrobial medical device, preferably an antimicrobial
ophthalmic device, more preferably an antimicrobial contact lens,
even more preferably an antimicrobial extended wear lens. The
method comprises the steps of: obtaining a polymerizable fluid
composition comprising a siloxane-containing macromer and a soluble
silver salt; forming a polymerizable dispersion comprising silver
nanoparticles and having a stability of at least about 60 minutes,
wherein the silver nanoparticles are obtained by adding into the
fluid composition at least one biocompatible reducing agent;
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.
[0014] The invention, in still another aspect, provides a method
for making an antimicrobial medical device, preferably an
antimicrobial ophthalmic device, more preferably an antimicrobial
contact lens, even more preferably an antimicrobial extended wear
lens. The method comprises the steps of: obtaining a
stabilized-silver nano-particle solution or lyophilized
stabilized-silver nano-particles; directly dispersing a desired
amount of the stabilized-silver nano-particle solution or the
lyophilized stabilized-silver nano-particles in a polymerizable
fluid composition comprising a siloxane-containing macromer to form
a polymerizable dispersion having a stability of at least about 60
minutes; 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.
[0015] The invention, in a further aspect, provides an
antimicrobial medical device, preferably an antimicrobial
ophthalmic device, more preferably an antimicrobial contact lens,
even more preferably an antimicrobial extended-wear contact lens.
The antimicrobial medical device of the invention comprises a
polymer matrix and silver nano-particles distributed therein in a
substantially uniform manner, wherein the polymer matrix includes a
polysiloxane unit, has a high oxygen permeability characterized by
a D.sub.k greater than 60 barrers and a high ion permeability
characterized by an ionoflux diffusion coefficient of great than
6.0.times.10.sup.-4 mm.sup.2/min, and comprises a water content of
at least 15 weight percent when fully hydrated, and wherein the
antimicrobial medical device exhibit at least a 5-fold reduction
(.gtoreq.80% inhibition), preferably at least a 1-log reduction
(.gtoreq.90% inhibition), more preferably at least a 2-log
reduction (.gtoreq.99% inhibition), of viable microorganisms.
[0016] The invention, in a still further aspect, provide an
antimicrobial extended wear contact lens. The antimicrobial
extended wear contact lens of the invention comprises a polymer
matrix and silver nano-particles distributed therein in a
substantially uniform manner, wherein the polymer matrix includes a
polysiloxane unit, has a high oxygen permeability characterized by
a D.sub.k greater than 60 barrers and a high ion permeability
characterized by an ionoflux diffusion coefficient of great than
6.0.times.10.sup.-4 mm.sup.2/min, and comprises a water content of
at least 15 weight percent when fully hydrated, and wherein the
antimicrobial medical device exhibit at least a 5-fold reduction
(.gtoreq.80% inhibition), preferably at least a 1-log reduction
(.gtoreq.90% inhibition), more preferably at least a 2-log
reduction (.gtoreq.99% inhibition), of viable microorganisms, over
a period of at least 7 days, preferably at least 14 days, even more
preferably at least 30 days.
[0017] These and other aspects of the invention will become
apparent from the following description of the presently preferred
embodiments. The detailed description is merely illustrative of the
invention and does not limit the scope of the invention, which is
defined by the appended claims and equivalents thereof. As would be
obvious to one skilled in the art, many variations and
modifications of the invention may be effected without departing
from the spirit and scope of the novel concepts of the
disclosure.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0018] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs.
Generally, the nomenclature used herein and the laboratory
procedures are well known and commonly employed in the art.
Conventional methods are used for these procedures, such as those
provided in the art and various general references. Where a term is
provided in the singular, the inventors also contemplate the plural
of that term. The nomenclature used herein and the laboratory
procedures described below are those well known and commonly
employed in the art. As employed throughout the disclosure, the
following terms, unless otherwise indicated, shall be understood to
have the following meanings.
[0019] A "medical device", as used herein, refers to a device or a
part thereof having one or more surfaces that contact tissue,
blood, or other bodily fluids of patients in the course of their
operation or utility. Exemplary medical devices include: (1)
extracorporeal devices for use in surgery such as blood
oxygenators, blood pumps, blood sensors, tubing used to carry blood
and the like which contact blood which is then returned to the
patient; (2) prostheses implanted in a human or animal body such as
vascular grafts, stents, pacemaker leads, heart valves, and the
like that are implanted in blood vessels or in the heart; (3)
devices for temporary intravascular use such as catheters, guide
wires, and the like which are placed into blood vessels or the
heart for purposes of monitoring or repair; (4) artificial tissues
such as artificial skin for burn patients; (5) dentifices, dental
moldings; (6) ophthalmic devices; and (7) cases or containers for
storing ophthalmic devices or ophthalmic solutions.
[0020] An "ophthalmic device", as used herein, refers to a contact
lens (hard or soft), an intraocular lens, a corneal onlay, other
ophthalmic devices (e.g., stents, glaucoma shunt, or the like) used
on or about the eye or ocular vicinity.
[0021] "Biocompatible", as used herein, refers to a material or
surface of a material, which may be in intimate contact with
tissue, blood, or other bodily fluids of a patient for an extended
period of time without significantly damaging the ocular
environment and without significant user discomfort.
[0022] "Ophthalmically compatible", as used herein, refers to a
material or surface of a material which may be in intimate contact
with the ocular environment for an extended period of time without
significantly damaging the ocular environment and without
significant user discomfort. Thus, an ophthalmically compatible
contact lens will not produce significant corneal swelling, will
adequately move on the eye with blinking to promote adequate tear
exchange, will not have substantial amounts of protein or lipid
adsorption, and will not cause substantial wearer discomfort during
the prescribed period of wear.
[0023] "Ocular environment", as used herein, refers to ocular
fluids (e.g., tear fluid) and ocular tissue (e.g., the cornea)
which may come into intimate contact with a contact lens used for
vision correction, drug delivery, wound healing, eye color
modification, or other ophthalmic applications.
[0024] A "hydrogel" refers to a polymeric material which can absorb
at least 10 percent by weight of water when it is fully hydrated.
Generally, a hydrogel material is obtained by polymerization or
copolymerization of at least one hydrophilic monomer in the
presence of or in the absence of additional monomers and/or
macromers.
[0025] A "silicone hydrogel" refers to a hydrogel obtained by
copolymerization of a polymerizable composition comprising at least
one silicone-containing vinylic monomer or at least one
silicone-containing macromer.
[0026] "Hydrophilic," as used herein, describes a material or
portion thereof that will more readily associate with water than
with lipids.
[0027] The term "fluid" as used herein indicates that a material is
capable of flowing like a liquid.
[0028] A "monomer" means a low molecular weight compound that can
be polymerized actinically or thermally or chemically. Low
molecular weight typically means average molecular weights less
than 700 Daltons.
[0029] As used herein, "actinically" in reference to curing or
polymerizing of a polymerizable composition or material or a
lens-forming material means that the curing (e.g., crosslinked
and/or polymerized) is performed by actinic irradiation, such as,
for example, UV irradiation, ionized radiation (e.g. gamma ray or
X-ray irradiation), microwave irradiation, and the like. Thermal
curing or actinic curing methods are well-known to a person skilled
in the art. Lens-forming materials are well known to a person
skilled in the art.
[0030] A "vinylic monomer", as used herein, refers to a low
molecular weight compound that has an ethylenically unsaturated
group and can be polymerized actinically or thermally. Low
molecular weight typically means average molecular weights less
than 700 Daltons.
[0031] The term "olefinically unsaturated group" is employed herein
in a broad sense and is intended to encompass any groups containing
at least one >C.dbd.C< group. Exemplary ethylenically
unsaturated groups include without limitation acryloyl,
methacryloyl, allyl, vinyl, styrenyl, or other C.dbd.C containing
groups.
[0032] A "hydrophilic vinylic monomer", as used herein, refers to a
vinylic monomer which is capable of forming a homopolymer that can
absorb at least 10 percent by weight water when fully hydrated.
[0033] A "hydrophobic vinylic monomer", as used herein, refers to a
vinylic monomer which is capable of forming a homopolymer that can
absorb less than 10 percent by weight water.
[0034] A "macromer" refers to a medium to high molecular weight
compound or polymer that contains functional groups capable of
undergoing further polymerizing/crosslinking reactions. Medium and
high molecular weight typically means average molecular weights
greater than 700 Daltons. Preferably, a macromer contains
ethylenically unsaturated groups and can be polymerized actinically
or thermally.
[0035] "Molecular weight" of a polymeric material (including
monomeric or macromeric materials), as used herein, refers to the
number-average molecular weight unless otherwise specifically noted
or unless testing conditions indicate otherwise.
[0036] A "polymer" means a material formed by
polymerizing/crosslinking one or more monomers, macromers and or
oligomers.
[0037] A "prepolymer" refers to a starting polymer which can be
cured (e.g., crosslinked and/or polymerized) actinically or
thermally or chemically to obtain a crosslinked and/or polymerized
polymer having a molecular weight much higher than the starting
polymer. A "crosslinkable prepolymer" refers to a starting polymer
which can be crosslinked upon actinic radiation to obtain a
crosslinked polymer having a molecular weight much higher than the
starting polymer.
[0038] "Surface modification", as used herein, means that an
article has been treated in a surface treatment process (or a
surface modification process), in which, by means of contact with a
vapor or liquid, and/or by means of application of an energy source
(1) a coating is applied to the surface of an article, (2) chemical
species are adsorbed onto the surface of an article, (3) the
chemical nature (e.g., electrostatic charge) of chemical groups on
the surface of an article are altered, or (4) the surface
properties of an article are otherwise modified. Exemplary surface
treatment processes include, but are not limited to, a surface
treatment by energy (e.g., a plasma, a static electrical charge,
irradiation, or other energy source), chemical treatments, the
grafting of hydrophilic monomers or macromers onto the surface of
an article, and layer-by-layer deposition of polyelectrolytes. A
preferred class of surface treatment processes are plasma
processes, in which an ionized gas is applied to the surface of an
article. Plasma gases and processing conditions are described more
fully in U.S. Pat. Nos. 4,312,575 and 4,632,844, which are
incorporated herein by reference. The plasma gas is preferably a
mixture of lower alkanes and nitrogen, oxygen or an inert gas.
[0039] "LbL coating", as used herein, refers to a coating that is
not covalently attached to an article, preferably a medical device,
and is obtained through a layer-by-layer ("LbL") deposition of
polyionic (or charged) and/or non-charged materials on an article.
An LbL coating can be composed of one or more layers, preferably
one or more bilayers.
[0040] The term "bilayer" is employed herein in a broad sense and
is intended to encompass: a coating structure formed on a medical
device by alternatively applying, in no particular order, one layer
of a first polyionic material (or charged material) and
subsequently one layer of a second polyionic material (or charged
material) having charges opposite of the charges of the first
polyionic material (or the charged material); or a coating
structure formed on a medical device by alternatively applying, in
no particular order, one layer of a first charged polymeric
material and one layer of a non-charged polymeric material or a
second charged polymeric material. It should be understood that the
layers of the first and second coating materials (described above)
may be intertwined with each other in the bilayer.
[0041] Formation of an LbL coating on a medical device, in
particular, an ophthalmic device, may be accomplished in a number
of ways, for example, as described in commonly-owned U.S. Pat. No.
6,451,871 (herein incorporated by reference in its entirety) and
commonly-owned pending U.S. patent applications (application Ser.
Nos. 09/774,942, 09/775,104, 10/654,566), herein incorporated by
reference in their entireties. One coating process embodiment
involves solely dip-coating and dip-rinsing steps. Another coating
process embodiment involves solely spray-coating and spray-rinsing
steps. However, a number of alternatives involve various
combinations of spray- and dip-coating and rinsing steps may be
designed by a person having ordinary skill in the art.
[0042] A medical device having a core material and an LbL coating,
which comprises at least one layer of a charged polymeric material
and one layer of a non-charged polymeric material that can be
non-covalently bonded to the charged polymeric material, can be
prepared according to a method disclosed in a co-pending U.S.
application, U.S. Ser. No. 10/654,566, entitled "LbL-COATED MEDICAL
DEVICE AND METHOD FOR MAKING THE SAME", filed on Sep. 11, 2002,
herein incorporated by reference in its entirety.
[0043] A "polyquat", as used herein, refers to a polymeric
quaternary ammonium group-containing compound.
[0044] As used herein, a "polyionic material" refers to a polymeric
material that has a plurality of charged groups, such as
polyelectrolytes, p- and n-type doped conducting polymers.
Polyionic materials include both polycationic (having positive
charges) and polyanionic (having negative charges) materials.
[0045] An "antimicrobial medical device", as used herein, refers to
a medical device that exhibit at least a 5-fold reduction
(.gtoreq.80% inhibition), preferably at least a 1-log reduction
(.gtoreq.90% inhibition), more preferably at least a 2-log
reduction (.gtoreq.99% inhibition), of viable microorganisms.
[0046] An "antimicrobial agent", as used herein, refers to a
chemical that is capable of decreasing or eliminating or inhibiting
the growth of microorganisms such as that term is known in the
art.
[0047] "Antimicrobial metals" are metals whose ions have an
antimicrobial effect and which are biocompatible. Preferred
antimicrobial metals include Ag, Au, Pt, Pd, Ir, Sn, Cu, Sb, Bi and
Zn, with Ag being most preferred.
[0048] "Silver nanoparticles" refer to particles which is made
essentially of silver (Ag) and have a size of less than 1
micrometer. Silver nanoparticles contain silver in Ag.sup.0
oxidation state and optionally in Ag.sup.1+ and/or Ag.sup.2+
oxidation states. The formation of silver nano-particles in a
solution or lens-forming formulation can be confirmed by UV
spectroscopy with an absorption peak located in a wavelength range
from about 390 nm to about 450 nm, a characteristic of silver
nano-particles.
[0049] "Antimicrobial metal-containing nanoparticles" refer to
particles having a size of less than 1 micrometer and containing at
least one antimicrobial metal present in one or more of its
oxidation states.
[0050] "Antimicrobial metal nanoparticles" refer to particles which
is made essentially of an antimicrobial metal and have a size of
less than 1 micrometer. The antimicrobial metal in the
antimicrobial metal nanoparticles can be present in one or more of
its oxidation states.
[0051] "Stabilized antimicrobial metal nanoparticles" refer to
antimicrobial metal nanoparticles (e.g., silver nanoparticles)
which are stabilized by a stabilizer during their preparation or in
an LbL coating procedure after their preparation. Stabilized
antimicrobial metal nano-particles can be either positively charged
or negatively charged or neutral, largely depending on a material
(or so-called stabilizer) which is present in a solution for
preparing the nano-particles or for coating the nano-particles in a
layer-by-layer (LbL) coating process and can stabilize the
resultant nano-particles. A stabilizer can be any known suitable
material. Exemplary stabilizers include, without limitation,
positively charged polyionic materials, negatively charged
polyionic materials, polymers, surfactants, acrylic acid, salicylic
acid, alcohols and the like.
[0052] Formation of an LbL coating on nano-particles may be
accomplished by contacting dry or wet nano-particles with one or
more coating solution of a stabilizer, for example, as described in
commonly-owned U.S. Pat. No. 6,451,871 (herein incorporated by
reference in its entirety) and commonly-owned pending U.S. patent
applications (application Ser. Nos. 09/774,942, 09/775,104,
10/654,566, 60/530,959), herein incorporated by reference in their
entireties. For example, nano-particles can be stabilized in a
coating process, which comprises (1) applying a coating of one or
more polyionic materials onto the surfaces of nano-particles by
contacting the nano-particles with a solution of the one or more
polyionic materials; filtering the solution with nano-particles,
optionally washing the filtered nano-particles; and optionally
drying the filtered nano-particles coated with the one or more
polyionic materials.
[0053] "Visibility tinting" in reference to a lens means dying (or
coloring) of a lens to enable the user to easily locate a lens in a
clear solution within a lens storage, disinfecting or cleaning
container. It is well known in the art that a dye and/or a pigment
can be used in visibility tinting a lens.
[0054] "Dye" means a substance that is soluble in a solvent and
that is used to impart color. Dyes are typically translucent and
absorb but do not scatter light. Any suitable biocompatible dye can
be used in the present invention.
[0055] A "Pigment" means a powdered substance that is suspended in
a liquid in which it is insoluble. A pigment can be a fluorescent
pigment, phosphorescent pigment, pearlescent pigment, or
conventional pigment. While any suitable pigment may be employed,
it is presently preferred that the pigment be heat resistant,
non-toxic and insoluble in aqueous solutions.
[0056] The "oxygen transmissibility" of a lens, as used herein, is
the rate at which oxygen will pass through a specific ophthalmic
lens. Oxygen transmissibility, Dk/t, is conventionally expressed in
units of barrers/mm, where t is the average thickness of the
material [in units of mm] over the area being measured and
"barrer/mm" is defined as:
[(cm.sup.3 oxygen)/(cm.sup.2)(sec)(mm.sup.2
Hg)].times.10.sup.-9
[0057] The intrinsic "oxygen permeability", Dk, of a lens material
does not depend on lens thickness. Intrinsic oxygen permeability is
the rate at which oxygen will pass through a material. Oxygen
permeability is conventionally expressed in units of barrers, where
"barrer" is defined as:
[(cm.sup.3 oxygen)(mm)/(cm.sup.2)(sec)(mm.sup.2
Hg)].times.10.sup.-10
These are the units commonly used in the art. Thus, in order to be
consistent with the use in the art, the unit "barrer" will have the
meanings as defined above. For example, a lens having a Dk of 90
barrers ("oxygen permeability barrers") and a thickness of 90
microns (0.090 mm) would have a Dk/t of 100 barrers/mm (oxygen
transmissibility barrers/mm).
[0058] The cornea receives oxygen primarily from the corneal
surface which is exposed to the environment, in contrast to other
tissues which receives oxygen from blood flow. Thus, an ophthalmic
lens which may be worn on the eye for extended periods of time must
allow sufficient oxygen to permeate through the lens to the cornea
to sustain corneal health. One result of the cornea receiving an
inadequate amount of oxygen is that the cornea will swell.
Therefore, the oxygen transmissibility of an extended-wear lens
from the outer surface to the inner surface must be sufficient to
prevent any substantial corneal swelling during the period of
extended wear. It is known that the cornea swells approximately 3%
to 4% during overnight periods of sleep when the eyelids are
closed, as a result of oxygen deprivation. It is also known that
wearing a typical contact lens, such as ACUVUE (Johnson &
Johnson), for a period of about 8 hours (overnight wear) causes
corneal swelling of about 11%. However, a preferred extended-wear
contact lens will produce, after wear of about 24 hours, including
normal sleep periods, corneal swelling of less than about 8%, more
preferably less than about 6%, and most preferably less than about
4%. A preferred extended-wear contact lens will produce, after wear
of about 7 days, including normal sleep periods, corneal swelling
of less than about 10%, more preferably less than about 7%, and
most preferably less than about 5%.
[0059] The oxygen permeability of a lens and oxygen
transmissibility of a lens material may be determined by the method
disclosed by Nicolson et al. (U.S. Pat. No. 5,760,100), herein
incorporated by reference in its entirety. In accordance with the
invention, a high oxygen permeability in reference to a material or
an ophthalmic device characterized by having an apparent (directly
measured) oxygen permeability of at least 60 barrers or larger
measured (preferably with a sample (film or lens) of 100 microns in
thickness) according to a coulometric method described in
Examples.
[0060] The "ion permeability" through a lens correlates with both
the Ionoflux Diffusion Coefficient and the Ionoton Ion Permeability
Coefficient.
[0061] The Ionoflux Diffusion Coefficient, D, is determined by
applying Fick's law as follows:
D=-n'/(A.times.dc/dx)
where
[0062] n'=rate of ion transport [mol/min]
[0063] A=area of lens exposed [mm.sup.2]
[0064] D=Ionoflux Diffusion Coefficient [mm.sup.2/min]
[0065] dc=concentration difference [mol/L]
[0066] dx=thickness of lens [mm]
[0067] The Ionoton Ion Permeability Coefficient, P, is then
determined in accordance with the following equation:
ln(1-2C(t)/C(O))=-2APt/Vd
where:
[0068] C(t)=concentration of sodium ions at time t in the receiving
cell
[0069] C(0)=initial concentration of sodium ions in donor cell
[0070] A=membrane area, i.e., lens area exposed to cells
[0071] V=volume of cell compartment (3.0 ml)
[0072] d=average lens thickness in the area exposed
[0073] P=permeability coefficient
[0074] An Ionoflux Diffusion Coefficient, D, of greater than about
0.2.times.10.sup.-3 mm.sup.2/min is preferred, while greater than
about 0.64.times.10.sup.-3 mm.sup.2/min is more preferred and
greater than about 1.0.times.10.sup.-3 mm.sup.2/min is most
preferred.
[0075] It is known that on-eye movement of the lens is required to
ensure good tear exchange, and ultimately, to ensure good corneal
health. Ion permeability is one of the predictors of on-eye
movement, because the permeability of ions is believed to be
directly proportional to the permeability of water.
[0076] It has been theorized by Nicolson et al. (U.S. Pat. No.
5,760,100), herein incorporated by reference in its entirety, that
water permeability is an exceptionally important feature for an
extended-wear lens which includes oxyperm polymers such as those
disclosed herein. Siloxane-containing materials having high oxygen
permeability and low water permeability tend to adhere strongly to
the eye, thereby stopping on-eye movement. The ability to pass
water through the lens is believed to allow a siloxane-containing
polymeric lens to move on the eye, where the movement occurs via
forces exerted by water being sqeezed out of the lens. The water
permeability of the lens is also believed important in replenishing
lens water content once pressure is removed.
[0077] Nicolson et al. (U.S. Pat. No. 5,760,100) also found that
above a certain threshhold of ion permeability through a lens, from
the inner surface of the lens to the outer, or vice versa, the lens
will move on the eye, and below the threshold the lens will adhere
to the eye. The ion permeability through a lens correlates with
both the Ionoflux Diffusion Coefficient and the Ionoton Ion
Permeability Coefficient.
[0078] The water permeability of a lens may be determined by the
Hydrodell Technique described by Nicolson et al. in U.S. Pat. No.
5,849,811. This technique may be used to determine the likelihood
of adequate on-eye movement.
[0079] The ophthalmic lenses of one embodiment of the present
invention have a Hydrodell Water Permeability Coefficient of
greater than about 0.2.times.10.sup.-6 cm.sup.2/min. The ophthalmic
lenses in a preferred embodiment of the invention have Hydrodell
Water Permeability Coefficient of greater than about
0.3.times.10.sup.-6 cm.sup.2/min. The ophthalmic lenses in a
preferred embodiment of the invention have Hydrodell Water
Permeability Coefficient of greater than about 0.4.times.10.sup.-6
cm.sup.2/min.
[0080] The water content of a lens can be measured according to
Bulk Technique as disclosed in U.S. Pat. No. 5,760,100, herein
incorporated by reference in its entirety. Preferably, the lens has
a water content of at least 20 weight percent when fully hydrated,
based on the total lens weight.
[0081] The present invention is generally directed to methods for
making an antimicrobial medical device having silver nano-particles
distributed uniformly therein and to an antimicrobial medical
device made therefrom. The present invention is partly based on the
discovery that silver nano-particles distributed in a medical
device can impart to the medical device an effective antimicrobial
capability over a long period of time. It is believed that silver
nano-particles can release, at an extremely slow rate, silver ions
which in turn can leach slowly out of a medical device and
therefore decrease or eliminate or inhibit the growth of
microorganisms. The present invention is also partly based on the
discovery that uniform incorporation of silver nano-particles in a
contact lens has a negligible adverse impact on the optical
properties of the contact lens. The present invention further is
partly based on the discovery that an antimicrobial medical device,
which has silver nano-particles incorporated and distributed
uniformly in the polymer matrix of the ophthalmic device to impart
antimicrobial capability without significantly adverse effects on
the desired bulk properties of the ophthalmic device, such as
oxygen permeability, ion or water permeability, can be produced
according to one of cost-effective and efficient processes
developed herein.
[0082] By using a process of the invention, one can prepare, in an
easy and non-intrusive manner, a polymerizable dispersion
containing silver nano-particles and having a stability of at least
about 60 minutes, preferably at least about 4 hours, more
preferably at least about 8 hours, even more preferably at least
about 15 hours. As used herein, the term "stability" in reference
to a dispersion means a period of time over which no observable
agglomeration and/or precipitation occurs in the dispersion. The
term "non-intrusive" in reference to a polymerizable dispersion
preparation means that during its preparation minimal or no
undesirable partial polymerization occurs in the prepared
polymerizable dispersion. Typically, vigoriously stirring and/or
sonication is used to disperse particles in a solution to form a
dispersion. However, when preparing a polymerizable dispersion for
making an ophthalmic device, such vigoriously stirring and
sonication, especially sonication for relatively extended period of
time, should be avoided to minimize or eliminate partial
polymerization.
[0083] There are several unique advantages associated with a method
of the invention.
[0084] First, according to a method of the invention, a
polymerizable dispersion containing siliver nano-particles can be
easily prepared from any lens formulation for making any contact
lenses with minimal modification of preparing procedure. Exemplary
lens formulations include without limitation the formulation of
nelfilcon, lotrafilcon A, lotrafilcon B, etafilcon A, genfilcon A,
lenefilcon A, polymacon, acquafilcon A, balafilcon, and the
like.
[0085] Second, one can prepare a silver nanoparticle-containing
polymerizable dispersion having any desired concentration of silver
nano-particles.
[0086] Third, because of its high stability, a silver
nanoparticle-containing polymerizable dispersion can be prepared in
well advance before production of contact lenses. Therefore, one
can have flexibility in production scheduling of lens
productions.
[0087] Fourth, because of its high stability, silver nano-particles
can be uniformly distributed in a contact lens. Unstable
polymerizable dispersion containing silver nanoparticles may not be
suitable for production of antimicrobial contact lenses comprising
siver nano-particles uniformly distributed therein.
[0088] By using a process of the invention, a prepared
antimicrobial medical device can have at least one of bulk
properties selected from the group consisting of: a high oxygen
permeability characterized by a D.sub.k greater than 60 barrers; a
high ion permeability characterized by an ionoflux diffusion
coefficient of great than 6.0.times.10.sup.-4 mm.sup.2/min; a water
content of at least 15 weight percent when fully hydrated; an
antimicrobial activity characterized by having at least a 5-fold
reduction (.gtoreq.80% inhibition), preferably at least a 1-log
reduction (.gtoreq.90% inhibition), more preferably at least a
2-log reduction (.gtoreq.99% inhibition), of viable microorganisms
(e.g., Pseudomonas aeruginosa GSU #3, or Staphylococcus aureus ATCC
#6538); a prolong antimicrobial activity (i.e., effective
antimicrobial activity after direct contact with a body fluid over
an extended period of time).
[0089] As used herein, a "prolong antimicrobial activity" is
characterized by having at least a 5-fold reduction (.gtoreq.80%
inhibition), preferably at least a 1-log reduction (.gtoreq.90%
inhibition), more preferably at least a 2-log reduction
(.gtoreq.99% inhibition), of viable microorganisms (e.g.,
Pseudomonas aeruginosa GSU #3, or Staphylococcus aureus ATCC #6538)
after at least 5, preferably at least 10, more preferably at least
20, even more preferably at least 30 consecutive soaking/rinsing
cycles, each cycle comprising soaking/rinsing one lens in a
phosphate buffered saline (PBS) for a period of time from about 24
to about 72 hours, as shown in Example.
[0090] The invention, in one aspect, provides a method for making
an antimicrobial medical device, preferably an antimicrobial
ophthalmic device, more preferably an antimicrobial contact lens,
even more preferably an antimicrobial extended wear lens. The
method comprises the steps of: obtaining a polymerizable fluid
composition comprising a siloxane-containing macromer and a vinylic
monomer capable of reducing silver cations; forming a polymerizable
dispersion comprising silver nanoparticles and having a stability
of at least about 60 minutes, preferably at least about 4 hours,
more preferably at least about 8 hours, even more preferably at
least about 15 hours, wherein the silver nanoparticles are obtained
by adding a desired amount of a soluble silver salt into the fluid
composition; 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.
[0091] In a preferred embodiment, the resultant antimicrobial
medical device comprises at least ppm, preferably at least 25 ppm,
more preferably at least 40 ppm, even more preferably at least 60
ppm silver nanoparticles.
[0092] In accordance with the present invention, a polymerizable
fluid composition can be a solution or a solvent-free liquid or
melt at a temperature below 60.degree. C.
[0093] In accordance with the present invention, a polymerizable
fluid composition can be any formulations for making soft contact
lenses. Exemplary formulations include without limitation the
formulation of lotrafilcon A, lotrafilcon B, etafilcon A, genfilcon
A, lenefilcon A, polymacon, acquafilcon A, and balafilcon.
[0094] Where a polymerizable fluid composition is a solution, it
can be prepared by dissolving at least one siloxane-containing
macromer and all other desired components in any suitable solvent
known to a person skilled in the art. Examples of suitable solvents
are water, alcohols, such as lower alkanols, for example ethanol or
methanol, and furthermore carboxylic acid amides, such as
dimethylformamide, dipolar aprotic solvents, such as dimethyl
sulfoxide or methyl ethyl ketone, ketones, for example acetone or
cyclohexanone, hydrocarbons, for example toluene, ethers, for
example THF, dimethoxyethane or dioxane, and halogenated
hydrocarbons, for example trichloroethane, and also mixtures of
suitable solvents, for example mixtures of water with an alcohol,
for example a water/ethanol or a water/methanol mixture.
[0095] In accordance with the present invention, any know suitable
siloxane-containing macromer can be used to prepare a polymerizable
fluid composition.
[0096] Preferably, the polymerizable fluid composition comprises a
siloxane-containing macromer selected from the group consisting of
Macromer A, Macromer B, Macromer C, and Macromer D.
Macromer A
[0097] Macromer A is a polysiloxane macromer having 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 said
macromer has a number-average molecular weight of 2000 to
10,000.
[0098] A preferred polysiloxane macromer segment is defined by the
formula
CP-PAO-DU-ALK-PDMS-ALK-DU-PAO-CP
where PDMS is a divalent poly(disubstituted siloxane); CP is an
isocyanatoalkyl acrylate or methacylate, preferably isocyanatoethyl
methacrylate, where the urethane group is bonded to the terminal
carbon on the PAO group; PAO is a divalent polyoxyalkylene (which
may be substituted), and is preferably a polyethylene oxide, i.e.,
(--CH.sub.2CH.sub.2--O--).sub.mCH.sub.2CH.sub.2-- where m may range
from about 3 to about 44, more preferably about 4 to about 24; DU
is a diurethane, preferably including a cyclic structure, where an
oxygen of the urethane linkage (1) is bonded to the PAO group and
an oxygen of the urethane linkage (2) is bonded to the ALK group;
and ALK is an alkylene or alkylenoxy group having at least 3 carbon
atoms, preferably a branched alkylene group or an alkylenoxy group
having 3 to 6 carbon atoms, and most preferably a sec-butyl (i.e.,
--CH.sub.2CH.sub.2CH(CH.sub.3)--) group or an ethoxypropoxy group
(e.g., --O--(CH.sub.2).sub.2--O--(CH.sub.2).sub.3--).
[0099] It will be noted that the DU group can be formed from a wide
variety of diisocyanates or triisocyanates, including aliphatic,
cycloaliphatic or aromatic polyisocyanates. These isocyanates
include, without limitation thereto, ethylene diisocyanate;
1,2-diisocyanatopropane; 1,3-diisocyanatopropane;
1,6-diisocyanatohexane; 1,2-diisocyanatocyclohexane;
1,3-diisocyanatocyclohexane; 1,4-diisocyanatobenzene,
bis(4-isocyanatocyclohexyl)methane;
bis(4-isocyanatocyclohexyl)methane; bis(4-isocyanatophenyl)methane;
1,2- and 1,4-toluene diisocyanate;
3,3-dichloro-4,4'-diisocyanatobiphenyl;
tris(4-isocyanatophenyl)methane; 1,5-diisocyanatonaphthalene;
hydrogenated toluene diisocyanate;
1-isocyanatomethyl-5-isocyanato-1,3,3-trimethylcyclohexane (i.e.,
isophorone diisocyanate); 1,3,5-tris(6-isocyanatohexyl)biuret;
1,6-diisocyanato-2,2,4-(2,4,4)-trimethylhexane;
2,2'-diisocyanatodiethyl fumarate;
1,5-diisocyanato-1-carboxypentane; 1,2-, 1,3-, 1,6-, 1,7-, 1,8-,
2,7- and 2,3-diisocyanatonaphthalene; 2,4- and
2,7-diisocyanato-1-methylnaphthalene;
1,4-diisocyanatomethylcyclohexane;
1,3-diisocyanato-6(7)-methylnaphthalene; 4,4'-diisocyanatobiphenyl;
4,4'-diisocyanato-3,3'-dimethoxybisphenyl; 3,3'- and
4,4'-diisocyanato-2,2'-dimethylbisphenyl;
bis(4-isocyanatophenyl)ethane; bis(4-isocyanatophenyl ether); 1,2-
or 1,4-toluene diisocyanate; and mixtures thereof. Preferably DU is
formed from isophorone diisocyanate or toluene diisocyanate, and
more preferably, isophorone diisocyanate, where one isomeric
diurethane structure of isophorone diisocyanate is defined
above.
[0100] A preferred polysiloxane macromer segment has the following
formula:
##STR00001##
wherein: R.sub.1 and R.sub.2 are selected from C.sub.1-C.sub.6
alkyl; R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are selected from
C.sub.1-C.sub.6 alkylene; R.sub.7 and R.sub.8 are selected from
linear or branched alkylene and bivalent cycloalkylene; R.sub.9,
R.sub.10, R.sub.11, and R.sub.12 are selected from C.sub.1-C.sub.2
alkylene; R.sub.13 and R.sub.14 are selected from C.sub.1-C.sub.6
alkylene; R.sub.15 and R.sub.16 are selected from linear or
branched lower alkenylene; m and p, independently of one another,
are about 3 to about 44; and n is about 13 to about 80, wherein
said macromer has a number-average molecular weight of 2000 to
10,000.
[0101] The polysiloxane macromer may be synthesized by the
following preferred process. At about room temperature (about
200-25.degree. C.), poly(dimethylsiloxane)dialkanol having
hydroxyalkyl (e.g., hydroxy-sec-butyl) or hydroxyalkoxy (e.g.,
hydroxyethylpropoxy) end groups and having a molecular weight of
about 2000 to 3000 preferably about 2200, i.e., having about 28
repeating siloxane groups) is reacted with isophorone diisocyanate
at about a 1:2 molar ratio, using about 0.2 weight percent (based
on polydimethylsiloxane)dibutyltin dilaurate added as a catalyst
The reaction is carried out for about 36 to 60 hours. To this
mixture is added poly(ethylene glycol) having a molecular weight of
about 400 to 1200 (more preferably about 500 to 700) at about a 2:1
or 2.1:1 molar ratio with respect to the PDMS, about 0.4 to 0.5
weight percent dibutyltin dilaurate (based on polyethylene glycol
weight), and chloroform sufficient to ensure substantial mixture
homogeneity. The mixture is agitated for about 12 to 18 hours, then
held at a temperature of about 44.degree. to 48.degree. C. for
about 6 to 10 hours. Excess chloroform is evaporated therefrom at
about room temperature to produce a composition having about 50
weight percent solids. Then, isocyanatoethyl methacrylate is added
to the mixture in about a 2:1 to 2.3:1 molar ratio with respect to
PDMS. The mixture is agitated at room temperature for about 15 to
20 hours. The resulting solution contains a polysiloxane macromer
having the composition described above and a number-average
molecular weight of about 2000 to 10,000, more preferably about
3000 to 5000.
Macromer B
[0102] Macromer B is a polysiloxane-comprising perfluoroalkyl ether
and has the formula:
P.sub.1--(Y).sub.m-(L-X.sup.1).sub.p-Q-(X.sup.1-L).sub.p-(Y).sub.m--P.su-
b.1
In which each P.sub.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.sub.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).sub.k-Z--CF.sub.2--(OCF.sub.2).sub.x--(OCF.sub.2CF.sub.2).sub.y--OCF-
.sub.2--Z-(E).sub.k-,
[0103] where x+y is a number in the range of from 10 to 30; [0104]
each Z, independently of the others, is a divalent radical having
up to 12 carbon atoms or Z is a bond; [0105] each E, independently
of the others, is --(OCH.sub.2CH.sub.2).sub.q--, where q has a
value of from 0 to 2, and where the link --Z-E- represents the
sequence --Z--(OCH.sub.2CH.sub.2).sub.q--; and [0106] k is 0 or 1;
(b)
##STR00002##
[0106] where n is an integer from 5 to 100; Alk is alkylene having
up to 20 carbon atoms; 80-100% of the radicals R.sub.1, R.sub.2,
R.sub.3 and R.sub.4, independently of one another, are alkyl and
0-20% of the radicals R.sub.1, R.sub.2, R.sub.3 and R.sub.4,
independently of one another, are alkenyl, aryl or cyanoalkyl;
and
(c) X.sub.2--R--X.sub.2,
[0107] where R is a divalent organic radical having up to 20 carbon
atoms, and [0108] each X.sub.2, independently of the others, is
--NHCO--, --CONH--, --NHCONH--, --COO--, --OCO--, --NHCOO-- or
OCONH--;
[0109] 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.
[0110] The number of segments (b) in the polymer fragment Q is
preferably greater than or equal to the number of segments (a). The
ratio between the number of segments (a) and (b) in the polymer
fragment Q is preferably 3:4, 2:3, 1:2 or 1:1. The molar ratio
between the number of segments (a) and (b) in the polymer fragment
Q is more preferably 2:3, 1:2 or 1:1.
[0111] The mean molecular weight of the polymer fragment Q is in
the range of about 1000 to about 20000, preferably in the range of
about 3000 to about 15000, particularly preferably in the range of
about 5000 to about 12000.
[0112] The total number of segments (a) and (b) in the polymer
fragment Q is preferably in the range of 2 to about 11,
particularly preferably in the range of 2 to about 9, and in
particular in the range of 2 to about 7. The smallest polymer unit
Q is preferably composed of one perfluoro segment (a), one siloxane
segment (b) and one segment (c).
[0113] In a preferred embodiment of the polymer fragment Q, which
preferably has a composition in the above-mentioned ratios, the
polymer fragment Q is terminated at each end by a siloxane segment
(b).
[0114] The compositions in a bivalent polymer fragment Q always
correspond above and below to a mean statistical composition. This
means that, for example, even individual block copolymer radicals
containing identical recurring units are included, so long as the
final mean statistical composition is as specified.
[0115] X.sub.1 is preferably --NHCONH--, --NHCOO-- or --OCONH--,
particularly preferably --NHCOO-- or --OCONH--.
[0116] The X.sub.2--R--X.sub.2 segment is preferably a radical
derived from a diisocyanate, where each X.sub.2, independently of
the other, is NHCONH--, --NHCOO-- or --OCONH--, in particular
--NHCOO-- or --OCONH--.
[0117] Z is preferably a bond, lower alkylene or --CONH-arylene, in
which the --CO-- moiety is linked to a CF.sub.2 group. Z is
particularly preferably lower alkylene, in particular
methylene.
[0118] q is preferably 0, 1, 1.5 or 2, particularly preferably 0 or
1.5.
[0119] The perfluoroalkoxy units OCF.sub.2 and OCF.sub.2 CF.sub.2
with the indices x and y in segment (a) can either have a random
distribution or be in the form of blocks in a chain. The sum of the
indices x+y is preferably a number in the range of 10 to 25,
particularly preferably of 10 to 15. The ratio x:y is preferably in
the range of 0.5 to 1.5, in particular in the range of 0.7 to
1.1.
[0120] A free-radical-polymerizable group P.sub.1 is, for example,
alkenyl alkenylaryl or alkenylarylenealkyl having up to 20 carbon
atoms. Examples of alkenyl are vinyl, allyl, 1-propen-2-yl,
1-buten-2-, -3- and 4-yl, 2-buten-3-yl, and the isomers of
pentenyl, hexenyl, octenyl, decenyl and undecenyl. Examples of
alkenylaryl are vinylphenyl, vinylnaphthyl or allylphenyl. An
example of alkenylarylenealkyl is o-, m-, or p-vinylbenzyl.
[0121] P.sub.1 is preferably alkenyl or alkenylaryl having up to 12
carbon atoms, particularly preferably alkenyl having up to 8 carbon
atoms, in particular alkenyl having up to 4 carbon atoms.
[0122] Y is preferably --COO--, --OCO--, --NHCONH--, --NHCOO--,
--OCONH--, NHCO-- or --CONH--, particularly preferably --COO--,
--OCO--, NHCO-- or --CONH--, and in particular, --COO-- or
--OCO--.
[0123] In a preferred embodiment, the indices, m and p, are not
simultaneously zero. If p is zero, m is preferably 1.
[0124] L is preferably alkylene, arylene, a saturated bivalent
cycloaliphatic group having 6 to 20 carbon atoms, arylenealkylene,
alkylenearylene, alkylenearylenealkylene or
arylenealkylenearylene.
[0125] Preferably, L is a divalent radical having up to 12 carbon
atoms, particularly preferably a divalent radical having up to 8
carbon atoms. In a preferred embodiment, L is furthermore alkylene
or arylene having up to 12 carbon atoms. A particularly preferred
embodiment of L is lower alkylene, in particular lower alkylene
having up to 4 carbon atoms.
[0126] The divalent radical R is, for example, alkylene, arylene,
alkylenearylene, arylenealkylene or arylenealkylenearylene having
up to 20 carbon atoms, a saturated bivalent cycloaliphatic group
having 6 to 20 carbon atoms or cycloalkylenealkylenecycloalkylene
having 7 to 20 carbon atoms.
[0127] In a preferred embodiment, R is alkylene, arylene,
alkylenearylene, arylenealkylene or arylenealkylenearylene having
up to 14 carbon atoms or a saturated divalent cycloaliphatic group
having 6 to 14 carbon atoms. In a particularly preferred
embodiment, R is alkylene or arylene having up to 12 carbon atoms
or a saturated bivalent cycloaliphatic group having 6 to 14 carbon
atoms.
[0128] In a preferred embodiment, R is alkylene or arylene having
up to 10 carbon atoms or a saturated bivalent cycloaliphatic group
having 6 to 10 carbon atoms.
[0129] In a particularly preferred meaning, R is a radical derived
from a diisocyanate, for example from hexane 1,6diisocyanate,
2,2,4-trimethylhexane 1,6-diisocyanate, tetramethylene
diisocyanate, phenylene 1,4diisocyanate, toluene 2,4-diisocyanate,
toluene 2,6diisocyanate, m- or p-tetramethylxylene diisocyanate,
isophorone diisocyanate or cyclohexane 1,4-diisocyanate.
[0130] In a preferred meaning, n is an integer from 5 to 70,
particularly preferably 10 to 50, in particular 14 to 28.
[0131] In a preferred meaning, 80-100%, preferably 85-100%, in
particular 90-100%, of the radicals R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 are, independently of one another, lower alkyl having up to
8 carbon atoms, particularly preferably lower alkyl having up to
4-carbon atoms, especially lower alkyl having up to 2 carbon atoms.
A further particularly preferred embodiment of R.sub.1, R.sub.2,
R.sub.3 and R.sub.4 is methyl.
[0132] In a preferred meaning, 0-20%, preferably 0-15%, in
particular 0-10%, of the radicals R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 are, independently of one another, lower alkenyl,
unsubstituted or lower alkyl- or lower alkoxy-substituted phenyl or
cyano(lower alkyl).
[0133] Arylene is preferably phenylene or naphthylene, which is
unsubstituted or substituted by lower alkyl or lower alkoxy, in
particular 1,3-phenylene, 1,4-phenylene or methyl-1,4-phenylene,
1,5-naphthylene or 1,8-naphthylene.
[0134] Aryl is a carbocyclic aromatic radical which is
unsubstituted or substituted preferably by lower alkyl or lower
alkoxy. Examples are phenyl, tolyl, xylyl, methoxyphenyl,
t-butoxyphenyl, naphthyl and phenanthryl.
[0135] A saturated bivalent cycloaliphatic group is preferably
cycloalkylene, for example cyclohexylene or cyclohexylene(lower
alkylene), for example cyclohexylenemethylene, which is
unsubstituted or substituted by one or more lower alkyl groups, for
example methyl groups, for example trimethylcyclohexylenemethylene,
for example the bivalent isophorone radical.
[0136] For the purposes of the present invention, the term "lower"
in connection with radicals and compounds, unless defined
otherwise, denotes, in particular, radicals or compounds having up
to 8 carbon atoms, preferably having up to 4 carbon atoms.
[0137] Lower alkyl has, in particular, up to 8 carbon atoms,
preferably up to 4 carbon atoms, and is, for example, methyl,
ethyl, propyl, butyl, tert-butyl, pentyl, hexyl or isohexyl.
[0138] Alkylene has up to 12 carbon atoms and can be straight-chain
or branched. Suitable examples are decylene, octylene, hexylene,
pentylene, butylene, propylene, ethylene, methylene, 2-propylene,
2-butylene, 3-pentylene, and the like.
[0139] Lower alkylene is alkylene having up to 8 carbon atoms,
particularly preferably up to 4 carbon atoms. Particularly
preferred meanings of lower alkylene are propylene, ethylene and
methylene.
[0140] The arylene unit in alkylenearylene or arylenealkylene is
preferably phenylene, unsubstituted or substituted by lower alkyl
or lower alkoxy, and the alkylene unit therein is preferably lower
alkylene, such as methylene or ethylene, in particular methylene.
These radicals are therefore preferably phenylenemethylene or
methylenephenylene.
[0141] Lower alkoxy has, in particular, up to 8 carbon atoms,
preferably up to 4 carbon atoms, and is, for example, methoxy,
ethoxy, propoxy, butoxy, tert-butoxy or hexyloxy.
[0142] Arylenealkylenearylene is preferably phenylene(lower
alkylene)phenylene having up to 8, in particular up to 4, carbon
atoms in the alkylene unit, for example phenyleneethylenephenylene
or phenylenemethylenephenylene.
[0143] Macromer B can be prepared by known processes, for example
as described in U.S. Pat. No. 5,849,811, herein incorporated by
reference.
Macromer C
[0144] Macromer C are a class of macromers which contain free
hydroxyl groups. This class of macromers are built up, for example,
from an amino-alkylated polysiloxane which is derivatized with at
least one polyol component containing an unsaturated polymerizable
side chain. Polymers can be prepared on the one hand from this
class of macromers according to the invention by
homopolymerization. The macromers mentioned furthermore can be
mixed and polymerized with one or more hydrophilic and/or
hydrophobic comonomers. A special property of the macromers
according to the invention is that they function as the element
which controls microphase separation between selected hydrophilic
and hydrophobic components in a crosslinked end product. The
hydrophilic/hydrophobic microphase separation is in the region of
less than 300 nm. The macromers are preferably crosslinked at the
phase boundaries between, for example, an acrylate comonomer on the
one hand and an unsaturated polymerizable side chain of polyols
bonded to polysiloxane on the other hand, by covalent bonds and
additionally by reversible physical interactions, for example
hydrogen bridges. These are formed, for example, by numerous amide
or urethane groups. The continuous siloxane phase which exists in
the phase composite has the effect of producing a surprisingly high
permeability to oxygen.
[0145] In an embodiment, macromer c comprises at least one segment
of the formula (I):
##STR00003##
in which (a) is a polysiloxane segment, (b) is a polyol segment
which contains at least 4 C atoms, Z is a segment (c) or a group
X.sub.1, (c) is defined as X.sub.2--R--X.sub.2, wherein R is a
bivalent radical of an organic compound having up to 20 C atoms and
each X.sub.2 independently of the other is a bivalent radical which
contains at least one carbonyl group, X.sub.1 is defined as
X.sub.2, and (d) is a radical of the formula (II):
X.sub.3-L-(Y).sub.k--P.sub.1 (II)
in which P.sub.1 is a group which can be polymerized by free
radicals; Y and X.sub.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 C atoms of an
organic compound.
[0146] A polysiloxane segment (a) is derived from a compound of the
formula (III):
##STR00004##
in which n is an integer from 5 to 500; 99.8-25% of the radicals
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6
independently of one another are alkyl and 0.2-75% of the radicals
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6
independently of one another are partly fluorinated alkyl,
aminoalkyl, alkenyl, aryl, cyanoalkyl, alk-NH-alk-NH.sub.2 or
alk-(OCH.sub.2).sub.m--(OCH.sub.2).sub.p--OR.sub.7, R.sub.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.
[0147] The alkylenoxy groups --(OCH.sub.2CH.sub.2).sub.m and
--(OCH.sub.2).sub.p in the siloxane of the formula (III) are either
distributed randomly in a ligand
alk-(OCH.sub.2CH.sub.2).sub.m--(OCH.sub.2).sub.p--OR.sub.7 or are
distributed as blocks in a chain.
[0148] A polysiloxane segment (a) is linked a total of 1-50 times,
preferably 2-30 times, and in particular 4-10 times, via a group Z
with a segment (b) or another segment (a), Z in an a-Z-a sequence
always being a segment (c). The linkage site in a segment (a) with
a group Z is an amino or hydroxyl group reduced by one
hydrogen.
[0149] In a preferred embodiment, a polysiloxane segment is derived
from a compound of the formula (III) in which the radicals R.sub.1,
R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are a total of 1-50
times, more preferably 2-30 times, and in particular 4-10 times,
independently either terminally or pendently aminoalkyl or
hydroxyalkyl, the other variables being as defined above.
[0150] In a preferred embodiment, a polysiloxane segment is derived
from a compound of the formula (III) in which 95-29% of the
radicals R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6
independently of one another are alkyl and 5-71% of the radicals
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6
independently of one another are partly fluorinated alkyl,
aminoalkyl, alkenyl, aryl, cyanoalkyl, alk-NH-alk-NH.sub.2 or
alk-(OCH.sub.2CH.sub.2).sub.m--(OCH.sub.2).sub.p--OR.sub.7, and in
which the variables are as defined above.
[0151] In a preferred meaning, n is an integer from 5 to 400, more
preferably 10 to 250 and particularly preferably 12 to 125.
[0152] In a preferred meaning, the two terminal radicals R.sub.1
and R.sub.6 are aminoalkyl or hydroxyalkyl, the other variables
being as defined above.
[0153] In another preferred meaning, the radicals R.sub.4 and
R.sub.5 are 1-50 times, more preferably 2-times and in particular
4-10 times pendently aminoalkyl or hydroxyalkyl and the other
variables are as defined above.
[0154] In another preferred meaning, the radicals R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are a total of 1-50 times,
more preferably 2-30 times and in particular 4-10 times,
independently both terminally and pendently aminoalkyl or
hydroxyalkyl and the other variables are as defined above.
[0155] If Z is X.sub.1, X.sub.1 is a bivalent group which contains
at least one carbonyl group. A carbonyl group mentioned is flanked
in any manner, if appropriate, by --O--, --CONH--, --NHCO-- or
--NH--.
[0156] Examples of bivalent groups Z are typically carbonyls,
esters, amides, urethanes, ureas or carbonates.
[0157] X.sub.1 is preferably an ester, amide, urethane or urea
group, in particular an ester or amide group.
[0158] X.sub.2 is defined in the same way as X.sub.1 and is
preferably an ester, amide, urethane, carbonate or urea group, more
preferably an ester, amide, urethane or urea group and in
particular an amide, urethane or urea group.
[0159] If Z in formula (I) is X.sub.1, a polyol segment b is
preferably understood as meaning a polyol derived from a
carbohydrate, carbohydrate monolactone or carbohydrate dilactone. A
carbohydrate is understood as meaning a mono-, di-, tri-, tetra-,
oligo- or polysaccharide. A carbohydrate lactone is understood as
meaning the lactone of an aldonic or uronic acid. An aldonic or
uronic acid is, for example, a carboxylic acid formed by oxidation
of a mono-, di-, tri-, tetra-, oligo- or polysaccharide. Examples
of aldonic acid lactones are gluconolactone, galactonolactone,
lactobionolactone or maltoheptaonolactone; examples of uronic acid
lactones are glucuronic acid lactone, mannuronic acid lactone or
iduronic acid lactone. An example of a carbohydrate dilactone is
D-glucaro-1,4:6,3-dilactone.
[0160] A carbohydrate lactone reacts, for example, with a primary
amino group or a hydroxyl group of segment (a) to form a covalent
amide or ester bond of the type X.sub.1. Such linkages are the
constituent of a further preferred embodiment of macromers
according to the invention. Such macromers have an alternating
distribution of segments of type (a) and (b) which are interrupted
by X.sub.1.
[0161] In another embodiment, macromer C is defined by the formula
(IV):
##STR00005##
in which the variables are as defined above.
[0162] In another embodiment, macromer C is defined by the formula
(V):
##STR00006##
in which the polysiloxane segment (a) contains q pendent ligands; x
is 0, 1 or 2; q has an average numerical value of 1-20, preferably
1-10, and in particular 1-5; and the segments (b) in a macromer
according to the formula (V) are linked in total (per molecule)
with up to 20, preferably with up to 15, and in particular with up
to 6 polymerizable segments (d).
[0163] In another embodiment, macromer C has the formula (VI):
##STR00007##
in which a linear sequence is present; x is 0, 1 or 2; q has an
average numerical value of 1-20, preferably 1-10, and in particular
1-5; and the segments (b) in a macromer according to the formula
(VI) are linked in total (per molecule) with up to 20, preferably
with up to 15, and in particular with up to 6 polymerizable
segments (d).
[0164] In another embodiment, macromer C has the formula (VII):
##STR00008##
in which x is 0, 1 or 2; and the average number of segments (d) per
molecule of the formula (VII) is preferably in the range from 2 to
5, and very preferably is in the range from 3 to 4.
[0165] A polyol segment (b) is derived from a polyol which carries
no lactone group if the group Z is a segment (c). Examples of such
polyols are a 1,2-polyol, for example the reduced monosaccharides,
for example mannitol, glucitol, sorbitol or iditol, a 1,3-polyol,
for example polyvinyl alcohol (PVA), which is derived from partly
or completely hydrolysed polyvinyl acetate, and furthermore
amino-terminal PVA telomers, aminopolyols, aminocyclodextrins,
aminomono-, -di-, -tri-, -oligo- or -polysaccharides or
cyclodextrin derivatives, for example hydroxypropylcyclodextrin. An
abovementioned carbohydrate dilactone can be reacted, for example,
with preferably 2 equivalents of an amino-terminal PVA telomer to
give a polyol macromer which carries, in the central part, the
carbohydrate compound derived from the dilactone. Such polyols of
this composition are likewise understood to be a suitable
polyol.
[0166] As illustrated in formula (I), a segment (b) carries at
least one vinylic polymerizable segment (d), a linkage of a segment
(d) via the bivalent radical X.sub.3 thereof to an amino or
hydroxyl group, of a segment (b), reduced by a hydrogen atom being
intended.
[0167] A vinylic polymerizable segment (d) is incorporated either
terminally or pendently preferably 1-20 times, more preferably 2-15
times, and in particular 2-6 times, per macromer molecule according
to the invention.
[0168] A vinylic polymerizable segment (d) is incorporated
terminally and also pendently as desired (as a terminal/pendent
mixture) preferably 1-20 times, more preferably 2-15 times and in
particular 2-6 times, per macromer molecule according to the
invention.
[0169] A group P.sub.1 which can be polymerized by free radicals
is, for example, alkenyl, alkenylaryl or alkenylarylenealkyl having
up to 20 C atoms. Examples of alkenyl are vinyl, allyl,
1-propen-2-yl, 1-buten-2- or -3- or -4-yl, 2-buten-3-yl and the
isomers of pentenyl, hexenyl, octenyl, decenyl or undecenyl.
Examples of alkenylaryl are vinylphenyl, vinylnaphthyl or
allylphenyl. An example of alkenylarylenealkyl is vinylbenzyl.
[0170] P.sub.1 is preferably alkenyl or alkenylaryl having up to 12
C atoms, more preferably alkenyl having up to 8C atoms and in
particular alkenyl having up to 4 C atoms.
[0171] L is preferably alkylene, arylene, a saturated bivalent
cycloaliphatic group having 6 to 20 carbon atoms, arylenealkylene,
alkylenearylene, alkylenearylenealkylene or arylenealkylenearylene.
In a preferred meaning, L furthermore is preferably a bond.
[0172] In a preferred meaning, L is a divalent radical having up to
12 C atoms, and more preferably a divalent radical having up to 8 C
atoms. In a preferred meaning, L furthermore is alkylene or arylene
having up to 12 C atoms. A very preferred meaning of L is lower
alkylene, in particular lower alkylene having up to 4C atoms.
[0173] Y is preferably a carbonyl, ester, amide or urethane group,
in particular a carbonyl, ester or amide group, and very preferably
a carbonyl group.
[0174] In another preferred meaning, Y is absent, i.e., k is 0.
[0175] In a preferred meaning, X.sub.3 is a urethane, urea, ester,
amide or carbonate group, more preferably a urethane, urea, ester
or amide group, and in particular a urethane or urea group.
[0176] A vinylic polymerizable segment (d) is derived, for example,
from acrylic acid, methacrylic acid, methacryloyl chloride,
2-isocyanatoethyl methacrylate (IEM), allyl isocyanate, vinyl
isocyanate, the isomeric vinylbenzyl isocyanates or adducts of
hydroxyethyl methacrylate (HEMA) and 2,4-tolylene diisocyanate
(TDI) or isophorone diisocyanate (IPDI), in particular the 1:1
adduct.
[0177] A preferred embodiment of segment (d) is incorporated either
terminally or pendently or as a terminal/pendent mixture 5
times.
[0178] The diradical R is, for example, alkylene, arylene,
alkylenearylene, arylenealkylene or arylenealkylenearylene having
up to 20 carbon atoms, a saturated bivalent cycloaliphatic group
having 6 to 20 carbon atoms or cycloalkylenealkylenecycloalkylene
having 7 to 20 carbon atoms.
[0179] In a preferred meaning, R is alkylene, arylene,
alkylenearylene, arylenealkylene or arylenealkylenearylene having
up to 14 carbon atoms or a saturated bivalent cycloaliphatic group
having 6 to 14 carbon atoms.
[0180] In a preferred meaning, R is alkylene, arylene,
alkylenearylene or arylenealkylene having up to 14 carbon atoms, or
a saturated bivalent cycloaliphatic group having 6 to 14 carbon
atoms.
[0181] In a preferred meaning, R is alkylene or arylene having up
to 12 carbon atoms, or a saturated bivalent cycloaliphatic group
having 6 to 14 carbon atoms.
[0182] In a preferred meaning, R is alkylene or arylene having up
to 10 carbon atoms, or is a saturated bivalent cycloaliphatic group
having 6 to 10 carbon atoms.
[0183] In a very preferred meaning, a segment (c) is derived from a
diisocyanate, for example from hexane 1,6-diisocyanate,
2,2,4-trimethylhexane 1,6-diisocyanate, tetramethylene
diisocyanate, phenylene 1,4-diisocyanate, toluene 2,4-diisocyanate,
toluene 2,6-diisocyanate, m- or p-tetramethylxylene diisocyanate,
isophorone diisocyanate or cyclohexane 1,4-diisocyanate.
[0184] A preferred embodiment of segment (c) is furthermore derived
from a diisocyanate in which the isocyanate groups have different
reactivities. The different reactivity is influenced, in
particular, by the spatial requirements and/or electron density in
the neighbourhood of an isocyanate group.
[0185] The average molecular weight of a macromer according to the
invention is preferably in the range from about 300 to about
30,000, very preferably in the range from about 500 to about
20,000, more preferably in the range from about 800 to about
12,000, and particularly preferably in the range from about 1000 to
about 10,000.
[0186] In a preferred embodiment, macromer C has a segment sequence
of the formula (VIII):
b-Z-a-{c-a}.sub.r-(Z-b).sub.t (VIII)
in which r is an integer from 1 to 10, preferably from 1 to 7, and
in particular from 1 to 3; t is 0 or 1, and preferably 1; a linear
(c-a) chain which may or may not be terminated by a segment (b) is
present (t=1); and the above preferences apply to the total number
of segments (d), which are preferably bonded to a segment (b).
[0187] In another preferred embodiment, macromer C has a segment
sequence of formula (IX):
b-Z-a-{c-a-(Z-b).sub.t}.sub.r (IX)
in which the sequence (c-a)-(Z-b)t hangs pendently r times on the
segment (a) and may or may not be terminated by a segment (b); r is
an integer from 1 to 10, preferably from 1 to 7, and in particular
from 1 to 3; t is 0 or 1, and is preferably 1; Z is a segment (c)
or a group X.sub.1; and the above preferences apply to the total
number of segments (d), which are preferably bonded to a segment
(b).
[0188] Another preferred embodiment of macromer C has a segment
sequence of formula (X):
b-c-{a-c}.sub.s-B (X)
in which s is an integer from 1 to 10, preferably from 1 to 7, and
in particular from 1 to 3; B is a segment (a) or (b); and the above
preferences apply to the number of segments (d), which are bonded
to a segment (b).
[0189] Another preferred embodiment of macromer C has a segment
sequence of the formula (XI):
B-(c-b).sub.s-Z-a-(b).sub.t (XI)
in which the structures are linear; s is an integer from 1 to 10,
preferably from 1 to 7, and in particular from 1 to 3; B is a
segment (a) or (b); t is 0 or 1, and the above preferences apply to
the number of segments (d), which are bonded to a segment (b).
[0190] The ratio of the number of segments (a) and (b) in a
macromer according to the Material "C" embodiment of the invention
is preferably in a range of (a):(b)=3:4, 2:3, 1:2, 1:1, 1:3 or 1:4.
The total sum of segments (a) and (b) or, where appropriate, (a)
and (b) and (c) is in a range from 2 to 50, preferably 3 to 30, and
in particular in the range from 3 to 12.
[0191] Alkyl has up to 20 carbon atoms and can be straight-chain or
branched. Suitable examples include dodecyl, octyl, hexyl, pentyl,
butyl, propyl, ethyl, methyl, 2-propyl, 2-butyl or 3-pentyl.
[0192] Arylene is preferably phenylene or naphthylene, which is
unsubstituted or substituted by lower alkyl or lower alkoxy, in
particular 1,3-phenylene, 1,4-phenylene or methyl-1,4-phenylene; or
1,5-naphthylene or 1,8-naphthylene.
[0193] Aryl is a carbocyclic aromatic radical, which is
unsubstituted or substituted by preferably lower alkyl or lower
alkoxy. Examples are phenyl, toluoyl, xylyl, methoxyphenyl,
t-butoxyphenyl, naphthyl or phenanthryl.
[0194] A saturated bivalent cycloaliphatic group is preferably
cycloalkylene, for example cyclohexylene or cyclohexylene-lower
alkylene, for example cyclohexylenemethylene, which is
unsubstituted or substituted by one or more lower alkyl groups, for
example methyl groups, for example trimethylcyclohexylenemethylene,
for example the bivalent isophorone radical. The term "lower" in
the context of this invention in connection with radicals and
compounds, unless defined otherwise, means, in particular, radicals
or compounds having up to 8 carbon atoms, preferably having up to 4
carbon atoms.
[0195] Lower alkyl has, in particular, up to 8 carbon atoms,
preferably up to 4 carbon atoms, and is, for example, methyl,
ethyl, propyl, butyl, tert-butyl, pentyl, hexyl or isohexyl.
[0196] Alkylene has up to 12 carbon atoms and can be straight-chain
or branched. Suitable examples include decylene, octylene,
hexylene, pentylene, butylene, propylene, ethylene, methylene,
2-propylene, 2-butylene or 3-pentylene.
[0197] Lower alkylene is alkylene having up to 8, and particularly
preferably having up to 4-carbon atoms. Particularly preferred
examples of lower alkylenes are propylene, ethylene and
methylene.
[0198] The arylene unit of alkylenearylene or arylenealkylene is
preferably phenylene, which is unsubstituted or substituted by
lower alkyl or lower alkoxy, and the alkylene unit of this is
preferably lower alkylene, such as methylene or ethylene, in
particular methylene. Such radicals are therefore preferably
phenylenemethylene or methylenephenylene.
[0199] Lower alkoxy has, in particular, up to 8 carbon atoms,
preferably up to 4 carbon atoms, and is, for example, methoxy,
ethoxy, propoxy, butoxy, tert-butoxy or hexyloxy.
[0200] Partly fluorinated alkyl is understood as meaning alkyl in
which up to 90%, preferably up to 70%, and in particular up to 50%,
of the hydrogens are replaced by fluorine.
[0201] Arylenealkylenearylene is preferably phenylene-lower
alkylene-phenylene having up to 8, and in particular having up to 4
carbon atoms in the alkylene unit, for example
phenylenethylenephenylene or phenylenemethylenephenylene.
[0202] A monosaccharide in the context of the present invention is
understood as meaning an aldopentose, aldohexose, aldotetrose,
ketopentose or ketohexose.
[0203] Examples of an aldopentose are D-ribose, D-arabinose,
D-xylose or D-lyose; examples of an aldohexose are D-allose,
D-altrose, D-glucose, D-mannose, D-gulose, D-idose, D-galactose,
D-talose, L-fucose or L-rhamnose; examples of a ketopentose are
D-ribulose or D-xylulose; examples of a tetrose are D-erythrose or
threose; and examples of a ketohexose are D-psicose, D-fructose,
D-sorbose or D-tagatose. Examples of a disaccharide are trehalose,
maltose, somaltose, cellobiose, gentiobiose, saccharose, lactose,
chitobiose, N,N-diacetylchitobiose, palatinose or sucrose.
Raffinose, panose or maltotriose may be mentioned as an example of
a trisaccharide. Examples of an oligosaccharide are maltotetraose,
maltohexaose, chitoheptaose and furthermore cyclic
oligosaccharides, such as cyclodextrins.
[0204] Cyclodextrins contain 6 to 8 identical units of
.alpha.-1,4-glucose. Some examples are .alpha.-, .beta.- and
.gamma.-cyclodextrin, derivatives of such cyclodextrins, for
example hydroxypropylcyclodextrins, and branched cyclodextrins.
[0205] Macromer C can be prepared by processes known per se, for
example, according the procedures disclosed in U.S. Pat. No.
5,849,811.
Macromer D
[0206] MacromerD is a siloxane-containing macromer which is formed
from a poly(dialkylsiloxane) dialkoxyalkanol having the following
structure:
##STR00009##
where n is an integer from about 5 to about 500, preferably about
20 to 200, more preferably about 20 to 100; the radicals R.sub.1,
R.sub.2, R.sub.3, and R.sub.4, independently of one another, are
lower alkylene, preferably C.sub.1-C.sub.6 alkylene, more
preferably C.sub.1-C.sub.3 alkylene, wherein in a preferred
embodiment, the total number of carbon atoms in R.sub.1 and R.sub.2
or in R.sub.3 and R.sub.4 is greater than 4; and R.sub.5, R.sub.6,
R.sub.7, and R.sub.8 are, independently of one another, are lower
alkyl, preferably C.sub.1-C.sub.6 alkyl, more preferably
C.sub.1-C.sub.3 alkyl.
[0207] The general structure of macromer D is:
[0208] ACRYLATE-LINK-ALK-O-ALK-PDAS-ALK-O-ALK-LINK-ACRYLATE where
the ACRYLATE is selected from acrylates and methacrylates; LINK is
selected from urethanes and dirurethane linkages, ALK-O-ALK is as
defined above (R.sub.1--O--R.sub.2 or R.sub.30-R.sub.4), and PDAS
is a poly(dialkylsiloxane).
[0209] For example, macromer D may be prepared by reacting
isophorone diisocyanate, 2-hydroxyethyl(meth)acrylate and a
poly(dialkylsiloxane)dialkoxyalkanol in the presence of a
catalyst.
[0210] A preferred macromer D may be prepared by reacting a slight
excess of isocyanatoalkyl methacrylate, especially isocyanatoethyl
methacrylate (IEM), with a poly(dialkylsiloxane)dialkoxyalkanol,
preferably poly(dimethylsiloxane)dipropoxyethanol, in the presence
of a catalyst, especially an organotin catalyst such as dibutyltin
dilaurate (DBTL). The primary resulting structure is as
follows:
##STR00010##
where n is an integer from about 5 to about 500; R.sub.1, R.sub.2,
R.sub.3, and R.sub.4, independently of one another, are lower
alkylene; R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are, independently
of one another, are alkyl, R.sub.9 and R.sub.11 are alkylene; and
R.sub.10 and R.sub.12 are methyl or hydrogen.
[0211] Macromer A, Macromer B, Macromer C or Macromer D can be
prepared according to the procedures described in U.S. Pat. No.
5,760,100, herein incorporated by reference in its entirety.
[0212] In accordance with the present invention, a polymerizable
fluid composition can also comprise siloxane-containing monomer.
Any known suitable siloxane-containing monomers can be used in the
present invention. Exemplary siloxane-containing monomers include,
without limitation, methacryloxyalkylsiloxanes,
tristrimethylsilyloxysilylpropyl methacrylate (TRIS),
3-methacryloxy propylpentamethyldisiloxane and
bis(methacryloxypropyl)tetramethyldisiloxane. A preferred
siloxane-containing monomer is TRIS, which is referred to
3-methacryloxypropyltris(trimethylsiloxy)silane, and represented by
CAS No. 17096-07-0. The term "TRIS" also includes dimers of
3-methacryloxypropyltris(trimethylsiloxy)silane.
[0213] In accordance with the present invention, a polymerizable
fluid composition can also comprise a hydrophilic monomer. Nearly
any hydrophilic monomer that can act as a plasticizer can be used
in the fluid composition of the invention. Suitable hydrophilic
monomers are, without this being an exhaustive list,
hydroxyl-substituted lower alkyl (C.sub.1 to C.sub.8)acrylates and
methacrylates, acrylamide, methacrylamide, (lower allyl)acrylamides
and -methacrylamides, ethoxylated acrylates and methacrylates,
hydroxyl-substituted (lower alkyl)acrylamides and -methacrylamides,
hydroxyl-substituted lower alkyl vinyl ethers, sodium
vinylsulfonate, sodium styrenesulfonate,
2-acrylamido-2-methylpropanesulfonic acid, N-vinylpyrrole,
N-vinyl-2-pyrrolidone, 2-vinyloxazoline,
2-vinyl-4,4'-dialkyloxazolin-5-one, 2- and 4-vinylpyridine,
vinylically unsaturated carboxylic acids having a total of 3 to 5
carbon atoms, amino(lower alkyl)--(where the term "amino" also
includes quaternary ammonium), mono(lower alkylamino)(lower alkyl)
and di(lower alkylamino)(lower alkyl)acrylates and methacrylates,
allyl alcohol and the like.
[0214] Among the preferred hydrophilic monomers are
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 N,N-dimethyacrylamide
(DMA).
[0215] A polymerizable fluid composition can also comprises a
hydrophobic monomer. By incorporating a certain amount of
hydrophobic monomer in a polymerizable fluid composition, the
mechanical properties (e.g., modulus of elasticity) of the
resultant polymer may be improved. Examples of suitable hydrophobic
vinylic comonomers include methylacrylate, ethyl-acrylate,
propylacrylate, isopropylacrylate, cyclohexylacrylate,
2-ethylhexylacrylate, methylmethacrylate, ethylmethacrylate,
propylmethacrylate, vinyl acetate, vinyl propionate, vinyl
butyrate, vinyl valerate, styrene, chloroprene, vinyl chloride,
vinylidene chloride, acrylonitrile, 1-butene, butadiene,
methacrylonitrile, vinyl toluene, vinyl ethyl ether,
perfluorohexylethyl-thio-carbonyl-aminoethyl-methacrylate,
isobornyl methacrylate, trifluoroethyl methacrylate,
hexafluoro-isopropyl methacrylate, hexafluorobutyl methacrylate,
tris-trimethylsilyloxy-silyl-propyl methacrylate,
3-methacryloxypropyl-pentamethyl-disiloxane and
bis(methacryloxypropyl)-tetramethyl-disiloxane. TRIS, which may act
both to increase oxygen permeability and to improve the modulus of
elasticity, is a particularly preferred hydrophobic monomer.
[0216] In a preferred embodiment, a polymerizable fluid composition
suitable for making an ophthalmic device will include (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. More
preferably, the siloxane-containing monomer is TRIS.
[0217] In accordance with the present invention, a polymerizable
fluid composition can further comprise various components, such as
cross-linking agents, initiator, UV-absorbers, inhibitors, fillers,
visibility tinting agents, and the like.
[0218] Cross-linking agents may be used to improve structural
integrity and mechanical strength. Examples of cross-linking agents
include without limitation allyl(meth)acrylate, lower alkylene
glycol di(meth)acrylate, poly lower alkylene glycol
di(meth)acrylate, lower alkylene di(meth)acrylate, divinyl ether,
divinyl sulfone, di- or trivinylbenzene, trimethylolpropane
tri(meth)acrylate, pentaerythritol tetra(meth)acrylate, bisphenol A
di(meth)acrylate, methylenebis(meth)acrylamide, triallyl phthalate
or diallyl phthalate. A preferred cross-linking agent is ethylene
glycol dimethacrylate (EGDMA).
[0219] The amount of a cross-linking agent used is expressed in the
weight content with respect to the total polymer and is in the
range from 0.05 to 20%, in particular in the range from 0.1 to 10%,
and preferably in the range from 0.1 to 2%.
[0220] Initiators, for example, selected from materials well known
for such use in the polymerization art, may be included in the
polymerizable fluid composition in order to promote, and/or
increase the rate of, the polymerization reaction. An initiator is
a chemical agent capable of initiating polymerization reactions.
The initiator can be a photoinitiator or a thermal initiator.
[0221] A photoinitiator can initiate free radical polymerization
and/or crosslinking by the use of light. Suitable photoinitiators
are benzoin methyl ether, diethoxyacetophenone, a benzoylphosphine
oxide, 1-hydroxycyclohexyl phenyl ketone and Darocur and Irgacur
types, preferably Darocur 1173.RTM. and Darocur 2959.RTM.. Examples
of benzoylphosphine initiators include
2,4,6-trimethylbenzoyldiphenylophosphine oxide;
bis-(2,6-dichlorobenzoyl)-4-N-propylphenylphosphine oxide; and
bis-(2,6-dichlorobenzoyl)-4-N-butylphenylphosphine oxide. Reactive
photoinitiators which can be incorporated, for example, into a
macromer or can be used as a special monomer are also suitable.
Examples of reactive photoinitiators are those disclosed in EP 632
329, herein incorporated by reference in its entirety. The
polymerization can then be triggered off by actinic radiation, for
example light, in particular UV light of a suitable wavelength. The
spectral requirements can be controlled accordingly, if
appropriate, by addition of suitable photosensitizers
[0222] Examples of suitable thermal initiators include, but are not
limited to, 2,2'-azobis(2,4-dimethylpentanenitrile),
2,2'-azobis(2-methylpropanenitrile),
2,2'-azobis(2-methylbutanenitrile), peroxides such as benzoyl
peroxide, and the like. Preferably, the thermal initiator is
azobisisobutyronite (AIBN).
[0223] Examples of preferred pigments include any colorant
permitted in medical devices and approved by the FDA, such as
D&C Blue No. 6, D&C Green No. 6, D&C Violet No. 2,
carbazole violet, certain copper complexes, certain chromium
oxides, various iron oxides, phthalocyanine green, phthalocyanine
blue, titanium dioxides, etc. See Marmiom DM Handbook of U.S.
Colorants for a list of colorants that may be used with the present
invention. A more preferred embodiment of a pigment include (C.I.
is the color index no.), without limitation, for a blue color,
phthalocyanine blue (pigment blue 15:3, C.I. 74160), cobalt blue
(pigment blue 36, C.I. 77343), Toner cyan BG (Clariant), Permajet
blue B2G (Clariant); for a green color, phthalocyanine green
(Pigment green 7, C.I. 74260) and chromium sesquioxide; for yellow,
red, brown and black colors, various iron oxides; PR122, PY154, for
violet, carbazole violet; for black, Monolith black C-K (CIBA
Specialty Chemicals).
[0224] It has been found that some classes of monomers can reduce
silver ions into silver nano-particles. Examples of such monomers
include without limitation 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.
[0225] Exemplary N-vinyl lactams include without limitation
N-vinyl-2-pyrrolidone (NVP), N-vinyl-2-piperidone,
N-vinyl-2-caprolactam, N-vinyl-3-methyl-2-pyrrolidone,
N-vinyl-3-methyl-2-piperidone, N-vinyl-3-methyl-2-caprolactam,
N-vinyl-4-methyl-2-pyrrolidone, N-vinyl-4-methyl-2-caprolactam,
N-vinyl-5-methyl-2-pyrrolidone, N-vinyl-5-methyl-2-piperidone,
N-vinyl-5,5-dimethyl-2-pyrrolidone,
N-vinyl-3,3,5-trimethyl-2-pyrrolidone,
N-vinyl-5-methyl-5-ethyl-2-pyrrolidone,
N-vinyl-3,4,5-trimethyl-3-ethyl-2-pyrrolidone,
N-vinyl-6-methyl-2-piperidone, N-vinyl-6-ethyl-2-piperidone,
N-vinyl-3,5-dimethyl-2-piperidone,
N-vinyl-4,4-dimethyl-2-piperidone, N-vinyl-7-methyl-2-caprolactam,
N-vinyl-7-ethyl-2-caprolactam, N-vinyl-3,5-dimethyl-2-caprolactam,
N-vinyl-4,6-dimethyl-2-caprolactam and
N-vinyl-3,5,7-trimethyl-2-caprolactam.
[0226] A person skilled in the art will know how to determine which
monomers are capable of reducing silver ions into silver
nano-particles. In a preferred embodiment, a monomer capable of
reducing silver ions into nano-particles is N-dimethylacrylamide
(DMA) or N-vinyl-2-pyrrolidone (NVP).
[0227] In a preferred embodiment, a polymerizable fluid composition
also comprises a biocompatible reducing agent.
[0228] Any suitable biocompatible reducing agents can be used in
the invention. Examples of biocompatible reducing agents includes
without limitation ascorbic acid and biocompatible salts thereof,
and biocompatible salts of citrate.
[0229] Any known suitable soluble silver salts can be used in the
present invention. Preferably, silver nitrate is used.
[0230] It has been found that a siloxane-containing macromer having
hydrophilic units can stabilize silver nano-particles. A
polymerizable dispersion containing silver nano-particles and a
siloxane-containing macromer having hydrophilic units can be stable
for a relatively long period of time, for example, at least two
hours. A stable polymerizable dispersion can provide more
flexibility in producing antimicrobial ophthalmic devices in which
silver nano-particles are uniformly distributed. It should be
understood that the addition of a hydrophilic and/or hydrophobic
can also improve the stability of the polymerizable dispersion with
silver nano-particles, probably due to synergy among them. For
example, a polymerizable dispersion prepared from a lens
formulation can be more stable than a dispersion prepared from each
individual components of that lens formulation.
[0231] In a preferred embodiment of the invention, a polymerizable
fluid composition comprises a stabilizer for stabilizing silver
nano-particles. A "stabilizer" refers to a material which is
present in a solution for preparing the nano-particles and can
stabilize the resultant nano-particles. A small amount of a
stabilizer present in the polymerizable dispersion can improve
greatly the stability of the polymerizable dispersion. In
accordance with the present invention, a stabilizer can be a
polyanionic material, a polycationic material, or a
polyvinylpyrrolidone (PVP).
[0232] A polycationic material used in the present invention can
generally include any material known in the art to have a plurality
of positively charged groups along a polymer chain. For instance,
suitable examples of such polycationic materials can include, but
are not limited to, poly(allylamine hydrochloride) (PAH),
poly(ethyleneimine) (PEI), poly(vinylbenzyltriamethylamine) (PVBT),
polyaniline (PAN or PANI) (p-type doped) [or sulphonated
polyaniline], polypyrrole (PPY) (p-typed doped), and
poly(pyridinium acetylene).
[0233] A polycationic material used in the present invention can
also include polymeric quaternary ammonium compounds (polyquats).
When polyquats are used in the coating of an ophthalmic lens, they
may impart antimicrobial properties to the ophthalmic lens.
[0234] A polyanionic material used in the present invention can
generally include any material known in the art to have a plurality
of negatively charged groups along a polymer chain. For example,
suitable polyanionic materials can include, but are not limited to,
polymethacrylic acid (PMA), polyacrylic acid (PAA),
poly(thiophene-3-acetic acid) (PTAA), poly(4-styrenesulfonic acid)
(PSS), sodium poly(styrene sulfonate) (SPS) and poly(sodium styrene
sulfonate) (PSSS).
[0235] The foregoing lists are intended to be exemplary, but
clearly are not exhaustive. A person skilled in the art, given the
disclosure and teaching herein, would be able to select a number of
other useful polyionic materials including a synthetic polymer, a
biopolymer or a modified biopolymer.
[0236] A preferred stabilizer is polyacrylic acid (PAA),
poly(ethyleneimine) (PEI), PVP, acrylic acid, or a polyionic
material having carboxy, amino and/or sulfur-containing groups.
[0237] Exemplary sulfur-containing groups include, without
limitation, thiol, sulfonyl, sulfonic acid, alkyl sulfide, alkyl
disulfide, substituted or unsubstituted phenyldisulfide,
thiophenyl, thiourea, thioether, thiazolyl, thiazolinyl, and the
like.
[0238] The amount of a stabilizer in a polymerizable fluid
composition is less than 1% percent by weight, preferably less than
0.5% by weight, more preferably less than 0.1% by weight.
[0239] Alternatively, a stabilizer can be added into a
polymerizable fluid composition together with soluble silver salt
(e.g., a solution of AgNO.sub.3 and PAA). The concentration ratio
of a stabilizer to silver nano-particles is preferably from 0.1 to
10, more preferably from 0.5 to 5.
[0240] It should point out that where a stabilizer is
--COOH-containing polymer (e.g., PAA), an amino-containing
polycationic polymer, or a sulfur-containing polyionic polymer, the
concentration of the stabilizer should be at a level below which
silver ions can be reduced into silver nano-particles. If the
stabilizer concentration is too high, the reduction of silver ions
into silver nano-particles can be extremely slow or almost
inhibited.
[0241] In accordance with the present invention, a method of the
invention can also comprise a step of adding a biocompatible
reducing agent while mixing thoroughly the mixture so as to
facilitate the formation of the polymerizable dispersion containing
silver nano-particles.
[0242] Medical devices of the invention can be made in a manner
known per se from a polymerizable fluid composition by a
polymerization reaction in molds for making the medical devices
with which the expert is familiar. For example, an ophthalmic lens
may be manufactured, generally, by thoroughly mixing the polymer
composition of the present invention, applying an appropriate
amount of the mixture to a lens mold cavity, and initiating
polymerization. Photoinitiators, such as those commercially
available photoinitiators, e.g., DAROCUR.RTM. 1173 (a photoinitator
available from Ciba-Geigy Corporation), may be added to the polymer
composition to aid in initiating polymerization. Polymerization may
be initiated by a number of well known techniques, which, depending
on the polymerizable material, may include application of radiation
such as microwave, thermal, e-beam and ultraviolet. A preferred
method of initiating polymerization is by application of
ultraviolet radiation.
[0243] Methods of forming mold sections for cast-molding a contact
lens are generally well known to those of ordinary skill in the
art. The process of the present invention is not limited to any
particular method of forming a mold. In fact, any method of forming
a mold can be used in the present invention. However, for
illustrative purposes, the following discussion has been provided
as one embodiment of forming a contact lens mold.
[0244] In general, a mold comprises at least two mold sections (or
portions) or mold halves, i.e. first and second mold halves. The
first mold half defines a first optical surface and the second mold
half defines a second optical surface. The first and second mold
halves are configured to receive each other such that a contact
lens forming cavity is formed between the first optical surface and
the second optical surface. The first and second mold halves can be
formed through various techniques, such as injection molding. These
half sections can later be joined together such that a contact
lens-forming cavity is formed therebetween. Thereafter, a contact
lens can be formed within the contact lens-forming cavity using
various processing techniques, such as ultraviolet curing.
[0245] Examples of suitable processes for forming the mold halves
are disclosed in U.S. Pat. Nos. 4,444,711 to Schad; 4,460,534 to
Boehm et al.; 5,843,346 to Morrill; and 5,894,002 to Boneberger et
al., which are also incorporated herein by reference.
[0246] Virtually all materials known in the art for making molds
can be used to make molds for making contact lenses. For example,
polymeric materials, such as polyethylene, polypropylene, and PMMA
can be used. Other materials that allow UV light transmission could
be used, such as quartz glass.
[0247] Thermal curing or photo curing methods can be used to curing
a polymerizable composition in a mold to form an ophthalmic lens.
Such curing methods are well-known to a person skilled in the
art.
[0248] The invention, in another aspect, provides a method for
making an antimicrobial medical device, preferably an antimicrobial
ophthalmic device, more preferably an antimicrobial contact lens,
even more preferably an antimicrobial extended wear lens. The
method comprises the steps of: obtaining a polymerizable fluid
composition comprising a siloxane-containing macromer and a soluble
silver salt; forming a polymerizable dispersion comprising silver
nanoparticles and having a stability of at least about 60 minutes,
preferably at least about 4 hours, more preferably at least about 8
hours, even more preferably at least about 15 hours, wherein the
silver nanoparticles are obtained by adding into the fluid
composition at least one biocompatible reducing agent; 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.
[0249] In accordance with this aspect of the invention, a
polymerizable fluid composition can be a solution or a solvent-free
liquid or melt at a temperature below 60.degree. C.
[0250] In a preferred embodiment, the resultant antimicrobial
medical device comprises at least ppm, preferably at least 25 ppm,
more preferably at least 40 ppm, even more preferably at least 60
ppm silver nanoparticles.
[0251] In this aspect of the invention, the above described
siloxane-containing macromers, siloxane-containing monomers,
hydrophilic monomers, hydrophobic monomers, solvents, stabilizers
for stabilizing silver nano-particles, soluble silver salts,
cross-linking agents, initiators, UV-absorbers, inhibitors,
fillers, and visibility tinting agents can be used in preparation
of a polymerizable fluid composition comprising a
siloxane-containing macromer and a soluble silver salt. The
formulations of soft contact lenses (such as lotrafilcon A,
lotrafilcon B, etafilcon A, genfilcon A, lenefilcon A, polymacon,
acquafilcon A, and balafilcon) can also be used.
[0252] Any suitable biocompatible reducing agents can be used in
the invention. Examples of biocompatible reducing agents includes
without limitation ascorbic acid and biocompatible salts thereof,
and biocompatible salts of citrate.
[0253] In accordance with this aspect of the invention, a
stabilizer can be added together with the biocompatible reducing
agent or before adding the biocompatible reducing agent.
[0254] The invention, in still another aspect, provides a method
for making an antimicrobial medical device, preferably an
antimicrobial ophthalmic device, more preferably an antimicrobial
contact lens, even more preferably an antimicrobial extended wear
lens. The method comprises the steps of: obtaining a
stabilized-silver nano-particle solution or lyophilized
stabilized-silver nano-particles; directly dispersing a desired
amount of the stabilized-silver nano-particle solution or the
lyophilized stabilized-silver nano-particles in a polymerizable
fluid composition comprising a siloxane-containing macromer to form
a polymerizable dispersion having a stability of at least about 60
minutes, preferably at least about 4 hours, more preferably at
least about 8 hours, even more preferably at least about 15 hours;
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.
[0255] In a preferred embodiment, the resultant antimicrobial
medical device comprises at least ppm, preferably at least 25 ppm,
more preferably at least 40 ppm, even more preferably at least 60
ppm silver nanoparticles.
[0256] Any known suitable methods can be used in the preparation of
stabilized silver nano-particles. For example, silver ions or
silver salts can be reduced by means of a reducing agent (e.g.,
NaBH.sub.4, ascorbic acid, citrate, or the like) or of heating or
UV irradiation in a solution in the presence of a stabilizer to
form silver nano-particles. A person skilled in the art will know
how to choose a suitable known method for preparing silver
nano-particles. Then, the prepared dispersion containing stabilized
silver nano-particles can be lyophilized (dry-freezed).
[0257] In accordance with this aspect of the invention, a
polymerizable fluid composition can be a solution or a solvent-free
liquid or melt at a temperature below 60.degree. C.
[0258] In this aspect of the invention, the above described
siloxane-containing macromers, siloxane-containing monomers,
hydrophilic monomers, hydrophobic monomers, solvents, stabilizers
for stabilizing silver nano-particles, soluble silver salts,
cross-linking agents, initiators, UV-absorbers, inhibitors,
fillers, and visibility tinting agents can be used in preparation
of a polymerizable fluid composition comprising a
siloxane-containing macromer and a soluble silver salt. The
formulations of soft contact lenses (such as lotrafilcon A,
lotrafilcon B, etafilcon A, genfilcon A, lenefilcon A, polymacon,
acquafilcon A, and balafilcon) can also be used.
[0259] Any one of the above described methods of the invention can
be used to prepare an antimicrobial medical device, in particular
an antimicrobial ophthalmic device, which is another aspect of the
invention.
[0260] The invention, in a further aspect, provides an
antimicrobial ophthalmic device, preferably an antimicrobial
contact lens, even more preferably an antimicrobial extended-wear
contact lens. The antimicrobial medical device of the invention
comprises a polymer matrix, silver-nanoparticles distributed
therein and a dye or pigment distributed therein in a substantially
uniform manner, wherein the polymer matrix includes a polysiloxane
unit, has a high oxygen permeability characterized by a D.sub.k
greater than 60 barrers and a high ion permeability characterized
by an ionoflux diffusion coefficient of great than
6.0.times.10.sup.-4 mm.sup.2/min, and comprises a water content of
at least 15 weight percent when fully hydrated, wherein the
antimicrobial medical device exhibit at least a 5-fold reduction
(.gtoreq.80% inhibition), preferably at least a 1-log reduction
(.gtoreq.90% inhibition), more preferably at least a 2-log
reduction (.gtoreq.99% inhibition), of viable microorganisms, and
wherein the dye or pigment, in combination with the color of the
silver nano-particle, provides a desired color. Preferably, the
antimicrobial ophthalmic device has a prolong antimicrobial
activity characterized by by having at least a 5-fold reduction
(.gtoreq.80% inhibition), preferably at least a 1-log reduction
(.gtoreq.90% inhibition), more preferably at least a 2-log
reduction (.gtoreq.99% inhibition), of viable microorganisms (e.g.,
Pseudomonas aeruginosa GSU #3, or Staphylococcus aureus ATCC #6538)
after at least 5, preferably at least 10, more preferably at least
20, even more preferably at least 30 consecutive soaking/rinsing
cycles, each cycle comprising soaking/rinsing one lens in a
phosphate buffered saline (PBS) for a period of time from about 24
to about 72 hours, as shown in Example.
[0261] In a preferred embodiment, an antimicrobial medical device
of the invention comprises at least 10 ppm, preferably at least 25
ppm, more preferably at least 40 ppm, even more preferably at least
60 ppm silver nanoparticles.
[0262] Above described polymerizable fluid compositions can be used
in the preparation of an antimicrobial ophthalmic device according
to any methods of the invention. The ophthalmic lenses of the
present invention preferably have a surface which is biocompatible
with ocular tissue and ocular fluids during the desired extended
period of contact.
[0263] In one preferred embodiment, the ophthalmic lenses of the
present invention include a core material, as defined above,
surrounded, at least in part, by a surface which is more
hydrophilic and lipophobic than the core material. A hydrophilic
surface is desirable in order to enhance the compatibility of the
lens with the ocular tissues and tear fluids. As surface
hydrophilicity increases, undesirable attraction and adherence of
lipids and proteinaceous matter typically decreases. There are
factors other than surface hydrophilicity, such as immunological
response, which may contribute to deposit accumulation on the lens.
Deposition of lipids and proteinaceous matter causes haze on the
lens, thereby reducing visual clarity. Proteinaceous deposits may
also cause other problems, such as irritation to the eye. After
extended periods of continuous or intermittent wear, the lens must
be removed from the eye for cleaning, i.e., deposit removal.
Therefore, increased surface hydrophilicity, and concomitant
reductions in deposits of biological matter, allows increased wear
time.
[0264] There are a variety of methods disclosed in the art for
rendering a surface of a material hydrophilic. For example, the
lens may be coated with a layer of a hydrophilic polymeric
material. Alternatively, hydrophilic groups may be grafted onto the
surface of the lens, thereby producing a monolayer of hydrophilic
material. These coating or grafting processes may be effected by a
number of processes, including without limitation thereto, exposing
the lens to plasma gas or immersing the lens in a monomeric
solution under appropriate conditions.
[0265] Another set of methods of altering the surface properties of
a lens involves treatment prior to polymerization to form the lens.
For example, the mold may be treated with a plasma (i.e., an
ionized gas), a static electrical charge, irradiation, or other
energy source, thereby causing the prepolymerzation mixture
immediately adjacent the mold surface to differ in composition from
the core of the prepolymerization mixture.
[0266] A preferred class of surface treatment processes are plasma
processes, in which an ionized gas is applied to the surface of an
article. Plasma gases and processing conditions are described more
fully in U.S. Pat. Nos. 4,312,575 and 4,632,844, which are
incorporated herein by reference. The plasma gas is preferably a
mixture of lower alkanes and nitrogen, oxygen or an inert gas.
[0267] In a preferred embodiment, an ophthalmic lens is subjected
to a plasma treatment in the presence of a mixture of (a) a
C.sub.1-6 alkane and (b) a gas selected from the group consisting
of nitrogen, argon, oxygen, and mixtures thereof. In a more
preferred embodiment, the lens is plasma treated in the presence of
a mixture of methane and air.
[0268] In another preferred embodiment, an ophthalmic lens has an
LbL coating thereon. Formation of an LbL coating on an ophthalmic
device may be accomplished in a number of ways, for example, as
described in U.S. Pat. No. 6,451,871 (herein incorporated by
reference in its entirety) and pending U.S. patent applications
(application Ser. Nos. 09/774,942, 09/775,104, 10/654,566), herein
incorporated by reference in their entireties. One coating process
embodiment involves solely dip-coating and dip-rinsing steps.
Another coating process embodiment involves solely spray-coating
and spray-rinsing steps. However, a number of alternatives involve
various combinations of spray- and dip-coating and rinsing steps
may be designed by a person having ordinary skill in the art.
[0269] In accordance with a more preferred embodiment of the
invention, an ophthalmic device comprises: an antimicrobial coating
which comprises at least one antimicrobial agent selected from the
group consisting of a polyquat which exhibits antimicrobial
activity, furanones, antimicrobial peptides, isoxazolinones, and
organic selenium compounds. Such medical device may exhibit
antimicrobial synergy of silver and one or more antimicrobial
agents and therefore may possess a higher antimicrobial efficacy
and a broader spectrum of antimicrobial activities.
[0270] Any polyquats which exhibit antimicrobial activity can be
used in the present invention. Exemplary preferred polyquats are
those disclosed in copending U.S. patent application Ser. No.
10/287,091 filed Nov. 4, 2002, entitled "Medical Devices Having
Antimicrobial Coatings thereon", herein incorporated by reference.
The methods for applying such coating onto an ophthalmic device
have been described fully in the copending U.S. patent application
Ser. No. 10/287,091 and are incorporated by reference in its
entirety.
[0271] Any antimicrobial peptides can be used in the present
invention. Exemplary antimicrobial peptides include without
limitation Cecropin A melittin hybrid, indolicidin, lactoferricin,
Defensin 1, Bactenecin (bovin), Magainin 2, functionally equivalent
or superior analogs thereof, mutacin 1140, and mixtures
thereof.
[0272] Any furanones, which exhibit antimicrobial activity, can be
used in the present invention. Exemplary preferred furanones are
those disclosed in PCT published patent applications WO01/68090A1
and WO01/68091A1, incorporated herein by reference in their
entireties.
[0273] Any organic selenium compounds, which exhibit an
antimicrobial activity, can be used in the present invention.
Examples of antimicrobial organic selenium compounds includes
without limitation those disclosed in U.S. Pat. Nos. 5,783,454,
5,994,151, 6,033,917, 6,040,197, 6,043,098, 6,043,099, 6,077,714,
herein incorporated by reference in their entireties.
[0274] Any isoxazolinones, which exhibit an antimicrobial activity,
can be used in the present invention. Examples of isoxazolinones
include without limitation those disclosed in U.S. Pat. Nos.
6,465,456 and 6,420,349 and US Patent application No. 2002/0094984,
herein incorporated by reference in their entireties.
[0275] An antimicrobial agent can be covalently attached to a
medical device by first functionalizing the surface of a preformed
medical device to obtain function groups and then covalently
attaching an antimicrobial agent. Surface modification (or
functionalization) of a medical device is well known to a person
skilled in the art. Any known suitable method can be used.
[0276] For example, the surface modification of a contact lens
includes, without limitation, the grafting of monomers or macromers
onto polymers to make the lens biocompatible, wherein monomers or
macromers contain functional groups, for example, such as hydroxyl
group, amine group, amide group, sulfhydryl group, --COOR (R and R'
are hydrogen or C.sub.1 to C.sub.8 alkyl groups), halide (chloride,
bromide, iodide), acyl chloride, isothiocyanate, isocyanate,
monochlorotriazine, dichlorotriazine, mono- or di-halogen
substituted pyridine, mono- or di-halogen substituted diazine,
phosphoramidite, maleimide, aziridine, sulfonyl halide,
hydroxysuccinimide ester, hydroxysulfosuccinimide ester, imido
ester, hydrazine, axidonitrophenyl group, azide, 3-(2-pyridyl
dithio)proprionamide, glyoxal, aldehyde, epoxy.
[0277] It is well known in the art that a pair of matching
functional groups can form a covalent bond or linkage under known
reaction conditions, such as, oxidation-reduction conditions,
dehydration condensation conditions, addition conditions,
substitution (or displacement) conditions, 2+2 cyclo-addition
conditions, Diels-Alder reaction conditions, ROMP (Ring Opening
Metathesis Polymerization) conditions, vulcanization conditions,
cationic crosslinking conditions, and epoxy hardening conditions.
For example, an amino group is covalently bondable with aldehyde
(Schiff base which is formed from aldehyde group and amino group
may further be reduced); an hydroxyl group and an amino group are
covalently bondable with carboxyl group; carboxyl group and a sulfo
group are covalently bondable with hydroxyl group; a mercapto group
is covalently bondable with amino group; or a carbon-carbon double
bond is covalently bondable with another carbon-carbon double
bond.
[0278] Exemplary covalent bonds or linkage, which are formed
between pairs of crosslinkable groups, include without limitation,
ester, ether, acetal, ketal, vinyl ether, carbamate, urea, amine,
amide, enamine, imine, oxime, amidine, iminoester, carbonate,
orthoester, phosphonate, phosphinate, sulfonate, sulfinate,
sulfide, sulfate, disulfide, sulfinamide, sulfonamide, thioester,
aryl, silane, siloxane, heterocycles, thiocarbonate, thiocarbamate,
and phosphonamide.
[0279] Another example is amination of the surface of a medical
device. If the surface of a core material has hydroxy groups, the
medical device may be placed in a bath of an inert solvent, such as
tetrahydrofuran, and tresyl chloride. The hydroxy groups on the
surface are then tresylated. Once tresylated, the surface may be
aminated in a water solution of ethylene diamine, which results in
bonding the group --NH--CH.sub.2--CH.sub.2--NH.sub.2 to the carbon
atom thereon. Alternatively, for example, a contact lens made from
a hydrogel, can be dipped into or sprayed with a solution
containing a diaziridine compound, which is subsequently attached
covalently to the surface of the contact lens via a thermal
process, so as to functionalize the contact lens. Such
functionalized lenses can be used in covalently attaching of a
layer of antimicrobial agents.
[0280] Antimicrobial agents can be bound covalently to the coating
(e.g., an LbL coating) of an antimicrobial medical device of the
invention, through the reactive sites of the coating. For example,
an LbL coating containing reactive sites (e.g., amino groups,
--COOH groups, etc) is applied to an antimicrobial medical device
of the invention and then a layer of at least one antimicrobial
agent is covalently attached to some of those reactive sites.
[0281] This may be either a direct reaction or, preferably, a
reaction in which a coupling agent is used. For example, a direct
reaction may be accomplished by the use of a reagent of reaction
that activates a group in the LbL coating or the antimicrobial
agent making it reactive with a functional group on the
antimicrobial agent or LbL coating, respectively, without the
incorporation of a coupling agent. For example, one or more amine
groups on an LbL coating may be reacted directly with
isothiocyanate, acyl azide, N-hydroxysuccinimide ester, sulfonyl
chloride, an aldehyde, glyoxal epoxide, 25 carbonate, aryl halide,
imido ester, or an anhydride group in an antimicrobial agent.
[0282] Alternatively, coupling agents may be used. Coupling agents
useful for coupling antimicrobial agent to the LbL coating of a
medical device include, without limitation, N.
N'-carbonyldiimidazole, carbodiimides such as
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ("EDC"), dicyclohexyl
carbodiimide, 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide,
diisopropyl carbodiimide, or mixtures thereof. The carbodiimides
also may be used with N-hydroxysuccinimide or
N-hydroxysulfosuccinimide to form esters that can react with amines
to form amides.
[0283] Amino groups also may be coupled to the LbL coating by the
formation of Schiff bases that can be reduced with agents such as
sodium cyanoborohydride and the like to form hydrolytically stable
amine links. Coupling agents useful for this purpose include,
without limitation, N-hydroxysuccinimide esters, such as
dithiobis(succinimidylpropionate),
3,3'-dithiobis(sulfosuccinimidylpropionate), disuccinimidyl
suberate, bis(sulfosuccinimidyl)suberate, disuccinimidyl tartarate
and the like, imidoesters, including, without limitation, dimethyl
adipimate, difluorobenzene derivatives, including without
limitation 1,5-difluoro-2,4 dinitrobenzene, bromofunctional
aldehydes, including without limitation gluteraldehyde, and his
epoxides, including without limitation 1,4-butanediol diglycidyl
ether. One ordinarily skilled in the art will recognize that any
number of other coupling agents may be used depending on the
functional groups present in the LbL coating.
[0284] The previous disclosure will enable one having ordinary
skill in the art to practice the invention. In order to better
enable the reader to understand specific embodiments and the
advantages thereof, reference to the following examples is
suggested.
Example 1
[0285] Unless otherwise stated, all chemicals are used as
received.
Synthesis of Macromer
[0286] 51.5 g (50 mmol) of the perfluoropolyether Fomblin.RTM. ZDOL
(from Ausimont S.p.A, Milan) having a mean molecular weight of 1030
g/mol and containing 1.96 meq/g of hydroxyl groups according to
end-group titration is introduced into a three-neck flask together
with 50 mg of dibutyltin dilaurate. The flask contents are
evacuated to about 20 mbar with stirring and subsequently
decompressed with argon. This operation is repeated twice. 22.2 g
(0.1 mol) of freshly distilled isophorone diisocyanate kept under
argon are subsequently added in a counterstream of argon. The
temperature in the flask is kept below 30.degree. C. by cooling
with a waterbath. After stirring overnight at room temperature, the
reaction is complete. Isocyanate titration gives an NCO content of
1.40 meq/g (theory: 1.35 meq/g).
[0287] 202 g of the .alpha.,.omega.-hydroxypropyl-terminated
polydimethylsiloxane KF-6001 from Shin-Etsu having a mean molecular
weight of 2000 g/mol (1.00 meq/g of hydroxyl groups according to
titration) are introduced into a flask. The flask contents are
evacuated to approx. 0.1 mbar and decompressed with argon. This
operation is repeated twice. The degassed siloxane is dissolved in
202 ml of freshly distilled toluene kept under argon, and 100 mg of
dibutyltin dilaurate (DBTDL) are added. After complete
homogenization of the solution, all the perfluoropolyether reacted
with isophorone diisocyanate (IPDI) is added under argon. After
stirring overnight at room temperature, the reaction is complete.
The solvent is stripped off under a high vacuum at room
temperature. Microtitration shows 0.36 meq/g of hydroxyl groups
(theory 0.37 meq/g). 13.78 g (88.9 mmol) of 2-isocyanatoethyl
methacrylate (IEM) are added under argon to 247 g of the
.alpha.,.sigma.-hydroxypropyl-terminated
polysiloxane-perfluoropolyether-polysiloxane three-block copolymer
(a three-block copolymer on stoichiometric average, but other block
lengths are also present). The mixture is stirred at room
temperature for three days. Microtitration then no longer shows any
isocyanate groups (detection limit 0.01 meq/g). 0.34 meq/g of
methacryl groups are found (theory 0.34 meq/g).
[0288] The macromer prepared in this way is completely colourless
and clear. It can be stored in air at room temperature for several
months in the absence of light without any change in molecular
weight.
Formulations
[0289] The above prepared siloxane-containing macromer is use in
preparation of two formulations used in the following examples.
Each components and its concentration are listed in Table 1.
TABLE-US-00001 TABLE 1 Formulation Macromer TRIS DMA Darocure .RTM.
1173 Ethanol I* 37.4 15.0 22.5 0.3 24.8 II** 25.9 19.2 28.9 1 25
*Unless otherwise indicated in the text, Formulation I does not
contain tinting agents (colorants). **Formulation II contains about
50 ppm of copper phthalocyanine (CuP).
[0290] Lenses are extracted with isopropanol (isopropyl alcohol)
for at least 2 hours and then subjected plasma treatment according
to procedures described in published US patent application No.
2002/0025389 to obtain plasma coatings. Oxygen and ion permeability
measurements are carried out with lenses after extraction and
plasma coating.
Oxygen Permeability and Transmissibility Measurements.
[0291] The oxygen permeability of a lens and oxygen
transmissibility of a lens material is determined according to a
technique similar to the one described in U.S. Pat. No. 5,760,100
and in an article by Winterton et al., (The Cornea: Transactions of
the World Congress on the Cornea 111, H. D. Cavanagh Ed., Raven
Press: New York 1988, pp 2.sup.73-280), both of which are herein
incorporated by reference in their entireties. Oxygen fluxes (J)
are measured at 34.degree. C. in a wet cell (i.e., gas streams are
maintained at about 100% relative humidity) using a Dk1000
instrument (available from Applied Design and Development Co.,
Norcross, Ga.), or similar analytical instrument. An air stream,
having a known percentage of oxygen (e.g., 21%), is passed across
one side of the lens at a rate of about 10 to 20 cm.sup.3/min.,
while a nitrogen stream is passed on the opposite side of the lens
at a rate of about 10 to 20 cm.sup.3/min. A sample is equilibrated
in a test media (i.e., saline or distilled water) at the prescribed
test temperature for at least 30 minutes prior to measurement but
not more than 45 minutes. Any test media used as the overlayer is
equilibrated at the prescribed test temperature for at least 30
minutes prior to measurement but not more than 45 minutes. The stir
motor's speed is set to 1200.+-.50 rpm, corresponding to an
indicated setting of 400.+-.15 on the stepper motor controller. The
barometric pressure surrounding the system, P.sub.measured, is
measured. The thickness (t) of the lens in the area being exposed
for testing is determined by measuring about 10 locations with a
Mitotoya micrometer VL-50, or similar instrument, and averaging the
measurements. The oxygen concentration in the nitrogen stream
(i.e., oxygen which diffuses through the lens) is measured using
the DK1000 instrument. The apparent oxygen permeability of the lens
material, Dk.sub.app, is determined from the following formula:
Dk.sub.app=Jt/(P.sub.oxygen)
where J=oxygen flux [microliters O.sub.2/cm.sup.2-minute]
[0292] P.sub.oxygen=(P.sub.measured-P.sub.water vapor)=(% O.sub.2
in air stream) [mm Hg]=partial pressure of oxygen in the air
stream
[0293] P.sub.measured=barometric pressure (mm Hg)
[0294] P.sub.water vapor=0 mm Hg at 34.degree. C. (in a dry cell)
(mm Hg)
[0295] P.sub.water vapor=40 mm Hg at 34.degree. C. (in a wet cell)
(mm Hg)
[0296] t=average thickness of the lens over the exposed test area
(mm) where Dk.sub.app is expressed in units of barrers.
[0297] The oxygen transmissibility (Dk/t) of the material may be
calculated by dividing the oxygen permeability (Dk.sub.app) by the
average thickness (t) of the lens.
Ion Permeability Measurements.
[0298] The ion permeability of a lens is measured according to
procedures described in U.S. Pat. No. 5,760,100 (herein
incorporated by reference in its entirety. The values of ion
permeability reported in the following examples are relative
ionoflux diffusion coefficients (D/D.sub.ref) in reference to a
lens material, Alsacon, as reference material. Alsacon has an
ionoflux diffusion coefficient of 0.314.times.10.sup.-3
mm.sup.2/minute.
Example 2
[0299] This example illustrates unexpected discoveries that,
without adding any extra reducing agent, one can obtain a
relatively stable polymerizable dispersion containing silver
nano-particles (Ag NP) by simply adding silver salt (e.g.
AgNO.sub.3, or AgClO.sub.4) into a polymerizable composition
comprising a siloxane-containing macromer with hydrophilic units, a
siloxane-containing monomer, a hydrophilic monomer capable of
reducing silver ions into silver nano-particles.
Addition of AgNO.sub.3 in Formulation I
[0300] A silver nitrate solution is added into a volume of
formulation I to make the concentration of silver nitrate equal to
about 50 ppm. Before mixing, both silver nitrate and formulation I
are clear/colorless in appearance under the examination of naked
eyes. However, formulation I turns into yellowish appearance after
adding silver nitrate therein, indicating the formation of silver
nano-particles. The formation of silver nano-particles is also
confirmed by UV spectroscopy with absorption peaks around 420-430
nm, a characteristic of silver nano-particles. When monitoring the
UV absorption spectrum of the formulation I after adding silver
nitrate, the intensity of a UV absorption peak around 430 nm is
observed to increase with mixing time but reaches a plateau in
about 8 hours, as shown in Table 2. Silver nano-particles are
formed when adding 50 ppm of silver nitrate into the formulation
I.
TABLE-US-00002 TABLE 2 Time (minutes) 10 30 60 240 480 720 1800
3540 5160 Peak position (nm) 430 430 431 435 427 425 417 420 421
Peak Intensity 0.213 0.342 0.526 0.700 0.834 0.891 0.881 0.838
0.879
[0301] In another experiment, a silver nitrate solution is added
into a volume of formulation I to make the concentration of silver
nitrate equal to about 610 ppm. When monitoring the UV absorption
spectrum of the lotrafilcon A formulation after adding silver
nitrate, it is observed that the intensity of a UV absorption peak
around 430 nm increases from about 1.1 at about 30 minutes, to
about 1.34 at about 90 minutes, and to about 1.34 at about 180
minutes. Silver nano-particles are formed when adding 610 ppm of
silver nitrate into formulation I.
[0302] The absorption peak position and peak intensity depends on
the concentration of added silver salt. when the concentration of
AgNO.sub.3 increased from about 80 ppm, to 800 ppm, to 1600 ppm,
the peak position changes from 423 nm, to 430 nm and then to 433
nm, respectively.
Addition of AgClO.sub.4 in Formulation I
[0303] A silver perchlorate (AgClO.sub.4) solution is added into a
volume of formulation I to obtain a concentration of 60 ppm of
silver perchlorate (AgClO.sub.4). When monitoring the UV absorption
spectrum of the formulation I after adding silver perchlorate
(AgClO.sub.4), it is observed that the intensity of a UV absorption
peak around 430 nm increases with mixing time but reaches a plateau
in about 8-10 hours, as shown in Table 3. Silver nano-particles are
formed when adding 60 ppm of silver perchlorate (AgClO.sub.4) into
the lotrafilcon A formulation.
TABLE-US-00003 TABLE 3 Time (minutes) 10 30 60 240 480 720 1800
3540 5160 Peak position (nm) 430 430 431 438 427 425 417 420 421
Peak Intensity 0.242 0.394 0.576 0.875 0.887 0.965 0.989 0.857
0.950
Extremely Slow Formation of Ag NP in Ethanol
[0304] 0.0397 g AgNO.sub.3 solid is added into 20 ml of ethanol at
room temperature. It took almost 1 hour to completely dissolve
AgNO.sub.3 in ethanol under vigorous stirring. No UV peak is
observed after 5 hours. After 5 days, a tiny absorption peak around
367 nm is observed, indicating the formation of some silver
nano-particles (Ag-NPs). To speed up the reduction of Ag.sup.+ to
(Ag.sup.0).sub.n, reducing agent (in this case, sodium borohydride,
NaBH.sub.4) and stabilizer (polyacrylic acid, PAA, Mw=2000) is
added into the ethanol solution. It turned out that reducing
process is still very slow with added reducing agent. After 6 days,
a tiny peak around 365 nm is observed. Results indicate that Ag NPs
can be formed in an extremely slow manner in ethanol.
Formation of Unstable Ag NP in Dimethyl Acrylamide (DMA)
[0305] When adding silver nitrate (0.01113 g or 0.1113 g) into DMA
(50 ml), its color changes from colorless to yellowish, indicating
the formation of silver nano-particles. The formation of silver
nano-particles is also confirmed by UV spectroscopy, as listed in
Table 4. However, the silver nano-particles can not form a stable
dispersion in DMA. Instead, the silver nano-particles precipitate
on the wall of the container and forms a "silver mirror within a
hour"
TABLE-US-00004 TABLE 4 Time (minutes) 40 60 90 120 Peak position
(nm) 430 430 431 435 Peak Intensity.sup.1 0.657 1.191 1.421 1.406
Peak position (nm) 0.213 0.342 0.526 0.700 Peak Intensity.sup.2
1.509 1.583 1.397 1.299 .sup.1Adding 0.01113 g AgNO.sub.3 in 50 ml
of DMA, equivalent of 222 ppm of AgNO.sub.3 .sup.2Adding 0.1113 g
AgNO.sub.3 in 50 ml of DMA, equivalent of 2226 ppm of
AgNO.sub.3
Formation of Ag NP in N-vinylpyrrolidone (NVP)
[0306] When 0.1113 gram of silver nitrate is added into 10 ml of
NVP (about 11130 ppm of AgNO.sub.3) at room temperature, the color
of NVP changes from clear to yellow after about 10 min, indicating
the formation of silver nano-particles. This is confirmed by a UV
absorption peak at 440 nm. At 3 hours the absorption intensity is
about 0.10. After 24 hours at 4.degree. C., the absorption
intensity increases to about 0.19. No precipitation of particles is
observed after about 24 hours.
No Formation of Ag NP in HEMA
[0307] When adding 0.0015 gram of silver nitrate in 30 ml of
hydroxyethyl methacrylate (HEMA) (50 ppm of AgNO.sub.3), no color
change is observed.
No Formation of Ag NP in TRIS
[0308] Qualitatively, when adding silver nitrate in TRIS, no color
change is observed.
Formation of Unstable Ag-NP in a Mixture of DMA and TRIS
[0309] When adding 197 or 1310 ppm of silver nitrate into 1:1
(volume ratio) mixtures of DMA and TRIS, the formation of silver
nano-particles is observed from the color change. Where AgNO.sub.3
concentration is 197 ppm, the color of the solution changes from
clear to gold yellow, then to brown yellow. After 3 hr, deposit is
found on the wall of the container. Where AgNO.sub.3 concentration
is 1310 ppm, after one hour, the color changes to black and deposit
is found on the wall of the container.
Formation of Ag-NP in a Mixture of DMA and Siloxane-Containing
Macromer
[0310] When adding silver nitrate in 1.66:1 (volume ratio) mixtures
of DMA and macromer prepared in Example 1, the formation of silver
nano-particles is observed from the color change. The concentration
of silver nitrate in this experiments ranges from about 84 ppm to
840 ppm. The color of the solution changes from clear to yellow
after about 20 minutes. The mixture is stirred for about 5 hours.
About one hour after stopping stirring, some deposit can be
found.
Formation of Ag-NP in a Siloxane-Containing Macromer Solution
[0311] Qualitatively, when adding silver nitrate in a macromer
(prepared in Example 1) solution, there is no immediate color
change from the macromer solution. When observed again on 2nd day
(after about 24 hour), the slight yellow color of the macromer
solution does indicate the formation of silver nano-particles. Some
deposit can be found after two days.
Example 3
Dispersion of Nano-Sized Activated Silver Powder in Formulation
I
[0312] To test if the nanosize activated silver powder (99.9+% Ag,
from Aldrich) can be dispersed evenly (uniformly) in formulation I,
an appropriate amount of silver powder is added directly into a
volume of formulation to make up a solution with 500 ppm of silver
powder. The nanosize activated silver powder does not dissolve in
the formulation. Stirring or sonication is used to help the
dispersion. After more than 1 hr of stirring, the solution appears
clear with gray particles suspended within the solution. Some of
the gray particles can also be seen on the stirring bar. In about
10 minutes after the stirring is stopped, gray particles are seen
on the stirring bar and on the bottom of the container. In the case
of sonication, the solution become cloudy after 30 minutes of
sonication at 0.degree. C. In about 20 minutes after the sonication
is stopped, gray particles are seen in the bottom of the container.
These experiments indicates that nanosize activated silver powder
can not be dispersed in formulation I to form a stable dispersion
(i.e., precipitation of particles occurs in less than 30 minutes)
and that sonication may cause some partial polymerization of
formulation I. Unstable polymerizable dispersion containing silver
nanoparticles may not be suitable for production of antimicrobial
contact lenses comprising siver nano-particles uniformly
distributed therein.
Example 4
Lenses Made from Non-Degassed Formulations with 50 ppm of
AgNO.sub.3 Added
[0313] A polymerizable dispersion is prepared by adding calculated
amount (50 ppm) of silver nitrate into a calculated amount of
formulation I. The mixture of formulation I with silver salt is
stirred for 1 hr at room temperature to form silver nano-particles
before making contact lenses by means of molding in polypropylene
molds. An amount of the polymerizable dispersion with silver
nano-particles is introduced into each polypropylene molds and
cured for 30 minutes under UV light to form contact lenses. The
lenses are then extracted in isopropyl alcohol (IPA) overnight,
then packaged and autoclaved in phosphate buffered saline.
[0314] All lenses prepared as described above are transparent with
a very light yellowish hue. The lenses show a UV absorption peak
around 400 nm, characteristic of Ag NP. The intensity of the peak
is about 0.03 absorption unit per lens. The peak (peak position and
peak intensity) is stable over time. The refractive index of the
lenses is measured to be 1.427, which is the same value as lenses
made from formulation I without Ag NP therein.
Example 5
Lenses Made from Non-Degassed Formulations with 5000 ppm of
AgNO.sub.3 Added
[0315] A polymerizable dispersion is prepared by adding a
calculated amount (5000 ppm) of silver nitrate into a calculated
amount of formulation I. The mixture of formulation I with silver
salt (5000 ppm) is stirred for 1 hr at room temperature before
making contact lenses by means of molding in polypropylene molds.
An amount of the mixture is introduced into each polypropylene
molds and cured for 60 minutes under UV light to form contact
lenses. The lenses are then extracted in isopropyl alcohol (IPA)
overnight, then packaged and autoclaved in phosphate buffered
saline.
[0316] All contact lenses prepared as described above are dark
brown in color due to high concentration of silver nano-particles.
The lenses show a UV absorption peak at about 404 nm,
characteristic of Ag NP. The intensity of the peak is above 1.2
absorption unit per lens.
Example 6
Lenses Made from Degassed Formulations with 50 ppm of Added
AgNO.sub.3
[0317] A polymerizable dispersion of silver nitrate is prepared by
adding calculated amount (50 ppm) of silver nitrate into a
calculated amount of formulation I. The mixture of formulation 1
and 50 ppm of silver salt is stirred for 1 hr before being
degassed. Then the mixture containing silver is degassed to remove
oxygen from the mixture. An amount of the degassed mixture is
introduced into each polypropylene molds in a nitrogen glove box
and cured under UV light to form contact lenses. The lenses are
then extracted in IPA, then packaged and autoclaved in phosphate
buffered saline.
[0318] The lenses are transparent with a very light yellowish hue.
The lenses show a UV absorption peak at about 400 nm,
characteristic of Ag NP. The refractive index of the lenses is
measured to be 1.4257, which is the same value as the lotrafilcon A
lenses without Ag NP therein.
[0319] The ion permeability (IP) of the lenses is measured to be
1.20. Control lenses made from formulation I without silver
nano-particles normally have an IP value of about 1.0 or higher.
These results indicate that the presence of silver nano-particles
formed in situ in a lens formulation containing 50 ppm of
AgNO.sub.3 does no have adverse effects on the ion permeability of
lenses.
[0320] The oxygen permeability (Dk) of the lenses is measured to be
109.5 barrer.
Example 7
Lenses Made from Degassed Formulations with 500 ppm of Added
AgNO.sub.3
[0321] A polymerizable dispersion 500 ppm of silver nitrate is
prepared by adding a calculated amount (500 ppm) of silver nitrate
into a calculated mount of formulation I. The mixture of
formulation with silver salt is stirred for 1 hr before being
degassed. Then the mixture containing silver is degassed to remove
oxygen from the mixture. An amount of the degassed mixture
containing silver is introduced into each polypropylene molds in a
nitrogen glove box and cured under UV light to form contact lenses.
The lenses are then extracted in IPA, then packaged and autoclaved
in phosphate buffered saline.
[0322] The lenses are transparent with a very light yellowish hue.
The lens show a UV absorption peak at about 400 nm, characteristic
of Ag NP. The refractive index of the lens is measured to be
1.4259, which is the same value as control lenses without Ag NP
therein.
[0323] The ion permeability (IP) of the lenses is measured to be
1.508. Control lenses without Ag NP therein normally have an IP
value of higher than 1.0. These results indicate that the presence
of silver nano-particles formed in situ in formulation I containing
500 ppm of AgNO.sub.3 does no have adverse effects on the ion
permeability of lenses.
[0324] The oxygen permeability (Dk) of the lenses is measured to be
108.66 barrer.
Example 8
Formation of Ag NP in Formulation I in the Presence of a
Stabilizer
[0325] When silver nitrate is added directly to formulation I, the
formed silver nano-particles are usually stable only up to about
two or more hours depending on silver nitrate concentration. For
examples, for 100 ppm silver nitrate in formulation I, severe
precipitation of particles can be found after overnight. However,
when PAA as stabilizer is used appropriately, the stability of the
silver nano-particles in formulation I is significantly increased
to at least 3 days for a mixture of formulation I with 100 ppm of
silver nitrate.
[0326] Polyacrylic acid (PAA) can function as a stabilizer of
silver nanoparticles in aqueous medium to prevent the aggregation
of silver nano-particles. It is discovered that when a small amount
of PAA is added into formulation I, the stability of the silver
nanoparticles in the formulation is further improved. The order of
adding PAA is important. The PAA can be added alone into the
formulation, or the mixture of PAA and silver salt can be added
into the formulation, or the mixture of DMA+PAA+silver salt can be
added into the formulation. The ratio of DMA/PAA/AgNO.sub.3 could
be varied from 1/1/1 to x/y/1, here x can be greater or small than
1, y can be greater or smaller than 1. Preferably, x is between 0.1
and 10, y is between 0.1 and 10, more preferably, x is between 5
and 0.5, and y is between 0.5 and 5. The concentration of PAA in
the formulation can be between 1 ppm and 500 ppm, more preferably
between 1 and 300 ppm.
Example 9
Formation of Ag NP in Formulation II
[0327] A polymerizable dispersion is prepared by adding a
calculated amount (50 ppm) of silver silver nitrate) into a
calculated mount of formulation II. The mixture of formulation II
with silver salt is stirred for 1 hr before being cast. The mixture
is then cast into polypropylene molds at ambient condition and
cured under UV light for 30 min to form lenses. The lenses are then
extracted in IPA, then packaged and autoclaved in phosphate
buffered saline.
[0328] The lenses are transparent with a very very light bluish
hue. The lens show a UV absorption peak at about 400 nm,
characteristic of Ag NP.
Example 10
Preparation of Ag NP-Containing Polymerizable Dispersion by Mixing
Preformed Ag NP into Formulation I
[0329] Stabilized-Ag nano-particles (Ag NP) are prepared as
follows. 1 mL of 0.01M AgNO.sub.3 is mixed with 0.5 mL of 4% (by
weight) PAA solution. PAA functions as a stabilizer for Ag NP. The
mixture is then keep at 0.degree. C. using ice-water mixture. Ice
cold water is used to prepare 98.5 mL of 1 mM NaBH.sub.4 solution,
which is also kept in 0.degree. C. using ice-water mixture. The
mixture of AgNO.sub.3 and PAA is then added rapidly into 98.5 mL of
1 mM NaBH.sub.4 solution with vigorous stirring. The beaker is
surrounded by ice to keep at about 0.degree. C.
[0330] It should be understood that the Ag.sup.+ reduction reaction
can be carried at various temperatures, for example, at any
temperature between 0.degree. C. and elevated temperature,
preferably between 0.degree. C. and the room temperature, and for a
period of time from a few minutes to 24 hours or longer. PAA with
different molecular weight can be used. It should be also
understood that UV irradiation, heating, or hydrogen can also be
used to reduce Ag+ to form Ag nano-particles.
[0331] Direct adding aqueous stabilized-Ag NP solution into
formulation I causes the formulation to become cloudy and therefore
is not feasible for making contact lenses.
[0332] It is found that a lyophilized stabilized Ag silver
nanoparticles can be successfully dispersed in formulation I. The
PAA-stabilized Ag NP dispersion is lyophilized (i.e., freeze dried)
to obtain lyophilized stabilized-Ag nano-particles, which appear a
color of brown or black. Re-suspending the stabilized-Ag NP
directly in formation I leads to a quasi-homogeneous solution which
is yellowish in color and has a UV absorption around 440 nm. This
provides an alternative and effective way for preparing a
polymerizable dispersion which contains Ag NP.
Example 11
Antimicrobial Activity Assay
[0333] Antimicrobial activity of a contact lens with or without
silver nanoparticles in the lenses of the invention is assayed
against Pseudomonas aeruginosa GSU #3, which is isolated from a
corneal ulcer. Bacterial cells of Pseudomnas aeruginosa GSU #3 is
stored in a lyophilized state. Bacteria are grown on an Tryptic Soy
agar slant for 18 hours at 37.degree. C. The cells are harvested by
centrifugation and washed twice with sterile, Delbeco's phosphate
buffered saline. Bacterial cells are suspended in PBS and adjusted
to Optical Density of 10.sup.8 cfu. The cell suspension is serially
diluted to 10.sup.3 cfu/ml.
[0334] Antimicrobial activity of some contact lenses with or
without silver nanoparticles in the lenses of the invention is also
assayed against Staphylococcus aureus ATCC #6538. Bacterial cells
of S. aureus #6538 is stored in a lyophilized state. Bacteria are
grown on an Tryptic Soy agar slant for 18 hours at 37.degree. C.
The cells are harvested by centrifugation and washed twice with
sterile, Delbeco's phosphate buffered saline. Bacterial cells are
suspended in 1/20th strength Tryptic Soy Broth (TSB) and adjusted
to Optical Density of 10.sup.8 cfu. The cell suspension is serially
diluted to 10.sup.3 cfu/ml in 1/20th strength TSB.
[0335] Lenses having silver in them are tested against the control
lenses (i.e., without silver). 200 .mu.l of from about
5.times.10.sup.3 to 1.times.10.sup.4 cfu/ml of P. aeruginosa GSU #3
or S. aureus #6538 is placed on the surface of each lens. Incubate
at 25.degree. C. for 24 hours. Aspirate 50 .mu.l out of the lens,
serially dilute and plate out on agar plates to determine the
microbial load of each lens. At 24 hours, colony counts are
taken.
In-Vitro Zone of Inhibition Test
[0336] Tryptic Soy Agar (TSA) slants are inoculated with
Pseudomonas challenge organisms and are incubated 18-24 hours at
37.degree. C. with 5% CO.sub.2. Following incubation the TSA slants
are flooded with DPBS to suspend the cells. The cell suspension is
centrifuged and the supernatant decanted. The cell pellet is washed
once via re-suspension in DPBS, centrifugation and decanting. The
final washed cell pellet is then re-suspended in DPBS and the
suspension density adjusted to approximately 1.times.10.sup.8
CFU/mL using a spectrophotometer. The cell suspension is serially
diluted in PBS to a final concentration of approx. 5.times.10.sup.5
CFU/mL. TSA plates are seeded with Pseudomonas by spread plating
0.1 mL of the above suspension and allowing the plates to dry for
15 minutes at ambient temperature.
[0337] Each TEST or CONTROL lens is aseptically transferred to the
surface of the TSA plates previously seeded with Pseudomonas
challenge organism. If necessary, the lenses are aseptically cut
along their radius (pinwheel fashion) in order to facilitate full
and direct contact with the plate surface. The plates are then
incubated at 37.degree. C. w/o CO.sub.2 for approximately 18-24
hours and observed for growth periodically for 72 hours.
[0338] Following incubation the Pseudomonas challenge organism
should exhibit confluent growth over the entire plate surface. A
"clear zone" observed surrounding the lens indicates leaching of
microbicidal agent(s) from the lens into the surrounding media in
sufficiently high concentration to inhibit the growth of the
Pseudomonas challenge organism. The diameter of this zone can be
measured as an indication of the relative degree of inhibition.
In-Vitro Antimicrobial Activity of Lenses from Example 4
[0339] Antimicrobial activity of a contact lens with silver
nano-particles is assayed against Pseudomonas aeruginosa GSU #3
according to the procedure described above. The lenses with silver
nano-particles show antimicrobial activity, characterized by at
least 88% inhibition of viable cells as compared to the control
lenses. Averaged CFU/lens for control lenses (without silver
nanoparticles) is about 2.9.times.10.sup.4.
[0340] No zone of inhibition is found, which indicated no leaching
of high concentration of silver within the test period of time.
In-Vitro Antimicrobial Activity of Lenses from Example 6
[0341] Antimicrobial activity of a contact lens with silver
nano-particles is assayed against Pseudomonas aeruginosa GSU #3
according to the procedure described above. The lenses with silver
nano-particles show antimicrobial activity, characterized by 100%
inhibition of viable cells as compared to the control lenses.
Averaged CFU/lens for control lenses (without silver nanoparticles)
is about 2.9.times.10.sup.4
[0342] No zone of inhibition is found, which indicated no leaching
of high concentration of silver within the test period of time.
In-Vitro Antimicrobial Activity of Lenses from Example 7
[0343] Antimicrobial activity of a contact lens with silver
nano-particles is assayed against Pseudomonas aeruginosa GSU #3
according to the procedure described above. The lenses with silver
nano-particles show antimicrobial activity, characterized by 100%
inhibition of viable cells as compared to the control lenses.
Averaged CFU/lens for control lenses (without silver nanoparticles)
is about 2.9.times.10.sup.4
[0344] No zone of inhibition is found, which indicated no leaching
of high concentration of silver within the test period of time.
In-Vitro Antibacterial Activity of Lenses from Example 9
[0345] Antimicrobial activity of a contact lens with silver
nano-particles is assayed against Pseudomonas aeruginosa GSU #3
according to the procedure described above. The lenses with silver
nano-particles show antimicrobial activity, characterized by 100%
inhibition of viable cells as compared to the control lenses.
Averaged CFU/lens for control lenses (without silver nanoparticles)
is about 2.9.times.10.sup.4.
Example 12
Control the Color of Silver Nanoparticles Solutions
[0346] Normally, yellow is the color for silver nano-particles
solutions formed either in aqueous solution using reducing agent
(e.g. NaBH.sub.4) or in formulation I or II. It is unexpected
discovered that colors other than yellow can be generated by
exposing a PAA-AgNO.sub.3 mixture solution to a certain UV
treatment.
[0347] 1. Aqua blue silver nano-particle solution: [0348] A
solution of PAA-AgNO.sub.3 mixture with 1:1 molar ratio of --COOH
and AgNO.sub.3 is prepared by dissolve calculated amount of PAA and
AgNO.sub.3 into appropriate volume of water. The pH of the solution
is about 3.3-3.4 for a 10 mM solution. The solution is clear with
no color. Then the solution is exposed to a LQ-400 Grobel lamp
whose UV spectrum covers from 250 nm to 660 nm. The exposure time
varies from 10 sec to 180 sec. It is discovered that at 35 sec
exposure, the solution remains clear; after 50 sec exposure, the
solution turned into aqua blue; after 180 sec exposure, the
solution remains aqua blue. [0349] The blue color cannot be
produced when the PAA-AgNO.sub.3 mixture solution is exposed to a
fluorescent tube with a UV spectrum of 350 to 440 nm. [0350] It is
also discovered that the blue color disappear when the pH of the
solution is adjusted to 2.5 using nitric acid.
[0351] 2. Pink silver nano-particle solution [0352] Another
unexpected and interesting discovery is that when the pH of the
solution is first adjusted to 5.0, the solution turned from clear
to pink when exposed to a LQ-400 Grobel lamp for 30 sec or longer.
In addition the color progressed from light pink to medium pink and
then to dark pink when the exposure time increased from 30 sec, to
65 sec and then to 120 sec.
[0353] 3. Green silver nano-particle solution [0354] When adding a
drop of 1 mM NaBH.sub.4 solution to 10 mM of PAA-AgNO.sub.3 (1:1)
mixture solution, the solution turned from clear to light yellow.
Interestingly, the solution then turned into green color after
exposed for 65 sec to a LQ-400 Grobel lamp.
Example 13
Preparation of Clear and/or Visitinted Lenses from Formulation I
Containing Silver Nano-Particles and Colorant
[0355] Normally, lenses containing silver nano-particles may have a
yellowish tint or appear yellowish depending on the concentration
of silver in the lenses. It is discovered that the yellowish tint
or color can be compensated by using a colorant. One example is to
use carbazole violet, an FDA approved pigment used in color contact
lenses, for examples, Freshlook color contact lenses.
[0356] Lenses with different color appearance are made from
mixtures of formulation I with variable concentrations of carbazole
violet. Firstly, formulation I containing silver nao-particles are
prepared according the procedure described in Example 4. The
formulation with silver nano-particles are usually yellowish in
color. Secondly, the color of the yellowish dispersion is adjusted
by adding either a carbazole violet stock solution (.about.2%
carbazole violet in hydroxyethyl methacrylate (HEMA)) or carbazole
violet powder. Then an amount of the dispersion with carbazole
violet and silver nano-particles is introduced into each
polypropylene molds and cured for 5 minutes under UV light to form
contact lenses. The lenses are then extracted in isopropyl alcohol
(IPA), then packaged and autoclaved in phosphate buffered
saline.
[0357] As listed in Table 5, clear and visited lenses containing
silver nano-particles are successfully prepared.
TABLE-US-00005 TABLE 5 [Carbazole [AgNO.sub.3] violet] Color of
Carbzaole ppm ppm formulation Color of lens violet source 50 0
yellow yellowish tint / 50 20 Lilac purple clear Stock solution 100
50 purple light purple tint Stock solution 100 100 dark purple
purple tint Stock solution 100 45 dark purple pink tint powder 100
90 dark purple purple tint powder
Example 14
[0358] All of the lenses in this example are cast at ambient
condition, UV cured and IPA extracted.
Control Lenses Made from Formulation II without Silver
Nano-Particles
[0359] Control lenses are prepared from formulation II without
adding any silver salt or silver nano-particles. An amount of
formulation II is introduced into each polypropylene molds and
cured for 60 minutes under UV light to form contact lenses. The
lenses are then extracted in isopropyl alcohol (IPA), then packaged
and autoclaved in phosphate buffered saline.
Lenses Made from Formulation II Containing Silver
Nano-Particles
[0360] A polymerizable dispersion is prepared by adding silver
nitrate in a volume of formulation II to have AgNO.sub.3
concentration equal to 500 ppm. Silver nitrate is dissolved easily
in formulation II under stirring. An amount of the dispersion is
introduced into each polypropylene molds and cured for 60 minutes
under UV light to form contact lenses. The lenses are then
extracted in isopropyl alcohol (IPA), then packaged and autoclaved
in phosphate buffered saline.
[0361] When examining obtained lenses under dark field microscope,
silver nano-particles are found to be distributed uniformly within
the lenses.
Lenses Made from Formulation II with Silver Powder in the
Formulation.
[0362] A polymerizable mixture is prepared by adding nanosize
activated silver powder (99.9+% Ag, from Aldrich) in an amount of
formulation II to have the concentration of nanosize activated
silver powder equal to about 500 ppm. The nanosize activated silver
powder does not dissolve in the formulation, and therefore by
sonication large particles are forced to be dispersed in the
formulation, which caused the change of transparent blue
formulation into cloudy blue formulation. An amount of the mixture
is introduced into each polypropylene molds and cured for 60
minutes under UV light to form contact lenses. The lenses are then
extracted in isopropyl alcohol (IPA), then packaged and autoclaved
in phosphate buffered saline.
[0363] Under dark field microscope, whitish particles are observed
and the distribution of the particles is not uniform comparing with
other lenses prepared in this example.
Example 15
Contact Lenses Containing Ag NP and Different Concentration of
Stabilizer
[0364] A polymerizable dispersion is prepared by adding calculated
amount of silver stock solution (SSS) into a calculated amount of
formulation I. The silver stock solution is prepared by adding
calculated amount of polyacrylic acid (PAA) and silver salt (such
as silver nitrate) into a given amount of dimethylacrylamide (DMA).
The mixture of formulation I with silver stock solution is stirred
for 4 hr or longer at room temperature to form silver
nano-particles before making contact lenses by means of molding in
polypropylene molds. An amount of the polymerizable dispersion with
silver nano-particles is introduced into each polypropylene molds
and cured for 30 minutes under UV light to form contact lenses. The
lenses are then extracted in isopropyl alcohol (IPA), then packaged
and autoclaved in phosphate buffered saline.
[0365] The silver-nano particle formation is controlled by the
relative concentration of silver to PAA, as indicated by the color
change of the formulation. For formulations with either 300 ppm or
500 ppm of silver nitrate, when the molar ratio of AgNO.sub.3/PAA
(note that the molar ratio is calculated based on the molecular
weight of silver nitrate and the molecular weight of the repeating
unit of PAA) changes from 4/1, 2/1, 1/1, 1/2, 1/4, to 1/8, the
color of the formulation changes from obvious yellow, to less
obvious yellow, and to even almost no color. Since yellow is the
characteristic color of silver nano-particles, this phenomena
indicates that the formation of the PAA-stabilized silver
nano-particles can be controlled by the relative concentration of
silver to PAA.
[0366] The in-vitro activity of the formed contact lenses are
assayed against S. aureus #6538 according the procedures described
in example 11. It is discovered that the activity is controlled by
silver concentration and the relative concentration of silver to
PAA. For lenses made from formulations with either 300 ppm or 500
ppm of silver nitrate, the lenses may or may not show in-vitro
antimicrobial activity, characterized by about 99% to almost 0%
inhibition of viable cells as compared to the control lenses,
depending on the molar ratio of AgNO.sub.3/PAA (note that the molar
ratio is calculated based on the molecular weight of silver nitrate
and the molecular weight of the repeating unit of PAA). Ag/PAA
ratio from 4/1 to 1/4 is preferred, and more preferably from 1/2 to
2/1 is preferred. Ag/PAA of 1/8 is generally not preferred. Similar
results are found for blue formulation I (formulation I which
contains copper phthalocyanine blue pigments).
[0367] It is understood that the molecular weight of PAA used here
is about 2000. PAA with molecular weight higher or lower than 2000
can also be used. Although the sodium salt of PAA (PAANa) is not
preferred.
Example 16
Visibility-Tinted Contact Lenses Containing PAA Stabilized Ag NP
and Different Colorants
[0368] A contact lens prepared from formulation I with AgNP or PAA
stabilized AgNP may appears to be yellowish. A color adjuster (e.g.
a pigment or a dye, such as copper phthalocyanine (CuP blue),
and/or carbazole violet (CV), phthalocyanine green (PCN green), or
reactive blue dyes (e.g., blue HEMA)) is used to impart the lenses
with desired color appearance and handling tint. CuP blue or PCN
green pigment is dispersed in TRIS. Polymerizable dispersions are
prepared by adding calculated amount of silver stock solution (SSS)
into a calculated amount of formulation I contains certain
concentration of color adjuster. The silver stock solution is
prepared by adding calculated amount of polyacrylic acid (PAA) and
silver salt (such as silver nitrate) into a given amount of
dimethylacrylamide (DMA). The mixture of formulation I with silver
stock solution is stirred for 4 hr or longer at room temperature to
form silver nano-particles. The formulations are then stored at
4.degree. C. until being degassed to remove oxygen and then ready
for making contact lenses by means of molding in polypropylene
molds. An amount of the polymerizable dispersion with silver
nano-particles is introduced into each polypropylene molds and
cured for 30 minutes under UV light to form contact lenses. The
lenses are then extracted in isopropyl alcohol (IPA), then packaged
and autoclaved in phosphate buffered saline.
[0369] The in-vitro activity of the formed contact lenses are
assayed against Pseudomonas aeruginosa GSU #3 according the
procedures described in example 11. As shown in Table 6, the color
adjusters impart the contact lens with handling color tint and do
not appear to adversely affect the in-vitro activity against
Pseudomonas aeruginosa.
TABLE-US-00006 TABLE 6 Colorant and concentration [AgNO.sub.3] ppm
[PAA] ppm % of Inhibition CuP, 60 ppm 500 212 >99% CuP, 90 ppm
456 212 >99% CuP, 90 ppm 200 93 >99% CuP, 120 ppm 456 212
>99% CuP, 120 ppm 200 93 >99% CuP, 60 ppm, CV, 8 ppm 456 212
>99% PCN, 60 ppm 456 212 >99% PCN, 60 ppm 200 93 >99%
[0370] Colorants (such as CuP and PCN) may also be modified by
amphiphilic copolymers (e.g. poly(ethyl acrylate)-polyacrylic acid
(PEA-PAA) copolymer)
Example 17
Different Stabilizers for Silver Stock Solution Preparation
[0371] To prepare a formulation containing AgNP, one of the
approaches is to prepare a silver stock solution (SSS) and then mix
the SSS with the formulation. Generally there is no AgNP formation
in SSS, or only a percentage of Ag+ is converted to AgNP in SSS.
All or majority of AgNP forms in-situ when mixing SSS with
formulation. In addition to PAA as a stabilizer for silver stock
solution preparation, other stabilizers are also studied. Both
small molecules and polymers are studied. Small molecules that can
function as stabilizer in silver stock solution preparation
includes acrylic acid, citric acid, etc. For polymers, both charged
and non-charger polymers and amphiphilic polymers are studied. Some
of the examples of stabilizers include PAA and polyvinylpyrrolidone
(PVP) of different molecular weights. The sodium salt of PAA
(PAANa) is also tried to be used as a stabilizer in silver stock
solution preparation. Other polymers, including polyethylene glycol
(PEG), polyethylene imine (PEI), polydimethylsiloxane-polyacrylic
acid (PDMS-PAA) copolymer, poly(ethyl acrylate)-polyacrylic acid
(PEA-PAA) copolymer, are also studied and they appears to be not as
good as compared to PAA.
Example 18
"Step-by-Step" Preparation of Formulation Containing AgNP
[0372] As disclosed in example 17, to prepare a formulation
containing AgNP, one of the approaches is to prepare a silver stock
solution (SSS) and then mix the SSS with the formulation. Instead
of mixing SSS with formulation which consists of macromer, TRIS,
DMA, Darocure and ethanol as shown in example 1, another approach
is to mix SSS with formulation components. Since the formulation
consists of multiple components, there are multiple possibilities
in which SSS can be mixed in. However, the order of mixing SSS, or
in other words, to mix SSS with which component first, is very
important to form a formulation with stable AgNP suspension. As an
example, the SSS is mixed with TRIS first, then the mixture of Tris
and SSS is immediately (within about 1 min) added into macromer.
The mixture of macromer and TRIS/SSS is stirred for about 20 min.
Then DMA is added into the mixture and stirred for 20 min, followed
by ethanol. The mixture is then stirred for 60 min before Darocure
is added. The final mixture is stirred for another 90 min. The
formulation prepared in this way contains AgNP as indicated by the
characteristic UV absorption peak around 400 nm.
Example 19
Preparation of Formulation Containing AgNP Using Stabilized
AgNP-Ethanol Solution
[0373] Another approach to prepare a formulation containing AgNP is
to use stabilized AgNP-ethanol solution. After studying different
stabilizers which are capable of forming stabilized AgNP in
ethanol, polyvinylpyrrolidone (PVP) is chosen as the stabilizer in
this approach. PVP-stabilized AgNP solution in ethanol is prepared
by dissolving calculated amount of PVP in ethanol, followed by
adding desired amount of silver salt (e.g. silver nitrate). The
AgNP is then produced by using a reducing agent, such as sodium
borohydride (NaBH.sub.4). The PVP-stabilized AgNP-ethanol solution
is very stable over time, based on the constant UV adsorption peak
around 400 nm monitored over a week. This PVP-stabilized
AgNP-ethanol solution is then mixed with the other components
(macromer, Tris, DMA and Darocure) to form a formulation containing
AgNP. Depending on the preparation conditions (e.g., silver
concentration, PVP molecular weight, and PVP:Ag ratio, etc), some
particles may form when mixing PVP-stabilized AgNP-ethanol solution
into the formulation components. Those obvious particles formed
during the process can be easily removed by filtration.
[0374] As an example, a PVP-stabilized AgNP-ethanol is prepared by
dissolving 0.0588 gram of PVP (Mw of 55000) into 300 gram of
ethanol. After 20 min of stirring, 0.06 gram of silver nitrate
solid as added. After another 20 min stirring, a calculated amount
of NaBH.sub.44 aqueous solution is added into the mixture, to
achieve a molar ratio of 1.5:1:1 for PVP:AgNO.sub.3:NaBH.sub.4. A
stirring of at least 20 min is allowed. The final solution is clear
with a golden color due to the presence of PVP-stabilized AgNP,
which is also confirmed by a characteristic UV absorption peak
around 400 nm. It is obvious to those who are skill in the art that
PVP of other molecular weights and different PVP:Ag ratios can be
used
[0375] A formulation I with 60 ppm of CuP, 50 ppm of AgNO.sub.3 and
49 ppm of PVP is then prepared by mixing appropriate amount of
macromer, Tris-CuP, DMA, Darocure and PVP-stabilized AgNP-ethanol
solution. The formulation is filtered to remove any particles which
are bigger than 5 microns and degassed for casting lenses. The
in-vitro activity of the formed contact lenses are assayed against
Pseudomonas aeruginosa GSU #3 according to the procedures described
in example 11. The lenses with PVP-stabilized silver nano-particles
show antimicrobial activity, characterized by 98% inhibition of
viable cells as compared to the control lenses.
Example 20
Prolong In-Vitro Antimicrobial Activity of AgNP-Containing Contact
Lenses
[0376] The prolong in-vitro antimicrobial activities of Ag
nanoparticle-containing contact lenses are studied by testing their
in-vitro antimicrobial activities against Pseudomonas aeruginosa
GSU #3 and Staphylococcus aureus ATCC #6538 after at least 5
consecutive soaking/rinsing cycles, each cycle comprising
soaking/rinsing each lens in a phosphate buffered saline (PBS) or
ClearCare.RTM. (CIBA Vision) for a period of time from about 24 to
about 72 hours. After a desired numbers of consecutive
soaking/rinsing cycles, each lens is challenged with viable
microorganisms and in-vitro antimicrobial activities are tested
according to the method described in Example 11.
[0377] It is understood that in studies of the prolong in-vitro
antimicrobial activities of Ag nanoparticle-containing contact
lenses, any appropriate test solution can be used in
soaking/rinsing lenses.
Phosphate Buffered Saline
[0378] Studies of the prolong in-vitro antimicrobial activities of
Ag nanoparticle-containing contact lenses are performed in sterile
glass or plastic (10 mL) lens vials as follows. One lens is placed
in each vial and about 2.0 mL of PBS is aseptically delivered to
the vial. Care is taken to ensure that the lens is submerged within
PBS. Soaking/rinsing solution (PBS) is exchanged almost daily.
However, solution exchanges are not performed on weekends or
holidays. In such instances solution exchange occurs on the next
work day. The vial is capped and left at ambient temperature until
the next work day. After about 24-72 hours the old soaking/rinsing
solution is decanted and about 2.0 mL of fresh soaking/rinsing
solution is aseptically delivered to the vial as described above.
In most studies 30 cycles are conducted over a 6 week period (no
cycling is performed on weekends or holidays). After 30 consecutive
soaking/rinsing cycles in PBS, lenses are subsequently challenged
with P. aeruginosa GSU#3 and S. aureus 6538 respectively. The
results are reported in Table 8.
ClearCare.RTM. Solution
[0379] ClearCare.RTM. solution (CIBA Vision) is one-bottle, no-rub,
no-rinse hydrogen peroxide-based lens care solution for soft
contact lenses. Studies of the prolong in-vitro antimicrobial
activities of Ag nanoparticle-containing contact lenses are
performed by testing their in-vitro antimicrobial activities
against Pseudomonas aeruginosa GSU #3 and Staphylococcus aureus
ATCC #6538 after at least 5 consecutive soaking/rinsing cycles,
each cycle comprising soaking/rinsing each lens in ClearCare.RTM.
solution. Soaking/rinsing of lenses is performed in the AOcup (lens
care case provided with ClearCare.RTM. and having disc-on-stem
configuration) with a platinum neutralizer disc. One lens is placed
in each of the right and left lens baskets. ClearCare.RTM. solution
is manually squirted into the case up to the fill line (approx
10-11 mL). Soaking/rinsing solution (ClearCare.RTM.) is exchanged
almost daily. However, solution exchanges are not performed on
weekends or holidays. In such instances solution exchange occurs on
the next work day. The case cap is closed and finger-tightened and
the filled cases left at ambient temperature until the next day.
After about 24-72 hours the old soaking/rinsing solution is
decanted and the case filled once again with fresh ClearCare.RTM.
as described above. In most studies 30 cycles are conducted over a
6 week period (no cycling is performed on weekends or holidays).
After 5 consecutive soaking/rinsing cycles in ClearCare.RTM. lens
disinfecting solution, lenses are subsequently challenged with P.
aeruginosa GSU#3 and S. aureus 6538 respectively and the results
are reported in Table 7. After 30 consecutive soaking/rinsing
cycles in ClearCare.RTM. lens disinfecting solution, lenses are
subsequently challenged with P. aeruginosa GSU#3 and S. aureus 6538
respectively and results are reported in Table 8.
TABLE-US-00007 TABLE 7 Pecentage of inhibition of viable cells as
compared to control lenses* LENS 0 CYCLE 5 CYCLEs in PBS 5 cycles
in ClearCare .RTM. TYPE P. aeruginosa S. aureus P. aeruginosa S.
aureus P. aeruginosa S. aureus SPB3.0.sup.# >99.9 98.7 ND ND
97.5 99.7 *Control lenses are Lotrafilcon A (CIBA Vision) lenses.
Number of surviving organisms (cfu) recovered from lenses @ 24
hours assay contact time are 2110 cfu for P. aeruginosa and 7073
cfu for S. aureus. .sup.#Visibility-tinted contact lenses, prepared
according to the procedure described in Example 16 ([AgNO.sub.3]
500 ppm, [PAA]=212 ppm and [Cup]=60 ppm), contains PAA stabilized
Ag NP.
TABLE-US-00008 TABLE 8 Pecentage of inhibition of viable cells as
compared to control lenses* LENS 0 CYCLE 30 Cycles in PBS 30 Cycles
in ClearCare .RTM. TYPE P. aeruginosa S. aureus P. aeruginosa S.
aureus P. aeruginosa S. aureus SPB3.0.sup.1 99.8 93.5 99.9 91.3
92.6** 93.1 SPB3.x.sup.2 99.9 98.6 99.9 91.9 ND 98.9 *Control
lenses are Lotrafilcon A (CIBA Vision) lenses. Number of surviving
organisms (cfu) recovered from CONTROL lenses @ 24 hours assay
contact time are 34500 cfu for P. aeruginosa and 21167 cfu for S.
aureus. **Significant loss of antimicrobial activity after 30
soaking/rinsing cycles in ClearCare (>1.5 log reduction of
viable microorganisms) as compared to PBS cycled, however the
lenses still posses significant antimicrobial activity as compared
to control lenses. .sup.1.Visibility-tinted contact lenses,
prepared according to the procedure described in Example 16
([AgNO.sub.3]=500 ppm, [PAA]=212 ppm and [Cup]=60 ppm), contains
PAA stabilized Ag NP. .sup.2.Visibility-tinted contact lenses,
prepared according to the procedure described in Example 16
([AgNO.sub.3]=200 ppm, [PAA]=85 ppm and [Cup]=60 ppm), contains PAA
stabilized Ag NP.
[0380] Table 8 shows that there is no apparent change in
microbicidal activity against Staph. Aureus or against Pseudomonas
challenge organism even after 30 consecutive soaking/rinsing cycles
in PBS (after direct contact with PBS over a period of six
weeks).
[0381] Table 7 shows that there is no apparent change in
microbicidal activity against Staph. Aureus or against Pseudomonas
challenge organism even after 5 consecutive soaking/rinsing cycles
in ClearCare.RTM. (after direct contact with PBS over a period of
about 5 to 7 days). No apparent change is observed in microbicidal
activity against Staph. aureus. There is a significant reduction in
microbicidal activity against Pseudomonas aeruginosa after 30
consecutive soaking/rinsing cycles in ClearCare.RTM. (after direct
contact with ClearCare.RTM. over a period of six weeks).
Example 21
Silver Analysis of Lenses and Package Saline
[0382] The silver concentrations in lenses and in saline are
measured by graphite furnace atomic absorption (GFAA) or
Instrumental Neutron Activation Analysis (INAA). In typical GFAA,
silver in lenses is digested by 40% acidified magnesium solution
and digested solution is analyzed by GFAA for silver concentration.
In typical INAA, stable nuclides (.sup.AZ) in the sample undergo
neutron capture reactions in a flux of neutrons. The radioactive
nuclides (.sup.A+1Z) produced in this activation process will, in
most cases, decay through the emission of a beta particle (3-) and
gamma ray(s) with a unique half-life. A high-resolution gamma-ray
spectrometer is used to detect these "delayed" gamma rays from the
artificially induced radioactivity in the sample for both
qualitative and quantitative analysis. When a sample that contains
silver is irradiated, a fraction of the .sup.109Ag atoms in the
sample will capture a neutron and become .sup.110Ag. The .sup.110Ag
atoms are radio active and have a half-life of 24.6 seconds. When
the .sup.110Ag atoms beta decay to .sup.110Cd, a 658 keV gamma ray
is emitted 4.5% of the time. The amount of silver in the original
sample can be determined by measuring the number of 658 keV
gamma-rays emitted from the sample in a given time interval after
the sample has been exposed to a flux of neutrons.
[0383] Contact lenses are removed from saline, rinsed with
deionized H2O, and air dried overnight. Dried contacts are weighed
and sealed in baggy. Saline from individual lens package is mixed
and then transferred to a tarred vial and weighed. Samples are
analyzed in sequence, under identical irradiation, decay, and
counting conditions. Known Ag standards are inserted at a ratio of
about 10:1. Fluorine is present in these contact lenses.
Irradiation condition may be altered to reduce the background
caused by high F if lower Ag detection limits are desired. Spectra
are analyzed by determining peak and background areas and applying
a calibration factor derived from the standards used.
[0384] A batch of lenses is prepared from a formulation I
containing 50 ppm of AgNO.sub.3. Two of the lenses are analyzed by
INAA. The silver concentrations in lenses are 30.0.+-.2.43 ppm and
29.0.+-.2.35 ppm. The silver concentration in saline is
0.13.+-.0.02 ppm.
[0385] A batch of lenses is prepared from a formulation I
containing 500 ppm of AgNO.sub.3. Two of the lenses are analyzed by
INAA. The silver concentrations in lenses are 65.0.+-.4.16 ppm and
51.0.+-.3.47 ppm. Partial precipitation of silver nano-particles
from this formulation containing no stabilizer may be attributed to
the low silver concentration of lenses in this experiment. The
silver concentration in saline is 0.34.+-.0.03 ppm.
[0386] A batch of lenses is prepared from a formulation I
containing 300 ppm of AgNO.sub.3 and 127 ppm of PAA and 60 ppm of
copper phthalocyanine blue (PCN blue, also referred to as CuP). The
silver concentrations of lenses at different process steps are
analyzed by INAA. The data is presented in Table 9. Some silver
from the lenses is eluted to IPA during extraction and to saline
during storage.
TABLE-US-00009 TABLE 9 Samples Silver concentration (ppm) Three
lens, not extracted 127.0 .+-. 7.112, 122.0 .+-. 6.832, 113.0 .+-.
6.441 Three dry Lens, plasma coated 119.0 .+-. 6.664, 120.0 .+-.
6.720, 131.0 .+-. 7.336 Three plasma coated lenses, autoclaved in
62.1 .+-. 3.974, 69.4 .+-. 4.233, saline 74.5 .+-. 4.470 Combined
saline from three lenses 0.389 .+-. 0.029 IPA used in the
extraction 0.019 .+-. 0.009
[0387] Four batches of lenses are prepared from a formulation I
containing 500 ppm of AgNO.sub.3 and 60 ppm of CuP, and different
concentration of PAA (from 53 ppm to 424 ppm). The silver
concentrations in lenses and in saline are measured by INAA and
listed in table 10.
TABLE-US-00010 TABLE 10 Average silver concentration Formulation
Sample (ppm)* Formulation I, with 500 ppm of AgNO.sub.3, Lens 81.4
.+-. 12.40 60 ppm of CuP, and 53 ppm of PAA saline 0.40 .+-. 0.028
Formulation I, with 500 ppm of AgNO.sub.3, Lens 97.4 .+-. 29.34 60
ppm of CuP, and 106 ppm of PAA saline 0.60 .+-. 0.039 Formulation
I, with 500 ppm of AgNO.sub.3, Lens 75.13 .+-. 5.21 60 ppm of CuP,
and 212 ppm of PAA saline 0.30 .+-. 0.023 Formulation I, with 500
ppm of AgNO.sub.3, Lens 66.7 .+-. 31.53 60 ppm of CuP, and 424 ppm
of PAA saline 0.40 .+-. 0.029 *Average silver concentration from 3
lenses or combined saline
[0388] A batch of lenses is prepared from a formulation I
containing 300 ppm of AgNO.sub.3 and 127 ppm of acrylic acid (AA)
and 60 ppm of CuP. Two of the lenses are analyzed by INAA. The
silver concentrations in lenses are 235.0.+-.12.69 ppm and
210.0.+-.11.55 ppm. The silver concentration in saline is
0.43.+-.0.036 ppm.
[0389] Two batches of lenses are prepared from a formulation I
containing 120 ppm of CuP and different concentration of 500 ppm of
AgNO.sub.3 (from 200 to 456) and PAA (from 93 ppm to 212 ppm). The
silver concentrations in lenses and in saline are measured by INAA
and listed in table 11.
TABLE-US-00011 TABLE 11 Average silver concentration Formulation
Sample (ppm)* Formulation I, with 200 ppm of AgNO.sub.3, Lens 82.0
.+-. 4.95 120 ppm of CuP, and 93 ppm of PAA saline 0.40 .+-. 0.029
Formulation I, with 456 ppm of AgNO.sub.3, Lens 86.0 .+-. 5.10 120
ppm of CuP, and 212 ppm of PAA saline 0.40 .+-. 0.030 *Average
silver concentration from 3 lenses or combined saline
[0390] Three batch of lenses are prepared from formulation I
containing different pigments, such as copper phthalocyanine blue
(CuP), copper phthalocyanine green (PCNG), and/or carbazole violet
(CV) The silver concentrations in lenses and in saline are measured
by INAA and listed in table 12.
TABLE-US-00012 TABLE 12 Average silver concentration Formulation
Sample (ppm)* Formulation I, with 456 ppm of AgNO.sub.3, Lens 108.6
.+-. 6.38 60 ppm of PCNG, and 212 ppm of PAA saline 0.40 .+-. 0.031
Formulation I, with 200 ppm of AgNO.sub.3, Lens 112.0 .+-. 6.46 60
ppm of PCNG, and 93 ppm of PAA saline 0.30 .+-. 0.027 Formulation
I, with 456 ppm of AgNO.sub.3, Lens 87.3 .+-. 5.33 60 ppm of CuP, 8
ppm of CV, and saline 0.40 .+-. 0.030 212 ppm of PAA *Average
silver concentration from 3 lenses or combined saline
[0391] The silver concentration of some of the lenses is also
analyzed by GFAA. Table 13 listed the silver concentration of some
lenses and their package saline.
TABLE-US-00013 TABLE 13 Average silver concentration Formulation
Sample (ppm) Formulation I, with 456 ppm of AgNO.sub.3, Lens 207.3
.+-. 0.1 60 ppm of PCNG, and 212 ppm of PAA saline 0.566 .+-.
0.0006 Formulation I, with 200 ppm of AgNO.sub.3, Lens 132.3 .+-.
0.1 60 ppm of PCNG, and 93 ppm of PAA saline 0.355 .+-. 0.0006
Formulation I, with 456 ppm of AgNO.sub.3, Lens 97.5 .+-. 0.1 60
ppm of CuP, 8 ppm of CV, and saline 0.478 .+-. 0.0006 212 ppm of
PAA Formulation I, with 500 ppm of AgNO.sub.3, Lens 53.9 .+-. 0.1
and 106 ppm of PAA saline 0.507 .+-. 0.0006 Formulation I, with 500
ppm of AgNO.sub.3, Lens 44.4 .+-. 0.1 and 106 ppm of PAA saline
0.470 .+-. 0.006
Example 22
Effect of Lens Care Solution on the Silver Concentration in
Lenses
[0392] A batch of lenses is made from a formulation I containing
500 ppm of AgNO.sub.3 and 60 ppm of CuP and 212 ppm of PAA. Three
lenses are stored in original package in saline as control (Al to
A-3, Table 14). 4 groups of three lenses each (A-4 to A15, Table
14) are underwent 30 consecutive soaking/rinsing cycles in
different liquid media (e.g. PBS saline) or lens care solutions
(SoloCare.RTM., ClearCare.RTM., both from CIBA Vision,) according
to procedure described in Example 20 or lens care procedures
specified for the product by the manufacturer. After 30
soaking/rinsing cycles, all lenses are analyzed by INAA for silver
concentration. As indicated in Table 14, ClearCare.RTM. has the
most impact to the silver concentration, with about 90% loss of
silver from the lens after 30 soaking/rinsing cycles.
Soaking/rinsing with SoloCare.RTM. (5 minutes and 6 hours cycling
regimens) cause approximately 50% loss of silver from the lens
after 30 cycles.
TABLE-US-00014 TABLE 14 Sample ID Mass Silver (wt %) A-1 0.0154 g
46.5 ppm (.+-.3.534 ppm) A-2 0.0157 g 46.0 ppm (.+-.3.450 ppm) A-3
0.0161 g 50.6 ppm (.+-.3.593 ppm) Saline 1.382 g 0.5 ppm (.+-.0.037
ppm) A-4(5 min SoloCare .RTM.) 0.0165 g 21.1 ppm (.+-.2.700 ppm)
A-5(5 min SoloCare .RTM.) 0.0161 g 18.4 ppm (.+-.2.359 ppm) A-6(5
min SoloCare .RTM.) 0.0165 g 20.3 ppm (.+-.2.416 ppm) Saline 1.369
g 0.1 ppm (.+-.0.035 ppm) A-7(6 hr SoloCare .RTM.) 0.0164 g 24.9
ppm (.+-.2.639 ppm) A-A-8(6 hr SoloCare .RTM.) 0.0162 g 22.2 ppm
(.+-.2.531 ppm) A-9(6 hr SoloCare .RTM.) 0.0157 g 21.1 ppm
(.+-.2.659 ppm) Saline 1.376 g 0.1 ppm (.+-.0.033 ppm) A-10
(ClearCare .RTM.) 0.0160 g 4.5 ppm (.+-.2.650 ppm) A-11 (ClearCare
.RTM.) 0.0157 g <4.0 ppm A-12 (ClearCare .RTM.) 0.0154 g <4.0
ppm Saline 1.408 g <0.04 ppm A-13 (PBS) 0.0158 g 14.6 ppm
(.+-.2.292 ppm) A-14 (PBS) 0.0156 g 10.6 ppm (.+-.2.025 ppm) A-15
(PBS) 0.0152 g 23.6 ppm (.+-.2.478 ppm) Saline 1.426 g <0.04
ppm
Example 23
[0393] The silver concentration of 5 samples (formulation I with or
without AgNO.sub.3) are analyzed by INAA and listed in Table
15.
TABLE-US-00015 TABLE 15 Theoretical Measured Formulation [Ag] (PPm)
[Ag] (ppm) Formulation I, 0 <1.0 Formulation I, with 500 ppm of
AgNO.sub.3, 317.6 286.0 .+-. 14.58 60 ppm of CuP, and 212 ppm of AA
Formulation I, with 200 ppm of AgNO.sub.3, 127.1 117 .+-. 6.08 60
ppm of CuP, and 84.8 ppm of AA Formulation I, with 500 ppm of
AgNO.sub.3, 317.6 282.0 .+-. 14.38 60 ppm of CuP, and 212 ppm of
PAA Formulation I, with 200 ppm of AgNO.sub.3, 127.1 110 .+-. 5.720
60 ppm of CuP, and 84.8 ppm of PAA
[0394] Five batches of lenses are prepared from a lens-forming
material (formulation I containing 500 ppm of AgNO.sub.3, 60 ppm of
CuP, and 212 ppm of PAA) and each stored in saline in a package.
The silver concentrations in lenses and in saline are measured by
INAA and listed in Table 16. It appears that the silver
concentrations in lenses can be affected to a certain degree by
process conditions, for example, by the staging time (days after
the lenses are cured until they are further processed by IPA
extraction). The silver concentrations in saline for these five
batches of lenses are in the range of from 0.30 to 0.45 ppm.
TABLE-US-00016 TABLE 16 Average Lens batch #1 Staging time (days)
silver concentration (ppm)* #1 5 62.2 .+-. 3.76 (in lens) 0.35 .+-.
0.033 (in saline) #2 46 160.3 .+-. 8.91 (in lens) 0.45 .+-. 0.034
(in saline) #3 46 160.0 .+-. 8.90 (in lens) 0.34 .+-. 0.030 (in
saline) #4 5 44.8.0 .+-. 3.42 (in lens) 0.44 .+-. 0.034 (in saline)
#5 5 75.4 .+-. 8.90 (in lens) 0.41 .+-. 0.034 (in saline) *Average
silver concentration from 3 lenses or combined saline
Example 24
[0395] Contact lenses (referred to as test lenses) made from a
formulation in Example 16 (which contains 60 ppm of CuP and 500 ppm
of AgNO.sub.3 in the formulation) are evaluate on eyes. A
double-masked, contralateral study is conducted. The test lenses
and Focus Night & Day (FND) control lenses are randomly
assigned to either eye in all subjects. The duration of wear is 26
hours, including eight hours of eye closure (sleep). The clinical
results indicates that both the test and control lenses behaved
similarly during this study. No significant difference is observed
in lens surface characteristics when comparing the test lenses and
the FND control lenses. The silver particles are distinguishable
under bio-microscope but not to the naked eyes. The level of silver
used in the test lenses is safe for overnight wear as there are no
observable, adverse ocular effects resulted from their wear.
[0396] Although various embodiments of the invention have been
described using specific terms, devices, and methods, such
description is for illustrative purposes only. The words used are
words of description rather than of limitation. It is to be
understood that changes and variations may be made by those skilled
in the art without departing from the spirit or scope of the
present invention, which is set forth in the following claims. In
addition, it should be understood that aspects of the various
embodiments may be interchanged either in whole or in part.
Therefore, the spirit and scope of the appended claims should not
be limited to the description of the preferred versions contained
therein.
* * * * *