U.S. patent application number 10/732648 was filed with the patent office on 2005-01-13 for medical devices having antimicrobial coatings thereon.
Invention is credited to Kotov, Nicholas, Lally, John Martin, Qiu, Yongxing, Winterton, Lynn Cook.
Application Number | 20050008676 10/732648 |
Document ID | / |
Family ID | 32682137 |
Filed Date | 2005-01-13 |
United States Patent
Application |
20050008676 |
Kind Code |
A1 |
Qiu, Yongxing ; et
al. |
January 13, 2005 |
Medical devices having antimicrobial coatings thereon
Abstract
The present invention provides a medical device, preferably a
contact lens, which a core material and an antimicrobial
metal-containing LbL coating that is not covalently attached to the
medical device and can impart to the medical device an increased
hydrophilicity. The antimicrobial metal-containing coating on a
contact lens of the invention has a high antimicrobial efficacy
against microorganisms including Gram-positive and Gram-negative
bacterial and a low toxicity, while maintaining the desired bulk
properties such as oxygen permeability and ion permeability of lens
material. Such lenses are useful as extended-wear contact lenses.
In addition, the invention provides a method for making a medical
device, preferably a contact lens, having an antimicrobial
metal-containing LbL coating thereon.
Inventors: |
Qiu, Yongxing; (Duluth,
GA) ; Winterton, Lynn Cook; (Alpharetta, GA) ;
Lally, John Martin; (Lilburn, GA) ; Kotov,
Nicholas; (Stillwater, OK) |
Correspondence
Address: |
CIBA VISION CORPORATION
PATENT DEPARTMENT
11460 JOHNS CREEK PARKWAY
DULUTH
GA
30097-1556
US
|
Family ID: |
32682137 |
Appl. No.: |
10/732648 |
Filed: |
December 10, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60435003 |
Dec 19, 2002 |
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Current U.S.
Class: |
424/429 ;
424/618 |
Current CPC
Class: |
A61L 2300/608 20130101;
A61L 2300/61 20130101; A61L 29/106 20130101; A61L 2300/45 20130101;
A61L 31/088 20130101; G02B 1/043 20130101; A61L 2300/104 20130101;
A61L 31/10 20130101; A61K 31/14 20130101; Y10T 428/31678 20150401;
A61L 27/54 20130101; A61L 27/34 20130101; Y10T 428/31692 20150401;
A61K 9/5015 20130101; A61L 29/16 20130101; A61P 31/04 20180101;
A61L 31/16 20130101; Y10T 428/31681 20150401; A61L 2300/404
20130101; A61L 2300/624 20130101 |
Class at
Publication: |
424/429 ;
424/618 |
International
Class: |
A61K 009/00; A61K
033/38 |
Claims
What is claimed is:
1. A medical device comprising a core material and an antimicrobial
metal-containing LbL coating, wherein the antimicrobial
metal-containing LbL coating is not covalently attached to the core
material and imparts to the medical device a hydrophilicity
characterized by having an averaged contact angle of less than 80
degree.
2. A medical device of claim 1, wherein the antimicrobial
metal-containing LbL coating comprises a member selected from the
group consisting of: (a) one layer of charged antimicrobial metal
nano-particles; (b) one layer of charged antimicrobial
metal-containing nano-particles; (c) silver-polyelectrolyte
complexes formed between silver ions and a polycationic material
having amino groups; (d) silver-polyelectrolyte complexes formed
between silver ions and a polyionic material having
sulfur-containing groups; (e) silver nano-particles; and (f)
combinations thereof.
3. A medical device of claim 2, wherein the medical device further
comprises one or more antimicrobial agents selected from the group
consisting of polyquats which exhibit antimicrobial activity,
furanones, antimicrobial peptides, isoxazolinones, and organic
selenium compounds.
4. A medical device of claim 3, wherein said one or more
antimicrobial agents are covalently attached to the surface of the
core material.
5. A medical device of claim 3, wherein said one or more
antimicrobial agents are covalently attached to the antimicrobial
metal-containing LbL coating through the reactive sites of the
antimicrobial metal-containing LbL coating.
6. A medical device of claim 2, wherein the antimicrobial
metal-containing LbL coating comprises one capping layer of a
polyionic material.
7. A medical device of claim 2, wherein the antimicrobial
metal-containing LbL coating comprises one capping electrolyte
bilayer of a positively charged polyionic material and a negatively
charged polyionic material or one capping layer of a charged
polymeric material and a non-charged polymeric material that can be
non-covalently bonded to the charged polymeric material.
8. A medical device of claim 2, wherein the antimicrobial LbL
coating comprises at least one layer of an antimicrobial
polyquat.
9. A medical device of claim 2, wherein the medical device is a
hard or soft contact lens.
10. A contact lens of claim 9, wherein the antimicrobial
metal-containing LbL coating comprises: at least one layer of
charged antimicrobial metal nano-particles and/or charged
antimicrobial metal-containing nanoparticles; and at least one
layer of a polyionic material having charges opposite of the
charges of the charged antimicrobial metal nano-particles and/or
charged antimicrobial metal-containing nanoparticles.
11. A contact lens of claim 10, wherein said charged antimicrobial
metal nanoparticles are charged silver nanoparticles, and wherein
the charged antimicrobial metal-containing nanoparticles are
charged silver-containing nanoparticles.
12. A contact lens of claim 9, wherein the antimicrobial
metal-containing LbL coating comprises at least one layer of a
negatively-charged polyionic material and at least one layer of
silver-polyelectrolyte complexes formed between silver ions and a
polycationic material having amino groups.
13. A contact lens of claim 9, wherein the antimicrobial
metal-containing LbL coating comprises at least one layer of a
negatively-charged polyionic material and at least one layer of
silver-polyelectrolyte complexes formed between silver cations and
a polyionic material having sulfur-containing groups.
14. A contact lens of claim 9, wherein the antimicrobial
metal-containing LbL coating comprises at least one layer of a
silver-polyelectrolyte complex formed between silver ions and a
polyionic material having sulfur-containing groups.
15. A contact lens of claim 9, wherein the antimicrobial
metal-containing LbL coating comprises silver nano-particles.
16. A contact lens of claim 15, wherein the silver nano-particles
are obtained by first forming a transitional LbL coating composed
of at least one layer of a first polyionic material and at least
one layer of a second polyionic material having charges opposite of
the charges of the first polyionic material, wherein at least one
of the first and second polyionic materials is a
silver-polyelectrolyte complex formed between silver cations and a
positively-charged amino group containing polyionic material, a
silver-polyelectrolyte complex formed between silver cations and a
polyionic material with sulfur-containing groups; and then by
reducing silver ions in the transitional LbL coating by means of a
reducing agent, UV irradiation or heating.
17. A contact lens of claim 9, wherein the contact lens further
comprises one or more antimicrobial agents selected from the group
consisting of polyquats which exhibit antimicrobial activity,
furanones, antimicrobial peptides, isoxazolinones, and organic
selenium compounds.
18. A contact lens of claim 17, wherein said one or more
antimicrobial agents are covalently attached to the surface of the
core material.
19. A contact lens of claim 17, wherein said one or more
antimicrobial agents are covalently attached to the antimicrobial
metal-containing LbL coating through the reactive sites of the
antimicrobial metal-containing LbL coating.
20. A contact lens of claim 9, wherein the contact lens further
comprises a plasma coating on top of the antimicrobial
metal-containing LbL coating.
21. A medical device of claim 2, wherein the medical device is a
case or container for storing an ophthalmic device or an ophthalmic
solution.
22. A medical device of claim 21, wherein the case or container
further comprises one or more antimicrobial agents selected from
the group consisting of polyquats which exhibit antimicrobial
activity, furanones, antimicrobial peptides, isoxazolinones, and
organic selenium compounds.
23. A medical device of claim 22, wherein said one or more
antimicrobial agents are covalently attached to the surface of the
core material.
24. A medical device of claim 22, wherein said one or more
antimicrobial agents are covalently attached to the antimicrobial
metal-containing LbL coating through the reactive sites of the
antimicrobial metal-containing LbL coating.
25. A method for preparing a medical device having an antimicrobial
metal-containing LbL coating thereon, comprising the steps of: (a)
contacting said medical device with a solution of a first charged
material to form a layer of the first charged material on the
medical device; (b) optionally rinsing said medical device by
contacting said medical device with a first rinsing solution (c)
contacting said medical device with a solution of a second charged
material to form a layer of the second charged material on top of
the layer of the first charged material, wherein the second charged
material has charges opposite of the charges of the first charged
material; and (d) optionally rinsing said medical device by
contacting said medical device with a second rinsing solution,
wherein at least one of the first and second charged material is
selected from the group consisting of charged antimicrobial metal
nanoparticles, charged antimicrobial metal-containing
nano-particles, silver-polyelectrolyte complexes formed between
silver ions and a polycationic material having amino groups,
silver-polyelectrolyte complexes formed between silver ions and a
polyionic material having sulfur-containing groups, and
combinations thereof.
26. A method of claim 25, wherein at least one of said contacting
occurs by immersion said medical device in a solution.
27. A method of claim 25, wherein at least one of said contacting
occurs by spraying a solution onto the medical device.
28. A method of claim 25, wherein said method comprises repeating
steps (a) through (d) between 2 to 20 times.
29. A method of claim 25, wherein at least one of the first and
second charged material is selected from the group consisting of
silver-polyelectrolyte complexes formed between silver ions and a
polycationic material having amino groups, silver-polyelectrolyte
complexes formed between silver ions and a polyionic material
having sulfur-containing groups, and combinations thereof, and
wherein the method further comprises a step of reducing the silver
ions in the antimicrobial metal-containing LbL coating to form
silver nano-particles.
30. A method of claim 29, wherein said reducing occurs by means of
a reducing agent.
31. A method of claim 29, wherein said reducing occurs by means of
UV irradiation.
32. A method of claim 29, wherein said reducing occurs by means of
heating.
33. A method of claim 25, comprising, prior step (a), the step of
completely or partially coating the surface of the medical device
with 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, wherein said at least one antimicrobial agent
is covalently attached to the surface of the medical device.
34. A method of claim 25, further comprising the step of covalently
attaching at least one antimicrobial agent to the antimicrobial
metal-containing LbL coating through the reactive sites of the
antimicrobial metal-containing LbL coating, wherein said at least
one antimicrobial agent is selected from the group consisting of a
polyquat which exhibits antimicrobial activity, furanones,
antimicrobial peptides, isoxazolinones, and organic selenium
compounds.
35. A method of claim 25, further comprising the step of subjecting
the medical device with the antimicrobial metal-containing LbL
coating to a plsma treatment to form a plasma coating on top of the
antimicrobial metal-containing LbL coating.
36. A method for preparing a medical device having an antimicrobial
metal-containing LbL coating thereon, comprising the steps of
dipping said medical device in a solution containing a first
charged material and a second charged material for a desired period
of time so as to obtain the antimicrobial LbL coating characterized
by having an average contact angle of about 80 degrees or less,
wherein the second charged material has charges opposite of the
charges of the first charged material, wherein the first charged
material and the second charged material are present in an amount
such that the ratio of the charges of the first charged material to
the second charged material is from about 3:1 to about 100:1,
wherein at least one of the first and second charged material is
selected from the group consisting of charged antimicrobial metal
nanoparticles, charged antimicrobial metal-containing
nano-particles, silver-polyelectrolyte complexes formed between
silver ions and a polycationic material having amino groups,
silver-polyelectrolyte complexes formed between silver ions and a
polyionic material having sulfur-containing groups, and
combinations thereof.
37. A method of claim 36, wherein at least one of the first and
second charged material is selected from the group consisting of
silver-polyelectrolyte complexes formed between silver ions and a
polycationic material having amino groups, silver-polyelectrolyte
complexes formed between silver ions and a polyionic material
having sulfur-containing groups, and combinations thereof, and
wherein the method further comprises a step of reducing the silver
ions in the antimicrobial LbL coating to form silver
nano-particles.
38. A method of claim 37, wherein said reducing occurs by means of
a reducing agent, UV irradiation, or heating.
39. A method of claim 36, comprising, prior the step of dipping,
the step of completely or partially coating the surface of the
medical device with 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, wherein said at least one antimicrobial
agent is covalently attached to the surface of the medical
device.
40. A method of claim 36, further comprising the step of covalently
attaching at least one antimicrobial agent to the antimicrobial
metal-containing LbL coating through the reactive sites of the
antimicrobial metal-containing LbL coating, wherein said at least
one antimicrobial agent is selected from the group consisting of a
polyquat which exhibits antimicrobial activity, furanones,
antimicrobial peptides, isoxazolinones, and organic selenium
compounds.
41. A method of claim 36, further comprising the step of subjecting
the medical device with the antimicrobial metal-containing LbL
coating to a pisma treatment to form a plasma coating on top of the
antimicrobial metal-containing LbL coating.
42. A method for producing a contact lens having an antimicrobial
metal-containing LbL coating thereon, comprising the steps of: (a)
forming a mold for making the contact lens, wherein the mold
comprises a first mold portion defining a first optical surface and
a second mold portion defining a second optical surface, wherein
said first mold portion and said second mold portion are configured
to receive each other such that a contact lens-forming cavity is
formed between said first optical surface and said second optical
surface; (b) applying a transferable antimicrobial LbL coating,
using a layer-by-layer polyelectrolyte deposition technique, onto
at least one of said optical surface, wherein the transferable
antimicrobial LbL coating comprises at least one layer of a first
charged material and at least one layer of a second charged
material having charges opposite of the charges of the first
charged material, wherein at least one of the first and second
charged material is selected from the group consisting of charged
antimicrobial metal nano-particles, charged antimicrobial
metal-containing nanoparticles, silver-polyelectrolyte complexes
formed between silver ions and a polycationic material having amino
groups, silver-polyelectrolyte complexes formed between silver ions
and a polyionic material having sulfur-containing groups, and
combinations thereof; (c) positioning said first mold portion and
said second mold portion such that said mold portions receive each
other and said optical surfaces define said contact lens forming
cavity; (d) dispensing a polymerizable composition into said
contact lens-forming cavity; and (e) curing said polymerizable
composition within said contact lens-forming cavity such that the
contact lens is formed, whereby said transferable antimicrobial LbL
coating detaches from said at least one optical surface of said
mold portion and reattaches to said formed contact lens such that
said contact lens becomes coated with the antimicrobial
metal-containing LbL coating.
43. A method of claim 42, wherein the method further comprises a
step of reducing silver ions in the transferable antimicrobial LbL
coating or in the silver-containing antimicrobial LbL coating to
form silver nano-particles.
44. A method of claim 43, wherein said reducing occurs by means of
a reducing agent, UV irradiation, or heating.
45. A method of claim 42, further comprising the step of covalently
attaching at least one antimicrobial agent to the antimicrobial LbL
coating through the reactive sites of the antimicrobial LbL coating
on the contact lens, wherein said at least one antimicrobial agent
is selected from the group consisting of a polyquat which exhibits
antimicrobial activity, furanones, antimicrobial peptides,
isoxazolinones, and organic selenium compounds.
Description
[0001] This application claims under 35 USC .sctn. 119 (e) the
benefit of the filing date of U.S. Provisional Application No.
60/435,003 filed Dec. 19, 2002 and all references incorporated
therein.
[0002] The present invention generally relates to a medical device
having an antimicrobial metal-containing layer-by-layer coating
thereon and to a method for making the medical device of the
invention.
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 at 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. There
are some disadvantages associated with this approach for making
antimicrobial contact lenses. Polymeric composition's having
antimicrobial properties may not possess all properties desired for
contact lenses, especially extended-wear contact lenses, which
hinders their practice uses.
[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] Therefore, there is a need for antimicrobial coatings that
can provide high bactericidal efficacy and broad spectrum
antimicrobial activity coupled with low cytotoxicity. There is also
a need for new contact lenses having antimicrobial coatings, which
have high bactericidal efficacy, a broad spectrum of antimicrobial
activities, and minimal adverse effects on the wearer's ocular
health and comfort. Such contact lenses may have increased safety
as extended-wear contact lenses which could provide comfort,
convenience, and safety.
[0008] Moreover, surgical and device related infection remains to
be one of the main clinical and economic challenges in the field of
medical devices and in health care industry in general. Each year,
as many as 2 million hospital patients in the United States develop
nosocomial infections, and approximately 80% of the 80,000 annual
deaths due to nosocomial infections are device-related. A potent
and cost-effective antimicrobial coating for medical devices would
be a key to mitigate the infection-related clinical challenges and
economic burden of health care.
[0009] One object of the invention is to provide an antimicrobial
coating which has a high antimicrobial efficacy coupled with low
cytotoxicity.
[0010] Another object of the invention is to provide a medical
device having an antimicrobial coating that has a high
antimicrobial efficacy coupled with low cytotoxicity.
[0011] A further object of the invention is to provide a
cost-effective and efficient process for forming an antimicrobial
coating on a medical device.
SUMMARY OF THE INVENTION
[0012] These and other objects of the invention are met by the
various aspects of the invention described herein.
[0013] The invention, in one aspect, provides a medical device
having a core material and an antimicrobial metal-containing
layer-by-layer (LbL) coating that is not covalently attached to the
medical device and can impart to the medical device an increased
hydrophilicity. In a preferred embodiment, the antimicrobial
metal-containing LbL coating comprises a member selected from the
group consisting of: (a) one layer of charged antimicrobial metal
nanoparticles; (b) one layer of charged antimicrobial
metal-containing nano-particles; (c) silver-polyelectrolyte
complexes formed between silver ions and a polycationic material
having amino groups; (d) silver-polyelectrolyte complexes formed
between silver ions and a polyionic material having
sulfur-containing groups; (e) silver nano-particles; and (f)
combinations thereof.
[0014] The invention, in another aspect, provides a method for
preparing a medical device having an antimicrobial metal-containing
LbL coating thereon. The method comprises alternatively applying,
in no particular order, one layer of a first charged material and
one layer of a second charged material having charges opposite of
the charges of the first charged material onto a medical device to
form the antimicrobial metal-containing LbL coating, wherein at
least one of the first and second charged material is selected from
the group consisting of charged antimicrobial metal nanoparticles,
charged antimicrobial metal-containing nano-particles,
silver-polyelectrolyte complexes formed between silver ions and a
polycationic material having amino groups, silver-polyelectrolyte
complexes formed between silver ions and a polyionic material
having sulfur-containing groups, and combinations thereof.
[0015] 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
[0016] 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.
[0017] An "article" refers to an ophthalmic lens, a mold for making
an ophthalmic lens, or a medical device other than ophthalmic
lens.
[0018] 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.
[0019] 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.
[0020] "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.
[0021] "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.
[0022] "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.
[0023] A "monomer" means a low molecular weight compound that can
be polymerized. Low molecular weight typically means average
molecular weights less than 700 Daltons.
[0024] A "macromer" refers to medium and high molecular weight
compounds or polymers that contain functional groups capable of
further polymerization. Medium and high molecular weight typically
means average molecular weights greater than 700 Daltons.
[0025] "Polymer" means a material formed by polymerizing one or
more monomers.
[0026] "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.
[0027] "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 materials on an article.
[0028] 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.
[0029] 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.
patent application Ser. No. 10/654,566 filed Sep. 3, 2003, herein
incorporated by reference in its entirety.
[0030] As used herein, "asymmetrical coatings" on an ophthalmic
lens refers to the different coatings on the first surface and the
opposite second surface of the ophthalmic lens. As used herein,
"different coatings" refers to two coatings that have different
surface properties or functionalities.
[0031] A "capping layer", as used herein, refers to the last layer
of a coating material which is applied onto the surface of a
medical device.
[0032] A "capping bilayer", as used herein, refers to the last
bilayer of a first coating material and a second coating material,
which is applied onto the surface of a medical device.
[0033] A "polyquat", as used herein, refers to a polymeric
quaternary ammonium group-containing compound.
[0034] 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.
[0035] An "antimicrobial LbL coating", as used herein, refers to an
LbL coating that imparts to a medical device the ability to
decrease or eliminate or inhibit the growth of microorganisms on
the surface of the medical device or in an adjacent area extending
from the medical device. An antimicrobial LbL coating on a medical
device of the invention exhibit preferably at least a 1-log
reduction (.gtoreq.90% inhibition), more preferably at least a
2-log reduction (.gtoreq.99% inhibition), of viable
microorganisms.
[0036] 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.
[0037] "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.
[0038] "Antimicrobial metal-containing nanoparticles" refers 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. For example, silver-containing nanoparticles can
contain silver in one or more of its oxidation states, such as
Ag.sup.0, Ag.sup.1+, and Ag.sup.2+.
[0039] "Antimicrobial metal nanoparticles" refers to particles
which is made of one or more antimicrobial metals and have a size
of less than 1 micrometer. The antimicrobial metals in the
antimicrobial metal nanoparticles can be present in one or more of
its oxidation state.
[0040] An "averaged contact angle" refers to a contact angle
(Sessile Drop), which is obtained by averaging measurements of at
least 3 individual medical devices.
[0041] As used herein, "increased surface hydrophilicity" or
"increased hydrophilicity" in reference to a coated medical device
means that the coated medical device has a reduced averaged contact
angle compared with an uncoated medical device.
[0042] The present invention is directed to a medical device having
a core material and an antimicrobial metal-containing LbL surface
coating (hereinafter LbL coating) formed thereon and to a method
for making the same. The antimicrobial metal-containing LbL coating
imparts to the medical device an increased surface hydrophilicity
(hereinafter hydrophilicity) and exhibits at least 50% inhibition
of viable microorganisms. Preferably, the increased hydrophilicity
is characterized by having an averaged contact angle of about 80
degrees or less.
[0043] It has been discovered here that an antimicrobial metal,
silver, in particular silver nano-particles, and
silver-polyelectrolyte complexes can be incorporated
cost-effectively into an LbL coating according to one of the
methods of the invention. It is found that an silver-containing LbL
coating of the invention may possess several advantages as follows.
It can impart to a medical device not only an antimicrobial
activity but also an increased surface hydrophilicity. It has
minimal adverse effects on the desired bulk properties of, for
example, a contact lens, such as oxygen permeability, ion
permeability, and optical properties. An silver-containing LbL
coating of the invention formed on a medical device can adhere well
to a medical device and be stable, even after several cycles of
autoclaving treatments. The process for forming a silver-containing
LbL coating of the invention is well suited for automation and can
be used to coat a wide range of substrate (polymeric, glass,
quartz, ceramic, metal) and in any geometry. Out-diffusion of
silver from the silver-containing coating is controllable. In
addition, a medical device having an antimicrobial LbL coating of
the invention thereon can be further subjected to surface
modification, such as plasma treatment to obtain a coating
possessing advantages of both plasma coating and an antimicrobial
coating of the invention.
[0044] In accordance with the present invention, the core material
of a medical device (substrate) may be any of a wide variety of
polymeric materials. Exemplary core materials include, but are not
limited to, hydrogels, silicone-containing hydrogels, polymers and
copolymers of styrene, substituted styrenes, ethylene, propylene,
acrylates, methacrylates, N-vinyl lactams, acrylamides and
methacrylamides, acrylonitrile, acrylic acid, methacrylic acid, or
combinations thereof.
[0045] A preferred group of core materials to be coated are those
being conventionally used for the manufacture of biomedical
devices, e.g. contact lenses, in particular contact lenses for
extended wear, which are not hydrophilic per se. Such materials are
known to the skilled artisan and may comprise for example
polysiloxanes, perfluoroalkyl polyethers, fluorinated
poly(meth)acrylates or equivalent fluorinated polymers derived e.g.
from other polymerizable carboxylic acids, polyalkyl
(meth)acrylates or equivalent alkylester polymers derived from
other polymerizable carboxylic acids, or fluorinated polyolefins,
such as fluorinated ethylene or propylene, for example
tetrafluoroethylene, preferably in combination with specific
dioxols, such as perfluoro-2,2-dimethyl-1,3-dioxol. Examples of
suitable bulk materials are e.g. Lotrafilcon A, Neofocon,
Pasifocon, Telefocon, Silafocon, Fluorsilfocon, Paflufocon,
Silafocon, Elastofilcon, Balifilcon A, Fluorofocon, or Teflon AF
materials, such as Teflon AF 1600 or Teflon AF 2400 which are
copolymers of about 63 to 73 mol % of
perfluoro-2,2-dimethyl-1,3-dioxol and about 37 to 27 mol % of
tetrafluoroethylene, or of about 80 to 90 mol % of
perfluoro-2,2-dimethyl-1,3-dioxol and about 20 to 10 mol % of
tetrafluoroethylene.
[0046] Another group of preferred core materials to be coated is
amphiphilic-segmented copolymers comprising at least one
hydrophobic segment and at least one hydrophilic segment, which are
linked through a bond or a bridge member. Examples are silicone
hydrogels, for example those disclosed in PCT applications WO
96/31792 to Nicolson et al. and WO 97/49740 to Hirt et al.
[0047] A particular preferred group of core materials to be coated
comprises organic polymers selected from polyacrylates,
polymethacrylates, polyacrylamides, poly(N,N-dimethylacrylamides),
polymethacrylamides, polyvinyl acetates, polysiloxanes,
perfluoroalkyl polyethers, fluorinated polyacrylates or
-methacrylates and amphiphilic segmented copolymers comprising at
least one hydrophobic segment, for example a polysiloxane or
perfluoroalkyl polyether segment or a mixed
polysiloxane/perfluoroalkyl polyether segment, and at least one
hydrophilic segment, for example a polyoxazoline,
poly(2-hydroxyethylmeth- acrylate), polyacrylamide,
poly(N,N-dimethylacrylamide), polyvinylpyrrolidone polyacrylic or
polymethacrylic acid segment or a copolymeric mixture of two or
more of the underlying monomers.
[0048] The core material to be coated may also be any
blood-contacting material conventionally used for the manufacture
of renal dialysis membranes, blood storage bags, pacemaker leads or
vascular grafts. For example, the material to be modified on its
surface may be a polyurethane, polydimethylsiloxane,
polytetrafluoroethylene, polyvinylchloride, Dacron.TM. or
Silastic.TM. type polymer, or a composite made therefrom.
[0049] Moreover, the core material to be coated may also be an
inorganic or metallic base material without suitable reactive
groups, e.g. ceramic, quartz, or metals, such as silicon or gold,
or other polymeric or non-polymeric substrates. e.g., for
implantable biomedical applications, ceramics are very useful. In
addition, e.g. for biosensor purposes, hydrophilically coated base
materials are expected to reduce nonspecific binding effects if the
structure of the coating is well controlled. Biosensors may require
a specific carbohydrate coating on gold, quartz, or other
non-polymeric substrates.
[0050] The core material to be coated can be subjected to a surface
modification before applying an antimicrobial coating. 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.
[0051] The form of the core material to be coated may vary within
wide limits. Examples are particles, granules, capsules, fibers,
tubes, films or membranes, preferably moldings of all kinds such as
ophthalmic moldings, for example intraocular lenses, artificial
cornea or in particular contact lenses.
[0052] Coating materials for forming an antimicrobial
metal-containing LbL coating include, without limitation, polyionic
materials, non-charged polymeric materials, polymerized vesicles
(liposomes and micelles) with surface charges, charged
antimicrobial metal nanoparticles (preferrably charged silver
nano-particles), charged antimicrobial metal-containing
nanoparticles (preferably charged silver-containing nanoparticles),
silver-polyelectrolyte complexes formed between silver ions and a
polyionic material having sulfur-containing groups,
silver-polyelectrolyte complexes formed between silver ions and a
polycationic material having amino groups, a negatively charged
polyionic material having --COOAg groups, and combinations
thereof.
[0053] The polyionic materials that may be employed in the present
invention include polyanionic and polycationic polymers. Examples
of suitable polyanionic polymers include, for example, a synthetic
polymer, a biopolymer or modified biopolymer comprising carboxy,
sulfo, sulfato, phosphono or phosphato groups or a mixture thereof,
or a salt thereof, for example, a biomedical acceptable salt and
especially an ophthalmically acceptable salt thereof when the
article to be coated is an ophthalmic device.
[0054] Examples of synthetic polyanionic polymers are: a linear
polyacrylic acid (PAA), a branched polyacrylic acid, a
polymethacrylic acid (PMA), a polyacrylic acid or polymethacrylic
acid copolymer, a maleic or fumaric acid copolymer, a
poly(styrenesulfonic acid) (PSS), a polyamido acid, a
carboxy-terminated polymer of a diamine and a di- or polycarboxylic
acid (e.g., carboxy-terminated Starburst.TM. PAMAM dendrimers from
Aldrich), a poly(2-acrylamido-2-methylpropanesulfonic acid)
(poly-(AMPS)), an alkylene polyphosphate, an alkylene
polyphosphonate, a carbohydrate polyphosphate or carbohydrate
polyphosphonate (e.g., a teichoic acid). Examples of a branched
polyacrylic acid include a Carbophil.RTM. or Carbopol.RTM. type
from Goodrich Corp. Examples of a copolymer of acrylic or
methacrylic acid include a copolymerization product of an acrylic
or methacrylic acid with a vinyl monomer including, for example,
acrylamide, N,N-dimethyl acrylamide or N-vinylpyrrolidone. Examples
of polyanionic biopolymers or modified biopolymers are: hyaluronic
acid, glycosaminoglycanes such as heparin or chondroitin sulfate,
fucoidan, poly-aspartic acid, poly-glutamic acid, carboxymethyl
cellulose, carboxymethyl dextrans, alginates, pectins, gellan,
carboxyalkyl chitins, carboxymethyl chitosans, sulfated
polysaccharides.
[0055] A preferred polyanionic polymer is a linear or branched
polyacrylic acid or an acrylic acid copolymer. A more preferred
anionic polymer is a linear or branched polyacrylic acid. A
branched polyacrylic acid in this context is to be understood as
meaning a polyacrylic acid obtainable by polymerizing acrylic acid
in the presence of suitable (minor) amounts of a di- or polyvinyl
compound.
[0056] A suitable polycationic polymer as part of the bilayer is,
for example, a synthetic polymer, biopolymer or modified biopolymer
comprising primary, secondary or tertiary amino groups or a
suitable salt thereof, preferably an ophthalmically acceptable salt
thereof, for example a hydrohalogenide such as a hydrochloride
thereof, in the backbone or as substituents. Polycationic polymers
comprising primary or secondary amino groups or a salt thereof are
preferred.
[0057] Examples of synthetic polycationic polymers are:
[0058] (i) a polyallylamine (PAH) homo- or copolymer, optionally
comprising modifier units;
[0059] (ii) a polyethyleneimine (PEI);
[0060] (iii) a polyvinylamine homo- or copolymer, optionally
comprising modifier units;
[0061] (iv) a poly(vinylbenzyl-tri-C.sub.1-C.sub.4-alkylammonium
salt), for example a poly(vinylbenzyl-tri-methyl
ammoniumchloride);
[0062] (v) a polymer of an aliphatic or araliphatic dihalide and an
aliphatic N,N,N',N'-tetra-C.sub.1-C.sub.4-alkyl-alkylenediamine,
for example a polymer of (a) propylene-1,3-dichloride or -dibromide
or p-xylylene dichloride or dibromide and (b)
N,N,N',N'-tetramethyl-1,4-tetr- amethylene diamine;
[0063] (vi) a poly(vinylpyridine) or poly(vinylpyridinium salt)
homo- or copolymer;
[0064] (vii) a
poly(N,N-diallyl-N,N-di-C.sub.1-C.sub.4-alkyl-ammoniumhalid-
e);
[0065] (viii) a home or copolymer of a quaternized
di-C.sub.1-C.sub.4-alky- l-aminoethyl acrylate or methacrylate, for
example a
poly(2-hydroxy-3-methacryloylpropyltri-C.sub.1-C.sub.2-alkylammonium
salt) homopolymer such as a a
poly(2-hydroxy-3-methacryloylpropyltri-meth- ylammonium chloride),
or a quaternized poly(2-dimethylaminoethyl methacrylate or a
quaternized poly(vinylpyrrolidone-co-2-dimethylaminoeth- yl
methacrylate);
[0066] (ix) polyquat; or
[0067] (x) a polyaminoamide (PAMAM), for example a linear PAMAM or
a PAMAM dendrimer such as an amino-terminated Starbust.TM. PAMAM
dendrimer (Aldrich).
[0068] The above mentioned polymers comprise in each case the free
amine, a suitable salt thereof, for example a biomedically
acceptable salt or in particular an ophthalmically acceptable salt
thereof, as well as any quaternized form, if not specified
otherwise.
[0069] Suitable comonomers optionally incorporated in the polymers
according to (i), (iii), (vi) or (viii) above are, for example,
hydrophilic monomers such as acrylamide, methacrylamide,
N,N-dimethyl acrylamide, N-vinylpyrrolidone and the like.
[0070] Examples of polycationic biopolymers or modified biopolymers
that may be employed in the bilayer of the present invention
include: basic peptides, proteins or glucoproteins, for example, a
poly-.epsilon.-lysine, albumin or collagen, aminoalkylated
polysaccharides such as a chitosan or aminodextranes.
[0071] Particular polycationic polymers for forming the bilayer of
the present invention include a polyallylamine homopolymer; a
polyallylamine comprising modifier units of the above formula (II);
a polyvinylamine homo- or -copolymer or a polyethyleneimine
homopolymer, in particular a polyallylamine or polyethyleneimine
homopolymer, or a poly(vinylamine-co-acrylamid) copolymer.
[0072] 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.
[0073] It has been discovered previously and disclosed in U.S.
application Ser. No. 10/654,566 filed Sep. 3, 2003 (herein
incorporated by reference in its entirety) that one layer of a
charged polymeric material and one layer of a non-charged polymeric
material, which can be non-covalently bonded to the charged
polymeric material, can be alternatively deposited onto a substrate
to form a biocompatible LbL coating. The non-charged polymeric
material according to the invention can be: a homopolymer of a
vinyl lactam; a copolymer of at least one vinyl lactam in the
presence or in the absence of one or more hydrophilic vinylic
comonomers; or mixtures thereof.
[0074] The vinyl lactam has a structure of formula (I) 1
[0075] wherein R is an alkylene di-radical having from 2 to 8
carbon atoms; R.sub.1 is hydrogen, alkyl, aryl, aralkyl or alkaryl,
preferably hydrogen or lower alkyl having up to 7 and, more
preferably, up to 4 carbon atoms, such as, for example, methyl,
ethyl or propyl; aryl having up to 10 carbon atoms, and also
aralkyl or alkaryl having up to 14 carbon atoms; and R.sub.2 is
hydrogen or lower alkyl having up to 7 and, more preferably, up to
4 carbon atoms, such as, for example, methyl, ethyl or propyl.
[0076] The invention, in one aspect, provides a medical device
having an antimicrobial metal-containing antimicrobial LbL coating
that is not covalently attached to the medical device and having an
increased hydrophilicity, preferably characterized by having an
averaged contact angle of 80 degrees or less.
[0077] In a preferred embodiment, the antimicrobial LbL coating
comprises at least one member selected from the group consisting
of: (a) one layer of charged antimicrobial metal nanoparticles; (b)
one layer of charged antimicrobial metal-containing nano-particles;
(c) silver-polyelectrolyte complexes formed between silver ions and
a polycationic material having amino groups; (d)
silver-polyelectrolyte complexes formed between silver ions and a
polyionic material having sulfur-containing groups; (e) silver
nano-particles; and (f) combinations thereof.
[0078] In accordance with a more preferred embodiment, the charged
antimicrobial metal nanoparticles are silver nanoparticles.
[0079] Antimicrobial metal nano-particles can be either positively
charged or negatively charged, largely depending on a material (or
so-called stabilizer) which is present in a solution for preparing
the nano-particles and can stabilize the resultant nano-particles.
A stabilizer can be any known suitable material. Exemplary
stabilizers include, without limitation, positively charged
polyelectrolytes, negatively charged polyelectrolytes, surfactants,
salicylic acid, alcohols and the like. Where charged antimicrobial
metal nanoparticles are silver nanoparticles, a stabilizer
preferably is a chemical with at least one sulfur-containing group.
It is known that sulfur binds tightly to silver.
[0080] 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.
[0081] Any known suitable methods can be used in the preparation of
silver or other antimicrobial metal nano-particles. For example,
silver ions or silver salts can be reduced by means of a reducing
agent (e.g., NaBH.sub.4 or ascorbic acid or salts thereof) 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. Exemplary silver salts include, without
limitation, silver nitrate, silver acetate, silver citrate, silver
sulfate, silver lactate, and silver halide.
[0082] In accordance with the invention, charged antimicrobial
metal-containing nanoparticles can comprises at least one
antimicrobial metal selected from the group consisting of Ag, Au,
Pt, Pd, Ir, Sn, Cu, Sb, Bi and Zn. Preferably, the charged
antimicrobial metal-containing nanoparticles are silver-containing
nanoparticles.
[0083] Any known suitable methods can be used to prepare charged
antimicrobial metal-containing nanoparticles. For example,
TiO.sub.2 nanoparticles are mixed with AgNO.sub.3 solution to form
a mixture, which is subsequently exposed to UV irradiation to coat
completely or partially TiO.sub.2 nanoparticles with silver. The
TiO.sub.2 nanoparticles having a silver coating thereon can be
further coated with one or more polyionic materials by
layer-by-layer deposition techniques, to form charged
silver-containing nanoparticles.
[0084] Alternatively, one or more antimicrobial metals can be
coated onto nanoparticles made of any biocompatible materials, by
using vapor deposition techniques. Physical vapor deposition
techniques, which are well known in the art, all deposit the metal
from vapor, generally atom by atom, onto a substrate surface. The
techniques include vacuum or arc evaporation, sputtering,
magnetronsputtering and ion plating. The nanoparticles having an
antimicrobial metal coating thereon can be further coated with one
or more polyionic materials by layer-by-layer deposition
techniques, to form charged antimicrobial metal-containing
nanoparticles.
[0085] In another preferred embodiment, the antimicrobial LbL
coating of the invention formed on a medical device comprises: at
least one layer of charged antimicrobial metal nano-particles or
charged antimicrobial metal-containing nanoparticles; and at least
one layer of a polyionic material having charges opposite of the
charges of the charged antimicrobial metal nano-particles or
charged antimicrobial metal-containing nanoparticles.
[0086] In another preferred embodiment, the antimicrobial coating
of the invention formed on a medical device comprises: at least one
layer of a negatively-charged polyionic material and at least one
layer of silver-polyelectrolyte complexes formed between silver
cations and a positively-charged amino group containing polyionic
material. Exemplary complexes include, without limitation,
complexes formed between silver ions and polyethyleneimine (PEI),
complexes formed between silver ions and polyamidoamine (PAMAM)
dendrimer, complexes formed between silver ions and a polyquat, and
the like.
[0087] In another preferred embodiment, the antimicrobial LbL
coating of the invention formed on a medical device comprises: at
least one layer of silver-polyelectrolyte complexes formed between
silver ions and a polyionic material with sulfur-containing groups
and at least one layer of a polyionic material having charges
opposite of the charges of the polyionic material with
sulfur-containing groups.
[0088] In another preferred embodiment, the antimicrobial LbL
coating of the invention formed on a medical device comprises
silver nano-particles which are obtained by first forming a
transitional LbL coating composed of at least one layer of a first
polyionic material and at least one layer of a second polyionic
material having charges opposite of the charges of the first
polyionic material, wherein at least one of the first and second
polyionic materials is selected from the group consisting of
silver-polyelectrolyte complexes formed between silver cations and
a positively-charged amino group containing polyionic material;
silver-polyelectrolyte complexes formed between silver cations and
a polyionic material with sulfur-containing groups, and
combinations thereof; and then by reducing silver ions in the
transitional LbL coating by means of a reducing agent, UV
irradiation or heating.
[0089] In a more preferred embodiment, the antimicrobial LbL
coating of the invention formed on a medical device comprises at
least two members selected from the group consisting of one layer
of charged antimicrobial metal nano-particles, one layer of charged
antimicrobial metal-containing nanoparticles, one layer of
silver-polyelectrolyte complexes formed between silver ions and a
polyionic material with sulfur-containing groups, and one layer of
silver-polyelectrolyte complexes formed between silver cations and
a positively-charged amino group containing polyionic material.
Even more preferably, an antimicrobial metal-containing
antimicrobial LbL coating further comprises at least one layer of a
polyquat which exhibits antimicrobial activity. Such antimicrobial
LbL coating of the invention may exhibit antimcirobial synergy of
an antimicrobial metal and the polyquat and therefore may possess a
higher antimicrobial efficacy and a broader spectrum of
antimicrobial activities.
[0090] Any polyquats which exhibit antimicrobial activity can be
used in the present invention. Exemplary preferred polyquats are
those disclosed in copending US patent application, entitled
"Medical Devices Having Antimicrobial Coatings thereon", filed on
Nov. 4, 2002, herein incorporated by reference. Those preferred
polyquats polymeric quaternary ammonium salt compound (polyquat) of
formula (II) or (III) 2
[0091] wherein R.sub.3, R.sub.4, R.sub.5 and R.sub.6 independently
of each other are C.sub.1-C.sub.10 hydrocarbon radicals, preferably
C.sub.1 to C.sub.6 alkyl radicals or C.sub.1 to C.sub.6 alkyl
radicals having one or more hydroxyl groups; A and B independent of
each other are n-alkylene groups having 3 to 15 carbon atoms or
n-alkylene groups having 3 to 15 carbon atoms and one or more
hydroxyl groups; Y is a number from about 10 to 500; n is a number
from about 100 to 5000; X is chlorine, bromine, or iodine; R.sub.7
and R.sub.8 independently of each other are n-alkyl groups having 1
to 10 carbon atoms or n-alkyl groups having 1 to 10 carbon atoms
and one or more hydroxyl groups.
[0092] In accordance with a more preferred embodiment of the
invention, the surface of a medical device is first coated
(completely or partially) with 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, and then coated
with an antimcirobial metal-containing LbL coating of the invention
on top of the coat of the at least one antimicrobial agent. The
antimicrobial agents are covalently attached to the surface of the
medical device.
[0093] In accordance with another more preferred embodiment of the
invention, a medical device comprises: an antimicrobial
metal-containing LbL coating that is not covalently attached to the
medical device; and at least one antimicrobial agent which is
covalently attached to the LbL coating through the reactive sites
of the LbL coating, wherein said at least one antimicrobial agent
is selected from the group consisting of a polyquat which exhibits
antimicrobial activity, furanones, antimicrobial peptides,
isoxazolinones, and organic selenium compounds.
[0094] Such medical device may exhibit antimicrobial synergy of
antimicrobial metal and one or more antimicrobial agents and
therefore may possess a higher antimicrobial efficacy and a broader
spectrum of antimicrobial activities.
[0095] 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.
[0096] Cecropin A-melittin hybride has an amino acid sequence of
Lys-Trp-Lys-Leu-Phe-Lys-Lys-Ile-Gly-Ala-Val-Leu-Lys-Val-Leu-COOH
(or --NH.sub.2).
[0097] Cecropin A is a 37-residue peptide and has an amino acid
sequence of
Lys-Trp-Lys-Leu-Phe-Lys-Lys-Ile-Glu-Lys-Val-Gly-Gln-Asn-Ile-Arg-Asp-Gl-
y-Ile-Ile-Lys-Ala-Gly-Pro-Ala-Val-Ala-Val-Val-Gly-Gln-Ala-Thr-Gln-Ile-Ala--
Lys-NH.sub.2 (or --COOH)
[0098] Cecropin P1 has an amino acid sequence of
Ser-Trp-Leu-Ser-Lys-Thr-A-
la-Lys-Lys-Leu-Glu-Asn-Ser-Ala-Lys-Lys-Arg-Ile-Ser-Glu-Gly-lle-Ala-Ile-Ala-
-Ile-Gln-Gly-Gly-Pro-Arg.
[0099] Lactoferricin (bovine) has an amino acid sequence of
Arg-Arg-Trp-Gln-Trp-Arg-Met-Lys-Lys-Leu-Gly.
[0100] Bactenecin (bovine) is a cyclic cationic dodecapeptide
isolated from bovine neutrophil granules. It has an amino acid
sequence of Arg-Leu-Cys-Arg-Ile-Val-Val-Ile-Arg-Val-Cys-Arg.
[0101] Defensin 1 is a endogenous antibiotic peptide (T. Ganz, et
al., J. Clin. Invest., 76, 1427 (1985), M. E. Selsted, et al., J.
Clin. Invest., 76, 1436 (1985)., T. Ganz, M. E. Selsted, and R. I.
Lehrer, Eur. J. Haematol, 44,1 (1990)) and has an amino acid
sequence of
Ala-Cys-Tyr-Cys-Arg-Ile-Pro-Ala-Cys-Ile-Ala-Gly-Glu-Arg-Arg-Tyr-Gly-Thr-C-
ys-Ile-Tyr-Gln-Gly-Arg-Leu-Trp-Ala-Phe-Cys-Cys.
[0102] Indolicidin is 13-residue peptide amide and has an amino
acid sequence of
Ile-Leu-Pro-Trp-Lys-Trp-Pro-Trp-Trp-Pro-Trp-Arg-Arg-NH.sub.2 (or
--COOH).
[0103] Magainin 2 is a hemolytic and antimicrobial peptide (A. Mor
et al., Biochemistry, 30, 8824 (1991)) and has an amino acid
sequence of
Gly-lle-Gly-Lys-Phe-Leu-His-Ser-Ala-Lys-Lys-Phe-Gly-Lys-Ala-Phe-Val-Gly-G-
lu-Ile-Met-Asn-Ser.
[0104] "Functionally equivalent or superior analogs" of an
antimicrobial peptide refers to derivatives of a native
antimicrobial peptide in which one or more amino acid residues have
been replaced by a different amino acid (conservative amino acid
substitution or others) or deleted or inserted to provide equal or
better biological activity (i.e., antimicrobial activity). A
functionally equivalent or superior analog can be a substitution
analog, a deletion analog, or an addition analog.
[0105] A "substitution analog" is a peptide in which one or more
amino acid residues have been replaced by a different amino acid
(conservative amino acid substitution or others) to provide equal
or better biological activity (i.e., antimicrobial activity). A
deletion analog is a peptide in which one or more amino acid
residues have been deleted to provide equal or better antimicrobial
activity. An addition analog is peptide in which one or more amino
acid residues have been inserted to provide equal or better
biological activity (i.e., antimicrobial activity). A person
skilled in the art will know how to design and prepare a
substitution analog. For example, U.S. Pat. Nos. 5,792,831 and
5,912,231 (herein incorporated by reference in their entireties)
describe substitution and deletion analogs of Magainin 2.
[0106] Antimicrobial peptides can be obtained from commercial
suppliers or can be synthesized according to any known suitable
method, for example, using an Applied Biosystems Model 430A peptide
synthesizer. It is understood in the art that there are other
suitable peptide synthetic devices or that manual peptide synthesis
could be carried out to produce the peptides of the present
invention. Automated solid phase peptide synthesis is described,
e.g., in Stewart et al. (1984). Solid Phase Peptide Synthesis,
Pierce Chemical Company, Rockford, Ill.).
[0107] It is known to a person skilled in the art that an
anitmicrobial peptide can be produced by expression in a suitable
bacterial or eukaryotic host. Suitable methods for expression are
described by Sambrook, et al., (In: Molecular Cloning, A Laboratory
Manual, 2nd Edition, Cold Spring Harbor Press, Cold Spring Harbor,
N.Y. (1989)), or similar texts, herein incorporated by reference in
its entirety.
[0108] 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. Those furanones generally has the structure of formula
(IV): 3
[0109] wherein R.sub.11 and R.sub.12 are independently H, halogen,
alkyl, alkoxy, oxoalkyl, alkenyl, aryl or arylalkyl whether
unsubstituted or substituted, optionally interrupted by one or more
heteroatoms (i.e., O, N, or S), straight chain or branched chain,
hydrophilic or fluorophilic; R.sub.9 and R.sub.10 are independently
H, halogen, alkyl, aryl or arylalkyl, alkoxy; R.sub.9 or
R.sub.10+R.sub.12 can be a saturated or an unsaturated cycloalkane;
and () represents a single bond or a double bond provided that at
least one of R.sub.11, R.sub.12, R.sub.9 and R.sub.10 is halogen
The term "alkyl" used either alone or in compound words preferably
denotes a lower alkyl of 1 to carbon atoms.
[0110] 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.
[0111] 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 U.S. patent application No.
2002/0094984, herein incorporated by reference in their
entireties.
[0112] 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.
[0113] 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.
[0114] 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.
[0115] 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.
[0116] 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.
[0117] A medical device, which comprises an antimicrobial
metal-containing LbL coating that is not covalently attached to the
medical device and a layer of at least one antimicrobial agent
which is covalently attached to the LbL coating through the
reactive sites of the LbL coating, can be made by first applying an
antimicrobial metal-containing LbL coating to a preformed medical
device according to one of the below-described coating methods and
then by covalently attaching a layer of at least one antimicrobial
agent to some of those reactive sites.
[0118] Antimicrobial agents can be bound covalently to the LbL
coating. 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.
[0119] 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-cylcohexyl-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.
[0120] 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.
[0121] In accordance with the invention, the above-described
antimicrobial LbL coating of the invention preferably further
comprises at least one capping layer of a polyionic material, more
preferably at least one capping bilayer of two oppositely charged
polyionic materials or at least one capping layer of a charged
polymeric material and a non-charged polymeric material that can be
non-covalently bonded to the charged polymeric material, on top of
the outmost antimicrobial metal-containing layer. One or more
capping layers or bilayers can be served as a diffusion barrier to
control the diffusion of silver or other antimicrobial metal ions
out of the antimicrobial LbL coating.
[0122] In accordance with the invention, the above-described
antimicrobial LbL coating of the invention preferably is further
capped with a plasma coating (i.e, a medical device with an
antimicrobial metal-containing LbL coating thereon is subjected to
a plasma treatment to form a plasma coating on top of the
antimicrobial metal-containing LbL coating.
[0123] A medical device having an antimicrobial metal-containing
LbL coating thereon can be prepared by applying the antimicrobial
metal-containing LbL coating onto a preformed medical device
according to any known suitable polyelectrolyte deposition
techniques.
[0124] Application of an LbL coating may be accomplished in a
number of ways as described in pending U.S. patent applications
(application Ser. Nos. 09/005,317, 09/774,942, 09/775,104), herein
incorporated by reference in their entireties. It has been
discovered and disclosed in U.S. application Ser. No. 09/005,317
that complex and time-consuming pretreatment of a core material
(medical device) is not required prior to binding of a polyionic
material to the core material. By simply contacting a core material
of a medical device, for example, a contact lens, with one or more
solutions each containing one or more polyionic materials, an LbL
coating can be formed on a medical device.
[0125] Contacting of a preformed medical device with a coating
solution can occur by dipping it into the coating solution or by
spraying it with the coating solution. One coating process
embodiment involves solely dip-coating and optionally 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.
[0126] For example, a solely dip-coating process involves the steps
of: (a) immersing a medical device in a first coating solution of a
first polyionic material; (b) optionally rinsing the medical device
by immersing the medical device in a first rinsing solution; (c)
immersing said medical device in a second coating solution of a
second polyionic material to form a first polyelectrolyte bilayer
of the first and second polyionic materials, wherein the second
polyionic material has charges opposite of the charges of the first
polyionic material; (d) optionally rinsing said medical device by
immersing the medical device in the rinsing solution; and (e)
optionally repeating steps (a) to (d) for a number of times to form
additional polyelectrolyte bilayers. A thicker LbL coating can be
produced by repeating steps (a) to (d) preferably for 2 to 40
times. A preferred number of bilayers is about 5 to about 20
bilayers. While more than 20 bilayers are possible, it has been
found that delamination may occur in some LbL coatings having an
excessive number of bilayers.
[0127] The immersion time for each of the coating and rinsing steps
may vary depending on a number of factors. Preferably, immersion of
the core material into the polyionic solution occurs over a period
of about 1 to 30 minutes, more preferably about 2 to 20 minutes,
and most preferably about 1 to 5 minutes. Rinsing may be
accomplished in one step, but a plurality of rinsing steps can be
quite efficient.
[0128] Another embodiment of the coating process is a single
dip-coating process as described in U.S. Application No. 09 775104,
herein incorporated by reference in its entirety. Such single
dip-coating process involves dipping a core material of a medical
device in a solution containing a negatively charged polyionic
material and a positively charged polyionic material in an amount
such that the molar charge ratio of said solution is from about 3:1
to about 100:1. Multiple bilayers can be formed on a medical device
by using this single dip-coating process.
[0129] Another embodiment of the coating process involves a series
of spray coating techniques. For example, a solely spray-coating
process generally includes the steps of: (a) spraying a medical
device with a first coating solution of a first polyionic material;
(b) optionally rinsing the medical device by spraying it with a
rinsing solution; (c) spraying said medical device with a second
coating solution of a second polyionic material to form a first
polyelectrolyte bilayer of the first and second polyionic
materials, wherein the second polyionic material has charges
opposite of the charges of the first polyionic material; (d)
optionally rinsing said medical device by spraying it with the
rinsing solution; (e) optionally repeating steps (a) to (d) for a
number of times. A thicker LbL coating can be produced by repeating
steps (a) to (d) preferably for 2 to 40 times.
[0130] The spray coating application may be accomplished via a
process selected from the group consisting of an air-assisted
atomization and dispensing process, an ultrasonic-assisted
atomization and dispensing process, a piezoelectric assisted
atomization and dispensing process, an electromechanical jet
printing process, a piezo-electric jet printing process, a
piezo-electric with hydrostatic pressure jet printing process, and
a thermal jet printing process; and a computer system capable of
controlling the positioning of the dispensing head of the spraying
device on the ophthalmic lens and dispensing the coating liquid.
Those spraying coating processes are described in U.S. Application
No. 60/312,199, herein incorporated by reference in its entirety.
By using such spraying coating processes, an asymmetrical coating
can be applied to a medical device. For example, the back surface
of a contact lens can be coated with a hydrophilic and/or lubricous
coating material and the front surface of the contact lens can be
coated with an antimicrobial metal-containing LbL coating. It is
also possible to produce a coating on a contact lens, the coating
having a functional pattern so as to provide simultaneously
multiple benefits to a wearer.
[0131] In the above-described processes, at least one of the first
and second charged material is selected from the group consisting
of charged antimicrobial metal nano-particles, charged
antimicrobial metal-containing nano-particles,
silver-polyelectrolyte complexes formed between silver ions and a
polycationic material having amino groups, silver-polyelectrolyte
complexes formed between silver ions and a polyionic material with
sulfur-containing groups, and combinations thereof.
[0132] In accordance with the present invention, polyionic material
solutions can be prepared in a variety of ways. In particular, a
polyionic solution of the present invention can be formed by
dissolving the polyionic material(s) in water or any other solvent
capable of dissolving the materials. When a solvent is used, any
solvent that can allow the components within the solution to remain
stable in water is suitable. For example, an alcohol-based solvent
can be used. Suitable alcohols can include, but are not limited to,
isopropyl alcohol, hexanol, ethanol, etc. It should be understood
that other solvents commonly used in the art can also be suitably
used in the present invention.
[0133] Whether dissolved in water or in a solvent, the
concentration of a polyionic material in a solution of the present
invention can generally vary depending on the particular materials
being utilized, the desired coating thickness, and a number of
other factors. However, it may be typical to formulate a relatively
dilute aqueous solution of polyionic material. For example, a
polyionic material concentration can be between about 0.001% to
about 0.25% by weight, between about 0.005% to about 0.10% by
weight, or between about 0.01% to about 0.05% by weight.
[0134] In general, the polyionic solutions mentioned above can be
prepared by any method well known in the art for preparing
solutions. For example, in one embodiment, a polyanionic solution
can be prepared by dissolving a suitable amount of the polyanionic
material, such as polyacrylic acid having a molecular weight of
about 90,000, in water such that a solution having a certain
concentration is formed. In one embodiment, the resulting solution
is a 0.001 M PAA solution. Once dissolved, the pH of the
polyanionic solution can also be adjusted by adding a basic or
acidic material. In the embodiment above, for example, a suitable
amount of 1N hydrochloric acid (HCl) can be added to adjust the pH
to 2.5.
[0135] However, where a coating solution containing a first
polyionic material is used to form an innermost layer of a
biocompatible LbL coating of the invention on the surface of a
medical device, it is desirable that the concentration of the first
charged polymeric material in the solution is sufficiently high
enough to increase the hydrophilicity of the LbL coating.
Preferably, the concentration of the charged polymeric material in
a solution for forming the innermost layer of an LbL coating is at
least three folder higher than the concentration of a coating
material in a coating solution for forming subsequent layers of the
LbL coating. More preferably, the concentration of the charged
polymeric material in a solution for forming the innermost layer of
an LbL coating is at least ten folder higher than the concentration
of a coating material in a coating solution for forming subsequent
layers of the LbL coating.
[0136] Polycationic solutions can also be formed in a manner as
described above. For example, in one embodiment, poly(allylamine
hydrochloride) having a molecular weight of about 50,000 to about
65,000 can be dissolved in water to form a 0.001 M PAH solution.
Thereafter, the pH can also be adjusted to 2.5 by adding a suitable
amount of hydrochloric acid.
[0137] In some embodiments of the present invention, it may be
desirable to use a solution containing both polyanionic and
polycationic materials within a single solution. For example, a
polyanionic solution can be formed as described above, and then
mixed with a polycationic solution that is also formed as described
above. In one embodiment, the solutions can then be mixed slowly to
form the coating solution. The amount of each solution applied to
the mix depends on the molar charge ratio desired. For example, if
a 10:1 (polyanion:polycation) solution is desired, 1 part (by
volume) of the PAH solution can be mixed into 10 parts of the PAA
solution. After mixing, the solution can also be filtered if
desired.
[0138] In order to alter various characteristics of the coating,
such as thickness, the molecular weight of the polyionic materials
including polyquats can be varied. In particular, as the molecular
weight is increased, the coating thickness generally increases.
However, if the increase in molecular weight increase is too
substantial, the difficulty in handling may also increase. As such,
polyionic materials used in a process of the present invention will
typically have a molecular weight M.sub.n of about 2,000 to about
150,000. In some embodiments, the molecular weight is about 5,000
to about 100,000, and in other embodiments, from about 75,000 to
about 100,000.
[0139] In addition to polyionic and non-charged polymeric
materials, a coating solution for forming the bilayer or part of
it, can also contain additives. As used herein, an additive can
generally include any chemical or material. For example, active
agents, such as antimicrobials and/or antibacterials can be added
to a solution forming the bilayer, particularly when used in
biomedical applications. Some antimicrobial polyionic materials
include polyquaternary ammonium compounds, such as those described
in U.S. Pat. No. 3,931,319 to Green et al. (e.g.
POLYQUAD.RTM.).
[0140] Moreover, other examples of materials that can be added to a
coating solution are polyionic materials useful for ophthalmic
lenses, such as materials having radiation absorbing properties.
Such materials can include, for example, visibility-tinting agents,
iris color modifying dyes, and ultraviolet (UV) light tinting
dyes.
[0141] Still another example of a material that can be added to a
coating solution is a polyionic material that inhibits or induces
cell growth. Cell growth inhibitors can be useful in devices that
are exposed to human tissue for an extended time with an ultimate
intention to remove (e.g. catheters or Intra Ocular Lenses (IOL's),
where cell overgrowth is undesirable), while cell growth-inducing
polyionic materials can be useful in permanent implant devices
(e.g. artificial cornea).
[0142] When additives are applied to a coating solution, such
additives, preferably, have a charge. By having a positive or
negative charge, the additive can be substituted for the polyionic
material in solution at the same molar ratio. For example,
polyquaternary ammonium compounds typically have a positive charge.
As such, these compounds can be substituted into a solution of the
present invention for the polycationic component such that the
additive is applied to the core material of an article in a manner
similar to how a polycationic would be applied.
[0143] A preferred number of bilayers in an antimicrobial LbL
coating of the invention are about 5 to about 20 bilayers. While
more than 20 bilayers are possible, it has been found that
delamination may occur in some LbL coating having excessive number
of bilayers.
[0144] An antimicrobial LbL coating of the invention can be formed
from at least one polyionic material, preferably two polyionic
materials having charges opposite to each other.
[0145] An antimicrobial LbL coating of the invention preferably
comprises at least one layer of a lubricious coating material which
is selected from the group consisting of PAMAM dendrimers,
PAAm-co-PAA, PVP-co-PAA, glycosaminoglycanes, fucoidan,
poly-aspartic acid, poly-glutamic acid, carboxymethyl cellulose,
carboxymethyl dextrans, alginates, pectins, gellan, carboxyalkyl
chitins, carboxymethyl chitosans, sulfated polysaccharides,
glucoproteins, and aminoalkylated polysaccharides.
[0146] Silver ions can be reduced to silver or silver
nano-particles either by means of a reducing agent or by means of
heating (e.g., autoclave) or by UV irradiation. During the
manufacturing of medical devices, for example, contact lenses,
autoclave can be used to sterilize the medical devices while
reducing silver ions into silver nano-particles.
[0147] A medical device of the invention can also be made by first
applying an antimicrobial metal-containing LbL coating (described
above) to a mold for making a medical device and then
transfer-grafting the antimicrobial metal-containing LbL coating to
the medical device made from the mold, in substantial accordance
with the teachings of U.S. patent application (Ser. No.
09/774,942), herein incorporated by reference in its entirety.
[0148] 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 on which an
antimicrobial metal-containing LbL coating can be formed in
accordance with the present invention.
[0149] 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.
[0150] 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.
[0151] 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.
[0152] Once a mold is formed, a transferable antimicrobial
metal-containing LbL coating of the invention (described above) can
be applied onto the optical surface (inner surface) of one or both
mold portions by using the above-described LbL deposition
techniques. The inner surface of a mold portion is the
cavity-forming surface of the mold and in direct contact with
lens-forming material. A transferable antimicrobial
metal-containing LbL coating can be applied onto the mold portion
defining the posterior (concave) surface of a contact lens or on
the mold section defining the anterior surface of a contact lens or
on both mold portions.
[0153] Once a transferable antimicrobial metal-containing LbL
coating is applied onto the optical surface of one or both mold
portions, a lens material can then be dispensed into the contact
lens forming cavity defined by the assembled mold halves. In
general, a lens material can be made from any polymerizable
composition. In particular, when forming a contact lens, the lens
material may be an oxygen-permeable material, such as fluorine- or
siloxane-containing polymer. For example, some examples of suitable
substrate materials include, but are not limited to, the polymeric
materials disclosed in U.S. Pat. No. 5,760,100 to Nicolson et al.,
which is incorporated herein by reference. The lens material can
then be cured, i.e. polymerized, within the contact lens-forming
cavity to form the contact lens, whereby at least a portion of the
transferable coating detaches from the optical surface and
reattaches to the formed contact lens.
[0154] 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.
[0155] An antimicrobial metal-containing LbL coating of the present
invention may find particular use in extended-wear contact lenses.
The LbL coating of the invention may have a minimal adverse effects
on the desirable bulk properties of the lens, such as oxygen
permeability, ion permeability, and optical properties. Moreover,
the out diffusion of silver or other antimicrobial metals from the
antimicrobial metal-containing LbL coating of the present invention
is believed to be minimized. It is surprised to find that although
an antimicrobial LbL coating of the invention contains silver
nano-particles instead of silver ions, it still imparts to a
medical device a desired level of antimicrobial activity.
[0156] The invention, in another aspect, provides a method for
forming an antimicrobial metal-containing LbL coating on a medical
device. The method comprises alternatively applying, in no
particular order, one layer of a first charged material and one
layer of a second charged material having charges opposite of the
charges of the first charged material onto a medical device to form
the antimicrobial LbL coating, wherein at least one of the first
and second charged material is selected from the group consisting
of charged antimicrobial metal nano-particles, charged
antimicrobial metal-containing nanoparticles,
silver-polyelectrolyte complexes formed between silver ions and a
polycationic material having amino groups, silver-polyelectrolyte
complexes formed between silver ions and a polyionic material
having sulfur-containing groups, and combinations thereof.
[0157] 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
[0158] Contact Angle
[0159] The contact angle generally measures the surface
hydrophilicity of a medical device, e.g., a contact lens. In
particular, a low contact angle corresponds to more hydrophilic
surface. Average contact angles (Sessile Drop) of contact lenses
are measured using a VCA 2500 XE contact angle measurement device
from AST, Inc., located in Boston, Mass.
[0160] Antimicrobial Activity Assay
[0161] Antimicrobial activity of a contact lens with or without a
silver-containing antimicrobial LbL coating of the invention is
assayed against Pseudomonas aeruginosa GSU # 3, which is isolated
from a corneal ulcer. Bacterial cells of Pseudomonas aeruginosa GSU
# 3 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 108 cfu. The cell
suspension is serially diluted to 10.sup.3 cfu/ml.
[0162] Lenses having a silver-containing antimicrobial LbL coating
are tested against the control lenses (i.e., without a
silver-containing antimicrobial LbL coating of the invention). 200
.mu.l of from about 5.times.10.sup.3 to 1.times.10.sup.4 cfu/ml of
P. aeruginosa GSU #3 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.
[0163] Antimicrobial activity of some contact lenses with or
without silver nanoparticles and/or polyquat 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 {fraction (1/10)} th strength TSB
and adjusted to Optical Density of 10.sup.8 cfu. The cell
suspension is serially diluted to 10.sup.3 cfu/ml in {fraction
(1/10)}th strength TSB.
[0164] Lenses having a silver and/or polyquat in them are tested
against the control lenses (i.e., without a silver). 200 .mu.l of
from about 5.times.10.sup.3 to 1.times.10.sup.4 cfu/ml of 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.
[0165] Ag Nano-Particles Preparation
[0166] Unless otherwise stated, Ag nano-particles are prepared by
reducing AgNO.sub.3 using NaBH.sub.4, or ascorbic acid or salts
thereof as reducing agent and PM as stabilizer. It should be
understood that the Ag 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.
[0167] 1 mL of 0.01 M AgNO.sub.3 was mixed with 0.5 mL of 4% (by
weight) PAA solution. 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 PM is then
added rapidly into 98.5 mL of 1 mM NaBH.sub.4 solution with
vigorous stirring. The beaker was surrounded by ice to keep at
about 0.degree. C.
[0168] The above described preparation procedure was used for
preparing several batches of silver nanoparticles under various
conditions listed in Table 1. The prepared Ag nano-particle
solutions generally appear yellowish-gold in color and with a UV
peak around 410 nm, depending on fabrication conditions.
1 TABLE 1 Volume of Sample AgNO.sub.3.sup.1 PAA.sup.2
NaBH.sub.4.sup.3 Stirring time pH of colloids A 1 mL 0.5 mL 98.5 mL
1 h 6.5 B 1 mL 0.5 mL 98.5 mL 2 h 6.5 C 1 mL 0.5 mL 98.5 mL 12 h
6.3 D 0.5 mL 0.5 mL 99 mL 12 h 6.3 E 1 mL 0.5 mL 98.5 mL 13 h 5.6 F
1 mL 0.5 mL 98.5 mL 12 h 7.0 .sup.1[AgNO.sub.3] = 0.01 M;
.sup.2[PAA] = 4% (wt/v); .sup.3[NaBH.sub.4] = 1 mM
Example 2
[0169] Polyacrylic acid (PAA) solution: A solution of polyacrylic
acid having a molecular weight of about 2,000, from PolyScience, is
prepared by dissolving a suitable amount of the material in water
to form a 4% PAA solution.
[0170] Poly(diallyldimethylammonium chloride) (PDDA) solution: A
solution of PDDA having a molecular weight of about 400,000 to
500,00 from Aldrich, is prepared by dissolving a suitable amount of
the material in water to form a 0.5% PDDA solution. The pH is
adjusted by adding 0.1M NaOH solution until the pH is about
8.0.
[0171] A coating having multiple bilayers of PDDA/Ag--NP is formed
on a glass slide. The glass slide is dipped in the PDDA solution
for 10 min. The glass slide with a first layer of PDDA is then
dipped in the PAA solution for 10 minutes. Then the glass slide is
dipped again in PDDA for 10 min and then dipped in the Ag--NP
solution for 10 minutes. Finally, the steps of dipping in the PDDA
solution for 10 minutes followed by dipping in the Ag--NP solution
for 10 minutes are repeated for a desired number of times to build
up a desired number of bilayers of PDDA/Ag--NP on the lens (or
silicon wafer). There is rinsing step involved in the above coating
process.
[0172] Building up of multiple bilayers of PDDA/Ag--NP can be
monitored by using UV/visible absorption spectroscopy. Using silver
nano-particles from Sample F, a coating with an increasing number
of bilayers of PDDA/Ag--NP (from 1 to 10 bilayers)) are
successfully built up on a substrate. The absorbance at 411 nm
(around the absorption peak) of the coating increases linearly as
the number of bilayers of PDDA/Ag--NP increases. The presence of
Ag--Np in the coating was also confirmed by using AFM.
Example 3
[0173] Polyacrylic acid (PAA) solution: A solution of polyacrylic
acid having a molecular weight of about 90,000, from PolyScience,
is prepared by dissolving a suitable amount of the material in
water to form a 0.001M PM solution. The PM concentration is
calculated based on the repeating unit in PM. Once dissolved, the
pH of the polyanionic PM solution is adjusted by adding 1N
hydrochloric acid until the pH is about 2.5.
[0174] Poly(diallyldimethylammonium chloride) (PDDA) solution: PDDA
is a polyquat. A solution of PDDA having a molecular weight of
about 400,000 to 500,00 from Aldrich, is prepared by dissolving a
suitable amount of the material in water to form a 0.5% PDDA
solution. The pH is adjusted by adding 0.1M NaOH solution until the
pH is about 8.0.
[0175] A coating having multiple bilayers of PDDA/Ag--NP is formed
on a soft contact lens made of a fluorosiloxane hydrogel material,
lotrafilcon A (CIBA Vision). The contact lens is dipped in the PM
solution (0.001M, pH 2.5) for 30 minutes to form a first layer on
the lens. The lens with a first layer of PM is then dipped in the
PDDA solution (0.5%, pH 8.0) for 5 minutes and then dipped in the
Ag--NP solution for 5 minutes. Finally, the steps of dipping in the
PDDA solution for 5 minutes followed by dipping in the Ag--NP
solution for 5 minutes are repeated for a desired number of times
to build up a desired number of bilayers of PDDA/Ag--NP on the lens
(or silicon wafer). There is rinsing step involved in the above
coating process.
[0176] Using Ag--NP from Sample A, a coating with 10 bilayers of
PDDA/Ag--NP was made. The coated lenses were autoclaved in water or
in PBS. An UV peak at about 410 nm, characteristic of Ag NP, was
observed for lens both autoclaved in water or in PBS. No peak at
about 410 nm was observed from the packaging/storage solution
(water or PBS) of theses lenses, indicating no detectable amount of
Ag--NP in the packaging/storage solution (water or PBS). Or in
other words, by UV method, no detectable amount of Ag--NP is
leaching from the lens to packaging/storage solution (water or
PBS). As listed in Table 2, the coated lenses are hydrophilic with
contact angles of about 50.about.60 degrees, as compared to the
uncoated lenses with a contact angle of about 110 degrees.
2 TABLE 2 Autoclave medium water PBS Contact angle* 61 .+-. 4 54
.+-. 5 Bacterial Inhibition.sup.# 99.9% 99.9% *Average contact
angle from 3 lenses. .sup.#Averaged CFU/lens for control lenses is
about 2.9 .times. 10.sup.4.
[0177] Antimicrobial activity of a contact lens with a
silver-containing antimicrobial LbL coating of the invention was
assayed against Pseudomonas aeruginosa GSU # 3 according to the
procedure described in Example 1. The control lenses were
Lotrafilcon A contact lenses without a silver-containing
antimicrobial LbL coating. All lenses with an antimicrobial LbL
coating of the invention, which are autoclaved in either water or
PBS, show antimicrobial activity, characterized by at least a 3-log
reduction (99.9% inhibition) of viable cells as compared to the
control lenses (Table 2).
Example 4
[0178] Using the same PAA and PDDA solution and the coating
procedure as in example 3, and using Ag--NP of Sample B, a coating
with 10 bilayers of PDDA/Ag--NP was made. The coated lenses were
autoclaved in water or in PBS. An UV peak at about 410 nm,
characteristic of Ag NP, was observed for lens both autoclaved in
water or in PBS. No peak at about 410 mm was observed from the
packaging/storage solution (water or PBS) of theses lenses,
indicating no detectable amount of Ag--NP in the packaging/storage
solution (water or PBS). Or in other words, by UV method, no
detectable amount of Ag--NP is leaching from the lens to
packaging/storage solution (water or PBS). As listed in Table 3,
the coated lenses are hydrophilic with contact angles of about 60
degrees, as compared to the uncoated lenses with a contact angle of
about 110 degrees.
3 TABLE 3 Autoclave medium water PBS Contact angle* 61 .+-. 4 59
.+-. 9 Bacterial Inhibition.sup.# 99.9% 99.9% *Average contact
angle from 3 lenses. .sup.#Averaged CFU/lens for control lenses is
about 2.9 .times. 10.sup.4.
[0179] Antimicrobial activity of a contact lens with a
silver-containing antimicrobial LbL coating of the invention was
assayed against Pseudomonas aeruginosa GSU # 3 according to the
procedure described in Example 1. The control lenses were
Lotrafilcon A contact lenses without a silver-containing
antimicrobial LbL coating. All lenses with an antimicrobial LbL
coating of the invention, which are autoclaved in either water or
PBS, show antimicrobial activity, characterized by at least a 3-log
reduction (99.9% inhibition) of viable cells as compared to the
control lenses (Table 3).
Example 5
[0180] Using the same PAA and PDDA solution and the coating
procedure as in example 3, and using Ag--NP from Sample C, a
coating with 10 bilayers of PDDA/Ag--NP was made. The coated lenses
were autoclaved in water or in PBS. An UV peak at about 410 nm,
characteristic of Ag NP, was observed for lens both autoclaved in
water or in PBS. No peak at about 410 nm was observed from the
packaging/storage solution (water or PBS) of theses lenses,
indicating no detectable amount of Ag--NP in the packaging/storage
solution (water or PBS). Or in other words, by UV method, no
detectable amount of Ag--NP is leaching from the lens to
packaging/storage solution (water or PBS). As listed in Table 4,
the coated lenses are hydrophilic with contact angles of about 50
degrees, as compared to the uncoated lenses with a contact angle of
about 110 degrees. All lenses passed Sudan black staining test.
4 TABLE 4 Autoclave Medium water PBS Contact angle* 49 .+-. 8 53
.+-. 8 Bacterial Inhibition.sup.# 99.9% 99.9% *Average contact
angle from 3 lenses. .sup.#Averaged CFU/lens for control lenses is
about 2.9 .times. 10.sup.4.
[0181] Antimicrobial activity of a contact lens with a
silver-containing antimicrobial LbL coating of the invention was
assayed against Pseudomonas aeruginosa GSU # 3 according to the
procedure described in Example 1. The control lenses were
Lotrafilcon A contact lenses without a silver-containing
antimicrobial LbL coating. All lenses with an antimicrobial LbL
coating of the invention, which are autoclaved in either water or
PBS, show antimicrobial activity, characterized by at least a 3-log
reduction (99.9% inhibition) of viable cells as compared to the
control lenses (Table 4).
Example 6
[0182] Using the same PAA and PDDA solution and the coating
procedure as in example 3, and using Ag--NP from Sample E, a
coating with 10 bilayers of PDDA/Ag--NP was made. The coated lenses
were autoclaved in water or in PBS. An UV peak at about 410 nm,
characteristic of Ag NP, was observed for lens both autoclaved in
water or in PBS. No peak at about 410 nm was observed from the
packaging/storage solution (water or PBS) of theses lenses,
indicating no detectable amount of Ag--NP in the packaging/storage
solution (water or PBS). Or in other words, by UV method, no
detectable amount of Ag--NP is leaching from the lens to
packaging/storage solution (water or PBS). As listed in Table 5,
the coated lenses are hydrophilic with contact angles of about 50
degrees, as compared to the uncoated lenses with a contact angle of
about 110 degrees. All lenses passed Sudan black staining test.
5 TABLE 5 Autoclave medium water PBS Contact angle* 49 .+-. 8 53
.+-. 8 Bacterial Inhibition.sup.# 99.9% 99.9% *Average contact
angle from 3 lenses. .sup.#Averaged CFU/lens for control lenses is
about 2.9 .times. 10.sup.4.
[0183] Antimicrobial activity of a contact lens with a
silver-containing antimicrobial LbL coating of the invention was
assayed against Pseudomonas aeruginosa GSU # 3 according to the
procedure described in Example 1. The control lenses were
Lotrafilcon A contact lenses without a silver-containing
antimicrobial LbL coating. All lenses with an antimicrobial LbL
coating of the invention, which are autoclaved in either water or
PBS, show antimicrobial activity, characterized by at least a 3-log
reduction (99.9% inhibition) of viable cells as compared to the
control lenses (Table 5).
Example 7
[0184] Poly(ethyleneimine) (PEI) solution: A solution of PEI having
a molecular weight of about 70,000 from Polyscience, is prepared by
dissolving a suitable amount of the material in water to form a
0.001M PEI solution. The PEI concentration is based on the
repeating unit in PEI. The pH of the PEI solution is adjusted by
adding 0.1M nitric acid until the pH is about 8.0.
[0185] Polyacrylic acid-silver (PAA-Ag) solution: A PM-Ag solution
is prepared by dissolving a suitable amount of PAA (molecular
weight of 90,000, from PolyScience) and silver nitrate (AgNO.sub.3)
in water to form a 0.01M of PAA and 0.01M of AgNO.sub.3. The PAA
concentration is calculated based on the repeating unit in PAA.
Once dissolved, the pH of the PM-Ag solution is adjusted by adding
1N nitric acid until the pH is about 2.5.
[0186] Sodium borohydride (NaBH.sub.4) solution: a solution of
NaBH.sub.4 solution is prepared by dissolving a suitable amount of
sodium borohydride solid (from Aldrich) in water to form 0.00.1M
NaBH.sub.4 solution.
[0187] A coating having multiple bilayers of PM-Ag/PEI is formed on
a silicone wafer and a soft contact lens made of a fluorosiloxane
hydrogel material, lotrafilcon A (CIBA Vision). The contact lens
(and also the silicone wafer) is dipped in four PM solutions
(0.001M, pH 2.5) for 5 min each and a total of 20 minutes to form a
first layer on the lens. The lens with a first layer of PAA is then
dipped in the PAA-Ag solution for 5 minutes and then dipped in the
PEI solution for 5 minutes. Then the steps of dipping in the PM-Ag
solution for 5 minutes followed by dipping in the PEI solution for
5 minutes are repeated for a desired number of times to build up a
desired number of bilayers of PM-Ag/PEI on the lens (or silicon
wafer). Finally, the lens is dipped in NaBH.sub.4 solution for 5
min. There is rinsing step involved in the above coating process.
All the lenses are then released and autoclaved in water or in
PBS.
[0188] The coating thickness on silicone wafer is about 21 nm as
measured by ellipsometry. As listed in Table 6, the coated lenses
are hydrophilic with contact angles of about 30.about.65 degrees,
as compared to the uncoated lenses with a contact angle of about
110 degrees. All lenses passed Sudan black staining test.
6 TABLE 6 Autoclave medium water PBS Contact angle* 29 65 Bacterial
Inhibition.sup.# 99.9% 97.5% *Average contact angle from 3 lenses
.sup.#Averaged CFU/lens for control lenses is about 1.0 .times.
10.sup.4.
[0189] Antimicrobial activity of a contact lens with a
silver-containing antimicrobial LbL coating of the invention was
assayed against Pseudomonas aeruginosa GSU # 3 according to the
procedure described in Example 1. The control lenses were
Lotrafilcon A contact lenses without a silver-containing
antimicrobial LbL coating. All lenses with an antimicrobial LbL
coating of the invention, which are autoclaved in either water or
PBS, show antimicrobial activity, characterized by a 97.5% to 99.9%
inhibition of viable cells as compared to the control lenses (Table
6).
Example 8
[0190] Polyacrylic acid (PAA) solution: A solution of polyacrylic
acid having a molecular weight of about 90,000, from PolyScience,
is prepared by dissolving a suitable amount of the material in
water to form a 0.001M PAA solution. The PAA concentration is
calculated based on the repeating unit in PAA. Once dissolved, the
pH of the polyanionic PAA solution is adjusted by adding 1N nitric
acid until the pH is about 2.5.
[0191] Poly(ethyleneimine)-Ag+ (PEI-Ag+) solution: A PEI-Ag+
solution is prepared by dissolving a suitable amount of PEI
(molecular weight of 70,000, from PolyScience) and silver nitrate
(AgNO.sub.3) in water to form a 0.01M of PEI and 0.001M of
AgNO.sub.3. The PEI concentration is calculated based on the
repeating unit in PEI. Once dissolved, the pH of the PEI-Ag+
solution is adjusted by adding 1N nitric acid until the pH is about
6.0.
[0192] Polyacrylic acid-silver (PAA-Ag) solution: The same as in
Example 7
[0193] Sodium borohydride (NaBH.sub.4) solution: The same as in
Example 7
[0194] A coating having multiple bilayers of PM-Ag/PEI-Ag+ is
formed on a silicone wafer and a soft contact lens made of a
fluorosiloxane hydrogel material, lotrafilcon A (CIBA Vision). The
contact lens (and also the silicone wafer) is dipped in four PM
solutions (0.001M, pH 2.5) for 5 min each and a total of 20 minutes
to form a first layer on the lens. The lens with a first layer of
PAA is then dipped in the PAA-Ag solution for 5 minutes and then
dipped in the PEI-Ag+ solution for 5 minutes. Then the steps of
dipping in the PM-Ag solution for 5 minutes followed by dipping in
the PEI-Ag+ solution for 5 minutes are repeated for a desired
number of times to build up a desired number of bilayers of
PAA-Ag/PEI-Ag+ on the lens (or silicon wafer). Finally, the lens is
dipped in NaBH.sub.4 solution for 5 min. There is rinsing step
involved in the above coating process. All the lenses are then
released and autoclaved in water or in PBS.
[0195] The coating thickness on silicone wafer is about 24 nm as
measured by ellipsometry. As listed in Table 7, the coated lenses
are hydrophilic with contact angles of about 20 degrees, as
compared to the uncoated lenses with a contact angle of about 110
degrees. All lenses passed Sudan black staining test.
7 TABLE 7 Autoclave medium water PBS Contact angle* 18 23 Bacterial
Inhibition.sup.# 99.9% 99.9% *Average contact angle from 3 lenses
.sup.#Averaged CFU/lens for control lenses is about 1.0 .times.
10.sup.4.
[0196] Antimicrobial activity of a contact lens with a
silver-containing antimicrobial LbL coating of the invention was
assayed against Pseudomonas aeruginosa GSU # 3 according to the
procedure described in Example 1. The control lenses were
Lotrafilcon A contact lenses without a silver-containing
antimicrobial LbL coating. All lenses with an antimicrobial LbL
coating of the invention, which are autoclaved in either water or
PBS, show antimicrobial activity, characterized by at least a 3-log
reduction (99.9% inhibition) of viable cells as compared to the
control lenses (Table 7).
Example 9
[0197] Polyacrylic acid (PAA) solution: The same as in Example
7.
[0198] Poly(ethyleneimine)-Ag+ (PEI-Ag+) solution: A PEI-Ag+
solution is prepared by dissolving a suitable amount of PEI
(molecular weight of 70,000, from PolyScience) and silver nitrate
(AgNO.sub.3) in water to have a PEI concentration of about 7 mM and
a AgNO.sub.3 concentration of about 3 mM (solution A) or to have a
PEI concentration of about 1 mM and a AgNO.sub.3 concentration of
about 1 mM (solution B). The PEI concentration is calculated based
on the repeating unit in PEI. Once dissolved, the pH of the PEI-Ag+
solution is adjusted by adding 1N nitric acid until the pH is about
6.0.
[0199] Sodium borohydride (NaBH.sub.4) solution: The same as in
Example 7.
[0200] A coating having multiple bilayers of PAA/PEI-Ag.sup.+ is
formed on a silicone wafer and a soft contact lens made of a
fluorosiloxane hydrogel material, lotrafilcon A (CIBA Vision). The
contact lens (and also the silicone wafer) is dipped in four PAA
solutions (0.001M, pH 2.5) for 5 min each and a total of 20 minutes
to form a first layer on the lens. The lens with a first layer of
PAA is then dipped in the PAA solution for 5 minutes and then
dipped in the PEI-Ag+ solution for 5 minutes. Then the steps of
dipping in the PAA solution for 5 minutes followed by dipping in
the PEI-Ag+ solution for 5 minutes are repeated for a desired
number of times to build up a desired number of bilayers of
PA/PEI-Ag.sup.+ on the lens (or silicon wafer). Half of the lenses
are then released and autoclaved in water or in PBS. Finally, the
rest half of the lenses are dipped in NaBH.sub.4 solution for 5 min
and the lenses are then released and autoclaved in water or in PBS.
There is rinsing step involved in the above coating process.
[0201] As listed in Tables 8 and 9, the coated lenses are
hydrophilic w ith contact angles of about 20.about.65 degrees, as
compared to the uncoated lenses with a contact angle of about 110
degrees. All lenses passed Sudan black staining test.
8 TABLE 8 Autoclave medium water PBS water PBS Reduction by
NaBH.sub.4 before autoclave No No Yes Yes Contact angle* 30 45 60
65 Bacterial Inhibition.sup.# 99.9% 98% 99.9% 0% *Average contact
angle from 3 lenses .sup.#Averaged CFU/lens for control lenses is
about 1.0 .times. 10.sup.4.
[0202]
9 TABLE 9 Autoclave medium water PBS water PBS Reduction by
NaBH.sub.4 before autoclave no no yes yes Contact angle* 30 18 29
22 Bacterial Inhibition.sup.# 0% 0% 0% 0% *Average contact angle
from 3 lenses .sup.#Averaged CFU/lens for control lenses is about
1.0 .times. 10.sup.4.
[0203] Antimicrobial activity of a contact lens with a
silver-containing antimicrobial LbL coating of the invention was
assayed against Pseudomonas aeruginosa GSU # 3 according to the
procedure described in Example 1. The control lenses were
Lotrafilcon A contact lenses without a silver-containing
antimicrobial LbL coating. Depending on the silver concentration
and/or PEI/Ag.sup.+ concentration ratio, the lenses in this example
may or may not show antimicrobial activity based on in-vitro test.
Lack of antimicrobial activity for some lenses is presumably due to
low Ag.sup.+ concentration in the coating.
Example 10
[0204] Antimicrobial coating with a synergistic functions of
polyquat and silver nano particles
[0205] Two types of coatings are applied onto lotrafilcon A silicon
hydrogel contact lenses:
[0206] (1) A coating with both polyquat (PDDA) and PAA-stabilized
silve nano-particles (PAA-AgNP). The concentration of PDDA can
range from 0.1 mM to 100 mM, preferably from 1 mM to 30 mM. The
concentration of PMA-AgNP can range from 0.01 mM to 10 mM,
preferably from 0.1 mM to 5 mM. As an example, a coating with 10
bilayers of PDDA/PM-AgNP is made and autoclaved in PBS. 0.1 mM of
PAA-AgNP solution is prepared according to the procedure described
Example 1, 1 mM PM solution and 0.5% PDDA solution are prepared
according to the procedure described in Example 3. Other
concentrations of PAA-AgNP and PDDA solutions can also be used
[0207] (2) A coating with only polyquat (prepared from PDDA and
PM), but no silver nanoparticles. As an example, a coating with 10
bilayers of PDDA/PAA is made and autoclaved in PBS. 0.1 mM PM
solution and 0.50/% PDDA solution are prepared according to the
procedures described in Example 3. Other concentrations of PAA-AgNP
and PDDA solutions can also be used.
[0208] Antimicrobial activity of contact lenses with both coating
(1) and (2) are assayed against Pseudomonas aeruginosa GSU # 3 and
Staphylococcus aureus ATCC #6538 according to the procedure
described in Example 1. Lenses with both coatings show high
antimicrobial activity against Staphylococcus aureus, characterized
by 100% inhibition of viable cells. However, lenses with coating
(2) (with PDAA but no silver) show much lower inhibition against
Pseudomonas aeruginosa as compared to lenses with coating (1) (with
both PDDA and silver). This data indicates the potential advantage
of having both PDDA and silver in the coating.
Example 11
[0209] Coating with or without plasma coating on top of
PDDA/PAA-AgNP.
[0210] A coating with 5 bilayers of PDDA/PAA-AgNP on Lotrafilcon A
contact lenses is prepared, with or without a plasma coating layer
on top of the 5 bilayers of PDDA/PAA-AgNP. The coating process also
includes a primer dip coating step in PM solution. After coating,
some of lenses are released into PBS and then autoclaved in PBS.
Some of the lenses are released into water, then dried and plasma
coated. In this example, the concentration of PDDA used is 0.1 wt %
and the concentration of PAA-AgNP is 0.1 mM.
[0211] The average silver concentration in the coated lenses is
about 52 ppm, as determined by instrumental neutron activation
analysis (INNM). Antimicrobial activity of the both lenses with or
without plasma coating on top of the 5 bilayers of PDDA/PM-AgNP are
assayed against Staphylococcus aureus ATCC #6538 according to the
procedure described in Example 1. Both lenses show 100% inhibition
of viable cells.
[0212] The lenses with plasma coating on top of the PDDA/PAA-AgNP
is tried on-eyes in an over night trial modality. After the lenses
are worn, the activity of worn lenses is assay by challenging the
worn lenses with Staphylococcus aureus (Saur31) or Pseudomonas
aeruginosa (Paer6294). The worn lenses maintain efficacy against
both Pseudomonas and Staphylococcus, giving 66% and 57% reduction
of viable adhesion for Pseudomonas and Staphylococcus,
respectively.
Example 12
[0213] A coating with PDDA/PAA-AgNP on top of plasma coating
[0214] A coating with 5 bilayers of PDDA/PAA-AgNP on is prepared on
plasma coated Lotrafilcon A contact lenses. After coating, the
lenses are released into PBS and then autoclaved in PBS. As the
same as in example B, the concentration of PDDA used is 0.1 wt %
and the concentration of PAA-AgNP is 0.1 mM.
[0215] The average silver concentration in the coated lenses is
about 7 ppm, as determined by instrumental neutron activation
analysis (INAA). Antimicrobial activity of the coated lenses (with
5 bilayers of PDDA/PAA-AgNP on top of plasma coating) are assayed
against Staphylococcus aureus ATCC #6538 according to the procedure
described in Example 1 and show 100% inhibition of viable
cells.
Example 13
[0216] A non water rinse dip coating process A coating with
polyquat and silver nano particles on a Lotrafilcon A contact lens
is prepared by alternatively dipping the lens in PDDA-containing
solution and in PAA-AgNP containing solution, without water rinse
steps between dips in PDDA-containing solutions and in PAA-AgNP
containing solution.
[0217] The common practice in LbL dip coating normally involves
water rinse step or steps in between dips in polycationic solution
and polyanionic solution. It is desirable to reduce or to eliminate
the number of water rinse steps for a more efficient coating
process. An improved coating process is discovered by using PDDA
dominated solution (instead of PDDA solution).
[0218] PDDA dominated solution (referred to as PDDAd) is prepared
by mixing appropriate volume of PM-AgNP solution into PDDA
solution. The ratio of PDDA to PAA-AgNP can be controlled from 1/1
to 1/0.001, preferably from 1/0.1 to 1/0.01. It is also discovered
that of order of mixing may be important. Mixing of PAA-AgNP
solution into PDDA solution is preferred. As an example, a PDDAd
solution is made by mixing equal volume of 0.2 mM of PM-AgNP
solution into 2 mM PDDA solution. 0.2 mM of PM-AgNP solution is
prepared according to the procedure described Example 1. 2 mM of
PDDA solution is prepared according to the procedure described in
Example 3.
[0219] Four kinds of coatings with different numbers of bialyers of
PDDA/PAA-AgNP are applied onto Lotrafilcon A contact lenses. The
numbers of bilayers are 2, 3, 4, and 5, respectively. Lenses are
autoclaved in PBS.
[0220] Antimicrobial activity of contact lenses with different
numbers of bilayers are assayed against Staphylococcus aureus ATCC
#6538 according to the procedure described in Example 1. All lenses
show antimicrobial activity against Staphylococcus aureus (as shown
in Table 10)
10 TABLE 10 Number of bilayers of PDDA/PAA-AgNP 2 3 4 5 Bacterial
Inhibition against 99.8% 100% 99.8% 99.9% Staphylococcus
aureus.sup.# *Average contact angle from 3 lenses.
Example 14
[0221] A visitinted lens with PDDA/PAA-AgNP coating
[0222] Depending on coating conditions, lenses with PDDA/PM-AgNP
coating may appear to be clear or having a yellowish color. To
prepare visitinted lenses, uncoated green visitinted or blue
visitinted lenses are also used in the coating under coating
conditions similar to that described in Example 13. Green
visitinted or blue visitinted lenses are achieved in this
manner.
[0223] Uncoated green visitinted or blue visitinted Lotrafilcon A
lenses are fabricated from Lotrafilcon A formulations containing
green (copper phthalcyanine green) or blue (copper phthalcyanine
blue) pigments.
Example 15
[0224] A coating consisting of PEI-AgNP and with ascorbic acid as
reducing agent to form silver nano-particles (AgNP)
[0225] A coating with 2 bilayers of PEI-AgNP/PAA-AgNP on
Lotrafilcon A contact lenses is prepared, with or without a plasma
coating layer on top of the 5 bilayers of PEI-AgNP/PAA-AgNP.
[0226] In search for other reducing agent (other than sodium
borohydride, NaBH.sub.4), it is discovered that ascorbic acid (or
vitamin C) can reduce silver ions into silver particles. It is also
discovered that silver particles can form when mixing silver
nitrate into poly(ethylene imine) (PEI) solution. However, the
color of the PEI-AgNP solution deepen as time go on and the UV
absorption intensity of silver nano-particles peaks around 400 nm
also increase with time. It is then further discovered that
ascorbic acid (or vitamin C, VC) could speed up and/or stabilize
the process of silver nano-particle formation in PEI-AgNO3 system.
The solution of PEI-AgNP-VC is stable at least over the course of 2
days and the UV adsorption intensity remains also fairy consistent
over the course of at least 2 days.
[0227] In this example, the lenses are dipped first in a PAA-Ag
solution, followed by a dip in PEI-AgNP-VC solution, then in PAA-Ag
solution again. After certain number of bilayers of
PEI-AgNP-VC/PAA-Ag (for example, 2 bilayers in one example), the
lenses are dipped one time in a VC solution. Water rinse steps are
used between dips. After coating, lenses are released into water,
then dried and plasma coated.
[0228] The concentration silver concentration of PEI-AgNP-VC can
range from 0.01 mm to 10 mM, preferably from 0.1 mM to 2 mM. The
concentration of PM-Ag can range from 0.01 mM to 100 mM, preferably
from 0.1 mM to 10 mM. In this example, the silver concentration of
PEI-AgNP-Vc is 0.2 mM and the concentration of PM-Ag is 1 mM.
[0229] The average silver concentration in the coated lenses is
about 57 ppm, as determined by atomic adsorption (M). Antimicrobial
activity of the lenses are assayed against Staphylococcus aureus
ATCC #6538 according to the procedure described in Example 1. The
lenses show about 93.about.95% inhibition of viable cells.
[0230] The lenses are also subjected to 30 PBS rinsing cycles (one
rinse per day in PBS) and then assayed again against Staphylococcus
aureus ATCC #6538. After 30 cycles, the lenses maintain their
activity with about .about.95% inhibition of viable cells.
Example 16
[0231] Control the color of silver nanoparticles solutions
[0232] Normally, yellow is the color of a silver nano-particles
solution formed in aqueous solution using reducing agent (e.g.
NaBH.sub.4). 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.
[0233] 1. Aqua blue silver nano-particle solution:
[0234] A solution of PM-AgNO.sub.3 mixture with 1:1 molar ratio of
--COOH and AgNO.sub.3 is prepared by dissolve calculated amount of
PM and AgNO.sub.3 into appropriate volume of water. The pH of the
solution is about 3.3.about.3.4 for a 10 mM solution. The solution
is clear with no color. Then the solution is exposed to a LQ400
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 turns into aqua blue; after 180 sec
exposure, the solution remains aqua blue.
[0235] 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.
[0236] It is also discovered that the blue color disappear when the
pH of the solution is adjusted to 2.5 using nitric acid.
[0237] 2. Pink Silver Nano-Particle Solution
[0238] Another unexpected and interesting discovery is that when
the pH of the solution is first adjusted to 5.0, the solution turns
from clear to pink when exposed to a LQ-400 Grobel lamp for 30 sec
or longer. In addition the color progresses from light pink to
medium pink and then to dark pink when the exposure time is
increased from 30 seconds, to 65 seconds and then to 120
seconds.
[0239] 3. Green Silver Nano-Particle Solution
[0240] 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 turns from
clear to light yellow. Interestingly, the solution then turns into
green color after exposed for 65 seconds to a LQ-400 Grobel
lamp.
[0241] 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.
* * * * *