U.S. patent application number 14/135666 was filed with the patent office on 2014-04-24 for method for making medical devices having antimicrobial coatings thereon.
This patent application is currently assigned to Novartis AG. The applicant listed for this patent is Novartis AG. Invention is credited to John Martin Lally, Yongxing Qiu Qiu, Michael F. Rubner, Lynn Cook Winterton, Sung Yun Yang.
Application Number | 20140112994 14/135666 |
Document ID | / |
Family ID | 32682137 |
Filed Date | 2014-04-24 |
United States Patent
Application |
20140112994 |
Kind Code |
A1 |
Rubner; Michael F. ; et
al. |
April 24, 2014 |
Method for Making Medical Devices Having Antimicrobial Coatings
Thereon
Abstract
The present invention provides a method for preparing a medical
device, preferably a contact lens, having an antimicrobial
metal-containing LbL coating on a medical device, wherein the
antimicrobial metal-containing LbL coating comprises at least one
layer of a negatively charged polyionic material having --COOAg
groups and/or silver nanoparticles formed by reducing Ag.sup.+ ions
associated with the --COO.sup.- groups of the negatively charged
polyionic material. In addition, the present invention provides a
medical device prepared according to a method of the invention.
Inventors: |
Rubner; Michael F.;
(Westford, MA) ; Yang; Sung Yun; (Cambridge,
MA) ; Qiu; Yongxing Qiu; (Duluth, GA) ;
Winterton; Lynn Cook; (Keller, TX) ; Lally; John
Martin; (Benbrook, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Novartis AG |
Basel |
|
CH |
|
|
Assignee: |
Novartis AG
Basel
CH
|
Family ID: |
32682137 |
Appl. No.: |
14/135666 |
Filed: |
December 20, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13648379 |
Oct 10, 2012 |
8637071 |
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14135666 |
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10732543 |
Dec 10, 2003 |
8309117 |
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13648379 |
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Current U.S.
Class: |
424/490 ;
514/642 |
Current CPC
Class: |
A61L 2300/104 20130101;
Y10T 428/31692 20150401; A61K 31/14 20130101; A61L 2300/61
20130101; A61L 2300/624 20130101; A61L 29/16 20130101; A61L
2300/404 20130101; A61L 31/16 20130101; A61L 31/10 20130101; A61K
9/5015 20130101; G02B 1/043 20130101; Y10T 428/31681 20150401; A61P
31/04 20180101; Y10T 428/31678 20150401; A61L 29/106 20130101; A61L
27/34 20130101; A61L 2300/608 20130101; A61L 31/088 20130101; A61L
27/54 20130101; A61L 2300/45 20130101 |
Class at
Publication: |
424/490 ;
514/642 |
International
Class: |
A61K 9/50 20060101
A61K009/50; A61K 31/14 20060101 A61K031/14 |
Claims
1-18. (canceled)
19. A medical device comprising 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, wherein the antimicrobial
metal-containing LbL coating comprises at least one layer of a
negatively charged polyionic material having --COOAg groups and/or
silver nanoparticles formed by reducing Ag.sup.+ ions associated
with the --COO.sup.- groups of the negatively charged polyionic
material.
20. The medical device of claim 19, wherein the increased
hydrophilicity is characterized by having an averaged contact angle
of 80 degrees or less.
21. The medical device of claim 19, wherein the antimicrobial
metal-containing LbL coating further comprises at least one capping
layer of a polyionic material, 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.
22. The medical device of claim 19, wherein the antimicrobial
metal-containing antimicrobial LbL coating comprises at least one
layer of a polyquat which exhibits antimicrobial activity.
23. The medical device of claim 19, wherein the negatively charged
polyionic material is a linear or branched polyacrylic acid, a
polymethacrylic acid, a polyacylic acid or polymethacrylic acid
copolymer, a carboxy-terminated polymer of a diamine and a di- or
polycarboxylic acid, a maleic or fumaric acid copolymer, or
mixtures thereof.
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 compositions 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 method for forming
a silver nanoparticle-containing antimicrobial LbL coating on a
medical device. The method comprises: obtaining a medical device
with a polyelectrolyte LbL coating thereon, wherein the
polyelectrolyte LbL coating includes one or more bilayers of a
negatively charged polyionic material having --COOH groups and a
positively charged polyionic material; immersing the medical device
having the polyelectrolyte LbL coating in a solution containing
silver ions for a period of time sufficient to replace a desired
amount of H.sup.+ with silver ions; and reducing silver ions
contained in the polyelectrolyte LbL coating to form silver
nano-particles.
[0014] 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, at least one layer of a negatively charged
polyionic material having --COOAg groups and at least one layer of
a positively charged polyionic material onto a medical device to
form the antimicrobial metal-containing LbL coating.
[0015] The invention, in a further 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, wherein the antimicrobial metal-containing LbL
coating comprises at least one layer of a negatively charged
polyionic material having --COOAg groups and/or silver
nanoparticles formed by reducing Ag.sup.+ ions associated with the
--COO.sup.- groups of the negatively charged polyionic
material.
[0016] 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
[0017] 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.
[0018] An "article" refers to an ophthalmic lens, a mold for making
an ophthalmic lens, or a medical device other than ophthalmic
lens.
[0019] A "medical device", as used herein, refers to a device or a
part thereof having one or more surfaces that contact tissue,
blood, or other bodily fluids of patients in the course of their
operation or utility. Exemplary medical devices include: (1)
extracorporeal devices for use in surgery such as blood
oxygenators, blood pumps, blood sensors, tubing used to carry blood
and the like which contact blood which is then returned to the
patient; (2) prostheses implanted in a human or animal body such as
vascular grafts, stents, pacemaker leads, heart valves, and the
like that are implanted in blood vessels or in the heart; (3)
devices for temporary intravascular use such as catheters, guide
wires, and the like which are placed into blood vessels or the
heart for purposes of monitoring or repair; (4) artificial tissues
such as artificial skin for burn patients; (5) dentifices, dental
moldings; (6) ophthalmic devices; and (7) cases or containers for
storing ophthalmic devices or ophthalmic solutions.
[0020] An "ophthalmic device", as used herein, refers to a contact
lens (hard or soft), an intraocular lens, a corneal onlay, other
ophthalmic devices (e.g., stents, glaucoma shunt, or the like) used
on or about the eye or ocular vicinity.
[0021] "Biocompatible", as used herein, refers to a material or
surface of a material, which may be in intimate contact with
tissue, blood, or other bodily fluids of a patient for an extended
period of time without significantly damaging the ocular
environment and without significant user discomfort.
[0022] "Ophthalmically compatible", as used herein, refers to a
material or surface of a material which may be in intimate contact
with the ocular environment for an extended period of time without
significantly damaging the ocular environment and without
significant user discomfort. Thus, an ophthalmically compatible
contact lens will not produce significant corneal swelling, will
adequately move on the eye with blinking to promote adequate tear
exchange, will not have substantial amounts of protein or lipid
adsorption, and will not cause substantial wearer discomfort during
the prescribed period of wear.
[0023] "Ocular environment", as used herein, refers to ocular
fluids (e.g., tear fluid) and ocular tissue (e.g., the cornea)
which may come into intimate contact with a contact lens used for
vision correction, drug delivery, wound healing, eye color
modification, or other ophthalmic applications.
[0024] A "monomer" means a low molecular weight compound that can
be polymerized. Low molecular weight typically means average
molecular weights less than 700 Daltons.
[0025] 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.
[0026] "Polymer" means a material formed by polymerizing one or
more monomers.
[0027] "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.
[0028] "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.
[0029] 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.
[0030] 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.
[0031] 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.
[0032] 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.
[0033] 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.
[0034] A "polyquat", as used herein, refers to a polymeric
quaternary ammonium group-containing compound.
[0035] 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.
[0036] 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.
[0037] 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.
[0038] "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.
[0039] "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+.
[0040] "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.
[0041] An "averaged contact angle" refers to a contact angle
(Sessile Drop), which is obtained by averaging measurements of at
least 3 individual medical devices.
[0042] 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.
[0043] The invention, in one aspect, provides a method for forming
a silver nanoparticle-containing antimicrobial LbL coating on a
medical device. The method comprises: obtaining a medical device
with a polyelectrolyte LbL coating thereon, wherein the
polyelectrolyte LbL coating includes one or more bilayers of a
negatively charged polyionic material having --COOH groups and a
positively charged polyionic material; immersing the medical device
having the polyelectrolyte LbL coating in a solution containing
silver ions for a period of time sufficient to replace a desired
amount of H.sup.+ with silver ions; and reducing silver ions
contained in the polyelectrolyte LbL coating to form silver
nano-particles.
[0044] It has been discovered here that an antimicrobial metal,
silver, in particular silver nano-particles can be incorporated
cost-effectively into an LbL coating according to a method of the
invention. It is found that an silver nanoparticle-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
nanoparticle-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 nanoparticle-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.
[0045] 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 and substituted styrenes, ethylene,
propylene, acrylates and methacrylates, N-vinyl lactams,
acrylamides and methacrylamides, acrylonitrile, acrylic and
methacrylic acids.
[0046] 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.
[0047] 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.
[0048] 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-hydroxyethylmethacrylate), polyacrylamide,
poly(N,N-dimethylacrylamide), polyvinylpyrrolidone polyacrylic or
polymethacrylic acid segment or a copolymeric mixture of two or
more of the underlying monomers.
[0049] 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.
[0050] 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.
[0051] 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.
[0052] 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.
[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.
[0055] 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.
[0056] 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.
[0057] 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.
[0058] Examples of synthetic polycationic polymers are: [0059] (i)
a polyallylamine (PAH) homo- or copolymer, optionally comprising
modifier units; [0060] (ii) a polyethyleneimine (PEI); [0061] (iii)
a polyvinylamine homo- or copolymer, optionally comprising modifier
units; [0062] (iv) a
poly(vinylbenzyl-tri-C.sub.1-C.sub.4-alkylammonium salt), for,
example a poly(vinylbenzyl-tri-methyl ammoniumchloride); [0063] (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-tetramethylene diamine; [0064] (vi) a
poly(vinylpyridine) or poly(vinylpyridinium salt) homo- or
copolymer; [0065] (vii) a
poly(N,N-diallyl-N,N-di-C.sub.1-C.sub.4-alkyl-ammoniumhalide);
[0066] (viii) a homo- or copolymer of a quaternized
di-C.sub.1-C.sub.4-alkyl-aminoethyl acrylate or methacrylate, for
example a
poly(2-hydroxy-3-methacryloylpropyltri-C.sub.1-C.sub.2-alkylammonium
salt) homopolymer such as a
poly(2-hydroxy-3-methacryloylpropyltri-methylammonium chloride), or
a quaternized poly(2-dimethylaminoethyl methacrylate or a
quaternized poly(vinylpyrrolidone-co-2-dimethylaminoethyl
methacrylate); [0067] (ix) polyquat; or [0068] (x) a polyaminoamide
(PAMAM), for example a linear PAMAM or a PAMAM dendrimer such as an
amino-terminated Starbust.TM. PAMAM dendrimer (Aldrich).
[0069] 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.
[0070] 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.
[0071] 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.
[0072] 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.
[0073] 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.
[0074] 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.
[0075] The vinyl lactam has a structure of formula (I)
##STR00001##
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] A medical device having an LbL coating thereon can be
prepared by applying layers of polyionic materials and optionally
noncharged polymeric materials onto a preformed medical device
according to any known suitable polyelectrolyte deposition
techniques.
[0077] 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.
[0078] 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.
[0079] 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.
[0080] 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.
[0081] Another embodiment of the coating process is a single
dip-coating process as described in U.S. application Ser. No.
09/775,104, 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.
[0082] 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.
[0083] 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 electro-mechanical 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.
[0084] 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.
[0085] 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.
[0086] 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 0.001M 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.
[0087] 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.
[0088] 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 0.001M PAH solution.
Thereafter, the pH can also be adjusted to 2.5 by adding a suitable
amount of hydrochloric acid.
[0089] 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.
[0090] 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.
[0091] 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.).
[0092] 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.
[0093] 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).
[0094] 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.
[0095] A preferred number of bilayers in an LbL coating 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.
[0096] An LbL coating can be formed from at least one polyionic
material, preferably two polyionic materials having charges
opposite to each other.
[0097] An LbL coating 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.
[0098] Exemplary negatively charged polyionic materials having
--COOH groups include, without limitation, a linear or branched
polyacrylic acid (PAA), polymethacrylic acid (PMA), a polyacylic
acid or polymethacrylic acid copolymer, a carboxy-terminated
polymer of a diamine and a di- or polycarboxylic acid (e.g.,
carboxy-terminated Starburst.TM. PAMAM dendrimers from Aldrich),
and a maleic or fumaric acid copolymer.
[0099] It is believed that silver ions are incorporated into the
polyelectrolyte LbL coating via ion exchange mechanism to replace
H.sup.+ in the --COOH groups.
[0100] 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.
[0101] A medical device of the invention can also be made by first
applying an LbL coating (described above) to a mold for making a
medical device and then transfer-grafting the 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.
[0102] 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 LbL
coating can be formed in accordance with the present invention.
[0103] 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.
[0104] Examples of suitable processes for forming the mold halves
are disclosed in U.S. Pat. No. 4,444,711 to Schad; U.S. Pat. No.
4,460,534 to Boehm et al.; U.S. Pat. No. 5,843,346 to Morrill; and
U.S. Pat. No. 5,894,002 to Boneberger et al., which are also
incorporated herein by reference.
[0105] 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.
[0106] Once a mold is formed, a transferable LbL coating (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 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.
[0107] Once a transferable 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.
[0108] 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.
[0109] 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, at least one layer of a negatively charged
polyionic material having --COOAg groups and at least one layer of
a positively charged polyionic material onto a medical device to
form the antimicrobial metal-containing LbL coating.
[0110] The step of applying can be achieved according to any
methods, preferably described above. A negatively charged polyionic
material having --COOAg groups can be prepared according to any
known methods. For example, a negatively charged polyionic material
having --COOAg groups can be prepared by adding a soluble silver
salt into a solution of a negatively charged polyionic material
having --COOH groups. Exemplary negatively charged polyionic
materials having --COOH groups have been described above. Exemplary
silver salts include, without limitation, silver nitrate, silver
acetate, silver citrate, silver sulfate, silver lactate, and silver
halide.
[0111] In a preferred embodiment, Ag.sup.+ in the antimicrobial
metal-containing LbL coating on a medical device of the invention
can be further 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.
[0112] The invention, in a further 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, wherein the antimicrobial metal-containing LbL
coating comprises at least one layer of a negatively charged
polyionic material having --COOAg groups and/or silver
nanoparticles formed by reducing Ag.sup.+ ions associated with the
--COO.sup.- groups of the negatively charged polyionic
material.
[0113] The increased hydrophilicity is preferably characterized by
having an averaged contact angle of 80 degrees or less.
[0114] In a preferred embodiment, the antimicrobial LbL coating of
the invention formed on a medical device comprises at least one
layer of a negatively charged polyionic material having --COOAg
groups.
[0115] In another preferred embodiment, the antimicrobial LbL
coating of the invention formed on a medical device comprises
silver nanoparticles formed by reducing Ag.sup.+ ions associated
with the --COO.sup.- groups of the negatively charged polyionic
material which is one of coating materials used in preparing an
antimicrobial metal-containing LbL coating. The antimicrobial
metal-containing LbL coating can be formed by applying at least one
layer of a negatively charged polyionic material having --COOAg
groups and at least one layer of a positively charged polyionic
materials onto the medical device. Alternatively, the antimicrobial
metal-containing LbL coating can be formed by: dipping a medical
device having an LbL coating comprising at least one layer of a
negatively charged polyionic material with --COOH groups, into a
solution containing silver ions for a period of time sufficient to
replace a desired amount of H.sup.+ with silver ions; and then
reducing silver ions contained in the LbL coating to form silver
nano-particles by means of a reducing agent, UV irradiation or
heating.
[0116] In accordance with the invention, the above-described
antimicrobial LbL coating of the invention comprises preferably 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.
[0117] 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.
[0118] A medical device having a core material and an antimicrobial
metal-containing LbL coating preferably can have an increased
surface hydrophilicity and exhibit 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.
[0119] 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
Contact Angle
[0120] 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.
Antimicrobial Activity Assay
[0121] 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 Pseudomnas 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 10.sup.8 cfu. The cell
suspension is serially diluted to 10.sup.3 cfu/ml.
[0122] 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.
Example 2
Chemicals
[0123] Silver acetate (M.W. 166.9) is purchased from Aldrich
(product number 21, 667-4). Dimethylamine borane (DMAB) (M.W 58.92)
is used as a reducing agent for reducing silver ions to silver
nano-particles and purchased from Aldrich (product number
18,023-8). PAA (polyacrylic acid) with Mw.about.90,000 (25%
solution) is from Polyscience. PAAm (polyacrylamide) with
Mw.about.5,000,000 (1% solution) is from Polyscience. PAH
(polyallylamine hydrochloride) with Mw.about.70,000 is from
Aldrich. PAAm-co-PAANa (amide:acid=30:70, Mw.about.200,000, solid),
an anionic acrylamide polymer is from Polysciences. PAAm-co-PMAB
(amide:amine=80:20, Mw.about.50,000, 20% solution), a cationic
acrylamide polymer, is from Polysciences.
Solutions
[0124] Silver solution: The silver solution was prepared by
dissolving a suitable amount of silver acetate (0.1669 g/200 ml) in
water to form a 5 mM silver acetate solution. DMAB solution: The
DMAB solution was prepared by dissolving a suitable amount of DMAB
(0.05892 g/l L) to form a 1 mM DMAB solution. Solution S1: PAH,
about 10.sup.-2 M (0.935 g/litter), pH 3.0 Solution S2: PAA, about
10.sup.-2 M (2.88 g/litter), pH 3.0 Solution S3: PAAm, about
10.sup.-2 M (71 g/litter), pH 3.0 Solution S4: PAA, ca. 10.sup.-2 M
(2.88 g/litter), pH 2.0 for precoating Solution S5: PAAm-co-PMAB
(cationic), ca. 10.sup.-2 M (1.0438 g/litter), pH 3.0 Solution S6:
PAAm-co-PAANa, .about.10.sup.-2 M (0.72 g/litter), pH 3.0 Solution
S7: PAH, .about.10.sup.-2 M (0.935 g/litter)), pH 3.0
Coatings
[0125] Group A (polystyrene slides): 21 dips (15 minutes each dip)
with water rinse between dips,
S1/S2/S3/S2/S3/S2/S3/S2/S3/S2/S3/S2/S3/S2/S3/S2/S3/S2/S3/S2/S3.
Group B (polystyrene slides): 22 dips (15 minutes each dip) with
water rinse between dips:
S7/S4/S5/S6/S5/S6/S5/S6/S5/S6/S5/S6/S5/S6/S5/S6/S5/S6/S5/S6/S5/S6.
Group C (contact lenses, lotrafilcon B): 11 dips (5 minutes each
dip) with water rinse between dips:
S4/S5/S6/S5/S6/S5/S6/S5/S6/S5/S6.
Description of Samples
Group A.
[0126] #A1: 1 hr in silver acetate bath, 30 minute rinse, 10 min.
in DMAB reduction bath #A2: 1 hr in silver acetate bath, 5 minute
rinse, 2 min. in DMAB reduction bath #A3: 35 minutes dip in silver
acetate bath, 5 minute rinse, 2 min. in DMAB reduction bath #A4: 1
hr in silver acetate bath, 5 minute rinse, 2 min. in DMAB reduction
bath repeated this process 5 times (5 cycle loading) #A5: 1 hr in
silver acetate bath, 5 minute rinse, no reduction #A6: control, no
silver. Film as deposited and thermal-stabilized
Group B.
[0127] #B1: 10 min. in silver acetate bath, 5 minute rinse, 10 min.
in DMAB reduction bath
#B2: 20 min. in silver acetate bath, 5 minute rinse, 2 min. in DMAB
reduction bath #B3: 30 min. in silver acetate bath, 5 minute rinse,
2 min. in DMAB reduction bath #B4: 5 min. in silver acetate bath, 5
minute rinse, 2 min. in DMAB reduction bath #B5: 60 min. in silver
acetate bath, 5 minute rinse, 2 min. in DMAB reduction bath #B6: 10
min. in silver acetate bath, 5 minute rinse, no reduction #B7:
control, no silver. Film as deposited and thermal-stabilized
Group C. (Contact Lenses)
[0128] #C1: 5 min. in silver acetate bath, 5 minute rinse, 2 min.
in DMAB reduction bath #C2: 10 min. in silver acetate bath, 5
minute rinse, 10 min. in DMAB reduction bath #C3: 20 min. in silver
acetate bath, 5 minute rinse, 2 min. in DMAB reduction bath #C4: 30
min. in silver acetate bath, 5 minute rinse, 2 min. in DMAB
reduction bath #C5: 60 min. in silver acetate bath, 5 minute rinse,
2 min. in DMAB reduction bath #C6: 10 min. in silver acetate bath,
5 minute rinse, no reduction #C7: control, no silver. Film as
deposited and thermal-stabilized
[0129] Antimicrobial activity of Samples A1 to A5 is assayed
against Pseudomonas aeruginosa GSU #3 according to the procedure
described in Example 1. All samples show excellent antimicrobial
activity (characterized by at least a 3-log reduction, i.e. 99.9%
inhibition) of viable cells as compared to the control.
Example 3
Polyacrylic Acid (PAA) Solution
[0130] 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.
Poly(ethyleneimine) (PEI) Solution:
[0131] 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.
Polyacrylic Acid-Silver (PAA-Ag) Solution:
[0132] A PAA-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 PM and
0.01M of AgNO.sub.3. The PM concentration is calculated based on
the repeating unit in PAA. Once dissolved, the pH of the PAA-Ag
solution is adjusted by adding 1N nitric acid until the pH is about
2.5.
Sodium Borohydride (NaBH.sub.4) Solution:
[0133] a solution of NaBH.sub.4 solution is prepared by dissolving
a suitable amount of sodium borohydride solid (from Aldrich) in
water to form 0.001M NaBH.sub.4 solution.
[0134] A coating having multiple bilayers of PAA-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
PM is then dipped in the PM-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.
[0135] The coating thickness on silicone wafer is about 21 nm as
measured by ellipsometry. As listed in Table 1, the coated lenses
are hydrophilic with contact angles of about 30-65 degrees, as
compared to the uncoated lenses with a contact angle of about 110
degrees. All lenses passed Sudan black staining test.
TABLE-US-00001 TABLE 1 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.
[0136] 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
1).
[0137] 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.
* * * * *