Note: Descriptions are shown in the official language in which they were submitted.
12Z~7~
ANTIMICROBIA_OMPOSITIONS
Field of the Invention
This invention relates to compositions useful in
making medical devices and useful in providing antimi-
crobial coatings on medical devices. The invention
particularly relates to antimicrobial compositions use-
ful as coatings for medical connection devices and for
making medical connection devices which are susceptible
to touch contamination. These compositions are also
useful as antimicrobial coatings for access systems and
lead devices (for example, shunts, cannulae, catheters,
wires, enteral feeding tubes, endotracheal tubes, per-
cutaneous devices and other solid or hollow tubular
devices) used for a variety of medical purposes. In
addition, the compositions may be used as antimicrobial
coatings for wound coverings or in the manufacture of
thin, flexible, skin-like wound coverings.
Background of the Invention
Indwelling urethral catheterization is performed in
approximately 10 to 15 percent of hospitalized patients.
About 25 percent of these patients contract bacterial
infections of the urinary tract. Two studies of note
are, Garibaldi, R. A.; Burke, J. P.; Dickman, M. L.;
and Smith, C. B., "Factors Predisposing to Bacteriuria
During Indwelling Urethral Cathiterization". New Engl.
J. Med., 291:215, 1974 and Kunin, C. M. and McCormack,
R. C., "Prevention of Catheter-Induced Urinary-Tract
Infections by Sterile Closed Drainage". New Engl. J.
Med., 274:1155, 1966.
The incidence of catheter-induced urinary tract
infection still remains a problem despite various pro-
phylactic measures that have been tried. Attempts to
~z2~7~7~
reduce the incidence of urinary tract infections have
included the application of antibiotic ointments or
other bactericidal agents to the surface of the cathe-
ter, frequent bladder irrigation with concommittant
prophylactic administration of antibiotics, or inhibi-
tion of the growth of bacteria in urine drainage con-
tainers. See, Akiyama, H. and Okamoto, S., "Prophylaxis
of Indwelling Urethral Catheter Infection: Clinical
Experience with a Modified Foley Catheter and Drainage
System". The Journal of Urologv, 121:40, 1979. United
States Patent No. 4,054,139, OligodYnamic Catheter, to
Crossley, teaches a catheter, or the like, which com-
prises an oligodynamic agent such as metallic silver
or its compounds, alone or in association with other
heavy metals such as gold, for the purpose of reducing
infection associated with these devices.
It would be desirable to pro~ide compositions use-
ful as coatings for urinary catheters, lead devices,
medical connections susceptible to touch contamination
and the like, and compositions useful as a material
for making these various devices, whereby the proli-
feration of bacteria thereon or in relatively close
proximity thereto is inhibited. Inhibiting the proli-
feration of bacteria on urinary catheters and catheter
adapter connections would reduce the risk of urinary
tract infections caused by bacteria accessing the
urinary tract at these sites. It also would be de-
sirable for the compositions to be easily applied as
coatings on presently existing medical connections
and devices. A desirable characteristic of such a
composition would be an antimicrobial effect which is
long lasting without being physiologically incompatible
with nearby tissue.
1~47~7
Summary of the Invention
Varlous aspects of the invention are as follows:
An antimicrobial composition comprising:
30 to 85 percent by weight of a binder consisting
essentially of a material selected from the group consisting
of acrylonitrile-butadiene-styrene copolymers, polyvinyl
chloride, mixtures thereof, polyesters, polyurethanes,
styrene-block copolymers, natural and synthetic rubbers,
polycarbonates, nylon and silicone rubber; and,
15 to 70 percent by weight of an antimicrobial agent
selected from the group consisting of compounds of physio-
logical, antimicrobial metals and mixtures thereof.
An antimicrobial composition for coating articles
comprising:
30 to 85 percent by weight of a binder consisting
essentially of acrylonitrile-butadiene-styrene copolymers;
and,
15 to 70 percent by weight of an antimicrobial agent
selected from the group consisting essentially of silver
compounds and mixtures thereof whereby the particles of
silver compound are exposed on the coating layer on the
surface of the article and being sufficiently mobile to
produce, within 24 hours, a solution of at least 10 6 molar
concentration of silver ion concentration in a stagnant
film of urine in contact with said surface.
An antimicrobial composition for coating articles
comprising:
30 to 85 percent by weight of a binder consisting
essentially of a mixture consisting of 35 to 65 percent by
weight of acrylonitrile-butadiene-styrene copolymers and 35
to 65 percent by weight of polyvinyl chloride; and,
15 to 70 percent by weight of an antimicrobial agent
consisting essentially of silver oxide whereby the particles
of silver oxide are exposed on the coating layer on the
outermost surface of the article and being sufficiently
mobile to produce, within 24 hours, a solution of at least
10 6 molar concentration of silver ion concentration in a
stagnant film of urine in contact with said surface.
`~
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~escription of the Inventio
In accordance with this inventionr antimicrobial
compositions are provided which find particular utility
as coatings which inhibit the proliferation of bacteria
5 near the surface of urinary catheters and th~ connec-
tion between the catheter and the drainage tube, namely,
the catheter/catheter adapter ~unction site. Thc anti-
microbial coating on the catheter inhibits the prolifera-
tion of bacteria in the area between the catheter and
~0 the walls of the urethra, and the antibacterial coatinq
on the catheter adapter inhibits the pro1iferation of
bacteria in the closed area connecting the catheter and
the catheter adapter.
Catheters implanted in patients undergoing con-
15 tinuous ambulatory peritoneal dialysis also can becoated with an antimicrohial composition of this in-
vention. P.n antimicrobial composition Or this inven-
tion can be applied as a coatin~ to medical shunts !
cannulae, catheters, wires and other solid or ~ollow
20 tuhular devices used for medical purposes.
Preferably, the coating using an antimicrobia~
co~position is prepared by mixing a suitable resin and
a co~pound of a physiological, antimicrobial metal in
an appropriate solvent for the resin. The solvent
25 should not adversely effect the activity of the metal
compound as an antimicrobial agent. The coatinq can
be applied to a medica~ device by di~ping in the mix-
ture of resin, solvent, and physiological, antimicro-
bial metal compound and thereafter allowina the solvent
30 to evaporate. Both inside and outside surfaces may be
coated. Alternatively, the medical articles may be
sprayed with the mixture and the solvent allowed to
evaporate. Where appropriate, particularly with a
latex rubber resin, a volatile liquid carrier may be
- ~2247~7
used with the resin dispersed in the volatile liquid.
An article may be dipped or sprayed with this prepara-
tion. upon evaporation of the volatile liquid and
curing of the resin a coating for the article is pro-
vided.
Indeed, articles can be made from a composition
of a suitable resin and a compound of physiological,
antimicrobial metal by molding the composition to form
the article.
The resins used in formulating the mixture include,
for example, acrylonitrile-butadiene-styrene copolymer,
rigid polyvinyl chloride, curable silicones, alkoxy
cured RTV silicone rubber, polyesters, rubber latexes
(e.g., natural or synthetic polyisoprene), polyurethanes,
styrene-block copolymers (e.g., Kraton-D*and Kraton-5*,
manufactured by Shell), ethylene copolymers (e.g., vinyl
acetate, ethyl acrylate, or mixtures thereof), ethylene
copolymers of maleic anhydride, acrylic acid or both,
polycarbonates, nylons, and polymethyl methacrylate.
Into a mixture of resin and solvent is added a
quantity of physiological, antimicrobial metal compound.
Alternatively, a quantity of physiological, antimicro-
bial metal compound may be mixed with a resin for direct
molding of an article. Physiological, antimicrobial
metals are meant to include the precious metals, such
as silver, gold and platinum, and copper and zinc.
Physiological, antimicrobial metal compounds used herein
include oxides and salts of preferably silver and also
gold, for example: silver acetate, silver benzoate,
silver carbonate, silver citrate, silver chloride, sil-
ver iodide, silver oxide, silver sulfate, gold chloride
and gold oxide. Platinum compounds such as chloropla-
tinic acid or its salts (e.g., sodium and calcium chlo-
roplatinate) may also be used. Also, compounds of
* trade marks
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-- 5 --
copper and zinc may be used, for example: oxides and
salts of copper and zinc such as those indicated above
for silver. Single physiological, antimicrobial metal
compounds or combinations of physiological, antimicrobial
metal compounds may be used.
Preferred physiological, antimicrobial metal
compounds used in this invention are silver acetate,
silver oxide, silver sulfate, gold chloride and a
combination of silver oxide and gold chloride. Pre-
ferred quantities of physiological, antimicrobialmetal compound are those sufficient to produce, within
a 24 hour period, a solution of at least 10 6 molar
concentration of metal ion concentration in a stagnant
film of liquid in contact with a surface of an article
made from a composition of this invention or an article
coated with a composition of this invention.
~2Z4717
Brief Description of the Drawings
For a more complete under~tanding of this inven-
tion, reference should now be had to the embodiments
illustrated in greater detail in the accompanying
drawings.
In the drawings:
Figure 1 is an elevational view of a catheter
adapter showing one end coated with an antimicrobial
composition of this invention.
Figure 2 is an elevational view of a Foley catheter
showing the portion of the catheter typically inserted
into the urethra, coated with an antimicrobial compo-
sition of this invention.
Figure 3 is a perspective view of the catheter
adapter of this invention shown connecting a urinary
drainage tube and a catheter.
~2Z'~717
Detailed Description of the Drawings
Turning now to the drawings, Figure 1 shows a
conventional catheter adapter 10 after it has been
coated with an antimicrobial composition of this in-
vention. Catheter adapter 10 has drainage tube end
12, catheter end 14, and injection site 16.
Catheter end 14 is spray coated or dip coated with
an antimicrobial composition of this invention. The
shaded portion of catheter end 14 is illustrative of
the coating.
Figure 2 shows urinary catheter 18. Catheter 18
has drainage connection 20 and inflation connection 22
for inflating the catheter balloon.
The shaded portion of catheter 18 illustrates the
area coated by an antimicrobial composition of this
invention. Typically, this coating will be applied
to that portion of catheter 18 which resides in the
urethra of a patient.
A typical connection of catheter adapter 10 is
illustrated in Figure 3. Catheter adapter 10 has the
coated catheter end 14 connected to drainage connec-
tion 20 of the catheter. Drainage tube end 12 is
connected to drainage tube 24 to complete the connec-
tion. Drainage tube 24 drains into a urinary drainage
bag (not shown).
The risk of touch contamination of catheter end
14 is reduced by coating catheter end 14 of catheter
adapter 10 with an antimicrobial composition of the
present invention. Reducing the risk of touch contami-
nation of catheter end 14 reduces the risk of subsequent
urinary tract infection caused by a contaminated catheter
adapter.
The antimicrobial composition coating catheter
18 inhibits the proliferation and migration of bacteria
~224717
in a stagnant film between the coated catheter walls
and the walls of the urethra. By inhibiting the pro-
liferation and migration of bacteria through this
route, subsequent urinary tract infection caused by
such proliferation and migration of bacteria is re-
duced.
The examples below are offered for illustrative
purposes only and are not intended to limit the scope
of the invention of this application, which is as de-
fined in the claims below.
EXAMPLE 1
A mixture was made of 50 milliliters of methylenechloride, 5 grams of acrylonitrile-butadiene-styrene
copolymer (LUSTRAN 240-29, a trademark of the Monsanto
Company), and 1.2 grams of silver oxide powder. The
mixture was stirred for approximately one hour. A
polyvinyl chloride catheter adapter, used to connect
a urinary catheter and drainage tubing for a urinary
drainage connector, was coated on the exterior and
the interior by dipping the connector into the mixture.
Upon evaporation of the solvent, an antimicrobial coat-
ing remained bonded to the catheter adapter. Catheter
adapters can also be sprayed with the mixture.
E XAM PLE 2
A mixture was made by combining 50 milliliters
of tetrahydrofuran, 5 grams of polyvinyl chloride (Alpha
Plastics and Chemicals, clear rigid vinyl 2212/7-118),
and 1.2 grams of silver oxide powder. The mixture was
stirred for about one hour.
Vinyl compatible catheter adapters may be either
dip coated or spray coated with this mixture. By dip
coating the catheter adapter, the exterior and interior
~ZZ~717
surfaces may be conveniently coated. Upon ev~poration
of the solvent, tetrahydrofuran, an antimicrobial coat-
ing will remain bonded to the device.
EXAMPLE 3
Equivalent results may be obtained when a mixture
is made by combining 25 milliliters of tetrahydrofuran,
25 milliliters of methylene chloride, 2.5 grams of
acrylonitrile-butadiene-styrene copolymer (LUSTR~I
240-29), 2.5 grams of polyvinyl chloride (Alpha Plastics
and Chemicals, clear rigid vinyl 2212/7-118), and 1.2
grams of silver oxide powder. The mixture may be stirred
for about one hour.
A catheter adapter may be either dip coated or
spray coated with this mixture. Upon evaporation of
the solvents, an antimicrobial coating will remain
bonded to the device.
EXAMPLE 4
A mixture was made by combining 10 milliliters of
alkoxy curing RTV rubber, 65 milliliters of FREON TF
solvent (FREON is a trademark of E. I. du pont de Nemours
& Co.), and 5 grams of silver oxide powder. The mixture
was stirred for about one hour.
A silicone rubber Foley catheter was dipped into
this mixture and upon evaporation of the solvent and
curing of the RTV, a flexible, antimicrobial coating
on the interior and exterior surfaces of the silicone
rubber catheter was provided. The coating adhered
well to the catheter. Spray coating of the catheter
is a viable alternative.
EXAMPLE 5
A mixture was made by combining 100 milliliters
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-- 10 --
of tetrahydrofuran, 5 grams of acrylonitrile-butadiene-
styrene copolymer (LUSTRAN 240-29), and 1 gram of silver
acetate. The mixture was stirred for about one hour.
Acrylonitrile-butadiene-styrene compatible devices may
be spray or dip coated with the mixture. Upon evapora-
tion of the solvent, an antimicrobial coating will remain
on the device.
EXAMPLE 6
Equivalent results may be obtained when a mixture
is made by combining 100 milliliters of methylene chlo-
ride, 5 gra~s of acrylonitrile-butadiene-styrene copoly-
mer (LUSTRAN 240-29), and 1 gram of silver sulfate. The
mixture may be stirred for about one hour. Acrylonitrile-
butadiene-styrene compatible devices may be spray or dip
coated with the mixture. Upon evaporation of the solvent,
an antimicrobial coating will remain on the device.
EXA~PLE 7
Equivalent results may be obtained when a mixture
is made by combining 50 milliliters of tetrahydrofuran,
5 grams of polyvinyl chloride (Alpha Plastics and
Chemicals, clear rigid vinyl 2212/7-118), and 1.2 grams
of gold chloride powder. The mixture may be stirred
for about one hour. Polyvinyl chloride compatible de-
vices may be spray or dip coated with the mixture. Upon
evaporation of the solvent, an antimicrobial coating
will remain on the device.
EXAMPLE 8
Equivalent results may be obtained when a mixture
is made by combining 25 milliliters of tetrahydrofuran,
25 milliliters of methylene chloride, 2.5 grams of
acrylonitrile-butadiene-styrene copolymer tLUSTRAN
~22~17
240-29), 2.5 grams of polyvinyl chloride (Alpha Plastics
and Chemicals, clear rigid vinyl 2212/7-118), and 1.2
grams of gold chloride powder. The mixture may be stirred
for about one hour. Devices may be either dip coated
or spray coated with this mixture. Upon evaporation of
the solvents, an antimicrobial coating remains bonded
to the device.
EXAMPLE 9
Equivalent results may be obtained when a mixture
is made by combining 10 milliliters of alkoxy curing
RTV, 65 milliliters of FREON TF solvent and 5 grams of
gold chloride powder. The mixture may be stirred for
about one hour.
A silicone rubber Foley catheter or other silicone
lS rubber medical device mav be dipped into this mixture
and upon evaporation of the solvent and curing of the
RTV, a flexible, antimicrobial coating for the silicone
rubber catheter will be provided. Spray coating of the
catheter is also a viable alternative.
EXAMPLE 10
Equivalent results may be obtained when a mixture
is made by combining 50 milliliters of tetrahydrofuran,
5 grams of polyvinyl chloride (Alpha Plastics and
Chemicals, clear rigid vinyl 2212/7-118), 1.2 grams
of silver oxide powder, and 0.1 gram of gold chloride
powder. The mixture may be stirred for about one hour.
Vinyl compatible catheter adapters or other medi-
cal devices may be either dip coated or spray coated
with this mixture. Upon evaporation of the solvent,
tetrahydrofuran, an antimicrobial coating will remain
on the device.
~224717
- 12 -
EXAMPLE 11
Equivalent results may be obtained when a mixture
is made by combining 25 milliliters of tetrahydrofuran,
25 milliliters of methylene chloride, 2.5 grams of
acrylonitrile-butadiene-stryrene copolymer (LUSTRAN
240-29), 2.5 grams of polyvinyl chloride (Alpha Plastics
and Chemicals, clear rigid vinyl 2212/7-ll~), 1.2 grams
of silver oxide powder, and 0.1 gram of gold chloride
powder. The mixture may be stirred for about one hour.
Devices may be either dip coated or spray coated with
this mixture. Upon evaporation of the solvents, an
antimicrobial coating will remain on the device.
EXAMPLE 12
Equivalent results may be obtained when a mixture
is made by combining 10 milliliters of alkoxy curing
RTV, 65 milliliters of FREON TF solvent, 5 grams of
silver oxide powder, and 0.5 gram of gold chloride
powder. The mixture may be stirred for about one
hour.
A silicone rubber Foley catheter or other silicone
rubber medical device may be dipped into this mixture
and upon evaporation of the solvent and curing of the
RTV, a flexible, antimicrobial coating for the silicone
rubber catheter is provided. Spray coating of the
catheter is also an alternative application means.
EXAMPLE 13
Equivalent results may be obtained when a mixture
is made by combining 100 milliliters of natural rubber
latex with 10 grams of silver oxide powder. The mixture
may be stirred until the silver oxide is dispersed.
Cured latex rubber devices may be dip coated with this
~2Z~7~7
mixture. Upon evaporation of the volatile liquid car-
rier and curing of the coating mixture, an antimicrobial
coating having high elastomeric characteristics will
remain adhered to the device.
EXAMPLE 14
Equivalent results may be obtained when a mixture
is made by combining 50 milliliters of methylene chlo-
ride, 5 grams of acrylonitrile-butadiene-styrene copoly-
mer (LUSTRAN 240-29), and 1.2 grams of copper oxide
powder. The mixture may be stirred for about one hour.
A catheter adapter may be either dip coated or spray
coated with this mixture. Upon evaporation of the
solvent, an antimicrobial coating will remain bonded
to the device.
EXAMPLE 15
Equivalent results may be obtained when a mixture
is made by combining 50 milliliters of methylene chlo-
ride, 5 grams of acrylonitrile-butadiene-styrene copoly-
mer (LUSTRAN 240-29), and 1.2 grams of zinc oxide powder.
The mixture may be stirred for about one hour. A cathe-
ter adapter may be either dip coated or spray coated
with this mixture. Upon evaporation of the solvent,
an antimicrobial coating will remain bonded to the de-
vlce .
WHAT IS CLAIMED IS:
