U.S. patent application number 15/700446 was filed with the patent office on 2017-12-28 for antimicrobial coatings for medical devices.
The applicant listed for this patent is Covidien LP. Invention is credited to Robert F. ALMEIDA, Eric W. DAHL, Brent MARSDEN, Sharathkumar K. MENDON, James W. RAWLINS, Valentino J. TRAMONTANO.
Application Number | 20170368233 15/700446 |
Document ID | / |
Family ID | 55066819 |
Filed Date | 2017-12-28 |
United States Patent
Application |
20170368233 |
Kind Code |
A1 |
TRAMONTANO; Valentino J. ;
et al. |
December 28, 2017 |
ANTIMICROBIAL COATINGS FOR MEDICAL DEVICES
Abstract
Antimicrobial formulations and coatings for medical devices and
processes therefor are disclosed. The formulations include at least
one water permeable polymer with at least one antimicrobial agent
in a liquid medium and are prepared by wet milling the components
and can form antimicrobial coatings having uniformly dispersed
particles having an average size of no greater than 50 microns.
Inventors: |
TRAMONTANO; Valentino J.;
(Brockton, MA) ; MARSDEN; Brent; (Reading, MA)
; ALMEIDA; Robert F.; (Norton, MA) ; DAHL; Eric
W.; (Ann Arbor, MI) ; RAWLINS; James W.;
(Hattiesburg, MS) ; MENDON; Sharathkumar K.;
(Hattiesburg, MS) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Covidien LP |
Mansfield |
MA |
US |
|
|
Family ID: |
55066819 |
Appl. No.: |
15/700446 |
Filed: |
September 11, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14567183 |
Dec 11, 2014 |
9789228 |
|
|
15700446 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61L 27/34 20130101;
A61L 2300/602 20130101; A61L 2300/45 20130101; A61L 29/16 20130101;
A61L 2420/02 20130101; A61L 2300/224 20130101; A61L 31/10 20130101;
A61L 2300/404 20130101; A61L 2300/104 20130101; A61L 27/54
20130101; A61L 31/16 20130101; A61L 17/145 20130101; A61L 2420/06
20130101; A61L 2300/206 20130101; A61L 29/085 20130101 |
International
Class: |
A61L 29/08 20060101
A61L029/08; A61L 27/54 20060101 A61L027/54; A61L 17/14 20060101
A61L017/14; A61L 31/10 20060101 A61L031/10; A61L 31/16 20060101
A61L031/16; A61L 27/34 20060101 A61L027/34; A61L 29/16 20060101
A61L029/16 |
Claims
1. A medical device comprising an antimicrobial coating, wherein
the coating comprises at least one water permeable polymer and
uniformly dispersed particles therein of at least one antimicrobial
agent, and wherein the particles and any agglomerations of the
antimicrobial agent have an average size of no greater than 50
microns.
2. The medical device of claim 1, wherein the average size is no
greater than 20 microns.
3. The medical device of claim 2, wherein the average size is no
greater than 5 microns.
4. The medical device of claim 1, wherein the at least one water
permeable polymer encapsulates the at least one antimicrobial
agent.
5. The medical device of claim 1, wherein the at least one water
permeable polymer includes at least one of a polyurethane or a
thermoplastic polyurethane elastomer.
6. The medical device of claim 1, wherein the at least one polymer
includes at least one of a polyurethane, thermoplastic polyurethane
elastomer, polyester, polylactic acid, polyglycolic acid,
polytetramethylene glycol, polyacrylamide, polyacrylic acid,
polyacrylate, poly(2-hydroxyethyl methacrylate),
polyethylene-imine, poly-sulfonate and copolymers thereof.
7. The medical device of claim 1, wherein the at least one polymer
has a weight average molecular weight of from about 70,000 to about
120,000 Daltons.
8. The medical device of claim 1, wherein the at least one
antimicrobial agent comprises silver sulfadiazine, and wherein the
coating has a release profile wherein at least 0.50 micrograms per
centimeter (.mu.g/cm) of silver is continuously released after 72
hours.
9. The medical device of claim 1, wherein the coating further
comprises chlorhexidine diacetate, and at least 10 .mu.g/cm of
chlorhexidine diacetate is continuously released after 72
hours.
10. The medical device of claim 1, wherein the at least one
antimicrobial agent comprises a silver-based salt and a
polybiguanide salt.
11. The medical device of claim 10, wherein the silver-based salt
is silver sulfadiazine, and the polybiguanide salt is chlorhexidine
diacetate.
12. The medical device of claim 11, wherein the coating comprises
from about 2 weight percent (wt. %) to about 10 wt. % of silver
sulfadiazine, wherein the coating comprises at least 9 wt. % of
chlorhexidine diacetate, and wherein the coating comprises from
about 70 wt. % to about 90 wt. % of the water permeable
polymer.
13. The medical device of claim 12, wherein the coating comprises
from about 3.5 wt. % to about 7 wt. % silver sulfadiazine.
14. The medical device of claim 13, wherein the coating has a
release profile wherein at least 0.50 .mu.g/cm of silver is
continuously released after 150 hours.
15. The medical device of claim 12, wherein the coating comprises
at least 11 wt. % of chlorhexidine diacetate.
16. The medical device of claim 15, wherein the coating has a
release profile wherein at least 10 .mu.g/cm of chlorhexidine
diacetate is continuously released after about 150 hours.
17. The medical device of claim 1, wherein the coating has a
thickness of between about 20 microns to about 80 microns.
18. An antimicrobial formulation for coating a medical device
prepared according to a process comprising: milling at least one
water permeable polymer which is dissolved in a liquid medium with
at least one antimicrobial agent which is insoluble in the liquid
medium to form the antimicrobial formulation in which the at least
one water permeable polymer encapsulates the at least one
antimicrobial agent; and adding a primary C.sub.1-6 alcohol to the
antimicrobial formulation, wherein the at least one antimicrobial
agent includes a silver-based antimicrobial agent, and wherein the
at least one water permeable polymer includes at least one of a
polyurethane or a thermoplastic polyurethane elastomer.
19. The antimicrobial formulation of claim 18, wherein the at least
one antimicrobial agent includes a combination of the silver-based
antimicrobial agent and a polybiguanide or salt thereof.
20. The antimicrobial formulation of claim 18, wherein the at least
one antimicrobial agent includes a combination of silver
sulfadiazine and chlorhexidine diacetate.
Description
[0001] This application is a divisional of U.S. patent application
Ser. No. 14/567,183, filed Dec. 11, 2014, which is incorporated
herein by reference in its entirety.
TECHNICAL FIELD
[0002] The present disclosure relates to antimicrobial formulations
and coatings for medical devices and in particular implantable
medical devices.
BACKGROUND
[0003] Implantable medical devices used for patient treatment can
be a source of microbial infection in such patients. For example,
insertion or implantation of a medical device into a patient can
introduce microbes that can cause infection. To reduce or minimize
the impact of the introduction of microbes to a patient, many
medical devices, such as catheters, have been coated with
antimicrobial agents.
[0004] However, many antimicrobial agents that are useful in
coating medical devices tend to be insoluble in formulations used
to coat the device and tend to form agglomerated particles on the
surface of the medical device. These agglomerated particles
increase the surface roughness of the medical device, thus
increasing the chance for thrombus formation on the surface of the
medical device, and are more readily detached from the surface
thereby reducing the long term efficacy of the antimicrobial
coating. Further, agglomerated particles in the antimicrobial
formulation that is used to coat the medical device may lead to
active material precipitating out of the formulation and therefore
not being coated onto the medical device, or otherwise interfering
with the coating process. Accordingly, a need exists for improved
antimicrobial coatings on implantable medical devices.
SUMMARY OF THE DISCLOSURE
[0005] An advantage of the present invention is an implantable
medical device having an antimicrobial coating including a water
permeable polymer and uniformly dispersed particles therein of at
least one antimicrobial agent. The present disclosure provides an
antimicrobial formulation with little to no agglomerated particles,
which can be stored over a long period of time before coating a
medical device. Also, once coated onto a medical device, the
coating provides a consistent elution of antimicrobial agents over
a longer period of time.
[0006] These and other advantages are satisfied, at least in part,
by a process of forming an antimicrobial formulation for coating a
medical device. The process comprises milling at least one water
permeable polymer with at least one antimicrobial agent in a liquid
medium to form the antimicrobial formulation. Advantageously, the
milling causes the water permeable polymer to encapsulate at least
a portion of the antimicrobial agent.
[0007] An aspect of the present disclosure includes an
antimicrobial formulation for coating a medical device. The
formulation includes at least one water permeable polymer and
particles of at least one antimicrobial agent in a liquid medium,
wherein the formulation includes uniformly dispersed particles in
the liquid medium with no agglomerated particles greater than 50
microns in size. The formulation can be prepared by milling the
formulation.
[0008] Embodiments include any one or more of the following
features, individually or combined. For example, the at least one
polymer can include at least one of a polyurethane, thermoplastic
polyurethane elastomer, polyester, polylactic acid, polyglycolic
acid, polytetramethylene glycol, polyacrylamide, polyacrylic acid,
polyacrylate, poly(2-hydroxyethyl methacrylate),
polyethylene-imine, poly-sulfonate and copolymers thereof. In some
embodiments, the at least one polymer has a weight average
molecular weight of from about 70,000 to about 120,000 Daltons. In
various embodiments, the at least one antimicrobial agent includes
a combination of a silver-based antimicrobial agent and a
polybiguanide or salt thereof. In still further embodiments, the
silver-based antimicrobial agent includes one or more of silver
particles, a silver nitrate, silver halide, silver acid salt,
silver permanganate, silver sulfate, silver nitrite, silver
chromate, silver carbonate, silver phosphate, silver (I) oxide,
silver sulfide, silver azide, silver sulfite, a silver thiocyanate
or a silver sulfonamide. In various embodiments, the polybiguanide
or salt thereof includes one or more of chlorhexidine
dihydrochloride, chlorhexidine diacetate or chlorhexidine
digluconate. In some embodiments, the at least one antimicrobial
agent includes a combination of silver sulfadiazine and
chlorhexidine diacetate. In various embodiments, the liquid medium
includes one or more of an alcohol; an ether; a ketone; an organic
acid; an organic ester; an amide; a hydrocarbon; or a halogenated
solvent or liquid. In still further embodiments, the liquid medium
includes an ether and a primary C.sub.1-6 alcohol. In various
embodiments, the at least one antimicrobial agent is insoluble in
the formulation and the formulation is milled until the insoluble
antimicrobial agent has a mean particle size of no greater than
about 50 microns. In some embodiments, the formulation includes
from about 70 wt % to 90 wt % of a polyurethane polymer, from 2 wt
% to about 10 wt % silver sulfadiazine, and at least 9 wt % of
chlorhexidine diacetate.
[0009] In an aspect of the present disclosure, the process can
comprise initially preparing a polymer solution having a viscosity
in a range of from about 100 centipoise (cP) to about 1000 cP, for
example, by dissolving the polymer in the liquid medium and then
adding the antimicrobial agent to the solution followed by milling
the formulation. The process can further comprise adding a second
antimicrobial agent to the formulation after milling, and further
milling the formulation with the second antimicrobial agent and
further comprise adding a primary C.sub.1-6 alcohol to the
formulation after milling the formulation with the second
antimicrobial agent.
[0010] In another aspect of the present disclosure, the process of
forming an antimicrobial formulation for coating a medical device
can comprise milling at least one water permeable thermoplastic
polyurethane elastomer with a silver-based antimicrobial agent and
a polybiguanide or salt thereof antimicrobial agent in a liquid
medium to form the antimicrobial formulation. The process can
further comprise: preparing a solution having a viscosity of from
about 100 centipoise (cP) to about 1000 cP by dissolving the
thermoplastic polyurethane elastomer in the liquid medium; adding
the silver-based antimicrobial agent to the solution followed by
milling to form a formulation; adding the polybiguanide or salt
thereof antimicrobial agent to the formulation followed by milling
to form the antimicrobial formulation; and adding a primary
C.sub.1-6 alcohol to the antimicrobial formulation. Advantageously,
the milling can result in a formulation with significantly
uniformly dispersed particles and with no, or very few,
agglomerated particles greater than 50 microns.
[0011] Another aspect of the present disclosure includes a process
of forming an antimicrobial coating on a medical device. The
process comprises applying an antimicrobial formulation having at
least one water permeable polymer and at least one antimicrobial
agent on a medical device to form an antimicrobial coating on the
medical device, wherein the antimicrobial formulation is formed by
milling the at least one polymer with the at least one
antimicrobial agent in a liquid medium.
[0012] Embodiments include any one or more of the features
described for the process of forming the antimicrobial formulation
and/or formulation and/or any one or more of the following
features, individually or combined. In addition, the medical device
can be selected from the group consisting of a dialysis catheter, a
urological catheter, an enteral feeding tube, a surgical staple, a
trocar, an implant, suture, a respiratory tube, a surgical plate, a
surgical screw, a wire, and a hernia mesh. In some embodiments, the
coating has a thickness in a range of between about 20 microns to
about 80 microns. In various embodiments, applying the formulation
on the medical device comprises dip-coating the medical device in
the formulation and then drying the antimicrobial formulation by
driving off the liquid medium to form the antimicrobial coating on
the medical device. In embodiments, the at least one polymer
includes a polyurethane polymer and the at least one antimicrobial
agent includes a combination of a silver-based antimicrobial agent
and a polybiguanide or salt thereof. In various embodiments, the at
least one antimicrobial agent includes a combination of silver
sulfadiazine and chlorhexidine diacetate.
[0013] Another aspect of the present disclosure includes a device
having an antimicrobial coating, wherein the coating comprises a
polymer and uniformly dispersed particles of at least one
antimicrobial agent and wherein the particles and any
agglomerations of the antimicrobial agent have an average size of
no greater than 50 microns.
[0014] Embodiments include any one or more of the features
described for the antimicrobial formulation and/or the process of
forming the antimicrobial formulation and/or the process of forming
the coating on the medical device and/or any one or more of the
following features, individually or combined. In addition, the at
least one antimicrobial agent can be a silver-based antimicrobial
agent. In some embodiments, the at least one antimicrobial agent is
a silver sulfadiazine. In various embodiments, the at least one
antimicrobial agent is a silver sulfadiazine and wherein the
coating has a release profile wherein at least 0.50 .mu.g/cm of
silver is continuously released after 72 hours. In still further
embodiments, the coating further comprises chlorhexidine diacetate
and/or the coating further comprises chlorhexidine diacetate and at
least 10 .mu.g/cm of chlorhexidine diacetate is continuously
released after 72 hours. In various embodiments, the antimicrobial
coating is formed on the device by applying an antimicrobial
formulation having at least one water permeable polymer and at
least one antimicrobial agent on the medical device. In
embodiments, the antimicrobial formulation is formed by milling the
at least one polymer with the at least one antimicrobial agent in a
liquid medium. In some embodiments, the antimicrobial coating
includes from about 70 wt % to 90 wt % of a polyurethane polymer,
from 2 wt % to about 10 wt % silver sulfadiazine, and at least 9 wt
% of chlorhexidine diacetate.
[0015] Additional advantages of the present invention will become
readily apparent to those skilled in this art from the following
detailed description, wherein only the preferred embodiment of the
invention is shown and described, simply by way of illustration of
the best mode contemplated of carrying out the invention. As will
be realized, the invention is capable of other and different
embodiments, and its several details are capable of modifications
in various obvious respects, all without departing from the
invention. Accordingly, the drawings and description are to be
regarded as illustrative in nature, and not as restrictive.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] Reference is made to the attached drawings, wherein elements
having the same reference numeral designations represent similar
elements throughout and wherein:
[0017] FIG. 1 is a chart showing the release profile of a catheter
coated with chlorhexidine acetate (CHA) prepared in accordance with
the present disclosure compared to a commercial catheter having an
antimicrobial coating including CHA.
[0018] FIG. 2 is a chart showing the release profile of silver from
an antimicrobial coating in accordance with the present disclosure
compared to a commercially available catheter having an
antimicrobial coating including silver.
[0019] FIG. 3 is a chart showing the results of bacterial challenge
testing (BAC) for catheter samples having an antimicrobial coating
in accordance with the present disclosure compared to two catheter
samples of a commercially available catheter having an
antimicrobial coating.
[0020] FIGS. 4A and 4B are SEM images of antimicrobial coatings on
medical devices. FIG. 4A shows an SEM image of an antimicrobial
coating that was prepared from an antimicrobial formulation which
was prepared by milling the components of the formulation and FIG.
4B shows an SEM image of an antimicrobial coating from the same
formulation which was prepared by mixing, not milling the
components.
[0021] FIGS. 5A and 5B are SEM images of antimicrobial coatings on
medical devices. FIG. 5A shows an SEM image of an antimicrobial
coating prepared in accordance with the present disclosure. FIG. 5B
shows an SEM image of a commercially available catheter having an
antimicrobial coating.
[0022] FIGS. 6A and 6B are SEM images of antimicrobial coatings on
medical devices. FIG. 6A shows an SEM image of an antimicrobial
coating prepared in accordance with the present disclosure. FIG. 6B
shows an SEM image of a commercially available catheter having an
antimicrobial coating.
[0023] FIG. 7 is a particle size distribution chart of an
antimicrobial formulation prepared in accordance with the present
disclosure.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0024] The present disclosure is directed to antimicrobial
formulations that can be applied to medical devices to form
antimicrobial coatings thereon. The present disclosure is
particularly applicable to implantable medical devices, such as
catheters, enteral feeding tubes, surgical staples, respiratory
tubes, surgical plates, surgical screws, wires, and hernia mesh,
and forming antimicrobial coatings thereon.
[0025] Since many polymers and/or antimicrobial agents that are
useful for forming antimicrobial coatings on medical devices are
not readily soluble, such ingredients tend to form agglomerated
particles in the formulations used to coat a medical device as well
as on the surface of the medical device. Agglomerated particles can
form in sizes as large as several hundred microns even when the
initial size of the particles used in preparing a formulation is as
small as several microns. These agglomerated particles are due to
the agglomeration of many smaller sized particles that agglomerate
during the coating process.
[0026] These agglomerated particles adversely increase the surface
roughness of the medical device. In addition, the size and shape of
the agglomerated particles can adversely affect the dissolution or
release of the antimicrobial agent from the coating.
[0027] Antimicrobial formulations of the present disclosure are
prepared by milling the various ingredients, thereby minimizing the
size of the insoluble particles and their tendency to agglomerate.
Surprisingly, it has been found that by milling the various
components as set forth below, not only is the coating prepared
from the formulation more smooth once coated on a medical device,
but also the elution rate of the antimicrobial agents becomes more
consistent over time, and the release rate appears to be better
controlled over a longer period of time. Further, re-agglomeration
of the insoluble antimicrobial components is eliminated, or nearly
eliminated.
[0028] In practicing embodiments of the present disclosure, an
antimicrobial formulation for coating a medical device can be
formed by milling at least one polymer with at least one
antimicrobial agent in a liquid medium to form the antimicrobial
formulation. Preferably, the milling is done by a high-shear miller
that reduces particle size and prevents agglomeration of particles
in the formulation. Formulations containing one or more insoluble
ingredients are particularly useful in practicing the present
disclosure. Such formulations contain a liquid medium, at least one
polymer, and at least one antimicrobial agent that is not soluble
in the formulation. The formulation can also include other
ingredients that are useful in forming antimicrobial coatings on
implantable medical devices.
[0029] Polymers useful for practicing the present disclosure
include those that are water permeable and are used for coating
medical devices such as, for example, a polyurethane, such as a
thermoplastic polyurethane elastomer, a polyester, polylactic acid,
polyglycolic acid, polytetramethylene glycol, polyacrylamide,
polyacrylic acid, polyacrylate, poly(2-hydroxyethyl methacrylate),
polyethylene-imine, poly-sulfonate and copolymers thereof such as
poly(lactic acid-co-glycolic acid) (PLA/PGA),
polyacrylic-co-hydroxylated-acrylate, poly(acrylic
acid-co-2-hydroxy ethyl methacrylate). In one aspect of the present
disclosure, the polymer is a thermoplastic polyurethane elastomer,
such as Pellethane which is available from Lubrizol Advanced
Materials, USA.
[0030] The molecular weight of the polymer is preferably high
enough to form a useful coating on the medical device but not so
high as to prevent the formulation from flowing over the medical
device and forming the coating. Such polymers have a weight average
molecular weight, for example, of from about 20,000 to about
500,000 Daltons, e.g. between about 50,000 to about 200,000,
between about 70,000 to about 120,000 Daltons. The weight average
molecular weights can be determined by using GPC analysis having a
refractive index detector coupled with a light scattering detector
for absolute molecular weight measurement of weight average
molecular weight (M.sub.w).
[0031] Antimicrobial agents that are useful for the present
disclosure include, for example, silver-based antimicrobial agents;
polybiguanides and salts thereof; chlorhexidine and salts thereof
such as the dihydrochloride, diacetate and digluconate salt of
chlorhexidine; hexachlorophene; cyclohexidine; chloroaromatic
compounds such as triclosan; para-chloro-meta-xylenol.
[0032] Silver-based antimicrobial agents include, for example,
silver particles; a silver nitrate; silver halides, e.g., silver
fluoride, chloride, bromate, iodate; silver acid salts, e.g.,
silver acetate, silver salicylate, silver citrate, silver stearate,
silver benzoate, silver oxalate; silver permanganate; silver
sulfate; a silver nitrite; silver dichromate; silver chromate;
silver carbonate; silver phosphate; silver (I) oxide; silver
sulfide; silver azide; silver sulfite; silver thiocyanate; and
silver sulfonamide, such as a silver sulfadiazine. Antimicrobial
agents that are not readily soluble in a formulation are
particularly advantageous in the present disclosure.
[0033] In one embodiment of the present disclosure, the
antimicrobial agents include a combination of a silver-based salt
and a polybiguanide salt, i.e., a combination of silver
sulfadiazine and chlorhexidine diacetate.
[0034] The liquid medium of the present disclosure includes one or
more liquids that are useful for coating a medical device and
dissolving or suspending the polymer and/or antimicrobial agent.
Such liquids include, for example, one or more of the following: an
alcohol and lower alcohol, e.g., a C.sub.1-12 alcohol, such as
methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol,
furfuryl alcohol; a polyhydridic alcohol, such as ethylene glycol,
a butanediol, a propanediol; an ether, such as a linear, branched
or cyclic lower ether, dimethyl ether, ethyl ether, methyl ethyl
ether, tetrahydrofuran; a ketone such as a linear, branched or
cyclic lower ketone, such as acetone, methyl ethyl ketone,
cyclohexanone; an organic acid, such as formic acid, acetic acid,
butyric acid, benzoic acid; an organic ester, such as a formate,
ethyl or methyl acetate, propionate; an amide such as a linear,
branched or cyclic lower amide, such as dimethylacetamide (DMAC),
pyrrolidone, 1-Methyl-2-pyrrolidinone (NMP), a hydrocarbon, such as
a linear, branched or cyclic alkane, such as a pentane, hexane,
heptane, octane, cyclohexane, a linear, branched or cyclic alkene,
an aromatic solvent or liquid; and a halogenated solvent or liquid
such as a chlorinated solvent or liquid.
[0035] In one aspect of the present disclosure, the liquid medium
includes a primary alcohol, e.g., a primary C.sub.1-6 alcohol such
as methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol
in the formulation. It was found that use of a primary C.sub.1-6
alcohol, such as n-propanol, facilitates coating of the medical
device. It was found that n-propanol has a beneficial balance
between the length of the aliphatic chain and the hydroxyl group.
Also, when used with THF, n-propanol has a desirable boiling point
of 99.degree. C., which allows it to stay at the coating surface
longer than THF which in turn improves flow and leveling of the
coating on the medical device surface.
[0036] Milling the one or more polymers and antimicrobial agents in
liquid media offers the advantage of forming uniform antimicrobial
formulations that can be used to coat medical devices. It is
believed that milling, rather than mixing such as with a high shear
mixer, a liquid medium including the at least one water permeable
polymer with the at least one antimicrobial agent enables the
antimicrobial agent to be uniformly dispersed in the liquid medium
and/or to be encapsulated within the polymer such that the
antimicrobial agent does not re-agglomerate prior to and during
coating of a medical device. The encapsulated agent in the
formulation is believed to provide a more consistent elution rate
and prevent the re-agglomeration of particles over time. Milling
the formulation can be carried out using a high-shear miller such
as a roll mill. Milling media useful for the present disclosure
include Yttria stabilized zirconia grinding media, 3/8 inch
cylinder shape, from Inframat Advanced Materials.
[0037] In one aspect of the present disclosure, at least one
antimicrobial agent is insoluble in the formulation and the
formulation is milled until the insoluble antimicrobial agent has a
mean particle size of no greater than about 50 microns, such as no
greater than 40 microns, 30 microns, 20 microns, 10 microns, 5
microns and numbers therebetween. In one embodiment, the mean
particle size is approximately 5 microns. Mean particle size
determinations can be made by a laser diffraction particle size
analyzer, such as the Microtrac S3500 with a circulating loop to
suspend the sample during analysis.
[0038] In an embodiment of the present disclosure, the milling
process can include initially preparing a polymer solution. Such
polymer solutions preferably have a viscosity and wetting
properties that allows the formulation to smoothly flow over the
surface of the device to facilitate forming a uniform coating on
the medical device. The amount of the polymer in the formulation to
provide an appropriate viscosity will depend on the polymer, liquid
medium and molecular weight of the polymer.
[0039] Viscosities suitable for the formulation range from about
100 centipoise (cP) to about 10,000 cP, e.g. from about 100 cP to
about 1,000 cP, preferably from about 500 cP to about 1000 cP.
Typically from about 5 wt % to 30 wt % of the polymer can be
combined with the liquid medium to form the solution with the
appropriate viscosity. In an embodiment of the present disclosure,
preparing an antimicrobial formulation includes initially preparing
a polymer solution having a viscosity of from about 100 centipoise
(cP) to about 1,000 cP by dissolving the polymer in the liquid
medium and then adding the antimicrobial agent to the solution
followed by milling the formulation.
[0040] Additional antimicrobial agents can be added to such a
formulation. Such additional antimicrobial agents can be added neat
or in a solution with a liquid medium such as in a primary
C.sub.1-6 alcohol. After adding additional antimicrobial agents,
the formulation can be milled to form a more or less homogeneous
mixture with particles having a mean particle size of no greater
than about 50 microns, such as no greater than 40 microns, 30
microns, 20 microns, 10 microns, 5 microns and numbers there
between.
[0041] Medical devices can be prepared having antimicrobial
coatings from the formulations of the present disclosure. In
practicing certain embodiments of the present disclosure, an
antimicrobial coating on a medical device can be prepared by
applying an antimicrobial formulation having at least one polymer
and at least one antimicrobial agent on a medical device. The
application of the formulation to the device can be by a
dip-coating process or by a spraying process, for example. As
described above, a formulation including at least one insoluble
ingredient is particularly advantageous in practicing the present
disclosure. The formulation is formed by milling the at least one
polymer with the at least one antimicrobial agent in a liquid
medium.
[0042] Medical devices that can be coated by the processes
described in the present disclosure include, for example, any
medical device intended to be implanted in a patient such as
dialysis catheters, urological catheters, enteral feeding tubes,
staples, trocars, implants, titanium implants, respiratory tubes,
surgical plates, surgical screws, wires, hernia mesh, and
sutures.
[0043] This formulation can be applied to the medical device in any
way that allows the formulation to flow over and coat the device.
For example, the formulation can be applied by a dip-coating
process wherein the medical device is dipped into a container
holding the formulation and then removed from the container. The
formulation is then allowed to dry on the device. Drying can
include heating the coated medical device or allowing the medical
device to dry at room temperature. In an embodiment of the present
invention, the formulation includes a polyurethane polymer and an
antimicrobial agent that includes a combination of a silver based
antimicrobial agent and a polybiguanide or salt thereof, i.e., a
combination of silver sulfadiazine and chlorhexidine diacetate.
[0044] The thickness of the antimicrobial coating on the medical
device will depend on the application of the medical device. For
example, when coating a dialysis catheter the coating can have a
thickness of between about 20 microns to about 80 microns (e.g.,
between about 65 to about 45 microns such as about 55 microns).
Different implantable medical devices can have the same thickness
of coatings depending on the intended use.
[0045] In practicing embodiments of the present disclosure, a
medical device can be prepared having an antimicrobial coating
which includes a polymer and particles of at least one
antimicrobial agent wherein the particles of the antimicrobial
agent have an average size of no greater than the average particle
size of the antimicrobial agent in the initial formulation. That
is, the mean particle size of the antimicrobial agent on or in the
coating is no greater than about 50 microns, 40 microns, 30
microns, 20 microns, 10 microns, 5 microns and numbers
therebetween.
[0046] Advantageously, the particles formed in the formulation
after milling resist agglomeration both in the bulk formulation and
when prepared as a coating on the medical device. The coating can
contain particles having a mean particle size and mean
agglomeration size of no greater than about 50 microns, 40 microns,
30 microns, 20 microns, 10 microns, 5 microns, and numbers
therebetween.
[0047] The solubility of the antimicrobial agents and the water
permeability of the polymer will affect the release rate of the
antimicrobial agent from the coating. For example more soluble
antimicrobial agents such as chlorhexidine gluconate will have a
high release rate whereas the relatively water insoluble
hydrochloride salt releases slowly. In one embodiment of the
present disclosure, the coating on the medical device has a nominal
formulation that includes from about 70 wt % to 90 wt % of a
polyurethane polymer, from 2 wt % to about 10 wt % silver
sulfadiazine, e.g. from about 3.5 wt % to about 7 wt % and a
minimum amount of CHA of about 9 wt %, 10 wt %, or about 11 wt %.
Such a coating can be formed to have a release profile wherein at
least 0.50 .mu.g/cm of silver is continuously released after 75
hours, e.g., after about 100 hours, 150 hours and higher, and
wherein at least 10 .mu.g/cm of chlorhexidine diacetate is
continuously released after 75 hours e.g., after about 100 hours,
150 hours and higher.
EXAMPLES
[0048] The following examples are intended to further illustrate
certain preferred embodiments of the invention and are not limiting
in nature. Those skilled in the art will recognize, or be able to
ascertain, using no more than routine experimentation, numerous
equivalents to the specific substances and procedures described
herein.
[0049] A series of antimicrobial formulations were prepared by
initially preparing an approximate 12 wt % polymer solution. This
was accomplished by combining a thermoplastic polyurethane
elastomer polymer (Pellethane 2363-80A thermoplastic polyurethane
polymer available from Lubrizol) with Tetrahydrofuran (THF) in a
polymer reactor. Four different thermoplastic polyurethane
elastomer polymers were used which had weight average molecular
weights of about 82,400, 89,700, 90,400, and 105,900 Daltons, which
were determined by GPC equipped with a refractive index detector
coupled with a light scattering detector for absolute molecular
weight measurement (M.sub.w). These polymer solutions had
Brookfield viscosity values of 1167, 1686, 1533, and 3965 cP,
respectively as determined from a Brookfield viscometer in THF with
approximately 12.5 wt % solids. The polymer reactor was configured
with a reflux condenser, stirring mechanism and Nitrogen gas inlet
to provide a constant Nitrogen blanket in the reactor. THF was
added to the reactor and the polyurethane polymer was added to a
level of 12.3 weight percent solids, and the mixture was heated
with mixing at 45-55.degree. C. for 16 hours, then cooled to
ambient temperature to form the solution containing the polymer.
The percent solids of the polyurethane polymer solution was
measured gravimetrically, by placing a sample on an aluminum
weighing dish in a lab oven at 110.degree. C. for 60 minutes.
[0050] A mixture containing the polymer solution utilizing the
polyurethane having a molecular weight of 89,700 Daltons and a
silver-based antimicrobial agent was then prepared by combining
181.22 grams of the polyurethane polymer/THF solution with 91.78
grams of THF and with 2.81 grams of silver sulfadiazine (AgSD) in a
one (1) quart sealed glass jar milling vessel together with milling
media, i.e., zirconia grinding media. This mixture was then milled
for 24 hours in the sealed glass jar milling vessel on a roll mill
using 555 grams (114 media pieces) of Yttria stabilized Zirconia
grinding media 3/8 inch cylinder shape (available from Inframat
Advanced Materials). The milling rate was set to about 50 rpm for
this and subsequent milling.
[0051] A mixture of chlorhexidine acetate (CHA) (available from
Medichem, S.A., Barcelona Spain) was separately prepared by
combining 4.64 grams of CHA with 9.30 grams of methanol with mixing
until complete dissolution was achieved. Then 12.4 grams of THF was
slowly added to the CHA/methanol solution with mixing.
[0052] The CHA/methanol/THF solution was then added to the milling
vessel containing the polyurethane/THF/AgSD mixture, with mixing,
in increments of equal volume at approximately every 1 hour
interval for a total 6 hour time period. This mixture was then
milled for 24 hours.
[0053] Additional processing aids and solvents can be added to the
milled mixture. For this example, approximately 98.6 grams of
n-propanol was added in increments of equal volume over 2 hours
while milling, and the mixture was milled for an additional 3 hours
to provide an antimicrobial formulation. Milling was conducted
throughout the n-propanol addition. N-propanol was added in 2
increments of equal volume, then milled for an additional 3 hours.
For this example, n-propanol was the let-back solvent used to
dilute the formulation to reduce the overall amount of the THF, and
to provide improved flow/leveling of the coating on drying. This
formulation had the following weight percentages:
TABLE-US-00001 TABLE 1 Example Antimicrobial Formulation Ingredient
Approximate Weight % Polyurethane polymer 8.41 AgSD 0.70 CHA 1.16
THF 62.81 Methanol 2.32 n-propanol 24.60 Total 100
[0054] The percent solids of the formulation was measured
gravimetrically, by placing a sample on an aluminum weighing dish
in a lab oven at 110.degree. C. for 60 minutes. The viscosity of
the formulation was measured using a Brookfield viscometer.
[0055] The particle sizes for AgSD after milling is shown in FIG.
7. The particle sizes for AgSD after milling had a distribution
wherein the 50 percentile value was approximately 5.4 microns and
90% of the particles were 30 microns or less. The mean particle
size was 5.4 microns. The foregoing particle sizes were determined
by a laser diffraction particle size analyzer, the Microtrac S3500
with a circulating loop to suspend the sample during analysis.
Specifically, the formulation was stirred on a lab stir plate with
a stir bar at 600 rpm for 2 hours. The formulation was diluted with
tetrahydrofuran (THF) solvent to adjust the viscosity into the
appropriate range for the instrument, and automatic mixing of the
sample was maintained throughout the particle size measurements to
generate the particle size distribution chart shown in FIG. 7.
While the particle size distribution shows few particles over 100
microns, it is believed, based on SEM images of the coating, that
few particles are actually over 50 microns, and that the population
at the high end of the distribution chart may actually be the laser
detecting multiple particles in close proximity to each other while
the diluted sample was mixing during analysis.
[0056] The antimicrobial formulation was used to prepare an
antimicrobial coating on the exterior of the dialysis catheter
surface. This was accomplished by placing the formulation in a
suitable vessel inside an automated dip-coating apparatus
(appropriately vented) and submerging the catheter shaft into the
formulation. The catheter was then dried in a vented oven at
60.degree. C. for 5 days to remove the solvents. The coating
prepared in this example was composed approximately of 81.88 wt %
polyurethane polymer, 11.30 wt % CHA and 6.82% AgSD. The thickness
of the coating was measured by obtaining a cross-section of the
catheter at various intervals and obtaining the coating thickness
by measurement on a Scanning Electron Microscope. The thickness was
determined to be about 55 microns.
[0057] Catheters prepared according to this example were tested for
the release rates of the antimicrobial agents in phosphate buffered
saline (PBS) solution. The release rates were determined by taking
samples of PBS solution from a container holding cut samples of the
coatings of each catheter. For each catheter, several samples of
the coating were prepared by cutting the coated catheter to a
particular size. The cut samples were then combined with PBS
solution in a sample container mounted on a shaker which was set to
37.degree. C. and 120 rpm. The cut coating samples were then
removed from the container and placed in new sample containers with
PBS solutions first at the 4 hour mark, then at every 24 hours
thereafter. The PBS solutions were then analyzed for antimicrobial
content. Chlorhexidine was analyzed by HPLC and silver
concentration was analyzed by ICP-MS.
[0058] Release rates for the antimicrobial agents were measured as
described above and the results plotted in the charts shown in
FIGS. 1 and 2. FIGS. 1 and 2 also plot the release rates of a
commercially available catheter, the ARROWgard Blue.TM.
hemodialysis catheter available from Teleflex Medical (Research
Triangle Park, N.C.), having an antimicrobial coating including
AgSD and CHA. The ARROWgard Blue.TM. catheter has been commercially
available since approximately 1990, and it is believed, based on
Food and Drug Administration filings, that the only change to the
antimicrobial coating since its commercial release has been an
increase in the antimicrobial material amounts. The ARROWgard
Blue.TM. catheter samples were prepared and analyzed in PBS as
described above. As shown in FIGS. 1 and 2, catheters coated with a
formulation according to the present disclosure had at least 10
.mu.g/cm of chlorhexidine diacetate released after 72 hours and a
release profile wherein at least 0.50 .mu.g/cm of silver was
released after 72 hours. For this particular example, the 10
.mu.g/cm of chlorhexidine diacetate released after 150 hours and
had a release profile wherein at least 0.50 .mu.g/cm of silver was
released after 150 hours.
[0059] Catheters prepared according to this example were also
compared to the commercially available ARROWgard Blue.TM. catheter
for antimicrobial effectiveness. FIG. 3 shows Bacterial Challenge
(BAC) Testing of the catheters. The data show that catheters coated
with formulations of the present disclosure had superior
antimicrobial activity across all 3 microorganisms as compared to
the commercially available catheter.
[0060] To demonstrate the benefits of milling the components of an
antimicrobial formulation, a comparative example was undertaken.
Two separate antimicrobial formulations were prepared with the same
polymer, antimicrobial agents and liquid media. One formulation was
prepared by milling the components while the other formulation was
prepared by mixing the components. Coatings were then prepared from
the two formulation and the coatings were analyzed by SEM. The SEM
images are shown in FIGS. 4A and 4B. FIG. 4A shows an SEM image of
an antimicrobial coating that was prepared from the formulation
with milling and FIG. 4B shows an SEM image of the formulation
prepared by mixing, not milling the components.
[0061] As shown in FIGS. 4A and 4B, the antimicrobial formulation
that was prepared by a process that included milling of the
components resulted in a coating with uniformly dispersed
particles, with uniformly sized particles and with no agglomerated
particles greater than 20 microns. As can be seen from FIG. 4B, the
antimicrobial formulation prepared without milling resulted in a
coating with a non-uniform distribution of particles and
agglomerated particles of greater than 50 microns. In FIG. 4B, a 53
micron and 322 micron agglomerated particle were visible in the
image.
[0062] Similarly, SEM imaging was conducted of an antimicrobial
coating that was prepared from the formulation of the present
disclosure (shown in FIG. 5A), as well as the commercially
available ARROWgard Blue.TM. catheter (shown in FIG. 5B). As shown
in FIG. 5A, the antimicrobial formulation that was prepared by a
process that included milling of the components as described above
resulted in a coating with uniformly dispersed particles, with
uniformly sized particles and with no agglomerated particles
greater than 20 microns. As can be seen from FIG. 5B, the
antimicrobial coating on the commercially available ARROWgard
Blue.TM. catheter has a coating with a non-uniform distribution of
particles and agglomerated particles of greater than 20
microns.
[0063] SEM imaging was conducted of an antimicrobial coating that
was prepared from the formulation of the present disclosure (shown
in FIG. 6A), as well as the commercially available ARROWgard
Blue.TM. catheter (shown in FIG. 6B) to show the surface texture.
As shown in FIG. 6A, the antimicrobial formulation that was
prepared by a process that included milling of the components as
described above resulted in a coating with a smooth outer surface.
As can be seen from FIG. 6B, the antimicrobial coating on the
commercially available ARROWgard Blue.TM. catheter has a coating
with a surface texture that is less smooth in appearance than that
of the coating of the present disclosure.
[0064] Only the preferred embodiment of the present invention and
examples of its versatility are shown and described in the present
disclosure. It is to be understood that the present invention is
capable of use in various other combinations and environments and
is capable of changes or modifications within the scope of the
inventive concept as expressed herein. Thus, for example, those
skilled in the art will recognize, or be able to ascertain, using
no more than routine experimentation, numerous equivalents to the
specific substances, procedures and arrangements described herein.
Such equivalents are considered to be within the scope of this
invention, and are covered by the following claims.
* * * * *