U.S. patent application number 11/031607 was filed with the patent office on 2005-06-09 for triclosan and silver compound containing medical devices.
Invention is credited to Modak, Shanta, Sampath, Lester.
Application Number | 20050124725 11/031607 |
Document ID | / |
Family ID | 23079122 |
Filed Date | 2005-06-09 |
United States Patent
Application |
20050124725 |
Kind Code |
A1 |
Modak, Shanta ; et
al. |
June 9, 2005 |
Triclosan and silver compound containing medical devices
Abstract
The present invention relates to polymeric medical articles
comprising combinations of triclosan and silver-containing
compounds. It is based, at least in part, on the discovery that
these agents act synergistically, thereby permitting the use of
relatively low levels of both agents. While it had been previously
found that triclosan can be particularly useful when used in
conjunction with chlorhexidine, it has been further discovered that
medical articles having suitable antimicrobial properties may be
prepared, according to the present invention, which contain
triclosan without chlorhexidine. Such medical articles offer the
advantage of preventing or inhibiting infection while avoiding
undesirable adverse reactions to chlorhexidine by individuals that
may have sensitivity to chlorhexidine.
Inventors: |
Modak, Shanta; (River Edge,
NJ) ; Sampath, Lester; (Nyack, NY) |
Correspondence
Address: |
BAKER & BOTTS
30 ROCKEFELLER PLAZA
NEW YORK
NY
10112
|
Family ID: |
23079122 |
Appl. No.: |
11/031607 |
Filed: |
January 6, 2005 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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11031607 |
Jan 6, 2005 |
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09777121 |
Feb 5, 2001 |
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6843784 |
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09777121 |
Feb 5, 2001 |
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09281872 |
Mar 31, 1999 |
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6224579 |
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Current U.S.
Class: |
523/122 |
Current CPC
Class: |
D06M 16/00 20130101;
A01N 59/16 20130101; A61L 2300/21 20130101; A61L 2300/41 20130101;
Y10T 428/1352 20150115; A61L 2300/45 20130101; D06M 11/83 20130101;
A61L 2300/406 20130101; A61L 29/16 20130101; A01N 31/12 20130101;
A01N 31/08 20130101; A01N 25/34 20130101; A01N 31/16 20130101; A01N
59/16 20130101; A01N 2300/00 20130101; A61L 31/16 20130101; A61L
2/18 20130101; A61L 2300/104 20130101; A61L 15/44 20130101; A61L
2300/202 20130101; A61L 17/005 20130101; A61L 2300/404 20130101;
A01N 59/16 20130101; A61L 27/54 20130101; D06M 13/432 20130101 |
Class at
Publication: |
523/122 |
International
Class: |
C08K 003/00 |
Claims
1-31. (canceled)
32. A method of preparing an anti-infective medical article
comprising exposing a polymer-containing medical article, for an
effective period of time, to a treatment solution comprising
between about 0.1 and 5 percent of a metal compound, between about
0.1 and 20 percent triclosan, and between about 0.5 and 10 percent
of a hydrogel.
33. The method of claim 32, where the metal compound is a silver
compound.
34. The method of claim 32, where the hydrogel comprises
polyvinylpyrrolidone.
35. A method of preparing an anti-infective medical article
comprising exposing a polymer-containing medical article, for an
effective period of time, to a treatment solution comprising
between about 0.1 and 5 percent of a silver compound, between about
0.1 and 20 percent of triclosan, and between about 1 and 5 percent
of an anti-inflammatory agent.
36. The method of claim 35, where the anti-inflammatory agent is
salicylic acid or a derivative thereof.
37. The method of claim 35, where the treatment solution further
comprises an additional antimicrobial agent.
38. The method of claim 34, where the additional antimicrobial
agent is selected from the group consisting of chlorhexidine, a
chlorhexidine salt, gramicidin, polymixin, norfloxacin, sulfamylon,
polyhexamethylene biguanide, alexidine, minocycline, iodine
benzalkonium chloride and rifampicin.
Description
1.0 INTRODUCTION
[0001] The present invention relates to medical devices comprising
synergistic combinations of triclosan and silver containing
compounds.
2.0 BACKGROUND OF THE INVENTION
[0002] Whenever a medical device comes in contact with a patient, a
risk of infection is created. Thus, a contaminated examination
glove, tongue depressor, or stethoscope could transmit infection.
The risk of infection dramatically increases for invasive medical
devices, such as intravenous catheters, arterial grafts,
intrathecal or intracerebral shunts and prosthetic devices, which
not only are, themselves, in intimate contact with body tissues and
fluids, but also create a portal of entry for pathogens.
[0003] A number of methods for reducing the risk of infection have
been developed which incorporate anti-infective agents into medical
devices, none of which have been clinically proven to be completely
satisfactory. Such devices desirably provide effective levels of
anti-infective agent during the entire period that the device is
being used. This sustained release may be problematic to achieve,
in that a mechanism for dispersing anti-infective agent over a
prolonged period of time may be required, and the incorporation of
sufficient amounts of anti-infective agent may adversely affect the
surface characteristics of the device. The difficulties encountered
in providing effective antimicrobial protection increase with the
development of drug-resistant pathogens.
[0004] One potential solution to these problems is the use of a
synergistic combination of anti-infective agents that requires
relatively low concentrations of individual anti-infective agents
which may have differing patterns of bioavailability.
[0005] Two well-known anti-infective agents are chlorhexidine and
triclosan. The following patents and patent application relate to
the use of chlorhexidine and/or triclosan in medical devices.
[0006] U.S. Pat. No. 4,723,950 by Lee relates to a microbicidal
tube which may be incorporated into the outlet tube of a urine
drainage bag. The microbicidal tube is manufactured from polymeric
materials capable of absorbing and releasing anti-microbial
substances in a controllable sustained time release mechanism,
activated upon contact with droplets of urine, thereby preventing
the retrograde migration of infectious organisms into the drainage
bag. The microbicidal tube may be produced by one of three
processes: (1) a porous material, such as polypropylene, is
impregnated with at least one microbicidal agent, and then coated
with a hydrophilic polymer which swells upon contact with urine,
causing the leaching out of the microbicidal agent; (2) a porous
material, such as high density polyethylene, is impregnated with a
hydrophilic polymer and at least one microbicidal agent; and (3) a
polymer, such as silicone, is compounded and co-extruded with at
least one microbicidal agent, and then coated with a hydrophilic
polymer. A broad range of microbicidal agents are disclosed,
including chlorhexidine and triclosan, and combinations thereof.
The purpose of Lee's device is to allow the leaching out of
microbicidal agents into urine contained in the drainage bag;
similar leaching of microbicidal agents into the bloodstream of a
patient may be undesirable.
[0007] U.S. Pat. No. 5,091,442 by Milner relates to tubular
articles, such as condoms and catheters, which are rendered
antimicrobially effective by the incorporation of a non-ionic
sparingly soluble antimicrobial agent, such as triclosan. The
tubular articles are made of materials which include natural
rubber, polyvinyl chloride and polyurethane. Antimicrobial agent
may be distributed throughout the article, or in a coating thereon.
A condom prepared from natural rubber latex containing 1% by weight
of triclosan, then dipped in an aqueous solution of chlorhexidine,
is disclosed. U.S. Pat. Nos. 5,180,605 and 5,261,421, both by
Milner, relate to similar technology applied to gloves.
[0008] U.S. Pat. Nos. 5,033,488 and 5,209,251, both by Curtis et
al., relate to dental floss prepared from expanded
polytetrafluoroethylene (PTFE) and coated with microcrystalline
wax. Antimicrobial agents such as chlorhexidine or triclosan may be
incorporated into the coated floss.
[0009] U.S. Pat. No. 5,200,194 by Edgren et al. relates to an oral
osmotic device comprising a thin semipermeable membrane wall
surrounding a compartment housing a "beneficial agent" (that is at
least somewhat soluble in saliva) and a fibrous support material
composed of hydrophilic water-insoluble fibers. The patent lists a
wide variety of "beneficial agents" which may be incorporated into
the oral osmotic device, including chlorhexidine and triclosan.
[0010] U.S. Pat. No. 5,019,096 by Fox, Jr., et al. relates to
infection-resistant medical devices comprising a synergistic
combination of a silver compound (such as silver sulfadiazine) and
chlorhexidine.
[0011] International Patent Application No. PCT/GB92/01481,
Publication No. WO 93/02717, relates to an adhesive product
comprising residues of a copolymerisable emulsifier comprising a
medicament, which may be povidone iodine, triclosan, or
chlorhexidine.
[0012] International Patent Application No. PCT/US96/20932,
Publication No. WO 97/25085, relates to polymeric medical articles
comprising synergistic combinations of chlorhexidine and triclosan
which utilize relatively low levels of these agents.
[0013] In contrast to the present invention, none of the
above-cited references teach medical articles comprising
synergistic combinations of triclosan and silver compounds which
utilize relatively low levels of these agents and provide effective
levels of antimicrobial activity, even in the absence of
chlorhexidine.
3.0 SUMMARY OF THE INVENTION
[0014] The present invention relates to polymeric medical articles
comprising combinations of triclosan and/or other chlorinated
phenols and silver-containing compounds. It is based, at least in
part, on the discovery that these agents act synergistically,
thereby permitting the use of relatively low levels of both agents.
While it had been previously found that triclosan can be
particularly useful when used in conjunction with chlorhexidine, it
has been further discovered that medical articles having suitable
antimicrobial properties may be prepared, according to the present
invention, which contain triclosan and a silver compound without
chlorhexidine. Such medical articles offer the advantage of
preventing or inhibiting infection while avoiding undesirable
adverse reactions to chlorhexidine by individuals that may have a
sensitivity to chlorhexidine, such as a chlorhexidine allergy.
[0015] The present invention is also based, at least in part, on
the discovery that the surface of medical articles, especially
catheters, impregnated with triclosan and silver compounds
generally were found to be smoother and shinier in comparison with
catheters impregnated with triclosan and chlorhexidine. Even when
the triclosan-silver compound impregnated catheters exhibited
commensurate or smaller zones of inhibition compared to
triclosan-chlorhexidine catheters, there was little or no bacterial
adherence observed on the former when exposed to bacterial culture.
Microbial adherence on the surfaces of medical devices are the
result of a deposition of fibrinogen and fibronectin on the surface
which forms a host biofilm. Because bacteria tend to adhere to this
biofilm, glycocalyx forms which serves as a bacterial reservoir
causing blood stream infections. Without being bound by any
particular theory, it is believed that medical articles of the
invention, by virtue of their smooth surfaces, may be less
physically irritating than prior art devices, may be less likely to
provoke fibrinogen and/or fibronectin deposition, and therefore may
avoid bacterial colonization.
4.0 DETAILED DESCRIPTION OF THE INVENTION
[0016] The present invention relates to medical articles comprising
combinations of triclosan and/or another chlorinated phenol and one
or more silver-containing compound (hereafter, "silver
compound").
[0017] While not being bound or limited by any particular theory,
it is believed that the combination of triclosan and a silver
compound forms a soluble complex. This would explain observations,
such as those set forth in Example Section 5 below, that the
presence of triclosan improves the solubility of various silver
compounds, thereby improving their bioavailability.
[0018] As shown in Example Sections 7, 9-17 and 19, medical
articles, which may be hydrophilic or hydrophobic, treated with
combinations of triclosan and various silver compounds exhibit
desirable antimicrobial properties. As shown in Example Sections 8,
13 and 14 such articles exhibit smooth surfaces that tend to resist
bacterial adherence, which may be at least partly responsible for
their antimicrobial quality.
[0019] The present invention provides for medical articles treated
with chlorinated phenols other than triclosan in combination with
one or more silver compound. As shown in Example Section 18, such
combinations result in enhanced antimicrobial activity. Suitable
chlorinated phenols include parachlorometaxylenol ("PCMX")) and
dichlorometaxylenol ("DCMX"). The amount of chlorinated phenol
which may be used is as set forth below for triclosan, but may be
adjusted for differences in potency when tested against a
particular microbe. For example, in specific, non-limiting
embodiments of the invention polymeric medical articles may be
prepared using treatment solutions comprising between about 0.1 and
5 percent, preferably between about 0.3 and 1.5 percent, of a
silver compound, and between about 0.1 and 20 percent, preferably
between about 0.1 and 8 percent, of a chlorinated phenol,
preferably PCMX. The present invention also provides for medical
articles comprising triclosan in addition to another chlorinated
phenol.
[0020] In additional embodiments, the present invention provides
for medical articles having anti-infective activity which comprise
triclosan and/or another chlorinated phenol, a silver compound, and
an anti-inflammatory agent. It has been found that the addition of
an anti-inflammatory compound enhances the antimicrobial activity
of such devices (see Section 17 below).
[0021] In still further embodiments, the present invention provides
for medical articles which have been treated with a hydrogel, and
further comprise a metal compound.
[0022] The term triclosan ("TC"), as used herein, refers to a
compound also known as 2,4,4'-trichloro-2'-hydroxydiphenyl ether
and also known as 5-chloro-2-(2,4-dichlorophenoxy)phenol.
[0023] The term silver compound, as used herein, refers to a
compound comprising silver, either in the form of a silver atom or
a silver ion unlinked or linked to another molecule via a covalent
or noncovalent (e.g., ionic) linkage, including but not limited to
covalent compounds such as silver sulfadiazine ("AgSD") and silver
salts such as silver oxide ("Ag.sub.2O"), silver carbonate
("Ag.sub.2CO.sub.3"), silver deoxycholate, silver salicylate,
silver iodide, silver nitrate ("AgNO.sub.3"), silver
paraaminobenzoate, silver paraaminosalicylate, silver
acetylsalicylate, silver ethylenediaminetetraacetic acid ("Ag
EDTA"), silver picrate, silver protein, silver citrate, silver
lactate and silver laurate.
[0024] The terms "medical article" and "medical device" are used
interchangeably herein. Medical articles that may be treated
according to the invention are either fabricated from or coated or
treated with biomedical polymer (and hence may be referred to as
"polymer-containing medical articles") and include, but are not
limited to, catheters including urinary catheters and vascular
catheters (e.g., peripheral and central vascular catheters), wound
drainage tubes, arterial grafts, soft tissue patches (such as
polytetrafluoroethylene ("PTFE") soft tissue patches), gloves,
shunts, stents, tracheal catheters, wound dressings, sutures, guide
wires and prosthetic devices (e.g., heart valves and LVADs).
Vascular catheters which may be prepared according to the present
invention include, but are not limited to, single and multiple
lumen central venous catheters, peripherally inserted central
venous catheters, emergency infusion catheters, percutaneous sheath
introducer systems and thermodilution catheters, including the hubs
and ports of such vascular catheters. The present invention may be
further applied to medical articles that have been prepared
according to U.S. Pat. No. 5,019,096 by Fox, Jr. et al.
[0025] The following are descriptions of particular embodiments of
the invention.
[0026] Percentages recited herein refer to weight/volume (w/v),
except as indicated otherwise.
[0027] The present invention provides, in various non-limiting
embodiments, for: (1) treatment solutions comprising between about
0.1 and 5 percent, and preferably between about 0.3 and 1.5 percent
of a silver compound; and between about 0.1 and 20 percent and
preferably between about 0.1 and 8 percent of triclosan and/or
other chlorinated phenol; (2) treatment solutions comprising
between about 0.1 and 10 percent, and preferably between about 1
and 5 percent of one or more hydrophilic or hydrophobic polymer;
between about 0.1 and 5 percent, and preferably between about 0.3
and 1.5 percent of a silver compound; and between about 0.1 and 20
percent, and preferably between about 0.1 and 8 percent of
triclosan and/or other chlorinated phenol; (3) polymer-containing
medical articles treated with a treatment solution as set forth in
(1) or (2) above, and articles physically equivalent thereto (that
is to say, articles prepared by a different method but having
essentially the same elements in the same proportions); (4)
polymer-containing medical articles treated with treatment
solutions set forth in (1) or (2) above wherein the articles are
dried and thereafter coated with an anti-infective and/or polymeric
coating in accordance with a two-step process. The treatment
solutions set forth in (1) or (2) may optionally further comprise
(i) an organic acid, at a concentration of between about 0.1 and 5
percent, preferably between about 0.1 and 2 percent; (ii) an
anti-inflammatory agent, at a concentration of between about 1 and
5 percent, preferably between about 0.1 and 1 percent; (iii) an
antimicrobial other than a silver compound or triclosan at a
concentration of between about 0.1 and 10 percent; and/or (iv) a
hydrogel at a concentration of between about 0.5 to 10 percent,
preferably between about 1 and 5 percent. In preferred non-limiting
embodiments of the invention, the amount of silver present as
silver atom or silver ion is about 0.9%. In preferred non-limiting
embodiments of the invention, the treatment solution and/or medical
article does not contain chlorhexidine or a chlorhexidine salt. The
medical articles are "treated" by exposing them, for an effective
period of time, to the treatment solution, where an "effective
period of time" is that period of time sufficient to introduce
anti-infective quantities of triclosan and/or other chlorinated
phenol and silver compound. Where the concentration of gtriclosan
and/or other chlorinated phenol in the treatment solution is
between 0.1 and 8 percent, the effective period of time may be
between about 30 seconds and one hour; where the concentration of
tricolsan and/or other chlorinated phenol in the treatment solution
is between about 9 and 20 percent, the effective period of time may
be between about 10 seconds and 2 minutes. Longer periods of
exposure may be used provided that undesirable deterioration of the
medical article does not occur.
[0028] The term "about" indicates a variation within 20
percent.
[0029] In particular non-limiting embodiments of the invention,
where the medical article is a vascular catheter, such as a central
venous catheter, the amount of triclosan contained is about 100-600
.mu.g/cm, preferably about 400-500 .mu.g/cm and the amount of
silver atom or ion is 25 to 100 .mu.g/cm, preferably 30 to 80
.mu.g/cm. The triclosan and silver are in releasable form, i.e.,
extractable by a solvent that does not substantially dissolve the
catheter.
[0030] Medical articles prepared according to the invention may be
treated on their external surface, internal surface, or both. For
example, and not by way of limitation, where the medical article is
a catheter, the internal surface and/or external surface of the
catheter may be treated according to the invention. For example,
where it is desired to treat both internal and external surfaces,
an open-ended catheter may be placed in a treatment solution such
that the treatment solution fills the catheter lumen. If only the
external surface is to come in contact with treatment solution, the
ends of the catheter may be sealed before it is placed in the
treatment solution. If only the internal surface is to come in
contact with treatment solution, the solution may be allowed to
pass through and fill the lumen but the catheter is not immersed in
the treatment solution.
[0031] Medical articles may be dipped, soaked, or otherwise have a
surface coated. The term "dipped" suggests briefer exposure to
treatment solution relative to soaking, and preferably is for a
period of time less than fifteen minutes.
[0032] Successful treatment of a medical article with a polymer
comprising an anti-infective agent may be problematic, particularly
where the medical article has a hydrophobic surface. The adherence
of the polymer may depend upon (1) the polymeric matrix in which
the anti-infective agent is suspended; (2) compatibility (or lack
thereof) between the agent-polymeric matrix and the surface of the
article; (3) the solvent system; and (4) the thickness of
polymer/anti-infective agent desirably applied. Furthermore, the
rates of release of various anti-infective agents from diverse
polymers may differ. To address these issues, the present invention
provides for two different methods for treating medical articles: a
one-step method, and a two-step method, both of which are set forth
below.
[0033] Polymers, triclosan, and silver compounds used according to
the invention may be sparingly soluble in certain solvents or
solvent mixtures. It therefore may be desirable to first dissolve
the relevant material in a solvent or component of a solvent system
which favors dissolving. For example, where polyurethane,
triclosan, and a silver compound are desirably incorporated into an
alcohol/tetrahydrofuran ("THF") solvent system, the polyurethane
may first be dissolved in THF and the triclosan and silver compound
may be dissolved in alcohol (in certain instances with the addition
of an aqueous solution of ammonia (referred to interchangeably
herein as either ammonia, ammonium hydroxide, or NH.sub.3) to
facilitate solubilization of the silver compound), before the THF
and alcohol components are mixed. The use of a solvent system
comprising ammonia may be particularly desirable when a silver salt
is used.
[0034] 4.1 Hydrophilic Article Treated with a Solution of a
Hyrdophilic Polymer
[0035] In one particular set of non-limiting embodiments, the
present invention provides for a hydrophilic polymeric medical
article (i.e., a medical article fabricated from a hydrophilic
polymer) treated by coating, dipping or soaking the article in a
treatment solution of a hydrophilic polymer comprising a silver
compound and triclosan (and/or other chlorinated phenol) wherein
the silver compound and triclosan or other chlorinated phenol are
present in amounts such that their combination, in the treated
article, has effective anti-microbial activity. The term "effective
antimicrobial activity" refers to an ability to decrease the number
of colony-forming units of a bacterium or yeast, in a 24 hour
period, by a factor of ten or more and preferably a factor of 100
or more. The terms "treat", "treated", etc., as used herein, refer
to coating, impregnating, or coating and impregnating a medical
article with anti-infective agent. The term "hydrophilic polymer",
as used herein, refers to polymers which have a water absorption
greater than 0.6 percent by weight (and, in preferred embodiments,
less than 2 percent by weight; as measured by a 24 hour immersion
in distilled water, as described in ASTM Designation D570-81)
including, but not limited to biomedical polyurethanes (e.g.,
ether-based polyurethanes and ester-based polyurethanes, as set
forth in Baker, 1987, in Controlled Release of Biologically Active
Agents, John Wiley and Sons, pp. 175-177 and Lelah and Cooper,
1986, Polyurethanes in Medicine, CRC Press, Inc., Fla pp. 57-67;
polyurethanes comprising substantially aliphatic backbones such as
Tecoflex.TM. 93A; polyurethanes comprising substantially aromatic
backbones such as Tecothane.TM.; and Pellethane.TM.), polylactic
acid, polyglycolic acid, natural rubber latex, and gauze or
water-absorbent fabric, including cotton gauze and silk suture
material. In specific, non-limiting embodiments, the hydrophilic
medical article is a polyurethane catheter which has been treated
with (e.g., coated, dipped or soaked in) a treatment solution
comprising (i) between about 0.1 and 10 percent, and preferably
between about 1 and 5 percent, of one or more biomedical
polyurethane; (ii) between about 0.1 and 5 percent, and preferably
between 0.3 and 1.5 percent, of a silver compound; and (iii)
between about 0.1 and 20 percent, and preferably between about 0.1
and 8 percent, of triclosan and/or other chlorinated phenol.
[0036] 4.2. Hydrophilic Article Treated with a Solution of a
Hydrophobic Polymer
[0037] In another set of particular non-limiting embodiments, the
present invention provides for a hydrophilic polymeric medical
article treated by coating, dipping or soaking the article in a
treatment solution of a hydrophobic polymer comprising a silver
compound and triclosan (and/or other chlorinated phenol), wherein
the silver compound and triclosan and/or other chlorinated phenol
are present in amounts such that their combination, in the treated
article, has effective anti-microbial activity. The term
"hydrophobic polymer", as used herein, refers to a polymer which
has a water absorption of less than 0.6% and includes, but is not
limited to, silicone polymers such as biomedical silicones (e.g.,
Silastic Type A) or elastomers (e.g., as set forth in Baker, 1987,
in Controlled Release of Biologically Active Agents, John Wiley and
Sons, pp. 156-162), Dacron, polytetrafluoroethylene ("PTFE", also
"Teflon"), polyvinyl chloride ("PVC"), cellulose acetate,
polycarbonate, and copolymers such as silicone-polyurethane
copolymers (e.g., PTUE 203 and PTUE 205 polyurethane-silicone
interpenetrating polymer). In one specific, non-limiting
embodiment, the medical article is a polyurethane catheter which
has been dipped or soaked in a treatment solution comprising (i)
between about 0.1 and 10 percent, and preferably between about 1
and 5 percent, of a polyurethane-silicone copolymer; (ii) between
about 0.1 and 5 percent, and preferably between about 0.3 and 1.5
percent, of a silver compound; and (iii) between about 0.1 and 20
percent, and preferably between about 0.1 and 8 percent, of
triclosan and/or other chlorinated phenol.
[0038] 4.3 Hydrophobic Article Treated with a Solution of a
Hydrophobic Polymer
[0039] In another set of particular non-limiting embodiments, the
present invention provides for a hydrophobic polymeric medical
article treated by coating, dipping or soaking the article in a
treatment solution of hydrophobic polymer comprising a silver
compound and triclosan and/or other chlorinated phenol, wherein the
silver compound and triclosan and/or other chlorinated phenol are
present in amounts such that their combination, in the treated
article, has effective antimicrobial activity. In one specific,
non-limiting embodiment, the medical article is a silicone catheter
or a polyvinylchloride catheter which has been dipped or soaked in
a treatment solution comprising (i) between about 0.1 and 10
percent, and preferably between about 1 and 5 percent, of a
silicone polymer: (ii) between about 0.1 and 5 percent, and
preferably between about 0.3 and 1.5 percent, of a silver compound;
and (iii) between about 0.1 and 20 percent, and preferably between
about 0.1 and 8 percent, of triclosan and/or other chlorinated
phenol.
[0040] 4.4. Hydrophobic Article Treated with a Solution of a
Hydrophilic Polymer
[0041] In yet another set of particular non-limiting embodiments,
the present invention provides for a hydrophobic polymeric medical
article treated by coating, dipping or soaking the article in a
treatment solution of hydrophilic polymer comprising a silver
compound and triclosan and/or other chlorinated phenol, wherein the
silver compound and triclosan and/or other chlorinated phenol are
present in amounts such that their combination, in the treated
article, has effective anti-microbial activity. In a specific,
non-limiting embodiment, the medical article is a silicone catheter
or Teflon graft which has been dipped, coated or soaked in a
treatment solution comprising (i) between about 0.1 and 10 percent,
and preferably between about 1 and 5 percent, of a biomedical
polyurethane polymer; (ii) between about 0.1 and 5 percent, and
preferably between about 0.3 and 1.5 percent, of a silver compound;
and (iii) between about 0.1 and 20 percent, and preferably between
about 0.1 and 8 percent, of triclosan and/or other chlorinated
phenol.
[0042] 4.5 Medical Articles Impregnated with Triclosan and a Silver
Compound by a One-Step Method
[0043] According to the one-step method of the invention, a
polymeric medical article may be treated with a solution comprising
one or more silver compounds, triclosan and/or other chlorinated
phenol, and optionally containing a biomedical polymer, dissolved
in one or more solvents, wherein the solvent(s) selected is (are)
capable of swelling the polymeric medical article to be treated;
such a solution is referred to herein as an "impregnating solution"
(which is a species of treatment solution), and the process by
which the article is treated with triclosan and a silver compound
is referred to as "impregnation". Suitable solvents include, but
are not limited to, tetrahydrofuran ("THF"), dichloromethane,
carbon tetrachloride, methanol, ethanol, methyl ethyl ketone,
heptane, M-Pyrol and hexane, and mixtures thereof. The term
"reagent alcohol" as used herein refers to a solution containing
essentially 5% v/v methanol, 5% v/v isopropanol, and 90% v/v
ethanol. The biomedical polymer may be hydrophilic or hydrophobic,
and includes the various polymers set forth above.
[0044] If a hydrophilic polymeric medical article is to be
impregnated with a silver compound and triclosan and/or other
chlorinated phenol, the impregnating solution may, in specific
non-limiting embodiments, comprise the following (percentages of
solvents in this paragraph being volume/volume (v/v) except where
noted to be weight/volume (w/v)): 95% ethanol/5% water; 95% reagent
alcohol/5% water; 70% ethanol/30% water; 70% reagent alcohol/30%
water; 50% ethanol/50% water; 50% reagent alcohol/50% water; 30%
ethanol/70% THF; 30% reagent alcohol/70% THF; 30% methanol/70% THF;
10% ethanol/10% ammonia/80% THF; 10% reagent alcohol/0% ammonia/80%
THF; 90% ethanol/10% THF; 90% reagent alcohol/10% THF; 90%
methanol/10% THF; 100% ethanol or 100% reagent alcohol. The
treatment solutions may comprise between about 0.1 and 10 percent
(w/v), and preferably between about 1 and 5 percent (w/v), of one
or more dissolved polymer (e.g., one or more species of
polyurethane, silicone, or hydrogel). Preferred soaking times
according to the one-step method vary between 15 seconds and 1
hour, depending upon the polymer selected. A shorter soaking time
in a drug/solvent system is preferred since it is less likely to
negatively affect the physical integrity of the polymeric device,
particularly polyurethane catheters. In order to attain a
sufficient drug uptake using a shorter soaking time, it is
preferred that the amount of triclosan or other chlorinated phenol
in the treatment solution be between about 10 and 20 percent (w/v).
For a specific example of a method that uses higher levels of
triclosan and a shorter soaking time see Section 9 below.
[0045] If a hydrophobic polymeric medical article is to be
impregnated with a silver compound and triclosan and/or other
chlorinated phenol, the impregnating solution may, in specific
non-limiting embodiments, comprise the following (percentages of
solvents in this paragraph being volume/volume (v/v) except where
noted to be weight/volume (w/v)): 10% methanol/90% THF; 10%
ethanol/90% THF; 10% reagent alcohol/90% THF; 10% ethanol 10%
ammonia/80% THF; 10% reagent alcohol/10% ammonia/80% THF; 30%
ethanol 70% THF; 30% reagent alcohol/70% THF; 30% methanol/70% THF;
1-5 percent (w/v) silicone polymer in 10% methanol/90% THF; 1-5
percent (w/v) silicone polymer in 10% ethanol/90% THF; 1-5 percent
(w/v) silicone polymer in 10% reagent alcohol/90% THF; 1-2 percent
(w/v) polylactic acid in 10% methanol/90% THF; 1-2 percent w/v
polylactic acid in 10% ethanol/90% THF; 1-2 percent (w/v)
polylactic acid in 10% reagent alcohol/90% THF; 1-5 percent (w/v)
silicone polymer in 30% methanol/70% THF; 1-5 percent (w/v)
silicone polymer in 30% ethanol/70% THF; 1-0.5 percent (w/v)
silicone polymer in 30% reagent alcohol/70% THF; 1-2 percent (w/v)
polylactic acid in 30% methanol/70% THF; 1-2 percent (w/v)
polylactic acid in 30% ethanol/70% THF; 1-2 percent (w/v)
polylactic acid in 30% reagent alcohol/70% THF; 1-5 percent (w/v)
silicone polymer in 100% methyl ethyl ketone; and 1-2 percent (w/v)
polyurethane in 30% ethanol/70% THF. In general, such treatment
solutions may comprise between 0.1 and 10 percent, and preferably
between about 1 and 5 percent, of one or more dissolved polymer.
For specific examples, see Sections 11-12, below, and Section 10,
which shows examples of hydrophilic medical articles (e.g., latex
urinary catheters) or hydrophobic medical articles (e.g., PTFE soft
tissue hernia graft patches) impregnated with triclosan and silver
using a solution without polymer.
[0046] The medical article, or a portion thereof, may be immersed
in the impregnating solution to swell, after which the article may
be removed and dried at room temperature until all solvent has
evaporated and the article is no longer swollen. Other methods may
also be used, such that a substantially uniform coat of
impregnating solution is applied. During the swelling process,
triclosan or other chlorinated phenol and silver compound (and
small amounts of polymer when present in the impregnating solution)
may be distributed within the polymeric substrate of the article;
during drying, the triclosan or other chlorinated phenol and silver
compound and biomedical polymer (where present) may migrate
somewhat toward the surface of the article. In the case of PTFE
devices, no apparent swelling occurs, however, the drugs are
trapped in the interstices of the substrate. After drying, the
article may be rinsed in either water or alcohol and wiped to
remove any excess triclosan or other chlorinated phenol, silver
compound, and/or polymer at the surface. This may leave a
sufficient amount of triclosan or other chlorinated phenol and
silver compound just below the surface of the article, thereby
permitting sustained release over a prolonged period of time.
[0047] 4.6. Two-Step Method of Preparing Anti-Infective Medical
Articles
[0048] According to the two-step method of the invention, the
one-step method may be used to impregnate a medical article with
triclosan and/or other chlorinated phenol and a silver compound,
and then the medical article may be dipped into a second treatment
solution containing triclosan and/or other chlorinated phenol
and/or a silver compound and/or one or more polymer, and dried.
This method forms a coating on the article and further controls the
rate of release of triclosan or other chlorinated phenol and silver
compound. For a non-limiting specific example, see Section 7,
below.
[0049] 4.7 Medical Articles Having Anti-Adherent Properties
[0050] It has been discovered that medical articles treated with
mixtures of silver compounds and triclosan exhibit anti-adherent
qualities and anti-microbial effectiveness, even in the absence of
chlorhexidine. While not being bound to any particular theory, it
is believed that triclosan and silver compounds form a
triclosan-silver compound complex, such that impregnation of this
triclosan-silver compound complex into medical articles increases
resistance to microbial adherence to the surfaces by rendering the
surfaces smooth and shiny. It has further been discovered that the
combination of silver compounds and other compositions, such as
other chlorinated phenolic compounds, anti-inflammatory agents,
hydrophilic and hydrophobic polymers and hydrogels each separately
contribute to enhanced and prolonged antimicrobial efficacy of the
antimicrobial agents. The synergistic combinations of triclosan and
silver compounds that are sparingly soluble are especially suitable
for forming a smooth surface and for providing a sustained and
prolonged release of anti-microbial agents.
[0051] In a specific example of a method of direct impregnation of
triclosan and a silver compound into a Dacron device, a treatment
solution may be prepared including 1 to 6 percent triclosan and 0.1
to 0.2 percent of a silver compound in a solvent mixture containing
(v/v) 10 percent ammonia, 10 percent alcohol and 80 percent THF.
The device may be soaked for 1 to 10 minutes, dried and rinsed. In
variations of this example, between about 1 and 10 percent of a
hydrophilic polymer or a hydrophobic polymer may be included in the
treatment solution. Suitable hydrophilic polymers include, but are
not limited to, one or more of polyurethane, polycaprolactone, and
polyactic acid. Suitable hydrophobic polymers include, but are not
limited to, silicone polymers.
[0052] 4.8 Medical Articles Comprising Triclosan, a Silver
Compound, and an Anti-Inflammatory Agent
[0053] Anti-inflammatory agents such as salicylic acid,
paraaminosalicylic acid, and acetylsalicylic acid were impregnated
along with triclosan and a silver compound into medical devices to
reduce inflammatory reaction around the wound at the insertion site
and thus enhance wound healing. Surprisingly, it has been
discovered that incorporation of these anti-inflammatory agents
along with the triclosan and a silver compound enhances the
anti-microbial activity of the composition. Since the
anti-inflammatory agents do not give zones of inhibition when used
alone, it appears that increased zone sizes, observed when the
anti-inflammatory agents are added to the triclosan and silver
compound combination, is not a result of an additive effect but
rather due to potentiation of the activity of the complex. Thus,
the present invention provides for medical articles treated with
treatment solutions comprising triclosan and/or other chlorinated
phenol, a silver compound, and an anti-inflammatory agent, such as
salicylic acid or a derivative thereof. In further non-limiting
embodiments, the treatment solution may also include an additional
anti-infective agent such as those set forth below, or
chlorhexidine, or a chlorhexidine salt (at a concentration of
between about 0.1 and 5 percent).
[0054] 4.9 Addition of Other Anti-Infective Agents
[0055] Because a major route of entry of pathogens during
implantation of medical devices occurs at the insertion site and
occurs at the time of implantation, it is important to have an
effective broad spectrum antimicrobial field around the device
during implantation. In order to enhance the antimicrobial field
around a device, antibiotic and anti-microbial agents may be added
to medical articles comprising triclosan or other chlorinated
phenol and a silver compound including, but not limited to,
macrolides, aminoglycosides, penicillins, cephalosporins,
quinolones, antifungal agents, chlorhexidine or biguanides other
than chlorhexidine, chlorinated phenols, sulfonamides, quarternary
ammonium compounds, picloxydine, phenolic compounds (e.g.,
orthophenylphenol), and polymeric quarternary ammonium compounds.
Examples of specific agents which can be used include rifampicin,
gramicidin, gentamycin, fusidic acid, miconazole, norfloxacin,
polymixin, sulfamylon, furazolidine, alexidine, octenidine
hydrochloride, cetrimide, polyhexamethylene biguanide,
triclocarban, benzalkonium chloride, minocycline, iodine and iodine
complexes such as povidone iodine, pluronic-iodine complex, benzoic
acid, sorbic acid, and ethylenediamine tetraacetic acid (EDTA).
[0056] These agents used in addition to the triclosan and/or other
chlorinated phenol and silver compound combination provide an
effective broad spectrum anti-microbial field of activity
initially, which inactivates pathogens that otherwise can heavily
contaminate the sterile field during implantation. For a
non-limiting specific example, see Section 15.
[0057] The anti-adherent surface of these devices continues to
prevent adherence of microbes that may enter the device tract
during and subsequent to implantation. Once these additional agents
are diffused out of the devices, the anti-adherent surface
continues to prevent adherence of microbes which may contact the
device surface through hematogenous seeding or contaminated
infusate. Further, without being bound to any particular theory, it
is believed that sustained and prolonged release of the
anti-microbial agents occurs from the putative triclosan-silver
compound complex which provides a longer period of protection.
[0058] 4.10 Medical Articles Comprising a Hydrogel
[0059] According to the present invention, it has been determined
that the use of hydrogel polymers increases the antimicrobial
efficacy of hydrophilic or hydrophobic matrix systems. In a
particular embodiment, the present invention provides for a
hydrophilic or hydrophobic medical article which has been
impregnated, coated or impregnated and coated with a treatment
solution comprising (i) a hydrophilic or hydrophobic polymer, (ii)
one or more metal compounds comprising metal atoms or ions or
complexes comprising a metal atom or ion selected from the group
consisting of silver, copper, zinc, calcium, aluminum and
magnesium, (iii) triclosan or other chlorinated phenol, and (iv) a
hydrogel. Such medical articles may further comprise, or the
treatment solution may comprise, a biguanide such as chlorhexidine
or a chlorhexidine salt. In other embodiments, the present
invention provides for a metallic or ceramic medical article coated
with a treatment solution of (i) to (iv) as set out above. In a
preferred embodiment, the hydrogel comprises polyvinyl pyrrolidone
("PVP"). In another preferred embodiment, the hydrophobic polymer
polyvinyl chloride ("PVC") may be used to create a hydrophobic
matrix into which PVP and antimicrobial agents may be impregnated.
Other useful hydrogels that may be used to promote enhanced
antimicrobial efficacy include polyethylene oxide, pluronics, ethyl
and methyl cellulose, hydroxy ethyl and hydroxy methyl cellulose,
incroquats, and polyhydroxyethyl methacrylate.
[0060] For a specific, non-limiting example, see Section 19,
below.
[0061] The following working examples are intended to illustrate
but not to limit the scope of the present invention.
5.0 EXAMPLE
Triclosan Improves the Solubility of Silver Compounds
[0062] Table 1 illustrates the solubility of the silver salt,
silver carbonate, mixed at various molar ratios with ammonia, which
is used in a treatment solution, in the absence and the presence of
triclosan at various molar ratios. Table 2 illustrates the
solubility of the silver salt, silver oxide, mixed at various molar
ratios with ammonia in the absence and presence of triclosan at
various molar ratios. The solubility results demonstrated in Tables
1 and 2 indicate that silver salts are much more soluble in the
presence of triclosan, which suggests that the silver compound and
triclosan may form a complex.
[0063] When ammonia and silver carbonate were mixed at a high molar
ratio of 400 to 10, the silver salt remained insoluble in the
solvent system. In contrast, in the presence of 30 .mu.mole of
triclosan, the molar ratio of ammonia to silver carbonate needed to
solubilize was 50 to 10. Achieving a low molar ratio of ammonia to
silver salt is preferred because the surface of devices impregnated
with a solvent system containing higher amounts of ammonia can be
damaged, thereby enhancing the likelihood of microbial adherence to
the surface. In the case of silver oxide, only 10 .mu.mole of
ammonia was needed to solubilize more than 90% of 10 .mu.mole of
silver oxide in the presence of 10 .mu.mole of triclosan. Further,
only 20 .mu.mole of triclosan was needed to completely solubilize
10 .mu.mole of silver oxide in the presence of only 10 .mu.mole of
ammonia.
1TABLE 1 Silver Carbonate Ammonia Triclosan (.mu.mole) (.mu.mole)
(.mu.mole) Solubility 10 100 0 Not Soluble 10 200 0 Not Soluble 10
300 0 Not Soluble 10 400 0 Not Soluble 10 0 30 Not Soluble 10 50 10
Partially Soluble 10 100 10 Partially Soluble 10 150 10 Soluble 10
75 20 Partially Soluble 10 50 30 Soluble
[0064]
2TABLE 2 Silver oxide Ammonia (.mu.mole) (.mu.mole) TC (.mu.mole)
Solubility (.mu.mole) 10 10 0 Not soluble 10 100 0 Soluble 10 10 10
>90% Soluble 10 10 20 Soluble
6.0 EXAMPLE
Evaluation of the Anti-Microbial Efficacy of Triclosan-Silver
Compound Combinations in Broth Cultures
[0065] The synergistic anti-microbial efficacy of the
triclosan/silver compound combination, triclosan/silver
sulfadiazine, is illustrated by the results shown in Table 3, and
were determined by the following protocol. Drug solutions
containing 10% ammonia were prepared in ethanol, and 0.1 ml of each
solution was added to 0.9 ml of bacterial culture (50% trypticase
soy broth+50% Bovine Calf Serum containing 10.sup.8 cfu S.
aureus/ml). After 10 minutes, a 0.1 ml aliquot was removed and
added to 0.9 ml drug inactivating media (LTSB). 0.1 ml from this
media was then added to another 0.9 ml of LTSB and 0.2 ml was
subcultured on trypticase soy agar plate and incubated at
37.degree. C. for 24 hours. The colony counts were then determined.
Control cultures contained similar amounts of ammonia and ethanol
as in the test culture.
3 TABLE 3 Solution Growth in Culture Triclosan (%) Silver
Sulfadiazine (%) (cfu/ml) 0 0 2.1 .times. 10.sup.7 0.25 0 1.2
.times. 10.sup.7 0.5 0 1 .times. 10.sup.7 0 0.5 5 .times. 10.sup.6
0 1.0 1.5 .times. 10.sup.6 0.5 0.5 8.3 .times. 10.sup.5 0.5 1.0 1.4
.times. 10.sup.4
[0066] These results show the synergistic activity of triclosan and
silver sulfadiazine. In the control, in the absence of either
triclosan or silver sulfadiazine, there was growth in culture of
the magnitude of 2.1.times.10.sup.7 cfu/ml. Comparing the relative
reduction of growth in culture by the introduction of triclosan and
silver sulfadiazine, the addition of triclosan alone at 0.25 and
0.5 percent each resulted in a reduction in growth in culture of
less than a power of 10 compared to the control. The addition of
silver sulfadiazine alone at 0.5 and 1.0 percent each resulted in a
1 log reduction of growth in culture compared to the control.
[0067] Comparing the relative reduction of growth in culture by the
introduction of triclosan and silver sulfadiazine in combination,
the combination of 0.5 percent triclosan and 0.5 percent silver
sulfadiazine resulted in a 2 log reduction in growth in culture
compared with the control. The combination of 0.5 percent triclosan
and 1.0 percent silver sulfadiazine resulted in a 3 log reduction
in cell growth in culture compared with the control. Moreover, the
addition of 0.5 percent of silver sulfadiazine from 0.5 to 1.0 in
the presence of 0.5 triclosan resulted in a 1 log reduction in
growth in culture, whereas the increase of 0.5 to 1.0 percent
silver sulfadiazine in the absence of triclosan did not result in a
significant decrease. The cell growth in culture in the presence of
0.5 percent triclosan alone added to the cell growth in culture in
the presence of 0.5 percent of silver sulfadiazine, the combined
presence of 0.5 triclosan and 1.0 silver sulfadiazine resulted in a
3 log reduction in growth in culture, and the increase of 0.5 to
1.0 percent silver sulfadiazine compared to the growth in culture
at 0.5 percent triclosan results in a 1 log decrease.
[0068] The effects of triclosan and silver carbonate combinations
on S. aureus growth in culture were also determined using the same
protocol. The results are presented in Table 4.
4TABLE 4 Solution Growth in Culture Triclosan (%) Silver Carbonate
(%) (cfu/ml) 0 0 5 .times. 10.sup.7 .25 0 2 .times. 10.sup.7 .5 0
1.2 .times. 10.sup.7 0 .06 1 .times. 10.sup.5 0 .125 2 .times.
10.sup.3 0 .25 5 .times. 10.sup.2 .5 .06 3.2 .times. 10.sup.4 .5
.125 0 .5 .25 0
[0069] The results shown in Table 4 illustrate the synergistic
activity of triclosan and silver carbonate. In the control, in the
absence of both triclosan and silver carbonate the growth in cell
culture was of the magnitude of 5.times.10.sup.7 cfu/ml. Combining
0.5 percent triclosan and 0.25 percent silver carbonate resulted in
a 7 log reduction in growth in culture. The addition of 0.5 percent
triclosan alone resulted in a 0 log reduction, and the addition of
0.25 silver carbonate alone resulted in a 5 log reduction.
Therefore one would expect a 5 log reduction of growth in cell
culture upon combining the two compositions. However, due to a
synergistic activity present when triclosan is combined with silver
carbonate an additional 2 log reduction was observed.
[0070] Alone, 0.06 percent and 0.125 percent silver carbonate
caused a 2 log and a 4 log reduction in growth in culture,
respectively, and 0.5 percent triclosan alone caused a 0 log
reduction. However, 0.06 percent and 0.125 percent silver carbonate
each combined with 0.5 percent triclosan resulted in, respectively,
a 3 log reduction and a 7 log reduction of growth in culture.
7.0 EXAMPLE
Antimicrobial Efficacy of Catheters Impregnated with (1) Triclosan,
Silver Salts and Various Organic Acids and (2) Triclosan, Silver
Salts, and Chlorhexidine
[0071] Catheters impregnated with triclosan, silver compounds and
various organic acids, with and without chlorhexidine, were
evaluated for effectiveness and duration of antimicrobial efficacy.
Treatment solutions comprising triclosan, a silver compound, and an
organic acid or chlorhexidine as well as polyurethane polymers were
prepared by first dissolving the triclosan, silver compound, and
acid or chlorhexidine in methanol, dissolving the polymers in THF,
and then mixing the methanol solution with the THF solution in a
30% v/v methanol solution/70% v/v THF solution solvent system.
Polyurethane central venous catheter segments were then dipped for
one minute in the treatment solution, then allowed to dry. The
final concentrations (percentages based on w/v) of active agents
and polymers in the treated catheters are set forth in Table 5.
[0072] In related experiments, polyurethane catheter segments were
treated by a two-step process. In the first step, catheters were
dipped in a 70% v/v THF+30% v/v reagent alcohol treatment solution
having final concentrations of 3% w/v 93A polyurethane and 1% 60D
polyurethane, either with or without silver carbonate at a final
concentration of 0.6% (the various components were dissolved in
either THF or reagent alcohol before mixing the two to produce the
treatment solution, as set forth above). The catheters were allowed
to dry. Then, in the second step, the catheters were soaked for one
minute in a 20% v/v THF+80% v/v methanol solvent mixture containing
either triclosan alone, triclosan and citric acid, or triclosan and
chlorhexidine at concentrations set forth in Table 6.
[0073] The zones of inhibition were studied against S. epidermidis
and P. aeruginosa over a two day period. The results, shown in
Tables 5 and 6, indicate that the combination of citric acid,
triclosan and silver compound (silver carbonate) resulted in
superior antimicrobial activity against Pseudomonas aeruginosa,
compared to other organic acids tested.
5 TABLE 5 Zones of Inhibition (mm) S. epidermidis P. aeruginosa
Treatment Solution Day 1 Day 2 Day 1 Day 2 6% TC + 0.6%
Ag.sub.2CO.sub.3 + 3% 20 18 9 0 93A PU + 1% 60D PU 6% TC + 0.6%
Ag.sub.2CO.sub.3 + 2% 20 18 11 0 salicylic acid + 3% 93A PU + 1%
60D PU 6% TC + 0.6% Ag.sub.2CO.sub.3 + 2% 20 18 8 0 mandelic acid +
3% 93A PU + 1% 60D PU 6% TC + 0.6% Ag.sub.2CO.sub.3 + 2% 20 18 8 0
deoxycholic acid + 3% 93A PU + 1% 60D PU 6% TC + 0.6%
Ag.sub.2CO.sub.3 + 2% 20 19 11 8 citric acid + 3% 93A PU + 1% 60D
PU 6% TC + 0.3% Ag.sub.2CO.sub.3 + 2% 21 20 13 12 CHX + 3% 93A PU +
1% 60D PU
[0074]
6 TABLE 6 Zones of Inhibition (mm) First Step Second Step S.
epidermidis P. aeruginosa Treatment Solution Treatment Solution Day
1 Day 2 Day 1 Day 2 3% 93A PU + 1% 60D PU 6% TC + 4% Citric Acid 20
18 0 0 3% 93A PU + 1% 60D 6% TC 20 18 9 0 PU + 0.6%
Ag.sub.2CO.sub.3 3% 93A PU + 1% 60D 6% TC +4% Citric Acid 20 18 10
7 PU + 0.6% Ag.sub.2CO.sub.3 3% 93A PU + 1% 60D PU 6% TC + 2% CHX
21 17 12 11
8.0 EXAMPLE
Methods of Preventing Adherence on Medical Articles
[0075] The following techniques were used to impregnate 93A
polyurethane catheter segments with triclosan and various silver
compounds. The resulting surface characteristics, scored on a scale
of 1 to 4, with 4 being the most lubricious surface, are shown in
Tables 7 and 8. Soaking time varied from 15 seconds to 1 hour.
[0076] Method A: The outer surfaces of catheter segments were
impregnated by dipping the segments in a treatment solution of 70%
v/v THF (containing 93A polyurethane and 60D polyurethane)+30% v/v
(2:1 reagent alcohol:ammonia containing triclosan and silver
compound), having final concentrations of 3% w/v 93A polyurethane,
1% w/v 60D polyurethane, 0.3% w/v silver atom or ion, and 6% w/v
triclosan.
[0077] Method B: Catheter segments had their ends sealed and were
soaked for 5 minutes in a treatment solution of 90% v/v (8:1
reagent alcohol/ammonia containing triclosan and silver
compound)+10% THF, having final concentrations of 6% w/v triclosan
and 0.3% silver (atom or ion).
[0078] Method C: The ends of the catheter segments were sealed and
the segments were dipped in a treatment solution of 70% v/v THF
(containing 60D polyurethane)+30% v/v reagent alcohol having a
final concentration of 2% w/v 60D polyurethane. The catheter
segments were then dried for one hour, and then were soaked for 5
minutes in a treatment solution of 90% v/v (8:1 ethanol/ammonia
containing triclosan and silver compound)+10% THF, having final
concentrations of 6% w/v triclosan and 0.3% silver (the treatment
solution used in Method B).
[0079] Method D: Catheter segments were dipped in a treatment
solution of 70% v/v THF (containing 93A polyurethane and 60D
polyurethane)+30% v/v (2:1 reagent alcohol:ammonia containing a
silver compound), having final concentrations of 3% w/v 93A
polyurethane, 1% w/v 60D polyurethane, and 0.3% w/v silver (atom or
ion) (the treatment solution used in Method A, but without the
triclosan).
[0080] The surface characteristics of catheter segments treated
according to Methods A-D are shown in Table 7.
7 TABLE 7 Surface Characteristics Silver Salt A B C D 0 (only
triclosan) 3 3 4 -- Silver carbonate 4 4 4 3 Silver deoxycholate 4
4 4 Rough Silver oxide 4 4 4 3 Silver salicylate 4 4 4 2 Silver
iodide 3 3 3 2 Silver sulfadiazine 3 2 2 2 Silver nitrate 4 4 4
4
[0081] Table 8 shows the results when the outer surfaces of
catheter segments were impregnated by dipping the catheters in a
treatment solution of 70% v/v THF (containing 93A and 60D
polyurethanes) and 30% v/v reagent alcohol (containing triclosan,
an organic acid, and a silver compound), having final
concentrations of 3% w/v 93A polyurethane, 1% w/v 60D polyurethane,
0.3% w/v silver (atom or ion), 6% w/v triclosan, and 1% w/v organic
acid.
8 TABLE 8 Metal Salts and Acid in TC Complex Surface
Characteristics Silver carbonate + salicylic acid 3.5 Silver
carbonate + deoxycholic acid 3.5 Silver sulfadiazine + salicylic
acid 3 Silver sulfadiazine + deoxycholic acid 3 Silver carbonate +
citric acid 4 Silver sulfadiazine + citric acid 4 Silver
sulfadiazine + palmitic acid 3.5 Silver sulfadiazine + propionic
acid 3.5 Silver sulfadiazine + aspartic acid 3.5
9.0 EXAMPLE
Anti-Microbial Polyurethane Catheters Prepared by a Shorter Soaking
Time (15 Seconds) and Higher Triclosan Levels (Up to 15%) in the
Impregnation Solution
[0082] A shorter soaking time is preferred in a drug/solvent system
since it is less likely to negatively affect the physical integrity
of a polymeric device, particularly a polyurethane catheter. In
order to attain sufficient drug uptake using a shorter soaking
time, it is preferred to increase the amount of triclosan in
solution to a range of 10% to 15%. For example, polyurethane
catheters were dipped in a solution containing 2% 60D polyurethane
dissolved in 70% THF+30% reagent alcohol and allowed to dry for 1
hour. They were then soaked for 15 seconds in a solution prepared
by dissolving enough triclosan and AgNO.sub.3 in an 8:1 reagent
alcohol/ammonia solution such that when a treatment solution was
prepared containing 10% THF and 90% of the reagent
alcohol/ammonia/triclosan/AgNO.sub.3, the treatment solution
contained 15% triclosan and 0.48% AgNO.sub.3. As a comparison,
catheters were prepared as above with the following changes: the
triclosan concentration was reduced to 6% and the soaking time was
increased to 1 minute. The initial drug levels, measured
spectrophotometrically, and zones of inhibition against S.
epidermidis and P. aeruginosa were determined for catheter samples
of both groups and are shown in Table 9.
9 TABLE 9 Zones of Inhibition (mm) .mu.g vs. Treatment TC/cm S.
epidermidis vs. P. aeruginosa 15 sec .times. (15% TC + 0.48% 436 11
4 AgNO.sub.3) 1 min .times. (6% TC + 0.48% 410 13 4 AgNO.sub.3)
[0083] As illustrated in Table 9, both initial drug uptake and zone
of inhibition data indicate that a similar efficacy is obtainable
using a higher concentration of drug and a shorter soaking time. In
addition, a shorter soaking time in a drug/solvent system is less
likely to negatively affect the physical integrity of the
device.
10.0 EXAMPLE
Impregnation of Triclosan-Silver Combination in Latex Urinary
Catheter and PTFE Soft Tissue Patches (STP)
[0084] Segments of latex urinary catheters and PTFE soft tissue
patches (STP) were impregnated by soaking these materials (or
suctioning under vacuum in the case of PTFE STP) for 1 hour in a
treatment solution prepared by mixing 80% v/v THF and 10% v/v
reagent alcohol/10% v/v ammonia (containing triclosan and silver
carbonate), having final concentrations of 1% w/v triclosan and
0.2% w/v silver carbonate. The impregnated materials were dried and
then rinsed in water and dried again. The antimicrobial properties
of the material were then tested by measuring the zones of
inhibition produced against S. aureus, P. aeruginosa, E. aerogenes
and C. albicans after placing the treated material on a trypticase
soy agar plate seeded with 0.3 ml of 10.sup.8 cfu/ml bacterial or
yeast culture and incubating at 37.degree. C. for 24 hours. The
results are shown in Table 10.
10 TABLE 10 Zones of inhibition (mm) Urinary Catheter STP S. aureus
21 >30 P. aeruginosa 6 7 E. aerogenes 10 25 C. albicans 7 12
11.0 EXAMPLE
Antimicrobial Efficacy of Subcutaneous Cuffs Containing Fabrics
Consisting of Dacron, Acrylic and PTFE
[0085] The antimicrobial efficacy of subcutaneous cuff material
containing fabrics made of Dacron, Acrylic and PTFE were
impregnated with a treatment solution prepared by mixing 10% v/v
ammonia/10% v/v reagent alcohol (containing silver carbonate,
triclosan and chlorhexidine) and 80% v/v THF (containing 93A and
60D polyurethanes), having final concentrations of 4% w/v 93A
polyurethane, 1% w/v 60D polyurethane, 0.2% w/v silver carbonate,
0.1% w/v triclosan and 0.5% w/v chlorhexidine, The resulting
material was then dried for 24 hours and the zones of inhibition
against S. aureus and P. aeruginosa were determined. The zones of
inhibition are shown in Table 11.
11 TABLE 11 Zone of Inhibition (mm) Cuff Material S. aureus P.
aeruginosa Dacron 20 12 Acrylic 19 12 PTFE 18 10
12.0 EXAMPLE
Method of Impregnation of Left Ventricular Assist Device (LYAD)
Drive Lines
[0086] Left ventricular assist device (LVAD) drive lines, which are
made of Dacron material and are attached to silicone tubing, were
impregnated with a polymeric matrix containing triclosan and silver
salts.
[0087] Dacron material was treated with one of two different
treatment solutions as follows.
[0088] In a first case, Dacron material was uniformly spread with a
treatment solution which was 10% v/v ammonia, 10% v/v reagent
alcohol (containing silver carbonate and triclosan)+80% THF
(containing 93A and 60D polyurethanes), having final concentrations
of 0.2% w/v silver carbonate, 0.1% w/v triclosan, 4% w/v 93A
polyurethane, and 1% w/v 60D polyurethane. As in previous examples,
the silver carbonate and triclosan were first dissolved in 1:1
ammonia/reagent alcohol, and the polyurethanes were first dissolved
in THF, and then the ammonia/reagent alcohol and THF were mixed to
achieve the proper final ratios.
[0089] In a second case, Dacron material was uniformly spread with
a treatment solution which was 10% v/v ammonia, 10% v/v reagent
alcohol (containing silver carbonate, triclosan and
chlorhexidine)+80% THF (containing 93A and 60D polyurethanes),
having final concentrations of 0.2% w/v silver carbonate, 0.5% w/v
chlorhexidine, 0.1% w/v triclosan, 4% w/v 93A polyurethane, and 1%
w/v 60D polyurethane.
[0090] Dacron material having a polymer-drug film prepared as above
was then attached to silicone tubing, thereby creating a drive
line, and dried. This method is particularly important for devices
in which tissue ingrowth is intended to occur after implantation
(e.g., cuffs). Antimicrobial activity was evaluated after 24 hours
by measuring the zones of inhibition produced by placing 0.25 cm
length of drive line on trypticase soy agar seeded with 0.3 ml of
10.sup.8 cfu/ml bacteria and incubated at 37.degree. C. for 24
hours. The zones of inhibition w ere measured after 24 hours, and
the results are shown in Table 12.
12 TABLE 12 Zones of Inhibition (mm) Drugs in Catheter S. aureus P.
aeruginosa 0.2% Ag.sub.2CO.sub.3, 0.1% TC 16 6 0.2%
Ag.sub.2CO.sub.3, 0.1% TC, 0.5% CHX 20 12
[0091] As shown in Table 12, drive line treated with polymer,
silver carbonate, and low levels of triclosan had antimicrobial
activity against both S. aureus and P. aeruginosa. The
antimicrobial effect was improved by the addition of
chlorhexidine.
[0092] In related experiments, subcutaneous cuffs containing
fragments consisting of Dacron, acrylic or PTFE were impregnated by
dipping in a treatment solution which is 10% v/v ammonia, 10% v/v
reagent alcohol (containing silver carbonate, triclosan and
chlorhexidine)+80% THF (containing 93A and 60D polyurethanes),
having final concentrations of 0.2% w/v silver carbonate, 0.5% w/v
chlorhexidine, 0.1% w/v triclosan, 4% w/v 93A polyurethane, and 1%
w/v 60D polyurethane. The treated material was allowed to dry, and
then tested for antimicrobial activity as set forth above. The
results are shown in Table 13.
13 TABLE 13 Zone of Inhibition (mm) Cuff Material S. aureus P.
aeruginosa Dacron 20 12 Acrylic 19 12 PTFE 18 10
13.0 EXAMPLE
Bacterial Adherence on Triclosan-Silver Compound Impregnated
Catheters Post Implantation in Rats
[0093] The ability of catheters impregnated with triclosan and a
silver compound to resist bacterial adherence was tested by
introducing and maintaining treated catheters in vivo in rats,
removing the catheters, exposing the catheters to bacterial
cultures, and then measuring the amount of bacteria adhered to the
extracted catheter segments.
[0094] The catheter segments were impregnated with triclosan and
various silver compounds and/or chlorhexidine diacetate (CHA),
using treatment solutions having the final concentrations of agents
set forth in Table 14, below. In each case, the amount of silver
compound in the treatment solution contributed silver atom/ion at a
concentration of 0.3% w/v. The treatment solutions comprised THF
and reagent alcohol mixed solutions, where polyurethane components
were dissolved in the THF and triclosan and silver compounds were
dissolved in the reagent alcohol prior to mixing. The amount of
THF/polyurethane was generally 70% (v/v). The amount of reagent
alcohol was 30% (v/v). Where indicated by an asterisk in Table 16,
the solvent was simply reagent alcohol; otherwise, the solvent
system was reagent alcohol/ammonia in a 2:1 ratio (accounting for
20% and 10%, respectively, on a volume to volume basis). Polymers
in the treatment solutions were initially dissolved in the THF
component and had final concentrations of 3% w/v 93A polyurethane
and 1% w/v 60D polyurethane. Catheter segments were dipped in the
treatment solution, and then dried for three days prior to use.
Unimpregnated catheter segments were used as controls.
[0095] Six 3 cm segments of catheters from each catheter group were
implanted in a subcutaneous pocket on the dorsal side of laboratory
rats. After seven days the catheters were removed and rinsed twice
in saline and processed as follows: Each group of catheter segments
(6.times.3 cm) were transferred to 18 ml of 10% BCS+90% TSB
containing 3.0 ml of 10.sup.7 cfu S. epidermidis/ml at 37.degree.
C. in a rotary shaker for 4 hours. Then the catheters were removed,
blotted, rinsed twice in saline, blotted and rolled over the
surface of drug neutralizing agar plates (D/E plates) and incubated
for 24 hrs at 37.degree. C. The colony counts observed in Table 14
were then determined for each catheter group.
14TABLE 14 Agents No. In Treatment of Catheter Segments Catheter
Segments Solution Not Colonized Colonized (10.sup.2-10.sup.4
cfu/cm) 6% TC + 0.75% 0 6 AgSD 6% TC + 0.79% 0 6 Ag paraamino
salicylic acid 6% TC + 0.8% 0 6 Ag acetylsalicylic acid 0.75% AgSD
+ 4% 0 5 CHA* 6% TC + 0.6% 1 5 Ag salicylate 6% TC + 0.8% 1 5 Ag
laurate 6% TC + 1.5% 1 5 Ag deoxycholate 6% TC 1 4 6% TC + 0.32% 2
4 Ag oxide 6% TC + 1% Ag 3 3 Paraamino benzoic acid 6% TC + 0.4% 4
2 Ag Carbonate 6% TC + 0.48% 5 1 Ag Nitrate 6% TC + 0.4% 5 1 Ag
Carbonate* control 1 0 4 control 2 1 5 *solution does not contain
ammonia
[0096] As evidenced from the results of Table 14, the catheter
groups containing triclosan-silver salt combinations were effective
in preventing bacterial adherence on catheters after being
implanted for seven days in rats.
[0097] A further two sets of experiments were carried out to
determine the antimicrobial efficacy of catheters treated according
to the invention. In particular, one set of experiments involved an
"initial infection model" where the initial catheter wound site was
inoculated with bacteria, and another set of experiments involved a
"delayed infection model" in which catheters implanted in rats for
ten days were removed and exposed to bacterial cultures in vitro.
In these two sets of experiments, the results of which are shown in
Table 15, long term and short term efficacy of treated catheters
was evaluated and compared.
[0098] In experiments involving the "initial infection model", the
dorsal side of a rat was shaved and a 7 cm segment of catheter
treated with the agents set forth in Table 15 (with both ends
sealed with silicone plugs) was implanted subcutaneously through a
0.5 cm incision just above the shoulder area. The catheter was kept
in place, and the tract and insertion site were inoculated with 20
.mu.l of bacterial culture having 10.sup.8 cfu of S. aureus per
milliliter. The wound was then closed with surgical clips. After
ten days, the catheters were removed and swab cultures of the
insertion site and tract were taken. Only the control group had a
positive swab culture. Bacterial adherence on the outer surface of
the catheters was determined by sonicating the catheters in drug
neutralizing media and then subculturing on a trypticase soy agar
plate.
[0099] In experiments involving the "delayed infection model",
catheter segments (3 cm each, with sealed ends, treated with the
agents set forth in Table 15, in solvent systems that were 70% v/v
THF and 30% v/v reagent alcohol and contained 3% w/v 93A and 1% w/v
60D polyurethanes) were implanted subcutaneously in rats (6
segments of catheters treated with the same agents per rat). After
ten days in vivo, the catheters were excised and rinsed twice with
saline. Then each group of six segments was incubated in 18 ml of a
log-phase culture of S. epidermidis (10.sup.7 cfu/ml of 10% bovine
adult serum+90% TSB) in a rotary shaker for four hours. The
bacterial adherence was determined by sonicating the catheters in
drug neutralizing media and then subculturing on a trypticase soy
agar plate.
[0100] Untreated catheters were implanted in rats of both models to
serve as controls.
15TABLE 15 10 Days Initial Post Catheter Group Contamination*
Contamination* Control 1 .times. 10.sup.3 >10.sup.5 1.5% CHA +
0.75% AgSD 10 5 .times. 10.sup.5 2% CHA + 2% TC + 0.75% 0 1 .times.
10.sup.4 AgSD 6% TC + 0.36% AgNO.sub.3 33 26 6% TC + 0.4%
Ag.sub.2CO.sub.3 90 1 .times. 10.sup.2 6% TC + 0.75% AgSD Not Done
1 .times. 10.sup.4 *colony forming units (cfu) per 1 cm
catheter.
[0101] As shown in Table 15, triclosan/silver nitrate and
triclosan/silver carbonate treated catheter surfaces were found to
be more lubricious (as indicated by lower cfu associated with
catheters 10 days post-implantation), even though their
antimicrobial activity appeared to be lower than that of
chlorhexidine/silver sulfadiazine or chlorhexidine/triclosan/silver
sulfadiazine treated catheters (as reflected by lower cfu in the
initial contamination models). It appears from these results that
surface characteristics play an important role in the prevention of
delayed infection. Chlorhexidine containing catheters were more
effective in preventing initial infections while triclosan/silver
compound catheters were more effective in preventing later
infections. The latter catheters showed significantly lower
bacterial adherence compared to control catheters when infected
initially.
14.0 EXAMPLE
Ability of Treated PTFE Patches to Resist Infection in an Animal
Model
[0102] The ability of PTFE soft tissue patches, treated with
combinations of triclosan and/or chlorhexidine and the silver salt,
silver carbonate, to resist infection was tested as follows. Disks
of PTFE patches were impregnated with treatment solutions prepared
by dissolving triclosan and/or chlorhexidine and silver carbonate
in 1:1 reagent alcohol/ammonium hydroxide, and then mixing with THF
to produce a 80% v/v THF, 10% reagent alcohol, 10% v/v ammonium
hydroxide solution having triclosan, chlorhexidine, and silver
carbonate final concentrations as specified in Table 16 below. The
patch material was soaked in treatment solution for 1 hour under a
vacuum. The patches were implanted subcutaneously in a pocket in
the abdominal area of rats and infected with 10 .mu.l of 10.sup.8
CFU S. aureus. After 7 days, they were removed and bacterial
adherence was determined by sonicating the catheters in drug
neutralizing media and then subculturing on a trypticase soy agar
plate. The efficacy of patches in resisting infection due to
contamination at the time of implantation is illustrated by the
bacterial adherence data provided in Table 16.
16 TABLE 16 Bacterial Adherence Impregnation Solution CFU/DISK
0.25% TC + 0.2% Ag.sub.2CO.sub.3 + 0.5 CHX 4 1.0% TC + 0.2%
Ag.sub.2CO.sub.3 1 0.5% CHX + 0.2% Ag.sub.2CO.sub.3 15 0.5% TC +
0.25% CHA + 0.25% CHX 15 Unimpregnated 7.6 .times. 10.sup.3
[0103] As shown in Table 16, all of the above groups with and
without chlorhexidine were observed to be similarly efficacious
relative to the control, unimpregnated group.
15.0 EXAMPLE
Enhancement of the Anti-Microbial Activity of Devices Containing
Silver and Triclosan Using Other Soluble Anti-Infective Agents
[0104] Polyurethane catheter segments were impregnated by dipping
in a treatment solution prepared by mixing 10% v/v ammonia/20% v/v
reagent alcohol (containing triclosan, silver carbonate, and,
except for the control, an additional antibiotic) with 70% v/v THF
(containing 93A and 60D polyurethanes), having final concentrations
of 3% w/v 93A polyurethane, 1% w/v 60D polyurethane, 6% w/v
triclosan, 0.4% w/v Ag.sub.2CO.sub.3 and 0.5% of the antibiotics
set forth in Table 17, below. The treated catheter segments were
then dried for 24 hours and evaluated for antimicrobial activity by
determining the zones of inhibition created in cultures of various
microbes. The antimicrobial properties of the material were then
tested by measuring the zones of inhibition produced against S.
aureus, P. aeruginosa, E. aerogenes and C. albicans after placing
the treated material on a trypticase soy agar plate seeded with 0.3
ml of 10.sup.8 cfu/ml bacterial/yeast culture and incubating at
37.degree. C. for 24 hours.
[0105] Table 17 shows the enhanced effective broad spectrum
anti-microbial field around a catheter produced by the addition of
soluble anti-infective agents. Using antibiotics along with the
triclosan-silver salt combination may reduce the risk of
development of antibiotic resistant microbes.
17TABLE 17 Agents in Zones of Inhibition (mm) Treatment S. Solution
aureus P. aeruginosa E. aerogens C. albicans 6% TC + 0.4% 14 6 7 7
Ag.sub.2CO.sub.3 + 0.5% Gramicidin 6% TC + 0.4% 17 16 15 7
Ag.sub.2CO.sub.3 + 0.5% Polymixin 6% TC + 0.4% 19 18 18 10
Ag.sub.2CO.sub.3 + 0.5% Norfloxacin 6% TC + 0.4% 12 12 13 9
Ag.sub.2CO.sub.3 + 0.5% Sulfamylon 6% TC + 0.4% 21 5 5 0
Ag.sub.2CO.sub.3 + 0.5% Rifampicin 6% TC + 0.4% 13 6 6 5
Ag.sub.2CO.sub.3 + NO ANTIBIOTIC (CONTROL)
16.0 EXAMPLE
Antimicrobial Activity of Various Triclosan-Silver Compound
Combinations
[0106] Polyurethane catheter segments were treated by dipping in a
treatment solution having final concentrations of triclosan and/or
silver compound as set forth in Table 18, below, where the solvent
system was 70% v/v THF and 30% v/v reagent alcohol and contained 3%
w/v 93A and 1% w/v 60D polyurethanes. Six catheter segments from
each group were placed vertically on a trypticase soy agar plate
seeded with 0.3 ml of 10.sup.8 cfu/ml bacterial/yeast culture and
incubated at 37.degree. C. for 24 hours. The results are shown in
Table 18.
18 TABLE 18 Zones of Inhibition (mm) Drug in Impregnation S. P.
Enterobacter Candida Solution aureus aeruginosa aerogenes albicans
6% TC 15 0 6 0 1% AgSD 8 5 0 0 0.5% Ag.sub.2CO.sub.3 8 7 0 6 0.6%
AgSalicylate 9 6.5 0 7.3 0.32% Ag Oxide 9 7 0 11 1.5% Ag 1 4 0 5
Deoxycholate 6% TC + 1% 17 6 5 5 AgSD 6% TC + 0.5% 22 9 6 7
Ag.sub.2CO.sub.3 6% TC + 0.6% 20 10 7 11 Ag Salicylate 6% TC +
0.32% 22 10 6 15 Ag Oxide 6% TC + 1.5% Ag 17 7 5 10 Deoxycholate 2%
TC + 1% 17 11 12 13 AgSD + 2% CHX 6% TC + 0.7% Ag 17 7 6 5
ParaaminoBenzoate acid 6% TC + 0.79% 19 7 6 4 Ag Paraamino
Salicylate 6% TC + 0.8% Ag 19 8 7 9 AcetylSalicylate 0.7% Ag
Paraamino 3.5 4.0 0 0 Benzoate 0.79% Ag 5.5 7.5 3.3 0
ParaaminoSalicylate 0.8% Ag 7.0 8.0 4.7 0 Acetyl Salicylate
[0107] It is noted that the combination of triclosan with either
silver paraaminobenzoate, silver paraaminosalicylate, or silver
acetylsalicylate resulted in unexpected efficacy against C.
albicans as compared with each of the agents tested alone. Also
illustrated by Table 18 is the synergistic effect achieved by the
presence of triclosan in combination with silver salts.
17.0 EXAMPLE
Impregnation of Anti-Inflammatory Agents Along with Triclosan and
Silver Salts
[0108] The following experiments demonstrated that the addition of
the anti-inflammatory agent salicylic acid and its derivatives to
combinations of triclosan and silver compounds improved
antimicrobial activity.
[0109] LVAD drive lines made of Dacron were impregnated with
triclosan, silver sulfadiazine and chlorhexidine, with or without
salicylic acid, as follows. One set of pieces of Dacron were
uniformly spread with a treatment solution prepared by mixing 30%
v/v reagent alcohol (containing triclosan (TC), silver sulfadiazine
(AgSD), and chlorhexidine (CHX)) and 70% v/v THF (containing 93A
and 60D polyurethanes), having final concentrations of 0.1% w/v
triclosan, 0.2% w/v silver sulfadiazine, 0.5% w/v chlorhexidine, 4%
w/v 93A polyurethane, and 1% w/v 60D polyurethane. Another set of
Dacron pieces were uniformly spread with a second treatment
solution having the same components, but also having a final
concentration of 0.5% w/v salicylic acid (the salicylic acid being
initially dissolved in the reagent alcohol component). As a
control, one set of Dacron pieces was treated with a third
treatment solution containing salicylic acid and polymer but
lacking triclosan, silver sulfadiazine, and chlorhexidine. The
Dacron pieces were dried for 24 hours prior to antimicrobial
testing.
[0110] In an analogous set of experiments, polyurethane catheters
were impregnated with triclosan and silver carbonate, with or
without salicylic acid or one of its derivatives. One set of
polyurethane catheter segments were therefor dipped in a treatment
solution prepared by mixing 20% v/v reagent alcohol/10% v/v ammonia
(containing triclosan and silver carbonate) and 70% v/v THF
(containing 93A and 60D polyurethanes), having final concentrations
of 6% w/v triclosan, 0.4% w/v silver carbonate, 3% w/v 93A
polyurethane and 1% w/v 60D polyurethane. Three other sets of
catheter segments were treated with the same solution further
having a final concentration of 0.5% w/v salicylic acid, 0.5% w/v
acetylsalicylic acid, or 0.5% w/v paraaminosalicylic acid,
respectively (the salicylic acid or derivative thereof being first
dissolved in the ethanol/ammonia solution). As controls, another
three sets of catheters were impregnated using treatment solutions
as above, containing either 0.5% w/v salicylic acid, 0.5% w/v
acetylsalicylic acid, or 0.5% w/v paraaminosalicylic acid and
polymer, but lacking triclosan or silver carbonate. The treated
catheters were dried for 24 hours prior to antimicrobial
testing.
[0111] Antimicrobial testing was performed by placing the Dacron
drive line or catheter-segment on trypticase soy agar seeded with
5.times.10.sup.8 cfu of Pseudomonas aeruginosa. The zones of
inhibition were measured after inclubation of the plates at
37.degree. C. for 24 hours. The results, presented in Table 19,
illustrate that both hydrophilic (polyurethane) and hydrophobic
(Dacron) medical devices can be rendered infection resistant and
that anti-inflammatory agents such as salicylates enhance
antimicrobial activity.
19 TABLE 19 Zones of Inhibition (mm) against P. aeruginosa LVAD
Polyurethane Agents in Treatment Solution DriveLine Catheters 0.1%
TC + 0.2% AgSD + 0.5% CHX 12 -- 0.1% TC + 0.2% AgSD + 0.5% CHX +
0.5% 15 -- Salicylic acid 0.5% Salicylic Acid 0 -- 6% TC + 0.4%
Ag.sub.2CO.sub.3 -- 7 6% TC + 0.4% Ag.sub.2CO.sub.3 + 0.5% -- 11
Salicylic Acid 6% TC + 0.4% Ag.sub.2CO.sub.3 + 0.5% -- 11
Acetylsalicylic Acid 6% TC + 0.4% Ag.sub.2CO.sub.3 + 0.5% -- 11
Paraaminosalicylic Acid 0.5% Salicylc Acid -- 0 0.5%
Acetylsalicylic Acid -- 0 0.5% Paraaminosalicylic Acid -- 0
18.0 EXAMPLE
Anti-Microbial Efficacy of Combinations of Silver Salts and
Chlorinated Phenolic Compounds
[0112] Silver compounds, in particular silver salts and various
phenolic compounds were combined to study prolonged anti-microbial
efficacy of the various compositions. Catheter segments for study
were prepared by treating a polyurethane catheter segment in a
treatment solution having 70% v/v THF and 30% v/v reagent alcohol
and concentrations of 3% w/v 93A polyurethane and 1% w/v 60D
polyurethane, having final concentrations of agents set forth in
Table 20. Then segments were placed on petri dishes seeded with
Pseudomonas aeruginosa. Table 3 illustrates the zones of inhibition
of Pseudomonas aeruginosa over a three day period of
Ag.sub.2CO.sub.3 and Ag.sub.2CO.sub.3 in combination with three
phenolic compositions, (1) parachlorometaxylenol (PCMX), (2)
o-phenyl phenol and (3) p-tertiary amyl phenol, and compared their
respective efficacy to triclosan and Ag.sub.2CO.sub.3. As shown in
Table 20 it appears that a synergistic effect occurs when
chlorinated phenols are combined with silver salt exhibiting
prolonged anti-microbial activity.
20 TABLE 20 Zones of Inhibition (mm) Drugs in Catheter DAY 1 2 3 6%
triclosan + 0.6% Ag.sub.2CO.sub.3 11 10 6 6% PCMX + 0.6%
Ag.sub.2CO.sub.3 12 10 7 6% 0-phenyl phenol + 0.6% Ag.sub.2CO.sub.3
10 0 0 6% p-tertiary amyl phenol + 0.6% Ag.sub.2CO.sub.3 10 0 0
0.6% Ag.sub.2CO.sub.3 10 0 0
19.0 Antimicrobial Efficacy of Hydrophilic or Hydrophobic Matrix
Systems by Addition of Hydrogel Polymer
[0113] We tested the effect on antimicrobial activity of adding a
hydrogel polymer such as polyvinyl pyrrolidone (PVP) to treatment
solutions containing triclosan, silver compound, and polyurethanes,
and then using such solutions to treat medical devices.
Polyurethane catheter segments were dipped in one of the following
two treatment solutions:
[0114] (i) a treatment solution prepared by mixing 30% v/v reagent
alcohol (containing triclosan and silver carbonate) with 70% v/v
THF (containing 93A and 60D polyurethanes), having final
concentrations of 6% w/v triclosan, 0.4% w/v silver carbonate, 3%
w/v 93A polyurethane, and 1% w/v 60D polyurethane; or
[0115] (ii) a treatment solution prepared by mixing 30% v/v reagent
alcohol (containing triclosan and silver carbonate) with 70% v/v
THF (containing 60D polyurethane and PVP), having final
concentrations of 6% w/v triclosan, 0.4% w/v silver carbonate, 3%
w/v 60D polyurethane, and 2% w/v PVP.
[0116] The treated catheter segments were then dried for 24 hours
and then tested for antimicrobial activity by measuring the zones
of inhibition The antimicrobial properties of the material were
then tested by measuring the zones of inhibition produced against
S. epidermidis and P. aeruginosa after placing the treated material
on a trypticase soy agar plate seeded with 0.3 ml of 10.sup.8
cfu/ml bacterial culture and incubating at 37.degree. C. for 24
hours. In addition, the amount of triclosan present per centimeter
of catheter was determined spectrophotometrically. The results are
shown in Table 21.
21 TABLE 21 Zones of Inhibition (mm) Compounds in .mu.g vs. vs.
Treatment Solution TC/cm S. epidermidis P. aeruginosa 6% TC + 0.4%
Ag.sub.2CO.sub.3 + 3% 425 11 6.5 93A PU + 1% 60D PU 6% TC + 0.4%
Ag.sub.2CO.sub.3 + 3% 397 18 10 60D PU + 2% PVP
[0117] In other experiments, the effect of PVP incorporated into a
hydrophobic article, ie., Dacron material for LVAD drive lines, was
determined. In particular, pieces of Dacron were uniformly spread
with one of the two following treatment solutions:
[0118] (iii) a treatment solution prepared by mixing 10% v/v
reagent alcohol (containing triclosan, chlorhexidine diacetate
(CHA), chlorhexidine free base (CHX) and silver sulfadiazine) with
90% v/v THF (containing 93A and 60D polyurethanes), having final
concentrations of 0.2% w/v triclosan, 0.3% w/v chlorhexidine
diacetate, 0.2% w/v chlorhexidine free base, 0.2% w/v silver
sulfadiazine, 4% w/v 93A polyurethane, and 1% w/v 60D polyurethane,
or
[0119] (iv) a treatment solution prepared by mixing 10% v/v reagent
alcohol (containing triclosan, chlorhexidine diacetate (CHA),
chlorhexidine free base (CHX) and silver sulfadiazine) with 90% v/v
THF (containing 93A and 60D polyurethanes and PVP and
polyvinylchloride ("PVC")), having final concentrations of 0.2% w/v
triclosan, 0.3% w/v chlorhexidine diacetate, 0.2% w/v chlorhexidine
free base, 0.2% w/v silver sulfadiazine, 4% w/v 93A polyurethane,
1% w/v 60D polyurethane, 2% w/v PVP and 4% w/v PVC.
[0120] The treated Dacron was allowed to dry for 24 hours and then
attached to the outer surface of silicon tubing using a silicon
adhesive to produce a drive line. The resulting drive lines were
then tested for antimicrobial activity by measuring the zones of
inhibition produced against S. epidermidis, P. aeruginosa, and C.
albicans after placing the treated material on a trypticase soy
agar plate seeded with 0.3 ml of 10.sup.8 cfu/ml bacterial or yeast
culture and incubating at 37.degree. C. for 24 hours. In addition,
the amounts of triclosan and chlorhexidine present per centimeter
of Dacron were determined spectrophotometrically. The results are
shown in Table 22.
22 TABLE 22 Zones of Inhibition (mm) Group .mu.g TC/cm .mu.g CHX cm
v. S. epidermidis v. P. aeruginosa v. C. albicans LXI 387 662 17
11.5 14 LXII 420 480 22 15 16
[0121] As illustrated in Tables 21 and 22, the use of a hydrogel
such as PVP in a hydrophilic (e.g., polyurethane) or hydrophobic
(e.g., PVC) matrix allows better drug release as evidenced by
greater zones of inhibition.
[0122] Various publications are cited herein, which are hereby
incorporated by reference in their entireties.
* * * * *