| United States Patent Application |
20040116551
|
| Kind Code
|
A1
|
|
Terry, Richard N.
|
June 17, 2004
|
Antimicrobial compositions containing colloids of oligodynamic metals
Abstract
The present invention relates to antimicrobial compositions, methods for
the production of these compositions, and use of these compositions with
medical devices, such as catheters, and implants. The compositions of the
present invention advantageously provide varying release kinetics for the
active ions in the compositions due to the different water solubilities
of the ions, allowing antimicrobial release profiles to be tailored for a
given application and providing for sustained antimicrobial activity over
time. More particularly, the invention relates to polymer compositions
containing colloids comprised of salts of one or more oligodynamic metal,
such as silver. The process of the invention includes mixing a solution
of one or more oligodynamic metal salts with a polymer solution or
dispersion and precipitating a colloid of the salts by addition of other
salts to the solution which react with some or all of the first metal
salts. The compositions can be incorporated into articles or can be
employed as a coating on articles such as medical devices. Coatings may
be on all or part of a surface.
| Inventors: |
Terry, Richard N.; (Conyers, GA)
|
| Correspondence Name and Address:
|
JOHN S. PRATT, ESQ
KILPATRICK STOCKTON, LLP
1100 PEACHTREE STREET
SUITE 2800
ATLANTA
GA
30309
US
|
| Serial No.:
|
649595 |
| Series Code:
|
10
|
| Filed:
|
August 26, 2003 |
| U.S. Current Class: |
523/122; 524/403 |
| U.S. Class at Publication: |
523/122; 524/403 |
| Intern'l Class: |
C08K 003/10; C08K 003/00 |
Claims
What is claimed is:
1. A composition comprising: at least one polymer; and a colloid
comprising a salt or oxide of one or more oligodynamic metals; wherein
the salt or oxide of one or more oligodynamic metals inhibits microbial
adherence of one or more organisms to the composition.
2. The composition of claim 1 wherein the salt or oxide of one or more
oligodynamic metals creates a zone of inhibition to the one or more
pathogens when placed on a culture of the one or more pathogens.
3. The composition of claim 1 wherein the salt or oxide of one or more
oligodynamic metals does not create a zone of inhibition to the one or
more pathogens when placed on a culture of the one or more pathogens.
4. The composition of claim 1 wherein the salt or oxide of one or more
oligodynamic metals is a silver salt.
5. The composition of claim 1 wherein the silver salt is selected from
silver chloride, silver iodide, silver citrate, silver lactate, silver
acetate, silver propionate, silver salicylate, silver bromide, silver
ascorbate, silver laurel sulfate, silver phosphate, silver sulfate,
silver oxide, silver benzoate, silver carbonate, silver sulfadiazine, and
silver gluconate.
6. The composition of claim 1 wherein the colloid comprises the salt of
more than one oligodynamic metal.
7. The composition of claim 1 wherein the one or more oligodynamic metal
salts comprise salts having different solubilities in water.
8. The composition of claim 1 wherein the at least one polymer is selected
from polyurethanes, polyvinylpyrrolidones, polyvinyl alcohols,
polyethylene glycols, polypropylene glycols, polyoxyethylenes,
polyacrylic acid, polyacrylamide, carboxymethyl cellulose, dextrans,
polysaccharides, starches, guar, xantham and other gums, collagen,
gelatins, biological polymers, polytetrafluoroethylene, polyvinyl
chloride, polyvinylacetate, poly(ethylene terephthalate), silicone,
polyesters, polyamides, polyureas, styrene-block copolymers, polymethyl
methacrylate, polyacrylates, acrylic-butadiene-styrene copolymers,
polyethylene, polystyrene, polypropylene, natural and synthetic rubbers,
acrylonitrile rubber, cellulose, and mixtures, derivatives, and
copolymers thereof.
9. The composition of claim 1 wherein the silver salt is silver chloride
and the composition contains silver chloride present in an amount between
about four and about six percent based on the total weight of solids in
the composition.
10. An article comprising the composition of claim 1.
11. The article of claim 10, wherein the article comprises a substrate
material and a coating on at least part of one or more surfaces of the
substrate material and the coating comprises the composition.
12. The article of claim 11 wherein the coating covers part of at least
one surface of the substrate and does not cover another part of the
surface.
13. The article of claim 12 wherein the part of the surface that is not
covered is sufficiently transparent to allow visual inspection of the
interior of the article.
14. The article of claim 11 wherein the coating comprises multiple coating
layers.
15. The article of claim 10 wherein the article comprises a medical
device.
16. The article of claim 10 wherein the one or more salt or oxides of
oligodynamic metals are present in a concentration of between about 10
and about 15 micrograms per square centimeter of surface area of the
articles.
17. A method for the manufacture of an article comprising the steps of (1)
forming a solution, dispersion, or combination thereof comprising the
composition of claim 1; and (2) drying the solution to create a solid
polymeric article.
18. A method for the manufacture of an article comprising the steps of:
(1) forming the composition of claim 1; (2) drying the composition; and
(3) processing the composition with the application of heat to form the
article.
19. A method for the manufacture of an article comprising the steps of (1)
forming the composition of claim 1; (2) compounding the composition
formed in (1) with one or more polymers; and (3) processing the
composition formed in (2) with the application of heat to form the
article.
20. A method for the manufacture of an article comprising dipping a form
in the composition of claim 1.
21. A method for the manufacture of an article comprising casting the
composition of claim 1 into a preselected shape.
20. A method for delivery of one or more oligodynamic metals, salts of
oligodynamic metals, oxides of oligodynamic metals, or combinations
thereof to a desired location comprising: providing the composition of
claim 1, and implanting, administering, inserting, or otherwise placing
the composition under conditions effective to deliver oligodynamic
metals, salts of oligodynamic metals, oxides of oligodynamic metals, or
combinations thereof, to the desired location.
21. A method of treatment of a cell, tissue, or organism, comprising
implanting, administering, inserting, or otherwise placing the
composition of claim 1 under conditions effective to deliver one or more
oligodynamic metals, salts of oligodynamic metals, oxides of oligodynamic
metals, or combinations thereof to the cell, tissue, organism, or a
portion of the cell, tissue, or organism.
22. The use of the composition of claim 1 in the preparation of an article
or medicament for delivery of one or more oligodynamic metals, salts of
oligodynamic metals, oxides of oligodynamic metals, or combinations
thereof to the cell, tissue, organism, or a portion of the cell, tissue,
or organism.
Description
PRIOR RELATED APPLICATIONS
[0001] This application is a continuation-in-part application of U.S.
patent application Ser. No. 09/461,846, filed Dec. 15, 1999. This
application also claims the benefit of U.S. provisional patent
application serial No. 60/405,936, filed Aug. 26, 2003, U.S. provisional
patent application serial No. 60/406,343, filed Aug. 26, 2002, U.S.
provisional patent application serial No. 60/406,384, filed Aug. 26,
2002, U.S. provisional patent application serial No. 60/406,496, filed
Aug. 28, 2002, and U.S. provisional patent application serial No.
60/406,497, filed Aug. 28, 2002.
FIELD OF THE INVENTION
[0002] The present invention relates generally to polymer compositions and
their use for making or coating articles, such as medical devices. More
specifically the invention relates to antimicrobial compositions
containing a polymer and oligodynamic salts. Further, the present
invention relates to compositions containing active agents as well as
oligodynamic salts and their use.
BACKGROUND OF THE INVENTION
[0003] For many years silver and silver salts have been used as
antimicrobial agents. An early medicinal use of silver was the
application of aqueous silver nitrate solutions to prevent eye infection
in newborn babies. Silver salts, colloids, and complexes have also been
used to prevent and to control infection. For example, colloidal metallic
silver has been used topically for conjunctivitis, urethritis, and
vaginitis.
[0004] Other metals, such as gold, zinc, copper, and cerium, have also
been found to possess antimicrobial properties, both alone and in
combination with silver. These and other metals have been shown to
provide antimicrobial behavior even in minute quantities, a property
referred to as "oligodynamic."
[0005] Additionally, silver is known for antimicrobial use with medical
devices, such as catheters, cannulae, and stents. One conventional
approach for obtaining antimicrobial medical devices is the deposition of
metallic silver directly onto the surface of the substrate, for example,
by vapor coating, sputter coating, or ion beam coating. However, these
noncontact deposition coating techniques suffer many drawbacks. These
drawbacks include poor adhesion, lack of coating uniformity, and the need
for special processing conditions, such as preparation in darkness due to
the light sensitivity of some silver salts. One particular drawback of
these coatings is that the processes by which the coatings are formed do
not adequately coat hidden or enclosed areas, such as the interior lumen
of a catheter or stent. Additionally, these methods produce coatings that
are very much like metallic silver in that they do not release silver
from the coating and require contact with the coating to provide
antimicrobial action. Though high concentrations of silver may be
deposited on the substrate, very little free ionic silver is released on
exposure to aqueous fluid. As a result, these coatings provide only
limited antimicrobial activity. They essentially retard colonization of
microbial agents on the surface of the device. However, because they do
not release sufficient silver ions into aqueous fluids, they offer little
or no protection from bacteria carried into the body upon insertion of
the device and do not inhibit infection in the surrounding tissue.
[0006] Another method of coating silver onto a substrate involves
deposition or electrodeposition of silver from solution. Drawbacks of
these methods include poor adhesion, low silver pick-up on the substrate,
the need for surface preparation, and high labor costs associated with
multistep dipping operations usually required to produce the coatings.
Adhesion problems have been addressed by inclusion of deposition agents
and stabilizing agents, such as gold and platinum metals, or by forming
chemical complexes between a silver compound and the substrate surface.
However, inclusion of additional components increases the complexity and
cost of producing such coatings.
[0007] With many medical devices, it is preferred to have a lubricious
coating on the device. Lubricious coatings aid device insertion, reduce
the trauma to tissue, and reduce the adherence of bacteria. Another
drawback to conventional methods which apply silver and other metals
directly onto the surface of a medical device for which a lubricious
coating is also desired is that a second, lubricious coating must be
applied to the device over the antimicrobial coating, adding to
manufacturing cost and time.
[0008] Some of these coatings release, to varying degrees, silver ions
into the solution or tissue surrounding the substrate. However,
activation of such coatings often requires conditions that are not
suitable for use with medical implants, such as catheters, stents, and
cannulae. These conditions include abrasion of the coating surface,
heating to a temperature above 180.degree. C., contact with hydrogen
peroxide, and treatment with an electric current.
[0009] Another conventional approach for obtaining antimicrobial medical
devices is the incorporation of silver, silver salts, and other
antimicrobial compounds into the polymeric substrate material from which
the article is formed. An oligodynamic metal may be physically
incorporated into the polymeric substrate in a variety of ways. For
example, a liquid solution of a silver salt may be dipped, sprayed or
brushed onto the solid polymer, for example, in pellet form, prior to
formation of the polymeric article. Alternatively, a solid form of the
silver salt can be mixed with a finely divided or liquefied polymeric
resin, which is then molded into the article. Further, the oligodynamic
compound can be mixed with monomers of the material prior to
polymerization.
[0010] There are several disadvantages to this approach. One such
disadvantage is that larger quantities of the oligodynamic material are
required to provide effective antimicrobial activity at the surface of
the device. A second disadvantage is that it is difficult to produce
articles that allow for the release of the oligodynamic material because
most device polymers absorb little, if any, water to aid in the diffusion
and release of the oligodynamic material, resulting in articles that
provide only a limited antimicrobial effect.
[0011] Yet another approach for obtaining antimicrobial medical devices is
the incorporation of oligodynamic agents into a polymeric coating which
is then applied to the surface of the article. Typically, an oligodynamic
agent is incorporated into the coating solution in the form of a solution
or a suspension of particles of the oligodynamic agent. Problems
associated with this approach include poor adhesion of the coating to the
substrate, settling and agglomeration of the oligodynamic particles, and
inadequate antimicrobial activity over time.
[0012] Settling of particles of the oligodynamic agent occurs as a result
of the size and density of the particles. Settling of the particles from
such solutions can cause unpredictable changes in the concentration of
the oligodynamic agent in the composition. These changes in concentration
result in several drawbacks to producing commercial products. First,
unpredictable changes in the concentration of the oligodynamic agent make
it difficult to produce a composition having a specific concentration of
antimicrobial ions and, thus, a particular effectiveness. Additionally,
these changes make it difficult to produce multiple batches of the
composition having the same antibacterial concentration. Further, the
concentration of the antimicrobial ions can affect other properties of
the composition, such as its adhesive and lubricious properties.
Consistency of antimicrobial activity is essential in the production of
medical devices.
[0013] Another problem associated with particle suspensions is
agglomeration of the particles. Particle agglomeration produces larger
particle sizes which increases settling of particles from solution.
Additionally, the agglomeration of particles in suspensions and coating
solutions can produce particles in the coating that are large enough to
be noticeable to the touch on the coated surface. Articles produced using
such coatings have decreased patient comfort and, therefore, are
undesirable.
[0014] Many researchers have attempted to overcome these problems. For
example, U.S. Pat. No. 4,592,920 to Murtfeldt et al. discloses a process
that attempts to overcome the settling and agglomeration problems in the
art through the use of a comminuted metal having a particle size of 30
microns or less. The coating of the Murtfeldt patent, however, exhibits
several disadvantages. For example, the Murtfeldt coating exhibits poor
adhesion which is overcome by the use of the following methods. First,
the Murtfeldt patent recommends pretreatment of the catheter to leach
undesirable compounds that interfere with the bonding of the coating to
the surface of the catheter. Second, the Murtfeldt patent recommends the
use of a bridging compound, or primer, to attach the coating to the
surface of the catheter to increase adhesion. This adds an additional
manufacturing step to the fabrication of a coated device. In addition to
these disadvantages, it is likely that the process used to manufacture
and coat the catheters in Murtfeldt will result in settling and
agglomeration problems even with the use of silver having smaller
particle sizes.
[0015] U.S. Pat. No. 4,849,223 to Pratt et al. attempts to overcome
settling and agglomeration of the particles in his invention by using
solutions that contain high concentrations of polymer or monomer solids
and are, thus, viscous. Suspending particles in high viscosity coating
solutions containing high polymer solids is a common method for reducing
settling and agglomeration of the particles. The coatings made by this
method are usually very thick and, as a result, are often not uniform.
Thick coatings are also more costly, dry more slowly than thin coatings,
and are more difficult to manufacture. The coatings of the Pratt patent
also exhibit poor adhesion. To increase adhesion, the Pratt patent
recommends using coating materials which are similar to the substrate to
be coated, pretreating the surface of the substrate before the coating
composition is applied, or applying an additional coating layer between
the substrate and the coating.
[0016] U.S. Pat. No. 5,019,096 to Fox, Jr. et al. discloses a method for
increasing the antibacterial activity of silver by incorporating a
synergistic amount of chlorhexidine and a silver salt in a matrix-forming
polymer. The polymer is such that it allows for release of the
antimicrobial agent over an extended period of time. Fox, however, relies
on dispersation of silver particles into coating solutions and will be
susceptible to problems associated with particle settling and
agglomeration.
[0017] U.S. Pat. No. 4,677,143 to Laurin et al. discloses a method to
enhance release of the antimicrobial metal ions from the surface of a
device by incorporating the antimicrobial metal into a binder having a
low dielectric constant that coats or forms the device. The nature of the
binder allows the particles to form chain-like structures among
themselves. These chain-like structures allow the surface particles to
dissolve to provide an initial dose of the antimicrobial agent and to
create a pathway for interior particles to come to the surface to provide
additional doses of the antimicrobial agent over time. Laurin, however,
also relies on dispersation of silver particles into coating solutions
and is susceptible to problems associated with particle settling and
agglomeration.
[0018] U.S. Pat. No. 4,933,178 to Capelli discloses a polymer coating
containing an oligodynamic metal salt of a sulfonylurea. The Capelli
patent attempts to improve the solubility and stability of the
antimicrobial metal in the coating and to provide for the sustained
release of the antimicrobial agent by adding a carboxylic acid to the
coating composition. The particular carboxylic acids and the proportions
in which they are mixed determine the rate of release of the
antimicrobial agent from the polymer coating composition.
[0019] U.S. Pat. No. 5,848,995 to Walder discloses the solid phase
production of polymers containing AgCl as an antimicrobial agent. In the
Walder process, solid polymer pellets are first soaked in a solution of
silver nitrate which is absorbed into the pellets. The pellets are then
rinsed, dried, and soaked in a solution of a sodium chloride. The
chloride ions of the salt are absorbed into the polymer matrix of the
pellets where they react with the silver nitrate to form silver chloride.
The pellets are then rinsed, dried, and melt processed. The compositions
of the Walder patent are limited to hydrophilic polymers, must be
thermoformed, and do not contain other silver salts to provide multiple
release rates, or other oligodynamic or medicinal agents to enhance
antimicrobial effectiveness.
[0020] Therefore, there is a need in the art to provide a method for
rendering articles, such as medical devices, resistant to infection, on
the surface of the article, in tissue surrounding articles, or in both
locations. There is also a need in the art for compositions which can be
incorporated into articles to provide antimicrobial activity. Further,
there is a need for compositions which can be employed as coatings for
articles that exhibit improved adhesion. There is also a need for
compositions that overcome the solubility, settling, and agglomeration
problems of conventional oligodynamic compositions, and exhibit enhanced,
sustained release of oligodynamic agents. There is further a need for
compositions that allow delivery of one or more active agents to
locations.
SUMMARY OF THE INVENTION
[0021] Stated generally, the present invention comprises antimicrobial
compositions which in a first aspect provide the advantage of reduced
settling and agglomeration by producing a minimal particle size of the
oligodynamic salts in the compositions. The use of colloids in the
compositions also permits incorporation of higher quantities of
antimicrobial ions without the difficulties associated with the
suspensions used in the prior art.
[0022] In another aspect, the compositions of the present invention
provide the advantage of varying release kinetics for the active
oligodynamic ions due to the different water solubilities of the
different salts in the compositions. These varying release kinetics allow
for an initial release of oligodynamic ions that provides antimicrobial
activity immediately upon insertion, followed by a continual, extended
release of the oligodynamic ions from the composition, resulting in
sustained antimicrobial activity over time.
[0023] Stated somewhat more specifically, the present invention relates in
one aspect to compositions that comprise a polymer and a colloid
containing salts of one or more oligodynamic agents. In one disclosed
embodiment, the polymer is a hydrophilic polymer. In another disclosed
embodiment, the polymer is a hydrophobic polymer, while in yet another
embodiment, the polymer is a combination of these two types of polymers.
[0024] In one disclosed embodiment, the invention comprises one or more
salts of silver as the oligodynamic agent. In another embodiment, the
composition optionally contains additional salts of other oligodynamic
metals, such as zinc, gold, copper, cerium and the like. In yet another
embodiment, the composition optionally comprises additional salts of one
or more noble metals to promote galvanic action. In still another
embodiment, the composition optionally comprises additional salts of
platinum group metals such as platinum, palladium, rhodium, iridium,
ruthenium, osmium, and the like.
[0025] In a further aspect, the compositions optionally contain other
components that provide beneficial properties to the composition, that
improve the antimicrobial effectiveness of the composition, or that
otherwise serve as active agents to impart additional properties to the
compositions.
[0026] In another aspect, the present invention relates to a process for
producing these antimicrobial compositions. The process comprises the
formation of colloids of oligodynamic agents in solutions, dispersions,
or combinations of polymers solutions and dispersions. The terms "polymer
composition" and "polymer solution" are used interchangeably throughout
the specification and claims and both means any polymer solution,
dispersion, or combination of polymer solutions and dispersions. The
colloid can be formed first and then added to the polymer composition or
can be formed in situ in the polymer composition. Preferably, the colloid
is formed in situ in the polymer composition.
[0027] The process of forming the colloids comprises, for example,
combining two or more salts, wherein at least one of the salts is the
salt of an oligodynamic agent. These salts will be referred to herein as
salt A and salt B. Salt A comprises one or more oligodynamic agents. Salt
B comprises one or more salts that can react with salt A to form a
colloid. Salts A and B can be combined in any amount and in any order. In
some embodiments, it is preferred that salt A be present in a
stoichiometric amount or in excess when compared to salt B. In some
embodiments, it is preferred that salt B be present in a stoichiometric
amount or in excess when compared to salt A.
[0028] Optionally, additional components can be added to the antimicrobial
compositions of the present invention. These components include, but are
not limited to, additional oligodynamic agents, additional soluble salts,
salts which provide galvanic action, and any other components which
provide the compositions with beneficial properties or enhance the
antimicrobial activity of the compositions. Such components include, but
are not limited to, antimicrobial agents, antibiotics, and other
medicinal agents.
[0029] In one disclosed embodiment, the antimicrobial composition of the
invention is produced by forming a solution, dispersion, or combination
of solutions and dispersions of one or more polymers. Next, a solution
comprising salt A is added to the polymer composition. Then, a solution
comprising salt B is added to the polymer composition to precipitate fine
colloidal salt(s) of the oligodynamic agent(s). Where the oligodynamic
agent is a metal salt, the metal cation of salt A reacts with the anion
of salt B to form a less soluble salt which precipitates as a fine
colloid. Salt B is added to the polymer composition in an amount
sufficient to react with some or all of salt A. Optionally, other salts
are then added in amounts to react with some or all of the remaining
amount of salt A.
[0030] In another disclosed embodiment, salt B is added to the polymer
composition, followed by the addition of an excess or stoichiometric
amount of salt A. In yet another embodiment, salts A and B can be
combined to form a colloid which is then added to the polymer
composition.
[0031] The final polymer composition formed by these processes contains
one or more colloidal salts, composed of the oligodynamic cations of salt
A and the anions of salt B, and one or more soluble salts, composed of
the anions of salt A and the cations of salt B.
[0032] The compositions are used to coat substrate materials. Thus,
another aspect of the invention is a coating containing the composition
of the invention. These coatings may comprise either a single layer or
multiple layers. The compositions of the present invention are used alone
or in combination with other polymer coatings to provide advantageous
properties to the surface of the substrate. These compositions are used,
for example to deliver pharmaceutical agents that, for example, prevent
infection, reduce encrustation, inhibit coagulation, improve healing,
inhibit restenosis, or impart antiviral, antifungal, antithrombogenic or
other properties to coated substrates.
[0033] The compositions are also used to inhibit algae, fungal, mollusk,
or microbial growth on surfaces. The compositions of the invention are
also used as herbicides, insecticides, antifogging agents, diagnostic
agents, screening agents, and antifoulants.
[0034] In another aspect, the present invention relates to an article of
manufacture which comprises the antimicrobial compositions of the present
invention. In one embodiment, the composition is used to form an article
or a portion of the article, for example by molding, casting, extrusion,
etc. Thus, at least part of the formed article is composed of one or more
of the compositions of the present invention, alone or in admixture with
other polymeric components. In another disclosed embodiment, the
composition is applied to a preformed article or part of an article as a
coating. The coated article may be produced, for example, by dipping the
article into the composition or by spraying the article with the
composition and then drying the coated article. In a preferred
embodiment, the compositions are used to coat medical devices.
[0035] It is therefore an object of the present invention to provide
compositions containing a polymer and a colloid wherein the colloid
contains a salt or oxide of an oligodynamic metal.
[0036] It is another object of the present invention to provide
compositions that provide antimicrobial, antibacterial, antiviral,
antifungal, or antibiotic activity or some combination thereof.
[0037] It is another object of the present invention to provide
compositions that, reduce encrustation, inhibit coagulation, improve
healing, inhibit restenosis, or impart antiviral, antifungal,
antithrombogenic or other properties to coated substrates.
[0038] It is yet another object of the present invention to provide
herbicidal or insecticidal compositions.
[0039] It is an object of the present invention to provide compositions
that inhibit the growth of algae, mollusks, bacterial, bioslime, or some
combination thereof on surfaces.
[0040] It is a further object of the present invention to provide
compositions for the delivery of active agents including, but not limited
to, pharmaceutical or therapeutic agents, growth factors, cytokines, or
immunoglobulins. It is yet another object of the invention to provide
compositions that comprise a silane copolymer and a biguanide.
[0041] It is a further object of the present invention to provide
compositions that comprise a silane copolymer and chlorhexidine or a salt
of chlorhexidine.
[0042] It is another object of the present invention to provide
compositions that comprise a silane copolymer and an antibiotic.
[0043] It is yet another object of the present invention to provide
topical compositions for the delivery of pharmaceutical agents.
[0044] It is a further object of the present invention to provide
compositions for the delivery of growth factors, cytokines, or
immunoglobulins.
[0045] It is a further object of the present invention to provide articles
comprising the compositions of the invention including, but not limited
to articles formed in whole or in part of the compositions and articles
coated in whole or in part with the compositions.
[0046] It is a further object of the present invention to provide methods
of making the compositions of the invention.
[0047] It is a further object of the present invention to provide methods
of making the articles of the invention.
[0048] It is a further object of the present invention to provide methods
of coating articles with the composition of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0049] FIG. 1 depicts an endotracheal tube partially coated with a coating
of the present invention. Part of the tube is not coated.
[0050] FIG. 2 shows the cumulative probability of the absence of
endotracheal tube colonization with P. aeruginosa and aerobic bacteria
among dogs receiving endotracheal tubes coated with a coating of the
present invention and that among dogs receiving uncoated tubes. The tubes
were involved in the dog intubation study in Example 16 herein.
[0051] FIG. 3 shows box plots of tissue bacterial concentrations for all
aerobic bacteria and P. aeruginosa for endotracheal tubes having a
coating of the present invention and for uncoated tubes. The tubes were
involved in the dog intubation study in Example 16 herein. Boxes
represent 25.sup.th to 75.sup.th percentiles with the 50.sup.th
percentile (solid line) shown within the boxes. The 10.sup.th and
90.sup.th percentiles are shown as capped bars.
[0052] FIG. 4 is a scatter plot of histology scores (x-axis) plotted
against the lung tissue concentration of total aerobic bacteria (y-axis).
The plotted data was generated by the dog intubation study in Example 16
herein. The regression line is shown.
[0053] FIG. 5 depicts plots of microbial adherence values of endotracheal
tubes coated with a coating of the present invention and uncoated
endotracheal tubes. The raw data upon which the plots are based appear in
Example 20 herein.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0054] The Composition
[0055] In a first aspect, the present invention provides antimicrobial
compositions. The compositions comprise a polymer and a colloid comprised
of the salts of one or more oligodynamic agents. The term "oligodynamic
agents" as used in the present invention refers to any compound that can
provide antimicrobial activity, even when present in small quantities.
[0056] Any polymer may be employed in the present invention, including
hydrophilic polymers, hydrophobic polymers, and mixtures of these two
types of polymers. The use of hydrophilic polymers is preferred because
such polymers have additional benefits. These benefits include increased
lubricity for patient comfort, increased absorption of aqueous fluids
from the body which aids in the release of oligodynamic ions from the
composition, inhibition of bacterial attachment, and improved solubility
for some metal salts. Hydrophilic polymers best suited to the invention
are those that are soluble in water or in organic solvents containing
water. The ability to add water to the polymer composition without
precipitating the polymer facilitates the addition of water-soluble salts
directly to the coating composition. Water facilitates the formation of
salt colloids within the polymer composition. For this reason, it is
preferred that the polymer solution contain from 1 to 50% water by
weight, more preferably from 5 to 30% water by weight.
[0057] However, the use of water is not limiting, as salt colloids can
also be formed using alcohols, organic solvents, or both that contain
little or no water. The use of alcohols and organic solvents, containing
from 0 to 1% water are preferred when hydrophobic polymers are employed
in the present invention.
[0058] Examples of polymers which may be used to form the compositions
include, but are not limited to, polyurethanes, including polyether
polyurethanes, polyester polyurethanes, polyurethaneureas, and their
copolymers; polyvinylpyrrolidones; polyvinyl alcohols; polyethylene
glycols and their copolymers; polypropylene glycols and their copolymers;
polyoxyethylenes and their copolymers; polyacrylic acid; polyacrylamide;
carboxymethyl cellulose; glycoproteins; proteoglycans;
glycosaminoglycans; lipoproteins; liposaccharides; cellulose and its
derivatives; dextrans and other polysaccharides; starches; guar; xantham
and other gums and thickeners; collagen; gelatins; other naturally
occurring polymers; polytetrafluoroethylene; polyvinyl chloride (PVC);
polyvinylacetate; poly(ethylene terephthalate); silicone; polyesters;
polyamides; polyureas; styrene-block copolymers; polymethyl methacrylate;
acrylic-butadiene-styrene copolymers; polyethylene; polystyrene;
polypropylene; natural and synthetic rubbers; acrylonitrile rubber; and
mixtures and copolymers of any of the above. The preferred polymer
depends upon the substrate to be coated. In some preferred, the polymer
is a polyurethanes and polyurethane copolymers, such as polyether
polyurethaneurea. In some embodiments, hydrophobic polymers that are
chemically similar or identical to the substrate are used alone or in
combination with hydrophilic polymers to form coatings that enhance
adhesion of the coating to the substrate.
[0059] The colloid of the present invention comprises one or more
oligodynamic salts. In the discussion of the process below, the
oligodynamic metal cations come from the salts referred to as salt A. In
a preferred embodiment, the oligodynamic salts comprise one or more salts
of oligodynamic metals. The salts may be different salts of the same
oligodynamic metal or may be salts of different oligodynamic metals.
Oligodynamic metals useful in the present invention include, but are not
limited to, silver, platinum, gold, zinc, copper, cerium, gallium,
osmium, and the like. The preferred oligodynamic metal is silver.
[0060] Salts of other metals may be employed to form the colloid. In the
discussion of the process below, these salts are referred to as salt B.
These salts contain cationic ions that include, but are not limited to,
calcium, sodium, lithium, aluminum, magnesium, potassium, manganese, and
the like, and may also include oligodynamic metal cations such as copper,
zinc, and the like. These salts contain anions that include, but are not
limited to, acetates, acetylsalicylates, ascorbates, benzoates,
bitartrates, bromides, carbonates, chlorides, citrates, folates,
carbonates, deoxycholates, gluconates, iodates, iodides, lactates,
laurates, oxalates, palmitates, para-aminobenzoates,
para-aminosalicylates, perborates, phenosulfonates, phosphates, picrates,
propionates, salicylates, stearates, succinates, sulfadiazines, sulfates,
sulfides, sulfonates, tartrates, thiocyanates, thioglycolates,
thiosulfates, and the like, as well as silver proteins and silver
ethylenediaminetetraacetic acid. The invention may also be practiced with
oxides serving as Salt B, including, but not limited to oxides of
calcium, sodium, lithium, aluminum, magnesium, potassium, manganese, and
the like, and may also include oligodynamic metal cations such as copper,
zinc, and the like.
[0061] The compositions can contain auxiliary components. Examples of such
auxiliary components include, but are not limited to, viscosity and flow
control agents, antioxidants, conventional pigments, air release agents
or defoamers, and discolorants. The composition may also contain
conventional dyes and pigments to impart color or radiopacity or to
enhance the aesthetic appearance of the compositions. The compositions
can also contain additional lubricating agents and other additives that
enhance patient comfort and tissue health.
[0062] While not wishing to be bound by the following mechanism, it is
believed that many of the advantageous properties of some embodiments of
the present compositions result from the differences in the solubility of
the different metal salts present in the colloid. These differing
solubilities of the metal salts in the colloid provide varying release
kinetics for the active oligodynamic metal(s). For example, with a
medical device composed of, or coated with, the compositions of the
present invention, those salts that have high water solubility will be
released from the coating rather quickly, providing a high initial dose
of antimicrobial activity to kill bacteria introduced upon insertion of
the device in the patient. This initial dose is sometimes referred to as
"quick kill," and this antimicrobial activity is identified by the
ability of a coated device or composition to create zones of no bacterial
growth around the device or composition when it is placed in a bacterial
culture. This test is known as a "zone of inhibition" assay. Those salts
having lower water solubilities will be released more slowly from the
composition, resulting in a sustained or extended antimicrobial activity
over time.
[0063] Selection of salts having varying degrees of solubility in the
composition allows tailoring of the composition to the specific
application of the article comprising the composition. In one embodiment,
compositions of the invention are tailored to kill bacteria introduced
during the insertion of a medical device, both on the surface of the
device and in the surrounding fluid and tissue, by the quick release of
antimicrobial metal salts, followed by prolonged inhibition of bacterial
migration and growth by the slower release of less soluble antimicrobial
metal salts over an extended period of time. In another embodiment, the
compositions contain silver salts with a very low solubility, thus
reducing the release of silver into the fluid surrounding the article in
order to reduce tissue exposure to silver ions while maintaining
inhibition of microbial adherence on the surface of the coated article.
The ability to tailor the release of the oligodynamic agent is
advantageous over conventional antimicrobial compositions, as it provides
for both immediate and sustained antimicrobial activity.
[0064] The composition may contain any amount of one or more oligodynamic
metal salts, oxides, or combination of salts and oxides. In some
embodiments, the composition contains between about 40% and about 50%
(based on weight of total solids in the composition) of the one or more
oligodynamic metal salts, oxides, or combination of salts and oxides. In
some embodiments, the composition contains between about 30% and about
40% (based on weight of total solids in the composition) of the one or
more oligodynamic metal salts, oxides, or combination of salts and
oxides. In some embodiments, the composition contains between about 20%
and about 30% (based on weight of total solids in the composition) of the
one or more oligodynamic metal salts, oxides, or combination of salts and
oxides. In some embodiments, the composition contains between about 15%
and about 25% (based on weight of total solids in the composition) of the
one or more oligodynamic metal salts, oxides, or combination of salts and
oxides. In some embodiments, the composition contains between about 10%
and about 20% (based on weight of total solids in the composition) of the
one or more oligodynamic metal salts, oxides, or combination of salts and
oxides. In some embodiments, the composition contains between about 5%
and about 15% (based on weight of total solids in the composition) of the
one or more oligodynamic metal salts, oxides, or combination of salts and
oxides. In some embodiments, the composition contains between about 3%
and about 8% (based on weight of total solids in the composition) of the
one or more oligodynamic metal salts, oxides, or combination of salts and
oxides. In some embodiments, the composition contains between about 4%
and about 6% (based on weight of total solids in the composition) of the
one or more oligodynamic metal salts, oxides, or combination of salts and
oxides. In some embodiments, the composition contains about 5% (based on
weight of total solids in the composition) of the one or more
oligodynamic metal salts, oxides, or combination of salts and oxides. In
some embodiments, the composition contains greater than zero and up to
about 5% (based on weight of total solids in the composition) of the one
or more oligodynamic metal salts, oxides, or combination of salts and
oxides. In some embodiments, the composition contains greater than zero
and up to about 2% (based on weight of total solids in the composition)
of the one or more oligodynamic metal salts, oxides, or combination of
salts and oxides. In some embodiments, the composition contains between
about 3% and about 4% (based on weight of total solids in the
composition) of the one or more oligodynamic metal salts, oxides, or
combination of salts and oxides. In some embodiments, the composition
contains about 2.5% (based on weight of total solids in the composition)
of the one or more oligodynamic metal salts, oxides, or combination of
salts and oxides. In some embodiments, the composition contains about 1%
(based on weight of total solids in the composition) of the one or more
oligodynamic metal salts, oxides, or combination of salts and oxides.
[0065] In some embodiments, coated articles will reduce adherence of one
or more bacteria, fungi, or other microbes to the article as compared to
uncoated articles. In one embodiment, the coating results in an in vitro
decrease in microbial adherence of 5-95%. In another embodiment, the
coating results in a decrease in microbial adherence of at least about
30%. In another embodiment, the coating results in a decrease in
microbial adherence of at least about 50%. In another embodiment, the
coating results in a decrease in microbial adherence of at least about
75%. In another embodiment, the coating results in a decrease in
microbial adherence of at least about 90%. In another embodiment, the
coating results in a reduction of at least about 95%. Embodiments exist
with any degree of reduction of adherence used. As used herein, reduction
of microbial adherence is determined using the procedures set forth in
EXAMPLE 18 herein.
[0066] In some embodiments, the coated articles have antimicrobial effects
upon surrounding tissues and fluids, as can be demonstrated through zone
of inhibition testing on one or more species or strains of bacteria,
fungi, or other microorganisms. Examples of antimicrobial effects
include, but are not limited to, inhibition of growth, killing, and any
other deleterious effect on microbes. In other embodiments, no zone of
inhibition is created. In still other embodiments, limited zones of
inhibition are created. Embodiments also exist in which zones of
inhibition are created for some strains in a species but not others, or
for some species but not others. Embodiments also exist in which zones of
inhibition differ between microbes. As used herein, zones of inhibition
is determined using the procedures set forth in EXAMPLE 19 herein. In one
desirable embodiment, an article is coated with a composition comprising
colloidal silver chloride. The resulting article reduces or eliminates
adherence of microbes on the surface of the endotracheal tube but
releases silver to surrounding tissues at such a slow rate due to the low
solubility of silver chloride that the article does not produce zones in
the zone of inhibition assay.
[0067] By tailoring the release profile of the oligodynamic metals, it is
possible to develop any article having any combination of antimicrobial
effects on the surface and surrounding tissues and fluids. Thus, any of
the above combinations of effects are achieved. For example, in some
embodiments microbial adherence of a specific species or strain of
organisms is reduced (including any of the % reductions noted above)
while these embodiments produce little or no zone of inhibition for the
same species or strain. Embodiments also exist in which both zone of
inhibition and microbial adherence differ between organisms.
[0068] In some embodiments, the use of the coatings reduces the risk of
infection. This action can operate by affecting the surface of the
article, affecting surrounding tissues and fluids, or both. For example,
use of endotracheal tubes containing a coating of the present invention
resulted in reduction of pneumonia occurrence as compared to uncoated
tubes. This reduction occurs even though tubes with a similar or the same
coating show limited or substantially no zone of inhibition in in vitro
testing for the microbes administered to test subjects.
[0069] The present invention further comprises methods of treatment and
delivery of substances as well as devices in which anywhere from 5-100%
of the oligodynamic metals in the compositions are released in the first
24 hours. A variety of release profiles from a single type of article are
therefore achieved. In some embodiments, between 75% and 100% of the
oligodynamic metal in the coating is released in the first 24 hours. In
other embodiments, between 50% and 75% of the oligodynamic metal in the
coating is released in the first 24 hours. In other embodiments, between
25% and 50% of the oligodynamic metal in the coating is released in the
first 24 hours. In other embodiments, between 0% and 25% of the
oligodynamic metal in the coating is released in the first 24 hours. In
other embodiments, about 75% of the oligodynamic metal is released in the
first 24 hours. In other embodiments, about 75% of the oligodynamic metal
is released in the first 24 hours. In other embodiments, about 40% of the
oligodynamic metal is released in the first 24 hours. Other embodiments
involve releases over a longer period of time. In one embodiment, about
38% is released the first day, and about 80% of the oligodynamic metal is
release within 21 days. As used herein, release is determined using the
procedures set forth in the elution tests in EXAMPLE 20 herein.
[0070] Another advantage of the coating compositions is the wet
coefficients of friction (COF) achievable. Coating compositions are
manipulated so that highly lubricious coatings are made or hydrophilic
coatings with little lubricity are made. Embodiments exist with any
achievable COF value. In some medical device embodiments, intermediary
COF values ranging between about 0.100 and about 0.0300 are used to
reduce the risk of unwanted slippage or movement of a coated article
after placement in a location in the body such as a cavity or lumen while
providing enough hydrophilicity to reduce tissue irritation and
inflammation. In other embodiments where a highly lubricious surface is
desired, a COF ranging between about 0.040 and about 0.060 (after one
hour immersion in water) is achieved. In some embodiments, a COF ranging
between about 0.300 and about 0.400 (after one hour immersion in water is
achieved. In other embodiments, a COF ranging between about 0.100 and
about 0.200 after one hour immersion is achieved. In other embodiments, a
COF ranging between about 0.200 and about 0.300 after one hour immersion
is achieved.(0.04-0.06) and a not so lubricious (0.1-0.3) and leave it at
that. In another embodiment, a COF ranging between about 0.337 and about
0.373 after one hour immersion is achieved. In other embodiments, a COF
ranging between about 0.040 and about 0.060 after one hour immersion is
achieved. In other embodiments, a COF ranging between about 0.100 and
about 0.300 after one hour immersion is achieved. As used herein, COFs
are determined using the procedures set forth in EXAMPLE 21 herein.
Although that example deals with endotracheal tubes, it may be used for
any coated surface having the same dimensions.
[0071] Another advantage of the compositions of the present invention is
that the formation of colloids within the polymer composition produces
ultra-fine particles that possess a minimal particle size for the metal
salts. This minimal particle size retards settling and agglomeration. The
use of colloids in the composition also permits incorporation of higher
quantities of antimicrobial metal without the difficulties associated
with the suspensions used in the prior art.
[0072] By reducing or eliminating the problems associated with
conventional antimicrobial polymer compositions, the present invention
provides reproducible compositions having specific antimicrobial ion
concentration with a specific antimicrobial ion release profiles that can
be tailored through the specific salt combinations selected to provide
optimum antibiotic activity over an extended period of time. For example,
compositions of the invention can be tailored to release the bulk of
their oligodynamic agents within 5 days for a medical device with a short
term use in the body, such as a wound drain, within 14 days for a device
such as an endotracheal tube with an intermediary term use, or within 30
days for a device with a longer term use, such as a foley catheter.
Longer and shorter terms are possible.
[0073] The tailored delivery embodiment of the invention will now be
further described in terms of a polyurethane composition containing a
colloid of specific silver salts. It is to be understood that this is
simply an example of one embodiment of the invention and that one of
skill in the art, based upon the present disclosure, can pick and choose
salts having differing solubilities to provide a composition having a
suitable release profile for a particular purpose.
[0074] A coating solution is formed from a 4.7% solution of a polyether
polyurethane-urea block copolymer available from CardioTech
International, Inc. in a mixture of THF/alcohol in a 75/25 ratio by
weight. A sufficient quantity of 10% silver nitrate (AgNO.sub.3) solution
in water is added to the copolymer solution to produce a final silver
concentration of approximately 15%, based on the weight of coating solids
in the solution.
[0075] Aqueous solutions of sodium chloride, zinc iodide, sodium citrate,
sodium acetate, and sodium lactate (each 1.0% solutions) are added to the
copolymer solution in sufficient amounts for each salt to react with 15%
of the silver nitrate present in the composition. Colloids of silver
chloride, silver iodide, silver citrate, silver acetate, and silver
lactate are formed in the final coating composition. The coating
composition also contains 25% unreacted soluble silver nitrate, as well
as the silver nitrate and zinc nitrate salt products. The differences in
the solubility of the different salts in the composition will result in
different and prolonged rates of release of the oligodynamic silver in
the coating composition when a device coated with the composition is
exposed to body fluid.
[0076] Silver nitrate is the most soluble of the salts present in the
composition and will be released rapidly upon initial exposure of the
coating to body fluid. Sodium lactate, which has a lower solubility than
silver nitrate but a higher solubility than the other salts present, will
be released next. Then, the silver acetate, followed by the silver
citrate, and then the silver chloride, and, lastly, the silver iodide
will be released from the coating composition based upon their relative
solubilities.
[0077] The initial release and the duration of release of the oligodynamic
agents from the composition depends upon several factors. These factors
include the relative water solubilities of the particular salts formed in
the colloid and the concentration of the salts in the colloid. This
release can range, for example, from a few days to several months, and
can be tailored through the choice and number of salts formed in the
composition for the intended purpose of the device to be coated.
[0078] The compositions of the invention can also be tailored to provide
other desired properties, such as surface lubricity. Further, the
compositions may contain other medicinal or otherwise beneficial agents.
[0079] Incorporation of Additional Active Agents into the Copolymer
[0080] In some embodiments, the compositions of the present invention
contain one or more additional active agents in addition to the
oligodynamic metal salts or oxides. The active agents are either retained
in the composition or released from the composition at a desired rate or
having a desired release profile. Nonlimiting examples of such active
agents include antimicrobial agents, such as antibacterial agents, immune
boosting agents, anticancer agents, angiogenic agents, polymyxins,
antifungal agents, antiviral agents and antibiotics; growth factors,
cytokines, immunoglobulins, pharmaceuticals, nutraceuticals, angiostatic
agents, including, but not limited to, antithrombogenic agents,
antitumoral agents, growth factors, antiangiogenic agents, spermicides,
anesthetics, analgesics, vasodilation substances, wound healing agents,
plant extracts, and other therapeutic and diagnostic agents. Other active
agents useful in the present invention include herbicides, insecticides,
algaecides, antifoulants, antifogging agents, and UV and other screening
agents. Of these agents, those which can be used for medical applications
are preferred. The compositions can also contain salts of metals that
enhance the antimicrobial effect of the oligodynamic metal, such as the
platinum group metals, or other metals that promote galvanic action. In
some embodiments, the combination of additional antimicrobial compounds
with oligodynamic metal compounds provide for enhanced antimicrobial
activity, for example, by resulting in synergistic antimicrobial
activity.
[0081] The active agent is advantageously present in the composition in
any amount. Desirable amounts include from about 0.1% to about 50% of the
dry weight of the composition. Preferred amounts of the active agent are
1% to 30% of the composition based upon the dry weight of the
composition.
[0082] The following agents have antimicrobial, antibacterial, antiviral,
or antifungal activity and are examples of the types of agents that can
accompany the polymer and colloid in the composition of the present
invention. It will be understood by one of ordinary skill in the art that
these are nonlimiting examples and that other active agents can be
incorporated into the copolymers of the present invention in a manner
similar to the incorporation of the specifically recited agents.
[0083] The compositions of the present invention can also contain
additional components. For example, the compositions can contain salts of
metals that enhance the antimicrobial effect of the oligodynamic metal,
such as the platinum group metals, or other metals that promote galvanic
action. Further, the composition can include agents that affect the
release of the oligodynamic metal.
[0084] In some embodiments, the active agent comprises one or more
biguanides, many of which have antimicrobial, antiviral, antibacterial,
or antifungal activity, or some combination thereof. As used herein, the
term "biguanide" includes poly (hexamethylene biguanide) hydrochloride
and chlorhexidine compounds. Chlorhexidine is the term denoting the
chemical compound N,N"-bis(4-chlorophenyl)-3,12-diimino-2,4,11,13-Tetraaz-
atetradecanediimidamide (CAS registry number 55-56-1). Chlorhexidine
compounds include chlorhexidine free base as well as chlorhexidine salts,
including but not limited to chlorhexidine diphosphanilate, chlorhexidine
digluconate, chlorhexidine diacetate, chlorhexidine dihydrochloride,
chlorhexidine dichloride, chlorhexidine dihydroiodide, chlorhexidine
diperchlorate, chlorhexidine dinitrate, chlorhexidine sulfate,
chlorhexidine sulfite, chlorhexidine thiosulfate, chlorhexidine di-acid
phosphate, chlorhexidine difluorophosphate, chlorhexidine diformate,
chlorhexidine dipropionate, chlorhexidine di-iodobutyrate, chlorhexidine
di-n-valerate, chlorhexidine dicaproate, chlorhexidine malonate,
chlorhexidine succinate, chlorhexidine succinamate, chlorhexidine malate,
chlorhexidine tartrate, chlorhexidine dimonoglycolate, chlorhexidine
mono-diglycolate, chlorhexidine dilactate, chlorhexidine
di-.alpha.-hydroxyisobutyrate, chlorhexidine diglucoheptonate,
chlorhexidine di-isothionate, chlorhexidine dibenzoate, chlorhexidine
dicinnamate, chlorhexidine dimandelate, chlorhexidine di-isophthalate,
chlorhexidine isoethionate chlorhexidine di-2-hydroxy-napthoate, and
chlorhexidine embonate. Preferred chlorhexidine salts include the
acetates, formates, gluconates, hydrochlorides, isoethionates, lactates,
and succinamates of chlorhexidine. These biguanide compounds are known in
the art and can be prepared by conventional methods. Numerous other
biguanides are known and contemplated for use by the present invention.
Biguanides can also form polymers. Use of these biguanide polymers is
also contemplated by the present invention.
[0085] Chlorhexidine is one preferred active agent because it also
provides antimicrobial activity. Any effective amount of chlorhexidine
can be used. In some embodiments, chlorhexidine is used in an amount
greater than zero 0 and up to about 50% based on total solids in the
composition by weight. In some embodiments, chlorhexidine is used in an
amount greater than 0 and up to about 10% based on total solids in the
composition by weight. In some embodiments, chlorhexidine is used in an
amount between about 10% and about 50% based on total solids in the
composition by weight. In some embodiments, chlorhexidine is used in an
amount between about 2 and about 10% based on total solids in the
composition by weight. In some embodiments, chlorhexidine is used in an
amount between about 10% and about 20% based on total solids in the
composition by weight. In some embodiments, chlorhexidine is used in an
amount between about 20% and about 30% based on total solids in the
composition by weight. In some embodiments, chlorhexidine is used in an
amount between about 20% and about 30% based on total solids in the
composition by weight. In some embodiments, chlorhexidine is used in an
amount between about 25% and about 50% based on total solids in the
composition by weight. In some embodiments, chlorhexidine is used in an
amount between about 30% and about 40% based on total solids in the
composition by weight. In some embodiments, chlorhexidine is used in an
amount between about 40% and about 50% based on total solids in the
composition by weight.
[0086] In some embodiments, the active agent comprises one or more
chlorinated phenols, many of which have antimicrobial, antibacterial,
antiviral, or antifungal activity, or some combination thereof.
Chlorinated phenol compounds which may be used according to the invention
include but are not limited to parachlorometaxylenol,
dichlorometaxylenol, triclosan (2,4,4'-trichloro-2 hydroxy di-phenyl
ether), 2-chlorophenol, 3-chlorophenol, 4-chlorophenol,
2,4-dichlorophenol, 2,4,6-trichlorophenol, 2,3,4,6-tetrachlorophenol,
pentachlorophenol, 4-chlororesorcinol, 4,6-dichlororesorcinol,
2,4,6-trichlororesorcinol, alkylchlorophenols (including
p-alkyl-o-chlorophenols, o-alkyl-p-chlorophenols, dialkyl-4-chlorophenol,
and tri-alkyl-4-chlorophenol), dichloro-m-xylenol, chlorocresol,
o-benzyl-p-chlorophenol, 3,4,6-trichlorphenol, 4-chloro-2-phenylphenol,
6-chloro-2-phenylphenol, o-benzyl-p-chlorophenol, and
2,4-dichloro-3,5-diethylphenol. Preferred chlorinated phenols include
triclosan and parachlorometaxylenol.
[0087] In some embodiments, the active agent comprises one or more
quaternary ammonium compounds including but not limited to monomeric and
polymeric quaternary ammonium compounds, many of which have
antimicrobial, antibacterial, antiviral, or antifungal activity or some
combination of the foregoing activities. Examples of quaternary ammonium
compounds include, but are not limited to, benzalkonium chloride,
benzethonium chloride, other benzalkonium or benzethonium halides,
cetylpyridinium chloride, dequalinium chloride, N-myristyl-N-methylmorpho-
linium methyl sulfate, poly[N-[3-(dimethylammonio)propyl]-N'-[3-(ethyleneo-
xyethylene dimethylammonio)propyl]urea dichloride],
alpha-4-[1-tris(2-hydroxyethyl)ammonium chloride-2-butenyl]-omega-tris(2--
hydroxyethyl)ammonium chloride, alpha-4-[1-tris(2-hydroxyethyl)ammonium
chloride-2-butenyl]poly[1-dimethyl ammonium chloride-2-butenyl]-omega-tri-
s(2-hydroxyethyl)ammonium chloride, poly [oxy-ethylene(dimethyliminio)ethy-
lene (dimethyliminio)-ethylene dichloride], ethyl hexadecyl dimethyl
ammonium ethyl sulfate, dimethyl ammonium ethyl sulfate,
dimethylethylbenzyl ammonium chloride, dimethylbenzyl ammonium chloride,
and cetyldimethylethyl ammonium bromide. One preferred quaternary
ammonium compound is benzalkonium chloride.
[0088] In a further embodiment, the active agent comprises typical
antimicrobial agents, growth factors, cytokines, immunoglobulins, or
pharmaceuticals and nutraceuticals. Typical active agents that are useful
in the present invention as antimicrobial, antiinfective, antiviral, and
antibacterial agents include, but are not limited to, alexidine,
aminoglycosides (such as gentamicin and Tobramycin), amoxicillin,
amphotericin, ampicillin, bacitracin, beclomethasone, benzocaine, benzoic
acid, beta-lactams such as pipracil and aztneonam, betamethasone, biaxin,
cephalosporins such as ceftazidime, cetrimide, chloramphenicol,
clarithromycin, clotrimazole, cyclosporin, docycline, erythromycin,
ethylenediamine tetraacetic acid (EDTA), furazolidine, fusidic acid, ,
gramicidin, iodine and iodine complexes such as povidone iodine and
pluronic-iodine complex, macrolides, miconazole, minocycline, neomycin,
nystatin, octenidine hydrochloride, ofloxacin, parachlorometaxylene,
penicillin, pentoxifylline, phenolic compounds (e.g., orthophenylphenol),
phenoxymethylpenicillin, picloxydine, polymixin, quinolone antibiotics
(such as Norfloxacin, oxolinic acid, ciprofloxacin; Pefloxacin, Enoxacin,
AM-833, Pipemidic acid and Piromidic acid, 6,8-difluoro-1-(2-fluoroethyl)-
-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-quinoline-3-carboxylic acid,
naladixic acid, and salts thereof) rifampicin, sorbic acid, sulfamylon,
sulfonamides, tetracycline, triclocarban, vancomycins, zithromax,
derivatives, metabolites, and mixtures thereof, or compounds having
similar antimicrobial activity.
[0089] Growth factors useful in the present invention include, but are not
limited to, transforming growth factor-.alpha. ("TGF-.alpha."),
transforming growth factor-.beta.("TGF-.beta."), vascular epithelial
growth factor ("VEGF"), basic fibroblast growth factor, insulin-like
growth factor (IGF), vascular endothelial growth factor (VEGF) and
mixtures thereof. Cytokines useful in the present invention include, but
are not limited to, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9,
IL-10, IL-11, IL-12, IL-13, TNF-.alpha., and TNF-.beta.. Immunoglobulins
useful in the present invention include, but are not limited to, IgG,
IgA, IgM, IgD, IgE, and mixtures thereof.
[0090] Some other specific examples of pharmaceutical agents that are
useful as active agents include, but are not limited to, nonoxynol 9,
acebutolol, acetylcysteine, acetylsalicylic acid, acyclovir, AZT,
alprazolam, alfacalcidol, allantoin, allopurinol, ambroxol, amikacin,
amiloride, aminoacetic acid, aminodarone, amitriptyline, amlodipine,
ascorbic acid, aspartame, astemizole, atenolol, benserazide, bezafibrate,
biotin, biperiden, bisoprolol, bromazepam, bromhexine, bromocriptine,
budesonide, bufexamac, buflomedil, buspirone, caffeine, camphor,
captopril, carbamazepine, carbidopa, carboplatin, cefachlor, cefalexin,
cefatroxil, cefazolin, cefixime, cefotaxime, ceftazidime, ceftriaxone,
cefuroxime, selegiline, chloramphenicol, chlor-pheniramine,
chlortalidone, choline, cilastatin, cimetidine, cisapride, cisplatin,
clavulanic acid, clomipramine, clozapine, clonazepam, clonidine, codeine,
cholestyramine, cromoglycic acid, cyanocobalamin, cyproterone,
desogestrel, dexamethasone, dexpanthenol, dextromethorphan,
dextropropoxiphen, diazepam, diclofenac, digoxin, dihydrocodeine,
dihydroergotamine, dihydroergotoxin, diltiazem, diphenhydramine,
dipyridamole, dipyrone, disopyramide, domperidone, dopamine, doxycycline,
enalapril, ephedrine, epinephrine, ergocalciferol, ergotamine, estradiol,
ethinylestradiol, etoposide, Eucalyptus globulus, famotidine, felodipine,
fenofibrate, fenoterol, fentanyl, flavin mononucleotide, fluconazole,
flunarizine, fluorouracil, fluoxetine, flurbiprofen, furosemide,
gallopamil, gemfibrozil, Gingko biloba, glibenclamide, glipizide,
Glycyrrhiza glabra, grapefruit seed extract, grape seed extract,
griseofulvin, guaifenesin, haloperidol, heparin, hyaluronic acid,
hydrochlorothiazide, hydrocodone, hydrocortisone, hydromorphone,
ipratropium hydroxide, ibuprofen, imipenem, indomethacin, iohexol,
iopamidol, isosorbide dinitrate, isosorbide mononitrate, isotretinoin,
ketotifen, ketoconazole, ketoprofen, ketorolac, labetalol, lactulose,
lecithin, levocamitine, levodopa, levoglutamide, levonorgestrel,
levothyroxine, lidocaine, lipase, imipramine, lisinopril, loperamide,
lorazepam, lovastatin, medroxyprogesterone, menthol, methotrexate,
methyldopa, methylprednisolone, metoclopramide, metoprolol, miconazole,
midazolam, minocycline, minoxidil, misoprostol, morphine,
N-methylephedrine, naftidrofuryl, naproxen, nicardipine, nicergoline,
nicotinamide, nicotine, nicotinic acid, nifedipine, nimodipine,
nitrazepam, nitrendipine, nizatidine, norethisterone, norfloxacin,
norgestrel, nortriptyline, omeprazole, ondansetron, pancreatin,
panthenol, pantothenic acid, paracetamol, phenobarbital, derivatives,
metabolites, and other such compounds have similar activity. It should be
noted that for any term in the foregoing paragraphs that is expressed as
a singular term but is sometimes interpreted as describing a class of
compounds shall mean any of the group of compounds (e.g. all
tetracyclines, all erythromycins, etc.)
[0091] Other pharmaceutical agents useful in the present invention
include, but are not limited to, other antibacterial, antiviral,
antifungal, or antiinfective agents, antithrombogenic agents,
anti-inflammatory agents, antitumoral agents, antiangiogenic agents,
spermicides, anesthetics, analgesics, vasodilation substances, wound
healing agents, other therapeutic and diagnostic agents, and mixtures of
these.
[0092] In another embodiment, the active agent comprises one or more
herbicide, insecticide, algaecide, antifoulant, antifogging agent, or UV
or other screening agent.
[0093] The compositions of the present invention can contain any
combination of these or other active agents. The compositions can also
contain additional components such as colorants, discoloration
inhibitors, agents that affect the release or rate of release of the
active agent, surfactants, adhesion agents, agents that enhance the
activity of the active agent, solubilizing agents, agents that enhance
the lubricity of the compositions, and other agents which provide
beneficial properties to the compositions.
[0094] In some embodiments, the compositions contain combinations of two
or more of the active agents. Any combination that produces desired
results may be used. Some include (along with the polymer and
oligodynamic metal colloid): a combination of a biguanide (especially a
chlorhexidine compound), a quaternary ammonium compound and a chlorinated
phenol (for example, chlorhexidine with benzalkonium chloride and
parachlorometaxylenol or triclosan); triclosan and another agent (for
example ramicidin, polymixin, norfloxacin, sulfamylon, polyhexamethylene
biguanide, alexidine, minocycline, iodine, benzalkonium chloride and
rifampicin); chlorhexidine plus triclosan (optionally with silver
sulfadiazine either as a part of the colloid or in addition to the
colloid); combinations including a chlorhexidine free base and triclosan
or a complex resulting from the combination of those two agents. Other
examples include silver sulfadiazine (either as a part of the colloid or
in addition to the colloid) and sodium piperacillin; silver sulfonamides
(either as a part of the colloid or in addition to the colloid) with
piperacillin; silver (either as a part of the colloid or in addition to
the colloid) with a chlorinated phenol and another antiinfective or
antimicrobial agent.
[0095] Process for Preparing the Composition
[0096] In a second aspect, the present invention relates to a process for
producing the compositions of the invention. In general terms, the
process comprises the formation of colloids of oligodynamic agents in
polymer solutions. The colloid can be formed first and then added to the
polymer composition or can be formed in situ in the polymer composition.
Preferably, the colloid is formed in situ in the polymer composition.
[0097] The process of forming the colloids comprises, for example,
combining two or more salts, wherein at least one of the salts is the
salt of an oligodynamic agent. These salts will be referred to as salt A
and salt B. Salt A comprises one or more oligodynamic agents. Salt B
comprises one or more salts that can react with salt A to form a colloid.
Salts A and B can be combined in any amount and in any order. In some
embodiments, salt A is present in a stoichiometric amount or in excess
when compared to salt B. In some embodiments, salt B is present in a
stoichiometric amount or in excess when compared to salt A.
[0098] Optionally, additional components can be added to the compositions.
These components include, but are not limited to, additional oligodynamic
agents, additional soluble salts, salts which provide galvanic action,
and any other components which provide the compositions with beneficial
properties or enhance the antimicrobial activity of the compositions.
Such components include, but are not limited to, antimicrobial agents,
antibiotics, and other medicinal agents.
[0099] In one disclosed embodiment, the composition is produced by forming
a solution, dispersion, or combination of solutions and suspensions of
one or more polymers. Next, a solution comprising salt A is added to the
polymer composition. Then, a solution comprising salt B is added to the
polymer composition to precipitate fine colloidal salt(s) of the
oligodynamic agent(s) of salt A. Where the oligodynamic agent is a metal
salt, the metal cation of salt A reacts with the anion of salt B. Salt B
is added to the polymer composition in an amount sufficient to react with
some or all of salt A. Optionally, other salts are then added in amounts
to react with some or all of the remaining amount of salt A.
[0100] In another disclosed embodiment, salt B is added to the polymer
composition, followed by the addition of an excess or stoichiometric
amount of salt A. In yet another embodiment, salts A and B can be
combined to form a colloid which is then added to the polymer
composition.
[0101] The final polymer composition formed by these processes contains
one or more colloidal salts, composed of the oligodynamic cations of salt
A and the anions of salt B, and one or more soluble salts, composed of
the anions of salt A and the cations of salt B. Additionally, other salts
may be added to the composition that do not react in solution but provide
some beneficial effect such as stabilization of the colloid, modification
of antimicrobial ion release rate, promotion of galvanic action, increase
in antimicrobial effectiveness, or enhancement of biocompatibility.
Further, other compounds may be added to the composition, including, but
not limited to, medicinal agents, lubricants, nutritional agents,
antioxidants, dyes and pigments, and other additives.
[0102] As noted above, any polymer can be used to form the compositions of
the present invention. When hydrophilic polymers are used, it is
preferable that the polymers be soluble in water or in organic solvents
containing some water. The ability to add water to the polymer
composition without precipitating the polymer allows the addition of
water-soluble salts directly to the coating composition. The use of water
in the polymer composition increases the solubility of the salts,
resulting in the formation of finer, more stable colloids. However, it
takes longer for the coating compositions to dry when the water content
is very high. For this reason, the preferred amount of water in the
hydrophilic polymer compositions is about 50% or less. Such
concentrations provide for faster drying times while maintaining the
beneficial properties provided by the water in the composition.
[0103] In contrast, when hydrophobic polymers are used either alone or in
combination with hydrophilic polymers, it is desirable to limit the
amount of water present in the composition to avoid precipitation of the
hydrophobic polymer with the colloid. In such instances the amount of
water present in the polymer composition is preferably 1% or less. While
it is possible to practice the invention in the absence of water in the
composition, it is preferable to have some water present. Thus, when
hydrophobic polymers are employed in the present invention, the preferred
water content of the polymer compositions is between about 0.1% and 1% by
weight. It is advantageous to employ salts that are soluble in alcohols
or organic solvents when hydrophobic polymers employed.
[0104] Examples of water-soluble silver salts suitable for use in the
present invention include, but are not limited to, silver nitrate, silver
acetate and silver lactate. Persons skilled in the art will recognize
that many of the "Salt B" salts listed above are soluble in water and
suitable for use as a water-soluble salt herein. Examples of salts which
are soluble in alcohols and organic solvents include, but are not limited
to, silver nitrate, sodium iodide, sodium lactate, sodium propionate,
sodium salicylate, zinc chloride, zinc acetate, zinc salicylate, gold
trichloride, gold tribromide, palladium chloride and
hydrogen-hexachloroplatinate. Examples of alcohols that are useful in the
present invention include, but are not limited to, methanol, ethanol,
propanol, isopropanol, and butanol. Examples of organic solvents that can
be used to form solutions of the oligodynamic salts include, but are not
limited to, acetone, tetrahydrofuran (THF), dimethylformamide (DMF),
dimethlysulfoxide (DMSO), and acetonitrile. These organic solvents are
especially useful when they contain a small amount of water.
[0105] It is also possible to prepare polymer compositions from
supercritical fluids. The most common of these fluids is liquefied carbon
dioxide.
[0106] In a preferred embodiment, the polymer composition in which the
colloid is formed is a hydrophilic polyether polyurethaneurea. This
polymer is a substantially noncovalently crosslinked reaction product of
one or more diols, water and an organic diisocyanate. The urea segments
of the polymer provide improved strength, increased viscoelasticity, and
decreased water absorption. These polymers typically absorb water in
amounts from 50 to 100% their weight while remaining strong and elastic.
[0107] Diols useful in the formation of these polymers include, but are
not limited to, medium and long chain poly(oxyethylene) glycols having a
number average molecular weights between 250 and 20,000. Example of such
diols are "Carbowax" compounds sold by Union Carbide.
[0108] Organic diisocyanates useful to form these polymers include, but
are not limited to, tetramethylene diisocyanate, hexamethylene
diisocyanate, trimethylhexamethylene diisocyanate, dimer acid
diisocyanate, isophorone diisocyanate, diethylbenzene diisocyanate,
decamethylene 1,10-diisocyanate, cyclohexylene 1,2-diisocyanate,
cyclohexylene 1,4-diisocyanate, methylene bis(cyclohexyl-4-isocyanate),
2,4- and 2,6-tolylene diisocyanate, 4,4-diphenylmethane diisocyanate,
1,5-naphthaliene diisocyanate, dianisidine diisocyanate, tolidine
diisocyanate, xylylene diisocyanate, and tetrahydronaphthalene-1,5-diisoc-
yanate.
[0109] In another preferred embodiment, the polymer coating composition
comprises a combination of a hydrophilic polyurethane, a polymer that is
similar or identical to the polymer substrate to be coated, and,
optionally, other polymers which aid coating adhesion and physical
properties. Antimicrobial salt colloids are prepared in this composition
as disclosed previously, with the exception that, depending on the second
polymer used, some or all of the water used to prepare salt solutions can
be replaced with alcohols or other organic solvents to prevent
precipitation of the second polymer. Another exception is that the salts
elected must be soluble in solvents compatible with those in which the
polymers are soluble. As an example of this preferred embodiment, a
solution of a hydrophilic polyether polyurethaneurea in THF can be
combined with a solution of polyvinyl chloride (PVC) in methylene
chloride or THF in equal amounts. Then, silver nitrate can be dissolved
in ethanol and added to the solution without precipitation. Ethanol is
used to dissolve the silver nitrate instead of water because PVC has a
tendency to precipitate when water is added to the solution. Finally, a
dilute solution of zinc chloride in ethanol/water can be slowly added to
the polymer composition to produce a fine silver chloride colloid without
precipitation of the PVC. The final concentration of water in the coating
is less than 1%. The coating solution is then used to dip-coat PVC
catheters. The finished coating is well adhered, durable, lubricious when
wetted, and contains colloidal antimicrobial salts.
[0110] In another embodiment, the polymer composition comprises a
hydrophilic polymer as defined in application Ser. No. 09/189,240, filed
Nov. 10, 1998, herein incorporated by reference. In general, the polymer
is a polyurethane-urea-silane copolymer prepared from the following
ingredients: (1) one or more polyisocyanate, (2) one or more lubricious
polymer having at least two functional groups, which may be the same or
different and are reactive with an isocyanate functional group, and (3)
one or more organo-functional silanes having at least two functional
groups, which may be the same or different and are reactive with an
isocyanate functional group and another functional group that is reactive
with a silicone rubber substrate. While these copolymers may be prepared
in a variety of ways, preferably they may be prepared by first forming a
prepolymer from the polyisocyanate(s) and lubricious polymer(s) followed
by reaction with the organo-functional silane(s). A catalyst is
optionally employed during reaction of the isocyanate with the polyol.
[0111] Isocyanates useful to form these polymers include, but are not
limited to, 4,4'-diphenylmethane diisocyanate and position isomers
thereof, 2,4- and 2,6-toluene diisocyanate (TDI) and position isomers
thereof, 3,4-dichlorophenyl diisocyanate, dicyclohexylmethane-4,4'-diisoc-
yanate (HMDI), 4,4'-diphenylmethane diisocyanate (MDI), 1,6-hexamethylene
diisocyanate (HDI) and position isomers thereof, isophorone diisocyanate
(IPDI), and adducts of diisocyanates, such as the adduct of
trimethylolpropane and diphenylmethane diisocyanate or toluene
diisocyanate.
[0112] Polyols useful to form these polymers include, but are not limited
to, polyethylene glycols, polyester polyols, polyether polyols, castor
oil polyols, and polyacrylate polyols, including Desmophen A450,
Desmophen A365, and Desmophen A160 (available from Mobay Corporation),
poly(ethylene adipates), poly(diethyleneglycol adipates),
polycaprolactone diols, polycaprolactone-polyadipate copolymer diols,
poly(ethylene-terephthalate)diols, polycarbonate diols,
polytetramethylene ether glycol, ethylene oxide adducts of
polyoxypropylene diols, and ethylene oxide adducts of polyoxypropylene
triols.
[0113] Catalysts useful to form these polymers include, but are not
limited to, tertiary amines, such as N,N-dimethylaminoethanol,
N,N-dimethyl-cyclohexamine-bis(2-dimethyl aminoethyl) ether,
N-ethylmorpholine, N,N,N',N',N"-pentamethyl-diethylene-triamine, and
1-2(hydroxypropyl) imidazole, and metallic catalysts, such as tin,
stannous octoate, dibutyl tin dilaurate, dioctyl tin dilaurate, dibutyl
tin mercaptide, ferric acetylacetonate, lead octoate, and dibutyl tin
diricinoleate.
[0114] Silanes useful to form these polymers include, but are not limited
to, N-beta-(aminoethyl)-gamma-aminopropyl-trimethoxy silane and
diamino-alkoxysilanes, such as N-(2-aminoethyl)-3-aminopropylmethyl-dimet-
hoxy silane.
[0115] These polymers preferably have from 7 to 12% by weight silane based
upon the weight of the entire polymer. The preferred ratio of isocyanate
functional groups to alcohol or other isocyanate reactive functional
groups is from 1.1:1 to 2:1. Viscosity of the polymer solution is a
function of molecular weight of the polymer and the solids content of the
solution and is controlled by addition of solvent to the solution. The
preferred copolymer solution for dip coating has a kinematic viscosity in
the range of about 1.5 cS to about 20 cS (centistokes), and a solids
content in a range of about 0.4 to about 5.
[0116] In yet another embodiment, the polymer composition comprises a
solution of a hydrophilic polymer as defined in U.S. Pat. No. 5,290,585,
which is hereby incorporated by reference. The polymer is a
polyurethane-polyvinyl pyrrolidone prepared by mixing the appropriate
amounts of isocyanate, polyol, and polyvinyl pyrrolidone (PVP) stock
solution. Additional solvents can be added to adjust the viscosity and
solids content. Solids content may be in the range of 0.4 to 15% by
weight, depending on the solvent used and other considerations. The
stoichiometric ratio of total NCO groups in the isocyanate to total OH
groups in the polyol may vary from 0.75 to 3.0. Preferably, the
isocyanate has at least two NCO groups per molecule and the polyol has at
least two OH groups per molecule. The ratio of polyurethane formed in
situ to PVP ranges from 0.05 to 3.0 by weight.
[0117] The PVP employed to form these polymers preferably has a mean
molecular weight from about 50,000 to 2.5 million Daltons. Specific
preferred PVP polymers are Kollidon 90, Luviskol K90, Luviskol K80, and
Luviskol K60, all available from BASF Corp. (Parsippany, N.J.) and
Plasdone 90, PVP K90, and PVP K120, all available from GAF Corporation.
[0118] Isocyanates suitable to form these polymers include, but are not
limited to, polymethylenepolyphenyl isocyanate, 4,4'-diphenylmethane
diisocyanate and position isomers thereof, 2,4-tolylene diisocyanate and
position isomers thereof, 3,4-dichlorophenyl diisocyanate, isophorone
isocyanate, and adducts or prepolymers of isocyanates, such as the
isocyanate prepolymer available as Vorite 63 from CasChem, Inc. (Bayonne,
N.J.). Other examples of polyisocyanates useful in the present invention
are those listed in ICI Polyurethanes Book, by George Woods, published by
John Wiley and Sons, New York, N.Y. (1987).
[0119] Polyols useful to form these polymers include, but are not limited
to, polyester polyols, polyether polyols, modified polyether polyols,
polyester ether polyols, castor oil polyols, and polyacrylate polyols,
including Desmophen A450, Desmophen A365, and Desmophen A160 available
from Mobay Corporation (Pittsburgh, Pa.). Preferred polyols include
castor oil and castor oil derivatives, such as DB oil, Polycin-12,
Polycin 55, and Polycin 99F available from CasChem, Inc. Preferred diols
include, but are not limited to, Desmophen 651A-65, Desmophen 1300-75,
Desmophen 800, Desmophen-550 DU, Desmophen-1600U, Desmophen-1920D, and
Desmophen-1150, available from Mobay Corporation, and Niax E-59 and
others available from Union Carbide (Danbury, Conn.).
[0120] Suitable solvents for use in the formation of these polymers are
those which are capable of dissolving the isocyanate, the polyol, and the
polyvinyl pyrrolidone without reacting with any of these components.
Preferred solvents include, but are not limited to, methylene chloride,
dibromomethane, chloroform, dichloroethane, and dichloroethylene.
[0121] When a composition containing this polymeric solution is to be used
as a coating, the coating is cured, after application to the substrate,
at a temperature in the range of approximately 75.degree. F. to
approximately 350.degree. F. for a period in the range of about 2 minutes
to about 72 hours.
[0122] The process of the invention will now be further described in terms
of the formation of a colloid of silver chloride from silver nitrate and
sodium chloride in a polyurethane polymer coating solution. It is to be
understood that this is simply an example of one preferred embodiment of
the invention and that any polymer or combination of polymers and any
mixture of salts that will form a colloid within the polymer solution can
be employed in the present invention.
[0123] First, a 4.7% solution of a polyether polyurethane-urea block
copolymer is prepared in a mixture of THF/ethanol in a 75/25 ratio by
weight. A sufficient quantity of 10% silver nitrate (AgNO.sub.3) solution
in water is added to the CardioTech copolymer solution to produce a final
silver concentration of approximately 15%, based on coating solids in the
solution. An aqueous solution of 1.0% sodium chloride (NaCl) is then
slowly added to the solution with stirring in an amount sufficient to
react with 50% of the AgNO.sub.3. The NaCl reacts with the AgNO.sub.3 to
produce a colloidal suspension of the poorly water soluble salt, AgCl,
and the soluble salt, NaNO.sub.3, from half of the AgNO.sub.3. The amount
of water in the final coating solution is about 30% of the total solvent
weight. The final polymer concentration in the coating solution is 3.3%,
based upon solvent and polymer weights.
[0124] A 16 Fr latex Foley catheter can then be coated with the
composition by dipping it into the composition solution, withdrawing it
at a controlled rate and drying it using standard methods. The finished
coating contains both the water soluble, and therefore fast releasing,
AgNO.sub.3, and the water insoluble, and therefore slow releasing, AgCl.
[0125] Preparation of Compositions Containing an Additional Active Agent
[0126] The active agent can be incorporated into the compositions of the
present invention by any suitable method. For example, in one embodiment,
the active agent is mixed with the components of the copolymer
composition in a solvent suitable for both the composition and the active
agent. Such solvents include, but are not limited to, those discussed
above in the process for making the composition.
[0127] In another embodiment, the active agent or agents are mixed with
the monomers that form the copolymer prior to polymerization. In this
embodiment it is desirable that the active agent will not be deactivated
by polymerization conditions and will not interfere with polymerization.
The monomeric components are then polymerized by methods known in the
art.
[0128] In yet another embodiment, the copolymer is formed as described
above, followed by addition of the active agent to the copolymer
solution.
[0129] The active agent may be soluble or insoluble in the polymer
compositions of the invention or may be a combination of soluble and
insoluble agents. Solubilized active agents may be achieved by any means.
In some embodiments, the active agent is first dissolved in a suitable
solvent before addition to any of the solutions used to produce the
compositions of the invention. In some embodiments, an active agents is
solubilized by adding the dry active agent directly to a solution of the
compositions of the invention, in which it then dissolves.
[0130] Insoluble active agents are used in some embodiments of the
invention. In one embodiment, the active agent is dispersed into a
separate solvent before addition to the solutions of the invention. In
another embodiment, the active agent is dispersed directly into any
solution of the used to produce the compositions of the invention.
Combinations of these techniques are also used.
[0131] Uses Of The Composition
[0132] In a third aspect, the present invention relates to an article of
manufacture. In a preferred embodiment, the antimicrobial composition can
be used as a coating on a preformed article to provide antimicrobial
activity to the surface of the article and to the environment surrounding
the article through the continual release of oligodynamic ions. Any
article can be coated with the antimicrobial compositions of the present
invention. The composition is particularly suited for the production of
medical devices, which include, but are not limited to, catheters (as
used throughout this application, the term "catheter" denotes any type of
catheter including, but not limited to, urinary catheters, vascular
catheters, dialysis catheters, and port catheters), cannulae, stents,
guide wires, implant devices, contact lenses, IUDs, peristaltic pump
chambers, endotracheal tubes, gastroenteric feeding tubes, arteriovenous
shunts, condoms, oxygenator and kidney membranes, gloves, pacemaker
leads, and wound dressings.
[0133] The coatings can be applied to all or part of any surface or group
of surfaces on an article. In some embodiments, one or more entire
surfaces of an article are coated. In other embodiments, only part of one
or more surfaces is coated. In other embodiments, some surfaces are
coated in their entirety while other surfaces are coated only partially.
Any combination of surfaces, partial surfaces, or both may be selected
for coating or remaining uncoated. Partial coating may be accomplished
by, for example, dipping only part of an article into a coating
composition or spraying a coating composition on to only a part of the
article.
[0134] For example, in some embodiments in which underlying articles are
transparent while coatings are opaque or translucent, a portion of the
article may remain uncoated to allow visual inspection of the inside of
those portions of the article, including any lumen therein. In
embodiments involving endotracheal tubes, for example, it may be
desirable to leave a portion of the tube that will be outside the mouth
of the patient uncoated so that it is possible to view the inner lumen of
the tube to determine whether a patient is breathing properly.
[0135] An example of such an endotracheal tube 10 is shown in FIG. 1. The
endotracheal tube comprises an elongate tubular body 12 having an upper
end 14 and a lower end 16. A connector 18 is coupled to the body 12 at
its upper end 14 for connecting the endotracheal tube to a mechanical
ventilator. An inflatable cuff 20 is provided adjacent the lower end 16
of the endotracheal tube 10. The cuff 10 is inflated by means of a valve
30, which is in fluid communication with the cuff 20 by means of an
inflation tube 32 and an inflation lumen (not shown) formed in the wall
of the tubular body 12. The cuff is inflated in the conventional manner,
such as by infusing a air through the valve 30 with a syringe.
[0136] The inner and outer surfaces of the endotracheal tube 10 are dipped
in a coating solution, such as the one of the compositions described
above, which forms an opaque or translucent layer when applied to the
tube and permitted to dry. The dipping process coats both the interior
and exterior surfaces of the endotracheal tube 10. However, to prevent
the entire endotracheal tube from becoming opaque, a portion 40 adjacent
the upper end 14 of the tubular body 12 is not coated. The uncoated
portion may be provided in any suitable manner, such as by not dipping
the upper portion 40 into the coating solution, or by masking the wall of
the endotracheal tube adjacent the upper end to prevent the coating
composition from coating the upper portion.
[0137] The resulting endotracheal tube has an opaque coating applied to
substantially the entire endotracheal tube except for the uncoated
portion 40 which, when a patient is intubated and the tube is used in its
normal manner, resides outside the patient. The physician can thus
visualize the presence or absence of moisture or "fogging" through the
uncoated walls of the upper portion 40, as an indication of whether the
patient is breathing properly. In the disclosed embodiment of the
endotracheal tube 10, the uncoated portion 40 is approximately five
centimeters in length. It will be understood, however, that the portion
40 can be shorter or longer, as appropriate, so long as at least a
sufficient portion of the tube is coated to provide intended
antimicrobial or other effects, and so long as at least a part of the
uncoated portion 40 resides outside the patient when the tube is used
normally and in its intended manner.
[0138] It will also be appreciated that the disclosed practice of leaving
a portion of the endotracheal tube uncoated so as to visualize moisture
or fogging through the walls of the tube is not limited to the disclosed
coatings but includes other coatings, including but not limited to
antimicrobial, bactericidal and germicidal coatings, coatings containing
active agents of any type, lubricious coatings, and the like, especially
coatings which are translucent or opaque when applied to the tube and
permitted to dry.
[0139] While the embodiment disclosed above contemplates the coating of
both the interior and exterior surfaces of the endotracheal tube 10, the
invention is equally applicable to coatings which are applied only to the
exterior surface or only to the interior surface of the tubular body 12.
[0140] In some embodiments, the composition of the invention is prepared
as a high solids solution and used alone or mixed with other polymers to
form an article rather than a coating on an article. Polymers which are
useful to form the articles of the invention include, but are not limited
to, natural and synthetic rubber, especially latex rubber, acrylonitrile
rubber, PVC plastisol, PVC, polyurethanes, silicone, polycarbonates,
acrylates, polyamides, polypropylenes, polyethylenes,
polytetrafluoroethylenes, polyvinylacetate, poly(ethylene terephthalate),
polyesters, polyamides, polyureas, styrene-block copolymers, polymethyl
methacrylate, acrylic-butadiene-styrene copolymers, polystyrene,
cellulose, and derivatives and copolymers of any of the above.
[0141] As nonlimiting examples, compositions of the invention can be
admixed into latex rubber for fabrication of catheters, gloves, and other
dipped latex products by standard form dipping methods, and vinyl
plastisols can be mixed with compositions of the invention to provide
dippable and castable antimicrobial PVC devices. Thus, the final article
can be composed of one or more of the compositions of the present
invention in admixture with other polymeric components.
[0142] Alternatively, compositions of the invention can be formulated into
high solids coating compositions that can be used to dip-fabricate a
variety of medical devices, such as catheters, stents, gloves, condoms,
and the like.
[0143] By another method, compositions of the invention can be dried and
melt processed, for example, by injection molding and extrusion.
Compositions used for this method can be used alone or compounded with
any other melt-processable material for molding and extrusion of
antimicrobial articles.
[0144] When used as a coating, the compositions can be applied by any
means, including those methods known in the art. For example, the
compositions can be brushed or sprayed onto the article, or the article
can be dipped into the composition. For example, the article can be
dipped into the antimicrobial polymer solution at a rate of about 10-80
inches per minute (ipm), preferably about 40 ipm. The article is allowed
to remain in the antimicrobial polymer solution for a period of about
0-30 seconds, preferably about 5-15 seconds. The article is then
withdrawn at a rate of about 10-80 ipm, preferably about 15-30 ipm. Once
the article has been coated with the copolymer of the invention, it is
allowed to air dry for a period of at least about 10 minutes before
drying is completed in an oven for a period of about 5-60 minutes at a
temperature in the range of about 40-100.degree. C. Preferably, oven
drying occurs for a period of about 15 minutes at a temperature of about
50.degree. C. The coated article can optionally be dried with a hot air
stream at a temperature in the range of approximately 40.degree. C. to
approximately 100.degree. C. for a period of about 5-60 minutes to remove
residual solvent. Persons skilled in the art will understand that the
parameters in the foregoing paragraph are merely examples and will vary
based on the composition of the substrate and coating and the desired
features of the coated objects.
[0145] The invention allows manipulation of the amount of oligodynamic
metal compounds contained in the article per surface area (expressed in
units such as micrograms of oligodynamic metal compound per square
centimeter of surface area, or .mu.g/cm.sup.2). Manipulation of this
parameter provides an additional means of controlling release rate or
release profile. Any achievable concentration may be used. In some
embodiments, the article contains between about 40 and about 50
.mu.g/cm.sup.2 oligodynamic metal compound or compounds. In some
embodiments, the article contains between about 50 and about 100
.mu.g/cm.sup.2 oligodynamic metal compound or compounds. In some
embodiments, the article contains between about 50 and about 75
.mu.g/cm.sup.2 oligodynamic metal compound or compounds. In some
embodiments, the article contains between about 50 and about 60
.mu.g/cm.sup.2 oligodynamic metal compound or compounds. In some
embodiments, the article contains between about 25 and about 50 .mu.g/cm
oligodynamic metal compound or compounds. In some embodiments, the
article contains between about 30 and about 40 .mu.g/cm.sup.2
oligodynamic metal compound or compounds. In some embodiments, the
article contains between about 20 and about 30 .mu.g/cm.sup.2
oligodynamic metal compound or compounds. In some embodiments, the
article contains between about 25 and about 30 .mu.g/cm.sup.2
oligodynamic metal compound or compounds. In some embodiments, the
article contains between about 10 and about 20 .mu.g/cm.sup.2
oligodynamic metal compound or compounds. In some embodiments, the
article contains between about 15 and about 20 .mu.g/cm.sup.2
oligodynamic metal compound or compounds. In some embodiments, the
article contains between about 10 and about 15 .mu.g/cm.sup.2
oligodynamic metal compound or compounds. In some embodiments, the
article contains between about 5 and about 15 .mu.g/cm.sup.2 oligodynamic
metal compound or compounds. In some embodiments, the article contains
between about 5 and about 10 .mu.g/cm.sup.2 oligodynamic metal compound
or compounds. In some embodiments, the article contains between about 4
and about 7 .mu.g/cm.sup.2 oligodynamic metal compound or compounds. In
some embodiments, the article contains between about 11 and about 14
Ag/cm.sup.2 oligodynamic metal compound or compounds. In some
embodiments, the article contains about 13 .mu.g/cm.sup.2 oligodynamic
metal compound or compounds. In some embodiments, the article contains
about 8 .mu.g/cm.sup.2 oligodynamic metal compound or compounds. In some
embodiments, the article contains about 8 Ag/cm.sup.2 oligodynamic metal
compound or compounds. In some embodiments, the article contains about 28
Ag/cm.sup.2 oligodynamic metal compound or compounds. The foregoing
ranges are obtained with coated articles as well as with articles formed
from the composition.
[0146] Use of the Compositions Containing an Additional Active Agent
[0147] As discussed above, in one embodiment, the compositions of the
present invention can be coated onto the surface of a substrate or used
to form an article. Preferred articles are medical devices. The same is
true when the composition comprises one or more active agents.
[0148] In one embodiment, an article is first coated with a layer of
silver as described, for example in U.S. Pat. Nos. 5,395,651; 5,747,178;
and 5,320,908 to Sodervall et al., the disclosures of which are
incorporated by reference herein. The composition of the present
invention is then coated over the silver coated article in a manner as
described above.
[0149] In some embodiments, the compositions of the invention comprising
the active agent are used in combination with one or more additional
coating compositions to coat a surface. Alternatively, the composition is
used to form an article to which one or more coatings is thereafter
applied. The following is a description of some of the possible coating
combinations contemplated by the present invention. This description
exemplifies the invention in terms of two layers, a primer or base coat
and a top coat. However, the invention encompasses the use of more than
two layers, any of which can include the active agents of the present
invention. The following combinations of coatings are not intended to be
exclusive. One having ordinary skill in the art with the following
information would readily recognize additional combinations and be
capable of practicing the present invention with such additional
combinations. Any combination of coatings may be used.
[0150] Some multi-coating embodiments comprise the use of two compositions
to provide two distinct coatings on the device or a formed article and a
coating. It should be understood that the invention is also practiced
with multiples layers following the same principles as described below.
[0151] The coatings may contain the same composition or different
compositions, so long as one of the coatings comprises the composition of
the present invention. Where two or more coating layers are employed in
the invention, it is convenient to refer to the coating layer closest to
the substrate surface as a primer or base coat and to the coating layer
most exterior as the top coat.
[0152] The compositions of the present invention can be employed as the
base coat, the top coat, or both. They can also be employed as
intermediate coating layers when used with other coatings of the present
invention or known in the art.
[0153] In some embodiments, the substrate base coat comprises a polymeric
composition that improves adherence of the other coating layers to the
article. In some embodiments, top coats that provide a dry elastic
coating that becomes lubricious when wet.
[0154] Any of the coating layers can comprise one or more active agents in
addition to the colloid. Where multiple coatings contain an active agent,
the active agents in the coatings may be the same or different. Further,
one or more of the coatings can contain additional agents that provide
advantageous properties to the device. For example, any of the coatings,
regardless of whether it contains an active agent, can also contain
agents that affect the release or rate of release of the active agent.
The coatings can also contain agents that improve adhesion of the
coatings to the substrate or to the base coat, improve wet lubricity of
the surface, inhibit discoloration of the compositions containing active
agents that discolor, provide additional therapeutic activity, enhance
the activity of the active agent, provide galvanic action for
oligodynamic metal, and the like.
[0155] Further, the particular polymeric compositions of the coatings can
be designed to provide some of the properties listed above, such as
improved adhesion, improved lubricity, or to enhance or inhibit release
of the active agent.
[0156] As with coatings that do not contain active agents, the preferred
substrates are medical devices. Such medical devices include, for
example, catheters, guidewires, implant devices, contact lenses, IUDs,
peristaltic pump chambers, endotracheal tubes, gastroenteric feed tubes,
arteriovenous shunts, condoms, and oxygenator and kidney membranes. Use
of particular active agents in the various coating layers provides
particular beneficial effects. For example, use of antibiotics or
antimicrobials, inhibits the adherence of bacteria to the surface of the
device and can prevent infection in the surrounding tissue.
[0157] Although the compositions of the present invention have many
application in connection with medical devices, their use is not limited
to such embodiments. In some embodiments, the compositions of the present
invention are used to coat consumer products and other surfaces to
provide an active agent on the surface. The compositions may be used for
any suitable purposes. In some embodiments, the compositions of the
present invention are used to coat glass beads, chromatography packing
material, and other substances for use as diagnostic agents. An example
of such embodiments is use of active agents incorporated in such
compositions that can detect the desired chemical or substance to be
detected. Detection of the appropriate substance can be performed by
conventional methods, such as ELISA assays, radioimmunoassays, NMR,
fluorescent spectroscopy, and the like.
[0158] While it is preferred to dip coat medical devices, such as
catheters and stents, the compositions of the present invention can be
coated by any other means including, but not limited to spray or brush
coatings.
[0159] Other applications for which the copolymer compositions of the
present invention are useful include coating the compositions onto
surfaces in contact with bodies of water such as the walls of pools or
spas, the hulls of boats or ships, and the like to provide algaecidic
activity, antifoulant activity, or both. For example, the coatings of the
invention can be applied to ship hulls to prevent attachment of
invertebrate encrustation (e.g. arthropod or molluscan encrustation), or
to pool liners to prevent bioslime.
[0160] Other Methods of Use, Including Substance Delivery, and Treatment
[0161] Methods of use of compositions of the present invention and
articles comprising those compositions also include, but are not limited
to, methods of delivering oligodynamic metals, in forms including, but
not limited to, ions, salts and oxides of one or more oligodynamic metals
or combinations thereof, to a desired location as well as methods of
treatment of cells, tissues, and organisms.
[0162] In some embodiments in which compositions contain additional active
agents, the compositions of the present invention can also be used as
delivery agents to deliver one or more active agents to a desired
location. The method includes delivery of any active agent or combination
of agents, including any of the active agents listed above. In some
embodiments, the methods provide delivery of beneficial agents to
patients. For such uses, the compositions of the present invention are
used, for example, as coatings on substrates, such as medical devices,
bandages, or devices known in the art for topical delivery of
pharmaceutical agents or to form the articles or parts of such articles.
[0163] Some embodiments of methods involve delivery of substances to one
or more desired locations. Delivered substances include, but are not
limited to, compositions comprising both the polymers and the colloids of
oligodynamic compounds, the oligodynamic metal compounds themselves, or
oligodynamic metal ions. In embodiments in which the composition contains
one or more additional active agents, the delivered substances include
such agent or agents. Preferred locations include, but are not limited
to, an orifice, tissue, cavity, fluid, or other component of the body of
an organism. Other preferred methods include in vitro delivery to
tissues, tissue cultures, suspensions of cells, or other substances or
preparations. In some embodiments, methods include placing a composition
of the present invention in conditions effective to cause delivery of one
or more oligodynamic metals or ions, salts or oxides thereof (optionally
including additional active agents as well) to the desired location.
Examples of such conditions include, but are not limited to an aqueous
fluid that will allow diffusion of the oligodynamic metal ions or one or
more other active agents from the composition and a location in the body
of an organism that will allow diffusion of oligodynamic metal salts or
oxides or one or more other active agents into a tissue or a fluid in the
body.
[0164] Methods of the present invention are useful in treatments of
organisms, cells, or tissues. An example of such methods involves placing
the polymer composition comprising one or more oligodynamic metal
compounds and one or more other active agents, or articles comprising
such compositions, under conditions effective to deliver ions or
compounds of oligodynamic metals to the target organisms, cells, or
tissues. Such compositions may, for example, be implanted, administered,
inserted, or otherwise placed in conditions effective to cause the
oligodynamic metal salts or ions or one or more other active agents to be
delivered to the cells, tissue, organisms, or parts of organisms.
Examples of treatments include, but are not limited to, for example,
antifungal treatments, antiviral treatments, anti-inflammatory
treatments, anesthetic treatments, antiseptic treatments, analgesic
treatments, stimulant treatments, depressant treatments, tranquilizer
treatments, hormone administration, germicidal treatments, antiprotozoal
treatments, antiviral treatments, antineoplastic treatments,
antiparasitic treatments, antirheumatic treatments, antibacterial
treatments, emetic treatments, antiseptic treatments, treatments for
inhibiting restenosis, methods of inhibiting healing, methods of reducing
thrombus formation, methods of anticoagulation, methods of reducing
encrustation, methods of providing topical protection, methods of
deodorization (e.g. of wounds or ulcers), methods of preventing or
combating infection, methods of preventing or combating microbial or
parasitic infestation, methods of promoting healing, methods of producing
a styptic or astringent effect, methods of causing formation of eschars
or scars, methods of preventing the formation of eschars or scars,
methods of contraception, and methods of treating ulcers, slowly
granulating wounds, vaginitis, fistulas, dermatitis, or popodermatitis.
Additional examples regarding treatments are disclosed in the discussion
of the effects of the composition above, and in the example below.
[0165] Any of the terms used in the preceding paragraph to describe
effects or treatments are defined to have their broadest possible
meanings. Terms that refer to being "anti" a type of target organism or
agent (e.g. antimicrobial, antiviral, antibacterial) refers to having any
deleterious effects upon those organisms or their ability to cause
symptoms in a host or patient. Examples include, but are not limited to,
inhibition or prevention of growth or reproduction, killing, and
inhibiting any metabolic activity of the target organisms. Terms that
refer to being "anti" a type of symptom or condition, or as being a
"treatment" for a type of condition or symptom, include but are not
limited to any effect that prevents, reduces, cures, accelerates cure or
healing, or reduces the severity of one or more conditions or symptoms.
[0166] As discussed above, the use of salts and oxides of differing
solubilities allows control of release profiles of oligodynamic metals.
The methods, compositions, and articles herein may also include other
means of controlling release profiles. In some embodiments, articles
comprising the compositions are shaped in a specific way to affect
release profile. For example, diffusion of oligodynamic metals (and,
optionally, one or more other active agents) from polymer compositions
comprising the salts is enhanced by fragmenting or pulverizing the
polymer compositions. In some embodiments, pulverized compositions are
applied to a wound site, ingested, or formed into another shape such as a
capsule or a tablet. In other embodiments, release is affected by
applying an elevated or reduced temperature, an electric field, a
magnetic field, or an electric current to the oligodynamic metal
compositions before, during, or after application. Release is also
affected by coating compositions and articles with other substances or
preparing laminates in which layers have different release profiles or
combinations thereof. Layering an object with one or more coatings that
dissolve over a given period of time, for example, affords another level
of control of release profile. The coatings, envelopes, and protective
matrices may be made, for example, from polymeric substances, waxes,
oligomeric substances, or combinations thereof. The compositions may also
contain additional chemicals that affect the release profile of the
oligodynamic metal compounds.
[0167] Methods of treatment and methods of delivery of oligodynamic metal
salts and oxides (and, optionally, one or more other active agents) can
include release from articles containing the compositions including, for
example, catheters, cannulae, stents, guide wires, implant devices,
contact lenses, IUDs, peristaltic pump chambers, endotracheal tubes,
gastroenteric feeding tubes, arteriovenous shunts, condoms, oxygenator
and kidney membranes, gloves, pacemaker leads, and wound dressings. The
compositions of the present invention may be combined with
pharmaceutically or cosmetically acceptable carriers and administered as
compositions in vitro or in vivo. Forms of administration include but are
not limited to implantation or insertion of a medical device comprising
the composition, injections, solutions, lotions, slaves, creams, gels,
implants, pumps, ointments, emulsions, suspensions, microspheres,
particles, microparticles, nanoparticles, liposomes, pastes, patches,
tablets, transdermal delivery devices (such as patches), sprays,
aerosols, or other means familiar to one of ordinary skill in the art.
Such pharmaceutically or cosmetically acceptable carriers are commonly
known to one of ordinary skill in the art. Pharmaceutical formulations of
the present invention can be prepared by procedures known in the art
using well known and readily available ingredients. For example, the
compounds can be formulated with common excipients, diluents, or
carriers, and formed into tablets, capsules, suspensions, powders, and
the like. Examples of excipients, diluents, and carriers that are
suitable for such formulations include the following: fillers and
extenders (e.g., starch, sugars, mannitol, and silicic derivatives);
binding agents (e.g., carboxymethyl cellulose and other cellulose
derivatives, alginates, gelatin, and polyvinyl-pyrrolidone); moisturizing
agents (e.g., glycerol); disintegrating agents (e.g., calcium carbonate
and sodium bicarbonate); agents for retarding dissolution (e.g.,
paraffin); resorption accelerators (e.g., quaternary ammonium compounds);
surface active agents (e.g., cetyl alcohol, glycerol monostearate);
adsorptive carriers (e.g., kaolin and bentonite); emulsifiers;
preservatives; sweeteners; stabilizers; coloring agents; perfuming
agents; flavoring agents; dry lubricants (e.g., talc, calcium and
magnesium stearate); solid polyethyl glycols; and mixtures thereof.
[0168] The terms "pharmaceutically or cosmetically acceptable carrier" or
"pharmaceutically or cosmetically acceptable vehicle" are used herein to
mean, without limitations, any liquid, solid or semi-solid, including but
not limited to water or saline, a gel, cream, salve, solvent, diluent,
fluid ointment base, ointment, paste, implant, liposome, micelle, giant
micelle, and the like, which is suitable for use in contact with living
animal or human tissue, desirably without causing excessive adverse
physiological or cosmetic responses, and without excessively interacting
with the other components of the composition in a deleterious manner.
Other pharmaceutically or cosmetically acceptable carriers or vehicles
known to one of skill in the art may be employed to make compositions for
delivering the molecules of the present invention.
[0169] In some embodiments, formulations are constituted so that they
release the active ingredient only or preferably in a particular
location, over a period of time, or a combination thereof. Such
combinations provide yet a further mechanism for controlling release
kinetics.
[0170] Methods of in vivo administration of the compositions of the
present invention, or of formulations comprising such compositions and
other materials such as carriers of the present invention that are
particularly suitable for various forms include, but are not limited to,
urethral administration, oral administration (e.g. buccal or sublingual
administration), anal administration, rectal administration,
administration as a suppository, topical application, aerosol
application, inhalation, intraperitoneal administration, intravenous
administration, transdermal administration, intradermal administration,
subdermal administration, intramuscular administration, intrauterine
administration, vaginal administration, administration into a body
cavity, implantation, surgical administration at the location of a tumor
or internal injury, administration into the lumen or parenchyma of an
organ, and parenteral administration. Techniques useful in the various
forms of administrations above include but are not limited to, topical
application, ingestion, inhalation, insertion, surgical administration,
injections, sprays, transdermal delivery devices, osmotic pumps, applying
directly on a desired site, or other means familiar to one of ordinary
skill in the art. Sites of application can be external, such as on the
epidermis or into an orifice, or internal, for example a gastric ulcer, a
surgical field, or into the lumen of a duct or organ, or elsewhere.
[0171] The compositions of the present invention can be applied in the
form of creams, gels, solutions, suspensions, liposomes, particles, or
other means known to one of skill in the art of formulation and delivery
of therapeutic and cosmetic compounds. Ultrafine size particles
containing the composition can be used for inhalation delivery. Some
examples of appropriate formulations for subcutaneous administration
include but are not limited to implants, depot, needles, capsules, and
osmotic pumps. Some examples of appropriate formulations for vaginal
administration include but are not limited to creams, cervical caps, and
rings. Some examples of appropriate formulations for oral administration
include but are not limited to: pills, liquids, syrups, and suspensions.
Some examples of appropriate formulations for transdermal administration
include but are not limited to creams, pastes, patches, sprays, and gels.
Formulations suitable for parenteral administration include but are not
limited to aqueous and non-aqueous sterile injection solutions which may
contain anti-oxidants, buffers, bacteriostats and solutes which render
the formulation isotonic with the blood of the intended recipient; and
aqueous and non-aqueous sterile suspensions which may include suspending
agents and thickening agents. Extemporaneous injection solutions and
suspensions may be prepared from sterile powders, granules and tablets
commonly used by one of ordinary skill in the art.
[0172] Embodiments in which the compositions of the invention are combined
with, for example, one or more pharmaceutically or cosmetically
acceptable carriers or excipients may conveniently be presented in unit
dosage form and may be prepared by conventional pharmaceutical
techniques. Such techniques include the step of bringing into association
the compositions containing the active ingredient and the pharmaceutical
carrier(s) or excipient(s). In general, the formulations are prepared by
uniformly and intimately bringing into association the active ingredient
with liquid carriers. Preferred unit dosage formulations are those
containing a dose or unit, or an appropriate fraction thereof, of the
administered ingredient. It should be understood that in addition to the
ingredients particularly mentioned above, formulations comprising the
compositions of the present invention may include other agents commonly
used by one of ordinary skill in the art. The volume of administration
will vary depending on the route of administration. For example,
intramuscular injections may range in volume from about 0.1 ml to 1.0 ml.
[0173] This invention is further illustrated by the following examples,
which are not to be construed in any way as imposing limitations upon the
scope of the invention.
EXAMPLES
Example 1
[0174] To form the coating solution, a 4.7% solution of a polyether
polyurethane-urea block copolymer available from CardioTech
International, Inc. was prepared in a mixture of THF/alcohol in a 75/25
ratio by weight. A sufficient quantity of 10% silver nitrate (AgNO.sub.3)
solution in water was added to the CardioTech copolymer solution to
produce a final silver concentration of approximately 15%, based on the
weight of coating solids in the solution. An aqueous solution of 1.0%
sodium chloride (NaCl) was added to the solution in an amount sufficient
to react with 50% of the AgNO.sub.3 to produce a colloid of the poorly
water soluble salt, AgCl, from half of the AgNO.sub.3 in the coating
solution. The NaCl solution was added slowly to the polymer solution and
the solution began to turn cloudy with the formation of the fine
colloidal AgCl. The amount of water in the final coating solution was
about 30% of the total solvent weight. The final polymer concentration in
the coating solution was 3.3%, based upon solvent and polymer weights.
[0175] A 16 Fr latex Foley catheter was then coated by dipping it into the
coating solution, withdrawing it at a controlled rate to control the
thickness of the coating and drying the catheter coating using standard
methods. The finished coating contained both the water soluble, and
therefore fast releasing, AgNO.sub.3 and the water insoluble, and
therefore slow releasing, AgCl.
Example 2
[0176] The process of Example 1 was repeated, except that a 1.0% solution
of zinc chloride was used in place of the 1.0% solution of sodium
chloride, resulting in the formation of a silver chloride colloid and
zinc nitrate from half the silver nitrate in the coating solution. Zinc
chloride was added in an amount of one half the amount of NaCl added in
Example 1 because one mole of zinc chloride reacts with 2 moles of silver
nitrate.
Example 3
[0177] The process of Example 1 was repeated, except that a 1.0% solution
of copper chloride was used in place of the 1.0% solution of sodium
chloride, resulting in the formation of a silver chloride colloid and
copper nitrate from half the silver nitrate in the coating solution.
Copper chloride was added in an amount of one half the amount of NaCl
added in Example I because one mole of copper chloride reacts with 2
moles of silver nitrate.
Example 4
[0178] The process of Example 1 was repeated, except that the 1.0%
solution of sodium chloride was replaced with a 1.0% solution of sodium
iodide, resulting in the formation of a silver iodide colloid and sodium
nitrate from half the silver nitrate in the coating solution. Silver
iodide is a local antiinfective agent and has a lower water solubility
than silver chloride, providing a slower releasing silver salt than
silver chloride.
Example 5
[0179] The process of Example 1 was repeated, except that the 1.0%
solution of sodium chloride was replaced with a 1.0% solution sodium
propionate, resulting in the formation of a silver propionate colloid and
soluble sodium nitrate, along with the remaining silver nitrate in the
solution. Silver propionate is a local antiinfective and is more water
soluble than AgCl or AgI, providing a faster releasing salt than silver
chloride or silver iodide.
Example 6
[0180] The process of Example 1 was repeated, except that the 1.0%
solution of sodium chloride was replaced with a 1.0% solution of sodium
lactate, resulting the formation of a silver lactate colloid and sodium
nitrate, along with the remaining silver nitrate in the coating solution.
Silver lactate is a local antiinfective and is more water soluble than
sodium propionate, AgCl or AgI, providing one of the fastest releasing
silver salts, other than the soluble silver nitrate.
Example 7
[0181] The process of Example 1 was repeated, except that the 1.0%
solution of sodium chloride was replaced with a solution of sodium
acetate, resulting in the formation of a silver acetate colloid and
sodium nitrate, along with the remaining silver nitrate in the solution.
Silver acetate is a local antiinfective that is more water soluble than
sodium propionate, silver chloride, or silver iodide, but less water
soluble than silver lactate.
Example 8
[0182] The process of each of Examples 1, 2, 3, 4, 5, 6, and 7 was
repeated, except that the salt solution was added in an amount sufficient
to react with 75% of the AgNO.sub.3.
Example 9
[0183] The process of each of Examples 1, 2, 3, 4, 5, 6, and 7 was
repeated, except that the salt solution was added in an amount sufficient
to react with 100% of the AgNO.sub.3.
Example 10
[0184] The process of each of Examples 1, 2, 3, 4, 5, 6, and 7 was
repeated, except that the salt solution was added in an amount sufficient
to react with 25% of the AgNO.sub.3.
Example 11
[0185] The process of Example 1 was repeated, except that the NaCl salt
solution was added in an amount sufficient to react with 25% of the
silver nitrate. Then a 1.0% solution of sodium iodide was added in an
amount sufficient to react with another 25% of the silver nitrate to
produce a combination of silver chloride and silver iodide colloids from
50% of the silver nitrate.
Example 12
[0186] The process of Example 1 was repeated, except that the NaCl salt
solution was added in an amount sufficient to react with 25% of the
silver nitrate to produce the poorly soluble silver chloride colloid.
Then a 1.0% solution of sodium propionate was added in an amount
sufficient to react with another 25% of the silver nitrate to produce the
slightly water soluble silver propionate colloid. Next, a 1.0% solution
of sodium acetate was added in an amount sufficient to react with another
25% of the silver nitrate to produce the somewhat water soluble silver
acetate colloid in combination with the poorly soluble silver chloride
colloid and the slightly soluble silver propionate colloid from 75% of
the silver nitrate.
Example 13
[0187] The process of Example 12 was repeated, except that an additional
amount of zinc iodide was added to convert 10% of the remaining silver
nitrate to a colloid of silver iodide. This produced a coating containing
15% silver nitrate, 25% of the somewhat soluble silver acetate colloid,
25% of the slightly soluble sodium propionate colloid, 25% of the poorly
soluble silver chloride colloid, and 10% of the very poorly soluble
silver iodide colloid, along with the soluble sodium nitrate and zinc
nitrate salt products.
[0188] As shown by the above examples, any combination of additional salts
in any combination of different amounts can be used to convert some or
all of the soluble oligodynamic metal salts into insoluble colloidal
salts within a polymer composition.
Example 14
[0189] Somewhat water soluble silver salts, such as silver lactate or
silver acetate, can be used alone or in combination with the very soluble
silver nitrate to produce other compounds that can have antiseptic
activity. For example, silver acetate at a 4:1 molar ratio with zinc
chloride produces 50% silver chloride colloid and the zinc acetate
counter salt, which is also an antiseptic, and leaves 50% unreactive
silver acetate. Similarly, other silver salts can be used alone or in
combination to produce multiple counter salts that have antiseptic or
other desirable activity.
[0190] For example, the process of Example 2 was repeated except that a
soluble combination of silver nitrate, silver acetate, and silver lactate
was used in place of the 10% silver nitrate solution. When the zinc
chloride is added, a colloid of silver chloride is formed in the polymer
composition and the soluble counter salts zinc nitrate, zinc acetate, and
zinc lactate are produced. The zinc acetate and zinc lactate provide
antiseptic activity in addition to the antimicrobial activity of the
silver salts. In this example any metal salt other than zinc chloride
which produces counter salts with the nitrate, acetate, and lactate that
have a desired effect, such as antiseptic or antimicrobial activity, can
be used. An example of such a salt is copper chloride.
[0191] Different oligodynamic salts have different water solubilities.
This allows for tailoring of the composition to provide a specific
release profile of the antimicrobial agent(s) from the composition. For
example, sodium chloride, zinc iodide, sodium citrate, sodium acetate,
and sodium lactate can be added to a coating composition containing
silver nitrate to produce a coating which contains the water soluble
salts silver nitrate and zinc nitrate, the somewhat water soluble salts
silver lactate (67 mg/ml water) and silver acetate (10 mg/ml water), the
slightly soluble salt silver citrate (0.3 mg/ml water), the poorly
soluble salt silver chloride (0.002 mg/ml water), and the very poorly
soluble salt silver iodide (0.00003 mg/ml water). By adjusting the
proportions of salts having different solubilities in the composition,
the release rate of the active oligodynamic agent(s) can be altered to
provide a shorter or longer release profile over time.
[0192] For example, the process of Example 1 was repeated, except that in
addition to the NaCl salt solution, 1% solutions of zinc iodide, sodium
citrate, sodium acetate and sodium lactate were added, each in an amount
sufficient to react with 15% of the silver nitrate, to produce colloids
of silver chloride, silver iodide, silver citrate, silver acetate, and
silver lactate in the final coating composition, along with 25% unreacted
silver nitrate, and the silver nitrate and zinc nitrate salt products.
The difference in solubility of the different silver salts will produce
different and prolonged rates of silver ion release in the coating when
exposed to body fluid.
Example 15
[0193] To form the coating composition for PVC catheters, a 3.3% solution
of a polyether polyurethane-urea block copolymer available from
CardioTech International, Inc. was prepared in THF. A 3.3% solution of
Polyvinyl chloride (PVC) was then prepared in methylene chloride. The two
solutions were then combined in equal amounts to provide a 50/50 ratio by
weight of the two polymers in solution. A sufficient quantity of 10%
silver nitrate (AgNO.sub.3) solution in alcohol was then added to the
polyurethane-urea/PVC polymer solution to produce a final silver
concentration of approximately 5%, based on coating solids in the
solution. A 1% zinc chloride solution in a 75/25 mixture by weight of
ethanol/water was added to the coating solution in an amount sufficient
to react with 50% of the AgNO.sub.3 to produce a colloid of the poorly
water soluble salt AgCl from half of the AgNO.sub.3. The ZnCl.sub.2
solution was added slowly to the polymer solution with stirring, and the
solution began to turn cloudy with the formation of the fine colloidal
AgCl. The amount of water in the final coating solution was slightly less
than about 1% of the total solvent weight. A PVC endotracheal tube was
then coated by dipping it into the coating composition, followed by
drying using standard methods. The finished coating contained both the
water soluble, and therefore fast releasing, AgNO.sub.3 and the poorly
water soluble, and therefore slow releasing, AgCl.
Example 16
Dog Intubation Study
[0194] Twelve adult mongrel dogs were orally intubated. Dogs were randomly
assigned to be orally intubated either with an endotracheal tube with a
coating of the present invention or a noncoated endotracheal tube. The
animal care providers were blinded to the animals' study group
assignments and all interpretation of the microbiology data and histology
data were performed by blinded observers. The animals were assigned to
their study groups using a random-number generator. Cuffed endotracheal
tubes (Intermediate Hi-Lo, 7.5 mm internal diameter, Mallinckrodt
Medical, St. Louis, Mo.) were used for the control animals. For the test
animals, the inner and outer surfaces of identical endotracheal tubes
were coated with a coating of the present invention.
[0195] The test coating was composed of a polymer blend that was 50%
polyvinyl chloride (PVC) and 50% polyurethane. The coating had a silver
content on the device surface of 3.3 micrograms/cm.sup.2. The silver was
a colloid of silver chloride that had been prepared by combining sodium
chloride with silver nitrate in a polymer solution. The tubes for the
control and test groups were repackaged and sterilized with ethylene
oxide.
[0196] Twelve mongrel adult dogs (17 to 31 kg; Levon Thalen; Strathmore,
AB, Canada) were used in the study. Six animals were assigned to receive
the coated endotracheal tubes, while six animals received standard
noncoated endotracheal tubes. All animals were healthy and free of
disease prior to the initiation of the study. Animals that had received
any antibiotics <1 week prior to the study were excluded.
[0197] The animals were anesthetized with a single injection of sodium
pentobarbital (30 mg/kg) and were maintained in a state of anesthesia by
providing sodium pentobarbital at approximately 1 mg/kg/h. They were
placed in the dorsal recumbent position for the duration of the
mechanical ventilation proposed in the study protocol (i.e., up to 4 days
of mechanical ventilation). Animals were provided lactated Ringers
solution at a rate of 100 mL/h, and urinary catheters were placed to
provide urinary drainage. Following tracheal intubation, animals were
placed on a ventilator (Harvard Biosciences; South Natick, Mass.) set to
deliver 350 to 500 mL tidal volume of room air (50% relative humidity) at
a rate of 15 to 20 breaths/min. The tidal volume delivered to the animals
was selected and maintained to provide peak airway pressures of <30 cm
H.sub.2O throughout the duration of mechanical ventilation. All animals
received a level of positive end expiratory pressure of 5 cm H.sub.2O.
[0198] Prior to the bacterial challenge, blood and buccal culture samples
were taken from each animal. After sedation and tracheal intubation, each
animal was challenged twice (at 1 and 8 hours (h) after the tracheal
intubation) with a respiratory isolate of Pseudomonas aeruginosa (strain
PAO1). For each challenge, 5 mL of approximately 10.sup.7 cfu/mL of a
log-phase culture of P. aeruginosa was instilled into the buccal pouch of
the animals. The animals were positioned with their heads turned so that
any excess fluid drained out from the mouth, rather than down into the
pharynx.
[0199] Buccal culture samples were taken every 24 hours after intubation
and were plated quantitatively on both nutrient agar and P. aeruginosa
isolation agar to identify the total amount of aerobic bacteria and the
challenge bacteria. Using sterile suctioning tubes and mucous specimen
traps, animals were suctioned via the inner lumen of their endotracheal
tubes three times per day to remove secretions. However, a minimal amount
of recovered tracheal aspirate hindered any attempt to quantitatively
assess the bacterial burden from these samples. Rather, the presence of
bacteria within the endotracheal tubes was assessed by daily sampling of
the endotracheal tube lumens with a cotton culture swab.
[0200] Body temperature was monitored continuously and was recorded three
times daily to determine the presence of fever in the animals. Blood
samples were taken daily from each animal and were cultured using an
automated blood culture system (Bactec NR 860; Becton-Dickinson; Franklin
Lakes, N.J.). The bacteria were identified as P. aeruginosa, other
pathogenic aerobic bacteria, or contaminants, using standard
microbiological methods.
[0201] Animals were sacrificed by an overdose of sodium pentobarbital
after receiving 96 hours of mechanical ventilation. Postmortem
examinations were conducted within 4 to 6 hours of death for all animals
using criteria that were determined prospectively in the study protocol.
Any indwelling devices (e.g., IV catheter or urinary catheter) were
cultured. Gross postmortem examinations were conducted on each dog. The
endotracheal tube was removed by dissection, rather than by being pulled
out, to prevent the removal of adherent bacteria and secretions. The
lungs and the trachea were removed from each animal and weighed.
[0202] The gross lung appearance was recorded and scored according to the
following scheme: 0, normal; 1, hyperemia, edema, and congestion
involving <10% of examined lungs; 2, hyperemia, edema, and congestion
involving 10 to 29% of the lungs; 3, hyperemia, edema, and congestion
involving 30 to 60% of the lungs; and 4, hyperemia, edema, and congestion
involving >60% of the lungs.
[0203] The gross appearance of the endotracheal tube also was assessed
using the following scheme: 0, no mucus or purulent material on the
surface of the endotracheal tube; 1, mucus covering <10% of the
endotracheal tube length and <10% obstruction of the endotracheal tube
lumen; 2, mucus or purulent material covering or obstructing 10 to 25% of
the endotracheal tube surface and/or lumen; 3, mucus covering or
obstructing 25 to 50% of the endotracheal tube surface and/or lumen; and
4, mucus covering or obstructing >50% of the surface and/or lumen of
the endotracheal tube.
[0204] Tissue samples from each identified primary lung lobe were
collected for quantitative cultures (i.e., total bacteria and P.
aeruginosa) and histologic examination. As all animals were placed in the
dorsal recumbent position, the diaphragmatic lobes (caudal lobes) were
determined to be in a dependent position. Additionally, samples from the
mid-portions of the two mainstem bronchi and the trachea (i.e., proximal
trachea [i.e., upper third of the trachea], middle trachea [i.e., just
above the cuff of the endotracheal tube], and distal trachea [i.e.,
tracheal surface in contact with the cuff of the endotracheal tube]) were
collected for quantitative microbiology.
[0205] Cultures from the inner lumen surface of the endotracheal tube were
collected at the postmortem examination from three 1-cm segments of the
tube. The three samples were taken from the proximal third of the
endotracheal tube, from the portion of the tube just proximal to the
cuff, and from the cuffed portion of the endotracheal tube. The inner
lumen surface from the cut pieces of the endotracheal tubes were swabbed
with cotton-tipped applicators to identify the bacteria. The applicators
then were sonicated and plated onto the appropriate medium to enumerate
the amount of total bacteria as well as that of P. aeruginosa.
[0206] Microbiology
[0207] For each tested tissue sample, a weighed, aseptically prepared
tissue portion was homogenized in sterile phosphate-buffered saline
solution (5 mL). This was serially diluted, and 100 .mu.l was
spread-plated onto nutrient agar and P. aeruginosa isolation agar to
obtain quantitative cultures using techniques described in: Baselski VS,
et al. "The standardization of criteria for processing and interpreting
laboratory specimens in patients with suspected ventilator-associated
pneumonia." Chest 1992; 102[suppl]:571S-579S.
[0208] Histologic Interpretation
[0209] All microscopic samples were scored based on the grading scale
described below by an animal pathologist (MEO) and were scored
independently by a second animal pathologist (BGH). Both pathologists
were blinded to the experimental protocol and the region of sampling. The
histologic classification of lung tissue specimens was similar to that
employed by other investigators (Baron et al. "Classification and
identification of bacteria." In: Murray PR, ed. Manual of clinical
microbiology. Washington, D.C.: ASM Press, 1995; 249-264; Marquette, et
al. "Characterization of an animal model of ventilator-acquired
pneumonia." Chest 1999; 115:200-209). Fresh tissue samples were fixed in
10% neutral buffered formalin. After fixation for >24 h, samples were
dehydrated in ethanol and xylene and were embedded in paraffin. After
sectioning, tissue samples were stained with hematoxylin-eosin. Sections
were examined and photographed on a light microscope (Nikon; Tokyo,
Japan), after which each photograph was assigned a unique and permanent
identification number.
[0210] Histology samples of the lung were scored using several scales.
[0211] Hyperemia: 0, no hyperemia; 1, (slight) capillaries distended with
blood; 2, (moderate) capillaries distended with blood and some alveoli
filled with serous fluid and/or blood; and 3, (severe) capillaries are
distended with blood and most alveoli are filled with serous fluid and/or
blood.
[0212] Edema: 0, no edema; 1, slight interstitial fluid accumulation; 2,
serous fluid in alveoli and moderate interstitial fluid accumulation; and
3, large amounts of serous fluid in alveoli and excessive interstitial
fluid accumulation.
[0213] Cellular infiltration: 0, no cellular infiltration into alveolar or
interstitial space; 1, occasional neutrophils; lymphocytes and/or large
mononuclear cells in the alveoli and interstitial space associated with
some alveoli; 2, moderate numbers of neutrophils, lymphocytes, and large
mononuclear cells in the alveoli and interstitial space associated with
most alveoli; and 3, large numbers of neutrophils, lymphocytes, and large
mononuclear cells in the alveoli and interstitial space of most alveoli.
[0214] Bacteria: 0, no bacteria visible; 1, occasional bacteria evident
within phagocyte; 2, bacteria within most phagocytes and occasional free
bacteria; and 3, large numbers of bacteria present within phagocytes and
within the alveolar and interstitial spaces.
[0215] Data were reported as the mean .+-.SD. All primary comparisons
between the test and control animals were based on the data for each
lobe, unless otherwise noted. The Fisher's Exact Test was used to compare
categoric data, and the Mann-Whitney test was used to compare non-normal,
continuous data. The Spearman rank test was used to correlate histologic
and microbiology data for each lobe. The K statistic was used to assess
the interobserver agreement for lung infiltration with neutrophils.
[0216] Intubation was performed without difficulty and was achieved on the
first attempt for all animals. Six of the animals that had received
noncoated endotracheal tubes and five that had received silver-coated
tubes completed the study protocol and were included in the data
analysis. One animal receiving a silver-coated endotracheal tube died 6 h
after intubation. This animal mistakenly received an initial tidal volume
of >500 mL, resulting in pneumothorax and subsequent death by an
overdose of sodium pentobarbital. The lungs appeared normal at necropsy,
and this animal was not included in the data analysis as it did not
receive the bacterial challenge with P. aeruginosa. There was no
statistical difference in the duration of mechanical ventilation and the
day of death for dogs receiving either the noncoated or the silver-coated
endotracheal tubes (3.0.+-.1.5 vs. 3.6.+-.0.5 days, respectively;
p=0.330). Three of five animals (60.0%) that had been treated with
silver-coated endotracheal tubes survived to the end of the study period
at 96 h compared to three of the six control animals (50.0%; p>0.999).
The cause of death for the dogs receiving silver-coated endotracheal
tubes included euthanasia for the three dogs completing the protocol, and
cardiac arrest and renal failure for the two dogs not completing the
study protocol, which were expected complications among mechanically
ventilated dogs. The cause of death for the dogs receiving noncoated
endotracheal tubes included euthanasia for the three dogs completing the
protocol, septic shock from P. aeruginosa bacteremia in two animals, and
excessive purulent secretions resulting in endotracheal tube occlusion in
one animal.
[0217] Buccal Cultures: For both test and control dogs, the concentration
of P. aeruginosa in the buccal secretions increased within 24 h after
anesthesia administration and inoculation to >10.sup.8 cfu/g aspirate.
No statistical differences were seen between the two groups for the
degree of buccal colonization throughout the duration of the study
period.
[0218] Endotracheal Tube Lumen Cultures: The average time until
colonization with P. aeruginosa of the inner lumens of the noncoated and
silver-coated endotracheal tubes was 1.8.+-.0.4 and 3.2.+-.0.8 days,
respectively (p=0.016). On day 2 of mechanical ventilation, the inner
lumens of six of six (100.0%) noncoated endotracheal tubes were colonized
by aerobic bacteria and 1 of 5 (20.0%) silver-coated endotracheal tubes
were colonized with aerobic bacteria (p =0.015). Three of six noncoated
endotracheal tubes (50.0%) and one of five silver-coated endotracheal
tubes (20.0%) were colonized with P. aeruginosa on day 2 of mechanical
ventilation (p=0.546). FIG. 2 shows the cumulative probability of the
endotracheal tubes having cultures negative for P. aeruginosa or aerobic
bacteria for the 3 days following intubation and inoculation of the dogs.
[0219] The concentration of aerobic bacteria from the sampled inner lumen
segments of the endotracheal tubes at the time of necropsy was greater
than that for the noncoated endotracheal tubes compared to the
silver-coated endotracheal tubes (6.1.+-.1.3 vs. 4.1.+-.2.1 log cfu/cm,
respectively; p=0.009). Similarly, the concentration of P. aeruginosa
from the sampled inner lumen segments of the endotracheal tubes was
greater for the noncoated endotracheal tubes (4.1.+-.1.0 vs. 2.6.+-.1.9
log cfu/cm, respectively; p=0.076).
[0220] Tracheal and Bronchial Cultures: The trachea and mainstem bronchi
were heavily colonized with P. aeruginosa at postmortem examination. The
upper, mid-portion, and distal trachea, and the mainstem bronchi were
more heavily colonized with P. aeruginosa, and all aerobic bacteria,
among dogs receiving noncoated endotracheal tubes compared to dogs
receiving silver-coated endotracheal tubes (Table 1). However, these
differences did not reach statistical significance.
1TABLE 1
Bacterial Counts in the Trachea and
Mainstem Bronchi*
P aeruginosa All Aerobic Bacteria
Dogs
Dogs
Dogs receiving Dogs receiving
receiving Silver-
receiving Silver-
Noncoated Coated Noncoated Coated
Endotracheal Endotracheal p Endotracheal Endotracheal P
Location
Tubes (n = 6) Tubes (n = 5) Value Tubes (n = 6) Tubes (n = 5) Value
Proximal 6.2 .+-. 0.8 5.5 .+-. 0.7 0.234 6.9 .+-. 0.6 6.1 .+-.
0.5 0.083
trachea
Mid- 5.8 .+-. 0.6 5.3 .+-. 0.7 0.272 7.1
.+-. 0.9 6.4 .+-. 0.8 0.315
trachea
Distal 5.8 .+-. 0.7 4.8
.+-. 0.8 0.054 6.7 .+-. 0.8 6.3 .+-. 1.2 0.647
trachea
Mainstem 4.4 .+-. 2.4 3.6 .+-. 2.0 0.111 5.6 .+-. 1.0 4.5 .+-. 1.0 0.054
bronchi
*Values given as mean log cfu/g (.+-. SD),
unless otherwise indicated.
[0221] Lung Parenchymal Cultures: Bacteria were cultured from all lung
tissue samples that were taken at necropsy. The total aerobic bacterial
burden in the lung parenchyma was statistically lower among the dogs that
had received the silver-coated endotracheal tubes (4.8.+-.0.8 vs.
5.4.+-.0.9 log cfu/g lung tissue, respectively; p=0.010) (Shown in FIG.
3). The tissue concentration of P. aeruginosa among dogs in the
silver-coated group was also lower compared to dogs in the noncoated
endotracheal tube group (4.3.+-.1.2 vs. 4.4.+-.2.1 log cfu/g lung tissue,
respectively; p=0.055). The achieved thresholds of P. aeruginosa among
the 36 lung lobes from dogs receiving noncoated endotracheal tubes were
29 (80.6%) with .gtoreq.10.sup.4 cfu/g, 19 (52.8%) with .gtoreq.10.sup.5
cfu/g, and 6 (16.7%) with .gtoreq.10.sup.6 cfu/g, compared to 20 (66.7%)
with .gtoreq.10.sup.4 cfu/g, 7 (23.3%) with .gtoreq.10.sup.5 cfu/g, and 3
(10.0%) with .gtoreq.10.sup.6 cfu/g among the 30 lung lobes from dogs
receiving silver-coated endotracheal tubes (p=0.105). The achieved
aerobic bacterial thresholds among the 36 lung lobes from dogs receiving
noncoated endotracheal tubes were 34 (94.4%) with 10.sup.4 cfu/g, 24
(66.7%) with .gtoreq.10.sup.5 cfu/g, and 13 (36.1%) with .gtoreq.10.sup.6
cfu/g, compared to 25 (83.3%) with 10.sup.4 cfu/g, 9 (30.0%) with
.gtoreq.10.sup.5 cfu/g, and 4 (13.3%) with .gtoreq.10.sup.6 cfu/g among
the 30 lobes from dogs receiving silver-coated endotracheal tubes
(p=0.028).
[0222] Blood Cultures: Bacteria blood cultures were seen in three of six
(50.0%) control animals and in one of the five animals receiving
silver-coated endotracheal tubes. P aeruginosa bacteremia was seen in two
of six control animals and in zero of five test animals. Staphylococcus
aureus was isolated from the blood of one dog receiving a noncoated
endotracheal tubes and in one dog receiving a silver-coated endotracheal
tube. For the three control animals, the positive blood cultures were
found on days 2, 3, and 4. The positive blood culture was seen in the
test animal on day 4.
[0223] Postmortem Examination
[0224] Endotracheal Tubes Gross Appearance: Five of six of the noncoated
endotracheal tubes (83.3%) and zero of five of the silver-coated
endotracheal tubes (0.0%) had at least a 50.0% narrowing of their lumens
due to the presence of mucus at necropsy (p=0.015). The mean gross
appearance score for the noncoated endotracheal tubes was statistically
greater than for the silver-coated endotracheal tubes (3.6.+-.1.2 vs.
1.2.+-.0.8, respectively; p=0.030).
[0225] Lungs: There was no statistical difference in the mean weight of
the lungs for the animals receiving the noncoated and silver-coated
endotracheal tubes (634.+-.130 vs. 592.+-.53 g, respectively; p=0.524).
The mean scores for the gross appearance of the entire lung for the dogs
receiving noncoated and silver-coated endotracheal tubes were 3.2.+-.1.2
and 1.2.+-.0.4, respectively (p=0.030). The major pathologic findings
were congestion and hyperemia in both groups. Both veterinary
pathologists found statistically significant differences in the
histologic evaluation of the dogs receiving noncoated endotracheal tubes
compared to the dogs receiving silver coated endotracheal tubes (MEO:
7.1.+-.1.6 vs. 2.8.+-.1.2, respectively [p<0.001]; BGH: 3.0.+-.0.7 vs.
2.1.+-.1.3, respectively [p=0.001]). FIG. 4 depicts a scatter plot of
histology scores (x-axis) plotted against the lung tissue concentration
of total aerobic bacteria (y-axis). The regression line is also shown.
[0226] The most prominent histologic changes consisted of diffuse
neutrophil infiltration into the alveolar walls and capillaries, which
was noted primarily in the dogs receiving noncoated endotracheal tubes.
One observer (BGH) noted that 21 of 33 lung lobes (63.6%) from dogs
receiving noncoated endotracheal had large numbers of interstitial
neutrophils present compared to only 1 of 28 lung lobes (3.6%) from dogs
receiving silver-coated endotracheal tubes (p<0.001). Similarly, the
second observer (MEO) scored 17 of 33 lung lobes (51.5%) and none of 28
lung lobes (0.0%) from the same groups of animals, respectively, as
having large numbers of interstitial neutrophils (p<0.001). The
.kappa. statistic for agreement between these two observers was 0.3642
(p=0.005) for scoring neutrophil infiltration in the alveolar walls and
capillaries.
[0227] Correlation of Microbiological and Histologic Findings: A
statistically significant correlation was found between the concentration
of aerobic bacteria in the lung tissue specimens and the observed
histology scores (Spearman rank correlation coefficient, 0.430;
p<0.001, see FIG. 3). Similarly, a statistically significant
correlation was found between the concentration of P. aeruginosa in the
lung tissue specimens and the observed histology scores (Spearman rank
correlation coefficient, 0.356; p=0.005).
Example 17
Rabbit Study
[0228] A study was conducted in rabbits to assess whether silver-coated
endotracheal tubes reduce the colonization and migration of a bacteria
challenge as compared to non-coated tubes. Observations were also made
regarding the biocompatibility of the silver-coated device.
[0229] 12 adult female New Zealand White rabbits were anesthetized and
intubated with 3 mm inner diameter (ID) endotracheal tubes. Six rabbits
received endotracheal tubes (referred to throughout this application as
ETTs or ET tubes) coated with a polymer coating in which the polymer was
50% PVC and 50% polyurethane. The coating contained 5%
colloidal silver
chloride by weight. (The tubes were coated using procedures essentially
identical to those of EXAMPLE 25). Six additional rabbits served as a
control group and received ETTs that were identical to these tubes except
that they were not coated. The tube's exterior within the oral cavity of
the rabbits was inoculated at 0 and 6 hours with a respiratory P.
aeruginosa isolate (PAO1, 1 ml each time, 9.times.10.sup.9 CFU/ml in a
saline solution). Subjects were positions to prevent the inocula from
draining down the tube. The animals were maintained under anesthesia for
16 hours without incident and sacrificed. The endotracheal tube and
adjacent trachea distal to the larynx were aseptically removed by
dissection. Samples of the proximal (ventilator end), middle, and distal
(patient end) portions from both the endotracheal tubes and tracheal
tissue and were taken for quantitative microbiology (total aerobic
bacteria and P. aeruginosa).
[0230] The proximal 1 centimeter, middle 1 cm, and distal 1 cm of the
trachea in contact with the endotracheal tube for each animal were
removed and placed in 1 ml of phosphate buffered saline. These samples
were sonicated for 5 minutes then diluted 10-fold in PBS. The solutions
were plated on tryptic soy agar and Pseudomonas isolation agar.
[0231] The proximal 1 centimeter, middle 1 cm, and distal 1 cm of each
endotracheal tube were removed and placed in 1 ml of phosphate buffered
saline. The lumen of the tube was disinfected with a 70% alcohol soaked
swab. These samples were sonicated for 5 minutes then 10-fold diluted in
PBS. The solutions were plated on tryptic soy agar and Pseudomonas
isolation agar.
[0232] A lung sample from each animal was collected in a pre-weighed vial
containing 1 ml of phosphate buffered saline. The samples were sonicated
for 5 minutes then 10-fold diluted in PBS. The solutions were plated on
tryptic soy agar and Pseudomonas isolation agar.
[0233] Samples of trachea and endotracheal tube were also collected for
visualization under a scanning electron microscope.
[0234] Bacterial burden was determined by manual plate count. Bacterial
burden on the proximal, middle, and distal samples from the tubes and
trachea were found to be not statistically different by the F test for
analysis of variance. Accordingly, the proximal, medial, and distal
samples were grouped for subsequent analysis. The histopathology of
tracheal samples was also assessed.
[0235] For P. aeruginosa , 6/6 of the control tubes were colonized
compared to 2/6 of the silver-coated tubes. As well, 6/6 of the control
rabbits' tracheal tissues were colonized compared to 3/6 of the test
rabbits. P. aeruginosa had migrated to the lung tissue of 4/6 control
rabbits, but no (0/6) test rabbits showed P. aeruginosa in the lungs.
Histopathology of the control rabbit tracheas consistently demonstrated
large numbers of inflammatory cells (polymorphonuclear leukocytes or
PMNs) and blunted cilia. For the test rabbits, only one rabbit was
characterized by having large numbers of inflammatory cells (PMNs), two
rabbits had PMNs with intact epithelium, and three rabbits were
characterized as having normal tissue. Histopathology observations appear
in Table 2. Bacteria counts appear in Tables 3 and 4.
2TABLE 2
Histopathology of tracheal samples removed
from rabbits
Rabbit ID Histopathology Description
1 Large numbers of inflammatory cells (PMN's) within the lumen of the
Uncoated trachea. Inflammatory cells present between the ciliated
columnar
epithelial cells and in the submucosal space. Cilia are
blunt and in some
cases sparse.
2 Inflammatory cells
(PMN's) within the lumen of the trachea.
Uncoated Inflammatory
cells present between the ciliated columnar epithelial cells
and
in the submucosal space. Cilia are blunt and in some cases sparse.
3 Large numbers of inflammatory cells (PMN's) within the lumen of the
Uncoated trachea. Inflammatory cells present between the ciliated
columnar
epithelial cells and in the submucosal space. Some
tracheal areas denuded
of epithelial cells. Cilia are blunt and
in some case sparse.
4 Large numbers of inflammatory cells
(PMN's) within the lumen of the
Uncoated trachea. Inflammatory
cells present between the ciliated columnar
epithelial cells and
in the submucosal space. Many tracheal erosions are
evident and
there is extensive PMN infiltration at these sites. Cilia are
blunt and in some cases sparse.
5 Large numbers of inflammatory
cells (PMN's) within the lumen of the
Uncoated trachea.
Inflammatory cells present between the ciliated columnar
epithelial cells and in the submucosal space. Many tracheal erosions are
evident and there is extensive PMN infiltration at these sties.
Cilia are
blunt and in some cases sparse.
6 Large numbers
of inflammatory cells (PMN's) within the lumen of the
Uncoated
trachea. Much of the epithelial lining is absent Inflammatory cells
present
in the submucosal space. Many tracheal erosions are
evident and there is
extensive PMN infiltration at these sites.
Cilia are blunt and In some cases
sparse
7 Inflammatory
cells (PMN's) within the lumen of the trachea. Epithelial
Coated
lining is intact and there are no erosions. Occasional inflammatory cells
present in the submucosal space. Cilia are blunt and in some case
sparse.
8 Inflammatory cells (PMN's) within the lumen of the
trachea. Epithelial
Coated lining is intact and there are no
erosions. Occasional inflammatory cells
present in the submucosal
space. Cilia are blunt and in some case sparse.
9 The tissue
appears normal.
Coated
10 The tissue appears in general
normal. Occasional Inflammatory cells
Coated (PMN's) within the
lumen of the trachea.
11 The tissue appears normal.
Coated
12 Large numbers of inflammatory cells (PMN's) within the lumen of
the
Coated trachea. Much of the epithelial lining is absent.
Inflammatory cells
present in the submucosal space. Many tracheal
erosions are evident and
there is extensive PMN infiltration at
these sites. Cilia are blunt and in
some cases sparse
[0236]
3TABLE 3
Total bacterial Counts on Endotracheal
Tube, Trachea and Lung
Total Bacterial Count (TSA)
Endotracheal Tube (cfu/cm) Trachea (cfu/cm)
Rabbit Proximal Mid
Distal Proximal Mid Distal Lung (cfu/g)
1 (control) 3.0e6
1.9e6 8.0e5 1.7e5 1.0e5 7.0e5 4.0e5
2 (control) 1.8e4 1.9e4 3.4e5
3.5e4 2.1e4 1.4e4 5.8e5
3 (control) 1.9e4 4.0e4 4.4e4 1.0e6 6.0e5
5.5e5 4.5e5
4 (control) 2.4e5 2.9e5 1.2e6 4.4e5 7.3e4 6.0e4 1.0e5
5 (control) 6.4e5 6.6e5 1.9e6 6.2e5 3.0e4 3.1e4 2.9e5
6
(control) 4.0e4 2.5e6 2.5e5 1.5e5 2.4e4 1.4e5 NG
7 (test) 1.4c3
2.0e4 1.9e3 6.0e2 7.9e3 2.4e2 NG
8 (test) 1.3e2 NG NG 1.9e3 2.2e3
1.4e2 NG
9 (test) NG NG NG NG NG NG NG
10 (test) 8.0e3
7.5e4 2.2e4 1.7e5 1.0e5 3.0e5 NG
11 (test) NG NG NG NG NG NG NG
12 (test) 5.0e2 7.5e2 3.5e3 2.0e3 1.1e5 9.0e5 NG
[0237]
4TABLE 4
Pseudomonas Counts on Endotracheal Tube,
Trachea and Lung
Pseudomonas Count (PIA)
Endotracheal Tube
(cfu/cm) Trachea (cfu/cm)
Rabbit Proximal Mid Distal Proximal Mid
Distal Lung (cfu/g)
1 (control) 1.0e5 7.0e5 6.6e5 4.0e4
5.0e4 1.1e4 2.0e3
2 (control) 3.9e2 4.4e3 7.2e3 3.1e4 4.5e3 1.2e4
NG
3 (control) 1.0e3 6.0e3 4.2e3 1.9e3 1.1e3 9.4e2 1.6e3
4 (control) 1.0e3 2.4e3 5.5e4 4.0e4 3.3e4 6.7e3 5.6c3
5 (control)
2.7e3 3.6e4 3.0e4 4.2e3 7.7e3 1.1e2 4.3e4
6 (control) NG 5.0e4
5.0e3 1.5e3 6.5e3 3.8e4 NG
7 (test) 7.0e2 1.1e2 2.0e2 1.0e2 3.5e2
5.5e2 NG
8 (test) NG NG NG NG NG NG NG
9 (test) NG NG NG
NG NG NG NG
10 (test) 3.1e3 2.4e4 8.5e3 4.5e4 2.5e4 4.5e4 NG
11 (test) NG NG NG NG NG NG NG
12 (test) NG NG NG 2.5e2 2.0e2
1.0e2 NG
[0238] Numbers are presented in exponential notation. For example, "5.0e2"
refers to 5.times.10.sup.2.
[0239] Table 5 summarizes the quantitative microbiological findings for
which log.sub.10 reductions of 2-4 were measured for the groups receiving
the silver-coated ETTs.
5 TABLE 5
Aerobic Bacteria.sup.a
Pseudomonas.sup.a
ETT Trachea Lung ETT Trachea Lung
Non-coated 5.42 .+-. 0.78 5.08 .+-. 0.61 4.58 .+-. 2.26 3.84 .+-. 1.33
3.83 .+-. 0.72 2.48 .+-. 1.99
Silver- 1.95 .+-. 1.90 2.66 .+-.
2.20 0.54 .+-. 1.32 1.05 .+-. 1.62 1.54 .+-. 1.77 0.00 .+-. 0.00
coated
p Values.sup.b <0.0001 0.0010 0.0167 <0.0001 0.0004
0.0208
.sup.aMean .+-. SD for log.sub.10 CFU per cm tube
or gram tissue.
.sup.bMann-Whitney Rank Sum test.
Based
on the histopathology of the two groups, the coating did not appear to
adversely affect host tissue.
Example 18
In Vitro Microbial Adherence Studies
[0240] Microbial adherence assays were performed on coated tubes with
different silver levels and adherence was compared to a non-coated PVC ET
tube. The coating was a polymer composition of 50% PVC and 50%
polyurethane with silver present as
colloidal silver chloride (prepared
from silver nitrate and sodium chloride). The first step in device
colonization is adherence of organisms to the surface, and this step
occurs in a relatively short time (minutes). The assay assesses microbial
adherence relative to a non-coated control by exposing portions of the
tubes to high concentrations of various organisms (10.sup.8-10.sup.9
CFU/ml) for 2 hours. An alternative procedure is used for Candida because
their adherence occurs slowly and with few organisms. Coated samples of
known size are prepared from coated endotracheal tubes and compared with
uncoated controls.
[0241] Procedure for Organisms Other Than Candida
[0242] Cultures were prepared for each organism as follows. 200 ml of
sterile media was inoculated with bacteria from a starter culture.
Bacteria were then grown in Trypticase Soy Broth at 37.+-.1.degree. C. on
a rotary shaker (approximately 150 rpm) for 12-18 hours. Cells were
harvested by centrifugation for approximately 10 minutes at 4000.times.g
at approximately 25.degree. C., then washed twice using approximately 30
ml of 0.9% saline and centrifugation as described above.
[0243] Cells were suspended in minimal broth and adjusted to an optical
density at 600 nm corresponding to a cell density of approximately
2.times.10.sup.8 cells/ml. This suspension was then incubated at
37.+-.1.degree. C. with rotary shaking (approximately 150 rpm) for 1 hour
.+-.10 minutes. L-[3, 4, 5.sup.-3 H]-leucine was then added at a volume
of 0.05% of the volume of the cell suspension (e.g., 20 .mu.l leucine
would be added to 40 ml of cell suspension). Incubation was continued for
an additional 20.+-.5 minutes. Cells were harvested and washed twice
using approximately 30 ml of 0.9% saline and centrifugation at
4000.times.g at approximately 25.degree. C. The pellet was then suspended
in 0.9% PBS to a final concentration of approximately 10.sup.8 cells/ml.
[0244] Samples (coated and uncoated) were incubated with rotary shaking
(.about.150 rpm) for 2 hours in the radiolabeled cell suspension at
37.+-.2.degree. C. The volume of cell suspension completely covered the
sample. At the end of incubation, samples were immersed five times
(approximately 1 second each time) in each of three successive volumes
(approximately 160 ml) of 0.9% saline. Excess saline was then shaken from
each piece and samples were placed in separate 20 ml glass scintillation
vials containing 10 ml Opti-Fluor7 scintillation cocktail (Packard
Instrument Co.). DPM was measured in each vial using a liquid
scintillation counter (LS-5801, Beckman Instruments).
[0245] The number of organisms, as colony-forming units (CFU),
corresponding to the radioactivity (DPM) was determined by serially
diluting and plating labeled organisms and determining the radioactivity
of the sample in DPM. A calibration chart was first prepared by measuring
the DPM of samples containing a known number of radiolabeled CFU. The
calibration chart was then used to convert DPM measurements to CFU.
Microbial adherence is reported below for all samples (other than Candida
spp.) as CFU per surface area of the device sample (CFU/mm.sup.2). Within
each testing batch, the coated samples are compared to the non-coated
samples, and a percent reduction in adherence is determined.
[0246] Procedure Used for Candida spp.
[0247] Cultures were prepared for Candida species as follows. 200 ml of
sterile media was inoculated with cells from a starter culture. Cells
were then grown in Sabouraud Dextrose Broth (SDB) at 25.+-.1.degree. C.
in a rotary shaker (approximately 150 rpm) for 24 hours. Cells were
harvested by centrifugation for approximately 10 minutes at 4000.times.g
at approximately 25.degree. C., then washed twice using approximately 30
ml of 0.9% saline and centrifugation as described above.
[0248] Test samples were prepared for each suspension by cutting pieces of
the tube. Samples were incubated with rotary shaking (.about.150 rpm) for
18 hours in the cell suspension at 37.+-.2.degree. C. The volume of cell
suspension was sufficient to completely cover the sample. At the end of
incubation, samples were removed and immersed five times (approximately 1
second each time) in each of three successive volumes (approximately 160
ml) of 0.9% saline. Excess saline was shaken from each piece and the
rinsed test samples were each transferred into corresponding vials of PBS
containing L-[3, 4, 5- .sup.3H]-leucine at a volume of 0.05% of the total
media volume and incubated at 37.+-.1.degree. C. with rotary shaking
(approximately 150 rpm) for 30.+-.5 minutes.
[0249] At the end of incubation, each test piece was immersed five times
(approximately 1 second each time) in each of three successive volumes
(approximately 160 ml) of 0.9% Saline. Excess saline was shaken from each
piece and each piece was placed in separate 20 ml glass scintillation
vials containing 10 ml Opti-Fluor7 scintillation cocktail (Packard
Instrument Co.). DPM was measured in each vial with a liquid
scintillation counter, (LS-5801, Beckman Instruments). Data was corrected
for background decay. For Candida, adherence values are in scintillation
units of DPM, rather than CFU.
[0250] Microorganisms relevant to the study of respiratory infections were
used in the assay. Clinical isolates from airway and sputum samples from
hospital laboratories and American Type Culture Collection (ATCC) were
used. Greater differences in adherence were seen in organisms that adhere
in greater numbers. Table 6 below summarizes the results.
6TABLE 6
Summary of In Vitro Microbial Adherence
Studies
Score Comparison to Non-Coated ETT
2
Statistically less adherence on Silver-Coated ETT, >90% reduction
1 Statistically less adherence on Silver-Coated ETT, >range
30%-90% reduction
0 Statistically equivalent adherence
-1
Statistically greater adherence to Silver-Coated ETTs
[0251]
7
Performance
Non-coated Silver.sup.a
Silver.sup.a Silver.sup.a
Organism ID# CFU/mm.sup.2 5.5
.mu.g/cm.sup.2 13.0 .mu.g/cm.sup.2 20.4 .mu.g/cm.sup.2
Pseudomonas aeruginosa ATCC 27853 3.91 .times. 10.sup.5 2 2 2
Pseudomonas aeruginosa NGH 52461-02 3.62 .times. 10.sup.5 2 2 2
Pseudomonas aeruginosa ATCC 27318 2.36 .times. 10.sup.5 2 2 2
Pseudomonas aeruginosa GSU-3 1.39 .times. 10.sup.5 2 2 2
Pseudomonas aeruginosa ATCC 17831 1.38 .times. 10.sup.5 2 2 2
MRSA
U Cinn 4.05 .times. 10.sup.4 1 1 1
Enterobacter cloacae U Cinn
1.93 .times. 10.sup.4 1 1 1
Enterobacter aerogenes ATCC 13048 1.50
.times. 10.sup.4 1 1 1
Staphylococcus aureus ATCC 700698 1.34
.times. 10.sup.4 1 1 1
Klebsiella pneumoniae ATCC 8047 1.13
.times. 10.sup.4 1 0 1
Enterobacter aerogenes U Cinn 9.06 .times.
10.sup.3 1 1 1
Acinetobacter baumannii U Cinn 5.29 .times.
10.sup.3 1 0 0
Klebsiella pneumoniae NGH 52461-03 3.18 .times.
10.sup.3 1 0 -1
Serratia marcescens ATCC 43422 2.84 .times.
10.sup.3 1 0 0
Enterobacter cloacae NGH 52287 2.43 .times.
10.sup.3 0 -1 -1
Acinetobacter ATCC 19001 2.05 .times. 10.sup.3 1
1 1
Acinetobacter ATCC 27251 2.02 .times. 10.sup.3 0 1 0
Enterobacter aerogenes NGH 52328 1.67 .times. 10.sup.3 0 0 0
Candida albicans ATCC 11651 N/A 0 0 0
Candida albicans ATCC 32089
N/A 0 0 0
Candida glabrata ATCC 38326 N/A 0 0 -1
Silver levels result from original dipping solutions containing 2.5, 5.0,
and 7.5% silver, respectively.
NGH, GSU, and U. Cinn. refer to
clinical isolates from, respectively: Newton General Hospital, Covington,
Georgia; Georgia State University; and the University of Cincinnati.
"MRSA" refers to Methicillin-resistant S. aureus.
Example 19
Zone of Inhibition Testing
[0252] Zone of inhibition testing was performed to demonstrate the low
migration of silver ions from a coating containing
colloidal silver
chloride. This is an important factor in considering whether silver from
could move down into the lungs. Test samples of a PVC tube were coated
with a polymer containing 50% polyurethane/50% PVC containing
colloidal
silver chloride in three concentrations: greater than 30 .mu.g/cm.sup.2);
13 .mu.g/cm.sup.2; and 5.5 .mu.g/cm.sup.2. Using sterile scissors and
forceps, test samples were prepared from sections ({fraction (1/4)}' to
{fraction (1/2)}" lengths) of each of the tubes. The tests were run in
triplicate for each of the following organisms:
[0253] Candida albicans, ATCC 32089 and ATCC 11651.
[0254] Enterobacter aerogenes, NGH 52328
[0255] Enterobacter cloacae, NGH 52287
[0256] Klebsiella pneumoniae, ATCC 8047 and NGH 52461-03
[0257] Pseudomonas aeruginosa, ATCC 17831 and ATCC 27318
[0258] Staphylococcus aureus NGH 52461-01
[0259] Organisms were incubated onto sample plates using known methods.
Samples were then placed onto plates, each of which had been cultured
with one of the organisms. The plates were then incubated to allow growth
of the organism.
[0260] After incubation each of the sample plates was examined for
inhibition of growth of the test organism surrounding the test article.
If inhibition of a test organism was noted, the distance from the edge of
the sample to the closest visible colony was measured and the zone in
millimeters (mm) was recorded. For each of the test organisms the
enumeration plates (either the 1:100 dilution from the stock or the
1:1000 dilution from the stock) were recorded. The approximate starting
count for each organism was recorded.
[0261] Results are as Follows.
[0262] For samples with coating at greater than 30 .mu.g/cm.sup.2:
[0263] No zones of inhibition for any of the samples against the
following:
[0264] Enterobacter cloacae- NGH 52287, Enterobacter aerogenes- NGH 5232,
Klebsiella pneumonia (ATCC 8047 and NGH 52461-03).
[0265] Limited zones (for 1 of the 3 samples) were observed on
Staphylococcus aureus-NGH 52461-01 (a 1 mm zone), Pseudomonas
aeruginosa-ATCC 17831 (a 1 mm zone), and Candida albicans-ATCC 11651 (a 2
mm zone).
[0266] Zones were observed on all three samples for Candida albicans-ATCC
32089 (2-3 mm zones) and Pseudomonas aeruginosa-ATCC 27318 (1 mm zones).
[0267] For samples with coating at 13 .mu.g/cm.sup.2:
[0268] No zones of inhibition for any of the samples against the
following: Pseudomonas aeruginosa-ATCC 17831, Enterobacter cloacae-NGH
52287, Enterobacter aerogenes-NGH 52328 and Klebsiella pneumonia (ATCC
8047 and NGH 52461-03).
[0269] Limited zones (for 1 of the 3 samples) were observed for
Staphylococcus aureus-NGH 52461-01 (1 mm zone) and Candida albicans-ATCC
11651 (1 mm zone).
[0270] Zones were observed for 2 of the 3 samples for Candida
albicans-ATCC 32089 (1 mm zones) and Pseudomonas aeruginosa-ATCC 27318 (1
mm zones).
[0271] For samples with coating at 5.5 .mu.g/cm.sup.2:
[0272] No zones of inhibition for all three samples against the following:
Candida albicans-ATCC 11651, Candida albicans-ATCC 32089, Enterobacter
cloacae-NGH 52287, Enterobacter aerogenes-NGH 52328, Klebsiella
pneumoniae-ATCC 8047, Klebsiella pneumoniae-NGH 52461-03, Pseudomonas
aeruginosa-ATCC 17831 and Staphylococcus aureus-NGH 52461-01.
[0273] Zones of 1 mm were observed on all three samples of Pseudomonas
aeruginosa-ATCC 27318.
Example 20
Elution Testing and Microbial Adherence Testing After Elution Testing
[0274] Elution profile testing was conducted on ETTs to simulate and
evaluate the release of the silver when exposed to body fluids. The
incubation solution was 0.90% saline solution. Cuffed tracheal tubes made
of PVC and having a diameter of 7.5 mm were obtained. The tubes were
coated with a polymer coat in which the polymer was 50% PVC and 50%
polyurethane. The coating also contained 5%
colloidal silver chloride
prepared by combining silver nitrate and sodium chloride (using the
procedures of Example 25). Sterile coated tubes were cut into 1.0 cm
pieces starting about 1 cm from edge of where the cuff is adhered. The ET
tube pieces were separated as they were cut for assay of total silver,
bacterial adherence after elution, and assay for total silver after
elution. All total silver analyses (also referred to as "silver assays"
"total silver assays") in this Example and anywhere else in this
application involved verified assay methods.
[0275] Samples of coated tubes for total silver assay after elution and
bacterial adherence after elution were placed into pre-heated vials (3
pieces per vial) containing the incubation solution and incubated for 1
hour at 37.degree. C. in an oven. Pieces were then removed from the
vials, drained on the inner vial walls, placed in a second set of vials,
each containing 30 ml incubation solution, and incubated for another hour
at 37.degree. C., for a cumulative incubation time of 2 hours. Pieces
were then removed from the vials, drained on the inner vial walls, placed
in a third set of labeled, pre-heated vials containing 30 ml of the
incubation solution, and incubated for 2 more hours at 37.degree. C., for
a cumulative incubation time of 4 hours. Pieces were then removed,
drained on the inner vial walls, placed in a fourth set of labeled,
pre-heated vials containing 30 ml incubation solution and incubated for 4
more hours in an oven at 37.degree. C., for a cumulative incubation time
of 8 hours. Pieces were then removed from the fourth set of vials,
drained on the inner vial walls, placed in a fifth set of labeled,
pre-heated vials containing 30 ml incubation solution, and incubated for
16 more hours in an oven at 37.degree. C., for a cumulative incubation
time of 24 hours.
[0276] At the conclusion of 24 hours, three samples were removed and
subjected to total silver analysis. At the same time, six samples were
removed, dried, sterilized with ethylene oxide, and subjected to
bacterial adherence testing using Pseudomonas aeruginosa pursuant to the
procedures in Example 18 above. All other samples were removed from the
vials, drained on the inner vial walls, placed in another set of vials,
each containing 30 ml incubation solution, and incubated for another 48
hours (two days) at 37.degree. C., changing incubation solution daily,
for a cumulative incubation time of three days.
[0277] At the conclusion of three days, three samples were removed and
subjected to total silver analysis. At the same time, six samples were
removed, dried, sterilized with ethylene oxide, and subjected to
bacterial adherence testing using Pseudomonas aeruginosa pursuant to the
procedures in Example 18 above. All other samples were removed from the
vials, drained on the inner vial walls, placed in another set of vials,
each containing 30 ml incubation solution, and incubated for another 96
hours (four days) at 37.degree. C., changing incubation solution daily,
for a cumulative incubation time of seven days.
[0278] At the conclusion of seven days, three samples were removed and
subjected to total silver analysis. At the same time, six samples were
removed, dried, sterilized with ethylene oxide and subjected to bacterial
adherence testing using Pseudomonas aeruginosa pursuant to the procedures
in Example 18 above. All other samples were removed from the vials,
drained on the inner vial walls, placed in another set of vials, each
containing 30 ml incubation solution, and incubated for another 168 hours
(7 days) at 37.degree. C., changing incubation solution daily, for a
cumulative incubation time of 14 days.
[0279] At the conclusion of 14 days, three samples were removed and
subjected to total silver analysis. At the same time, six samples were
removed, dried, sterilized with ethylene oxide, and subjected to
bacterial adherence testing using Pseudomonas aeruginosa pursuant to the
procedures in Example 18 above. All other samples were removed from the
vials, drained on the inner vial walls, placed in another set of vials,
each containing 30 ml incubation solution, and incubated for another 168
hours (7 days) at 37.degree. C., changing incubation solution daily, for
a cumulative incubation time of 21 days.
[0280] At the conclusion of 21 days, three samples were removed and
subjected to total silver analysis. At the same time, the six remaining
samples were removed, dried, sterilized with ethylene oxide, and
subjected to bacterial adherence testing using Pseudomonas aeruginosa
pursuant to the procedures in Example 18 above.
[0281] Samples that were not eluted were also assayed using total silver
analysis. These non-eluted samples provided the initial (pre-elution)
silver concentration values for each tube.
[0282] Total Silver Analysis results were used to calculate silver loss
for each tube at each interval. The percent loss of silver was calculated
by dividing the concentration of silver remaining on the soaked pieces by
the initial silver concentration and multiplying the result by 100.
Results are presented in Table 7.
8TABLE 7
% Silver Loss and Supporting Data
Time Conc. (ug/cm.sup.2) After Soak. (ug/cm.sup.2) % Loss
24 hours 12.61 7.79 38.23
3 days 13.42 5.33 60.31
7
days 14.21 2.19 84.57
14 days 14.47 3.71 74.40
21 days
13.28 2.63 80.20
[0283] The saline elution model indicates that after 14 days approximately
25% of the silver remains.
[0284] Uncoated tubes were then prepared for comparison of microbial
adherence by subjecting them to the same elution procedures as for the
test samples
[0285] Results of the bacterial adherence testing after saline elution of
the samples for 1, 3, 7, 14, and 21 days are shown in Table 8 and appear
in the graph set forth in FIG. 5.
9 TABLE 8
Mean CFU/mm.sup.2 Standard deviation
Day Uncoated Coated Uncoated Coated
1 5.78E+04
7.27E+03 3.29E+03 5.57E+02
3 3.53E+04 6.66E+03 8.41E+03 9.33E+02
7 3.00E+04 1.28E+04 2.07E+03 1.26E+03
14 6.80E+04 1.12E+04
9.48E+03 6.09E+03
21 6.26E+03 1.12E+04 1.02E+03 1.32E+03
[0286] All saline-eluted coated samples were found to have better
microbial adherence performance, i.e., reduced microbial adherence in
terms of CFU/mm.sup.2, as compared to uncoated controls for up to 14 days
of elution.
Example 21
Coefficient of Friction Testing
[0287] Sixty (60) coated and sixty uncoated samples of each type and
diameter tube were used in this testing and testing was conducted in
pairs, resulting in 30 data points per tube size. Substrate tubes were
PVC. For coated tubes, the coating was a polymer solutions in which the
polymers were 50% PVC and 50% polyurethane. The coating also contained
silver in a concentration of 5%, present as
colloidal silver chloride.
Coefficient of friction (COF) was determined by measuring the force
needed to draw an object resting on a pair of tubes along a portion of
the length of those two tubes. In each test, a pair of identical samples
previously hydrated in water at 37.degree. C. for 1 hour, 1 day, 7 days,
14 days or 21 days, was placed in a trough of 37.degree. C. water. A
stainless steel sled weighing 390 grams and having a flat bottom surface
and horizontal dimensions of 2.5 inches by 2.5 inches was wrapped with a
cellulose membrane (dialysis tubing, Spectrapor #1, Spectrum Medical
Industries, Inc.). The sled was then pulled mechanically in a
longitudinal direction along the surfaces of the pairs of samples for a
distance of approximately 5 inches at a constant rate of 6 inches/minute.
The force required to pull the sled at this rate was recorded
continuously and averaged over the test period the sled was pulled. Force
measurements used a Chatillon Model DGGHS force gauge. Pull force data
points were measured in grams and divided by the weight of the sled to
generate a unitless coefficient of friction number. The COF numbers are
averaged to give an average COF value for the thirty data points. Results
for the uncoated (U/C) and coated (C) tubes are present in Table 9.
10TABLE 9
COEFFICIENT OF FRICTION DATA
Type
1 hr. 1 day 7 days 14 days 21 days
6.0 mm inner diameter
tubes
U/C 0.277 .+-. 0.125 0.292 .+-. 0.034 0.414 .+-. 0.079 0.430
.+-. 0.074 0.297 .+-. 0.047
C 0.360 .+-. 0.031 0.347 .+-. 0.035
0.298 .+-. 0.032 0.292 .+-. 0.030 0.246 .+-. 0.025
7.5 mm inner
diameter tubes
U/C 0.342 .+-. 0.060 0.350 .+-. 0.065 0.347 .+-.
0.054 0.315 .+-. 0.066 0.328 .+-. 0.057
C 0.337 .+-. 0.042 0.336
.+-. 0.034 0.262 .+-. 0.033 0.226 .+-. 0.037 0.231 .+-. 0.035
10.0
mm inner diameter tubes
U/C 0.332 .+-. 0.076 0.318 .+-. 0.059
0.317 .+-. 0.059 0.272 .+-. 0.069 0.299 .+-. 0.063
C 0.373 .+-.
0.037 0.269 .+-. 0.031 0.200 .+-. 0.023 0.161 .+-. 0.030 0.138 .+-. 0.039
Example 22
[0288] Samples containing different concentrations of silver salts in the
coatings were prepared to evaluate the effect of different concentrations
of silver salts in the coating used on endotracheal (ET) tubes. PVC
endotracheal tubes were coated with a polymer coating in which 50% of the
polymer was PVC and 50% was polyurethane. The coatings were prepared with
colloidal silver chloride by adding silver nitrate and sodium chloride.
Coatings were prepared containing 1%, 2.5%, 5%, 10%, and 15% silver by
dry coating weight. Uncoated samples and samples with coatings containing
each of these silver concentrations were tested for coefficient of
friction (COF) using the procedures of Example 21, above; zone of
inhibition, using the procedures of Example 19, above; and microbial
adherence using the procedures of Example 18, above. Total Silver
Analysis was also performed using validated methods.
[0289] COF Results
[0290] Testing was performed on endotracheal tubes from each dosage
concentration after a 1 hr, 1 day, 7 day, 14 day, and 21 day soak in
heated water. Results are presented in Table 10.
11TABLE 10
Coefficient of Friction for Different
Concentrations
After Soaking for Different Periods of Time
CONC 1 hr. 1 day 7 days 14 days 21 days
1% 0.140 .+-.
0.020 0.133 .+-. 0.023 0.095 .+-. 0.004 0.104 .+-. 0.008 0.101 .+-. 0.012
2.5% 0.215 .+-. 0.023 0.229 .+-. 0.022 0.152 .+-. 0.031 0.105 .+-.
0.016 0.107 .+-. 0.012
5% 0.357 .+-. 0.051 0.368 .+-. 0.036
0.254 .+-. 0.026 0.172 .+-. 0.050 0.116 .+-. 0.023
10% 0.373 .+-.
0.030 0.354 .+-. 0.019 0.230 .+-. 0.025 0.230 .+-. 0.020 0.229 .+-. 0.034
15% 0.371 .+-. 0.026 0.380 .+-. 0.025 0.276 .+-. 0.017 0.309 .+-.
0.048 0.224 .+-. 0.016
[0291] Zone of Inhibition Results:
[0292] The 1% concentration produced no zone of inhibitions against the
following: Pseudomonas aeruginosa, Staphylococcus aureus, and Candida
albicans.
[0293] The 2.5% concentration produced no zone of inhibitions against the
following: Pseudomonas aeruginosa, Staphylococcus aureus, and Candida
tropicalis.
[0294] The 5% concentration produced no zone of inhibitions against the
following: Pseudomonas aeruginosa, and Staphylococcus aureus. Candida
tropicalis produced a zone on one of three samples but was measured to be
less than 1 mm.
[0295] The 10% concentration produced no zone of inhibitions against the
following: Pseudomonas aeruginosa, Staphylococcus aureus, and Candida
albicans.
[0296] The 15% concentration produced no zone of inhibitions against the
following: Pseudomonas aeruginosa, and Staphylococcus aureus. Candida
tropicalis produced a zone on two of three samples.
[0297] Bacterial Adherence Results:
[0298] Results in DPM and (except Candida) in CFU/MM.sup.2 are presented
in Tables 11 through 15. All controls (referred to as "CONT" in the
tables below) were uncoated silicone. Coated tubes are provided as "ET
TUBE."
12TABLE 11
Bacterial Adherence Data
Staphylococcus aureus ATCC 700698
CFU/mm.sup.2 CONT ET TUBE 1.0% S
2.5% S
1 2.65E+04 4.27E+04 1.24E+04 1.27E+04
2
3.43E+04 3.84E+04 1.33E+04 1.14E+04
3 2.97E+04 3.87E+04 1.11E+04
1.28E+04
4 3.42E+04 3.72E+04 1.42E+04 1.16E+04
5 3.10E+04
4.36E+04 1.21E+04 ??
AVG 3.11E+04 4.01E+04 1.26E+04 1.22E+04
s.d. 3.28E+03 2.83E+03 1.20E+03 7.22E+02
[0299]
13TABLE 12
Bacterial Adherence Data
Pseudomonas aeruginosa ATCC 17831
CFU/mm.sup.2 CONT ET TUBE 1.0% S
2.5% S
1 3.55E+04 5.79E+04 1.00E+04 9.09E+03
2
4.42E+04 6.27E+04 9.14E+03 8.85E+03
3 3.93E+04 7.16E+04 9.59E+03
9.05E+03
4 4.03E+04 8.52E+04 8.62E+03 1.21E+04
5 3.93E+04
7.87E+04 9.30E+03 7.67E+03
AVERAGE 3.97E+04 7.12E+04 9.33E+03
9.35E+03
s.d. 3.11E+03 1.12E+04 5.15E+02 1.65E+03
[0300]
14TABLE 13
Adherence Data
C. albicans ATCC
11651
DPM CONT ET TUBE 2.5% S 5% S 10% S 15% S
#1
184381 640012 26935 36675 26708 24970
#2 116794 512099 35359 24761
26694 16840
#3 174946 273695 28715 11643 26084 21918
#4
200527 618035 22848 23747 26018 22977
#5 107633 273231 28576 23195
16054 22027
Background 55 46 55 51 54 53
Surface 428 560
560 560 560 560
Area (mm.sup.2)
#1 430.668 1142.796 48 65.4
47.596 44.495
#2 272.755 914.380 63.043 44.125 47.571 29.977
#3 408.624 488.659 51.179 20.7 46.482 39.045
#4 468.393 1103.552
40.702 42.314 46.364 40.936
#5 251.350 487.830 50.930 41.329
28.571 39.239
Average 366.358 827.444 50.771 42.774 43.317 38.738
s.d. 97.879 321.463 8.060 15.838 8.264 5.36
[0301]
15TABLE 14
Bacterial Adherence Data
Staphylococcus aureus ATCC 700698
CFU/mm.sup.2 CONT ET TUBE 2.5% S
5% S 10% S 15% S
1 1.05E+04 2.64E+04 9.13E+03 1.17E+04
1.21E+04 1.57E+04
2 2.35E+04 2.65E+04 9.81E+03 1.15E+04 1.11E+04
1.24E+04
3 1.42E+04 2.52E+04 1.02E+04 1.31E+04 1.60E+04 1.32E+04
4 1.38E+04 2.76E+04 9.86E+03 1.12E+04 1.64E+04 1.47E-04
5
1.71E+04 2.27E+04 1.21E+04 1.27E+04 1.28E+04 1.26E+04
AVG 1.58E+04
2.57E+04 1.02E+04 1.20E+04 1.37E+04 1.37E+04
s.d. 4.92E+03
1.86E+03 1.14E+03 8.21E+02 2.36E+03 1.44E+03
[0302]
16TABLE 15
Bacterial Adherence Data
Pseudomonas aeruginosa ATCC 17831
CFU/mm.sup.2 CONT ET TUBE 2.5% S
5% S 10% S 15% S
1 4.62E+04 1.04E+05 8.96E+03 8.89E+03
9.01E+03 5.57E+03
2 5.86E+04 1.09E+05 8.30E+03 8.47E+03 1.17E+04
8.19E+03
3 4.69E+04 1.12E+05 1.15E+04 8.38E+03 9.27E+03 7.90E+03
4 4.45E+04 1.18E+05 8.01E+03 8.10E+03 9.06E+03 6.55E+03
5
4.68E+04 1.07E+05 9.39E+03 1.12E+04 8.15E+03 1.59E+04
AVG 4.86E+04
1.10E+05 9.23E+03 9.01E+03 9.44E+03 8.81E+03
s.d. 5.67E+03
5.09E+03 1.38E+03 1.27E+03 1.33E+03 4.07E+03
[0303] Summary:
[0304] All concentrations tested were found to have reduced bacterial
adherence against Pseudomonas aeruginosa when compared to a PVC control
tube.
[0305] All concentrations tested were found to have reduced bacterial
adherence against Staphylococcus aureus when compared to a PVC control
tube.
[0306] All concentrations tested were found to have reduced bacterial
adherence against Candida albicans when compared to a PVC control tube.
[0307] Total Silver Analysis results. The results (from on five samples
for each concentration) are presented in Table 16.
17TABLE 16
Average
% Silver Silver
measured in .mu.g/cm.sup.2 .mu.g/cm.sup.2 (n = 5)
1% 2.01, 1.95, 2.00, 1.80, 2.18 1.99
2.5% 5.37, 5.61, 5.42, 5.69,
5.92 5.60
5% 12.81, 13.10, 11.85, 12.81, 12.87 12.69
10%
29.95, 27.89, 28.13, 29.41, 28.74 28.82
15% 44.80, 44.45, 49.89,
42.75, 48.08 46.00
Example 23
Exposure to Drugs and Chemicals
[0308] Testing was conducted to evaluate the interaction of the
silver/hydrogel coating with various chemicals to which the device could
be expected to come into contact during normal use.
[0309] Interaction with Nebulized Atropine Sulfate, Albuterol Sulfate, and
Acetylcysteine
[0310] Separate ET tubes were exposed to one of the following drugs:
Atropine Sulfate, (NDC 10019-250-20), Albuterol Sulfate, USP, 0.083%, NDC
59930-1500-6, and Acetylcysteine, USP, NDC 0074-3308-03. These are drugs
commonly used for respiratory therapy. In each case, the drugs were
nebulized into a chamber containing a cuffed endotracheal tube coated
using the procedures of EXAMPLE 25, below. The nebulizer system comprised
a compressor, reservoir hose, 5-ml-medicine cup, and a T connector. The T
connector was joined to a 2-liter jar modified to receive the T connector
through the jar sidewall. The jar lid was modified to have a small port
acting as a pressure relief valve. One end of the reservoir hose was
connected to the hose port of a nebulizer. The coated tube was then
placed into the 2-liter container, or chamber, and the lid was secured.
The T connector was inserted into the 2-liter chamber, port located on
the sidewall. 3 ml of the drug was placed into the 5-ml.-medicine cup.
The loose end of the reservoir hose was placed in the underside of the
5-ml.-medicine cup. The nebulizer was then turned on, and run until all
the drug had been nebulized. The nebulizer was then turned off, and the
samples were allowed to remain in the chamber for 30 minutes after the
nebulizer had been switched off. The test product was removed and rinsed
using deionized (DI) water by dipping sample in clean DI water twice for
a total of 10 seconds.
[0311] Coefficient of friction (COF) testing was performed on endotracheal
tubes from each drug exposure using the procedures set forth in Example
21 above. COF results were collected after a 1 hr, 1 day, 7 day, 14 day,
and 21 day soak in 37.degree. C. water. Results are presented in Table
17.
18TABLE 17
Drug 1 hr. 1 day 7 days 14 days 21 days
Acet. 0.301 .+-. 0.154 .+-. 0.097 .+-. 0.090 .+-. 0.017
0.087 .+-. 0.017
0.037 0.026 0.002
A.S. 0.329 .+-. 0.192
.+-. 0.084 .+-. 0.079 .+-. 0.017 0.107 .+-. 0.030
0.024 0.011
0.009
Albut 0.275 .+-. 0.228 .+-. 0.076 .+-. 0.086 .+-. 0.016
0.108 .+-. 0.011
0.027 0.021 0.003
Acet. =
Acetylcysteine
A.S. = Atropine sulfate
Albut. = Albuterol
sulfate
[0312] The total silver was determined using verified techniques. Results
are presented in Table 18.
19TABLE 18
Total Silver Analysis
Drug
Silver Concentration (.mu.g/cm.sup.2) n = 3
Acet. 12.92
.+-. 0.69
A.S. 15.01 .+-. 3.85
Albut. 13.75 .+-. 0.67
Acet. = Acetylcysteine
A.S. = Atropine sulfate
Albut. = Albuterol sulfate
[0313] Exposure to Lidocaine Jelly, Lidocaine HCl, and Lubricating Jelly
[0314] Separate ET tubes were exposed to Lidocaine Jelly, Lidocaine HCl,
and Lubricating Jelly. A container was filled with enough lidocaine jelly
(2% lidocaine hydrochloride in a solution of water,
hydroxypropylmethylcellulose, and preservatives or equivalent topical
lidocaine containing formulation) such that when 3 ET tubes were immersed
the jelly will cover the ET tubes 1 inch past the coating transition
line. ET tubes were then immersed in the container filled with lidocaine
jelly for approximately 30 minutes. The product was removed after soaking
and excess lubricant was allowed to drain off surface of catheter. The
product was rinsed using deionized (DI) water by immersing sample in
clean DI water bath for 5 minutes and then in another fresh DI water bath
for 1 minute. The same procedures were repeated using lidocaine HCl (2%)
in water and K-Y.RTM. lubricating jelly.
[0315] Samples were visually inspected, tested for coefficient of friction
using the procedures in Example 21 above, and subjected to total silver
analysis using verified methods to determine whether exposure to these
substances adversely affected these characteristics. No coating
delamination, discoloration, or other affects were observed. Coefficient
of friction testing was performed on endotracheal tubes from each drug
exposure. COF results were collected after a 1 hr, 1 day, 7 day, 14 day,
and 21 day soak in heated water. Results are presented in Table 19 below.
20TABLE 19
Drug 1 hr. 1 day 7 days 14 days 21 days
Lube 0.217 .+-. 0.164 .+-. 0.143 .+-. 0.086 .+-. 0.005
0.072 .+-. 0.004
0.021 0.023 0.022
Lid. 0.327 .+-. 0.223
.+-. 0.092 .+-. 0.079 .+-. 0.004 0.084 .+-. 0.012
HCL 0.013 0.021
0.013
Lid. 0.370 .+-. 0.228 .+-. 0.097 .+-. 0.088 .+-. 0.008 0.107
.+-. 0.030
Jelly 0.021 0.032 0.012
Lube =
Lubricating jelly
Lid HCL. = Lidocaine HCl in water
Lid
Jelly = Lidocaine Jelly
[0316] Total silver analysis results are presented in Table 20 below.
21 TABLE 20
Drug Silver Concentration
(.mu.g/cm.sup.2) n = 3
Lube 13.53 .+-. 3.24
Lid.
HCL 14.37 .+-. 1.98
Lid. Jelly 14.62 .+-. 0.42
Lube = Lubricating jelly
Lid HCL. = Lidocaine HCl in water
Lid Jelly = Lidocaine Jelly
[0317] The ETT coating is not compromised when exposed to lubricating
jelly.
Example 24
Magnetic Resonance Imaging Interaction Testing.
[0318] Tests were conducted with coated endotracheal tubes to determine
whether magnetic resonance (MR) such as that used in magnetic resonance
imaging (MRI) would produce any effects that would be adverse to a
patient in which such a tube was used. The samples included an
endotracheal tube made from PVC coated with a polymer composition in
which 50% of the polymer was PVC and 50% of the polymer was polyurethane.
The coating contained silver chloride in amounts greater than 30
.mu.g/cm. MR source was a 1.5 Tesla 64 MHz MR system (Sigma MR System,
General Electric Medical Systems, Milwaukee, Wis.).
[0319] Magnetic Field Interaction.
[0320] Translational attraction testing was conducted using a "deflection
angle test," which is described, for example, in American Society for
Testing and Materials Method No. F 2052. Each individual ET tube was
suspended by a 20-cm length of thin thread (weighing less than 5% the
weight of the ET tube) and attached to a plastic protractor so that the
angle of deflection from the vertical could be measured. The test was
conducted at the position in the 1.5-Tesla MR system where the spatial
gradient had been determined to be at a maximum in order to determine the
translational attraction with regard to an extreme magnetic field
exposure condition. It was found that the highest spatial gradient for
the system used for testing occurs at an off-axis position that is 35-cm
inside the opening of the bore of the system. The magnetic spatial
gradient at this position was found to be 450 gauss per centimeter.
[0321] Evaluation was also performed to determine qualitatively the
presence of magnetic field-induced torque for the ET tube. A flat plastic
material with a millimeter grid on the bottom was used (coefficient of
friction was 0.07). Each tube was placed on the test apparatus in an
orientation that was 45 degrees relative to the static magnetic field of
the MR system. The test apparatus with ET tube was then positioned in the
center of the MR system, where the effect of torque from the static
magnetic field was determined to be the greatest based on a previous
magnetic field survey for the MR system. Each ET tube was directly
observed for any possible movement with respect to alignment or rotation
relative to the static magnetic field of the MR system. The observation
process was facilitated by having the investigator inside of the bore of
the MR system during the test procedure. The ET tube was then moved 45
degrees relative to its previous position and again observed for
alignment or rotation. This process was repeated to encompass a full 360
degrees rotation of positions for ET tube in the MR system. The following
qualitative scale of torque was applied to the results: 0, no torque; +1,
mild or low torque, the implant slightly changed orientation but did not
align to the magnetic field; +2, moderate torque, the implant aligned
gradually to the magnetic field; +3, strong torque, the implant showed
rapid and forceful alignment to the magnetic field; +4, very strong
torque, the implant showed very rapid and very forceful alignment to the
magnetic field.
[0322] Two tested samples were found to have a deflection angle of 4
degrees and a qualitative torque of zero. It was thus concluded that the
tubes would have relatively minor MR field interactions and that use of
the coated tubes would create no additional risk to a patient with
respect to movement or dislodgment for the tested tube.
[0323] Heating Due to MRI
[0324] Heating due to MRI was then determined. An extreme radiofrequency
(RF) power exposure experiment was performed with each ET tube placed
inside of a specially-constructed, gel-filled phantom. A plastic phantom
was prepared and filled with a semi-solid gel to simulate human tissue.
The gelling agent was hydroxyethyl-cellulose (HEC) in an aqueous solution
(91.48% water) along with 0.12% NaCl to create a dielectric constant of
approximately 80 and a conductivity of 0.8 S/m at 64 MHz. The phantom had
dimensions and configuration to approximate the size of the human torso.
The phantom was constructed as a torso that is a 24" high by 17" wide
rectangle with a protrusion centered in the top of the torso to simulate
a head. The protrusion was 11.5 inches high and 6.5 inches wide. The
torso lacked a flow to simulate blood flow and thus would be expected to
experience a more localized heating effect than in the human body. The ET
tube was fixed to a plastic frame to facilitate positioning in the
phantom and MR system during the heating experiment. The Sigma system
described above was used, and the body coil served to send and to receive
RF energy.
[0325] A T1-weighted spin echo pulse sequence was used for imaging, as
follows: total imaging time, 20 minutes; axial plane; 135 msec; echo
time, 20 msec; field of view, 48 cm; imaging matrix, 256.times.128;
section thickness, 20.0 mm; number of section locations, 4; number of
excitations, 27; number of echoes, 4; phasing direction, anterior to
posterior; transmitter gain, 200. The pulse sequence produced a whole
body average specific absorption rate (SAR) of 1.2 W/kg and a spatial
peak SAR of 2.5 W/kg. This level of exposure exceeds that typically used
for clinical MRI procedures.
[0326] Temperature recordings were obtained in this experiment using a
Luxtron Model 3100 Fluoroptic Thermometry system previously demonstrated
to be MRI-compatible and unperturbed at static magnetic field strengths
up to 9.0-Tesla (i.e. an MR spectrometer). This thermometry system has
small fiber-optic probes (0.5 mm diameter) that respond rapidly (response
time, 0.25 seconds), with an accuracy and resolution of .+-.0.1.degree.
C. The ET tube that underwent assessment for MRI-related heating had two
thermometry probes attached to record representative temperature during
the experiment. The probes were placed: at 0.5 mm from the end of the ET
tube (Probe #1); at 0.5 mm from the center of the ET tube (Probe #2); and
in the gel-phantom at a position removed (approximately 40 cm away) from
the ET tube to record a reference temperature during the heating
experiment (Probe # 3). The gel phantom with the ET tube and thermometry
probes was placed inside of the MR system. The gel-filled phantom was
allowed to equilibrate to the temperature of the environmental
temperature for a period of one hour. The room temperature and
temperature of the bore of the MR system were 20.6.degree. C., with a
relative humidity of 45%. The MR system fan was not on during the
experiment. Baseline temperatures were recorded at 20-sec. Intervals for
5 minutes. MRI was then performed for 20 minutes with temperatures
recorded at 20-sec. Intervals. The highest temperature changes were
+0.5.degree. C. for Probe #1, +0.5 0.degree. C. for Probe #2, and
+0.4.degree. C. for Probe #3.
[0327] Induced Electrical Currents
[0328] A comprehensive analysis of the interaction of the ET tube with MRI
time-varying fields was performed. Measurements were made with an HP
digital multimeter using a pair of needle probes. The probes were pressed
into the tubing to make good electrical contact. The following sections
of the ET tube were checked: main tube, end connector, flue rod, and
inflation cuff. All sections exhibited an impedance in excess of 1
M.OMEGA. when the voltmeter probes were 1 cm apart. Thus, the ET tube is
essentially an insulator when compared to conductivity of tissue. The
only conducting section of the tube is the spring at the end of the air
tube. The spring has a length of about 7 mm, a diameter of about 3 mm and
has about 7 turns. The wire has a radius of about 0.1 mm. The spring is
covered by plastic insulating material of about 3 mm thickness. The
resistance of the spring is calculated a approximately 0.21 .OMEGA.. It
was determined by calculation that RF-induced temperature rise may occur
near the flanks and end of the tube that is approximately twice the
background rise, but that this would be expected to be no more than will
already occur due to the electrical heterogeneities in the body.
RF-induced heating should be otherwise imperceptible. Heating by pulse
gradient current would expect to result in a temperature rise less than
0.008.degree. C.
[0329] Artifact Test
[0330] MRI artifacts were assessed for one sample of the ET tube. This
test was accomplished by performing MR imaging with the ET tube placed
inside of a gel-filled phantom. The phantom had a rectangular shape with
the following dimensions: 30-cm width, 55-cm height, 75-cm length. The ET
tube was attached to a plastic frame to facilitate positioning and MR
imaging within this phantom. MR imaging was conducted using the Sigma
system described above, with a send-receive body coil.
[0331] A T1-weighted spin echo pulse sequence was used for imaging, as
follows: repetition time, 500 msec; echo time, 20 msec; field of view, 30
cm; matrix size, 256.times.256; section thickness, 5 mm; number of
excitations, 2; bandwidth, 16 kHz. A gradient echo (GRE) pulse sequence
was also used, repetition time, 100 msec; echo time, 15 msec; flip angle,
30 degrees; field of view, 30 cm; matrix size, 256.times.256; section
thickness, 5 mm; number of excitations, 2; bandwidth, 16 kHz. The imaging
planes were oriented to encompass the long axis and short axis of the ET
tube. The frequency encoding direction was parallel to the plane of
imagine. The planimetry software provided with the MR system was used to
measure the cross-sectional areas for the artifacts associated with the
ET tube. The accuracy of this planimetry method is .+-.10.
[0332] The artifacts that appeared on the MR images were shown as
localized signal voids (i.e. signal loss) easily recognized on images. In
general, the GRE pulse sequence produced larger artifacts that the
T1-weighted, spin echo pulse sequence for the ET tube. It was concluded
that the artifacts should not affect the function of MR systems unless
the imaging area of interest is in the exact same position or close to
the device. Results appear below in Table 21.
22TABLE 21
Summary of MRI Artifact Information for
ET Tube
Signal Void 2,406 mm.sup.2 161 mm.sup.2
2,598 mm.sup.2 184 mm.sup.2
Size
Static Magnetic 1.5 1.5
1.5 1.5
Field (T)
Pulse Sequence T1-SE T1-SE GRE GRE
TR (sec.) 500 500 100 100
TE (sec.) 20 20 15 15
Flip Angle
N/A N/A 30.degree. 30.degree.
Bandwidth 16 kHz 16 kHz 16 kHz 16
kHz
Field of View 30 cm 30 cm 30 cm 30 cm
Matrix Size 256
.times. 256 256 .times. 256 256 .times. 256 256 .times. 256
Section 5 mm 5 mm 5 mm 5 mm
Thickness
Maximum 6.3 mT/m 6.3
mT/m 6.3 mT/m 6.3 mT/m
Readout
Gradient
Strength
Imaging Plane parallel perpendicular parallel perpen-
dicular
Phantom Filler gel gel gel gel
(T-1-SE,
T1-weighted spin echo; GRE, gradient echo; N/A, not applicable; values
for artifact size indicated in mm.sup.2; Note that the T1 and T2 values
for the gel used for the phantaom filler are similar to the values of
skeletal muscle or organ tissue.)
Example 25
[0333] A coating composition for PVC catheters was prepared as follows: a
3.2% solution of a polyether polyurethane-urea block copolymer available
from CardioTech International, Inc. was prepared in a mixture of
THF/alcohol in a 75/25 ratio by weight. A 4.0% solution of Polyvinyl
chloride (PVC) was then prepared in THF. The two solutions were then
combined in amounts that provide a 50/50 ratio by weight of the two
polymers in solution. A sufficient quantity of 10% silver nitrate
(AgNO.sub.3) solution in water was then added to the
polyurethane-urea/PVC polymer solution to produce a final silver
concentration of approximately 5%, based on coating solids in the
solution. A 2% sodium chloride solution in water was added to the coating
solution in an amount sufficient to react with 100% of the AgNO.sub.3 to
produce a colloid of the poorly water soluble salt AgCl from all of the
AgNO.sub.3. The NaCl solution was added slowly to the polymer solution
with stirring, and the solution began to turn cloudy with the formation
of the fine colloidal AgCl. The amount of water in the final coating
solution was about 4.8% of the total solvent weight. The amount of
alcohol in the solution was about 13.3% of the total solvent weight. A
PVC endotracheal tube was then coated by dipping it into the coating
composition, followed by drying using standard methods. The tube was
dipped to within about 4 cm from the end that resides outside the
patient. The finished coating contained only the poorly water soluble,
and therefore slow releasing, AgCl to provide primarily surface
antimicrobial activity and limit the amount of silver released that could
find its way into the lungs.
[0334] Finally, it will be understood that the preferred embodiments have
been disclosed by way of example, and that other modifications may occur
to those skilled in the art without departing from the scope and spirit
of the appended claims.
