Note: Descriptions are shown in the official language in which they were submitted.
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SILVER-BASED ANTIMICROBIAL COMPOSITIONS
FIELD OF THE INVENTION
' The present invention relates to silver-based antimicrobial compositions and
processes
for making such compositions that are suitable for use in the treatment and
prevention of
infections.
BACKGROUND OF THE INVENTION
1. Antimicrobial Agents
Antimicrobial a<,ents are chemical compounds that either destroy microbes,
prevent
their pathogenic action, or prevent their growth. Antimicrobial agents. often
referred to as
anti-infective absents, are frequently applied topically to the skin and
mucous membranes in
the form of a solution. cream. or ointment: appropriate formulations may be
applied to
wounds and body cavities, and to the eyes, nose, and mouth.
I s In general. topical antimicrobial a<~ents are directed at bacteria.
viruses. and fungi.
They have been used successfully in the prevention and treatment of a number
of infections.
includin!, impetigo. candidiasis. tinea pedis (athletes foot), acne vulearis,
and infections
resulting from burns and suretical wounds.
Most agents have a limited spectrum of activity For example. some are specific
for
'_'0 particular !gram (+) organisms, while others are specific for particular
~~ram (-) organisms.
Moreover. bactericidal absents typically are not tun~Ticidal. while
fun~licidal a'_ents typically are
not bactericidal.
In addition, due to the widespread use and frequent over-prescribin!~ of
antimicrobial
a«ents. there is an increasin~~ incidence of microbes acquiring_ dru~_-
resistance. fn other words,
?S a microbe that was once susceptible (I.e., inhibited or killed) to a
particular antimicrobial
a~_ent is no longer susceptible. This is especially important with regard to
bacteria.
Acquired dru~~ resistance is usually caused by a mutation within the genome of
the
microbe or by the acquisition of a plasmid. For example. one of the major
mechanisms of
resistance to the (3-lactam antibiotics. including,.: penicillins. is the
production of ~i-lactamases.
;0 Moreover, resistance to one member of a class of agents le.;~., the
aminopeniciilin ampicillin)
can result in complete cross-resistance to other members of that class
(e.~,~., the
aminopenicillin amoxicillin).
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II. Topical Silver-Containing Agents
A. Currently Used Therapeutic Agents
Two formulations co~Ztaining silver have been utilized for
therapeutic purposes, silver nitrate and silver
sulfadiazine. As ser_ forth hereafter, each is associated
with potentially se-aere adverse effects and other
limitations.
A 1~ silver nitrate ophthalmic solution can be used in
newborns for the prophylaxis of gonococcal ophthalmia
(gonococcal ophthalmia neonatorum). Because the silver ion
is precipitated by chloride, the salver nitrate solution
does not readily penetrate into tissue. Unfortunately, the
silver salts stain t=issue black as a result, of the
deposition of reduced silver; some of the staining may
persist :indefinitely. Thus, silver nitrate is not used
topically for other indications (e. g., Impetigo).
Silver sulfadiazine 1% topical cream is routinely used as an
adjunct in the prevention and treatment of infection in burn
victims. [See U.S. Patent. No. 3,761,590 to Fox] Silver
sulfadiazine, produced by the reaction of silver nitrate
with sulfadiazine, rnas been associated with necrosis of the
skin. In addition, :~ulfadiazine may accumulate in patients
with impaired hepatic or renal function, requiring in severe
cases examination of the patients urine for sulfonamide
crystals. Moreover, patients allergic to sulfa agents may
exhibit cross-hypersensitivity with silver sulfadiazine.
[See generally; AHF~~ Drug Information. Gerald K. McKevoy,
ed., pp. 1704-05 and 2215-16 (1993)].
B. Newer Antimicrobial Silver-Containing Compositions
One of the reasons why there are few commercially available
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silver-containing therapeutic formulations is the difficulty
of making such formulations photostable. That is, such
formulations turn a dark color and frequently lose
antimicrobial efficacy upon short-term (e. g., 3-4 days)
exposure to ambient light.
There have been several recent efforts to produce a silver-
containing formulation that exhibits high antimicrobial
efficacy and photost~abil:ity. For_ example, LJ.S. Patent No.
5,326,567 to Capelli, describes an antimicrobial composition
comprising a stabilizing acyclic polyether polymer, silver
ion, and a stabilizing h<~lide. T:he composition may be used
in several manners, including topical application to a
subject <~nd incorpo:ration into a medical device.
In addition, a new c:l.ass of silver-containing agents, the
silver thiosulfate Lion complexes, has recently been
disclosed in U.S. Patent No 5,429,819 to Oka et al.
(hereafter "the Oka Patent"). [See also Tomioka et al.,
"Synthes:is of
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.~ntimicrobial Agent Composed of Silver-Thiosulfate Complex Ion." Nippon
Ka«aku Kaishi
10:848-50 ( 1995)). The Oka Patent describes an antiviral composition that
contains l) a
thiosulfate salt and ii) at least one thiosulfate complex salt of a metal and
iii) a porous
particulate carrier; the metal is either silver, copper or zinc. and the salts
are carried on the
porous particulate carrier. According to the Oka Patents teachings, the
thiosulfate complex
salt and thiosulfate metal complex salt are first prepared as a solution.
Thereafter, a porous
carrier such as silica gel is impre~.:nated with the solution. Finally, the
thiosuifate complex
and thiosulfate metal complex salt are immobilized on the porous carrier
through drying.
This metal-containing porous carrier is then formulated into the compositions
described in the
Oka Patent.
The antimicrobial compositions taught in the Oka Patent are associated with
several
notable shortcomings. First. the silver thiosulfate ion complex compositions
contain a
relatively larvae concentration of waste salts. resultin<, from the
complexation oY a thiosulfate
salt, sulfite salt, and a silver salt, and are thus relatively impure. For
example, producing I
1 S part of a silver thiosulfate ion complex using l part of silver nitrate
(or silver acetate) to 2
parts sodium thiosulfate and/or 2 parts sodium sulfite will result in I part
waste sodium nitrate
(or sodium acetate); the inclusion of these salts results in a lower
concentration of silver.
Similarly, as indicated above. the silver thiosulfate ion complex requires the
use of porous
carrier particles; the necessity of these carrier particles limits the
concentration of thiosulfate
~0 complex snit and thiosulfate metal complex salt. Thus, the amount of porous
carrier particles
needed to provide silver at antimicrobial concentrations is hush. and. as a
result. a topical
antimicrobial composition would feel !~rittv and would be irritating= to the
skin or wound. In
addition, if the concentration of thiosulfate complex salt and thiosulfate
metal complex salt
carried on the porous carrier is too high, the composition may discolor.
'_'S Finally, the compositions tau';ht by the Oka Patent cannot be easily
incorporated into a
polymer matrix at hi~,~h concentrations. As stated above. incorporation of
silver at
antimicrobial concentrations requires concomitant incorporation of a large
amount of porous
carrier. This can cause undesirable changes in the polymer matrix' physical
properties (c.,y., a
hydrocolloid matrix that is stiff and less absorptive). In addition. such
incorporation can be
s0 unwieldy. For example, in an alrinate matrix containing_ water-insoluble
fibers, the silver-
containing porous carrier cannot be incorporated into the al~~inate fibers; as
a result, the
porous carrier must be mixed loosely within the alginate fibers.
Unfortunately, the porous
carrier can fall out when the al~linate matrix is handled.
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From the above. it should be clear that the commercially-available silver-
based
antimicrobiai agents have limited applications and can be associated with
severe adverse
effects. Moreover, many recent efforts to develop a topical silver-containing
formulation are
connected with drawbacks. as exemplified by the prior art requirement of a
carrier. What is
needed is a stable silver-containinv~ antimicrobial composition which is
suitable for use in the
treatment and prevention of a broad range of infections and that is not
associated with the
adverse effects and limitations of the agents that have previously been
described.
SUMMARY OF THE INVENTION
The present invention relates generally to silver-based antimicrobial
compositions and
processes for making such compositions suitable for use in the treatment and
prevention of
infections. In particular. the present invention relates to stable silver-
based antimicrobial
compositions, and processes for makin<~ such compositions. comprising carrier-
free, suspended
silver thiosulfate ion complexes in a base. Preferably, the silver thiosulfate
ion complexes are
I ~ homo~=eneously suspended in an anhydrous base. .alternatively, the silver
thiosulfate ion
complexes of the present invention can be incorporated into a matrix and used
with a medical
device. Pharmaceutical compositions can also be produced by combining the
silver thiosulfate
ion complexes with medicinal agents, including but not limited to
antimicrobial a~,ents,
steroids, and anesthetics.
~'0 One advantage of providin'= silver thiosulfate ion complexes in a carrier-
free form is
the ability to produce antimicrobial compositions containin« high
concentrations of silver
thiosulfate ion complexes so as to provide potent antimicrobial activity :~
further advanta~_e
of the carrier-free compositions is the elimination of irritation that may
result from the carrier
upon topical administration. Thus. the invention contemplates a method of
treating, or
preventin~, infections in comprising applying topically to the site (or
potential site) of
infection an etfective amount of the foregoing composition.
.-~s alluded to above, the invention also contemplates methods of making the
stable
silver-based antimicrobial compositions. It is preferred that the silver
complexes of the
present invention are derived from the complexation of silver cations from
silver halides
s0 (preferably silver chloride) with anions from the sodium thiosulfate salts;
the molar ratio of
the thiosulfate anions to the silver canons is preferably at least 1:l and
more preferably at
least I.s:l. It is desirable that the silver thiosulfate ion complexes are
solid and essentially
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pure. i.e.. they do not contain si~mificant amounts of waste salts or other
substances that
interfere with their antimicrobial activity; in addition, they do not require
carrier particles.
The compositions are able to contain high concentrations of silver thiosulfate
ion
complexes. thereby providing strong antimicrobial activity. Moreover, the
compositions may
be used in combination with other pharmaceutical (c~.~=., topical) agents
(e.~~., Bactroban"
[mupirocin], SmithKline Beecham). Such combination may serve to avoid
antimicrobial
resistance, increase the spectrum of activity, and have a synergistic effect.
The silver thiosulfate ion complexes of the present invention may be
incorporated into
medical devices, including medical implants, wound care devices, body cavity
and personal
protection devices, and the like. By way of illustration. purified silver
thiosulfate ion
complexes may be incorporated with an anhydrous polymer matrix that is used to
coat a
urinary catheter in order to prevent infection. Similarly, the silver
thiosulfate ion complexes
may be used in cosmetics and personal care products to make them resistant to
antimicrobial
contammauon. Examples of cosmetics include lipsticks and ~,losses. lip
pencils, mascaras, eye
liners, eve shadows, moisturizers. liquid and powder makeup foundations,
powder and cream
blushes, perfumes, colognes, various creams and toners, etc.. and assorted
applicators like
combs, brushes. sponv~es, and cotton swabs and balls. and examples of personal
care products
include deodorants. razors, shaving creams, shampoos, conditioners, various
hair treatments
like mousses and sprays, toothpastes, mouthwashes. dental flosses and tapes,
sunscreens.
'_'0 moisturizers. tampons. sanitary napkins. panty shields, diapers, baby
wipes, facial tissues.
toilet tissues, etc.
The present invention contemplates a composition. comprisin~~ carrier-tree
suspended
silver thiosultate ion complexes suspended in a base. In one embodiment, the
base is
anhydrous. It is contemplated that the concentration of silver thiosulfate ion
complexes within
the base is sufficient to provide a therapeutic benefit. Speciticallv, the
present invention
contemplates concentrations of silver thiosulfate ion complexes within the
base from 0.01% to
s0% (wiw) and from 0.1°i° to _s.0°'° (w/w) The
preferred concentration of silver thiosultate
ion complexes within the base is from 0.2% to 1.5°i° (wiw). In
one embodiment, the base is
selected from the <croup consisting of polyethylene glycol. .-~quaphor". and
white petrolatum.
s0 The present invention also contemplates a method of treating or preventing
a topical
microbial infection. comprisinv= the steps of a) providin~~ i j a subject
infected with a topical
microbial infection and ii) an effective amount of carrier-free suspended
silver thiosuifate ion
complexes in a base: and b) administering topically the effective amount of
the carrier-tree
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suspended silver thiosuifate ion complexes in a base to the subject. thereby
treating or
preventing the topical microbial infection. In one embodiment, the base is
anhydrous.
It is contemplated that the concentration of silver thiosulfate ion complexes
within the
base is sufficient to provide a therapeutic benefit. For example, the present
invention
specifically contemplates concentrations of silver thiosulfate ion complexes
within the base
from 0.01% to 30% (w/w) and from 0.1% to 3.0% (wiv,~). The preferred
concentration of
silver thiosulfate ion complexes within the base is from 0.?°% to I.5%
(w/w). In one
embodiment, the base is selected from the ~_roup consisting, of polyethylene
~~lycol.
Aquaphor~, and white petrolatum.
The present invention further contemplates a method of imparting antimicrobial
protection to an object, comprisin~~ the steps of: a) providinv; i) an object
and ii) an effective
amount of carrier-free suspended silver thiosulfate ion complexes; and b)
applyin~l the
effective amount of the carrier-free suspended silver thiosulfate ion
complexes in a base to the
object, thereby imparting antimicrobial protection to the object. It is
preferred that the object
I S is solid and chemically inert.
In one embodiment, the concentration of silver thiosulfate ion complexes is
sufficient
to provide a therapeutic benefit. Specifically, the present invention
contemplates
concentrations of silver thiosulfate ion complexes from 0.01°% to 30%
(w/w) and from 0.1%
to 3.0°~ (w/w) The preferred concentration of silver thiosulfate ion
complexes is from 0.2%
?0 to I 5°% (w/w).
In still further embodiments, the object is a medical device. In particular
embodiments. the medical device comprises a matrix. In some embodiments the
matrix is a
holvmer. while it is anhydrous in still Further embodiments
The present invention also contemplates a process for producing, essentially
anhydrous
silver thiosulfate ion complexes. comprising_: a) makings an aqueous solution
of silver
thiosulfate ion complexes; b) addin~s a solvent to the solution to create a
biphasic separation
wherein the silver thiosulfate ion complexes separate into one phase: c)
collectin~~ the phase
containing the silver thiosulfate ion complexes; and d) removin~T water from
the collected
phase such that the silver thiosulfate ion complexes are essentially
anhydrous. In particular
s0 embodiments. the ratio of thiosulfate ions to silver ions is ~sreater than
or equal to 2:1 and
preferably less than 3:1.
In some embodiments. the aqueous solution of silver thiosuifate ion complexes
is
formed by reacting a silver halide and sodium thiosulfate. In other
embodiments, the molar
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ratio of silver cations from the silver halide to thiosulfate anions from the
sodium thiosulfate
is preferably at least 1:1 and more preferably at least 1.3:1. In still
further embodiments, the
silver halide is silver chloride.
In other embodiments. the solvent is water-miscible. The solvent is selected
from the
group consisting of ethyl alcohol, isopropyl ai,cohol, methyl alcohol,
acetone, and
tetrahvdrofuran in certain embodiments.
Additionally. the present invention contemplates a process for producing
essentially
anhydrous silver thiosulfate ion complexes, comprising: a) makings an aqueous
solution of
silver thiosulfate ion complexes; b) adding a solvent to the solution to
precipitate the silver
thiosulfate ion complexes; c) collectinv; the precipitated silver thiosulfate
ion complexes; and
d) removing water from the collected silver thiosulfate ion complexes such
that the silver
thiosulfate ion complexes are essentially anhydrous. In particular
embodiments. the ratio of
thiosulfate ions to silver ions is less than 2:1 and preferably ~_reater than
I: I
In some embodiments, the aqueous solution of silver thiosulfate ion complexes
is
I s formed by reacting a silver halide and sodium thiosulfate. In other
embodiments, the molar
ratio of silver cations from the silver halide to thiosulfate anions from the
sodium thiosulfate
is preferably at least I : I and more preferably at least I. 3:1 In still
further embodiments, the
silver halide is silver chloride.
In other embodiments, the solvent is water-miscible. The solvent is selected
from the
'_'0 ''roup consistin~~ of ethyl alcohol, isopropyl alcohol, methyl alcohol,
acetone, and
tetrahvdrofuran in certain embodiments.
The present invention also contemplates a pharmaceutical mixture. comprisin~~:
a) a
medicinal av~ent; and b) silver thiosulfate ion complexes. In preferred
embodiments, the silver
thiosulfate inn complexes are carrier-free. In particular embodiments. the
pharmaceutical
~s mixture further comprises an anhydrous base; in some embodiments, the base
is selected from
the group consisting, of polyethylene glycol. Aquaphor", and white petrolatum.
In some embodiments of the present invention. the concentration of the silver
thiosulfate ion complexes in the pharmaceutical mixture is from 0.01% to
30°/> (weight to
wei'~itt). In further embodiments, the concentration of silver thiosulfate ion
complexes is
s0 from 0 1% to 3.0% (weight to wei~,ht), while in still further embodiments
the concentration is
from 0.2°i° to f .5°% (weight to wei~.:ht).
In particular embodiments. the medicinal absent of the pharmaceutical mixture
is an
antimicrobial agent. In some embodiments. the antimicrobial a~.:ent is
selected from the ~.:roup
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consisting of acyclovir. chloramphenicol, chlorhexidine. chlortetracycline.
itraconazole,
mafenide. metronidazole. mupirocin, nitrofurazone, oxvtetracycline,
penicillin. and
tetracycline. When the medicinal agent is an antimicrobial absent, in some
embodiments the
pharmaceutical mixture has a broader spectrum of antimicrobial protection than
the silver
thiosulfate ion complexes.
Furthermore, the medicinal went of the pharmaceutical mixture is a steroid in
certain
embodiments. In particular embodiments. the steroid is selected from the group
consisting of
betamethasone benzoate, betamethasone valerate, desonide, fiuocinolone
acetonide,
halcinonide, hydrocortisone. and metandienone.
Finally, the medicinal went of the pharmaceutical mixture is an anesthetic in
still other
embodiments. In certain embodiments. the anesthetic is selected from the group
consistinv~ of
benzocaine. dibucaine. lidocaine. pramoxine hydrochloride and tetracacine.
DEFINITIONS
I s To facilitate understanding, of the invention set forth in the disclosure
that follows, a
number of terms are defined below.
The term "carrier" refers to a substance. like an inor~fanic oxide, in which a
material
can be impregnated and then, if necessary, immobilized throu~_h drviny;. For
example, the
Oka Patent describes the impre~~nation of a porous particulate carrier
(c.~.~,1., silica ~,;el) with a
?0 solution containing thiosulfate complex salt and thiosulfate metal complex
salt. In contrast,
the term "carrier" does not refer to the mere suspension of materials like
silver thiosulfate ion
complexes in a base. The term "carrier-free" refers to bein<_ without such
thing's as carrier
particles. porous particulate carriers. and the like used as carriers for
other materials. For
example, the compositions of the present invention are "carrier-free" in that
they comprise
silver thiosulfate ion complexes that do not require such a carrier.
The term "base" refers to any substance useful for the suspension of the
silver
thiosulfate ion complexes of the present invention. In a preferred embodiment.
the base iv
"anhydrous" (e.~,r., an ointment) and can be used to suspend a medicinal
absent for topical
administration. Useful anhydrous bases include. but are not limited to. white
petrolatum.
s0 .~quaphor' ointment base, and polvethvEene glycol (PEG) polymers with
molecular weights
';reater than 600. The preferred anhydrous base is a PEG ointment composition;
an ointment
made up of PEGS can absorb and associate with a small amount of water so that
the water is
not free to hydrolyze the thiosulfate ligand. It should be noted that some
water is tolerable in
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the final product but that, yenerallv speaking. the presence of water will
reduce the shelf-life
of the composition. For example. an anhydrous base which contains no water and
few, if
any, hydroxy or acid groups should have a shelf life of many years, while a
base containing
small amounts of water (e.~J., less than ~%) would have a shorter shelf-life
(e.y., less than (l
months). If a PEG ointment base has a verv small amount of water (c~.~., much
less than
I%), the silver thiosulfate ion complexes should be stable enough to provide
the product with
an acceptable shelf-life (~.~_., greater than one vear). In one embodiment.
the base is
semisolid.
The term "silver thiosulfate ion complexes" refers to the silver-containing
material
produced by the process of the present invention and incorporated into the
compositions of
the present invention. More specificallv, the silver thiosulfate ion complexes
are obtained by
addin!_= a silver halide, c~.~., silver chloride. to an aqueous solution and
then addin<_J a
thiosuifate salt. c.,~=., sodium thiosulfate, to the solution. Thou_=h the
benetit provided by the
complexes of the present invention is not limited by an understanding_ of the
precise nature of
I S the complexes. the chemical formula of the primary silver thiosulfate ion
complexes formed
when a large excess of thiosulfate salt is used is represented by [Ag(S,O,),]'-
. By
comparison, the chemical formula of the primary silver thiosulfate ion
complexes formed
when only a small excess of thiosulfate salt is used is represented by
[Ayu;(S,O~),]'- The
preferred silver thiosulfate ion complexes are those represented by
[A~=(S,O,),]~~. The
?0 resultin'; silver thiosulfate ion complexes are in a relatively pure solid
form, and are stable,
i~i~~hlv water soluble and antimicrobialiv active.
The term "essentially anhydrous silver thiosulfate ion complexes" refers t~
silver
thiosulfate ion complexes that may be essentially free of all remnant water.
i.~~.. they may
contain a small amount of water ( ~~enerallv less than s°% of the
original amount of water
present, preferably less than I°,~o, and most preferably less than 0
I°%), provided that the water
does not interfere with the antimicrobial function of the complexes.
The term "suspended" revers broadly to the dispersion (i.c~., not dissolution)
of material
(e.,L~., silver thiosulfate ion complexes) in the base. The material is
preferably finely divided
and preferably dispersed homo~ eneously throughout the base.
s0 The term "aqueous solution" refers to a liquid mixture containin~~, among,
other thing's,
water.
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The term "solvent" refers to a liquid that is capable of dissolving a
substance. The
term "water-miscible solvent" refers to a solvent that is capable of beiny~
mixed with water
and remaining so after completion of the mixing process.
The term "phase" refers to a physically distinct and separable portion of a
heterogeneous system. The term "biphasic separation" refers to the creation of
two phases:
';eneral(v speakin~~, a "biphasic separation" allows a material (~.,~~.,
silver thiosulfate ion
complexes) to be partitioned into one of the resulting phases, thereby
facilitatin~,~ isolation of
that material. As described in further detail below, the addition of an
appropriate solvent
(e.~~., ethyl alcohol) to an aqueous solution of silver thiosulfate ion
complexes results in a
biphasic separation. A smaller, denser, liquid phase primarily contains the
silver thiosulfate
ion complexes associated with water; there is little, if any, solvent in this
phase. A larger
liquid phase primarily contains the waste salts and the solvent.
The terms "collectin~l." "collect" and the like refer to the !general
processes of isolatin~~,
partitioning, etc. one material from another. For example. a desired material
may partition
I ~ into one phase of a biphasic system: the phase containin~~ that material
(c.~,~., the silver
thiosulfate ion complexes of the present invention) can be removed from the
biphasic system
using well known means (e.,~~., pipet and separatory funnel).
The term "removing;" refers broadly to the use of methods for the complete or
partial
elimination of water from the phase containing the silver thiosulfate ion
complexes (i.c., the
~0 collected phase). The present invention is not limited to any particular
method: rather.
~~enerallv known methods ot~ removal (e. ~., freeze drvin~~. oven drvin~~.
evaporation. and
solvent extraction) may be used in conjunction with the present invention.
The term "effective amount" refers to that amount of essentially anhydrous
silver
thiosulfate ion complexes that is required to provide some "therapeutic
benefit". The present
invention is not limited by the nature or scope of the therapeutic benefit
provided. The
de'_ree of benefit may depend on a number of factors, r.,~~., the severity of
a .f. crnrmr.,~
infection and the immune status of the individual.
The term "therapeutic composition" refers to a composition that includes
essentially
anhydrous silver thiosulfate ion complexes in a pharmaceutically acceptable
form. The
s0 characteristics of the form will depend on a number of factors, including
the site of topical
administration and the method by which the form will be used. For example. a
composition
for use in conjunction with personal care products must be formulated such
that the
composition retains its antimicrobial properties while not adversely
affecting= the
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characteristics of the personal care product itself. The therapeutic
composition may contain
diluents. adjuvants and excipients. among other things.
The terms "subject" and "host" refer to humans and animals.
The term "approximately" refers to the actual value being within a ran~,~e of
the
indicated value. In general, the actual value will be between 5% (plus or
minus) of the
indicated value.
The terms "topical," "topically." and the tike include, but are not limited
to, the
surface of the skin and mucosal tissue, in wounds. in the eves, nose. mouth,
anus and vagina.
The term "wound" includes a burn, cut sore, blister. rash or any other lesion
or area of
disturbed skin. The term "wound dressing" includes foam dressin'=s, thin film
dressings, burn
dressin~~s, surgical dressin<~s, absorptive dressings, gauze, sheets or other
types of medical
device used to treat wounds.
The terms "microbe. "microbial." and the like include bacteria, fungi. and
viruses. The
terms "antimicrobial" and "antimicrobial activity" refer to the ability to
kill or inhibit the
I S ~~rowth of microbes.
The term "photostable" means that an object or material is resistant to
discoloration
when exposed to ambient li~~ht for a period of at least 7~ hours.
The terms "matrix," "matrices" and the like refer broadly to materials in
which the
silver thiosulfate ion complexes of the present invention can be embedded in.
attached to, or
'_'0 otherwise associated with. ~ "polymer matrix" is one type of matrix
comprisinv.: one or more
natural or synthetic compounds. usually of hi'Th molecular wei~~ht. in the
form of repeated
linked units. The term "anhydrous polymer nlatfi\" refers to ilflV soled
material that may be
tree of water or that may contain a small amount of water f ~~enerallv less
than ~°,'° by wei~.~.ht),
provided that the water does not interfere with the antimicrobial function of
the complexes
carried by the matrix. The preferred anhydrous polymer matrix materials are
materials
compatible with the silver thiosulfate ion complexes of the present invention.
The most
preferred polymer matrix materials are those bein<~ compatible with the silver
thiosulfate ion
complexes and havin<~ some capacity to absorb and/or swell in the presence of
water.
Examples of anhydrous polymer matrix materials, include. but are not limited
to. adhesives
such as acrylic-based pressure sensitive adhesives; biopolvmers such as silk;
hydrocolloid
materials such as sodium carboxvmethvlcellulose. either alone or when bound in
a polymer;
and polymers such as polyurethane in the form of coatin~~s, films. foams. etc.
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The term "medical device" refers broadly medical implants, wound care devices,
body
cavity and personal protection devices, and the like. )Vledical implants
include, but are not
limited to, urinary and intravascular catheters, dialysis shunts. wound drain
tubes, skin sutures,
vascular grafts and implantable meshes, intraocular devices, and heart valves.
Wound care
devices include, but are not limited to, general wound dressings, non-adherent
dressings, burn
dressings, biological ~,~ratt materials, tape closures and dressings, and
surgical drapes. Finally,
body cavity and personal protection devices include, but are not limited to,
tampons, sponges,
surgical and examination gloves, toothbrushes. intrauterine devices,
diaphra~~ms, and condoms.
The silver thiosulfate ion complexes of the present invention can be use to
impart
antimicrobial protection to objects includin~~, but not limited to. medical
devices.
The term "puritied" means that the material has been subjected to a process
(c.~~.,
extraction) to remove impurities. Followin~T the process. the material may be
free from
contamination of extraneous matter or, more commonly, only contain impurities
at levels that
do not interfere with the intended function. For example, it is advantageous
to produce silver
I s thiosulfate ion complexes that do not contain significant amounts of waste
salts (c.,s,~., sodium
nitrate or sodium acetate); if such waste salts are incorporated into
compositions or medical
devices. they may be irritating to the skin or other tissue. tn addition. they
may reduce the
concentration of antimicrobiallv active silver. For example, if the silver
thiosulfate ion
complexes are made using, silver iodide silver salt and sodium thiosulfate
salt, the resultinrr
'_'0 waste salt would be sodium iodide. The iodide ion would a'~gressivelv
compete for the
dissociated ("free") silver ion. resulting in reduced concentration of
antimicrobiallv active
silver
DET.-AILED DESCRIPTION OF THE INVENTION
The present invention relates to silver-based antimicrobial compositions, and
processes
for making such compositions. that are suitable for use in the treatment and
prevention of
infections. In particular. the present invention relates to stable silver-
based antimicrobial
compositions, and processes for making such compositions, comprising carrier-
free. suspended
silver thiosulfate ion complexes in an a base. and silver thiosulfate ion
complexes
s0 incorporated into an anhydrous polymer matri~c and used with a medical
device.
The description of the invention is divided into the following parts: I)
Processes To
Obtain Silver Thiosulfate Ion Complexes In A Solid Form; II) Compositions
Containin<=
Silver Thiosulfate Ion Complexes: III) Therapeutic Use Of Compositions
Containing Silver
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Thiosulfate Ion Complexes. and IV) Incorporation Of Silver Thiosulfate Ion
Complexes Into
Matrices For Use In Medical Devices. Each of these parts will be discussed in
turn.
I. PROCESSES TO OBTAIN SILVER THIOSULFATE ION COMPLElCES
MATERIAL iN A SOLID FORM
As previously indicated. the compositions of the Oka Patent contain a
thiosulfate salt,
at least one thiosulfate salt of a metal, and a porous particulate carrier.
The carrier was
required because the thiosulfate salt and the thiosulfate salt of a metal can
"hardly be obtained
as a simple substance in a solid state". [Oka Patent, col. 2, l1. 45-46). In
contrast to the Oka
IO Patent. the present invention is directed at a process for obtaining
carrier-free silver thiosulfate
ion complexes. Based on the prior arts acknowledged difficulty in obtaining
silver
thiosulfate ion complexes in a carrier-tree solid state. the discovery of the
process disclosed
I~ereatter was both surprisin<~ and unexpected. Mtoreover. the process of the
present invention
also results in carrier-free silver thiosulfate ion complexes in hi~~h yields.
another surprisinu
I S and unexpected result.
The present invention contemplates the production of carrier-free silver
thiosulfate ion
completes wherein the ratio of thiosulfate ion to silver ion is preferably at
least 1.3 to I. To
optimize the antimicrobial effectiveness of the final products containing_ the
silver thiosulfate
ion complexes. it is preferable that the complexes be purified (e.,~~.,
subjected to methods to
'_'0 remove contaminants such as waste salts in an amount that adversely
interferes with the silver
concentration obtainable).
The present invention provides nvo processes of producin~~ purified silver
thiosulfate
ion complexes from thiosulfate ions and silver ions. The first process is
preferred when the
ratio of thiosulfate ions to silver ions is greater than or equal to ?-to-I.
and the second process
is preferred when the ratio is less than 2-to-1.
A. Process For Producing Silver Thiosulfate Ion Complexes
When The Ratio Of Thiosulf~te Ions To Silver Ions Is
Greater Thin Or Equal To 2-to-1
s0 The process for producing.: essentially anhydrous silver thiosulfate ion
complexes when
the ratio of thiosulfate ions to silver ions is greater than 2-to-I involves
four major steps. The
first step consists of makin<~ an aqueous solution of silver thiosulfate ion
complexes. The
aqueous solution of the silver thiosulfate ion complexes is obtained by first
adding, a silver
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halide. such as silver chloride. silver bromide. etc.. to an aqueous solution.
Thereafter. a
thiosuifate salt. such as sodium thiosuifate or potassium thiosulfate, is
added to the aqueous
solution.
The use of a silver halide instead of another silver-containing molecule is
preferred
because the silver thiosulfate ion complexes produced are associated with
increased short-term
stability. This is especially important when the concentration of the silver
thiosulfate ion
complexes is high and/or the ratio of thiosulfate ions to silver ions is low.
Likewise, the use
of a silver halide promotes stability when making a solution of the silver
thiosulfate ion
complexes when the concentration of silver thiosulfate ion complexes in the
resulting aqueous
solution is hi~~h. As indicated above. when making silver thiosulfate ion
complexes where the
primary silver ion complexes formed is represented by the formula
[~g(S,O,),]'', the preferred
proportions of thiosulfate salt to silver salt are equal to or ~~reater than ?
moles of thiosulfate
salt for I mole of silver salt. The most preferred proportions of thiosulfate
salt to silver salt
are equal to or greater than 3-to-1.
I ~ In making the aqueous solution of the silver thiosulfate ion complexes,
the preferred
silver halide is silver chloride. It should be noted that the silver chloride,
as well as other
silver halides, can be made in .~~inr in the aqueous solution In this way. a
mater-soluble silver
salt such as silver nitrate or silver acetate is first dissolved in the
aqueous solution. .fin
equivalent or greater molar amount of a halide salt containin~~ the chloride
ion, such as
?0 sodium chloride, potassium chloride, and the like, is then added, resuitin~
in the precipitation
of the silver chloride salt.
~dditionallv. in makin<~ the aqueous solution of the silver thiosuifate ion
complexes. it
is preferred that the concentration of the initial silver halide in the
aqueous solution be less
than ?S°~ 1-Ii~,her concentrations of the silver halide can lead t0
Illstabtlitv of the resultin~~
silver thiosulfate solution; that is to say, the silver thiosulfate ion
complexes within the
aolution will "break down" or decompose. leadin~l to discoloration of the
solution and
precipitation of silver sulfide.
The second step in the process entails the addition of a solvent to the
aqueous solution
resultin'_ from the first step to create a biphasic separation: in this way,
the silver thiosulfate
~0 ion complexes separate into one phase. The preferred solvents are those
which are water
miscible. Solvents such as ethyl alcohol, isopropyl alcohol. methyl alcohol.
acetone.
tetrahvdrofuran. and the like, are examples of solvents which are useful in
causin~~ phase
separation. The solvent is added to the silver thiosulfate ion complexes
solution in an amount
_ 1 ~t _
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such that the solution separates into two phases. Durin~~ the formation of two
distinct phases,
the silver thiosulfate ion complexes separate into one phase. Tvpicallv, the
volume of the
phase containing the silver thiosulfate ion complexes is onlv a fraction
(e.~,r., less than 20%)
of the total volume of liquid; this denser liquid phase resembles a liquid
mixture containing a
heavy oil and an aqueous solution where the heavy oil accumulates at the
bottom of the vessel
containinvu the liquid mixture.
The phase containing the silver thiosulfate ion complexes is thought to
consist of a
hi~,;h concentration (i.~.. 50 - 70% of the total volume) of relatively pure
silver thiosuifate ion
complexes and water. Excess thiosulfate salts, waste salts, solvent, and other
contaminants
are thought to remain in the other (larger) phase of the biphasic solution.
In the third step, the separated phase containing the silver thiosulfate ion
complexes
can be collected using! well known means. For example. the phase can be drawn
up using, a
pipet and removed from the solution. Likewise, a separatorv funnel can be used
to separate
the phase from the solution.
After the liquid phase containing the silver thiosulfate ion complexes has
been
collected, the fourth step involves treatment of the collected phase to create
essentially
anhydrous silver thiosulfate complexes. The silver thiosulfate complexes are
purified,
containin~~ insignificant amounts of waste salts (~.,~~., sodium nitrate or
sodium acetate) and
other extraneous materials. Treatments which are useful include. but are not
limited to,
'_'0 evaporation, oven drying, freeze drvin!;, solvent extraction. and the
like. Atter the treatment.
the essentially anhydrous silver thiosulfate complexes are ~_round into a fine
powder.
Q. Process For 1'rodncing Silver Thiosnlfate Ion Complexes
When The Ratio Of Thiosulfate Ions To Silver Ions Is Lcss
Than 2-to-I
The process for producing.: essentially anhydrous silver thiosulfate ion
complexes when
the ratio of thiosuifate ions to silver ions is less than 2-to-I involves four
major steps. Tlje
first step, making_ an aqueous solution of silver thiosulfate ion complexes.
is analogous to the
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first step of the process where the ratio is ~~reater than 2-to-I. The mayor
difference of this
process from that where the ratio is y_reater than 2-to-1 is that the second
step of this process
involves precipitation of the silver thiosulfate ion complexes from the
aqueous solution
(described below).
In the second step, a solvent is added to the aqueous solution of silver
thiosulfate ion
complexes to precipitate the silver thiosulfate ion complexes. The preferred
solvents are those
solvents which are water miscible. Solvents such as ethyl alcohol. isopropyl
alcohol, methyl
alcohol. acetone, tetrahydrofuran. etc., are examples of solvents which are
useful in causing,
precipitation. The solvent is added to the silver thiosulfate ion complexes
solution in an
amount such that the complexes precipitate.
In the third step, the silver thiosulfate ion complexes precipitate can be
separated from
the solution using any standard. well-known technique. Filtration represents
one preferred
separation technique. Tire silver thiosulfate ion complexes are relatively
pure. containing
insi'~niticant amounts of waste salts (o.,~~., sodium nitrate or sodium
acetate) and other
extraneous materials like excess thiosulfate salts that are thou~~ht to remain
in solution (i.e.,
they do not form a solid precipitate).
Following,_ separation. the fourth and final step of removing essentially all
remnant
water from the complexes from the collected phase creates essentially
anhydrous silver
thiosulfate ion complexes. Methods which are useful include, but are not
limited to,
~0 evaporation, oven drying, freeze drying, and the like. ~t~ter the
treatment. the essentially
anhydrous silver thiosulfate ion complexes are aground into a tine powder.
C. The iVatnre Of The Silver Thiosult'ate Ion (~ompiexes
While the benefit provided by the complexes of the present invention is not
limited by
an understandins: of the precise nature of the complexes, the solid material
produced by the
two processes described above is thought to consist of a salt where the silver
thiosulfate ion
complexes are represented by the formulas [A';(S,O,),]'-, [.agr(S,O,),]'-.
[A~,;,(S,O,),J'-,
[Ay~,(S=O,);]' ~, and similar complexes. Unexpectedly, it was found that the
form of the silver
thiosultate ion complexes produced is very dependent on the ratio of
thiosulfate ion to silver
;0 ion.
If the ratio of the thiosulfate ion to silver ion is low (i.c~., less than 2:1
), silver
thiosulfate ion complexes represented by the formulas [A';=(S,O,),]'~,
[.a~~,,(S,O,),]'- and the
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like can be produced. The preferred silver thiosulfate ion complexes are those
represented by
[Ay~,(S,O.,),]~-, which can be produced in accordance with the following
chemical equation:
3 Na,S,O, + 2 AgCI --~ NaaA~,(S,O,), + ~ NaCI
Conversely, if the ratio of the thiosulfate ion to silver ion is high (i.e.,
greater than 2:l),
relatively pure silver thiosulfate ion complexes represented by the formulas
[Ag(S,O,)~]'-,
[Ag(S,O,),]'' and the like can be produced.
The preferred sliver thiosulfate ion complexes are those produced when the
ratio of the
thiosulfate ion to silver ion is low. The purified silver thiosulfate ion
complexes are carrier-
free, photostable, highly water soluble, non-staining and antimicrobiallv
active. This
combination of features is not present in anv commercialfv available or
previously described
silver-containin~, composition.
i1. COMPOSITIONS CONTAINING SILVER THIOSUL~ATE lON
1 ~ COMPLEYES
Topical antimicrobial agents include therapeutic heavy metal compounds such as
silver-containing compounds. Silver, in its ionic state (A~_ ), possesses a
broad spectrum of
antibacterial, antifungal, and antiviral properties and is reiativelv safe.
Early studies showed
that the silver ion is oligodynamic. i.r., active at verv low concentrations.
[.fc~c~ ,~~crrcr-crllo,
~'0 Russell e~ crl.. Antimicrobial Activity and Action of Silver," Progress in
Medicinal Chemistry
31:351-70 ( 1994))
The present invention is directed at. amon~~ other thin<,s, carrier-free
silver thiosuifate
ion complexes compositions. Tl~e provision of carrier-tree silver thiosulfate
ion complexes is
advanta~_eous for at least two reasons. First. it provides the ability to make
antimicrobial
ailver thiosuffate ion complexes compositions without the need for potentially
irritatin~~ porous
carrier particles. Second, it provides the ability to produce antimicrobial
silver thiosulfate ion
complexes compositions which can contain hi~_h concentrations of silver.
resultin~T in
compositions with potent antimicrobial activity.
As set forth above, the carrier-tree silver thiosulfate ion complexes are
stable.
~0 However. the complexes are not stable in all pharmaceutically-acceptable
compositions.
Indeed. it was found that the silver thiosulfate ion complexes decompose when
incorporated
into certain base compositions (,fe~c~ Experimental Section. irrJior). The
decomposition of the
silver thiosulfate ion complexes results in the silver-based composition both
chan~,~iny; to a
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black color and losing_ antimicrobial activity. Given the instability of
silver thiosulfate ion
complexes when incorporated in certain base compositions. it was surprising
and unexpected
to discover silver thiosulfate ion complexes compositions which were, in fact,
stable.
The stable silver thiosulfate ion complexes compositions of the present
invention
comprise carrier-free suspended silver thiosulfate ion complexes in a base.
The preferred base
is anhydrous. and in one embodiment the base is semisolid. The stable silver-
based
compositions maintain their antimicrobial activity. Moreover, the amount of
silver in the
compositions can be varied over a large ranue of concentrations to provide
compositions with
different levels of antimicrobial potency.
f 0 During the first step of the previously-described process for producing
essentially
anhydrous silver thiosulfate ion complexes, an aqueous solution of the
complexes is made. It
should be noted that aqueous solutions of silver thiosulfate ion complexes can
be added to an
ointment or cream base to make an antimicrobial ointment or cream composition;
in other
words. a composition can be made after completing only the first of the four
steps. However,
1 ~ the resulting antimicrobial ointment or cream composition suffers from two
major drawbacks.
First, the resulting_ silver thiosulfate ion complexes compositions will
contain large quantities
of excess thiosulfate salts as well as waste salts (e~.,~f., sodium nitrate,
potassium nitrate, and
potassium acetate). When applied topically. the antimicrobial composition
containin~~ these
impurities may be irritatin«. The second major problem is that ointment or
cream
~0 compositions made with silver thiosulfate ion complexes from such an
aqueous solution are
not stable for lone periods of time That is to say, over a period of time the
resultin~l silver-
based antimicrobial compositions will turn black and lose antimicrobial
efficacy.
This destabilization occurs whether or not the silver-based compositions are
stored in
an opaque container or a clear container Therefore. the destabilization is not
a photo-
reduction of the silver. Rather. what occurs is that the thiosulfate ion
component of the silver
thiosuifate ion complexes experiences a chemical breakdown The effect of this
chemical
process is the breakdown of the silver thiosulfate ion complexes.
.-~~_ain. while an understanding of the mechanisms involved is not necessary.
it is
believed that the thiosulfate ion which makes up the silver thiosulfate ion
complexes is
s0 formed by adding a sulfur atom to a sulfite ion in a complex reaction that
can be summarized
by the following chemical equation: S + SO,=- --~ S,O,='. The sulfur atom that
is added to
the sulfite ion to ~_ive S,O,-- is somewhat labile; thus, S,O,w may
appropriately be
represented as S-SO,~ -. In aqueous solutions. thiosulfate decomposes over
time. .fit
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moderately low pH levels the sulfur atom readily splits oft. nominally
yielding sulfur as
follows:
S-SO,' - + H- -~ S + HSO,' -
While the acid decomposition of the thiosulfate ion nominally yields sulfur,
it should be
s mentioned that very finely divided particles of sulfur in an acidic aqueous
solution have the
character of polysultide ions. [Levenson: Complementary Processes (Ch. 14), in
The 7%~c~~u-v
y/nhc l'hrno~~-crphic l'rr~ce.ss, Fourth Ed. MacMillan Publishing Co.. Inc.,
New York ( 1977)].
As a result of the instability of the thiosulfate ion. when dissolved in water
silver
thiosuffate ion complexes also chemically decompose over time. It is believed
that when the
thiosulfate component of the silver thiosulfate ion complexes chemically
breaks down, it
releases silver ions which react with the released sulfur ions to form silver
sulfide. Silver
sulfide is a black material havin_~ the molecular formula of A~ ,S. Due to
silver sulfide's high
dissociation constant (pK = -l~). I ), silver sulfide is essentially non-
antimicrobial. That is to
say, the silver ion is bound tightly to the sulfur ion so that it can only
ionize very slowly
I ~ from the silver sulfide salt. As a result, little, if any, ionized silver
is available to provide
antimicrobial activity.
Likewise, silver thiosulfate ion complexes. when added to either an ointment
base
which contains a small proportion of water or a water-containin~~ cream base
in order to form
an antimicrobial composition, will decompose over a r-elativelv short period
of time. The
?0 resulting antimicrobial composition will turn black as the silver
thiosulfate ion complexes in
the composition decompose to silver sulfide. :~dditionallv. the composition
will lose its
antimicrobial efficacy with decomposition of the silver thiosultate ion
complexes.
In contrast, the previously described four-step process for producing_=
essentially
anhydrous silver thiosulfate ion complexes allows the production of
compositions that are
~'S stable over long periods of time. The stable silver thiosulfate ion
complexes compositions of
this invention comprise carrier-tree suspended silver thiosultate ion
complexes in a base. The
bases v.vhich are most useful for the present invention entail any compound or
mixture which
is capable of suspending the complexes. Preferably, the base is essentially
anhydrous and can
be used topically to deliver a medicinal a~~ent. I3y way of illustration.
bases that are useful
,0 include white petrolatum. .Aquaphor~ ointment base, polaxomers. and
polyethylene glycol
(PEG) polymers with molecular wei~,hts ~=renter than 600 The preferred base is
a PEG
ointment composition containiny~ a combination of PEG polymers with molecular
wei~~hts
greater than 1.000 and polaxomers.
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The methods for suspendin<~ the purified silver thiosulfate ion complexes, in
the form
of a tine powder, into a base to form a silver-based antimicrobial composition
are well known
in the art. For example, one method involves heating the base until it has
liquefied; then,
while the base cools. adding the silver thiosulfate ion complexes and stirring
until the base
has resolidified. This method produces a suspension of the silver thiosulfate
ion complexes
within the base, preferably a homo~_eneous suspension.
The concentration of the silver thiosulfate ion complexes within the base is
such as to
provide antimicrobial activity. The preferred concentration of the silver
thiosulfate ion
complexes is 0.1% to 3.0°,%. However, silver thiosulfate ion complexes
concentrations can
range up to 10% to 30% depending on the antimicrobial potency required. The
most
preferred concentration is between 0.2% and 1.5%. Generalfv speaking, the
effective
concentration is that concentration which is higher than the minimum
inhibitory concentration
for a particular microbe. :~s would be expected. certain microbes are more
sensitive to silver
than other microbes. ~.,~1., gram (-) microbes are generally more sensitive
than ,Tram (+)
I s microbes ~s a result, a concentration less than 0 !% could be effective
depending on the
microbe and the intended use of the final product.
The resulting silver thiosulfate ion complexes compositions of the present
invention
are antimicrobially active and stable when compared to compositions that use
bases which ar-e
not anhydrous. Additionally, the silver-based antimicrobial compositions of
this invention
'_'0 show no photo-discoloration when exposed to ambient room light over a 72
hour period.
Though the compositions must be in an anhydrous base in order to maintain
their
atabilim. it is not intended that the compositions of the present invention be
limited by the
particular nature of the therapeutic preparation for example. the present
invention
contemplates compositions that include phvsiolo~,icallv tolerable diluents,
adjuvants and
excipients. such as pharmaceutical grades of mannitol. lactose. starch.
magnesium stearate.
sodium saccharin, cellulose. ma!_nesium carbonate, and the like. These
compositions typically
contain I°o-95% of active ingredient. preferably ?°0-
70°~~. In addition. if desired the
compositions may contain minor amounts of auxiiiarv substances such as
stabilizin~~ or pH
bufferin~~ a~=ents or preservatives.
;0
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III. THERAPEUTIC IISE OF COMPOSITIONS CONTAINING SILVER
THIOSULFATE ION COMPLEXES
The silver thiosulfate ion complexes compositions of the present invention can
be used
topically, for example, on skin, in wounds, in the eyes, nose. and mouth, in
the treatment and
prevention of infection. As alluded to above, the compositions are effective
against bacteria,
viruses, and fungi. For example. 1:. cw/i and many species of Kleh.sicllcr,
!'ro~eu.s,
l'.,~enclunnour.s, .ftcrphvlncnccvr.s. and ('crndidcr may be inhibited or
killed by the compositions of
the present invention. In general, the dosage required for therapeutic
efficacy will vary
according to the microbe involved, the type of use and mode of administration,
as well as the
particularized requirements of individual hosts.
The therapeutic preparations can be administered for clinical use in humans
and for
veterinary use. such as with domestic animals. in manners known in the art and
similar to
either therapeutic a~_ents. Thou~Th not limited to any particular means of
application, the
antimicrobial compositions can be applied using gloved hands or by an
applicator. Likewise.
I 5 the antimicrobiai compositions can be applied to the surface of a
dressinv~, which can then be
applied topically. Ophthalmic infections can be treated using standard
procedures in the art,
such as by pulling, down the lower eyelid to form a pocket and applying the
composition
thereto. 'By way of further illustration, infections of the mouth can be
treated by applying,.: the
composition with a sponge applicator or a toothbrush.
'_'0 Bacterial resistance to silver is known to occur in certain situations;
more specifically,
1~:.~c~l~cric~hicr c.wli and .fcrlrrrnrrrlkr rylrinnrnirrr7r are known to
develop plasmid-encoded
resistance to silver. [Russell e~ cr/.. Pro~_ress in Medicinal Chemistry , I
:351-70 ( 1994)]. Two
related methods are commonly used to prevent and combat dm~_ resistance.
The first method entails the combination of two or more therapeutic a<_ents
into a final
composition. For example. the ~i-lactamase inhibitor clavulanate potassium has
been added to
amoxicillin. resulting in a combination preparation (Au~,~mentinT"':
SmithKline Beecham) with
expanded antimicrobial activity While clavuianic acid has only weak
antibacterial activity
when used alone. its combination with amoxicillin results in a svner~~istic
effect.
The second method entails the concomitant administration of two or more
distinct
s0 antimicrobial a~,ents. This method is based on the principle that a microbe
that is resistant to
une a~=ent may be susceptible to another. This is especially important. r.;;.,
in tuberculosis,
which is caused by A~It~cmhacmrium nrhorcnrlo.si.,~. Particular ~l./
mhcrcvrln.~~i.~~ bacteria that cause
tuberculosis are known to display resistant to each of the primary therapeutic
absents. As a
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result. treatment of tuberculosis often requires combinations of three or more
druta for
periods exceeding one year. [Se.~e Dooly e~ al. "~lultidru~J-resistant
tuberculosis," Ann. Int.
Med. I I 7:257-59 ( 1992); Nadler "Wultidru'_ resistant tuberculosis," N. Eng.
J. Med.
327:1 I 72-75 ( 1992)].
The present invention contemplates combinin~~ a topical silver-containing
preparation
with another medicinal a.=ent to form a pharmaceutical composition. Indeed.
the present
invention contemplates the use of many diverse medicinal a~_ents, including
antimicrobial
agents. topically active drugs, and systemicalfv active drugs. The preferred
medicinal agents
contemplated for use in the pharmaceutical compositions of the present
invention are those
that can be used as antimicrobial agents in the treatment and prevention of
infection and
disease. Suitable antimicrobial a<_ents include, but are not limited to.
penicillin, tetracycline,
oxytetracycline. chlortetracycline. chloramphenicol. chlorhexidine. mupirocin.
metronidazole.
miconazole. acvclovir. itraconazole and sulfonamides. :additional
antimicrobial absents include
antimicrobial peptides such as ma~~ainins, cecropins. prote~=rins,
bacteriocins and defensins.
I ~ The pharmaceutical compositions of the present invention possess an
additional broad
spectrum of antimicrobial protection by combining antimicrobial medicinal
agents in a stable
fashion with silver thiosulfate ion complexes. Furthermore. as previously
indicated, the use of
silver thiosulfate ion complexes with an antimicrobial medicinal agent may aid
in preventing=
the formation of drug-resistant microbes. ~1oreover, since silver ions are
oli~,odvnamic and
~0 are not immediately exhausted (i.c.. they have a lon~,-Iastin~T or
"residual" effect), the presence
of silver ions in the pharmaceutical compositions results in compositions
which are Ion<~er
iastin~_ than those containin~~ a sin~sle antimicrobial absent
i~1edicinal ay_ents besides antimicrobial a'=ents are also contemplated for
use in the
pharmaceutical compositions of the present invention, includin!= topically
active drugs for the
treatment of diseases. Suitable topically active drugs include, but are not
limited to. acne
preparations such as isotretinoin. benzovl peroxide. salicylic acid and
tetracycline; anesthetics
for topical administration such as dibucaine. lidocaine, benzocaine.
tetracacine, deperodon and
pramoxine hydrochloride; anti-inflammatory agents such as betamethasone
benzoate.
betamethasone valerate. desonide. Iluocinolone acetonide. halcinonide.
hydrocortisone;
_~0 antiperspirants and medications used in the treatment of hvperhidrosis
such as '~lutaraldehvde.
methenamine, glycopyrrolate, scopolamine hvdrobromide; antipruritic and
external analgesic
agents such as camphor. menthol. salicylic acid. methvlsalicviate; cleansin~T
a~_ents such as
soaps and shampoos: keratolvtic. cvtotoxic, and destructive a!rents such as
anthralin.
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cantharidin. tluorouracil, podophyllotoxin. resorcinol: and pigmenting
and'~i'dpi~Ffienti7ig
agents. sunscreens such as hvdroquinone. monobenzone, trioxsalen and p-
aminobenzoic acid;
anabolic steroids for building up tissues under wound healing such as
methandienone;
proteolvtic a<.:ents for the decomposition of fibrin such as trypsin;
vasodilating substances for
improving the flow of blow during wound healing such as tolazoline; thrombosis-
hampering
substances such as heparin; certain biologically active substances which
affect tissue formation
and tissue stabilization such as ascorbic acid and EGF (epidermal <,rowth
factor), EGF-URo
(EGF-uro~;astron). somatostatin. somatotropin asellacrine. and TGF; and
mucolvtic and
antiviral medicaments which are globulins such as lysozvme.
A pharmaceutical composition with a broad spectrum of antimicrobial protection
is
produced by combining one or more topicaliv active drugs in a stable fashion
with a
pharmaceutical composition containing= silver thiosulfate ion complexes. In
situations where
the topically active drugs are used to treat a disease which has an abundance
of dead tissue
(c.,y., a fun~~atinv; tumor or a decubitus ulcer), the addition ot~
antimicrobial silver ions will aid
I s in the prevention of a secondary infection at the diseased site.
Furthermore, the presence of
ionized silver in the pharmaceutical composition can aid in the prevention of
malodor caused
by anaerobic and aerobic microbes at the diseased site. Finally. combining= a
topically active
drus: with the silver thiosulfate ion complexes minimizes the need to apply
additional topical
antimicrobial compositions which may be incompatible with the medicinal
a~=ent. resulting in
~0 both time and cost savings.
In addition to medicinal a~_ents which are antimicrobial a~,ents or topically
active
absents. the present invention also contemplates the use of systemically
active dm~~s in the
pharmaceutical compositions of the present invention. The systemically active
drur;s are
absorbed by the body surface when applied topically, either neat or with the
aid of a solvent.
Suitable systemically active dnrgs include, but are not limited to. sedatives
and hvpnotics such
as pentobarbital sodium. Phenobarbital, secobarbital sodium, carbromal. and
sodium
Phenobarbital; psychic energizers such as 3-(?-I-aminopropyl)-indole acetate
and 3-(2-
aminobutvl)-indole acetate; tranquilizers such as reserpine. chlorpromazine
hydrochloride, and
thiopropazate hydrochloride; hormones such as adrenocorticosteroids. for
example. 6-a.-
s0 methvlprednisolone. cortisone, cortisol, and triamcinolone: andro~~enic
steroids, for example,
methyl-testosterone, and tluoxvmesterone: estrogenic steroids. for example,
estrone,
17p-estradiol and ethinyl estradiol; Pro~;estational steroids, for example 17-
cc-
hydroxyprogesterone acetate. medroxvprogesterone acetate. 19-norpro~~esterone,
and
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norethindrone; and thyroxine; antipyretics such as aspirin. salicylamide. and
sodium salicvlate:
antispasmodics such as atropine. methscopolamine bromide. and methscopolamine
bromide
with Phenobarbital: antimalarials such as the 4-aminoquinolines. 8-
aminoguinolines, and
pyrimethamine; and nutritional agents such as vitamins. essential amino acids.
and essential
fats.
:~ pharmaceutical composition with a broad spectrum of antimicrobial
protection is
produced by combining one or more systemically active drugs in a stable
fashion with silver
thiosulfate ion complexes. The addition of silver thiosulfate ion complexes
with one or more
systemically active drugs to produce a pharmaceutical composition assists in
the preservation
of the pharmaceutical composition by protecting it from microbial
proliferation and
over~~rowth, which could otherwise lead to spoilage of the medicinal
composition containing
the systemically active drug's.
f=inally, the antimicrobial compositions may be useful in making_ infection-
resistant
cosmetics and personal care products.
IS
IV. INCORPORATION OF SILVER THiOSULFATE ION COMPLEXES
INTO MATRICES AND THE USE OF SUCH MATRICES
This section describes the incorporation of silver thiosulfate ion complexes
into
matrices. most preferably anhydrous polymeric matrices. In turn, the matrices
products can
'_'0 be used in conjunction with medical devices for the treatment and
prevention of infections
and diseases. In ~_eneral. the silver thiosulfate ion complexes can be
incorporated into the
polymer matrix either (i) durin~~ the production of the polymer matrix or (ii)
after the polymer
matrix has been produced. It is most preferred that the complexes are
homo~_eneouslv
dispersed in the matrix
A. The Nature of Silver Thiosulfate lon-Containing Anhydrous
Polymeric iYlatrices
Similar to the situation described above re~,ardin~s compositions. aqueous
solutions of
aiiver thiosulfate ion complexes which have not been purified can be
incorporated into
~0 polymer matrices to render the matrices compositions antim~icrobial.
However. the resultin~;
matrices compositions will contain large quantities of excess thiosulfate
salts as well as waste
salts such as sodium nitrate, potassium nitrate. potassium acetate. etc. .~s
set forth above,
these impurities may be irritatin~~ when the matrices compositions are applied
topically.
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Furthermore. the presence of the waste salts may have a negative impact on the
physical
characteristics (c~.~,~, feel. strength, and stiffness) of the final matrices
compositions.
The purifred carrier-free silver thiosulfate ion complexes of this invention
can be
incorporated into an anhydrous polymer matrix to produce photostable
antimicrobial matrices
compositions: these compositions are useful in making medical devices. The
present
invention contemplates that anv solid material that does not contain a
si~~nificant amount of
water may be used as an anhydrous polymer matrix. The preferred anhydrous
polymer matrix
material is any material that is compatible (i.e., does not contain reactive
components which
could lead to the destruction of the thiosulfate ligand, thereby destabilizing
the silver
thiosulfate ion complexes) with the silver thiosulfate ion complexes of this
invention. The
most preferred polymer matrix material is one that is compatible with the
silver thiosulfate ion
complexes of this invention and has some capacity to absorb and/or swell in
the presence of
water; the ability of the polymer matrix to absorb andior swell in the
presence of water assists
in the dissolution and diffusion of the silver thiosulfate ion complexes from
the polymer
I ~ matrix.
It should be noted that the silver thiosulfate ion complexes of the present
invention can
be used with anhydrous polymer matrices which do have reactive components as
lon~~ as the
media is such that the reactive chemical component of the polymer matrices
cannot react with
the silver thiosulfate ion complexes. For example. when incorporated into a
solution of
~O aly~inate material (which contains a number of chemical reactive ~Troups
such as carboxylic
acid). the silver thiosulfate inn complexes of the resultin!~ composition are
unstable over lone
periods: the water in the solution acts as a media in which the reactive
groups of the alginate
materials can destabilize the silver thiosulfate ion complexes However. when
the al~~inate
material is dry. the silver thiosulfate ion complexes remain stable
anhydrous polymer matrix materials useful in this invention include. but are
not
limited to, the followings: adhesives such as acrylic-based. pressure-
sensitive adhesives;
biopolvmers such as silk. al:.linate materials, etc.: hvdrocolloid materials
such as sodium
carboxvmethvlcellulose. either alone or when bound in a polymer; polymers such
as
polyurethane, silicone. etc. in the form of coatin~.a, films or foams. and the
like. These
s0 anhydrous polymer matrix compositions can be used alone or as a component
of another
material, such as a medical device.
The concentration of the silver thiosulfate ion complexes within the anhydrous
polymeric matrix should be such as to provide antimicrobial activity. The
preferred
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concentration of the silver thiosulfate ion complexes in the final polymeric
matrix is 0.1% to
3.0%. However. silver thiosulfate ion complexes concentrations can range up to
10% to 30%,
depending on the antimicrobial potency required and the permeability of the
polymeric matrix.
The most preferred concentration is between 0.2°,% and I
.5°'°. The resulting silver thiosulfate
ion complexes-containin~~ matrices compositions of this invention are
antimicrobiallv active
and stable. Additionally, the compositions of this invention show no photo-
discoloration
when exposed to ambient room li~~ht over a 72-hour period
It should be noted that the silver thiosuifate ion complexes-containing
matrices
compositions of the present invention can be used alone in the treatment and
prevention of
infection in a manner analogous to the compositions described above.
>Vloreover, as
previously alluded to, the matrices compositions can be used to make medical
devices such as
dressin~~s, tamponades, etc. which can be used in the treatment and prevention
of infection.
B. Incorporation During Production Of Polymer Matrix
The method of incorporatin~~ the silver thiosulfate ion complexes durin~~ the
production
of the polymer matrix itself will be dependent on the production process for
that polymer
matrix. The methods of incorporation for several polymer matrices follows. Of
course,
deviations from these methods as well as the use of different matrices than
those specifically
mentioned are within the scope of the present invention.
~0 The first method of incorporation is useful if the polymer matrix is
produced from a
aolvent solution of polymer matrix material. In this situation. the silver
thiosulfate ion
complexes in a solid powder form can be added to that solution and mixed
thorou~Thlv l:pon
elimination of the solvent throu~~h standard means in the art. the remaining_
polymer matrix
material will have the silver thiosulfate ion complexes dispersed: preferably
the complexes are
~'s dispersed homo'_eneouslv. For example. in an adhesive material dissolved
in a solvent, the
silver thiosulfate ion complexes in a powder form are thorouuhlv mixed in. The
mixture is
then coated on a liner and dried. The resultin~, adhesive film has the silver
thiosuitate ion
complexes incorporated as a dispersion.
Another method of incorporation is useful if the production process for the
polymer
,0 matrix involves the use of water as a solvent. (i.r.. latex polymer
systems. solvent extraction
systems) or as a reactant (i.e., polyurethane foam production. al<~inate fiber
production. etc.l.
With this method. the silver thiosulfate ion complexes can be dissolved in the
water prior to
the production process. To illustrate, if a polymer film is bein_~ produced by
coatinu with a
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polymer latex solution. the silver thiosulfate ion complexes can be added
directly to the latex
solution. Once added. the silver thiosulfate ion complexes will dissolve.
otter coating and
drvin~" the resulting polymer elm will have the silver thiosulfate ion
complexes
homo~,eneousiy dispersed in the film.
Likewise, in producing a polyurethane foam matrix by reacting the polyurethane
prepotymer with water. the silver thiosulfate ion complexes can be dissolved
in the water
prior to reacting it with the prepolvmer. after the polyurethane foam has
reacted and been
dried, the silver thiosulfate ion complexes will be dispersed throu~_hout the
foam matrix.
additionally, in producing: a water insoluble al<~inate material by reacting
an alginate
solution with an aqueous calcium chloride bath, the silver thiosulfate ion
complexes can be
dissolved in either the water makings up the al~~inate solution or the calcium
chloride bath.
The al~~inate solution. when extruded into the calcium chloride bath. will
result in crossiinked
al~_inate fibers which incorporate the silver thiosulfate ion complexes. Upon
drying of these
tibers, the silver thiosulfate ion complexes will be dispersed throu'_hout the
alv~inate matrix.
I ~ Another method of incorporation can be used in conjunction with the
production of
polymer matrices such as a hvdrocolloid matrix made up of a hvdrocolloid
material (c~.~,~.,
carboxymethvlcellulose) in a polymer binder. In this situation. the silver
thiosulfate ion
complexes. in a solid form. can be mixed directly with the Itvdrocolloid
material prior to the
production process. Likewise. the silver thiosulfate ion complexes can be
dissolved in water
?0 which is then used to treat the hvdrocolloid material so that the solution
is absorbed by the
I~vdrocolloid material and then dried. Thereafter. the treated hydrocolloid
material is
processed using standard procedures to produce the hydrocolloid polymer matrix
which
contains the silver thiosulfate ion complexes dispersed in the hvdrocolloid
component of the
matnx.
C. Incorporation after Production Of Polymer Matrix
In addition to incorporation prior to or durin~~ the production of the polymer
matrix,
silver thiosulfate ion complexes can be incorporated after the polymer matrix
has been
produced. One approach is to form an aqueous solution of the silver
thiosulfate ion
complexes and then apply this solution to the tinished polymer matrix. This
silver thiosuftate
,0 ion complexes solution can be applied to the polymer matrix by spravin~=,
dipping, paintin« or
other suitable means.
By way of illustration. an aliquot of the silver thiosulfate ion complexes can
be applied
onto and absorbed into a tinished foam dressing_=. After drvin~_, the silver-
based foam
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composition will be stable and antimicrobial. Likewise. the silver thiosulfate
ion complexes
solution can be sprayed on the surface of a polymer or adhesive film which,
after drying, will
be stable and antimicrobial.
D. Precautions During Incorporation
Regardless of the method of incorporating the silver thiosulfate ion complexes
with the
polymeric matrix, certain precautions need to be considered. First. if
incorporation of the
silver thiosulfate ion complexes into the polymeric matrix involves the use of
water, it is verv
important that the water be removed from the polymeric matrix. If the water is
not removed,
the silver thiosulfate ion complexes will become destabilized within the
polymeric matrix over
time.
Second. thou~lh the water can be removed using inv standard method. if the
water is
removed by drying the polymeric matrix in an oven. care should be taken to use
only
moderate temperatures: temperatures of 20°C to 70°C IllaV be
used. while temperatures of
I S 30°C to 50°C are preferred. If the temperature becomes too
hot, rapid destabilization of the
silver thiosulfate ion complexes can occur.
Finally. when the silver thiosulfate ion complexes are in solution_ contact
with metal
surfaces should be avoided. The silver thiosulfate ion complexes solution can
be destabilized
upon contact with metal surfaces such as aluminum and copper. An effort should
be made to
?0 ensure that the solution comes into contact with materials such as ~~lass
or plastic. which
appear to be less destabiliziny~.
E\PERIMEIY'1'AL
In the disclosure which follows, the foilowin'; abbreviations apply: L
(liters); ml
(milliliters); yi (microliters); g (;=rams); m~; (milliL~rams); ~tv~
(micro~~rams); mol (moles);
mmol (millimoles); tunol (micromoles); cm (centimeters l: mm (millimeters); nm
(nanometers); °C (de<~rees Centi'==ride); MW and M1.W. (molecular
weight); N (normal); w/w
(wei!~ht-to-weight); wiv (wei~lfn-to-volume); min. (minutes): No. (number);
ICP (inductively
coupled plasma); CFU (colony forming, units); PEG (polyethylene <glycol); MHM
(Mueller
s0 Hinton Medium); ZOI (zone of inhibition); .-~TCC (American Tvpe Culture
Collection.
Rocf:ville. MD); USP (United States Pharmacopeia); NCCLS (National Committee
for
Clinical Laboratory Standards); NIOSH (National Institute of Safety ind
Health); Avitar
(.Avitir. Inc.. Canton. MA); Aldrich ()Vlilwaukee. WI); Avery Dennison. lnc.
(Mill Hall, PA);
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BASF (BASF Corp., Chemical Division; Parsippany, NJ); Belersdorf Inc. (BDF
Plaza
Nor-walk. CT); Columbus (Columbus Chemical Industries: Columbus. WI); Cook
Composites
and Polymers (Kansas Citv, MO); Difco (Difco Laboratories, Detroit, MI);
Hampshire
(Hampshire Chemical Co.. Lexington, MA); Johnson & Johnson Medical, Inc.
{Arlington,
Tx); Owen Laboratories (San Antonio, TX); Protan (Drammen, Norway); Roundy
(Roundy's
Inc., Milwaukee, WI); Si~~ma (Sigma Chemical Company, St. Louis, MO);
SmithKline
Beecham (Philadelphia. PA); Steriseal (Steriseal Ltd, En~~land); Whatman
(Whatman
International Ltd., England); WOHL (Wisconsin Occupational Health Laboratory,
Madison,
wI).
The followiny~ examples serve to illustrate certain preferred embodiments and
aspects
of the present invention and are not to be construed as limiting the scope
thereof. The
experimental disclosure which follows is divided into: t) Processes To Obtain
Silver
Thiosuifate Eon Complexes: I1) Compositions Containin<~ Silver Thiosulfate ton
Complexes;
fII) Antimicrobial Activity Of Compositions Containing Silver Thiosulfate Ion
Complexes:
I S IV) Use Of Silver Thiosulfate Ion Complexes in Medical Devices, and V) Use
Of Silver
Thiosulfate Ion Complexes in Combination With Other Medicinal A~~ents.
I. PROCESSES TO OBTAIN SILVER TI-IIOSULC'ATE ION COMPLEXES
'0 EXAMPLE 1
Process For Makin~~ Silver Thiosulfate Ion Complexes Usin~~ Silver
Chloride When The Ratio Of Thiosulfate Ions To Silver- Ions is Cheater Than ?-
to-I
This example illustrates the process for producing silver thiosulfate ion
complexes
when the ratio of thiosulfate ions to silver ions. is greater than 2-to-I.
That is. a biphasic
separation is employed in this example.
The silver thiosulfate ion complexes were produced by tirst making a silver
chloride
precipitate in an aqueous solution (hereafter. "silver chloride
precipitate/aqueous solution").
The silver chloride precipitate/aqueous solution was made by mixin!= 20 ml of
a silver nitrate
s0 (Aldrich: deionized water as the diluent) solution ( 1 mmol/m~l) with 2? ml
of a sodium
chloride solution ( 1 mmol/ml) (Aldrich; deionized water as the diluent) in a
X00 ml separatorv
funnel. To the resulting silver chloride precipitate/aqueous solution was
added 60 mi of a
sodium thiosulfate (Columbus; deionized water as the diluent) solution ( I
mmol/ml). The
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resuitin~~ mixture was agitated by shaking the separatorv funnel until all of
the silver chloride
precipitate was dissolved.
The silver thiosulfate ion complexes produced were separated by adding 200 ml
of
ethyl alcohol to the container. C.!pon addition of the ethyl alcohol, the
solution became cloudy
and separated into two separate phases. The two phases were separated using
the separatory
funnel. The wei~~ht of the material in the phase containinSr the silver
thiosulfate ion
complexes was approximately 17 <'. This phase was then treated by adding 70 ml
ethyl
alcohol and 40 ml of acetone to make the silver thiosulfate ion complexes
essentially
anhydrous. After sittiny~ overnight, the silver thiosulfate ion complexes were
in the form of a
pure, white solid material in the bottom of the container Thereafter, the
solvent was
decanted and the white solid was dried in an oven (62°C) and ground to
a tine white powder
using a mortar and pestle. The wei~~ht of the dried silver thiosulfate ion
complexes was
10.03 ~~
The silver thiosulfate ion complexes were analyzed for silver. sodium and
sulfur using,
I ~ Inductively Coupled Plasma Argon Emission Spectrometry. The analysis,
performed by
Wisconsin Occupational Health Laboratory (WOHL), included measurement of the
amount of
silver using a method based on NIOSH 5182. Briefly, a representative portion
of the silver
thiosulfate ion complexes was wei<shed and diluted (/1000 in a dilute nitric
acid solution.
Thereafter, an aliquot of the sample was analyzed (Jarrel .-ASH ICP: Franklin,
MA); the
'_'0 analysis ~~ave the following results !expressed as percenta~_es of the
air dried samples):
Silver-
Sodium 17%
Sulfur ;?%
The results of the analysis suu'~est that the silver thiosultate ion complexes
were
relatively pure and corresponded to the formula: Va,H[A~_(S~Ot),] (Silver:
?0.1 I°,o (w/w),
Sodium: 17.13% (wiw), Sulfur: ;; 75~% (wiw)).
The calculated yield of silver thiosuftate ion complexes usiny~ the process of
this
example is 9 3.7%.
;0
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EXAMPLE 2
Process For Making Silver Thiosulfate Ion Complexes Using Silver
Chloride When The Ratio Of Thiosulfate Ions To Silver Ions Is Equal To 2-to-1
This example illustrates the process for producing silver thiosulfate ion
complexes
when the ratio of thiosultate ions to silver ions is equal to ?-to-I. The
silver thiosulfate ion
complexes were isolated throu~~h the use of a biphasic separation.
In this example, silver thiosulfate ion complexes were produced by first
making a
silver chloride precipitate in an aqueous solution by mixing_ 10 ml of a
silver nitrate (Aldrich;
deionized water as the diluent) solution ( I mmol/ml) with 10 ml of a sodium
chloride
(Aldrich; deionized water as the diluent) solution ( I mmol/ml) in a 100 ml
specimen
container. To this silver chloride precipitateiaqueous solution was added 20
rnl of a sodium
thiosulfate (Columbus: deionized water as the diluent) solution ( i mmol/ml).
The resulting_
mixture was agitated by shakings the container until all of the silver
chloride precipitate was
I s dissolved.
Thereafter. the silver thiosulfate ion complexes were separated by addin'= s0
ml of
acetone to the container. Upon addition of the acetone. the solution became
cloudy and
separated into two separate phases. The nvo phases were separated into
individual containers
using a pipet. The phase containin!, the silver thiosulfate ion complexes was
treated by
''0 uddin~_ >0 ml of acetone to make tire silver thiosulfate ion complexes
essentially anhydrous.
.-otter sittings overniy~ht, the silver thiosultate ion complexes were in the
t'orm of a pure
white solid material. Thereafter. the solvent was decanted and the white Solid
was dried in an
oven ((>?°C) and aground to a tine white powder tisin~; a mortar and
pestle. The wei~,ht of the
dried silver thiosulfate ion complexes was 3.07 <drams.
The resultin~~ silver thiosulfate ion complexes material was analyzed for
silver, sodium
and sulfur usin~~ an Inductively Coupled Plasma (ICP; described above). The
analysis ~~ave
the tollowin~T results:
S i lver 25%
Sodium 17%
_;c) Sulfur 30%
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The results of the analysis indicate that the silver thiosulfate ion complexes
were
relatively pure corresponding with the following theoretical formula:
Na,[Ag(S,O,)~]~2H.,0.
(Silver: ?4.7% (w/w), Sodium: 15.78% (w/w), Sulfur: X9.3% (w/w)).
The calculated yield of makin<~ silver thiosulfate ion complexes using the
process of
this invention is 90.8%.
EXAIViPLE 3
Process For Making Silver Thiosulfate ton Complexes Usin;> Silver
Chloride When The Ratio Of Thiosulfate Ions To Silver tons is Less Than 2-to-1
This example further illustrates the process for producin~, silver thiosulfate
ion
complexes when the ratio of thiosulfate ions to silver ions is less than 2-to-
I. .-~s in the
preceding_ example, the silver thiosulfate ion complexes were isolated through
the formation of
a precipitate rather than a biphasic separation.
I 5 In this example, silver thiosulfate ion complexes were made by tirst
making a silver
chloride precipitate in an aqueous solution by mixing 10 ml of a silver
nitrate (Aldrich;
deionized water as the diluentl solution ( I mmol/ml) with ''0 ml of a sodium
chloride
(Aldrich; deionized water as the diluent) solution ( 1 mmol/ml) in a 100 ml
specimen
container. To this silver chloride precipitate/aqueous solution was added I 5
ml of a sodium
~0 thiosulfate (Columbus; deionized water as the diluent) solution ( I
mmol/ml). The resultin!s
mixture was a<~itated by shakin~l the container until all of the silver
chloride precipitate was
dissolved.
Thereafter, the silver thiosulfate ion complexes were precipitated from the
solution by
oddin~_ ~0 ml of acetone to the container. The precipitated silver thiosuifate
ion completes
were in the form of a pure white solid material. The solvent was decanted and
the white
solid was dried in an oven (62°C) and ~,~round to a tine white powder
using a mortar and
pestle.
The silver thiosulfate ion complexes were analyzed for silver. sodium and
sulfur usin~~
an Inductively Coupled Plasma ( ICP: described above) The analysis ~,ave the
following=
.,0 results:
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Silver
Sodium 14%
Sulfur 29%
The results of the analysis indicate that the silver thiosulfate ion complexes
were
relatively pure corresponding with the following theoretical formula
Na,[Ag,(S~O,),,J~H_,O.
(Silver: 32.6% (w/w) , Sodium: 13.9% (w/w), Sulfur: 29.0% (w/w}).
EXAMPLE 4
Process For Making Silver Thiosulfate Ion Complexes Usin~~ Silver Bromide
In makinz the aqueous solution of silver thiosulfate ion complexes. the
preferred silver
halide is silver chloride (Examples I-3): this example illustrates that other
silver halides may
be used.
t > In this example, the silver thiosulfate ion complexes were produced by
first making a
silver bromide precipitate in an aqueous solution (hereafter. "silver bromide
precipitate/aqueous solution") by miring, 2 ml of a silver nitrate (Aldrich:
deionized water as
the diluent) solution ( 1 mmol/ml) with 2.? ml of a sodium bromide (Aldrich;
deionized water
as the diluent) solution ( I mmol/ml) in a ~0 ml beaker. To this silver
bromide
?0 precipitate/aqueous solution was added 6.0 ml of a sodium thiosulfate
(Columbus; deionized
water as the diluent> solution ( 1 mmol/ml). Tl~e resultin~_ mixture was
a~sitated (v stirrin!,
until all of the sodium bromide precipitate was dissolved.
The silver thiosulfate ion complexes were separated by addin~~ X0.0 ml of
acetone to
the container. Upon addition of the acetone, the solution separated into two
phases. The
'_'S phase containin<, the silver thiosulfate ion complexes was collected and
treated by addin~= 7.0
ml ethyl alcohol and ~.0 ml of acetone to make the silver thiosulfate ion
complexes
anhydrous. after sitting overnight. the silver thiosulfate ion complexes were
in the tone of a
white solid material at the bottom of the container. The solvent was decanted
and the w ~f~ite
solid was dried in an oven (62°C) and v~round to a tine white powder
using a mortar and
s0 pestle. The resultin'~ weight of the dried silver thiosulfate ion complexes
was 0.88 V;.
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EXANtPLE 5
Process For Making Silver Thiosulfate
Ion Complexes Devoid Of A Phase Separation Procedure
To illustrate the importance of makin<~ silver thiosulfate ion complexes using
the
processes of this invention, silver thiosulfate ion complexes were made by a
process which
did not use a phase separation procedure when the ratio of thiosulfate ions to
silver ions is
'heater than 2-to- I .
This comparison process was performed by first making a silver chloride
precipitate in
IO an aqueous solution (hereafter, "silver chloride precipitateiaqueous
solution") by mixing 2 ml
of a silver nitrate (Aldrich; deionized water as the diluent) solution ( f
mmol/ml) with 2.2 ml
of a sodium chloride (Aldrich: deionized water as the diluent) solution ( l
mmol/ml) in a ~0
ml beaker. To this silver chloride precipitate/aqueous solution was added 6.0
mi of a sodium
thiosulfate (Columbus; deionized water as the diluent) solution ( I mmol/ml).
The resulting
I s mixture was agitated by stirrings until all of the sodium chloride
precipitate was dissolved.
The resulting silver thiosulfate ion complexes solution was placed in a
convection
oven at ~2 °C overni~~ht to evaporate the water. The solid material
produced had a splotchy
tan color with areas which had a deep brown color. The lack of a pure white
solid indicates
that this process leads to a breakdown or decomposition of silver thiosulfate
ion complexes.
'0
II. COMPOSITIONS CONT;~INING SILVER TIiIOSIJLfATE ION
(_'OMPLE\ES
EXAI\~tPLE 6
=' Stable Antimicrobial Composition - PEG Base
The previous examples were directed at processes for makin« silver thiosulfate
ion
complexes. This example, as well as Examples 7-9 that follow. compare various
antimicrobial compositions containin~~ tire silver thiosulfate ion complexes.
In this example. a
s0 silver-based antimicrobial composition was produced in a PEG base.
Speciticallv. ~0 ~~ of a
poivethvlene y~lycol (PEG) base (PEG 600:PEG 1000 = 0 3:0.7: Aldrich) was
melted. While
cooling, 0.47 '; of the silver thiosulfate ion complexes of Example I were
stirred into the
melted PEG base. The stirrings vsas continued until the silver thiosulfate ion
complexes were
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homo~~eneously suspended. While stirrin<" the melted PEG/silver thiosulfate
ion complexes
composition was cooled to produce a semisolid base. The amount of silver in
this silver-
based antimicrobial composition was equivalent to 0.5°,o silver
nitrate.
EXAMPLE 7
Stable Antimicrobial Composition - Aquaphor"
To further illustrate a silver-based antimicrobial composition of this
invention, 40 g of
Aquaphor~ Cholesterolized Absorbent Eurcerite Ointment Base was melted.
AquaphorN is a
I (7 stable, neutral. odorless, anhydrous ointment base (Belersdorf Inc).
While cooling, I .?6 ~ of
the silver thiosulfate ion complexes of Example I were stirred into the melted
Aquaphor"
base. The stirring_ was continued until the silver thiosulfate ion complexes
were
homo''eneouslv suspended. While stirrin<_, the melted Aquaphor"/silver
thiosulfate ion
complexes composition was cooled to a semisolid base. The amount of silver in
this silver-
I S based antimicrobial composition was equivalent to I .0°,r silver
nitrate.
EXAMPLE 8
Stable Antimicrobial Composition - White Petrolatum USP
?0 To illustrate an alternative silver-based antimicrobial composition of the
present
invention. 40 ~~ of white petrolatum USP (Roundv~s Pure Petroleum Jelly. White
Petrolatum
ElSP) was melted. \Vhile coolin~~, '.5? '~ ot~ the silver thiosulfate ion
complexes ot~ Example 1
were stirred into the melted wf~ite petrolatum base. The stirrin<, was
continued until the silver
thiosultate ion complexes were homo'~eneouslv suspended. lVhile stirring, the
melted white
petrolatumisilver thiosulfate ion complexes composition was cooled to a
semisolid base. The
amount of silver in this silver-based antimicrobial composition was equivalent
to 2.0°,'o silver
nitrate.
EXAMPLE 9
Stability Of Anhydrous rind Hydrated Antimicrobial Compositions
This example illustrates the instability of hydrated silver-based
antimicrobial
compositions comprisin~1 silver thiosulfate ion complexes. The experiments of
this example
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utilize the compositions produced in Examples C-8. as well as a composition
containing a
different base. Velvachol ~ Cream.
EXAMPLE 9A
PEG Base Plus Water
r~ hydrated silver-based antimicrobial composition was made where the
composition
base was PEG. The composition was made by mixin~~ 9 « of the silver-based
antimicrobial
composition of Example 6 with I ml of water. This silver-based antimicrobial
composition
contained approximately 10% water by weight.
EXAMPLE 9I3
-~quaphor" Plus Water
,A hydrated silver-based antimicrobial composition was made where the
composition
base was Aquaphor" The composition was made by mixing- 9.5 ~= of the silver-
based
antimicrobial composition of Example 7 with 0.5 ml of water. This silver-based
antimicrobial
composition contained approximately s°'° water.
EXAMPLE 9C
White Petrolatum Plus Water
-\ hydrated silver-based antimicrobial composition was made where the
composition
base was white petrolatum. The composition was made bwnixing 9.s <, of the
silver-based
'_'S antimicrobial composition of Example 8 with Q.s ml of water. This silver-
based antimicrobial
composition contained approximately ~°% water.
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EXAMPLE 9D
Velvachol Cream
A silver-based antimicrobial composition containing 0.47 ~ of the silver
thiosulfate ion
complexes of Example 1 were stirred into 20 g of Velvachol "' (Owen
Laboratories).
Velvachol~ is a neutral. hydrophilic cream which contains some water (amount
unknown).
The amount of silver in this silver-based antimicrobial composition was
equivalent to 1.0%
silver nitrate.
The stability of the silver-based compositions of Examples G, 7, 8,and 9A-D
was
evaluated over time. The stability of the compositions was determined by
measuring the
change of color, if any. when the compositions were stored in transparent
containers in
ambient li~lht. Chan<~e of color indicates decomposition of the silver
thiosulfate ion
complexes. Table I below indicates the initial color of each composition and
the change in
color on days 7 and 14 and after I month.
I S .As depicted by the results of this study, the silver-based compositions
described in
Examples 6, 7 and 8 demonstrated no chan~~e in color. In contrast, the
hydrated silver-based
compositions, Examples 9A-D, demonstrated major chancres in color. some after
only 7 days
(Examples 9B and 9D): all of these compositions, i.c.~., Examples 9A-D.
changed from their
initial color to a brown or black color. Thus, the results of this study
indicate that the
anhydrous compositions of this invention were stable. while the analo~~ous
hydrated samples
were not.
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TABLE 1
Stability Of Silver-Based Comnnsi~innc
S APpear:~nce
l Of
Ointment
amp
e
Dxv Day 7 Day 14 Month Month Month
I 1 3 7
Eaantplc (~: PEG GrayishNo No No No No
Composition White Change Change Change Change Change
Ex:1t11pIC 7: Slight No NO NO No No
Aquaphor"
Composition Yellow Change Change Chance Change Change
Eaamplc H: White Slight No No No No No
Petrolatum CotnpositionYellow Change Change Change Change Change
Eaample'lA: HydratedGrayishNo Slight Brown Brown Black
Tan
PEG Composition White Chance
Eaantplc'JB: HydratedSlight Slight Brown Dark Black Black
Aquaphor"' CompositionYcllon Tnn Brown
Exantplc'JC': Sliglu No T:m Black Black Black
Hydrated
\Vltitc I'ctrolatumY'cllowC'hanr;c
Composition
Exantple'JD: Velvachol~White Tan Brown Black Black Black
Crc:tm
?0 III. .-~NTIMICROI31AL ACTIVITY OF COMPOSITIONS CONTAINING
SILVER TH10SULFATE ION COMPLE\ES
EXAMPLE l0
Antimicrobial ,Activity Of Silver Tltiosulfate Ion Complexes
,;
The iir t~iwn antimicrobial activity was evaluated by tindin~_ the minimum
inhibitory
concentration for the powder of silver thiosulfate ion complexes from Example
_s. This
powder was tested in serial two-told dilutions ranging_ from I.~)5 to 250
tt~/ml. Broth
microdilution was performed in serial dilution of the silver thiosulfate
powder in tryptic soy
s0 broth (Ditto). Each dilution was inoculated with 0.005 ml of a 24-hour
~,rowth of a microbe
f 10' to 10' CFU/ml). After the dilutions were incubated at ,7°C
overnit-rht, the lowest
dilution of the silver thiosulfate ion complexes that was without evidence of
~~rowth (i.c~.. was
not cloudy) was the minimum inhibitory concentration (>\11C) reported in terms
of l.t~.:/ml.
The results shown in Table ? demonstrate that the silver thiosulfate ion
complexes
s5 powder has antimicrobial activity a~,ainst both ~~ram (+) and ~~ram (-)
microbes (Difco).
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TABLE 2
Isolate ATCC Accession Silver Thiosolt:lte Ion Complexes
No. (~c~,/ml)
.5'. nlrreu.v ?i9~3 ' 1.95
.~~. C'l7lC~C'1'llllll(.1'I~2?5 ! I.r)j
l.. call Z~~)22 < 1.95
l'. nerr~t'inn.vn2753 < I.')s
EXAMPLE l t
t 0 Antimicrobial Activity Of Silver-Based Compositions
The antimicrobial activity of the silver-based compositions of Eramples ~. 7.
and 8
were evaluated usin<~ a zone of inhibition (ZOI) protocol In this ZOI
protocol. I cm-
diameter discs (Whatman Filter Paper, Quantitative l ) were coated with a thin
layer of the
I ~ compositions from Examples 6. 7. and 8. These coated discs were placed on
)V1ueller Hinton
fvledium (MHIVI; Difco) with lawns of,f. ur~rm.~~ (ATCC '_'923; ?4 hours
~~rowth from MHM
plate). :otter incubation at 3G °C for 18 hours. the size of the zone
of ~Trowth inhibition was
measured' (in mm j from the ed_'e of the disc to the point of microbial
urowth. Table 3 shows
the ZOI results for each composition on Day I and at one month.
TABLE 3
~ntimicrobi:vl Activim Of Silver-Based C'onlnositions
Zone of Inhibition
S Imml 1.5'. urtrcusl
l
amp
e
Day I 1 Month
Exanlplc c,: PEG CompositionI s.~ mnl I-t.lt mm
Exanlplc 7 .~quapilor"
1
C OIIlpOS1110I1 I (1,11 111111 I .s.1) Illlll
Exaulplc 1: White
Pctroiallnn
COIIIpOS1l1011 111.1) 111111 Il).~ 111111
.-~s can be seen by the results of this study, the silver-based compositions
of this
.,0 invention (E~camples 6. 7 and 8) demonstrated wood antimicrobial activity
that was stable for
the duration of the study period. That is to say. the size of the zone of
growth inhibition was
essentially unchan~~ed over the one month period.
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IV. USE OF SILVER THIOSULFATE ION COMPLEXES IN MEDICAL
DEVICES
EXAMPLC 12
Foam Dressin~_=s Containing, Silver Thiosulfate Ion Complexes
,as previously indicated. the silver thiosulfate ion complexes of the present
invention
can be used in conjunction with medical devices. This example illustrates the
use of silver
thiosulfate ion complexes to prepare a medical device made up of a foam
polymer matrix. In
this example, the complexes were incorporated into the matrix durin'_ the
manufacturing of
the polymer matrix.
-~ foam dressin~~ was produced by first dissolvin~~ 0.~4 ~_= of silver
thiosulfate ion
completes powder in 150 ml of a 0 5°o Platonic L-62 (l3r~SF) ac)ueous
solution. This
solution was the mixed with 140 ~, of a polyurethane prepolvmer (Hypo) 2002,
Hampshire) in
I S a I-liter disposable plastic beaker The resultin'1 mixture instantly
be<,an to react to form a
foam. :otter 10 minutes the foam was removed from its container and sliced to
produce
individual foam dressinss (approximately 7.5 cm in diameter The slices of foam
dressings
were dried at 50°C in a dark convection oven.
These foam dressin<,s were light stable and antimicrobially active. In this
example and
'_'0 Examples 13-18 that follow, the terms "li';ht stable." "photostable," and
the like mean that the
samples did not discolor after 7'_' hours of exposure to ambient room li~sht.
In this example
and Examples I ,-13 that follow. the term "antimicrobiallv active" means that
a small piece
1 nominally I cm x 1 cm or I cm strands in the case of al«inate fibers I
produced zones of
inhibition when placed on both a lawn of.f. mrrc-rr.~~ (r~TCC '_'S9?;) and a
lawn of l:. c.wli
(.~TCC 2593?). The lawns were produced by plating ?4-(tour growth microbes on
MHM
plates: after incubation For ?4 hours. each sample was examined to determine
whether a zone
of inhibition was present
This foam dressing,_= can be used for a larvae variety of medical
applications, includin~s
as an antimicrobial absorptive foam dressings.
s0
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EXA1VIPLE 13
Foam Dressing Containing Silver Thiosulfate Ion Complexes
This example further illustrates the use of silver thiosulfate ion complexes
to prepare a
medical device made up of a foam polymer matrix. In contrast to the previous
example, the
silver thiosulfate ion complexes were incorporated into polymer matrix
following the matrix'
manufacture.
In this example, a foam dressing (Hvdrasorb ~ Sponge Foam Dressing ( 10 cm x
10
cm); Avitar) was submerged in an aqueous solution containing silver
thiosulfate ion
complexes powder from Example 3 (0. 1 ~ per liter). The foam dressing samples
were
removed and dried at SO°C in a convection oven. These silver
thiosulfate ion compiexes-
containin<s foam dressin<~s were li<sht stable and antimicrobiallv active. As
indicated in the
previous example. these foam dressin~~s can be used for a lar~_e variety of
medical
applications. including as an antimicrobiai absorptive foam dressin'as.
IS
EXAV1PLE t4
Hydrocolloid Dressing Containin~_ Silver Thiosulfate Ion Complexes
This example illustrates the use of the silver thiosulfate ion complexes to
prepare a
?0 medical device which is made up of a hvdrocolloid absorbent polymer matrix.
In this
example. the complexes were incorporated into the matrix Burin<s the
manufacturing= of the
polymer matrix.
-~ hydrocolioid dressin~_ containin~T silver thiosulfate ion complexes was
produced by
first thorou~_hly mixing 0. 157 ~; of silver thiosulfate ion complexes powder
(mesh l00) from
?5 Example I with l0.0 '; of sodium carboxvmethvl cellulose (Aldrich).
Thereafter. ~! <, of this
treated carboxvmethyl cellulose was mixed thorou~ahfy with ~ '; of a
polyurethane prepolvmer
(Aquapol 035-0031. Cook Composites and Polymers). This mixture was then
pressed
between a polyurethane film and a silicone-treated hvdrocoiloid matrix and was
allowed to
cure for 2=1 hours.
s0 The resulting silver thiosulfate ion complexes-containin~~ hvdrocolloid
dressing was
photostable and antimicrobially active. This type of dressing is useful on
exudating,
malodorous wounds.
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EXAMPLE 15
Hydrocolloid Dressing Containing: Silver Thiosuifate Ion Complexes
This example further illustrates the use of silver thiosuifate ion complexes
of this
invention to prepare a medical device which is made up of an hydrocolloid
absorbent polymer
matrix. However. in this example the silver thiosulfate ion complexes were
incorporated into
the polymer matrix by a different procedure than that presented in the
preceding example.
The hydrocolloid dressing was produced by first dissolving 0.157 ~1 of a
silver
thiosulfate ion complexes powder (mesh >100) from Example i in 10.0 ml of
water. To this
solution was added 100 g of sodium carboxymethyl cellulose (Aldrich,
Milwaukee, W1) which
absorbed the solution The treated sodium carboxymethvl cellulose was allowed
to dry at
room temperature. Thereatter. -1 ~_ of the dried treated carboxvmethvl
cellulose was mixed
thorou~~hly with 4 V1 of a polyurethane prepolvmer (Aquapol 035-0031. Cook
Composites and
Polymers). This mixture was then pressed between a polyurethane tilm and a
silicone treated
1 ~ liner and was allowed to cure for 2=1 hours.
As with the silver thiosulfate ion complexes-containin~~ hvdrocolloid
dressin~~ produced
in the precediny~ example. the hvdrocolloid dressing is photostabie and
antimicrobialiv active
and is useful on exudating, malodorous wounds.
-'0 EXAMPLE IG
-adhesive Films Containing Silver Thiosulfate Ion Complexes
This example illustrates the use of silver thiosulfate ion complexes to
produce adhesive
films. Specifically, a pressure sensitive adhesive (PSA) containing silver
thiosulfate ion
complexes was produced in this example. Adhesive films are. among other
things, especially
useful in covering painful abrasive-type skin wounds and partial skin graft
sites.
The silver thiosulfate ion complexes-containing PSA was made by mixing 0.25 ~~
of
the silver thiosulfate ion complexes powder from Example I in An adhesive
solution
consisting of 45 '_ of a proprietary medical <,rade acrylic based latex (s8%
solids) (Avery
~0 Dennison. Inc.) and > g polyethylene ~.:lycol (M.W. 600) (.aldrich) was
first prepared. Then.
0.?5 '; of the silver thiosulfate ion complexes powder from Example I was
mixed with the
adhesive solution. forming an adhesive mixture. This adhesive mixture. when
coated and
dried, produces a tacky. adhesive film.
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The adhesive film is photostable and antimicrobiallv active. This adhesive
film can be
laminated to dressing backing materials to produce dressin~Ts which are
antimicrobiallv active.
Dressings with the silver thiosulfate ion complexes-containin~1 PSA are
especially useful in
covering painful abrasive-type skin wounds and partial skin graft sites.
EXAMPLE 17
Alginate Materials Containins_~ Silver Thiosulfate Ion Complexes
This example illustrates the use of silver thiosulfate ion complexes to
produce a
medical device which is made up of non-adherent alginate material.
Specifically, the method
of this example involves the use of a calcium chloride bath which results in
crosslinked
al~~inate fibers that incorporate the silver thiosulfate ion complexes.
First. water-swellable aluinate fibers were produced containin'1 silver
thiosulfate ion
complexes. The alginate fibers were made by using a svrin'~e to inject a
s°,'° sodium alginate
I S solution (Pronova LV ~1 Sodium al~_inate. Protan) into a bath consisting,
of a 10% calcium
chloride solution (Aldrich. deionized water as diiuent) containing 0.1
~;iliter silver thiosulfate
ion complexes powder from Example 3. The alginate solution immediately formed
water-
insoluble alginate fibers upon contact with the calcium chloride/silver
thiosulfate ion
complexes bath. The fibers were pulled from the bath and allowed to dry
(50°C).
'_'0 The resulting fibers are photostable and antimicrobiallv active. These
fibers can be
used to make antimicrobial al<sinate dressing=s and tamponades. -~l~_inate
materials containin~~
silver thiosulfate ion complexes are especially useful in coverin<_ painful
abrasive-type ,kin
wounds and wound ulcers as well as for tilliny~ in deep wounds and cavities.
EXAMPLE 18
Alginate Materials Containin<~ Silver Thiosulfate !on Complexes
To further illustrate the use of the silver thiosulfate ion complexes of this
invention to
produce a medical device which is made up on non-adherent al<.:inate material.
this example
s0 utilizes a method that does not include a calcium chloride bath.
First. an aqueous solution containing, 0. I y'/liter of a silver thiosulfate
ion complexes
from Example 3 was prepared. The resulting aqueous solution was then applied
to a 9.5 cm
O.S cm al~_inate dressing (Steriseal Sorbsan Sur~~ical Dressin~~. Steriseal)
by spravinv~ the
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solution onto the dressings. ~Iternative(y, the silver thiosulfate ion
complexes solution can be
applied by dipping the alginate dressin'; into the solution. The al~~inate
Ebers of the dressing
absorbed the applied solution; thereafter, the treated alginate dressin~l was
allowed to dry
(room temperature).
The alginate dressing was light stable and was antimicrobially active, and, as
noted in
the preceding example. it is especially useful for malodorous wounds as well
as for coverin~~
painful abrasive-type skin wounds and wound ulcers.
V. USE OF SILVER THIOSULFATE ION COMPLEXES IN COMBINATION
WITH OTHER MEDICINAL AGENTS
EXAMPLE l9
Pharmaceutical Composition (~ombinin~~ Vlupirocin
With Silver Thiosulfate Ion Complexes
To illustrate an antimicrobial pharmaceutical composition consisting of a
combination
of the silver thiosulfate ion complexes of the present invention with one or
more absents, 0.02
~; of the silver thiosulfate ion complexes from Example ? were blended into
?.0 g of a
mupirocin ointment (Bactroban' ['_'°o mupirocin acid in a PEG base],
SmithKline Beecham).
'_'0 The mupirocin ointment is a topical antimicrobial with excellent gram (+)
antimicrobial
properties. The silver thiosulfate inn comple~ces were blended into the
mupirocin ointment by
first meltin« the mupirocin ointment and then stirrings the silver thiosulfate
ion complexes into
the melted ointment. The ointment mas stirred continually until it cooled and
resolidified.
EXA1V1PLE 20
Pharmaceutical Composition Combining Mafenide
With Silver Thiosulfate Ion Complexes
To further illustrate an antimicrobial pharmaceutical composition consisting
of a
s0 combination of the silver thiosulfate ion complexes of this invention with
one or more a~,ents.
0.25 ~_ of mafenide (Si';ma) (y-aminomethvlbenzesulfonamide) and 0.?5 v~ of
the silver
thiosulfate ion complexes of Example 3 were blended into ?-I.50 g of a PEG
composition
("PEG Composition"); the PEG Composition was produced by melting to~~ether a
blend of
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40% PEG (M.W. 3450) and 60% PEG (M.W. 600). The pharmaceutical composition was
produced by first melting the PEC Composition and then stirrin~l in the silver
thiosulfate ion
complexes and mafenide. The resulting pharmaceutical composition was stirred
continually
until cooled and resolidified. The resulting pharmaceutical composition has
use as a broad
spectrum topical antimicrobial.
EXAMPLE 21
Pharmaceutical Composition Combining Metronidazole
With Silver Thiosulfate Ion Complexes
To further illustrate an antimicrobial pharmaceutical composition consisting
of a
combination of the silver thiosulfate ion complexes of the present invention
with one or more
absents. 0.?5 ~1 of metronidazoie (Siv~mal and 0.25 yz of the silver
thiosulfate ion complexes of
Example _> were blended into 24.50 g of a PEG composition ("PEG Composition");
the PEG
I 5 Composition was produced by melting together a blend of 40% PEG (M.W.
3450) and 60%
PEG (M.W 600). The pharmaceutical composition was produced by first meltin~~
the PEG
Composition and then stirrin~,~ in the silver thiosulfate ion complexes and
metronidazole. The
resulting pharmaceutical composition was stirred continually until it cooled
and resolidified.
This pharmaceutical composition has use as a broad spectrum topical
antimicrobial and is
?0 especially useful in the treatment of malodorous wounds.
CXAh~IPLE 22
Pharmaceutical Composition Combinin~, Chlorhexidine
With Silver Thiosulfate lon Complexes
,;
To further illustrate an antimicrobial pharmaceutical composition consisting
of a
combination of the silver thiosulfate ion complexes of the present invention
with one or more
a<.~.ents. 0.25 ~ of chlorhexidine diacetate hydrate (Aldrich) and 0.35 ~1 of
the silver thiosulfate
ion complexes of Example 3 were blended into 24.5 y~ of Aquaphor" (a
cholesterolized
,0 absorbent Eucerite" ointment base produced by Belersdorf Inc.). The
pharmaceutical
composition was produced by first meltiny~ the Aquaphor" ointment and then
stirrin<' in the
silver thiosulfate ion complexes and chlorhexidine. The resulting=
pharmaceutical composition
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was stirred continually until it cooled and resolidified. This pharmaceutical
composition has
use as a broad spectrum topical antimicrobial.
EXAMPLE 23
Pharmaceutical Composition Combinin~_ Triciosan
With Silver Thiosulfate Ion Complexes
To further illustrate an antimicrobial pharmaceutical composition consisting
of a
combination of the silver thiosulfate ion complexes of the present invention
with one or more
f 0 medicinal agents, 0.50 ~ of triclosan (Irgasan DP 300, Ciba-Geigy,
Greensboro, NC) and 0.50
~; of the silver thiosulfate ion complex of Example 3 were blended into 24.00
~ of Aquaphor"
(a cholesterolized absorbent Eucerite" ointment base produced by Belersdorf
inc.). The
pharmaceutical composition was produced by tirst meltin~~. the Acluaphor"
ointment and then
stirring in the silver thiosulfate ion complexes and triclosan. The resulting
pharmaceutical
I S composition was stirred continually until it cooled and resolidified. This
pharmaceutical
composition has use as a broad spectrum topical antimicrobial.
EXAMPLE 2~t
Pharmaceutical Composition Combining Hydrocortisone
'-0 With Silver Thiosulfate Ion Complexes
To further illustrate an antimicrobiai pharmaceutical composition consistin~,
of a
combination of the silver thiosulfate ion complexes of the present invention
with one or more
ay.:ents. 0.50 ~ of Hydrocortisone ? I-Acetate (Sigma) and 0.50 '~ of the
silver thiosulfate ion
'_'s complexes of Example 3 were blended into 2.00 '; of Aduaphor" (a
cholesterolized absorbent
Eucerite~ ointment base produced by Belersdorf Inc.). The pharmaceutical
composition was
produced by tirst meltin~~ the Ac~uaphor' ointment and then stirrin_1 in the
silver thiosulfate
ion complexes and hydrocortisone. The resulting pharmaceutical composition was
stirred
continually until it cooled and resoliditied. This pharmaceutical composition
has use topically
30 as an anti-inflammatory and an anti-itch treatment which also has
antimicrobial properties to
prevent a secondary infection when applied topically to blistered wounds
caused by dermatitis.
insect bites. poison ivy, etc.
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EXAMPLE 25
Pharmaceutical Composition Combinin~_ Lidocaine With
Silver thiosulfate Ion Complexes
To further illustrate an antimicrobial pharmaceutical composition consisting
of a
combination of the silver thiosulfate ion complexes of the present invention
with one or more
av.:ents. 0.50 ~ of lidocaine (Sigma) and 0.50 ~ of the silver thiosulfate ion
complexes of
Example 3 were blended into 24.00 g of PEG composition ("PEG Composition");
the PEG
Composition was produced by melting together a blend of 40% PEG (M.W. 3450)
and 60%
PEG (MI.W.). The pharmaceutical composition was produced by first melting the
PEG
Composition and then stirrinv~ in the silver thiosulfate ion complexes and
lidocaine. The
resulting_ pharmaceutical composition was stirred continually until it cooled
and resolidified.
This pharmaceutical composition has use as a topical anesthetic which also has
antimicrobial
properties to prevent a secondary infection when applied to exposed tissues or
wounds.
t~
EXAIV1PLE 2G
Pharmaceutical Composition Combining Pramoxine With
Silver Thiosulfate ion Complexes
.0 To further illustrate an antimicrobial pharmaceutical composition
consisting, of a
combination of the silver thiosulfate ion complexes of the present invention
with one or more
absents. 1.00 ~, of pramoxine hydrochloride (Si«ma) and 0 ~0 ~~ of the silver
thiosulfate ion
complexes of Example _i were blended into ?3.5U ~.; of PEG composition ("PEG
CVO IIIpUSILIOn"); the PEG Composition was produced by meltin« touether a
blend of 40°..o PEG
(M.W. 3450) and 60% PEG (N1.W O00). The pharmaceutical composition was
produced by
first meltin'T the PEG Composition and then stirrin~~ in the silver
thiosulfate ion complexes
and pramoxine. The resulting pharmaceutical composition was stirred
continually until it
cooled and resolidified. This pharmaceutical composition has use as a topical
anesthetic
which also has antimicrobial properties to prevent a secondary infection when
applied to
~0 exposed tissues or wounds.
From the above, it should be evident that the present invention provides for
silver-
based antimicrobial compositions and processes for makin~l such compositions
that are
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suitable for use in the treatment and prevention of infections. It should be
understood that the
present invention is not limited to the specific compositions shown nor to the
uses of the
compositions described. In light of the fore~roiny~ disclosure, it will be
apparent to those
skilled in the art that substitutions, alterations, and modifications are
possible in the practice
of this invention without departins: from the spirit or scope thereof. .
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