Note: Descriptions are shown in the official language in which they were submitted.
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SILVER-BASED a'4NTIMICROBIAL COMPOSITIONS
This application is a divisional of ~~anadian Patent
Application No. 2,263,473, which was filed on August 15, 1997.
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 agents are chemical compounds that either destroy microbes,
prevent
their pathogenic action. yr prevent their growth. Antimicrobial agents. often
referred to as
anti-infective agents. are frequently applied topically to the skin and mucous
membranes in
the form of a solution. cream, or ointment: appropriate i'ormulations may be
applied to
wounds and body cavities. and to the eyes, nose, and mouth.
I S In general, topical antimicrobial agents are directed at bacteria.
viruses. and fungi.
They have been used successfully in the prevention and treatment of a number
of infections,
including impetigo. candidiasis. tines pedis (athlete's food, acne vulgaris,
and infections
resulting from burns and surgical 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
gram (-) organisms.
Moreover. bactericidal aLents typically are not functicidal. while funs~icidal
agents typically are
not bactericidal.
In addition, due to the widespread use and frequent over-prescribine of
antimicrobial
auents. there is an increasing incidence of microbes acquirinu drug-
resistance. In other words;
25 a microbe that was once susceptible (i.~~., inhibited or killed) to a
particular antimicrobial
agent is no longer susceptible. This is especially important with rergard to
bacteria.
Acquired drug 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.
i0 Moreover, resistance to one member of a class of agents (r.tr., the
aminopenicillin ampicillin)
can result in complete.cross-resistance to other members of that class
(~~.~~., the
aminopenicillin amoxicillin).
- 1 -
CA 02383742 2002-04-09
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2
II. Topical Silv~r-Containing Agents
A. Currently Used Therapeutic Agents
Two formulations containing silver have been utilized for
therapeutic purposes, silver nitrate and silver
sulfadiazine. As set forth hereafter, each is associated
with potentially severe 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 silver nitrate solution
does not readily penetrate into tissue. Unfortunately, the
silver salts stain tissue 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, has been associated with necrosis of the
skin. In addition, sulfadiazine 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; AHFS Drug Information. Gerald K. McKevoy,
ed., pp. 1704-05 and 2215-16 (1993)].
H. Newer Antimicrobial Silver-Containing Compositions
One of the reasons why there are few commercially available
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2a
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 photostability. For example, U.S. Patent No.
5,326,567 to Capelli, describes an antimicrobial composition
comprising a stabilizing acyclic polyether polymer, silver
ion, and a stabilizing halide. The composition may be used
in several manners, including topical application to a
subject and incorporation into a medical device.
In addition, a new class of silver-containing agents, the
silver thiosulfate ion complexes, has recently been
disclosed in U.S. Patent No 5,429,819 to Oka et al.
thereafter "the Oka Patent"). [See also Tomioka et al.,
"Synthesis of
CA 02383742 2002-04-09
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rlntimicrobial Agent Composed of Silver-Thiosulfate Complex Ion." Nippon
Kagaku Kaishi
10:848-SO ( 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
s porous particulate carrier. According to the Oka Patent"s teachings, the
thiosulfate complex
salt and thiosuifate metal complex salt are first prepared as a solution.
Thereafter, a porous
carrier such as silica gel is impree:nated with the solution. Finally, the
thiosulfate 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 antimicrobiai compasitions taught in the Oka Patent are associated with
several
notable shortcominsts. First. the silver thiosulfate ion complex compositions
contain a
relatively large concentration of waste salts. resuttinst from the
complexation of a thiosulfate
salt. sulfite salt. and a silver :salt. and are thus relatively impure. For
example, producing I
I S part of a silver thiosulfate ion complex using 1 part of silver nitrate
(ar silver acetate) to 2
parts sodium Ihiosulfate,and/or 3 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 salt and thiosulfate metal complex salt. Thus, the amount of
porous carrier particles
needed to provide silver at antimicrobial concentrations~is hiuh, and. as 1
result. 1 topical
antimicrobial composition would feel gritty and would be irritatinu to the
skin or wound. In
addition, if the concentration of thiosulfate complex salt and thiosuifate
metal complex salt
carried on the porous .carrier is too high, the composition may discolor.
'S Finally, the compositions taught by the Oka Patent cannot be easily
incorporated into a
polymer matrix at high concentrations. As stated above. incorporation of
silver at
antimicrobial concentrations requires concomitant incorporation of a large
amount of porous
carrier. This can cause undesirable chances in the polymer matrix' physical
properties (c-.~,~., a
hvdrocolloid matrix that is stiff and less:absarptive). In addition. such
incorporation can be
30 unwieldy. ~ For example, in an alginate matrix containinL water-insoluble
fibers, the silver-
containing porous carrier cannot be incorporated into the alginate fibers; as
a result. the
porous carrier must be mixed loosely within the 'alginate fibers.
Unfortunately, the porous
carrier can fall out when the alLinate matrix is handled. _
-3-
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From the above. it should be clear that the commercially-available silver-
based
antimicrobial 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
s needed is a stable silver-containing antimicrobial composition which is
suitable for use in the
treatmem 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 makinc; 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 making such compositions. comprising: carrier-
free. suspended
silver thiosulfate ion complexes in a base. Preferably, the silver thiosulfate
ion complexes are
1 S homoLeneously 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 auents. including but not limited to
antimicrobial agents,
steroids. and anesthetics.
?0 One advantaue of proyidinL silver thiosulfate ion complexes in a carrier-
free form is
the ability to produce lntimicrobial compositions containing hiLh
concentratioiis~ot' silverw
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
p reventini infections in comprisins: applyins: topically to the site f or
potential site) of
infection an et~fective amount of the foregoinL composition.
As alluded to above, the invention also contemplates methods of makins~ the
stable
silver-based antimicrobial compositions. It is preferred chat the silver
complexes of the
present invention are derived from the complexation ~of silver nations from
silver halides
,0 (preferably silver chloride) with anions from the sodium thiosulfate salts;
the molar ratio of
the thiosulfate anions to the silver cations is preferably at (east I :1 and
more preferably at
least 1. ~:I. it is desirable that the silver thiosuifate ion complexes are
solid and essentially
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CA 02383742 2002-04-09
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pure, i.e.. they do not contain sis:nificant 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 sliver thiosulfate
ion
complexes, thereby providing strong antimicrobial acrivity. Moreover, the
compositions may
be used in combination with other pharmaceutical (e.~., topical) agents (e.g.,
Bactrobanø
[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
contamination. Examples of cosmetics include lipsticks and glosses. lip
pencils, mascaras, eye
I ~ 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, sponges,. and cotton swabs and balls. and examples of personas
care products .
include deodorants_ razors, shaving creams, shampoos, conditioners, various
hair treatments
like mousses and sprays, toathpastes, 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. comprisinL carrier-free
suspended
silver thiosulfate 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
'_s the base is sufficient to provide a therapeutic benefit. Specitically, the
present invention
contemplates concentrations of silver thiosulfate ion complexes within the
base from O.OI% to
;0% (wiw) and from U. l% to 3.0% (w/w). The preferred concentration of silver
thiosulfate
ion complexes within the base is from 0.2% to I.S% (w!w). In one embodiment,
the base is
selected from the .group consisting of polyethylene glycol. :~quaphor". and
white petrolatum.
,0 The present invention also contemplates a method of treating or preventing
a topical
microbial infection. comprising the steps of a) providing l) a subject
infected with a topical
microbial infection and ii) an effective amount of carrier-free suspended
silver thiosulfate ion
complexes in a base; and b) administering topically the effective amount of
the carrier=free
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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, t:he present
invention
s 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% (wfw). The preferred
concentration of
silver thiosulfate ion complexes within the base is from 0.3°,% to t
.5% (w/w). In one
embodiment, the base is selected from the s:roup consistinu of polyethylene
~:lycol,
Aquaphor'~, and white petrolatum.
The present invention further contemplates a method of imparting antimicrobial
protection to an object, comprisinu the steps of: a) providing l) an object
and ii) an effective
amount of carrier-tree suspended silver thiosulfate ion complexes: and b)
applying the
ettective amount of the carrier-free suspended silver thiosuifate 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 thiosutfate ion complexes is
sufficient
to provide a therapeutic benefit. Speciticallv, the present invention
contemplates
concentrations of silver thiosulfate ion complexes from O.Ot°l°
to 30% (w/w) and from 0.1°!°
to 3.0°.'° (wlw). The preferred concentration of silver
thiosulfate ion complexes is from 0.2%
t0 1.5% (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
polymer. while it is anhydrous in still further embodiments.
..The present invention also contemplates a process tar producing essentially
anhydrous
_s silver thiosulfate ion complexes. romprisinu: a) making an aqueous solution
of silver
thiosulfate ion complexes; b) adding a solvent to the solution to create a
biphasic separation
wherein the silver thiosulfate ion complexes separate into one phase: c)
collecting the phase
containing the silver thiosulfate ion complexes; and d) removinu water from
the collected
phase such that the silver thiosulfate ion complexes are essentially
anhydrous. In particular
embodiments. the ratio of thiosulfate ions to silver ions is greater than or
equal to 2: I and
preferably less than 3:1.
In some embodiments, the aqueous solution of silver thiosulfate ion complexes
is
formed by reacting a silver halide and sodium thiosulfate. (n other
embodiments, the molar
_h_
SUBSTITUTE. SHEET (RULE '2~) ' .
CA 02383742 2002-04-09
wo 9sro6zso rc~rrt~s9~n~~
ratio of silver canons from the silver halide to thiosulfate anions from the
sodium thiosulfate
is preferably at least l :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
s group consisting of ethyl alcohol, isopropyl alcohol, 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) making an aqueous
solution of
silver thiosulfate ion complexes; b) adding a solvent to the solution to
precipitate the silver
thiosulfate ion complexes; c) collecting the precipitated silver thiosulfate
ion complexes; and
d) removing water from the collected silver thiosulfate ion complexes such
that the silver
thiosulfate ton complexes are essentially anhydrous. In particular
embodiments. the ratio of
thiosulfate ions to silver ions is less than ?:1 and preferably greater than
I:1.
In some embodiments, the aqueous solution of silver thiosulfate ion complexes
is
( s formed by reacting a sliver 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: l 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
'_'0 group consisting of ethyl alcohol, isopropyl alcohol; methyl alcohol.
acetone, and
tetrahydrofuran: in certain embodiments.
The present invention also contemplates a pharmaceutical mixture. comprisinu:
a) a
medicinal agent; and b) silver thiosulfate ion complexes. In preferred
embodiments. the silver
thiosulfate ion complexes are carrier-free. In particular embodiments. the
pharmaceutical
?5 mixture further comprises an anhydrous base; in some embodiments, the base
is selected From
the group consistinu 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 U.01% to 30%
(weight to
weight). In further embodiments. the concentration of silver thiosulfate ion
complexes is
30 from 0. I% to 3.0% (weight to wei~:ht), while in still further embodiments
the concentration is
from 0.2°.io to 1.5°% _(wei5ht to weiszht).
In particular embodiments. the medicinal agent of the pharmaceutical mixture
is an
antimicrobiat agent. In some embodiments, the antimicrobial a~:ent is selected
from the group
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SUBS1'~TU.TE SMEET°(RUL,E 213) ~~
CA 02383742 2003-O1-31
74667-106D
consisting of acyclovir, chloramphenicol, chlorhexidine,
chlortetracycline, itraconazole, mafenide, metronidazole,
mupirocin, nitrofurazone, oxytetracycline, penicillin, and
tetracycline. When the medicinal agent is an antimicrobial
agent, in some embodiments the pharmaceutical mixture has a
broader spectrum of antimicrobial protection than the silver
thiosu:lfate ion complexes.
Furthermore, the medicinal agent 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, fluocinolone acetonide, halcinonide,
hydrocortisone, and metandienone.
Finally, the medicinal agent of the pharmaceutical
mixture is an anesthetic in still other embodiments. In
certain embodiments, the anesthetic is selected from the
group consisting of benzocaine, dibucaine, lidocaine,
pramoxine hydrochloride and tetracacine.
According to one aspect of the present divisional
application, there is provided a method for producing
essentially anhydrous silver thiosulfate ion complexes,
comprising: a) providing an aqueous solution of silver
thiosulfate ion complexes, wherein said complexes are formed
by reacting a silver halide with a sodium thiosulfate;
b) adding a water-miscible solvent to said solution to
create a biphasic separation wherein said silver thiosulfate
ion complexes separate into a single phase; c) collecting
said single phase containing said silver thiosulfate ion
complexes; and d) removing water from said single phase such
that said silver thiosulfate ion complexes are essentially
anhydrous.
8
CA 02383742 2003-O1-31
74667-106D
According to another aspect of the present
divisional application, there is provided a method for
producing essentially anhydrous silver thiosulfate ion
complexes, comprising: a) providing an aqueous solution of
silver thiosulfate ion complexes, wherein said complexes are
formed by reacting a silver halide with sodium thiosulfate;
b) adding a water-miscible solvent to said aqueous solution
to precipitate said silver thiosulfate ion complexes;
c) collecting said precipitated silver thiosulfate ion
complexes; and d) removing water from said collected silver
thiosu.lfate ion complexes such that said silver thiosulfate
ion complexes are essentially anhydrous.
DB~INITIONS
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
inorganic oxide, in which a material can be impregnated and
then, if necessary, immobilized through drying. For
example, the Oka Patent describes the impregnation of a
porous particulate carrier (e.g., silica gel) with a
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 being without such things 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.
8a
CA 02383742 2003-O1-31
74667-106D
The term '~base~~ refers to any substance useful fox
the suspension of the silver thiosulfate ion complexes of
the present invention. Tn a preferred embodiment, the base
is "anhydrous" (e. g. an ointment) and can be used to suspend
a medicinal agent for topical administration. Useful
anhydrous bases include, but are not limited to white
petrolatum. Aquaphor° ointment base, and polyethylene
glycol (PEG) polymers with molecular weights greater 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
Sb
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WO 98/06260 PCT/US97114697
the tinal product but that, generally speakinst. the presence of water will
reduce the shelf-fife
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 (c.b~., less than 5%) would have a shorter shelf life
(c.g., less than 6
s months). If a PEG ointment base has a very small amount of water {e. fi.,
much less than
1%), the silver thiosulfate ion complexes should be stable enough to provide
the product with
an acceptable shelf life (e.~~., greater than one year). In one embodiment.
the base is
semisol id.
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 specifically, the silver thiosulfate ion complexes
are obtained by
adding a silver halide. c.~,~., silver chloride.~to an aqueous solution and
then adding a
thiosulfate salt. c-.~,r., sodium thiosulfate, to the solution. Thoush the
benefit provided by the
complexes of the present invention is not limited by an understanding of the
precise nature of
I 5 the complexes. the chemical formula of the primary silver thiosuifate ion
complexes formed
when a large excess of thiosulfate salt is used is represented by
[Ag(S~O,),,]3'. By '-
comparison, the chemical formula of the primary silver thiosuifate ibn
corripieXes formed
when only a small excess of thiosulfate salt is used is represented by
[Ast~(S,O,),]' '. The
:.~ preferred silver thiosulfate ion complexes are those represented by
[,Ag=(S=O,),]''. The
30 resulting silver thiosulfate ion complexes are in a relatively pure solid
form, and are stable,
histhlv water soluble and antimicrobially acti~~e.
The term "essentially anhydrous silver thiosuifate ion complexes" refers to
silver
thiosulfate ion complexes that may be essentially free of all remnam water.
i:r.. they may
contain a small amount of water tgenerally less than ~% of the original amount
of water
'S present, preferably less than I%. and most preferably less 'than 0.1%),
provided that the water
does not interfere with the antimicrobial function of the complexes.
The term "suspended" refers broadly to the dispersion (i.c~., not dissolution)
of material
~(~.~~., silver thiosulfate ion complexes) in the base. The material is
preferably finely divided
and preferably .dispersed homoLeneously throuLhout the base.
;0 The term "aqueous solution" refers to a liquid mixture containing, among
other things,
rvater.
_g_
SUBSTITUTE SHEET (RUl:E.26)
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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 being
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:
generally speaking, a "biphasic separation" allows a material (r.s,~., silver
thiosulfate ion
complexes) to be partitioned into one of the resulting phases. thereby
facilitatinu isolation of
that material. As described in further detail below, the addition of an
appropriate solvent
(c~.~,~., ethyl alcohol) to an aqueous solution of silver thiosuifate ion
complexes results in a
biphasic separation. .~ 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 "collecting." "collect" and the like refer to the ~enerai processes
of isolating,
partitioning, etc. one material from another. For example. a desired material
may partition
I ~ into one phase of a biphasic system: the ptSase containing that material
(~~.~~., the silver
thiosulfate ion complexes of the present invention) can be removed from the
biphasic system
using well known means te.i,~ , piper 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 sliver thiosulfate ion
complexes (i.r:, the
_'0 collected phase). The present invention is not limited.to any particular
method; rather:
etenerally known methods of removal (r.,~~., 'freeze drv~ins~. oven dryinu,
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
thiosuifate ion complexes that is required to provide some "therapeutic
benetit". The present
invention is not limited by the nature or scope of the therapeutic benetit
provided. The
decree of benefit may depend on a number of factors, r.,~~., the severity of a
S. eu~rc~r~.v
infection and the immune status of the individual.
The term "therapeutic composition" refers to a composition that includes
essentially
anhydrous silver thiosuifate ion complexes in a pharmaceutically acceptable
form. The
,0 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
affectin~t the _
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CA 02383742 2002-04-09
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characteristics of the personal care product itself. The therapeutic
composition may contain
diluencs. adjuvants and excipients. among other thins.
The terms "subject" and "host" refer to humans and animals.
The term "approximately" refers to the actual value being within a range of
the
s indicated value. In general, the actual value will be between 5% (plus or
minus) of the
indicated value.
The terms "topical," "topically." and the like 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 dressiness, thin film
dressings, burn
dressings, surgical dressings, absorptive dressings, gauze, sheets or ether
types of medical
device used to treat wounds.
The terms "microbe. "microbial." and the like include bacteria, funLi, and
viruses. The
terms "antimicrobial" and "antimicrobial activity" refer to the ability to
kill or inhibit the
growth of microbes.
The term "photostabie" means that an object or material is resistant to
discoloration
when exposed to ambient light 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. ~1 "polymer matrix" is one type of matrix
comprising one or more
natural or synthetic compounds. usually of high molecular weis!ht, in the form
of repeated
linked units. The term "anhydrous polymer matrix" refers to any solid material
that may be
free of water or that may contain a small amount of water t~enerallv less than
5% by weight),
provided that the water does not interfere with the antimicrobial function of
the complexes
''S 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 being compatible with the silver
thiosulfate ion
complexes and having some capacity to absorb andlor sv4~el1 in the presence of
water.
E=xamples of anhydrous.polymer matrix materials, include. but are not limited
to, adhesives
;0 such as acrylic-based pressure sensitive adhesives; biopolymers such as
silk; hydrocolloid
materials such as aodium .carboxymethyicellufose, either alone or when bound
in a polymer;
and polymers such as polyurethane in the form of coatings. 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 tike. Medical implants
include, but are not
limited to, urinary and intravascular catheters. dialysis shunts. wound drain
tubes, skin sutures,
vascular grafts and impiantabie meshes, intraocular devices. and heart valves.
Wound care
devices include, but are not limited to, general wound dressings, non-adherent
dressings, burn
dressings, biological graft 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,
diaphras~ms, and condoms.
The silver thiosulfate ion complexes of the present invention can be use to
impart
antimicrobiai protection to objects including, but not limited to, medical
devices.
The term "purified" means that the material has been subjected to a process
(o.~,r ,
extraction) to remove impurities. Following 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 ~ thiosulfate ion complexes that do not contain significant amounts of waste
salts (c~.~,~., sodium
nitrate or sodium acetate); if such waste salts are incorporated into
compositions or medical
devices. they rnay be irritating to the skin or other tissue. (n addition.
they may reduce the
concentration of antimicrobially active silver. For example, if the silver
thiosulfate ion
complexes are made using silver iodide silver sait,and sodium thiosutfate
salt, the resultinc:
'0 waste salt would be sodium iodide. The iodide ion would aggressively
compete for the
dissociated ("free")silver ion. resulting in reduced concentration of
antimicrobiaily active
silver.
DETAlI.ED DESCRIPTION OF THE INVENTION
~s The present invention relates to silver-based antimicrobial compositions,
and processes
for makins: 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, comprisins: carrier-
free. suspended
silver thiosulfate ian complexes in an a base, and silver thiosulfate ion
complexes
30 incorporated into an anhydrous polymer matrix and used with a medical
device.
The description of the invention is divided into the- following parts: 1)
Processes To
Obtain Silver Thiosulfate lon Complexes In A Solid Form; II) Compositions
Containing
,Silver Thiosulfate _lon 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.
t. PROCESSES TO OBTAIN SILVER THIOSULFATE ION COMPLEYES
s 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, cot. 2, 11. 45-4b]. In
contrast to the Oka
I0 Patent. the present invention is directed at a process for obtaining
carrier-free silver thiosuifate
ion complexes. Based on the prior art's acknowledged difficulty in obtaining
silver
thiosulfate .ion complexes in a carrier-tree solid state. the discovery of the
process disclosed
Itereatter was both surprising and unexpected. Moreover. the process of the
present invention
also results in carrier-free silver thiosulfate ion complexes in high yields.
another surprising
I S and unexpected result.
The present invention contemplates the productiowof carrier-free silver
thiosulfate ion
complexes wherein the ratio of thiosulfate ion to silver ion is preferably at
least 1.3 to 1. To
optimize the antimicrobial effectiveness of the final products containinL the
silver thiosulfate
r ion complexes. it is preferable that the complexes be purified (c~.~,~.,
subjected to methods to
'_'0 remove contaminants such as waste salts in an amount that adversely
interferes with the silver
~;oncentration obtainable).
The present invention provides nvo processes of producins puritied 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 3-to-1.
and the second process
3s is preferred when the ratio is less than 2-to-I. .
A. Process For Producing Silver Thiosulfate Ion Complexes
When The Ratio Of Thiosulfttte Ions To Silver tons Is
Greater Thain Ur Equal To 2-to-1
;0 The process for producing essentially anhydrous silver thiosuifate ion
complexes when
the ratio of thiosulfate ions to silver ions is greater than 2-to-1 involves
four major steps. The
first step consists of making an aqueous solution of silver thiosulfate ion
complexes. The
aqueous solution of the silver thiosulfate ion complexes is obtained by tirst
adding a silver
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halide. such as silver chloride. silver bromide. etc., to an aqueous solution.
Thereafter. a
thiosulfate salt, such as sodium thiosulfate or potassium thiosulfate, is
added to the aqueous
solution.
The use of a silver halide instead of another silver-containing molecule is
preferred
s because the silver thiosulfate ion complexes produced are associated with
increased short-term
stabilitv. This is especially important when the concentration of the silver
thiosulfate ion
complexes is high and/or the ratio of thiosulfate ions to sliver 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 thiosuifate ion complexes in the
resulting aqueous
solution is high. ~s indicated above, when making silver thiosulfate ion
complexes where the
primary silver ion complexes formed is represented by the formula
[~lg(S,O,);]'', the preferred
proportions of ihiosulfate salt to silver salt are equal to or greater than 2
moles of thiosulfate
salt for 1 -mole of silver salt. The most preferred proportions of thiosulfate
salt to silver salt
are equal to or greater than 3-to-!.
I S In making the aqueous solution of the silver ihiosulfate 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 i~r .,lm in the aqueous solution. In this evav, a
water-soluble silver
salt such as silver nitrate or silver acetate is first dissolved in the
aqueous solution. An
equivalent or greater molar amount of a halide salt containing the chloride
ion, such as
''0 podium chloride, potassium chloride, and the like, is then added,
resulting in the precipitation
of the silver chloride salt.
.~dditionalty. in makinu the aqueous solution of the silver thiosulfate ion
complexes, it
is preferred that the concentration of the initial silver halide in the
aqueous solution be less
than ?5°r. , 1-lis:her concentrations of the silver halide can lead to
instability of the resulting,
silver thiosulfate solution; that is to say, the silver thiosulfate ion
complexes within the
:solution wilt "break down" or decompose, leadins~ to discoloration of the
solution arid
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
~4 ion complexes separate into one phase. The preferred solvents are those
which Ire 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~T phase
separation. The solvent is added to the silver thiosulfate ion complexes
solution in an amount
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such that the solution separates into two phases. During: the formation of two
distinct phases.
the silver thiosulfate ion complexes separate into one phase. Typically, 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
containing the liquid mixture.
The phase containing the silver thiosuifate ion complexes is thought to
consist of a
high concentration (i.~., 50 - 70% of the total volume) of relatively pure
silver thiosulfate ion
complexes and water. Excess thiosuifate salts, waste salts, solvent. and other
contaminants
are thouLht to remain in the other (larser) phase of the biphasic solution.
tn the third step, the separated phase containing the silver thiosulfate ion
complexes
can be. collected usinst well known means. For example. the phase can be drawn
up usinu a
piper and removed from the solution. Likewise, a separatorv funnel can be used
to separate
the phase tom the solution.
I 5 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,
containing insignificant amounts of waste salts (~~.,~~., sodium nitrate or
sodium acetate) and
other extraneous materials. Treatments vyhich are useful include. but are not
limited to,
''0 evaporation, oven drying, freeze drying, solvent extraction. and the like.
After the treatment.
the essentially anhydrous silver thiosuifate complexes are :round into a tine
powder.
13. Process rror Producing Silver Thiosulfate ion (:omplexes
When The Ratio Uf Thiosulfate Ions To Silver Ions Is Less
=, Than 1-to- l
The process for producing essentially anhydrous silver thiosulfate ion
complexes when
the ratio of thiosulfate ions to silver ions is less than 2-to-I involves four
major steps. The
first step, making an aqueous solution of silver thiosulfate ion complexes. is
analogous to the
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tirst step of the process where the ratio is greater than 2-to-1. The major
difference of this
process from that where the ratio is greater 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 thiosuifate ion complexes. The preferred
solvents are those
solvents which ace water miscible. Solvents such as ethyl afcohol_ 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
l0 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. F filtration represents
one preferred
separation technique. The silver thiosulfate ion complexes are relatively
pure. containine:
insis:niticant amounts of waste salts (c~.~,r., sodium nitrate or sodium
acetate) and other
I s 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 removins: essentially all
remnant
water from the complexes from the collected phase creates essentially
anhydrous silver
thiosulfate ion complexes. Methods which are useful include, Gut are not
limited to,
~0 evaporation, oven drying, freeze drying, and the like. After the treatment,
the essentially
anhydrous silver thiosulfate ion complexes are around into a tine powder.
C. The Nature Of The Silver Thiosulfs~te fon Complexes
..While the benefit provided by the complexes of the present invention is not
limited by
=s an understandinst 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 tie silver
thiosulfate ion
complexes are represented by the formulas [Ag(S,O,)~]'', [a~;(S,O,),]''.
(A~:,(S=O,),]~',
(A~:.,(S,O,),]'', and similar complexes. Unexpectedly, it was found that the
form of the silver
thiosulfate ion complexes produced is very dependent on five ratio of
thiosulfate ion to silver
30 ion.
(f the ratio of the thiosulfate ion to silver ion is low (i.cr., less than 2:1
), silver
thiosulfate ion complexes represented by the formulas [A~:,(S,O,),]'',
[:~g.,(S,O,,),]'' and the
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like can be produced. The preferred silver thiosulfate ion complexes are those
represented by
(Ag~(S,O,).~]'', which can be produced in accordance with the followins:
chemical equation:
3 Na~S,O, + ? ASC1 --> Na,Ag,(S,O,)., +'_ NaCI
Conversely, if the ratio of the thiosulfate ion to silver ion is high (i.e.,
greater than 2:1),
relatively pure sliver thiosulfate ion complexes represented by the formulas
(Ag(S~O,),]'',
(Ag(S,O,),J;' and the like can be produced.
The preferred silver thiosulfate ion complexes are those praduced when the
ratio of the
thiosulfate ion to silver ion is low. The purified silver thiosulfate ion
complexes are carrier-
tree, photostable,, highly water soluble, non-staining and antimicrobially
active. This
combination of features is not present in any commercially available or
previously described
silver-containinu composition.
11. COMPOSITIONS CONTAINING.SILVER TNIOSUL~A't'E ION
COMPLEXES
Topical antimicrobial agents include therapeutic heavy metal compounds such as
silver-containing compounds. Silver, in its ionic state (.aL~), possesses a
broad spectrum of
antibacterial. antifungal, and antiviral properties and is relatively sate.
Early studies showed
that the silver ion is oligodynamic. i.c., active at very low concentrations.
[Se~e ~,jwnrcrl%v,
'~0 Russell r~ crl., Antitaicrobial Activity and Action of Silver." Progress
in Medicinal Chemistry
31:351-74 ( 199x)]. .
The present invention is directed at. among other thin~a, carrier-tree silver
thiosulfate
ion complexes compositions. The provision of carrier-tree silver thiosuifate
inn complexes is
advantaueous for at least two reasons. First. it provides the ability to make
antimicrobial
'_, silver thiosulfate ion complexes compositions without the need for
potentially irritating porous
carrier particles. ~ Second. it provides the ability to produce antimicrobial
silver thiosulfate 'ton
complexes compositions which can contain his:h concentrations of silver.
resulting in
compositions with potent antimicrobial activity.
As set forth above, the carrier-free 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 (.Sce Experimental Section. iufrcr). The
decomposition at the
silver thiosulfate ion complexes results in the silver-based composition both
changin~~ to a
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WO 98106260 PCTlUS97/14697
black color and losins: antimicrobial activity. Given the instability of
silver thiosulfate ion
complexes when incorporated in certain base compositions. it was surprising
arid 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 range of concentrations to provide
compositions with
different levels of antimicrobiat potency.
During the first step of the previously-described process for producing
essentially
anhydrous silver thiosulfate ion complexes, an aqueous solution at the
complexes is made. It
should be noted that aqueous solutions of silver thiosuifate ion complexes can
be added to an
caintment or cream base to make an antimicrobial ointment or cream
composition: in other
words, a composition can be made utter completing only the first of the four
steps. However,
1 s the resulting antimicrobial ointment or cream composition sutlers from two
major drawbacks.
First, the resulting silver thiosulfate ion complexes compositions will
contain lame quantities
of excess thiosulfate salts as well as waste salts (e.,~~., sodium nitrate,
potassium nitrate, and
potassium acetate). When applied topically, the antimicrobial cotttposition
containing these
impurities may be irritating. The second mtijor problem is that ointment or
cream
'_0 compositions made with silver thiosulfate.ion complexes tiom such an
aqueous solution are
not stable for long: periods of time. That is to say, over a pet~iod of.time
the r'esultint_~ silver-
based antimicrobial compositions will turn black and lose antimicrobial
etfiicacy.
This destabilization occurs wrhether or not the silver-based compositions are
stored in
an opaque container or a clear container. Therefore. the destabilization is
not a photo-
~s reduction of the silver. .Rather. what occurs is that the thiosulfate ion
component of the silver
thiosulfate ion complexes experiences a chemical breakdown. The etlect of this
chemical
process is the breakdown of the silver thiosulfate ion complexes.
As: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
~0 formed by addine a sulfur atom to a sulfite ion in a complex reaction that
can be summarized
by the following chemical equation: S + SO,'' -~ S,C);,-'. The sulfur atom
that is added to
the sulfite ion to uive S,O,'' is somewhat labile; thus, S,O,-' - may
appropriately be
represented as S-SO,' -. In aqueous solutions, thiosultate decomposes over
time. .fit _
_ 1g ,
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WO 98!06260 PGT/US97/14697
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 poiysulfide ions. [Levenson: Complementary Processes (Ch. 14), in
Thc.~ 77~evrv
nf'lhe I'ham~~r-aphic 1'race~xo. Fourth Ed. MacMillan Publishing Co., Inc..
New York ( 1977)].
As a result of the instability of the thiosulfate ion. when dissolved in water
silver
thiosulfate 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 sliver ions which react with the released sulfur ions to form silvet~
sulfide. Silver
sulfide-is a black material havins: the molecular formula of :~~~,S. Due to
silver sulfide's high
dissociation constant (pK = ~I~.I 1, 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
IS 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-containing cream base in
order to form
an antimicrobial composition. will decompose over a relatively short period of
time. The
?0 resulting antimicrobial composition will turn black as the silver
thiosulfate ion complexes in
the composition decotnpose:to silver sulfide. .Additionally. .the composition
will lose its
antimicrobial et~icacy with decomposition of the silver thiosulfate 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
'_5 stable over long periods of time: The stable silver thiosulfate ion
complexes compositions of
this invention comprise carrier-free suspended -silver thiosulfate ion
complexes in a base. The
bases which are most useful for the present invention entail any compound or
mixture which
is capable of suspending the complexes. Preterabiv, the base is essentially
anhydrous and can
be used topically to deliver a medicinal agent. By way of illustration, bases
that are useful
;0 include white petrolatum. Aquaphor" ointment base, poiaxomers, and
polyethylene Llycol
(PEG) polymers with molecular weights greater than 600. The preferred base is
a PEG
ointment composition containinu a combination of PEG polymers with molecular
weights
greater than 1.000 and polaxomers. _
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The methods for suspending the purified silver thiosulfate ion complexes, in
the form
of a fine powder, into a base to form a silver-based antimicrobiai composition
are well known
in the art. For example, one method involves heating the base until it has
liquefied; then,
while the base cools, addint the silver thiosuifate 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 homos~eneous suspension.
The concentration of the silver thiosulfate ion complexes within the base is
such as to
provide antimicrobiai activity. The preferred concentration of the silver
thiosulfate ion
complexes is O. l% to 3.0°,%. However, silver thiosulfate ion complexes
concentrations can
range up to 10% to 30% dependins~ on the antimicrobial potency required. The
most
preferred concentration is between 0.2% and 1.5°l°. Generally
speaking, the effective
concentration is that concentration which is hither than the minimum
inhibitory concentration
for a particular microbe. .~s would be expected. certain microbes are more
sensitive to silver
than other microbes, c~.r~~., gram (-) microbes are generally more sensitive
than gram (+)
I s microbes. As a result. a concentration less than 0.1% 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 are
not anhydrous. Additionally, the silver-based antimicrobiai compositions of
this invention
'0 show no photo-discoloration when erposed to ambient room light over a 72
hour period.
Thoue:h the compositions must be in. an. anhydrous base in order. to maintain
their
aabiliw. 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 physioio~:icaily tolerable diluents,
adjuvants and
~_s excipients. such as pharmaceutical grades of mannitol, lactose. starch.
ma~tnesium steatate.
aodium saccharin, cellulose. maLnesium carbonate, and the like. These
compositions typically
contain !°'°-95°l° of active ingredient.
preferably 2",o-70°i°. In addition. if desired the
compositions may contain minor amounts of auxiliary substances such as
stabilizing or pH
butferin~: auents or preservatives.
,0
0 _ _
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III. THERAPEUTIC USE OF COMPOSITIONS CONTAINING SILVER
THIOSULFATE ION CO1VIPLEXES
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. La. cvli and many species of Kle~hsir,~Iln,
Prnlerrs,
l'.verrdr~mrnrcrs, .Sluphvlrx:r~ccu~. and ( ~nrdida 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
usher therapeutic a~:ents. Though not limited to any particular means of
application, the
antimicrobial compositions can be applied using gloved hands or by an
applicator. Likewise.
the antimicrobial compositions can be applied to the surface of a dressing,
which can then be
applied topically. Ophthalmic infections can be treated using standard
procedures im the art.
such as by pulling down the lawer eyelid to farm 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,
I;.vchcnichiu, cull and .~crtmurrcllu nphimnrirrm are known to develop piasmid-
encoded .
resistance to silver. [Russell cr crl.. Prostress in Medicinal Chemistry
31:351-?0 ( 1994)]. Two
(elated methods are commonly used to prevent and combat druu resistance.
The first method entails the cambination of twa or more therapeutic aLents
into a final
'_'S composition. For example, the (3-lactamase inhibitor clavulanate
potassium has been added to
amoxiciflin, resulting in a combination preparation (AugmentinT"'; SmithKline
Beecham) with
expanded antimicrobial activity. While clavulanic acid has only weak
antibacterial activity
when used alone. its combination with amoxicillin results in a synergistic
effect.
The second method entails the concomitant administration of two or more
distinct
_;0 antimicrobial agents. This method is based on the principle that a microbe
that is resistant to
une agent may be susceptible to another. This is especially important.
c~.~,~., in tuberculosis,
which is caused by A~~4'C:rJhCICIG'r'llll)r lrll)C'r'G'lrl(ll'i.1'. Particular
rLl ~rrhcrcrrlvsi.~ bacteria that cause
tuberculosis are known to displlv 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
drugs for
periods exceeding one year. [Se~e Dooly e~~ girl. "~lultidru~r-resistant
tuberculosis," Ann. Int.
Med. ! ( 7:257-59 ( 1992); Nadler "R4ultidru~: resistant tuberculosis," N.
Eng. J. Med.
327:1172-75 ( 1992)].
s The present invention contemplates combining a topical silver-containin5
preparation
with another medicinal agent to form a pharmaceutical composition. Indeed, the
present
invention contemplates the use of many diverse medicinal assents, including
antimicrobial
agents, topically active drugs, and systemically active drugs. The preferred
medicinal agents
contemplated for use in the pharmaceutical compositions of the present
invention are those
i U that can be used as antimicrobial agents in the treatment and prevention
of infection and
disease. Suitable antimicrobial auents include, but are not limited to,
penicillin, tetracycline,
oxytetracycline, chlortetracycline. chloramphenicol. ehlorhexidine. mupirocin,
metronidazole,
miconazole. acvclovir. itraconazole and sulfonamides. .-additional
~tntimicrobial auents include
antimicrobial peptides such as massainins, cecropins. prates:rins,
bacteriocins and defensins.
1 ~ The pharmaceutical compositions of the present invention possess an
additional broad
spectrum of antimicrobial protection by combining antimicrobiai medicinal
agents in a stable
fashion with silver thiosuifate ion complexes. Furthermore. as previously
indicated, the use of
silver thiasulfate ion complexes with an antimicrobial medicinal a~:ent may
aid in preventing
the fonnation of dross-resistant microbes. htareover, since silver ians are
oli~:odynamic and
'_0 are not immediately .exhausted (i.c~.. they have a long-fasting or
"residual"effect),°the presence
of silver ions in the pharmaceutical compositions results.in compositions
which are IonLer
lttstim_ than those containing a sin~:le antimicrobial agent.
f~ledicinal assents besides antimicrobial assents are also contemplated for
use in the
pharmaceutical compositions of the present invention, including topically
active drugs for the
'_'S treatment of diseases. Suitable topically active drugs include. but are
not limited to, acne
preparations such as isotretinoin, ben.zoyi peroxide. salicylic acid and
tetracycline; anesthetics
for topical administration such as dibucaine, lidocaine. benzocaine.
tetracacine, deperodon and
pramoxine hydrochloride; anti-intiammatory assents such as betamethasone
benzoate,
betamethasone valerate. desonide. tluocinolone acetonide. halcinonide.
hydrocortisone:
:0 antiperspirants and medications used in the treatment of hvperhidrosis such
as ~:lutaraldehyde.
methenamine, glycopyrrolate. scopolamine hydrobromide: antipruritic and
external analLesic
a~:ents such as camphor. menthol. salicylic acid. methylsalicyfate: cleansinu
a~:ents such as
soaps and shampoos: keratolvtic. cvtotoxic, and destructi~-e agents such as
anthralin.
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cantharidin, fluorouracil, podophyllotoxin. resorcinol; and pigmenting
arid'b'dp~~i'fefiitttlg
agents. sunscreens such as hydroquinone, monobenzone. trioxsalen and p-
aminobenzoic acid;
anabolic steroids for buildins: up tissues under wound healinct such as
methandienone;
proteolytic agents for the decomposition of fibrin such as trvpsin;
vasodilating substances for
s improving the t7ow 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 growth
factor), EGF-URo
(EGF-urogastron). somatostatin, sornatotropin aseilacrine. and TGF: and
mucolytic and
antiviral medicaments which are globuiins such as (ysozyme.
I0 ~ pharmaceutical composition with a broad spectrum of antimicrobial
protection is
produced by combining one or more topically active drugs in a stable fashion
with a
pharmaceutical composition containing silver thiosulfate ion complexes. In
situations where
the topicailv active drugs are used to treat a disease which has an abundance
of dead tissue
(c~.~,~., a fungating tumor or a decubitus ulcer), the addition of
antimicrobial silver ions will aid
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
drug with the silver thiosulfate .ion complexes minimizes the need to apply
additional topical
antimicrobial compositions which may be incompatible with the medicinal agent,
resulting in
.0 both time and cost savings.
In addition to medicinal ascents which are antimicrobial aLents or topically
active
auents. the present invention also contemplates the use of systemically active
drugs in the
pharmaceutical compositions of the present invention. The systemically active
drugs are
absorbed by the body surface when applied topically, either neat or with the
aid of a solvent.
Suitable systemically active drugs include. but are not limited to. sedatives
and hypnotics such
as pentobarbital sodium. Phenobarbital, secobarbital sodium. carbromal. and
sodium
Phenobarbital: psychic energizers such as 3-("'-t-aminopropvl)-indole acetate
and 3-(2-
antinobutvl)-indole acetate: tranquilizers such as reserpine. chlorpromazine
hydrochloride, and
. a thiopropazate hydrochloride; hormones such as adrenocorticosteroids_ for
example, 6-oe-
;t) methylprednisolone. cortisone. cortisol. and triamcinolone: andro~:enic
steroids, for example,
methyl-testosterone, and tluoxymesterone: estrogenic steroids. for example.
estrone,
17~i-estradiol and ethinyi estradiol: progestational steroids. for example 17-
a-
hydroxyprogesterone acetate. medroxypros~esterone acetate. I ~-
norproLesterone. and
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norethindrone: and thyroxine: antipyretics such as aspirin. salicyiamide. and
sodium salicyiate;
antispasmodics such as atropine. methscopolamine bromide, and methscopoiamine
bromide
with phenobarbital: antimalarials such as the 4-aminoquinolines, 8-
aminoguinolines, and
pyrimethamine; and nutritional agents such as vitamins. essential amino acids.
and essential
s fats.
.4 pharmaceutical composition with a broad spectrum of antimicrobiai
protection is
produced by combining one or more systemically active drv~,~s 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
I 0 of the, pharmaceutical ,composition by protecting it from microbial
proliferation and
overurowth, which could otherwise lead to spoilage of the medicinal
composition containing
the systemically active drugs.
f=inally. the antimicrobial compositions may be useful in making infection-
resistant
cosmetics and personal care products.
i5
IV.. INCORPORATION OF SILVER THtOSUI,FtITE'ION COMPLEXES
INTO MATRICES AND THE USE OF SUCH ~i.~TRIC:ES
This section describes the incorporation of ~siiver thiosuifate ion complexes
into
matrices. most preferably anhydrous polymeric tt~atrices. In turn, the
matrices products can
30 y . be used in conjunction with medical devices for the treatment and
prevention of infections ~' ' '
and. diseases. In .ueneral. the silver .thiosulfate ion complexes can be
incorporated into the '
Ix~lyn~er matrix either (l) during.! the production of the polymer matrix or
(ii) after the polymer
matria;has been produced. It is most preferred that the complexes aye
homogeneously
dispersed in the matrix.
,;
A. The Nature of Silver Thiosulfate lon-Containing Anhydrous
Polymeric iNatriees
Similar to the situation described above retarding compositions. aqueous
solutions of
silver thiosulfate ion complexes which have not been purit'ied can be
incorporated into
~0 polymer matrices to render the matrices compositions antimicrobial.
However. the resulting
matrices compositions will contain large quantities of excess thiosuifate
salts as well as waste
salts. such as sodium nitrate, potassium nitrate; potassium acetate, etc. As
set forth above,
these impurities may be irritating when the matrices compositions are applied
topically.
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Furthermore. the presence of the waste salts may have a neuative impact on the
physical
characteristics (c~.~,~, feel, strength, and stiffness) of the final matrices
compositions.
The purified 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 any solid material that does not contain a
significant 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
i 0 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 and/or swell in the
presence of water assists
in the dissolution and diffusion of the silver thiosulfate ion complexes from
the polymer
1 ~ matr~:~.
It should be noted that the silver thiosuifate ion complexes of the present
'invention can
be used with anhydrous polymer matrices which do have reactive components as
long 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
~0 . alginate material (which contains a number of chemical reactive groups
such as carboXyiic
acid). the salver thiosulfate ion complexes of the resulting composition are
unstable over long
periods: the water in the solution acts as a media in which the reactive
groups of the aluinate
materials can destabilize the silver thiosulfate ion complexes. However. when
the alginate
material is dry, the silver thiosulfate ion compieres remain stable.
=s anhydrous polymer matrix materials useful in this invention include. but
are not
limited to. the following: adhesives such as~acrylic-based. pressure-sensitive
adhesives:
biopolymers such as silk. alginate materials. etc.; hydrocolloid materials
such as sodium
carboxymethvlcelluiose. either alone or when bound in a polymer; polymers such
as
polyurethane. silicone. etc. in the form of coatinsa, films or foams. and the
like. These
;O anhydrous polymer matrix compositions can be used alone or as a component
of another
material, such as a medical device:
The concentration of the siV°er 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 1.5°.'°.
The resulting silver thiosulfate
ion complexes-containing matrices compositions of this invention are
antimicrobially active ,
and stable. Additionally, the compositions of this invention show no photo-
discoloration
when exposed to ambient room lis;ht over a 72-hour period.
It should be noted that the silver thiosulfate 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. Moreover,
as
previously alluded to, the matrices compositions can be used to make medical
devices such as
dressinsrs. tamponades, etc. which can be used in the treatment and prevention
of infection.
B. Incorporation During Production Of Polymer Mrtrix
I S The method of incorporating: the silver thiosulfate ion complexes durins~
the production
of the polymer matrix itself will be dependent on the production process for
that polymer
matrix. The methods -of incorporation tar several polymer matrices follows. Of
course,
deviations from these methods as well as the use of different matrices than
those specifically
mentioned ace within the scope of the present invention.
'_'0 , The first method of incorporation is tt~efuf if the. polymer rtratrix
is produced fronwa
solvent solution of polymer matrix,rnaterial. In this situation. the silver
thiosultate ion ~~ .
compleres in a solid powder form can be added to that solution and mixed
thorouLhlv. t:pon
elimination of the solvent through standard means in the art. the rernaininL
polymer matrix
material vviil have the silver thiosulfate ion complexes dispersed: preferably
the complexes are
.5 dispersed homogeneously. For example, in an adhesive material dissolved in
a solvent, the
silver thiasulfate ion complexes in a powder form are thorouuhlv mixed in. The
miwure is
then coated an a liner and dried. 'fhe resulting adhesive film has the silver
thiosuifate 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.c~.. latex polymer
systems, solvent extraction
systems) or as a reactant (i.r., polyurethane t'oam production, aluinate fiber
production, etc.).
With this method. the silver thiosulfate ion complexes can be dissolved in the
water prior to
flue production process. To illustrate, if a polymer film is being 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 thiosuifate ion complexes mill dissolve.
After coating and
dryings, the resulting polymer film will have the silver thiosulfate ion
complexes
homos~eneously dispersed in the film.
s Likewise, in producing a polyurethane foam matrix by reacting the
polyurethane
prepolymer with water. the silver thiosulfate ion complexes can be dissolved
in the water
prior to reacting it with the prepolymer. After the polyurethane foam has
reacted and been
dried, the silver thiosulfate ion complexes will ~be dispersed throus:hout the
foam matrix.
Additionally, in producing a water insoluble alginate material by reacting an
alginate
solution with an aqueous calcium chloride bath, the silver thiosuifate ion
complexes can be
dissolved in either the water making up the alginate solution or the calcium
chloride bath.
The alginate solution. when extruded into the calcium chloride bath. will
result in crossiinked
al~:inate fibers which incorporate the silver thiosuifate ion complexes. Upon
drying of these
tibers. the silver thiosulfate ion complexes will be dispersed throus!hout the
alginate matrix.
1 S Another method of incorporation can be used in conjunction with the
production of
polymer matrices such as a hydrocolloid matrix made up of a hydrocolloid
material (e.~,~.,
carboxvmethyicelluiose) in a polymer binder. !n this situation. the silver
thiosuifate ion
complexes. in a solid farm. can be mixed directly with the hvdrocolloid
material prior to the
production process. Likewise. the silver thiosulfate ion complexes can be
dissolved in water
30 whicll 'is then used to treat the hydrocolloid material so that--the
solution is absorbed by the
hvdrocolloid material and then dried. Thereat'ter. the treated hvdrocolloid
material is
processed usinu standard procedures to produce the hvdrocolloid polymer matrix
which
contains the silver thiosultate ion complexes dispersed in the hydrocolloid
component of the
matnx.
'_'S C. Incorportltion After Production 4f Polymer vYlatrix
In addition to incorporation prior to or durin~z 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 finished polymer matrix. This
silver thiosulfate
~0 ion complexes solution can be applied to the polymer matrix by spraying,
dipping, paintinu or
other suitable means.
By way of illustration. an aliquot of the silver thiosulfate ion complexes can
be applied
onto and absorbed into a finished foam dressins:. .After drying, the silver-
based foam -
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composition will be stable and antimicrobial. Likewise. the silver thiosuifate
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 ton 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 very
important that the water be removed from the polymeric matrix. If the water is
not removed,
t0 the silver thiosulfate ion complexes will become destabilized within the
polymeric matrix over
time..
Second. thoyh the water can be removed usins: any 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 may be
used. while temperatures of
1 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 thiosu)fate ion complexes solution cad
be destabilized
upon contact with metal surfaces such as aluminum and copper. An effort should
be made to
20 ensure that the solution comes into contact.with materials such~as's.=lass
or plastic. which
appear to be less destabilizins~_
E1PERIMEN'1'AL
In the disclosure which follows, the following: abbreviations apply: L
(liters); ml
(milliliters); ~tl (microliters); g (scrams); mu (milligrams); ~tg
(microurams); mol (moles);
mmol imillimoles); Ltmol (micromoles); cm (centimeters); mm (millimeters); nm
(nanometers); °C (de~:rees Centiurade); MW and M.W. (molecular
4veight); N (normal); wfw
tweight-to-weight); wfv (weight-to-volume); min. (minutes): No. (number): ICP
(inductively
coupled plasma); CFU (colony formint! units): PEG (polyethylene p;lycol); MHM
(Mueller '
s0 Hinton Medium); ZOI (zone of inhibition); ATCC (American Type Culture
Collection.
Rockville_ MD); USP (United States Pltarmacopeia): NCCLS (National Committee
for
Clinical Laboratory Standards); NIOSH (National Institute of Safety and
Health); Avitar
(Avitar. lnc.. Canton. MA); Aldrich (Milwaukee, W1); Avery Dennison, )nc.
(Mill Ha~l, PA);
_ 2g _
SUBSTITUTE SHEET (RU4E 26)
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BASF (BASF Corp., Chemical Division; Parsippany, NJ); Belersdorf Inc. (BDF
Plaza
Norwalk. CT); Columbus (Columbus Chemical Industries; Columbus, Wi); Cook
Composites
and Polymers (Kansas Citv, MO); Difco (Difco Laboratories, Detroit, MI);
Hampshire
(Hampshire Chemical Co.. Lexin~aon, MA); Johnson & Johnson Medical, Inc.
(Arlington,
Tx); Owen Laboratories (San Antonio, T1); Proton (Drammen, Norway); Roundy
(Roundy's
lnc.. Milwaukee, WI); Sigma (Sigma Chemical Company, St. Louis, MO);
SmithKline
Beecham (Philadelphia, PA); Steriseal (Steriseat Ltd, England); Whatman
(Whatman
International Ltd., Enc:land); WOHL (Wisconsin Occupational Health Laboratory,
Madison,
WI).
The following 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: I) Processes To Obtain
Silver
Thiosulfate !on Complexes: II) Compositions Coniainin~~ Silver Thiosulfate ton
Complexes:
III) Antimicrobial Activity Of Compositions C',ontaining Silver Thiosulfate
lon Complexes;
I S IV) Use Of Silver Thiosulfate Ian Complexes in Medical Devices, and V) Use
Of Silver
'Thiosulfate ton Complexes in Combination With Other Medicinal Agents.
I. PROCESSES TO OBTAIN SILVER THiOSULFATE ION COMPLEXES
. ~ EXAMPLE t
Process f'or Making Silver Thiosulfate ton CompieKes Usins: Silver
Chloride When The Ratio Of Thiosulfate Ions To Sifver Ions is Greater Than ?-
to-1
This e:~ample illustrates the process for producing silver thiosulfate ion
complexes
'_S 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 first making a silver
chloride
precipitate in an aqueous solution (hereafter, "silver chloride
precipitatelaqueous solution").
The silver chloride precipitateJaqueous solution was made by mixine~. 20 ml of
a silver nitrate
;0 (Aldrich: deionized water as the diluent) solution ( 1 mmol/mi) with 23 ml
of a sodium
chloride solution ( I mmol/ml) (Aldrich; deionized water as the diluent) in a
500 ml separatory
funnel. To the resulting silver chloride precipitate/aqueous solution was
added 60 mf of a
sodium thiosulfate (Columbus; deionized water as the diluent) solution ( I
mmol/ml). '>:he
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resulting mixture was agitated by shaking the separaton~ tunnel until all of
the silver chloride
precipitate was dissolved.
The silver thiosulfate ion complexes produced were separated by adding 2Q0 ml
of
ethyl alcohol to the container. Upon addition of the ethyl alCOhol. the
solution became cloudy
and separated into two separate phases. The two phases were separated usinf:
the separatory
funnel. The wei~:ht of the material in the phase containing the silver
thiosulfate ion
complexes was approximately 17 ~~. This phase was then treated by adding ?0 ml
ethyl
alcohol and 40 ml of acetone to make the silver thiosulfate ion complexes
essentially
anhydrous. After sitting 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°C1 and around to
a tine white powder
usins~ a mortar and pestle. The weight of the dried silver thiosulfate ion
complexes was
I 0.03 ~~.
The silver thiosulfate ion complexes were analyzed for silver. sodium and
sulfur using
t5 Inductively Coupled Plasma Argon Emission Spectrometry. The analysis,
pertbrmed by
Wisconsin Occupational Health Laboratory (WOHL), included measurement of the
amount of
silver using a method based on NIOSH S 18~. Briefly, a representative portion
of the silver
thiosulfate ion complexes was weisthed and diluted I/t000 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 percenttiges of ttie air
dried samples):
Silver ~ ' oo~°
Sodium 17%
Sulfur 33%
=s The results of the analysis suggest that the silver thiosultate ion
complexes were
relatively pure and corresponded to the formula: '~Ia,H[As~(S;O,),] (Silver:
30.1 I°.'o (wlw),
Sodium: 17.13% (wlw), Sulfur: 36.75% (wrw)).
The calculated yield of silver thiosulfate ion complexes usins: the process of
this
example is 93.7%.
;0
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EXAMPLE 2
Process For Makinu Silver Thiosulfate Ion Complexes Using Silver
Chloride When The Ratio Of Thiosulfate Ions To Silver Ions Is Equal To 2-to-1
s This example illustrates the process far producing silver thiosulfate ion
complexes
when the ratio of thiosulfate ions to silver ions is equal to 2-to-I . The
silver thiosulfate ion
complexes were isolated through 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 rnl of a
silver nitrate (Aldrich;
deionized water as the diluent) solution ( I mtnollml) with l0 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 precipitatelaqueous solution was added 20
ml of a sodium
thiosulfate (Columbus: deionized water as the drluent) solution ( 1 mmol/ml).
The resulting
mixture was agitated by shakinu the container until all of the silver chloride
precipitate was
dissolved.
Thereafter, the silver thiosulfate ion complexes were separated by adding s0
ml of
acetone to the container. Upon addition of the acetone, the solution became
cloudy and
Separated into two separate phases. The t'vo phases were separated into
individual containers
usinu a pipet. The phase containing the silver thiosuifate ion complexes was
treated by
'_'0 addinu s0 mi of acetone to make the silver throsulfate ion complexes
essentially anhydrous.
.~t~er sitting overnight, the silver thiasulfate ion complexes were in the
form of a pure
evhite solid material. 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 weis:ht of the
dried silver thiosulfate ion complexes was 3.97 :rams.
=s The resulting silver thiosulfate ion complexes material was analyzed for
silver'. sodium
and sulfur using: an Inductively Coupled Pllsma (1CP; described above). The
analysis gave
the following results:
Silver '35%
Sodium I '/%
;0 Sulfur
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The results of the analysis indicate that the silver thiosulfate ion complexes
were
relatively puce corresponding with the following theoretical formula:
Na,[Ag(S~O,)~]~2H,0.
(Silver: X4.7% (w/w), Sodium: 15.78% (w/w), Sulfur: '9.3% (w/w)).
The calculated yield of making: silver thiosulfate ion complexes using the
process of
s this invention is 90.8%. ,
EXAMPLE 3
Process For Making Silver Thiosulfate Ion Complexes Using Silver
Chloride When The Ratio Of Thiosulfate Ions To Silver Ions Is Less Than 2-to-t
This example further illustrates the process for producing silver thiosulfate
ion
complexes when the ratio of thiosulfate ions to silver ions is less than 3-to-
t. As in the
preeedin~= example. the silver thiasulfate ion complexes were isolated through
the formation of
a precipitate rather than a biphasic separation.
In this example, silver thiosulfate ion complexes were made 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 ( 1 mmol/ml) with 20 ml of a sodium
chloride
(Aldrich: deionized water as the diluent) solution (t mmollml) in a 100 ml
specimen
container. To this silver chloride precipitate/aqueous solution was added l5
ml of a sodium
'_0 thiosulfat~e (Columbus: deionized water as the dituent) solution ( f
rnmol/ml). 'The resulting
mixture was agitated by shaking the container until all of tlqe silver
chloride precipitate was
~iissnlved.
Thereafter, the silver thiosutfate ion.complexes were precipitated from the
solution by
adding: ~0 ml of acetone to the container. Tl~e precipitated silver
thiosulfate ion complexes
=s were in the form of a pure white solid material. The solvent was decanted
and the white
solid was dried in an oven (G2°C) and ground 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 have the
following '
s0 results:
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S l Iver 32%
Sodium l .4%
Sulfur 29%
The results of the analysis indicate that the silver thiosulfate ion complexes
were
relatively pure corresponding with the followins: theoretical formula
Na,[Ag,(S,O.,),]~H,O.
(Silver: 32.6% (w/w) , Sodium: 13.9% (wlw), Sulfur: '_9.0% (wlw)).
EXA1VIPLE 4
Process For iNakin~ Silver Thiosulfate Ion Comple~ces Using Silver Bromide
In making the aqueous solution of silver thiosulfate ion complexes, the
preferred silver
halide is silver chloride (Examples I->): this example illustrates that other
silver halides may
be used.
I S 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 rnixinu 2 ml of a silver nitrate (Aidrich;
deionized water as
the diluentj solution ( l mmol/ml) with 2.3 ml of a sodium bromide (Aldrich;
deionized water
as the diluent) solution ( I mmol/ml) in a SO ml beaker. To this silver
bromide
30 precipitate/aqueous solution was added 6.0 rrrl of a sodium thiosulfate
(Columbus; deionized
water as the _diluent> solution ( I mmollmll. The resultinL mi~cture was
ac:itated by stirrin~_
until alt of the sodium bromide precipitate was dissolved.
The silver thiosulfate ion complexes were separated by adding! 20.0 ml of
acetone to
the container. Upon addition of the acetone, the solution separated into two
phases. The
'_'S phase containing the silver thiosulfate ion complexes was collected and
treated by adding 7.0
ml ethyl alcohol and X4.0 ml of acetone to make the silver thiosulfate ion
complexes
;u~hydrous. after sitting overniLht. the silver thiosulfate ion complexes were
in the form of a
white solid material at the bottom of the container. The solvent was decanted
and the white
solid was dried in an oven (GZ°C) and ground to a tine white powder
using a mortar and
,0 laestie. The resulting weight of the dried silver thiosuifate ion complexes
was 0.88 g.
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EXAMPLE 5
Process For Making Silver Thiosulfate
Ion Complexes Devoid Of A Phase Separation Procedure
To illustrate the importance of makinu silver thiosulfate ion complexes using
the
processes of this invention, silver thiosuifate 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
greater than 2-to-1.
This comparison process was performed by first making a silver chloride
precipitate in
an aqueous .solution (hereafter. "silver chloride precipitate/aqueous
solution") by mixing 2 ml
of a silver nitrate (Aldrich; deionized water as the diluent) solution ( 1
mmol/ml) with 2.2 ml
of a sodium chloride (Aldrich; deionized water as the diluent) solution ( 1
mrnol/ml) in a ~0
ml beaker. To this silver chloride precipitatelaqueous solution was added 6.0
ml of a sodium
thiosulfate (Columbus; deionized water as the diluent) solution ( 1 mmol/ml).
The resulting
1 S mixture was agitated by stirring until all of the sodium chloride
precipitate was dissolved.
The resulting silver thiosulfate ion complexes solution was placed in a
convection
oven at 62 °C overnight 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.
If. ' COMPOSITIONS CONTAINING StLVEIt THIOStILEATC lON
COMPLE\ES
EXAA1PLE 6
Stable Antimicrobial Composition - PEG Base
The previous examples were directed at processes for making silver thiosulfate
ion
complexes. This example, .~s well as Examples 7-9 that fallow. compare various
antimicrobial compositions containing the silver thiosulfate ton complexes. In
this example. a
30 silver-based antimicrobial composition was produced in a PEG base.
Specifically, =t0 ~; of a
polyethylene glycol (PEG) base (PEG 600:PEG 1000 = 0.3:0.7; Aldrich) was
melted. While
roofing, U.47 g of the silver thiosulfate ion complexes of Example 1 were
stirred into the
melted PEG base. The stirring was continued until the silver thiosulfate tan
complexes were
sues wEEraAUt:E'2s~ ,p.
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homogeneously suspended. While stirrins~, the melted PEG/silver thiosulfate
ion complexes
composition was cooled to produce a semisolid base. The amount of silver in
this silver-
based antimicrobiai composition was equivalent to 0.5°,ro silver
nitrate.
EXAMPLE 7
Stable Antimicrobial Composition - Aquaphor"
To further illustrate a silver-based antimicrobial composition of this
invention, 40 ~ of
Aquaphor~ Cholesterolized Absorbent Eurcerite Ointment Base was melted.
Aquaphor6 is a
stable, neutral. odorless, anhydrous ointment base (Belersdorf Inc). tVhile
cooling, 1.2G g of
the silver thiosulfate ion complexes of Example I were stirred into the melted
Aquaphor"
base. The stirrins: was continued until the silver thiosuifate ion complexes
were
homo~:eneouslv suspended. While stirring, 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 1.0% silver nitrate.
EXAMPLE 8
Stable Antimicrobial Composition - White Petrolatum USP
To illustrate an Rlternative silver-based antimicro~ill composition of the
present
invention, :~0 a of white petrolatum .USP (Roundv's Pure Petroleum lellv.
White Petrolatum
1.!SP) was melted. While cooling, ?.52 g of the silver thiosulfate ion
complexes of Example l
were stirred into the melted white petrolatum base. The stirring was continued
until the silver
thiosulfate inn complexes were homoc:eneauslv suspended. While stirring, the
melted white
petrolatumlsilver 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°'° silver
nitrate.
EXAMPLE 9
;0 Stability Of Anhydrous And Hydrated Antimicrobial Compositions
This example illustrates the instability of hydrated silver-based
antimicrobial
compositions comprisins~_ silver thiosulfate ion complexes. The experiments of
this example
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utilize the compositions produced in Examples 6-8. as well as a composition
containing a
different base. Velvachol ' Cream.
EXAMPLE 9A
PEG Base Plus Water
A hydrated silver-based antimicrobial composition was made where the
composition
base was PEG. The composition was made by mixing 9 ~~ of the silver-based
antimicrobial
composition of Example 6 with ! ml of water. This silver-based antimicrobial
composition
contained approximately 10°I° water by weight.
EXAlYIPLE 9I3
.~quaphor' Pius Water
I S A hydrated silver-based antimicrobiai composition was made where the
composition
base was Aquaphor'. The composition was made by mixing: 9.5 g of the silver-
based
antimicrobial composition of Example 7 with 0.5 ml of water. This silver-based
antimicrobial
composition contained approximately 5°'° water.
" EXAMPLE 9C , , ..
White Petrolatum Plus Water
.~ hydrated silver-based antimicrobial composition was made wivere the
composition
base was white petrolatum. The composition was made by mixing ~:S ~_ of the
silver-based
_'S antimicrobial composition of Example 8 with O.s ml of water. This silver-
based antimicrobiai
composition contained lpproximatelv S°% water.
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EXAMPLE 9D
Velvachol Cream
A silver-based antimicrobial composition containing 0.47 g of the silver
thiosulfate ion
s complexes of Example 1 were stirred into 20 g of Velvachol'' (tJwen
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 i.0%
silver nitrate.
The stability of the silver-based compositions of Examples 6, 7, 8,and 9A-D
was
I U 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 light. Chans:e of color indicates decomposition of the silver
thiosulfate ion
complexes. Table i below indicates the initial color ot~ each composition and
the change in
color on days 7 and i 4 and after I month.
15 As depicted by the results of this study, the silver-based,compositions
described in
Examples b. 7 and 8 .demonstrated no change in color. In contrast, the
hydrated silver-based
compositions, Examples 9r1-D, demonstrated major chans:es 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
30 anhydrous compositions of this invention were stable. while the analogous
hydrated samples
were not.
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TABLE t
Stability OC Siit~er-Based Compositions
Appearance
Ot'
Ointment
Sample
Day Duy 7 Dny I-t Month Month Munth
1 1 3 7
Eeamplc G: PEG GrayishNo No No No No
Cotnposition White Change Change Change Change Change
Example t: Aquaphor"Slight No No No No No
Composition Yellow Change Change Ch.~nt:eChange Change
Eaampie tt: WhiteSlight No No No No No
Petrolatum CompositionYellow Change Change Change Change Cl><tngc
E~.~ntple'lA: GrayishNo Slight Brown Brown Black
Hydrated Tan
PECr Composition White Change
Example')B: 'HydratedSlight Slight Brown Dark Black Black
Aquaphor" CompositionYellow T:m ' Brown
Examplc'lC: HydnttcdSlil:lttNo T;m Bl:tck Black Black
White Petrolatum Yellow Change
Composition
Eaample'lD: Velvachol"White Tan Brown Black Black Black
Cream
30 II1. :~NTIMICROBIAL ACTIVITY OF COMPOSITIONS CONTAINING
SILVER THIOSULFATE ION COMPLE1ES
EXANtPLE l0
Antimicrobial Activity Of Silver Thiosulfate Ion Complexes
The in rilrn antimicrobial activity mas evaluated by tindinu the minimum
inhibitory
concentration for the powder of silver thiosulfate ion complexes from Example
3. This
powder was tested in serial two-told dilutions ranging from 1.95 to 250
~t~/mt. Broth
microdilution was performed in serial dilution of the silver thiosulfate
powder in tryptic soy
:0 broth (Difco). Each dilution was inoculated with 0.005 ml of a 24-hour
~_rowth of a microbe
( 10' to 10' CFU/ml). After the dilutions were incubated at ,7°C
overniLht, 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 (nilC) reported in terms
of LttJml.
The results shown in Table 2 demonstrate that fhe sliver thiosulfate ion
complexes
s5 powder has antimicrobial activity as~,ainst both :ram (+) and gram (-)
microbes (Difco).
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TABLE 2
fHtlute ATCC Accession Silver Thiosulfute ton Complexes
No. jul,,Jml)
.S', aureuv 35')23 < I.~)5
.1. cpirlerrnidic1222ti ' l.')5
I~. cnli 25922 ; 1.95
I'. ncrut'imrxo27ti53 I ~ I.')5
~
EXAI~IPLE I1
Antimicrobial Activity Of Silver-Based Compositions
The antimicrobial activity of the silver-based compositions of Examples ~. 7.
and 8
were evaluated using a zone of inhibition iZOI) protocol. In this ZOI
protocol. 1 cm-
diameter discs (Whatman Filter Paper, Quantitative ! ) were coated with a thin
Layer of the
is compositions tom E~camples 6. 7.,and 8. These coated discs were placed on
Mueller Hinton
Medium (MHM; Difco) with lawns of S. crrrrerrs (ATCC ''5923; ?4 hours growth
:from MI3M
plate>. after incubation at 36 °C for 18 hours, the size of the zone of
growth inhibition was
measured tin mm) from the edue of the disc to the point of microbial growth.
Table 3 shows
the ZOI results for each composition on Day I and at one month.
_'0 TABLE 3
Antimicrobi;ll Activiy Of Silver-Bused Contpositiom
Zunc of tahihitisn
tmmt (S. urrrrrrxt
Sxmplr
Duv I 1 Month
Eaamplc o: PEG Composition1 :.; nun t.t.tt mm .
Example 7: aquuphor'
'_s Cotnpositiolt Itl.t1 mm I?.tl nun
Ea:tntplc H: ~VUitc lu.tl nntt Ia.S nun
Petrol:uutll
COIIIpOSllloll
..~s can be seen by the results of this study. the sil4~er-based compositions
of this
,0 invention (Examples 6. 7 and 8) demonstrated food anrimicrobial activity
that was stable for
the duration of the study period. That is to say. the size of the zone of
growth inhibition was
essential iv unchan~:ed over the one month period.
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IV. USE OF SILVER THIOSULFATE ION COMPLEXES IN tI~IEDICAL
DEVICES
EXAMPLE 12
Foam Dressings Containint Silver Thiosulfate Ion Complexes
As previously indicated, the silver thiosuifate 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
I'0 this example, the complexes were incorporated into the matrix during the
manufacturing of
the polymer matrix.
.a foam dressins~ was produced by first dissolving 0.~4 ~: of silver
thiosulfate ion
complexes powder in 150 ml of a t).s°'o Pluronic L-62 (BASF) aqueous
solution. This
solution was the mixed with 140 g of a polyurethane prepolymer (Hypo) 2002,
Hampshire) in
I S a I-liter disposable plastic beaker. The resultinu mixture instantly
bes:an to react to form a
foam. After 10 minutes the foam was removed from its container and sliced to
produce
individual foam dressins=.s (approximately 7.5 cm in diameter. The slices of
foam dressings
were dried at 50°C in a dark convection oven.
These foam dressings were 1i4.~ht stable and antimicrobialiy active. In this
example and
'_'0 Examples 1~-18 that follow, the terms "light stable," "photostabie," and
the like mean that the '
samples did not discolor after 72 hours of exposure to ambient room lis~ht. In
this example '
and E:vamples I~~-I8 that follow. the term "antimicrobially active" means that
a small piece
tnom-i~ailv I cm x I cm or I cm strands in the case of alginate fibers!
produced zones of
inhibition when placed on both a lawn of S. crrrrcrr., (ATCC .59231 and a lawn
of l:. cirli
'S (ATCC 259?3). The lawns were produced by plating 24-hour Lrowth microbes on
MHM
plates; after incubation for ?4 hours. each sample was examined to determine
whether n zone
~.~f inhibition was present.
This foam dressinct can be used for a lar~:e varienr of medical applications.
includins~
us an antimicrobial absorptive foam dressinst.
.~ 0
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EXAMPLE i3
Foam Dressing Containing Silver Thiosulfate lon Complexes
This example further illustrates the use of silver thiosulfate ion complexes
to prepare a
medical device made up of a foam polymer matrix. tn 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 (Hydrasorb~ Spon~xe Foam Dressing (10 cm x 10
crn); Avitar) was submerged in an aqueous solution containing silver
thiosulfate ion
complexes powder from Example 3 (0.1 g per liter). The foam dressing samples
were
removed and dried at 50°C in a convection oven. These sliver
thiosuifate ion complexes-
containinL foam dressinsts were iiuht stable and antimicrobiallv active. :~s
indicated in the
previous example, these foam dressings can be used for a large variety of
medical
applications, including as an antimicrobial .absorptive foam dressings.
EXAIVIPLE t4
Hydrocotloid Dressing Containins_: Silver Thiosulfate Ion Complexes
This example illustrates the use of the silver thiosulfate ion complexes to
prepare a
30 medical device which is made up of a hydrocolioid absorbent polymer.
matrix: In- this
example. the complexes were incorporated into the matrix during the
manufftcturing of the
holvmer matrix.
a hvdrocolloid dressinL containing silver thiosulfate ion complexes was
produced by
tirst thorous:hfy mixins 0.157 g of sliver thiosulfate ion complexes powder
(mesh :100) from
~i Example 1 with 10.0 g of sodium carboxvmethyl cellulose t:~ldrich).
Thereafter, 4 g of this
treated carboxvmethyt cellulose was mixed thoroughly with ~ a: of a
polyurethane prepolymer
(Aquapol 03S-0031, Cook Composites and Polymers). This mixture was then
pressed
between a polyurethane film and a silicone-treated hydrocolloid matrix and was
allowed to
cure for 24 hours.
,0 The resulting silver thiosulfate ion complexes-containing hydrocolioid
dressing: was
photostable and antimicrobially active. This type of dressing is useful on
exudating,
malodorous wounds.
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EXAMPLE IS
Hydrocolloid Dressing Containing Silver Thiosulfate lon Complexes
This example further illustrates the use of silver thiosulfate 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 g of a silver
thiosulfate ion complexes powder (mesh >100) from Example 1 in 10.0 ml of
water. To this
f0 solution was added 100 g of sodium carboxvmethyl cellulose (Aldrich,
Milwaukee, Wl) which
ab~prbed the solution. The treated sodium carboxymethyl cellulose was allowed
to dry at
room temperature. Thereafter. -1 a of the dried treated carboxvmethvl
cellulose was mixed
thoroughly with 4 ~! of a polyurethane prepolVmer (Aquapol 035-0031. Cook
t'omposites and
Polymers). This mixture was then pressed between a polyurethane film and a
silicone treated
1 S liner and was allowed to cure for 24 hours.
As with the silver thiosulfate ion complexes-containing: hydrocolloid dressing
produced
in the preceding example. the hydrocolloid dressing is photostable and
antimicrobiaiiy active
and is useful on exudating, malodorous wounds.
EXAMPLE t6 . . '
adhesive Films Containing Silver Thiosulfate lon t.'omplexes
This example illustrates the use of silver thiosuifate icm complexes to
produce adhesive
films. Specifically, a pressure sensitive adhesive (PSA) containinu silver
thiosulfate ion
'_'s complexes was produced in this example. adhesive films are, among other
thines, especially
useful in covering painful abrasive-type skin wounds and partial skin graft
sites.
The silver thiosuifate ion complexes-containinc! PSA was made by mixing 0.25 g
of
the silver thiosulfate ion complexes powder from Example i in An adhesive
solution
~;;onsistins: of 45 g of a proprietary medical tirade acrylic based latex (58%
solids) (Avery
30 Dennison. Inc.) and S g polyethylene ulycol (M.W. ti00) (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. vvhen
coated arid
dried, produces a tacl:v. 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 dressints which are
antimicrobially active.
Dressings with the silver thiosulfate ion complexes-containing, PSA are
especially useful in
covering painful abrasive-tope skin wounds and partial skin staff sites.
EXAMPLE 17
Alginate Materials Containing 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
alginate fibers that incorporate the silver thiosulfate ion complexes.
First, water-swellable ahinate fibers were produced containin~_~ silver
thiosulfate ion
complexes. The alginate fibers were made by using a syrinste to inject a 5%
sodium alginate
solution (Pronova LV M Sodium alginate. Protan) into a bath consistinL of a
10% calcium
chloride solution (Aldrich. deionized water as diluent) containing 0.1 gfliter
silver thiosulfate
ion complexes powder from Example 3. The alginate solution immediately formed
water-
insoluble alginate fibers upon contact with the calcium chloridelsilver
thiosulfate ion
complexes bath. The fibers were pulled tfom the bath and allowed to dry
(SO°G).
.0 The resulting fibers are photostable and antimic~robially active. These
fibers can be
used to make antimicrobial alginate dressinLS and tamponades. .~l~.:inate
materials containing
5iiver thiosulfate ion complexes are especially useful in covering: painfut
abrasive-type skin
rvounds and wound ulcers as well as for tilling in deep wounds and ca~~ities.
EXAMPLE 18
.als~inate Materials Containing Silver Thiosulfate Ion 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 alLinate material.
this example
~0 utilizes a method that does not include a calcium chloride bath.
First. an aqueous solution containing 0. I g/liter of a silver thiosulfate ion
complexes
from Example 3 4vas prepared. The resultinc: aqueous solution was then applied
to a 9.5 cm x
~.S cm als:inate dressinu (Steriseal Sorbsan Surs:icat Dressing:. Steriseal)
by spraying the
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solution onto the dressing. alternatively, the silver thiosulfate ion
complexes solution can be
applied by dipping the alstinate dressing into the solution. The alginate
fibers of the dressing
absorbed the applied solution; thereafter, the treated alginate dressings 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 covering
painful abrasive-type skin wounds and wound ulcers.
V. USE OF SILVER THiOSULFATE ION COMPLEXES tN COMBINATION
WITH OTHER MEDICINAL AGENTS
EXAMPLC l9
Pharmaceutical Composition C:ombinin« ~lupirocin
With Silver Thiosulfate Ion Complexes
1S
To illustrate an antimicrobial pharmaceutical composition consisting of a
combination
of the silver thiosulfate ion complexes of the present invention with one or
more agents. 0.02
g of the silver thiosulfate ion complexes from Example 2 were blended into ?.0
g of a
mupirocin ointment (Bactroban" (~_°a mupirocin acid in a PEG base],
SmithKlirie Beecham).
~0 The mupirocin ointment is a topical antimicrobial with excel)ent gram (+)
antim'icrobial
properties. The silver thiosulfate ion completes were blended into the
mupirocin ointment by
first meltinsr the mupirocin ointment and then stirring the silver thiosulfate
ion complexes into
the melted ointment. The ointment was stirred continually until it rooled and
resolidified.
EXAMPLE ZU
Pharmaceutical Composition Combining Mafenide
With Silver Thiosulfate lon Complexes
To further illustrate an antimicrobial pharmaceutical composition consistinst
of a
;0 combination of the silver thiosulfate _ion complexes of this invention with
one or more assents,
0.?S ~; of mafenide (Sigma) (p-am.inomethvlbenzesulfanamide) and 0.?5 ~; of
the silver
thiosuifate ion complexes of Example 3 were blended into 3:x.50 g of a PEG
composition
("PEG Composition"); the PEG Composition was produced by meltinL together a
blend of
suesmurs sHE~r~~RU~ as)-'
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40% PEG (M.W. 3450) and 60% PEG (M.W. 600). The pharmaceutical composition was
produced by tirst melting the PEG Composition and then stirring: 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
a~tents. 0.?5 g of metronidazoie (Sigmal and 0.25 g of the silver thiosulfate
ion complexes of
Example 3 were blended into 34.50 g of a PEG composition ("PEG Composition");
the PEG
I ~ 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 melting
the PEG
Composition and then stirring in the silver thiosulfate ion complexes and
metronidazole. The
resulting pharmaceutical composition was stirred eontinuallv 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.
EXAMPLE 22
Pharmaceutical Composition Cornbinin~: Chlorhexidine
With Silver Thiosulfate Ion Complexes
11
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
agents. 0.35 g of chlorhexidine diacetate hydrate (Aldrich) and 0.35 ~= of the
silver thiosulfate
ion complexes of.Example 3 were blended into ?4.5 g of Aquaphor' (a
cholesterolized
.,4 absorbent Eucerite' ointment base produced by Belersdorf Inc.). . The
pharmaceutical
composition was produced by tirst melting the Aquaphor" ointment and then
stirring in the
silver thiosuffate ion complexes and chiorhexidine. 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.
EXA1VIPLE 23
Pharmaceutical Composition Combining Triciosan
With Silver Thiosulfate ion Complexes
To further illustrate an antimicrobial pharmaceutical composition consisting
of a
combination of the silver thiosuifate ion complexes of the present invention
with one or mare
medicinal agents, 0.50 g of triclosan (Irgasan DP 300, Ciba-Geigy, Greensboro,
NC) and 0.50
a of, the silver thiosulfate ion complex of Example 3 were blended into 24.00
g of Aquaphor"~
(a cholesterolized absorbent Eucerite~ ointment base produced by Belersdorf
lnc.). The
pharmaceutical composition was produced by first melting the Aquaphor"
ointment and then
stirring in the silver thiosulfate ion complexes and triclosan. The resulting
pharmaceutical
l5 composition was stirred continually until it cooled and resolidified. This
phanmaeeutical
composition has use as a broad spectrum topical antimicrobial.
EXAMPLE 14
Pharmaceutical Composition Combininu Hydrocortisone
With Silver Thiosulfate ton Complexes w
To further illustrate an antimicrobial pharmaceutical composition consistinu
of a
combination of the silver thiosulfate ion complexes of the present invention
with one or more '
agents. 0.50 g of Hydrocortisone 21-Acetate iSigmal and 0.50 ~: of the silver
thiosuifate ion
~5 complexes of Example 3 were blended into 34.00 ~: of Aquaphor" f a
choiesterofized absorbent
Eucerite" ointment base produced by Belersdorf lnc. ). The pharmaceutical
composition was
produced by first melting the Aquaphor' ointment xnd then stirrinic in the
silver thiosuffate
ion complexes and hydrocortisone. The resulting pharmaceutical composition was
stirred
continually unfit it cooled and resolidified. This pharmaceutical composition
loos 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 mounds
caused by'dermatitis,
insect bites. poison ivy, etc.
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EXAMPLE 25
Pharmaceutical Composition Combinins: Lidocaine With
Silver thiosulfate Ion Complexes
s 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
agents. 0.50 g of lidocaine (Sigma) and 0.50 g 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 (M.W.). The pharmaceutical composition was produced by first melting the
PEG
Composition and then stirrinsr in the silver thiosuifate ion complexes and
lidocaine. The
resultine pharmaceutical composition was stirred continually until it cooled
and resolidified.
This pharmaceutical composition has use as a topical anesthetic which also has
antimiccobial
properties to prevent a secondary infection when applied to exposed tissues or
wounds.
l;
EXAMPLE 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
agents. I.00 g of pramoxine hydrochloride (Sigma) and 0.~0 ~~ of the silver
thiosulfate ion
complexes of Example 3 were blended into 23.50 g of PEG composition ("PEG
Composition"); the PEG Composition was produced by melting tostether a blend
of 40% PEG
3:: (M.W. 3.50) and 60°t° PEG (M.W. G00). The pharmaceutical
composition was produced by
first melting the PEG Composition and then stirring 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
s~) exposed tissues or wounds.
From the above, it should be evident that the present invention provides for
silver-
based antimicrobial compositions and processes for making such CUnIpOSItlOnS
tllat ark
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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 lictht of the fores~oins~ disclosure, it will be
'apparent to those
skilled in the art that substitutions. alterations. and modifications are
possible in the practice
s of this invention without departing from the spirit or scope thereof. .
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