U.S. patent number 3,761,590 [Application Number 05/038,031] was granted by the patent office on 1973-09-25 for silver sulfadiazine used in the treatment of burns.
This patent grant is currently assigned to Research Corporation. Invention is credited to Charles L. Fox, Jr..
United States Patent |
3,761,590 |
Fox, Jr. |
September 25, 1973 |
SILVER SULFADIAZINE USED IN THE TREATMENT OF BURNS
Abstract
Silver sulfadiazine has been found to be useful in burn therapy
by applying to the affected surface silver sulfadiazine, preferably
dispersed in a water-dispersible hydrophilic carrier.
Inventors: |
Fox, Jr.; Charles L. (New York,
NY) |
Assignee: |
Research Corporation (New York,
NY)
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Family
ID: |
21897719 |
Appl.
No.: |
05/038,031 |
Filed: |
May 18, 1970 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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653830 |
Jul 17, 1967 |
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Current U.S.
Class: |
514/157;
424/DIG.13; 514/938; 514/495 |
Current CPC
Class: |
A61K
9/0014 (20130101); A61K 31/635 (20130101); Y10S
424/13 (20130101); Y10S 514/938 (20130101) |
Current International
Class: |
A61K
31/63 (20060101); A61K 31/635 (20060101); A61K
47/00 (20060101); A61k 027/00 () |
Field of
Search: |
;424/228,290,DIG.13,170 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
merck Index 8th Ed., 1968, pp. 980-1 .
Remington, Pharmaceutical Sciences, 13th Ed., 1965, pp. 533-537
.
Remington, Pharmaceutical Sciences, 13th Ed., 1965, p. 1426 .
Merck Index 8th Ed., 1968, pp. 590-591.
|
Primary Examiner: Meyers; Albert T.
Assistant Examiner: Schenkman; Leonard
Parent Case Text
This application is a continuation-in-part of patent application
Ser. No. 653,830 filed July 17, 1967 now abandoned. The disclosures
of application Ser. No. 653,830 are herein incorporated and made
part of this disclosure.
Claims
I claim:
1. A method of treating burns in man and animal which comprises
topically applying an effective anti-bacterial amount of silver
sulfadiazine to the affected surface.
2. A method in accordance with claim 1 wherein said silver
sulfadiazine is applied as a dispersion in a water-dispersible,
hydrophilic carrier.
3. A method in accordance with claim 1 wherein said silver
sulfadiazine is applied as a dispersion in a semi-soft or
cream-like, water-dispersible or water-soluble oil-in-water
emulsion carrier.
4. A method in accordance with claim 1 wherein said silver
sulfadiazine is applied as a dispersion in a water-dispersible,
hydrophilic carrier, said carrier containing an amount in the range
from about 0.1 to about 10 percent by weight of silver sulfadiazine
dispersed therein.
5. A method in accordance with claim 1 wherein silver sulfadiazine
is applied as a dispersion in a semi-soft or cream-like,
water-dispersible or water-soluble oil-in-water emulsion carrier,
said carrier containing an amount in the range from about 0.1 to
about 10 percent by weight of silver sulfadiazine dispersed
therein.
6. A method in accordance with claim 2 wherein said dispersion
consists essentially of 0-25 percent by weight petrolatum, 7-45
percent by weight of a long chain fatty alcohol having a carbon
atom content in the range C.sub.16 -C.sub.22, 0.1-10 percent by
weight silver sulfadiazine, 4-16 percent by weight of a non-ionic
emulsifying agent, 7-40 percent by weight of a humectant selected
from the group consisting of propylene glycol, sorbitol and
glycerin, 0-15 percent by weight of an emollient and an amount of
water, when required, sufficient to bring the total of the
percentages of the above-identified components to 100 percent.
Description
The work on which this application is based was financed in part by
the National Institutes of Health, Department of Health, Education
& Welfare.
This invention relates to silver sulfadiazine and particularly to
silver sulfadiazine-containing compositions. In accordance with one
embodiment this invention is concerned with the treatment of
infections in animals and man. In accordance with a special
embodiment, this invention is concerned with the treatment of
thermal burns in man and animal. In accordance with another
embodiment this invention is directed to anti-bacterial
compositions.
Numerous compounds are known to possess anti-bacterial properties.
Known anti-bacterial compounds include silver nitrate, the various
sulfonamides, such as sulfadiazine, sulfamerazine, sulfanilamide
and Sulfamylon and the antibiotics, such as the penicillins. The
existence of silver salts of p-amino-benzene sulfonamides and their
chemotherapeutic activity are also known, see U.S. Pat. No.
2,422,688. This patent discloses the preparation of compounds such
as silver sulfathiazole, silver sulfanilamide, silver sulfadiazine
and silver sulfapyridine. The disclosures of this patent are herein
incorporated and made part of this disclosure.
In the publication entitled "The Sciences", published by The New
York Academy of Sciences, Vol. VI, No. 9, February, 1967, pages
1-5, two treatments for thermal burns in humans are described. One
treatment involves the application of 0.5% silver nitrate solution.
This treatment, although effective, tends to produce
difficult-to-control fluid and electrolyte alterations in many
patients during treatment. It appears that the hypotonic silver
nitrate solution during treatment causes loss of sodium, potassium
and chloride from the body fluids. For example, silver nitrate
reacts with the chloride in body fluids to form the insoluble
silver chloride, thereby removing chloride from the body. The other
treatment, so-called Sulfamylon burn therapy involves the
application of an ointment containing Sulfamylon mafenide
(.alpha.-amino-p-toluenesulfonamide) acetate manufactured by
Winthrop Laboratories usually in a cream base. In this therapy the
Sulfamylon is applied directly to the burned areas of the patient.
One disadvantage of the Sulfamylon burn therapy is the fact that
Sulfamylon is an inhibitor of carbonic anhydrase and has resulted
in respiratory acidosis and other electrolyte alterations in the
patients undergoing treatment. Another disadvantage of the
Sulfamylon burn therapy is the severe burning pain experienced when
this material is applied to burned surfaces.
It is an object of this invention to provide a burn therapy which
provides the advantages of the above-described silver nitrate and
Sulfamylon burn therapy without their attendant disadvantages.
It is another object of this invention to provide anti-bacterial
compositions useful in burn therapy.
Still another object of this invention is to provide a method of
combatting and/or preventing infection in man and animals.
Yet another object of this invention is to provide a method of
treating burns.
How these and other objects of this invention are attained will
become apparent in the light of the accompanying disclosure made
with reference to the accompanying drawings, wherein FIGS. 1 and 2
graphically illustrate the efficacy and the advantages obtainable
in the practice of this invention, particularly when the special
anti-bacterial agents or compositions described herein are employed
in burn therapy.
Silver sulfadiazine and silver sulfadiazine-containing compositions
of materials, particularly silver sulfadiazine dispersed in a
water-dispersible hydrophilic carrier or ointment have been found
to be especially useful in burn therapy. Broadly, silver
sulfadiazine when employed in the treatment of infections in man
and animals exhibits anti-bacterial properties, antifungal
properties and anti-protozoal properties, e.g. useful in the
treatment of trichomonas vaginitis and also exhibits spermicidal
activity.
Silver sulfadiazine is stable, insoluble in water, alcohol and
ether and does not appear to stain or darken like other silver
salts, such as silver nitrate. Silver sulfadiazine, when exposed to
body fluids, such as when employed in burn therapy, appears to
yield the combined properties of oligodynamic action of silver in
addition to the advantages of an anti-bacterial agent. For example,
when silver sulfadiazine is applied in an ointment to burn wounds,
the silver sulfadiazine presents the advantages of silver and an
anti-bacterial agent without the use of hypotonic solutions and
without withdrawing body electrolytes. The silver sulfadiazine
appears to react only gradually with the body fluids when used in
burn therapy with the result that silver sulfadiazine when employed
in burn therapy evidences a sustained active, effective
concentration for as long as 24-72 hours after a single
application. In contrast, a water-soluble, anti-bacterial agent,
such as sodium sulfadiazine, would be used up rapidly and none
would be left after a few days. Silver sulfadiazine when used in
burn therapy, i.e. when applied to and/or exposed to body fluids,
also appears to react with organic sulfhydryl groups or compounds
in contact therewith.
Silver sulfadiazine is prepared by reacting an aqueous solution of
a water-soluble silver salt, such as silver nitrate, with an
aqueous solution of a water-soluble sulfadiazine, such as sodium
sulfadiazine. For example, a solution containing 0.1 mol of silver
nitrate, such as a 10 percent by weight aqueous silver nitrate
solution, is reacted by pouring the silver nitrate solution into a
0.1 mol solution of sodium sulfadiazine. Upon the addition of the
silver nitrate solution immediate reaction takes place and silver
sulfadiazine is precipitated. Upon further addition and stirring a
viscous emulsion having the consistency of whipped cream is formed.
Aliquots of the suspension are centrifuged or filtered and the
supernatant liquid or filtrate tested for excess silver nitrate by
addition of sodium chloride or for excess sulfadiazine by adding a
drop or two of dilute aqueous silver nitrate solution. In the
preparation of silver sulfadiazine in accordance with this
invention an excess of sulfadiazine, such as sodium sulfadiazine,
may be employed.
When the precipitation of the silver sulfadiazine is complete the
silver sulfadiazine is recovered, such as by filtration or
centrifugation, and washed, preferably with distilled or deionized
water. Desirably, the first wash water contains about 0.01%
HNO.sub.3 in order to insure removal of excess silver. Following
water washing the silver sulfadiazine is washed with water and
ether and then dried. The resulting produced solver sulfadiazine is
a dry white powder.
When the silver sulfadiazine is employed in burn therapy in
accodance with one embodiment of the practice of this invention it
appears that the silver sulfadiazine penetrates necrotic skin and
burned infected tissue. Sizeable amounts appear to enter the blood
as demonstrated by the observed level of sulfonamide (sulfadiazine)
in the blood and its excretion in the urine. However, when silver
sulfadiazine is used in burn therapy the amount of sulfonamide
(sulfadiazine) which is absorbed by the body, even in the treatment
of a very extensive burn, is well below the 4-10 grams daily used
in conventional systemic sulfonamide therapy and the sulfonamide
levels in the blood and urine are much lower than those observed in
systemic sulfonamide therapy.
An amount of silver sulfadiazine upwards of 0.0001% by weight in a
suitable carrier, e.g. in an aqueous suspension is effective to
inhibit the growth of a wide variety of gram positive and gram
negative bacteria, as well as Candida. When silver sulfadiazine is
employed in burn therapy it is especially useful when employed in
an effective anti-bacterial amount dispersed in a water-dispersible
hydrophilic carrier. An amount of silver sulfadiazine upwards of
about 0.1-0.2% by weight, such as an amount in the range
0.5-10.0percent by weight, e.g., 1.0, 2.0, 3.0, 5.0 and 7.5percent
by weight, dispersed in a water-dispersible hydrophilic carrier
provides effective results.
In the preparation of a silver sulfadiazine-containing composition,
such as silver sulfadiazine dispersed in a hydrophilic ointment or
carrier, suitable compositions are prepared by merely incorporating
or homogeneously admixing finely divided silver sulfadiazine with
the hydrophilic carrier or base or ointment. One technique in
accordance with this invention for incorporating silver
sulfadiazine in a hydrophilic ointment, such as an oil-in-water
emulsion, involves reacting equimolar aqueous solutions of silver
nitrate and sulfadiazine, such as sodium sulfadiazine, to yield an
aqueous reaction admixture containing silver sulfadiazine. The
resulting aqueous reaction admixture, a white paste, is then mixed
or blended with the candidate hydrophilic ointment, such as the
oil-in-water emulsion, to yield a composition comprising silver
sulfadiazine dispersed in the ointment. In the preparation of such
a product it was observed that when equimolar aqueous solutions of
silver nitrate and sodium sulfadiazine are reacted the resulting
aqueous reaction admixture first becomes hard and gradually becomes
soft and fluffy. This fluffy material (silver
sulfadiazine-containing aqueous reaction admixture) is the
incorporated in the candidate hydrophilic carrier. When, however,
the aqueous silver sulfadiazine reaction mixture is incorporated in
the candidate hydrophilic ointment, such as an oil-in-water
emulsion, the resulting composition develops a softness similar to
that of crudled sour cream or yogurt and exhibits very little
resistance to flow and can be applied to burned tissue with very
little effort and pressure.
Compositions in accordance with this invention containing silver
sulfadiazine dispersed in a water-dispersible hydrophilic carrier
or ointment, e.g. a hydrophilic oil-in-water emulsion, are usually
characterized by the following components and percentages by
weights set forth in accompanying Table I:
TABLE I
Component % By Weight Petrolatum 0-25 Water-insoluble C.sub.16
-C.sub.22 fatty alcohol 7-45 Emollient 0-15 Emulsifying Agents,
preferably non-ionic 4-16 Humectant 7-40 Silver sulfadiazine 0.1-10
Preservative 0-0.3 Deionized or Distilled Water q.s. 100
The fatty alcohols, stearyl alcohol, cetyl alcohol, lauryl alcohol
and myristyl alcohol are useful in the preparation of silver
sulfadiazine compositions in accordance with this invention. These
preferential oil-soluble fatty alcohols act as a stiffener in the
resulting composition. As the emollient, isopropyl myristate,
lanolin, lanolin derivatives, isopropyl palmitate, isopropyl
stearate and the corresponding sebacates and other known emollients
are suitable. As the emulsifying agent sorbitan monooleate, such as
an amount in the range 0.5-4 percent by weight, and polyoxyl 40
stearate in an amount in the range 7-12 percent by weight, both
non-ionic emulsifying agents are satisfactory. A suitable humectant
would be propylene glycol, sorbitol or glycerin and mixtures
thereof, all being water-soluble compounds. A suitable preservative
would be any of the useful conventional water-soluble preservatives
which exhibit anti-microbial activity, such as sorbic acid, benzoic
methylparaben and propylparaben and mixtures thereof.
In the formulation of a silver sulfadiazine composition having the
composition set forth in Table I hereinabove, as the amount of
aqueous phase is increased the solid content, i.e. the
water-immiscible or water-insoluble components, e.g. fatty alcohol,
such as stearyl alcohol, and/or petrolatum, must also be increased
relatively to help stiffen the composition. The preservative e.g.
methylparaben, is employed in the formulation only as a
preservative for the overall composition and, as indicated,
methylparaben was found to be a satisfactory preservative.
Methylparaben, as indicated, however, may also be used in
combination with propylparaben.
Accordingly, compositions useful in the practices of this invention
would include compositions comprising 0-25 percent by weight
petrolatum, 7-45 percent by weight stearyl alcohol, 0-15 percent by
weight isopropyl myristate, 5-20 percent by weight of an
emulsifying agent, 7-40 percent by weight propylene glycol, 0.5-10
percent by weight silver sulfadiazine, the remainder being water,
as required to bring the total percentages to 100 percent. Other
compositions useful would include compositions consisting
essentially of 0.5-2 percent by weight silver sulfadiazine 7-8
percent by weight propylene glycol, 38-44 percent by weight water,
14-18 percent by weight petrolatum, 14-18 percent by weight stearyl
alcohol, 5-8 percent by weight isopropyl myristate, 0.5-2 percent
by weight sorbitan monooleate and 6-10 percent by weight polyoxyl
40 stearate. Another composition useful in the practice of this
invention would include the composition consisting essentially of
0-25 percent by weight petrolatum, 7-45 percent by weight of an
aliphatic fatty alcohol having a carbon atom content in the range
C.sub.16 -C.sub.22, 0-15 percent by weight of an emollient, 7-16
percent by weight of an emulsifying agent, 7-14 percent by weight
of a humectant and 0.2-10 percent by weight silver
sulfadiazine.
The following examples are illustrative of a water-washable or
water-dispersible hydrophilic ointment in accordance with this
invention.
EXAMPLE NO. 1
Group Component % By Weight White Petrolatum 16.43 Stearyl Alcohol
16.43 A Isopropyl Myristate 6.57 Sorbitan Monooleate 1.10 Polyoxyl
40 Stearate 8.76 C Propylene Glycol 7.67 Silver Sulfadiazine 1.00 B
Methylparaben 0.30 Deionized water (q.s.) 41.74
The ingredients of Group A are weighed into a stainless steel tank,
heated sufficiently to melt and then agitated. The Group A
ingredients are heated to 75.degree.C. and agitation is continued
until all of the Group A ingredients are melted and mixed.
Group B ingredients are heated to 75.degree.C. in a separate tank
and the water is stirred until all the methylparaben is dissolved.
The water phase (Group B ingredients) at 75.degree.C. is added to
the oil phase (Group A ingredients) at 65.degree.-73.degree.C. with
stirring. Stirring is continued until the resulting cream reaches
60.degree.-65.degree.C. Group C ingredients are prepared by placing
about five-sixths of the required amount of propylene glycol in a
tank, stirring rapidly and adding the silver sulfadiazine. Stirring
is continued until all of the silver sulfadiazine is well
suspended. This is then added to the cream, the remaining one-sixth
of propylene glycol is used to wash out the transfer container, and
the cream is stirred until uniform. It is filled into containers at
48.degree.-50.degree.C. The quantities of the ingredients can be
varied widely as is shown by the ingredient ranges to produce an
acceptable cream formulation. Temperatures can also be varied
within reason without any substantial processing difficulty.
EXAMPLE NO. 2
Effective silver sulfadiazine-containing compositions in accordance
with this invention having the formulation set forth in Example No.
1 hereinabove are prepared save propylene glycol is replaced by
sorbitol and glycerin.
EXAMPLE NO. 3
Effective silver sulfadiazine-containing compositions in accordance
with this invention having the formulation of Example No. 1 are
prepared save a waxy granular form of polyoxyl 40 stearate as sold
by Atlas Chemical Co. under the tradename Myrj 52S is employed.
EXAMPLE NO. 4
Effective silver sulfadiazine-containing compositions in accordance
with this invention having the formulation as set forth in Example
No. 1 are prepared wherein the petrolatum and stearyl alcohol each
are present in an amount of 25 percent by weight with a
corresponding percentage reduction in the water content.
EXAMPLE NO. 5
Effective silver sulfadiazine-containing compositions in accordance
with this invention in accordance with the formulation of Example
No. 1 are prepared without any petrolatum but having a stearyl
alcohol content of 45 percent and an isopropyl myristate content of
about 15 percent so as to provide a rather stiff cream-like,
water-dispersible hydrophilic composition.
EXAMPLE NO. 6
Effective silver sulfadiazine-containing compositions in accordance
with this invention are prepared with the formulation of Example
No. 1 with the petrolatum and stearyl alcohol each in an amount of
10 percent by weight and with the isopropyl myristate in an amount
of about 6 percent by weight, the percentage of water being
adjusted accordingly.
EXAMPLE NO. 7
Effective, very soft cream-like silver sulfadiazine-containing
compositions in accordance with this invention are prepared
according to the formulation of Example No.1 without isopropyl
myristate or petrolatum but including 25 percent by weight stearyl
alcohol.
EXAMPLE NO. 8
Effective silver sulfadiazine-containing composition in accordance
with this invention are prepared with the formulation of Example
No. 1 save cetyl alcohol is used in place of stearyl alcohol.
In the preparation of the silver sulfadiazine-containing
compositions in accordance with this invention wherein the silver
sulfadiazine is dispersed in a water-dispersible, hydrophilic
ointment or carrier, such as a water-dispersible, oil-in-water
emulsion, various techniques may be employed. The technique
described hereinabove in connection with Example No. 1 may be
employed or the previously described technique wherein an aqueous
reaction mixture containing silver sulfadiazine is directly
incorporated in a hydrophilic carrier may also be employed.
If desired, dry, finely divided silver sulfadiazine, such as
micronized silver sulfadiazine wherein about 95 percent of the
silver sulfadiazine particles having a particle size below 100
microns, may be added or otherwise homogeneously incorporated in
the desired water-dispersible, hydrophilic ointment to provide the
silver sulfadiazine compositions. Finely divided silver
sulfadiazine having a particle size, smaller or larger, than the
aforementioned particle size, is useful in the practice of this
invention. For example, silver sulfadiazine having the following
particle size analyses are usefully employed in the practice of
this invention for the preparation of effective silver
sulfadiazine-containing compositions:
Silver Sulfadiazine Batch No. 1 -- particle size distribution 90%
by weight between 1.2-28.6 microns and 70-75 percent by weight
below 10 microns, particle size analysis being determined by the
Coulter Counter.
Silver Sulfadiazine Batch No. 2 -- 96 percent by weight particles
smaller than 44 microns and 100 percent by weight smaller than 53
microns.
Silver Sulfadiazine Batch No. 3 -- having the particle size
analysis, 2 percent by weight larger than 840 microns, 20 percent
through a 20 on a 30 mesh screen (590-840 microns), 14 percent
through a 30 on a 40 mesh screen (420-590 microns) and 65 percent
through a 40 mesh screen (less than 420 microns).
As indicated hereinabove, the composition of the water-dispersible
hydrophilic ointment base or carrier for the silver sulfadiazine
may vary. Numerous suitable commercially available hydrophilic or
water-dispersible removable ointments or carriers are available.
For example, the following hydrophilic or oil-in-water emulsion
bases are available and suitable in the preparation of silver
sulfadiazine-containing compositions in accordance with this
invention, Neobase manufactured by Burroughs-Wellcome, Unibase
manufactured by Parke-Davis, Emulsion Base manufactured by Almay,
Dermabase manufactured by Marcelle, Cetaphil manufactured by Texas
Pharmacel, Multibase manufactured by Ar-Ex, Vanibase manufactured
by Warren-Teed and Solucream manufactured by Lascoff. In general,
hydrophilic bases, such as hydrophilic bases of the oil-in-water
emulsion type are characterized by the ease which they may be
removed from the skin by washing with water.
Useful in the preparation of silver sulfadiazine-containing
compositions in accordance with this invention is the
water-dispersible hydrophilic oil-in-water emulsion ointment sold
under the tradename Neobase. Neobase is a semi-solid, oil-in-water
emulsion base which is water-miscible, slightly acid (1:10 aqueous
mixture has a pH 5.8 to 6.2) and contains a high proportion of
water combined with polyhydric alcohol esters, propylene glycol, a
small quantity of liquid petrolatum, wetting agents and a
perservative. When an ointment containing silver-sulfadiazine
dispersed in a water-washable or water-dispersible hydrophilic
carrier, as exemplified by an ointment comprising 1 percent by
weight silver sulfadiazine dispersed in a hydrophilic carrier, e.g.
Neobase, is applied to a very tender area, such as a raw wound or
an opened burn surface or granulation there is no pain felt
whatsoever. Rather, the application of the silver sulfadiazine
ointment in accordance with this invention is pleasurable and feels
good to the patient and appears to have anesthetic properties. This
pleasurable and good feeling is in contrast to the sharp pain
usually felt when Sulfamylon ointment or other such medicaments are
applied.
By way of explanation, the soothing effect experienced when a
silver sulfadiazine-containing ointment is applied to a raw wound
or an open burn may be due to the fact that the silver sulfadiazine
is insoluble and is in suspension and not in solution and does not
appear to dissolve in the body fluids except only gradually. In
contrast, normally soluble substances when applied to a raw wound
are irritating, probably due to the hypertonicity due to the high
concentration of the substance which occurs when a soluble
substance is dissolved immediately in a body fluid. The
insolubility of silver sulfadiazine which might appear first to be
a disadvantage thus appears to be an advantage when topically
applied to a burned surface.
When patients having large burns are dressed with a silver
sulfadiazine-containing hydrophilic ointment in accordance with
this invention, such as an ointment or dressing made up of Neobase
and containing about 1-3 percent by weight sliver sulfadiazine, no
morphine or other pain relieving drug need be given prior to
dressing changes. This is in marked contrast with other forms of
local therapy. Gauze bandages impregnated with a silver
sulfadiazine ointment as described herein do not adhere to burned
skin surfaces even after two or three days. In contrast, Vaseline
coated and other bandages when applied to burned skin surfaces
become adherent and it is often necessary to forcefully pull the
gauge bandages away from the wound. This causes severe pain and for
this reason morphine is usually given to the patient in such
instances prior to dressing change. In contrast, dressing coated
with or impregnated with a silver sulfadiazine-containing ointment
in accordance with this invention, such as a bandage impregnated
with silver sulfadiazine dispersed in a hydrophilic ointment, are
painless when removed. Indeed, a silver sulfadiazine-containing
ointment in accordance with this invention because this application
is painless and even pleasurable can readily and generously be
applied and rubbing the ointment over the raw tissue even in the
instance of large burns.
In vitro tests demonstrating the efficacy of the silver
anti-bacterial agents of this invention were carried out. In these
tests 0.5 cm square pieces of filter paper were soaked in
suspensions of the silver sulfadiazine so that each piece of filter
paper contained approximately 0.04 mg. of the silver sulfadiazine.
The test squares were placed on plain nutrient agar inoculated with
various strains of Pseudomonas aeruginosa isolated from hospital
patients. Of the 13 strains of Pseudomonas aeruginos tested all
were inhibited.
In vivo tests were also carried out to demonstrate the
effectiveness of silver sulfadiazine in burn therapy. In these
tests scalded mice contaminated with Pseudomonas aeruginosa were
employed. The scaled mice were contaminated by dipping their tails
in a solution of an overnight broth culture of Pseudomonas
aeruginosa. Local therapy was initiated several hours later by
either immersing the mice into a 0.5 percent by weight solution of
silver nitrate or by buttering 10 percent by weight Sulfamylon
hydrochloride ointment or silver sulfadiazine ointment (1 percent
silver sulfadiazine in Neobase) over the hairy bodies and tails.
After a few preliminary trails of more frequent treatment these
experiments were conducted by a once-daily application of the
ointment or dipping into the solution or sus-pension. The mice were
kept in cages with wood shavings which were changed daily. After
death of the mice, cultures of the heart blood were made in some
instances. These tests were positive to Pseudomonas.
Typical experiments after a small burn (tail and both thighs),
about 25-30 percent of the body surface area, and large burns,
approximately 65 percent of the body surface area, are shown in
FIGS. 1 and 2 of the drawings which graphically show the
superiority of compositions in accordance with this invention when
employed in burn therapy. In accompanying Table II in vivo test
results are summarized. ##SPC1##
The superiority of the silver sulfadiazine in terms of increased
and prolonged survival as reported in accompanying Table II and
illustrated in FIGS. 1 and 2 is obvious
After the burn and with the silver sulfadiazine treatment the
eschar separated in about three weeks and pink, healthy-looking
epithelium appeared. The tissues and fur of the mice treated with
silver nitrate darkened. With respect to the few mice surviving
without any anti-bacterial therapy the separation of the eschar did
not occur within three weeks. In other experiments which were
terminated within three weeks similar evidence of healing appeared.
In two experiments therapy was discontinued after seven days in
one-half of the surviving mice, see FIG. 2 of the drawings. In many
instances, mortality increased suddenly suggesting either
reinfection or persistence of virulent organisms. Daily tubing in
water or saline solution with removal of crusts and nectrotic
tissue as done in man would undoubtedly improve the results and
prevent reinfection. In some experiments the length of viable tail
was measured. The results of these tests are shown in accompanying
Table III:
TABLE III
VIABLE TAIL LENGTHS AT 18 DAYS POST-BURN
Therapy viable tail lengths cm (Averages) Normal Tail (22-24 g
mice) 9.0 Neobase Ointment only .9* AgNO.sub.3 Solution - 0.5% by
wt. 1.9* Sulfamylon Ointment 2.5* Silver Sulfadiazine ointment 3.2
(Burn of lower third of body at 70.degree.C. for 6 sec.) *Average
of few survivors - See Table II
these results only partially reveal the superiority of silver
sulfadiazine. These results demonstrate that post-burn infection
plays a major role in causing considerable loss of skin and muscle
from tails and extremities.
In tests an ointment containing 1 percent by weight silver
sulfadiazine in a water-soluble hydrophilic base, e.g., Neobase,
was found to be soothing and painless, substantially stain free,
i.e., did not stain tissues or linen.
Toxicity of silver sulfadiazine as judged in burned mice treated
with 1 percent by weight silver sulfadiazine suspension or ointment
was not apparent. Absorption was evaluated by excretion of
sulfadiazine in the urine after implanation in the cutaneous
tissues of dogs. Doses of 100 mg. either in 1 percent suspension or
0.5 percent ointment result in levels of less than 10 mg. per 100
ml. of urine daily for three days. These low values are in marked
contrast to the high levels obtained after implantation of the
soluble sodium salts. After application of 300 gm of the 1 percent
by weight silver sulfadiazine ointment to 1 square meter burned
surface in patients the blood levels of sulfadiazine ranged from
2.0 to 3.7 mg % and from 116 to 336 mg% of free sulfadiazine was
excreted in the urine in the succeeding 24 hours. This represents
from 4 to 13 percent of the total amount applied to the burned
surfaces.
Intraperitoneal injection of the suspension of silver sulfadiazine
causes convulsions and death after 0.04 g/kg body weight but no
symptoms appeared and no deaths occurred in 48 hours after 0.01
g/kg body weight in groups of ten mice. These experiments were
conducted in parallel with equimolar solutions of silver nitrate
and the toxicity values were found to be identical. Silver
sulfadiazine is non-toxic when applied topically and this is in
accordance with observations already made with respect to other
topically applied silver compounds.
The results of these tests indicate that burned mice are highly
susceptible to contact infection with Pseudomonas aeruginosa. The
once-daily local application of 0.5% silver nitrate solution or 10
percent by weight Sulfamylon ointment reduced the mortality from 80
percent to approximately 50 percent. In contrast the local
application once-daily of a hydrophilic ointment containing 1
percent by weight of silver sulfadiazine reduced the mortality of
between 5 percent and 20 percent in eight days or longer in
numerous experiments involving approximately 980 mice. In addition,
post-burn destruction of skin and muscle by infection was greatly
diminished in surviving mice treated with the silver sulfadiazine
ointment. These experiments indicate that in burned mice infected
with Pseudomonas aeruginosa silver sulfadiazine is superior to
other agents in terms of overall survival, wound-healing and
absence of toxicity and with no staining of tissues. The use of an
insoluble silver anti-bacterial agent, such as silver sulfadiazine,
to produce anti-bacterial activity in body fluids represents a new
approach in topical chemotherapy.
In accordance with anothe aspect of this invention silver
sulfadiazine may be employed in combination with one or more
therapeutic agents. For example, mixtures of silver sulfadiazine
and antibiotics, including the silver salts thereof, e.g. the
silver penicillins, are useful. Also, in addition to silver
sulfadiazine other agents known to be useful in burn therapy as an
aid in getting rid of dead tissue may be employed in combination
therewith. Also, other materials of specific value in burn therapy
and compatible with silver sulfadiazine may be employed.
Tests have also been carried out on humans and the results are
promising. Tests carried out on human patients suffering from
extensive burns have shown that silver sulfadiazine in a
water-soluble or water-dispersible, hydrophilic ointment base
completely eliminates infection from Pseudomonas aeruginosa and
many other organisms. No pain is experienced upon the application
of the silver sulfadiazine ointment which actually "felt good" when
applied to the burned skin surfaces. The dressings were easily
removed and no sticking to the wound or burned surfaces was
experienced. Good healing of partial thickness (second degree)
burns, which did not require skin grafting, was observed. Also,
growing skin grafts tolerated the applied ointment well and post
graft infections were avoided.
Silver sulfadiazine-containing compositions in accordance with this
invention have been employed extensively in burn therapy. Silver
sulfadiazine has been tested clinically at over 20 burn centers and
on hundreds of patients with serious burns. In these trails the
silver sulfadiazine-containing compositions described hereinabove
have performed very satisfactory and substantially no significant
side effects have been observed.
Although in the practice of this invention emphasis has been placed
in burn therapy on the use of silver sulfadiazine dispersed in a
water-dispersible, hydrophilic ointment, other carriers or modes of
application of the silver sulfadiazine may be employed. For
example, as may be indicated during therapy the silver sulfadiazine
may be applied as a dispersion in a substantially water-insoluble
hydrophobic carrier, such as Vaseline or petrolatum. The silver
sulfadiazine in burn therapy may also be applied, as might be
indicated under the circumstances, by dusting the silver
sulfadiazine onto the surface, are or site to be treated or by
suspending silver sulfadiazine in a liquid aqueous carrier, such as
water, and applying the resulting suspension. Silver sulfadiazine
may be incorporated in a solid carirer, such as a bandage, either
dispersed in or associated with a hydrophilic ointment or a
substantially water-insoluble (petrolatum) ointment or otherwise
incorporated in the bandage. Aerosol containers for dispensing the
silver sulfadiazine either as a dry or wet spray or foam might also
be employed. Silver sulfadiazine is also useful in other
treatments, such as the treatment of deep-site infections and skin
infections.
As will be apparent to those skilled in the art in the light of the
foregoing disclosure many substitutions, alterations and
modifications are possible in the practice of this invention
without departing from the spirit or scope thereof.
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