|Publication number||US3761590 A|
|Publication date||Sep 25, 1973|
|Filing date||May 18, 1970|
|Priority date||May 18, 1970|
|Publication number||US 3761590 A, US 3761590A, US-A-3761590, US3761590 A, US3761590A|
|Original Assignee||Research Corp|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (4), Non-Patent Citations (4), Referenced by (76), Classifications (13), Legal Events (2)|
|External Links: USPTO, USPTO Assignment, Espacenet|
United States Patent [191 Fox, Jr.
1 SILVER SULFADIAZINE USED IN THE TREATMENT OF BURNS  Inventor: Charles L. Fox, Jr., New York, NY.
 Assignee: Research Corporation, New York,
 Filed: May 18, 1970  Appl. No.: 38,031
Related US. Application Data  Continuation-impart of Ser. No. 653,830, July 17,
3,215,600 11/1965 Thompson et a1. 424/228 [451 Sept. 25, 1973 2,838,440 6/1958 Thurmon 424/228 X OTHER PUBLICATIONS 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 ExaminerAlbert T. Meyers Assistant ExaminerLe0nard Schenkman Att0rneyRobert S. Dunham, P. E. Henninger, Lester W. Clark, Gerald W. Griffin, Thomas F. Moran, Howard J. Churchill, R. Bradlee Boal, Christopher C. Dunham and Henry T. Burke  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.
6 Claims, 2 Drawing Figures PATENTEU 39251973 SHEET 1 BF 2 INVENTOR.
R J X m cm L L a J m M M c V1 Q B MN QM QQMQ b MN ATTORNEY SILVER SULFADIAZINE USED IN THE TREATMENT OF BURNS This application is a continuation-in-part of patent application Ser. No. 653,830 filed July 17, I967 now abandoned. The disclosures of application Ser. No. 653,830 are herein incorporated and made part of this disclosure.
Thework on which this application is based was flnanced inpart 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 antibacterial compositions.
Numerous compounds are known to possess antibacterial 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. Vl, 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 (a-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 abovedescribed silver nitrate and Sulfamylon burn therapy without their attendant disadvantages.
It is another object of this invention to provide antibacterial 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 watersoluble, 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, ie 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 ofa water-soluble sulfadiazine, such as sodium sulfadiazine. For example, a soiution 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% l-INO; 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 suifonamide levels in the blood and urine are much lower than those observed in systemic sulfonamide therapy.
An amount of silver sulfadiazine upwards of 0.000 1 by weight in a suitable carrier, e.g. in an aqueous suspension is effective toinhibit the growth of a wide variety of gram positive and gramnegative 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 waterdispersible hydrophilic carrier. An amount of silver sulfadiazine upwards of about 01-02% by weight, such as an amount inthe 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 anoil-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 waterdispersible 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 -C fatty alcohol 7-45 Emollient O-l 5 Emulsifying Agents, preferably non-ionic 4-16 l-lumectant 7-40 Silver sulfadiazine 0.1-l0 Preservative 0-0 .3 Deionized or Distilled Water q.s.
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 1 hereinabove, as the amount of aqueous phase is increased the solid content, i.e. the water-immiscible or waterinsoluble 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 (S -C O-lS per cent by weight of an emollient, 7-l6 percent by weight of an emulsifying agent, 7-14 percent by weight of a humectant and 0.2- percent by weight silver sulfadiazine.
The following examples are illustrative of a waterwashable 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 lsopropyl Myristate 6.57 Sorbitan Monooleate 1.10
- Polyoxyl 40 Stearate 8.76
C Propylene Glycol 7.67 Silver Sulfadiazine 1.00 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 75C. and agitation is continued until all of the Group A ingredients are melted and mixed.
Group B ingredients are heated to 75C. in a separate tank and the water is stirred until all the methylparaben is dissolved. The water phase (Group B ingredients) at 75C. is added to the oil phase (Group A ingredients) at 6573C. with stirring. Stirring is continued until the resulting cream reaches 60 -65C. 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. Thisis 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 48-50C. 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 reasonwithout 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. l 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 preparedsave a waxy granular form of polyoxyl 40 stearate as sold by Atlas Chemical Co. under the tradename Myrj 528 is employed.
EXAMPLE NO. 4
Effective silver sulfadiazine-containing compositions in accordance with this invention having the formulation as set forth in Example No. l are prepared wherein the petrolatum and stearyl alcohol each are present in an amount of 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. l with the petrolatum and stearyl alcohol each in an amount of 10 percent by weight and with the isopropyl myristate inan amount of about 6 percent by weight, the percentage of water being adjusted accordingly.
EXAMPLE NO. 7
Effective, very soft cream-like silver sulfadiazinecontaining 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 sulfadiazinecontaining 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 percent of the silver sulfadiazine particles having a particle size below microns, may be added or otherwise homogeneously incorporated in the desired waterdispersible, 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. l 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 waterdispersible removable ointments or carriers are available. For example, the following hydrophilic or oil-inwater emulsion bases are available and suitable in the preparation of silver sulfadiazine-containing compositions in accordance with this invention, Neobase manu factured 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 case which they may be removed from the skin by washing with water.
Useful in thepreparation of silver sulfadiazinecontaining 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 l 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. I
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 sulfadiazinc 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 percent of the body surface area, are shown in N68. 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.
'mtsir [Mice with 30% burn challenged with tall immersed in P. Aeruginoaa culture 1:1 dilutlon. Local therapy begun 4-6 hours after (llflllttlgt and daily for 8 days or more] Death, days after burn- Total 1n0r- No. tality, Therapy mice 1-3 4-7 8-11 1245 1631 percent Untreated 7'0 31 29 3 90. O 1% by wt. silver sulfadiazinc in Neobase... 84 3 6 6 2 O 20. 2 Sulfadiazine 20 2 14 0 0 AgNO; sol.0.5% by wt 40 4 8 8 5 2 67. 5 Sultamylon 40 1 21 7 l 5 87. 5 Ag-p-amlnobenzoate. 20 10 9 1 Ag-p-nitrobenzoate. 20 6 13 1 100 Ointment (Neobase). 20 4 8 0 0 l 65 NaCl sol.0.9% by wt. 20 2 7 6 .2 1 5. 0
1 Mice scalded but not infected with P. Aerugz'nosa do not succumb. Data were also obtained in similar tests carried out with other organisms, such as Staphylococcus aureus. and these data show that silver sulfadiazinu was effective in reducing the mortality rate.
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 Ill:
TABLE III VIABLE TAIL LENGTI-IS AT 18 DAYS POST-BURN Therapy viable tail lengths cm (Averages) Normal Tail (22-24 g mice) 9 (Burn of lower third of'body at 70C. for 6 sec.)
Average of few survivors See Table II These results only partially reveal the superiority of silver sulfadiazine. These results demonstrate that postburn 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 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 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 chernotherapy.
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 waterdispersible, 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 theburned 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 maybe indicated during therapy the silver sulfadiazine may be applied as a dispersion in a substantially waterinsoluble 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. 7
l. A method of treating burns in man and animal which comprises topically applying an effective antibacterial 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 waterdispersible, hydrophilic carrier.
3. A method in accordance with claim 1 wherein said silver sulfadiazine is applied as a dispersion in a semisoft 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 waterdispersible, 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 I wherein silver sulfadiazine is applied as a dispersion in a semi-soft or cream-like, water-dispersible or water-soluble oil-inwater 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 025 percent by weight petrolatum, 7-45 percent by weight of a long chain fatty alcohol having a carbon atom content in the range G -C 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, sorbitoi 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 aboveidentified components to percent.
i k I t
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|U.S. Classification||514/157, 424/DIG.130, 514/495, 514/938|
|International Classification||A61K47/00, A61K31/635, A61K9/00|
|Cooperative Classification||Y10S424/13, A61K31/635, Y10S514/938, A61K9/0014|
|European Classification||A61K9/00M3, A61K31/635|
|Apr 11, 1988||AS02||Assignment of assignor's interest|
Owner name: RESEARCH CORPORATION
Owner name: RESEARCH CORPORATION TECHNOLOGIES, INC., 6840 EAST
Effective date: 19880405
|Apr 11, 1988||AS||Assignment|
Owner name: RESEARCH CORPORATION TECHNOLOGIES, INC., 6840 EAST
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:RESEARCH CORPORATION;REEL/FRAME:004851/0630
Effective date: 19880405
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:RESEARCH CORPORATION;REEL/FRAME:4851/630
Owner name: RESEARCH CORPORATION TECHNOLOGIES, INC.,ARIZONA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:RESEARCH CORPORATION;REEL/FRAME:004851/0630
Owner name: RESEARCH CORPORATION TECHNOLOGIES, INC., ARIZONA