COMPOSITION CONTAINING SILVER SULFADIAZINE AND BENZOCAINE FOR USE IN THE TREATMENT OF WOUNDS FOLLOWING LASER SURGERY

Abstract: Topical compositions containing benzocaine and silver sulfadiazine have been found effective for use in the treatment of wounds and the relief of pain. Said wounds include burn wounds caused by, for example, the removal of skin lesions such as anogenital warts, carcinoma precursor lesions, and so on, by either laser surgery or electrosurgery.

Description: COMPOSITION CONTAINING SILVER SULFADIAZINE AND BENZOCAINE FOR USE IN THE TREATMENT OF WOUNDS FOLLOWING LASER SURGERY FIELD OF THE INVENTION This invention relates to novel topical compositions containing as active ingredients silver sulfadiazine and benzocaine for use in the treatment of wounds and the relief of pain. BACKGROUND OF THE INVENTION Silver sulfadiazine in an emollient cream base is the treatment of choice in most brrn centers for treating and preventing infections in wour: > . Background information on silver sulfadiazine may be found in United States Patent No. 3,761,590 - Research Corporation, September 27, 1973. Silver sulfadiazine is merchandised in association with the trade marks FLAMAZINE and SILVADENE. Benzocaine was selected because it is representative of some local anesthetics which are poorly soluble in water and consequently too slowly absorbed to be toxic. It can be applied directly to wounds and ulcerated surfaces where it remains localized for long periods of time to produce a sustained anesthetic action (reference Goodman and Gilman's "The Pharmacological Basis of Therapeutics", Seventh Edition, 1985, p.312) . Laser is one of the most effective surgical treatments for removing a great variety of skin lesions. Initially, the cost of the laser unit was a prohibitive factor; however, in recent years lasers became available at lower prices and in many practices their use is time shared. Another disadvantage of laser ablation was the extensive pain that patients experienced following surgical removal of SUBSTITUTE SHEET extensive lesions and those located in high pain intensity areas such as the lower genital skin. An alternative therapeutic modality to laser has been loop electrosurgical excision and fulguration procedure (LEEP) . LEEP uses alternating current in the spectrum of radio frequency of the order of 500 kHZ (kiloHertz) for excising (with loop electrodes) and fulgurating (with ball electrodes) anogenital warts. The major advantage of LEEP over laser ablation (eg. , C02 laser) is the lower cost of the electrosurgical generator ($5,000.00 versus $50,000.00 and up for C02 laser) . LEEP, as is the case with C02 laser ablation, is performed under colposcopy to control depths of tissue destruction and the thermocoagulation injury at treatment sites is similar to that observed after laser ablation. As a result, the overall treatment results, complications, and side effects including discomfort from 2nd degree burns are similar. Our investigations have shown that by combining benzocaine directly with silver sulfadiazine into a cream formulation, we obtain a mode of burn treatment which not only alleviates pain (a fact proven in clinical trials versus FLAMAZINE) but also unexpectedly exhibits enhanced antimicrobial activity. In a preliminary in-vitro study, the antimicrobial activity of the 1% silver sulfadiazine plus 5% benzocaine cream formulation was compared against the same base formulation containing only 1% silver sulfadiazine, the base plus 5% benzocaine, the base alone, and FLAMAZINE (1% silver sulfadiazine) . It is to be noted that burns as defined herein refer to either accidentally or surgically caused burns and include first, second and third degree burns as discussed in the literature. OBJECTS OF THE INVENTION SUBSTITUTE SHEET A general object of the present invention is to provide a composition and a method for the treatment of wounds and the relief of pain involving the use of silver sulfadiazine/benzocaine formulations. A r'jre specific object of the invention is to establish a composition and an effective method of burn therapy involving the use of silver sulfadiazine/benzocaine formulations. It is a further object of the invention to provide anti¬ bacterial compositions particularly designed to be used in burn therapy. Another object of the invention is the providing of a composition and a method for the treatment of wounds and the relief of pain resulting from surgical removal of lesions such as anogenital warts, carcinoma precursors, etc. , by the carbon dioxide laser and electrosurgical excision and fulguration procedure (LEEP) . The method comprises applying topically to the wound surface a novel composition containing as active ingredients silver sulfadiazine and benzocaine. Yet another object is to provide topical cream or lotion formulations containing up to 5% silver sulfadiazine and up to 20% benzocaine for the treatment of wounds and the relief of pain resulting from for example the surgical removal of lesions by carbon dioxide laser, as well as to provide a method of treatment using such formulations that will in all respects be superior to burn therapy treatment using silver sulfadiazine by itself. SUMMARY OF THE INVENTION Thus the present invention, in general, provides a method SUBSTITUTE SHEET for the treatment of wounds and the relief of pain comprising applying topically to the wound surface a composition containing as active ingredients silver sulfadiazine and benzocaine. In accordance with a further general aspect, the present invention provides a composition for use in the treatment of wounds and the relief of pain, wherein said composition contains as active ingredients silver sulfadiazine and benzocaine. In accordance with the present invention, the active ingredients may, for example, be dispersed in an oil-in- water e olient cream emulsion. In accordance with the present invention, the composition may comprise, by weight, from about 1% to about 5% silver sulfadiazine and from about 5% to about 20% benzocaine; the composition may, in particular, contain from about 0.9% to about 1.1% silver sulfadiazine and from about 4.5% to about 5% benzocaine. In accordance with the present invention, a cream emulsion may include an emollient, a humectant and an emulsifier. The applicant sponsored a study to determine the pain- relieving effect of a cream containing 1.0% silver sulfadiazine and 5.0% benzocaine (to be marketed as SILCAINE) by comparison with a cream containing 1.0% silver sulfadiazine (available as FLAMAZINE) when applied to anogenital skin treated by both carbon dioxide laser surgery and electrosurgical excision and fulguration procedure (LEEP) . In this study, in each patient half of the lesional area was treated with C02 laser surgery and the other half with loop electrosurgical excision procedure. In this way, we SUBSTITUTE SHEET could compare the pain-relieving effect of Silcaine vs Flamazine on both laser treated and LEEP-ed regions in the same patient. Data on repair as well as post-treatment recurrences have also been obtained. The study was conducted over an eight month period as a double-blind clinical trial with emphasis on the pain- relieving effect of Silcaine vs Flamazine. The investigators were Alex Ferenczy, M.D., Professor of Pathology and Obstetrics & Gynecology, The Sir Mortimer B. Davis Jewish General Hospital and McGill University, Montreal, Quebec; and Jocelyne Arseneau, M.D., Assistant Professor of Pathology, Pathology Institute, Royal Victoria Hospital and McGill University, Montreal, Quebec. The carbon dioxide laser and LEEP are among the most important and effective tools in a clinician's armamentarium for the removal of genital condylomata and carcinoma precursor lesions. Both genital warts and cancer precursors have reached epidemic proportions in current medical practice. Basic tissue interactions and technical aspects of laser treatment and LEEP have been published. The areas to undergo either laser treatment or LEEP are visualized at high magnification with the aid of a colposcope. The appropriate power to be used in a given case is set. When laser is used, the carbon dioxide laser light and the He-Ne guiding beam are aligned and the laser beam is moved horizontally and vertically across the treatment field. Vaporization of tissue is achieved because carbon dioxide laser energy is selectively absorbed by intracellular water; the over 100° heat generated by amplification of carbon dioxide photons instantaneously boils intracellular water, produces steam and results in cellular explosion by vaporization. The laser crater is cleaned from ashes (produced by thermo-coagulated water-free proteins in the BSTITUTE SHEET cells) and of thermo-coagulated tissue debris. The depth of lesional tissue vaporized is controlled by direct colposcopic visualization of the crater produced. When using LEEP, appropriately chosen loop electrodes serve respectively to excise and fulgurate previously anesthetized anogenital condylomata. The cutting and coagulation power outputs are 36 and 50 watts respectively. The heat generated by rapid sparks of alternating current is absorbed by intracellular water as is laser generated energy, and the resulting steam explodes cells when cutting and superficially thermocoagulates them when fulguration is applied. The depths of excision and fulguration is controlled under the guidance of high magnification colposcopy and the escar produced after fulguration is wiped off with a wet cotton- tipped applicator. In general, the depth of laser and LEEP craters ranges between 1mm and 2mm and extends into the papillary to superficial reticular dermis of the external anogenital skin. As such, a second degree surgical and a third degree histologic burn is produced. Patients who undergo LEEP and laser treatment for vulvar, perianal or penile lesions under general anesthesia are discharged from the hospital (unless otherwise indicated) four hours after the procedure. Those lased under local anesthesia are discharged from the clinic immediately upon completion of the procedure. Patients are instructed to follow a self-care program of after treatment. In general, this after program consists of taking 15 minute sitz baths with ocean salt added, twice a day for a period of 10 to 30 days. After each bath, the area is gently blow dried with the aid of an electric hair dryer followed by the application of silver sulfadiazine cream. The side effects of both laser therapy and LEEP are almost entirely associated with pain due to nerve ending SUBSTITUTE SHEET stimulation during periods of repair of thermo-coagulated wounds. The genital region displaying the greatest sensitivity is the anus, followed closely by the vulva and penis. In preliminary evaluations of the applicant's cream preparation containing 1% silver sulfadiazine and 5% benzocaine, it was observed that there were many fewer telephone calls complaining about pain than were encountered with FLAMAZINE therapy alone. In follow-up observations and discussions with patients, it was found that the wound healing process with the preparation according to the invention was similar to that of FLAMAZINE but of greater significance was the fact that pain was not a dominant issue in the days following either laser therapy or LEEP. In the foregoing discussion we have referred to formulations of our novel product as consisting of active ingredients in the specific amounts of 5% benzocaine and 1% silver sulfadiazine. However, these active ingredients may, for example, be utilized in the following ranges: Benzocaine - up to 20% Silver sulfadiazine - up to 5% DETAILED DESCRIPTION OF THE INVENTION Example 1 A preferred formulation is as follows: Ingredients Quantity (% by weight) 1. Stearyl alcohol 6.0% 2. Heavy mineral oil 13.0% 3. Benzocaine 5.0% SUBSTiTUTE SHEET 4. Glyceryl stearate + PEG 100 distearate 3.0% 5. Polysorbate 60 3.2% 6. Polysorbate 80 2.8% 7. Purified water 61.0% 8. Glycerine 5.0% 9. Silver sulfadiazine 1.0% Mineral oil is an emollient and may be exchanged for other suitable emollients such as isopropyl myristate, pal itate or stearate; lanolin or lanolin derivatives; petrolatum, etc. Glycerine is a humectant, but others such as propylene glycol or sorbitol may also be used. Polysorbates and glyceryl stearate + PEG 100 distearate are emulsifiers but numerous others may be substituted. Stearyl alcohol is an emulsion stabilizer and thickener but others such as cetyl alcohol, stearic acid, xanthan gum, carbomers, cellulose gums, etc. can be also used in such formulations. Any suitable base cream or lotion could be used such as water-in-oil emulsions. Those described above are creams and of an oil-in-water type. The foregoing formulation has provided an unexpected bonus in that the antimicrobial property of the silver sulfadiazine plus benzocaine combination displays slightly enhanced antimicrobial properties to that of Flamazine. The results of the preliminary study and a more recent study involving clinical strain micro-organisms are tabulated below. The physical stability of the above formulation stored in 50ml amber glass jars for 27 months has shown no evidence of deterioration, such as discoloration, and chemical analysis of benzocaine for this same formulation is 5.3% as determined by High Performance Liquid Chromatography SUBSTITUTE SHEET (HPLC) and silver sulfadiazine is 1.02% as determined by a stability-indicating HPLC procedure published in a recent issue (March-April 1990) of United States Pharmacopoea (USP) Forum. As of further interest we include here details of a manufacturing formula, batch size 4000.0 gms, together with a specific manufacturing order, as well as antimicrobial test results. Procedure A. In a suitable stainless steel container equipped with propellor stirring, charge 7. Purified water 2000.0 8. Glycerine 200.0 and heat to 70° C with moderate stirring. B, In a suitable stainless steel container equipped with propellor stirring, charge 1. Lorol C 18 240.0 Gms SUBSTITUTE SHEET 520.0 Gms 200.0 Gms 120.0 Gms 128.0 Gms 100.0 Gms and heat to 70°C with stirring. C. Add STEP B to STEP A with good agitation and continue stirring at 70°C for 20 minutes. D. In a suitable container charge 9. Purified water 240.0 Gms 10. Tween 80 12.0 Gms and stir until completely uniform. E. To STEP D, add with stirring 11. Silver sulfadiazine 40.0 Gms 12. Purified water 200.0 Gms and stir until completely uniform. F. Cool the bath to 45°C and with continuous stirring add STEP E and stir for 20 minutes. G. Cool the bath to 25°C with stirring, remove the stirring equipment, and cover. Antimicrobial Study: This study was conducted on various silver sulfadiazine and benzocaine formulations to determine their relative antimicrobial activities. The antimicrobial method was a variation of agar diffusion methods published by Nathan et al in Burns, volume 4, pages 177-187, 1978 and Hart et al in Journal of Applied Bacteriology, volume 87, pages 317- 327, 1989. In this method, large Mueller Hinton agar plates, 150mm in diameter are used. Evenly spaced 7mm wells are cut in the agar using sterile stainless steel SUBSTITUTE SHEET cork borers and the resulting plugs removed by suction. The cream formulations are introduced into the wells using sterile syringes with 18 gauge stainless steel needles. The exact amount of formulation delivered into the well is measured by the differences in weights before and after delivery of the formulation. Test tubes containing 7 milliliters of the same agar is melted and cooled to 45°c A freshly prepared bacterial suspension is then admixed with the molten medium and poured onto the previously prepared plate containing the formulation to be tested. The micro-organisms tested were Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli. The holes are completely filled with agar and the overlay evenly distributed. After solidification, the plates were inverted and incubated at 37°C for 24 hours. Clear zones around test wells was evidence that the formulation was active against the bacteria being evaluated while a hazy appearance around the well was indicative of bacteriostatic action. The diameters of the zones of inhibition reflected the degree of antimicrobial activity. Formulations: B D SUBSTITUTE SHEET 7 . 0 8 . 0 8 . 0 The zones of inhibition values (mm) above represent single determinations. This study was repeated using the 1% silver sulfadiazine + 5% benzocaine and Flamazine formulations, twelve millimeter diameter wells instead of seven, and an average of " 125mg formulation per well. In addition, the micro-organisms used were obtained from American Type Culture Collection (ATCC) as well as from strains isolated and characterized from patients in clinical burn centers. The values below represent the average values of six determinations. The results demonstrate the enhancement effect of benzocaine on antimicrobial activity of silver sulfadiazine particularly against E.coli, Enterobacter cloacae, Listeria monocytogenes and MIcrococcus SP. ANTIMICROBIAL ACTIVITY OF SILCAINE VERSUS FLAMAZINE Zones of Inhibition, mm (mg/well) Micro-organism Silcaine Flamazine Staphylococcus epidermidis 13.0(120) 12.9(120) (ATCC 12228) Pseudomonas Aeruginosa 14.3(130) 14.4(120) (ATCC 27853) Escherichia coli 14.2(127) 13.3 (113) (ATCC 25922) Enterobacter cloacae 13.1(120)** SUBSTITUTE SHEET 11.5(113)** (ATCC 13047) Pseudomonas aeruginosa 13.5(123) 13.4(117) (ATCC 35422) Listeria monocytogenes 14.0(125) 13.4(117) (clinical 0396) Escherichia coli 13.7(130) 13.4(117) (clinical) Staphylococcus aureus 13.3(120)** 13.5(120)** (clinical) Micrococcus SP 19.4(123) 18.4(123) (clinical) **Hazy Zones The results demonstrate the enhancement effect of benzocaine on the antimicrobial activity of silver sulfadiazine, especially against E.coli, Enterobacter, Listeria and Micrococcus micro-organisms. Persons skilled in the art will realize that the invention as described may be modified and substituted within reasonable limits without department from its scope or intent. SUBSTITUTE SHEET

Claims: CLAIMS The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: 1. A method for the treatment of wounds and the relief of pain comprising applying topically to the wound surface a composition containing as active ingredients silver sulfadiazine and benzocaine. 2. A method of claim 1, wherein said wound results from a burn. 3. A method of claim 1, wherein said wound results from accidental exposure to heat which has caused burns or thermal damage of biologically live tissue. 4. A method of claim 1, wherein said wound results from the surgical removal of skin lesions by laser therapy or electrosurgery. 5. The method of claim 1, wherein said wound results from the surgical removal of anogenital lesions by laser therapy or electrosurgery. 6. The method of claim 1, wherein said wound results from the surgical removal of carcinoma precursors by laser therapy or electrosurgery. 7. The method of claim 1, wherein the active ingredients are dispersed in an oil-in-water emollient cream emulsion. 8. The method of claim 7, wherein the composition contains from about 1.0% to about 5.0% by weight silver sulfadiazine and from about 5% to about 20% by weight benzocaine. SUBSTITUTE SHEET 9. The method of claim 8, wherein the composition contains from about 1.0% to about 5% by weight silver sulfadiazine and from about 5% to about 20% by weight benzocaine and wherein the cream emulsion includes an emollient, a humectant and an emulsifier. 10. A composition for use in the treatment of wounds and the relief of pain, wherein said composition contains as active ingredients silver sulfadiazine and benzocaine. 11. The composition of claim 10, wherein said wound results from a burn. 12. A composition of claim 10, wherein said wound results from accidental exposure to heat which has caused burns or thermal damage of biologically live tissue. 13. The composition of claim 10, wherein said wound results from the surgical removal of skin lesions by laser therapy or electrosurgery. 14. The composition of claim 10, wherein said wound results from the surgical removal of anogenital lesions by laser therapy or electrosurgery. 15. The composition of claim 10, wherein said wound results from the surgical removal of carcinoma precursors by laser therapy or electrosurgery. 16. The composition of claim 10, wherein the active ingredients are dispersed in an oil-in-water emollient cream emulsion. 17. The composition of claim 16 containing from about 1% to about 5% by weight silver sulfadiazine and from about 5% to about 20% by weight benzocaine. SUBSTITUTE SHEET 18. The composition of claim 16 containing from about 0.90% to about 1.10% by weight silver sulfadiazine and from about 4.5 to about 5.5% by weight benzocaine. 19. The composition of claim 17, wherein the cream emulsion includes an emollient, a humectant and an emulsifier. 20. The composition of claim 19 having the following ingredients in combination: Ingredients Quantity (by weight) 1. Stearyl alcohol 6.0% 2. Heavy mineral oil 13.0% 3. Benzocaine 5.0% 4. Glyceryl stearate + PEG 100 distearate 3.0% 5. Polysorbate 60 3.2% 6. Polysorbate 80 2.8% 7. Purified water 61.0% 8. Glycerine 5.0% 9. Silver sulfadiazine 1.0% SUBSTITUTE SHEET

Inventors: FERENCZY ALEX, SIMMONS DONALD LESLIE, FERENCZY, ALEX, SIMMONS, DONALD, LESLIE
Applicants: FERENCZY ALEX, SIMMONS DONALD LESLIE, FERENCZY, ALEX, SIMMONS, DONALD, LESLIE
Application year: 1991
Main classification: A61K31
IPC codes: A61K31