CA2024220A1 - Composition containing silver sulfadiazine and benzocaine for use in the treatment of wounds following laser surgery - Google Patents
Composition containing silver sulfadiazine and benzocaine for use in the treatment of wounds following laser surgeryInfo
- Publication number
- CA2024220A1 CA2024220A1 CA002024220A CA2024220A CA2024220A1 CA 2024220 A1 CA2024220 A1 CA 2024220A1 CA 002024220 A CA002024220 A CA 002024220A CA 2024220 A CA2024220 A CA 2024220A CA 2024220 A1 CA2024220 A1 CA 2024220A1
- Authority
- CA
- Canada
- Prior art keywords
- composition
- benzocaine
- silver sulfadiazine
- wound results
- electrosurgery
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ELECTRICAL OR ELECTRONICAL MOTOR CONTROL
ABSTRACT
An electrical or electronical motor control composed of a switch and of an electromechanical component, each chosen from a group of different types of respectively switches and electromechanical components. A switch and an electromechanical component together form a control box. In a preferred embodiment, the electromechanical component includes a universal multiple pin connector whereas the switch is provided with a complementary multiple pin connector and the connection between those connectors is such that only the appropriate pins required to produce the appropriate result for a particular switch/ electromechanical component combination are activated.
ABSTRACT
An electrical or electronical motor control composed of a switch and of an electromechanical component, each chosen from a group of different types of respectively switches and electromechanical components. A switch and an electromechanical component together form a control box. In a preferred embodiment, the electromechanical component includes a universal multiple pin connector whereas the switch is provided with a complementary multiple pin connector and the connection between those connectors is such that only the appropriate pins required to produce the appropriate result for a particular switch/ electromechanical component combination are activated.
Description
FIELD OF THE INVENTION
This invention relates to novel topical compositions containing as active ingredients silver sulfadiazine and benzocaine ~or use in the treatment of wounds and the relief of pain.
BACKGROUN~ OF THE INVENTION
Silver sulfadiazine in an emollient cream base is the treatment of choice in most burn centers for treating and preventing infections in wounds. 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 s~luble in water and conse~uently too slowly absorbed to be toxic. It can be applied directly to wounds and ulcerated surfaces where it remains localized for long periods oE time to produce a sustained anesthetic action (reference Goodman and Gilman 1 5 "The Pharmacological Basis of Therapeutics", Seventh Edition, 1985~ po312)~
Laser is one of the most effective surgical treatments for removing a great variety of skin lesions. Initially, the cost o~ 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 extensive lesions and those located in high pain intensity areas such as the lower genital skin.
, -L .
, '' :` ' ,~, , An alternative therapeutic modality to laser has been loopelectrosurgical excision and fulguration procedure (LEEP). LEEP
uses alternating current in ~he spectrum of radio frequPncy of the order of 500 kHZ tkiloHert~) for excising (with loop electrodes) and fulguratiny (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.
1~ 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 de~ree burns as discussed in the literature.
OBJECTS OF THE INVENTION
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 more specific object of the invention is to establish a composition and an efEective 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 therapyO
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 oE 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 a:Ll respects be superior to burn therapy treatment using silver sulfadiazine by itself.
SU~RY OF THE INVENTION
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 sulEadiazine (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 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 V5 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 ef~ective 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 ~ield. Vaporization of tissue is achieved because carbon dioxide laser energy is selectively ''~,, absorbed by intracellular water; the over 1003 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 cells) and of thermo-coagulated tissue debrisO The depth of lesional tissue vaporized is controlled by direct colposcopic visualization of the crater produced.
lo 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 cutt~ng 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 lmm 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 vul~ar, 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 , j" ~., , . ~ ,, 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 stimulation during periods of repair of thermo-coagulated wounds, The genital region displaying the greatest sensitivity is the anus, followed closely ~y the vulva and penis. In preliminary evaluations of the applicant's cream pr~paration containing 1% silver sulfadiazine and 5% benzocaine, it was observed that there were many fewer telephone calls ~omplaining 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, but point out here that those active ingredients may be utilized in the following limited ranges:
Benzocaine - up to 20%
Silver sulfadiazine - up to 5~
DETAILED DESCRIPTION OF THE INVENTION
_xamPle 1 Our preferred formulation is as follows:
r-,..~, ~
:~ ' Inqredients ~uantity 1. Stearyl alcohol 6.0%
This invention relates to novel topical compositions containing as active ingredients silver sulfadiazine and benzocaine ~or use in the treatment of wounds and the relief of pain.
BACKGROUN~ OF THE INVENTION
Silver sulfadiazine in an emollient cream base is the treatment of choice in most burn centers for treating and preventing infections in wounds. 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 s~luble in water and conse~uently too slowly absorbed to be toxic. It can be applied directly to wounds and ulcerated surfaces where it remains localized for long periods oE time to produce a sustained anesthetic action (reference Goodman and Gilman 1 5 "The Pharmacological Basis of Therapeutics", Seventh Edition, 1985~ po312)~
Laser is one of the most effective surgical treatments for removing a great variety of skin lesions. Initially, the cost o~ 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 extensive lesions and those located in high pain intensity areas such as the lower genital skin.
, -L .
, '' :` ' ,~, , An alternative therapeutic modality to laser has been loopelectrosurgical excision and fulguration procedure (LEEP). LEEP
uses alternating current in ~he spectrum of radio frequPncy of the order of 500 kHZ tkiloHert~) for excising (with loop electrodes) and fulguratiny (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.
1~ 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 de~ree burns as discussed in the literature.
OBJECTS OF THE INVENTION
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 more specific object of the invention is to establish a composition and an efEective 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 therapyO
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 oE 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 a:Ll respects be superior to burn therapy treatment using silver sulfadiazine by itself.
SU~RY OF THE INVENTION
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 sulEadiazine (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 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 V5 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 ef~ective 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 ~ield. Vaporization of tissue is achieved because carbon dioxide laser energy is selectively ''~,, absorbed by intracellular water; the over 1003 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 cells) and of thermo-coagulated tissue debrisO The depth of lesional tissue vaporized is controlled by direct colposcopic visualization of the crater produced.
lo 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 cutt~ng 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 lmm 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 vul~ar, 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 , j" ~., , . ~ ,, 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 stimulation during periods of repair of thermo-coagulated wounds, The genital region displaying the greatest sensitivity is the anus, followed closely ~y the vulva and penis. In preliminary evaluations of the applicant's cream pr~paration containing 1% silver sulfadiazine and 5% benzocaine, it was observed that there were many fewer telephone calls ~omplaining 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, but point out here that those active ingredients may be utilized in the following limited ranges:
Benzocaine - up to 20%
Silver sulfadiazine - up to 5~
DETAILED DESCRIPTION OF THE INVENTION
_xamPle 1 Our preferred formulation is as follows:
r-,..~, ~
:~ ' Inqredients ~uantity 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 61n 0%
8. Glycerine 5.0%
9. Silver sulfadiazine 1.0%
Mineral oil is an emollient and may be exchanged ~or other suitable emollients such as isopropyl myristate, palmitate or stearate;
lanolin or lanol:in derivatives; petrolatum, etc. Glycerine is a humectant, buk 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 providPd 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 o~ the preliminary study and a more recent study involving clinical strain micro-organisms are tabulated below.
The physical stability of khe above formulation stored in 50ml : . :
::
:., , ~, ..
, ' ' , ~ ! . ' , . . .
,f 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 Per~ormance Liquid Chromatography ~HPLC~ and silver sulfadiazine is 1.02% as determined by a stability-indicating HPLC procedure published in a recen~ issue (March-April 1990) of United States Pharmacopoea tUSP) 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.
Manufacturinq Formula:~uantity (Gms) In~redients 1. Lorol C 18 240.0 2. Drakeol 35 520.0 3. Benzocaine 200.0 4. Arlacel 165 120.0 5. Tween 60 128.0 6. Tween 80 100.0 7. Purified water2000.0 8. Glycerine 200.0 9. Purified water 240.0 10. Tween 80 12.0 11. Silver sulfadiazine40.0 12. Purified water 200.0 Trade mark Procedure A. In a suitable stainless steel container equipped with propellor stirring, charge 7. Purified water2000.0 8. Glycerine 200.0 and heat to 70 C with moderate stirring.
l ~
, B. In a suitable stainless steel container equipped with propellor stirring, charge 1. Lorol C 18 240.0 Gms 2. Drakeol 35 520.0 Gms 3. Benzocaine 200.G Gms 4. Arlacel 165 120.0 Gms 5. Tween 60 128.0 Gms 6~ Tween 80 lO0.0 Gms and heat to 70C with stirring.
C. Add STEP ~ to STEP A with good agitation and continue stirring at 70C for 20 minutes.
D. In a suitable container charge 9. Purified water 240.0 Gms lO. Tween 80 12.0 Gms and stir until completely uniform.
E. To STEP D, add with stirring 11. Silver sulfadiazine40.0 Gms 12. Purified water 200.0 Gms and stir until completely uniform.
F. Cool the bath to 45C and with continuous stirring add STEP
E and stir for 20 minutes.
G. Cool the bath to 25C 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, pag~s 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 cork borers and the resulting plugs removed by suction. The cream formulations are introduced into the wells using sterile syringes with 1~ gauge stainless steel needles. The exact amount of formulation delivered into the well is measured by the differences in weigh~s before and after delivery of the formulation. Test tubes containing 7 milliliters of the same agar is melted and cooled to 45DC. 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 37C 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:
Inaredients (q/lOOq) A B C D E F
1. Lorol C 13 6.0 5.0 6.0 6.0 6.0 FLAMAZINE
30 2. Drakeol 35 13.013.0 13.013.0 13.0 3. Benzocaine 5.0 5.0 5.0 - -4. Arlacel 165 3.0 3.0 3.0 3.0 3.0 5. Tween 60 3.2 3.2 3.2 3.2 3.2 6. Tween 80 2.8 2.8 2.8 2.8 2.8 .~
7. Purified water 60.7 61.0 62.06~.0 67.0 8. Glycerine 5.0 5.0 5.0 ~.0 5.0 9. Methyl Paraben 0.3 lO.Silver Sulfadiazine 1.0 1.0 - 1.0 A B C D E F
E. Coli 8.0mm8.0mm haze 7.Q O7.0 (93mg)(lllmg~ (119mg) (94mg) S. Aureus 9.5 9.0 0 8.00 8.0 (lOlmg) (96mg) (122mg) (122mg) (8~) Pseudomo 10.5 10.0 0 8.0 09.o (104mg) (103mg)(125mg) (115mg) (97mg) 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 ~125m~ formulation per well. In addition, the micro-organisms used were obtained fxom 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-orqanism 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)** 11.5(113~**
(A~CC 13047) .:
l. ` ~, 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.
--,, ''
Mineral oil is an emollient and may be exchanged ~or other suitable emollients such as isopropyl myristate, palmitate or stearate;
lanolin or lanol:in derivatives; petrolatum, etc. Glycerine is a humectant, buk 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 providPd 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 o~ the preliminary study and a more recent study involving clinical strain micro-organisms are tabulated below.
The physical stability of khe above formulation stored in 50ml : . :
::
:., , ~, ..
, ' ' , ~ ! . ' , . . .
,f 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 Per~ormance Liquid Chromatography ~HPLC~ and silver sulfadiazine is 1.02% as determined by a stability-indicating HPLC procedure published in a recen~ issue (March-April 1990) of United States Pharmacopoea tUSP) 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.
Manufacturinq Formula:~uantity (Gms) In~redients 1. Lorol C 18 240.0 2. Drakeol 35 520.0 3. Benzocaine 200.0 4. Arlacel 165 120.0 5. Tween 60 128.0 6. Tween 80 100.0 7. Purified water2000.0 8. Glycerine 200.0 9. Purified water 240.0 10. Tween 80 12.0 11. Silver sulfadiazine40.0 12. Purified water 200.0 Trade mark Procedure A. In a suitable stainless steel container equipped with propellor stirring, charge 7. Purified water2000.0 8. Glycerine 200.0 and heat to 70 C with moderate stirring.
l ~
, B. In a suitable stainless steel container equipped with propellor stirring, charge 1. Lorol C 18 240.0 Gms 2. Drakeol 35 520.0 Gms 3. Benzocaine 200.G Gms 4. Arlacel 165 120.0 Gms 5. Tween 60 128.0 Gms 6~ Tween 80 lO0.0 Gms and heat to 70C with stirring.
C. Add STEP ~ to STEP A with good agitation and continue stirring at 70C for 20 minutes.
D. In a suitable container charge 9. Purified water 240.0 Gms lO. Tween 80 12.0 Gms and stir until completely uniform.
E. To STEP D, add with stirring 11. Silver sulfadiazine40.0 Gms 12. Purified water 200.0 Gms and stir until completely uniform.
F. Cool the bath to 45C and with continuous stirring add STEP
E and stir for 20 minutes.
G. Cool the bath to 25C 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, pag~s 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 cork borers and the resulting plugs removed by suction. The cream formulations are introduced into the wells using sterile syringes with 1~ gauge stainless steel needles. The exact amount of formulation delivered into the well is measured by the differences in weigh~s before and after delivery of the formulation. Test tubes containing 7 milliliters of the same agar is melted and cooled to 45DC. 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 37C 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:
Inaredients (q/lOOq) A B C D E F
1. Lorol C 13 6.0 5.0 6.0 6.0 6.0 FLAMAZINE
30 2. Drakeol 35 13.013.0 13.013.0 13.0 3. Benzocaine 5.0 5.0 5.0 - -4. Arlacel 165 3.0 3.0 3.0 3.0 3.0 5. Tween 60 3.2 3.2 3.2 3.2 3.2 6. Tween 80 2.8 2.8 2.8 2.8 2.8 .~
7. Purified water 60.7 61.0 62.06~.0 67.0 8. Glycerine 5.0 5.0 5.0 ~.0 5.0 9. Methyl Paraben 0.3 lO.Silver Sulfadiazine 1.0 1.0 - 1.0 A B C D E F
E. Coli 8.0mm8.0mm haze 7.Q O7.0 (93mg)(lllmg~ (119mg) (94mg) S. Aureus 9.5 9.0 0 8.00 8.0 (lOlmg) (96mg) (122mg) (122mg) (8~) Pseudomo 10.5 10.0 0 8.0 09.o (104mg) (103mg)(125mg) (115mg) (97mg) 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 ~125m~ formulation per well. In addition, the micro-organisms used were obtained fxom 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-orqanism 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)** 11.5(113~**
(A~CC 13047) .:
l. ` ~, 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.
--,, ''
Claims (20)
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, 2, 3, 4, 5 or 6, 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 1.0 to 5.0% silver sulfadiazine and from 5 to 20% benzocaine.
9. The method of claim 8, wherein the composition contains from 1.0% to 5% silver sulfadiazine and from 5 to 20% 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, 11, 12, 13, 14 or 15, wherein the active ingredients are dispersed in an oil-in-water emollient cream emulsion.
17. The composition of claim 16 containing from 1% to 5% silver sulfadiazine and from 5% to 20% benzocaine.
18. The composition of claim 16 containing from 0.90 to 1.10%
silver sulfadiazine and from 4.5 to 5.5% benzocaine.
silver sulfadiazine and from 4.5 to 5.5% benzocaine.
19. The composition of claim 17 or 18, 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 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%
Ingredients Quantity 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%
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002024220A CA2024220A1 (en) | 1990-08-29 | 1990-08-29 | Composition containing silver sulfadiazine and benzocaine for use in the treatment of wounds following laser surgery |
| AU84113/91A AU8411391A (en) | 1990-08-29 | 1991-08-28 | Composition containing silver sulfadiazine and benzocaine for use in the treatment of wounds following laser surgery |
| EP91914895A EP0549606A1 (en) | 1990-08-29 | 1991-08-28 | Composition containing silver sulfadiazine and benzocaine for use in the treatment of wounds following laser surgery |
| PCT/CA1991/000307 WO1992004029A1 (en) | 1990-08-29 | 1991-08-28 | Composition containing silver sulfadiazine and benzocaine for use in the treatment of wounds following laser surgery |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002024220A CA2024220A1 (en) | 1990-08-29 | 1990-08-29 | Composition containing silver sulfadiazine and benzocaine for use in the treatment of wounds following laser surgery |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2024220A1 true CA2024220A1 (en) | 1992-03-01 |
Family
ID=4145839
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002024220A Abandoned CA2024220A1 (en) | 1990-08-29 | 1990-08-29 | Composition containing silver sulfadiazine and benzocaine for use in the treatment of wounds following laser surgery |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0549606A1 (en) |
| AU (1) | AU8411391A (en) |
| CA (1) | CA2024220A1 (en) |
| WO (1) | WO1992004029A1 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9981069B2 (en) | 2007-06-20 | 2018-05-29 | The Trustees Of Columbia University In The City Of New York | Bio-film resistant surfaces |
| US9687429B2 (en) | 2007-06-20 | 2017-06-27 | The Trustees Of Columbia University In The City Of New York | Antimicrobial compositions containing low concentrations of botanicals |
| EP2166840B1 (en) | 2007-06-20 | 2017-01-11 | The Trustees of Columbia University in the City of New York | Bio-film resistant surfaces |
| US9511040B2 (en) | 2007-06-20 | 2016-12-06 | The Trustees Of Columbia University In The City Of New York | Skin and surface disinfectant compositions containing botanicals |
| PL2552440T3 (en) * | 2010-03-30 | 2019-04-30 | Helperby Therapeutics Ltd | Novel combination and use |
| WO2013067150A2 (en) | 2011-11-03 | 2013-05-10 | The Trustees Of Columbia University In The City Of New York | Composition with sustained antimicrobial activity |
| US9968101B2 (en) | 2011-11-03 | 2018-05-15 | The Trustees Of Columbia University In The City Of New York | Botanical antimicrobial compositions |
| TW201330856A (en) | 2011-12-06 | 2013-08-01 | Univ Columbia | Broad spectrum natural preservative composition |
| US20160038235A1 (en) * | 2013-04-02 | 2016-02-11 | Leo Laboratories Limited | Ingenol mebutate in combination with laser therapy for the treatment of hyperkeratotic skin lesions |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PH10639A (en) * | 1967-07-17 | 1977-07-22 | Research Corp | Method of treatment and composition containing silver sulfadiazine |
| DE3828044A1 (en) * | 1988-01-29 | 1989-08-10 | Minninger Konrad | SILVER-SULFADIAZIN-CONTAINING MEANS FOR THE LOCAL EXTERNAL THERAPY OF HERPES LABIALIS, HERPES GENITALIS, HERPES CORPORIS, ZOSTERS (HERPES ZOSTER, WINCH POAKS AND EKZEMA HERPETICATUM AND BURNS 11TH AND 111TH DEGREES IN THE FIELD OF HUMAN MEDICINE |
-
1990
- 1990-08-29 CA CA002024220A patent/CA2024220A1/en not_active Abandoned
-
1991
- 1991-08-28 EP EP91914895A patent/EP0549606A1/en not_active Withdrawn
- 1991-08-28 AU AU84113/91A patent/AU8411391A/en not_active Abandoned
- 1991-08-28 WO PCT/CA1991/000307 patent/WO1992004029A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO1992004029A1 (en) | 1992-03-19 |
| AU8411391A (en) | 1992-03-30 |
| EP0549606A1 (en) | 1993-07-07 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued | ||
| FZDE | Discontinued |
Effective date: 19960229 |