Note: Descriptions are shown in the official language in which they were submitted.
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.
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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
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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
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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
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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
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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:
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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
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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.
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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
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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
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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)
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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.
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