U.S. patent application number 10/562392 was filed with the patent office on 2007-11-22 for anesthetic composition for topical administration comprising lidocaine, prilocaine and tetracaine.
Invention is credited to Fernando Bouffard Fita.
Application Number | 20070269465 10/562392 |
Document ID | / |
Family ID | 33547868 |
Filed Date | 2007-11-22 |
United States Patent
Application |
20070269465 |
Kind Code |
A9 |
Fita; Fernando Bouffard |
November 22, 2007 |
Anesthetic composition for topical administration comprising
lidocaine, prilocaine and tetracaine
Abstract
It comprises a mixture of lidocaine, prilocaine and tetracaine,
or their pharmaceutically acceptable salts. The preferred
composition comprises the following components in the indicated
approximate w/w percentages: 1.5% of lidocaine base; 1.5% of
prilocaine base; 4% of tetracaine base; 10% of methylpynrolidone;
2% of dimethyl sulfoxide; 0.08% of topical hyaluronidase; 1.5% of
guar gum; 1% of Tween-20; 0.5% of Tween-80, and the necessary
amount of water to 100%. It exhibits a a high concentration on
skin, a deep anesthetic effect and a significantly more rapid onset
of the anesthetic effect than comparable transdermal
anesthetics.
Inventors: |
Fita; Fernando Bouffard;
(Barcelona, ES) |
Correspondence
Address: |
BERENBAUM, WEINSHIENK & EASON, P.C
370 17TH STREET
SUITE 4800
DENVER
CO
80202
US
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20060140986 A1 |
June 29, 2006 |
|
|
Family ID: |
33547868 |
Appl. No.: |
10/562392 |
Filed: |
June 1, 2004 |
PCT Filed: |
June 1, 2004 |
PCT NO: |
PCT/EP04/50967 |
371 Date: |
December 19, 2005 |
Current U.S.
Class: |
424/400;
514/537 |
Current CPC
Class: |
A61K 31/165 20130101;
A61K 47/22 20130101; A61P 23/02 20180101; A61K 31/165 20130101;
A61K 31/167 20130101; A61K 47/20 20130101; A61K 9/0014 20130101;
A61K 47/42 20130101; A61K 31/245 20130101; A61K 31/245 20130101;
A61K 47/32 20130101; A61P 23/00 20180101; A61K 47/36 20130101; A61K
2300/00 20130101; A61K 31/167 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
424/400;
514/537 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/24 20060101 A61K031/24 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 19, 2003 |
ES |
P200301548 |
Claims
1. A pharmaceutical composition for topical administration
comprising: (i) a therapeutically safe and effective amount of
lidocaine or of a pharmaceutically acceptable salt thereof; (ii) a
therapeutically safe and effective amount of prilocaine or of a
pharmaceutically acceptable salt thereof; and (iii) a
therapeutically safe and effective amount of tetracaine or of a
pharmaceutically acceptable salt thereof.
2. The pharmaceutical composition according to claim 1, further
comprising water.
3. The pharmaceutical composition according to claim 1, wherein
lidocaine or its salt on the one side, and prilocaine or its salt
on the other side, form an eutectic mixture.
4. The pharmaceutical composition according to claim 3, wherein one
or more of lidocaine or its salt is in an amount from about 0.5% to
about 5% w/w, prilocaine or its salt is in an amount from about
0.5% to about 5% w/w, and tetracaine or its salt is in an amount
from about 0.5% to about 8% w/w.
5. The pharmaceutical composition according to claim 4, wherein
lidocaine or its salt is in an amount of about 1.5% w/w, and
prilocaine or its salt is in an amount of about 1.5% w/w.
6. (canceled)
7. The pharmaceutical composition according to claim 4, wherein
tetracaine or its salt is in an amount of about 4% w/w.
8. The pharmaceutical composition according to claim 1, further
comprising appropriate amounts of pharmaceutically acceptable
excipients to constitute a topical formulation.
9. The pharmaceutical composition according to claim 8, wherein the
excipients comprise one or a combination of two or more of at least
one skin penetration enhancer, at least one spreading agent, at
least one viscosity increasing agent, at least one surfactant, and
at least one preservative.
10. The pharmaceutical composition according to claim 9, wherein
the skin penetration enhancer includes one or both of
methylpyrrolidone and dimethyl sulfoxide (DMSO).
11. The pharmaceutical composition according to claim 10, wherein
methylpyrrolidone is in an amount from about 5% to about 20%
w/w.
12. The pharmaceutical composition according to claim 11, wherein
methylpyrrolidone is in an amount of about 10% w/w.
13. (canceled)
14. The pharmaceutical composition according to claim 10, wherein
dimethyl sulfoxide is in an amount from about 0.5% to about 5%
w/w.
15. The pharmaceutical composition according to claim 14, wherein
dimethyl sulfoxide is in an amount of about 2% w/w.
16. (canceled)
17. The pharmaceutical composition according to claim 9, wherein
the spreading agent is selected from hyalurodinases and derivatives
of mucopolysaccharidases.
18. (canceled)
19. The pharmaceutical composition according to claim 9, wherein
the viscosity increasing agent is selected from guar gum and a
carbomer.
20. The pharmaceutical composition according to claim 9, wherein
the viscosity increasing agent is in an amount from about 0.5% to
about 2% w/w.
21. (canceled)
22. The pharmaceutical composition according to claim 9, wherein
the surfactant is a non-ionic surfactant.
23. (canceled)
24. The pharmaceutical composition according to claim 8, wherein
the topical formulation is selected from the group consisting of
lotions, creams, gels, sticks, sprays, ointments and pastes.
25. A pharmaceutical composition for topical administration
comprising the following components in the indicated approximate
w/w percentages: 1.5% of lidocaine base; 1.5% of prilocaine base;
4% of tetracaine base; 10% of methylpyrrolidone; 2% of dimethyl
sulfoxide; 0.08% of topical hyaluronidase; 1.5% of guar gum; 1% of
Tween-20; 0.5% of Tween-80, and the necessary amount of water to
100%.
26. A method of use of a combination comprising lidocaine,
prilocaine and tetracaine, any of which being as such or as a
pharmaceutically acceptable salt, for the preparation of a topical
anesthetic pharmaceutical composition; the method comprising:
providing a combination of lidocaine, prilocaine and tetracaine
themselves or as pharmaceutically acceptable salts thereof; and,
administering the combination topically.
Description
[0001] This invention relates to the field of human medicine, and
specifically to topical anesthetic formulations which include
mixtures of several anesthetic agents.
BACKGROUND ART
[0002] Surgical techniques can only be performed after the highly
sensitive nerve endings in the skin are anesthetized. Anesthetic
agents are pharmacologically active agents that block nerve
impulses conduction in sensory and motor nerve fibers when applied
in therapeutically effective amounts. Their action is reversible,
their use being followed by the complete recovery in nerve function
with no evidence of structural damage to nerve fibers or cells.
[0003] To be effective, a topical anesthetic should contain
sufficient concentration of the active agent to produce an
anesthetic effect, it should penetrate intact skin sufficiently to
deliver a therapeutic dose, it should exhibit a rapid onset of
anesthetic action and have a prolonged anesthetic effect. Potency
of anesthetics in clinical situations depends on both their ability
to reach the nerve fibers and their intrinsic blocking activities.
Factors such as nerve penetration, vascular absorption, and local
tissue binding are all of them determinants for anesthetic
potency.
[0004] Local anesthetics are traditionally injected into the
desired site with a syringe. Most formulations of local anesthetics
are aqueous solutions designed for injection into tissue, around
nerves, or into the epidural spaces. The use of syringe is
disadvantageous because the needle itself causes pain on
penetration, the volume of anesthetic dissolution can cause
stretching at the site (also causing pain), and furthermore
preservatives contained in the aqueous dissolution can cause
stinging at the wound site. Pain relief is especially important in
the area of pediatrics, where even minimal pain may result in an
anxious and uncooperative patient.
[0005] It is known the use of topical anesthetics. Transdermal
delivery is advantageous over intravenous delivery because the
former avoids risks associated with parenteral treatment and
eliminates gastrointestinal adverse effects due to pharmaceutical
active ingredients, preservatives, etc. However, the use of
transdermal anesthetics (i.e. through the skin) is often
problematic, and fluid and in gel compositions have often proven
unsuccessful.
[0006] The amide of formula (I), known as lidocaine, has a melting
point of 68-69.degree. C. and it is the most commonly used local
anesthetic, especially in the form of aqueous dissolutions of its
hydrochloride, which are administered intravenously or topically,
as jelly, ointment or spray (cf. U.S. Pat. No. 2,441,498).
Unfortunately, when administered topically, these formulations are
not effectively absorbed transdermally, but only through mucosal
surfaces. ##STR1##
[0007] The amide of formula (II), known as prilocaine, is a local
anesthetic agent which takes the form of crystalline needles having
a melting point of 37-38.degree. C. (cf. GB 839.943-A). Its
hydrochloride is crystallized from ethanol and isopropyl ether and
it is readily soluble in water. Unfortunately, methemoglobinaemia
and cyanosis appear to occur more frequently with prilocaine than
with other local anesthetics. Methemoglobinaemia is a disease state
of the erythrocyte consisting in the formation of oxidized iron
compound in the heme protein of the erythrocyte. Symptoms usually
occur when doses of prilocaine hydrochloride exceed about 8 mg per
kg body-weight although the very young may be more susceptible.
This fact severely limits the size of the area to be
anesthetized.
[0008] Enhancement of drug absorption through the skin has been a
challenge for researchers for many years. Research has been also
focused on finding effective topical formulations of an anesthetic
which provide a rapid onset and a long duration of anesthesia. When
applied onto intact skin, currently available topically used
anesthetic preparations are generally ineffective or only partially
effective.
[0009] One approach to the prolongation of anesthesia involves the
combination of topical anesthetics with a vasoconstrictor, but also
involves considerable adverse side effects. Another approach
involves the combination of several anesthetic agents and different
topical excipients (cf. e.g. EP 43.738-A, WO 9633706-A). In fact,
at present, the most successful commercially available preparation
for dermal anesthesia is the lidocaine-prilocaine cream named EMLA
(a registered trademark in some countries) of Astra Lakemedel AB,
Sweden (cf. U.S. Pat. No. 4,562,060). In some clinical tests, EMLA
cream has been found preferable to lidocaine or to ethylchoride.
EMLA is an oil-in-water emulsion in which the organic phase is an
eutectic mixture of lidocaine and prilocaine bases (2.5% and 2.5%
by weight) in water which is thickened with carbomer
(Carbopol.RTM.). An eutectic mixture has a melting point lower than
the one of any of its ingredients. EMLA cream is applied as a thick
layer under an occlusive or semiocclusive dressing for inducing a
rapid absorption through the skin.
[0010] A major inconvenience of EMLA is that its onset time for
anesthesia is relatively long, approximately one hour or more. This
onset time is not very practical for several clinical procedures.
For more invasive procedures such as split skin graft harvesting,
EMLA has to be applied at least two hours prior to surgical
operation. Such delay is a problem for both patients and for
medical staff, particularly in the area of pediatrics. Moreover,
EMLA is formulated at pH 9.0 to incorporate the anesthetic agents
in base form. The skin, which has an acidic pH (5 to about 5.5) is
sensitive to such a high basic pH and significant skin irritation
can occur. Dermal application of EMLA may cause a transient, local
blanching followed by a transient, local redness or erythema.
Another disadvantage of EMLA is that for deep penetrative effect it
is necessary that the cream is applied under occlusive
dressing.
[0011] There have been several attempts trying to improve EMLA
cream. One example are topical anesthetic compositions which
additionally include a vasodilator. A formulation including
lidocaine base, prilocaine hydrochloride, dibucaine, a vasodilator
and carrier is described in the patent application WO 01/54679-A.
Another example is the topical anesthetic composition comprising an
eutectic mixture of lidocaine and prilocaine in a lipophilic base
described in the U.S. Pat. No. 5,993,836. It has been reported that
this anesthetic formulation has significantly more rapid onset than
similar transdermal anesthetics, such as EMLA cream.
[0012] Tetracaine hydrochloride (amethocaine) is a local anesthetic
of the ester type with formula (III) (cf. U.S. Pat. No. 1.889.645).
There are many topical formulations in the market containing
tetracaine hydrochloride, one of them is AMETOP of T.J. Smith &
Nephew Limited, England (cf. GB 2.258.397-A) which contains 40 mg
of active ingredient (4%, w/w), an aqueous gelling agent and a
pharmaceutically acceptable salt.
[0013] Thus, it appears to be highly desirable to have a topical
anesthetic composition which provides a rapid and deep anesthesia,
with a high concentration on skin. In particular, it would be
desirable to have a topical anesthetic with the benefits of
lidocaine and prilocaine, but free of the above-described
limitations associated therewith.
SUMMARY OF THE INVENTION
[0014] It has now been surprisingly found that a topical anesthetic
composition comprising a mixture of lidocaine, prilocaine and
tetracaine, exhibit a significantly more rapid onset of the
anesthetic effect than comparable transdermal anesthetics, such as
EMLA cream.
[0015] Thus, an aspect of the present invention relates to a
pharmaceutical composition for topical administration comprising:
(i) a therapeutically safe and effective amount of lidocaine or of
a pharmaceutically acceptable salt thereof; (ii) a therapeutically
safe and effective amount of prilocaine or of a pharmaceutically
acceptable salt thereof, and (iii) a therapeutically safe and
effective amount of tetracaine or of a pharmaceutically acceptable
salt thereof.
[0016] In a particular embodiment the composition further comprises
water. When tetracaine is as its hydrochloride, it can be dissolved
in water and added to the previously prepared mixture of lidocaine
and prilocaine. When tetracaine is as such, water is not necessary,
so tetracaine can be added to the mixture of lidocaine and
prilocaine directly. Optionally, the mixture of lidocaine,
prilocaine and tetracaine can also be dissolved in alcohols (e.g.
ethanol, isopropanol and mixtures thereof).
[0017] In another embodiment, lidocaine or its salt on the one
side, and prilocaine or its salt on the other side, form an
eutectic mixture. As an eutectic mixture, the compositions remain
liquid at room temperature and the penetration through the skin is
enhanced, giving as a result, a shorter time of effect
establishment, a higher efficacy and less adverse effects.
Particularly, lidocaine or its salt can be in an amount from about
0.5% to about 5%, w/w, and prilocaine or its salt can be in an
amount from about 0.5% to about 5%. More particularly, lidocaine,
prilocaine, or their salts are in an amount of about 1.5%, w/w. On
the other hand, tetracaine or its salt can be in an amount from
about 0.5% to about 8%, w/w, and more particularly, in an amount of
about 4%, w/w.
[0018] In another embodiment, the pharmaceutical composition
further comprises appropriate amounts of pharmaceutically
acceptable excipients to constitute a topical formulation. The
composition can comprise different types of excipients: skin
penetration enhancers, spreading agents, viscosity increasing
agents, surfactants and preservatives. Optionally, other components
can be added to the compositions of this invention in appropriate
amounts to enhance their pharmaceutical acceptability, as it will
be obvious to a person skilled in the art.
[0019] The composition can comprise at least one skin penetration
enhancer which enhances dermal absorption of the active ingredients
by reversibly altering the barrier of skin. Preferred skin
penetration enhancer agents that may be used are dipolar aprotic
solvents as methylpyrrolidone and dimethyl sulfoxide (DMSO) which
are rapidly absorbed through the skin and enhance dermal absorption
of many other chemicals. In a particular embodiment,
methylpyrrolidone is in an amount from about 5% to about 20%, w/w.
In a more particular embodiment, methylpyrrolidone is in an amount
of about 10%, w/w. In another particular embodiment, the skin
penetration enhancer is dimethyl sulfoxide (DMSO), which is in an
amount from about 0.5% to about 5%, w/w, and more particularly in
an amount of about 2%, w/w.
[0020] The composition can comprise at least one spreading agent,
which facilitates uniform spread of anesthetic agents. In
particular embodiments, the spreading agent is selected from
hyalurodinases and/or derivatives of mucopolysaccharidases. They
prevent the elevation of extracellular tissue pressure and also
prevent focal accumulations of local anesthetic agents, which at
high enough levels may cause neurotoxic damage.
[0021] The composition can further comprise at least one viscosity
increasing agent, also known as thickening agents. Thickeners that
may be used include those known to one skilled in the art, such as
hydrophilic and hydroalcoholic gelling agents frequently used in
cosmetics, food products and pharmaceutical formulations.
Preferably, a commercial carbomer will be used, Carbopol N-940.
Another preferred gelling polymer includes guar gum. In particular
embodiments, the viscosity increasing agent is in an amount from
about 0.5% to about 2%, w/w.
[0022] The composition can comprise at least one surfactant, also
known as emulsifier. These compounds are widely used in the
preparation of stable pharmaceutical, cosmetic and food emulsions.
In a preferable embodiment the surfactant is a non-ionic surfactant
and in a more particular embodiment, polysorbates are used (e.g.
polysorbate 20 and 80).
[0023] The compositions of the present invention may be prepared
and packaged under sterile conditions. Alternatively, at least one
suitable antimicrobial agent may be incorporated into the
formulations as preservatives. Some known preservatives useful in
this invention include methylparaben and propylparaben in their
acidic form or as sodium salts.
[0024] The topical formulations of the present invention may be
made into a wide variety of product forms, as it is well known in
the art. These include, among others, lotions, creams, gels,
sticks, sprays, ointments and pastes. In order to facilitate the
application of the compositions, they can be, for instance, in a
dispenser or on the surface of a dressing, a patch or a pad. These
product forms may comprise several types of carriers including,
among others, dissolutions, aerosols, emulsion gels, solids and
liposomes.
[0025] Another aspect of the present invention relates to a
pharmaceutical composition for topical administration comprising
the following components in the indicated approximate w/w
percentages: 1.5% of lidocaine base; 1.5% of prilocaine base; 4% of
tetracaine base; 10% of methylpyrrolidone; 2% of dimethyl
sulfoxide; 0.08% of topical hyaluronidase; 1.5% of guar gum; 1% of
Tween-20; 0.5% of Tween-80, and the necessary amount of water to
100%.
[0026] The application of the compositions of the present invention
comprises contacting an area of skin with a thin layer of the
composition. When an intravenous device is used, the application of
the compositions of the present invention will be preferably at its
site of insertion. The composition is allowed to act for an
appropriate time for the onset of anesthesia. The term "onset of
anesthesia" means the time until peak effect on the nerve endings.
For the compositions of the present invention, this time is shorter
than with other commercial compositions. In a preferred method of
using, three consecutive applications may be done: a first
application followed by ten minutes of resting to achieve the
anesthetic effect; a second application followed by ten minutes
more, and a third application followed by five minutes of resting.
After these twenty-five minutes in all, the composition can be
removed and the surgical operation can be done or the medical
device can be inserted. The duration of anesthetic effect for the
compositions of the present invention is from about one to about
five hours, depending on the subject metabolism. The effect is much
more durable and increases in time compared with other available
compositions.
[0027] In addition to the rapid onset, the formulations of the
present invention are advantageous for not depending on the
application of an occlusive or a semiocclusive dressing for getting
a rapid absorption through the skin. Even if it is not necessary,
occlusion may be applied. The compositions of the invention may be
applied directly to the skin or by the use of transdermal treatment
systems, including patches or pads, which are semipermeable
membranes with the active compound applied to the surface.
[0028] The compositions of the present invention are particularly
useful before superficial dermatological treatments. These include,
among others, surface verruca extirpation, infiltrations or
molluscum extraction. The same applies before esthetic treatments
such as peelings, filling micropuncture of wrinkles, laser or
application of facial filling; and before the insertion of a
medical device.
[0029] The term "safe and effective amount" as used herein, means
an amount of an active ingredient or a composition high enough to
deliver the desired skin benefit, but low enough to avoid serious
side effects within the scope of medical judgment. The term
"pharmaceutically acceptable" as used herein, means suitable for
use in contact with the tissues without undue toxicity, irritation,
incompatibility, instability, allergic response, and the like. All
numerical ranges used herein, are meant to be inclusive of their
upper and lower limits. Unless noted otherwise, all percentages in
the compositions of the invention are on a weight-to-weight basis.
Throughout the description and claims the word "comprise" is not
intended to exclude other technical features, additives,
components, or steps. The abstract of this application is
incorporated herein as reference. Additional objects, advantages
and features of the invention will become apparent to those skilled
in the art upon examination of the description or may be learned by
practice of the invention. The following particular embodiments are
provided by way of illustration, and is not intended to be limiting
of the present invention.
DETAILED DESCRIPTION OF PARTICULAR EMBODIMENTS
Preparation of the Composition
[0030] Tubes of 30 g were prepared with the composition per tube
described in the following table: TABLE-US-00001 Component % (w/w)
Dissolution A Distilled water 31.82% Nipagin M-Ac 0.08% Nipasol
M-Ac 0.02% Tween-20 1.00% Guar gum 1.50% Dissolution B Tetracaine
HCl 4.00% Distilled water 45.00% Dissolution C Lidocaine base 1.5%
Prilocaine base 1.5% Dissolution D Distilled water 1.00% Topical
hyaluronidase 0.08% Dissolution E Tween 80 0.50% Dissolution F
Methylpyrrolidone 10% Dissolution G DMSO 2.00%
[0031] Lidocaine base and prilocaine base were weighed and sieved
through a 2 mm mesh. Components of dissolutions A, B, D, E, F and G
were weighed separately. The amounts of required distilled water
for each dissolution were also prepared in 100 mL recipients.
Distilled water for dissolution A was heated in an appropriate
recipient and Nipagin and Nipasol were added until dissolved. The
mixture was left to cool. Then, Tween-20 was added and the mixture
was shacked with a stripping knife without lathering. Guar gum was
added to the mixture and shacked during ten minutes with a glass
stick. In the 100 mL recipient containing distilled water,
tetracaine HCl was added and it was dissolved with a magnetic
agitator during fifteen minutes at a regular speed. Tetracaine
dissolution was added over dissolution A and shacked during ten
minutes until homogenized. Lidocaine base was mixed with prilocaine
base in a mortar during fifteen minutes until obtaining the
liquefaction and consequently the total fusion of the eutectic
mixture. The eutectic mixture was added over the preceding mixture
and shacked during ten minutes until complete homogenization. The
resulting product was transferred to a 100 mL recipient.
Hyaluronidase was mixed with the corresponding amount of distilled
water and shacked with a glass stick. This dissolution was added to
the preceding mixture. Dissolution E, F and G were finally added
consecutively and shacked until complete homogenization. The 30 g
of the resulting product was transferred to an aluminum tube.
Comparative Clinical Study Between a Topical Anesthetic Composition
of the Invention and EMLA Cream: Efficacy and Adverse Effects
[0032] The aim of the study was to compare the efficacy between a
topical anesthetic composition of the invention versus EMLA cream.
Adverse effects of both compositions were also evaluated. The study
was executed during two years over a 2700 individual population
with ages comprised between fifteen and sixty-five years. Different
superficial dermatological procedures were made such as surface
verruca extirpation, infiltrations, application of facial filling,
laser or filling micropuncture of wrinkles.
[0033] The topical anesthetic composition of the invention was
applied to the half of the population during thirty minutes
previous to the surgical operation and without occlusion. EMLA was
applied to the other half of the population during sixty minutes
previous to the surgical operation and with occlusion. The degree
of pain was evaluated by the patient himself with a visual
analogous scale (VAS) with a minimum value (equivalent to no pain)
"0" and a maximum value (equivalent to maximum pain) "10". The
degree of pain was evaluated during the execution of the
dermatological procedure while the evaluation of adverse effects
emergence was evaluated from the anesthetic application to the end
of the dermatological procedure.
[0034] Table 1 shows the results in terms of anesthetic efficacy.
Tables 2 and 3 shows the results of the evaluation of adverse
effects emergence during and after the application of both creams.
Table 2 shows the results in terms of adverse effects of the
composition of the invention and table 3 in terms of adverse
effects of EMLA. In both cases few patients with adverse effects
were registered, although in the case of EMLA these effects were
more acute and in the case of the composition of the invention the
effects were softer, of short length and with spontaneous
resolution. TABLE-US-00002 TABLE 1 degree of pain (VAS) 0 1 2 3 4 5
6 7 8 9 10 EMLA -- -- 338 270 135 270 135 135 135 -- -- the
composition of 702 162 149 162 108 67 -- -- -- -- -- the invention
total patients 2700
[0035] TABLE-US-00003 TABLE 2 adverse effects null soft moderate
severe erythema 89% 10% .sup. 1% 0 edema 99% 1% 0 0 itching 90% 10%
0 0
[0036] TABLE-US-00004 TABLE 3 adverse effects null soft moderate
severe erythema 92.5% 0 7.5% 0 itching 97.5% 0 2.5% 0 cutaneous
rash 100% 0 0 0
[0037] From the results shown in the tables, it is clear that the
composition of the 10 invention proves a larger efficacy and a
shorter time of effect establishment versus EMLA for the same type
of dermatological and/or dermoesthetic procedure. The effectiveness
of EMLA is practically the half with a double time of
application.
* * * * *