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Description  |
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The present invention relates to an iontophoresis device for epidermal
application, more specifically to an iontophoresis device having a light
weight and capable of directly and very easily being applied to the human
skin.
Recently, iontophoresis has come into increasing attention as an effective
method for topical application of ionic agents or drugs by promoting
absorption through the skin. Iontophoresis techniques are disclosed in,
for example, Glass, J. M. et al., Int. J. Dermatol. 19,519 (1980); Russo
J., Am. J. Hosp. Pharm. 37,843 (1980); Gangarosa, L. P. et al., J.
Pharmacol. Exp. Ther. 212,377 (1980); Kwon, B. S. et al., J. Infect. Dis
140,1014 (1979); Hill, J. M. et al., Ann. N.Y. Acad. Sci. 284,604 (1977)
and Tannebaum, M. Phys. Ther. 60,792 (1980).
The iontophoresis disclosed in these prior arts is usually carried out by
connecting the output terminal of a continuous direct current generator or
pulsed direct current generator to a first or active electrode composed of
a metal plate or other conductive substances covered with a moistened pad
of porous material impregnated with an aqueous solution of ionic drug and
a second or indifferent electrode structured similar to the first
electrode but not soaked with the drug. From the above, it is clear that
actual application of iontophoresis is very troublesome. While
iontophoresis is a very effective method for drug application, this
troublesome application had limited its spread. Further, the first and
second electrodes have usually been fixed to the affected area of the body
by means of, for example, rubber band, and the electric current flows
through the skin. This has made it easy for burns to occur due to poor
contact between the skin and the electrodes. Thus, an ammeter must be
continually monitored during the application. For these reasons,
conventional iontophoresis cannot become popularized as a home curative
means, although it can be used in hospitals and clinics.
An object of the present invention is to eliminate the above-mentioned
problems in the prior arts by providing an iontophoresis device having a
light weight and capable of directly and very easily being applied to the
patient's skin with a simple operation and even for a long time.
Other objects and advantages of the present invention will be apparent from
the description set forth hereinbelow.
In accordance with the present invention, there is provided an
iontophoresis device comprising:
(a) a first conductive electrode consisting essentially of a conductive gel
layer containing or capable of containing an ionic agent and a
current-distribution conductive member layer, the two layers being
integrally laminated together;
(b) a second conductive electrode consisting essentially of a conductive
gel layer and a current-distribution conductive member layer, the two
layers being integrally laminated together; and
(c) a lightweight battery, said first and second electrodes being
electrically connected to said lightweight battery so that a closed
circuit is formed when the above members are applied to the patient's skin
.
The present invention now will be illustrated in detail with reference to
the accompanying drawings, wherein:
FIG. 1 is a plan view illustrating a first embodiment of the present
iontophoresis device;
FIG. 2 is a cross-sectional view of the first embodiment of the present
iontophoresis device, taken along the line II--II of FIG. 1;
FIG. 3 is a bottom plan view of the first embodiment of the present
iontophoresis device;
FIG. 4 is a cross-sectional view of a second embodiment of the present
iontophoresis device;
FIG. 5 is a cross-sectional view of a third embodiment of the present
iontophoresis device; and
FIG. 6 is a cross-sectional view of a fourth embodiment of the present
iontophoresis device.
Referring to FIGS. 1 to 3, illustrating a first embodiment of the present
iontophoresis device, iontophoresis device 1 comprises first electrode 2,
second electrode 3, and button battery 8. First electrode 2 is composed of
conductive gel layer 4, in the form of a flexible sheet or film containing
or capable of containing an ionic agent and of current-distribution
conductive member layer 5, which layer 5 is formed by aluminum foil or
another metallic foil a conductive rubber or resin film. Gel layer 4 and
current distribution conductive member layer 5 are integrally laminated
together.
Second electrode 3 is composed of conductive gel layer 6 formed as a
flexible sheet or film and of current-distribution conductive member layer
7, which layer 7 is formed by a metallic foil or a conductive rubber or
resin film. Gel layer 6 and current distribution conductive member layer 7
are integrally laminated together.
Button battery 8 is arranged near the central portion of the top surface of
first electrode 2 in such a manner that one of the poles of battery 8, for
example, negative pole (-), contacts current-distribution conductive
member layer 5 of first electrode 2. The positive pole (+) of battery 8 is
connected to current-distribution conductive member layer 7 of second
electrode 3 by means of lead wire 9 made of, for example, aluminum foil.
The bottom surface of lead wire 9, other than the both end portions
thereof, is provided with an insulating coating.
Iontophoresis device 1 is also provided with insulating backing layer 10.
Insulating backing layer 10 is composed of, for example, a flexible sheet
or film made of a nonconductive synthetic resin. First and second
electrodes 2 and 3 are fixed on insulating backing layer 10 in such a
manner that first electrode 2 is separated from second electrode 3. First
and second electrodes 2 and 3 and battery 8 are integrally connected
together by means of insulating backing layer 10.
Iontophoresis device 1 is applied to the human body by placing first
electrode 2, containing the desired ionic agent or drug, in conductive gel
layer 4, in contact with the intended portion of the patient's body. Thus,
electrodes 2 and 3 form a closed circuit through the human body, thereby
promoting the penetration or absorption of the ionic agent or drug
contained in conductive gel layer 4 of first electrode 2 through the skin.
Referring to FIG. 4, in a second embodiment of the present iontophoresis
device, iontophoresis device 1 comprises first electrode 11, second
electrode 3, and button battery 8. First electrode 11 is composed of
conductive gel layer 4 containing or capable of containing an ionic agent
or drug and of current-distribution conductive member layer 14. Gel layer
4 and current-distribution conductive member layer 14 are integrally
laminated together. Current distribution conductive member layer 14 of
this embodiment is formed by vapor deposition of aluminum on a portion of
insulating backing 13 composed of a flexible nonconductive sheet or film
made of, for example, polyvinylidene chloride. Button battery 8 is
arranged on the upper surface of current-distribution conductive member
layer 7 of second electrode 3 in such a manner that the positive pole of
second electrode 3 directly contacts the upper surface of
current-distribution conductive member layer 7. On the other hand,
current-distribution conductive member layer 14 of first electrode 11 is
connected with the negative pole of button battery 8. Second electrode 3
is fixed on the portion of insulating backing 13 where
current-distribution conductive member layer 14 is not formed. Thus, first
electrode 11, second electrode 3, and button battery 8 are integrally
connected together and supported by insulating backing 13.
The second embodiment of the present iontophoresis device enables a
flexible, very thin iontophoresis device since the first electrode is
composed of a laminate substantially containing two layers.
Referring to FIG. 5, in a third embodiment of the present iontophoresis
device, iontophoresis device 1 comprises first electrode 2, second
electrode 3, and sheet battery 15 as the lightweight battery.
Current-distribution conductive member layers 16 and 17 composed of, for
example, copper foil or a carbon fiber nonwoven fabric are placed on one
surface of sheet battery 15. Conductive gel layer 4 containing an ionic
agent or drug is laminated on the one of the poles of sheet battery 15 and
conductive gel layer 6 not containing ionic agent or drug is laminated on
the another pole.
The third embodiment of the present iontophoresis device enables a very
thin, flexible and flat iontophoresis device since the sheet battery is
very thin (i.e., about 0.5 to 2 mm). The output terminal of the sheet
battery may be formed as a flat face. This output terminal also functions
as the current-distribution conductive member layer.
Referring to FIG. 6, in a fourth embodiment of the present iontophoresis
device, iontophoresis device 1 comprises first electrode 2, second
electrode 3, and button battery 8. The one pole of button battery 8 is
connected to current-distribution conductive member layer 5. The another
pole of button battery 8 is connected, through lead wire 18, to
current-distribution conductive member layer 7 of second electrode 3.
The fourth embodiment of the present iontophoresis device enables the first
electrode to be applied to the body apart from the second electrode by any
distance, limited only by the length of the lead wire. Thus, the
iontophoresis device can be easily applied to the intended portion of
patient even when the portion is very small or has a relatively large
curvature radius. Furthermore, when a large amount of perspiration comes
out on the skin, especially at a high temperature and high humidity, the
iontophoresis device is not affected by the electric current flowing on
the surface of the skin during application since the two electrodes are
separately placed.
The constituents of the iontophoresis device of the present invention will
now be explained in detail hereinbelow.
Conductive gel layers
The conductive gel layers of the first and second electrodes of the present
iontophoresis device are composed of various hydrophilic natural or
synthetic resins: for example, natural resinous polysaccharides such as
karaya gum, tragacanth gum, and Xanthan gum; vinyl resins such as
partially saponified polyvinyl alcohol, polyvinyl formal, polyvinyl methyl
ether and copolymers thereof, polyvinyl pyrrolidone, and polyvinyl
methacrylate; and acrylic resins such as polyacrylic acid and sodium salts
thereof, polyacryl amide and partially hydrolyzed products thereof,
partially saponified products of polycrylic acid esters, and copoly
(acrylic acid-arylamide). These hydrophilic natural or synthetic resins
are softened and plasticized with water and/or polyols such as ethylene
glycol, propylene glycol and glycerine and are molded to the form of a
flexible sheet or film. The resultant gel layer has a shape retention
property and adhesiveness to the skin.
An ionic agent or drug is further included, or is to be included just
before application to the skin, in the conductive gel layer of the first
electrode, whereby the conductivity of the gel layer increases. If
desired, a supporting electrolyte is optionally added to the gel layer as
in the case of the so-called electrophoresis gel.
If desired or necessary, various electrolytes, such as sodium chloride,
sodium carbonate, and potassium citrate, can be added to the conductive
gel layer of the second electrode to provide a sufficient conductivity.
The electrolyte is usually added in an amount of about 1% to 15% by
weight, based on the total weight of the gel layer.
The resultant conductive gel layers suitable for use in the present
invention are in the form of a flexible sheet or film and can closely
adhere to the skin. Therefore, the skin contact resistance is low. As a
result, the ionic agent or drug effectively penetrates into the skin.
Furthermore, it is advantageous from the viewpoint of practical
application that the iontophoresis device can be directly applied to the
intended skin without using any adhesive means such as a
pressure-sensitive adhesive tape.
If the gel layer of the second electrode is composed of an adhesive gel as
mentioned above and the gel layer of the central active electrode, as
shown in FIG. 1, is composed of nonadhesive hydrogel, such as agar gel, as
mentioned hereinbelow, the above-mentioned advantages can also be
obtained.
Especially when the above-mentioned natural resinous polysaccharides such
as karaya gum are used as the basic material of the gel layers, gel layers
having not only electrochemically good conductivity but also desirable
skin compatibility or adaptability can be obtained. This is due to the pH
buffer action (pH 4-5) or skin protecting property based on the natural
high polymer acid structure, remarkably high water-retention
characteristics, and moderate skin adhesiveness thereof.
When karaya gum is used as the above-mentioned polysaccharide, the gel
composition selected is usually 20 to 70 parts by weight of karaya gum and
80 to 30 parts by weight of a polyol, such as glycerine or propylene
glycol (containing 0% to 50% by weight of H.sub.2 O based on the weight of
the polyol), depending upon its intended use. Since the resultant gel has
sufficient water-retention characteristics, an ionic agent or drug in the
form of aqueous solution can added to the gel layer before usage. The
addition of electrolytes to the second electrode is not necessarily
required since gel composed of karaya gum has sufficient conductivity by
itself.
When the gel layers are compounded or prepared, the same electrochemical
considerations should be given as with the preparation of the so-called
electrophoresis gel. Generally, the gel layer is prepared so as to provide
the desired ion mobility or conductivity, depending upon the kind of the
ionic agent or drug, the administered amount (dose required), the
application period, the output power of the battery, the contact area to
the skin, and other factors.
Examples of the preparation and composition of the conductive gel layers
suitable for use in the present iontophoresis device are given below. The
examples are given in reference to the conductive gel layers for the
second electrodes, however, the conductive gel layers of the first
electrodes can be prepared in the same manner except that all or part of
the electrolytes such as sodium chloride is replaced with the desired
ionic agent or drug. The desired ionic agent or drug can be incorporated
into the gel layer at the time when the gel layer is prepared or just
before the iontophoresis device is actually applied to the skin.
1. Thirty grams of powdered polyvinyl alcohol having a weight-average
molecular weight of 440,000 and a saponification value of about 60% was
prepared in a conventional manner. Forty grams of a 10% NaCl solution in
distilled water, preheated to a temperature of 80.degree. C., and 30 g of
glycerine were added to the powdered polyvinyl alcohol. The mixture was
thoroughly stirred. The resultant mixture was hot-pressed for about 20
minutes at a pressure of 0.6 kg/cm.sup.2 G in a hot press heated to a
temperature of 80.degree. C. Thus, a flexible sheet having a thickness of
3 mm was obtained. The flexible sheet thus obtained had a sufficient
adhesiveness to the skin and a specific resistance of 0.8
k.OMEGA..multidot.cm.
2. Electrically conductive gel layers in the form of a flexible sheet
having the following compositions were prepared in the same manner as
described above.
EXAMPLE A
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Polyvinyl pyrrolidone (a weight-average
20 g
molecular weight of 360,000; PVP-K90
manufactured by GAF Corporation)
10% NaCl solution in distilled water
40 g
Glycerine 40 g
______________________________________
The resultant sheet had a sufficient adhesiveness to the skin and a
specific resistance of 0.2 k.OMEGA..multidot.cm.
EXAMPLE B
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Polyvinyl formal (a weight-average molecular
15 g
weight of 1,600,000, a formalization degree
of 15%, and a saponification degree of the
starting polyvinyl alcohol of 60%)
5% NaCl solution in distilled water
70 g
Propylene glycol 15 g
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The resultant sheet had a sufficient adhesiveness to the skin and a
specific resistance of 1.0 k.OMEGA..multidot.cm.
EXAMPLE C
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Polyvinyl acetoacetal (a weight-average
40 g
molecular weight of 440,000, an acetali-
zation degree of 30%, and a saponification
degree of the starting polyvinyl alcohol
of 70%)
15% NaCl solution in distilled water
50 g
Ethylene glycol 10 g
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The resultant sheet had a sufficient adhesiveness to the skin and a
specific resistance of 0.75 k.OMEGA..multidot.cm.
3. Forty grams of sodium polyacrylate having a weight-average molecular
weight of 12,000,000 to 13,000,000 (Acoflock A-130 manufactured by Mitsui
Cyanamide Co.) was uniformly mixed with 30 g of a 10% NaCl solution in
distilled water and 60 g of glycerine. The resultant mixture was heated
under pressure at a temperature of 80.degree. C. for 10 minutes to provide
a flexible sheet. The sheet thus prepared had a moderate adhesiveness to
skin and a specific resistance of 0.5 k.OMEGA..multidot.cm after allowing
to stand for 1 day.
4. Thirty grams of polyacryl amide having a weight-average molecular weight
of 13,000,000 to 15,000,000 (Acoflock N-100 manufactured by Mitsui
Cyanamide Co.) was uniformly mixed with 50 g of a 10% NaCl solution in
distilled water and 20 g of glycerine and then hot pressed to form a sheet
in the same manner as mentioned above. The specific resistance of the
resultant sheet was 0.9 k.OMEGA..multidot.cm.
5. Thirty grams of karaya gum was uniformly mixed with 30 g of 5% NaCl
solution in distilled water and 40 g of glycerine and then hot-pressed to
form a sheet in the same manner as mentioned above. The specific
resistance of the resultant sheet was 0.65 k.OMEGA..multidot.cm.
In addition to the above-exemplified hydrophilic polymeric substances,
various known hydrophilic polymeric substances usable as so-called
bioelectrode materials can also be used. Such materials are disclosed in,
for example, Japanese patent application Laid-Open (Kokai) Nos. 52-95895,
54-77489, 55-52742, 56-15728, 56-36939, and 56-36940; Japanese patent
publication (Kokoku) Nos. 48-28747, 50-27317, and 52-9946; U.S. Pat. Nos.
3,490,440, 3,640,741, 3,665,064, 3,989,050, 3,998,215, 4,016,869,
4,066,078, and 4,125,110; British Pat. No. 1,557,254; and Japanese patent
application Nos. 56-14936 and 56-46531. Typical examples of such materials
are polyethylene glycol, carboxy polymethylene, methyl cellulose, sodium
alginate and polyethylene oxides.
Thus, any hydrophilic polymeric substances which can be softened and
plasticized with water and/or polyols to form viscoelastic gels, desirably
having adhesiveness to the skin, can be used as the basic gel material of
the conductive gel layers of the present iontophoresis device. These
substances are generally selected taking into consideration the
compatibility thereof with the ionic agent or drug to be used, the
compatability with the skin, and the electrical conductivity. These gel
layers can be disposed or reused.
As is clear from the above examples, wide varieties of hydrophilic
polymeric substances can be used, in the formation of conductive gel
layers suitable for use in the present invention, by softening and
plasticizing said substances with water and/or alcohols. There are no
limitations on the special basic materials or the special composition
thereof. Generally speaking, the gel composition is selected from those
containing 10% to 70% by weight of hydrophilic polymeric substances and
the remainder of water and/or polyols in order to obtain the desired shape
retentiveness.
Although the above-mentioned conductive gel layers have a sufficient
adhesiveness to the skin by themselves, additional pressure-sensitive
adhesive components such as acrylic type adhesives, and vinyl acetate
emulsion type adhesives can be incorporated into the gel layers, if
desired. On the other hand, when nonadhesive hydrogels such as agar gels
are used, skin adhesive means such as pressure-sensitive adhesive tapes
should be arranged on, for example, the outer circumferential portion of
the present iontophoresis device, as shown in FIG. 1.
Ionic Agent or Drug
Various kinds of agents or drugs can be used in the present iontophoresis
device so long as they can dissociate into ions in water or polyols.
Examples of ionic agents or drugs usable in the present invention are
potassium iodide, procaine hydrochloride, methacholine, various skin
vitamins such as vitamins B.sub.1, B.sub.2, B.sub.6, and C, histamine,
sodium salicylate, dexamethasone, epinephrine, hydrocortisone,
idoxuridine, and undecylenic acid salts.
Lightweight Battery And Output Thereof
The term "lightweight battery" used herein means batteries light enough
that they will not cause the iontophoresis device to release from the
skin. Generally speaking, batteries having a weight of 20 g or less,
preferably 5 g or less, down to, for example, 0.2 g, are used in the
present invention.
The batteries usable in the present invention can be in any form. For
example, so-called button batteries, coin batteries, sheet batteries,
paper batteries, bar batteries, and so-called microbatteries can be used.
Button batteries and sheet batteries can be desirably used for the reasons
that they are small or flexible.
The current values required for the iontophoresis are generally 600
.mu.A/cm.sup.2 or less. Accordingly, since the contact resistance between
the electrodes and the skin is several kiloohms to several dozen kiloohms,
the output of the battery is generally about 0.5 V to 10 V, although it
depends on the applying times, and also on the contact area between the
electrodes and the patient's skin. If necessary, two or more batteries can
be arranged or laminated to each other in the present iontophoresis
device. In addition, a constant current element and a luminescent element
for indicating the current flow can be mounted in the iontophoresis
device, if desired. For instance, known constant current circuits
containing transistors and resistors can be formed as a small and compact
chip and can be mounted on, for example, a button battery so as to keep
the current constant.
Furthermore, any known polarity exchange means for freely exchanging the
polarity (i.e., positive and negative poles) of the electrode, depending
upon the polarity of the ionic agent or drug, can be mounted in the
present iontophoresis device.
The present invention will now be further illustrated by, but is by no
means limited to, the following application examples.
EXAMPLE 1
An iontophoresis device as illustrated in FIGS. 1 to 3 was formed. The
electrically conductive viscoelastic gel layers had a thickness of 1.5 mm
and an area of 48 cm.sup.2 and comprised 20% by weight of the polyacryl
amide mentioned above, 30% by weight of distilled water, and 40% by weight
of glycerine. The gel layer of first electrode further contained 5% by
weight of sodium salicylate. The gel layer of second electrode 3 having an
area of 56 cm.sup.2, further contained 3% by weight of sodium chloride.
Current-distribution conductive member layers 5 and 7 were composed of
aluminum foil. The negative poles of two button batteries (Matsushita
Electric Ind. Co., Ltd; BR1225, Li/(CF)n; 0.85 g) 8, each having an output
of 3 V, were directly connected, in series, to first electrode 2. The
positive poles were connected to second electrode 3. The entire assembly
was then integrally laminated with polyethylene film 10 by means of a heat
sealing method to form an iontophoresis device. The skin contact impedance
of the resultant iontophoresis device was several kiloohms.
The iontophoresis device thus prepared was applied to the patient's skin
for 2 hours. The injected amount of the salicylic acid anion was about 8
mg (i.e., about 40% of the theoretical amount). This amount was about 3 to
10 times that of the so-called ordinary cataplasm containing methyl
salicilate as a main constituent.
The iontophoresis device of this example can be used as an analgesic and
antiphlogistic agent. However, since the so-called galvanization effecting
vasodilative function is also conducted, it should be noted that this
iontophoresis device exhibits remarkable synergestic effects on disorders
such as neuralgia, arthralgia, and rheumatoid arthralgia. The present
iontophoresis device can also be used for curing various skin disorders
and for injecting various cosmetic skin nutrients including various skin
vitamins.
The present iontophoresis device having a first electrode separated from a
second electrode as shown in FIG. 6 can be desirably used for curing skin
disorders such as trichophytosis on the sole of the foot.
EXAMPLE 2
This example illustrate the application of an iontophoresis device as shown
in FIGS. 1 to 3. Conductive gel layers 4 and 6 having the following
compositions (% by weight) were used.
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Gel layer 4
Gel layer 6
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Glycerine 50 60 (containing 2% NaCl)
Karaya gum 45 40
Water 5 5 (saturated with NaCl)
______________________________________
The thickness of gel layers 4 and 6 were 1.5 mm and the areas of gel layers
4 and 6 were 6 cm.sup.2 and 12 cm.sup.2 respectively.
The current-distribution conductive member layers 3 and 7 were made of
carbon containing conductive rubber film. The negative pole of button
battery 8 (Matsushita; BR1225) having an output of 3 V was directly
connected to first electrode 2 and the positive pole was connected through
lead wire 9 to second electrode 3. The entire assembly was then integrally
laminated with polyethylene film 10 by means of a heat sealing method to
form an iontophoresis device 1.
The iontophoresis device thus prepared was applied to the face skin of
patient. Before the application, about 0.2 ml of 10% aqueous solution of
sodium ascorbate (stored in an ampule) was dropwise impregnated into
conductive gel layer 4 and, then, the iontophoresis device was applied to
the affected skin.
The concentration of vitamin C in the skin tissue was about 10 micromol/g
after 1 hour application at a current of 50 .mu.A. This concentration is
remarkably higher than the following data reported in Katsu Takenouchi, et
al., Vitamines, 28,501 (1963).
______________________________________
micromol/g
______________________________________
Normal skin tissue 0.057
One hour after venoclysis of
0.400
5 g of vitamin C
Effective concentration for
0.500
completely inhibiting the
formation of melanin (in vitro)
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As is well-known in the art, vitamin C (ascorbic acid) or the derivatives
thereof such as sodium ascorbate are effective for curing
chromatodermatosis such as the so-called moth patch, freckle, various
melanosises. However, as mentioned above, conventional iontophoresis has
not been popularized due to the troublesome application although it is
known that the iontophoresis is very effective method for curing
chromatodermatosis and the like. Contrary to this, the present
iontophoresis device can be very effectively and advantageously used for
curing various skin disorders and for injecting various cosmetic skin
nutrients by very simple operation. This is a dramatical progress in this
field.
When this iontophoresis device was applied to the face, vitamin C (i.e.
ascorbic acid anion) was injected into the epidermal tissue and the upper
layer of the true skin in an extremely high concentration of about 10 or
more .mu.mol/g tissue for 1 or 2 hours application at about 10 to 30
.mu.A/cm.sup.2. The above-mentioned concentration was retained in the
tissue for a long time and effecting to inhibit melanin formations in
melanocytes.
The invention has been described in detail with particular reference to
certain preferred embodiments thereof, but it will be understood that
variations and modifications can be effected within the spirit and scope
of the invention.
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