U.S. patent number 3,856,934 [Application Number 05/325,687] was granted by the patent office on 1974-12-24 for skin depigmentation.
Invention is credited to Albert Montgomery Kligman.
United States Patent |
3,856,934 |
Kligman |
December 24, 1974 |
SKIN DEPIGMENTATION
Abstract
The specification discloses that synergistic compositions for
depigmentation by topical application have been found which
comprise a mixture of hydroquinone, retinoic acid and a
corticosteroid formulated in a pharmaceutically-cosmetically
acceptable vehicle. An illustrative composition comprising from
about 2 percent to about 5 percent hydroquinone, from about 0.05
percent to about 0.1 percent retinoic acid and from about 0.05
percent to about 0.1 percent dexamethasone was particularly
effective.
Inventors: |
Kligman; Albert Montgomery
(Philadelphia, PA) |
Family
ID: |
26727256 |
Appl.
No.: |
05/325,687 |
Filed: |
January 22, 1973 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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49523 |
Jun 24, 1970 |
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Current U.S.
Class: |
424/62;
514/171 |
Current CPC
Class: |
A61K
8/463 (20130101); A61K 8/41 (20130101); A61K
8/63 (20130101); A61K 8/466 (20130101); A61K
8/361 (20130101); A61K 8/86 (20130101); A61K
8/347 (20130101); A61K 8/37 (20130101); A61Q
19/02 (20130101); A61K 8/368 (20130101); A61K
8/671 (20130101); A61K 8/69 (20130101) |
Current International
Class: |
A61K
8/34 (20060101); A61K 8/63 (20060101); A61K
8/67 (20060101); A61K 8/36 (20060101); A61K
8/69 (20060101); A61K 8/72 (20060101); A61K
8/368 (20060101); A61K 8/37 (20060101); A61K
8/46 (20060101); A61K 8/41 (20060101); A61K
8/86 (20060101); A61K 8/30 (20060101); A61Q
19/02 (20060101); A61k 007/12 () |
Field of
Search: |
;424/62 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Wells et al., - Cosmetics and the Skin, (1964), pages 109 and 609.
.
The Merck Index - 7th edition, (1960), page 1097..
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Primary Examiner: Rosen; Sam
Attorney, Agent or Firm: Magee, Jr.; James
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATION
This application is a continuation-in-part of copending application
Ser. No. 49,523, filed June 24, 1970, now abandoned.
Claims
What is claimed is:
1. A skin depigmenting composition for topical appplication to the
skin comprising a melanin inhibiting amount of hydroquinone,
retinoic acid and a corticosteroid.
2. A composition according to claim 1 comprising a melanin
inhibiting amount of hydroquinone, retinoic acid, and a
corticosteroid selected from the group consisting of dexamethasone,
hydrocortisone, hydrocortisone-17-valerate, and progesterone.
3. The composition of claim 2 consisting essentially of from about
2 to about 5 weight percent hydroquinone, from about 0.05 to about
0.1 weight percent retinoic acid, and from about 0.05 to about 0.1
weight percent dexamethasone in a pharmaceutically acceptable
vehicle for topical application.
4. A composition according to claim 2 consisting essentially of
from about 2 to about 5 weight percent hydroquinone, from about
0.05 to about 0.1 weight percent hydrocortisone-17-valerate, and
from about 0.05 to about 0.1 weight percent retinoic acid in a
pharmaceutically acceptable vehicle for topical application.
5. A method for inhibiting the production of melanin which
comprises topical application of a composition comprising
hydroquinone, retinoic acid, and a corticosteroid, in amounts
sufficient to cause depigmentation.
6. The method of claim 5 wherein said composition consists
essentially of hydroquinone, retinoic acid, and dexamethasone.
7. A method according to claim 5 which comprises topical
application to pigmented skin of a composition comprising from
about 2 to about 5 weight percent hydroquinone, from about 0.05 to
about 0.1 weight percent retinoic acid, and from about 0.05 to
about 0.1 weight percent hydrocortisone-17-valerate in a
pharmaceutically acceptable vehicle for topical application and
continuing such application until depigmentation is achieved.
8. A method according to claim 5 which comprises topical
application to pigmented skin of a composition comprising from
about 2 to about 5 weight percent hydroquinone, from about 0.05 to
about 0.1 weight percent retinoic acid, and from about 0.05 to
about 0.1 weight percent dexamethasone in a pharmaceutically
acceptable vehicle for topical application.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a synergistic and non-sensitizing
composition for depigmentation of mammalian skin for use by topical
application.
2. Description of the Prior Art
So-called compositions for bleaching skin have been known for many
years. The use of hydroquinone and its derivatives as agents in
bleaching creams is shown in the following publications:
A. U.S. Pat. No. 3,060,097, issued Oct. 23, 1962 to a
skin-bleaching composition comprising sodium hypochlorite,
hydroquinone monobenzyl ether and a "penetrant." Three British Pat.
Nos. 763,029, 856,431 and 965,869 issued to the same inventor on
similar compositions.
B. French Pat. No. 1,513,395, issued Jan. 8, 1968 to a
skin-bleaching composition comprising hydroquinone monobenzyl ether
or a derivative thereof in combination with tyrothricin or a
derivative thereof.
C. French Pat. No. 1,270,854, issued July 24, 1961 to a
skin-bleaching composition comprising hydroquinone benzyl ether (l'
ether de benzylhydroquinone) and an anti-oxidant. The product may
be formulated to contain vitamins, amino acids, cholesterol,
etc.
D. U.S. Pat. Nos. 2,274,725 (Mar. 3, 1942), 2,376,884 (May 29,
1945) and 2,377,188 (May 29, 1945) are to sunscreen preparations
comprising hydroquinone as the active sunfilter agent. These
preparations are stabilized by the addition of certain
anti-oxidants.
E. Zschr. Haut-Geschl.-Krkh. 42, 17: 711- 716 reports studies of
bleaching the skin using hydroquinone monobenzyl ether. When a
subject was found to have sensitive skin, 5 percent hydroquinone
monobenzyl ether and 4 percent prednisolone was used to prevent or
control the contact dermatitis produced by the hydroquinone
monobenzyl ether. No mention is made of an improved bleaching
effect when the preparation contained prednisolone.
F. Some other articles reporting on skin-bleaching by the use of
hydroquinone or its derivatives are:
1. Archives of Dermatology, 84, No. 1 131-184 (July, 1961).
2. Clinical Medicine, 70, No. 6, 1111- 1114 (June, 1963).
3. Clinical Medicine, 73, No. 3, 87-80 (Mar., 1966).
4. Postgraduate Medicine, 37, No. 2, 198-201 (Feb., 1965).
5. J. Investigate Dermatology, 18, 119-135 (1952).
6. J. Am. Medical Assoc., 152, No. 7, 577-582 (June 13, 1953).
7. Dermatologica, 134, 125-128 (1967).
8. Archives of Dermatology, 93, No. 5 589-600 (May, 1966).
SUMMARY OF THE INVENTION
Broadly stated the instant invention is concerned with a method for
lightening or depigmenting mammalian skin and to compositions which
are synergistic with respect to depigmentation and essentially
nonsensitizing to the skin. These compositions comprise
hydroquinone or a nonsensitizing derivative thereof, retinoic acid,
and a corticosteroid.
The composition is used by applying, preferably on a regular
treatment schedule to the area of skin to be treated until
relatively complete and permanent depigmentation is achieved. The
composition can be applied to the skin with or without any dressing
but occlusive dressing has been found to facilitate depigmentation.
In general, the depigmentation is reversible and cessation of
treatment may lead to repigmentation unless a sustaining regimen to
treatment is continued. Such a regimen may include less frequent
application of the herein disclosed composition or daily treatment
with hydroquinone alone.
It has long been desirable that certain skin disorders or diseases
of the skin be treated to reduce hyperpigmentation generally caused
by the deposition of excess quantities of melanin. This
hyperpigmentation is generally viewed as cosmetically undesirable
and psychologically disabling. Examples of such hyperpigmentation
include freckles, senile lentigo, lentigines (liver spots),
melasma, contact allergy pigmentation, vitiligo, sunburn
pigmentation, post-inflammatory hyperpigmentation due to abrasion,
burns, wounds, dermatitis, phototosic reaction and other similar
small, fixed pigmented lesions. It is also often desirable to
decolorize normally pigmented skin to generally increase "fairness"
of appearance or to blend hypopigmented areas into surrounding
normal skin, for example in the treatment of generally dark-skinned
people suffering from vitiligo.
It is an object of this invention to provide an effective treatment
for hyperpigmentation of skin.
Another object of the invention is to provide compositions which do
not induce sensitization reactions in subjects treated for
hyperpigmentation.
A further object of the invention is to provide an effective method
for reduction of melanin levels in the tissue in both
hyperpigmented and normally pigmented skin.
A still further object of the invention is to provide compositions
which can effectively reduce pigmentation by a process which
involves either or both the production of melanin or its transfer
but without damage to the melanoblasts themselves.
These and other related objects are achieved by the compositions of
this invention which comprise retinoic acid, a corticosteroid, and
a depigmentation agent which operates by interfering with or
inhibiting the normal pigmentation process. More specifically, a
composition comprising retinoic acid, hydroquinone, and a
corticosteroid has been found to be particularly effective in
achieving a controllable degree of depigmentation of both
hyperpigmentated and normally pigmented skin. Depigmentation is
controllable to the extent that pigmentation in normally pigmented
skin can be preserved at the normal level thus allowing blending of
normal and hyperpigmented areas.
Compounds heretofore known as skin bleaching agents include
hydroquinone, hydroquinone monoethyl ether, hydroquinone monobenzyl
ether, ammoniated mercury, zinc peroxide, mercurous chloride and
bichloride of mercury. These compounds are associated with
disadvantages which include sensitization, ineffectiveness,
irritation and lack of predictable results. For the most part,
useful levels of active ingredient provide only partial
depigmentation. This is true even of hydroquinone, the material
most widely recognized in the treatment of pigmentation conditions.
However, when used in combination with retinoic acid and a
corticosteroid, the melanin-inhibiting ability of the hydroquinone
is synergistically and unexpectedly enhanced.
It has been found that a preparation containing about 2%
hydroquinone without other ingredients is unpredictable and not
always effective. Similar results have been reported in the
literature, i.e., Clinical Medicine, 73, No. 3, 87-88 [Mar., 1966]
wherein 35 percent of those subjects treated showed excellent
results, 5 percent good, 35 percent fair and 25 percent poor.
Moreover, combinations of a corticosteroid such as dexamethasone
and hydroquinone even under occlusion did not provide complete
depigmentation after 6 to 8 weeks of twice-daily treatment.
Similarly, the combination of hydroquinone and retinoic acid was
ineffective to provide complete depigmentation, i.e., less
pigmentation than is normally present in persons having white
skin.
Other compounds capable of causing exfoliation of skin was
substituted for retinoic acid but were not effective in achieving
complete depigmentation.
Corticosteroids which can be used include those usually used in the
topical treatment of skin conditions. Illustrative compounds
include corticosteroids selected from the group comprising
hydrocortisone, cortisone, prednisolone, prednisone, dexamethasone,
betamethasone, fluocinolone acetonide, triamcinolone, fluocinolone,
triamcinolone acetonide, methylprednisolone, fluorometholone, or an
ester thereof when chemically possible, formulated in a
pharmaceutically-cosmetically acceptable vehicle. Esters of
corticosteroids are disclosed in U.S. Pat. Nos. 3,694,471;
3,152,154; and 3,147,249.
Subsequent investigations to improve depigmentation has
unexpectedly shown that a composition containing hydroquinone,
dexamethasone, and retinoic acid produced good to excellent results
in essentially all of the subjects treated. Results equivalent to
those obtained with the combination can not be achieved by any of
the individual components alone.
The compositions of the present invention are applied according to
the following general regimen:
In the case of the formulation of example 1, the composition was
applied two to three times daily to the areas to be bleached. The
composition is preferably applied three times a day for 2 days,
then two times a day till irritation (mild inflammation) can be
seen. Depending upon the degree of irritation, the composition is
applied once or twice a day till depigmentation occurs.
Depigmentation usually begins to occur 5 to 21 days after the
initial application. Depigmentation is usually complete within 6 to
10 weeks.
In patients with recurrent or permanent hyperpigmentation (Negroes,
other dark-skinned races), depigmentation can be maintained by
several applications per week.
The results produced by the application of the above composition
are exceptionally good. In almost 100 percent of the subjects so
treated, good to excellent depigmentation was obtained. The results
were particularly dramatic in normal Negro skin, whereon the skin
was bleached white in the majority of subjects so treated.
The active ingredients of this composition can be formulated into
any cosmetically or pharmaceutically acceptable vehicle or base.
Such vehicle formulations are well-known and are disclosed in the
literature, e.g., in Cosmetics and The Skin by Wells and Lubowe,
Reinhold Publishing Corporation, N.Y., 1964. A particularly
suitable vehicle comprises a 1 to 1 mixture of ethanol and
propylene glycol and may also include a stabilizer, perfumes and
other usual adjuants.
The following examples illustrate formulations of hydroquinone,
retinoic acid and suitable corticosteroid.
EXAMPLE 1
Hydroquinone 2% Retinoic Acid 0.05% Fluorometholone 0.025%
Fragrance q.s. Propylene glycol Ethanol (95%) aa q.s. ad 100
ml.
Finely pulverize the hydroquinone, retinoic acid and
fluorometholone and dissolve in about 80 ml. of the 50:50 mixture
of propylene glycol and ethanol. Add the fragrance and q.s. ad to
100 ml. Mix well and apply to area to be bleached.
EXAMPLE 2
Substitution in the formula of Example 1 for the fluorometholone
used therein of 0.025 percent of desamethasone produces an
equivalent formulation.
EXAMPLE 3
Hydroquinone 2% Retinoic acid 0.05% Fluorometholone 0.025%
Vanishing Cream base q.s. as 100 gm.
Finely pulverize the hydroquinone, retinoic acid and
fluorometholone. Add a small quantity of the vanishing cream base
and mix well to obtain a gritless paste. Add additional vanishing
cream base to make 100 gm. of product. Mix well and apply.
EXAMPLE 4
Hydroquinone 2% Retinoic acid 0.05% Fluorometholone 0.025% Emolient
lotion q.s. ad 100 ml.
Finely pulverize the hydroquinone, retinoic acid and
fluorometholone. Add a small quantity of the emolient lotion to the
powder to make a gritless paste. Add sufficient lotion to make 100
ml. Mix well and apply.
EXAMPLE 5
Hydroquinone 2% Retinoic acid 0.05% Hydrocortisone 2.5% Vanishing
cream base q.s. ad 100 gm.
This formulation was prepared according to Example 3.
EXAMPLE 6
Hydroquinone 5% Retinoic acid 0.05% Fluoromethonone 0.05% Vanishing
cream base q.s. ad 100 gm.
This formulation was prepared according to Example 3.
A particularly preferred formulation for depigmentation was found,
by trial and error, to comprise dexamethasone about 0.1 percent,
retinoic acid about 0.1 percent, and hydroquinone about 5.0 percent
in a hydrophillic ointment (V.S.P.) base to make 100 percent by
weight. This composition was found to regularly depigment black
skin when used twice daily for a period of 4 to 5 weeks.
In general, it has been found that effective formulations having an
unexpected degree of activity can contain from about 1 to about 5
weight percent hydroquinone and preferably from about 2 to about 5
weight percent hydroquinone.
The amount of retinoic acid can range from about 0.05 to about 2
percent by weight with the preferred range being from about 0.05 to
about 0.1 weight percent.
Similarly the amount of corticosteroid can range from about 0.05 to
about 2 weight percent depending on the particular steroid used. In
a preferred formulation dexamethasone in amounts of from about 0.05
to about 0.1 weight percent has been found to give excellent
results.
In a series of clinical studies, 69 patients with melasma were
treated with topical preparations identified as A, B and C in a
double blind manner. The composition of preparations A, B and C are
set forth below.
______________________________________ Preparation A -- 2%
hydroquinone Preparation B -- 2% hydroquinone, 0.05% retinoic acid,
and 0.05% dexamethasone Preparation C -- 5% hydroquinone, 0.1%
retinoic acid, and 0.1% dexamethasone
______________________________________
Results are expressed in terms of excellent, good, fair, and poor
based on the observation of the melasma at the beginning and the
end of the study and upon photographic comparisons.
Table I, below shows the number of subjects and the classification
of results obtained for each of the test compositions.
Table I ______________________________________ A B C
______________________________________ Excellent 3 10 9 Good 2 3 7
Fair 8 1 3 Poor 4 3 1 Incomplete 6 6 3
______________________________________
Table II shows the total number of subjects falling into the
excellent and good classes and the corresponding percentage for
these completing the study for each composition.
Table II ______________________________________ A B C
______________________________________ Number 5 13 16 Percentage
29% 76% 80% ______________________________________
These results indicate that the presence of retinoic acid and
dexamethasone unexpectedly increase the degree of depigmentation
which can be achieved by the hydroquinone and that increasing the
amounts of the active ingredients above the level of composition B
does not greatly alter the results.
Some of the topical medication used in the above study invoked
moderate irritation. This irritation was present within the first 1
to 4 days of use of medication and became more severe with
continued twice a day application. Those patients who discontinued
the medication for 1 to 2 days and then gradually resumed use of
the topical medication at once daily or occasionally twice daily,
were able to tolerate the medication. Although in some patients the
inflammation continued throughout the study it could be easily
managed by occasionally skipping a day of use of the medication or
reducing the frequency of use to once a day. Many of the patients
who noted inflammation believed that the improvement or lightening
of the skin followed soon after the period of inflammation. Those
patients who made this observation were therefore motivated to
continue the use of the medication and these patients seemed to
improve more than the other subjects. Most patients who improved
did so during the second and third week of use of the medication,
although some did not improve unitl after the 6th week.
There were no incidences of contact dermatitis, allergic
manifestations to medicine, or idiosyncratic reactions. The only
side effect was the inflammation discussed above. In all cases the
inflammation was quickly reversible with discontinuation of the
medication. At its worst it consisted of erythema, itching, minimal
desqualmation and some mild burning of the skin.
* * * * *