Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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COMPOSITIONS AND METHODS FOR TREATMENT OF VITILIGO
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent
Application No.
61/288,688 filed on December 21, 2009, entitled "Compositions and Methods for
Treatment of
Vitiligo" and U.S. Provisional Patent Application No. 61/315,672 filed March
19, 2010, entitled
"Formulations for Skin Cream Compositions" by Sarah Bacus, both of which are
hereby
incorporated by reference.
TECHNICAL FIELD
[0002] The present invention relates to a novel skin composition that
stops progression of
vitiliga The invention further relates to a composition containing a compound
functioning to
inhibit T-cell killing in the melanocytes. More specifically, the invention
relates to a composition
containing rapamycin as an active ingredient. In addition, the invention can
contain fibroblast
growth factor as an active ingredient. The invention further relates to a
composition for promoting
the formation of collagen in the skin, wherein the composition comprises the
aforementioned
compound or compounds. The invention also relates to a method of treating
related skin signs of
aging (hollowing or sagging of skin) through use of the composition.
BACKGROUND
[0003] The aging process has multiple effects on the overall thickness and
elasticity of the
cells which comprise the skin. As skin ages, the amount of collagen produced
is decreased and the
type of collagen changes. In addition, the elastin in the skin decreases, the
melanin granules
collect into areas of dark-colored blemishes, the cells of the skin become
older and the layers of
expired cells increases. There are some remedies available to address these
problems.
Traditionally, retin-A is used to increase collagen production, decrease
elastin loss, decrease
production of metalloproteases ( which may cause oxidative damage to the
skin), disperse
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melanin granules and exfoliate the layers of dead skin cells from the skin.
However, retin-A has
some undesirable side effects and requires monitoring of sun exposure while
treating skin. There
are additional treatments for aging skin such as hydroquinone (bleaches skin
and slows melanin
production), alpha hydroxy acid (acts similar to retin-A), anti-oxidants (e.g.
Cellex-C, Prevage or
Revale). There is a continuing need for the development of skin care products
that aid in the
appearance of younger, more vibrant, healthy looking skin.
[0004] Vitiligo is an autoimmune disease presenting with progressive loss
of skin
pigmentation. Vitiligo is a cutaneous disease in which the melanocytes are
destroyed in discrete
patches, resulting in lightened areas of variable size and location
distributed throughout the skin
of the body. Melanocytes are cells located in the stratum basale (bottom
layer) of the skin's
epidermis. They are also located in the eye, ear, meninges, bones and heart.
Melanocytes
produce a pigment called melanin, a derivative of the amino acid tyrosine,
through the process of
melanogenesis. Variations in the activity of melanocytes and the production of
melanin is a
primary determinant of human skin color. The condition of vitiligo can also
affect eye
pigmentation and ear ftinction, as melanin is expressed in both the ear and
the uveal tract of the
eye. The lightened lesions of the skin are immunocompromised and generally
have greater
susceptibility to the damaging effects of the sun, premature aging and
possible cancer of the skin.
The disease strikes about 1% of the world population, generally during teenage
years. The
progressive loss of melanocytes from depigmenting vitiligo skin is accompanied
by cellular
infiltrates containing T lymphocytes. Infiltrating cytotoxic T cells with high
affinity T cell
receptors have likely escaped clonal deletion in the thymus, allowing such T
cells to enter the
circulation. It is thought that through the expression of cutaneous lymphocyte
antigen, these T
cells home to the skin where they express type 1-cytokine profiles and mediate
melanocyte
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apoptosis via the granzyme/perforin pathway. As this condition affects the
skin and is readily
visible to the public eye, there are many psychological and social problems
that can result.
Hence, there is a great need for continuing development of treatments that can
be used to
minimize the visible consequences of a condition such as vitiligo, as well as
other conditions
which manifest themselves as discolorations of the skin (aging spots, liver
spots, etc.).
SUMMARY OF THE INVENTION
[0005] Compositions are disclosed for cosmeceuticals that aid in the
retardation of the
progression of vitiligo. Methods for preparing cosmeceutical compositions for
treating vitiligo
are also disclosed. More specifically, the methods herein disclose the use of
rapamycin for
preventing the progression of vitiligo and the use of rapamycin and fibroblast
growth factor for
promoting collagen formation. In addition, methods for preparing cosmeceutical
compositions
resulting in a promotion of collagen are also disclosed. More specifically,
the methods herein
disclose the use of rapamycin and fibroblast growth factor for promoting
collagen formation.
[0006] In one aspect of the invention, the composition contains rapamycin
in a
cosmeceutically acceptable medium/vehicle that functions to reduce T-cell
degradation of
melanocytes and lessen the visual signs of vitiligo.
[0007] In another aspect of the invention, the composition contains
additional ingredients,
such as fibroblast growth factor to aid in collagen formation.
[0008] In yet another aspect of the invention, the composition contains
vitamin E.
[0009] In additional aspects of the invention, the composition contains
tromethamine,
glutathione peroxidase, and catalase.
[00101 In one embodiment, the invention is adminstered topically.
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[0011] In another embodiment, the compositions is formulated as a leave-on
product.
[0012] In yet another aspect of the invention, the composition contains
about 0.001 to 0.5%
by weight rapamycin.
[00131 In another embodiment, the composition contains about 0.1 to 0.2% by
weight
rapamycin
[00141 In yet another embodiment, the composition contains about 0.15% by
weight
rapamycin.
100151 In an additional embodiment the composition is used in a method of
treating vitiligo
involving topical administration of one of the rapamycin compositions
disclosed.
100161 In another embodiment, the composition is used in a method of
promoting collagen
production involving topical administration of one of the rapamycin
compositions disclosed
[0017] Another embodiment is a method of inhibiting T cells in melanocytes
by
administering an about 0.1uM to 100 uM of rapamycin composition to the cells.
DESCRIPTION OF THE DRAWINGS
[00181 These and other advantages of the present invention will be readily
understood with
reference to the following specifications and attached drawings wherein:
[0019] FIG. 1. Western blot of protein expression in Human Hepatocarcinoma,
HH, (T-
cell lymphoma) cells treated with increasing doses of rapamycin (0.1 ¨ 100
uM).
DETAILED DESCRIPTION
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[0020] Preferred embodiments of the present invention will be described
hereinbelow with
reference to the accompanying drawings. In the following description, well-
known functions or
constructions are not
[0021] In one aspect, the present invention is based on the discovery that
drugs, such as
rapamycin, actively inhibit T-cells and inhibit the process of T-cell
maturation in the
melanocytes. It has been further discovered that the use of rapamycin in
cosmeceutical medium
is an effective topical treatment for vitiligo. The response of vitiligo skin
cells to treatment with
rapamycin over a course of treatment (twice a day application of 2.5 uM
cosmeceutical
rapamycin composition) has shown response via reduction of the discoloration
and reduction in
the progression of the disease. In another aspect of the present invention,
the use of rapamycin
and fibroblast growth factor (FGF) promotes the production of collagen and
reduces the visible
effects of aging.
10022] Rapamycin (also called sirolimus) inhibits the response to
interleukin-2 (IL-2) and
blocks activation of T- and B-cells. Rapamycin binds to the cytosolic protein
FK-binding
protein 12 (FKBP12) and inhibits the mammalian target of rapamycin (mTOR)
pathway by
directly binding the mTOR Complex 1 (mTORC1).
100231 The treatment of vitiligo and the production of collagen with a
rapamycin
composition, an FGF composition or a rapamycin and FGF composition of the
present invention
has many desired effects in management of skin and skin disorders, including
anti-ageing, anti-
wrinkle and/or an anti-cellulite effects, minimizing the appearance of
wrinkles, blemishes, skin
lines, oily skin, acne, dry skin, xerosis, ichthyosis, dandruff, brownish
spots, keratoses, melasma,
lentigines, age spots, dark circles around eyes, skin pigmentation, topical
inflammation, liver
spots, pigmented spots, wrinkles, blemishes, skin lines, oily skin, acne,
warts, eczema, pruritic
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skin, psoriasis, inflammatory dermatoses, disturbed keratinization, dandruff,
bacterial infection,
fungal infection, wound healing, body odor, and skin changes associated with
aging.
[0024] Cosmetically acceptable vehicle
[00251 The composition according to the invention also comprises a
dermatologically/cosmetically acceptable vehicle to act as a diluent,
dispersant or carrier for the
rapamycin. The vehicle can comprise materials commonly employed in skin care
products such
as water, liquid or solid emollients, silicone oils, emulsifiers, solvents,
humectants, thickeners,
powders, propellants and the like. Other agents which can be employed in the
present
application as the dermatologically acceptable vehicle include fibroblast
growth factor (FGF),
tromethamine, glutathione peroxides, catalase, sphingoid and phospholipid
derivatives,
antioxidants and vitamins, antiinflammatories, botanical agents, moisturizing
agents, skin
whitening agents, peptides, caffeine and sunscreens and UV absorbers. Examples
of vehicle
ingredients include water, glycerin, hydrogenated polyisobutene, cetearyl
alcohol, ceteareth-20,
macadamia integrifolia seed oil (macademia nut oil), dimethicone, tocopheryl
acetate,
stearoxytrimethylsilane, stearyl alcohol, panthenol, farnesol, benzyl alcohol,
phenoxyethanol,
acrylates/C10-30 alkyl acrylate crosspolymer, sodium hydroxide, citric acid
for lotions or water,
petrolatum, glyceryl polymethacrylate, dicaprylyl ether, glycerin,
dimethicone, glyceryl stearate,
cetyl alcohol, prunus amygdalus dulcis (sweet almond) oil, PEG-30 glyceryl
stearate, tocopheryl
acetate, benzyl alcohol, phenoxyethanol, sodium hydroxide, acrylates/C10-30
alkyl acrylate
crosspolymer, disodium EDTA, propylene glycol for creams. A preferred vehicle
is Cetaphil .
Examples of some of the agents that can be added to the vehicle include:
sphingoid and
phospholipid derivatives (e.g. ceramides, phytosphingosine, sphingosine,
pseudoceramides,
phospholipids, lysophospholipids); antioxidants and vitamins (e.g. tocopherol
and derivatives,
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ascorbic acid and derivatives, niacinamide and derivatives, vitamin complexes,
alpha-lipoic acid,
retinol and derivatives, panthenol); antiinfiammatories (e.g. bisabolol,
allantoin, phytantriol,
Coenzyme Q10, Idebenone); botanical agents such as polyphenolics, flavonoids
or isofiavones;
moisturizing agents (e.g. amino acids, hyaluronic acid and derivatives,
creatine and derivatives,
trimethylglycine, myoinositol, pyroglutamatic acid and derivatives, taurine,
guanidine and
derivatives and hydroxy acids); skin whitening agents (e.g. kojic acid,
arbutin, vitamin C and
derivatives, hydroquinone); peptides, modified peptides, protein hydrolysates.
[00261 Formulation Table
Rapamycin (FW=914.17)
200 mg in 500 ul DMSO (0.4 mg/up
Desired Desired Total Amount Amount Amount of Stock
Conc. Percent Volume/Mass Active Active
Conc. (% Desired Ingredient Ingredient
w/v) (mgs)
0.005 0.5 15 gms 0.075 gms 75 mgs 187.5 uls of the 0.4
0.001 0.1 15 gms 0.015 gms 15 mgs 37.5 uls of the 0.4
0.0005 0.05 15 gms 0.0075 gms 7.5 mgs 18.75 uls of the 0.4
0.0001 0.01 15 gms 0.0015 gms 1.5 mgs 3.75 uls of the 0.4
0.00005 0.005 15 gms 0.00075 gms 0.75 mgs 1.875 uls of the 0.4
[00271 The cosmeceutically effective amount of rapamycin that is used in
the
cosmeceutically acceptable composition has a concentration of about 0.5% to
0.00001%
rapamycin preferably from about 0.5% to 0.1%. The cosmeceutically effective
amount of
rapamycin is partially dependent on the cells or the individual being treated
and higher
concentrations may be necessary to achieve desired results, in addition higher
concentrations
may result in increased side effects. The Formulation Table shows exemplary
calculations for
producing products of 0.01% and 0.005% rapamycin, similar calculations can be
used to produce
a cosmeceutically acceptable composition at the desired concentration. For
example some
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preferred amounts of ingredients that may be used in any combination in the
composition with
gms of vehicle are indicated: addition of about 15 mgs of rapamycin is
preferred (about
0.15% by weight), addition of about 0.5 ugm to about 1.5 ugm of fibroblast
growth factor is
preferred (about 0.00005% to 0.00015% by weight), addition of about 0.5 gins
of tromethamine
is preferred (about 0.5% by weight), addition of about 30 mgs of glutathione
peroxides is
preferred (about 0.3% by weight), addition of about 30 mgs of catalase is
preferred (about 0.3%
by weight), and addition of about 500 mgs of vitamin E is preferred (about
0.5% by weight).
[0028] The dermatologically acceptable vehicle will usually form from about
80% to about
99.999%, preferably from about 95% to about 99.985% and most preferably about
99.985% by
weight of the composition, and can, in the absence of other cosmetic adjuncts,
form the balance
of the composition. In a preferred embodiment, the rapamycin is maintained at
a concentration
of about 0.15% by weight in a cosmeceutically acceptable medium. In another
preferred
embodiment, the fibroblast growth factor is maintained at a therapeutically
effective
concentration of about 0.000015% to about 0.00005% in a cosmeceutically
acceptable medium.
In another embodiment, the rapamycin and FGF together, comprise about 0.15% by
weight in a
cosmeceutically acceptable medium.
[0029] The skin care formulation can be an aqueous solution, a water-in-oil
(w/o)
emulsion, an oil-in-water (o/w) emulsion, a dispersion of lipids, an aqueous,
water-alcohol, oil or
oil-alcohol gel, a solid stick, a wet-wipe or an aerosol. If the
dermatologically acceptable vehicle
itself is an (w/o) or (o/w) emulsion, it can contain 5 to 50% of an oilphase
and 47 to 94.95%
water, with respect to the weight of the whole formulation.
[0030] Product Preparation, Form, Use and Packaging
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[0031] To prepare the topical composition according to the present
invention, the usual
manner for preparing skin care products may be employed. The active components
are generally
incorporated in a dermatologically acceptable carrier in conventional manner.
The active
components can suitably be dissolved or dispersed in a portion of the water or
another solvent or
liquid to be incorporated in the composition. The preferred compositions are
oil-in-water or
water-in-oil emulsions.
[0032] The composition may be in the form of conventional skin-care
products such as a
cream, gel or lotion or the like. The composition can also be in the form of a
so-called "rinse-off'
product, e.g., a bath or shower gel, possibly containing a delivery system for
the actives to
promote adherence to the skin during rinsing. Most preferably, the product is
a "leave-on"
product; a product to be applied to the skin without a deliberate rinsing step
soon after its
application to the skin.
[0033] The composition may be packaged in any suitable manner such as in
ajar, a bottle,
tube, roll-ball, or the like, in the conventional manner.
[0034] The active ingredients described in the present invention may be
applied one or
more times daily to the portion of skin requiring treatment. The improvement
in skin appearance
will usually become visible after two weeks of treatment, depending on the
status of the initial
skin condition, the concentration of the active components used in the
composition, the volume
of composition used and the frequency of application.
[0035] In one embodiment, a small quantity, about 0.25 ml, of the
composition is applied
to the skin from a suitable container or applicator and spread over and/or
rubbed into the skin
using the hands or fingers or a suitable device. The composition is formulated
as a "leave-on"
product and does not require any gloves or special applicators for effective
use. Once applied to
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the skin in the affected area, the composition will begin to elicit the
desired effects for treating
vitiligo and promoting collagen production.
[0036] Example 1
100371 As shown in Fig. 1, Human Hepatocarcinoma, HH, cells were treated
with
increasing doses of rapamycin (0.1 ¨ 100 uM) and the protein expression
profile was analyzed by
Western blot. The rapamycin treatment resulted in increased expression of
pAcc
(phosphorylated acetyl-CoA carboxylase), slightly increased expression of
peEF2
(phosphorylated eukaryotic elongation factor 2) and decreased expression of
pS6
(phosphorylated ribosomal protein S6). The expression levels of Actin are
maintained and serve
as a loading control. The increased expression of pAcc and peEF2, and the
decreased expression
of pS6 illustrate an inhibition of T-cells.
[0038] Example 2¨ Vitiligostop
[0039] Natural sources of anti fungal agents help to stop the rejection of
melanin
producing cells which causes the depigmentation of the skin. Vitilogstop is
not a cure, but
provides a noticeable diminishment of discoloration and enlargement of
vitiligo spots usually
after three months. Combined with other active ingredients, stimulation of new
melanin occurs
over time. Apply twice a day on affected sites. The cream may oxidize and
darken
with time but will remain effective throughout use.
Vitilgostop Amount per 10gms
Rapamycin 15 milligrams
Fibroblast Growth Factor 2 1.5 micrograms
Tromethamine 0.5%
Glutathaion Peroxides 30 milligrams
Catalase 30 milligrams
Vitamin E 500 milligrams
Vehicle 10 grams
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100401 Formulation Example:
[0041] A 0.4 mg/ul Rapamycin composition is made in DMSO as a stock
solution, from
which an aliquot of 187.5 uls of the stock solution is added to 200 gms of
lotion or
cosmeceutically acceptable medium and mixed thoroughly. An FGF composition is
made
following a similar protocol for a cosmeceutically acceptable medium and mixed
thoroughly.
Additional concentrations can be made from a concentrated stock solution by
methods known to
one of ordinary skill in the art. The cosmeceutical formulation (lotion) can
be stored at ambient
temperature for topical use on those areas of the skin wherein additional
lipid production is
desired.
100421 While the present invention has been described with respect to what
is presently
considered to be the preferred embodiments, it is to be understood that the
invention is not
limited to the disclosed embodiments. To the contrary, the invention is
intended to cover various
modifications and equivalent arrangements included within the spirit and scope
of the appended
claims. The scope of the following claims is to be accorded the broadest
interpretation so as to
encompass all such modifications and equivalent structures and functions.
[0043] All U.S. and foreign patent documents, all articles, brochures, and
all other
published documents discussed above are hereby incorporated by reference into
the Detailed
Description of the Preferred Embodiment.
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