U.S. patent application number 09/116632 was filed with the patent office on 2001-05-31 for compositions and methods of treating skin conditions.
Invention is credited to ACHKAR, CHARLES.
Application Number | 20010002396 09/116632 |
Document ID | / |
Family ID | 22368338 |
Filed Date | 2001-05-31 |
United States Patent
Application |
20010002396 |
Kind Code |
A1 |
ACHKAR, CHARLES |
May 31, 2001 |
COMPOSITIONS AND METHODS OF TREATING SKIN CONDITIONS
Abstract
A composition is described comprising a vitamin D analog and a
retinoid, wherein: (a) the vitamin D analog is capable of binding a
vitamin D receptor or being converted in vivo into a compound
capable of binding a vitamin D receptor; and (b) the retinoid is
selected from the group consisting of a compound capable of binding
a retinoic acid receptor, retinol in a concentration of at least
about 0.1% and a compound in a concentration of at least about 0.%
capable of being converted in vivo into retinol. Further, methods
of treating disorders characterized by abnormal cell-proliferation
and/or cell-differentiation are also described.
Inventors: |
ACHKAR, CHARLES; (NORTH
BERGEN, NJ) |
Correspondence
Address: |
CHARLES C ACHKAR
7855 BOULEVARD EAST # 26G
NORTH BERGEN
NJ
07047
|
Family ID: |
22368338 |
Appl. No.: |
09/116632 |
Filed: |
July 16, 1998 |
Current U.S.
Class: |
514/167 |
Current CPC
Class: |
A61P 17/06 20180101;
A61Q 19/08 20130101; A61K 31/59 20130101; A61K 2300/00 20130101;
A61K 31/215 20130101; A61K 31/07 20130101; A61K 31/20 20130101;
A61K 31/59 20130101; A61P 17/00 20180101; A61Q 5/065 20130101; A61K
31/59 20130101; A61Q 19/007 20130101; A61K 31/59 20130101; A61K
31/59 20130101; A61K 8/671 20130101; A61K 45/06 20130101; A61K 8/67
20130101; A61K 31/59 20130101; A61K 31/59 20130101; A61P 17/14
20180101; A61Q 7/00 20130101; A61Q 19/00 20130101; A61P 43/00
20180101 |
Class at
Publication: |
514/167 |
International
Class: |
A61K 031/59 |
Claims
What is claimed is:
1. A composition comprising a vitamin D analog and a retinoid,
wherein: (a) the vitamin D analog is capable of binding a vitamin D
receptor or being converted in vivo into a compound capable of
binding a vitamin D receptor; and (b) the retinoid is selected from
the group consisting of a compound capable of binding a retinoic
acid receptor, retinol in a concentration of at least about 0.1%
and a compound in a concentration of at least about 0.1% capable of
being converted in vivo into retinal.
2. A topical composition according to claim 1.
3. The composition of claim 1, wherein the vitamin D analog is
selected from the group consisting of cholecalciferol, calcifediol,
calcitriol, calcipotriol, ergocalciferol, dihydrotachysterol,
1,25-dihydroxyergocalci- ferol, and
25-hydroxydihydrotachysterol.
3. The composition of claim 1, wherein the vitamin D analog is
calcitriol.
4. The composition of claim 1, wherein the vitamin D analog is
calcipotriol.
5. The composition of claim 1, wherein the retinoid is retinal.
6. The composition of claim 1, wherein the retinoid is a retinyl
ester.
7. The composition of claim 1, wherein the vitamin D analog is
calcitriol or calcipotriol at a concentration of about 0.005% and
the retinoid is a retinyl ester at a concentration of about 5%.
8. The composition of claim 6, wherein the retinyl ester is retinyl
palmitate.
9. The composition of claim 1, wherein the retinoid is retinal.
10. A method of treating a subject suffering from a disorder
characterized by abnormal cell-proliferation and/or
cell-differentiation, in which a composition according to claim 1
is administered to the subject in need of such treatment.
11. A method of treating a subject suffering from a disorder
selected from the group consisting of psoriasis, acne, eczema,
rosacea, actinic keratosis, seborrheic dermatitis, and congenital
keratinization disorders, in which a composition according to claim
1 is administered to the subject in need of such treatment.
12. The method of claim 11, wherein the disorder is psoriasis.
13. The method of claim 11, wherein the disorder is eczema.
14. The method of claim 11, wherein the disorder is acne.
15. A method of treating one or more conditions of the skin
selected from the group consisting of dry skin, photodamaged skin,
age spots, aged skin, increasing stratum corneum flexibility,
wrinkles, fine lines, actinic blemishes, skin dyschromias, and
ichthyosis, comprising applying to the skin having said one or more
condition the composition of claim 1.
16. A composition comprising retinol in a concentration of at least
about 1.5% or a compound in a concentration of at least about 1.5%
capable of being converted in vivo into retinol.
17. A method of treating one or more conditions of the skin
selected from the group consisting of dry skin, photodamaged skin,
age spots, aged skin, increasing stratum corneum flexibility,
wrinkles, fine lines, actinic blemishes, skin dyschromias,
ichthyosis and acne, comprising applying to the skin having said
one or more condition the composition of claim 16.
18. The method of claim 17, wherein the skin condition is acne.
19. The method of claim 17, wherein the skin condition is actinic
blemishes.
20. The method of claim 16, wherein the skin condition is fine
wrinkles.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to compositions comprising
certain retinoids and vitamin D analogs useful in inducing
differentiation and inhibiting undesirable proliferation of cells,
such as cancer cells and skin cells. The present invention also
relates to methods of using the above compositions in the treatment
of diseases and conditions characterized by abnormal cell
differentiation and/or cell proliferation.
DESCRIPTION OF THE RELATED ART
[0002] Abnormal cell differentiation and/or cell differentiation is
associated with many conditions and diseases. For instance,
hyperproliferation of epithelial cells is associated with psoriasis
causes the skin to shed itself too rapidly, every three to four
days. The goal in treating psoriasis is to reduce inflammation and
to slow down rapid skin cell division.
[0003] U.S. Pat. No. 4,866,048 discloses that certain vitamin D
derivatives, in particular calcitriol (1 alpha,25-dihydroxy-vitamin
D.sub.3 or) and calcipotriol are able to stimulate the
differentiation of cells and inhibit excessive cell proliferation,
and it has been suggested that these compounds are useful in the
treatment of diseases characterized by abnormal cell
differentiation and/or cell differentiation such as leukemia,
myelofibrosis, psoriasis and acne.
[0004] Certain retinoids are also known for their antiproliferative
and differentiation activity. For instance, retinol (vitamin A) is
an endogenous compound which occurs naturally in the human body and
is essential for normal cell differentiation of certain cell types
such as epithelial cells. Retinoic acid is believed to be an active
derivative of retinol. Thus, retinoic acid is believed to be more
effective than retinol and retinyl esters at providing skin
benefits.
[0005] Natural and synthetic vitamin A derivatives (including
retinoic acid) have been used extensively in the treatment of a
variety of skin and hyperproliferation disorders. For example,
retinoic acid has been employed to treat certain types of leukemia
like acute apromyelocytic leukemia as well as a variety of skin
conditions such as acne, wrinkles, psoriasis, age spots and
discoloration (Vahlquist, A. et al., J. Invest. Dermatol., Vol. 94,
Holland D. B. and Cunliffe, W. J. (1990), pp. 496-498; Ellis C. N.
et al., "Pharmacology of Retinols in Skin", Vasel, Karger, Vol. 3,
(1989), pp.249-252; Lowe, N. J. et al., Vol. 3, (1989), pp.
240-248; PCT Patent Application No. WO 93/19743). Although
retinoids have been viewed classically as cancer prevention agents,
considerable laboratory evidence supports their testing as
antitumor drugs as well (Cancer Treat Rep 1987; 71: 493-515 May,
1987).
[0006] It is important to note that while clinical experience with
either retinoids or vitamin D derivatives against conditions
associated with abnormal cell differentiation and/or cell
differentiation has met with certain amount of success in some
instances, these compounds have frequently been unable to provide
the desired clinical results.
[0007] For instance, the synthetic Vitamin D, calcipotriol, or
retinoic acid which are available in prescription form are somewhat
useful for individuals with localized psoriasis. However, these
compound are not very effective on most patients.
[0008] Therapeutic regimens for acne involve local and systemic
therapies, although the former is indicated in the vast majority of
cases. Topical application of a variety of chemical application
which include mainly sulfur, resorcinol, salicylic acid, benzoyl
peroxide, and retinoic acid are frequently used to treat acne. All
the foregoing agents are known as "peeling" or "drying" agents
which are believed to exert their therapeutical effect by causing
erythema, irritation, and desquamination of the skin to expel
comedones. The therapeutic efficacy of these agents, however, is
rather variable, and their utility is limited partially because of
the irritation caused by their application (see U.S. Pat. No.
3,932,665). Oral formulations of retinoic acid are also used but
serious side effects are associated with the oral use of this
compound including severe fetal malformation in pregnant women.
SUMMARY OF THE INVENTION
[0009] It is an object of the present invention to provide
compositions comprising certain vitamin D and retinoid compounds at
particular concentrations which are useful for the treatment of
disorders characterized by abnormal cell-proliferation and/or
cell-differentiation.
[0010] In one embodiment, the present invention provides a
composition comprising a vitamin D analog and a retinoid,
wherein:
[0011] (a) the vitamin D analog is capable of binding a vitamin D
receptor or being converted in vivo into a compound capable of
binding a vitamin D receptor; and
[0012] (b) the retinoid is selected from the group consisting of a
compound capable of binding a retinoic acid receptor, retinol in a
concentration of at least about 0.1% and a compound in a
concentration of at least about 0.1% capable of being converted in
vivo into retinol.
[0013] In yet another embodiment, the present invention provides a
composition comprising retinol in a concentration of at least about
1.5% or a compound in a concentration of at least about 1.5%
capable of being converted in vivo into retinol.
DETAILED DESCRIPTION OF THE INVENTION
[0014] In accordance with the invention, It has been surprisingly
discovered that a composition comprising (i) a vitamin D analog;
and (ii) a retinoid selected from the group consisting of a
compound capable of binding a retinoic acid receptor, retinol in a
concentration of at least about 0.1% and a compound in a
concentration of at least about 0.1% capable of being converted in
vivo into retinol, is useful in treating a subject suffering from a
disorder characterized by abnormal cell-proliferation and/or
cell-differentiation more effectively than either a composition
comprising a vitamin D analog without the above defined retinoid or
a composition comprising the above retinoid without a vitamin D
analog. Preferably, the abnormal cell proliferation is associated
with cancer cells and more preferably with skin cancer such as
melanoma. Also more preferably, the abnormal cell proliferation is
associated with cancer cells that can at least partially respond to
hormone or retinoid treatment.
[0015] The present invention also provides a method of treating a
subject suffering from a disorder selected from the group
consisting of psoriasis, acne, eczema, rosacea, actinic keratosis,
seborrheic dermatitis, and congenital keratinization disorders, in
which any composition of the present invention is administered to
the subject in need of such treatment. Preferably, the disorder is
psoriasis, eczema, or acne.
[0016] The present invention further provides a method of treating
one or more conditions of the skin selected from the group
consisting of dry skin, photodamaged skin, age spots, aged skin,
increasing stratum corneum flexibility, wrinkles, fine lines,
actinic blemishes, skin dyschromias, and ichthyosis, comprising
applying to the skin having said one or more condition any
composition of the present invention. Preferably, the skin
condition is actinic blemishes or fine wrinkles.
[0017] For the purpose of this invention, the term "vitamin D
analog" is defined as a compound capable of binding a vitamin D
receptor (not necessarily all) or being converted in vivo into a
compound capable of binding a vitamin D receptor (not necessarily
all). The term "vitamin D analog" includes but is not limited to
vitamin D.sub.2 and virtaminD.sub.3 derivatives such as
cholecalciferol, calcifediol, calcitriol, calcipotriol, ergosterol,
ergocalciferol, dihydrotachysterol, 1, 25- dihydroxyergocalciferol,
25-hydroxydihydrotachysterol, and the vitamin D analogs disclosed
in U.S. Pat. No. 4,866,048. Preferred analogs are cholecalciferol,
calcifediol, calcitriol, calcipotriol and the vitamin D analogs
disclosed in U.S. Pat. No. 4,866,048. More preferred analogs are
cholecalciferol, calcifediol, calcitriol and calcipotriol. Most
preferred analogs are calcitriol and calcipotriol.
[0018] The concentration of the vitamin D analog may vary from
about 0.0001% to about 10% by weight of the total composition of
the invention. Preferably, the concentrations employed of vitamin D
analogs that can directly bind to the vitamin D receptors, range
from about 0.0001% to about 1%, more preferably from about 0.0005%
to about 0.05%, still more preferably from about 0.009% to about
0.5%, yet still more preferably from about 0.001 to about 0.008%,
and most preferably at about 0.005%.
[0019] Preferably, the concentration employed of vitamin D analogs
that can be converted in vivo to a compound capable of binding a
vitamin D receptor is from about 0.001% to about 10%, more
preferably from about 0.01% to about 8%, still more preferably from
about 1% to about 6%, and most preferably from about 2% to about
5%.
[0020] The retinoids that are capable of binding to a retinoic acid
receptor (not necessarily all) include but are not limited to many
synthetic retinoids such as etretineate, all-trans-retinoic acid,
9-cis-retinoic acid, 4-oxo-retinoic acid, 4-oxo-retinol, and
4-oxo-retinal. The preferred retinoid that is capable of binding to
retinoic acid receptors is all-trans-retinoic acid and
4-oxo-retinol. Most preferably, 4-oxo-retinol. Preferably, the
concentration of these retinoids in the compositions of the
invention ranges from about 0.001% to about 1%, more preferably
from about 0.025% to about 0.1%, most preferably about 0.05%.
[0021] Also, for the purpose of this invention, the term "retinol"
includes but is not limited to the following: 4-oxo-retinol,
all-trans-retinol, 13-cis-retinol, 11-cis-retinol, 9-cis-retinol,
3,4-didehydro-retinol. Preferred isomers are all-trans-retinol,
13-cis-retinol, 3,4-didehydro-retinol, and 9-cis-retinol. Most
preferred is all-trans-retinol due to its wide commercial
availability. The concentration employed of retinol is at least
about 0.1%, preferably at least 0.3% by weight of the total weight
of the composition. More preferably, the concentration such
retinoid is from about at 0.3% to about 20%, more preferably from
about 0.5% to about 15%, still more preferably from about 0.5% to
about 10%, still more preferably from about 1% to about 10%, still
more preferably from about 2% to about 10%, and most preferably
about 5%.
[0022] The retinoids that can be converted in vivo to a compound
capable of binding a retinoic acid receptor (not necessarily all)
include but are not limited to retinyl esters, 4-oxo-retinyl
esters, retinyl-glucoronides, retinoicacid-glucoronides, retinal,
3,4-didehydro-retinol, 13-cis-retinoic acid, 9-cis-retinoic acid.
Some retinoids bind a retinoic acid receptor and can also be
converted in vivo to a compound capable of binding a retinoic acid
receptor such as 13-cis-retinoic acid, 9-cis-retinoic acid, and
4-oxo-retinol. Compounds that are converted spontaneously by
isomerization are also included in the compounds of the
invention.
[0023] Retinyl ester is an ester of retinol and is capable of being
converted in vivo into retinol. Retinyl esters suitable for use in
the present invention include but are not limited to
C.sub.1-C.sub.30 esters of retinol, preferably C.sub.2-C.sub.20
esters, and most preferably C.sub.2, C.sub.3, and C.sub.6 esters
because they are commonly available. Examples of retinyl,esters
include but are not limited to: retinyl palmitate, retinyl formate,
retinyl acetate, retinyl propionate, retinyl butyrate, retinyl
valerate, retinyl isovalerate, retinyl hexanoate, retinyl
heptanoate, retinyl octanoate, retinyl nonanoate, retinyl
decanoate, retinyl undecandate, retinyl laurate, retinyl
tridecanoate, retinyl myristate, retinyl pentadecanoate, retinyl
heptadecanoate, retinyl stearate, retinyl isostearate, retinyl
nonadecanoate, retinyl arachidonate, retinyl behenate, retinyl
linoleate, and retinyl oleate.
[0024] The preferred retinyl esters for use in the present
invention are retinyl palmitate, retinyl acetate, retinyl
propionate and retinyl linoleate. More preferred retinyl esters are
retinyl palmitate and retinyl acetate. The most preferred retinyl
ester is retinyl palmitate.
[0025] The concentration employed of the retinoid that can be
converted in vivo to a compound capable of binding a retinoic acid
receptor is at least about 0.1%, preferably at least 0.3% by weight
of the total weight of the composition. More preferably, the
concentration such retinoid is from about at 0.3% to about 20%,
more preferably from about 0.5% to about 15%, still more preferably
from about 0.5% to about 10%, still more preferably from about 1%
to about 10%, still more preferably from about 2% to about 10%, and
most preferably about 5%.
[0026] It has also been surprisingly discovered that a composition
comprising retinol in a concentration of at least about 1.5% or a
compound in a concentration of at least about 1.5% capable of being
converted in vivo into retinol is as effective as retinoic acid in
treating one or more conditions of the skin selected from the group
consisting of dry skin, photodamaged skin, age spots, aged skin,
increasing stratum corneum flexibility, wrinkles, fine lines,
actinic blemishes, skin dyschromias, ichthyosis and acne. The term
"retinol" and the compounds capable of being converted into retinol
has been defined above. Preferably, for this composition, the
concentration employed of retinol or of the compound capable of
being converted in vivo into retinol is at least about 1.8%, more
preferably at least about 2% by weight of the total weight of the
composition. More preferably, the concentration such retinoid is
from about at 2% to about 20%, more preferably from about 2% to
about 15%, still more preferably from about 2% to about 10%, and
most preferably about 5%.
[0027] The compositions of the present invention are preferably
topical and/or pharmaceutical. They may be in the form of a cream,
ointment, and gel. They may also comprise a cosmetically acceptable
vehicle to act as a diluent, dispersant or carrier for the active
components in the composition, so as to facilitate their
distribution when the composition is applied to the skin.
[0028] Vehicles other than water can include liquid or solid
emollients, solvents, humectants, thickeners and powders. An
especially preferred nonaqueous carrier is a polydimethyl siloxane
and/or a polydimethyl phenyl siloxane. Silicones of this invention
may be those with viscosities ranging anywhere from about 10 to
10,000,000 centistokes at 25.degree. C. Especially desirable are
mixtures of low and high viscosity silicones. These silicones are
available from the General Electric Company under trademarks
Vicasil, SE and SF and from the Dow Corning Company under the 200
and 550 Series. Amounts of silicone which can be utilized in the
compositions of this invention range anywhere from 5% to 95%,
preferably from 25% to 90% by weight of the composition.
[0029] The cosmetically acceptable vehicle will usually form from
5% to 99.9%, preferably from 25% to 80% by weight of the emulsion,
and can, in the absence of other cosmetic adjuncts, form the
balance of the composition.
[0030] An oil or oily material may be present in the claimed
compositions, together with an emulsifier to provide either a
water-in-oil emulsion or an oil-in-water emulsion, depending
largely on the average hydrophilic-lipophilic balance (HLB) of the
emulsifier employed.
[0031] Various types of active ingredients may be present in
cosmetic compositions of the present invention. Various types of
active ingredients may be present in cosmetic compositions of the
present invention. Actives are defined as skin benefit agents other
than emollients and other than ingredients that merely improve the
physical characteristics of the composition. Although not limited
to this category, general examples include sunscreens and tanning
agents.
[0032] Sunscreens include those materials commonly employed to
block ultraviolet light. Illustrative compounds are the derivatives
of PABA, cinnamate and salicylate. For example, octyl
methoxycinnamate and 2-hydroxy-4-methoxy benzophenone (also known
as oxybenzone) can be used. Octyl methoxycinnamate and
2-hydroxy-4-methoxy benzophenone are commercially available under
the trademarks, Parsol MCX and Benzophenone-3, respectively. The
exact amount of sunscreen employed in the emulsions can vary
depending upon the degree of protection desired from the sun's UV
radiation.
[0033] Another preferred optional ingredient is selected from
essential fatty acids (EFAs), i.e., those fatty acids which are
essential for the plasma membrane formation of all cells (in
keratinocytes, EFA deficiency makes cells hyperproliferative).
Supplementation of EFA corrects this. EFAs also enhance lipid
biosynthesis of epidermis and provide lipids for the barrier
formation of the epidermis. The essential fatty acids are
preferably chosen from linoleic acid, gamma -linolenic acid, homo-
gamma -linolenic-acid, columbinic-acid, eicosa-(n-6,9,13)-trienoic
acid, arachidonic acid, gamma -linolenic acid, timnodonic acid,
hexaenoic acid and mixtures thereof.
[0034] Emollients are often incorporated into cosmetic compositions
of the present invention. Levels of such emollients may range from
about 0.5% to about 50%, preferably between about 5% and 30% by
weight of the total composition. Emollients may be classified under
such general chemical categories as esters, fatty acids and
alcohols, polyols and hydrocarbons.
[0035] Esters may be mono- or di-esters. Acceptable examples of
fatty di-esters include dibutyl adipate, diethyl sebacate,
diisopropyl dimerate, and dioctyl succinate. Acceptable branched
chain fatty esters include 2-ethyl-hexyl myristate, isopropyl
stearate and isostearyl palmitate. Acceptable tribasic acid esters
include triisopropyl trilinoleate and trilauryl citrate. Acceptable
straight chain fatty esters include lauryl palmitate, myristyl
lactate, oleyl eurcate and stearyl oleate. Preferred esters include
coco-caprylate/caprate (a blend of coco-caprylate and
coco-caprate), propylene glycol myristyl ether acetate, diisopropyl
adipate and cetyl octanoate.
[0036] Suitable fatty alcohols and acids include those compounds
having from 10 to 20 carbon atoms. Especially preferred are
compounds such as cetyl, myristyl, palmitic and stearyl alcohols
and acids.
[0037] Among the polyols which may serve as emollients are linear
and branched chain alkyl polyhydroxyl compounds. For example,
propylene glycol, sorbitol and glycerin are preferred. Also useful
may be polymeric polyols such as polypropylene glycol and
polyethylene glycol. Butylene and propylene glycol are also
especially preferred as penetration enhancers.
[0038] Exemplary hydrocarbons which may serve as emollients are
those having hydrocarbon chains anywhere from 12 to 30 carbon
atoms. Specific examples include mineral oil, petroleum jelly,
squalene and isoparaffins.
[0039] Another category of functional ingredients within the
cosmetic compositions of the present invention are thickeners. A
thickener will usually be present in amounts anywhere from 0.1 to
20% by weight, preferably from about 0.5% to 10% by weight of the
composition. Exemplary thickeners are cross-linked polyacrylate
materials available under the trademark Carbopol from the B. F.
Goodrich Company. Gums may be employed such as xanthan,
carrageenan, gelatin, karaya, pectin and locust beans gum. Under
certain circumstances the thickening function may be accomplished
by a material also serving as a silicone or emollient. For
instance, silicone gums in excess of 10 centistokes and esters such
as glycerol stearate have dual functionality.
[0040] Powders may be incorporated into the cosmetic composition of
the invention. These powders include chalk, talc, Fullers earth,
kaolin, starch, smectite clays, chemically modified magnesium
aluminum silicate, organically modified montmorillonite clay,
hydrated aluminum silicate, fumed silica, aluminum starch octenyl
succinate and mixtures thereof.
[0041] Other adjunct minor components may also be incorporated into
the cosmetic compositions. These ingredients may include coloring
agents, opacifiers, perfumes and preservatives (e.g.,
imidazolidinyl urea, dimethyl imidazolidinone and diazolidinyl
urea). Amounts of these materials may range anywhere from 0.001% up
to 20% by weight of the composition.
[0042] The composition according to the invention is intended
primarily but not exclusively as a product for topical application
to human skin are as a product to modulate cell differentiation. In
use, a small quantity of the composition, for example from 1 to 5
ml, is applied to exposed areas of the skin, from a suitable
container or applicator and, if necessary, it is then spread over
and/or rubbed into the skin using the hand or fingers or a suitable
device.
[0043] The topical skin treatment composition of the invention can
be formulated as a lotion having a viscosity of from 4,000 to
10,000 mPas, a fluid cream having a viscosity of from 10,000 to
20,000 mPas or a cream or a gel having a viscosity of from 20,000
to 100,000 mPas or above. The composition can be packaged in a
suitable container to suit its viscosity and intended use by the
consumer. For example, a lotion or fluid cream can be packaged in a
bottle or a roll-ball applicator, or a capsule, or a
propellant-driven aerosol device or a container fitted with a pump
suitable for finger operation. When the composition is a cream, it
can simply be stored in a non-deformable bottle or squeeze
container, such as a tube or a lidded jar.
[0044] The invention accordingly also provides a closed container
containing a cosmetically acceptable composition as herein
defined.
[0045] The following specific examples further illustrate the
invention, but the invention is not limited thereto.
EXAMPLE 1
[0046] This example compares therapeutically applied retinyl
palmitate, retinoic acid, calcitriol, and combinations thereof in a
cream at different concentrations with the effectiveness of the
cream without any of the above compounds present in treating acne.
The cream used is the commercially available LUBRIDERM cream. The
different compounds at different concentrations were added to the
cream and mixed very well. Sixty six volunteers were recruited and
were randomly assigned to each of the groups. The subjects were
selected on the basis of their having moderate to severe
papular-pustular acne. Each group consisted of 3 males and 3
females. No other acne treatment was permitted during the period.
Preparations were applied to the face in the morning and evening
after washing the face with ordinary soap. Observations were made
at time 0, 1, 4, and 8 weeks to assure that treatment was carried
out according to direction. Judgments of "worse", "no change",
"mild", and "good" were made after 8 weeks of treatment. Table 1
illustrates the results.
1TABLE 1 Results of treatment with various compounds on acne no
Treatment worse change mild good Control 2 4 0 0 0.1% retinoic acid
0 2 3 1 0.1% retinyl 2 3 1 0 palmitate 1% retinyl palmitate 0 4 2 0
1.5% retinyl 0 1 3 2 palmitate 5% retinol 0 1 2 3 10% retinol 0 0 3
3 0.0025% calcitriol 2 3 1 0.1% retinoic acid 0 1 3 2 and 0.0025%
calcitriol 0.1% retinyl 1 2 2 1 palmitate and 0.0025% calcitriol
0.5% retinyl 0 1 3 2 palmitate and 0.0025% calcitriol 5% retinyl
palmitate 0 0 1 5 and 0.0025% calcitriol
[0047] Table 1 illustrates that retinyl palmitate in concentrations
at about 1.5% and more shows a remarkable improvement over lower
concentrations in treating acne. In addition, the combination of
retinoic acid and calcitriol shows a synergistic effect when
compared with either retinoic acid and calcitriol. A synergistic
effect is also seen when calcitriol is combined with retinyl
palmitate particularly at concentrations of 0.5% of retinyl
palmitate.
[0048] The use of each of retinoic acid and calcitriol caused skin
irritation while the use of retinyl palmitate did not.
EXAMPLE 2
[0049] This example compares therapeutically applied retinyl
palmitate, retinoic acid, calcitriol, and combinations thereof in a
cream at different concentrations with the effectiveness of the
cream without any of the above compounds present in treating
psoriasis. The cream used is the commercially available LUBRIDERM
cream. The different compounds at different concentrations were
added to the cream and mixed very well. Also, commercially
available 0.005% calcipotriol (DOVONEX) and commercially available
0.005% calcipotriol supplemented with 5% retinyl palmitate were
employed in treating psoriasis. Two different and distant psoriatic
spots were selected on the skin of patients diagnosed with
psoriasis for different treatment. Each patient used two type of
creams twice a day, one cream on each selected spot.
[0050] Group I consisting of five patients applied on one selected
spot (spot A) control LUBRIDERM cream and on the other selected
spot (spot B) cream containing 0.1% retinoic acid. None of the
patients showed any improvement in either spots even after 12 weeks
of treatment.
[0051] Group II consisting of five patients applied on one selected
spot (spot A) control LUBRIDERM cream and on the other selected
spot (spot B) cream containing 0.1% retinyl palmitate. Three out of
five patients showed mild improvement in itching after 3 days in
spot B but no improvement in stopping scaling which results from
cellular hperproliferation. The rest of the spots showed no
improvement.
[0052] Group III consisting of five patients applied on one
selected spot (spot A) control LUBRIDERM cream and on the other
selected spot (spot B) cream containing 1% retinyl palmitate. Four
out of five patients showed good improvement in itching after 3
days in spot B but no improvement in stopping scaling which results
from cellular hperproliferation. The rest of the spots showed no
improvement.
[0053] Group III consisting of five patients applied on one
selected spot (spot A) control LUBRIDERM cream and on the other
selected spot (spot B) cream containing 5% retinyl palmitate. Five
out of five patients showed good improvement in itching after 3
days in spot B but no improvement in stopping scaling which results
from cellular hperproliferation. The rest of the spots showed no
improvement.
[0054] Group IV consisting of five patients applied on one selected
spot (spot A) control LUBRIDERM cream and on the other selected
spot (spot B) cream containing 0.005% calcipotriol. Two out of five
patients showed partial clearance (average of 35% of spot area) in
spot B after 4 weeks of treatment. However, even in the spots
showing improvement and partial clearance, a certain amount of
scaling is still occurring. The rest of the spots showed no
improvement.
[0055] Group V consisting of five patients applied on one selected
spot (spot A) a cream containing 0.0025% calcipotriol and on the
other selected spot (spot B) cream containing 0.0025% calcipotriol
and 0.1% retinyl palmitate. One out of five patients showed partial
clearance (about 20% of spot area) in spot A after 4 weeks of
treatment. However, even in spot A that is showing improvement and
partial clearance, a certain amount of scaling is still occurring.
Two out of Five patients showed considerable amount of clearance
(about 40% of spot area) in spot B and with little scaling and
itching. The rest of the spots showed no improvement.
[0056] Group VI consisting of five patients applied on one selected
spot (spot A) a cream containing 0.0025% calcipotriol and on the
other selected spot (spot B) cream containing 0.0025% calcipotriol
and 0.5% retinyl palmitate. Two out of five patients showed partial
clearance (about 25% of spot area) in spot A after 4 weeks of
treatment. However, even in spots A that are showing improvement
and partial clearance, a certain amount of scaling is still
occurring. Three out of Five patients showed considerable amount of
clearance (about 50% of spot area) in spot B and with barely
noticeable scaling and no itching. The rest of the spots showed no
improvement.
[0057] Group VII consisting of five patients applied on one
selected spot (spot A) a cream containing 0.0025% calcipotriol and
on the other selected spot (spot B) cream containing 0.0025%
calcipotriol and 1% retinyl palmitate. Two out of five patients
showed partial clearance (about 20% of spot area) in spot A after 4
weeks of treatment. However, even in spots A that are showing
improvement and partial clearance, a certain amount of scaling is
still occurring. Four out of Five patients showed considerable
amount of clearance (about 50% of spot area) in spot B and with
barely noticeable scaling and no itching. The rest of the spots
showed no improvement.
[0058] Group VIII consisting of five patients applied on one
selected spot (spot A) a cream containing 0.0025% calcipotriol and
on the other selected spot (spot B) cream containing 0.0025%
calcipotriol and 5% retinyl palmitate. One out of five patients
showed partial clearance (about 30% of spot area) in spot A after 4
weeks of treatment. However, even in spot A that is showing
improvement and partial clearance, a certain amount of scaling is
still occurring. Five out of Five patients showed considerable
amount of clearance (average about 85% of spot area and one
complete clearance) in spot B and with no scaling and itching. The
rest of the spots showed no improvement.
[0059] Group IX consisting of five patients applied on one selected
spot (spot A) a cream containing 0.0025% calcipotriol and on the
other selected spot (spot B) cream containing 0.0025% calcipotriol
and 10% retinyl palmitate. One out of five patients showed partial
clearance (about 15% of spot area) in spot A after 4 weeks of
treatment. However, even in spot A that is showing improvement and
partial clearance, a certain amount of scaling is still occurring.
Five out of Five patients showed considerable amount of clearance
(average about 90% of spot area and two complete clearance) in spot
B and with no scaling and itching. The rest of the spots showed no
improvement.
[0060] Group X consisting of five patients applied on one selected
spot (spot A) a cream containing 0.005% calcipotriol and on the
other selected spot (spot B) cream containing 5% Cholecalciferol
and 5% retinyl palmitate. Two out of five patients showed partial
clearance (about 15% of spot area) in spot A after 4 weeks of
treatment. However, even in spots A that are showing improvement
and partial clearance, a certain amount of scaling is still
occurring. Five out of Five patients showed considerable amount of
clearance (average about 75% of spot area and one complete
clearance) in spot B and with no scaling and itching. The rest of
the spots showed no improvement.
[0061] This data clearly indicates the synergistic effect of using
retinoic acid or retinyl esters above 0.1% particularly at higher
concentrations in treating psoriasis. Similar experiments were
carried out using retinol rather than retinyl palmitate with
similar results.
EXAMPLE 3
[0062] Three patients diagnosed with eczema were treated with cream
containing 0.0025% calcipotriol and 5% retinyl palmitate. A
significant improvement was noticed in all three patients within 5
days and two had normal-looking skin after two weeks.
EXAMPLE 4
[0063] Various types of human melanoma, breast cancer and prostate
cancer cells will be cultured according to standardized procedures.
These cells will be incubated with in the presence of various
concentrations of retinol, retinoic acid, retinyl esters,
calcitriol or a combination thereof. Cell growth of at least some
of these cells will be shown to be significantly inhibited in the
presence of calcitriol and high concentrations of retinol (about
10.sup.-5M) as compared with cells incubated in the absence of the
above compounds or in the presence of each of the above compounds
alone.
EXAMPLE 4
[0064] Various types of human melanoma, breast cancer and prostate
cancer cells will be cultured according to standardized procedures.
These cells will be incubated with in the presence of various
concentrations of retinol, retinoic acid, retinyl esters,
calcitriol or a combination thereof. Some cells will also be
incubated in media collected from F9 mouse teratocarcinoma cells
after these F9 cells were incubated in the presence of 10.sup.-5M
retinal for 12-48 hours .+-. calcitriol. Cell growth of at least
some of these cell lines will be shown to be significantly
inhibited in the presence of calcitriol and high concentrations of
retinal (about 10.sup.-5M) or in the presence F9 cultured media
containing calcitriol prior to incubation with F9 cells or
after.
[0065] The invention has been described in terms of preferred
embodiments thereof, but is more broadly applicable as will be
understood by those skilled in the art. The scope of the invention
is therefore limited only by the following claims.
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