U.S. patent number RE33,107 [Application Number 07/241,630] was granted by the patent office on 1989-11-07 for compositions containing 1.alpha.-hydroxycholecalciferol for topical treatment of skin disorders and methods employing same.
This patent grant is currently assigned to Yissum Research Development Company of the Hebrew University of Jerusalem. Invention is credited to Shabtay Dikstein, Abraham Hartzshtark.
United States Patent |
RE33,107 |
Dikstein , et al. |
November 7, 1989 |
**Please see images for:
( Certificate of Correction ) ** |
Compositions containing 1.alpha.-hydroxycholecalciferol for topical
treatment of skin disorders and methods employing same
Abstract
Cosmetic and dermatological compositions containing
1.alpha.-hydroxycholeciferol and a suitable carrier useful in
topical treatment of skin disorders and methods employing same are
disclosed. Compositions containing
1.alpha.,25-dihydroxycholecalciferol and a suitable carrier and
methods employing same are also disclosed for dermatological and
cosmetic uses. Various formulations of the compositions including
creams, lotions, ointments and sprays are disclosed for use in
accordance with this invention. The compositions and formulations
may contain additional active ingredients.
Inventors: |
Dikstein; Shabtay (Jerusalem,
IL), Hartzshtark; Abraham (Jerusalem, IL) |
Assignee: |
Yissum Research Development Company
of the Hebrew University of Jerusalem (Jerusalem,
IL)
|
Family
ID: |
27270956 |
Appl.
No.: |
07/241,630 |
Filed: |
September 8, 1988 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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Reissue of: |
590072 |
Mar 15, 1984 |
04610978 |
Sep 9, 1986 |
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Foreign Application Priority Data
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Mar 22, 1983 [IL] |
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68196 |
Mar 22, 1985 [IL] |
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68195 |
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Current U.S.
Class: |
514/46; 514/167;
514/863; 514/861 |
Current CPC
Class: |
A61K
8/671 (20130101); A61K 8/678 (20130101); A61K
9/0014 (20130101); A61K 31/59 (20130101); A61K
47/06 (20130101); A61K 47/44 (20130101); A61Q
19/00 (20130101); A61Q 7/00 (20130101); A61Q
19/007 (20130101); A61Q 19/08 (20130101) |
Current International
Class: |
A61K
47/06 (20060101); A61K 47/44 (20060101); A61K
31/59 (20060101); A61K 8/67 (20060101); A61K
8/30 (20060101); A61Q 19/00 (20060101); A61K
031/59 (); A61K 031/70 () |
Field of
Search: |
;514/46,167,861,863 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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68195 |
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Mar 1983 |
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IL |
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68196 |
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Mar 1983 |
|
IL |
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Other References
Van de Kerkhof et al., British J. Dermatol., 120:661-664 (1989).
.
Morimoto et al., British J. Dermatol., 115:421-429 (1986). .
Kato et al., British J. Dermatol., 115:431-433 (1986). .
Smith et al., J. Amer. Acad. Dermatol., 19(3):516-528 (Sep. 1988).
.
Kragballe et al., British J. Dermatol., 119:223-230 (1988). .
Chemical Abstracts 84:53879j, 1976 (Popovici). .
Wells, Amer. Perf. & Essen, Oil Review, pp. 117 and 120,
(1953)..
|
Primary Examiner: Schenkman; Leonard
Attorney, Agent or Firm: White; John P.
Claims
What is claimed is:
1. A composition for use in topical treatment of skin disorders
selected from the group consisting of dermatitis, eczema,
psoriasis, lack of adequate skin firmness, dermal hydration and
sebum secretion, which comprises between about 0.001 .mu.g and 1.0
.mu.g per gram of the composition of a compound of the formula:
##STR2## wherein R is H or OH, and a suitable carrier selected from
the group consisting of a cream, an ointment and a lotion.
2. A composition according to claim 1, wherein R is H.
3. A cosmetic composition comprising a composition according to
claim 1, wherein .[.the effective amount.]. .Iadd.the compound
.Iaddend.is .Iadd.present in the composition in an amount
.Iaddend.from about 0.001 .mu.g/gm to about 0.03 .mu.g/gm of the
composition.
4. A dermatological composition comprising a composition according
to claim 1, wherein .[.the effective amount.]. .Iadd.the compound
.Iaddend.is .Iadd.present in the composition in an amount
.Iaddend.from about 0.03 .mu.g/gm to about 1 .mu.g/gm of the
composition.
5. A cream useful in the topical treatment of skin disorders
comprising a composition according to claim 1, wherein the suitable
carrier comprises a mixture of water, self-emulsifying beeswax,
mineral oil and almond oil.
6. A cream according to claim 5, wherein the mixture includes in
the following proportions:
water, about 40 parts;
self-emulsifying beeswax, about 20 parts;
mineral oil, about 40 parts; and
almond oil, about 1 part.
7. An ointment useful in the topical treatment of skin disorders
comprising a composition according to claim 1, wherein the suitable
carrier comprises a mixture of vegetable oil and white soft
paraffin.
8. An ointment according to claim 7, wherein the vegetable oil is
almond oil which is present in the amount of about 30% and the
white soft paraffin is present in the amount of about 70%, both on
the basis of weight.
9. A lotion useful in the topical treatment of skin disorders
comprising a composition according to claim 1, wherein the suitable
carrier comprises propylene glycol.
10. A composition according to claim 1 which further comprises an
effective amount of a compound capable of inducing
epithelialization.
11. A composition according to claim 10, wherein the compound is a
retinoid.
12. A composition according to claim 11, wherein the retinoid is
Vitamin A and the effective amount is about 0.003-0.3% by weight
based on the weight of the composition.
13. A composition according to claim 10, wherein the compound is a
chromanol.
14. A composition according to claim 13, wherein the chromanol is
Vitamin E and the effective amount is about 0.1-10% by weight based
on the weight of the composition.
15. A composition according to claim 1 which further comprises an
effective amount of a .beta.-agonist.
16. A composition according to claim 15, wherein the agonist is
isoproterenol and the effective amount is about 0.1-2% by weight
based on the weight of the composition.
17. A composition according to claim 15, wherein the agonist is
cyclic-AMP and the effective amount is about 0.1-1% by weight based
on the weight of the composition.
18. A composition according to claim 1 which further comprises an
effective amount of an anti-inflammatory agent.
19. A composition according to claim 18, wherein the
anti-inflammatory agent is a corticosteroid.
20. A composition according to claim 19, wherein the corticosteroid
is hydrocortisone or its acetate and the effective amount is about
0.25-5% by weight based on the weight of the composition.
21. A composition according to claim 19, wherein the corticosteroid
is dexamethasone and the effective amount is about 0.025-0.5% by
weight based on the weight of the composition.
22. A composition according to claim 1 which further comprises an
effective amount of a keratoplastic agent.
23. A composition according to claim 22, wherein the keratoplastic
agent is coal tar and the effective amount is about 0.1-20% by
weight based on the weight of the composition.
24. A composition according to claim 22, wherein the keratoplastic
agent is anthralin and the effective amount is about 0.05-2% by
weight based on the weight of the composition.
25. A method for treating skin disorders which comprises applying
an effective amount of a dermatological composition according to
claim 4 topically to the skin.
26. A method for treating skin disorders which comprises applying
an effective amount of a cosmetic composition according to claim 3
topically to the skin. .Iadd.27. A method for treating skin
disorders selected from the group consisting of dermatitis, eczema,
psoriasis, lack of adequate skin firmness, dermal hydration and
sebum secretion which comprises topically applying to the skin an
effective amount of a compound of the formula: ##STR3##
wherein R is H or OH. .Iaddend. .Iadd.28. A method of claim 27,
wherein R is OH. .Iaddend. .Iadd.29. A dermatological method of
claim 27, wherein the skin disorder is dermatitis, eczema,
psoriasis, or lack of dermal hydration. .Iaddend. .Iadd.30. A
method of claim 29, wherein the skin disorder is psoriasis.
.Iaddend.
Description
BACKGROUND OF THE INVENTION
Skin disorders as the term is used herein encompasses numerous skin
conditions ranging in severity from severe dermatitis, eczema,
psoriasis, etc., which have typically been treated with
compositions termed "dermatological" to less severe conditions such
as lack of adequate skin firmness, dermal hydration or sebum
secretion, etc., which are nonetheless unsightly and may cause
physical discomfort. The latter type of skin disorders typically
have been treated with compositions termed "cosmetic" which are
used with the aim of preserving, conditioning or protecting the
skin. Dermatological and cosmetic preparations have long been
sought which are effective in the topical treatment of such skin
disorders and which do not produce untoward side effects, including
both systemic effects and such local effects as decreased skin
elasticity.
Hitherto the treatment of skin disorders has been largely based on
non-specific drugs, and only limited success has been achieved.
Dermatitis, for example, which may be accompanied by severe
scaling, fissures, edema, oozing, erosion, itching and thickening
of the skin has been commonly treated with corticosteriods. Such
compounds provide symptomatic relief for some patients. Steroids,
however, are known to produce many local and systemic side effects,
and their long term use may not be desirable.
Similarly, Vitamin D is therapeutically effective in treating
certain skin disorders, but only as dosages which are associated
with undesirable side effects. Vitamin D at the dose ranges used in
currently marketed topical preparations is not therapeutically
effective against contact dermatitis.
Prior to this invention, no compositions were known for the topical
treatment of the above-mentioned skin disorders which contain
materials having both calciferol-related structure and high
activity in the induction of calcium binding protein. While there
has been extensive use of fish liver oil, which is rich in
cholecalciferol, and of various other preparations containing
ergocalciferol or cholecalciferol, such preparations are known to
have only limited activity.
Ergocalciferol and cholecalciferol have also been used topically as
general healing and soothing preparations, usually in
concentrations no greater than five (5) micrograms/g because of
concern for side effects. Such preparations, however, have achieved
clinical results of only low efficacy. One possible reason for the
limited efficacy of these preparations, although the inventors do
not wish to be bound by this theory, is that ergocalciferol and
cholecalciferol have a low potency for inducing calcium binding
protein. It is known that an increase in the calcium binding
protein level increases the concentration of intracellular calcium
in skin cells, which in turn increases the cyclic-AMP content of
the cells, see Corradino, Endocrinol., 94: 1607 (1974).
Low cyclic-AMP concentrations in skin cells are known to be
associated with certain skin disorders such as psoriasis,
dermatitis and alopecia. The inventors have found that low
cyclic-AMP levels are also encountered in various other skin
disorders such as undue skin softness and slackening of the skin.
Attempts to increase the cyclic-AMP content of the skin have been
described in the literature.
In pursuing this approach to the study of skin disorders, the
inventors have unexpectedly discovered that particular
cholecalciferol derivatives are highly effective in the treatment
of certain skin disorders.
SUMMARY OF THE INVENTION
This invention relates to compositions containing
1.alpha.-hydroxycholecalciferol or
1.alpha.,25-dihydroxycholecalciferol for the topical treatment of
certain skin disorders and methods of employing the disclosed
compositions. In one aspect of this invention dermatological
compositions for the topical treatment of disorders such as
dermatitis, psoriasis, eczema, solar keratosis and certain stages
of wound healing are provided. Methods employing the dermatological
compositions are also provided. In another aspect of this
invention, cosmetic compositions for the topical treatment of
wrinkles, dry skin (lack of dermal hydration) and skin slackness
(lack of skin firmness) and methods employing the cosmetic
compositions are provided. The cosmetic compositions are also
useful for general skin care and in combating the aging process of
skin. Various formulations for the dermatological and cosmetic
compositions are provided and may include additional active
ingredients.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compositions for use in the topical
treatment of skin disorders which comprise an effective amount of a
compound of the formula ##STR1## where R is H or OH, or lower alkyl
esters thereof and a suitable carrier. Where R is H the compound is
1.alpha.-hydroxycholecalciferol. Where R is OH, the compound is
1.alpha.,25-dihydroxycholecalciferol.
In one aspect of this invention dermatological compositions,
formulations thereof and methods of using same are provided for the
topical treatment of skin disorders such as eczema; psoriasis;
dermatitis; dry skin (lack of dermal hydration); solar keratosis;
and certain stages of alopecia and wound healing.
Such dermatological compositions contain from about 0.03 .mu.g to
about 1.0 .mu.g of 1.alpha.-hydroxycholecalciferol per gram of
composition. Alternately, effective dermatological compositions in
accordance with this invention may be prepared with
1.alpha.,25-dihydroxycholecalciferol instead of
1.alpha.-hydroxycholecalciferol. In that case, the effective amount
of the dihydroxy compound is also from about 0.03 .mu.g to about
1.0 .mu.g per gram of the composition. Since such low dosages are
required, risk of undesired side-effects and systemic effects is
minimized.
The dermatological compositions are formulated preferably as
creams, lotions, sprays, ointments and the like by choice of
appropriate carriers. Suitable carriers include vegetable or
mineral oils, white petrolatum (white soft paraffin), branched
chain fats or oils, animal fats and high molecular weight alcohols
(greater than C12). The preferred carriers are those in which the
active ingredient is soluble. Emulsifiers, stabilizers and
antioxidants may also be included, as well as agents imparting
color or fragrance if desired.
Dermatological creams are preferably formulated from a mixture of
mineral oil, self-emulsifying beeswax and water in which mixture
the active ingredient, preferably 1.alpha.-hydroxycholecalciferol,
dissolved in a small amount of an oil such as almond oil is
admixed.
Dermatological ointments may be formulated by mixing a solution of
the active ingredient in an oil such as almond oil with warm white
soft paraffin and allowing the mixture to cool.
Dermatological lotions may be conveniently prepared by dissolving
the active ingredient, preferably 1.alpha.-hydroxycholecalciferol,
in a suitable high molecular weight alcohol such as polyethylene
glycol.
One or more additional substances which have therapeutic effects on
the skin may also be incorporated in the dermatological
compositions. Thus in one embodiment of this invention the
composition also contains one or more compound capable of
increasing cyclic-AMP levels in the skin. Suitable compounds
include adenosine, in an amount of about 0.1-1% and papaverine, in
an amount of about 0.5-5%, both by weight based on the weight of
the composition. Also suitable are .beta.-adrenergic agonists such
as isoproterenol, in an amount of about 0.1-2% or cyclic-AMP, in an
amount of about 0.1-1%, again both by weight based on the weight of
the composition. Other suitable types of additional active
ingredients which may be incorporated in the compositions of this
invention include compounds capable of inducing epithelialization.
Such compounds include retinoids such as Vitamin A, in an amount of
about 0.003-0.3% by weight and chromanols such as Vitamin E or
derivatives thereof in an amount of about 0.1-10% by weight, both
based on the weight of the composition. Anti-inflammatory agents
such as corticosteroids are also suitably incorporated in the
compositions. Such corticosteroids include, for example,
hydrocortisone or its acetate in an amount of about 0.25-5% by
weight and dexamethasone, in an amount of about 0.025-0.5% by
weight, both based on the weight of the composition. Also suitable
for use as additional ingredients in the compositions of this
invention are keratoplastic agents such as anthralin and coal tar
in an amount of about 0.05-2% for anthralin and 0.1-20% for coal
tar, both by weight based on the weight of the composition.
Topical application of dermatological compositions of this
invention to the affected areas of the skin was found to be
therapeutically effective in the treatment of dermatitis (contact
and atopic) within a few days. In cases of psoriasis, topical
application of dermatological compositions of this invention
resulted in the disappearance of itching and scaling within a few
weeks. Acceleration of wound healing was also observed. At the same
time, levels of calcium and phorphorus in the blood of patients
were monitored. No significant change was observed during
treatment.
The therapeutic effects of compositions according to this invention
were compared with the effects of compositions containing other
calciferol derivatives. Patients with dermatitis (contact or
atopic) were treated by the topical application of an ointment
containing, in the case of a composition in accordance with this
invention, 10 .mu.g of 1.alpha.-hydroxycholecalciferol, 30 gm of
almond oil and 70 gm of white soft paraffin. Patients with
psoriasis were treated by the topical application of an ointment
containing, in the case of a composition in accordance with this
invention, 10 .mu.g of 1.alpha.-hydroxycholecalciferol, 1000 U/g of
Vitamin A dissolved in a minimum amount of vegetable oil, 30 gm of
almond oil and 70 gm of white soft petrolatum. The other calciferol
derivatives studied were ergocalciferol, cholecalciferol and
24,25-dihydroxycholecalciferol. An ointment containing
1.alpha.,25-dihydroxycholecalciferol was also studied and was found
to be of equivalent therapeutic efficacy to ointments containing
1.alpha.-hydroxycholecalciferol. The results are summarized in
Table I, which also provides the reported relative calcium binding
protein inducing activity of the calciferol derivatives
employed.
Table I also illustrates another advantage of the compositions of
this invention in addition to efficacy in the topical treatment of
dermatitis and psoriasis, i.e., that the high potency of the
subject compositions may also correlate with increased safety and
specificity of action over prior compositions. It is well known
that ergocalciferol and cholecalciferol are absorbed into the
bloodstream through the skin. Topical compositions containing
ergocalciferol or cholecalciferol, especially when applied in large
dosages or to large areas of the skin, may thus cause systemic
effects as well as undesirable local effects. Indeed, at the high
dosage of ergocalciferol indicated in Table I, systemic effects are
observed with only minimal therapeutic benefit. Furthermore at
active dosage levels ergocalciferol was found to decrease skin
elasticity. Compositions of the present invention, however,
resulted in significant therapeutic benefit at one hundredth the
dosage level as prior compositions and without the systemic effects
or untoward local side effects thereof.
Such high activity especially in the preferred dermatological
topical compositions containing 1.alpha.-hydroxycholecalciferol is
surprising in light of the generally accepted view that to become
therapeutically active the compound must first be metabolized in
the liver to the 1.alpha.,25-dihydroxy compound. No such topical
metabolic conversion is known to take place in the skin.
TABLE I
__________________________________________________________________________
Clinical Efficacy of Compositions Containing Various Calciferol
Derivatives Concentration Relative Calcium Binding Calciferol
Derivative (.mu.g/g) Clinical Efficacy Protein Inducing
Activity.sup.a
__________________________________________________________________________
ergocalciferol 10 little improvement in 1 dermatitis, no improve-
ment in psoriasis cholecalciferol 10 as above 10 24,25-dihydroxy-
10 as above 30 cholecalciferol 1.alpha.-hydroxychole- 0.1 marked
improvement in 10,000 calcieferol psoriasis, practically complete
disappearance of dermatitis 1.alpha.,25-dihydroxy- 0.1 as above
10,000 cholecalciferol
__________________________________________________________________________
.sup.a reported in Corradino, J. Steroid Brochem., Vol. 9, page
1185 (1978) (assayed by organ cultured chuck duodenum)
Clinical trials of a composition containing
1.alpha.-hydroxycholecalciferol also demonstrated the therapeutic
efficacy of the composition in the topical treatment of contact
dermatitis. The composition evaluated was an ointment containing
0.1 .mu.g of 1.alpha.-hydroxycholecalciferol per gram of ointment
in a petrolatum-almond oil base. The control composition was
identical except that it did not contain the active agent
1.alpha.-hydroxycholecalciferol. The patients were treated in an
out-patient clinic. They were instructed to use the preparation
three times a day.
The ointment was as far as possible applied to a single lesion, or
to an area of the disease, of total extent not greater than three
times the volar surface of the hand. In cases of bilateral
dermatitis of the hands the patient himself was able to apply the
ointment to both surfaces of one hand and to the palmar surface of
the other. Preferably, however, only one hand was treated with the
help of an assistant, or with a disposable glove. Small amounts of
the ointment were first "dotted" over the area at a distance of
about 3 cm from each other, and these were merged and gently
massaged into the lesion for 30 seconds. This technique was
demonstrated to the patient for the first application by the
investigator. The the ointment and its container were weighed
before the treatment started and returned with any unused contents
for reweighing at the end of the treatment.
The area of the lesion treated was estimated and recorded, and the
lesion photographed as required, together with suitable "control"
lesions. The latter were preferably lesions of similar size and
stage of development, either in the vicinity of the treated lesion
or symetrically contralalateral. Relevant details of the
photographic procedure were recorded so as to be reproduced when
the lesions were next photographed (distance, aperture, angle,
background etc.) The ointment was applied twice daily as described
above, and preferably left uncovered. If a dressing was necessary,
this was noted and described on the Record Sheet. The "control"
lesions were left untreated, but if this were not possible the
treatment used on them was noted.
Evaluations of nine (9) parameters were conducted at weekly
intervals by a physician. The nine (9) parameters were redness,
scaling, thickening, fissures, edema, oozing, crust formation,
erosion and itching. The final evaluation was usually carried out
at the end of two weeks of treatment. In isolated instances the
treatment continued for up to four weeks. In this case the final
score was determined at the end of the treatment period.
Table II summarizes the distribution of success or failure between
patients treated with 1.alpha.-hydroxycholecalciferol and those
treated with the control. The results of Table II are highly
significant according to a Chi-square test.
TABLE II ______________________________________ COMPARATIVE
EVALUATION OF THE EFFICIENCY OF TREATMENT OF CONTACT DERMATITIS
WITH A COMPOSITION CONTAINING 1.alpha.-HYDROXYCHOLECALCIFEROL Cases
showing Cases showing improvement no improvement
______________________________________ Ointment with 0.1 .mu.g/gm
19 2 1.alpha.-hydroxycholecalciferol Oinment without 0 8
1.alpha.-hydroxycholecalciferol
______________________________________
An evaluation of the therapeutic results obtained with the twenty
one (21) patients treated with the ointment containing 0.1 .mu.g/mg
1.alpha.-hydroxycholecalciferol is summarized in Table III. Table
III shows that the average overall improvement after treatment is
approximately 61%. The efficacy of the treatment is poorest in
alleviating redness, itching, and thickening. The lack of 100%
efficacy is not due to lack of improvement of severe cases of
contact dermititis. In fact some cases of contact dermatitis showed
dramatic improvement, while some less severe cases showed
relatively little improvement.
More complete healing may be achieved by adding 0.5% hydrocortisone
acetate (w/w) to the preparation described above. This is
illustrated in Table IV which summarizes the results obtained in
the topical treatment of contact dermatitis with such an ointment.
Surprisingly, despite the fact that the dermatitis had been treated
with topical corticoids during the previous three (3) years with
insufficient therapeutic effect, the addition of 0.5% (w/w)
hydrocortisone acetate to the 1.alpha.-hydroxycholecalciferol
composition according to this invention led to more complete
healing.
Another aspect of this invention provides cosmetic compositions,
formulations thereof and methods of using same for the topical
treatment of such skin disorders as dry skin (lack of dermal
hydration), undue skin slackness (i.e., insufficient skin firmness)
and insufficient sebum secretion. The cosmetic compositions are
also effective in the general preservation, conditioning and
protecting of the skin, e.g., against the symptoms of aging,
including wrinkles.
Cosmetic compositions for use in the above-mentioned topical
treatment of skin comprise a cosmetically effective amount of
1.alpha.-hydroxycholecalciferol or
1.alpha.-dihydroxycholecalciferol or lower alkyl esters thereof and
a suitable carrier.
TABLE III
__________________________________________________________________________
Evaluation.sup.a of Therapeutic Results Obtained in the Topical
Treatment of Contact Dermititis with an Ointment Containing 0.1
.mu.g/gm 1.alpha.-hydroxycholecalciferol CHANGE DUE BEFORE AFTER TO
IMPROVEMENT.sup.b SYMPTOMS TREATMENT TREATMENT TREATMENT (%)
__________________________________________________________________________
Redness 2.4 .+-. 0.3 1.3 .+-. 0.4 1.1 .+-. 0.3 45 Scaling 2.7 .+-.
0.2 1.1 .+-. 0.3 1.6 .+-. 0.2 58 Thickening 2.8 .+-. 0.2 1.4 .+-.
0.3 1.4 .+-. 0.2 50 Fissures 2.6 .+-. 0.3 0.9 .+-. 0.4 1.7 .+-. 0.3
66 Edema 2.2 .+-. 0.2 0.9 .+-. 0.3 1.3 .+-. 0.2 60 Oozing 2.1 .+-.
0.3 0.7 .+-. 0.7.sup.c 1.4 .+-. 0.6 69 Crusting 1.9 .+-. 0.2 0.4
.+-. 0.3.sup.c 1.6 .+-. 0.2 81 Erosion 2.1 .+-. 0.2 0.7 .+-.
0.4.sup.c 1.4 .+-. 0.3 68 Itching 3.3 .+-. 0.2 1.8 .+-. 0.4 1.5
.+-. 0.3 51
__________________________________________________________________________
.sup.a scoring of symptoms as follows: 0 = normal, no symptoms; 2 =
moderate; 3 = marked; 4 = very marked or severe .sup.b two to four
weeks after start or treatment .sup.c not significantly different
from zero (0), p .ltoreq. 0.05, i.e. complete cure.
TABLE IV ______________________________________ Topical Treatment
of Dermititis with an Ointment Containing 0.1 .mu.g
1.alpha.-hydroxycholecalciferol per gram and 0.5% (w/w)
hydrocortisone acetate DAY DAY IMPROVE- SYMPTOMS.sup.a DAY 0 DAY 7
14 21 MENTS(%) ______________________________________ Redness 4 3 2
1 75 Scaling 4 4 1 1 75 Thickening 4 4 3 2 50 Fissures 4 4 3 2 50
Pustules 4 4 2 0 100 Edema 3 3 3 1 67 Papules 3 3 1 0 100 Vesicles
4 3 2 1 75 Oozing 4 1 0 0 100 Crusts 3 2 1 1 67 Erosions 4 3 1 1 75
Itching 4 4 3 0 100 ______________________________________ .sup.a
Scoring of symptoms as folows: 0 = normal, no symptoms; 1 = sight;
2 = moderate; 3 = marked; 4 = very marked or severe
A cosmetically effective amount of either compound or a lower alkyl
ester thereof for use in accordance with this invention is from
about 0.001 .mu.g to about 0.03 .mu.g per gm of composition. A
concentration of 0.01 .mu.g per gm of the composition is
preferred.
The cosmetic compositions of this invention are formulated
preferably as creams, lotions, sprays, ointments and the like by
choice of appropriate carriers. Suitable carriers include vegetable
or mineral oils, white petrolatum (white soft paraffin), branched
chain fats or oils, animal fats and high molecular weight alcohol
(greater than C.sub.12). The preferred carriers are those in which
the active ingredient is soluble. Emulsifiers, stabilizers and
antioxidants may also be included as well as agents imparting color
or fragrance is desired.
Cosmetic creams are preferably formulated from a mixture of mineral
oil, self-emulsifying beeswax and water in which mixture the active
ingredient, preferably, 1.alpha.-hydroxycholecalciferol, dissolved
in a small amount of an oil such as almond oil is admixed.
Cosmetic ointments may be formulated by mixing a solution of the
active ingredient in an oil such as almond oil with warm soft
paraffin and allowing the mixture to cool.
Cosmetic lotions may be conveniently prepared by dissolving the
active ingredient, preferably, 1.alpha.-hydroxycholecalciferol, in
a suitable high molecular weight alcohol such as polyethylene
glycol.
One or more additional substances which have therapeutic effects on
the skin may also be incorporated in the cosmetic compositions.
Thus in one embodiment of this invention the composition also
contains one or more compounds capable of increasing cyclic-AMP
levels in the skin. Suitable compounds include adenosine or a
nucleic acid hydrolysate in an amount of about 0.1-1% and
papaverine, in an amount of about 0.5-5%, both by weight based on
the weight of the composition. Also suitable are .beta.-adrenergic
agonists such as isoproterenol, in an amount of about 0.1-2% or
cyclic-AMP, in an amount of about 0.1-1%, again both by weight
based on the weight of the composition. Other suitable types of
additional active ingredients which may be incorporated in the
compositions of this invention include other compounds known to
have a beneficial effect on skin. Such compounds include retinoids
such as Vitamin A, in an amount of about 0.003%-0.3% by weight and
chromanols such as Vitamin E or a derivative thereof in an amount
of about 0.1-10% by weight, both based on the weight of the
composition.
Topical application of cosmetic compositions of this invention was
found to be cosmetically effective in field studies. In a typical
example, topical application of an ointment containing 0.01 .mu.g
of 1.alpha.-hydroxycholecalciferol per gram of ointment to the
forehead for two weeks resulted in improved skin condition.
Indentometry readings decreased by 0.008 cm, reflecting improvement
in dermal hydration, as measured by the method of Hartzshstark, A.
and Dikstein, S., "Mechanical Testing of Human Skin in vivo", Rev.
Pure Appl. Pharmacol. Sci. 3:83-122 (1983). Skin slackness
decreased by 30%, as measured by levarometry, see id; the hourly
rate of sebum secretion was almost doubled as measured by
sebumetry, see id; and the general smoothness and appearance of the
skin was markedly improved.
The cosmetic efficacy of compositions containing
1.alpha.-hydroxycholecalciferol or
1.alpha.,25-dihydroxycholecalciferol in accordance with this
invention was compared with that of compositions containing other
calciferol-related compounds. The results are summarized in Table
V. As Table V illustrates topical application of cosmetic
compositions according to the present invention increased dermal
hydration and decreased skin slackness without adversely affecting
skin elasticity.
Such activity is in marked contrast with that of compositions
containing ergocalciferol or cholecalciferol. Topical application
of compositions containing ergocalciferol, for instance, were of
low cosmetic efficacy and in fact resulted in decreased skin
elasticity (Table V). Moreover, since it is known that
ergocalciferol and cholecalciferol are absorbed into the
bloodstream through the skin, it is likely that doses of such
compounds applied to large areas of the skin or applied
chronically, even in the minimal active dose, cause systemic
effects. Since cosmetic compositions in accordance with this
invention may contain less than one hundredth of the minimum active
dose of ergocalciferol or cholecalciferol, no systemic effect was
expected or observed.
TABLE V
__________________________________________________________________________
Comparative Cosmetic Effects of Compositions Containing Selected
Calciferol-Related Compounds.sup.a Relative Maximum Decrease
Duration Calcium Decrease in Elastic in Skin of Binding
Concentration.sup.b Indentometry Recover Slackness Effects Protein
Compound (.mu.g/ml) (cm).sup.c Decrease.sup.d (Levarometry).sup.e
(hrs) Induction.sup.f
__________________________________________________________________________
7-dehydro- 15 0.000 very large none 24 unknown cholesterol
ergocalcieferol 7.5 0.010 significant slight 7 1 2.5 no effect none
none 0 cholecalciferol 7.5 0.011 none significant 9 10 2.7 no
effect none none 0 24,25-dihydroxy- 7.5 0.004 none none 0 30
cholecalciferol 1.alpha.-hydroxychole- 0.01 0.007 none significant
7 10,000 calciferol 0.03 0.010 none large 9 1.alpha.,25-dihydroxy-
0.03 0.010 none large 9 10,000 cholecalciferol
__________________________________________________________________________
.sup.a Methods of Dikstein et al., Bioengineering and the Skin
(Lancaster MTP Press, 1981), pp. 54-53 .sup.b Dissolved in acetone
or vegetable oil or olive oil (lavarometry) .sup.c In essence
measures improved dermal hydration, Hartzhark, et al., Rev. Pure
Appl. Pharm. Sci. 3: 83-122 (1982) .sup.d in essence measures skin
elasticy; decrease indicated less elastic or deterioated skin
.sup.e a measurement of wrinkles or tendency to wrinkle, as due to
aging .sup.f values obtained by Corradino, R. A., J. Steroid
Biochem, Vol. 9, page 1185 (1978)
The following examples illustrate embodiments of this
invention.
EXAMPLE 1
Dermatological Cream Containing 1.alpha.-hydroxycholecalciferol
In 1 gm of almond oil was dissolved 10 .mu.g of
1.alpha.-hydroxycholecalciferol. To this solution was added 40 gm
of mineral oil and 20 gm of self-emulsifying beeswax. The mixture
was heated to liquify. After the addition of 40 ml hot water, the
mixture was mixed well. The resulting cream contains approximately
0.1 .mu.g of 1.alpha.-hydroxycholecalciferol per gram of cream.
EXAMPLE 2
Dermatological Cream Containing
1.alpha.,25-dihydroxycholecalciferol
In 1 gm of almond oil was dissolved 10 .mu.g of
1.alpha.,25-dihydroxycholecalciferol. To this solution was added 40
gm of mineral oil and 20 gm of self-emulsifying beeswax. After the
addition of 40 ml hot water, the mixture was mixed well. The
resulting cream contains approximately 0.1 .mu.g of
1.alpha.,25-dihydroxycholecalciferol per gram of cream.
EXAMPLE 3
Dermatological Ointment Containing
1.alpha.-hydroxycholecalciferol
In 30 gm of almond oil was dissolved 10 .mu.g of
1.alpha.-hydroxycholecalciferol. To this solution was added 70 gm
of white soft paraffin which had been warmed just enough to be
liquified. The ointment was mixed well and allowed to cool. This
ointment contains approximately 0.1 .mu.g
1.alpha.-hydroxycholecalciferol per gram of ointment.
EXAMPLE 4
To the ointment of Example 3 was added with thorough mixing 0.5 gm
of adenosine and 2.0 gm of papaverine base, both dissolved in a
minimum quantity of dimethyl sulfoxide. The additional ingredients
are present to the extent of about 0.5 wt % (adenosine) and 2 wt %
(papaverine base).
EXAMPLE 5
To the ointment of Example 3 was added with thorough mixing 10,000
U of Vitamin A dissolved in a minimum quantity of vegetable oil.
The resultant ointment contains about 100 U Vitamin A per gram of
the ointment.
EXAMPLE 6
Dermatological ointments are prepared as in Example 3, 4 and 5 but
with 1.alpha.,25-dihydroxycholecaliferol substituted for
1.alpha.-hydroxycholecalciferol.
EXAMPLE 7
Dermatological Lotion Containing
1.alpha.-hydroxycholecalciferol
A dermatological lotion is prepared by dissolving 10 .mu.g of
1.alpha.-hydroxycholecalciferol in 100 gm of dry propylene glycol.
The lotion is stored in a refrigerator in a brown bottle and
contains about 0.1 .mu.g of 1.alpha.-hydroxycholecalciferol per
gram of lotion.
EXAMPLE 8
Dermatological Lotion Containing
1.alpha.,25-dihydroxycholecalciferol
A dermatological lotion is prepared according to Example 7, but
with 1.alpha.-25-dihydroxycholecalciferol substituted for
1.alpha.-hydroxycholecalciferol.
EXAMPLE 9
Cosmetic Cream Containing 1.alpha.-hydroxycholecalciferol
In 1 gm of almond oil is dissolved 2 .mu.g of
1.alpha.-hydroxycholecalciferol. To the solution is added 40 gm of
mineral oil and 20 gm of self-emulsifying beeswax, followed by 40
ml of hot water. The mixture is mixed well to produce a cosmetic
cream containing about 0.02 .mu.g of
1.alpha.-hydroxycholecalciferol per gram of cream.
EXAMPLE 10
To a cosmetic cream prepared according to Example 9 was added 100
mg adenosine. The cream was mixed well and contains about 0.1 wt %
adenosine.
EXAMPLE 11
Cosmetic creams were prepared according to Examples 9 and 10, but
with 1.alpha.,25-dihydroxycholecalciferol substituted for
1.alpha.-hydroxycholecalciferol.
EXAMPLE 12
Cosmetic Ointment Containing 1.alpha.-hydroxycholecalciferol
In 30 gm of almond oil was dissolved 1 .mu.g of
1.alpha.-hydroxycholecaliferol. To the solution so produced was
added 70 gm white soft paraffin which had been warmed just enough
to be liquified. The ointment was mixed well and allowed to cool.
The ointment so produced contains about 0.01 .mu.g of
1.alpha.-hydroxycholecalciferol per gram of ointment.
EXAMPLE 13
To the cosmetic ointment of Example 12 was added with thorough
mixing 200 U/gm Vitamin A dissolved in a minimum amount of
vegetable oil.
EXAMPLE 14
Cosmetic ointments were prepared according to Examples 12 and 13
but with 1.alpha.,25-dihydroxycholecalciferol substituted for
1.alpha.-hydroxycholecalciferol.
EXAMPLE 15
Cosmetic Lotion Containing 1.alpha.-hydroxycholecalciferol
A cosmetic lotion is prepared by dissolving 3 .mu.g of
1.alpha.-hydroxycholecalciferol in 100 gm of dry propylene glycol.
The lotion is stored in a refrigerator in a brown bottle and
contains about 0.03 .mu.g 1.alpha.-hydroxycholecalciferol per gram
of lotion.
EXAMPLE 16
A cosmetic lotion is prepared according to Example 15 with
1.alpha.,25-dihydroxycholecalciferol substituted for
1.alpha.-dihydroxycholecalciferol.
* * * * *