U.S. patent application number 10/603262 was filed with the patent office on 2003-12-18 for gel composition for the topical treatment of rashes, dermatoses and lesions.
Invention is credited to McCadden, Michael E..
Application Number | 20030232086 10/603262 |
Document ID | / |
Family ID | 29552742 |
Filed Date | 2003-12-18 |
United States Patent
Application |
20030232086 |
Kind Code |
A1 |
McCadden, Michael E. |
December 18, 2003 |
Gel composition for the topical treatment of rashes, dermatoses and
lesions
Abstract
Composition for topical administration comprising (a) a
corticosteroid, (b) a drying agent, and (c) a broad spectrum
anti-fungal agent that treats both dermatophytes and yeast.
Inventors: |
McCadden, Michael E.; (St.
Louis, MO) |
Correspondence
Address: |
SENNIGER POWERS LEAVITT AND ROEDEL
ONE METROPOLITAN SQUARE
16TH FLOOR
ST LOUIS
MO
63102
US
|
Family ID: |
29552742 |
Appl. No.: |
10/603262 |
Filed: |
June 25, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10603262 |
Jun 25, 2003 |
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09652381 |
Aug 31, 2000 |
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60152067 |
Sep 2, 1999 |
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Current U.S.
Class: |
424/486 |
Current CPC
Class: |
A61K 31/56 20130101;
A61K 31/56 20130101; A61K 31/59 20130101; A61K 31/59 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/486 |
International
Class: |
A61K 009/14 |
Claims
1. A composition for topical administration, the composition
comprising (a) a mid-potency or high-potency corticosteroid, (b)
calamine, and (c) an imidazole anti-fungal agent, the composition
being in the form of a gel.
2. The composition of claim 1 wherein the composition contains
about 0.005% to about 0.1% by weight of a mid potency
corticosteroid.
3. The composition of claim 2 wherein the mid potency steroid is
selected from the group consisting of fluocinolone acetonide,
hydrocortisone butyrate, hydrocdrtisone propionate, hydrocortisone
valerate, and prednicarbate.
4. The composition of claim 1 wherein the composition contains
about 0.0005% to about 0.05% by weight of a mid potency or high
potency corticosteroid.
5. The composition of claim 4 wherein the mid potency or high
potency steroid is selected from the group consisting of
flumethasone pivolate, clocortolone pivolate, triamcinolone
acetonide, prednicarbate, fluticasone propionate, flurandrenolide,
mometasone furoate, desoximetasone, betamethasone, betamethasone
dipropionate, betamethasone valerate, betamethasone propionate,
betamethasone benzoate, diflorasone diacetate, fluocinonide,
halcinonide, amcinonide, halobetasol propionate, and clobetasol
propionate.
6. The composition of claim 5 wherein the composition comprises at
least two drying agents, one of the drying agents is calamine,
another is zinc oxide and the ratio of calamine to zinc oxide is
about 0.5:1 to about 10:1.
7. The composition of claim 1 wherein the composition comprises at
least two drying agents, one of the drying agents is calamine,
another is zinc oxide and the ratio of calamine to zinc oxide is
about 0.5:1 to about 10:1.
8. The composition of claim 7 wherein the imidazole anti-fungal
agent is clotrimazole.
9. The composition of claim 7 wherein the imidazole anti-fungal
agent is miconazole, clotrimazole, butoconazole, tioconazole,
econazole, ketoconazole, oxiconizole or sulconazole.
10. The composition of claim 1 wherein the imidazole anti-fungal
agent is clotrimazole.
11. A process for treating diaper rash, intertrigo, atinea
infection, seborrhea, psoriasis or lichen simplex chronicus, the
process comprising topically applying a composition to the affected
area, the composition comprising (a) a mid-potency or high-potency
corticosteroid, (b) calamine, and (c) an imidazole anti-fungal
agent, the composition being in the form of a gel.
12. The process of claim 11 wherein the composition contains about
0.005% to about 0.1% by weight of a mid potency corticosteroid.
13. The process of claim 12 wherein the mid potency steroid is
selected from the group consisting of fluocinolone acetonide,
hydrocortisone butyrate, hydrocortisone propionate, hydrocortisone
valerate, and prednicarbate.
14. The process of claim 11 wherein the composition contains about
0.0005% to about 0.05% by weight of a mid potency or high potency
corticosteroid.
15. The process of claim 14 wherein the mid potency or high potency
steroid is selected from the group consisting of flumethasone
pivolate, clocortolone pivolate, triamcinolone acetonide,
prednicarbate, fluticasone propionate, flurandrenolide, mometasone
furoate, desoximetasone, betamethasone, betamethasone dipropionate,
betamethasone valerate, betamethasone propionate, betamethasone
benzoate, diflorasone diacetate, fluocinonide, halcinonide,
amcinonide, halobetasol propionate, and clobetasol propionate.
16. The process of claim 15 wherein the composition comprises at
least two drying agents, one of the drying agents is calamine,
another is zinc oxide and the ratio of calamine to zinc oxide is
about 0.5:1 to about 10:1.
17. The process of claim 11 wherein the composition comprises at
least two drying agents, one of the drying agents is calamine,
another is zinc oxide and the ratio of calamine to zinc oxide is
about 0.5:1 to about 10:1.
18. The process of claim 17 wherein the imidazole anti-fungal agent
is clotrimazole.
19. The process of claim 17 wherein the imidazole anti-fungal agent
is miconazole, clotrimazole, butoconazole, tioconazole, econazole,
ketoconazole, oxiconizole or sulconazole.
20. The process of claim 11 wherein the imidazole anti-fungal agent
is clotrimazole.
Description
REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application based on U.S.
Ser. No. 09/652,381 filed Aug. 13, 2000, which claims priority from
provisional application Ser. No. 60/152,067 filed Sep. 2, 1999.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to a composition for the
treatment of rashes, dermatoses or lesions, which are known to be
treated topically to improve or favorably alter the disease
condition. Such rashes, dermatoses or lesions include acute,
inflammatory reactions of the skin resulting from exposure to an
adverse local environment (e.g., diaper rash, intertrigo, lichen
simplex chronicus, balanitis, balanoposthitis), rashes, dermatoses
or lesions caused by a fungal or yeast infection (e.g., tinea
cruris, tinea pedis, tinea corporis, tinea versicolar, Candidal
infections), rashes, dermatoses or lesions caused by an allergic or
irritant reaction (such as that caused by poison ivy, poison oak or
poison sumac, or other forms of contact dermatitis), rashes,
dermatoses or lesions of a chronic nature (e.g. seborrheic
dermatitis, psoriasis, atopic dermatitis) or caused by infection,
irritation or aggravation of another condition such as occurs with
acne, and other rashes, dermatoses or lesions.
[0003] Diaper rash is an irritant contact dermatitis, often
secondarily infected with Candida organisms. It occurs as a result
of constant exposure to an adverse local environment. Constant
dampness is the main causative event, but numerous irritants add to
the problem, including feces, urea, intestinal enzymes, detergent
in the diaper, and even some medications. Moisture from the diaper
further weakens the skin barrier, making the rash worse. The rash
is often very red, may become raw, and can be quite painful for the
child. Erythematous papules, vesicles or erosions, oozing, and
ulceration may occur.
[0004] A variety of methods exist for treating diaper rash,
including hydrocortisone cream (1% by weight), zinc oxide ointment,
undecylenic acid, zinc undecylenate, nystatin cream, clotrimazole
cream, or miconazole cream. Individually these therapies do not
treat both the irritant dermatitis and the secondary Candida or
dermatophyte infection.
[0005] Bowring et al (Bowring A W, Mackay D, Taylor F R: "The
treatment of napkin dermatitis: a double-blind comparison of two
steroid-antibiotic combinations," Pharmatherapeutica (1984) vol. 3,
#9; 613-617) compared a composition containing miconazole (2% by
weight) and hydrocortisone (1% by weight) with a composition
containing nystatin (100,000 i.u. /gm), benzalkonium chloride (0.2%
by weight), dimethicone (10% by weight), and hydrocortisone (0.5%
by weight) in a study of 62 infants with moderate to severe diaper
rash. Clinical assessments were made of erythema, weeping, tissue
maceration, and infant irritability. Both treatments were reported
to produce a high and similar overall cure rate (80% and 84%
respectively), with a significant improvement within 48 hours in
the majority of cases. While these results are encouraging, a more
rapid and complete clinical response is desired.
[0006] Shankland et al.(Shankland G S, Richardson M D: "Comparative
in-vivo activity of clotrimazole and a clotrimazole/hydrocortisone
combination in the treatment of experimental dermatophytosis in
guinea pigs," Journal of Antimicrobial Chemotherapy (1990) 25,
825-830), describe the use of formulations containing
hydrocortisone and clotrimazole for the treatment of dermatophyte
infections. Guinea pigs infected with Trichophyton mentagrophytes
var. mentagrophytes were treated with once daily application of 1%
by weight clotrimazole alone, 1% by weight hydrocortisone alone,
base alone, a combination of 1% by weight clotrimazole and 1% by
weight hydrocortisone, or no treatment at all. Clinically, the
animals receiving combination therapy (clotrimazole plus
hydrocortisone) were reported to have improved most quickly and
cultures were negative after two treatments. Histological
examination showed resolution of the infection and little
inflammation.
[0007] An open, non-comparative study was performed to assess the
effectiveness, acceptability and tolerability of a 1% by weight
clotrimazole plus 1% by weight hydrocortisone cream in the
treatment of 112 infants with napkin dermatitis (diaper rash)
(Jaffe G V, Grimshaw J J: "An open trial of clotrimazole plus
hydrocortisone cream in the treatment of napkin dermatitis in
general practice," Pharmatherapeutica, (1985), 4, 314-318). There
was significant improvement in erythema, irritation and pustulation
in all but a few patients, and 92% of the patients were considered
to have been cured or markedly improved after 7 to 14 days of twice
daily application. Again, while these results are encouraging, a
more rapid and complete clinical response is desired.
[0008] A variety of methods have been used for the treatment of
fungal infections including the use of potassium iodide,
Castellani's paint, gentian violet, Whitfield's ointment,
undecylenic acid, antibiotics (e.g. nystatin, fungizone and
amphotericin B), griseofulvin, the imidazole antifungal agents such
as miconazole, clotrimazole, econazole, ketoconazole, oxiconizole
and sulconazole, the allylamine antifungal agents such as naftifine
and terbinafine, the benzylamines such as butenafine HCl, the
hydroxypyridone agents such as ciclopirox, the chlorinated
iodopropynyl trichlorophenyl ether agents such as haloprogin, as
well as tolnaftate, thymol, and tinver. Nystatin, fungizone,
naftifine, and terbinafine, however, are only effective against
yeast (Candida) and the imidazole compounds while effective in
treating both dermatophytes and yeasts (Arndt, Kenneth A., Manual
of Dermatologic Therapeutics, 5th edition, 1995, Little, Brown and
Co., page 290) often do not provide rapid relief.
[0009] The fungal infections are commonly associated with signs of
erythema and scaling and with symptoms of itching or painful
burning. Clinical treatment for fungal disease requires at least
two to four weeks for complete relief of symptoms. More recently,
it has been found that fungal infections can be effectively treated
with a combination product containing corticosteroids and imidazole
antifungal agents (see above referenced studies). It is known that
the sensitivity of fungal organisms varies with their life cycles;
spores are more resistant to treatment than are mycelia. Steroids
may induce fungal spores to produce mycelia, thereby making them
more sensitive to treatment. Also, steroids are known to produce
vasoconstriction at the site of application. This activity may
delay or prevent the elimination of the antifungal agent from the
application site, permitting the antifungal agent to remain in the
epidermis for longer periods of time. It is therefore believed that
a locally applied anti-inflammatory agent would offer direct and
immediate relief for the inflammatory component of the lesion. The
combination product should then provide fast relief of symptoms and
eradicate the infection. Based on this concept, certain
combinations of an antifungal agent and an anti-inflammatory agent
have recently been developed for treatment of fungal disease.
Currently, the commercially available combination products using
this concept are Lotrisone cream (clotrimazole 1% by
weight/betamethasone dipropionate 0.05% by weight), Daktacort cream
(miconazole nitrate 2% by weight/hydrocortisone 1% by weight) and
Canesten HC cream (clotrimazole 1% by weight/hydrocortisone 1% by
weight).
[0010] It has been reported Lotrisone cream was therapeutically and
mycologically better than clotrimazole 1% by weight and
betamethasone dipropionate 0.05% by weight alone. See e.g.,
Wortzel, M. Y., H., Cutis 30: 258 (1982) and Katz et al. Cutis,
34(2), 183-8 (1984). Notwithstanding its clinical advantages,
Lotrisone cream possesses some undesirable attributes. It contains
a rather strong fluorinated steroid, betamethasone dipropionate,
which can be cutaneously dangerous to use in intertrigious regions
for extended periods. Potential side effects include skin atrophy,
rebound phenomenon, telangiectasia, and danger to infants and small
children due to possible suppression of the
hypothalamic-pituitary-adrenal axis if used it too large a
quantity. The corticosteroid triamcinalone is also a fluorinated
steroid. It is mixed with nystatin in Mycolog. Triamcinalone
possess the same risks as betamethasone dipropionate listed
above.
[0011] Other marketed combination products of this type, e.g.
Daktacort cream and Canesten HC cream, are combinations of
low-potency steroids and imidazoles in a cream form. Such
combination products in this cream vehicle often fail to provide
the fast relief of the inflammatory symptoms which is normally
desired for the treatment of a fungal infection, especially when
the eruption is acutely inflamed, moist, and/or in an
intertriginous area.
[0012] None of the above agents' vehicles provide rapid drying of a
moist, oozing rash while helping to absorb further moisture and
keep the skin dry, and at the same time treat both the irritant
dermatitis and secondary Candida or dermatophyte infection.
[0013] There are several other papulosquamous skin diseases that
can present and behave in a similar fashion to diaper dermatitis.
These include intertrigo, tinea versicolar, contact dermatitis such
as poison ivy and others, Candida skin infections, seborrheic
dermatitis, inverse psoriasis, interdigital tinea pedis, tinea
cruris, genital lichen simplex chronicus, balanoposthitis,
balanitis, and others. All of these conditions (except tinea
versicolar) can present with an intertriginous rash that can become
moist, weeping, and quite irritated. The non-fungal rashes can also
become secondarily infected with Candida and/or dermatophyte fungi.
Current therapeutic options do not always clear these conditions as
rapidly as desired.
SUMMARY OF THE INVENTION
[0014] Among the objects of the present invention, therefore, is
the provision of a composition for topical treatment of rashes,
dermatoses and lesions, the provision of such a composition which
is easily applied to the skin, the provision of such a composition
which contains a corticosteroid of the appropriate potency for the
condition being treated (e.g., one which is safe to apply anywhere,
such as in intertriginous or genital areas, and in any age group,
such as infants with diaper rash and other rashes), the provision
of such a composition which promotes rapid drying of moist areas
and coats the skin with the drying agent for protection and
healing, the provision of such a composition which may be used to
treat and cure combination rashes, i.e. fungal rashes that are
associated with an irritant dermatitis, or an eczema or other
dermatosis that is secondarily infected with a fungus, especially
moist exudative rashes and/or rashes in moist, intertriginous
areas.
[0015] Briefly, therefore, the present invention is directed to a
composition for topical administration comprising (a) a
corticosteroid, (b) a drying agent, and (c) an anti-fungal agent
that treats both dermatophytes and yeast.
[0016] These and other objects of the present invention will be
more fully understood in the light of the specific examples and
description set forth below.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0017] The composition of the present invention may be in the form
of a solution, spray, lotion, cream, gel or ointment. The preferred
form of the composition depends upon the condition being treated
and the desired therapeutic effect. For example, treatment of a
moist, acutely inflamed rash is preferably treated with a lotion,
whereas treatment of a chronic dry patch is often treated more
effectively with a cream or ointment. In general, the effectiveness
of the composition is directly related to the form of the
composition with ointment forms of corticosteroid being stronger
than gels, gels being stronger than creams, creams being stronger
than lotions and solutions. For example, ointment preparations of
the same corticosteroid in the same concentration are generally
stronger than the cream preparation.
[0018] The lotions of the present invention include liquid
suspensions and dispersions. Solid-in-liquid suspensions are
preparations of finely divided, undissolved drugs or other
particulate matter dispersed in liquid vehicles. These suspensions
require shaking before application to ensure uniform distribution
of solid in the vehicle. Liquid-in-liquid dispersions generally
contain a higher water content than cream emulsions and are
pourable. Lotions provide a protective, drying, and cooling effect
and may act as a vehicle for other agents. The addition of alcohol
increases the cooling effect. If an astringent, such as aluminum is
present, it will precipitate protein and dry and seal exudating
surfaces.
[0019] In a preferred embodiment, the composition of the present
invention is a shake lotion containing a solid-in-liquid suspension
or a liquid-in-liquid dispersion. For example, the shake lotion may
be formed by combining a corticosteroid and an anti-fungal agent
with a solid-in-liquid suspension or liquid-in-liquid emulsion
drying lotion. In this embodiment, such compositions preferably
contain at least about 15% by weight water, more preferably at
least about 20%, still more preferably at least about 30%, and
still more preferably about 40% to about 60% by weight water but no
emulsifier. Exemplary water-based, solid-in-liquid suspensions and
liquid-in-liquid emulsions include calamine lotions.
[0020] In general, preferred compositions of the present invention
contain up to about 5% by weight of a corticosteriod, up to about
7% by weight of an antifungal agent, up to about 60% by weight
drying agent, one or more optional ingredients (for example, one or
more anti-itch agents; anti-foaming agents; buffers, neutralizing
agents, and agents to adjust pH; coloring agents and decoloring
agents; emollients; emulsifying agents, emulsion stabilizers and
viscosity builders; humectants; odorants; preservatives,
antioxidants, and chemical stabilizers; solvents; and thickening,
stiffening, and suspending agents), and a balance of water or
solvent.
[0021] Vehicles
[0022] Topical therapy may be delivered by any of various vehicles,
typically solutions, sprays, lotions, gels, creams, and ointments,
progressing in order from least to most hydrating and conversely,
most to least drying. Alternatively, the composition may be
delivered via a liposome, nanosome, rivosome, or nutri-diffuser
vehicle. In another alternative embodiment, the vehicle is a
barrier cream which comprises a hydrogel polymer such as
carboxymethylcellulose, 2-hydroxyethyl methacrylate (also known as
Hydron), guar gum, locust bean gum and aloe vera; hydrogels can be
deposited on the skin in a water-resistant, non-gummy, hydroscopic,
flexible, and pliable thin film.
[0023] The chemical composition of the vehicle may affect the
bioavailability and thus, the therapeutic effectiveness of the
composition. In general, acute inflammation is treated with aqueous
drying preparations, and chronic inflammation is treated with
hydrating preparations. Powder-in-water suspension type lotions,
solutions (medications dissolved in a solvent) and gels are for
hairy and intertriginous areas. Oil-in-water emulsion type lotions,
creams and ointments tend to be more absorbable and more effective
hydrating agents, appropriate for dry scaly eruptions, but are
greasy and therefore often undesirable. In general, solutions,
powder-in-water suspension type lotions, lotions and gels are
preferred and, for many applications such as the treatment of
contact dermatitis (e.g., diaper rash), powder-in-water lotions
(sometimes referred to as "shake lotions") are particularly
preferred.
[0024] Preferred vehicles of the present invention include calamine
containing lotions and gels. Calamine lotions are preferably
shake-lotions containing calamine, zinc oxide, glycerin, thickening
agent(s), water and one or more optional ingredients identified as
additional agents elsewhere herein. Calamine gels generally contain
the same ingredients as the calamine lotions and are, for example,
gels of water, acetone, alcohol, or propylene glycol thickened with
organic polymers such as carbopols. Preferred lotions typically
include calamine (about 2% to about 20% by weight, preferably about
4% to about 15% by weight, more preferably about 6% to about 10% by
weight), zinc oxide (about 2% to about 20% by weight, preferably
about 4% to about 15% by weight, more preferably about 6% to about
10% by weight), glycerin (about 1% to about 10% by weight,
preferably about 2% to about 5% by weight), bentonite magma (about
1 to about 30% by weight, preferably about 2% to about 25% by
weight), and calcium hydroxide in sterile water (to make 100% by
weight). Preferred optional ingredients additionally include talc
(about 2% to about 30% by weight, preferably about 5% to about 15%
by weight, more preferably about 10% by weight), peanut oil (about
20% to about 80% by weight, preferably about 25% to about 75% by
weight, more preferably about 50% by weight), phenol (up to about
5% by : weight), alcohol (up to about 50% by weight) and tannic
acid (up to about 5% by weight). Calamine gels may additionally
include, for example, microcrystalline cellulose gel (about 20% to
about 60% by weight, preferably about 30% to about 50% by weight,
more preferably about 45% by weight), and carmellose sodium (up to
about 5% by weight).
[0025] Corticosteroid
[0026] The corticosteroid preferably provides the desired
therapeutic effect with little or no risk of causing atrophy of the
skin, induction of telangieclasia or, in infants, suppression of
hypothalamic-pituitary-a- drenal axis. The corticosteroid selected
and the concentration thereof in the composition, therefore, will
depend, at least in part upon the therapeutic application and the
vehicle selected. For example, the therapeutic effectiveness of a
topical corticosteroid is related to the potency of the drug and
its percutaneous penetration. Therapeutic effectiveness is thus
significantly affected by the vehicle. For example, the potency of
two of the stronger preparations can be modified by alteration of
the corticosteroid moiety in one (clobetasol propionate) and
optimization of the vehicle in the other (betamethasone
dipropionate). Also, small changes in molecular structure related
to enhancing the intrinsic activity of the corticosteroid moiety,
increasing lipophiliciity to facilitate better skin penetration,
and retarding the metabolic inactivation of the molecule result in
significant alterations in clinical effectiveness. The
corticoseteroid, therefore, may be a high-potency, mid-potency or
low-potency corticosteroid. In general, mid-potency and low-potency
corticosteroids are preferred and the composition preferably
contains at least about 0.0005% and typically-up to about 5% by
weight of the corticosteriod.
[0027] For pediatric patients and for treatment of intertriginous
areas in any age group, low potency steroids are generally
preferred in view of certain disadvantages of high-potency
steroids. Fluorinated steroids such as betamethasone dipropionate
and triamcinalone can be cutaneously dangerous to use in
intertriginous regions and can cause undesirable effects including
skin atrophy, rebound phenomenon and telangiectasia. If applied to
large surface areas on infants, they can cause systemic effects
with suppression of hypothalamic-pituitary-adrenal axis. Exemplary
low-potency steroids (and concentrations expressed as a weight
percentage of the composition of the present invention)
include:
[0028] hydrocortisone (about 0.1% to about 5%, preferably about
0.25% to about 3.5%, :more preferably about 0.5 to about 2.5% by
weight);
[0029] hydrocortisone acetate (about 0.1% to about 5%, preferably
about 0.25 to about 3.5%, more preferably about 0.5% to about 2.5%
by weight);
[0030] cortisone (about 0.1% to about 5%, preferably about 0.25 to
about 3.5%, more preferably about 0.5 to about 2.5% by weight);
[0031] prednisone acetate (about 0.025% to about 1.25%, preferably
about 0.05% to about 1%, more preferably about 0.125% to about
0.75% by weight);
[0032] prednisone valerate (about 0.025% to about 1.25%, preferably
about 0.05% to about 1%, more preferably about 0.125% to about
0.75% by weight);
[0033] prednisolone (about 0.025% to about 1.25%, preferably about
0.05% to about 1%, more preferably about 0.125% to about 0.75% by
weight);
[0034] alclometasone dipropionate (about 0.01% to about 0.1%,
preferably about 0.025% to about 0.075%, more preferably about
0.05% by weight);
[0035] dexamethasone (about 0.005% to about 1%; preferably about
0.01% to about 0.5%; more preferably about 0.05% to about 0.1% by
weight);
[0036] methylprednisolone (about 0.01% to about 5%, preferably
about 0.05% to about 2.5%, more preferably about 0.5% to about 1%
by weight);
[0037] fluocinolone acetonide (about 0.0025 to about 0.025%,
preferably about 0.005% to about 0.0125%, more preferably about
0.01% by weight); and
[0038] desonide (about 0.01% to about 0.1%, preferably about 0.025%
to about 0.075%, more preferably about 0.05% by weight).
[0039] Some conditions, such as severe exudative diaper rash,
severe intertrigo, severe tinea infections, severe seborrhea,
recalcitrant psoriasis, or forms of lichen simplex chronicus will
require a mid-potency steroid for effective treatment. Exemplary
mid-potency steroids include:
[0040] fluocinolone acetonide (about 0.005% to about 0.075%,
preferably about 0.01% to about 0.05%, more preferably about 0.025%
by weight);
[0041] prednicarbate (about 0.01% to about 0.5%, preferably about
0.05% to about 0.25%, more preferably about 0.1% by weight);
[0042] hydrocortisone butyrate (about 0.01% to about 1%; preferably
about 0.05% to about 0.5%; more preferably about 0.1% by
weight);
[0043] hydrocortisone propionate (about 0.01% to about 1%;
preferably about 0.05% to about 0.5%; more preferably about 0.1% by
weight); and
[0044] hydrocortisone valerate (about 0.01% to about 1%; preferably
about 0.05% to about 0.5%; more preferably about 0.2% by
weight).
[0045] Some conditions in non-intertriginous areas and
non-pediatric patients require a fluorinated mid-potency steroid or
high-potency steroid for effective treatment. Exemplary fluorinated
mid-potency steroids and high-potency steroids include:
[0046] flumethasone pivolate (about 0.005% to about 0.1%,
preferably about 0.01% to about 0.05%, more preferably about 0.03%
by weight);
[0047] clocortolone pivolate (about 0.01% to about 1%, preferably
about 0.05% to about 0.5%, more preferably about 0.1% by
weight);
[0048] triamcinolone acetonide (about 0.001% to about 1%;
preferably about 0.01% to about 0.5%; more preferably about 0.025%
to about 0.1% by weight);
[0049] fluticasone propionate (about 0.0005% to about 0.5%;
preferably about 0.001% to about 0.1%; more preferably about 0.005%
to about 0.05% by weight);
[0050] flurandrenolide (about 0.005% to about 0.5%; preferably
about 0.01% to about 0.1%; more preferably about 0.025% to about
0.05% by weight);
[0051] mometasone furoate (about 0.01% to about 0.5%, preferably
about 0.05% to about 0.25%, more preferably about 0.1% by
weight);
[0052] desoximetasone (about 0.005% to about 1%; preferably about
0.01% to about 0.5%; more preferably about 0.05% to about 0.25% by
weight);
[0053] betamethasone (about 0.005% to about 0.5%; preferably about
0.01% to about 0.25%; more preferably about 0.05% to about 0.1% by
weight);
[0054] betamethasone dipropionate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight);
[0055] betamethasone valerate (about 0.01% to about 0.5%,
preferably about 0.05% to about 0.25%, more preferably about 0.1%
by weight);
[0056] betamethasone propionate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight);
[0057] betamethasone benzoate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight);
[0058] diflorasone-diacetate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight);
[0059] fluocinonide (about 0.005% to about 0.5%; preferably about
0.01% to about 0.1%; more preferably about 0.05% by weight);
[0060] halcinonide (about 0.01% to about 0.5%, preferably about
0.05% to about 0.25%, more preferably about 0.1% by weight);
[0061] amcinonide (about 0.01% to about 0.5%, preferably about
0.05% to about 0.25%, more preferably about 0.1% by weight);
[0062] halobetasol propionate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight); and
[0063] clobetasol propionate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight).
[0064] In general, the relative potency of topical steroids may be
determined by a vasoconstrictor assay. Such assays visually measure
the amount of vasoconstriction produced by the steroid with the
degree of pallor produced after application of the steroid over a
period of time increasing with the concentration of the steroid.
See, for example, McKenzie et al., Archives of Dermatology, vol.
86, pp. 608-610 (1962); Stoughton, Archives of Dermatology, vol.
99, pp. 753-756 (1969); Place et al., Archives of Dermatology,
vol.101, pp. 531-537 (1970); Staughton, Archives of Dermatology,
vol.106, pp. 825-827 (1972); Jackson et al., Journal of the
American Academy of Dermatology, vol. 20, pp. 791-796 (1989); and
Staughton, Archives of Dermatology,3vol. 123, pp.1312-1314 (1987).
To some extent, these assays are imprecise due to the variation
between observers and other parameters within an individual study.
Nevertheless, general trends emerge and the potency of a steroid
may be determined by reference to the potency of other steroids
which have been classified as low-potency, mid-potency, or
high-potency herein. For example, the potency of a steroid may be
determined in a vasoconstrictor assay of the type described by
these articles with reference to the low-potency, mid-potency and
high-potency corticosteroids identified herein with a
corticosteroid being considered a low-potency if it produces an
amount of vasoconstriction which is equivalent to the amount of
vasoconstriction produced by the low-potency steroids disclosed
herein. In Fitzpatrick, Thomas, D., et al., Dermatology in General
Medicine, (4th ed., 1993 McGraw-Hill, Inc., p. 2847), the potency
ranking for a number of commonly used corticosteroids is given as
determined by double-blind clinical studies and vasoconstrictor
assays. In general, the corticosteroids identified as low potency
corticosteroids herein fall within Groups 6 and 7 in this ranking,
the corticosteroids identified as mid-potency corticosteroids
herein fall within Groups 4 and 5 in this ranking and the
corticosteroids identified as high-potency steroids herein fall
within Groups 1, 2 and 3 of this ranking.
[0065] The composition of the present invention may contain each of
the above-identified steroids in solution, spray, lotion, cream,
gel or ointment form with the corticosteroid selected and the
concentration thereof in the composition, depending at least in
part, upon the therapeutic application and the vehicle
selected.
[0066] Antifungal
[0067] The composition of the present invention preferably contains
at least about 0.1% by weight, more preferably about 0.25% to about
10%, still more preferably about 0.4% to about 7% of an antifungal
agent, and, depending upon the antifungal agent, still more
preferably about 1% to about 2% by weight of an antifungal agent.
In general, the antifungal agent may be an imidazole antifungal
agent such as miconazole, clotrimazole, butoconazole, tioconazole,
econazole, ketoconazole, oxiconizole and sulconazole, a benzylamine
such as butenafine HCl, allylamines such as naftifine and
terbinafine, triazoles such as terconazole, hydroxypyridone agents
such as ciclopirox, halogenated phenolic ethers such as haloprogin,
thiocarbamates such as tolnaftate, selenium sulfide, zinc
pyrithione, and other antifungal agents such as thymol and tinver.
Preferably, the antifungal agent is an imidazole, and for many
applications, it is preferably clotrimazole (about 0.5% to about
5%, more preferably about 1% to about 2% by weight).
[0068] Drying Agent
[0069] The drying agent generally promotes rapid drying of moist
areas and coats the skin for protection and healing. In particular,
it acts to prevent irritation of the involved area and water loss
from the skin layer by forming a physical barrier on the skin.
Preferred drying agents include calamine; zinc containing drying
agents such as zinc oxide, zinc stearate and zinc sulfate; copper
sulfate; kaolin; potassium permanganate; Burow's aluminum solution;
talc; starches such as wheat and corn starch; silver nitrate, and
acetic acid. Calamine and zinc oxide are particularly
preferred.
[0070] In general, the composition of the present invention
contains at least about 2.5% by weight and no more than about 60%
by weight drying agent. Typically, the composition contains about
5% to about 50% by weight drying agent, and for many applications
such as the treatment of contact dermatitis (e.g., diaper rash),
the composition preferably contains about 7% by weight to about 25%
by weight drying agent. The composition may contain a single drying
agent, for example, calamine or zinc oxide, or a combination of
drying agents, for example, calamine and zinc oxide, calamine and
zinc stearate, or calamine and one or more starches. When the
composition contains calamine and one or more other drying agents
such as zinc oxide, the weight ratio of calamine to the other
drying agent(s) is generally about 0.5:1 to about 10:1,
respectively. For example, the weight ratio of calamine to
zinc-containing drying agents will preferably be about 1:1 to about
3:1, respectively, the weight ratio of calamine to talc will
preferably be about 1:1 to about 3:1, respectively, and the weight
ratio of calamine to starch drying agent(s) will preferably be
about 1:1 to about 10:1, respectively, in compositions containing
calamine and one or more other drying agents. Calamine (which is
zinc oxide with approximately 0.5% by weight ferric oxide) reduces
inflammation, redness and itching, as well as promoting drying of
excess oils and fluids; preferably, therefore, the composition
includes calamine in an amount between about 7 and 25 weight
percent and, more preferably, additionally includes zinc oxide in
an amount between 7 and about 25 weight percent. A particularly
preferred composition for contact dermatitis comprises calamine
(about 7% to about 10% by weight) and zinc oxide (about 7% to about
10% by weight).
[0071] Additional Agents
[0072] The composition of the present invention may comprise an
anti-itch agent such as phenol, camphor, menthol, benzocaine,
diphenylhydramine or pramoxine. In general, the concentration of
these anti-itch agents in the composition will be about 0.3 wt % to
about 1 wt % for each of menthol, camphor and phenol; about 0.5
wt.% to about 20 wt % benzocaine; about 0.1 wt.% to about 20 wt %,
more preferably about 0.5 wt % to about 5 wt.%, and still more
preferably about 1 wt % to about 2 wt % for diphenylhydramine; and
about 0.1 wt.% to about 20 wt %, more preferably about 0.5 wt % to
about 5 wt. %, and still more preferably about 1 wt % for
pramoxine. When an anti-itch agent is included, particularly if the
anti-itch agent is diphenylhdramine or pramoxine, the composition
preferably additionally comprises zinc acetate (about 0.01 wt % to
about 5 wt. %, more preferably about 0.05 wt. % to about 3 wt. %,
and still more preferably about 0.1 wt. % to about 1 wt. % zinc
acetate).
[0073] The composition of the present invention may include a wide
range of optional ingredients including, antifoaming agents;
buffers, neutralizing agents and agents to adjust pH; coloring
agents and decoloring agents; emollients; emulsifying agents;
emulsion stabilizers and viscosity builders; humectants; odorants;
preservatives, antioxidants, and chemical stabilizers; solvents;
and thickening, stiffening and suspending agents. Exemplary
antifoaming agents include cyclomethicone, dimethicone (e.g.,
dimethicone 350) and simethicone. Exemplary buffers, neutralizing
agents and agents to adjust pH include ammonium hydroxide, citric
acid, diisopropanolamine, hydrochloric acid, lactic acid, monobasic
sodium phosphate, sodium citrate, sodium hydroxide, sodium
phosphate, triethanolamine, and trolamine. Exemplary emollients
include caprylic/capric triglyerides, castor oil, ceteareth-20,
ceteareth-30, cetearyl alcohol, ceteth 20, cetostearyl alcohol,
cetyl alcohol, cetyl stearyl alcohol, cocoa butter, diisopropyl
adipate, glycerin, gyceryl monooleate, glyceryl monostearate,
glyceryl stearate, isopropyl myristate, isopropyl palmitate,
lanolin, lanolin alcohol, hydrogenated lanolin, liquid paraffins,
linoleic acid, mineral oil, oleic acid, white petrolatum,
polyethylene glycol, polyoxyethylene glycol fatty alcohol ethers,
polyoxypropylene 15-stearyl ether, propylene glycol stearate,
squalane, steareth-2 or -100, stearic acid, stearyl alcohol and
urea. Exemplary emulsifying agents include aluminum starch
octenylsuccinate, ammonium hydroxide, amphoteric-9, beeswax,
synthetic beeswax, carbomer 934, carbomer 934P, carbomer 940,
ceteareth-20, ceteareth-30, cetearyl alcohol, ceteth 20, cetyl
alcohol, cholesterol, cyclomethicone, diglycerides, dimethicone
(e.g., dimethicone 350), disodium monooleamidosulfosuccinate, NF
emulsifying wax, fatty acid pentaerythritol ester, glycerides,
glyceryl monooleate, glyceryl monostearate, lanolin, lanolin
alcohol, hydrogenated lanolin, magnesium stearate, mineral oil,
monoglycerides, polyethylene glycol, PEG 100 stearate, polyethylene
glycol 6000 distearate, polyethylene glycol 1000 monocetyl ether,
polyethylene glycol monostearate, polyethylene glycol 400
monostearate, polyoxyethylene glycol fatty alcohol ethers, polyoxyl
20 cetostearyl ether, polyoxyl 40 stearate,- polysorbate 20,
polysorbate 40, polysorbate 60, polysorbate 80, polysorbates,
PPG-26 oleate, propylene glycol stearate, quaternium-15,
simethicone, sodium laureth sulfate, sodium lauryl sulfate,
sorbitan esters, sorbitan monolaurate, sorbitan monooleate,
sorbitan monopalmitate, sorbitan monostearate, sorbitan palmitate,
sorbitan sesquioleate, steareth-2, steareth-100, stearic acid,
stearyl alcohol, triethanolamine and trolamine. Exemplary emulsion
stabilizers and viscosity builders include carbomer 934, carbomer
934P, carbomer 940, cetearyl alcohol, cetostearyl alcohol, cetyl
alcohol, cetyl stearyl alcohol, dextrin, diglycerides, disodium
edetate, edetate disodium, glycerides, glyceryl monostearate,
glyceryl stearate, hydroxypropyl cellulose, monoglycerides,
plasticized hydrocarbon gel, polyethylene glycol 300, polyethylene
glycol 400, polyethylene glycol 1450, polyethylene glycol 8000,
polyethylene glycols, propylene glycol stearate and stearyl
alcohol. Exemplary humectants include glycerine, propylene glycol,
sorbitol and urea. Exemplary odorants include hypoallergenic
perfume, and menthol. Exemplary preservatives, antioxidants, and
chemical stabilizers include alcohol, benzyl alcohol, butylated
hydroxyanisole, butylated hydroxytoluene, butylparaben, calcium
acetate, caster oil, chlorocresol, 4-chloro-m-cresol, citric acid,
disodium edetate, Dowicil 200 (Dow), edetate disodium, ethoxylated
alcohol, ethyl alcohol, glycerin, Glydant Plus (Lonza),
1,2,6-hexanetriol, Kathon CG (Rohm & Haas), Liquid Germall Plus
(ISP Sutton Labs), Liquipar (ISP Sutton Labs), methylparaben,
parabens, potassium sorbate, propyl gallate, propylene glycol,
propylparaben, sodium bisulfite, sodium citrate, sodium
metabisulfite, sorbic acid, tannic acid, triglycerides of saturated
fatty acids, Ucarcide (Union Carbide), and zinc stearate. Exemplary
solvents include alcohol, castor oil, diisopropyl adipate,
ethoxylated alcohol, ethyl alcohol, fatty alcohol citrate,
glycerin, 1,2,6-hexanetriol, hexylene glycol, isopropyl alcohol,
isopropyl myristate, isopropyl palmitate, mineral oil, phosphoric
acid, polyethylene glycol 300, polyethylene glycol 400,
polyethylene glycol 1450, polyethylene glycol 8000, polyethylene
glycol 1000 monocetyl ether, polyethylene glycol monostearate,
polyethylene glycol 400 monostearate, polyethylene glycols,
polyoxyl 20 cetostearyl ether, polyoxypropylene 15-stearyl ether,
polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80,
polysorbates, propylene carbonate, propylene glycol, purified
water, and SD alcohol 40, triglycerides of saturated fatty acids.
Exemplary thickening, stiffening and suspending agents include
aluminum stearate, beeswax, synthetic beeswax, carbomer 934,
carbomer 934P, carbomer 940, cetostearyl alcohol, cetyl alcohol,
cetyl esters wax, dextrin, glyceryl monostearate, hydroxypropyl
cellulose, kaolin, paraffin, petrolatum, polyethylene, propylene
glycol stearate, starch, stearyl alcohol, wax, white wax, xanthan
gum, and bentonite.
[0074] Other agents which may be added to the composition of the
present invention include aloe, arachis oil, benzoic acid, cocoa
butter (up to about 70% by weight); coenzyme Q10 ("ubiquinone"),
eucalyptus oil, resorcinol (up to about 5% by weight); retinol;
retinyl palmitate; retinyl acetate; fennel extract; whey protein;
ceramide; nystatin (about 50,000 International Units per gram to
about 300,000 International Units per gram, preferably about 75,000
International Units to about 125,000 International Units per gram),
fungizone, amphotericin B, undecylenic acid, silicone (about 1% to
about 50% by weight); alpha-hydroxy acids, beta-hydroxy acids,
sorbitol, vitamin A (about 500 International Units per gram to
about 300,000 International Units per gram provided, for example,
in the form of fish liver oil, cod liver oil or shark liver oil),
vitamin B (including panthenol and beta-carotene), vitamin C,
vitamin D (about 50 International Units per gram to about 500
International Units per gram), vitamin E (about 20 International
Units per gram to about 500 International Units per gram), and
vitamin K. Unless otherwise indicated, the composition will
generally contain less than about 5% by weight and typically less
than about 1% by weight of the above-ingredients.
[0075] Treatment/Administration
[0076] The composition of the invention is applied topically to the
involved area until it has healed. For example, for contact
dermatitis a composition containing hydrocortisone (about 1% by
weight), clotrimazole (about 1% by weight), calamine (about 8% by
weight), zinc oxide (about 8% by weight), glycerin (about 2% by
weight), bentonite magma (about 25% by weight) and calcium
hydroxide in sterile water (to 100% by weight) is preferably
administered two to four times a day for from one day to a week or
more until healing occurs.
[0077] In one embodiment, the composition of the present invention
comprises a nonpainful, soothing agent that will control the
irritant dermatitis (e.g., a corticosteroid safe to use under
occlusion, on an infant, on genital and intertriginous skin), that
will eradicate the secondary Candida infection (e.g., an antifungal
agent), and that will dry the area while providing a barrier (e.g.,
calamine). In addition, it can effectively provide fast relief of
symptoms and eradication of the fungal infection while minimizing
the risk of undesirable side effects caused by high-potency and/or
fluorinated steroids. For such uses, the composition preferably
contains a (i) low-potency steroid such as hydrocortisone,
hydrocortisone acetate, alclometasone dipropionate, fluocinolone
acetonide, dexamethasone, methylprednisolone or desonide, (ii) an
anti-fungal such as miconazole, clotrimazole, ketoconazole,
oxiconizole, butenafine HCl, naftifine, terbinafine, ciclopirox,
tolnaftate, and (iii) a drying agent such as a calamine containing
lotion or gel. For such uses, the composition more preferably
contains a (i) low-potency steroid such as hydrocortisone,
alclometasone dipropionate, or desonide, (ii) an anti-fungal such
as miconazole, clotrimazole, ketoconazole, oxiconizole,
terbinafine, tolnaftate, and (iii) a drying agent such as a
calamine, and is in the form of a lotion or gel. For such uses, the
composition still more preferably contains (i) hydrocortisone, (ii)
miconazole, clotrimazole, ketoconazole, terbinafine, or tolnaftate,
and (iii) a drying agent such as a calamine containing lotion or
gel. The concentration of the low-potency steroid in these
compositions is preferably about 0.25% to about 3.5% by weight,
more preferably about 0.5% to about 2.5% by weight for
hydrocortisone and hydrocortisone acetate; preferably about 0.025%
to about 0.075% by weight and more preferably about 0.05% for
alclometasone dipropionate and desonide; and preferably about
0.005% to about 0.0125% by weight and more preferably about 0.01%
for fluocinolone acetonide. The concentration of the anti-fungal
agents in these compositions is about 0.5% to about 5% and more
preferably about 1% to about 2% by weight for miconazole,
clotrimazole, ketoconazole, oxiconizole, butenafine HCl, naftifine,
terbinafine, ciclopirox, and tolnaftate.
[0078] In another embodiment, for conditions such as severe
exudative diaper rash, severe intertrigo, severe tinea infections,
severe seborrhea, recalcitrant psoriasis, or forms of lichen
simplex chronicus, the composition will include a mid-potency
steroid for more effective treatment. For such uses, the
composition preferably contains (i) a mid-potency steroid such as
hydrocortisone butyrate, hydrocortisone valerate, or prednicarbate,
(ii) an anti-fungal such as miconazole, clotrimazole, ketoconazole,
oxiconizole, butenafine HCl, naftifine, terbinafine, ciclopirox,
tolnaftate, and (iii) a drying agent such as a calamine, and is in
the form of a lotion or gel. For such uses, the composition more
preferably comprises (i) a mid-potency steroid such as
hydrocortisone butyrate or hydrocortisone valerate, (ii) an
anti-fungal such as miconazole, clotrimazole, ketoconazole,
oxiconizole, terbinafine, tolnaftate, and (iii) a drying agent such
as a calamine containing lotion or gel. For such uses, the
composition still more preferably contains (i) hydrocortisone
valerate, (ii) miconazole, clotrimazole, ketoconazole, terbinafine,
or tolnaftate, and (iii) a drying agent such as a calamine
containing lotion or gel. The concentration of hydrocortisone
butyrate and hydrocortisone valerate in such compositions is
preferably about 0.05% to about 0.5% and more preferably about 0.1
to about 0.2% by weight. The concentration of the prednicarbate is
preferably about 0.01% to about 0.5%, more preferably about 0.05%
to about 0.25%, more preferably about 0.1% by weight. The
concentration of the anti-fungal agents in these compositions is
about 0.5% to about 5% and more preferably about 1% to about 2% by
weight for miconazole, clotrimazole, ketoconazole, oxiconizole,
butenafine HCl, naftifine, terbinafine, ciclopirox, and
tolnaftate.
[0079] In still another embodiment, for conditions such as very
severe and recalcitrant exudative diaper rash, intertrigo, tinea
infections, seborrhea, psoriasis or licehn simplex chronicus, the
composition preferably includes a fluorinated mid-potency steroid
or high-potency steroid for more effective treatment; it should be
noted, however, that fluorinated steroids are generally safe for
diaper rash and intertrigo if used for relatively brief periods.
For such uses, the composition is preferably in the form of a
lotion or gel and it contains (i) a drying agent such as calamine,
(ii) an anti-fungal such as miconazole, clotrimazole, ketoconazole,
oxiconizole, butenafine HCL, naftifine, terbinafine, ciclopirox,
tolnaftate, and (iii) a fluorinated mid-potency or high-potency
steroid such as
[0080] triamcinolone acetonide (about 0.001% to about 1%;
preferably about 0.01% to about 0.5%; more preferably about 0.025%
to about 0.1% by weight);
[0081] fluticasdne propionate (about 0.0005% to about 0.5%;
preferably about 0.001% to about 0.1%; more preferably about 0.005%
to about 0.05% by weight);
[0082] flurandrenolide (about 0.005% to about 0.5%; preferably
about 0.01% to about 0.1%; more preferably about 0.025% to about
0.05% by weight);
[0083] mometasone furoate (about 0.01% to about 0.5%, preferably
about 0.05% to about 0.25%, more preferably about 0.1% by
weight);
[0084] desoximetasone (about 0.005% to about 1%; preferably about
0.01% to about 0.5%; more preferably about 0.05% to about 0.25% by
weight);
[0085] betamethasone (about 0.005% to about 0.5%; preferably about
0.01% to about 0.25%; more preferably about 0.05% to about 0.1% by
weight);
[0086] betamethasone dipropionate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight);
[0087] betamethasone valerate (about 0.01% to about 0.5%,
preferably about 0.05% to about 0.25%, more preferably about 0.1%
by weight);
[0088] betamethasone propionate (about 0.005% to about 0.5%;
preferably about 0.01% to about-0. 1%; more preferably about 0.05%
by weight);
[0089] betamethasone benzoate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight);
[0090] diflorasone diacetate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight);
[0091] fluocinonide (about 0.005% to about 0.5%; preferably about
0.01% to about 0.1%; more preferably about 0.05% by weight);
[0092] halcinonide (about 0.01% to about 0.5%, preferably about
0.05% to about 0.25%, more preferably about 0.1% by weight);
[0093] amcinonide (about 0.01% to about 0.5%, preferably about
0.05% to about 0.25%, more preferably about 0.1% by weight);
[0094] halobetasol propionate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight); and
[0095] clobetasol propionate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight).
[0096] For such uses, the composition more preferably comprises (i)
a drying agent such as calamine, (ii) an anti-fungal such as
miconazole, clotrimazole, ketoconazole, oxiconizole, terbinafine,
and tolnaftate, and (iii) a fluorinated mid-potency or high-potency
steroid such as
[0097] triamcinolone acetonide (about 0.001% to about 1%;
preferably about 0.01% to about 0.5%; more preferably about 0.025%
to about 0.1% by weight);
[0098] fluticasone propionate (about 0.0005% to about 0.5%;
preferably about 0.001% to about 0.1%; more preferably about 0.005%
to about 0.05% by weight);
[0099] mometasone furoate (about 0.01% to about 0.5%, preferably
about 0.05% to about 0.25%, more preferably about 0.1% by
weight);
[0100] desoximetasone (about 0.005% to about 1%; preferably about
0.01% to about 0.5%; more preferably about 0.05% to about 0.25% by
weight);
[0101] betamethasone (about 0.005% to about 0.5%; preferably about
0.01% to about 0.25%; more preferably about 0.05% to about 0.1% by
weight);
[0102] betamethasone dipropionate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight);
[0103] betamethasone valerate (about 0.01% to about 0.5%,
preferably about 0.05% to about 0.25%, more preferably about 0.1%
by weight);
[0104] betamethasone propionate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight);
[0105] betamethasone benzoate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight);
[0106] diflorasone diacetate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight);
[0107] fluocinonide (about 0.005% to about 0.5%; preferably about
0.01% to about 0.1%; more preferably about 0.05% by weight);
[0108] halobetasol propionate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight); and
[0109] clobetasol propionate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight).
[0110] For such uses, the composition still more preferably
comprises (i) a drying agent such as calamine, (ii) an anti-fungal
such as miconazole, clotrimazole, ketoconazole, terbinafine, or
tolnaftate, and (iii) a fluorinated mid-potency or high-potency
steroid such as
[0111] triamcinolone acetonide (about 0.001% to about 1%;
preferably about 0.01% to about 0.5%; more preferably about 0.025%
to about 0.1% by weight);
[0112] desoximetasone (about 0.005% to about 1%; preferably about
0.01% to about 0.5%; more preferably about 0.05% to about 0.25% by
weight);
[0113] betamethasone (about 0.005% to about 0.5%; preferably about
0.01% to about 0.25%; more preferably about 0.05% to about 0.1% by
weight);
[0114] betamethasone dipropionate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight);
[0115] betamethasone valerate (about 0.01% to about 0.5%,
preferably about 0.05% to about 0.25%, more preferably about 0.1%
by weight);
[0116] betamethasone propionate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight);
[0117] betamethasone benzoate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight);
[0118] diflorasone diacetate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight);
[0119] fluocinonide (about 0.005% to about 0.5%; preferably about
0.01% to about 0.1%; more preferably about 0.05% by weight);
and
[0120] clobetasol propionate (about 0.005% to about 0.5%;
preferably about 0.01% to about 0.1%; more preferably about 0.05%
by weight).
[0121] The concentration of-the antifungal agents in these
compositions for conditions such as very severe and recalcitrant
exudative diaper rash is about 0.5% to about 5% and more preferably
about 1% to about 2% by weight for miconazole, clotrimazole,
ketoconazole, oxiconizole, butenafine HCl, naftifine, terbinafine,
ciclopirox, and tolnaftate.
[0122] One of the problems with the prior creams containing
nystatin and hydrocortisone is that the antifungal coverage is not
as broad spectrum as with an imidazole antifungal agent like
miconazole or clotrimazole. Nystatin and other polyene antibiotics
only treat yeast (Candida) infections, while the azole (imidazole)
compounds treat both dermatophytes and yeast (Arndt, Kenneth A.,
Manual of Dermatologic Therapeutics, 5.sup.th edition, 1995,
Little, Brown and Co., page 290). In mixed infections, therefore,
where dermatophyte infections are present, the composition
containing hydrocortisone and nystatin will not provide the desired
full spectrum of activity while the imidazole antifungals will,
while still treating the Candida. The proposed invention will also
treat tinea cruis, tinea pedis (interdigital type), tinea corporis
and tinea versicolar. Nystatin will not treat these entities.
[0123] The following examples illustrate the invention.
1 Clinical Examples Composition A: Hydrocortisone 1% Clotrimazole
1% Calamine lotion 98% Composition B: Hydrocortisone 1%
Clotrimazole 2% Calamine lotion 97% Composition C: Hydrocortisone
0.5% Clotrimazole 1% Calamine lotion 98.5% Calamine Lotion Calamine
(U.S.P.) - 8 gm Zinc oxide - 8 gm Glycerin - 2 ml Bentonite magma -
25 ml Calcium hydroxide in sterile water - to 100 ml
[0124] Two infants presented with diaper rash. The first, an
18-month-old (DV) had the rash for about 1 week, and 1%
clotrimazole cream was not helping. He had multiple red papules,
confluent in areas into patches, located mainly on the suprapubic
and perineal areas. After 1 day of using composition A (2 or 3,
applications) the rash was clear. The second, a 3 year old,
presented with red patches and papules in his groin, present for 2
weeks. The rash improved greatly after 6 days of use. The mother
was so satisfied that she called for a refill 2 months later for
another episode of the diaper dermatitis.
[0125] Seventeen patients presented with intertrigo. In general,
the patients responded well to composition A. One patient (A. H.)
had a pruritic genital rash for 4 years, consisting of diffuse
erythema located on both upper inner thighs, within her groin and
gluteal cleft. She did not clear with Vytone 1% hydrocortisone,
hydrocortisone 0.5% combined with Nizoral cream, or plain Nizoral
cream at night with Zeasorb powder in the morning. She was
prescribed composition A. Within 5 weeks she showed marked
improvement. A 14 year old girl (D. B.) presented with more than a
month of a pruritic, beefy red, scaly rash on her genitalia that
had not responded to hydrocortisone 1% cream along with Zeasorb
powder, or to Tinactin. A culture for yeast was negative. After
using composition A for 9 days the genital rash was clear. Another
patient (J. H.) had a pruritic genital rash for a few days. Potent
fluorinated topical steroids provided no relief. Composition A
provided rapid relief. A 69 year old female (B. J.) had a pruritic,
malodorous rash in her groin for more than 5 years. A culture taken
5 years previously grew trichophyton rubrum fungus. On exam she had
erythematous macules of both inguinal folds. This was consistent
with intertrigo. She used Composition A and did not need to return
for follow-up. A man (P. K.) had inguinal intertrigo for several
years, treated with many different agents with only temporary
success. When, prescribed composition A, he had rapid improvement,
and the composition A cleared the inguinal intertrigo after 2
months of therapy. He subsequently developed a Candida infection on
his scrotum, which also cleared with composition A. A male patient
(D. K.) had a persistent groin rash, culture positive tinea cruris
that did not clear after 6 weeks of Oxistat (oxiconalole)
treatment. On exam he had diffuse erythema of both groin,
consistent with intertrigo. The rash improved when he used
composition A, but recurred when stopped. When persuaded to use the
medicine twice daily every day, he cleared after 1 month of
therapy. Three months later he returned with a flare of his rash,
complaining of rawness and blisters. He had macular erythema in his
left groin, and an erythematous patch with papulo-pustules. A
culture revealed Candida infection. Composition A provided good
improvement after 1 month of use. Another patient had an extremely
sore perianal rash, beefy red with a few erosions, which failed to
respond to Lotrisone, Spectazole or Des Owen creams. The eruption
showed dramatic improvement after 2 weeks of using composition A. A
47 year old female (K. S.) had a very pruritic rash under her
breasts that failed to respond to 2 weeks of Spectazole cream at
night and Zeasorb powder in the morning.
[0126] Composition A provided rapid relief. Another female (J. Z.)
with a very pruritic erythematous rash under her breasts and in her
groin (intertrigo) cleared in less than 2 weeks of using
composition A, and stated "the medication was easy to use." A 28
year old man (K. H.) with a fungal culture negative groin rash of
uncertain nature responded well to Composition B (containing 2%
clotrimazole).
[0127] One patient presented with balanoposthitis. The patient (G.
M.) had a red glistening shiny patch on his glans penis, consistent
with both balanoposthitis and a psoriasiform dermatitis. He had a
chronic rash on his penis for 5 years, which did not clear after
circumcision. Composition A cleared the rash in less than a
month.
[0128] Four patients presented with scrotal lichen simplex
chronicus (AKA scrotodynia, male itch). An 84-year old man (J. P.)
had a longstanding pruritic eruption on his scrotum, with a biopsy
showing a chronic eczema, consistent with lichen simplex chronicus
(LSC). Cutivate (fluticasone propionate) helped, but the rash
recurred when he stopped the medication. Micatin was without help.
On exam he had a thickened red patch on his scrotum. Composition A
cleared the eczema after only 2-3 days of twice daily use, and
remained clear for almost 2 months. Another patient (D. S.)
presented with a burning and pruritic red rash on his scrotum,
present for almost 5 months. Nizoral cream was without benefit.
Composition A provided marked improvement after 6 weeks of
therapy.
[0129] Four patients had the combination of seborrheic dermatitis
and psoriasis (sebo-psoriasis). A 42 year old man (K. H.) had a
chronic pruritic erythematous rash on his scrotum, penis, and
within the gluteal cleft. Composition A provided good relief, with
control of the eruption when used only every other day. Spectazole
cream had been without benefit. Composition C was tried, with
equally good results compared to using Composition A. Another
patient (W. P.) had a pruritic rash in his groin and buttocks for a
period of 2-3 years that would wax and wane.
[0130] On exam he had dusky red scaly patches in his groin and
gluteal cleft. After one month of using composition A twice daily,
he was much better. A patient with sebo-psoriasis and intertrigo
(J. L.) failed to respond to a combination of 1% hydrocortisone
plus Nizoral cream or to a combination of 2% hydrocortisone plus
Nizoral cream. When prescribed composition A, after 1 month he
stated the new compound was better. On physical exam he was much
improved. After 2 months of twice daily therapy, he was totally
clear. So the addition of calamine to the hydrocortisone and
imidazole made the difference.
[0131] One patient (S. H.) presented with tinea versicolar on her
neck, confirmed by microscopic KOH examination of skin scrapings.
On return exam 19 days later the neck was clear.
[0132] One patient (T. M.) with a past history of tinea cruris
presented with a 2 month flare of his groin rash. Topicort
(desoximetasone) cream was without help. On exam he had beefy-red,
slightly scaly patches on both upper inner thighs, extending into
the groin. KOH microscopic exam revealed hyphal elements, and
fungal culture grew the dermatophyte Trichophyton mentagrophytes.
Composition A applied twice daily cleared the infection within 6
weeks (and possibly sooner; we had to call the patient for
follow-up after 6 weeks).
* * * * *