U.S. patent application number 09/135657 was filed with the patent office on 2001-07-05 for antipsoriatic nail polish.
Invention is credited to BOHN, MANFRED, KRAEMER, KARL THEODOR.
Application Number | 20010006625 09/135657 |
Document ID | / |
Family ID | 7839551 |
Filed Date | 2001-07-05 |
United States Patent
Application |
20010006625 |
Kind Code |
A1 |
BOHN, MANFRED ; et
al. |
July 5, 2001 |
ANTIPSORIATIC NAIL POLISH
Abstract
This invention relates to a nail polish comprising one or more
glucocorticoids useful in treating nails which show changes due to
the syndrome of psoriasis.
Inventors: |
BOHN, MANFRED; (HOFHEIM,
DE) ; KRAEMER, KARL THEODOR; (LANGEN, DE) |
Correspondence
Address: |
FINNEGAN HENDERSON FARABOW
GARRETT & DUNNER
1300 I STREET NW
WASHINGTON
DC
200053315
|
Family ID: |
7839551 |
Appl. No.: |
09/135657 |
Filed: |
August 18, 1998 |
Current U.S.
Class: |
424/61 ; 424/401;
424/405; 424/78.02; 424/78.08 |
Current CPC
Class: |
A61K 8/63 20130101; A61K
31/573 20130101; A61K 31/58 20130101; A61K 9/7015 20130101; A61P
17/00 20180101; A61K 8/8152 20130101; A61P 17/06 20180101; A61Q
3/02 20130101 |
Class at
Publication: |
424/61 ; 424/401;
424/78.02; 424/78.08; 424/405 |
International
Class: |
A61K 007/04; A61K
031/74; A61K 006/00; A61K 007/00; A01N 025/00 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 21, 1997 |
DE |
197 36 112.9 |
Claims
We claim:
1. A nail polish comprising one or more glucocorticoids, one or
more physiologically tolerable solvents and one or more
water-insoluble film-forming agents.
2. A nail polish according to claim 1, which comprises, as a
glucocorticoid, alclometasone dipropionate, amcinonide,
beclomethasone dipropionate, bendacort, betamethasone benzoate,
betamethasone dipropionate, betamethasone valerate, budesonide,
chlorquinaldol, clioquinol, clobetasol propionate, clobetasone
butyrate, desonide, desoximetasone, dexamethasone, dichlorisone,
diflorasone diacetate, diflucortolone valerate, difluprednate,
fluazacort, flucinolone acetonide, fluclorolone acetonide,
fludroxycortide, flumethasone pivalate, fluocinolone acetonide,
fluocinonide, fluocortolone, fluorometholone, flupamesone,
fluprednidene, fluprednidene acetate, flurandrenolide, halcinonide,
halometasone, hydrocortamate, hydrocortisone butyrate,
methylprednisolone aceponate, mometasone furoate, prednicarbate,
prednisolone, prednisone, tixocortol, or triamcinolone
acetonide.
3. A nail polish according to claim 1, which comprises, as a
glucocorticoid, clobetasol propionate, desoximetasone,
betamethasone dipropionate, prednicarbate or halcinonide.
4. A nail polish according to claim 1, which comprises one more
glucocorticoids in a total concentration of 0.5% to 20% by
weight.
5. A nail polish according to claim 1, which comprises one or more
glucocorticoids in a total concentration of 2% to 15% by
weight.
6. A nail polish according to claim 1, where the glucocorticoids
are in the form of free alcohols or esters.
7. A nail polish according to claim 1, wherein the content of
glucocorticoid is at least 8% by weight.
8. A nail polish according to claim 1 wherein the glucocorticoid is
present in the amount of about 1% to about 4% by weight.
9. A nail polish according to claim 1, where the water-insoluble
film-forming agent comprises a cellulose derivative.
10. A nail polish according to claim 9, where the water-insoluble
film-forming agent comprises cellulose nitrate, ethylcellulose, or
mixtures thereof.
11. A nail polish according to claim 1, where the water-insoluble
film-forming agent comprises physiologically acceptable
polymers.
12. A nail polish according to claim 1, where the water-insoluble
film-forming agent comprises a poly(vinyl acetate), partially
hydrolyzed poly(vinyl acetate); copolymers of vinyl acetate with
acrylic acid, or crotonic acid or monoalkyl maleate; ternary
polymers of vinyl acetate with crotonic acid and vinyl
neodecanoate; ternary polymers of vinyl acetate with crotonic acid
and vinyl propionate; copolymers of methyl ethyl vinyl ether and
monoalkyl maleates; copolymers of fatty acid vinyl esters and
acrylic acid or methacrylic acid; copolymers of N-vinylpyrrolidone,
methacrylic acid, and alkyl methacrylates; copolymers of acrylic
acid and methacrylic acid, alkyl acrylates, or alkyl
methacrylates.
13. A nail polish according to claim 12, where the water-insoluble
film-forming agent is a copolymer of methyl vinyl ether and
monobutyl maleate.
14. A nail polish according to claim 12, where the water-insoluble
film-forming agent contains a quaternary ammonium group.
15. A nail polish according to claim 1, where the water-insoluble
film-forming agent comprises a polymer, copolymer, or mixture
comprising one or more of ethyl acrylate, methyl methacrylate,
trimethylammonioethyl methacrylate chloride, polyvinyl acetals,
polyvinyl butyrals, alkyl-substituted poly-N-vinylpyrrolidone,
alkyl esters of copolymers of olefins and maleic anhydride,
reaction products of colophony with acrylic acid, and benzoins.
16. A nail polish according to claim 1 where the water-insoluble
film-forming agent comprises ethyl acrylate, methyl methacrylate,
and trimethylammonioethyl methacrylate chloride in a molar ratio of
1:2:0.2.
17. A nail polish according to claim 1, where the physiologically
tolerable solvent comprises hydrocarbons, halogenated hydrocarbons,
alcohols, ethers, ketones, esters, and mixtures thereof.
18. A nail polish according to claim 17, where the physiologically
tolerable solvent comprises acetate esters of monohydric
alcohols.
19. A nail polish according to claim 18, where the physiologically
tolerable solvent comprises ethyl acetate, butyl acetate, mixtures
thereof, mixtures with aromatic hydrocarbons, and mixtures with
alcohols.
20. A nail polish according to claim 19 where the aromatic
hydrocarbon is toluene.
21. A nail polish according to claim 19 where the alcohols comprise
ethanol, isopropanol, or a mixture thereof.
22. A nail polish according to claim 1, further comprising as an
additive a plasticizer based on phthalate or camphor, a colorant or
color pigment, pearl luster agents, sedimentation retardants,
sulfonamide resins, silicates, aromatic substances, lanolin
derivatives, sunscreens, antimicrobial substances, and substances
having keratolytic activity, keratoplastic activity, or both, or
mixtures thereof.
23. A nail polish according to claim 22, where the additive
sunscreen is 2-hydroxy-4-methoxybenzophenone.
24. A nail polish according to claim 22, where the additive having
keratolyitc activity, keratoplastic activity, or both is ammonium
sulfite, esters and salts of thioglycolic acid, urea, allantoin,
enzymes, and salicylic acid, and mixtures thereof.
25. A method for preventing psoriasis of nails, comprising applying
an effective amount of a nail polish according to claim 1 to a nail
of a host.
Description
DESCRIPTION
Antipsoriatic Nail Polish
[0001] The involvement of the finger nails and toe nails in the
psoriasis syndrome is widespread. According to literature
references, up to 50% of all psoriasis patients also show changes
to the nails in addition to the characteristic skin symptoms. The
nail changes are found more frequently on the fingers than on the
toes and are identified in the order of their frequency by the
following symptoms:
[0002] Pitting (punctate or irregularly shaped depressions arranged
on the surface of the body of the nail in a certain pattern or
alternatively irregularly), discoloration of the nail bed,
onycholysis (detachment of the body of the nail from the nail bed),
subungual keratosis, or anomalies of the body of the nail.
[0003] For treatment of the nails affected by psoriasis, the
following four methods were used until now, but without sweeping
success, in addition to PUVA phototherapy:
[0004] One treatment method, the systemic method, consists in
administering methotrexate, retinoids or cyclosporin A orally. This
necessitates a long-term treatment, which according to experience
can lead to intoxication.
[0005] Another method consists in injecting intralesional
corticosteroids. This method is naturally very painful, so that the
patients are only initially ready to cooperate initially, but later
refuse treatment.
[0006] With a further method of surgically removing the affected
nails, good treatment results can indeed be achieved, but
intervention is only temporary because within one week after
regeneration of the body of the nail psoriasis may return.
[0007] A fourth, gentler, method consists in treating the nails
locally with specific, antipsoriatic substances such as dithranol,
vitamin D analogs, or corticosteroids. In this context, all sorts
of treatment methods have been attempted. Thus, in a combined
treatment the nails are first treated with solutions of the
antipsoriatic substances. Then cream dressings are applied at
night. Even this treatment method is naturally very unpleasant and
psychologically distressing for the patient. First, the treatment
of the nails with solutions is necessary several times daily.
Second, the treated nails must be covered with dressings at
night.
[0008] This leads to the results that the treatment of patients,
usually for many months, is often not completed. Patients become
disheartened and negligent and thus no therapeutic result
materializes. The success of treatment in this method is
furthermore adversely affected because the solutions and creams are
usually miscible with water or are hydrophilic and can therefore be
removed from the nail surface or dissolved out of the nail by
washing, bathing and showering and thus consequently then have to
be reapplied again. As a result of this, the treatment with these
topical agents is ineffective and, moreover, highly
uneconomical.
[0009] High hopes have therefore been placed in another method,
namely in the treatment of the affected nails with a 50:50 mixture
of commercially available corticosteroid-containing lotions, creams
or ointments with commercially available clear cosmetic varnishes
(U.S. Pat. No. 4,250,164). This method, however, although already
known for a long time, has not generally found its way into therapy
since a satisfactory result from these--naturally physically
unstable--mixtures do not appear, presumably for lack of sufficient
bioavailability of the active compound from the solid system
present after the drying of the mixture.
[0010] Therefore, many cases, in particular the severe cases, have
been treated as before using the surgical method described above or
using painful intralesional injections or using combined solution
and cream therapy.
[0011] WO 97/43644 discloses a topical formulation suitable for the
treatment of nail psoriasis comprising at least one glucocorticoid,
at least one spreading solvent, at least one readily volatile
solvent and a film-forming agent. This topical formulation has the
disadvantage that a spreading solvent is necessary. This additional
spreading solvent increases the price of the formulation and since
it is not clear if this spreading solvent is physiologically
acceptable, the approval of the formulation becomes more
complicated or even impossible.
[0012] The invention aims to make available a
glucocorticoid-containing formulation which does not have the
disadvantages described above or only has them to a minor extent.
In particular, the formulation should guarantee a good penetration
of the nail by the glucocorticoid and thus a good bioavailability
though a water-insoluble film-forming agent is used.
[0013] The invention further aims to make available a
glucocorticoid formulation, which does guarantee a good penetration
of the nail by the glucocorticoid and thus a good bioavailability,
comprising no additional spreading or penetration promoting solvent
or substance.
[0014] The object is achieved by the nail polish according to the
invention, comprising one or more glucocorticoids, a
physiologically tolerable, preferably readily volatile, solvent or
solvent mixture and one or more water-insoluble film-forming
agents.
[0015] Antipsoriatic glucocorticoids are, for example:
alclometasone dipropionate, amcinonide, beclomethasone
dipropionate, bendacort, betamethasone benzoate, betamethasone
dipropionate, betamethasone valerate, budesonide, chlorquinaldol,
clioquinol, clobetasol propionate, clobetasone butyrate, desonide,
desoximetasone, dexamethasone, dichlorisone, diflorasone diacetate,
diflucortolone valerate, difluprednate, fluazacort, flucinolone
acetonide, fluclorolone acetonide, fludroxycortide, flumethasone
pivalate, fluocinolone acetonide, fluocinonide, fluocortolone,
fluorometholone, flupamesone, fluprednidene, fluprednidene acetate,
flurandrenolide, halcinonide, halometasone, hydrocortamate,
hydrocortisone butyrate, methylprednisolone aceponate, mometasone
furoate, prednicarbate, prednisolone, prednisone, tixocortol,
triamcinolone acetonide.
[0016] The glucocorticosteroids can be present either as free
alcohols or in the form of their esters.
[0017] Suitable water-insoluble film-forming agents are, for
example, cellulose derivatives such as cellulose nitrate or
ethylcellulose or physiologically acceptable polymers such as are
customary, for example, in cosmetics. Mention may be made, for
example, of poly(vinyl acetate), and partially hydrolyzed
poly(vinyl acetate); copolymers of vinyl acetate with acrylic acid
or crotonic acid or monoalkyl maleate; ternary copolymers of vinyl
acetate with crotonic acid and vinyl neodecanoate, or crotonic acid
and vinyl propionate; copolymers of methyl vinyl ether and
monoalkyl maleates, and in particular monobutyl maleate; copolymers
of fatty acid vinyl esters and acrylic acid or methacrylic acid;
copolymers of N-vinylpyrrolidone, methacrylic acid and alkyl
methacrylates; copolymers of acrylic acid and methacrylic acid or
alkyl acrylates or alkyl methacrylates, in particular containing
quaternary ammonium groups; or polymers, copolymers or mixtures
comprising ethyl acrylate, methyl methacrylate or
trimethylammonioethyl methacrylate chloride or polyvinyl acetals
and polyvinyl butyrals, alkyl-substituted poly-N-vinylpyrrolidone-
, alkyl esters of copolymers of olefins and maleic anhydride,
reaction products of colophony with acrylic acid and also benzoins.
In the esters, the alkyl radicals are usually short-chain and
mostly do not have more than four carbon atoms.
[0018] Suitable physiologically tolerable solvents are substances
such as hydrocarbons, halogenated hydrocarbons, alcohols, ethers,
ketones and esters which are customary in cosmetics, in particular
acetate esters of monohydric alcohols such as ethyl acetate and
butyl acetate, optionally as a mixture with aromatic hydrocarbons
such as toluene and/or alcohols such as ethanol or isopropanol.
[0019] As is known, the combination of the solvents is of crucial
importance for the drying time, spreading ability, and other
important properties of the varnish or of the varnish film. The
solvent system preferably consists of an optimal mixture of
low-boiling components (solvents having a boiling point up to
100.degree. C.) and medium-boiling components (solvents having a
boiling point up to 150.degree. C.), optionally with a small
proportion of high-boiling components (solvents having a boiling
point up to 200.degree. C.).
[0020] Readily volatile solvents are understood as meaning
compounds which have a boiling point which is below 80.degree.
C.
[0021] The nail polishes according to the invention can further
contain additives customary in cosmetics, such as plasticizers
based on phthalate or camphor, colorants or color pigments, pearl
luster agents, sedimentation retardants, sulfonamide resins,
silicates, aromatic substances, lanolin derivatives, sunscreens
such as 2-hydroxy-4-methoxybenzophenone, antimicrobial substances,
and substances having keratolytic and/or keratoplastic action, such
as ammonium sulfite, esters and salts of thioglycolic acid, urea,
allantoin, enzymes, and salicylic acid.
[0022] Using the nail polish according to the invention, one can
achieve a drastic cure in the treatment of psoriatic nails, the
nail usually growing again without deformation. In view of the poor
therapeutic experiences until now, this is an extremely important
finding.
[0023] The nail polish according to the invention is also suitable
for prophylactic use against psoriatic nails, a sufficiently high
active compound depot being achieved in the nail such that a
possible recurrence does not break out.
[0024] The content of active compound in the nail polish according
to the invention is dependent on the structure of each active
compound and thus on its release from the varnish film, its
penetration behavior in the nail, and its potency.
[0025] In the nail polish according to the invention, (i.e., the
solvent-containing use form) the active compound is in general
contained in an amount from 0.5 to 20, preferably 2 to 15, percent
by weight. The minimum content of active compound in the medicinal
nail polishes (i.e., those for treatment) is preferably 8 percent
by weight; the nail polishes used for prophylaxis preferably
contain 1 to 4 percent by weight of active compound.
[0026] Colored or pigmented nail polishes have the advantage, for
example, that the preparation according to the invention can be
tailored to the esthetic perception of the patient.
[0027] The nail polish is prepared in a customary manner by mixing
together the individual components and--if necessary--further
processing tailored to the respective preparation.
[0028] The nail polish according to the invention has the following
composition:
EXAMPLE 1
[0029]
1 Clobetasol-17-propionate 8.0% 50% strength solution of a
copolymer 30.0% of methyl vinyl ether and monobutyl maleate in
isopropyl alcohol Isopropyl alcohol 31.0% Ethyl acetate 31.0% The
percentage quantitative data are by weight.
[0030] The nail polish is prepared by dissolving the various
components in the solvents.
EXAMPLE 2
[0031]
2 Desoximetasone 5.0% Ethyl acrylate/methyl methacrylate/ 12.0%
trimethylammonioethyl methacrylate chloride in a molar ratio of
1:2:0.2 (EUDRAGIT .RTM. RL 100) Ethanol 96% 60.0% Ethyl acetate
13.0% Butyl acetate 10.0%
EXAMPLE 3
[0032]
3 Betamethasone dipropionate 5.0% Ethylcellulose 11.0% Ethyl
acetate 30.0% Butyl acetate 34.0% Ethanol 96% 20.0%
EXAMPLE 4
[0033]
4 Prednicarbate 7.5% Polyvinyl butyral 4.7% Cellulose nitrate 4.3%
Dibutyl phthalate 0.6% Ethyl acetate 10.0% Ethanol 96% 72.9%
EXAMPLE 5
[0034]
5 Halcinonide 2.0% Methacrylic acid/ethyl acrylate 1:1 copolymer
6.5% Ethanol 96% 71.5% Ethyl acetate 20.0%
[0035] The action of the nail polish according to the invention is
demonstrated in permeation tests on cowhorn platelets and in
treatment experiments on subjects. The permeation test on cowhorn
platelets allows the release of an active compound from a certain
preparation and the subsequent permeation through keratin material
to be tested.
[0036] At present, there are still no topical preparations known
for the treatment of nail psoriasis with glucocorticoids from which
the active compound is released in sufficient amount, then
penetrates into the nails and can thus act in a therapeutic dose on
the underlying matrix or the nail bed.
[0037] As a control example, the following was used:
6 clobetasol-17-propionate 8.0% is dissolved in isopropyl alcohol
92.0%.
[0038] A) Permeation Test on Cowhorn Platelets
[0039] The measurement of the active compound permeation is carried
out by means of time-resolved ATR technique (time-resolved infrared
attenuated total reflection--see Th. M. Bayerl et al.; J. Invest.
Dermatol. 105:291-295,1995):
[0040] 100 .mu.l of the test preparation (test preparation or
control example) are applied to a defined area on the top of a
cowhorn platelet of 0.5 mm thickness. After a drying time of 15
minutes, the cowhorn platelet with the varnish layer was applied to
the measuring crystal and pressed on by an external device. The
contact pressure and the penetration depth of the measuring beam
were selected here such that the IR spectrum did not record any
portions of the cowhorn platelet. Spectra of the varnish layer were
recorded for 48 hours and the decrease in the active compound bands
which is to be attributed to the penetration of the active compound
into the keratin material was investigated.
[0041] It is seen here that the characteristic band of
clobetasol-17-propionate at 1660 cm.sup.-1 decreases to
approximately 60% of the starting value in the clear varnish film
of the nail polish according to the invention in the measurement
period of 48 hours, while the active compound precipitates almost
quantitatively from the control example on evaporating the solvent
and is thus no longer available for penetration into the keratin
material.
[0042] Moreover, it was possible to detect clobetasol-17-propionate
qualitatively on the back of the cowhorn platelet employed after
the application of the nail polish according to the invention,
while after the application of the control preparation it was not
possible to produce this detection.
[0043] Although in EP 0 226 984 similar penetration properties of
certain antimycotic hydroxypyridone compounds from solid varnish
films are described, this is nevertheless a surprising finding,
since it was not to be foreseen that glucocorticoids, which
constitute a bulky, rigid cyclopentanoperhydrophenanthrene
four-ring system, are more bioavailable from the water-insoluble
solid system present after the drying of the varnish preparation
and permeate into or through the keratin material better than from
the isopropanolic solution.
[0044] B) Activity Testing
[0045] 1) The antipsoriatic properties of the nail polish according
to the invention have been tested on 2 people with long-standing
two-handed thumb nail psoriasis. A daily treatment of the affected
nails for only four months with the nail polish according to the
invention according to Example 1 led to the growing out of
symptom-free new nail plates.
[0046] 2) The antipsoriatic properties of the nail polish according
to the invention have been tested on 14 people with nail psoriasis.
A treatment two times a week of the affected nails for only six
months with the nail polish according to the invention according to
Example 1 led to a lasting improvement of the nail plates or to the
growing out of symptom-free new nail plates in 86% of the cases (12
people out of 14).
* * * * *