Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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TOPICAL COMPOSlTlON COMPRISING A COMBINAT~ON OF ANT~HISTAMINTC COMPOUNDS
WlT~I TERPENO~D COMPOUNDS
The invention relates to the topical (= external) treatment of allergic and inflammatory skin
~ise~ses including atopic dermatitis with a~lil.isL~ i"ic compounds as well as to novel
topical pharmaceutical compositions comp~ g topically applicable antihistaminic
compounds.
The topical ~pplic~tion of antihistaminic compounds for the treatment of skin diseases, such
as pruritus or insect bites, is known in the art.
It has now surprisingly been found that by topical ~ppl ~. ~ on of an antihistaminic compound
together with a terpenoid compound the efficacy of the combination is enhanced in an
unexpected manner.
Therefore, the invention relates to the topical use of a topically ~pplic~hle antihistaminic
compound in combination with a terpenoid compound (for the manufacture of a topical
medicament) for the treatment of allergic and inflammatory skin diseases.
Allergic and inflammatory skin rlise~ces are, for example, pruritus, insect bites, sunburn,
others burns, urticaria, eczema, neurodermitis, atopic dermatitis or contact dermatitis.
A topically applicable antihistaminic compound is especially a H1 receptor antagonist and is,
for example, (a) an alkylamine derivative, e.g. acrivastine, bamipine, brompheniramine,
chlorpheniramine, dexchlorpheniramine (= d-form of chlorpheniramine), dimethindene,
Metron S, pheniramine, pyrrobutamine, thenaldine, tolpropamine or triprolidine; (b) an
aminoalkyl ether, e.g. bietanautine, bromodiphenhydramine, carbinoxamine, clemastine,
diphenylpyraline, doxylamine, embramine, medrylamine, mephenhydramine, p-methyl-diphenhydramine, orphenadrine, phenyltoloxamine, piprinhydrinate or setastine; (c) an
ethylenediamine derivative, e.g. alloclamide, p-bromtripelennamine, chloropyramine,
chlorothen, histapyrrodine, methafurylene, methaphenilene, methapyrilene,
phenbenzamine, pyrilamine, talastine, thenyldiarlline, thonzylamine hydrochloride,
tripelennamine or zolamine; (d) a piperazine, e.g. ceti,i~i"e, chlorcyclizine, cinnarizine,
clocinizine or hydroxyzine; (e) a phenothiazine tricyclic, e.g. ahistan, etymemazine,
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fenethazine, N-hydroxyethylpromethazine chloride, isopromethazine, mequitazine,
methdilazine, promethazine, pyrathiazine, thiazinamium methylsulfate or trimeprazine; ~f) a
tricyclic other than phenothiazines, e.g. azatadine, clobenzepam, cyproheptadine,
deptropine, isothipendyl, loratadine or prothipendyl; and (g) an antihistaminic compound of
another structure, e.g. antazoline, astemizole, ~7el~-ctine, cel.,~ci,,,e, clemizole,
clobenzl,opi,le, diphenazoline, diphenhydramine, ebastine, emedastine, levocabastine,
mebhydroline, phenindamine, terfenadine or tritoqualine.
The term "topically applicable antihistaminic compound" is to be understood as also to
include (1 ) any topically acceptable salt of a free compound (acid or base) mentioned
above, (2) any free compound (acid or base) or any other topically acceptable salt of a salt
mentioned above, and (3) any active metabolite of a compound mentioned above.
Examples for active metabolites are carebastine, which is the active metabolite of ebastine;
norastemizole, which is the active metabolite of astemizole, or terfenadine carboxilate,
which is the active metabolite of terfenadine.
A topically acceptable salt of an antihi:ila",inic compound having a basic group is e.g. an
acid addition satt. Suitable acid components may be, for example, strong inorganic acids,
typically mineral acids, e.g. sulfuric acid, phosphoric acids, e.g. orthophosphoric acid,
hydrohalic acids, e.g. hydrochloric acid, or strong organic carboxylic acids, typically lower
alkanecarboxylic acids which may be substituted, e.g. by halogen, such as acetic acid or
trifluoroacetic acid, dicarboxylic acids which may be unsaturated, e.g. oxalic, malonic,
succinic, maleic, fumaric, phthalic or terephthalic acid, hydroxycarboxylic acids, e.g.
ascorbic, glycolic, lactic, malic, tartaric or citric acid, amino acids, e.g. aspartic or glular"i" c
acid, or benzoic acid, or organic sulfonic acids, typically lower alkanesulfonic acids which
may be substituted, e.g. by halogen, typically methanesulfonic acid, or arylsulfonic acids
which may be substituted, e.g. by lower alkyl, typically p-toluenesulfonic acid.
A topically acceplt.ble salt of an antihistaminic compound having an acidic group is e.g. an
alkali metal or alkaline earth metal salt, e.g. the sodium, potassium, magnesium or calcium
salt, an aluminium salt or a transition metal salt, e.g. the zinc or copper salt, or a
corresponding salt with ammonia or organic amines. Organic amines that come intoconsideration are, for example, the following: alkylamines, such as mono-, di- or tri-lower
alkylamines, e.g. ethylamine, tert-butylamine, diethylamine, diisopropylamine,
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trimethylamine or triethylamine, alkylenediamines, such as lower alkylenediamines, e.g.
ethylenediamine, alkylamines substituted by phenyl, such as mono- or di-phenyl-lower
alkylamines, e.g. benzylamine or 1- or 2-phenyiethylamine, hydroxy-alkylamines, such as
mono-, di- or tri-hydroxy-lower alkylamines, e.g. mono-, di- or tri-ethanolamine or
diisopropanolamine, oligohydroxy-lower alkylamines, e.g. tris-(hydroxymethyl)-methylamine,
hydroxy-lower alkyl-di-lower alkylamines, e.g. N,N-dimethylamino- or N,N-diethylamino-
ethanol, amino sugars, such as those in which the amino group is optionally substituted by
at least one lower alkyl group, e.g. D-glucosamine, D-g~l~ctos~rnine or marmosamine
(derived from monosaccharides in which an alcoholic hydroxy group is replaced by an
amino group) or N-methyl-D-glucosamine (an N-lower alkylated amino sugar),
cycloalkylamines, such as mono- or di-cycloalkylamines, e.g. cyclohexylamine or
dicyclohexylamine, basic amino acids, e.g. arginine, histidine, Iysine or ornithine, or cyclic
amines, such as lower alkyleneamines or lower alkenyleneamines, e.g. azirine, pyrrolidine,
1-ethyl-pyrrolidine, 2-hydroxyethyl-pyrrolidine, piperidine, 1-ethyl-piperidine, 2-hydroxyethyl-
piperidine or pyrroline, or lower alkyleneamines or lower alkenyleneamines in which the
carbon chain is interrupted by aza (-NH-), N-lower alkylaza [-N(-lower alkyl)1, oxa (-O-)
and/or thia (-S-), e.g. imidazoline, 3-methylimidazoline, piperazine, 4-methyl- or 4-
ethylpiperazine, morpholine or thiomorpholine.
Preferred antihistaminic compounds are acrivastine, brompheniramine, chlorpheniramine,
dexchlorpheniramine, dimethindene, triprolidine; bromodiphenhydramine, clemastine,
phenyltoloxamine, piprinhydrinate, pyrilamine, tripelennamine, cetirizine, hydroxyzine;
methdilazine, promethazine, trimeprazine, ~t~-l;ne, cyproheptadine, loratadine,
astemizole, diphenhydramine, levocP.h~stine and terfenadine, or topically acceptable salts
thereof.
Particularly preferred antihistaminic compounds are dimethindene and clemastine, or a
topically acceptable salt thereof, e.g. dimethindene maleate or clemastine hyclrogen
fumarate.
A terpenoid compound is, for example, a monoterpenoid compound, a diterpenoid
compound, a triterpenoid compound or a sesquiterpenoid compound.
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A monoterpenoid compound is e.g. camphor, 3-carens, carvacrol, carvone, chrysanthemic
acid; cineol, e.g. 1,8-cineol; gefarnate, geraniol, linalool, limonene, menthol, pulegone,
thujone or thymot.
A diterpenoid compound is e.g. aphidicolin, forskolin, phytanic acid or phytol. J
A triterpenoid compound is, for example, glycyrrhetinic acid or a sapogenin, e.g. oleanolic
acid or diosgenin.
A sesquiterpenoid compound is e.g. farnesol or santonin.
The term "terpenoid compound" is intended also to cover any derivative and any topically
acceptable salt of a terpenoid compound. Preferred derivatives of a terpenoid compound
having one or more hydroxy groups are those wherein one or more of the hydroxy groups
are esterified by a carboxylic acid ( - terpenoid compound esters).
A carboxylic acid is, for example, a C1-C7-aliphatic, a cycloaliphatic, an aromatic, an
aromatic-Ct-C,-aliphatic, a heteroaromatic or a heteroaromatic-C,-C7-aliphatic carboxylic
acid, which carboxylic acid may be unsubstituted or substituted, for example by one or more
substituents selected from hydroxy, halogen, Cl-cralkoxy~ carboxy, C1-C7-alkoxycarbonyl,
cyano, amino, C1-C7-alkylamino, di-C1-C7-alkylamino, C,-C7-alkanoylamino, nitro, C1-C7-alkyl
and halogen-C,-C;7-alkyl (e.g.trifluoromethyl). More especially, a carboxylic acid is a C1-C7-
alkanoic acid which is unsubstituted or substituted by hydroxy, halogen, carboxy or amino, a
C3-C7-cycloalkanoic acid; a phenyl-Ct-C7-alkanoic acid, a benzoic acid or a naphthoic acid
in each of which the phenyl ring(s) may be uns~ ~hstituted or substituted by one or more
substituents selected from C1-C7-alkyl, halogen-Ct C7-alkyl, hydroxy, halogen, C1-C7-alkoxy,
carboxy, C1-C7-alkoxycarbonyl, cyano, amino, C,-C7-alkylamino, di-C1-C7-alkylamino, C,-C7-
alkanoylamino and nitro; or a heteroaromatic carboxylic acid or a heteroaromatic-C1-C7-
alkanoic acid in each of which the heteroaromate is selected from furan optionally
substituted by C,-C7-alkyl or halogen, thiophene optionally s~bstih~ted by C1-C7-alkyl or
halogen and pyridine optionally substituted by hydroxy, lower alkoxy, trifluoromethyl, cyano
or C,-C7-alkyl. In par~icular, a carboxylic acid is a C~-C7-alkanoic acid which is unsubstituted
or s~lhstit~ted by hydroxy.
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Preferred terpenoid compounds are menthol, menthol esters, especially menthyl lactate, or
cineol, more preferably menthol or menthyl lactate, and in one el"bodil.,ent menthol, and in
another embodiment menthyl lactate.
The structural formula of menthyl lactate is as follows:
CH3
[X~ OH
H3C CH3
As the compound contains 4 asymmetric carbon atoms, there are existing 16 different
stereoisomers. The term "menthyl lactate" is intended to cover each of these stereoisomers
as well as any racemates and any other mixtures of these stereoisomers. Preferred is the
racemate of the following structure
CH3
~
-
CH3 CH3
which is derived from the naturally occuring (-)-menthol. This compound is available
comm,ercially e.g. from Haarmann & Reimer GmbH (Germany) under the name
FRESCOi_AT, Type ML. It can also be readily made by processes known in the art by
esterifiying the hydroxy group of menthol with lactic acid.
The combination according to the invention can be applied, usually in the form of a topical
pharmaceutical composition, to any portion of the skin. tlowever, ~pplic~tion to the external
genitalia, or the cy~l -", or lips is not suggested, recommended, or usuaily desired.
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It has surprisingly been found that by combining an antihistaminic compound with a
térpenoid compound in a pharmaceutical composition for topical administration the
antiallergic and antiinflammatory efficacy of the combination is enhanced in an unexpected
manner. The antihistaminic compound and the terpenoid compound both act as topical
antiinflammatory agents but have different mechanisms of action and therefore act
complementarily. Moreover, the topical compositions of the invention are characterised by
an extremely good skin permeation of the drugs applied.
The topical pharmaceutical compositions of the invention have valuable pharmacological
properties. Especially they are beneficial in the treatment of allergic and inflammatory skin
diseases including atopic dermatitis.
The beneficial properties of the combinations of the invention can be demonstrated, for
example, in the following tests.
(1) Itch threshold to intracutaneous histamine and the "wheal and flare" reaction after
intracutaneous injection of histamine in human volunteers [see Lever et al., Pharmacol. 4
(1991) 109-112].
(2) Carrageenin-induced edema in hind paw of the rat as an assay for antiinflammatory
drugs [Winter et al., Proc. Soc. Exp. Biol. Med.111 (1962) 544-547].
(3) Inflammation induced with croton oil in the mouse ear [Tonelli et al., Endocrinology 77
(1965) 625-634].
(4) Model of intradermal histamine challenge in unanesthetized hairless rats ~M. Harada et
al., J. Pharm. Pharmacol. 23 (1971) 218]: In this test, the test substances are topically
applied to the abdominal skin of the animals. Then, after 0.5 h, they are removed, a tracer
dye is intravenously injected and challenge with intradermal hi~L~Il,;"e (0,25, 50, 75,100,
200 and 400 nmol/site) is performed within the treated zones. Efficacy is assessed by
comparison between the amount of dye liberated from the blood vessels in treated versus
untreated areas of skin. When comparing a gel CGIIldillillg 0.1% of dimethindene maleate
and 4.0% of menthol with an analogous gel containing 0.1 % of dimethindene maleate only,
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the dermal infiammation induced by histamine is reduced in a st~tictic~lly significant manner
(p<0.05) by the combination only.
The safety of the compositions of the invention is confirmed by Gl-csic~l toxicological
studies, such as the acute toxicity mice test, the acute rabbit skin/eye irritation test or
sensitization tests. Adverse effects, such as rough skin or skin irritation, are not observed.
In particular, the invention relates to the use of a mixture of an antihistaminic compound
with a terpenoid compound, in which mixture the antihistaminic compound is present in an
amount of from 0.01 up to 15%, and the terpenoid compound is present in an amount of
from 0.1 up to 15%, especially of from 0.1 up to 10%, very especially of from 0.5 up to 10%,
more especially of from 0.~ up to 8%, most especially of from 1 up to 8%, advantageously
of from 2 up to 8%, in particular of from 3 up to 8%, and first and foremost of from 4 up to
8%; further of from 3 up to 10%.
Normally, the combination of an antihistaminic compound and a terpenoid compound is
used in the form of a topical pharmaceutical composition which is also an object of the
present invention.
Thus the invention further relates to a topical pharmaceutical composition comprising at
least one topically applicable antihistaminic compound and at least one terpenoid
compound together with at least one topically accepL~ble carrier material.
Preferably, the topically administered pharmaceutical compositions according to the
invention comprise both the topically applicable antihistaminic compound(s) and the
terpenoid compound in pharmacologically effective amounts.
The daily dosage of the active ingredients depends on age and individual condition and on
the mode of administration. For example, the topical pharmaceutical compositions, for
example in the form of emulsion-gels, creams or ointments, may be applied once, twice or
three times daily. But also more frequent daily ~rplk~ions are possible: such can provide a
continual therapy which may lead to an even more rapid improvement of the conditions
treated.. Patches and bandages may be applied, for example, once daily or only once, twice
or three times a week.
=
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In a topical composition of the invention - as well in a mixture used according to the
irivention - the antihi~ r,linic compound(s) is (are) e.g. pleserll in an amount of from 0.01
up to 15%, especially of from 0.02 up to ~%, and in particular of from 0.02 up to
2.~%, of the total composition.
In a topical composition of the invention, the terpenoid compound is present in an amount
of from 0.1 up to 15%, especially of from 0.1 up to 10%, very especially of from 0.5 up to
10%, more especially of from 0.5 up to 8%, most especially of from 1 up to 8%,
advantageously of from 2 up to 8%, in particular of from 3 up to 8%, and first and foremost
of from 4 up to 8%; further of from 3 up to 10%.
The dosage of the active ingredients may depend on various factors, such as warm-
blooded species, sex, age, weight and individual condition of the warm-blooded animal.
Moreover, the invention relates to a method of treating allergic and inflammatory skin
diseases which comprises topically administering to a mammal in need of such treatment a
therapeutically effective amount of at least one antihistaminic compound together with a
therapeutically effective amount of at least one terpenoid compound.
Pharmaceutical compositions suitable for topical administration are e.g. creams, lotions,
ointments, microemuisions, fatty ointments, gels, emulsion-gels, pastes, foams, tinctures,
solutions, patches, bandages and transdermal therapeutic systems; preferred are emulsion-
gels, gels, creams, lotions, solutions, patches and bandages.
Creams or lotions are oil-in-water emulsions. As oily base there are used especially fatty
alcohois, especially those containing from 12 to 18 carbon atoms, for example lauryl, cetyl
or stearyl alcohol, fatty acids, especially those containing from 10 to 18 carbon atoms, for
example palmitic or stearic acid, fatty acid esters, e.g. glyceryl tricaprilocaprate (neutral oil)
or cetyl palmitate, liquid to solid waxes, for example isopropyl myristate, wool wax or
beeswax, and/or hydrocarbons, especially liquid, semi-solid or solid substances or mixtures
thereof, for example petroleum ielly (petrolatum) or paraffin oil. Suitable emulsifiers are
surface-active substances having predominantly hydrophilic properties, such as
corresponding non-ionic emulsifiers, for example fatty acid esters of polyalcohols and/or
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ethylene oxide ~dduct-c thereof, especially corresponding fatty acid esters with(poly)ethylene glycol, (poly)propylene glycol or sorbitol, the fatty acid moiety containing
especially from ~ 0 to 18 carbon atoms, especially partial glycerol fatty acid esters or partial
fatty acid esters of polyhydroxyethylene sorbitan, such as polyglycerol fatty acid esters or
polyoxyethylene sorbitan fatty acid esters (Tweens), and also polyoxyethylene fatty alcohol
ethers or fatty acid esters, the fatty alcohol moiety containing especially from 12 to 18
carbon atoms and the fatty acid moiety especially from 10 to 18 carbon atoms, such as
polyhydroxyethylenecetylstearyl ether (for example Cetomacrogol 1000) or polyhydroxy-
ethyleneglycerol fatty acid ester (for example Tagat S), or conesponding ionic emulsifiers,
such as alkali metal salts of fatty alcohol sulfates, especially having from 12 to 18 carbon
atoms in the fatty alcohol moiety, for example sodium lauryl sulfate, sodium cetyl sulfate or
sodium stearyl sulfate, which are usually used in the presence of fatty alcohols, for example
cetyl alcohol or stearyl alcohol. Additives to the aqueous phase are, inter alia, agents that
prevent the creams from drying out, for example humectants, such as polyalcohols, such as
g!ycerol, sorbitol, propylene glycol and/or polyethylene glycols, and also preservatives,
perfumes, gelling agents, etc..
Ointments are water-in-oil emulsions that contain up to 70%, but preferably fromapproximately 20% to approximately 50%, water or aqueous phase. Suitable as fatty phase
are especially hydrocarbons, for example petroleum Jelly, paraffin oil and/or hard paraffins,
which, in order to improve the water-binding capacity, preferably contain suitable hydroxy
compounds, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax
alcohols, or wool wax or beeswax. Emulsifiers are corresponding lipophilic substances, for
example of the type in~;c~ted above, such as sorbitan fatty acid esters (Spans), for
example sorbitan oleate and/or sorbitan isostearate. Additives to the aqueous phase are,
n r alia, humectants, such as polyalcohols, for example glycerol, propylene glycol, sorbitol
and/or polyethylene glycol, and also preservatives, perfumes, etc.
,
Microemulsions are isotropic systems based on the following four components: water, a
surfactant, for example a tensioactive, a lipid, such as a non-polar or polar oil, for example
paraffin oil, and an alcohol or polyalcohol containing lipophilic groups, for example 2-
octyldodecanol or ethoxalated glycerol or polyglycerol esters. If desired, other additives may
be added to the microemulsions.
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Fatty ointments are water-free and contain as base especially hydrocarbons, for example
paraffin, petroleum jelly and/or liquid paraffins, also natural or partially synthetic fat, such as
fatty acid esters of glycerol, for example coconut fatty acid triglyceride, or preferably
hardened oils, for example hydrogenated groundnut oil, castor oil or waxes, also fatty acid
partial esters of glycerol, for example glycerol mono- and di-stearate, and also, for example,
the fatty alcohols increasing the water-absol~lion capacity, emulsifiers and/or additives
mentioned in connection with the ointments.
With gels, a distinction is made between aqueous gels, water-free gels and gels having a
low water content, which gels consist of swellable, gel-forming materials. There are used
especially transparent hydrogels based on inorganic or organic macromolecules. High
molecular weight inorganic components having gel-forming properties are predominantly
water-containing silic~t~s~ such as aluminium s ii~- ~s, for example bentonite, magnesium
aluminium silicates, for example Veegum, or colloid~l silicic acid, for example Aerosil. As
high molecular weight organic substances there are used, for example, natural, semi-
synthetic or synthetic macromolecules. Natural and semi-synthetic polymers are derived, for
example, from polysaccharides containing a great variety of carbohydrate components,
such as celluloses, starches, tragacanth, gum arabic and agar-agar, and gelatin, alginic
acid and salts thereof, for example sodium alginate, and derivatives thereof, such as lower
alkylcelluloses, for example methyl- or ethyl-cellulose, carboxy- or hydroxy-lower
alkylcelluloses, for example carboxymethyl-or hydroxyethyl-cellulose. The components of
synthetic gel-forming macromolecules are, for example, suitably substituted unsaturated
aliphatic compounds such as vinyl alcohol, vinylpyrrolidine, acrylic or methacrylic acid.
Examples of such polymers are polyvinyl alcohol d~erivatives, such as polyviol,
polyvinylpyrrolidines, such as collidone, polyacrylates and polymethacrylates, especially
having a molecular weight of from approximately 80000 to approximately 1 million, or salts
thereof, such as Rohagit S, Eudispert or Carbopol ~Carbomer). Customary additives, such
as preservatives, humectants or perfumes, may be added to the gels.
Emulsion-gels - also called "emulgels" - represent topical compositions which combine the
properties of a gel with those of an oil-in-water emulsion. In conl,~s~ to gels, they contain a
lipid phase which due to its fat-restoring properties enables the formulation to be m~csAged
in whilst, at the same time, the direct al~sGr~.lion into the skin is experienced as a pleasant
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property. Furthermore, one can observe an increased solubility for lipophilic active
ingredients. One advantage of emulsion-gels over oil-in-water emulsions resides in the
enhanced cooling effect which is brought about by the coldness due to evaporation of the
additional alcohol component, if present. Furthermore, one can observe an improved
solubility of polar active ingredients.
Foams are administered, for example, from pressurised containers and are liquid oil-in-
water emulsions in aerosol form; unsubstituted hydrocarbons, such as alkanes, for example
propane and/or butane, are used as propellant. As oil phase there are used, inter alia,
hydrocarbons, for example paraffin oil, fatty alcohols, for example cetyl alcohol, fatty acid
esters, for example isopropyl myristate, and/or other waxes. As emulsifiers there are used,
inter alia, mixtures of emulsifiers having predominantly hydrophilic properties, such as
polyoxyethylene sorbitan fatty acid esters (Tweens), and emulsifiers having predominantly
lipophilic properties, such as sorbitan fatty acid esters (Spans). The customary additives,
such as preservatives, etc., are also added.
Tinctures and solutions generally have an ethanolic base, to which water may be added
and to which there are added, inter alia. polyalcohols, for example glycerol, glycols and/or
polyethylene glycol, as humectants for reducing evaporation, and fat-restoring substances,
such as fatty acid esters with low molecular weight polyethylene glycols, propylene glycol or
glycerol, that is to say lipophilic substances that are soluble in the aqueous mixture, as a
replacement for the fatty substances removed from the skin by the ethanol, and, if
necessary, other adjuncts and additives. Suitable tinctures or solutions may also be applied
in spray form by means of suitable devices.
Transdermal therapeutic systems with - in particular - local delivery of the active substances
contain an effective amount of each of the active ingredients optionally together with a
carrier: Useful carriers comprise absorbable pharmacological suitable solvents to assist
passage of the active ingredients through the skin. Transdermal delivery systems are, for
example, in the form of a patch comprising (a) a substrate ( = backing layer or film), (b) a
matrix containing the active ingredients, optionally carriers and optionally (but preferably) a
special adhesive for attaching the system to the skin, and normally (c) a protection foil ( =
release liner). The matrix (b) is normally present as a mixture of all components or may
consist of separate layers.
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The manufacture of the topically administrable pharmaceutical preparations is effected in a
manner known per se, for example by dissolving or suspending the active ingredients in the
base or, if necessary, in a portion thereof. When the active ingredients are administered in
the form of a solution, they are generally dissolved in one of the two phases before
emulsification.
The following exampies are intended to illustrate the invention.
Example 1: An emulsion-gel containing the maleate salt of dimethindene and menthyl
lactate is manufactured as follows.
ComPosition
(a) dimethindene maleate 0.1% by weight
(b) menthyl lactate 6.0% by weight
(c) isopropanol 20.0% by weight
(d) polyethylene glycol 300 3.0% by weight
(e) polyhydroxyethylene cetyl stearyl ether (Cetomacrogol 1000) 2.0% by weight
(f) paraffin oil, viscous 2.5% by weight
(g) Mygliol6 812 [ = a neutral oil (caprilo/capric triglyceride)] 2.5% by weight
(h) acrylic acid polymerisate (Carbopol0 934 P) 1.0% by weight
(i) diethylamine 0.7% by weight
a) sodium sulphite 0.1% by weight
(k) water, demineralised to make up to 100% by weight
The acrylic acid polymerisate is dispersed in a portion of water by means of a rotor-stator
homogeniser (for example Homorex~). A solution of the maleate salt of dimethindene,
diethylamine, sodium sulphite and polyethylene glyco! 300 in isopropanol and the remaining
water is added thereto and distributed homogeneo~sly. To form the fatty phase, the
polyhydroxyethylene cetyl stearyl ether, Mygliol~ 812 and the paraffin oil are melted together
at 75~. Menthyl lactate is added to the fatty phase, and then the whole fatty phase is slowly
added to the previously formed gel and emulsified.
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Example 2: An emulsion-gei containing the maleate salt of dimethindene and menthyl
lactate is manufactured as follows.
.
Composition
1~
a) dimethindene maleate 0.1% by weight
(b) menthyl lactate 6.0% by weight
(c) propylene glycol 15.0% by weight
(d) polyhydroxyethylene cetyl stearyl ether (Cetomacrogol 1000) 2.0% by weight
(e) paraffin oil, viscous 2.5% by weight
(f) Mygliol~ 812 2.5% by weight
(g) acrylic acid polymerisate (Carbopol~ 934 P)1.0% by weight
(h) sodium hydroxide 0.3% by weight
(i) butylhydroxytoluene 0.02% by weight
a) disodium edetate 0.05% by weight
(k) benzyl alcohol 0.5% by weight
(I) benzalkonium chloride 0.01% by weight
(m) water, demineralised to make up to 100% by weight
The acrylic acid polymerisate is dispersed in a portion of water by means of a rotor-stator
homogeniser (for example Homorex0). A solution of dimethindene maleate, NaOH,
butylhydroxytoluene, disodium edetate and benzalkonium chloride in a mixture of propylene
glycollwater is added thereto and distributed homogeneously. To form the fatty phase, the
polyhydroxyethylene cetyl stearyl ether, Mygliol0 812, the paraffin oil and benzyl alcohol are
melted together at 75~. The menthyl lactate is added to the fatty phase, and then the whole
fatty phase is slowly added to the previously formed gel and emulsified.
Example 3: An emulsion-gel containing the maleate salt of dimethindene and l-menthol has
the following composition and is manufactured in analogy to the examples 1 and 2.
Composition
(a) dimethindene maleate 0.1% by weight
CA 022~8~l3 l998- l2- l~
WO 98/00168 PCT/EP97/03421
- 14-
(b) I-menthol 4.0% by weight
(c) capryiic/capric acid esters of saturated fatty aicohols ~Cetiol0 LC) 2.5% by weight
(d) paraffin oil, viscous 2.5% by weight
(e) polyhydroxyethylene cetyl stearyl ether (Cetomacrogol 1000) 2.0% by weight
(f) propylene glycol 15.0% by weight
(g) disodium edetate dihydrate 0.05% by weight
(h) benzalkonium chloride 0.01% by weight
(i) benzyl alcohol 0.5% by weight
a3 butylhydroxytoluene 0.02% by weight
(k) sodium hydroxide 0.12% by weight
(I) acrylic acid polymerisate (Carbomer~ 974 P) 0.4% by weight
(m) water, purified to make up to 100% by weight
Exam~le 4: A lotion containing the maleate salt of dimethindene and menthyl lactate has
the following composition and is manufactured in analogy to the examples 1 and 2.
Com~osition
(a) dimethindene maleate 0.1% by weight
(b) menthyl lactate 6.0% by weight
(c) propylene glycol 15.0% by weight
(d) polyhydroxyethylene cetyl stearyl ether (Cetomacrogol 1000) 2.0% by weight
(e) paraffin oil, viscous 2.5% by weight
(f) Myglioi~ 812 2.5% by weight
(g) acrylic acid polymerisate (Carbopol0 934 P) 0.3% by weight
(h) sodium hydroxide 0.1% by weight
(I) butylhydroxytoluene 0.02% by weight
0 disodium edetate 0.05% by weight
(k) benzyl alcohol 0.5% by weight
(I) benzalkonium chloride 0.01% by weight
(m) water, demineralised to make up to 100% by weight
CA 022~8~l3 l998- l2- l~
Wo 98/0~168 PCT/EP97/03421
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Example 5: An emulsion-gel containing clemastine hydrogen fumarate and menthyl lactate
is manufactured as follows.
Composition
(a) clemastine hydrogen fumarate 0.04% by weight
(b) menthyl lactate 6.0% by weight
(c) isopropanol Z0.0% by weight
(d) polyethylene glycol 300 3.0% by weight
(e) polyhydroxyethylene cetyl stearyl ether (Cetomacrogol 1000) 2.0% by weight
(f) paraffin oil, viscous 2.5% by weight
(g) Mygliol~ 812 2.5% by weight
(h) acrylic acid polymerisate (Carbopol~ 934 P)1.0% by weight
(i) diethylamine 0.7% by weight
~) sodium sulphite 0.1% by weight
(k) water, demineralised to make up to 100% by weight
The acrylic acid polymerisate is dispersed in a portion of water by means of a rotor-stator
homogeniser (for example Homorex~). A solution of clemastine hydrogen fumarate,
diethylamine, sodium sulphite and polyethylene glycol 300 in isopropanol and the remaining
water is added thereto and distributed homogeneously. To form the fatty phase, the
polyhydroxyethylene cetyl stearyl ether, Mygliol~ 812 and the paraffin oil are melted together
at 75~. Menthyl lactate is added to the fatty phase, and then the whole fatty phase is slowly
added to the previously formed gel and emulsified.
