Note: Descriptions are shown in the official language in which they were submitted.
~2~3~7~
~he invention relates to agents for combatting psoriasis
disorders such as psoriasis and psoriasis related disorders,
and more particularly to the use of alkylphosphoric acid
compounds for combatting psoriasis disorders.
Alkylphosphoric acid compounds of formula I are known
substances having an anti-tumour effect. It has now been
found that compounds of this type of formula I or salts
therQof with physiologically acceptable acids are also
effective against psoriasis and related disorders.
According to the invention, the term psoriasis disorders
covers skin disorders associated with hyperkeratoses, such as
in particular psoriasis, Arthropathia psoriatica and
parapsoriasis disorders.
Corticosteroids are currently the most frequently used
treatment for psoriasis. Severe cases of psoriasis may even
be treated with cytostatics (for example methotrexate).
However, all these substances have pronounced and serious
side effects.
In contrast, the compounds of formula I in the dosages used
show no or only negligible side effects. For example the
effect of topical therapy using compounds of formula I is
clearly superior to that of conventional dermatological
agents used in psoriasis (keratolytic agents and corticoids).
The pharmaceutical formulations for use in psoriasis
disorders and disorders related thereto generally contain
between 1 to 1000, preferably 5 to 500 mg, in particular 10
to 100 mg per individual dose of component I (component I =
sum of the weights of the individual compounds of formula I)
in oral, parenteral, rectal, vaginal or inhalable forms.
7 ~
Should a formulation contain two or more single compounds of
formula I, these figures always apply to the total amount of
component I. This applies by analogy to the following
amounts which relate to component I (component I = sum o the
individual compounds of formula I) in connection with dosage
data and their weights in the corresponding pharmaceutical
formulations and to corresponding amounts in the claims.
Compound I is in each case understood to refer to the single
substance represented in formula I or its physiologicall~
acceptable salt.
For formulations for local application to the skin and mucous
membranes the amount of component I is for example between
0.1 mg and 1000 mg, preferably 0.1 to 500 mg.
Administration may for example be in the form of tablets,
capsules, pills, coated tablets, suppositories, ointments,
gels, creams, powder, dusting powder, aerosols or in liquid
form. Liquid forms which may for example be used are: oily
or alcoholic or a~ueous solutions as well as suspensions and
emulsions. Pre~erred forms of application are tablets
containing between 10 and 100 mg or solutions containing
between 0.01 and 10 percent by weight of component I~
~he individual dose of component I ~i.e. the total amount of
compounds I) can for example lie
a) in oral medicinal forms between 1 - 1000 mg, preferably
10 - 500 mg;
b) in parenteral medicinal forms (for example intravenous,
intramuscular) between 1 - 1000 mg, preferably 10 - 500
mg;
5 c) in medicinal forms for inhalation (solutions or aerosols)
between 1 - 1000 mg; preferably 10 - 500 mg;
- 2 -
2~ 27~
d~ in medicinal forms for rectal or vaginal application
between 1 - 1000 mg, preferably 10 ~ 500 mg;
e) in the case of medicinal forms for local application to
the skin and mucous membranes (for example in the form of
solutions, lotions, emulsions, ointments and the like)
between 0.1 mg 1000 mg, preferably 0.1 - 500 mg, the
concentration of the components I (i.e. the total amount
of compounds I) in such formulations being for example
0.01 to 12, in particular 0.1 - 8 percent by weight.
It is for example possible to recommend 1 to 3 tablets
containing 1 to 100 mg of component I (i.e. total amount I)
3 times daily or for example in the case of intravenous
injection one ampoule containing 1 to 10 mg with 1 to 100 mgl
of component I (i.e. total amount I) 1 to 3 times daily. In
the case of oral administration the minimum daily dose is for
example l mg; the maximum daily dose for oral administration
should not exceed 1000 mg.
For the treatment of dogs and cats the oral individual dose
of component I generally lies between about 0.01 and 60 mg/kg
body weight; the parenteral dose about between 0.01 and 60
mg/kg body weight.
For the treatment of horses and cattle the oral individual
dose o~ component I generally lies between about 0.05 and 100
mg/kg; the parenteral individual dose about between 0.05 and
100 mg/kg body weight.
The acute toxicity of compounds I in the mouse (expressed by
the LD 50 mg/kg; method after Miller and Tainter: Proc. Soc.
Exper. Biol. a. med. 57 (1944) 261) is for example
between 300 and 1000 mg/kg for oral application.
2~ 7~
The medicaments of the invention are characterized in that
they contain as active substance at least one compound of the
general formula I
R - Y - PO2 - X - Rl
or a physiologically acceptable salt thereof, optionally
together with conventional pharmacological additives and
diluents.
The following may preferably be used as active substances:
hexadecylpho~phocholine, oleylphosphocholine,
hexadecylphosphoric acid-(N,N)-bis-(2-chloroethyl)-amideO
Formula I also comprises possible enantiomers and
diastereomers. Should the compounds be racemates, these can
be split in a method known per se, for example using an
optically active acid, in which the optically active isomers
are split. Preference is, however, also given from the
outset to use of enantiomeric or optionally diastereomeric
starting substances, resulting in a correspondingly pure
optically active or diastereomeric compound as end product.
In the context of the invention, R is preferably an alkyl
group of the given chain length which is combined with the
oxygen of the glycol radical via a terminal carbon atom or
also via a carbon atom within the alkyl chain (for example
via the carbon atom 2 or carbon atom 3 or another central
carbon atom). This alkyl chain may be straight or branched.
The alkyl chain R may have one, two or three carbon double
bonds or triple bonds which may also be present in mixed form
and/or contain halogen substituents. Halogen atoms that may
be used are: fluorine, chlorine or bromine. One to three of
such halogen atoms may be present in the chain R, whereby
these may be located at one or at different carbon atoms of
the radical R. Apart from the saturated, straight-chain
2~27~
alkyl radicals, preference may also be given to those with
one or two carbon double bonds in the molecule~ Particularly
preferred are those substituents R which contain an alky]
radical with 14 to 20, preferably 15 to 20, in particular 16
to 20 carbon atoms or a corresponding alkenyl radical with 14
to 20, preferably 15 to 20, in particular 16 to 20 carbon
atoms.
Examples of halogen-substituted radicals R are:
chlorohexadecyl, bromohexadecyl, fluorohexadecyl, 9,10-
dibromooctadecyl, 2,3-dibromooctadecyl, 15,16-
dibromohexadecyl, bromotetradecyl.
Examples of unsaturated radicals R are:
9-octadecenyl radical (oleyl alcohol radical, R in formula I
represents in particular this g-octadecenyl radical), 15-
hexadecenyl radical, 9,12-octadecadienyl radical (linoleyl
radical~.
Should more than one double or triple bond be present/ these
are conjugated.
Examples of saturated and unsubstituted radicals R are:
tetradecyl radical, hexadecyl radical, octadecyl radical.
R preferably means for exampls the group -CH2-CHR3-CH2-Z-R4
when Y and X are oxygen and Rl is a Cl-C6-trialkylamino group
(in particular trimethylamino) which is associated with X via -:
a C2-C3-alkyl chain and where the positive charge of the
trialkylamine cation is neutralized by the phosphoric acid
anion.
The alkoxy groups R3 and R4 are preferably methoxy groups.
The C1-C24-alkyl radical R4 preferably consists of 10 to 20,
in particular 12 to 18 carbon atoms and is preferably not
branched.
-- 5 --
~ 3 ~ ~3 ~
Should Rl or R2 represent an unsubstituted alkyl group, this
consists for example of 1 - 6, preferably 1 - 4 carbon atoms.
Should Rl or R2 represent an unsaturated alkyl group, this
consists in particular of 3 to 6 carbon atoms, it being
necessary to have at least one simple C-C bond between the
unsaturated function of such an unsaturated alkyl group and
X. These are in particular C3-C6-alkenyl groups. Examples
hereof are: allyl, butenyl, pentenyl, hexenyl.
Should Rl or R2 be substituted, this is in particular a
straight chain alkyl or alkenyl radical, in this case Rl
preferably consists of 2 - 6 carbon atoms, whereby the given
substituents are preferably in the ~-position oE the alkyl or
alkenyl group Rl or R2; this is for example the ethyl or
straight propyl radical with one of the mentioned
substituents in -position (i.e. in 2-position in the
case of ethyl and 3-position in the case of propyl).
Should Rl be a 2-tert.-butyloxycarbonylaminoethyl radical or
a 2-tert.-butyloxycarbonylethyl radical, this is preferably
the D- or L-form.
Of the substitutents of Rl the trialkylammoniumethyl radical
is preferred, in particular when X is an oxygen atom, whereby
the trialkyl radicals preferably consist in each case of one,
two or three carbon atoms, preference being given to methyl
groups. The trimethylammoniumethyl xadical is therefore
particularly preferred. In this particularly preferred
embodiment the compounds of formula I are phosphatidylcholine
derivatives.
In the case of the C3-C8-cycloalkyl substituents, these
consist in particular of 3 - 6 carbon atoms (for example
cyclopropyl to cyclohexyl). In the case of the 2,3-
dihydroxypropyl~ group this is in particular the sn-1,2-
2 ~ 2, ~ 2 rl 8
dihydroxy-propylamino-(3)-structure or the sn-2,3-dihydroxy-
propylamino-(1)-structure.
Other examples of preferred compounds of formula I are:
oleyl-phospho-(N,N,M-trimethyl)-propanolamine,
oleyl-phospho-(N,N,N-trimethyl)-butanolamine,
oleyl-phospho-(N,N,N-trimethyl~-pentanolamine,
oleyl-phosphoserine, oleyl-phosphoethanolamine, oleyl-
phosphopropanolamine, oleyl-phosphobutanolamine, oleyl-
phosphoglycerol, hexadecyl-phospho-(N,N,N-tri- methyl)-
propanolamine,
l-octadecyl-2-methyl-sn-glycero-3-phosphocholine (for example
ET-18-OCH3, see German Patent 26 19 686).
1-Hexadecylmercapto-2-methoxymethyl-propanol-3-phosphocholine
(Ilmo~osin).
The salts may be inner salts (for example if R1 represents a
trimethylammonio-alkyl group) or salts with physiologically
acceptable cation~. The medicaments of the invention or the
compounds I may be present as inner salts, for example if R
contains an amino group. Should no inner salts be present,
or should the radical R1 contain no basic group, the negative
charge of the phosphoric acid group is saturated by a
physiologically acceptable cation. Physiologically
acceptable cations of this type may for example be: alkali
cations (Na, K), alkaline earth cations (Mg, Ca) or the
cations of organic amines, such as for example guanidinium-,
morpholinium, cyclohexylammonium cation, ethylene diammonium
cation, piperazonium cation (in both latter cases one or two
basic) or the cation derived from an amine of formula NRaRbRC
wherein the radicals Ra to Rc are the same or different and
represent hydrogen, Cl-C2-alkyl groups or oxyethyl groups.
Should cations be involved derived from an amine of formula
NRaRbRC, this is preferably the ammonium cation or an
ammonium cation substituted by one to ~hree Cl-C2-alkyl
groups or an ammonium cation substituted by one to three 2-
hydroxyethyl groups.
The negative charge of the compounds of formula I is thus for
example saturated by a basic amino group present in the
molecule or a low molecular weight mono-, di- or tri-C1-C6-
alkylamino group or by an additional physiologically
acceptable cation.
The preparation of the active substances according to the
general formula I is basically known and can for example take
place using methods known per se or analogous methodsO The
basic skeleton may easily be obtained by reacting a compound
of formula ROH or a functional derivative thereof with
phosphorus o~ychloride and triethylamine, reaction of the
product with a co~pound HXRl and acid splitting, where R, R
and X have the above meaning.
The pharmaceutical compositions or medicaments of the
invention contain as acti~e substance at least one compound
(component) of formula I, optionally mixed with other
pharmacologically or pharmaceutically active substances. The
preparation of the medicaments occurs in known manner, it
being possible to use known and conventional pharmaceutical
auxiliary substances and other conventional carriers and
diluents.
Carriers and diluents of this type that may be used are for
example substances recommended or listed in the following
literature references as auxiliary substances for
pharmaceutical, cosmetic and related fields: Ullmanns
Encyklopadie der technischen Chemie, Volume 4 (1953), page 1
to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963),
page 918 et seq.: H.v.Czetsch-Lindenwald, Hilfsstoffe fur
Pharmazie und angrenzende Gebiete; Pharm. Ind. issue 2
r~
(1961), paye 72 et seq.; Dr. ~.P. Fiedler, Lexikon der
Hilfsstoffe fur Pharmaæie, Kosmetik und angrenzende Gebiete,
cantor KG, Aulendorf in Wurttemberg 1981.
Examples hereof are gelatine, natural sugars such as raw
sugar or lactose, lecithin, pectin, starches (for example
corn starch), cyclodextrines and cyclodextrine derivatives,
polyvinylpyrrolidone, polyvinyl acetate, gelatine, gum
arabic, alginic acid, tylose, talcum, lycopodium, silica gel
(for example colloidal), cellulose, cellulose derivatives
(for example cellulose ethers in which the cellulose hydroxy
groups are partially etherified with lower saturated
aliphatic alcohols and/or lower saturated aliphatic
oxyalcohols, for example methoxypropyl cellulose, methyl
cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl
cellulosephthalate); fatty acids as well as magnesium,
calcium or aluminium salts of fatty acids with 12 to 22
carbon atoms, in particular saturated (for example
stearates), emulsifiers, oils and fats, in particular
vegetable (for example peanut oil, castor oil, olive oil,
sesame oil, cottonseed oil, corn oil, wheat germ oil,
sunflower seed oil, cod liver oil, in each case also
hydrated; mono-, di- and triglycerides of saturated fatty
acids C12H242 to ClgH36O2 and their mixtures,
pharmaceutically acceptable single or multivalent alcohols
and polyglycols such as polyethylene glycols as well as
derivatives thereof, esters of aliphatic saturated or
unsaturated fatty acids (2 to 22 carbon atoms, in particular
10 - 18 carbon atoms) with monovalent aliphatic alcohols (1
to 20 carbon atoms) or multivalent al~ohols such as glycols,
glycerol, diethylene glycol, pentaerythritol, soxbitol,
mannitol and the like, which may optionally also be
etherified, esters of citric acid with primary alcohols,
acetic acid, benzylbenzoate, dioxolanes, glycerol formals,
tetrahydrofurfuryl alcohol, polyglycol ethers with Cl-C12
alcohols, dimethylacetamide, lactamides, lactates, ethyl
~ $ ~ ~ ~3
carbonates, silicones (in particular medium viscous
polydimethyl siloxanes), calcium carbonate, sodium carbonate,
calcium phosphate, sodium phosphate, magnesium carbonate and
the like.
Other auxiliary substances that may be considered are
substances promoting disintegration (so-called disinte~rants)
such as: cross-linked polyvinylpyrrolidone, sodium carboxy
methyl starch, sodium carboxy methyl cellulose or
microcrystalline cellulose. It is also possible to use known
coating substances such as for example: polymerisates as well
as copolymerisates of acrylic acid and/or methacrylic acid
and/or their esters; copolymerisates o~ acrylic and
methacrylic acid esters with a low ammonium group content
(for example Eudragit~ RS), copolymerisates o~ acrylic and
methacrylic acid esters and trimethylammonium methacrylate
(for example EudragitR RL); polyvinyl acetate; fats, oils,
waxes, fatty alcohols; hydroxypropylmethylcellu].osephthalate
or -acetate succinate; cellulose-, starch as well as
polyvinylacetate phthalate; carboxymethyl cellulose;
methylcellulosephthalate, -succinate, -phthalate succinate as
well as -phthalate acid half ester; zein; ethyl cellulose as
well as -succinate; shellac, gluten; ethylcarboxyethyl
cellulose; ethacrylate-maleic acid anhydride-copolymer;
maleic acid anhydride-vinyl methyl ether copolymer; styrol-
maleic acid copolymerisate; 2-ethyl-hexyl- acrylate maleic
acid anhydride; crotonic acid-vinyl acetate copolymer;
glutaminic acid/glutaminic acid ester copolymer;
carboxymethylethyl-cellulose glycerol monooctanoate;
cellulose acetate succinate; polyarginin.
Plasticizing agents for coating substances that may be
considered are:
Citric and tartaric acid esters (acetyltriethyl-,
acetyltributyl-, tributyl-, triethyl citrate); glycerol and
-- 10 --
.
2 ~ 2 ~
glycerol esters (~lycerol diacetate; -triacetate, acetylated
monoglycerides, castor oil~; phthalic acid esters (dibutyl-,
diamyl-, diethyl-, dimethyl-, dipropyl phthalate), D-(2-
methoxy- or ethoxy ethyl)-phthalate, ethylphthalyl-,
butylphthalyl ethyl- and butyl glycolate; alcohols ~propylene
glycol, polyethylene glycol of various chain lengths),
adipates (diethyl-adipate, di(2-methoxy- or ethoxyethyl
adipate); benzophenone; diethyl- and dibutylsebacate,
succinate, -tartrate; diethylene glycol dipropionate;
ethylene glycol-diacetate, dibutyrate, -dipropionate;
tributyl phosphate, tributyrin; polyethylene glycol sorbitane
monooleate (polysorbates such as Polysorbat 80); sorbitane
monooleate.
To prepare solutions or suspensions it is for example
possible to use water or physiologically acceptable organic
solvents such as for example ethanol, propanol, isopropanol,
1,2-propylene glycol, glycerol-Cl-C12-alkyl ethers, in
particular l-glycerol-Cl-Cg-alkyl ethers such as for example
glycerol-1-n-propyl ether, glycerol-1-n-hexyl ether,
glycerol-1-n-nonylether polyglycols and their derivatives,
dimethylsulfoxide, fatty alcohols, triglyc~rides, partial
esters of glycerol, paraffins and the like.
For injectable solutions or suspensions it is for example
possible to use non-toxic parenterally acceptable diluents or
solvents such as for example: water, 1,3-butane diol,
ethanol, 1,2-propylene glycol, polyglycols in a mixture with
water, Ringer's solution, isotonic sodium chloride solution
or also hardened oils including synthetic mono- or
diglycerides or fatty acids such as oleic acid.
Known and conventional solubilizers or emulsifiers may be
used in the preparation of formulations. Solubilizers and
emulsifiers that may for example be considered are:
polyvinylpyrrolidone, sorbitane fatty acid esters such as
sorbitane trioleate, phosphatides such as lecithin, acacia,
~&7~2~
tragacanth, polyoxyethylated sorbitane monooleate and other
ethoxylated fatty acid esters of sorbitane, polyoxyethylated
fats, polyoxye~hylated oleotriglycerides, linolisated
oleotriglycerides, polyethylene oxide condensation products
of fatty alcohols, alkylphenols or fatty acids or also 1-
methyl-3-(2-hydroxyethyl) imidazolidone (2).
Polyoxyethylated here means that the substances in question
contain polyoxyethylene chains the degree of polymerization
of which generally lies between 2 and 40 and in particular
between 10 and 20. Polyoxyethylated substances of this type
may for example be obtained by reaction of hydroxyl group-
containing compounds (for example mono- or diglycerides or
unsaturated compounds such as for example those containing
oleic acid radicals) with ethylene oxide (for example ~0 Mol
ethylene oxide per Mol glyceride.
Examples of oleotriglycerides are olive oil, peanut oil,
castor oil, sesame oil, cottonseed oil, corn oil.
See also Dr. H.P. Fiedler "Lexikon der Hilfsstoffe fur
Pharmazie, Kosmetik und angrenzende Gebiete" 1971, p. 191-
195.
It is also possible to add conserving agents, stabilizers andbuffer substances, for example calcium hydrogen phosphate,
colloidal aluminium hydroxide, flavour enhancers, sweeteners,
colourants, antioxidants and complex formers (for example
ethylenediaminotetraacetic acid) and the like.
It is optionally also necessary to adjust to a pH range of
ca. 3 to 7 using physiologically acceptable acids or buffers
to stabilize the active substance molecule. Generally
speaking, as neutral to weakly acid (up to pH 5) a pH value
as possible is preferred.
To prepare dermally applicable formulations it is possible to
use the previously mentioned substances and spreadable or
liguid hydrocarbons such as Vaseline or paraffin or gels of
alkanes and polyethylene, fats and oils of plant or animal
7 ~
origin, which may in part also be hydrated, or synthetic ~ats
such as glycerides of fatty acids C8-C18, as well as beeswax
cetyl palmitate, wool wax, wool wax alcohols, fatty alcohols
such as cetyl alcohol, stearyl alcohol, polyethylene glycols
of molecular weight 200 to 20,000; liquid waxes such as
isopropyl myristate, isopropyl stearate, ethyloleate;
emulsifiers such as sodium, potassium, ammonium salts of
stearic acid or palmitinic acid as well as triethalolamine
stearate, alkali salts of oleic acid, castor oil acid, salts
of sulfurated fatty alcohols such as sodium lauryl sulphate,
sodium cetyl sulphate, sodium stearyl sulphate, salts of
gallic acid, sterols such as cholesterol, partial fatty acid
esters of multivalent alcohols such as ethylene glycol
monostearate, glycerol monostearate, pentaerythritol
monostearate, partial fatty acid esters of sorbitane, partial
fatty acid esters of polyoxyethylene sorbitane, sorbitol
ethers of polyoxyethylene, fatty acid esters of
polyoxyethylene, fatty alcohol ethers of polyoxyethylene,
fatty acid esters of saccharose, fatty acid esters of
polyglycerol, lecithin.
Antioxidants that may ~or example be used are sodium
metabisulphite, ascorbic acid, gallic acid, gallic acid alkyl
ester, butylhydroxyanisol, nordihydroguaiacic acid,
tocopherols as well as tocopherols + synergists (substances
that bind heavy metals through complex formation, for example
lecithin, ascorbic acid, phosphoric acid). The addition of
synergists substantially enhances the antioxygenic effect of
the tocopherols.
~onserving agents that may for example be considered are
sorbic acid, p-hydroxybenæoic acid esters (for example lower
alkyl esters), benzoic acid, sodium benzoate,
trichloroisobutyl alcohol, phenol, cresol, benzethonium
chloride and formalin derivatives.
- 13 -
rJ~
The pharmaceutical and galenic treatment of the compounds of
formula I is according to conventional standard methods. For
example active substance(s) and auxiliary or carrier
substances are well mixed by stirring or homogenization (for
example using conventional mixing devices), working generally
being at temperatures between 20 and 80C, preferably 20 to
50C, in particular at room temperature. Reference is made
in this context to the following standard work: Sucker,
Fuchs, Speiser, Pharmaæeutische Technologie, Thieme Verlag
Stuttgar~, 1978.
Application may be to the skin or mucous membrane or to the
inside of the body, for example oral, enteral, pulmonal,
rectal, nasal, vaginal, lingual, intravenous, intra-arterial,
intracardial, intramuscular, intraperitoneal, intracutaneous,
subcutaneous.
In the case of parenteral formulation forms, these are in
particular sterile or sterilized products.
The concentration of compound I (component I, i.e. the total
amount) in the medicinal forms for local application is 0.01
to 12, preferably 0.05 to 10, in particular 0.1 to 8 or also
0.5 to 6 percent by weight.
For the treatment of psoriasis the compounds I ~component I)
~5 are used in particular locally, for example in the form of
solutions, tinctures t suspensions, emulsions, ointments,
gels, creams, pastes, lotions or shampoos. Preference is
given to anhydrous formulations, facilitating the
simultaneous use of salicylic acid and/or urea. Formulations
of this type, which can also be made resistant to scrubbing
through the addition of surfactants, are described for
example in German Published Patent 36 03 859. The urea may
either be present as surfactant-urea inclusion compound or
also in free for~. Formulations containing neither urea nor
salicylic acid may of course also be used.
- 14 -
The concentrations of compound I used (in each c.ase the total
amount) are in this case for example 0.1 to 10 %
(weight/weight), preferably 0.5 to ~ %, in particular 1 to
6%. The concentrations of use of salicylic acid are for
example 0.1 to 10%, preferably 0.2 to 8%, in particular 0.5
to 5%. The concentrations of use of urea are for example 1
to 20%, preferably 3 to 18~, in particular 5 to 15%.
For topical application it has for example been found
beneficial to use the compounds I (component I) together with
at least one alkyl glycerol with 2 to 12 carbon atoms in the
alkyl radical which may be present in the form of an ether
yroup bound to on~ of the primary or secondary OH groups of
the glycerol. Alkyl glycerols of this type enhance or
improve the effect of the compounds I. Preference is given
here to alkyl glycerols with 3 to 9 carbon atoms alone or
mixed.
Particularly favourable effects are thus possessed by a
medicament which contains
a) one or several compounds of formula I (component I) and
b) an alkyl glycerol of the general formula II
H2C ~ R5
HC - O - R6
~2C - OH,
in which one of the radicals R5 and R6 represents an
alkyl group with 2 to I2 carbon atoms and the other
radical represents a hydrogen atom,
as well as optionally other conventional pharmacological
additives and diluents.
- 15 -
$
Use may preferably be made of a mixture of water and an
alkylglycerol mixture of nonyl or octyl glycerol, hexyl or
pentyl glycerol and propyl- or ethylglycerol. A
corresponding formulation for topical use contains for
example 1 to 100 mg of compound I (component I, i.e. total
amount I) per ml of alkyl glycerol of formula II or of a
corresponding alkylglycerol mixture with water.
A mixture of this type will hereinafter also be referred to
as a cascade.
The content of component I in mg/ml cascade is designated by
a suffixed index in such a way that for example a cascade
mixture containing 10 mg/ml of component I is termed a
cascade 10 and a mixture containing 60 mg of component I per
ml of cascade is referred to as cascade 60.
The preparation of alkyl glycerols is known, for example from
German Published Patent 33 43 530.8.
For example alkyl glycerol-water mixtures containing for
example nonyl glycerol, octyl glycerol, hexyl glycerol,
pentyl glycerol, propyl glycerol and ethyl glycerol are
preferred. Aqueous mixtures of this kype preferably contain
3 of the named glycerol ethers, namely one lower (ethyl,
propyl), one medium (pentyl, hexyl) and one higher (octyl,
nonyl) one where the amount by weight of the lower ether is
about the same as the sum of the amounts by weight of the two
other glycerol ethers. The amount of water is about the same
as the amount of the lower glycerol ether and is for example
half ~he total amount of the glycerol ethers present.
Examples of such glycerol ether-water mixtures are listed
below:
- 16 -
~2~2~
Water Glycerol-propyl- Glycerol-hexyl- Glycerol-
nonyl-
ether ether ether
Parts 2 : 2 : 1 : 1
by weight
Water Glycerol-ethyl- Glycerol-pentyl- Glycerol-
octyl-
ether ether ether
Parts 2 : 2
by weight
Medicaments with the alkyl glycerols of formula II are
particularly suitable for topical application. In order for
example to treat psoriasis and disorders related thereto, the
skin areas in question are for example rubbed twice to three
times daily with cascade 10 to cascade 80. No harmful side
effects have been observed to date.
The mode of preparation of the compounds I (component I) in
the form of the cascade (for example in the form of solutions
of cascade 10 to cascade 100, in particular cascade 40 to 60)
is also suitable for the preparation of suppositories for
rectal insertion. Psoriasis or psoriasis disorders may be
effectively treated herewith.
A particularly favourable carrier mixture for the component I
consists of a mixture of about 4 parts by weight of water, 4
~parts by weight o* propyl glycerol and 2 parts by weight each
of hexyl glycerol and nonyl glycerol.
- 17 -
i3 2 ~ ~
To prepare medicaments containing the component I in the
presence of a glycerol ether of formula II or a mixture of
glycerol ethers of this type of formula II, the component I
is for example used with lo,Ooo to 7, in particular 100 to
10, preferably 30 to 16 parts by weight (related in each case
to one part by weight) o~ at least one glycerol ether of
formula II or a mixture of glycerol ethers of this type as
well as optionally 7,700 to 0.05, in particular 400 to 2,
preferably 20 to 3 parts by weight of water (also related to
one part by weight of component I, that is in each case the
total amount of the compounds I)o This mixing with the
glycerol ethers may be carried out at the beginning of the
preparation of the corresponding medicament, but optionally
also at a later stage in the preparation.
Examples:
Example 1 (solution for topical use)
Hexadecylphosphocholine solution is prepared by dissolving
hexadecylphosphocholine in a solvent referred to as cascade
0.
Preparation of cascade 0
1000 g of water, 1000 g of glycerol-l-n~propyl ether, 500 g
of glycerol-l-n-hexyl ether and 500 g of glycerol-1-n-nonyl
ether are mixed in a suitable vessel.
Preparation of the solution
Ca. 2 litres of cascade 0 are filled into a suitable vessel
and 1~0 g of hexadecylphosphocholine dissolved therein with
stirring. The mixture is then filled up to 3 litres with
cascade 0. The density of the solution is 1.003 g/ml at
26C.
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~ ~ t~
This solution is filtered under aseptic conditions in a
sterile collecting vessel through a membrane filter o~ pore
size 0.2 um and filled into sterile dropping bottles of 10 ml
each. 1 ml of the solution contains 60 mg of
hexadecylphosphocholine.
Example 2 (capsules)
50 mg Hexadecylphosphocholine hard gelatine capsules ~-
250 g of hexadecylphosphocholine, 435.5 g of lactose
monohydrate DAB 9, 241.5 g of microcrystalline cellulose DAB
9, 14 g of talcum DAB 9, 7 g of highly disperse silicon
dioxide DAB 9 and 2 g of magnesium stearate DAB 9 are passed
through a sieve of mesh size 0.8 mm and then homogenized in a
suitable mixer ~or 30 mins.
This capsule mass is filled in 190 mg batches into size 2
hard gelatine two-piece capsules in a capsule filling
machine.
1 capsule contains 50 mg of hexadecylphosphocholine.
Example 3 (tablets3
100 mg hexadecylphosphocholine tablets
300 g o~ hexadecylphosphocholine and 600 g of lactose
monohydrate DAB 9 are passed through a 0,8 mm sieve, mixed in
a fluidized air bed granulating unit and granulated with 180
g of a 10% gelatine solution.
The fluidized air bed granulate, 82.8 g of microcrystalline
cellulose DAB 9, 120 g of corn starch, 16.8 g of talcum and
2.4 g of magnesium stearate are passed through a sieve of 0.8
mm mesh size. This tablet mass is pressed into tablets
weighing 380 mg and having a diameter of 10 mm using an
appropriate tablet press.
-- 19 --
f~
1 tablet contains 100 mg of hexadecylphosphocholine.
An example of the method of application used for the
compounds according to the present invention will now be
given.
The effect was tested in the course of ambulatory treatment
of six subjects suffering from psoriasis vulgaris. These
subjects had inflamed skin, encrustations on the skin, scaley
skin (over the whole body). Treatment consisted of topical
application of a 6-~ solution of hexadecylphosphocholin in a
mixture of water, glycerine propylether, glycerin hexylether
and glycerine nonylether in a proportion of 2~ 2 (parts by
weight). One ml of the above glycerine-ether-water mixture
thus contains 60 mg of the hexadecylphosphocholin (Kascade
60)
This solution was applied twice daily (morning and evening)
for a week. Application was in drops applied to the affected
areas of skin, which were massaged in ueing very light
pressure (with a finger stall or glove of polyvinylchloride
(PVC)). After one week, in all the patients, the scaling on
the lesions had improved and the thickness of the lesions had
been reduced.
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