DE3540175A1 - Dithranol-containing pharmaceutical formulation - Google Patents

Abstract

Dithranol-containing pharmaceutical formulations which contain at least one additive with a self-emulsifying and, at the same time, stabilising action are used for the treatment of skin disorders.

Description

The invention relates to a pharmaceutical preparation for topical application containing dithranol.

Such preparations are widely known. The active substance However, dithranol is relatively unstable because it is light is oxidized to danthrone. This known instability of Dithranol to oxygen and other substances (e.g. Water, alkali) resulted in the corresponding pharmaceutical preparations only with the help of mixtures from acids, antioxidants and reducing agents for one could be preserved for a short time e.g. B. in US 42 87 214, BE 8 94 777, BE 8 94 778, BE 8 94 779, BE 8 99 874-A, BE 8 99 975-A. The antioxidants will not tolerated without irritation by all patients. One finds frequently allergic reactions to compounds such as Butylated hydroxytoluene or butylated hydroxyanisole So far a major disadvantage is that in the manufacture of self-emulsifying ointments emulsifiers added must be, however, the dithranol oxidation in turn strongly promote. Even small additions of such emulsifiers, those in cosmetics and for the production of Medicines are common, such as. B. polyoxyethylene sorbitan fatty acid esters, Fatty alcohol polyglycol ether, polyoxyethylated Fatty acids and a., require complex, oxygen-removing Production measures, increased Addition of reducing agents and antioxidants, and one  receives products that only have a short shelf life. The increased addition of stabilizers also reduces skin tolerance.

The invention was based on the object of self-emulsifying pharmaceutical preparations containing dithranol to find the stable and stable against oxidative influences are durable for a long time.

It has surprisingly been found that certain Additives both a self-emulsifying as well have a stabilizing effect.

The invention relates to a pharmaceutical preparation for topical use containing dithranol, characterized in that it contains at least one self-emulsifying additive, in particular as an additive
a) an ester of a fatty acid glyceride with acetic acid, lactic acid, succinic acid, tartaric acid, lactyl lactic acid, mono- or diacetyl tartaric acid, citric acid
and or
b) a fatty acid ester of lactyl lactic acid and / or one of its alkali or alkaline earth metal salts
and or
c) a polyglycerol fatty acid ester
and or
d) a mono- or dicarboxylic acid 2-hydroxyalkyl ester of the general formula

R ² -A-COOR ¹

in the A an alkylene group with 1-4 carbon atoms, an alkylene group with 1-4 carbon atoms substituted by up to n hydroxyl groups, where n should not be greater than the number of carbon atoms, an ethylene group substituted by the methylene group, a 2-oxapropylene (1.3 ) - group, an unsubstituted or substituted by a methyl group or a phenylene group and R ^{1 is} a 2-hydroxyalkyl radical having 12-20 carbon atoms and R ^{2 is} hydrogen or a radical -COOR ¹ - with the proviso that when R ^{2 is} hydrogen A represents a methylene group substituted by chlorine or by the phenyl group and / or hydroxyl group or an ethylene group substituted by the hydroxyl group,
is used, the fatty acids each containing 12-18 carbon atoms, and a process for the preparation of a stable, self-emulsifying dithranol-containing pharmaceutical preparation, characterized in that dithranol at about 35-50 ° C in a melt of carriers and self-emulsifying additives Stir incorporated.

The invention further relates to the use of the Preparation according to the invention for the treatment of skin diseases, especially psoriasis.

Spreadable preparations come primarily Preparations such as ointments or creams in question, furthermore e.g. B. also lotions, pens or pastes.  

The content of dithranol in the inventive Preparations preferably about 0.1 to 5, in particular 1.0 to 3.5% by weight; the total content of emulsifiers is about 1 to 50, preferably about 5 to 30% by weight.

The fatty acids considered here have 12-18 carbon atoms, are unbranched or branched, saturated or unsaturated, preferably unbranched and saturated and mean therefore preference is given to laurin, myristine, palmitin, margarine, Stearic or oleic acid.

The fatty acid glycerides can be di- or triglycerides are present, one or two OH groups with the above Fatty acids are esterified. Another OH group is esterified with acetic acid, lactic acid, succinic acid, Tartaric acid, lactyl lactic acid, mono- or diacetyl tartaric acid or citric acid.

Also very suitable as stabilizing emulsifiers are fatty acid esters of lactyl lactic acid and / or their Alkali metal or alkaline earth metal salts, the above mentioned fatty acids are used.

The following emulsifiers are preferably used:

Lactic acid ester of glycerol monostearate, sodium salt of Lactyl lactic acid ester of stearic acid or polyglycerol ester of oleic acid, and also citric acid ester of Tallow fatty acid monoglycerides, lactyl lactic acid esters from Palmitic acid or its sodium salt, acetic acid ester of glycerol monopalmitate stearate, diacetyl tartaric acid ester of glycerol monooleate or polyglycerol ester of tallow fatty acid.  

Also suitable as self-emulsifying and stabilizing Additives are mono- and dicarboxylic acid 2-hydroxyalkyl esters, known from DE-PS 27 57 278, the general formula

R ² -A-COOR ¹

in which A, R ¹ and R ^{2 have} the meaning given above.

The preferred dicarboxylic acid components are malonic acid, Succinic acid, glutaric acid, adipic acid, maleic acid, Fumaric acid, malic acid, tartaric acid, tartronic acid, itaconic acid or citraconic acid.

The monocarboxylic acids are preferably glycolic acid, lactic acid, chloroacetic acid or mandelic acid. Mixtures with chain lengths around C _12/14 , C _16/18 or C _18/20 are preferably selected from the range of 2-hydroxyalkyl radicals with 12-20 C atoms.

The following emulsifiers are therefore preferably used:
Lactic acid 2-hydroxy-C _12/14 alkyl ester,
-C _16/18 alkyl esters, -C _18/20 alkyl esters,
2-hydroxy-C _16/18 alkyl chloroacetate,
Malonic acid di-2-hydroxy-C _12/14 alkyl ester,
-C _16/18 alkyl esters,
Succinic acid di-2-hydroxy-C _12/14 alkyl ester,
-C _16/18 alkyl esters, -C _18/20 alkyl esters,
Di-2-hydroxy-C _12/14 alkyl glutarate,
-C _16/18 alkyl esters,
Maleic acid di-2-hydroxy-C _12/14 alkyl ester,
-C _16/18 alkyl esters, -C _18/20 alkyl esters,
Fumaric acid di-2-hydroxy-C _12/14 alkyl ester,
-C _16/18 alkyl esters,
Malic acid di-2-hydroxy-C _12/14 alkyl ester,
-C _16/18 alkyl esters,
Tartaric acid di-2-hydroxy-C _12/14 alkyl ester,
-C _18/20 alkyl esters,
Adipic acid di-2-hydroxy-C _12/14 alkyl ester,
C _16/18 alkyl ester,
Di-2-hydroxy-C _16/18 alkyl tartronic acid,
Citraconic acid di-2-hydroxy-C _16/18 alkyl ester,
Itaconic acid di-2-hydroxy-C _16/18 alkyl ester,
Di-2-hydroxy-C _16/18 alkyl diglycolic acid,
Mucic acid di-2-hydroxy-C _16/18 alkyl ester,
Di-2-hydroxy-C _16/18 alkyl phthalate,
Hexadecenylsuccinic acid di-2-hydroxy-C _16/18 alkyl ester,
Mandelic acid 2-hydroxy-C _16/18 alkyl ester.

The pharmaceutical preparations according to the invention contain at least one self-emulsifying additive, but it can also be two or more different of the above emulsifiers can be added.

Hydrocarbons are preferably suitable as carriers or hydrocarbon mixtures such as petroleum jelly, Paraffins (solid or liquid), preferably petroleum jelly, also ceresin, squalene or polyethylene paraffin Gel.

Furthermore, in the preparations according to the invention other auxiliaries as well as odors and / or dyes be included, e.g. B. polyhydric alcohols such as 1,2-propanediol, glycerin or sorbitol, beeswax, wool wax alcohols, Cholesterol, walrus, higher fatty acids such as palmitic acid or stearic acid, fatty acid esters such as Isopropyl myristate or isopropyl palmitate, cetyl palmitate, Triglycerides, natural fats and oils, silicone oils or finely divided silica.  

The addition of small amounts of co-emulsifiers to the Preparations according to the invention, such as. B. oleyl oleate, Ethylene glycol stearate or propylene glycol stearate, fatty acid Protein condensates, alkali or amine salts of fatty alcohol sulfates, -phosphates or other common Water / oil emulsifiers are also possible.

Mixing the ingredients to make creams or ointments is done in such a way that one in a melt from carriers and self-emulsifying additives at about 35-50 ° C, preferably at 40-45 ° C, dithranol incorporated with stirring.

Thus, the treatment of skin diseases, in particular of psoriasis, self-emulsifying dithranol Funds are available that like no other additives Reducing agents, stabilizers or antioxidants, are storable, stable and skin-friendly.

Example 1): Manufacturing process a) Preparation of an ointment

A mixture of emulsifier, paraffin and petroleum jelly is melted clear by heating to 70 ° C and cooled to 40 ° C. in a cooling vessel with an agitator. With the help of a homogenizer this temperature the dithranol in the melt distributed, which then continued under permanent Stirring is cooled. It starts at around 35 ° C Solidification of the ointment, and between 25 and 22 ° C the cooling process can be ended.  

b) Creation of a cream

A mixture of emulsifier, paraffin and petroleum jelly is melted clear by heating to 70 ° C and in a cooling vessel with agitator and homogenizer kept at this temperature.

At the same time, demineralized water also becomes heated to 70 ° C and with the above mixture of the fat components combined. The emulsion formation is brought about by the homogenizer and then the initially liquid emulsion by cooling cooled to 45 ° C with constant stirring. Well now with the help of the homogenizer dithranol in the emulsion distributed and this with stirring to about 20 ° C. chilled.

c) making a pen

A mixture of emulsifying additive, fatty acid triglycerides and white petroleum jelly is melted clear and up to approx. 10 ° above the solidification point cooled down. At this temperature it will Dithranol with the help of an emulsifier in the casting compound evenly distributed and then in casting sleeves poured.

d) Preparation of a paste

A mixture of emulsifier, paraffin and petroleum jelly is melted clear by heating to 70 ° C and cooled to 40 ° C. in a cooling vessel with an agitator. The dry mixture of dithranol, titanium dioxide and Talc is sieved and with the help of a homogenizer distributed in the melt, which then under Stirring is cooled to about 25 ° C.  

Example 2)

According to Example 1 a), an ointment is produced from 0.1 g dithranol, 20.0 g lactic acid ester of glycerol monoostearate and 79.9 g of white petroleum jelly.

Example 3):

According to Example 1 a), an ointment is made from the following ingredients:
Dithranol 5.0 g citric acid ester from
Tallow fatty acid monoglycerides 10.0 g thick fl. Paraffin 20.0 g white petroleum jelly 65.0 g

Example 4)

According to Example 1 a), an ointment is made from the following ingredients:
Dithranol 2.0 g lactic acid ester from
Glycerol monostearate 15.0 g acetic acid ester of
Glycerol monopalmitate stearate 10.0 g white petroleum jelly 75.0 g.

Example 5):

According to Example 1 a), an ointment is made from the following ingredients:
Dithranol 1.0 g lactyl lactate from
Palmitic stearic acid or
its sodium salt 25.0 g myristyl myristate 10.0 g white petroleum jelly 64.0 g.

Example 6)

According to Example 1 a), an ointment is made from the following ingredients:
Dithranol 5.0 g lactic acid ester of
Glycerol monostearate 10.0 g thick fl. Paraffin 20.0 g white petroleum jelly 65.0 g

Example 7)

According to Example 1 b), a cream is produced from the following components:
Dithranol 5.0 g diacetyl tartaric acid ester of
Glycerol monooleate 5.0 g water 30.0 g white petroleum jelly 60.0 g.

Example 8)

According to Example 1 b), a cream is produced from:
Dithranol 1.0 g polyglycerol ester of oleic acid 20.0 g thick fl. Paraffin 10.0 g water 50.0 g white petroleum jelly 19.0 g.

Example 9):

According to Example 1 b), a cream is produced from:
Dithranol 0.1 g polyglycerol ester of oleic acid 18.0 g medium chain triglycerides 5.0 g white petroleum jelly 30.0 g water 46.9 g.

Example 10):

Production of a pencil according to 1 c) from:
Dithranol 5.0 g lactic acid ester of
Glycerinmonostearat20,0 g C ₁₈ -C ₃₆ -Fettsäuretriglycerid10,0 g C ₁₈ -C ₃₆ -Fettsäureglykolester 2.5 g of white Vaselin62,5 g.

Example 11)

Production of a pencil according to 1 c) from:
Dithranol 2.5 g lactyl lactate from
Palmitic stearic acid or
its sodium salt 25.0 g lecithin 5.0 g hard paraffin 5.0 g cetylstearyl alcohol 5.0 g white petroleum jelly 57.5 g.

Example 12):

Production of a paste according to 1 d) from:
Dithranol 2.0 g polyglycerol ester of oleic acid 5.0 g titanium dioxide 12.5 g talc 12.5 g thick. Paraffin 20.0 g white petroleum jelly 48.0 g.

Example 13)

Production of a paste according to 1 d) from:
Dithranol 3.5 g polyglycerol ester of tallow fatty acid 12.0 g titanium dioxide 12.5 g isopropyl myristate 10.0 g trilaurin 5.0 g white petroleum jelly 44.5 g.

Claims (4)

1. Pharmaceutical preparation for topical use containing dithranol, characterized in that it contains at least one self-emulsifying additive. 2. Pharmaceutical preparation according to claim 1, characterized in that as an additive
a) an ester of a fatty acid glyceride with acetic acid, lactic acid, succinic acid, tartaric acid, citric acid, lactyl lactic acid, mono- or diacetyl tartaric acid
and or
b) a fatty acid ester of lactyl lactic acid and / or one of its alkali metal or earth metal salts
and or
c) a polyglycerol fatty acid ester
and or
d) a mono- and dicarboxylic acid 2-hydroxyalkyl ester of the general formula R ² -A-COOR ¹ in which A is an alkylene group with 1-4 carbon atoms, an alkyl group with 1-4 carbon atoms substituted by up to n hydroxyl groups, where n is not larger than the number of carbon atoms is to be an ethylene group substituted by the methylene group, a 2-oxapropylene (1.3) group, an unsubstituted or substituted by a methyl group or a phenylene group and R ^{1 is} a 2-hydroxyalkyl group having 12-20 carbon atoms and R ^{2 represents} hydrogen or a radical -COOR ¹ - with the proviso that when R ^{2 represents} hydrogen, A represents a methylene group substituted by chlorine or by the phenyl group and / or hydroxyl group or an ethylene group substituted by the hydroxyl group,
is used, the fatty acids each containing 12-18 carbon atoms. 3. Process for the production of a self-emulsifying, stable, pharmaceutical preparation containing Dithranol, characterized in that one in a Melt from carriers and self-emulsifying Additives at about 35-50 ° C dithranol with stirring incorporated. 4. Use of a pharmaceutical preparation according to Claim 1 for the treatment of skin diseases.