DE3540175C2 - Dithranol-containing pharmaceutical preparation - Google Patents

Description

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

Such preparations are widely known. The active substance dithranol however, it is relatively unstable because it is easily oxidized to danthrone. These known instability of dithranol to oxygen and others Substances (eg water, alkali) had the consequence that the corresponding pharmaceutical preparations only with the help of mixtures of Acids, antioxidants and reducing agents are stable for a short time could be made described z. In US 4287214, BE 894777, BE 894778, BE 894779, BE 899874-A, BE 899975-A. The antioxidant Medications are not tolerated by all patients without irritation. One finds frequently allergic reactions to compounds such as butylated hydroxytoluene or butylhydroxyanisole. Furthermore, there is a great disadvantage in that in the production of self-emulsifying ointments emulsifiers added which, however, the dithranol oxidation turn strong promote. Even small additions of such emulsifiers that are used in cosmetics and are common for the manufacture of medicaments, such as. B. polyoxy ethylene sorbitan fatty acid esters, fatty alcohol polyglycol ethers, polyoxyethyl Lierte fatty acids u. a., require elaborate, oxygen-removing measure increased in production, increased addition of reducing agents and Antioxidants, and you get products that are only a short time shelf life. The increased addition of stabilizers also reduces the skin compatibility.

The invention was based on the object Selbstemulgierende, dithranol containing pharmaceutical preparations which are resistant to oxidative Influences stable and longer lasting.

It has surprisingly been found that certain additives both a self-emulsifying and stabilizing effect call.  

The invention relates to a pharmaceutical preparation for topical application containing dithranol, white vaseline and minde at least one self-emulsifying additive selected from a Group consisting of C₁₈-C₃₆-fatty acid triglyceride, G₁₈-C₃₆ fatty acid glycol ester, lactic acid ester of glycerol monostearate, lactyl lactic acid esters of stearic acid, polyglycerol esters of oleic acid, citric acid esters of tallow fatty acid monoglycerides, lactyl lactic acid ester of palmitin acid, acetic acid ester of glycerol monopalmitate stearate, diacetyl wine acid esters of glycerol monooleate or polyglycerol esters of tallow fat acid, and salts thereof, characterized in that the content of Dithranol 0.1 to 5 wt .-% and the emulsifier 1 to 50 wt .-% and the preparation is free from reducing agents, stabilizers and / or antioxidants, as well as a process for producing a self-emulsifying, stable pharmaceutical preparation containing Dithranol, characterized in that one in a melt Carrier and self-emulsifying additives at about 35-50 ° C. Dithranol incorporated with stirring.

As preparations come primarily spreadable preparations such as Ointments or creams in question, also z. As well as lotions, pens or Pastes.

The content of dithranol is in the preparations according to the invention preferably about 0.1 to 5, in particular 1.0 to 3.5 wt .-%; the Total content of emulsifiers is about 1 to 50, preferably about 5 to 30 wt .-%.

The fatty acids considered here have 12-18 C atoms, are unbranched or branched, saturated or unsaturated, preferably unbranched and saturated and therefore preferably lauric, myristic, palmitic, Margarine, stearic or oleic acid.

The fatty acid glycerides may be present as di- or triglycerides, wherein one or two OH groups are esterified with the above-mentioned fatty acids. Another OH group is esterified with acetic acid, lactic acid, Bern  tartaric acid, tartaric acid, lactyllactic acid, mono- or diacetyltartaric acid or citric acid.

Also suitable as stabilizing emulsifiers are fatty acid esters lactyl lactic acid and / or its alkali metal or alkaline earth metal salts, wherein the above-mentioned fatty acids are used.

The following emulsifiers are preferably used:
Lactic acid esters of glycerol monostearate, sodium salt of Lactylmilch acid ester of stearic acid or polyglycerol esters of oleic acid, also citric acid esters of tallow fatty acid monoglycerides, Lactylmilch acid ester of palmitic acid or its sodium salt, acetic acid ester of glycerol monopalmitate stearate, diacetyl tartaric acid ester of glycerol monooleate or polyglycerol esters of tallow.

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

R²-A-COOR

in which A, R¹ and R² have the abovementioned meaning.

Preferred dicarboxylic acid components are malonic acid, Bern tartaric acid, glutaric acid, adipic acid, maleic acid, fumaric acid, apples acid, tartaric acid, tartronic acid, itaconic acid or citraconic acid suitable.

The monocarboxylic acids are preferably glycolic acid, milk acid, chloroacetic acid or mandelic acid in question.

From the range of 2-hydroxyalkyl radicals having 12 to 20 carbon atoms, preference is given to mixtures having chain lengths of about C _12/14 , C _16/18 or C _18/20 .

Accordingly, the following emulsifiers are preferably used:
Lactic acid 2-hydroxy C _12/14 alkyl esters, C _16/18 alkyl esters, C _18/20 alkyl esters,
Chloroacetic acid 2-hydroxy-C _16/18 alkyl ester,
Malonic acid di-2-hydroxy-C _12/14 alkyl ester, -C _16/18 alkyl ester,
Succinic di-2-hydroxy-C _12/14 alkyl esters, -C _16/18 alkyl esters,
-C _18/20 alkyl ester,
Glutaric acid di-2-hydroxy C _12/14 alkyl esters, C _16/18 alkyl esters,
Maleic acid di-2-hydroxy-C _12/14 alkyl ester, -C _16/18 alkyl ester,
-C _18/20 alkyl ester,
Fumaric acid di-2-hydroxy-C _12/14 alkyl esters, -C _16/18 alkyl esters,
Malic acid di-2-hydroxy C _12/14 alkyl esters, C _16/18 alkyl esters,
Tartaric di-2-hydroxy-C _12/14 alkyl esters, C _18/20 alkyl esters,
Adipic acid di-2-hydroxy-C _12/14 alkyl ester, -C _16/18 alkyl ester,
Tartronic acid di-2-hydroxy-C _16/18 alkyl ester,
Citraconic acid di-2-hydroxy C _16/18 alkyl ester,
Itaconic acid di-2-hydroxy C _16/18 alkyl ester,
Diglycolic di-2-hydroxy-C _16/18 alkyl ester,
Mucic acid di-2-hydroxy-C _16/18 alkyl ester,
Phthalic acid di-2-hydroxy C _16/18 alkyl esters,
Hexadecenyl succinic di-2-hydroxy C _16/18 alkyl esters,
Mandelic acid di-2-hydroxy-C _16/18 alkyl ester.

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

Suitable carriers are preferably hydrocarbons or Hydrocarbon mixtures such as vaseline, paraffins (solid or liquid), preferably vaseline, and also ceresin, squalene or polyethylene Paraffin gel.  

Furthermore, in the preparations according to the invention further auxiliaries be included as well as odors and / or dyes, z. For example more Alcohols such as 1,2-propanediol, glycerol or sorbitol, beeswax, Wool wax alcohols, cholesterol, spermaceti, higher fatty acids like palmitin acid or stearic acid, fatty acid esters such as isopropyl myristate or isopropyl palmitate, Cetyl palmitate, triglycerides, natural fats and oils, sili konöle or finely divided silica.

The additives mentioned do not show any reductive, antioxidant or stabilizing agents dissolving properties.

The addition of small amounts of co-emulsifiers to the inventions preparations according to the invention, such as. B. Oleyloleat, ethylene glycol stearate or propylene glycol stearate, fatty acid-protein condensates, alkali or Amine salts of fatty alcohol sulfates, phosphates or other commonly used union water / oil emulsifiers is also possible.

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

Thus, for the treatment of skin diseases, in particular of Psoriasis, self-emulsifying dithranolhaltige means available, the without further additives such as reducing agents, stabilizers or antioxidants Dandien, storable, stable and skin-friendly.

example 1 production method

• a) Preparation of an ointment
  A mixture of emulsifier, paraffin and petroleum jelly is clearly melted by heating to 70 ° C and cooled to 40 ° C in a stirred-tank refrigerator. With the help of a homogenizer, the dithranol is distributed in the melt at this temperature, which is then cooled further with constant stirring. At about 35 ° C, the solidification of the ointment begins, and between 25 and 22 ° C, the cooling process can be stopped.
• b) Preparation of a cream
  A mixture of emulsifier, paraffin and petroleum jelly is clearly melted by heating to 70 ° C and held in a cooling vessel with stirrer and homogenizer at this temperature.
  At the same time demineralized water is also heated to 70 ° C and combined with the aforementioned mixture of fatty components. The emulsion formation is brought about by the homogenizer and then the initially liquid emulsion is cooled by cooling to 45 ° C. with constant stirring. Now dithranol is distributed in the emulsion with the aid of the homogenizer and then cooled to about 20 ° C. with stirring.
• c) Production of a pen
  A mixture of emulsifying additive, fatty acid triglycerides and white vaseline is clearly melted and cooled to about 10 ° C above the solidification point. At this temperature, the dithranol is evenly distributed in the casting compound with the aid of an emulsifier, and these are then poured into casting sleeves.
• d) Preparation of a paste
  A mixture of emulsifier, paraffin and petroleum jelly is clearly melted by heating to 70 ° C and cooled to 40 ° C in a stirred-tank refrigerator. The dry mixture of dithranol, titanium dioxide and talc is sieved and distributed in the melt using a Homogenisa, which is then cooled with stirring to about 25 ° C.

Example 2

According to Example 1a), an ointment is prepared from 0.1 g of dithranol, 20.0 g Lactic acid esters of glycerol monostearate and 79.9 g white vaseline.

Example 3

According to Example 1a), an ointment is prepared from the following constituents provides:

Dithranol | 5.0 g Citric acid esters of tallow fatty acid monoglycerides 10.0 g dickfl. paraffin 20.0 g white vaseline 65.0 g

Example 4

According to Example 1a), an ointment is prepared from the following constituents provides:

Dithranol | 2.0 g Lactic acid esters of glycerol monostearate 15.0 g Acetic acid esters of glycerol monopalmitate stearate 10.0 g white vaseline 75.0 g

Example 5

According to Example 1a), an ointment is prepared from the following constituents provides:

Dithranol | 1.0 g Lactylmylchsäureester of palmitinstearic acid or its sodium salt 25.0 g myristate 10.0 g white vaseline 64.0 g

Example 6

According to Example 1 a) is from the following ingredients an ointment herge provides:

Dithranol | 5.0 g Lactic acid esters of glycerol monostearate 10.0 g dickfl. paraffin 20.0 g white vaseline 65.0 g

Example 7

According to Example 1b) is made from the following ingredients a cream:

Dithranol | 5.0 g Diacetyl tartaric acid ester of glycerol monooleate 5.0 g water 30.0 g white vaseline 60.0 g

Example 8

According to Example 1b), a cream is prepared from:

Dithranol | 1.0 g Polyglycerol esters of oleic acid 20.0 g dickfl. paraffin 10.0 g water 50.0 g white vaseline 19.0 g

Example 9

According to Example 1 b) a cream is prepared from:

Dithranol | 0.1 g Polyglycerol esters of oleic acid 18.0 g medium chain triglycerides 5.0 g white vaseline 30.0 g water 46.9 g

Example 10

Production of a pencil according to 1c) from:

Dithranol | 5.0 g Lactic acid esters of glycerol monostearate 20.0 g C₁₈-C₃₆-chain fatty acid triglyceride 10.0 g C₁₈-C₃₆-Fettsäureglykolester 2.5 g white vaseline 62.5 g

Example 11

Production of a pencil according to 1c) from:

Dithranol | 2.5 g Lactylmylchsäureester of palmitinstearic acid or its sodium salt 25.0 g lecithin 5.0 g hard paraffin 5.0 g Cetylstearylalkohol 5.0 g white vaseline 57.5 g

Example 12

Preparation of a paste according to 1d) from:

Dithranol | 2.0 g Polyglycerol esters of oleic acid 5.0 g Titanium dioxide 12.5 g talc 12.5 g dickfl. paraffin 20.0 g white vaseline 48.0 g

Example 13

Preparation of a paste according to 1d) from:

Dithranol | 3.5 g Polyglycerol esters of tallow fatty acid 12.0 g Titanium dioxide 12.5 g isopropyl 10.0 g trilaurin 5.0 g white vaseline 44.5 g

Claims (2)

A topical pharmaceutical preparation containing dithranol, white vaseline and at least one self-emulsifying additive selected from a group consisting of C₁₈-C₃₆ fatty acid triglyceride, C₁₈-C₃₆ fatty acid glycol ester, lactic acid ester of glycerol monostearate, lactyl lactic acid ester of stearic acid, polyglycerol ester of oleic acid Citric acid esters of tallow fatty acid monoglycerides, lactyl lactic acid esters of palmitic acid, acetic acid esters of glycerol monopalmitate stearate, diacetylacid esters of glycerol monooleate or polyglycerol esters of tallow fatty acid, and their salts, characterized in that the content of dithranol is 0.1 to 5% by weight and that of Emulsifier content is 1 to 50 wt .-% and the preparation is free of reducing agents, stabilizers and / or antioxidants. 2. Method for producing a self-emulsifying, stable pharmaceutical preparation containing dithranol, characterized characterized in that one in a melt of carriers and self-emulsifying additives at about 35-50 ° C dithranol incorporated with stirring.