DE3315805A1 - Active substance compositions - Google Patents

Abstract

The invention relates to active substance compositions consisting of a non-lipoid surfactant, of a solvent which is partially miscible with water, and of an active substance which can be used in veterinary and/or human medicine, to processes for the preparation of the active substance compositions and to the use thereof in veterinary and/or human medicine.

Description

The invention relates to active ingredient preparations consisting of a non-lipoid surfactant, a partially water-miscible solvent and an active ingredient that can be used in veterinary and / or human medicine, processes for producing the active ingredient preparations and their use in veterinary and / or human medicine.

Liposomes, among other things, are used today as the common active ingredient and drug carriers. The particle diameter of the membrane aggregates with incorporated active ingredient is in the range from approx. 50 nm to a few µm. Problems for the application of the liposomes are a reproducible production of the sizes and the loss of active substance on contact with serum proteins.

Another way of formulating active ingredients is solubilization in micelles. A colloid-dispersed transport of active ingredients is possible here, but the solubilization capacity is low. One advantage of this formulation, however, is the small size of the micelles (diameter = 46 nm to 15.6 nm), which enables the active ingredients to be transported better through membranes.

More recent work tries to use the microemulsions for the formulation of active ingredients. According to the state of the art, it is now possible to use a complex emulsifier (surfactant + cosurfactant) oil and water within a three-phase area to produce a microemulsion, i.e. a clear, isotropic solution from the components. Linked to this, however, is the occurrence of several phases. In the case of high surfactant concentrations, the liquid-crystalline phases are particularly disturbing. Examples of the use of such microemulsions can be found in bath oils and partly in the wax washes of the car washes. When diluting with water, the "middle phase" or the "neat phase" of the coherent microemulsion moves into the area of the oil in water emulsion. The stable microemulsion breaks down into an emulsion.

The object of the invention is to formulate water-soluble preparations, active ingredients, dyes, etc. in microemulsions in such a way that dilution is possible without loss of stability and sufficiently high active ingredient concentrations are achieved. This object is achieved by active ingredient preparations consisting of a non-lipid surfactant, a solvent that is partially miscible with water and an active ingredient that can be used in veterinary and / or human medicine.

Active ingredient preparations are preferred which are composed of 20-90% by weight of a non-lipoid surfactant, 10-80% by weight of a partially water-miscible solvent and 1-10% by weight of a solvent which can be used in veterinary and / or human medicine Active ingredient.

Particularly preferred active ingredient preparations are those which consist of 50-75% by weight of a non-lipoid surfactant, 35-50% by weight of a partially water-miscible solvent and 1-5% by weight of a solvent used in veterinary and / or human medicine usable active ingredient exist.

Criteria for the solvent that is partially miscible with water, which are also referred to as oils or carrier oils, are, in addition to pharmacological safety, preferably a water solubility of 3 to 19%, a boiling point of> 70 ° C, in particular> 80 ° C, a molecular weight of < 300, in particular <250 and that they represent a solvent for the active ingredient (dye, preparation, etc.).

The essential criteria for the surfactant used in the active ingredient preparation are listed below.

As a binary system, the toxicologically harmless surfactant must not form solid, liquid-crystalline phases with water.

The surfactant preferably contains 10 EO groups and its lipophilic radical consists of more than 6 carbon atoms.

However, surfactants which form a miscibility gap with the carrier oil are not necessarily preferred.

Surfactants are surface-active substances whose molecules consist of a hydrophilic and an oleophilic part. In the table only exemplary nonionic surfactants are given, which illustrate the whole range of the compounds in question. From diethylene glycol butyl ether to hexyl glycol hexyl ether to decaglycol oleate, the differences in the efficiency of the surfactants are small.

Tween 80® is a pharmaceutically approved surfactant and Triton (G-110) ® is a non-toxic sugar surfactant.

Tween surfactants (Tween 20®, Tween 40®, Tween 60® and Tween 80®) surprisingly enable the production of dilutable microemulsions without the occurrence of liquid-crystalline phases. Polar oils especially for pharmaceutical use, the molecular weight of which is below 300, are for example

Benzyl alcohol, phenylethanol, phenylpropanol, phenoxyethanol, 1-phenoxy-2-propanol, triacetin, dibutyrin, glycerine ethers with C [deep] 4-C [deep] 8 ethers, glycerine esters made from glycerine and C [deep] 4-C [deep ] 8-carboxylic acids, oxyethylated salicylic acid esters, long-chain substituted N-alkylpyrrolidones, nonylphenol diethylene glycol ethers, nonylphenol tetraethylene glycol ethers, diethylene glycol phenyl ethers, benzoic acid glycol esters, benzoic acid propylene glycol esters, benzoic acid propylene glycol esters, and benzoic acid diethylene glycol groups [1 to 4] carboxylic acid diethylene glycol esters [1 to 4] carboxylic acid diethylene glycol esters [1 to 4] carboxylic acid groups [1 to 4] carbonate deeply 8 to 4-carboxylic acid diethylene glycol esters [1 to 4] carbonate glycol esters [1 to 4] carbonate [1] to 4-carboxylates of carbonate [1] to 4] carboxylic acid groups .

For a more detailed determination, the following information is given for the surfactants which can be used according to the invention:

Brij 97® decaoxyethylene oleyl ether

CH [deep] 3 (CH [deep] 2) [deep] 7CH = CH (CH [deep] 2) [deep] 8 (O-C [deep] 2H [deep] 4) [deep] 10-OH

C [low] 6EO [low] 6 hexaoxyethylene glycol hexyl ether

CH [deep] 3- (CH [deep] 2) [deep] 5- (O-C [deep] 2H [deep] 4) [deep] 6-OH

C [low] 4EO [low] 2 diethylene glycol butyl ether

CH [deep] 3- (CH [deep] 2) [deep] 3- (O-C [deep] 2H [deep] 4) [deep] 2-OH

Tween 20® polyoxyethylene sorbitan monolaurate

Tween 40® polyoxyethylene sorbitan monopalmitate

Tween 60® polyoxyethylene sorbitan monostearate

Tween 80® polyoxyethylene sorbitan monooleate

Triton (G-10® glucose octyl ether

X = 1 to 5, R is a mixture of 50% C [deep] 8 and 50% C [deep] 10 n-alkyl chains.

The invention also relates to a method by which water-soluble preparations are formulated by spontaneous emulsification using a carrier oil. What is new is the possibility of diluting the microemulsion without the active substance precipitating or the microemulsion breaking down to form a macroemulsion. A higher concentration is obtained than in micelles and a better distribution than in liposomes. In conjunction with suitable surfactants, carrier oil surfactant or carrier oil surfactant water concentrates can be formulated in such a way that dilution with water or physiological saline solution is possible without the occurrence of liquid-crystalline phases.

The isotropic microemulsions are temperature-stable from 5 ° C to the cloud point of the surfactant and offer advantages compared to the state-of-the-art formulation methods for:

Sublingual, intravenous and subcutaneous application of active ingredients. Such microemulsions can also be formulated in aqueous solutions of polymers (gelatin, polyvinyl alcohol, acrylamide). After drying, solid plates with dissolved active ingredient can be obtained which are again water-soluble.

Table 1

Examples

4,4'-dinitrodiphenyl sulfide

Concentrate: 40% (Brij 97® + isopropanol)

60% 2-butanone

Active ingredient content: 1.2%

1-aminopyrene

Camphene

Dye Sudan IV

Liquid crystals

Cholesterol acetate

Cholesterol oleyl carbonate

Pharmaceuticals

Since the Tween® surfactants used differ only in the chain length, the Tween® 80 is specified in the examples. It is the most effective of the Tween® surfactants. The data for the Triton® CG-10 refer to the pure substance.

Nimodipine

Febantel

Claims (10)

1. Active ingredient preparation consisting of a non-lipoid surfactant, a partially water-miscible solvent and an active ingredient that can be used in veterinary and / or human medicine. 2. Active ingredient preparation according to claim 1, characterized in that it consists of 20-90% by weight of a non-lipoid surfactant, 10-80% by weight of a partially water-miscible solvent and 1-10% by weight of one in the Animal and / or human medicine usable active ingredient consists. 3. Active ingredient preparation according to claim 1, characterized in that the particle sizes are in the range of 6-25 nm. 4. Active ingredient preparation according to claim 1, characterized in that it consists of 50-75% by weight of a non-lipoid surfactant, 35-50% by weight of a partially water-miscible solvent and 1-5% by weight of one in the Animal and / or human medicine usable active ingredient consists. 5. Active ingredient preparation according to claim 1, characterized in that it contains a Tween® surfactant as the surfactant. 6. Active ingredient preparation according to claim 1, characterized in that it contains Brij 97® as the surfactant. 7. Active ingredient preparation according to claim 1, characterized in that it contains phenoxyethanol as a partially water-miscible solvent. 8. Active ingredient preparation according to claim 1, characterized in that it contains a solvent from the group of butyl acetate, 2-butanone, aniline, benzyl alcohol, phenylethanol and triacetin as a partially water-miscible solvent. 9. Process for the preparation of active ingredient preparations, characterized in that a water-insoluble active ingredient which can be used in animal and / or human medicine is spontaneously emulsified in the presence of a non-lipoid surfactant and a solvent which is partially miscible with water (carrier oil). 10. Use of active ingredient preparations according to claim 1, characterized in that the active ingredient preparations, if appropriate after dilution with water or physiological saline solution, are administered sublingually, intravenously or subcutaneously to the human or animal body.