Etofenamate preparation

0001The present invention relates to a topically applicable, anti-inflammatory and analgesic drug preparation which contains 2- (2-hydroxyethoxy) ethyl-N- (a, a, a-trifluoro-m-tolyl) anthranilate, hereinafter etofenamate, as the active ingredient. Etofenamate has the following structure:<chemistry id="chem0001" num="0001"><img file="EP0130516B1_D0001.tif" /></chemistry>

0002Etofenamate is already known as a non-steroidal drug with good anti-inflammatory effects and excellent tolerability, cf. Drug research 27 (1), special issue 6b, 1299―1364, 1977. - Etofenamate has so far been used in the form of alcohol-containing gels. Due to the alcohol, the gel has a cooling effect when applied, which is not perceived as pleasant by outside patients. Furthermore, such a gel can only be applied to intact skin, so a desirable application for traumas with open wounds is not necessary. Such a formulation is only of limited suitability for patients with extremely dry skin.

0003It is therefore an object of the present invention to overcome the disadvantages described by providing a new preparation which, however, has the same anti-inflammatory and analgesic effect as the gel form.

0004Surprisingly, it was possible to find a cream preparation that has the required properties.

0005The present invention therefore relates to a cream preparation containing 2-30% by weight of etofenamate and 5-80% by weight of isopropyl myristate as an adjuvant.

0006Etofenamate is a highly viscous oil that is only slightly soluble in water. In a large number of pharmaceutical auxiliaries there is only a poor solubility, interactions such as hydrolysis, transesterification, esterification etc. take place, segregation, phase separation etc. occurs. Some formulations with etofenamate have proven to be homogeneous and stable, but have insufficient absorption compared to the known etofenamate-containing gel. These disadvantages do not occur with the preparation according to the invention. In the preparation according to the invention, etofenamate is excellently absorbed by the skin.

0007In addition to etofenamate and adjuvant, the cream preparation according to the invention therefore optionally contains consistency agents and / or emulsifiers and further auxiliaries, such as additives which promote blood circulation or warm or smell pleasant.

0008Based on these etofenamate adjuvant mixtures or solutions, various creams of consistency can be produced in liquid to semi-solid form:<ul id="ul0001" list-style="none"><li>1. Oil in water emulsions</li><li>2nd Water in oil emulsions and</li><li>3rd Microemulsions.</li></ul>

0009According to the invention, it is necessary that the cream consisting of active ingredient and adjuvant contains about 2 to about 30% by weight of etofenamate as active ingredient and about 5 to about 80% by weight of isopropyl myristate as adjuvant. The cream preparation preferably contains 5-15% by weight etofenamate, particularly preferably 6-12% by weight

0010Furthermore, the cream preparation can also contain one or more consistency enhancers and / or one or more emulsifiers and / or warmth-promoting additives and / or other auxiliaries, such as, for example, substances with a pleasant smell and / or other active ingredients.

0011In many cases, consistency generators and emulsifiers are identical, so strict separation is not possible.

0012One or more from the group can be used as a consistency agent: fatty alcohols of chain length C,_O to C_3o, such as stearyl alcohol, hydrocarbons such as petroleum jelly, paraffins, hard paraffins, waxes such as bees or carnauba wax. In addition, mono-, di- and triglycerides such as glycerol monostearate, glycerol distearate, metal soap such as aluminum stearate, Aerosil, polyglycols such as polyethylene glycols, polypropylene glycols can also be used.

0013The consistency of the aqueous phase of water-containing cream preparations can be adjusted by hydrogel formers such as Veegum, cellulose derivatives (for example methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose), carboxy vinyl polymers, alginic acid derivatives, gum arabic, etc.

0014One or more from the group of ionogenic or nonionic water-in-oil and oil in water emulsifiers can be used as the emulsifier.

0015; Salts are preferred higher fatty acids and bile acids, such as triethanolamine stearate, alkyl sulfates such as sodium lauryl sulfate, alkyl sulfonates such as N-Cetylsulfonat, higher fatty alcohols such as cetyl alcohol, Laurylkalkohol and steryl alcohol, sterol such as cholesterol, fatty acid ester of polyhydric alcohols and polyols such as Ethylenmonostearrat, glycerol monooleate, sorbitan monolaurate, sorbitan trioleate, Polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene sorbitol hexaoleate, Fatty alcohol ethers such as polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, fatty acid esters of sucrose such as sucrose distearate, lecithin and derivatives, betaines and sulfobetaines such as fatty acid amidoalkyl betaine and / or polyoxyethylene polyoxypropylene polymers such as Pluronics.

0016Blood circulation-promoting or warming additives, for example, benzyl nicotinate, salicylic acid esters, for example methyl salicylate, essential oils, capsaicin, capsicum extract or nonyl acid vanillyllamide can be used.

0017The usual pharmacologically acceptable substances can be used as odorants, provided that they are compatible with the active ingredient and adjuvant.

0018In addition to etofenamate and isopropyl myristate as adjuvant, the amount of the consistency adjuster and / or emulsifier in the cream preparation is up to about 70% by weight, preferably 5-25% by weight.

0019The cream preparation also contains water up to 85% by weight, preferably 40-60% by weight.

0020Cream preparations containing 2-30% by weight etofenamate, 5-80% by weight isopropyl myristate as adjuvant and 40-60% by weight water are particularly preferred.

0021The preparations, the composition of which can be seen from the examples, are also particularly preferred.

0022According to the invention, the anti-inflammatory, analgesic cream preparations are prepared by mixing the etofenamate dissolved in a suitable solvent with isopropyl myristate and possibly other melted fat / wax emulsifier constituents and then the aqueous phase brought to about the same temperature, which preservatives, buffers , etc. contains, is added with intensive mixing of the ingredients. Homogenization then takes place, for example by means of a rotor-stator device.

0023The homogenization temperature depends on the particular preparation and is generally between approx. 40 ° C and approx. 60 ° C.

0024The active ingredient is contained in a stable form in the cream preparation of etofenamate according to the invention and is able to penetrate the skin without the traction function of, for example, isopropanol. Comparative studies on etofenamate gel result in bioequivalent absorption, which could be demonstrated by approximately the same absorption rate, time of maximum plasma level, maximum plasma level concentration, elimination from the plasma, the area under the plasma play curves (AUC) and renal elimination in humans.

0025The equivalence of the absorption also results from clinical trials in which the effectiveness in the double-blind cross-over test against ointment containing 1- (p-chlorobenzoyl) -5-methoxy-2-methylindole-3-acetic acid and against salicylate-containing ointments was compared and where the cream preparation according to the invention, for example with Lumbago in terms of distance to Schober, spontaneous, movement and pressure pain compared to the first comparator had a significantly better effect (p &lt;0.05) and, for example, in acute gonathrosis with the target variables joint mobility, joint circumference, spontaneous and movement pain compared to the second comparator proved significantly more effective.

0026The present invention is further illustrated by the following examples.<tables id="tabl0001" num="0001"><img file="EP0130516B1_D0002.tif" /></tables><tables id="tabl0002" num="0002"><img file="EP0130516B1_D0003.tif" /></tables>