This invention relates to medicament preparations which contain 
2-(2-hydroxy-ethoxy)-ethyl 
N-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-anthranilate and dimethyl 
sulphoxide, a process for their preparation, and their use 
2-(2-Hydroxy-ethoxy)-ethyl 
N-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-anthranilate, named 
etofenamate according to INN, is a known active ingredient which has an 
antiinflammatory and antiphlogistic action and is used particularly in the 
form of gels (Arzneimittelforschung 27 (I), Special Edition 6b, 1299 to 
1364 (1977)). 
It is likewise known that dimethyl sulphoxide (DMSO) is capable of dragging 
medicaments dissolved in it through the skin into the bloodstream in a 
very short time (P. H. List, Arzneiformenlehre, 301, 4th edition, 1985). 
However, a prediction of whether an auxiliary such as DMSO is suitable as a 
"schlepper" for medicaments is not possible and depends on the properties 
of the active ingredient (Drug Metabolism Reviews 14 (2), 220 (1983)). For 
example, with ibuprofen ointment (Muktadir, A. et al., Drug Dev.Ind. 
Pharm. 12 (1986) 2521-40) and solutions of methotrexat (McCullough, JL., 
J. Invest. Dermatol. 66 (1976), 103-107), kanamycin (Zverev, VM., 
Antibiotiki 26, (1981) 102-4) and gentanycin (Rubinstein, E., Experientia 
36 (1980), 92-93) DMSO did not enhance or diminish the absorption of the 
drug. 
A recognized test for determining the activity of antiphlogistics and 
antiinflammatories is the test on inflammation models (kaolin or 
carrageenan edema) in rat paws (Jakobi et al, Drug Res. 27, 1326 ff. 
(1977)), in which the action of the active ingredients is determined. 
Investigations have shown that medicament preparations of etofenamate and 
DMSO do not exhibit an increase in the action within the scope of the 
tests on rat paws. 
The negative finding is confirmed in studies on other commercially 
available vehicles, for example laurocapran (Azone.RTM.) in humans and 
animals. For example, in a cross over trial on 6 human volunteers with 
Rheumon gel vs. Rheumon gel with 1% Azone no significant enhancement of 
etofenamate absorption was found. 
However, it has surprisingly been found that the absorption of etofenamate 
from medicaments containing etofenamate and DMSO is considerably increased 
in humans. 
The invention relates to medicament preparations which contain etofenamate 
and dimethyl sulphoxide. 
In the medicament preparations according to the invention, etofenamate and 
DMSO support themselves through a significant increase in absorption and 
more rapid absorption. 
The medicament preparations according to the invention contain etofenamate 
and DMSO in the weight ratio 1:15 to 1:1, preferably 1:1.7 to 1:5. 
The medicament preparations according to the invention can be applied in 
various forms. Topical applications, such as gels, creams, ointments, 
lotions, sprays and solutions, are preferred. In particular, gels and 
creams are preferred. 
Gel-like medicament preparations according to the invention generally 
contain, in addition to etofenamate and DMSO, gel formers, such as 
adjuvants, bodying agents and additives which are known per se. 
Adjuvants for the gel-like medicament preparations according to the 
invention may preferably be esters of monohydric and/or polyhydric 
alcohols of chain length C.sub.2 to C.sub.18 containing carboxylic acid 
components of chain length C.sub.6 to C.sub.18. 
In this case, alcohol and carboxylic acid components are generally 
straight-chain or branched hydrocarbon radicals. 
Alcohol components which may be mentioned are, in particular, monohydric 
alcohols having 2 to 6 carbon atoms and dihydric and polyhydric alcohols 
having 2 or 3 carbon atoms. 
Carboxylic acid components which may be mentioned are carboxylic acids 
having a chain length of 12 to 16 carbon atoms. 
Esters which may be mentioned as examples are: propylene glycol diesters, 
ethyl oleate, isopropyl myristate, isopropyl stearate, isopropyl 
palmitate, diisopropyladipate, diethyl sebacate, oleyl oleate, hexyl 
laurate and isooctyl stearate. In particular, diisopropyl adipate and 
isopropyl myristate are preferred. 
Adjuvants for the medicament preparations according to the invention may, 
in addition, preferably be higher alcohols having 10 to 24 carbon atoms. 
The hydrocarbon radical may be straight-chain or branched. In particular, 
higher alcohols having 12 to 18 carbon atoms are preferred. 
Higher alcohols which may be mentioned as examples are oleyl alcohol and 
2-octyl-dodecanol. In particular, 2-octyl-dodecanol is preferred. 
Medicament preparations may contain one or more, preferably 1 to 3, 
adjuvants. 
Bodying agents which may be mentioned as examples are: highly disperse 
silica, for example Aerosil, hydrogel formers such as Veegum, polyglycols, 
such as polyethylene glycol and polypropylene glycol, pharmaceutically 
usable cellulose derivatives, such as methylcellulose, 
hydroxyethylcellulose and carboxymethylcellulose, carboxyvinyl polymers 
such as Carbopol.RTM. (DE-A No. 2,641,210), alginic acid derivatives, such 
as salts of alginic acid and gum arabic. 
Additives which may be mentioned are additives which promote blood flow or 
warming and scents. 
Additives which promote blood flow or have a warming effect can be, for 
example, benzyl nicotinate, salicylic acid esters such as methyl 
salicylate, etherial oils, capsaicin, capsicum extract and 
N-vanillylnonanamide. 
Scents which can be employed are the conventional pharmacologically 
acceptable substances, as long as they are compatible with the active 
ingredients and the adjuvants. 
In addition, the gel-like medicament preparations according to the 
invention contain water and, if appropriate, lower alcohols 
(straight-chain or branched or aromatically substituted having 2 to 10 
carbon atoms). Isopropanol, benzyl alcohol and ethanol are preferred. 
Particularly preferred gel-like medicament preparations according to the 
invention generally contain 
2 to 30, preferably 4 to 12, parts by weight of etofenamate, 
10 to 30, preferably 15 to 20, parts by weight of DMSO, 
5 to 80, preferably 10 to 40, parts by weight of adjuvants, 
0.1 to 10, preferably 0.5 to 5, parts by weight of bodying agents, 
0.5 to 5, preferably 1 to 3.5, parts by weight of additives, 
15 to 80, preferably 20 to 40, parts by weight of water and 
0 to 40, preferably 20 to 35, parts by weight of lower alcohols. 
The gel-like medicament preparations according to the invention can be 
prepared as follows: etofenamate, DMSO, the adjuvants and the additives 
are dissolved in an alcohol, for example ethyl or isopropyl alcohol. The 
bodying agent is subsequently stirred into the solution. Gel formation is 
caused by neutralization by a basic substance (for example sodium 
hydroxide solution). 
Particularly preferred cream-like medicament preparations according to the 
invention generally contain 
20 to 30, preferably 5 to 15, parts by weight of etofenamate, 
5 to 30, preferably 10 to 20, parts by weight of DMSO, 
5 to 50, preferably 15 to 30, parts by weight of adjuvants, 
0 to 20, preferably 1 to 8, parts by weight of bodying agents, 
0 to 20, preferably 1 to 5, parts by weight of emulsifiers, 
0.5 to 5, preferably 1 to 3.5, parts by weight of additives, 
30 to 60, preferably 35 to 50, parts by weight of water and 
1 to 5, preferably 1.5 to 3, parts by weight of lower alcohols. 
Cream-like medicament preparations according to the invention generally 
contain, besides etofenamate and DMSO, cream formers, adjuvants and, if 
appropriate, bodying agents and/or emulsifiers and additives, such as 
substances which promote blood flow or have a warming effect, and also 
auxiliaries such as, for example, pleasantly smelling substances. 
Adjuvants, bodying agents and additives can generally contain the same 
substances as the gels. 
The emulsifiers which can be employed are one or more from the group 
comprising the ionogenic or nonionogenic water-in-oil and oil-in-water 
emulsifiers. 
Emulsifiers which are preferably employed are salts of higher fatty acids 
and bile acids, such as triethanolamine stearate, alkyl sulphates, such as 
Na lauryl sulphate, alkyl sulphonates, such as N-cetyl sulphonate, higher 
fatty alcohols, such as cetyl alcohol, lauryl alcohol and stearyl alcohol, 
sterine alcohols, such as cholesterol, fatty acid esters of polyhydric 
alcohols and polyols, such as ethylene monostearate, glycerol monooleate, 
sorbitan monolaurate, sorbitan trioleate, polyoxyethylene (20) sorbitan 
monolaurate, polyoxyethylene sorbitan hexaoleate, fatty alcohol ethers, 
such as polyoxyethylene lauryl ether and polyoxyethylene oleyl ether, 
fatty acid esters of saccharose, such as saccharose distearate, lecithin 
and derivatives, betaines and sulphobetaines, such as fatty acid 
amidoalkyl betaine and/or polyoxyethylene polyoxypropylene polymers such 
as Pluronics.RTM.. 
The cream preparations according to the invention are prepared by mixing 
etofenamate and DMSO with the other, optionally molten fat/wax emulsifier 
components, emulsifying the mixture with the aqueous phase of the 
preparation and subsequently subjecting the mixture to homogenization, for 
example using a rotor-stator device. 
The homogenization temperature depends on the composition of the 
preparation and is generally in the range from about 35.degree. and about 
60.degree. C. 
Compared to conventional etofenamate preparations, the medicament 
preparations according to the invention have a considerable increase in 
action. They are therefore preferably used as analgesics and 
antiphlogistics.

EXAMPLE 1 
In a randomized crossover experiment on 12 test subjects, significant 
differences were found with respect to absorption of etofenamate from 
cutaneously applicable etofenamate preparations, with and without DMSO. 
Both applications were carried out with the same active ingredient 
concentrations and application rates. The determination of the active 
ingredient level in human plasma was carried out by means of HPTLC [B. 
Beckermann et al., "Proc. 3rd Internat. Symposium on Instrumental High 
Performance Thin-Layer Chromatography" Wurzburg/FRG 1985, published by 
Institute for Chromatography, D-6702 Bad Durkheim/FRG, 15-24 (1985)]. 
The following differences were found between the two preparations: 
time for maximum plasma level t.sub.max after DMSO-Etofenamate Gel (DEG) 
compared to Etofenamate Gel (EG) significantly shorter: 4.2 instead of 19 
hours (p&lt;0.001) 
maximum plasma level concentration c.sub.max after DEG twice as high as 
after EG (p &lt;0.001) 
renal elimination after DEG in the first 12 and 24 hours post application 
significantly faster than after EG 
total absorption, measured from the area under the concentration time curve 
and from renal elimination, significantly greater after DEG than after EG 
(in each case p&lt;0.001) (paired t test, L. Sachs, Angewandte Statistik 
[Applied Statistics], pages 242-243 to (1984), Springer Verlag Berlin, 6th 
edition). 
EXAMPLE 2 
The absorption profile of DMSO-containing etofenamate preparations differs 
from that of DMSO-free preparations. It was possible to show that rapid 
cutaneous absorption of etofenamate in the presence of DMSO has a 
substantially identical time profile, for example rapid increase to peak 
plasma levels and decrease within one day to low values. In contrast to 
this, the DMSO metabolyte dimethyl sulphone (DMSO.sub.2) only reaches 
maximum levels after more than one day, with a subsequent slow decrease. 
The results on DMSO/DMSO.sub.2 kinetics correspond to the data in K. H. 
Kolb et al., Ann. N.Y. Acad. Sci. 141, 85-95 (1967), inter alia. 
In contrast, the substantially identical time profile of absorbed 
antiphlogistic (etofenamate) and DMSO is new. 
It proves that DMSO has a positive vehicle function for etofenamate. 
EXAMPLE 3 
(comparison) 
In the analgesia test in accordance with Randall-Selitto [L. D. Randall and 
J. J. Selitto, Arch. int. Pharmacodyn. 111, 409-419 (1957)], the activity 
of commercially available etofenamate gel (5% strength) and etofenamate 
gel containing 20% of DMSO was investigated comparatively on male Wistar 
II rats. In the case of applications of 50 mg of gel/kg of body weight in 
each case, the DMSO-containing etofenamate proved to have an equally 
strong analgesic action as the DMSO-free preparation. 
This shows that no significant increase in etofenamate resorption or 
potentiation of the analgesic action by DMSO occurs in rats. 
______________________________________ 
Examples 4 to 9 (gels) 
1 2 3 4 5 
______________________________________ 
Etofenamate 5.0 5.0 5.0 5.0 5.0 
DMSO 20.0 20.0 20.0 20.0 20.0 
Diisopropyl adipate 
7.5 10.0 -- -- 5.0 
Isopropyl pyristate 
-- -- 5.0 7.5 -- 
Isopropanol 30.0 33.0 25.0 30.0 30.0 
Etherial oils 
0.2 0.2 0.2 0.2 0.2 
Water 26.25 26.75 29.75 23.85 30.75 
Fatty alcohol 
6.0 -- 6.0 6.0 -- 
polyglycol ether 
Propylethylene 
3.0 3.0 3.0 3.0 3.0 
glycol 400 
Propylene glycol 
-- -- 3.0 3.0 4.0 
Hydroxypropyl- 
-- -- 1.0 -- -- 
cellulose 
Carboxyvinyl polymer 
1.3 1.3 1.3 1.3 1.3 
Sodium hydroxide 
0.75 0.75 0.75 -- 0.75 
solution, 10% strength 
Ammonia solution, 
-- -- -- 0.15 -- 
28% strength 
100.0 100.0 100.0 100.0 100.0 
______________________________________ 
______________________________________ 
Examples 10 to 14 (cream) 
Example No. 10 11 12 13 14 
______________________________________ 
Etofenamate 5.0 5.0 5.0 5.0 5.0 
DMSO 10.0 10.0 20.0 20.0 20.0 
Glycerol monodistearate 
12.0 12.0 9.0 11.0 -- 
Glycerol monostearate 
-- -- -- -- -- 
Diisopropyl adipate 
13.0 13.0 16.0 -- -- 
Isopropyl lyristate 
-- -- -- 16.0 17.0 
Cetyl alcohol 3.4 3.4 3.4 1.4 3.4 
Myrj 59 5.0 5.0 5.0 5.0 5.0 
Trisodium citrate 
0.5 0.5 0.5 0.5 0.5 
dihydrate 
Sodium hydrogen 
0.4 0.4 0.4 0.4 0.4 
citrate 
Benzyl alcohol 
1.5 1.5 1.5 1.5 1.5 
Water 49.2 49.2 39.2 39.2 37.2 
100.0 100.0 100.0 
100.0 100.0 
______________________________________ 
It is understood that the specification and examples are illustrative but 
not limitative of the present invention and that other embodiments within 
the spirit and scope of the invention will suggest themselves to those 
skilled in the art.