The invention relates to novel, transdermally applicable pharmaceutical preparations including sterolines or spiroketalines, a solvent selected from the group consisting of ethoxylated sterols and C12-C30 alcohols, and lipophilic ointment base. Methods of treatment using same.

FIELD OF THE INVENTION 
The invention relates to novel, transdermally applicable pharmaceutical 
preparations having a steroline and/or spiroketaline content. 
BACKGROUND OF THE INVENTION 
The glycosides of phytosterols, including cholesterol, are called 
sterolines. Phytosterols and their glycosides occur in nature in small 
amounts in all plants and often in microorganisms. It is possible to 
produce sterolines synthetically in relatively large yields by means of 
the known Konigs-Knorr synthesis with the use of the corresponding 
aglycones and a sugar acetate bromided at the C-1 position with the use of 
silver or cadmium catalysts. In nature, sterolines mostly occur in the 
form of monoglycosides, although some oligoglycosides are known. 
Additionally, sterolines occur in natural vegetable matter, partially also 
in the form of esters, namely in monobasic monocarboxylic acids. 
Mono- to triglycosides, derived from steroid saponine alcohols, which have 
a spiroketaline grouping connected in the C-16 and C-17 position of the 
steroid shell of aglycone, are called spiroketalines. The aglycones can be 
classified either as 5-En-steroid sapogenines or as 5-.alpha.-steroid 
sapogenines. In natural saponine material the aglycones are mainly present 
as glycosides and contain 3 or possibly more coupled monosaccharide units 
and can be hydrolytically decomposed to spiroketalines by means of 
enzymes. Synthesis of spiroketalines by the Konigs-Knorr method is also 
possible with good yields. It has been known for a long time that both 
sterolines as well as spiroketalines exhibit a multitude of 
pharmacological activities because they interact at the 
prostaglandinesynthetase level, as known from British Patent 2 039 217, as 
well as at the lipoxygenase level, as known from German Published, 
Non-examined Application DE-OS 34 16 112, for example. Thus sterolines and 
spiroketalines can be used not only for the treatment of inflammatory 
conditions, but also wherever it is necessary to normalize the arachidonic 
acid balance, for example with asthma, acne, psoriasis, abdominal 
rheumatism, gastric and intestinal ulcers, and thrombophlebitis. 
Up to now, in the use of sterolines in particular, it has been shown that 
excellent results in the course of in vitro testing could not be 
reproduced in vivo. In J. Pharm Sci., 1985, 74, pp 1259, J. Seki et al 
have noted an intestinal absorption of sitosterol glycoside of only 1 to 
2%. This often occurs because the extremely poor water solubility of the 
sterolines and the poor water solubility of spiroketalines makes it 
impossible to achieve sufficient resorption and thus blood levels. For 
this reason there has been a previous attempt to improve resorption, for 
example by reducing the particle size, by using more highly water-soluble 
derivatives such as hemiesters, or by using solubilizers, such as recited, 
for example, in U.S. Pat. No. 3,966,918. Tests using substances marked 
with .sup.14 C, however, clearly show that resorption can only be slightly 
improved by use of a micronizer or other reduction of the particle size, 
and that this is also true when an attempt is made to increase the amount 
of the compounds in the aqueous solution by using solubilizers. 
Thus there is still a need for pharmaceutical preparations containing 
sterolines and/or spiroketalines and having better resorptivity. 
SUMMARY OF THE INVENTION 
In accordance with the invention, pharmaceutical preparations which are 
administered transdermally are provided, which have a content of 
sterolines and/or spiroketalines with ethylene oxide addition compounds 
having approximately 20 to 30 ethylene oxide units of sterols or alcohols. 
In a completely surprising way, it is possible to dissolve the sterolines 
and spiroketalines, which are hard to dissolve not only in water, but as a 
rule also in lipophilic solvents, in an oil phase with the id of 
solubilizers and even if they are in the form of emulsions, to bring them 
to resorption transdermally, and this at a far higher resorption than has 
ever been possible orally or intravascularly. 
In accordance with the invention, the active ingredients are mixed together 
with ethoxylated sterols or C12-C30 alcohols, which had been reacted with 
ethylene oxide, and were dissolved in multivalent alcohols, such as 
1,2-propanediol or glycerine, with slight heating. All ethoxylated sterols 
or C12-C30 alcohols can be used as solubilizers and carriers, either in 
mixture or as mono compounds. These compounds which can be easily 
manufactured by reacting the free alcohols with ethylene oxide, are 
partially already known as solubilizers and commercially available as for 
example the products sold by Henkel KGaA under the name "Generol-E". They 
are mostly sitosterol or sterol mixtures with a degree of ethoxylatation 
between 20 to 30. Preferably an ethoxylated sitosterol with a chain length 
of 25 EO units is used. It is possible to use fatty alcohols, in 
particular, as alcohols with approximately 12 to 30 C atoms, but of course 
also naturally occurring branched, alicyclic or aromatic alcohols such as 
squalene or phytol derivates, for example, are usable. 
The solutions of sterolines or spiroketalines in solubilizers and 
multivalent alcohols in turn dissolve clearly in oil or melted fat. The 
customary ointment bases are mainly used for this such as, for example, 
central chain triglycerides, glycerol monostearate, lanolin, lard, etc. It 
has also been shown in a completely surprising manner that it is possible, 
after working the active ingredients into the fatty bases, to continue by 
making the latter into emulsion ointments, because the mixture can be 
readily emulsified with an equal amount of water. Regardless of whether 
the active ingredients are present in a water-free or aqueous fat base, 
tests with .sup.14 C marked active ingredients have shown that penetration 
into the skin and permeation follow at approximately the same amounts. Not 
only do the active ingredients penetrate the skin, they even permeate 
through the skin so that, with an application over a large area, it is 
possible to attain plasma levels to a degree not possible via the 
intestinal route. Surprisingly, in spite of the different chemical 
structure of sterolines and spiroketalines there is hardly any difference 
in respect to the transdermal resorption. As shown by the .sup.14 C tests, 
twenty-four hours after application approximately 10% of the active 
ingredients have permeated through the skin and approximately 6% have 
penetrated into the skin. 
The average composition for transdermal application is approximately 0.1% 
active ingredients, 1% ethylene oxide addition compounds and 10% 
multivalent alcohol. After dissolving, the clear solution is either mixed 
with a corresponding amount of waterless ointment base or, in a manner 
known per se, is mixed with approximately one half of the amount of 
ointment base with the addition of the customary amount of non-iogenic 
emulsifying agents as well as water and is emulsified in the customary way 
with the remaining amount under stirring. 
During clinical tests it has been possible to obtain particularly fast and 
persuasive results with the pharmaceutical preparations according to the 
invention in connection with those diseases, where an elevated leucotriene 
level is the basis or at least a mediator of the pathological event such 
as, for example, with allergies, eczemas, chronic itching, certain types 
of psoriasis, acne, but also with rheumatoid diseases and thrombophlebitis 
.

The invention is described in detail below by means of the examples. 
DETAILED DESCRIPTION 
Example 1 
0.1 g cholesterol glycoside, 80.0 g ethoxylated palmytilstearyl alcohol 
were dissolved in 100.0 g 1,2-propanediol. This solution, heated to 
70.degree. C., was added to a melt of 120.0 g adeps solidus, 100.0 g of 
central chain triglyceride and 120 g glycerine monostearate at a 
temperature of 70.degree. C. and was emulsified with water, also heated to 
the temperature indicated above, into a total amount of 1,000.0 g. Then 
the emulsion was stirred until cool. 
Example 2 
1.0 g diosgenin glycoside was dissolved in a mixture of 10.0 g ethoxylated 
soybean sterol (25 EO units) and 100.0 g 1,2-propanediol. This solution, 
heated to 70.degree. C. was then added to a melt, also heated to 
70.degree. C., of 100.0 g cetyl palmitate, 250.0 g stearyl heptanoate, 
100.0 g sorbitan monostearate and 60.0 g polyethylene sorbitan 
monostearate and was emulsified with water, also heated to 70.degree. C., 
to a total amount of 1,000.0 g. The emulsion was then stirred until cool 
in a manner known per se. 
Example 3 
1.0 g sitosterol glycoside was dissolved in 10.0 g ethoxylated soybean 
sterol (25 EO units) and 100.0 g 1,2-propanediol and was added at the 
temperatures indicated to a melt of 300.0 g hydrated coconut oil, 50.0 g 
central chain triglycerides, 120.0 g glycerine monostearate and 80.0 g 
ethoxylated cetyl stearyl alcohol (25 EO units). An emulsion was made with 
water heated to 70.degree. C. to a total amount of 1,000.0 g. The emulsion 
was then stirred until cool as usual. 
Example 4 
1.0 g sitosterol glycoside was dissolved in 10.0 g ethoxylated soybean 
sterol (25 EO units) and 100.0 g 1,2-propanediol and was added at the 
temperatures indicated to a melt of 300.0 g hydrated coconut oil, 50.0 g 
central chain triglycerides, 20.0 g glycerine monostearate and 80.0 g 
ethoxylated cetyl stearyl alcohol (25 EO units). An emulsion was made with 
water heated to 70.degree. C. to a total amount of 1,000.0 g. The emulsion 
was then stirred until cool as usual. 
Example 5 
Penetration or Permeation Measurements 
Male rabbits, about 10 weeks old and weighing approximately 2 kg, were used 
as test animals. On a shaved area of 10.times.5 cm on the back of the 
rabbit 1.0 g ointment having a radioactivity of 20 .mu. Ci of the 
respective (.sup.14 C-4) marked glycoside was applied, covered with 
aluminum foil and fixed with a waterproof bandage. After 24 hours the 
rabbits were put to sleep and the application area was repeatedly washed 
with ethanol moistened swabs. The radioactivity of the occlusive dressing 
and the swabs was measured after extraction with ethanol. The skin of the 
application area was treated for 24 hours with 2 m lye/methanol/triton X 
405 (6:3:1 v/v) at 55.degree. C. and was then washed with ethanol at 
40.degree. C. The radioactivity, measured with a liquid scintillation 
counter (Philips PW 4700), is a measurement for the percentage of 
penetration of the applied amount of the substance. Permeation during 24 
hours is calculated as follows: 100%--(activity of the washing 
liquid+activity of the penetration amount)=% permeation. Under the test 
condition cited, the result for cholesterol glycoside was a penetration of 
4.9% of the applied dosage and a permeation of 7.8% of the applied dosage. 
The results for diosgenin glycoside were 5.2 and 10.3% and for sitosterol 
glycoside the results were 6.2 and 10.6%.