Stable valepotriate compounds and process for their preparation

Stable valepotriate compositions are produced by a process wherein impurities are removed from the pharmaceutically active extract of the valerianacea fruits, followed by a mixing with pharmaceutically acceptable sheathing materials and the formation of microspheres therefrom.

BACKGROUND OF THE INVENTION 
The invention relates to stable valepotriate preparations and process for 
their production. 
Valepotriates designate a group of therapeutically valuable substances 
which may be obtained from the roots and rhizomes of various valerianacea 
and kentranthus species. The most important representatives of the 
valepotriates are valtratum, isovaltratum, didrovaltratum and 
acevaltratum. They may be extracted from the dried drug in amounts of up 
to approximately 5%. The proportions of the individual valepotriates with 
respect to each other vary in accordance with the origin of the substance. 
For example, didrovaltratum predominates in valepotriates of Asian origin 
and valtratum and isovaltratum predominates in valepotriates of European 
or Mexican origin. Acevaltratum, on the other hand, is always present in 
less significant proportions. 
Valepotriates are extremely sensitive substances and are rapidly decomposed 
by the effects of heat, light and chemial agents, and even of moisture 
though they are practically insoluble in water. Valepotriates cannot be, 
therefore, maintained in the stable condition under normal storage 
conditions for an adequate period of time, either in the drug form or in 
the isolated form. 
Because of these difficulties, there have been attempts to prepare 
valepotriates in a form that would remain stable over a longer period of 
time. 
One such attempt, West German Published application No. 22 30 626, 
describes a valerian product produced by means of the dissolution of a 
valerianacea extract in a multivalent alcohol, a fatty oil or an ethereal 
oil or mixtures thereof. This product purportedly exhibits no appreciable 
decomposition phenomena after storage for five months at room temperature. 
In storage at temperatures below 10.degree. C., the solution described is 
claimed to remain stable for at least 12 months. Without an indication of 
the details of its effects on the stability, microencapsulation of the 
above-described solution is also mentioned. The stability of 5 to 12 
months observed therein does not represent an adequate period of time for 
finished medicinal forms. Investigations extending over longer periods of 
time reveal the onset of decomposition phenomena even in preparations of 
this type. 
A further attempt to stabilize valerian extracts is found in West German 
Offenlegungsschrift No. 26 54 709 wherein preparations dehydrated to a 
residual water content of less than 0.5% is described. This proposal 
requires additional, in part extreme measures, such as for example working 
under nitrogen. Observations up to about 6 months demonstrate that 
preparations of this type attain only moderate stability. 
SUMMARY OF THE INVENTION 
It is, therefore, an object of the invention to provide valepotriate 
preparations which are stable over periods of time considered desirable 
for pharmaceutical preparations. At the same time, the valepotriate 
preparations of this invention avoid the disadvantages inherent in the 
state of the art. 
These objects and advantages are achieved by a process for the preparation 
of stable valepotriate compositions comprising removing non-specific 
impurities from a pharmaceutically active valerianacea extract to produce 
a purified valepotriate fraction, mixing the purified valepotriate 
fraction with an aqueous solution of a material capable of producing a 
pharmaceutically acceptable sheathing for a pharmaceutically active 
material, and forming microspheres from the mixture of purified 
valepotriate fraction and sheathing material. In the final valepotriate 
composition the microspheric form is stable for prolonged periods of time 
and contains from about 2% to about 40% by weight of a pharmaceutically 
active ingredient. 
The invention attains this object by forming of microspheric encapsulation 
of water soluble, physiologically indifferent and pharmaceutically 
acceptable sheathing materials and valerianacea extracts freed essentially 
from undesirable accompanying substances. 
These preparations surprisingly exhibit no decline in stability over 
periods of observation. Even for periods of one to three years, the 
preparations remain surprisingly stable without any extreme precautionary 
measures being observed. The preparations have a water content of 
approximately 3% (as determined by the method of Karl Fischer) and are 
present in the form of a pourable powder of microcapsules. The 
microencapsulated valepotriate preparations according to the invention 
transform the liquid or semisolid active ingredient into a dry powder, 
readily processable technically to the various galenic forms. The 
processing also coats the highly odor-sensitive valepotriates. It is not 
necessary to store them with cooling, as is required for the pure 
valepotriates or the known solutions. 
It has been discovered, however that it is extremely important that the 
extract used be essentially free of non-specific accompanying substances 
to provide the improved stability. This is accomplished by extracting the 
powdered drugs with low boiling lipophilic solvents at temperatures less 
than approximately 30.degree. C. and removing the solvent under vacuum 
again at temperatures less than approximately 30.degree. C. It is of 
advantage in the extraction to maintain a weakly acidic pH to the extent 
that the extraction mixture does not by itself display the abovementioned 
pH value as the result of acidic accompanying substances. The pH may then 
be adjusted by means of the addition of acidic substances. The raw extract 
obtained in this manner is dissolved in 90% acetic acid. The non-specific 
accompanying substances are subsequently extracted from the mixture of the 
raw extract and acetic acid, with gasoline or a similar solvent immiscible 
with water. The valepotriates are then concentrated out from the residual 
acetic acid phase after dilution with water to a volume of 1.5 to 2 times 
with low boiling lipophilic solvents immiscible with water. Following the 
removal of the solvent under vacuum, the valepotriates are obtained, 
depending on the origin of the drug, in the form of oily to semisolid, 
lardaceous masses resembling in appearance partially crystallized honey 
with their own odor, free of the specific odor of isovalerianic acid. This 
mass will be designated hereinafter as the "purified" or "genuine 
valepotriate fraction". It contains roughly 80% by weight valepotriate. A 
more detailed description of preferred procedures employed in obtaining 
the purified valepotriate fraction is found in U.S. Pat. Nos. 3,422,090 
and 3,869,476. The descriptive portions of these patents are incorporated 
herein by reference. 
The sheathing materials, aside from the fact that they must be soluble in 
water and physiologically neutral, are not required to satisfy any special 
conditions. The substances that may be considered are those customarily 
used for the microencapsulation of medications, preferably gum arabic, 
methylcellulose or mixed polymers of polyvinyl pyrrolidone and polyvinyl 
acetate. 
In the production of the preparations according to the invention, the 
sheathing material, possibly with heating, is dissolved in water and 
intensively mixed with the genuine valepotriate fraction and the mixture 
processed into microcapsules. In a preferred embodiment, the genuine 
valepotriate fraction is preheated prior to mixing. The microencapsulation 
may be effected in the conventional manner, by spray drying, for example. 
For the aqueous solutions of the sheathing materials, concentrations 
between 35 parts by weight sheathing materials and 65 parts by weight of 
water and 2.5 parts by weight sheathing materials and 97.5 parts by weight 
water are suitable. The ranges are determined by the fact that excessively 
concentrated and consequently viscous solutions cannot be spray dried, 
while overly dilute solutions are not economical in the spray drying 
process. The ratio of the genuine valepotriate fraction by the sheathing 
material may vary between 50:50 parts by weight and 2.5:97.5 parts by 
weight. Extract concentrations higher than 50% by weight (with respect to 
the finished microcapsule) are possible but do not yield dry, flowable 
powders, while the lower limit of 2.5% by weight is determined by aspects 
of dosage. With the above-mentioned content of 80% by weight of 
valepotriates in the genuine valepotriate fraction, concentrations are 
achieved in the final product corresponding to a content of active 
ingredients in the microcapsules of between 40 and 2% by weight.

EXAMPLES 
Three different stable valepotriate products are prepared. Genuine 
valepotriate fraction is prepared, according to the procedures of U.S. 
Pat. No. 3,422,090, from the raw drug of plants from the genus Valeriana 
and is mixed with various substances for the microencapsulation procedure. 
In Example 1, gum arabic and methylcellulose are employed as the 
microencapsulation adjuvant. In Example 2, gum arabic, methylcellulose and 
a mixed polymer of polyvinylpyrrolidone and polyvinylacetate is employed. 
In Example 3, gum arabic and a mixed polymer of polyvinylpyrrolidone and 
polyvinylacetate forms the microencapsulation adjuvant. The mixed polymer 
of polyvinylpyrrolidone and polyvinylacetate is a commercially available 
product known as Luviskol VA64 available from BASF comprising six parts 
polyvinylpyrrolidone, four parts polyvinylacetate. In each of the 
examples, the respective aqueous solutions of gum arabic, methylcellulose 
and Luviskol are mixed and heated at 40.degree. C. The molten genuine 
valepotriate fraction, also heated at 40.degree. C. is added under 
intensive agitation to the solution of the sheathing materials. In the 
case of Example 3, another 18.0 kg water are added to the solution. The 
mixture is homogenized by means of a colloid gear mill (Puc-Viscosator). 
The emulsion obtained is immediately thereafter spray dried in centrifugal 
atomizing dryer (Krause tower). 
The valepotriate in each example is determined by means of the so-called 
expoxy method. In the process, approximately 200 mg of the substance is 
exactly measured into a tall 50 ml beaker and mixed with 500 mg 
tetraethylammonium iodide. Following the addition of 30 ml of a mixture of 
50 parts chloroform, 30 parts glacial acetic acid and 20 parts acetic 
anhydride, the mixture is heated in 25 minutes to 65.degree. C. on an 
electrically heated magnetic agitator in a graphite bath. The bath should 
already be at the temperature specified when the beaker is placed on it. 
The beaker is covered with a watch glass. 
After exactly 25 minutes, the reaction mixture is titrated while still warm 
with 0.1 N perchloric acid by means of a metrohm-potentiograph. A 
combination glass electrode adjusted to a ph range of 14 is used. 
The calculation of the valepotriate content is effected by the following 
formula: 
##EQU1## 
TABLE 
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Example 1 
Example 2 
Example 3 
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Gum Arabic 3.0 kg 3.0 kg 2.5 kg 
Water 6.0 kg 6.0 kg 5.0 kg 
Methylcellulose 2.0 kg 2.0 kg -- 
25 cps 
Water 28 kg 22.0 kg -- 
Luviskol VA 64 -- 1.0 kg 5.0 kg 
Water -- 5.0 kg 18.0 kg 
Genuine Valepotriate 
Fraction 5.0 kg 5.0 kg 2.5 kg 
Initial % Valepotriate 
Immediately After 
Preparation 39.9 38.0 20.15 
% Valepotriate 
at 11 months 39.9 38.9 -- 
% Valepotriate 
at 36 months -- -- 22.0 
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