SK23493A3 - Method of extracting sennosides a,b and a1 - Google Patents

Abstract

The invention concerns a method of extracting sennosides A, B and A1. The method comprises the following steps: a sennoside mixture is reduced to the corresponding anthrone-8-glucosides, the aloe-emodin components are removed by liquid-liquid separation of the anthrone-8-glucosides, and the rheine-9-anthrone-8-glucoside obtained after the separation step is oxidized again to sennosides A, B and A1. The invention also concerns sennosides A, B and A1 obtained by this method and pharmaceutical agents containing them.

Description

Technical field

The invention relates to a process for obtaining sennosides A, B and A1 which are substantially free of sennosides C. D and D1 and of aloe-emodin components. as well as sennosides obtainable by the above method and pharmaceutical compositions containing these sennosides.

BACKGROUND OF THE INVENTION

Sennosides are laxative substances found in dried drugs from plants of the genera Cassia and Rheum. The hay drug consists of dried leaves and pods of hay plants, for example Indian hay (Cassia acutifolia).

The laxatively active sennosides are diantrone glucosides.

derived from rhein and aloeemodine. The most important are sennosides A,

B and Al,

C, D and D1. Corresponding to the following formula.

group

A1 represents sennosides A, Ba represents a substituent R for carboxylic acid and for sennosides

C. D a

Dl means

R is a hydroxymethyl group.

sennosides

A, B and

Al, substituent or C,

D and D1 are stereoisomers and are distinguished by carbon atoms 10 and 10.

by configuring each other to

In addition to sennozides, the crude drug also contains aglycones (sennidinyj, pologlycosidated sennidines, polymers, products by mass sennoside C, aloeemodine, formulas containing the following:

sennozidov degradation. aloeemodine and its derivatives and the like, which may cause undesirable side effects, such as nausea, vomiting, bloating and colic.

Methods for obtaining sennosides from a hay drug are described, for example, in DE-B-16 17 667, FR-M-6611. GB-A-832017 and DE-A-3200

131- The sennosides obtained according to these known methods contain, depending on the drug used, a mixture of sennosides with 1.5 to 5%

Dl. As mentioned above, the molecule moiety, derived from

OH

CH ₂ OH

It would be desirable to obtain sennosides which are substantially free of sennosides C, D and D1.

The virtually complete separation of sennosides C, D and D1 from the sennoside mixture is not known in the prior art.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide a process for obtaining sennosides A, B and B1 which are substantially free of undesirable accompanying substances, in particular sennosides C, D and D1.

This object has been solved by providing a method according to the invention, which is based on the fact that

A / a mixture of sennosides is reduced to rhein-9-anthrone-8-glucoside,

B) a liquid-liquid partitioning of the obtained compounds is made between a polar organic solvent, only partially miscible with water and an aqueous phase, and

The cis-rhein-9-anthrone-8-glucoside contained in the aqueous phase is oxidized to sennosides to A, B and B1 and these are obtained.

Step A Generally, mixtures of sennosides, which arise from the extraction of the drug from hay by the above-mentioned processes, are generally used as the starting material for the process of the present invention. For example, a sennoside mixture which is obtained according to the method described in DE-A-32 00 131. is useful as a starting material. According to this method, the senna drug is first extracted with aqueous methanol. The concentrate obtained after complete removal of methyl alcohol contains sennosides in the form of potassium salts. This concentrate can be used as a starting material for the process of the present invention.

The concentrate can still be purified by liquid-liquid extraction with partially water-soluble alcohols or ketones (e.g. 2-butanol, 2-butanone, acetone) (raffinate). The raffinate thus obtained is acidified to a pH of 1.5 to 2.0 and sennosides are brought to crystallization by seeding. The obtained mixture of crude sennosides is also useful as a starting product for the process of the present invention. If necessary, the mixture of crude sennosides can also be recrystallized.

Alternatively, a concentrate mixed with a partially water-soluble alcohol or ketone, especially 2-butanol, may be used as the starting product.

When extracting the drug from hay, the ratio of drug to extraction solvent is preferably 1 = 4 to 1:15, especially 1: 4 to 1:10.

The extraction is preferably carried out in the presence of a buffer. such as trisodium citrate, carbohydrate, sodium bicarbonate or sucrose.

According to the method of the present invention, these starting materials are completely reduced to the corresponding rhein-9-anthrone-8-glucoside (R = COOH) and the corresponding aloeemodine-9-anthrone-8-glucoside CR = CH 2 OH) of the formula

As reducing examples, for example

agents with a suitable stannous chloride, the reducing potential may be sulfur dioxide, alkali metal borohydrides and preferably alkali metal dithionates.

especially sodium dithionite (sodium dithionite).

To effect the reduction, the starting material may be presented in an aqueous solution or suspension and a reducing agent in solid form or dissolved in water is added. It can also be carried out in a biphasic mixture, in particular using the primary sennesia extract according to DE-A-32 00 31 (= aqueous concentrate), by adding a polar organic solvent, partially miscible with water, in particular 2-butanol or acetone. .

It can be reduced at ambient temperature or at elevated temperature. The reduction is preferably carried out at a temperature in the range of 40 to 60 ° C, in particular 50 to 55 ° C. The reaction is carried out at a weakly acidic to slightly alkaline pH of a solution of the starting sennosides or their suspensions, preferably at a pH in the range of 5 to 10.5. If necessary, the reduction can be carried out several times, in particular two to ten times.

The 9-anthrone-8-glucosides formed are precipitated by the preparation of an acid such as sulfuric acid, up to about pH 2-4.

The temperature should not exceed about 40 ° C. It is expedient to work on the precipitation of anthro-glucosides and their isolation (for example by filtration) under a protective nitrogen atmosphere in order to avoid uncontrolled oxidation of these compounds.

- 5 It is important that the reduction is complete. It is therefore expedient to use a reducing agent in a high excess. When sodium dithionate is used, one to four times the amount of dithionate, based on the sennoside content of the starting material, is usually used. In addition, the reducing agent is allowed to act for at least two hours, preferably for at least three hours. Usually the reduction is not longer than ten hours. Preferably, an additional reduction is performed under preferred conditions.

The product obtained is preferably precipitated before being introduced into the next step B. A pH of about 6-7 is added to the solution in aqueous solution by addition of a base (sodium hydroxide, potassium hydroxide). The aqueous solution is extracted with 2-butanol, acetone or 2-butanone and the product acidified to pH about 2-4 by addition of acid. again precipitates.

Grade B

In this step, the aloeemodine components, in particular aloeemodine-9-anthrone-8-glucoside, are removed. The liquid-liquid separation of the product obtained is carried out in a polar organic solvent with only limited miscible water, as opposed to the aqueous phase. Suitable polar organic solvents are alkanols of 4 to 5 carbon atoms and dialkyl ketones of 1 to 3 carbon atoms in the alkyl moieties. such as acetone, 1-butanol, 2-butanol and 2-butanone. Preferably, 2-butanol and acetone are used.

Preferably, a reducing agent is added to the aqueous phase so that the aqueous phase has throughout the liquid-redox liquid-potential distribution of 210 mV. or more negative. Conveniently, the same reducing agent used in step A is used. When using alkali metal dithionates as reducing agents, a solution with a concentration of 2-4% by weight is generally sufficient, at a pH in the range of 7 to 10.5, to maintain the potential conditions considered. . The pH is conveniently maintained by the addition of a buffer in the indicated range.

The volume ratios of the aqueous phase (heavy phase) to the organic phase (light phase) are generally in the range of 1 = 5 to 1:40.

Preferably, liquid-liquid extraction is performed in countercurrent. The mixture of anthrone compounds is supplied in the form of a solution. obtained after reduction. or when the anthrone compounds have been isolated, they are supplied in the form of a solution having a concentration of 3 to 15% by weight.

After separation, the desired rhein-9-anthrone-8-glucoside is in the aqueous phase. It is precipitated by acidifying the solution to pH about 2-4 with the addition of acid and obtained by conventional methods.

Stage C ^:

At this stage, rhein-anthrone-8-glucoside is again oxidized to the corresponding sennoside compounds. Suitable oxidizing agents include hydrogen peroxide, manganese dioxide, permanganate, and manganese acetone acetonate.

Preferably, however, the oxidation is carried out with oxygen. For example, air may serve as the oxygen source.

Since rhein-9-anthrone-8-glucoside is insoluble in water, it is carried out for oxidation to a soluble form. This is done, for example, by the addition of a suitable base up to a pH of about 6-7 to the alkali metal or calcium salt. If necessary, a small amount of solvent, such as 2-butanol in particular, may be added to the solution.

The oxidation is preferably carried out in a concentrated solution, since in this way it is preferred to form the desired sennions. frontally, the oxidation is carried out with a solution having contents of 25 ° C; 300 g of rhein-9-anthrone-8 ' -glucoside per liter of solvent is conveniently passed through the solution using oxygen as the oxidizing agent.

Oxygenation can be facilitated by the use of a catalyst. Suitable catalysts include, for example, palladium or iron (III) salts of trivalent catalysts, especially ferric chloride. The amount is usually in the range of 0.2 to 2¾ based on the amount of rhein-9-anthrone-8-glucosides and preferably in the range of

0.5 to 1¾ by weight.

Alternatively, the oxidation can be carried out using ferric salts such as ferric sulfate or ferric chloride at a pH in the range of 8 to 8.5. This is preferably carried out at a temperature of 30 to 50 ° C and in the presence of trisodium citrate.

The oxidation is carried out until no more rhein-9-anthrone-8-glucoside is detectable (UV-fluorescence of anthrone compounds).

The sennosides are obtained in a conventional manner by acidifying the solution obtained. Suitably, the solution is diluted to two to three times the remaining volume prior to the addition of the acid (water (2-butanol)). In this way, it is achieved that the rhein-8-glucoside formed as a by-product remains virtually completely in solution when the sennosides precipitate.

The separation of rhein-8-glucoside can also be carried out via the calcium salt, since the calcium salt of rhein-8-glucoside is insoluble and precipitates while the calcium salt of sennosides remains in solution.

The sennosides are precipitated by acidification by addition of an acid to a pH of about 2-4 and then recovered in the usual manner.

The sennosides obtained are essentially sennosides A,

B and Al. They are substantially devoid of sennosides C. D and D1 and other aloe-emodin compounds. The content of sennosides C, D and D1 in the product obtained by the process of the present invention is less than 100 ppm (determined by the analytical method given in the Example) The invention also relates to a mixture of sennosides A, B and Al. which are obtainable by the process according to the invention. as well as pharmaceutical compositions containing said mixture.

Field of application. the amounts applied and suitable dosage forms are already known from the above publication.

DETAILED DESCRIPTION OF THE INVENTION

The following examples serve to illustrate the present invention in more detail.

Example 1

Obtaining a mixture of sennosides. used as starting material

40 kg of hay drug (sennozide content about 1.5% by weight) is placed in two 250-liter percolators arranged in a row and covered with a perforated steel plate. The solvent used for the extraction was 70% methyl alcohol which was fed to the drug in the first percolator. The solution formed in the first percolator. The solvent is allowed to flow freely through the percolator.

A total of 160 liters of solvent is used to extract 40 kg of hay drug. After this volume of 70% methyl alcohol has been passed through both percolators and the corresponding percolate is collected, the percolator discharge hose is connected to the downstream tank and the methanol solvent is additionally passed through the percolators. Then, the first percolator is collected into the percolator and an additional lead of the remaining free upper portion of the second percolate is collected until a total of 120 liters is obtained. Then the first percolator is emptied, 40 kg of hay drug is refilled and the additional percolate is pumped onto the drug, with 120 liters of additional percolate sufficient to overlap the percolate drug. The temperature of the solution was then adjusted to 30 ° C, then allowed to stand overnight.

The percolator is then combined with the previously extracted percolator and the extraction is performed as described above.

For each 40 kg of drug, 160 liters of percolate are collected, from which methanol is then removed in a rotary evaporator equipped with a packed column. About 30 liters of concentrate are obtained.

This saturated process. concentrate 2-butanol. phase is separated and aqueous both phases are water d'aej Grade A Reduction of sennosides to rhein-9-anthrone-8-glucoside

1.0 l of the extracted concentrate is made alkaline to pH 7.5 with 48% by weight sodium hydroxide. Heat to 60 ° C and add 90 g of solid sodium dithionate to the solution over half an hour with stirring. After the addition was complete, the mixture was stirred for an additional hour. Concentrated sulfuric acid is then added with stirring until pH = 2. The mixture is cooled to ambient temperature over 2 hours, the precipitated crystalline precipitate is filtered off and washed with water containing sulfur dioxide.

If necessary. thus crude rhein-9-anthrone-8-glucoside is precipitated. The still wet cake is dissolved in a mixture of 15 parts by volume of 2-butanol and 85 parts by volume of water containing 0.5% by weight sodium pyrosulphite so as to obtain up to pH by adding 48% (w / w) sodium hydroxide solution.

10% solution (w / v). The solution is then acidified with concentrated hydrochloric acid to pH 2.8 or below and allowed to stand for 2 hours. The precipitated precipitate is filtered off, washed with water containing sulfur dioxide or sodium pyrosulphite and dried.

Yield - 90%.

With the product obtained by the above method, the reduction (post-reduction) is carried out again as follows;

3.0 g of crude dried rhein-9-anthrone-8-glucoside or the corresponding amount of wet product are dissolved together with 1.4 g of sodium dithionite and 2.3 ml of 5 N sodium hydroxide in 15 ml of water. It is then made up to 24 ml with water and the solution is heated at 55 ° C for 20 minutes. An additional 1.5 g of sodium dithionite is then added and the solution is heated at 55 ° C for 20 minutes. 0.9 ml of 5 N sodium hydroxide and 1.5 g of sodium dithionite are added. After heating for 20 minutes at 55 ° C, 0.9 ml of 5 N sodium hydroxide is added again. The solution thus obtained is introduced directly into a subsequent liquid-liquid extraction.

Grade B;

Separation of aloeemodine components

The separation of the aloeemodine components is carried out by liquid-liquid partitioning of the 9-anthrone-8-glucosides in countercurrent with the aid of an apparatus of 60 mixing-separating units (Mixer-Settler-Apparatur). A solution of 3.0 g of sodium dithionite in 3.5 ml of 5 N sodium hydroxide and 96 ml of water is used as the aqueous heavier phase. 2-Butanol or acetone (water-saturated) is used as the organic, lighter phase. Both phases are passed through the apparatus so that the volume ratio of the heavier phase to the lighter phase is 1:10.

The mixture to be separated is fed to the apparatus in the form of a freshly reduced solution or in the form of a solution having a corresponding pH and a concentration of 9-anthrone-8-glucosides, in such a way that 30 volumes of organic mixture are used per volume. phase.

The pH of the solution containing the mixture is maintained at 9-9.5 with glycine buffer. This buffer, consisting of 3 parts by volume of a 7.5% glycine solution and 1 part by volume of 1 N sodium hydroxide, is added in an amount of 240 ml of a buffer solution per 150 g of crude rhein-9-anthrone-8-glucose. The undesired aloeemodine compounds are enriched in the organic phase, while rhein-9-anthrone-8-glucoside remains in the aqueous phase. The aqueous phase is acidified to pH 2.8 with sulfuric acid, the precipitate formed is filtered off and washed with water and acetone and air-dried at ambient temperature. In this way, rhein-9-anthrone-8-glucoside is obtained with aloeemodine component content of 49 ppm (determined as aloeeroodine).

Yield 97 relative to rhein-8-anthrone-glucoside.

Grade C ·

Oxidation of rhein-9-anthrone-8-glucoside

18.8 g of the obtained rhein-9-anthrone-8-glucoside are dissolved in 56 in 1 of water and 11 ml of 2-butanol, 17 N sodium hydroxide is added until a pH of 6.5 is obtained. Air is bubbled through the solution in a cylindrical vessel with the aid of a glass frit for 5 hours with stirring. The air flow rate is 40 ml / min. The progress of the oxidation was monitored by HPLC.

«

When no more rhein-9-anthrone-8-glucoside is detectable, dilute the solution to about 200 mL with a mixture of water and butyl alcohol 56/11.

Concentrated hydrochloric acid is then added until the pH is 1.5-2.0 and the reaction mixture is stirred for hours at room temperature. The precipitated crystals are filtered off, washed with water and acetone and dried. 14.4 g (76 pure mixture of sennosides containing 41 ppm of aloeemodine components (determined as aloeemodine) are obtained according to the analytical procedure described in Example 2, step C.

Example 1 a d 2

The extraction of the hay drug and the reduction of the sennosides described in Example 1 is repeated, but the oxidation in step C is carried out as follows:

150 g of pure rhein-9-anthrone-8-glucosides and 75 g of ferric chloride hexahydrate are dissolved in 480 ml of water and 120 ml of 2-butanol. A 48% (w / w) sodium hydroxide solution is then added until a pH of 6.5 is reached and the rhein-9-anthrone-8-glucoside is dissolved. The solution is placed in a bottom-bottom vessel from a sintered plate and a live air stream is passed through the solution. Oxidation is complete after about 30 minutes. The solution is then diluted with a mixture of 120 ml of 2-butanol and 480 ml of water. 7.5 g of sodium dithionite are added and the pH of the solution is adjusted to 2.0 by addition of concentrated hydrochloric acid. The solution is stirred for 18 hours, the precipitate formed is filtered off, washed with 800 ml of acetone and dried. The content of anthranoid compounds in the product ranges from 94 to 95%.

The product is taken up in 200 ml of 2-butanol and precipitated with 800 ml of water with the addition of 5.5 g of sodium pyrosulphite. After filtration and drying of the precipitated precipitate, 95.4 g of product from anthranoid compounds are obtained with the following composition (HPLC. Typical experiment analysis):

Rhein-8-glucoside 1.5 49.7 % % % by weight sennosides B sennosides Al 13.3 weight sennosides A 33.6 •'about weight sennidin moriog1ucoz i dy 0.1 weight reí n 12:02 weight

99.22% by weight

Sennosides C and D and aloe-emodoglucoside were not possible with

HPLC proof. The total content of aloeemodine and its derivatives was determined at 30 ppm using the following method:

Sennosides C and D and aloe-emodine-8-glucoside can no longer be reliably determined as sennosides in the ppm-region as sennosides. It is therefore necessary to convert the test substance by oxidation with iron (III) chloride with simultaneous hydrolysis with hydrochloric acid in a biphasic mixture from aqueous solution and carbon tetrachloride to rhein. optionally aloeemodine. The rhein is then converted into salt.

so that it can be extracted into the aqueous phase and the aloe-emodin can be in the organic phase

In this way, the phase can be determined by HPLC.

total sennoside content

C and D and aloeemodine-8-glucosides and other aloeemodine components, expressed as aloeemodine.

Example 3

The extraction of hay drug and the reduction of sennosides described in Example 1 is repeated. The additional reduction is then carried out as follows:

Dissolve 14.8 g of sucrose, 4.5 g of sodium dithionite (85%) and 13.3 g of sodium acetate in 133 ml of water and add 1.3 ml of a 48% (w / w) sodium hydroxide solution and 17 ml of water, 3 g of potassium carbonate. Then it is mixed with 293 ml of acetone and 50 ml of water. The reaction mixture is shaken in a shaking funnel, then the phases are separated to give 375 ml of the upper phase (acetone phase) and 130 ml of the lower phase.

1.4 ml of a 48% (w / w) sodium hydroxide solution and 10 g of crude rhein-9-anthrone-8-glucoside are dissolved in 98 ml of the lower phase. The mixture is heated to a temperature in the range of 45 to 50 ° C and left at this temperature for 20 to 30 minutes. Then 1.0 ml of a 48% (w / w) sodium hydroxide solution and 3.4 g of sodium dithionite are added and heated for a further 20 to 30 minutes to a temperature in the range up to 50 ° C. Finally, 1.0 ml of a 48% (w / w) sodium hydroxide solution and 3.4 g of sodium dithionite are again added and reheated to 45 to 50 ° C for 20 to 30 minutes.

The separation of aloeemodine by liquid-liquid component separation is reduced to a solution in countercurrent against the above considered upper phase (acetone phase).

The effluent raffinate phase containing rhein-9-anthrone-8-glucoside is evaporated to a volume of 400 ml and mixed with 20 ml of 2-butanol, then acidified at a pH of 4.0 to 4 with a portion of hydrochloric acid or sulfuric acid. '2.

The precipitate formed is filtered off, washed with 400 ml of water and 30 ml of acetone and then dried. The following oxidation proceeds as in Example 2.

Example 4

The concentrate obtained after the extraction of the drug from hay is mixed with about 2 liters of 2-butanol. The reduction of the mixture of hay fruit concentrate and 2-butanol is then carried out in seven stages under a nitrogen atmosphere as shielding gas. After reduction step I, precipitation of crude rhein-9-anthrone-8-glucoside is performed.

Reduction stage I

100 liters of a mixture of hay-fruit concentrate and 2-butanol containing about 4 kg of sennosides are placed in a stirred tank and covered with a nitrogen atmosphere. While stirring, 6 liters of a 20% (w / w) sodium hydroxide solution are added, followed by 350 liters of water-saturated 2-butanol (e.g. from step II), and the mixture is stirred for 15 minutes. The batch is then heated to a temperature in the range of 42-50 ° C and stirred with 7 kg of sodium dithionite, whereupon the reaction mixture is stirred for a further 45 minutes. The pH is maintained with 20% (w / w) sodium hydroxide in the range of 7.5 to 8. The reduction potential (against Ag / AgCl-alektrode) is maintained below -630 mV by addition of sodium dithionite as necessary. After cooling to a temperature in the range of 30 to 35 ° C, the solution is precipitated by acidification with 10% (w / w) sulfuric acid to a pH of less than 4 within 1.5 hours. The resulting suspension is stirred at a temperature below 25 ° C for about 10 hours at slow speed of the stirrer. The resulting precipitate was filtered off. The precipitate is then suspended in 60 liters of 15% (w / w) 2-butanol, stirred for 30 minutes at a temperature in the range of 50 to 60 ° C and filtered again. The residue is washed with 100 liters of demineralized water. The crude yield of rhein-9-anthrone-8-glucoside relative to the sennoside used is greater than 82%.

Reduction stage II

3.3 kg of crude rhein-9-anthrone-8-glucoside from reduction step I is suspended in a mixture of 42 liters of demineralized water and 7.4 liters of 2-butanol. With 2 liters of 25% (w / w) sodium hydroxide and 9.9 kg of trisodium citrate, the suspension is dissolved and then mixed with 3.3 kg of sodium dithionite and 350 liters of water-saturated 2-butanol (e.g. from step III). . The batch is heated to a temperature in the range of 42-45 ° C. The pH is maintained with 25% (w / w) sodium hydroxide in the range of 8.5 to 9. The reduction potential (against Ag / AgCl electrode) is maintained below -750 mV by addition of sodium dithionate as necessary.

After standing for thirty minutes, the upper phase is removed and the lower phase is further processed in step III.

Reduction stage III

With the lower phase of step II, the reduction-extraction procedure described in step II is repeated with the addition of the following chemicals:

1,65 kg

0,8 1

350 l sodium dithionite% (w / w) sodium hydroxide water-saturated 2-butanol (e.g. from step IV).

Reduction stage IV - VII

The reduction-extraction procedure described in step II is repeated from the bottom phase of each step, with the addition of the following chemicals:

0,825 kg sodium dithionate 0.4 1 20% (w / w) sodium hydroxide 350 1 water-saturated 2-butanol (eg from the next step - countercurrent principle).

The lower phase, separated in step VII, is cooled to 30 to 35 ° C and the rhein-9-anthrone-8-glucoside precipitates as described in step I. The resulting precipitate is filtered off and washed with 100 liters of demineralized water. It is then covered with three liters of ferric sulphate solution (28 kg of ferric sulphate in 10 liters of demineralized water).

Reine-9-anthrone-8-glucoside is then converted to sennoside as described in Example 1 or 2.

Example 5

The oxidation of rhein-9-anthrone-8-glucoside may also proceed as follows ^:

6.0 kg of filtering moist rhein-9-anthrone-8-glucoside is mixed with 12.6 kg of trisodium citrate. This mixture was dissolved in 7.0 L of 1 N sodium hydroxide and stirred with 0.7 L of 2-butanol. Then the mixture is mixed with 8.8 liters of ferric sulphate solution (28 kg of ferric sulphate in 100 liters of demineralized water) and with an amount of 20% sodium hydroxide to achieve a pH of 8.3. The reaction mixture is allowed to react for 3 to 4 hours at about 40 ° C. It is then acidified with 52% sulfuric acid to a pH of 1.8-2.0 and worked up as in Example 1.

Example 6

Alternatively, it is made to a solution of rhein-9-anthrone-8-glucoside in 50 ml of water by adding a solution of calcium hydroxide and sucrose (produced by suspending 7.0 g of calcium hydroxide in a solution of 30.0 g of sucrose in 100 ml of water and removing undissolved calcium hydroxide) . 20 ml of 2-butanol are then added and air is bubbled into the solution for 90 minutes, then 5.0 g of calcium chloride dihydrate is added and the pH is adjusted to 8.5 with calcium hydroxide solution and sucrose. The precipitate formed is filtered off, the filtrate is diluted to 340 ml by the addition of water, mixed with 60 ml of 2-butanol and the pH is adjusted to 2.0 with concentrated hydrochloric acid. Further processing is carried out as described in Example 1.

Pharmacological tests

Laxative effect

The laxative effect of the sennoside mixture of the present invention was tested in mice. Male NMRIs are used, which are kept in plexiglass cages during the experiment and given a standard feed mix with tap water (1 = 1) in a slurry consistency. There is no separate supply of drinking water during the experiment.

The animals are given 100, 200 and 400 mg / kg of a mixture of sennosides in 10 ml of 0.5% sodium bicarbonate / kg using an esophagus probe.

After application of the test compounds, the animal's faeces and urine are collected for 24 hours and evaluated. The results obtained per kilogram of body weight are summarized in the following table

Table - laxative effect of the mixture of sennosides of the invention in mice

dose count number number soft droppings mg / kg animal pieces pieces % of total normal soft droppings droppings droppings

0 30 1265 0 0 100 40 587 144 28.0 200 30 223 239 56,0 400 30 236 282 60.0

From the above results, it is evident that sennosides show a good laxative effect, which is relatively rapid. However, the time to first soft droppings (.2 hours) has yet to be compared with the previous transit through the colon and take into account the colon microflora affecting sennozides. The dose-effect relationship is evident.

Acute ¹

Each of 10 Vistar male and female rats was given a single dose of sennoside at a dose of 2000-25000 mg / kg once a day using a esophagus probe.

Macroscopic organ damage caused by the administered substance was not observed in rats. The LD 50 values are as follows:

Male rats · 5,200+

- 720 female 3.530 + rats

- 340

In male and female mice (n = 5,000 mg / kg k applied) occurred in all mice, although LD50 values were for both sexes.

840 mg / kg

380 mg / kg.

The 8th NMRI strain) resulted in no death at all. Diarrhea is less than in rats and greater than 5,000 mg / kg.

Claims (13)

PATENT N ·· Λ A R 0 K Y ♦. ’· Ί ·· * Λ ' 1. A method for producing sennosides A, B a Al formula C ₆ H ₆ O ₅ -O OH i II \ ΟΗΟΗCOOH KT '' No ₆ Hh0 ₅ -0 OH which are essentially free of sennosides C, D and D1 aloeemodine components characterized in that: A) the mixture of sennosides is reduced to rhein-9-anthrone-8-glucoside and aloeemodine-9-anthrone-8-glucoside, B) a liquid-liquid partitioning of the obtained compounds between the polar organic solvent is only limitedly miscible with water and an aqueous phase, and The C-reine-9-anthrone-8-glucoside contained in the aqueous phase is re-oxidized to the corresponding sennosides and these are recovered. Method according to claim 1, characterized in that the mixture of sennosides is obtainable by extracting the drug from hay with methanol, preferably in the presence of a buffer. Process according to claim 1 or 2, characterized in that in step A an alkali metal dithionite is used as reducing agent. Method according to claim 3, characterized in that the pH is in the range from 5 to 10.5. Process according to one of the preceding claims, characterized in that 2-butanol is used as the polar organic solvent in step B. 6th Process according to one of Claims 1 to 4, characterized in that it is carried out in a step 7th use them A method as polar organic solvent acetone. according to any one of the preceding claims, characterized in that an aqueous phase is used in step B. its redox potential is - 210 mV or less. Method according to any one of the preceding claims, characterized in that the liquid-liquid partitioning in step B is carried out in countercurrent. Process according to one of the preceding claims, characterized in that the oxidation in step C is carried out by means of oxygen or ferric salts. The process according to claim 9, characterized in that the oxidation is carried out with oxygen at a weakly acidic pH. Process according to claim 9 or 10, characterized in that the oxidation by means of oxygen is carried out in the presence of catalysts, in particular iron (III) salts. 12. Sennosides A, B and A1, which are essentially single sennosides C, D and D1 and aloe-emodin components. A pharmaceutical composition comprising the sennosides according to claim 12, optionally together with the usual pharmaceutical carriers and excipients