CH642085A5 - METHOD FOR OBTAINING THE POLAR FRACTION WITH ANTIPSORIATIC EFFECTIVENESS OF AN EXTRACT FROM FERNPLANTS, AND A PREPARATION PRODUCED ACCORDING TO THIS METHOD. - Google Patents

Description

The invention relates to a process for obtaining the polar fraction with an antipsoriatic activity of an extract from fern plants and to a preparation produced according to this process.

Psoriasis and the skin disease summarized in the expression parapsoriasis have so far not been covered by scientific and therapeutic progress, and no medication is known to improve or even cure the pathological symptoms of the patient.

Knowledge of the disease can be traced back very far, and numerous attempts have been made to cure it over time, but no noteworthy results have been achieved in practice. In addition, the few agents with relative effectiveness lead to side effects that have serious consequences for the patient.

Significantly, one has recently returned to the well-known healing methods, since they are harmless and at least bring symptomatological relief, but never the healing or at least a remarkable improvement.

The problem is increasing as the number of patients with psoriasis continues to grow. This leads to the assumption that a genetic transmission takes place, with the disease appearing in the offspring openly or hiddenly or at least latently, in the latter case the acute form only occurs when certain pathological factors coincide, which occur Causing the clinical picture of psoriasis.

The disease can appear on any part of the surface of the body, the scalp being one of the most frequently affected areas and the psoriasis manifesting itself in the form of "dandruff". Often, this form is hardly noticed by the patient at the initial stage and initially only treated locally for a longer period, which only worsens the problem of the disease. The presence of "dandruff" can be observed in 90% of cases where psoriasis attacks other skin zones. Psoriasis not only spares no part of the body surface, but also no age group. The disease can therefore be observed in newborns as well as in the age of 60 or 70 years.

The geographic extent of psoriasis is total and does not spare any race, although the black race appears to be somewhat less susceptible.

The most common complication of psoriasis is expressed in the area of the joints, although liver and kidney tissues can also be affected at an advanced stage.

In a short summary it can be said: Psoriasis and parapsoriasis are clinical pictures that can be diagnosed without difficulty, even if an anatomically pathological diagnosis is required. The incidence of the disease is constantly increasing and, according to conservative estimates, 1% of the world's population suffers from psoriasis. So far, no effective cure is known, and the person suffering from psoriasis has only palliative care.

It has been found that the natural polar fraction isolated from rhizomes and leaves of Dryopteris crassirhizoma, Polypodium vulgare L., Polypodium leucotomos, Phelebodium decumanum, Cyathea taiwaniana and rhizomes of Polypodium aureum L. and Polypodium triseriale have curative effects in the Treat patients of both sexes and of any age who have psoriasis or parapsoriasis. The healing effects also include the descendants: esters, amides, etc. Over 300 patients with psoriasis were orally administered with a low dose, e.g. treated 5 mg per kg body weight daily. As a result of the treatment over a period of 3 months, it was found that the clinical picture had disappeared in 80% of the patients. Double-blind trials were carried out in a group of 50 patients, and the drug was shown to be effective compared to the placebo of the same size and shape. These fractions and their derivatives have been used in all forms of psoriasis and in various stages of the clinical picture.

No effect was found from the toxicological point of view. During research over a period of 12 years, blood tests and bone marrow tests, kidney and liver function tests, and urine samples showed no evidence of any changes. According to the guidelines of the Food and Drug Administration of the United States and in

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In accordance with the "Guidelines for Reproduction Studies for Safety Evalution of Drugs for Human Use", the compounds do not change fertility in rats and mice, nor in dogs, and no effects causing miscarriage were observed in four generations of rats and mice and two generations of dogs.

Carcinogenicity was also not found. In the corresponding studies in mice, a dose of 1 mg / kg body weight was orally administered daily for 24 weeks. The animals were examined from week 7 with and without the introduction of glass beads into the bladder. The methods used in these studies are described by Juli, J.W. in Brit. J. Cancer, 5,328 (1951), and the statistical evaluation used is described by Arcos and co-workers in "Chemical Induction of Cancer", p. 416, Academic Press Inc., New York (1963).

The invention relates to a process for obtaining the polar fraction with antipsoriatic activity of an extract from rhizomes and leaves of Dryopteris crassi-rhizoma, Polypodium vulgare L., Polypodium leucotomos, Phlebodium Decumanum J. Smith, Polypodium decumanum, Cyathea taiwaniana, and rhizomes of Polypodium aureum L. and Polypodium triseriale, which is characterized in that the rhizomes are cut into strips and the rhizome strips and the leaves are subjected to continuous drying at a temperature not exceeding 70 ° C., the dried material which has a residual moisture content of less than 8%. has, grinded to obtain particles with a diameter of up to 2 mm and a bulk density between 0.1 and 0.8 g / cm 3; extract this material with ethanol, methanol or chloroform, evaporate the solvent and clean the residue.

It is advantageous if the semi-solidified residue is taken up in n-hexane / water, left in a separator and the aqueous phase is separated off; the aqueous solution is passed over an exchange resin and then Ca (OH) 2 is added until neutralization, portions of activated carbon are added until the solution is clarified; evaporate up to 100% of the starting solution and precipitate with absolute alcohol, filter the precipitate with suction and evaporate the filtered aqueous solution again to obtain a second precipitate and finally dry the combined precipitates in vacuo until a white,

solid material remains.

Appropriate further developments of the invention are the subject of claims 3 to 5.

The invention further relates to a preparation produced according to the method according to the invention.

The polar fraction works through:

a) Increasing the permeability through the cell wall for sugar such as glucose, sucrose, fructose and amino acids such as valine, lisin and others to a lesser extent.

b) increasing the activity of the carriers of the cell wall.

c) Increasing the water exchange on the cell wall.

d) An increase in the activity of the hepatocytes was probably observed in connection with the above, which shows the great metabolic effect.

e) increase in the activity of growth and maturity of collagen.

The polar fraction according to the invention does not have the effectiveness of steroids. It has a pulse-slowing effect similar to that of digital preparations, probably due to the effect on the cell walls of the myocardium.

The method according to the invention enables extraction with industrial yield of this polar fraction of leaves and rhizomes of various fern herbs in sufficient quantities for use in the production of pharmaceutical preparations. In order to achieve an optimal yield, the leaves should be collected after the young sporangia have already developed.

The method according to the invention comprises the following steps, for example:

dry

The rhizomes are cut into strips 2 to 3 cm wide, the leaves are dried as they are collected. Drying takes place continuously, with the material being placed in a conventional dryer, e.g. a rotating metallic wire mesh with a width of approx. 5 m and a length of approx. 25 m, which is moved within a hot chamber, the temperature being not more than 70 ° C. By adjusting the speed of the rotating metallic wire mesh drum, almost half a ton of damp material can be dried per hour.

Grind

The dried material (residual moisture below 8%) is ground using a disk mill which is set in such a way that particles of 2 mm are obtained.

Extraction / evaporation

The extraction can be carried out with ethanol, methanol or chloroform, preferably with methanol in a volume ratio of 1: 4. Evaporation takes place until a residual of / s of the starting volume is obtained.

cleaning

1. The semi-solidified residue of the extraction-evaporation is distributed in a system of immiscible solvents n-hexane / water (10: 4). After being left in a separator overnight, lipids and resins are discarded in the hexane phase.

2. The separated and filtered solution is passed over an exchange resin.

3. Ca (OH2) is added until neutralization.

4. The solution is clarified by adding activated carbon.

5. This solution is evaporated down to 10% of the initial volume and precipitated in an anhydrous organic liquid which is miscible with water, e.g. absolute alcohol.

6. The precipitate is filtered off under suction and gives a first rod-shaped mass, the crystallized water is evaporated again, and a second pulverulent mass is obtained.

This powder is dried in a vacuum until it has a white color.

The second white, crystalline mass is not a defined chemical substance, but rather a composition which is determined by the nature of the starting material used and the process of extraction and purification.

The presence of D-glycose and D-fructose in a proportion of a total of 70% results from the usual qualitative studies and isolation

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and the complete determination of the acetated derivatives. Furthermore, the presence of acid compounds that are difficult to separate from the sugar could be demonstrated, both by chromatography and by conventional spectroscopic methods.

The pharmaceutical compositions are prepared by incorporating the polar fraction into pharmaceutical carriers in accordance with recognized pharmaceutical practice in conventional dosage forms. The active ingredient, i.e. the polar fraction is present in the compositions according to the invention in a sufficient amount to show the antipsoriatic activity.

The pharmaceutical compositions according to the invention preferably contain the active ingredient in a proportion of 10 to 100 mg per unit dose. The pharmaceutical carrier can e.g. be solid or liquid. Examples of solid carriers are lactose, magnesium stearate, Alba-Terra, cane sugar, talc, stearic acid, gelatin, agar, pectin, gum arabic, aerosil and the like. Examples of liquid carriers are alcohols such as ethanol or propylene glycol, water containing one Solubilizers such as polyethylene glycol, peanut oil, olive oil and the like. The carrier or diluent may contain a retarder such as glyceryl monostearate or glyceryl distearate, alone or with a wax.

A wide range of pharmaceutical forms can be used. Thus, if a solid carrier is used, the preparation can be converted into tablets, introduced into hard gelatin capsules in the form of a powder or granule, or it can be adapted to a lozenge or cookie shape. The amount of solid carrier can vary within a wide range, preferably it is between 25 and 300 mg. If a liquid carrier is used, the preparation can be in the form of a syrup, an emulsion, soft gelatin capsules, a suspension or liquid solution or in a sterile, injectable form for parenteral use, e.g. in an ampoule.

The pharmaceutical preparations produced in the form of suspensions or liquid solutions comprise non-simple suspensions or liquid solutions of active constituents in customary solvents which are not suitable for internal administration in order to produce the desired pharmaceutical activity.

A unit dosage in the form of tablets, capsules, troches, biscuits, liquid suspensions or sterile injectable liquids for internal administration is also possible in order to create antipsoriatic activity which contain a pharmaceutical carrier and a polar fraction in an amount sufficient to achieve the stated activity to obtain.

Administration can be oral or parenteral, preferably oral. The active ingredient is preferably administered in a daily dosage amount of about 50 to 900 mg, with the range of 100 to 300 mg being particularly preferred. It is advantageous to administer the same doses one to four times a day. When administered as described above, antipsoriatic activity is obtained.

Since psoriasis is a chronic, insidious phenomenon with a genetically causative disease, the capsule or tablet form is preferred in order to maintain stable blood concentrations, which allows the medication to have a continuous influence. Undoubtedly, intravenous injection or continuous dropwise delivery in serum to avoid the crisis can be used when treating serious psoriasis outbreaks caused by other medications, such as in the case of steroids or the disease itself.

It should be noted that the teardrop shape or emulsion is used in children for obvious reasons, while in the case of adults who have problems in the upper digestive tract, suppositories can be used.

The pharmaceutical compositions are prepared by conventional processing techniques such as mixing, granulating and compressing if necessary, or by mixing and dissolving the appropriate ingredients for the desired compositions.

The invention is explained in more detail below with the aid of examples.

example 1

12 kg of dry leaves, granulated over a No. 10 sieve (2.5 mm) were extracted with 48195% ethanol at 70 ° C for one and a half hours.

After evaporation, the residue is taken up in n-hexane / water (15: 101) and left in a separator overnight. The hexane phase is discarded and the aqueous phase is filtered.

The filtrate is passed over an exchange column and then neutralized with alkali. The neutralized solution is clarified and evaporated in a moderate vacuum for almost 48 hours until the drying time (yield: approx. 150 g). The dried solid mass is redissolved in methanol and crystallized out at 4 ° C. during the night.

Example 2

36 kg of a dry plant, granulated in a disk mill to pass through a No. 10 sieve (2.5 mm), was continuously extracted with n-hexane at room temperature. The hexane solution is concentrated and placed in a separator with water during the night. The hexane phase is discarded and the aqueous phase is evaporated.

The residue of the plant extracted with hexane is taken up in hot ethanol and left in a sufficient amount during the night to form a saturated solution. The solution is filtered and added to the aqueous phase and then passed over an exchange column. The solution is then neutralized and clarified and evaporated almost to dryness.

The solid mass is redissolved in 70% ethanol and crystallized out at room temperature during the night. The crystals are discarded and the liquid phase is evaporated (yield: 180 g) and dried in vacuo.

Example 3

12 kg of dry rhizomes were granulated in a disk mill and sieved through a No. 10 sieve (2.5 mm). The mixture was then extracted continuously with chloroform at room temperature. The solution is concentrated and redissolved in n-hexane / water. The hexane phase is discarded and the aqueous phase is evaporated.

The residue of the extracted rhizomes is taken up in hot methanol and left to stand for 16 hours. The solution is filtered and passed over an exchange column.

The extract is neutralized and clarified and then evaporated and placed in a crystallizer overnight in 95% ethanol. The crystals are discarded and the liquid phase is evaporated and then dried in vacuo (yield: 84 g).

Example 4

12 kg of a dried and granulated (No. 10 sieve, 2.5 mm) are refluxed for one and a half hours.

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Plant extracted with 90% methanol at 70 ° C. The extract is filtered, evaporated and placed in n-hexane / water (3: 2). The solution is left to stand overnight, the hexane phase is discarded and the aqueous phase is filtered and evaporated.

The residue was taken up in 90% hot ethanol and passed over an exchange column.

The extract is neutralized and evaporated to a tenth of the starting volume and then crystallized out in the cold. The solution is filtered, the crystals are discarded and the aqueous phase is dried in vacuo (yield: 240-250 g).

The following examples of pharmaceutical preparations are not to be interpreted as a limitation but as an explanation of the invention.

Example 1 a

component

amount

Polar fraction

40 mg

lactose

60 mg

The ingredients are mixed, sieved and placed in hard gelatin capsules. A capsule made according to the procedure described above is administered three times a day.

Example 2a

Component quantity

Polar fraction 60 mg

Strength 60 mg

Talc 5 mg

Kaolin 5 mg

15 polyvinylpyrrolidone 5 mg

The fraction and starch are mixed and granulated with a solution of 10% gelatin, including 20 polyvinyl pyrrolidone. The granules are sieved, dried and then mixed with kaolin and talc and converted into tablets.

B

Claims (7)

642 085 1. A process for obtaining the polar fraction with antipsoriatic activity of an extract from rhizomes and leaves of Dryopteris crassirhizoma, Polypodium vulgare L., Polypodium leucotomos, Phlebodium Decumanum J. Smith, Polypodium decumanum, Cyathea taiwaniana, and Rhizome von Polypodium aureum L. and Polypodium trise-riale, characterized in that the rhizomes are cut into strips and the rhizome strips and the leaves are subjected to continuous drying at a temperature not exceeding 70 ° C., the dried material, which has a residual moisture content of less than 8%, is ground, to obtain particles with a diameter of up to 2 mm and a bulk density between 0.1 and 0.8 / cm3; extract this material with ethanol, methanol or chloroform, evaporate the solvent and clean the residue. 2. The method according to claim 1, characterized in that the semi-solidified residue is taken up in n-hexane / water, left in a separator and the aqueous phase is separated off; the aqueous solution is passed over an exchange resin and then Ca (OH) 2 is added until neutralization, portions of activated carbon are added until the solution is clarified; evaporate to '/ io of the starting solution and precipitate with absolute alcohol, filter the precipitate with suction and evaporate the filtered aqueous solution again to obtain a second precipitate and finally dry the combined precipitates in vacuo until a white, solid material remains. 2nd PATENT CLAIMS 3. The method according to claim 1 or 2, characterized in that the rhizomes are cut into strips of 2 to 3 cm in width. 4. The method according to claim 1, 2 or 3, characterized in that the semi-solidified residue is taken up in n-hexane / water, the volume ratio of which is 10: 4. 5. The method according to any one of claims 1 to 4, characterized in that the semi-solidified residue taken up in n-hexane / water is left overnight in a separator. 6. Polar fraction with an antipsoriatic effect of an extract, prepared according to the method of claim 1. 7. Pharmaceutical preparations, characterized by the content of polar fraction of an extract according to claim 6.