NO792260L - PROCEDURE FOR THE EXTRACTION OF A NATURALLY EXISTING POLAR FRACTION WITH ANTIPSORIATIC EFFECT - Google Patents

Description

This invention relates to the production of a natural,

polar fraction with antipsoriatic effect, by extraction from leaves and rhizomes of various ferns.

Despite the scientific-therapeutic development, there is no drug capable of improving the condition of, let alone curing, patients suffering from psoriasis

and the dermatological problems associated with parapsoriasis.

Knowledge of psoriasis is very old, and many

Searches have been made to cure the disease. However, the efforts have only led to very modest results, and in most cases drugs and medications are used which can have fatal consequences for the patient within a short time.

Interestingly enough, people have now started to use the previous forms of treatment again, because they are harmless, and because

they provide the patient with some symptomatic relief. However, they are

never able to cure the disease or bring about any remarkable improvement in the condition.

The problem becomes much more serious as the number of psoriatic patients increases from day to day. It is assumed that this is a matter of genetic transmission of the disease, and that the disease either appears in the individuals of the family clearly and distinctly or in an initial form, or exists as a latent possibility, in which latter case the disease will manifest itself only if triggering pathological factors may come into play.

The entire body surface is affected, and one of main area

is the scalp, where the condition manifests itself in "dandruff", which the patient usually does not notice until many years have passed and

he becomes aware that the problem has worsened despite local treatment. The presence of "dandruff", when psoriasis attacks other parts of the skin, is observed in 90% of cases. The disease thus attacks any part of the body surface, regardless of the person's age. Therefore, newborn babies can like-

as well as old people in their 60s or 70s being attacked.

The disease is widespread all over the globe and does not discriminate between races. Possibly the frequency is somewhat less for the black race.

The most common complication associated with the disease,

is arthropathy, but the disease will also eventually affect the nobler tissues, such as liver and kidney tissue.

In short, psoriasis and parapsoriasis are pathological lesions that are easy to diagnose, even when anatomical-pathological diagnosis is required. It is conservatively estimated that 1% of the world's population suffers from the disease. So far, no effective drug has been found, and psoriatic patients have had to make do with palliatives.

It has now been shown that a natural fraction that is isolated

from rhizomes and leaves of Dryopteris crassirhizoma, Polypodium vulgare, Linn, Polypodium leucotomos, Phlebodium decumanum and Cyathea taiwaniana and from rhizomes of Polypodium aureum Linn and Polypodium triseriale, have healing properties when treated

of psoriatic and parapsoriatic patients of both sexes and all ages. The same also applies to derivatives of the fraction's substances, such as esters, amides, etc. More than 300 patients suffering from psoriasis were treated orally with a small amount, e.g. 5 mg daily per kg body weight. The result was that 80% of the patients. which was treated for approx. 3 months, was completely cured. A double blind test was performed on a group consisting of 50 patients. The drug proved to be effective compared to a placebo preparation that had the same organoleptic size,

form and characteristics. These fractions and derivatives of the active substances have been used for all forms of psoriasis and at all stages of this pathological lesion.

In toxicological terms, no effect was detected. During 12 years of research, haematological tests, bone marrow tests, tests with regard to the functioning of the liver and kidneys and urinalysis have never shown any changes. According to the guidelines given by the F.D.A. in the USA, and according to the "Guidelines for reproduction studies for safety evaluation of drugs for human use", the compounds do not alter fertility in rats and mice and other mammals (dogs). Nor has any theratofenic effect been demonstrated during four generations of rats and mice and two generations of dogs.

No carcinogenic effect has been demonstrated. These investigations were carried out on mice, which were given an oral dose of 1 mg per day for 24 weeks. kg body weight. Starting from the seventh week, the animals were euthanized with and without the introduction of glass particles into the urinary bladder. The methods used in these investigations are described by Jull, J.W. Brit J. Cancer 5 328 (1951), and the statistical evaluation used is described in Arcos et al., Chemical Induction of Cancer, Pag. Academic Press inc., New York (1963).

The polar fraction's mechanism of action is as follows:

(a) an increase in permeability, through the cell membrane,

of sugars such as glucose, sucrose and fructose, and for amino acids such as valine, lysine and others that occur in smaller amounts,

(b) an increase in the movement capacity of cell membrane carriers,

(c) an increase in water exchange at the cell membrane level,

(d) an increase in the activity of hepatocytes (this observed increase is possibly related to the above-mentioned increases), (e) an increase in the growth and maturation activity of the collagen.

The fraction has no steroidal activity. As regards its action on other organs and systems, it has a bradycardic effect similar to that of digitalis, possibly as a result of its action on the myocardial cell membranes.

The method according to the invention enables the extraction of this polar fraction in industrially acceptable yields and in acceptable quantities from the above-mentioned parts of the plants, for use in the manufacture of pharmaceutical preparations. To achieve an optimal yield, the leaves should be collected after the plants

have developed spores.

The method according to the invention includes the following steps:

Drying

The rootstocks should be present f-, e.g. in strips of length 2 -

3 cm, while the leaves are dried in the state in which they are collected. The drying takes place by continuously feeding the material to a conventional dryer such as can consist of a rotating metal wire cloth of width approx. 5 cm and length 25 m, which is moved in a warm room at a temperature of no more than 70°C. By adjusting the speed of the rotating metal wire cloth, approx. half a tonne of moist material is dried per hour.

Granulation

The dry material (with residual moisture less than 8%) is granulated in a disc mill which is set to give particles of

2 mm.

Evaporation of exhaust gases

The extraction can be carried out with any solvent (with a dielectric constant in the range from 1.890

to 9.08), which is preferably methanol used in the volume ratio 1:4.

The evaporation is carried out so that a residue corresponding to 1/5 of the original volume is obtained.

Cleaning

1. The semi-solid residue from the extraction and evaporation operation is taken up in a system of immiscible solvents, namely n-hexane and water (10:4). The mixture is allowed to stand overnight in separators, after which lipids and resins are separated in the hexane phase. 2. The separated and filtered aqueous solution is passed through an exchange column.

3. Ca(OH)2 is added for neutralization.

4. Portions of active carbon are added to the above solution until the solution is clear. 5. The solution is evaporated to 1/10 of the original volume, and precipitation is carried out in a water-miscible, anhydrous organic liquid, such as e.g. absolute alcohol. 6. The skimming is filtered off by suction, whereby a first, powdery mass is obtained, and the mother liquor is evaporated again, whereby a second, powdery mass is obtained.

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

The other, white, crystalline mass, which is the product obtained by the method according to the invention, is not a well-defined chemical substance, but a composite material that will vary with the nature of the drug used and with the extraction and purification methods used.

That D-glucose and D-fructose are present in a total amount of 70% has been demonstrated by usual qualitative tests in addition to the isolation and complete identification of the corresponding acetylated derivatives. The presence of the acidic compounds which cannot be easily separated from the sugars, on the other hand, is determined by chromatography and by conventional spectroscopic methods.

Pharmaceutical preparations in the conventional dosage forms are prepared by incorporating pharmaceutical carriers in the polar fraction obtained by the method according to the invention in accordance with normal pharmaceutical practice. The active ingredient, i.e. the polar fraction, will be present in the preparations in sufficient quantity to produce an antipsoriatic effect.

The preparations preferably contain from 10 to 100 mg of the active ingredient per unit dose. The pharmaceutical carrier can e.g. be a solid or a liquid. Lactose, magnesium stearate, alba terra, sucrose, talc, stearic acid, gelatin, agar, pectin, gum arabic, aerosil and the like are examples of solid carriers.

Examples of liquid carriers are alcohols (such as ethanol or propylene glycol), water containing a solubilizing agent such as polyethylene glycol, peanut oil, olive oil and the like. The carrier or dilution material may contain a retardant. agent, such as glyceryl monostearate or glyceryl di-stearate, alone or together with a wax.

A large number of pharmaceutical forms can be used. If a solid carrier is used, the preparation can be transferred to tablets, introduced into a hard gelatin capsule in the form of a powder or in the form of granules, or it can be given in the form of lozenges. The amount of solid carrier can vary within wide limits but is preferably from 25 to 300 mg. If a liquid carrier is used, the preparation can be given in the form of a syrup, an emulsion, soft gelatin capsules, a suspension or a liquid solution, or it can be given in a sterile, injectable form for parenteral use, e.g. in an ampoule.

The pharmaceutical preparations in liquid suspensions or solutions do not include the simple liquid suspensions or solutions of the active ingredient in the usual solvents which are unsuitable for internal administration to produce the desired pharmacological activity.

The administration can take place orally or parenterally, preferably orally. The active ingredient will preferably be administered in a daily dose of from 50 mg to 900 mg, preferably from 100 to 300 mg. It is advantageous to administer the preparations from 1 to 4 times per day. When the administration takes place as described above, an antipsoriatic activity is achieved.

As psoriasis is a chronic, insidious process with a genetic etiopathogenesis, it is advantageous to use capsule or

the tablet form, which maintains stable blood concentrations and which allows a continuous effect of the drug. In the treatment of severe outbreaks of psoriasis, which may be caused by the use of other drugs, such as steroids, or may be caused by the disease itself, no doubt intravenous injection or continuous, dropwise administration of serum may be used to avert the crisis.

It should also be pointed out that drops or emulsions have been used for children for obvious reasons, and in the case of adults with problems in the upper digestive tract, suppositories can be used.

The pharmaceutical preparations are prepared by conventional methods such as mixing, granulation and pressing, when this is necessary, or by mixing and dissolving the appropriate ingredients.

The following examples illustrate the invention.

Example 1

12 kg of dry leaves, granulated in a No. 10 sieve (2.5 mm) were extracted with 48 liters of 95% ethanol for one and a half hours at 70°C.

The residue was taken up in a mixture of n-hexane/water

(15:10 liters), and the whole was allowed to stand overnight in a separator. The hexane phase was separated and the aqueous phase was filtered.

The filtrate was passed through an exchange column, which was then neutralized with alkali.

The thus neutralized solution was clarified and evaporated almost to dryness under a moderate vacuum for 48 hours (yield: approx. 150 g).

The dry solid was redissolved in methanol and allowed to crystallize overnight at 40°C.

Example 2

36 kg, dry, whole plant, which was granulated, in a disc mill equipped with a No. 10 sieve (2.5 mm), was extracted for 16 hours with n-hexane at room temperature. The hexane solution was concentrated and allowed to stand in water overnight in a separator. The hexane phase was separated and the aqueous phase was evaporated.

The plant residue extracted with hexane was taken up in a sufficient amount of hot ethanol and allowed to stand overnight to form a saturated extract. The solution was filtered, added to the aqueous phase and passed through an exchange column.

The solution was then neutralized and clarified and then evaporated almost to dryness.

The substance obtained was then re-dissolved in 70% ethanol and allowed to crystallize overnight at room temperature. The crystals were separated, the excess liquid was evaporated,

and the yield (180 g) was dried under vacuum.

Example 3

12 kg of dry rhizomes, which had been granulated in a disc mill fitted with a No. 10 sieve (2.5 mm) were continuously extracted with chloroform at room temperature.

The extract was concentrated and redissolved in a mixture of n-hexane and water.

The hexane phase was separated and the aqueous phase evaporated.

The residue of the extracted rhizomes was taken odp i

hot methanol and allowed to stand for 16 hours. The mixture was filtered and passed through an exchange column.

The extract was neutralized and clarified, after which it was evaporated and placed overnight in 95% ethanol in a crystallizer. The crystals were separated, after which the excess liquid was evaporated and the residue obtained dried under vacuum (yield: 84 g).

Example 4

By heating with reflux for one and a half hours, 12 kg of granulated, dried plant (No. 10 sieve, 2.5 mm) was extracted with 90% methanol at 70°C.

The extract was filtered, evaporated and taken up in a mixture of hexane and water (3:2). The mixture was allowed to stand, after which the hexane phase was separated and the aqueous phase was filtered and evaporated.

The residue was dissolved in 90% hot ethanol and passed through an exchange column.

The extract was neutralized and evaporated to one-tenth of its original volume, after which it was allowed to crystallize cold.

After filtering the mixture, the crystals were separated and the mother liquor dried under vacuum (yield: 240-250 g).

The following examples of pharmaceutical preparations will further illustrate the invention.

Example 1

The ingredients were mixed, sieved and introduced into hard gelatin capsules. A capsule prepared as described above is administered three times per day.

Example 2

The fraction and the starch were mixed and granulated with a solution of 10% gelatin containing the polyvinylpyrrolidone. The granules were sieved, dried and then mixed with kaolin and talc. They were then sieved and transferred to tablets.

Claims (1)

Process for extracting a natural, polar fraction with antipsoriatic action, by extraction from rhizomes and leaves of Dr yo pteris crassirhizoma, Polypodium vulgare, Linn, Polypodium leucotomos, Phelbodium Decumanum J. Smith, Polypodium decumanum and Cyathea taiwaniana and rhizomes of Polypodium aureum Linn and Polypodium triseriales, characterized in that the rhizomes are cut into strips of length 2-3 cm and the rhizome strips and leaves are subjected to a continuous drying process at a temperature of at most 70°C, that the dry material, with a residual moisture less than 8%, is granulated into particles of diameter up to 2 mm and specific gravity approximately from 0.1 to 0.80, that the particles are subjected to extraction with a solvent having a dielectric constant in the range from 1.890 to 9.08, after which the solvent is removed by evaporation and the residue is purified, the semi-solid residue of the extract is taken up in n-hexane/water (10:4), after which the mixture is allowed to stand overnight one over into a separator and the water phase is separated, that the aqueous solution is passed through an exchange resin and CatOH^ is added to neutralize the solution, after which portions of active carbon are added until the solution is clear, that the solution is then evaporated to 1/10 of the original volume and skimming is carried out with absolute alcohol, and that the skimming is filtered off under suction and the filtrate is evaporated, whereby a new, powdery mass is obtained, which is dried in a vacuum until a very white solid is obtained.