CS215008B2 - Method of gaining natural polar fractions with antipsoriatic activity - Google Patents

Abstract

Fractions extracted from the rhyzomes or leaves of various ferns, in particular Dryopteris crassirhizoma, Polypodium vulgare, Linn, Polypodium leucotomos, Phelbodium Decumanun J. Smith, Polypodium decumanun, Cyathea taiwaniana, or rhyzomes of Polypodium aureum Linn or Polypodium triseriales, are effective in treatment of psoriasis. The fraction is extracted in a polar solvent by partitioning an extract between a polar solvent and a non-polar solvent e.g. water and n-hexane. Further purification of the fraction may occur e.g. by passing through an interchange column, neutralising with calcium hydroxide and recrystallising.

Description

The invention relates to a process for obtaining a natural polar fraction with antipsoriatic activity by etching from the leaves and rhizomes of various ferns.

Despite scientific and therapeutic advances, there is no drug capable of improving the condition, the less cure a patient suffering from psoriasis, and the dermatological problems caused by parapsoriasis.

These diseases have been known for a long time and many attempts have been made to cure them, but with only minor results, and the major obstacle is that in most cases substances or drugs are used that can be fatal to the patient in a short time.

The prior treatment method is now being used again, since these methods are harmless and provide some symptomatological relief to patients, although never cured or significantly improved.

The problem is getting worse due to the increasing number of psoriatic patients. It is possible that this is a genetic transfer, with the manifestation of the offspring manifestly or covertly, or it remains latent and occurs when pathological factors cause the discovery of the disease.

The entire body surface is affected, and one of the main areas is the skull, on which 'dandruff' is formed, which the patient usually does not pay attention to until after several years, even though local treatment has been used and the disease has worsened. The presence of 'dandruff' when psoriasis has affected other parts of the skin is observed in 90% of cases. The disease affects any part of the body surface regardless of age. Therefore, newborns as well as people in their sixties or seventies may be affected.

The geographical range is unlimited regardless of race, although the incidence of the black race is slightly lower.

The most common complication of the disease is arthropathies, but fine tissues such as liver and kidney tissue may also be affected.

. Psoriasis and parapsoriasis are pathological lesions that are easily recognized even when anatomical-pathological diagnosis is required.

At least 1% of the world's population suffers from this disease. No effective remedy for psoriasis has been found.

The natural polar fraction isolated from the rhizomes and leaves of Dryopteris crassirhizoma, Polypodium vulgare, Linn, Polypodium leucotomos, Phlebodium decumanum, Cyathea taiwaniana and the rhizomes of Polypodium aureum Linn and Polypodium triseriale have been found to have therapeutic properties in both psoriasis and psoriasis patients.

4 sex of any age. This also applies to their derivatives: esters, amides, etc. More than 300 patients suffering from psoriasis have been treated orally with a small amount, for example 5 mg daily per kg body weight. . As a result, 80% of patients treated for about 3 months were completely cured. A double blind was performed on a group of 50 patients and the drug was shown to be efficacious compared to the control group, using the same organoleptic size, shape and properties. These fractions and their derivatives have been used in all forms of psoriasis and at various degrees of pathological lesion.

No toxicological effect was found. During 12 years of research, there were no changes in hematology, bone marrow, kidney and liver function, nor in urine analysis. In accordance with the procedure proposed by the FDA of the United States of America and · according to the “Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use”. it has been found that these compounds do not alter the fertility of rats and mice or other mammals, e.g., dogs; and also no teratogenic effect was found in four generations of rats and mice and two generations of dogs.

There was also no evidence of carcinogenic activity. These studies were performed in mice by daily oral administration of 1 mg / kg body weight for 24 weeks. Animals were killed 7 weeks later with and without the introduction of glass particles into the bladder. Methods used in these studies are described in Jull, J. W. Brit. J. Cancer, 5, 328 [1951] and statistical evaluation is described in Arcos et al., Chemical Induction of Cancer, Pag. Academic Press Inc., New York [1963].

The polar fraction causes:

(a) enhancing cell membrane permeability for sugars such as glucose, sucrose, fructose, and. amino acids such as valine, lysine and others in minor amounts.

b) increasing the mobility capacity of the cell membrane carriers.

c) increasing the exchange of water on the membrane.

d) these effects are possibly related to those mentioned above, an increase in hepatocyte activity has been observed in which a large metabolic effect is induced.

e) increasing collagen growth and maturation activity.

The product does not have steroid activity. As far as its effect on other organs and systems is concerned, it has a bradycardiatic effect similar to digitalis, possibly due to action on myocardial cell membranes.

The process according to the invention permits the extraction of this polar fraction from the abovementioned plant parts in industrial yields and in an amount useful for the preparation of pharmaceutical preparations. To obtain the highest yield it is necessary to carry out. leaf collection when spores have already developed.

The method of the invention comprises the following steps:

Drying

For example, the rhizomes are cut to 2-3 cm increments, the leaves are dried immediately after harvesting. The drying is carried out by continuously feeding the material into a conventional dryer consisting, for example, of a rotating metal wire cloth of about. 5 cm and a length of 25 m moving in a hot environment with a temperature of 70 ° C or less. The speed of the rotating metal wire cloth is adjusted so that it can be dried. about 500 kg of wet material per hour.

Granulation

Dry material · with a residual moisture content of less than 8% se. granulated in a disc mill so that the resulting particles have a size of 2 mm.

Extraction — Evaporation

It can be carried out with any solvent having a dielectric constant of 1.890 to 9.08. Preferably 1: 4 methanol is used.

After evaporation, a residue of 1/5 of the original volume remains.

Purification

1. The semi-solid residue after evaporation was partitioned in a system of immiscible solvents, N-hexane / water [10: 4] and left to stand in separators overnight, whereupon the lipids and resins were separated in the hexane phase.

2. Pass the separated and filtered aqueous solution through an ion exchange column.

3. Neutralize Ca (OH 2).

4. Charcoal is added in portions to the above solution until the solution is clear.

5. This solution is evaporated to 1/10 the original volume and precipitated with a water miscible anhydride of an organic liquid, for example an absolute alcohol.

6. The precipitate is suction filtered to give a first powdery mass and after evaporation of the mother liquor a second powdery mass is obtained.

The powder is dried under vacuum until it becomes whitish.

The second white crystalline mass, inherent in the present invention, is not a defined chemical substance but a composition depending on the type of substance used and the extraction and purification procedures.

The qualitative test results indicate a total of 70% of D-glucose and D-fructose, which is also the result of isolation and overall characterization of the corresponding acetylated derivatives. On the other hand, the presence of acidic compounds that cannot be readily separated from sugars is tested by chromatography and conventional spectroscopic methods.

The pharmaceutical compositions of this invention are prepared in conventional dosage form by incorporating the polar fraction into a pharmaceutical carrier, according to the pharmaceuticals adopted. procedures. The resulting pharmaceutical compositions form an object of the present invention. The active ingredient, i.e., the polar fraction, will be present in the compositions of the invention in an amount capable of inducing antipsoriasis activity.

The compositions of the invention preferably contain from about 10 to about 100 mg per dosage unit of active ingredient. For example, the pharmaceutical carrier may be a solid or a liquid. Examples of solid carriers are lactose, magnesium stearate, alba terra, sucrose, talc, stearic acid, gelatin, agar, pectin, acacia, aerosil and the like.

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.

Many different pharmaceutical forms can be used. When a solid carrier is used, the preparation may be in the form of tablets, may be incorporated into hard gelatin capsules in the form of powder or granules, or may be in the form of a troche.

The amount of solid carrier may vary within wide limits, but is preferably from about 25 mg to about 300 mg. When a liquid carrier is used, the preparation may take the form of a syrup, emulsion, soft gelatin capsule, suspension or liquid solution, or be in sterile injectable form for parenteral use, for example, in an ampoule.

The pharmaceutical compositions of the present invention in liquid suspensions or solutions do not include simple liquid suspensions or solutions of the active ingredient in a solvent generally unsuitable for internal administration to produce the desired pharmacological activity.

another object of the invention is to divide the dosage unit in the form of tablets, capsules, troches, liquid suspensions or sterile injectable liquids for internal administration which produce antipsoriatic activity, comprising a pharmaceutical carrier and a polar fraction in an amount sufficient to cause such activity.

The route of administration may be oral or parenteral, preferably oral. The active ingredient will preferably be administered in a daily dose of about 50 mg to 900 mg, especially 100 to 300 mg. It is preferred to administer equivalent doses of 1 to 4 times daily. In this mode of administration, antipsoriatic activity is induced.

Since sporiasis is a chronic disease of genetic etiopathogenesis, it is preferable to use forms of tablets or capsules to maintain a constant concentration of the substance in the blood that permits sustained action of the drug. Undoubtedly, in the treatment of severe outbreaks of psoriasis caused by other drugs such as steroids, or spontaneous outbreaks of the disease itself, intravenous injection or continuous serum drip may be used to prevent a crisis.

For obvious reasons, the drug is used in the form of drops or emulsions in children and the use of suppositories in adults with upper gastrointestinal disorders.

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

The following examples illustrate the invention:

Example 1 kg of leaves granulated on a 2.5 mm sieve were extracted for one and a half hours with 48 liters of 95% ethanol at 70 ° C.

The residue was mixed with n-hexane / water, 15: 10 L, and allowed to stand overnight in a separator. The hexane phase was then separated and the aqueous phase was filtered.

The filtrate was neutralized with alkali after passing through the ion exchange column.

The neutralized solution was purified and evaporated to near dryness under a slight vacuum for 48 hours. The yield was about 150 grams.

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

Example 2 kg of dry plants granulated in a 2.5 mm disc mill were extracted for 16 hours with n-hexane at room temperature. The hexane solution was concentrated and allowed to stand in water in a separator overnight. The hexane phase was separated and the aqueous phase was evaporated.

Sufficient hot ethanol was added to the remainder of the hexane-extracted plants, and this mixture was left overnight to form a saturated extract. The solution was filtered, added to the aqueous phase and chromatographed on an ion exchange column.

The solution was then neutralized and purified

a. Evaporated to near dryness.

The solid was redissolved in 70% ethanol and crystallized at room temperature overnight. The crystals were separated and the succinate was evaporated and dried under vacuum. The yield was 180 g.

EXAMPLE 3 1.2 kg of dry rhizomes, granulated in a disk mill having an orifice size of 2.5 µm, were continuously extracted with chloroform at room temperature.

The extract was concentrated and redissolved in n-hexane / water.

The heixane phase was separated and the aqueous phase was evaporated.

The remainder of the extracted rhizomes was added to hot methanol and allowed to stand for 16 hours. It was then filtered and the filtrate was chromatographed on an ion exchange column.

The extract was neutralized, purified and evaporated and placed in a crystallizer in 95% ethanol overnight. The crystals were collected and the supernatant was evaporated and then dried in vacuo. The yield was 84 g.

Example 1 to d 4

Refluxing for 11/2 hours 12 kg of granular dried plants of particle size

2.5 mm was extracted with 90% methanol at 70 ° C.

The extract was filtered, evaporated, and added to the hexane / water mixture. 3: 2, allowed to stand and the hexane was then separated, and the aqueous phase was filtered and evaporated.

The residue was dissolved in 90% hot ethanol and chromatographed on an ion exchange column.

The extract was neutralized and evaporated to 1/10 the original volume and allowed to crystallize in the cold.

It was then filtered, the crystals were separated and the supernatant was dried under vacuum. The yield was 240-250 g.

The following pharmaceutical preparations illustrate but do not limit the invention:

Claims (1)

SUBJECT Method of obtaining natural polar fraction and antipsoriatic activity, extraction from rhizomes and leaves of different types of dryoipteris crassirhizoma, Polypodium vulgae Linn., Polypodium leucotomos, Phelbodium decu.manu.m 'J, Srnitli, Polypodium decumanum, Cysteanium and Cydenea taiku. And Polypodium triseriale, characterized in that the rhizomes are cut into 2-3 cm strips and the rhizomes and strips are dried in a continuous dryer at a temperature of not more than 70 ° C; then, the dry material with a residual moisture content of less than 8% is granulated to particles up to - 2 mm in diameter and a density of about - 0.1 to 0.8; extraction is carried out in a solvent having a dialectic constant of 1.890 to 9.08, the solvent is evaporated and the residue is purified; semi-solid residue - after extraction is at 8 Example 1 Quantity components Polar fraction 40 mg Lactose 60 mig The ingredients are mixed, sieved and placed in hard gelatin capsules. The capsules thus prepared are administered three times a day. Example 2 Quantity components Polar fraction 60mg Starch 60-mg Talek 5mg Kaolin 5mg Poles of guilt lpyrolidone 5mg The fraction and starch are mixed and granulated with a solution of 10% gelatin, including polyvinylpyrrolidone. The granules are sieved, dried and then blended with kaolin and talc. They are then sieved and formed into tablets. The irrigation on the intensive exchange column is carried out by applying the filtered solution, the product of the extraction of the plant, 12 kg of dry weight, to a glass column having a diameter of 20 cm, containing 500 g resin. The resin is a porous polystyrene, i.e. copolymers of styrene and di-vinylbenzene, of such a mixed type that it exchanges strongly acidic cationic and strongly basic anions. The particles have a diameter of 20 to 50 mm. The flow rate is 30 drops per second. Then the eluate is neutralized by the addition of calcium hydroxide. In Examples 1-4, the eluate was neutralized by the addition of calcium hydroxide, allowing the most efficient removal of pigments from the solution, since converted to salts are better absorbed by activated carbon. YNALEZU adds 10: 4 to n-hexane / water, allowed to stand overnight in a separator, the aqueous phase is separated, and the solution is passed through a 20 cm column containing 500 g of porous polystyrene resin, styrene-di-copolymers -vinylbenzene, which exchanges strongly acidic cations and strongly basic anions, at a rate of 30 drops - per second, neutralizes - is added by adding Ca [OH] 2 in portions, 1/10 of the original volume and precipitated with absolute alcohol, the precipitate is filtered off with suction and the mother liquor is evaporated to give a second powdered mass which is dried under vacuum until a very white solid is obtained.