GB2024622A - Anti-psoriatic fern extracts - 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

SPECIFICATION Natural polar fraction having anti-psoriatic activity This invention refers to a natural polar fraction having anti-psoriatic activity, by polar solvent extraction from leaves and rhyzomes of various ferns.

In spite of scientific-therapeutic advance, there is no medicament capable of alleviating, much less curing, a patient suffering from the skin diseas psoriasis and the associated dermatological problems related to parapsoriasis.

Knowledge of the disease is very old and many attempts have been made to cure it, ending only in very poor results. In the majority of the cases today, drugs or medicaments are used which can, even in the short term, be fatal for the patient.

Curiously, the formerly used treatments are again being used, since they are innocuous and the patients find some symptomatological relief, though there is never complete cure.

The problem is becoming worse due to the daily increase in the number of psoriatic patients. The hypothesis is that it is a problem of genetic transmission which may clearly manifest itself in descendants, or will at least remain latent and only manifest itself when triggered off by pathological factors.

The complete body surface is affected by red scaly patches and one of the main regions is on the skull in the form of "dandruff" to which the patient does not often pay attention until, after many years have lapsed and in spite of having used local treatments, he realises that his problem has become worse. The presence of "dandruff" when the psoriasis attacks other dermal parts, is observed in 90% of the cases. Thus, the disease attacks any part of the body surface, irrespective of age. Therefore, newborn babies as well as old people during the sixth or seventh decade of their life can be affected.

The geographical occurance of the disease is universal and it does not respect races; the index thereof being perhaps lower in the black race.

The most frequent complication is arthropathy, but it eventually also affects the noble tissues, such as the hepatic and renal tissues.

In short, psoriasis and parapsoriasis are pathological lesions which are readily diagnosed, even though an anatomo-pathological diagnosis is necessary. Conservatively speaking, 1% of the world's population suffers therefrom. Up to now there has been no effective medicament and psoriatic patients can only rely on the remedies.

It has now been found that the natural polar fraction isolated from rhyzome or leaves of various ferns have curing properties in the treatment of psoriatic and parapsoriatic patients of both sexes and all ages. This, furthermore, includes derivatives thereof e.g. esters and amides.

The present invention provides a process for obtaining a fraction effective in the treatment of psoriasis from plant matter comprising the rhyzomes or leaves of the ferns Dryopteris crassirhizoma, polypodium vulgare, Linn, Polypodium leucotomos, Phelbodium Decumanun J. Smith, Polypodium decumanun, Cyathea taiwaniana or rhyzomes of Polypodium aureum Linn or Polypodium triseriales, which comprises; I) forming a dry comminuted mass of the plant matter; li) solvent extracting the comminuted mass to form an extract; III) partitioning the extract between polar and non-polar solvent phases; IV) separating the solvent phases to obtain the polar phase comprising said fraction.

The invention also extends to a medicament comprising the fraction.

More than 300 patients suffering from psoriasis were treated orally with a small amount, for example, 5 milligrams daily per kilo of weight The result was that 80% of the patients, treated for approximately 3 months, were completely cured. A double blind test was carried out on a group of 50 patients and the drug demonstrated to be effective in comparison with a placebo using the same organoleptic size, shape and characteristics. These fractions and the derivatives thereof have been used in all the forms of psoriasis and in the different stages of this pathological lesion.

From a toxicological point of view, no ill-effects were found. Over 12 years of research, the haematological tests, bone-marrow tests, tests as to the renal and hepatic functioning, and urine analysis have never shown any alteration. Following the standards of the F.D.A. in the United States and according to "Guidelines for reproduction studies for safety evaluation of drugs for human use", these compounds do not alter the fertility in rats and mice or in mammals (dogs); neither has any theratopheny effect been seen in four generations of rats and mice and two generations of dogs.

Nor has carcinogenic activity been found. The studies were made on mice administered daily with an oral dose of 1 milligram per kilo of body weight, for 24 weeks. The aminals were slaughtered as from the 7th week onwards with and without the introduction of glass particles in the urinary bladder. The methods used in these studies are described by Jull, J.W. Brit J. Cancer 5328 (1951) and the statistic evaluation used is described in Arcos and collaborators, Chemical Induction of Cancer, Pag. Academic Press Inc., New York (1963).

The action mechanism of the polar fraction is believed to involve a) increase in permeability through the cellular membrane of the sugars, such as glucose saccharose, fructose and aminoacids, such as valine, lysine and others in a smaller quantity.

b) increase in the movement capacity of the cellular membrane carriers.

c) increase in the water interchange at the cellular membrane level.

d) possibly related to the former, there has been observed an increase in the activity of the hepatocytes from where the great metabolic effect thereof is emitted.

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

It does not have steroidal activity. Insofar as its effect on the other organs and systems, it has a bradycardiac effect similar to the digitalis, possibly due to the action thereof on the myocardium cellular membranes.

The method of the invention permits the extraction of this polar fraction from the aforementioned parts of the plants with industrial yields and in useful quantities for use in the preparation of pharmaceutical compositions. To obtain an optium yield, the leaves should be collected after sporelings have already developed.

The process preferably comprises the following steps: Drying The rhyzomes should, for example, be in strips of 2-3 cms., the leaves are dried as they are collected.

Drying takes place continuously-feeding the material into a conventional drier constituted, for example, by a rotary metallic wirecloth approximately 5 cm. in width and 25 m. in length which is moved within a heated compartment at a temperature not greater than 70"C. By adjusting the speed of the rotary metallic wirecloth, about half a ton of moist material can be dried per hour.

Granulating The dry material (residual humidity lower than 8%) is granulated in a disc mill adjusted to produce particles of 2 mm.

Extraction-Evaporation This can take place with any suitable solvent. The dielectric constant of the solvent is preferably from 1.89 to 9.08 e.g. n.-hexame or chloroform (dielectric constants 1.89 and 4.81 respectively) but may also be methanol (dielectric constant 32) methanol in a proportion of 1:4 by volume.

The extract is evaporated to leave a residue which corresponds to 1/5th of the original volume of the extract.

Purification 1. The semi-solid residue from the extraction-evaporation step is distributed in a system of immiscible solvents e.g. n-hexane/water (ratio 10:4) and is allowed to stand in a separator overnight, lypids and resins separating in the hexane phase..

2. The separated and filtered aqueous solution is then passed through an ion-exchange column.

3. Ca(OH)2 is added to neutralize the aqueous solution.

4. To the solution is then added activated carbon portions until the solution is clarified.

5. The solution is filtered and evaporated to 1/10th of its original volume and is precipitated in a water miscible anhydrous organic liquid, for example, absolute alcohol.

6. The precipitate is filtered by suction to yield a first powdered mass and the mother liquors are evaporated to yield a second powdered mass.

This second mass is dried under vacuum until it is very white.

The second white crystalline mass is not a well defined chemical substance, but has a composition imposed by the nature of the plant used and by the extraction and purification methods.

The presence of the D-glucose and D-fructose in a total amount of typically 70% has been shown by usual qualitative tests. The isolation and the complete characterization of the corresponding acetylated derivatives has also been undertaken. The presence of acid compounds which cannot be readily separated from the sugars has been shown by chromatography as well as by usual spectroscopic methods.

The pharamaceuticl compositions may be prepared in conventional dosage forms by incorporating the polar fraction in a pharmaceutical carrier, according to accepted pharmaceutical practice. The resultant pharmaceutical compositions constitute aspects of this invention. The active ingredient, that is to say the polar fraction, will be present in the compositions of this invention in a sufficient amount to produce antipsoriatic activity.

The compositions preferably contain from 10 to 100 mg per unit dosage ofthe active ingredient. The pharmaceutical carrier may be solid or liquid. Lactose, magnesium stearate, alba terra, saccharose, talc, stearic acid, gelatin, agar, pectin, gum arabic and aerosil 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 and olive oil. The carrier or diluent may include a retarding agent, such as glyceryl monstearate or glyceryl distearate, on its own or with a wax.

Awide variety of pharmaceutical forms can be used. Thus, if a solid carrier is used, the preparation may take the form of tablets introduced into a hard gelatin capsule in the form of a powder or granules, or it can adopt the trochiscus form. The amount of solid carrier can vary widely but is preferably from 25 mg to 300 mg. If a liquid carrier is used, the preparation can adopt the form of a syrup, emulsion, soft gelatin capsule, suspension or liquid solution, or a sterile injectable form for parenterai use, for example, in an ampoule.

The pharmaceutical compositions of this invention in liquid suspensions or solution, do not include simple liquid suspensions or solutions of the active ingredient in common unsuitable solvents for internal administration to produce the desired pharmacological activity.

The unit dosage in the form of tablets, capsule, trochiscus, liquid suspension or sterile injectable liquid for internal administration is such as will produce an anti-psoriatic activity; and is thus constituted by a pharmaceutical carrier and a polar fraction in a sufficient amount to produce said activity.

The mode of administration can be oral or parenteral, preferably oral. The active ingredient will preferably be administered in a daily dosage amount of 50 mg to 900 mg., and even better from 100to 300 mg. It is advantageous to administer equivalent dosages 1 to 4 times per day. When administration is as previously described, an anti-psoriatic activity is obtained.

Since psoriasis is a chronic insiduous disease having a genetic etiopathogeny, it is preferableto use the form of capsules or tablets, to maintain stable blood concentrations and to permit continued action of the medicament. However, when treating serious outbreaks of psoriasis,-possibly caused by somme other medicament (e.g. by the use of steriods) intravenous injection or continuous dropwise feeding of serum can be used to prevent the crisis.

It should also be pointed out that the medicament in the form of drops or an emulsion may be used in children, and in the case of adults having problems of the upper digestive canal, suppositories can be used.

The pharmaceutical compositions may be prepared by conventional techniques such as mixing, granulation and compression or by mixing and dissolving suitable ingredients to make the desired compositions.

The following examples illustrate the invention: Example I 12 Kgs. of dry leaves, granulated in a No. 10 screen (2.5 mm) were extracted for one and a half hours with 48 liters of 95% ethanol at 70"C, which was then evaporated to form a semi-solid residue.

The residue was taken up in a mixture of n-hexane/water (in ratio of 15:10) and was allowed to stand overnight in a separator. The hexane phase was separated off and the aqueous phase was filtered.

The aqueous filtrate was passed through an interchanging column and was then neutralized with alkali.

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

The dry solid was dissolved again in methanol and it was allowed to crystallise at 40 C overnight.

Example 2 36 Kgs. of dry plant granulated in a disc mill No. 10 screen (2.5 mm) 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 off and the aqueous phase was evaporated.

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

The solution was then neutralised, clarified and evaporated to almost dryness.

The solid was redissolved in 70% ethanol and allowed to cystallise at room temperature overnight. The crystals were separated and the supernatant was evaporated and dried under vacuum (yield: 180 gms).

Example 3 12 Kgs. of dry rhyzome, granulated in a disc mill No. 10 screen (2.5 mm), were continuously extracted with chloroform at room temperature.

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

The hexane phase was separated off and the aqueous phase was evaporated to form a residue.

The residue was taken up in hot methanol and allowed to stand for 16 hours. It was filtered and passed through an interchanging column.

The extract was neutralized clarified, evaporated and left in a cystalliser in 95% ethanol overnight. The crystals were separated and the supernatantwas evaporated and then dried under vacuum (yield: 84 gms).

Example 4 By refluxing for 1 1/2 hours, 12 Kgs. of granulated dried plant )no. 10 screen, 2.5 mm) were extracted with 90% methanol at 70do.

The extract was filtered, evaporated and taken up in a mixture of hexane/water (in a ratio 3.2). The mixture was allowed to stand and the hexane was separated off. The aqueous phase was then filtered and evaporated to leave a residue.

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

The ethanol solution was neutralised and evaporated to 1/10th of its original volume and allowed to crystallise in the cold.

The crystals were filtered off and the supernatant was dried under vacuum (yield 240-150 gms).

The following examples of pharmaceutical preparations are not limitative, but illustrative, of this invention.

Example 5 Ingredients Amounts Polar Fraction 40 mg Lactose 60 mg The ingredients are mixed, sifted and introduced into hard gelatin capsules. A capsule prepared as previously described in administered three times per day.

Example 6 Ingredients Amounts Polar Fraction 60 mg Starch 60 mg Talc 5 mg Kaolin 5 mg Polyvinylpyrrolidone 5 mg The fraction and the starch are mixed and granulated with a solution of 10% gelatin including the -polyvinylpyrrolidone. The granules are sifted, dried and then mixed with kaolin and talcum. The mixture is then sifted and converted into tablets.

Claims (18)

1. A process for obtaining a fraction effective in the treatment of psoriasis, from plant matter comprising the rhyzomes or leaves of the ferns Dryopteris crassirhizoma, Polypodium vulgare, Linn, Polypodium leucotomos, Phelbodium Decumanun J. Smith, Polypodium decumanun, Cyathea taiwaniana or rhyzomes of Polypodium aureum Linn or Polypodium triseriales, which comprises: I) forming a dry comminuted mass of the plant matter II) solvent extracting the comminuted mass to form an extract; III) partitioning the extract between polar and non-polar solvent phases; IV) separating the solvent phases to obtain the polar phase comprising said fraction.

2. A process according to Claim 1, wherein the separated polar phase is purified by passing over an ion-exchange resin and subsequently neutralising the solution produced.

3. A process according to Claim 2, wherein the solution is neutralised with calcium hydroxide.

4. A process according to claim 2 or 3, wherein the neutral solution is further purified by concentrating the solution and adding a water miscible an hydrous organic liquid thereto to form a precipitate, filtering off the precipitate, and isolating the fraction from the filtrate.

5. A process according to claim 4, wherein the anhydrous liquid is absolute alcohol.

6. A process according to any preceding claim, wherein the plant matter is dried at a temperature not greater than 70 to a residual water content less than 8%.

7. A process according to any preceding claim, wherein the dry matter is comminuted to form particles oi size less than 2 mm diameter.

8. A process according to any preceding claim, wherein the solvent extraction is performed using a solvent having a dielectric constant of from 1.89 to 34.

9. A process according to claim 7, wherein the solvent is n-hexane or chloroform.

10. A process according to any preceding claim, wherein the polar solvent is water and the non-polar solvent is n-hexane.

11. A process according to claim 9, wherein the ratio n-hexane to water is from 3:2 to 4:2.

12. A process for obtaining a natural polar fraction having an anti-psoriatic activity, by extraction from rhyzomes or leaves of the ferns Dryopteris crassirhizoma, Polypodium vulgare, Linn, Polypodium leucotomos, Phelbodium Decumanun J.Smith, Polypodium decumanun, Cyathea taiwaniana, or rhyzomes of Polypodium aureum Linn or Polypodium triseriales, wherein the rhyzomes are cut into strips of 2 - 3 cms.

and the strips of rhyzome and leaves are subjected to a continuous drying process at a temperature not greaterthan 70"C; subsequently granulating the dry material having a residual humidity lower than 8%to form particles of up to 2 mm. in diameter and a density of from 0.1 to 0.80; the extraction taking place with a solvent having a dielectric constant to form 1.89 to 9.08; the solvent then being evaporated and the residue purified; taking up the semi-solid residue of the extract in n-hexane/water, allowing to stand overnight in a separator and separating the aqueous phase, passing the aqueous solution through an interchanging resin; adding Ca(OH)2 to neutralise the solution; adding activated carbon until the solution is clarified; then evaporating the clear solution e.g. to 1/10 of the original volume and precipitating with absolute alcohol, filtering off the precipitate and evaporating the filtrate to yield a second powdered mass which is dried under vacuum until a white solid is obtained.

13. A process substantially as described in any of Examples 1 to 4.

14. A fraction effective in the treatment of psoriasis when produced by any preceding claim.

15. A medicament comprising the fraction of claim 13 or a derivative thereof.

16. A medicament which comprises the polar-solvent-soluble fraction from rhyzomes or leaves of Dryopteris crassirhizoma, Polypodium vulgare, Linn,, Polypodium leucotomos, Phelbodium Decumanun J.Smith, Polypodium decumanun, Cyathea taiwaniana or rhyzomes of Polypodium auream Linn or Polypodium triseriales, or a derivative thereof.

17. A medicament according to claim 15 or 16, which comprises 10 to 100 mg of the fraction per unit dose.

18. A medicament substantially according to Example 5 or 6.