FR2479690A1 - USEFUL MEDICINE, IN PARTICULAR FOR THE TREATMENT OF ARTHRITIS AND ITS PROCESS FOR OBTAINING EXTRACTION OF LEAVES AND RHIZOMES OF POLYPODIACEAE - Google Patents

Abstract

THE INVENTION CONCERNS AN ANTIARTHRITIC MEDICINAL PRODUCT BASED ON AN EXTRACT OF RHIZOMES AND LEAVES OF FERNS OF THE POLYPODIACEAE FAMILY AND ITS PREPARATION. THE PROCESS ACCORDING TO THE INVENTION INCLUDES THE FOLLOWING STEPS: 1. A MATERIAL CHOSEN FROM THE LEAVES AND RHIZOMES DRIED AND REDUCED INTO SMALL FRAGMENTS INDICATED HIGHER, THE LEAVES AND THE RHIZOMES OF THESE FOUESGER, THE LEAVES AND THE RHIZOMES INDICATED HIGHER. AND THE CAKE OBTAINED AFTER PRESSING IN THE FRESH STATE OF THESE LEAVES AND RHIZOMES, THE EXTRACT OBTAINED IN THIS CASE ADDED TO THE JUICE PRODUCED DURING THIS PRESSING OPERATION, THE VOLUME RATIO BETWEEN THE SOLID MATERIAL AND THE SOLVENT D 'EXTRACTION IS BETWEEN 1: 2 AND 1:10. 2. THE EXTRACT FROM THE PREVIOUS OPERATION IS MIXED WITH A NON-POLAR SOLVENT, THE LAYERS ARE SEPARATED AND THE NON-POLAR PHASE IS DISCARDED. 3. THE PARTIALLY PURIFIED POLAR EXTRACT OBTAINED DURING THE PREVIOUS OPERATION IS EVAPORATED UNTIL APPROXIMATELY 10 OF THE INITIAL VOLUME. 4. THE CONCENTRATED EXTRACT IS PURIFIED BY EXTRACTION ON ION-EXCHANGING RESINS WITH A NON-POLAR SOLVENT, CLARIFICATION ON ACTIVE CARBON AND, IF DESIRED, LYOPHILIZATION.

Description

The present invention relates to the obtaining of

  caments with curative effects and beneficial for pathological conditions

  which affect the osteolocomotor apparatus of the human organism, drugs from both the leaves and rhizomes of the ferns of the family Polypodiaceae. The pathological problems that affect the osteolocomotor apparatus and in particular the arthritis in their various forms, date back to antiquity because mummified skeletons have been observed indicative of degenerative arthritic processes which the individual has suffered. At the moment, in the last quarter of

  20th century, we have not yet found an effective therapeutic

  to treat these processes and, unfortunately, the drugs with the highest therapeutic efficacy are also

  those that give rise to toxic effects and to secondary reactions.

  the most important drugs, forcing most patients to suspend medication, which is

  a much more difficult situation because of their patho-

  initial logic was added iatrogenic acquired disease.

  There is no known drug, among those used in the affections of the osteolocomotor apparatus, which does not show a side effect, and this is how the aspirin itself, considered harmless at other times, when

  is used in large doses, in addition to the problem of irri-

  gastric damage, leads to changes in blood clotting, blood vessels, etc. As the potency of the effect of the drugs used increases, the toxic effects

secondary ones also increase.

  The drug according to the present invention, in addition to its effectiveness, has no side effects and has no

toxicity.

  The results are much more favorable in

  affections with regard to their etiopathogenesis, and this medi-

  cament has the advantage that it can be associated with

  other medicines to cure or remedy

  pathological conditions in which the etiopathogenesis is more obscure or uncertain, which makes it necessary

  symptomatic treatment to deliver the patient from his suffering.

  The drug according to the invention has the advantage that so.

  high metabolic power is of a physiological order since it activates organic systems depressed by the pathological situation4 of

  so that he is promising in geriatrics.

  As indicated below, it has been used in

  all the pathological processes that affect the osteo-

engine.

  The chemical compounds of the present invention obtain

  bare from the rhizomes and leaves of ferns of the family Foiypodiaceae. exert curative and ameliorative effects in many processes that affect the osteolocomotor apparatus of

  human being. In the Polypodiaceae family, we find the main

  Active compounds of the present invention in the following genera: Family Polypodiaceae Grammitideaceae Nevrodium Dicranoglossum Microgramma Pleopeltis Niphidium Campyloneuron Polypodium Plebodium. In order to obtain these active principles, a process has been developed, which is described below, making it possible to obtain industrial yields in sufficient quantities for the production of different pharmaceutical compositions. Since these

  investigations date back 15 years, cutting the leaf or using

  the rhizome are perfectly controlled so that, if

  during its life cycle this plant produces at a certain time

  a toxic substance (which is extremely unlikely)

  it never appeared in the product obtained industrially.

  The method of the invention essentially consists of

  obtain an extract of the leaves and rhizomes of the ferns in ques-

  and purify this extract to isolate the active ingredients,

  useful for the treatment of osteolocomotor conditions.

  The extraction operation can be performed either on the leaves and rhizomes of ferns, cut and dried, or on these leaves and rhizomes in the fresh state or on the wet cake produced by a pressing operation to extract the juice of the leaves and fresh rhizomes. In the latter case, the extract

  moist cake can be mixed with the fresh juice for

posterior boration.

  In what follows, we describe in more detail

the process according to the invention.

Drying

  The leaves and rhizomes are dried at a temperature of

around 650C.

  The rhizomes are cut previously into pieces of 2 to 3 cm; the leaves are dried in the state they are in after harvesting; the drying can be carried out continuously,

  discontinuous or natural. For example,. the material can be introduced

  in a dryer consisting of a wire cloth approximately 1 m wide and 25 m long, which moves inside a heated tunnel and is traversed by a stream of hot air. By adjusting the speed of the wire cloth, it is possible to dry approximately

  half a ton of wet matter per hour.

  Drying can also be done by convection and radiation using solar collectors. The solar collector is built with a lightweight material and its dimensions depend on the volume to be treated. The drying time varies between 24 and 36 hours until a residual moisture variable between 12% and 8%, to allow milling. The maximum indoor temperature obtained

in this case is 700C.

  Grinding To facilitate extraction, leaves and

  rhizomes can be milled.

  In the case of the rhizome, a grinder is used.

  knives. Dried rhizomes or fresh rhizomes are used.

  carefully selected and washed. The dimensions of the ground rhizome can vary between 3 and 6 mm. These dimensions are determined by a metal cloth against which the rhizomes are applied by

knives.

  The milling of the dry leaf is carried out in a hammer mill so as to divide it finely. The yield and ease with which the active ingredient is extracted depend on

the size of the ground leaf.

  Extraction As mentioned above, we can perform

  this one using the parts of the plant fresh or dried.

  Fresh 1. Rhizomes cut into pieces and fresh leaves into independent batches are subjected to the action of a press so as to

  extract by pressing the intercellular and intracellular juice.

  2. The residual cake is subjected to an alcoholic wash (water with% alcohol), using a ratio between the residual cake and the hydroalcoholic mixture of between 1: 2 and 1:10. This washing liquid may be added to the juice obtained during the previous phase so as to treat it jointly, or it may be treated independently; or 2'.The fresh leaves and rhizomes duly cut are subject to

  extraction with a polar solvent, whose dielectric constant

  range between 1.8890 and 80.37 between room temperature

and the boiling temperature.

  3. The phase 1 juice, phase 2 wash liquid, phase 2 'extract, or any mixture of these substances, is extracted with an equal volume of non-polar solvent, by

  hexane example, to separate the lipid substances.

  4. The mixture is stirred for 15 minutes, after which it is allowed to stand for about 2 hours and finally the nonpolar solvent phase is discarded and finally obtained.

an extract in the polar solvent.

  In the dry state: Dried and ground leaves and rhizomes are extracted with a solvent whose dielectric constant

varies between 1.8890 and 80.37.

  The weight / volume ratio (kg / liter) between the leaves or rhizomes and the solvent can vary between 1: 1 and 1:10, depending on the capacity of the containers used. The extraction can be done between the ambient temperature and the boiling temperature, and the times

vary accordingly.

  Then, the extract obtained in the polar liquid is subjected to a new liquid-liquid extraction with a non-polar solvent, for example hexane, to remove the lipid substances. Finally, the unpolished solvent phase, which is discarded, is separated.

  and an extract is obtained in the polar solvent.

Evaporation

  The final extract obtained during the operations is evaporated.

  using the plant in a dry or fresh state using

  continuous, semi-continuous or discontinuous porifiers, heated to the

  steam. This operation is continued until a volume is

  approximately 10% / of the initial volume of solvent used for extrac-

solid-liquid

  Purification The method followed to carry out the purification is the element which determines the composition of the final product obtained, and,

  therefore, its therapeutic activity.

  The concentrated liquid from the previous step is filtered and then passed through a column of anionic ion exchange resin. In this column, it is subjected to a countercurrent extraction by means of a non-polar solvent,

preferably hexane.

  Then, the liquid is passed through a cationic ion exchange column. To the eluate obtained, a weak base is added to neutralize it and then the

  neutral solution through another anionic ion exchange resin

  Picnic. To the solution obtained add activated charcoal for

  check. The solution obtained is concentrated by evaporation at

  % of its initial volume, and a viscous liquid is obtained.

amber tails of sweet and sour flavor.

  This viscous liquid, which constitutes the object of the invention

  can be freeze-dried, resulting in a white powder

  very hygroscopic choke that changes color quickly when

  is subject to ambient humidity.

  The following examples illustrate the invention without

however, limit its scope.

Example 1

  100 kg of rhizome are introduced into stainless steel containers which contain heating coils and

  uses steam to heat to reflux using as sol-

  600 liters of methanol at 64 ° C. After having warmed

  1 hour, the rhizome is separated from the methanol. We separate the mechanical rhizome

  nically and then press it to fully extract the principle.

active ingredient.

  The extract is concentrated to 1/3 of the initial volume so that it can be pumped into the exchange columns (mixed layer resins); then neutralized with sodium hydroxide to pass the extract through a mobile coal phase to bleach. Finally, it is filtered and concentrated to the permitted level at a temperature of 500C and a pressure of 600 mmHg, and finally about 6 liters of product are obtained,

Example 2

  100 kg of leaves are introduced into a stainless steel container and covered completely with 500 liters of ethanol. After heating at 720 ° C. for 1 hour, the mixture is concentrated to a volume of 50 liters and then the extract is passed through an ion exchange column (mixed layer resins) and then neutralized with calcium hydroxide. . We pass the

  neutralized product on columns of activated carbon for the decolo-

  completely. Finally, it is concentrated to 4 liters and a product very similar to bee honey is obtained. The yield obtained depends

  of the leaf or rhizome, the time of harvest and the

treatment conditions.

Example 3

  In a container 100 kg of leaves are introduced and

  500 liters of water and heated to 900C for 1 hour. We let repo-

  extract the extract for 24 hours to completely separate the resins; then filtered to obtain a clean filtrate. It is passed through the ion exchange column (mixed layer resins) and neutralized with calcium hydroxide; then, it is discolored and filtered and finally evaporated to a volume of 5 liters of a pleasant odor liquid whose color varies depending on the

duration of the final evaporation.

  The pharmaceutical compositions are prepared according to

  in conventional dosage forms, by incorporating into a pharmaceutical carrier the syrupy product which is obtained by the process according to the invention. The active ingredients should be used in the compositions in sufficient quantity to produce

  anti-arthritic activity. The resulting pharmaceutical compositions

  also constitute an object of the invention.

  Preferably, the compositions according to the invention

  contain the active ingredient in a proportion of 10 to 100 mg

  for each unit dose. The pharmaceutical vehicle can be

  solid or liquid. As examples of solid vehicles, it is possible to

  starch, lactose, magnesium stearate, kaolin, sucrose, talc, stearic acid, gelatin, agar,

  pectin, gum arabic, 1 "Aerosil" and similar products.

  As examples of the liquid vehicles, mention may be made of alcohols (such as ethanol or propylene glycol), the water containing a solubilizing agent such as polyethylene glycol, peanut oil,

  olive oil and similar substances. The vehicle or dissol-

  may contain a retarding agent such as monostearate

  glycerol or glycerol distearate, alone or with a wax.

  A wide variety of phar-

  ceutical. For example, if a solid carrier is used, the preparation can be made into tablets, filled into hard gelatin capsules in the form of powder or granules or in the form of cylinders or beads. The quantity of vehicle

  solid may vary within very wide limits, but it is

  preferably between 25 mg and 300 mg.

  If a liquid vehicle is used, the preparation may take the form of syrup, emulsion, soft gelatin capsule, suspension or liquid solution, or a sterile injectable form for parenteral use, for example in a ampoule. We can

  lyophilized powder in individual doses, for its reconstitution

  at the time of administration.

  The pharmaceutical compositions according to the invention in the form of suspensions or liquid solutions do not comprise simple liquid suspensions or solutions of the active ingredient in common solvents which are not suitable for internal administration in order to produce the desired pharmacological activity. Also included in the present invention are

  unit doses in the form of tablets, capsules, cylinders,

  sitettes, beads, liquid suspensions or sterile injectable fluids

  internal administration, for the purpose of exercising an activity

anti-arthritic life.

  The route of administration may be oral, parenteral or rectal and, preferably, oral. The active ingredient will preferably be administered with a daily dose of about 100 mg to 1500 mg and preferably 200 to 600 mg. Doses should be given one to four times daily. When the administration

  is done in the manner indicated, we obtain an anti-arthritic effect.

  Since arthritis and similar diseases are chronic, insidious and etiopathogenically

  it is preferable to use the form of gelatin capsules

  soft tine or tablets to maintain stable blood levels that allow prolonged action of the drug. It is obvious that in the case of an acute attack of arthritis, intravenous injection or conti-

  serum in order to cut the crisis.

  Pediatric drops or emulsions have also been used for obvious reasons and, in the case of adults with upper digestive problems and in children,

  we can resort to the use of suppositories.

  Pharmaceutical compositions are prepared by conventional techniques such as mixing, granulation and compression, where necessary, or by mixing and dissolving the

  suitable ingredients for the desired compositions.

  The following examples illustrate the compositions

pharmaceutical compositions according to the invention.

_if

Example A.

  Polar fraction according to the invention 100 mg Starch 250 mg Lactose 60 mg Magnesium stearate 5 mg The ingredients are mixed, screened and introduced into hard gelatin capsules. The dosage can

  vary between three and six capsules daily.

Example B.

  Polar fraction according to the invention 60 mg Aerosil 60 mg Starch 40 mg Polyvinylpyrrolidone 5 mg The polar fraction is mixed with aerosil, granulated with a wet starch paste and dried for 8 to 20 minutes.

  12 hours. The granules are sieved and turned into tablets.

  During a first part of the tests carried out in

  approximately 900 patients with rheumatoid arthritis were treated

  matoide, ankylopoietic spondylitis, psoriatic arthritis, connective tissue diseases, rheumatic fever, joint diseases

  degenerative diseases (osteoarthritis, osteoarthritis), rheumatism

  cular, infectious arthritis, traumatic arthritis and neuro-

  ticks, arthritis due to biochemical or endocrine problems, iatrogenic arthritis, as well as problems that affect certain parts of the elements that make up the joint as a whole,

for example tendons.

  The chemical compounds which are the subject of the present invention have been administered in their natural form of extraction, as well as in the form of derivatives. Before treating human patients, toxicological studies on experimental animals have been carried out according to the standards of the Guidelines for Human Use ("Standards for Reproductive Studies, to Ensure the Safety of Human Medicines"), and according to FDA standards of the United States of America on three animal species, one of which is not a rodent,

in this case, the dog.

  The results are totally satisfactory. L.DLe.

  The cost of experiments on these chemical compounds would have been greater than the maximum therapeutic dose used. Your evidence of fertility, theratogenesis, and carcinogenesis made with these animal species gives no evidence of alteration or injury.

pathology of this nature.

  The dose used with these animals is 100 mg / g body weight. The animals are sacrificed after 48 hours,

  6 weeks, 36 weeks and 52 weeks after administration. Pen

  During this time, animals are obviously subject to the effects of these

  medications and at the time of the autopsy no alterations are observed

  organic production. The methodology followed is described by Jull, J.W., Brit. J. Cancer 5,328 (1951) and the statistical evaluation used is described by Arcos et al., Chemical Induction of Cancer, Academic

Press Ing., New York, (1963).

  Patients are followed for 2 years and the doses

  daily doses range from 200 to 1,500 mg, depending on age.

  the sex, weight and osteolocomotor problem of the patient.

  The average dose is 3 mg / kg body weight. The results are very satisfactory when the elements most affected by the pathological process are the cartilages (as

  osteoarthritis) or collagen fibers (as in the case of

  conjunctivitis); in diseases that mainly affect the

  synovial brane (as in thumatotic arthritis), the results

  are quite favorable although less intense.

  The clinical experiments are carried out by the method

  double-blind, using as a control a placebo of a subset

  inert medicine and two comparative drugs, aspirin and phenyl-

  Butazone. Patients with different degrees of graft have been used.

  of the osteolocomotor process and all these patients get '

an upgrade.

  Without pretending to establish any theory, currently it is assumed that the mechanism of action is as follows: A) Increased activation process of growth and maturation of collagen, which produces a firmer collagen

and more resistant.

  B) Increased permeability to water and ions across the lisosomal membrane of both normal and pathological cells

  of the affected area. This increase in permeability of members

  branes explains the possible increase in the regenerative capacity of the cartilage and the cells (condrocytes) seen in use.

reading marked substances.

  C) There is also a positive exchange towards the interior of the cell of nutrients such as glucose, fructose and

  amino acids of the genus valine, lysine and others, which could

  risking cellular nutrition which is in a precarious state in this pathology. At the same time, there is a greater elimination of CO2 resulting from the high metabolism developed in the cell. D) Initial studies have shown that this drug produces

  an increase in the activity of carriers of the lipopro-

  tines, which also suggests a probable mechanism

action of the drug.

  E) Also, liver cell activity (hepatocytes) and a number of cell-specific enzymatic systems are activated, which explains the improvement observed by the patients.

with uric-type arthritis.

  F) Inflammation and pain are reduced by the high degree of metabolism produced by increased intake of oxcygene and

blood to the affected tissues.

  The product according to the invention has no effect or any activity of the steroid type, Its activity on the membranes

  Myocardial cells produce a very interesting bradycardic effect.

  for elderly patients, for whom the use of digitalis has been suspended because the product of

similar effect.

  It should be understood that the invention is not limited to the preferred embodiments described above by way of illustration and that those skilled in the art may make various modifications and changes thereof without departing from the scope of the invention. and the spirit

of the invention.

Claims (7)

R E V E N D I C A T I 0 N S   1 - Method for obtaining an anti-arthritic drug and for other diseases of the musculoskeletal system, this medicament being constituted by the natural polar fractions of rhizomes and leaves of ferns of the family Polypodiaceae, genera Gammitideaceae, Nevrodium, Dicranoglossum, Microgramma, Pelopeltis, Niphidium, Campyleneuron, Polypodium and Phlobodium; this process being characterized by the following operations: 1. a material chosen from the dried leaves and rhizomes reduced to small fragments of the ferns indicated above, the fresh cut leaves and rhizomes of these ferns, are extracted with a polar solvent; the cake obtained after fresh pressing of these leaves and rhizomes, the extract obtained being in this case added to the juice produced during this pressing operation, the weight / volume ratio between the solid material and the solvent extraction being between 1: 2 and 1:10; 2. the extract of the preceding operation is mixed with a non-polar solvent, the layers are separated and the non-polar phase is discarded; 3. the partially purified polar extract obtained in the course of the preceding operation is evaporated until it reaches approximately 10% of the initial volume; 4. the concentrated extract is purified by subjecting it to the following operations: a) - the concentrated liquid is filtered;   b) - it is then passed on a column of resin exchange   anionic ion, in which it is subjected to extrac-   countercurrent using a non-polar solvent; c) - it is then passed on a cationic ion exchange column;   d) - a weak base is added to the eluate obtained for neutralizing Liser;   e) - the neutral solution is passed on to another exchange resin anionic ion generator;   f) - active charcoal is added to the solution obtained for   VERIFY; g) - the evaporated solution is concentrated to about 1% of its initial volume to obtain a viscous amber liquid of sweet and sour flavor; and h) - if desired, the viscous liquid of the preceding step is lyophilized to obtain a white crystalline powder. 2 - Process according to claim 1, characterized in that the polar solvent has a dielectric constant between 1.8890 and 80.37.   3 - Process according to claims 1 and 2, characterized   in that the polar solvent is a hydroalcoholic mixture.   4 - Process according to any one of claims I   at 3, characterized in that the hydroalcoholic mixture is a hydroethanolic mixture, the non-polar solvent is hexane and the base   low used to neutralize is calcium hydroxide.   - Process according to any one of the claims   preceding, characterized in that the extraction takes place between the   room temperature and the boiling temperature of the solvent.   6 - New drug useful in particular for the treatment of affections of the osteolocomotor apparatus, characterized in that it contains as active ingredient the polar fraction obtained by the   process according to any one of claims 1 to 5.   7 - Pharmaceutical compositions intended for the treatment of affections of the osteolocomotor apparatus, characterized in that they are packaged so as to be administered orally, parenterally or rectally at daily doses of approximately   1500 mg in one to four doses.   8 - Pharmaceutical composition according to claim 7, characterized in that it is in hard gelatin capsules containing the composition composition following polar fraction according to the invention 100 mg starch 250 mg lactose 60 mg magnesium stearate 5 mg   9 - Pharmaceutical composition according to claim 7.   characterized in that it is in tablets of suiwaite composition; polar reaction according to the invention 60 mg ierosil 60 mg arnidcn 40 mg polyvinylpyrrolidone 5 mg.