CA1176173A - Process for obtaining a drug useful in the treatment of arthritis and other diseases of the locomotive system - Google Patents
Process for obtaining a drug useful in the treatment of arthritis and other diseases of the locomotive systemInfo
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- CA1176173A CA1176173A CA000374387A CA374387A CA1176173A CA 1176173 A CA1176173 A CA 1176173A CA 000374387 A CA000374387 A CA 000374387A CA 374387 A CA374387 A CA 374387A CA 1176173 A CA1176173 A CA 1176173A
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- extract
- rhyzomes
- polar solvent
- polar
- leaves
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/11—Pteridophyta or Filicophyta (ferns)
- A61K36/12—Filicopsida or Pteridopsida
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- Alternative & Traditional Medicine (AREA)
- Biotechnology (AREA)
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- Chemical & Material Sciences (AREA)
- Mycology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE INVENTION
This invention relates to the obtention of drugs hav-ing curing and benaficial effects in pathological diseases which affect the osteolocomotive system of a human being and originat-ing from ferns of the Polypodaceae family, both from the leaves as well as the rhyzomes thereof.
This invention relates to the obtention of drugs hav-ing curing and benaficial effects in pathological diseases which affect the osteolocomotive system of a human being and originat-ing from ferns of the Polypodaceae family, both from the leaves as well as the rhyzomes thereof.
Description
A .~ 7 6 1 7 3 This invention relates to the obtention of drugs having curing and beneficial effects in pathological dis-eases which affect the osteolocomotive system of a human being and originating from ferns of the Polypodaceae family, both from the leaves as well as the rhyzomes thereof.
The pathological diseases which affect the osteo-locomotive system, and particularly the diverse forms of arthritis, have long been known, and signs of denegerative arthritic processes suffered during life have been observed in mummified skeletons. During the last quarter of the twentieth century no effective thereapy for treating these diseases has been found and those drugs which are more effective therapeutically are unfortunately also those which produce greater toxic effects and secondary reactions, whereby administration thereof should be suspended in the majority of patients, these patients consequently being in a difficult position since to their initial pathological state should be added an acquired ioatrogenic disease.
All the drugs used in disorders of the osteolo-comotive system are known to produce secondary effects and even Aspirin (a trademark) itself, considered innocuous at other times, when administered in larger dosages, pro-duces, besides gastric irritation, general organic alter-ations, such as clotting of the blood, blood vessels, etc. As the strength of the effect of the drugs used in-creases, the secondary toxic effects also increase.
The present invention, besides being an effective drug, does not produce any secondary effect nor does it present toxicity.
~ ~ 76173 The results are much more favournble in pure diseases with respect to the etiopathogeny thereof, having the advantage that it can be associated Witll other drugs to cure and recover those pathological conditions wherein the etiopathogeny is more obscure or uncert~in, a symptomatis treatment having, therefore, - to be carried out to free the patient of his sufferings.
This invention has the advantage that the high met~-bolic power thereof is physiological, since it activates orca-nic systems which are depressed due to the pathological state, thereby resulting promising in geriatrics.
- As will subsequently be mentioned, it has been used in all pathologicAl diseases'affecting the osteolocomotive sys-tem.
SU~RY ~F THE INVENTION
The chemical compounds of this invention, obtained from the rhyzomes and leaves of ferns of the Polypodiaceae family, have curing and improving effects in many diseases af-fecting the osteolocomotive system of the human being. The main ingredients of this invention are found in the followin~
species pertaining to the l'olypodiaceae fnmily:
Polypodiaceae Family Grammitideaceae Nevrodium Dicranoglossum Microgramma Pleopeltis Niphidium Campyloneuro l'olypodium I'lebodium [~ mc1-llo~lo.Lo~ , wl~i,cll wil I snl>se-plel-tl~ e de~;cril-e~l, l ~76173 has been devised to obtain these nctive ingredienls. permitting sufficient amountq of industrial yields to be obtained for the carrying out of a nwnber of pharmaceutical formulae. Since these investigations date back to 15 years, cutting of the leaf or use of the rhyzome is perfectly controlled so that if this plant generates at anymoment during i*s vital cycle A toxic substance lwhich i~ very improbable), it h~ never appeared i~
the industrial obtention.
The method of thi~ invention essentially con~ists of obtaining an extract from the leave~ and rhyzomes of the men-tioned ferns and purifying this ex~ract to isolate the active ingredients useful in the treatment of osteolocomotive diseaYe~.
Extraction can be carried out on the cut and dried leave~ and rhyzomes of the fern~, on the fresh leaves and rhy-zomes, or on the wet cake resulting from a pressing operation to extract the juice or sap from the fre~h leaves and rhyzomes.
In this latter case, the extract of the wet cake can be mixed with the fre~h sap for the sub~equent elaboration thereof.
The proce~ of this invention shall now be describ-ed in more detail.
_r~ E
Both the rhyzomes and the leave3 are dried at a temperature of 65C (150F) approximately.
The rhyzomes are previously cut into ~trips of 2-3 cms.: the leave~ are dried and they are collected: drying take~ place continuously, di~continuously or naturnllyO For example, the material can be introduced in a drying machine comprising n metallic wirecloth having approxim~tely 5 m.
in width and 25 m. in length, which ii moved within a hot compartment throu~h which a ~tream of hot air is Pn~sed. ~y ad~ju~ting the spee-l of the metallic wirecloth, approximatel~
t ~76173 half a ton of moist material can be dried per hour.
Dryin~ can al-~o be carried out by con~ection and rndiation, using solar collectors. The solar collector iR
made of a light material, the dimensions of which depend on the volume in question. The drying time ran~es of from 24 to 3~ hours, until a residual moisture of from 12,h to ~~0 i9 reached to enable granulating. The maximum inner temperature reached in thi~ ca~e is of 70 C.
Granulating _ To facilitate extraction, the leaves and rh-zomes can be ~ubjected to granulation.
In the case of ~he rhyzome, a disc mill is used.
Dry or fresh rhyzomes, carefully selected and washed, are used.
The size of the granultated rhy~ome can vary of from 4 to ~ mm.
This size is determined by a metallic wirecloth against which it is pressed by the discs.
The dry leaf is granulated in a hammer mill until it i~ finely divided. The yield and ea~e with which the acti~e ingredient is extracted depends on the size of the granulated leaf.
Extraction A~ ~reviously indicated, extraction can be carried out on the fresh or dried parts of the plant.
Fre~h extrnction -1. The fresh rhyzomes cut in strips and the fresh lea~es pack-ed in ~eparate bat~hes are subjected to the action of a pre~s to extract, by pressin~, the inter and intracellular juice.
The pathological diseases which affect the osteo-locomotive system, and particularly the diverse forms of arthritis, have long been known, and signs of denegerative arthritic processes suffered during life have been observed in mummified skeletons. During the last quarter of the twentieth century no effective thereapy for treating these diseases has been found and those drugs which are more effective therapeutically are unfortunately also those which produce greater toxic effects and secondary reactions, whereby administration thereof should be suspended in the majority of patients, these patients consequently being in a difficult position since to their initial pathological state should be added an acquired ioatrogenic disease.
All the drugs used in disorders of the osteolo-comotive system are known to produce secondary effects and even Aspirin (a trademark) itself, considered innocuous at other times, when administered in larger dosages, pro-duces, besides gastric irritation, general organic alter-ations, such as clotting of the blood, blood vessels, etc. As the strength of the effect of the drugs used in-creases, the secondary toxic effects also increase.
The present invention, besides being an effective drug, does not produce any secondary effect nor does it present toxicity.
~ ~ 76173 The results are much more favournble in pure diseases with respect to the etiopathogeny thereof, having the advantage that it can be associated Witll other drugs to cure and recover those pathological conditions wherein the etiopathogeny is more obscure or uncert~in, a symptomatis treatment having, therefore, - to be carried out to free the patient of his sufferings.
This invention has the advantage that the high met~-bolic power thereof is physiological, since it activates orca-nic systems which are depressed due to the pathological state, thereby resulting promising in geriatrics.
- As will subsequently be mentioned, it has been used in all pathologicAl diseases'affecting the osteolocomotive sys-tem.
SU~RY ~F THE INVENTION
The chemical compounds of this invention, obtained from the rhyzomes and leaves of ferns of the Polypodiaceae family, have curing and improving effects in many diseases af-fecting the osteolocomotive system of the human being. The main ingredients of this invention are found in the followin~
species pertaining to the l'olypodiaceae fnmily:
Polypodiaceae Family Grammitideaceae Nevrodium Dicranoglossum Microgramma Pleopeltis Niphidium Campyloneuro l'olypodium I'lebodium [~ mc1-llo~lo.Lo~ , wl~i,cll wil I snl>se-plel-tl~ e de~;cril-e~l, l ~76173 has been devised to obtain these nctive ingredienls. permitting sufficient amountq of industrial yields to be obtained for the carrying out of a nwnber of pharmaceutical formulae. Since these investigations date back to 15 years, cutting of the leaf or use of the rhyzome is perfectly controlled so that if this plant generates at anymoment during i*s vital cycle A toxic substance lwhich i~ very improbable), it h~ never appeared i~
the industrial obtention.
The method of thi~ invention essentially con~ists of obtaining an extract from the leave~ and rhyzomes of the men-tioned ferns and purifying this ex~ract to isolate the active ingredients useful in the treatment of osteolocomotive diseaYe~.
Extraction can be carried out on the cut and dried leave~ and rhyzomes of the fern~, on the fresh leaves and rhy-zomes, or on the wet cake resulting from a pressing operation to extract the juice or sap from the fre~h leaves and rhyzomes.
In this latter case, the extract of the wet cake can be mixed with the fre~h sap for the sub~equent elaboration thereof.
The proce~ of this invention shall now be describ-ed in more detail.
_r~ E
Both the rhyzomes and the leave3 are dried at a temperature of 65C (150F) approximately.
The rhyzomes are previously cut into ~trips of 2-3 cms.: the leave~ are dried and they are collected: drying take~ place continuously, di~continuously or naturnllyO For example, the material can be introduced in a drying machine comprising n metallic wirecloth having approxim~tely 5 m.
in width and 25 m. in length, which ii moved within a hot compartment throu~h which a ~tream of hot air is Pn~sed. ~y ad~ju~ting the spee-l of the metallic wirecloth, approximatel~
t ~76173 half a ton of moist material can be dried per hour.
Dryin~ can al-~o be carried out by con~ection and rndiation, using solar collectors. The solar collector iR
made of a light material, the dimensions of which depend on the volume in question. The drying time ran~es of from 24 to 3~ hours, until a residual moisture of from 12,h to ~~0 i9 reached to enable granulating. The maximum inner temperature reached in thi~ ca~e is of 70 C.
Granulating _ To facilitate extraction, the leaves and rh-zomes can be ~ubjected to granulation.
In the case of ~he rhyzome, a disc mill is used.
Dry or fresh rhyzomes, carefully selected and washed, are used.
The size of the granultated rhy~ome can vary of from 4 to ~ mm.
This size is determined by a metallic wirecloth against which it is pressed by the discs.
The dry leaf is granulated in a hammer mill until it i~ finely divided. The yield and ea~e with which the acti~e ingredient is extracted depends on the size of the granulated leaf.
Extraction A~ ~reviously indicated, extraction can be carried out on the fresh or dried parts of the plant.
Fre~h extrnction -1. The fresh rhyzomes cut in strips and the fresh lea~es pack-ed in ~eparate bat~hes are subjected to the action of a pre~s to extract, by pressin~, the inter and intracellular juice.
2. The residual cake is subjected to an alcohol wash (water o~ S
containing 10% alcohol), using a residual cnke:b~F~alcoholic mixture ratio of from 1:2 to 1:10. This mother liquor can be added to tlle .juice or sap obtained in the prece~ing step ~ ~76173 to be treated jointly, or it can be treated separately.
2'. The fresh leave~ and rhyzomes duly cut are extracted with a polar solvent, the dielectric constant of which ranges of from 1.8890 to 80.37, at temperatures of from that of ambient to that of boiling point.
containing 10% alcohol), using a residual cnke:b~F~alcoholic mixture ratio of from 1:2 to 1:10. This mother liquor can be added to tlle .juice or sap obtained in the prece~ing step ~ ~76173 to be treated jointly, or it can be treated separately.
2'. The fresh leave~ and rhyzomes duly cut are extracted with a polar solvent, the dielectric constant of which ranges of from 1.8890 to 80.37, at temperatures of from that of ambient to that of boiling point.
3. The juice or sap of step 1, the mother li~uor nf step 2, the extract of step 2', or any mixture of these sub~tances is extracted with a like volume of non-polar aolvent, for exam-ple, hexane, to remove the lipidic substances.
4. The mixture is stirred for 15 minutes, it is then allowed to stand for about 2 hours, and fin~lly the non-polar solvent pllase is removed, which is discarded, obtaining a final ext~act in the polar solvent.
Dry Extraction The dry and granulated leaves and rhyzomes are ex-tracted with a solvent, the dielectric constant of which ran~es of from 1.8890 to ôO.37.
The ueight:volume ratio (Kg:liter) of leaves or rhyzomes to solvent can range of from 1:1 to 1:10, depending on the capacity of the containers used. Extraction can take place at temperatures of from that of ambient to that of boil-ing point, conse~uently varying the times.
Subsequently the extract obtained in the polar li-quid is subjected to anotller liquid~ uid extraction with a non-polar solvent, for example, hexane, to eliminate the lipi-dic substances. Finally, the non-polar phase, which is dis-carded, is removed, obtaining an extract in the polar solvent.
Evaporation The final extract obtained in the fresh or dry opera-tions is evaporated, using steam-heated continuous, semi-continuous or discontinuous evaporators. The operation con-l l76173 tinues until about 106 of the original volur,le of the solvent used is obtained in the 50~ liquid extrac-t.
Purificatiorl S The method followed to carry out purification determines the composition of the final produc. obtained and, therefore, the therapeutic activity thereoi.
The concentrated liquid of the preceding step is filtered and is then passed through an anionic exchange resin column. In rhis column it is subjected to a counter-current extraction with a non-polar solvent, preferably hexane.
It is then passed th^ough a calionic exchange colurr,n.
To the eluate obtained is added a wea~ base to neutralise it and then the neutral solution is passed through another anionic exchange resin column. Activated carbon is added to this solution obtained to clarify same.
The solution obtained is concentrated by evapora-tion until about 20% of the original volume thereof, thus obtaining a viscous liquid having a bitter-sweet taste and amber in colour.
This viscous liquid, object of the invention, can be lyophilized, obtaining a rather hygroscopic whitish powder which changes colour rapidly when subjec.ed -to the humidity of the air.
The following examples are given by way of illustra-tion and non-limiting of the invention.
EYAI~PL~ 1 100 Kg. of rhyzomes were introduced in a stainless steel container provided with heating coils, and steam was applied until it was heated to reflux using, as the solvent, 600 liters of methanol at 64C. After heating for 1 hour, the rhyzome was separated from the methanol. The rhyzome was mecha-nically separated and then pressed to completely extract the active ingredient.
The extract was concentrated to 1/3 of the ori~inal volume so that the interchangin~ columns (mixed-bed resins) can ~a /~ ,~ e"l f~ be pump-operated; then it is ~Y~40UH~r~ with sodium hydroxide to pass it through a movable carbon phase to whiten same. Final-ly it is filtered and concentrated to the permitted levels at a temperature of from 5~C and ~0 mm. of 11~., giving approxi-mately ~ liters of the product.
~X ~'LE 2 10~ Ks. of leavefi were introduced in a stainless steel container, completely covering same with 500 liters of ethanol. After heating at 72C for 1 hour, it was coneentrat-ed to a volume of 50 liters and then passed throu~h ionic in-terchanging columns (mixed-bed resins) and then neutralised with c~lcium hydroxide. The neutralised product was pas~ed through activated carbon columns until the complete decolori-sation thereof. k`inally, it was concentrated to 4 liters.
giving a product very similar to bee honey. The yield obtain-ed depended on the leaf or rhyzome, on the harvestin~ time, and on the processing conditions.
100 Kg. of leaves and 500 liters of water were in-troduced in a container and heated to 90 C for 1 hour. The extract was allowed to ~tand for 24 hours to completely seParate the resins; it wnS then filtered to obtain a clean filtrate.
It was passed throu~h the ionic interchangin~ column (mixed-bed resins) and neutralised with cnlciwlltlydroxide. lt was then decoloured and filtered to finally evaporate until a volume of 5 liters of a pleasant smelling liquid were obtained, ~ l76173 the colour whereof varied with tlle duration of the final evapora-tion.
The pharmaceutical co:npositions of this invention are , ~ Sy/~
prepared in conventional dosage forms by incorporatin~ the 4~æ~
product obtained with the process of the invention to a ph~rma-ceutical carrier. The resultant pfiarmaceutical compositions also constitute an object of this invention. The active in$re-dients should be used in the compo~itions in a sufficient amount to produce an anti-arthritic activity~
The compo itions of the in~ention preferablv contain from about 10 to about 100 mg of the active in~redient per unit dosage. The pharmaceutical carrier can, for example, be solid or liquid. Starch, lactose, magnesium stearate, alba terra, saccharose, talc, stearic acid, gelatin, agar, pectin, gum ara-bic, aero~il and the like are examples of solid carriers. Ex-amples of liquid carriers are alcohols (~uch aR ethanol or pro-pyleneglycol) water containing a solubilizing agent such as polye*hylenegylcol, peanut oil, olive oil and the like. The carrier or diluent can include a retarding agent such as ~ly-ceryl monostearate or glyceryl distearate , on its own or ~itll a wax.
A wide variety of pharmaceutical forms can be used.
Thus, if a ~olid carrier is used, the preparation can tnke 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 between wide ranges, but preferably from about 25 mg. to about 300 mg.
If a ~uid carrier is used, the preparation Ca~a~ODt the for~ of a syrup, emulsion, soft ~celatin capsule, suspension, or liquid solution, or a sterile in~jectable form for parenteral use, for example, in an ampule. The lyophilized powder can be 9 _ ! 1 76173 used in individual dosages to be reconstituted when ndlllini~tersd.
The pharmaceutical compositions of this invention in liauid suspensions or solution, do not include the simple liquid suspension~ or solutions of the active ingredient in the common unsuitable solvent for the internal administration to produce the desired pharmacological activity.
The unit dosages in the form of tablets, cap~ules, trochi~cus, ~uppositories, liquid su~pen~ion or sterile in~ject-able liquid for internal administration which can produce the anti-arthritic activity thereof, also form ~art of this inven-tion.
The mode of administration can be oral or parenteral, rectal, preferably oral. The active ingredient will preferabl~
be administered in a daily dosage amount of from about 100 m,~.
to about 1,5~0 mg., and even better of from 200 to 60~ mg. It is advantageous to administer dosages enuivnlent to 1 to 4 times per day. When administration is a~ previou~ly described, an anti-arthritic activity is obtained.
Since arthritis and the like are chronic insiduous disea~es havin,~ a genetic etiopatho~env, it is preferible lo use the form of soft gelatin capsules or tablets, to mailltnin stable blood concentrations and which permit a continued ac-tion of the medicament. Undoubtedly, when treatin$ serious attacks of arthritis the intravenou~ injection or the contin-uous dropwise feedin~ of serum can be used to prevent the crisis.
It should be pointed out that the form of drop~ or emulsion is used in pediatrics for obviou~ reasons, and in the case of adults havin~ problems of the upper di~estive canal and children, suppositories can be used.
The ~l~nrmncellticnl compositions nre prepnred by COllVentiOrlnL teCI~ cX ~llCIl ;IS IlliXill,~, ~rn~ L~tiol~ nl~d con-} 176173 pres~ion when neces~ary, or by mixing and dissolvin~ tlle ~uit-able ingredients for the desired compositions.
The following example~ illustrate the pharmaceutical compositions of the invention:
~XAMPLE A
rolar Fraction of this invention 100 mg Starch 250 mg Lactose 60 m,c Ma~nesi~n Stearate 5 mg The in~redient~ are mixed, sifted, and introduced in hard gelatin capsule~. The dosag~ can vary from 3 to ~ ca~sules per day.
XAMPL~ B
Polar fraction of this invention ~0 m~
p Aerosil 60m~
.~
Starch 40 m~
Polyvinylpyrrolidone 5 m~
The polar fraction is mixed with the aerosil, ~ranulat-ed with a wet strach dough and dried for 8 to 12 hours. The granules are ~ifted and converted into tablets.
During the first part of the clinical test about 900 patients suffering from rheumatoid arthritis, ankylopoitic spondylitis, p~oriatic arthritis, di~ease of the connective tis~ue, rheumatic fevers, articular degenerative diseases (osteoarthritis, o~teoarthrosis), non-articular rhewnatism, infectious arthritis, trawnatic and neurogenetic arthritis, arthriti~ due to biochemical or endocrinal disorder~, ioatro-~enic arthritis, as well a~ diseases affectin~ parts of some organisms forming the articulation as a whole, for example, the tendons, were treated.
'rhe chemical compollnds of this invention were ad-t~i ~r~l~Ar~
? ~76173 ministered in the form of natural extracts, a~ well as in the form of derivatives. Prior to treatment of the l-uman patients, toxicological studies were made on test animals following the rules of "Guidelines for Hwman V~e" and followin~ the rules of the F.D.A. of the U.S.A. on three animal species, one of which was not a mouse but, in our ca~e, a dog.
The re~ult~ were completely satisfactory. The DL~
found in our experiments for these chemical compounds were time greater than the maximum therapeutic dosage used. The ~tudies concerning fertility, teratogenesis and carcinogenesis made with these animal species showed no alteration or produc-tion of pathologies of this nature.
The dosa~e a~lini~tered to these Animnls was of 100 mg/kg per body weisht. The animals ~ere sacrificed 48 hours, 6 weeks, 36 ueeks and 52 weeks after administration, durin~
wllich periods they were clearly under the effects of these drugs, and no organic altsration was observed when carr~inc out an autopsy. The methodolo$y followed was that described by Jull, J.W. Brit. J. Cancer 5, 328 (1~51) and the statistical evaluation used was that described by Arcos y Col., Chemical Induction of Cancer, Academic l'ress In~., New York (1~3~.
The patients were observed for 2 years and the daily dosage administered rangéd from 200 to 1500 mg, dependin~c on ~ge, sex, wei~ht, and osteolocomotive disease of the patient.
The average dosage of 3 mg/ks per body weight was used. The results were very satisfactory in those cases where the patho'Logical disease attacked the cartila$es (as in osteo-arthrosis) or the colla~en fibers (a~ in connectivitisj and in those diseases which mainly affect the synovial membranes (as in rheumatoid arthritis), the results were sufficiently favour-~ble, althou$h Less intense.
I ~76173 Clinical tests were made using the dou~le blind test system nnd as the control the placebo of nn inert substance lnd two comparative dru~s, asprin and phenylbutazone. I'atients suf-fering from different de~ree~ of seriousnes~ of the osteolocomo-tive disease were used and in aIl of them an improvement was obtained.
Without bein~ bound to any theory presently the action mechanism is assumed to be the follouin~:
A) increase in tlle activation process of ~rowth and maturity of the collagen, thereby producin~ a firmer and more resistant colla~en.
B) increase in the permeability to water and to ions throu~h *he lysosome membrane of the cells, both normal and pathological, of the affected area. This increase in the permeability of the membranes e~plains the possible increase in the regenerative capacity of the cartilage and of the cells (chondrocyte) which have been observed using marked substances.
C) likewise, there is produced a positive inter-change towards the interior of the nutrient cells, such as ~lucose, fructose and aminoacids of valine lysine and ot21ers which would favour the cellular nutrition which is in n pre-carious position in this pathology. At the same time, we have observed a greater elimination of C02 as a result of the hi~h metabolism developed in the cell.
D) initial studies have demonstrated that this dru~
produces an increa~e in the acti~ity of the carriers, such ns lipoproteins, which result also implies a probable action mechanisrn of the dru~.
E) likew~se the activity of the hepatic cells (hepatocytes) is increase~ and a cood nwnber of en~atic s~rs-toms inherent to the cells is nctivnted which ex~lains the ~ I76173 improvement experienced by patients sufferint~ froll~ uric type arthritis .
Fj inflammation and pain diminish due to the hi~h degree of metabolism produced by a ~reater 5Upply of ox~v~en ~nd blood to the affected tissues.
The product of this invention does not produce ~
effect or activity of the steroidal ty~e. Its ~ctivitv on the cellular membranes of the myocardiwn produces a verv beneficial bradycardiac effect in.older patients on whom the u~e of di~
tali~ was ~uspended, since the product of this invention pro-duces an effect similar thereto.
Dry Extraction The dry and granulated leaves and rhyzomes are ex-tracted with a solvent, the dielectric constant of which ran~es of from 1.8890 to ôO.37.
The ueight:volume ratio (Kg:liter) of leaves or rhyzomes to solvent can range of from 1:1 to 1:10, depending on the capacity of the containers used. Extraction can take place at temperatures of from that of ambient to that of boil-ing point, conse~uently varying the times.
Subsequently the extract obtained in the polar li-quid is subjected to anotller liquid~ uid extraction with a non-polar solvent, for example, hexane, to eliminate the lipi-dic substances. Finally, the non-polar phase, which is dis-carded, is removed, obtaining an extract in the polar solvent.
Evaporation The final extract obtained in the fresh or dry opera-tions is evaporated, using steam-heated continuous, semi-continuous or discontinuous evaporators. The operation con-l l76173 tinues until about 106 of the original volur,le of the solvent used is obtained in the 50~ liquid extrac-t.
Purificatiorl S The method followed to carry out purification determines the composition of the final produc. obtained and, therefore, the therapeutic activity thereoi.
The concentrated liquid of the preceding step is filtered and is then passed through an anionic exchange resin column. In rhis column it is subjected to a counter-current extraction with a non-polar solvent, preferably hexane.
It is then passed th^ough a calionic exchange colurr,n.
To the eluate obtained is added a wea~ base to neutralise it and then the neutral solution is passed through another anionic exchange resin column. Activated carbon is added to this solution obtained to clarify same.
The solution obtained is concentrated by evapora-tion until about 20% of the original volume thereof, thus obtaining a viscous liquid having a bitter-sweet taste and amber in colour.
This viscous liquid, object of the invention, can be lyophilized, obtaining a rather hygroscopic whitish powder which changes colour rapidly when subjec.ed -to the humidity of the air.
The following examples are given by way of illustra-tion and non-limiting of the invention.
EYAI~PL~ 1 100 Kg. of rhyzomes were introduced in a stainless steel container provided with heating coils, and steam was applied until it was heated to reflux using, as the solvent, 600 liters of methanol at 64C. After heating for 1 hour, the rhyzome was separated from the methanol. The rhyzome was mecha-nically separated and then pressed to completely extract the active ingredient.
The extract was concentrated to 1/3 of the ori~inal volume so that the interchangin~ columns (mixed-bed resins) can ~a /~ ,~ e"l f~ be pump-operated; then it is ~Y~40UH~r~ with sodium hydroxide to pass it through a movable carbon phase to whiten same. Final-ly it is filtered and concentrated to the permitted levels at a temperature of from 5~C and ~0 mm. of 11~., giving approxi-mately ~ liters of the product.
~X ~'LE 2 10~ Ks. of leavefi were introduced in a stainless steel container, completely covering same with 500 liters of ethanol. After heating at 72C for 1 hour, it was coneentrat-ed to a volume of 50 liters and then passed throu~h ionic in-terchanging columns (mixed-bed resins) and then neutralised with c~lcium hydroxide. The neutralised product was pas~ed through activated carbon columns until the complete decolori-sation thereof. k`inally, it was concentrated to 4 liters.
giving a product very similar to bee honey. The yield obtain-ed depended on the leaf or rhyzome, on the harvestin~ time, and on the processing conditions.
100 Kg. of leaves and 500 liters of water were in-troduced in a container and heated to 90 C for 1 hour. The extract was allowed to ~tand for 24 hours to completely seParate the resins; it wnS then filtered to obtain a clean filtrate.
It was passed throu~h the ionic interchangin~ column (mixed-bed resins) and neutralised with cnlciwlltlydroxide. lt was then decoloured and filtered to finally evaporate until a volume of 5 liters of a pleasant smelling liquid were obtained, ~ l76173 the colour whereof varied with tlle duration of the final evapora-tion.
The pharmaceutical co:npositions of this invention are , ~ Sy/~
prepared in conventional dosage forms by incorporatin~ the 4~æ~
product obtained with the process of the invention to a ph~rma-ceutical carrier. The resultant pfiarmaceutical compositions also constitute an object of this invention. The active in$re-dients should be used in the compo~itions in a sufficient amount to produce an anti-arthritic activity~
The compo itions of the in~ention preferablv contain from about 10 to about 100 mg of the active in~redient per unit dosage. The pharmaceutical carrier can, for example, be solid or liquid. Starch, lactose, magnesium stearate, alba terra, saccharose, talc, stearic acid, gelatin, agar, pectin, gum ara-bic, aero~il and the like are examples of solid carriers. Ex-amples of liquid carriers are alcohols (~uch aR ethanol or pro-pyleneglycol) water containing a solubilizing agent such as polye*hylenegylcol, peanut oil, olive oil and the like. The carrier or diluent can include a retarding agent such as ~ly-ceryl monostearate or glyceryl distearate , on its own or ~itll a wax.
A wide variety of pharmaceutical forms can be used.
Thus, if a ~olid carrier is used, the preparation can tnke 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 between wide ranges, but preferably from about 25 mg. to about 300 mg.
If a ~uid carrier is used, the preparation Ca~a~ODt the for~ of a syrup, emulsion, soft ~celatin capsule, suspension, or liquid solution, or a sterile in~jectable form for parenteral use, for example, in an ampule. The lyophilized powder can be 9 _ ! 1 76173 used in individual dosages to be reconstituted when ndlllini~tersd.
The pharmaceutical compositions of this invention in liauid suspensions or solution, do not include the simple liquid suspension~ or solutions of the active ingredient in the common unsuitable solvent for the internal administration to produce the desired pharmacological activity.
The unit dosages in the form of tablets, cap~ules, trochi~cus, ~uppositories, liquid su~pen~ion or sterile in~ject-able liquid for internal administration which can produce the anti-arthritic activity thereof, also form ~art of this inven-tion.
The mode of administration can be oral or parenteral, rectal, preferably oral. The active ingredient will preferabl~
be administered in a daily dosage amount of from about 100 m,~.
to about 1,5~0 mg., and even better of from 200 to 60~ mg. It is advantageous to administer dosages enuivnlent to 1 to 4 times per day. When administration is a~ previou~ly described, an anti-arthritic activity is obtained.
Since arthritis and the like are chronic insiduous disea~es havin,~ a genetic etiopatho~env, it is preferible lo use the form of soft gelatin capsules or tablets, to mailltnin stable blood concentrations and which permit a continued ac-tion of the medicament. Undoubtedly, when treatin$ serious attacks of arthritis the intravenou~ injection or the contin-uous dropwise feedin~ of serum can be used to prevent the crisis.
It should be pointed out that the form of drop~ or emulsion is used in pediatrics for obviou~ reasons, and in the case of adults havin~ problems of the upper di~estive canal and children, suppositories can be used.
The ~l~nrmncellticnl compositions nre prepnred by COllVentiOrlnL teCI~ cX ~llCIl ;IS IlliXill,~, ~rn~ L~tiol~ nl~d con-} 176173 pres~ion when neces~ary, or by mixing and dissolvin~ tlle ~uit-able ingredients for the desired compositions.
The following example~ illustrate the pharmaceutical compositions of the invention:
~XAMPLE A
rolar Fraction of this invention 100 mg Starch 250 mg Lactose 60 m,c Ma~nesi~n Stearate 5 mg The in~redient~ are mixed, sifted, and introduced in hard gelatin capsule~. The dosag~ can vary from 3 to ~ ca~sules per day.
XAMPL~ B
Polar fraction of this invention ~0 m~
p Aerosil 60m~
.~
Starch 40 m~
Polyvinylpyrrolidone 5 m~
The polar fraction is mixed with the aerosil, ~ranulat-ed with a wet strach dough and dried for 8 to 12 hours. The granules are ~ifted and converted into tablets.
During the first part of the clinical test about 900 patients suffering from rheumatoid arthritis, ankylopoitic spondylitis, p~oriatic arthritis, di~ease of the connective tis~ue, rheumatic fevers, articular degenerative diseases (osteoarthritis, o~teoarthrosis), non-articular rhewnatism, infectious arthritis, trawnatic and neurogenetic arthritis, arthriti~ due to biochemical or endocrinal disorder~, ioatro-~enic arthritis, as well a~ diseases affectin~ parts of some organisms forming the articulation as a whole, for example, the tendons, were treated.
'rhe chemical compollnds of this invention were ad-t~i ~r~l~Ar~
? ~76173 ministered in the form of natural extracts, a~ well as in the form of derivatives. Prior to treatment of the l-uman patients, toxicological studies were made on test animals following the rules of "Guidelines for Hwman V~e" and followin~ the rules of the F.D.A. of the U.S.A. on three animal species, one of which was not a mouse but, in our ca~e, a dog.
The re~ult~ were completely satisfactory. The DL~
found in our experiments for these chemical compounds were time greater than the maximum therapeutic dosage used. The ~tudies concerning fertility, teratogenesis and carcinogenesis made with these animal species showed no alteration or produc-tion of pathologies of this nature.
The dosa~e a~lini~tered to these Animnls was of 100 mg/kg per body weisht. The animals ~ere sacrificed 48 hours, 6 weeks, 36 ueeks and 52 weeks after administration, durin~
wllich periods they were clearly under the effects of these drugs, and no organic altsration was observed when carr~inc out an autopsy. The methodolo$y followed was that described by Jull, J.W. Brit. J. Cancer 5, 328 (1~51) and the statistical evaluation used was that described by Arcos y Col., Chemical Induction of Cancer, Academic l'ress In~., New York (1~3~.
The patients were observed for 2 years and the daily dosage administered rangéd from 200 to 1500 mg, dependin~c on ~ge, sex, wei~ht, and osteolocomotive disease of the patient.
The average dosage of 3 mg/ks per body weight was used. The results were very satisfactory in those cases where the patho'Logical disease attacked the cartila$es (as in osteo-arthrosis) or the colla~en fibers (a~ in connectivitisj and in those diseases which mainly affect the synovial membranes (as in rheumatoid arthritis), the results were sufficiently favour-~ble, althou$h Less intense.
I ~76173 Clinical tests were made using the dou~le blind test system nnd as the control the placebo of nn inert substance lnd two comparative dru~s, asprin and phenylbutazone. I'atients suf-fering from different de~ree~ of seriousnes~ of the osteolocomo-tive disease were used and in aIl of them an improvement was obtained.
Without bein~ bound to any theory presently the action mechanism is assumed to be the follouin~:
A) increase in tlle activation process of ~rowth and maturity of the collagen, thereby producin~ a firmer and more resistant colla~en.
B) increase in the permeability to water and to ions throu~h *he lysosome membrane of the cells, both normal and pathological, of the affected area. This increase in the permeability of the membranes e~plains the possible increase in the regenerative capacity of the cartilage and of the cells (chondrocyte) which have been observed using marked substances.
C) likewise, there is produced a positive inter-change towards the interior of the nutrient cells, such as ~lucose, fructose and aminoacids of valine lysine and ot21ers which would favour the cellular nutrition which is in n pre-carious position in this pathology. At the same time, we have observed a greater elimination of C02 as a result of the hi~h metabolism developed in the cell.
D) initial studies have demonstrated that this dru~
produces an increa~e in the acti~ity of the carriers, such ns lipoproteins, which result also implies a probable action mechanisrn of the dru~.
E) likew~se the activity of the hepatic cells (hepatocytes) is increase~ and a cood nwnber of en~atic s~rs-toms inherent to the cells is nctivnted which ex~lains the ~ I76173 improvement experienced by patients sufferint~ froll~ uric type arthritis .
Fj inflammation and pain diminish due to the hi~h degree of metabolism produced by a ~reater 5Upply of ox~v~en ~nd blood to the affected tissues.
The product of this invention does not produce ~
effect or activity of the steroidal ty~e. Its ~ctivitv on the cellular membranes of the myocardiwn produces a verv beneficial bradycardiac effect in.older patients on whom the u~e of di~
tali~ was ~uspended, since the product of this invention pro-duces an effect similar thereto.
Claims (7)
1. A process for the production of a drug useful in the treatment of arthritis and other diseases of the locomotive system, said drug comprising natural polar frac-tions of rhyzomes and leaves of ferns of the Polypodiaceae family, species: Gammitideaceae, Nevrodium, Dicranoglossum, Microgramma, Pelopeltis, Piphidium, Campyleneorum, Polypodium and Phlebodium, which process comprises: (1) extracting, with a polar solvent, a material selected from the group con-sisting of dry, granulated leaves and rhyzomes of the afore-mentioned ferns, fresh, cut leaves and rhyzomes of said ferns, and the cake resulting from the pressing of said fresh leaves and rhyzomes, in which case the extract obtained is added to the juice or sap obtained from said pressing opera-tion, the weight:volume ratio of solid material to solvent extract being of from 1:2 to 1:10; (2) mixing the extract of step (1) with a non-polar solvent, allowing the layers to be separated and removing the non-polar phase; (3) evaporating the partially purified polar extract obtained in step (3) until at least 10% of the original volume is reached; and (4) purifying the concentrated extract includ-ing subjecting the extract to the following operations:
a) filtering the concentrated liquid; b) passing it through an anionic exchange resin column where it is subjected to a counter-current extraction with a non-polar solvent; c) passing it through a cationic exchange column, d) adding a weak base to the eluate obtained to neutralise it; e) passing the neutral solution through another anionic exchange resin column; f) adding activated carbon to the solution obtained to clarify it; g) concentr-ating the solution obtained by evaporation until approximat-ely 20% of its original volume to obtain a viscous liquid having a bitter-sweet taste and amber in colour.
a) filtering the concentrated liquid; b) passing it through an anionic exchange resin column where it is subjected to a counter-current extraction with a non-polar solvent; c) passing it through a cationic exchange column, d) adding a weak base to the eluate obtained to neutralise it; e) passing the neutral solution through another anionic exchange resin column; f) adding activated carbon to the solution obtained to clarify it; g) concentr-ating the solution obtained by evaporation until approximat-ely 20% of its original volume to obtain a viscous liquid having a bitter-sweet taste and amber in colour.
2. A process according to claim 1, in which lyo-philizing the viscous liquid of the step (4) (g) to obtain a white crystalline powder.
3. A process according to claim 1, wherein the dielectric constant of the polar solvent is from 1.8890 to 80.37.
4. A process according to claim 1, 2 or 3, wherein the polar solvent is an aqueous alcoholic mixture.
5. A process according to claim 1, 2 or 3, wherein the aqueous alcoholic mixture is an aqueous ethanol mixture, the non-polar solvent is hexane, and the weak base is calcium hydroxide.
6. A process according to claim 1, 2 or 3, wherein the extraction is carried out at a temperature from ambient to the boiling point of the solvent.
7. A drug useful in the treatment of arthritis and other diseases of the locomotive system, whenever prepared or produced by the process as claimed in claim 1, 2 or 3, or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES490.293 | 1980-04-02 | ||
| ES490293A ES8104315A1 (en) | 1980-04-02 | 1980-04-02 | Arthritis treatment with fern extracts |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1176173A true CA1176173A (en) | 1984-10-16 |
Family
ID=8480183
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000374387A Expired CA1176173A (en) | 1980-04-02 | 1981-04-01 | Process for obtaining a drug useful in the treatment of arthritis and other diseases of the locomotive system |
Country Status (7)
| Country | Link |
|---|---|
| AR (1) | AR224063A1 (en) |
| AU (1) | AU538973B2 (en) |
| CA (1) | CA1176173A (en) |
| DE (1) | DE3111056A1 (en) |
| ES (1) | ES8104315A1 (en) |
| FR (1) | FR2479690A1 (en) |
| GB (1) | GB2075834A (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0503208A1 (en) * | 1991-03-08 | 1992-09-16 | Maracuyama International, S.A. | Procedure for obtaining a natural water-soluble extract from the leaves and/or rhizomes of various immunologically active ferns |
| ES2088770B1 (en) * | 1995-02-23 | 1997-03-16 | Esp Farmaceuticas Centrum Sa | A PHARMACEUTICAL COMPOSITION WITH ACTIVITY IN THE TREATMENT OF COGNITIVE DYSFUNCTIONS AND / OR NEUROINMUNES. |
| US5614197A (en) * | 1995-02-13 | 1997-03-25 | Industrial Farmaceutica Cantabria, S.A. | Polypodium extract as photoprotectant |
| WO1999006058A1 (en) * | 1997-07-30 | 1999-02-11 | Helsint, S.A.L. | Hydrosoluble fractions of phlebodium decumanum and use thereof as nutritional complements in aids and cancer patients |
| ES2124675B1 (en) * | 1997-07-30 | 1999-10-01 | Helsint S A L | "FORMULATIONS BASED ON A WATER-SOLUBLE FRACTION OF PHLEBODIUM DECUMANUM, AND ITS USE IN THE TREATMENT OF THE KAQUECTIAL SYNDROME IN SICK PEOPLE WITH AIDS". |
| ES2137900B1 (en) * | 1998-06-02 | 2000-08-16 | Helsint S A L | USE OF FORMULATIONS BASED ON A WATER-SOLUBLE FRACTION OF PHLEBODIUM DECUMANUM AS A NUTRITIONAL SUPPLEMENT IN THE TREATMENT OF KAQUECTIC SYNDROME IN ONCOLOGICAL PATIENTS. |
| US6228366B1 (en) * | 1998-07-29 | 2001-05-08 | Helsint, S.A.L. | Water-soluble fractions of Phlebodium decumanum and its use as nutritional supplement in AIDS and cancer patients |
| ES2146555B1 (en) * | 1999-01-22 | 2001-03-01 | Helsint S A L | USE OF FORMULATIONS BASED ON HYDRO-Soluble FRACTIONS OF PHLEBODIUM DECUMANUM (EXPLY-37) AND / OR POLYPODIUM LEUCOTOMOS AS A NUTRITIONAL COMPLEMENT IN THE PREVENTION AND REVERSION OF THE PHYSICAL ENVELOPE SYNDROME. |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB256768A (en) * | 1925-07-17 | 1926-08-19 | Francesco Fumarola | Process for extraction of the active biological principles from the ether extract of male fern |
| US3395223A (en) * | 1965-05-13 | 1968-07-30 | Carter Wallace | Fern extract for treating gastric ulcers |
| ES470204A1 (en) * | 1978-05-24 | 1979-01-01 | Conrad Ltd | Natural terpenes having an antipsoriatic activity |
| ES471572A1 (en) * | 1978-07-07 | 1979-01-16 | Conrad Ltd | Anti-psoriatic fern extracts |
-
1980
- 1980-04-02 ES ES490293A patent/ES8104315A1/en not_active Expired
-
1981
- 1981-03-20 DE DE3111056A patent/DE3111056A1/en not_active Withdrawn
- 1981-03-25 AR AR284728A patent/AR224063A1/en active
- 1981-03-26 GB GB8109495A patent/GB2075834A/en not_active Withdrawn
- 1981-03-31 AU AU68934/81A patent/AU538973B2/en not_active Expired - Fee Related
- 1981-04-01 CA CA000374387A patent/CA1176173A/en not_active Expired
- 1981-04-01 FR FR8106562A patent/FR2479690A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| GB2075834A (en) | 1981-11-25 |
| AU6893481A (en) | 1981-10-08 |
| AU538973B2 (en) | 1984-09-06 |
| FR2479690B1 (en) | 1984-11-02 |
| ES490293A0 (en) | 1981-04-16 |
| AR224063A1 (en) | 1981-10-15 |
| DE3111056A1 (en) | 1982-02-11 |
| FR2479690A1 (en) | 1981-10-09 |
| ES8104315A1 (en) | 1981-04-16 |
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