Note: Descriptions are shown in the official language in which they were submitted.
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.
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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,
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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
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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-
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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
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I I76173
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.
EXAMPLE 3
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,
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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
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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-
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} 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~
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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.
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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
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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.
