LU81464A1 - PROCESS FOR OBTAINING A NATURAL POLAR FRACTION WITH ANTI-PSORIASIC ACTIVITY - Google Patents

Description

*! ] f ~ MX ^ i ‘‘ *, *, 1 v i; . . * 1 '.. - Λ. · - · .. *. '··' ·. · Ί i - · 1 EF.SIW1 ·; OF THE IEVKRïïôiî • · * “*” ”-v '“ * · ”-. ·” Λ “; I j. The present invention relates to obtaining! *! . K of a natural polar fraction with anti-activity! . soriasis, by extracting the leaves and rhizomes of 1 "t # ·. · _ _ 5 various ferns *.

! P '; 'r "; ·' T ..... MLECLDShLS LL Ι / ΏΤΤΕΗΐΙΟΕ? • ·. ί /.. i ·. To fight against psoriasis as a disease;. and against dermatological problems of the same type - 'included in The term parapsoriasis, we have so far, i,! j 10, despite advances in therapy,! no drug capable of improving, let alone curing, the patient 'who suffers from it .

"Knowledge of this disease is very old and the numerous attempts at treatment have all given L. 15, ultimately, very poor results and, what is more serious, in most cases use drugs or drugs that can, in one.

J ·; ·! promptly, be disastrous for the patient.

Curiously, we are currently going back to the old \ \ .20 treatments because they are harmless and j ·.

j allow the patient to get some relief from

T

I \ symptoms, although they never allow its healing î- · v or, at least, a noticeable improvement.

I Λ.

The problem is getting worse every day because the number of psoriatic patients is increasing, -j. Hence the hypothesis that it is a problem of transmission. genetic sion which, in the descendants, manifests itself, · · * * in a frank or concealed manner or, at least, will remain latent, and will manifest itself only in the latter case 30 when pathological factors which * - 2 · are combined ~, Μ. ί, ι - j. ι ôéο1euchercher its appearance.

] Touto the surface of the body is affected and · 1 '·, one of the main locations is at the level of * "t Ι". scalp in the form of “dandruff” to which “drank] '“ · 5 the beginning, the patient does not pay attention ”until the“ day when he discovers that many years feel • passed and that “despite some local treatments” his problem got worse. The presence of “dandruff” when; psoriasis affects other dermal regions' is! 10 observed in 90% of cases. The same way that the evil a- i i die respects no area of the body surface "she | also has no special preference for age i. · Γ determined by the patient. This is how both newborns and the elderly are affected in the sixth or seventh decade of their lives.

; ..., ’Its geographical extension is universal and i ~. it does not respect any race, although its incidence is; Perhaps lower in the black race.

j -. Its most frequent complication is arthro- I - · \ j. .20 p & thie but, in the long run, it also affects noble tissues such as liver tissue and renal tissue.

] \. In summary î psorio.sis and parapsoriasis Γ »♦ \ * * are pathological tables whose diagnosis is very easy 1 \ r although it is essential to carry out: · 2β an anatomico-pathological diagnosis. Its incidence increases. -. lie every day. Carefully, it is said that 1% of - the world's population suffers. So far, there are no effective drugs and the workarounds are. ‘. the only weapon the patient has.

m 'TïRROÎ? TPfPTOTJ T) K T / TTfirmTiTTON

,; ··,%., ...... - 7: ..... ”.........:“ '"' ~ 7 '.....: .... ......

; · ‘I · * · · î 1 *. ·; . . We have found that the natural polar fraction * i! · ’‘ '| I isolated cia rhizome and leaves of Dryoptcris jirasci ^ j - 'i "'” I · -. . rhizoma, Polyoodium vulgare. Linn. Polvnodium leucotomos,

J

1. -! Phlebodium d.ecxia & m-uru. Cyafthea taiwanisna and the rhizomes ’-i ·. *] ’5 from PolrDOdiufö aureur · linn and Poivrodium trineriale, i have A. ~ | tfiiHmV mViMm — ifl -rf ~ - • jummjié · —iiniwin-r.rijÎi'iMimm.MU i fftwl'i · ~ / rfi— * —- - r— - · '”..” “. kjm-ii.iimjm .i "- * j · i ·· Ύ * '": healing properties for the treatment of patients • 1. psoriatic and parapsoriatic of both sexes and j i-: all ages. This also applies to derivatives: Esters,!: Mides, etc. More than ^ 00 psoriatic patients have been treated on day 10 orally with small doses, for example - 5 milligrams per day per kg of body weight. ]: treatment, prolonged for 3 months, made it possible to whiten completely 80 $ of the patients, approximately. A group of 50 patients was subjected to an experiment carried out with 15 1. the double blind method which demonstrated i 'the efficacy of the drug in comparison with the placeb <I -; · used in the same way, with the same presentation and! r the same organoleptic characteristics. These fraction!';, and their derivatives have been used in all es the forms • · 3 i 20 · of psoriasis and in different states of gravity of this J pathological table.

! · \ From a toxicological point of view, i was only observed. ··; .

no effect. During the 12 years of research, examinations of blood, bone marrow, examinations of renal or hepatic function, as well as urinalysis. 'have never indicated alteration. Next \ . the standards of the E.D.A. from the United States and in accordance with ":" Guidelines for reproduction Studies for Safety Evalua-. ^ - tion of Drugs for Kuman Use ”, these compounds did not affect fertility, either in rats and mice or" h1 ". „: =» «,, ^ J · _ 1. . in other mammals (dog), and we don't have no]. - more observed teratogenic effect in 4 generations of: '\ i. · - · ... rats and mice and 2 generations of dogs «% | . Nor was any activity observed since · “I 5 -5 'kinogenetics * These studies were carried out on rats! · 'By administering them a daily dose of one milli- ’· gram per kilo of weight and orally, for 24 days. ··· - weeks. The animals were sacrificed from the seventh week, with and without implantation of a glass bead into the urinary bladder. The methods used in these studies are described by Juli, J.W "Brit, J. Cancer, 5 328 (1951) * and the statistical evaluation used 'is described by Arcos and collaborators,! I Chemical Induction of cancer, Pag. Academia Press Inc.,! ‘✓ 15 Hew York, (1963). ... '... - -' · The mechanism of action of the polar fraction '. acts by: - '· ,; a) Increase in the permeability of the mem-! · Cellular brane with sugars such as glucose, sucrose, ‘\ j ', 20 fructose and amino acids like valine, lysine and other I /’ ·' in less quantity. .

; . \. b) Increase in the activity capacity of i N cell membrane transporters.

‘.N \ \ c) Increase in water exchange at

J ‘* V

: 25 the cell membrane.

, _ - · * "’ d) An increased activity of *; hepatocytes has been observed, possibly related to the above.

which explains its great metabolic effect.

e) Increase in growth activity and VH mofnTO-f ··! nn ιΊν "λλΠ ϊκτοπο .1 ', - - 5 - j’. '1. The product has no sterile activity.

j. - roïde. With regard to its effect on other "organs and systems", it exhibits a hystericizing effect *... Similar to that of digitalis-based products, perhaps due to its action on cell membranes. - ..

; myocardial islets * i. The method according to the invention allows the extraction, with an industrial yield, of the polar fraction from the parts of the plant indicated above and in quantities useful for use in the preparation of compositions. pharmaceutical. To obtain optimum yield, the leaves should be collected when the young sporangia have already developed.

The method according to the invention comprises, the ✓ V? following phases: ------- -, · - ί · · DRYING.- i «————— \: j -. · The rhizomes must be divided into pieces \ i: 2 to 3 cm approximately; the leaves are dried in i / the state in which they are collected ^ drying is done by | - 20 continuously by introducing the raw material into 1 / 'a dryer of a suitable model, constituted for example by: i i \ 4 | a rotating metallic canvas about 3 cm high f \ and 25 m long, which moves inside a com-; part heated to a temperature not higher than 25 70SC. By adjusting the speed of the rotating wire mesh, about half a ton of wet material can be dried per hour.

'"GRINDING.- i ·" The dry matter (residual moisture lower than $ 0 to 8%) is ground in a disc mill set for --6-, · * · »j,'! I obtain particles of 2 ra, j · · '~ j j. I, ·. . These operations can be carried out in:! - ',' _ (any solvent (dielectric constant of; '' 5 1,890 to 9.08), preferably methanol with a volumetric ratio of-1: 4 * - ·; evaporate and obtains a residue which! ... · · corresponds to 1/5 of the original volume.

S, PURIFICATION

| '\ 10 1. The semi-solid residue from the extraction and evaporation operations is distributed in the | immiscible solvents, N-hexane / water (10 4) and on j. let stand in separators overnight. The i's. lipids and resins are released into the hexane phase.

! 2. The separated aqueous solution is passed through and filtered through an ion exchange resin.

| - - 5_. Ca (Oïlg) is added until neutralization.

i -. - '· 4. On the previous solution, J-activated carbon is added until the solution is clarified.

j - 20 5. This solution is evaporated to 1/10 i * 'i. of the original volume and precipitated in an organic liquid. '- anhydrous pic miscible with water, for example from 1- ’| k OL absolute alcohol.

'\ 6. The precipitate is filtered off with suction to give 25' a first mass in powder form and the ’- / 'p mother liquors are evaporated again to obtain a second mass in powder form.

This powder is dried under vacuum until it is very white.

30 "Tta κρΓ" .ίνηΓ * Ρ τηησορ rr-p-i n-hnll i np blnriebp πηή faith ·! · · ’Π ί" / · "., *, · 'Ι -.

'1 ι the object of the present invention, is not' "*, -, / <% * · * * i a chemical substance o.eiinie but a pre ·· * ...... · - parat ion of composition imposed by the nature vj of the drug used and by the extraction and purification methods *;: the presence of D-glucose and D fructose in p '• total amount of $ 70 results from usual qualitative tests, as well as from the isolation and complete characterization of the corresponding acetyl derivatives -10 * On the other hand, the presence of acid compounds hardly sepa ~: The saddles of sugars have been demonstrated, both by chromatography and by spectroscopic methods. ·. · ...._______.

Usual Scholars "." * I 15 ..... · The pharmaceutical compositions according to the invention; Yours are prepared in conventional doses by incor ~; poration of the polar fraction to pharmaceutical pharmaceutical vehicles, according to accepted pharmaceutical practices, j. . The resulting pharmaceutical compositions constitute the objects of the invention. The active ingredient, i.e. the polar fraction, is present in the compounds. . tions of the present invention in sufficient quantity 1. To produce anti-psoriatic activity.

Preferably, the compositions according to the invention 1, 25 contain the active ingredient in a proportion of - -. 10 to 100 mg approximately per unit dose. The pharmaceutical vehicle can be, for example, a solid or a liquid. By way of illustration of vehicles, solids - mention may be made of lactose, magnesium stearate, 50 terra alba. sucrose, talc, stés-oirvna 'acid - * - ο - ’. \ "1. <J /, j "'1 gelatin, 1 agar, reetino, gum arabiou" *.

I. - A, I aerosol and similar products "........ · ____ By way of illustration of liquid vehicles, in; 'Mention may be made of alcohols (such as ethanol or propylene j ·,. 5,.. glycol), water containing a solubilizing agent such as; - polyethylene glycol · / peanut oil, olive oil <: ...... and similar products. The vehicle or diluent can:. '' contain a delaying agent such as monostearate

1 -I

j glycerile or glycerile distearate, alone or with j 10 a wax. * '1 A wide variety of pharmaceutical forms can be used! 1 Thus, if a solid vehicle is used, the preparation can be transformed into; " not a word · \ ' . tablets, introduced in a hard gelatin capsule! . .. - '15 in powder or granular form or in the form'; , · Of trochisque or nuts. The quantity of solid vehicle i; .may vary within wide limits, but preferably 1. it is about 25 mg to 500 mg. If a liquid vehicle is used, the preparation can take the form cl · i \ j j. ' . 20 syrup, emulsion, soft gelatin capsule ", o · i suspension.

• 'liquid solution, or a sterile injectable form for \, \ parenteral use, for example in an ampoule.

> "". \. - ^ '· The pharmaceutical compositions according to the invention, in suspensions or liquid solutions, do not comprise the simple suspensions or liquid solutions of! .. - · the active ingredient in the common solvents not approved; - required for internal administration for the purpose of producing the desired pharmacological activity.

; . · '.> ·. A unit dose in tablet form, Λ θν \ Τλ + · * λλλΤλΪ λλιι λ r \ A ν mi λππ · Ϊ Λν \ 1 A ·! / 3 λ λπ "1 A / in ί / ίο. - 9 -; 1 sterile injectable for internal administration, with the aim of producing a psoriatic activity" constituted ij;.,... By a pharmaceutical vehicle and the polar fraction in j! -, an amount sufficient to produce this activity, consti-! .......:. .5 also kills an object of the invention.

--- --0 - - The route of administration can be oral or! '-' ** 'I; - I.. parenteral may, preferably, oral. Preferably, | | . the active ingredient will be administered according to a diet of | | daily dosage of approximately $ 0 to QOQ mg, and preferably 1 · 1 1Ö. a diet between 100 and "$ 00 mg. It is advantageous to administer equal doses 1 to 4 times a day.

ï V

that the administration is carried out as indicated! · 'above, anti-psoriatic activity is obtained.

I * “* | : - ------- Since psoriasis is an infection! ! -.15 chronic, insidious and endowed with an etiopathogenesis: ·. ·; genetics, it is best to use the cap- form. i. . ·· soot or tablets to maintain concentrations: stable blood allowing a continuous action of the drug. Without a doubt, when oh makes 5 \ 'acute attacks! 20. psoriasis, caused by other drugs, such as steroids or because of the disease itself, intravenous injection {. . *; or continuous drip in serum to cut the ’- \: crisis.

i 25. It should also be noted that in children - - - - · the form of drops or emulsion has been used for obvious reasons and, in the case of adults with upper digestive tract problems, recourse may also be had to the use of suppositories 2Λ ΛΛτηηΛΛΤ rinQ 'nhnr'îriérop.pnf * î ηποσ ολ-λΊ * ύλι- »Λ · ηογ» ΰΰ • ί' - 10 - '<i ..1— 1 pa? conventional techniques such as mixing, granulating, and compression when necessary or; ί. by mixing and dissolving the appropriate ingredients i *. * I ·. : for the desired compositions * j. . ·. . 5,. - The following examples illustrate the invention: i '' ·; · f '' 7 'EXAMPLE 1 .......; · ': / For an hour and a half, 12 kg are extracted; "1” of dry leaves, ground to mesh 10 (2.5 mm) | '' · 'with 4-8 liters of 95% ethanol? At, 70SC * ji 10; The evaporated product is collected in a |;. ... „„ .... mixture of n-hexane / water (15: 10 liters) and left to stand overnight in a separator. · 'J' "hexane phase and the aqueous phase is filtered.

! '.. -! '· The filtrate is passed through a column - I ul5 .. of exchange which is then neutralized with alkali.

I · The solution thus neutralized is clarified and j ~ / evaporated almost to dryness under moderate vacuum, for 48 i: · ...

] ’‘ Hours, (yield: about 150 g).

The dry solid is again dissolved in methanol and allowed to crystallize at 42 ° C. overnight.

! - EXAMPLE 2 - · 56 kg of dry plant, ground in a 10 mesh disc mill (2.5 mm), are extracted for 16 hours with n-hexane at room temperature. The * · " * * .

25. hexane solution is concentrated and the whole is left, mixed with water, in a separator overnight. The hexane phase is rejected and the aqueous phase is evaporated.

The residue is collected in ethanol chau <7Π ftvv "ns Λνν4- · Ί 4-λ ηη · η + · Λ v \ rvinT" μ A τνΛ un ûVf * PQT 4 * C * Ο Ή ΤΙ Τ'Λ. -η-- t} I. ...... · · -. . . .

, ·. ·· -; Ί. ···; solution is filtered, mixed with the phase; '' aqueous, and pass it through a discharge column.

1. , ", V **, ... ..’ · ···. .. t '·: ·; : '· - Then the solution is neutralized and clarified:' ’> -. · ·. ^ - ····· _.

Ι u -: - · fiee and one 1 evaporated almost dry. 'i j, ·. ···!?. X »ô solid est.dissout again in I ._ ...'.... 'Λ ethanol at 70% and allowed to crystallize at temperature i: overnight. The crystals are rejected and on 1 .. ·. : .... supernatant liquid is evaporated (yield: 180 ^ g) and | . *. ’If vacuum drying. - '/ ·; : '".i: · /' ·; '" - · j ·· -; .V- .10 i': · [. ‘: M? LE 3 ·. - i ν '. ··: v; 2 * '*.

| . , t i ·; . ί. Extraction is carried out continuously with chloro-1. - · Λ, - ·. . · F ... * v.i - forms at room temperature. 12 kg of dry rhizomes, d: '...'. . ground in a number 10 mesh disc mill i · ^ <V. .. - - ‘+; i ‘'. t v- '' ”·’ (2.5 mm). . . ·% -; ·:;. '"* c -’! * ‘.. y' * * #; · '15. ·’ .. Concentrate and dissolve again in? ·. n-hexane / water.: y '.

· '· - - The hexai phase is rejected and the% ·. "... aqueous phase is evaporated.. - V' ·. -V.

•. Is the residue from the extracted rhizomes collected? '· "' ''. ·· · \ |. 20 in hot methanol and left in contact for; '* · hours. Filter and pass through a column - *% _ · î.. \ D 'exchange.

j n ”N · · The extract is neutralized and clarified before i; ·, ... evaporate it and set it to crystallize in ï · ’· \ 1, l- ·: - ·.’ · 95% ethanol overnight. The crystals are rejected. it '^ ’; .. and the liquid which floats is evaporated and dried then l "**. · '* *.

i. . \ v under vacuum (yield 84 g). . · ·; "· · - -. EXAMPLE 4. * •>. One extracts at reflux, for one hour and a half * Ί 'Ί ν 4 ~ ic - β *;; -. 1: 90% nethanol, at 70SC. ; I *] [The extract is filtered, evaporated and is added to: ^ 1 * i - - .. J- a mixture of hexanc / water (5: 2) $ let it rest! \! · X> eüciant at night and .the hexane cm filtering * *, t ', 5 is thus accepted and, by evaporating the aqueous phase, i ·!: The residue is dissolved in hot ethanol • at 90% and passed through an exchange column, i 0: The extract is neutralized and evaporated to i ί 'tenth of its original volume and is set to crystallize i; · r ~ ··. ί 10 · cold.

1; * i · j - 'We filter, we reject the crystals and the liquid · I which floats is dried and placed under vacuum (Yield 240- I' · ·.

| -. 250 s). ; - J - · r. * · * ~.

I '* ·. ’Examples of pharmaceutical preparations that: . The following are given by way of illustration of the invention and therein "". * · * without any limiting nature.

; ; . KTOîPLB 1 -

INGREDIENTS, 'QUANTITIES

........ "., \ .........

Polar fraction. 40 mg i, ’'\ I .20 Lactose 60 mg I' The ingredients are mixed, sieved and intro J \ duits in hard gelatin capsules. A capsule prepared as described above is administered three times a day.

I ".

i - 25 ·. EXAMPLE 2

%. QUANTITY INGREDIENTS

Polar Eraction 60 mg. ^

Starch 60 mg .. .. Talc 5 mg

Claims (1)

j I, -— ”,. --13-. 3 · ”:. . · »·. ^.-.-: - -..- · ... ; . . -. -. : -. * 1 Polyvirjylepyrrolidoriô 5 Big \. - i. The fraction and the starch are mixed and -: ..... · "'' ·· .- granulated with a 10% gelatin solution οοπΐοιη-ηί, v,. - ~. - polyviôylpyrrôlidojiô. The granules are sieved, dried i · * -. 5 and mixed - then with kaolin, talc, and are, '<' 'sieved and then processed into tablets "!:: Of course, various modifications can be made. the IIomme de l'Art to devices or j 'processes which come from you described only by way of j '10 of nonlimiting example without leaving the framework of the invention I - | tion * ..:! " lOTOTOIOATIONS - | * (- '\ Process for obtaining natural polar fraction i' '] .. ·' le with anti-psoriatic activity, by extraction of i. - *! '15 rhizomes and. Leaves of Lryopteris crassirhizoma, Polypod 1Μΐ »ΜΜί« * - Ι ^ · »> ^ <8ΐΜΜί» · ΜΜ · ΙΙ 11 'Γ ~ ΙΙ ~ Τΐν llMlilii:.' · Vulgare, Linn, Polypodium leucotom.os ^ Phlebodium Decumanu i. ···. - * - ~ ί. -J "Smith, Polypodiurn decuaanuia, Cyathea taiv / aniana and; rhizomes of Polypodium aureum Linn and Polypodium trise i '. - - {' rials, characterized in that the rhizomes are cut into • i - \ j '20 pieces of 2 to 5 cm and the pieces of "." * · 1 * - 0 |' rhizomes and leaves are subjected to a drying operation conti i% i. nu, at a temperature not higher at 70 ° C; the material i \ - xsec, 'which has a residual humidity lower than i \ 8% being then subjected to a milling operation in order to form particles of up to 2 mm diameter, with a density of about 0.1 - 0.80; o n produces the extract - with a solvent endowed with a dielectric constant between 1.890 and 9 * 08, the solvent is evaporated and the residue is purii; the semi-solid residue from the extrri is collected in a mixture of n-hexane / water (10: 4-), leaving .‘V ..-- 14 -. . . . 4 y 1 '1 · - 1'. - - V - I -y 1 ·: rest during the night with a separator and by separating it. aqueous phase which is passed through - 'an exchange resin, and Ca (0Ho) is added, up to, \. '.. ·. . ^. 1] .. · 'neutralize the solution, to which we add charcoal j ··' to 5 ^, · active until the solution is clarified, and we -1 · '· evaporate this, last until to 1/10 of its original volume by precipitating with absolute alcohol, in such a way that the precipitate can be filtered by aspiration | Λ '·' ·. '- by evaporating from © new water to obtain a second urn of 10 powders of powder, which is dried under vacuum until an extremely white solid is obtained.>; '' 'Y 1. 1' -, y. I · S 1. 1 7, 1 ....... ^> ..... · »S '. - · jr> ii · .'2 j ^ \ 1' · i:; .... ''; \. · '/ \ 11 1 i 1. \ \ \ \' · •., A \ 1 '»· \ 2 *" \