Note: Descriptions are shown in the official language in which they were submitted.
~2~31~30~
--2--
The pre~ent invention i~ concerned with a proce~
for obtaining laxative c. ~u~d~ ~rom senna drug.
Senna drug con3i~ts of the dried leave~ and pods
of the 6enna plant, for exæmple of Indian senna
~Ca~ia anqustifolla) and of E ~ tian senna (Cas~ia
acutifolia). The laxative action o the ~enna drug i~
du~ to two c~ e~ of ~hemical e ~u,~, namely, 1) ~he
senno~ides and 2) the non-senno~ide laxative-active
~ub~tance~ ~hereinafter referred to as ~S~5).
The laxative-active s~bstances in the ~enna drug
are ~i ~ ular glyco~ide derivative~ of ths tw~
anthracene c~ r,~unds rhein and aloc ~ -'in. The mo~t
important are ~ennosides A~ B, Al, C and D. Sennoside~
A, B and Al are bis-~luco~ylrhein anthrones and ~enno~ides
c and D are glycosylrh~ln-glyco3yl~ n dianthrons
d~
I~ addition to the ~onnosides~ the crude drug also
contains aglucones (~ennidine~ ) and ~ther dec~ ion
p~du~L~ and dsrivatives o~ the ~enn~ide~. Some of
these can al~o have a laxatlve effect hut, at the sa~e
time, can also be toxic and give rise to ~nde~irable
side ef ects. :Side e~fect~ which are typical for ~enna
preparations include n~ e~, vomiting, ~nnd, ~olic a~d
diarrhoea.
Various pxoces~es~have ~een des~ibed for extract-
ing the laxative-a~tive ~ubsta~e~ fr~m the ~enna drug~
~he mo~t important laxative a~tlYe glu~o~lde~, i.eO
.
1~3t3(~9
-3-
sennoside~ A and B, were isolated from the s~nna drug
for the first time by Stoll et al. (see Helv. Chim.
Acta, XXXII, Fasciculus VI ~1949), 1892). Subsequently,
many patent ~pecification~ have been published which
describ~ processes for the preparation of ~enno~ide
~o~cen~rate~.
Hitherto, the preparation of the ^Qenna extract
h~ gen~rally ~een carried out in tw~ stages. In the
first stage, vegetable pigments, ~ata and other impur-
itiea are remo~ed with an appropriate ~olvent, for
e ~le chloro~on~, ether (see U.S. Pat~nt Speci~ication
No.3,089,814) or with 90~ methanol (see Federal Republic
of Ge_ y Patent Specification ~o.16 17 667)~ After
this prel~ n~ry extraction~ the active gluco~idea are
extracted from the drug in tw~ ~tagee wikh methanol,
aq~eous methanol, ~ueous o~hanolior only with water.
In order to faci}itate the extra~tion, the
methanol u3ed can be rendered ~lk~llne ~y t~e ~ddition
of organi~ ba3es (see Federal ~pu~l~c of Ge. - y Pat~nt
.5pecifi~tion ~o.23 397). The ~rganiG base~ fon~
methanol-~oluble ~alt3 with khe senno~ide~ which can
~ea~ily be~extracted. ~o~rs~er, a d~ad~antage o* this
proce~ i6 th~t the extract contain~ a high content of
impurities.
~t hag al80 keen ~ugge~ted to u~ extra~tio~
301vent~ acidified wi~h citric acid ~see ~l~nc~ Pa~ent v'
Speci~ication ~o. M 6611 (lg6g)) or with oxali~ a~id
I
12~3~30~3
-4-
~ee Brit~h Patent Specifica~ion No.832,017)O In the
latter case, 7~% ethanol wa~ used a~ solvent, If
acidic methanol or acidic a~uaou~ methanol i~ u~sd for
the extraction, the content of impurities in the extract
is ~maller than when the extraction i~ carried out with
basi~ 801vent~ or with water alone. ~owe~er, thi~
pro~e~s ha~ the disad~antage khat the sennosiden, which
are acidic cc ~-u-3-q, are, a~ free acids, only sp~rin~ly
soluble in the ~olvents used. ~onRequently, the amount
of 301vent required for the ex~ra~tion i~ very large
and can be as much a~ 15 to 20 time~ of the w0ight of
the drug u6ed~
For the extra~tion of the drug, it i8 al~o known
to use ~ixt~re~ of methanol-tetrah~L~furan, methanol-
dioxan and tetrahydrofuran-dioxan acidi~ied wi~h
pho~pho~ic acid ~ee ~ung. Telies, 6006 ~1973)) and
aqueou~ pho phoric acid (see Federal ~epublic of Ge_ 9ny
Patent Specification ~o. 1~ 17 667) a~ ~olvent~. IIo~. ver,
these solvents a~tivate the glucosidase enzyme ~o tha~
some of the active gluco3ide i~ hydrolysed, especially
when usi~g weaXly acidic ~olution~, the p~ value of
which corre~pon~R to that of the original plant material.
~hi8 re~ult~ in a ~e~uc~ion of ~he ~ - -L of a~tive
material in ~e extract ~ee also Fs~eral,~ep~hl;~ of
Germany Patent ~pecification ~o.29 15 063).
Ac~ording ~o the prior ~rt, the ~enno~id~ ~on~en_
trate i~ obtain~ fro~ the extra~t~ in various way~.
I
~z~!t31~0
A solid, sennoside-con~ n; n~ extract i~ obtained
by gentle drying of the extract (~ee Federal Republic
of Germany Patent Specification ~o. 16 17 667). ~he
product then contains all the ~ub~tances pre~ent in the
extract, th~ ~ennoside content of ~he product b~ing
about 17 ~o 1~%.
~ owever, the senno~ide~ can be separated more
selectively wh~n they are precipitated from a~ueous
sol~tiQn~ by the additio~ of organic ~olvents. ~he
product obtained contain~ le~s h~ t materials and
ha3 a sennoside content of 60 to 7~%. The precipit~tion
can be ~arried out by the addition of diethyl ether (~ee
French Patent Specification ~o. M 611; ~a~yar G. et al.,
~ung. Telje~, 6006 (1973?~ opropyl alcohol, after
treatment wi~h a trongly acid ion ~c~n~e re~in (see
Briti~ Patent Spe~ification ~o. 832,017) or ethanol
(~ee Finni~h Patent Specification ~o. 4158~). The
sennQ~ide~ ~n solution ca~ possi~ly be con~erted into
the calcium -~a~t3 (see U.S. Patent Spec;~ication ~o~
3,08~,814 and Finnish Patent ~pec;f;cation ~o. 41588)
and ~ubsQquently precipitated out by the addition o~
organi~ ~olv~nt~ so ~hat the a~tive glu~o~ide~ are
obtained as calcium 3alta. ~he conte~t o~ s~n~ofii~e~
in the precip~tated ~ucL ~hen ~ to abo-~t 60
to 7~%~
For obt~n~n~ pure ~enno~ides~a~ ~ree acids, the
~enno3ides ar~ i~olated a~ calcium ~alts a~d the~e sal~.s
I
~Z~38(~
--6--
then deco~L~sed wnth oxalic acid ~see Stoll et al.,
~elv. Chim. Acta, XXXII, Fa3ciculus VI (1949), 1892).
Thu~, according to these known proce~e~, extract~
and var~ou~ kind~ of co~centrate~ cont~ n~ laxative-
active ~ub~tance~ can be pro~nçe~ from the ~enna drug~
Th~ of laxative-active sub~tan~e~ in ~he con-
centrates ~pen~ upon the eontent of the~e ~ub~tance~
in the or~inA~ drug and upon the production proce~s
used. One dif~culty in the 3tandzrdisatio~ of the
~enna preparations i8 the determination of the ~en~a
glyco~ides. ~he dr~g contains various c~ ~ro~n~ which
are i~cluded in t~e deten~ination of ~he senna glyco~ides~
~o~.over~ the phy~iological action of the~e individual
comro~n~s is not t~e ~am~ Since, with the help of
~on~entional methods of determi~ation, it i~ not
pos~i~le to differentiate the senna glyco~ideo ~r~m ~he
o~her c~, Lnds ~ich ha~e different phy~iologic~l
aetions and po98ibly ~ide reacti~ns, it i~ di~ficult
to ~o.l~ce preparations~ startinS~ from ~ .vt:~t.iorlal
3er~a extract~ ich alway3 p~o~lu~e the sam~ and
reprod~ribl e action with ~he ~2me do3e,,
It iB an obje~t of the3 pre~er~t in~rentlon to p~o-
vide a proc:e~3~ for obt~ i n~ laxativ~ c~ fr~
the enna drug ~ h p~nnits t~e laxa~ive-active ~u~
stan~e~ to be o~tained in i, . ..~ed yield in the :rRost
~or~entrated form a po~3ible 5 whic:h are as f :r~e a~s
po~iblç3 from c ~ with unde~ired side effe~t~.
3L2Q3~30~
--7--
ThUB, according to the pre~ent invention, ~here
i~ provided a proce~s for obt~i ni n~ laxative ., . ~,~ul-d~
f rom senna drug, wherein
a) the ~enna drug i~ extracted with aqueous methanol
by countercurrent perc:olation and the extrac:t con-
centrated at a t~mperature of 6 50~C. until the
methanol ha~ b2en ~o~pletely ~. v~d fro~ ~he
~xtractS
,,
bl the extract o~tained i~ puri~ied by ~on~ o~R
liquid-liquid extra~tion w~th an organic~ ~olvent,
c) the refined material (raffinate) obtai~2ed i8 trans-
ferr~d to a cry~talli~atisn apparatu3, acidified,
while stirring, to a pH of about 1.5 to 2.0, ~ee~C~.
with senno ide ~:rystal~, left to cry~tall:ige while
~tirring an~ the cry~;t~ 1 i n~ ~rude ~a~n~o~i dea
obtained ~parated off,
d ) whereafter ~he crude senno~ide~ are, if desir~d,
recrystalli3ed a~d ~ptionally
e) 10 parts by ~eig~t o~ the mother liquor from ~tage
c3 mixed, while stirring, with ~ parts by w2ight
of ~odium chloride and ~he ~emi-~olid maB~ ~oagul-
ated on ~he ~urface i8 d~canted off, ~ Rhed and
optionally ~ Le~ ch 95% ~thanol and the
met~anol ~rac~tlon c~..ce~-1 L~tea and th2 r~sidue dr~ed.
For ~arrying out the proces~ as:~cording to t~h~
E~re~ent i~v~ntion, mixtures of Iaethar~ol and water ara
u~ed in whi~::h the ~nn~ ea are solubl~l, It i~
~2C)3~90a~
-8-
preferable to use 70~ methanol ~lnce the -
~solubility of the ~enno~ide~ lie~ at a methanol con-
centration of 60 to 70%. ~he extra~tion i~ carried out
in portion~ and preferably at a ~lightly elevated temp-
erature but at mo~t at a ~olvent temperature of ~35 & .
Since there iæ a danger that the Aennosidea would
~e~ ~-se, ele~ated temperature-~ have previously been
avoided. ~o~ ve , w~ have,~urpri~ingly, ~ound that
the ~ennoside.~ do not 'e~ e at a slightly elevated
temp2rature when methanol is u~ed as solvent.
q~he drug extraction i~ carried out in a ccunf,er-
current percolation plant. In general, 2 to 4 percol-
ator~ are u~ed. If the extraction ~olvent i ~ to be
rr^~, it is allowed to circulate through an external
heat e~h~n~er in which it i5 thereby ~. ~' to the
d~sired te~perature kut at mo~t to 35 & 9 Th~ more
per~olators are used, the le~s m~t the solvent be
warmed. The extract obtA~ne~ then contains le~s ~ar~-
ful impurities and the sennosides ~rystalli~e out com-
pletely ~r~m the mother l~quor.
Before the extraction, it ~3 p~eferable to 9well
the dry drug in a 301vent, for whi~h pUrpO8~ it i8
pref~rable to u~e the post-percolate from a previo~ly
ex~ ~L~d drug~ ~or thi~ pu~poae, the dry dru~ i~
pla~ed in a percolator, co~ered wQth a perforated plate
w~th a weight of about 0.7 ~g./dm2 and th~ ~olve~t or
po~t-percolate ~ ed in. The weight of the . ; ~ of
~L2~3~3~)0
g
~olvent required is about three times the weight of
the dry drug. It ia pre~erably left to stand ovexnight
and ~he extraction i8 ~ e' the next day.
~ he extraction take~ place over the cour~e o~
16 to 20 hour~, during which time the nece~a ~ u~,~
of 7~% ~ethanol iq allowed to flow through the dry mas~.
Since it i8 preferable to use eeveral percolator~, when
~arrying out the extraction the ~olven~ ir~t passed
into the percolator of the serie~ of percolator~ which
contain~ the weake~t drug, i.e. the one which ha~ already
been mo~t extracted and which i8 to ke the next one to
be emptied. The ~olvent i~ p~ed fr~m thi8 percolator
to the next percolator and ~o forth. ~he mai~ extract
iR taken fr~m the percolator which wa8 the la~t on~ to
be filled~ After removal of an appropriate -~ ~ of
extract, there i~ additionally obt~ne~ a poat-per~olat~
wh~ch can be u~ed ~or ~welling a new batch of dry drug.
For thi-~ purpo~e, the percolator cont~inln~ the w~ake~t
drug i3 smptied, ~illed with a quantity of drug, the
poqt-percolate pa~se~ in and the extraction carried out
on the next day~
A~cording to the pro~ess of the pre~en i~Yention,
it is po~sible to extract 1 part o ~he dry drug wn~h
only 4 part~ of extractio~ ~olvent. If 7~% m~thanol i~
u~ed at ambient temp~rature, then the r~sidual : ul~t of
substance in the drug i~ ~out 41~ per per~oIator in the
~eries of percola~or~. With tw~ percolators, the
~LZ03~30(~
--10--
extracti~n yield i9 (1 - 0.412) x 100 = 83% and with
three percolator~ connected in ~erieA it i~ 0.413)
x 100 - 93%.
After khe extraction, the methanol is ~ :ved
practically quantitatively from the percolate, the
volume of the bottom product obt~inla~ being a~out one
fifth of the volume o~ the percolate. The m~thanol .is
~ d with the u~e of a ~. distillation apparatu~
equipped wsth a fractionation column. Re~tl~e of the
danger of hydroly~is o~ the senno3ide~, the temperature
must not ~-~ce~ ~so&.
The conc~trate obtA; n~ contain~, in addition to
the senno~id~, all pLO~UC~8 which can be ~ cLed
w~th methanol fro~ the original plant material. The
CQ~entrate i8 preferably mixed with about 5% butan-2-ol
in ord~r to keep t~e fats in ~he co~ntrate in emulsion
and al~o to a~t as a pre~erva~-ive 90 that the grow~h of
mlcro-organi~m3 and pu~r~factio~ of the ~olution ~u~e~
thereby are inhi h; ted .
A~ter di~tilling off the methanol, t~e co~centrate
is purified by liquid-lisIuid extr~ction with an orgarlic
sslvent. ~e ~ol~nt used can be an alcohol or ketsne
wllich is partly soluble in water, for P. ~e, h~tanol,
me~hyl ethyl ~etone or met~yl i3c~propyl ketone~ the
pref~arred solvent being butarl-2-olO l!he li~uid~ uid
extraction i8 ~arried out as a continuon~ proce~ a
partitio~ing apparatu~ with a ~paration effect of a~o~t
12~13801~
--11
10 theoretical step~. The pH of the fed-in çon~entrate
801ution i~ thereby about 5.4 to 5.6 since, at thi~ pH,
the ~alts of the aglucone ~c ~ pre3ent in the
senna drug are hydroly~ed to ~uch an extent that the
aglucones are removed pra~tically quantitati~ely from
the raffinate.
B2fore use, the b~ta~ 2-ol e~ployed ~or the
~xtraction i8 preferably ~aturated ~ h ~ater. The *ed-
in conce~late which is to b~ c~ed i~ a very con-
centrated solution with a content of dry material of
about 20 to 3~%. It ~ntain~ salt~, ~ugar~, amino
acid~ a~d other water~oluble ~ which ori~inate
fro~ the plant mas~. The extr~tion i8 pr2ferab1y
carried out in such a ~nner that the run-off ratio of
butan-2-ol : raffina~e i~ ab~ut 0.7 to 0.8 : 1,
By means of the li.quid-liquid extraction, ~ata,
harmful plant pigment~ hlorophylls and carotin~id3,
f r~e f atty acids, steroid~, agluconi~ anthL~rle
derivatives, neutral glucoBides ~ ~eget~bla wa~e~ and
wax al~ohol ,~flavone~ and other ph~ , etc. are
removed fr~m ~h2 solutionO In thi~ way, ~h~ raffinate
obtain~d iB fr~ed from hA 'ul i~puriti~ to such an
e~t~ hat the ~ain ~ of the ~ennoelde~ can ka
cry~talli~ed out dire~tly ~ron th~ raffinat~ pha~e by
acidification with a ~ineral a~id to a p~ of about 1.2
tv 2.0, the ~ineral a~id u~d pre~erab~y being hydro-
chloric or ~ulphvric acid4
~2~3~30~9
-12-
In order to crystalli~e the senno~ides ~rom th~
raffinate pha~e, thi~ i~ placed in a contai~er and an
- -~r.~ of acid i8 p~e~ in, while stirring, until t~e
p~ value of the olution i~ a~out 1.5 to 2Ø The
~olUtioR i 7 then ~eeded with ~ennoside c ~tal~ and
left to crystallise for 1 week, while ~tirr$ng~
on the other hand, the cry~talli~ation can al90
be ~arried out in a continuou~ly operating cry8talïi3--
ation apparatuæ. ~h~ raffi~ate phase ~here~ ~
for about 1 week in this cry~tallisation apparatu3 and
iR there'Dy divided betwee~ 2 or more contai~ers cGn~ccLed
in ~erie3 which discharge into a de~ er. The crystall-
isation container~ are con~;m~o~Aly gently stirred and,
fox acidification, a ~olutio~ of the mineral a~id i8
introduced, with ~tirring, into the first containar.
The vertical l~m;nAr ~low in the container~ i8 ~bou
0.3 to 0~4 ~m./minute. Thi9 rat~ of flow en~ure~ a
~ati~facto~y ~e~ tion. The crystallised p~v~u~L
i~ filtered off, ~ ~h~d with water and methanol or
acetone and then dried. I~ de~ir~d, ~he ~rude product
i~ e~lysLalli~d, a~ Yr7~ne~ hereinaft~r.
A fractio~ o~ ~h~ ~e~na drug which is importa~t
with regard to tha biologi~al action~ i8 ~he fra~tion
~oa~in;~ the non ~nno~ide l~xati~e-~cti~e sub$tan~e~
(NSL~S)~ Thi~ fr~tion oc~ur~ in varying ~ -~u~t~ i~
crude drug~, extract~ a~d $enna p~eparation~
addition, the~e ~ubsta~ce~ are for~ed ~71ri n~ the drug
~2~3~(3~
--13--
extracti~n. ~he laxative activi~y of th~ crude ~SLAS
fraction amounts to about 6~% of the laxative activity
of the muxture of pure ~ennosides. However, the
intra~renous toxicity of the :rude ~SLAS f raction l~ Ul~
to about 20 time~ the toxicity of the mixt~re o~ the
pure s~nno~ides,. ~he che}nical propertie~ of the 2iSI~S
fraction, its so~ubility in variou~ ~olvents, the
partition propertie~ and *he behavivur in the case of
~alt for~nation L~. 'n~ one of the corre~pon~;ng prope~tie~
of the sennoside~.
The ~SLAQ fraction contain~ tbe re ddue~ of the
~enno~ide~ whi~h ~1 -;n in the mother liquor in the
caae of the c~yQtallisation o~ th~ raffinate phase
a~ter th~ purification extrastion with the organic
solventD ~he ~enno~ide content of the crude NSLAS
fraction æmounts to 5 to 10%. Thi~ fraction thereby
contain3 5 to 1~% o~ rhein-8-~lucoside a~d 80 to 9~%
of c~ , the chemi-al ~trueture and phy~iological
actions of which are hither~o unknown. The crude ~SLAS
fraction can b~ divided into approximat~ly two egually
large fractions by le~h;n~ ~ut wi~h 95% methanolO The
portion whi~h iB ;n~otuhle in 95% methanol i~ a brown
powder. ~hiæ hi~herto unknown c _- ' chromatograph~
in the ~a~e ~f gel chro~ato~L~ y li~ a ~om~ R
0~ UI~ and ha3 a r~tentio~ volu~ w~ orr~pond~
to a mol~ular weight of ro~ 1000 t9 10,000~ ~he
portion o~ ~he ~SLAS fra~tion w~i~h i~ ~oluble in 95%
3~0~;9
-14-
m~thanol consist~ of ~ ~,G~nd~ with low molecular
weight3. This fraction contain~ about 20~ of ~enno-
~ides. ~he main portion o~ this fraction con~i~ts of
~ompound~ which hav~ not previou~ly been identified in
the senna drug or are ~ ~etely unk~own.
The c~ude ~SLAS fraction can b2 readily ~eparated
when the mother liquor of the senno~ides i~ ~ixed wqth
a ~alt, for ~ e ~odiu~ chloride. Fsr thi~ pu~po e,
after filtering off the ~enno~ides, 2 part~ by weight
of ~olid ~odium chloride are gr~u~y added, with con-
tinuous ~tirring, to 10 part~ o the mother liquor and
stirring is continued for 1 to 2 hour~. Sub~equently,
tha semi-solid mass which ha~ coagulated on the ~urface
of the ~olid i 9 decant2d o~f fr~m the ~olutio~ A~
by 8u5p~n~i n~ in water, the ~ pPn~ on i~ R~irred over-
night and the pr~cipitate allow~d to ~ettls out ~he
next day, ~he~eafter th~ bulk of th~ wR~h solution i~
decanted of~. ~he pr~ipita~e i~ ~iltered off with a
~u~tion filter or with a ~iltration cen~rifuge, -~ ~h~
with water and anhydrou3 ~ethanol and dried in a
~urrent of air at a~bient t~mperature. When aen~a pod~
are u~ed a~ raw ~aterial, the yi~ld of ~rude ~SLA~
fraction i9 about 1.5 to 1.6~ o the weight of raw
~aterial u~edv The precipitat$on by ~al~ing ou ca~
al~o be ~arried out from a dilute ~olution.
~ he crude ~en~o~i~e~ ob ained after th~ erystall-
isati~n ~an, if de~ired, be recrystalli~d. For thia
~2al3801C~
-15-
purpo~e, the crude s~nno~ide~ are ~ pen~ed in a
mixture of acetone and water (50:50) to give an approx-
imately 10% su~pension, dissolved by the addition of
~odium hydroxide to a p~ o~ about 7.5 to 9, with ~odi~m
~alt formation, and the ~en~osides again precipitated
out ~y a~ju~ting the solution with hydrochloric acid
to a p~ of about 1.5 to 2, ~eparated off, wn~he~ with
~queous a~etone and dried.
A~cording to the pre~ent invention, the laxative-
active c~...~oul~d~ ~ont~i ne~ in the ~enna drug can be
divided into two fraction~, ~a~ely, into a 3~nnoside
fraction and into an ~SLAS fraction. The latter fraction
can be divided into two further fractio~s, ~amely, into
a Ure~in~ and into a low mole~ular wei~ht ~ra~tion.
The laxative activity o~ all fractions acco~nt3 for
about 9~% of ~he total laxative activity of the s~nna
drug. ~he valu~ for the laxative a~tivity ~nd the
intravenous toxicity of the fractions, which were
detenmi~ed by experiment~ on mice, are given in the
following Table:
~BL~
property ~enno~ide crude ~SLAS fraction
fraction
9~% ~ethanol- ar~in~
~oluble ~ra~tion fraction
laxative action 100 100 ~10
LD5~ . ~g~/~g.~100 4100 130
~2~3~0~1
--16--
~ hu~, ~th the process according to the preBent
invention, it is po~ible to obtain the ~nno~ide~ in
t lOOX purity from the crude drug. Furthermore,
it i8 al~o po~sible to i901~te the ~SLAS crude ~xaction
in a conc~n~rated form frorn the mother liquor~ of the
~eN~osides. In addition, in the case of the p~o~:e~
a~:cordin~ to the present invention ~or obt~ ~i ng
laxative-active ~ub~tance~ from ~enna dr~g, a prel i ~n_
ary extraction of the drug i~ no 1~n~er raquired, a~ i8
nece~ary in ~he ca~e c~f ~he previously known proc2sses,
Sirlce the ~ennosida~ obta~ned b~ the proca~
according to ~he pre~3erit inventiQ~ are ch~ically ~nd
p~ ogically c _ letely chara~cterised, t~ey can be
used for the for~u~ation of - 'içi n;~ i tio~ls with
definite galenical propertie~. In contradi~tinc:t1 on
thereto, acc~ordi~g to the previou~ly k~own pr~e~es,
only more or les~ inde~Einite galenie~l extract~ ca~ be
obtained.
q~he pre~ent inverltion a:l~o provides laxati~re
co~po3ition8 contA; ni n~ at least one laxati~re c _
obt~inP~ by the proc2s~ of th~ preserAt inv~ntiorl, in
a~xture with a ~olid or liquid ph~ 7.celltical ~i ~ U~T~t
or carrier.
q~he following :E3xa~ are given ~or the purpo~e
of illu~trating the pre~ent i~ tion:-
r le 1.
40 ks. ,~nl,~ of ~e~a d~g are plac:e!d into tw~
3~
.~7-
serie~-conne~ted percolator~ ~ th a volume of 250 litres
which are covered with perforated ~teel plates. The
sol~ent u~ed for the extraction i9 70% meth~nol which
is ~upplied to the drug in ~le fir~t percolator. A
bottom plate covered with a ~ilter ~loth i3 pre~ent on
the ~ottom of the percola~or. By ~eans of an emptying
coek provided below this plate, the ~olution i8 pa~sed
to the dxug pr~sent in the ~econd per~ola~or, the ~ol~ent
thereby being allowed to f1QW freely through the fir~t
percolator. The rate of flow of the ~olvent i~ adjusted
by means of the emptying coc~ on the firs-t percolator~
~he run-off o~ the .~eon~ percolator i~ adju~ted in
~uch a manner ~.hat the level of the ~ol~ent in the
second percolator i~ high ~nough to cover th~ p~rforated
~t~el plate, w~ich ha~ a weight of 0.7 kg~/~m2.
~ or the extra~tion of 40 kg. of senna drug, a
total of 160 litre3 of solvent are u~ed. After this
L of 7~% meth.anol has passed throug~ ~oth p~rcol-
ator~ and an appropriat~ ~ - ui~ of percolate ha~ been
collected, the emptyin~ pipe o the percolator i8
conn~ted to a po~t-p~rcolate ~ontainex and an additio~al
60 litre~ of 70~ m~tha~ol ar~ p~ed thr4~gh ~h~ percol-
ator~. Yherea~ter, residual free eol~ent i~ pa~Qd fro~
the ~ir~t percolator into the upp~r part of th~ ee~ond
per~olatbr and the po~t p~rcolate i~ ~olle~tsd until a
total o~ L20 litr~ hav~ been obtai~ed. Th~ fir~t
per~olator is then emptied, again ~illed with 40 Xg.
~03~0~
--18--
~3enna drug and the po~t-percolate i~ on to the
dnlg, 120 litres of po~t-percolate being sufficient to
~over the drug in the percolate. Sub~e~erltly, a
piped connec~ivn i~ made from the run-off to a pun~
and a heat G~srr~nger and from there to the cover o:E
th~ percolator and the ~olution i~ all~wed o circulate
until th~ te~perature of the ~olution iB ~t30 C. It i~
then left to ~tand overnightO
~ he followinçT day, thi~ per~olator i~3 ~onn~t~d
to the one previou~ly extracte~ and the extraction
carri~d out in the a~ve-described ----r.
For each 40 ~g. of drug there are collected 160
litres of percolate from whic~h the methanol i~ remo~red
in a vactlum rotary evaporator eqn;~pe~l with a pAt~ke~9
column. ~out 30 litre~ of bottom produc~t are c>btained
whic~ i8 extracted in the Nmixer-~settler~ apparatu~
( 10 stage ) using 40 litre~ of wat~r-~aturateZ butan-2-ol .
About 38 to 40 litre3 of aqueous raffinate are obtained
and about 3S:) to 32 litres of butim-2-ol extrac~. The
aqueous raffinate i~ acidified wi~h 93~ sulphuric: a~:id~
while stirring, duEins~ the ~our~e of 20 hours, 1~.69G by
volume ( re~erred to the ~olume of liquid ~o l~e acid:ii~3d )
thereby being u~ed. ~e acidified ~;olution then haE~ a
pH of 1.5 tc: 2.0~ ~t~r ~tirring for ~ further 6 daya,
the precipi~ate i~ allo~red to depo6it overnight, :l~ilt~red,
5he~ with water unl:il the wa~h wat~r i8 ~olourlea~,
hed wi~h m~than~l and dried in a current o ~ir a~
a ~
~v
--19--
ambient temp~rature. ~he yield per 40 kg. of raw
material is 760 to 790 g. (dry substance) with a
sennoside content of 90 to 9~%. ~hu~, the yield i~
about 70% of the amount of 3enno~ide pres~nt in the
raw material.
O. 5 kg" of crude produck iB sus3>ended in 5 litre~
of an acetone~ r mixture (1:1 v~v), 48% aqueo~ls
~odium hydroxide are added thereto, while stirring,
until the p~l of the ~olution i~ 80 5 to 9 . Insoluble
residue iæ filtered off and 35% hydrochloric acid i8
added to the filtrate u~til ~he p~ of the 301ution i~
1.5 ~o 2. Stirring i. conti~ued until cry~talli~ation
~c ~ 8 and then the s~lution iq left to cry~talll~e
for at least 3 hour~. The precipitate is filtered of~
~rom the ~olution, wa~hed on the filter with 0.5 litre
of water and 0.5 litre of acetone and dried at ambient
tempera~ure wikh a current of air. one fi~th of he
mother liquor can be mixed with wash water ~nd wa3h
acetone and thi~ ~olution u~ed a3 cry~talli~a~ion ~olve~t
for the next ~qually large portion of crude product. The
yield per 0.5 kg. of cxude product i~ 0,460 kg. ldry
~bstanc~ h a elmosid2 c~lsnl~e~l~ of 9B to 99X.
le 2.
q~he pros:eduxe d2ss:!ribed in ~ le ~ ~aploy~
b~ usi~g thr~e ~erie3-cvr~eeLed perc~olator~ and without
nq the 70% mçt~anolO Otherwi~e the pr~:edure i~ a~
describi~d in ~ 1, u~ing 160 litre~ of ~ol~er~t per
3~0~
-20-
40 kg. of drug. Prom 40 kg. of drug there i3 obtained
0.890 kg. o~ Qennoside crude product with a ~e~no~ide
content of 9~% (dry ~ub~tance)~ The crude product ca~
be recry~talli~ed a~ in r ,
r - le 3O
Extra~tion, r~moval of methanol fro~ th~ ~xtra~t
and liquid-liquid extraction are car~ied out a~ de~-
cribed in r-- le 1. A ter t~e treatm~nt wi~h but~n~2-
ol, th~ sennoside mixture i~ ~rystalli~ed from the
raffinate in a continuously-operating cry~talli~ation
apparatus. For ~he ~rystalli~ativn, u~e i3 made of
two containers, co~n~t~d one after the other, and a
third container a~ decanter, which i8 ~o~-n~c Led i~
0erie~ to the others. Se~i iation of the ~n~o~ide
mixture i 8 caxried ~ut in 'ch~ latter container, the
~ain æmount o~ the pre~ipitate there'~y being ~eparat~d
from the ~o~her liquor. For ~his purpo~e, the raffinate
pha~e obtained after the purifi~atio~ with hutan-2-ol
i8 ~QSe~ at a rate ~E about 2 litreR/hour ints:~ the
fir~t co~tainer~ 93% Sulphuric a~id i~ ~imul~n~ou~ly
, in an - ~u~ of 1.6% by volu~ of the raffi~ateD
into thi~ contain~r~ I~ order to pr~v~n~ ~e~ at
at ~hi~ point, ~he liquid in th~ first container i~
~tirr~d continuou~ly. '~he ~ pen~ion fr~m ~he fir~t
eontainer i~ ~hen pA~e~ via an ~nres~ te~ overflow
into ~he ~e~on~ ~ont~iner, whi~h i~ al~o equipped with
a 8ti rrer~ and from there, via an unre~tri~ted o~erflow
38~)~
-21-
into th2 third container, where the precipitate i~
allowed to .Qettle, the mother liquor being allowed to
run off vla an unre~tricted overflow to a wa3te ~olvent
container. The precipitate i~ d fr~m the third
decanter, throug~l a cock provided o~ the bottom thereof,
in the fonm of a thick ~usp~nsion which i~ filtered
wnth a ~uction filter, w~hs~ with water and ~thanol
and dried in a curr~nt of air at ambient temperature.
The yield p~r 40 kg. of ~ude material ~ed i~ 790 g.,
the ~en~oside cont~nt of ~hi~h i~ 91%.
The ~other liquor of r - ~le 1 (o~t~ine~ after
the cry~tallisation from the aqueous raffinate) i~
treated with ~odium chloride. For thi~ pu~po~e, 40
litres of mother liquor (Correspon~; n~ ko 40 kg. of
or;gin~lly u~ed raw ~aterial) are gr~t~Ally mixed,
while Rtirring, with 8 kg. of ~odium chloride. A
brownish, ~emi-solid pre~ipi~ate i~ th~reby obtainedO
S~irring i~ con~lnl~d for ~ hour~ a~d the precipitate
i8 macerat~d in ~he 501ution until the ~ext day. The
mother liq~tor ~ ~hen deca~ d ~ff from the pr~ipita~e,
the pre~ipit~te i5 ~u~n~e~ in 40 litre~ of water, ~he
3~t.~p~n.~ion i~ ~ irred for 20 hour~ ~nd the precipit~te
allowed to settle out. The precipitate i~ ~hen ~iltered
off wi~h a suction filter, ~ h~ Wit~ a copiou~ L-
~of ~ater, dried at ambi~nt temperature in a ~urrent of
air and the dried aubstan~e p~e~ khr~ugh a 0.5 ~.
me~h ~ieve. X~ yield i~ 0~60 ~gO
~Q31~0~
-22-
The high pre3~ure liquid chromatography (RPLC~
analysi~ shows that the precipitate contain~ about 5%
of senno~ides and al~o 5~ of rhein-8-gluco~ide. The
laxative activity o~ this material îs about 58% of the
laxative activity o~ the ~enno~ides. The toxicity,
determined ~y intra~enous ~ ni~tratio~ i~ LD50 =
430 mg./kg. (mouse)~ Thus, this fra~tion contain3
~nkno~l c~ whi~h, on the one hand, ha~e a
laxati~e acti~ity but, on ~e other hand, po~es~ ~
~reater toxicity than the s~nnnside~. The laxati~e
activity ~f thl~ non-~enno~ide fraction acc~ur,~s for
about 40% of the total laxat.ive activity of the original
drug and of the crude extrack.
48 g~ of the crude ~SLAS fra~tion a~e le~-he~ out
12 time~ wnth 500 mlO - ,unt~ of 95~ methanolO For
this purpo3e, the gr~und powder i~ stirred w~th each
portion of 95% ~ethanol for at lea~t 2 hour~. The
methanol wash fraction~ are c~ ~ n~ and evaporated to
dryn~ he weight of the residue obtained i~ 22 g.
Its laxative activity is ~he 3~me a~ in ~he ca~ of
th~ pure ~nnoside~ and it~ to~icity i~ L~50 i.v~ ~
4100 ~g~/kg~ (mou~e). m e xe~i~o~ portion, whi~h i8
in~ol~ble in 9~ methanol, i~ dri~d, ~he yield bei~g
20.8 g. The laxativ~ activity i~ than 10% of the
la~ative activity of t~e ~enno~lde and ~he toxicity i~
LD50 i.v. - 130 mg.~kgO ~hu~, the ~LA~ fraction l~olated
3~
-23-
from ~he mother liquor of the ~nn~ides by ~alting out
contain~ laxativ~-active, non-toxic co~pounds of unknown
chemical ~tructure which are ~oluble in 95% methanol ~nd
~ very toxic re~inous portion which has only a low
laxative activity and the chemical stru~ture of which
i 8 al 30 U~CI10~1.
r - le 5.
me ~xtractiLon, li~uid-liquid extraction and re-
~ry tallisation described in the following are illu~-
trated ~c~ -tically in Figure~ 1, 2 and 3 of the
i~lf - ~ -nyi~g drawing~.
The drug ii~ extra~ted at ambient temperature in
a 4-~tage cou~ter~urrent percolation plant. For thi~
pu~po~e, 40 kg. of ~enna pod~ are intLoil~ced daily into
one of four coni~al containers and weighed down wnth a
perforated plate.
7~% Methanol i~ pa~ed in countercurrent through
the battery of 4 percolators in an i . t aueh ~hat the
rre~hly intro~u~ pod~ are ~omp~etely ~overed with
liquid. Ater a maceration period of at least 1~ hour3,
per~olation i cont; n~le~ until a total o~ a~out 160
litr~s of 7~% m~hanol have pa~ed ~hrough. ~r~m the
~ontain~r co~ered with fr~h olv~nt, the extraction
liquid i~ th~n p~39e~ co~pletely into th~ next con~ainer
~o~ne~ted in ~eri2~ and ~he extraction re~idue dri~d
in order to L~ er ~he ~olvent. ~he co~tainer i~ n~w
ready to recei~e the next 40 ~g. batch o~ drug ana thi~
~38~
-24-
i~ 3witched o~er to the end of the battery. me
degree of efficiency of the extraction per percolation
~tage i8 about 6~%. ~rom each 40 kg. of senna pod~,
there are obtained about 120 litre~ of primary extract
which are con~entrated to about 30 litres under YaCuum
in a rotary evaporator equipped with a fractionating
column. The temperature in the product container mUBt
thereby n~t exceed 50C.
I~ order to keep the followqng liquid-liquid
extraction free rom dist~lrb~nce~ the methanol must
be c~mpletely removed. After a~er~ ni n~ ga~ chromato-
graphi~ally that the ~o~e~trate is free from methanol,
it is ~ubsequently mixed with akout 2% of ~utan-2-ol.
The pH value of thi~ extract i8 about 5.8.
For th~ subsequent liquid~ uid extr~tioh, the
ooncentrate i2 p~se~ in a 10-~tage mixer ~eparator
battery ~each ~tage about 5 litres), without pre~iou~
filtration, ~ounter to butan-2-ol. In the ca#e of a
run-in rate of butan-2-ol : extract ~n~ntrate of
1.5 : 1, the xatio o~ butan-2-ol extract : extra~t
ra~finat~ i~ 0.7 to 0~8 ~ ha a~era~e r2sidence
ti~e ~or ~a~h ~tag~ i8 about 20 minute~
~ he extract raffinate i~ than adju~ted with 94%
phUri~ a~id to a p~ of 2 and pa~ed to a 3-~tage
~rystalli~ation appar~t~
~ o initiate the cry~talli~ation, it i~ ~eed~d
an~ ~hen left to ~ry talli~e at ~mbient temperature
o~
--25--
for 5 day~ he cry~tal ~lurry obtained i~ rsmoved
from ~he bottoqn of the third cry~tallisation cont~iner.
q~e withdrawn cry~tal ~lurry 1~ ~uction filtered ar~d
the mother liquor returned to the crystalli sation
apparatus~, The cry~tal~ are sub~equ~ntly wa~hed with
water and then with methanol a~d dried in a vc.~u, at
40C. Crude enno~ide E3 are obtA; n~ with a d~sre~ of
purity o~ about 90%. For ecovi:ring the butan-2-ol,
the ~utan 2-ol extract i ~ completely evaporated, a
dark bro~ to blac~ re idue being obtained. g~h~
di~tillate is again used for the li~uid-liquid
extraction .
The crude senno~ide~ Qbtained are then sus~n~rlec~
in an acetone~ ter mixture (50/50) to give a 10%
suspen~ion and c . ~etely dissolved b~ the addition
of an a~ue~ls aolution of sodium hyd~4xid~ lmtil the
pH is a~ou~ 7 ~ 5, ~odiu~ ~alt formation thereby taking
plac~. The sennoside~ ar~ therl prec:ipitat{3d out again
by adjusting the pH of th~s ~olution to 2 wit~ hy~ochlvr:ic
acidO q~he pre~ipitated pL~ ci, i~ separated off, brie~ly
~ ~he~ with a~Eueous ac~eto~e and driedl In ~hi~ ~day,
the~e are obtain6~dl about ~ referr~d to th~ ~er~na pc~d
u~ed) of pure ~nno~iLdes (A and B~.,
