Note: Descriptions are shown in the official language in which they were submitted.
~SC2IPTION
This invention relates to adenosine derivatives of anti-
lnflammatory~ analgesic and antipyretic activity, and the
therapeutic compositions which contain them as their active
principle 7
The compounds of therapeutic activity according to the present
ir.vention ara of ~eneral formula
N~ R
~)n (I)
C~ ~S-R
O~
2 2
in which:
R is a linear or branched alkyl radical of 1-18 C atoms, or
phenylalkylene in which the alkylene chain has 1-6 C atoms
Rl is H~ an aliphatic acyl r3dical o- l-~f C atoms or an sromatic
acyl radical
R2 is H, an aliphatic acyl radical of 1-6 C atoms or an aromatic
acyl radical, or alternatively the radicals R2 together form an
isopropylidene chain
n is O or l~
Furthermore, ~lhen Rl is H9 the invention also relates to the
acid addition salts of the compounds of formula (I)~
Preferred meanin~s for R are. methy'9 ethyl~ propyl, isopropyl,
butyl~ isobutyl, sec.b~ltyl, pentyl9 hexylg heptyl, octyl1 decyl,
dodecyl, hexadecyll octadecyl or ber.3yl.
Preferred meanin~s for ~ are: hydrogen~acetyl~ propionyl~
butyrryl, ben~oyl or t G syl.
~referred meanings for R2 are: hydrogen~ acetyl, propionyl7
butyrryl, benzoyl or tosyl~
The prefe_red acid addition salts of the compounds of formula (I)
sre: chloride, sulphate9 phosphate~ form~e, acetate~ citrate,
tartrate, methanesulphonate or p-tcluenesulphonateO
The compounds of formula (I) are partly ~ew.
The compounds of formula (I) are prepared by various methods
according to the meanin~ of the var ous radicals.
For pre~aring the group of compounds of formula:
N~2
(Ia)
CH2-S-R
0~ OH
in which R has the aforesaid meanings, the Legraverand method
(Legra~-erand M~ Ibanez S., et al. (1977) Eur. J~ MedO Chem. 12~
105-108) has been followed, in which adenosine is converted into
5'~loro-5'-deoxyadenosine by reaction with thionyl chloride in
hexamethylphosphoramide.
The 5~-chloro-5'-deoxyadenosine is then conYerted into the required
thioether by reaction with tne corresponding mercaptan ir. a 2N
sodium hydroxide solution at &oc.
The thioethers obtained are purified by recryst~llisation from
water or from lower aliphatic alcohols.
The co~pounds (Ia) can ther be salified with the stoichiometric
quantity of the required acid.
The co~pounds of general formula
N~-R
(Ib)
C~ -S-R
<~
2 2
in which R, Rl, R2 are as heretofore defined, provided that R
and R2 are other than H or an isopropylidene chain, have been
prepared by the S~tom and I~bkino method (Satom K, Makino K
(1951) Nature I~7, 238) by reacting the corresponding compounds
of formula (Ia) with the required acyl chloride i~ anhydrous
pyridene. The products are preferably recrystallised from a
1:1 chloroform/~etroleum ether mixture.
The compounds of formula
- ~H2--S-~ ~Ic)
'' /()\
~C~
3 3
\
in which R and Rl are as heretofore defined, are prepared
by reacting the co-^responding compounds of formula (I), in
which R2 is H, with acetone in the presence of ZnG12~ again by
the Satom and l~a~ino method (referred to previously?. The
obtained products are purified preferably by crystallisation
from a 1:1 chloroform/petroleum ether mixture.
The compounds of formul.a
R1
.. CR2-~ (Id)
o
C~
~R2 ~R2 '
ir~ which R, ~ 2 are as heretofore defined, are prepared by
cxidation of the corresponding thioethers, obtained by the methods
herstofore indicate~, by means of bromile or hydrogen peroxide
in aqueous.solution (Green Stein J.P., '.linitz Ma (1961~-Chemistry
of the amino acids - Joh~ ~iley & Sons Inc. 2146)~. The products
obtained are purified by recrystallisation from water.
Of all the products prepared, the one which has proved particularly
interesting for the purposes of the present invention is 5'-deoxy-
5'-methylthioadenosine (~A) of formu;a
_ 6 -
NH2
(II)
2 3,H3
~ ~)X
which is a physiological compound already ~resent in living
organismsO
A method has been found for preparing this prcduct ~hic~ is
p~rticularly simple and economical from an industrial viewpointO
The new process consists essentia1ly of carryin~ GUt hydrolysis
of the S_adenosylmethlonine ~SAME) under strictly controlled
critical conditions, which lead to practically total hydrolysis
~nd complete crystallisation of the l~:TA
N}i~ . ,
~ , 12 ~0
,, CH2 ~ CH2-CH2~ COOH
... . ~ C~3
~ ~H
N~
12
t~ ~H2-S C~3
4 ~ ~O-CH2-CH2-CH COOH ~ X
i
-- 7 --
The ccntrolled hydrolysis process can be applied to SAME
prepared in any manner.
i~owever, the method ~f preparation of the SAME solution is also
an influencing factor in carrying out the new process in an
economically convenient manner.
The following operational stages provide the most economlcal
embodiment of the process:
a) rTormal bread yeast is enriched in SA~i~ by treatment with
methionine in accordance with the Schlenk method (Schlenk ~.
(19~5) Enzymologie 29, 283)
b) The yeast cells suspended in water are lysised byr treatment
with ethyl or methyl acetate at ambient te~perature (DT_GS P23
36401.4).
By adjusting the pH to between 4 and 6 arld filtering~ an 3queous
501ution iS obtained containing practically all the SAME present
in the iritial yeast
c) The solution is concentrated under vacuu at 35_40C to about
1/10 of its initial volume
d) The concentrate is boiled under ~efiux for about 30 minutes and
the pH adjusted to 7 with soda
e~ The solutlon is left to st~nd at 0-5 C, and the precipitated ~A
is collected practically completely and at good purity.
The stages c, d and e, which as stated are critlcally necessary for
obtaining complete selective hydrolysis of SA~E to i~A without
formation of by-products, are new.
The preparation of some products used according to the present
invention are described hereinafterO
~XAiiPLE 1
Preparation of 5'-deoxy-5'-methylthioaQenoslne (i~A)
11 litres of ethyl acetate and 11 litres Ot` water at ambient
temperature zre added to 90 kg of ~read yeast which has been
enriched in S~ by adding methionine until the SAME content
is 6.88 ~/kg.
After energetic stirring for 30 ~inut~s, the pH is adjusted to
4.5 with dilute H2S04, the mixture is filtered and the residue
is washed ~ith water to give 140 litres of solution with a SAME
content of 4.40 g/l, equal to 99.5,~ of i-he ~AME present in the
initial material.
Thè lysate thus obtained is concentrated under vacuum (30 mm ~g;
,5-40 C) to a volume of about 14 litres. The concentrated solut~on
is boiled under reflux at normal pressure for 30 minutes. It is
cooled to 20Cs the pH adjusted to 7 with 405~ soda, and left over-
night in a refrigeration cell (+3~C)
A white ~recipitate is formed which is fi tered~ dissolved in 10
litres of boili~g distilled wster and crystallised by cooling this
solution~
410 g of crystalTine ~A of high purity are obtained~ equal to a
yield of 90~ with respect to the ~AL~ subjected to hydrolysis.
The characteristics of the product obtained coincide ~ith those
of pure l~rA obtained by other means.
EXA~LE 2
Prepa.ation of 5'-deoxy-5'~ethylthioadenosine
1 kg of adenosine is d ssolved under a nitrogen atmosphere in 10 1
of hexamethylphosphoramide~ and 7s5 1 of thjonyl chloride are added
under cooling.
'rhe mixture is left to react at ambient temperature for 20 hours.
10 1 of water are added, 3nd the mixture neutralised with 2N NaOH.
_ 9 _
The 5' deoxy~ chloroadenosine which thus for~s is allowed to
crystallise overnight at 3 C. It is filtered off. 0.950 kg
o~ 5l-deoxy_5~_chloroadenosine are obtained (yield 89So) .
0.950 kg of 5'-deoxy-5'~chloroadenosine are dissolved in 10 1
of 2N N~OH~ and 200 ml of ethanethiol are added. The mixture
is heated to oOC and lefl to react fox 1 hourc It is neutralised
with glacial acetic acid. Tha 5' deoxy-5'-ethylthioadenosine which
thus forms is allowed to precipitate overnight at ~ C. It is
filtered off and recrystallised rom w~terO
o~830 kg of product are obtained (~ield 80% with respect to the
preceding stage).
EXAMPLE ~
Preparation of other compounds of class Ia
The method as described in example 2 is carried out, but using
prop3~ethiol,b~tanethiol, isobutanethioll pentanethiol; hexanethiol
and benzylthïol respectively~ in place of the ethanethiol.
E~A~1E 4
Preparation of N , 2', ~'-triacetyl~5'-deoxy-5'-thioadenosineO
1 ~g of ~ITA is suspended in 10 1 of anhydrous pyridine~ and 3 1
Of acetic anhydride are added. The mixture is left to react for
4 hours. 20 1 of water are added~ and the mixture concentr~ted
under vacuum to give an oily mass free from pyridinec This is
dissolved in a hot 1:1 mixture of petroleum ether/chloroform (10 1)
and left to crystallise. The product is recrystallised from a
1:1 petroleum ether/chloroform mixtureO 1.140 kg of product are
obtained (yield 80,oo).
EXhMPLE 5
Preparation of other compounds of class Ib
The ~ethod described in ex~mple 4 is carried out, but using other
~8~
thioethers or propionic anh~dride7 butylic anhydride9 benzoyl
chloride or tosyl chloride inste~d of ~A.
~XA~E 6
Preparation of ~'-deoxy~',3'-isopropylidene-5'-methylthioadenosine~
1 kg of MTA are suspended in 25 1 of anhydrous 3cetone~ and 2.5 kg
of molten ZnC12 are addedO Reaction is carried out under refl~
for 5 hours. The mixture- is then concentrated under vacuum to
1/3 of its initial volume~ and 7 5 kg of barium hydroxide octahydrate
in aqueous suspension are added. Carbon dioxide is then bubbled
through until neutral. The mixture is filtered and the residue
washed with acetone. The filtrate is concentra~ed under vacuum
to give a syrupy residueO It i9 taken up ~n a hot 1:1 chlorofor~
petroleum ether mixture (10 1)~ flltered and lelt to crystallise.
The product is recrystallised from 1:1 chloroform/petroleum ether~
to give 0.795 kg of product (yield 70%).
E~Ai~LE 7
Preparation o~ other compounds of class Ic.
The method as deccribed in example 6 is carried outg but startin~
from the corresponding adenosi~e de~iv~tives instead of ~A.
EXAilP~E 8
Preparation of I~A sulphoxide.
1 kg o~ lilTA are suspended in 10 1 of water, and bro~ine is added
under cooling.
The aqueous solution containing bromine is immediately decoloured
by the oxidation of the ~ITA to sulphoxide/
Addition of bromine is continued until the solution does not
decolourise further~
The solution is decolourised b~ further addition o~ small quantities
of ~;TAo
The aqueous solution is treated with ~mberlite IRA 93 resin
(registered trademark of Rohm and Haas for a ~eakly basic ion
exchange resin with a polystyrene matriY) until the reaction
of the bromide ions disappears.
The mixture is filtered and the residue washed with water.
The aqueous solution is concentrated to 10 1~ treated with
activated carbon (100 g) and lyophilised.
0.950 kg of product are obtained (yield 90~.
~XA~PLE 9
Preparation ~f other compounds of class Id
The method described in example 3 is followed~ but starting from
tne corresponding adenos~le derivatives instead of ~A~
As initially stated~ ~t has been found that the compounds of
ormula I possess strong antiinflammatory activity7 accompanied
by analge~ic and antipyretic action~
The antiinflammator~ activity was demonstrated initially for some
terms of the class by the test of experimental adema in the rat
bycarragen, by determining the percentage protection by the Winter
method (J. Pharm. exper. Therap. 141, 369 1963). The values
obtained are shown in Table lo
- 12 -
T A B L E
ComPound of formula (I) Dose ~dmln- Percent protec-
lstered tion calculated on
orally edema development
m~/kg
n = 0R = -CH2, R1 = R2 ~ H 37 50
3 l 2 23 (a) 50
n = 0 R = -CH2-C~Hs, R1 ~ R2 = H 47 lO
~ CH3
n - 0 R = -CH2-CH ' 1 2 5 62
~ C~3
n = 0 R = -(CH2)6~cH3l R1 R2 20
n = 0 R - -(CH2)ll-~H39 R1 ~2 112 10
n = 0 R = -(C~2)4~cH3~ R1 R2 25
n = O R = CH2-C~3~ Ri R2 80 44
n = 0 R = -(CH2)2-CH3. Rl R2 80 53
~ CH3
n ~ 0 R ~ -CH 9 R = R = H 80 45
~ CH3 1 2
n = C R = -(~H2)3~CH3 ' R1 R2 85 39
n = 0 ~ = CH-CH2-CH3 Ri R2
CH3
n = 0 R = -(cH2)7-CH39 Rl R2 100 47
n = 0 R = -(CH2)g-~H3~ R1 R2 106 33
3 1 2 156 50
n = 1 R - -CH3~ R1 = R2 = H 8,6 (a) 50
n R C 3~ 1 2 3 ll~ L~
~ 13 -
n = 0 R = CH3, R1 = ~2 = tosyl 204 15
n = O R = -CH3, ~1 = R2 ~~ C6H5 lG4 10
n = 0 R = -CH3, R1 = ~, R2-R1 = isopropyl 91 20
Indo~ethacine 9 5
(a) signiEies that the product was administered intr3muscularly
~s can ~e seen from this table, the ED50 f the ~ITA is 37 mg/kg,
and is thus the lowest of those of ~he compounds tested when
administered Drally.
In the same testS the ED50 of indomethacine is 9 ~g/kg. At
these doses7 there is the appearance of serious gastric lesions,
whereas at the ~D50 doses the MTA gives rise to no secondary
effect on the gastro-intestinal system. It shonld also be
noted that the ~D of indomethaGine in the rat is 12 mg/kg
(~Iartelli A. in Aspetti di farmacolo~ia dell'infia~mazione, page
73, published by Tamburini - Milan 1973)~ whereas the LD50 f
~ITA in the rat is > 200 mg~kg/oa
The following therapeutical lndices are therefore obtained:
Indomethacine TI = 1.3
MTA TI = > 54 05
The compounds according to the invention were also subjected to
a series of pharmacological tests for the purpose of confirming
their antiinfla~mator~ acti~ity and for demonstrating tneir
analgesic and antipyretic activity.
The results obtained in some of these tests with MTA are given
hereinafter, this being a product which in all cases p.roved to
be the most active when administered orally, and which is
cerlainly the safest as it is a compound physiologically present
in the organism9 as already stated.
Rgain from the industrial production vie~oint, the method for
producing ~A from SAl~E as discovered is by far the most simple
and economical, an~ enables it to be marketed at a particularly
low price.
As can be seen from the data of table 1~ methylthioadenosine
sulphoxide is particularly active when administered intramuscularly~
The greater activity of said compcund on intramuscular administration
was co firmed in all the testfi carried out. Some significant data
regarding ~TA sulphox~de are also given, howe~er it should be noted
that all the compounds tested were in all cases shown to be active,
although at different leveis.
A - Antiinflammatory activity
Tke products were tested by pleuritis induced in the rat by
carragen in accordance with the Velo method (Velo G.P. 7 DUNN
C.J~ et al. (1973) u. Path. 111? 149).
~TA at a dose of 75 m ~kg by oral administration gave a
protection of 42.4% calculated on the volume of the exudate~
and 48~8~ calculated on the total number of cells present in
the exudate.
A comparable protection was obtained with 10 mg/kg of indomethacille,
iOe. with a dose much closer to the LD50. In the same test,
the ~A sulphoxide gives a protection of 75~80,o calculated on
the volume of the exudate, and 76.4~ calculated on the total
number of cells present in the exudate when administered
intramuscularly at a dose of 80 m ~ kg.
B _ Antiinflamm~tory activity
In the granuloma test in the rat by cotton pellets (~,~linter C.A.,
Riseley E.A et al (1963) J. ~harm. Exper. Ther. 141, 369), which
is significant for chronic inflammation, the ~rrA gave a protection
of 30~ with an oral dGse of 9 mg/kg7 with a TI of 2Z2.
C _ The analgesic activity of the produ_ts was tested by two tests
considered very significantO
- In the hot plate test on the mouse according to ~oberts (Roberts
E. Simonsen D.G. (1966) Biochem. Pharmac. 15, 1875) the ~A gives
a protection of 50% with an oral dose of 37 mg/kg. An apprOX-
imately equivalent protection of 580~ is obtained with 100 mg/kg
of amidopyrine admin stered orallyO
In the same test MTA sulphoxide gives a protection of 50% at a
dose of 20 m~/kg when administered intramuscularly, and at a
dose of 100 m~ g when administered orally~
_ In the stretching test by phenylquinone (Siegmund E., Cadmus R.,
G0_1U ~1957~ Proc. Soc. Expo BiolO MedO 95~ 729), the ~A gives
a protection of 51% at an oral dose of 37 m~/kg.
In the same test~ ~A sulphoxide has an ED50 of 10 mg~kg ~rhen
adm;nistered intramuscularly.
D _ Ant~pvretic ac~ivity.
This was meesured for the new products by means of fever induced
in the rat by beer yeast (Winder C~V. et al (1961) J~ Pharmacol.
Exp. TherO 133~ 117) ~
~he antipyretic effect evaluated one hour after oral administration
of ~A at a dose of 300 mg/kg gave a temper3ture reduction of
4.59' with respect to the controls9 which were ~re~ted only with
yeast. Tnis percentage corresponded to a temperature lowering
from 38.8C to 37~4co
By comparisor, amidopyrine administered orally at a dose of 200 mg/kg
produced a temperature reduction of 4,69%, and intramuscular
_ 15 ~ 5
administr~tion ~f hrrA at a d~e of 80 m~r/Kg g~v~ ~ tcmperature
raduction of 2.35~
_ Platelet antiaggregation activity.
The com~ounds of -the invention have also been evaluated
with respect to their possible platelet antiaggregation
capacity.
Platelet aggreOation is known to be a com~lex phenomenon
~hich can be divided into a primary stage due to the
direct action of a stimulus ~for example adenosine
diphosphate~ i.e. ADP1 or epinephrin) and a secondary
stage due to the aggregation induced by the A~P released
by the platelets. In this respect~ when the platelets
come into contact with the subendothelial colls~en~ the
collagen initiates an entire series of reactions which
lead to the release of ~DP by the platelets. It is this
ADP which causes the second wave of platelet aggregation.
~he following tests were carried out in order to evaluate
the antiaggregation effect of the new compounds:
l) "in vitro" tests on platelet aggregation induced by ~3P
and collagen, in the presence of the new products;
2) "in vitro" tests on platelet aggregation induced by
arachidonic acid (AA);
3~ "in vivo" tests on platelet aggregation induced by A3P
and collagen in persons treated with the new products.
In this case the most significant results :;ere again obiained
~`lith i~A, because of ~hich the results obtained usin3 this
product are given as indicative of ihe behaviour of the
en~ire class.
- 17 ~ ~ ~ 9 ~10$
1) "in vitro" tests.
~lood was withdrat.m without stasis, and an anticoagulant
(3.8/o/ sodium citrate) was added to give a blood:citrate ratio
of 9:1. Plasma rich in platelets and plasma poor in
platelets were obtained by centrifuging at ambient temperature.
The platelet aggregation was estimated using the Born & Cross
method (G.V.R. Born and M.J, Cross~ JO Physiol., Lond. 168
178, 1963) on the plasma fraction rich in platelets.
The aggregating agents were used in the following concen-
trations: ADP (Sigma) 1 ~1~; collagen (Horn) 5/ug/ml;
arachidonic acid 4xlO lvl.
Adenosine a$ a concentration of lxlO 5~- was used as the
antiag~regation activity reference substanceO
The results obtained with ADP are shot~n on the graphs of
F-g~ 1, in which the abscissa indicates the time in minutes
and the ordinate the ~ercentage aggregation.
Curve 1 relates to the controls, curve 2 to the samples treated
with lxlO 5M adenosine, and curve 3 to the samples treated with
5xlO M ~A.
~rom the curve pattern it is apparent that ~l~A strongly reduces
primary platelet aggregation due to A3P, and as a consequence
inhibits the 2nd!aggreOatior wave.
The same tests carried out with collagen gave negative results,
i e~ ~!TA showed no inhibiting power towards platelet agOreOation
induced by collagen which was worthy of note.
~ 18 ~ 5
2) rig. 2 shows the effects of v3rious l~ concentratio~s on
platelet aggregation induced by AA at a concentra-tion of 4xlO li.
Curve 1 relates to the controls, curve 2 to i~lTA at a concentration
of 2.5xlO M, curve 3 to iiTA at a concentration of 5xlO Ivl, and
curve 4 to ;ITA at a concentration of 10 3M. As is apparent,
the platelet aggregation inhibiting effect of the ~rA is proportional
to its concentration. The capacity of ~iTA to increase the
inhibiting effect of prostacyclin (PGI2) in ag~regation induced by
~A was also investigated. In Fig. 3, curve 1 relates to the
controlsl curve 2 to i~l~A at a concentration of 5xlO ~i, cur~e 3
to FGI2 at a con~entration of 5xlO 9M, and curve 4 to a mixture
consisting of 5xlO iil~lrA and 5xlO 9M PGI2. It is apparent fro~
Fig. 3 that when used in mixture there i~ a strong increase in the
antiaO~regation action at concentrations ~lhich are in themselves
ineffective.
3) '1in vivo" tests.
Three apparently healthy volunteer subjects aged ~5, 42 and 48
years respectively, and ~ho had not taken any drug for at least
15 days, were submitted to a~gregation tests before and after
consumin~ the new products at a dose of 100 mg every 8 hours for
3 days, these tests then being evaluated. The blood sample for
the determination of the platelet aggregation ~as taken 2 hours
before consuming the last dose of product under test9
Fig. 4 shows ~he results obta-ned with Irr.~
i:ore ~recisely~ the full-line curves relate to he values obtained
:lith blood samples fro~ untreated patients, whereas the dashed-line
curves relate to the values obtained for the sane ~atients treated
;~ith ;:TA.
~ 19 -
It is a~parent that ~iT~ stron,ly inhibits platelet a~gregation
induced by A~P (l/ull) "in vivo".
The same tests repeated on adding 5 ~ ~ml of collagen to the
blood de~onstrated that J~A is not effective in inhibiting
platelet aggregation induced by collagen, but only len~thens the
latency time of the phenomenon.
The fact that ~ITA (snd in a more or less compar3ble manner the
other ~roducts of the same class) strongly inhibits platelet
aggregation induced by ADP, whereas it has practically no effect
on a~regation induced by collagen, indicates that I~I~A inhibits
the 1st aggregation wave, whereas it has a negligible direct
effect on the 2nd aggregation wave.
Its use in association with other knotm antiaggregation drugs
~hich are generally active towards the 2nd l~ave whereas are only
poorly effective towards the 1st ,~ave is therefore particularly
interesting.
~he de~onstrated activity su~ests the use of i~A (and of the other
com~o~nds of the series, even if less effective~ not only as a
platelet antiaggregation drug, but also as an antithroi~botic and
antiatherosclerotic drug, in that, besides being the basis of
throh~bogenesis mechanisms, the altered relationship between
platelets and vasal walls also plays a primary role in atherosclerotic
illness.
20 ~
_ Sleep inducing activity.
The Morris test was used (Morris R.W~ (1966) Arch. int. Pharmacodyn
161, No. 2, 380)
In this test~ the MTA increased by 8~ the duration of the sleep
induced by pentobarbital in the mouse7 at an intramuscular dose
of 20 m~/kg.
G _ ~cute toxicity-
The compounds of the present invention are practically free from
acute toxicity when administered orally~ They are practically
free from toxicity at therapeutic doses for any method o~
administration.
The following values are obtained for M~A and I~TA sulphoxide:
MTA - DL50 in the mouse orally ~ 2000 mg~kg
intravenously ~60 mg/kg
MTA sulphoxide - D~50 in the mouse
orally > 2000 mg/kg
intravenously 400 mg/kg
The adenosine derivatives of formula (I) can be administered~
diluted with suitable pharmacologically acceptable excipient~,
in any therapeutically useful form; orally, parenterally or by
venous or rectal means. They can also be used in products ~or
e~ternal use by topical aFplication~
Some examples of typical pharmaceutical compositions with ~A
are given hereinafter by way of e~ample:
100 mg ca~sules
MTA 100.2 mg
Mannitol 195.0 mg
Ma~nesium stearate5,0 mg
300.2 mg
50 mg capsules
MTA 50.1 mg
Mannitol 100.0 mg
Magnesium stearate3.0 mg
153,0 mg
100 mg t~blets
MTA 100.2 mg
Starch 100.0 mg
~Iagnesium stearate15.0 mg
Lsctose 8s.o mg
300.2 mg
50 mg tablets
~TA 50.1 mg
Starch 120.0 mg
Magnesium stearate15.0 mg
Lactose 115~0 mg
300.1 mg
100 mg su~positories
MTA 100.2 mg
Sup~ository msss1,700.0 mg
1,80002 mg
50 m~ su~po~itories
~A 50~1 mg
Suppository mass 1,450.0 mg
1,500.1 mg
50 m~ injectable phial
MTA . HCl (55.15 mg basicall~
equivalent~ 50 mg
Lidocain HCl 25 mg
Water to make up to 3 ml
25 mg in,jectable phi21
MT~ . HC1 (28.07 mg basically
equivalent) Z5 mg
Lidoc2in HCl Z0 mg
:~ater to make up to 2 ml
100 mg oral dose
MTA . ~Cl (112.3 mg basically
equivalent) 100 mg
Citrus flavo~ring 0,025 mg
Sugar 1 g
~ntifermenting agent 50 mg
Water to make up to 5 ml
50 m~ oral dose
~ITA . HCl (56.15 mg basically
equivalent) 50 mg
Citrus flavouring 0.015 ~g
Sugar -5
Antifermenting agent 30 mg
Water to make up to 5 ml
-- ~3
- 100 ~; ointment
Base for w~3ter-soluble
ointment~ to nia~e up to 100 g
Antioxidant 0.1 g
