Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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TRIAZOLOPYRIMIDINOL COMPOUNDS AND SALTS THEREOF
This invention relates to 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-
a]pyrimidin-5-of and enantiomers and pharmaceutically acceptable salts thereof
and
to pharmaceutical compositions containing them, to processes for their
preparation
and to their use in the treatment of seizures, neurological disorders such as
epilepsy
and/or conditions in which there is neurological damage such as stroke brain
trauma,
head injuries and haemorrhage.
Compounds of formula A
Rs
O ~ R~
Ra
R4 C-RS A
R3
N~N
R
N
R N
z
in which R~ represents H or optionally substituted alkyl, alkoxy or alkanoyl;
R2 and R3
independently represent H or optionally substituted alkyl, alkoxy, alkanoyl,
alkylthio,
alkylsulphinyl or sulphonyl; R4 and R5 independently represent H, alkyl or
together
with the carbon atom to which they are attached represent optionally
substituted
cycloalkylidene; and R6, R7 and R$ independently represent H, halo hydroxy,
mercapto, cyano or optionally substituted alkyl, alkanoyl, alkoxy,
alkoxycarbonyl,
carboxy, alkanoyloxy, alkylthio, alkylsulphinyl, alkylsulphonyl,
alkylsulphonylamino,
sulphamoyl, carbamoyl, alkylcarbamoyl or alkanoylamino; processes for their
preparation, and their use in the treatment and/or prophylaxis of seizures,
neurological disorders such as epilepsy and/or conditions in which there is
neurological damage such as stroke, brain trauma, head injuries and
haemorrhage
are described in W095/10521 (Knoll AG). A process for preparing these
compounds
is disclosed in W098/07724 (Knoll AG).
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One compound of particular interest in W095/10521 is (R)-7-[1-(4-
chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. In metabolic studies a
metabolite of this compound has been identified and surprisingly this
metabolite is
also active.
In particular the present invention provides isolated 7-[1-(4
chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-of and pharmaceutically
acceptable salts thereof in the form of individual enantiomers and mixtures
thereof
including the racemic mixture.
The term isolated is used to indicate that the compound of the invention is in
pure form and is not present in a human or an animal either in a free form or
in an
associated form.
7-[1-(4-Chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-of may form
salts with organic or inorganic acids or bases. Particularly suitable salts of
the
compound are formed with acids include for example, salts with inorganic acids
(such as hydrochloric, hydrobromic, hydriodic, nitric, sulphuric and
phosphoric acids),
salts with organic acids (such as malefic, acetic, citric, fumaric, tartaric,
succinic,
benzoic, pamoic, palmitic, methylsulphuric and dodecanoic acids) and salts
with
acidic amino acids (such as glutamic acid). Preferred compounds of the
invention
are salts of the compound formed with bases for example the potassium salt ,
the
sodium salt or a salt formed with a basic amino acid. Such salts are prepared
by
reacting the compound of the invention with a suitable acid or base in a
conventional
manner.
7-[1-(4-Chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-of or its salts
may exist in more than one crystal form and the present invention includes
each
crystal form and mixtures thereof.
7-[1-(4-Chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-of or its salts
may also exist in the form of solvates, (such as hydrates) and the present
invention
includes each solvate and mixtures thereof. The degree of solution may be non-
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stoichiometric and is preferably in the range 0 to 3, for example a
hemihydrate, a
monohydrate or a dehydrate.
7-[1-(4-Chlorophenoxy)ethyl)-1,2,4-triazolo[1,5-a]pyrimidin-5-of contains a
chiral centre and exists in different enantiomeric forms the (+) form and the
(-) form.
The present invention includes each enantiomer and mixtures thereof.
The enantiomers may be obtained by methods known to those skilled in the
art. Such methods typically include any of the following:
resolution via formation of diastereoisomeric salts or complexes which may be
separated, for example, by crystallisation;
formation of diastereoisomeric derivatives or complexes which may be separated
(for
example, by crystallisation, gas-liquid or liquid chromatography), followed by
the
liberation of the desired enantiomer from the separated derivative;
selective derivatisation of one enantiomer by reaction with an enantiomer-
specific
reagent (for example enzymatic esterification, oxidation or reduction),
followed by
separation of the modified and unmodified enantiomers;
use of gas-liquid or liquid chromatography in a chiral environment (for
example on a
chiral support such as silica with a bound chiral ligand, or in the presence
of a chiral
solvent);
asymmetric synthesis of a specific enantiomer using optically active reagents,
substrates, catalysts, solvents or enzymatic processes; and
asymmetric transformation of one enantiomer into the other.
It will be appreciated that where the active moiety is transformed by the
separation procedures described above, a further step may be required to
convert
the transformation product back to the active moiety.
7-[1-(4-Chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-of may exist in
different tautomeric forms or as different geometric isomers, and the present
invention includes each tautomer and/or geometric isomer and mixtures thereof.
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7-[1-(4-Chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-of may exist in
zwitterionic form and the present invention includes each zwitterionic form
and
mixtures thereof.
The present invention also relates to pharmaceutical compositions comprising
a therapeutically effective amount of isolated 7-[1-(4-chlorophenoxy)ethyl]-
1,2,4
triazolo[1,5-a]pyrimidin-5-of together with a pharmaceutically acceptable
diluent or
carrier. Such pharmaceutical compositions may be used for the treatment of
seizures and/or neurological disorders such as epilepsy and/or as
neuroprotective
agents to protect against conditions such as stroke.
As used hereinafter, the term "active compound" denotes isolated 7-[1-(4-
chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-ol. In therapeutic use,
the
active compound may be administered orally, rectally or parenterally. Thus the
therapeutic compositions of the present invention may take the form of any of
the
known pharmaceutical compositions for such methods of administration. The
compositions may be formulated in a manner known to those skilled in the art,
to give
a controlled release, for example rapid release or sustained release, of the
active
compound. Pharmaceutically acceptable carriers suitable for use in such
compositions are well known in the art of pharmacy. The compositions may
contain
from about 0.1 % to about 99% by weight of active compound and are generally
prepared in unit dosage form. Preferably the unit dosage of active ingredient
is from
about 1 mg to about 500 mg. The excipients used in the preparation of these
compositions are the excipients known in the pharmacist's art.
Preferably the compositions of the invention are administered orally in the
known pharmaceutical forms for such administration. Dosage forms suitable for
oral
administration may comprise tablets, pills, capsules, caplets,
multiparticulates
including: granules, beads, pellets and micro-encapsulated particles; powders,
elixirs, syrups, solutions and aqueous or oily suspensions.
Solid oral dosage forms, for example tablets, may be prepared by mixing the
active compound with one or more of the following ingredients or mixtures
thereof:
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inert diluents, for example calcium carbonate, calcium sulphate, compressible
sugar,
confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate
dihydrate, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin,
lactose,
magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline
5 cellulose, polymethacrylates, potassium chloride, powdered cellulose,
pregelatinized
starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc and
tribasic
calcium phosphate
disintegrating agents, for example alginic acid, carboxymethylcellulose
calcium,
carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose
sodium,
crospovidone, guar gum, magnesium aluminium silicate, methylcellulose,
microcrystalline cellulose, polacrilin potassium, powdered cellulose,
pregelatinized
starch, sodium alginate, sodium starch glycolate and starch; including maize
starch
and agar;
lubricating agents, for example calcium stearate, glyceryl monostearate,
glyceryl
palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light
mineral oil,
magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate sodium
lauryl
sulphate, sodium stearyl fumarate, stearic acid, talc and zinc stearate;
binders, for example acacia, alginic acid, carbomer, carboxymethylcellulose
sodium,
dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil,
hydroxyethyl
cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid
glucose,
magnesium aluminium silicate, maltodextrin, methylcellulose,
polymethacrylates,
povidone, pregelatinized starch, sodium alginate, starch including maize
starch, zein,
sugars (such as sucrose, molasses and lactose), and natural and synthetic gums
(such as extract of Irish moss, polyethylene glycol, waxes, microcrystalline
cellulose
and polyvinylpyrrolidone);
colouring agents, for example conventional pharmaceutically acceptable dyes;
sweetening and flavouring agents;
preservatives;
one or more pharmaceutically acceptable couple or couples (such as those
comprising an acid and a carbonate or bicarbonate salt), which effervesces to
aid
dissolution when the solid dosage form is added to water; and
other optional ingredients known in the art to permit production of oral
dosage forms
by known methods such as tabletting.
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Solid oral dosage forms may be formulated in a manner known to those
skilled in the art so as to give a sustained release of the compounds of the
present
invention. Film coated, solid oral dosage forms comprising compositions of the
invention may be advantageous, depending on the nature of the active compound.
Various materials, for example shellac and/or sugar, may be present as
coatings, or
to otherwise modify the physical form of the oral dosage form. For example
tablets
or pills may, if desired, be provided with enteric coatings by known methods,
for
example by the use of cellulose acetate phthalate and/or hydroxy propyl
methylcellulose phthalate.
Capsules or caplets (for example hard or soft gelatin capsules) comprising
the active compound (with or without added ~excipients such as a fatty oil),
may be
prepared by conventional means and, if desired, provided with enteric coatings
in a
known manner. The contents of the capsule or caplet may be formulated using
known methods to give sustained release of the active compound.
Liquid oral dosage forms comprising compositions of the invention may be an
elixir, suspension or syrup, for example, aqueous suspensions containing the
active
compound in an aqueous medium in the presence of a non-toxic suspending agent
(such as sodium carboxymethylcellulose), or oily suspensions containing the
active
compound in a suitable vegetable oil (such as arachis oil or sunflower oil).
Liquid
oral dosage forms may also comprise one or more sweetening agent, flavouring
agent, preservatives and mixtures thereof.
The active compound may be formulated into granules or powders with or
without additional excipients. The granules or powders may be ingested
directly by
the patient or they may be added to a suitable liquid carrier (for example
water)
before ingestion. The granules or powders may contain disintegrants (for
example a
pharmaceutically acceptable effervescent couple formed from an acid and a
carbonate or bicarbonate salt) to facilitate dispersion in the liquid medium.
Preferably each of the above oral dosage forms may contain from about 1 mg
to about 500 mg (for example 10 mg, 50 mg, 100 mg, 200 mg, or 400 mg) of the
active compound.
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Compositions of the invention may be administered rectally in the known
pharmaceutical forms for such administration, for example, suppositories with
hard
fat, semi-synthetic glyceride, cocoa butter or polyethylene glycol bases.
Compositions of the invention may also be administered parenterally, for
example by intravenous injection, in the known pharmaceutical forms for such
administration, for example sterile suspensions in aqueous or oily media, or
sterile
solutions in a suitable solvent.
The active compound may also be administered by continuous infusion either
from an external source (for example by intravenous infusion) or from a source
of the
compound placed within the body. Internal sources include implanted reservoirs
containing the compound to be infused which is continuously released (for
example
by osmosis) or implants. Implants may be liquid such as a suspension or
solution in
a pharmaceutically acceptable oil of the compound to be infused (for example
in the
form of a very sparingly water-soluble derivative such as a dodecanoate salt
or
ester). Implants may also be solid in the form of an implanted support
(forexample
a synthetic resin or waxy material) for the compound to be infused. The
support may
be a single body containing all the compound or a series of several bodies
each
containing part of the compound to be delivered. The amount of active compound
present in an internal source should be such that a therapeutically effective
amount
of the compound is delivered over a long period of time.
In some formulations it may be beneficial to use the active compound, or
pharmaceutical compositions containing them, in the form of particles of very
small
size, for example as obtained by fluid energy milling.
In the above compositions the active compound may, if desired, be
associated with other compatible pharmacologically active ingredients.
Isolated 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-of is
indicated for use as neuroprotective agents to protect against conditions such
as
stroke, and for the treatment of seizures and neurological disorders such as
epilepsy.
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The therapeutic activity of the compound has been demonstrated by means of
various in vivo pharmacological tests in standard laboratory animals. Such
tests
include those tests of convulsant activity in mice described below.
Accordingly, a further aspect of the present invention provides a method of
treating seizures and/or neurological disorders such as epilepsy and/or a
method of
neuroprotection to protect against conditions such as stroke, in animals
including
human beings, which comprises the administration to a patient in need thereof
a
therapeutically effective amount of the active compound and/or a
pharmaceutical
composition or compositions containing a therapeutically effective amount of
the
active compound. Thus isolated 7-(1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-
a]pyrimidin-5-of is useful for the inhibition of seizures and/or neurological
disorders
such as epilepsy and/or as neuroprotective agents to protect against
conditions such
as stroke, in animals including human beings.
Whilst the precise amount of the active compound administered in the
treatments outlined above will depend on a number of factors, for example the
severity of the condition, the age and past medical history of the patient,
and always
lies within the sound discretion of the administering pharmacist, physician or
veterinary a suitable daily dose of the active compound for administration to
human
beings, is generally from about 1 mg to about 5000 mg, more usually from about
5 mg to about 1000 mg, given in a single dose or in divided doses at one or
more
times during the day. Oral administration is preferred.
The active compounds may be used in adjunctive therapy with one or more
other compound or compounds having activity in the treatment of seizures
and/or
neurological disorders such as epilepsy and/or as neuroprotective agents to
protect
against conditions such as stroke, in animals including human beings. It will
be
appreciated that the term therapy as used herein includes prophylactic use of
the
active compound and pharmaceutical composition or compositions comprising a
therapeutically effective amount of the active compound, for example to
prevent the
onset of neurological disorders such as epileptic seizures, or as
neuroprotective
agents to protect against conditions such as stroke, in animals including
human
beings. The active compound and/or a pharmaceutical composition or
compositions
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comprising a therapeutically effective amount of the active compound may be
used to
provide a local and/or systemic therapeutic effect.
A still further aspect of the present invention provides use of the active
compound in the preparation of a medicament for the treatment of seizures
and/or
neurological disorders such as epilepsy and/or for neuroprotection to protect
against
conditions such as stroke, in animals including human beings.
Processes for the preparation of the above compound are part of the present
invention. 7-[1-(4-Chlorophenoxy)ethylj-1,2,4-triazolo[1,5-ajpyrimidin-5-of
may be
prepared by cyclising a compound of formula II
O
CI
~ ~N NOH II
HO N"N"H
optionally in the presence of an acid. Preferably the process is carried out
at a
temperature in the range 0° -250°C, more preferably in the range
50° -150°C.
Preferably the acid is polyphosphoric acid.
The anticonvulsant activity of 7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-
ajpyrimidin-5-of was demonstrated by the following pharmacological test.
The anticonvulsant activity involved observing the ability of a test compound
to inhibit seizures in mice induced by a maximal electroshock. Hereinafter,
this test
is referred to as 'MESM'.
In the MESM experiments, groups of male mice in the weight range 25 to 30
grammes had free access to food and water until the start of the experiment.
The
mice were divided into two groups, a control group and a test group to which
the test
compound would be administered. The control group received an oral dose of
10 ml/kg of a vehicle of 1 % aqueous methyl cellulose solution. The test group
received orally, suspended in the same dose of the methylcellulose vehicle,
the test
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compound at a dose of either 100 mg/kg for initial testing or, if enough
compound
was available, at a range of doses to determine an ED5° (see below).
One hour after
administration of all drugs an electroshock of duration 1.0 second was
administered
to all the mice in both groups through ear clip electrodes moistened with
saline. The
5 electroshock had an intensity of 99 mA, frequency of 50 Hz and pulse width
of
0.4 ms. Such a shock would generally be expected to induce a seizure in the
mice.
During the following two minutes the mice in each group were observed, the
number of mice in each group exhibiting tonic hind limb extension was recorded
and
10 thus the percentage of mice in which seizures had been inhibited was
determined.
The greater the anticonvulsant activity of the test compound, the higher was
the
percentage recorded in the MESM test.
If results at more than one dose were available, then a value for the dose
inhibiting seizures in 50% of the mice (ED5°) was calculated from the
regression
straight line plot of the percentage of mice in which seizures were inhibited
against
the dose of the test compound administered.
7-(1-(4-Chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-of was
administered at a dose of 100 mg/kg 60 min before tests either by the
intraperitoneal
(i.p.) or oral (p.o.) route. The test compound increased significantly the
threshold for
maximal electroshock-induced seizures following both i.p. (77% increase) and
p.o.
(22% increase) administration.
The invention will now be illustrated by the following non-limiting examples.
The final product of each example was characterised using one or more of the
following techniques: elemental analysis; infra-red spectroscopy; nuclear
magnetic
resonance spectroscopy; gas-liquid chromatography; and liquid chromatography.
Temperatures are given in degrees Celsius.
Example 1
1 a) A mixture of 2-(4-chlorophenoxy)propionic acid (30.0 g) in toluene (300
ml)
was added to a solution of thionyl chloride (22.0 ml) and dimethylformamide
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(2 ml) in toluene (150 ml) at 60-70°C with stirring. The mixture was
stirred for
18 hours at 70-80°C and then evaporated under reduced pressure to give
the
acid chloride. A solution of Meldrum's acid (23.5 g) in dichloromethane
(90 ml) was cooled to 0-5°C under nitrogen and pyridine (33 ml) was
added at
0-5°C. To this mixture was added a solution of the acid chloride
prepared
above in dichloromethane (90 ml) dropwise keeping the temperature below
5°C. The mixture was stirred for 1 hour at 0-5°C and then at
ambient
temperature for 18 hours. The mixture was diluted with dichloromethane
(150 ml) and washed with 2M hydrochloric acid (2 x 100 ml) and then with
saturated sodium bicarbonate solution (100 ml) and then water (100 ml). The
bicarbonate washes were acidified with 5M hydrochloric acid and extracted
into dichloromethane (2 x 50 ml). These dichloromethane extracts were
combined with the original dichloromethane solution and dried over
magnesium sulphate and evaporated to give the crude intermediate
Meldrum's acid derivative. This derivative was boiled under reflux with
methanol (400 ml) and methanolic hydrogen chloride solution (10 ml) for 6
hours and then left to stand at ambient temperature for 66 hours. The mixture
was evaporated under reduced pressure and the residue was partitioned
between ethyl acetate (100 ml) and water (100 ml). The ethyl acetate layer
was separated, washed with sodium bicarbonate solution (0.5M, 100 ml),
brine and then dried over magnesium sulphate and evaporated under
reduced pressure to give an oil which was distilled under high vacuum. The
distillate was purified by flash column chromatography on silica gel using
petroleum ether, b.p. 60-80°C / ethyl acetate 20:1 as the mobile phase
to give
methyl 4-(4-chlorophenoxy)-3-oxopentanoate as an oil.
b) Guanidine hydrochloride (1.87 g) was added with stirring to a solution of
sodium (0.41 g) in ethanol (15 ml). The mixture was stirred for 15 minutes
and then to this mixture was added a solution of methyl 4-(4-chlorophenoxy)-
3-oxopentanoate (5.0 g) in ethanol (15 ml). The mixture was stirred and
boiled under reflux for 16 hours. The mixture was cooled and then
evaporated to dryness under reduced pressure to give a solid. The solid was
triturated with water (10 ml) containing glacial acetic acid (2 ml) and
dichloromethane (20 ml) for 1 hour and then filtered. The residue obtained
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was washed with water (20 ml) and then with dichloromethane (20 ml) and
dried in vacuo to give 2-amino-4-[1-(4-chlorophenoxy)ethyl]-6-
hydroxypyrimidine, m.p. 125°C.
c) A mixture of 2-amino-4-[1-(4-chlorophenoxy)ethyl]-6-hydroxypyrimidine
(0.5 g), dimethylformamide dimethyl acetal (0.5 ml) and toluene (5 ml) was
stirred and boiled under reflux for 8 hours. The mixture was allowed to stand
at ambient temperature for 24 hours and then evaporated to dryness under
reduced pressure to give a solid which was triturated with diethyl ether
(2 x5ml) and filtered to give N-{4-[1-(4-Chlorophenoxy)ethyl]-6-
hydroxypyrimidin-2-yl}-N'N'-dimethylformamidine, m.p. 190°C.
d) Sodium hydride (62 mg of a 60% dispersion in mineral oil from which the
mineral oil had been removed by washing with petrol) was dissolved in
methanol (10 ml) and hydroxylamine hydrochloride (0.12 g) was added. The
mixture was stirred for 5 minutes and then theformamidine (0.5 g) obtained in
c) was added. The mixture was stirred at ambient temperature for 72 hours
and then evaporated under reduced pressure to give a residue which was
washed with water (2 x 5m1) and dried in vacuo to give N-{4-[1-(4-
chlorophenoxy)ethyl]-6-hydroxypyrimidin-2-yl}formamide oxime, m.p.
120°C.
e) The product from d) (5.0 g) and polyphosphoric acid (100 g) were stirred
and
heated on a steam bath for 4 hours. The mixture was allowed to cool to
ambient temperature and then ice (100 g) and ethyl acetate (100 ml) were
added. A solution of potassium carbonate (110 g) in water (total volume
100 ml) was added dropwise over 15 minutes to neutralise the mixture. The
mixture was separated and the aqueous layer was extracted with ethyl
acetate (100m1). The combined ethyl acetate layers were dried over
magnesium sulphate and evaporated under reduced pressure to give a solid
which was purified by flash column chromatography on silica gel using
dichloromethane / methanol (75:3) as the mobile phase to give 7-[1-(4-
chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidin-5-ol, m.p. 190°C.
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Example A
The use of compounds of the present invention in the manufacture of
pharmaceutical compositions is illustrated by the following description. In
this
description the term "active compound" denotes any compound of the invention
but
particularly any compound which is the final product of one of the preceding
Examples.
a) Ca sules
In the preparation of capsules, 10 parts by weight of active compound and
240 parts by weight of lactose are de-aggregated and blended. The mixture is
filled
into hard gelatin capsules, each capsule containing a unit dose or part of a
unit dose
of active compound.
b) Tablets
Tablets are prepared from the following ingredients.
Parts by weight
Active compound 10
Lactose 190
Maize starch 22
Polyvinylpyrrolidone 10
Magnesium stearate 3
The active compound, the lactose and some of the starch are de-aggregated,
blended and the resulting mixture is granulated with a solution of the
polyvinyl-
pyrrolidone in ethanol. The dry granulate is blended with the magnesium
stearate
and the rest of the starch. The mixture is then compressed in atabletting
machine to
give tablets each containing a unit dose or a part of a unit dose of active
compound.
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c) Enteric coated tablets
Tablets are prepared by the method described in (b) above. The tablets are
enteric coated in a conventional manner using a solution of 20% cellulose
acetate
phthalate and 3% diethyl phthalate in ethanol:dichloromethane (1:1).
d) Suppositories
In the preparation of suppositories, 100 parts by weight of active compound is
incorporated in 1300 parts by weight of triglyceride suppository base and the
mixture
formed into suppositories each containing a therapeutically effective amount
of active
ingredient.
