Method of medical treatment of addiction

The invention relates to the use of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carba zol-4-one and physiologically acceptable salts and solvates thereof in the relief or prevention of a withdrawal syndrome resulting from addiction to a drug or substance of abuse and/or for the suppression of dependence on drugs or substances of abuse.

This invention relates to a new medical use for a heterocyclic compound and 
pharmaceutical compositions containing it. In particular it relates to the 
use of 
1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carba 
zol-4-one and the physiologically acceptable salts and solvates thereof in 
the treatment of subjects addicted, recovering from addiction, or liable 
to become addicted, to drugs or substances of abuse. 
The aforementioned compound may be represented by the formula (I): 
##STR1## 
and is disclosed in UK Patent Specification No. 2153821A. 
Suitable physiologically acceptable salts of the compound of formula (I) 
include acid addition salts formed with organic or inorganic acids for 
example, hydrochlorides, hydrobromides, sulphates, phosphates, citrates, 
fumarates and maleates. The solvates may, for example, be hydrates. 
The aforementioned specification also discloses physiologically acceptable 
equivalents of the compound of formula (I), i.e. physiologically 
acceptable compounds which are converted in vivo into the parent compound 
of formula (I). 
The compound of formula (I) is described in the aforementioned 
specification as a potent and selective antagonist of 5-hydroxytryptamine 
(5-HT) at `neuronal` 5-HT receptors of the type located on terminals of 
primary afferent nerves. Receptors of this type are now designated as 
5-HT.sub.3 receptors and are also present in the central nervous system. 
5-HT occurs widely in the neuronal pathways in the central nervous system 
and disturbance of these 5HT containing pathways is known to alter 
behavioural syndromes such as mood, psychomotor activity, appetite and 
memory. 
The compound is described as being of use in the treatment of a human or 
animal subject suffering from a condition caused by a disturbance of 
neuronal 5-HT function, for example in the treatment of a human subject 
suffering from migraine pain or a psychotic disorder such as 
schizophrenia. It is also stated that the compound may be useful in the 
treatment of conditions such as anxiety, obesity and mania. 
We have now found that the compound of formula (I) may be used in the 
treatment of subjects addicted, recovering from addiction, or liable to 
become addicted, to drugs or substances of abuse. 
Repeated administration to a subject of certain drugs such as opiates (e.g. 
morphine), cocaine or benzodiazepines (e.g. diazepam, chlordiazepoxide or 
lorazepam), or substances of abuse such as alcohol or nicotine (e.g., 
smoking) can lead to physical and/or phychological dependence upon that 
drug or substance. When the drug or substance of abuse is withdrawn from a 
dependent subject, the subject develops certain symptoms, such as 
aggressive behaviour, agitation, and intense craving for the drug or 
substance of abuse. These symptoms may be collectively described as a 
withdrawal or abstinence sydrome. 
It has now been shown that administration of the compound of formula (I) 
can prevent, alleviate or reverse this withdrawal syndrome. The compound 
is therefore of use for the prevention or relief of a withdrawal syndrome 
resulting from addiction to drugs or substances of abuse. 
It has also been shown that the compound of formula (I) suppresses 
dependence on drugs or substances of abuse. The compound is therefore also 
of use in reducing the craving for a drug or substance of abuse after 
addiction to that drug or substance, and can therefore be used for 
maintainence therapy during remission from addition to drugs or substances 
of abuse. The compound may also be used for prophylactic treatment of 
subjects liable to become dependent on drugs or substances of abuse. 
The effectiveness of the compound of formula (I) in the treatment of a 
withdrawal syndome resulting from addiction to a drug or substance og 
abuse, and for the suppression of dependence on a drug or substance of 
abuse has been demonstrated in animals using, for example, the rat social 
interaction test, the light/dark exploration test in mice, a marmoset 
behavioural test and the drinkometer alcohol consumption test in rats. 
Accordingly the invention provides a method of treatment for the relief or 
prevention of a withdrawal syndrome resulting from addiction to a drug or 
substance of abuse and/or for the suppression of dependence on drugs or 
substances of abuse, which comprises administering to a human or animal 
subject an effective amount of the compound of formula (I) or a 
physiologically acceptable salt or solvate thereof. 
A preferred form of the compound of formula (I) is the hydrochloride, 
particularly in the hydrated form (e.g. the dihydrate). 
In a further aspect, the invention provides a pharmaceutical composition 
which comprises an effective amount of the compound of formula (I) or a 
physiologically acceptable salt or solvate (e.g. hydrate) thereof, for use 
in human or veterinary medicine, for the relief or prevention of a 
withdrawal syndrome resulting from addiction to a drug or substance of 
abuse and/or for the suppression of dependence on drugs or substances of 
abuse. 
In a yet further aspect, the invention provides for the use of the compound 
of formula (I) or a physiologically acceptable salt or solvate thereof, 
for the manufacture of a medicament for the relief or prevention of a 
withdrawal syndrome resulting from addiction to a drug or substance of 
abuse and/or for the suppression of dependence on drugs or substances of 
abuse. 
Pharmaceutical compositions for use in accordance with the present 
invention may be formulated in conventional manner using one or more 
physiologically acceptable carriers or excipients. 
Thus the compound of formula (I) and its physiologically acceptable salts 
and solvates may be formulated for oral, buccal, parenteral, rectal or 
transdermal administration or in a form suitable for administration by 
inhalation of insufflation (either through the mouth or the nose). 
For oral administration, the pharmaceutical compositions may take the form 
of, for example, tablets or capsules prepared by conventional means with 
pharmaceutically acceptable excipients such as binding agents (e.g. 
pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl 
methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or 
calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or 
silica); disintegrants (e.g. potato starch or sodium starch glycollate); 
or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated 
by methods well known in the art. Liquid preparations for oral 
administration may take the form of, for example, solutions, syrups or 
suspensions, or they may be presented as a dry product for constitution 
with water or other suitable vehicle before use. Such liquid preparations 
may be prepared by conventional means with pharmaceutically acceptable 
additives such as suspending agents (e.g. sorbitol syrup, cellulose 
derivatives or hydrogenated edible fats); emulsifying agents (e.g. 
lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, 
ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. 
methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations may 
also contain buffer salts, flavouring, colouring and sweetening agents as 
appropriate. 
Preparations for oral administration may be suitably formulated to give 
controlled release of the active compound. 
For buccal administration the compositions may take the form of tablets or 
lozenges formulated in conventional manner. 
The compound of formula (I) may be formulated for parenteral administration 
by injection e.g. by bolus injection or continuous infusion. Formulations 
for injection may be presented in unit dosage form e.g. in ampoules or in 
multi-dose containers, with an added preservative. The compositions may 
take such forms as suspensions, solutions or emulsions in oily or aqueous 
vehicles, and may contain formulatory agents such as suspending, 
stabilising and/or dispersing agents. Alternatively, the active ingredient 
may be in powder form for constitution with a suitable vehicle, e.g. 
sterile pyrogen-free water, before use. 
The compound of formula (I) may also be formulated in rectal compositions 
such as suppositories or retention enemas, e.g. containing conventional 
suppository bases such as cocoa butter or other glycerides. 
In addition to the formulations described previously, the compound may also 
be formulated as a depot preparation. Such long acting formulations may be 
administered by implantation (for example subcutaneously, transcutaneously 
or intramuscularly) or by intramuscular injection. Thus, for example, the 
compound of formula (I) may be formulated with suitable polymeric or 
hydrophobic materials (for example as an emulsion in an acceptable oil) or 
ion exchange resins, or as sparingly soluble derivatives, for example, as 
a sparingly soluble salt. 
A purposed dose of the compound of the invention for administration in man 
(of approximately 70 kg body weight) is 0.05 to 20 mg, preferably 0.1 to 
10 mg of the active ingredient per unit dose, expressed as the weight of 
free base. The unit dose may be administered, for example 1 to 4 times per 
day. The dose will depend on the route of administration. It will be 
appreciated that it may be necessary to make routine variations to the 
dosage depending on the age and weight of the patient as well as the 
severity of the condition to be treated. 
The compound of formula (I) may be prepared by the processes described in 
UK Patent Specification No. 2153821A. 
The following examples illustrate the preparation of the compound of 
formula (I). Temperatures are in .degree.C. Where indicated, solutions 
were dried over Na.sub.2 SO.sub.4 and solids were dried in vacuo over 
P.sub.2 O.sub.5 at 50.degree. overnight.

EXAMPLE 1 
1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-y1)methyl]-4H-carbaz 
ol-4-one hydrochloride 
A solution of 
2,3,4,9-tetrahydro-N,N,N,9-tetramethyl-4-oxo-1H-carbazole-3-methanaminium 
iodide (2.0 g) and 2-methylimidazole (5.0 g) in dry dimethylformamide (30 
ml) was stirred, under nitrogen, at 95.degree. for 16.75 h and then 
allowed to cool. The solid that crystallised was filtered off, washed with 
ice-cold, dry dimethylformamide (3.times.2 ml) and dry ether (2.times.10 
ml) and then dried. The resulting solid (0.60 g) was suspended in a 
mixture of absolute ethanol (30 ml) and ethanolic hydrogen chloride (1 
ml), and warmed gently to obtain a solution, which was filtered whilst 
warm. The filtrate was then diluted with dry ether to deposit a solid (0.6 
g) which was recrystallised from absolute ethanol to give the title 
compound as a solid (0.27 g) m.p. 186.degree.-187.degree.. 
EXAMPLE 2 
1,2,3,9-Tetrahydro-9-methyl-3-[2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazo 
l-4-one 
A solution of 
3-[(dimethylamino)methyl]-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one 
hydrochloride (1.7 g) in water (17 ml) was treated with 2-methylimidazole 
(1.4 g) and then heated under reflux for 20 h. The cooled mixture was 
filtered and the residue washed with water (3.times.15 ml) to give a 
product (1.7 g) m.p. 221.degree.-221.5.degree.. This material was 
recrystallised from methanol to give the title compound (1.4 g) m.p. 
231.degree.-232.degree.. 
EXAMPLE 3 
1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbaz 
ol-4-one hydrochloride dihydrate 
1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbaz 
ol-4-one (18.3 g) in a hot mixture of isopropanol (90 ml) and water (18.3 
ml) was treated with concentrated hydrochloric acid (6.25 ml). The hot 
mixture was filtered and the filtrate diluted with isopropanol (90 ml) and 
stirred at room temperature for 17 h, cooled to 2.degree. and the solid 
filtered off (21.6 g). A sample (6 g) was recrystallized from a mixture of 
water (6 ml) and isopropanol (10 ml) to give the title compound as a white 
crystalline solid (6 g) m.p. 178.5.degree.-179.5.degree.. 
Analysis Found: C,59.45;H,6.45;N,11.5. C.sub.18 H.sub.19 N.sub.3 
O.HCl.2H.sub.2 O requires C,59.1;H,6.6;N,11.5%. Water assay Found: 10.23% 
C.sub.18 H.sub.19 N.sub.3 O.HCl.2H.sub.2 O requires 9.85% 
The efficacy of the compound of formula (I) in the treatment of a 
withdrawal syndrome after addiction to a drug or substance of abuse, and 
for the suppression of dependence on a drug or substance of abuse has been 
demonstrated in the rat, mouse and marmoset using standard pharmacological 
tests for observing behavioural changes in animals, for example in the rat 
social interaction test, the light/dark exploration test in mice, a 
marmoset behavioural test and the `drinkometer` alcohol consumption test 
in rats. 
Test compound: 
1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carba 
zol-4-one hydrochloride dihydrate. 
RAT SOCIAL INTERACTION TEST 
Animals 
Male Hooded Lister rats (200-250 g), were housed 5 to a cage and kept in 
the laboratory environment for at least a week before testing. Rats paired 
in the test were taken from separate cages. 
PROCEDURES AND RESULTS 
The method was based on that described S. E. File, J. Neurosci. Meth., 
1980, 2, 219-238. The test arena consisted of an open-topped bo, 
62.times.62.times.33 cm with a 7.times.7 matrix of infra-red photocell 
beams in the walls, 2.5 cm from the floor. The light intensity at the 
floor of the arena was 3.5 lux under low light conditions. Rats were 
exposed to the arena in pairs for 10 minutes on the day before the 
experiment. Rats were paired with different partners on the test day. 
Drugs were tested by subjecting both members of a pair of rats to the same 
treatment at the pre-determined time before testing. Where a 45 minute 
pre-treatment time was used, the rats were placed singly in small cages 
immediately after dosing until they were tested. Where longer 
pre-treatment times were used, the rats were returned to their home cages 
after dosing and placed in the single cages 45 minutes before testing. All 
drugs were administered orally. 
Testing involved placing each member of a pair of rats in opposite corners 
of the arena and then leaving them undisturbed for 10 minutes while 
recording their behaviour remotely on videotape. The behavioural 
assessments were made subsequently from the recordings. The time spent in 
social interaction was measured and expressed as a cumulative total for a 
10 minute session. The behaviours that comprised social interaction were : 
following with contact, sniffing (but not sniffing of the hindquarters), 
crawling over and under, tumbling, boxing and grooming. Sniffing of the 
hindquarters was excluded because it was markedly influenced by the degree 
of urination and defaecation. 
Thus, in the present experiment, rats (n=8 pairs) were dosed with diazepam, 
40 mg/kg/day, for 7 days. Diazepam dosing was abruptly ceased and the rats 
were tested 24 h after the last dose under low light familiar conditions 
in the above described Social Interaction Test (A). 
Upon abrupt cessation of dosing with diazepam and administration of 
RO15-1788, 10 mg/kg 45 min. before testing, the rats displayed an 
abstinence syndrome manifest as a reduction in social interaction when 
examined, under low light, familiar conditions (B). This abstinence 
syndrome was reversed by administration of the test compound, 0.01 mg/kg 
45 min. before testing (C). Tests (B) and (C) were also conducted 24 h 
after the last dose of diazepam. 
Treatment of the rats with the test compound, 0.01 mg/kg, alone, had no 
effect on social interaction under the low light familiar conditions. 
______________________________________ 
Mean Social 
Treatment (mg/kg) Interaction(s) 
______________________________________ 
Vehicle/Vehicle 56.0 .+-. 9.3 
(A) Diazepam/Vehicle 44.7 .+-. 4.0 
40 
(B) Diazepam/R015-1788 11.0 .+-. 1.7.sup.1 2 
40 10 
(C) Diazepam/R015-1788 +Test Compound 
.sup. 38.3 .+-. 6.7.sup.3 
40 10 0.01 
______________________________________ 
Results are means .+-.s.e.m. (standard error of the mean). 
1 p&lt;0.01 vs vehicle/vehicle 
2 p&lt;0.01 vs diazepam/vehicle 
3 p&lt;0.05 vs diazepam/R015-1788 
Dunnett's t-test. 
LIGHT/DARK EXPLORATION TEST IN MICE 
Animals 
Male albino BKW mice, 25-30 g, were housed 10 to a cage and allowed free 
access to food and water. They were kept on a reversed light cycle with 
the lights on between 22.00 h and 10.00 h. 
PROCEDURE AND RESULTS 
The method was based on that described by J. Crawley and F. K. Goodwin, 
Pharmacol. Biochem. and Behaviours, 1980, 13, 167-170. 
The apparatus was an open-topped box, 45 cm long, 27 cm wide and 27 cm 
high, divided into a small (2/5) area and a large (3/5) area by a 
partition that extended 20 cm above the walls. There was a 7.5.times.7.5 
cm opening in the partition at floor level. The small compartment was 
painted black and the large compartment white. The floor of each 
compartment was marked into 9 cm squares. The white compartment was 
illuminated by a 100W tungsten bulb 17 cm above the box and the black 
compartment by a similarly placed 60W red bulb. The laboratory was 
illuminated with red light. 
All tests were performed between 13.00 h and 18.00 h. Each mouse was tested 
by placing it in the centre of the white area and allowing it to explore 
the novel environment for 5 minutes. Its behaviour was recorded on 
videotape and the behavioural analysis was performed subsequently from the 
recording. Five parameters were measured: the latency to entry into the 
dark compartments, the time spent in each area, the number of transitions 
between compartment, the number of lines crossed in each compartment and 
the number of rears in each compartment. Drugs were administered 
intraperitoneally. 
Thus, in the present experiment, mice (n=5-10 per group) were treated with 
nicotine 0.1 mg/kg, twice daily for 14 days. Nicotine dosing was then 
abruptly ceased and the mice were tested 8 h after the last dose whereupon 
they displayed an abstinence syndrome manifest as an increased tendency to 
stay in the dark area (A). Administration of the test compound (0.001 
mg/kg) at the same time as the last dose of nicotine resulted in the 
prevention of this abstinence syndrome as demonstrated when the mice were 
again tested 8 h after the last dose of nicotine (B). 
______________________________________ 
Rears/5 min 
Rears/5 min 
Treatment (mg/kg) (light) (dark) 
______________________________________ 
Vehicle 30.0 33.0 
(A) Nicotine withdrawal 
10.0.sup.1 52.7.sup.1 
(B) Nicotine withdrawal + 
52.0.sup.1 2 
12.0.sup.1 2 
Test compound 
0.001 
______________________________________ 
Results are means, s.e.m. less than 11.2%. 
1 p&lt;0.01 vs vehicle control 
2 p&lt;0.01 vs nicotine withdrawal 
Dunnett's t-test. 
MARMOSET BEHAVIOURAL TEST 
Marmosets show natural aggressive and protective behaviours towards 
strangers such as a human observer. Such behaviours include vocalisation, 
posturing, anal scenting, and spending time on the cage front. Following 
chronic treatment with alcohol administered in the drinking water and then 
abruptly withdrawn, these behaviours are markedly exacerbated. 
PROCEDURE AND RESULTS 
Common marmosets (Callithrix jacchus), body weights 315.+-.20 g, of both 
sexes were housed in single sex pairs. They were tested in their home 
cages. Only marmosets that responded consistently and reliably to 
confrontation by an observer (see below) were used in the experiments. It 
was essential to allow 1 or 2 days between test days and no marmoset was 
tested more than 3 times in a week. Marmosets were subjected to one test 
only on each test day. 
Drugs were injected subcutaneously (dissolved or suspended in saline) 
except where otherwise stated, each member of the pair receiving the same 
treatment. 45 minutes after drug treatment, the marmosets were confronted 
by an observer standing 0.6m in front of the cage. Over a 2 minute period, 
the number of "aggressive" postures shown by one member of the pair was 
recorded: tail erect with exposure of genitals, slit stare facial 
expression, scenting and arch piloerect locomotion (marmoset moves to and 
fro along perch with back arched and full body piloerection) (M. F. 
Stevenson and T. B. Poole, Animal Behaviour, 1976, 24, 428-451). In the 
following 2 minute period, the amount of time spent on the wire cage front 
was recorded. Any overt behavioural changes were also noted. The response 
of one member of each of the other treated pairs of marmosets were 
assessed before returning to the second member of the first pair. At least 
2 pairs of marmosets were tested on any one occasion. The intensity of 
response evoked in the marmosets varied between observers. Consequently, 
the experiments described here were performed by the same observer. 
Thus, in the present experiment marmosets (n=4) were treated with alcohol 
(2% v/v in drinking water) for 30 days. Alcohol dosing was abruptly 
withdrawn, and the marmosets displayed an abstinence syndrome manifest as 
less time spent on the cage front and an increase in aggressive posturing 
(A). Administration of the test compound (0.01 mg/kg) twice daily 
following withdrawal from alcohol resulted in a marked attentuation of 
this abstinence syndrome or abolition when the marmosets were tested on 
the sixth post-withdrawal day. 
Furthermore, on continuation of the treatment with the test compound, when 
the animals were given a free choice to consume drinking water which 
contained either alcohol or no alcohol, the marmosets preferred to abstain 
from further alcohol intake. 
______________________________________ 
Aggressive 
Time at Cage 
Treatment (mg/kg) Postures Front(s) 
______________________________________ 
Vehicle 9.0 29.4 
(A) Alcohol withdrawal 
13.8.sup.1 
10.6.sup.1 
(B) Alcohol withdrawal + 
3.0.sup.1 2 
77.6.sup.1 2 
Test compound 0.01 
______________________________________ 
Results are means, s.e.m. 5-25%. 
1p&lt;0.05 vs control 
2p&lt;0.05 vs alcohol withdrawal. 
Dunnettps t-test. 
The `Drinkometer` Alcohol Consumption Test in Rats 
Rats given free choice to drink either water containing 2% v/v alcohol or 
water will in time choose to drink alcohol solution. The alcohol consumed 
and characteristics of this consumption, such as drinking bouts, indicate 
that these animals can become dependent upon alcohol. In alcohol 
preferring animals, administration of the test compound twice daily in 
doses of up to 0.01 mg/kg subcutaneously, markedly reduced the amount of 
alcohol consumed over a 24 h period. 
The following examples illustrate pharmaceutical formulations for use 
according to the invention, containing 
1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) 
methyl]-4H-carbazol-4-one hydrochloride dihydrate as the active ingredient 
(1.25 g of the hydrochloride dihydrate contains 1.00 g of the free base). 
TABLETS FOR ORAL ADMINISTRATION 
Tablets may be prepared by the normal methods such as direct compression or 
wet granulation. 
The tablets may be film coated with suitable film forming materials, such 
as hydroxypropyl methylcellulose, using standard techniques. Alternatively 
the tablets may be sugar coated. 
______________________________________ 
Direct Compression 
Tablet mg/tablet 
______________________________________ 
Active Ingredient 4.688 
Calcium Hydrogen Phosphate BP* 
83.06 
Croscarmellose Sodium NF 
1.8 
Magnesium Stearate BP 0.45 
Compression weight 90.0 
______________________________________ 
*of a grade suitable for direct compression. 
The active ingredient is passed through a 60 mesh sieve, blended with the 
calcium hydrogen phosphate, croscarmellose sodium and arnesium stearate. 
The resultant mix is compressed into tablets using a Manesty F3 tablet 
machine fitted with 5.5 mm, flat bevelled edge punches. 
______________________________________ 
Sub-lingual Tablet 
mg/tablet 
______________________________________ 
Active Ingredient 2.5 
Compressible Sugar NF 
62.0 
Magnesium Stearate BP 
0.5 
Compression Weight 
65.0 
______________________________________ 
The active ingredient is sieved through a suitable sieve, blended with the 
excipients and compressed using suitable punches. Tablets of other 
strengths may be prepared by altering either the ratio of active 
ingredient to excipients or the compression weight and using punches to 
suit. 
______________________________________ 
Wet Granulation 
Conventional Tablet mg/tablet 
______________________________________ 
Active Ingredient 2.5 
Lactose BP 151.0 
Starch BP 30.0 
Pregelatinised Maize Starch BP 
15.0 
Magnesium Stearate BP 
1.5 
Compression Weight 200.0 
______________________________________ 
The active ingredient is sieved through a suitable sieve and blended with 
lactose, starch and pregelatinised maize starch. Suitable volumes of 
purified water are added and the powders are granulated. After drying, the 
granules are screened and blended with the magnesium stearate. The 
granules are then compressed into tablets using 7 mm diameter punches. 
Tablets of other strengths may be prepared by altering the ratio of active 
ingredient to lactose or the compression weight and using punches to suit. 
______________________________________ 
Sub-Lingual Tablet mg/tablet 
______________________________________ 
Active Ingredient 2.5 
Mannitol BP 56.5 
Hydroxypropylmethylcellulose 
5.0 
Magnesium Stearate BP 
1.0 
Compression Weight 65.0 
______________________________________ 
The active ingredient is sieved through a suitable sieve and blended with 
the mannitol and hydroxypropylmethylcellulose. Suitable volumes of 
purified water are added and the powders are granulated. After drying, the 
granules are screened and blended into tablets using suitable punches. 
Tablets of other strengths may be prepared by altering the ratio of active 
ingredient to mannitol or the compression weight and punches to suit. 
______________________________________ 
CAPSULES mg/tablet 
______________________________________ 
Active Ingredient 2.5 
*Starch 1500 96.5 
Magnesium Stearate BP 
1.0 
Fill Weight 100.0 
______________________________________ 
*a form of directly compressible starch. 
The active ingredient is sieved and blended with the excipients. The mix is 
filled into size No. 2 hard gelatin capsules using suitable machinery. 
Other doses may be prepared by altering the fill weight an if necessary 
changing the capsule size to suit. 
SYRUP 
This may be either a sucrose or sucrose free presentation. 
______________________________________ 
A. Sucrose Syrup mg/5 ml dose 
______________________________________ 
Active Ingredient 2.5 
Sucrose BP 2750.0 
Glycerine BP 500.0 
Buffer 
Flavour 
Colour as required 
Preservative 
Purified Water BP to 5.0 ml 
______________________________________ 
The active ingredient, buffer, flavour, colour and preservative are 
dissolved in some of the water and the glycerine is added. The remainder 
of the water is heated to dissolve the sucrose and is then cooled. The two 
solutions are combined, adjusted to volume and mixed. The syrup is 
clarified by filtration. 
______________________________________ 
B. Sucrose-Free mg/5 ml dose 
______________________________________ 
Active Ingredient 2.5 
Hydroxypropylmethylcellulose USP 
22.5 
(viscosity type 4000) 
Buffer 
Flavour 
Colour as required 
Preservative 
Sweetener 
Purified Water BP to 5.0 ml 
______________________________________ 
The hydroxypropylmethylcellulose is dispersed in hot water, cooled and then 
mixed with an aqueous solution containing the active ingredient and the 
other components of the formulation. The resultant solution is adjusted to 
volume and mixed. The syrup is clarified by filtration. 
______________________________________ 
INJECTION FOR INTRAVENOUS ADMINISTRATION 
mg/ml 
______________________________________ 
Active Ingredient 0.80 
Citric Acid Monohydrate BP 
0.50 
Sodium Citrate BP 0.25 
Sodium Chloride BP 9.00 
Water for Injections USP to 
1.0 ml 
______________________________________ 
The citric acid monohydrate, active ingredient, sodium citrate and sodium 
chloride are dissolved in the major portion of the water for injections, 
the solution is made to volume and mixed thoroughly. After filtration, the 
solution is filled under air into ampoules which are sealed by fusion of 
the glass. The ampoules are sterilised by autoclaving for at least 15 
minutes at 121.degree.-124.degree. C. 
______________________________________ 
SUPPOSITORY 
______________________________________ 
Active Ingredient 
5.0 mg 
*Witepsol H15 to 1.0 g 
______________________________________ 
*Witepsol H15 is a proprietary grade of Adeps Solidus Ph. Eur. 
A suspension of the active ingredient is prepared in the molten Witepsol 
and filled, using suitable machinery, into 1 g size suppository moulds.