Note: Descriptions are shown in the official language in which they were submitted.
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Anthelmintic Co~hositions
This invention relates to anthelmintic compositions. More particularly it
relates to
anthelmintic compositions containing niclosamide as active ingredient.
Niclosamide(2',5-dichloro-4'-nitrosalicylanilide) is a known anthelmintic sold
by
Bayer (Pty) Ltd. under the trade name "Lintex". Known compositions of
niclosamide
are in the form of a suspension of niclosamide in a liquid medium. These
suspensions
are conventionally administered to animals, in particular sheep, as a 20% (g
niclosamide/100 ml carrier) formulation at a dosage rate of 1 ml per 4 kg body
mass
for the control of Cestode and/or Conical Fluke infestations.
In the publication by Nurtaeva, K.S., Bekhill, A.F., and Vorobeva, Z.G., 1973
Med
Parazitol (Mosk) 42:86 a study of the anti-parasite efficacy of various salts
of
niclosamide was reported. The sodium salt showed good activity. The compounds
tested were provided as mixtures with 5% starch or suspensions in water.
SummarX~the Invention
It has now surprisingly been found that effective control of Cestode and/or
Conical
Fluke infestation may be achieved with niclosamide at a seemingly drastically
reduced
dosage rate if the niclosamide is administered in a composition according to
the
present invention.
According to the present invention there is provided an anthelmintic
composition in
the form of a solution comprising a pharmacologically acceptable organic
solvent; and
a pharmacologically acceptable dissolved salt of niclosamide in the organic
solvent.
The organic solvent may comprise a polar organic solvent and preferably the
solvent is
a solvent selected from the group consisting of propylene glycol; glycerin;
polyeth-
ylene glycol; glycofurol; isopropanol; 2-pyrrolidine; derivatives of 2-
pyrrolidine; and
mixtures of these solvents. In one embodiment of the invention the solvent may
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comprise a mixture of propylene glycol and glycerin, preferably in a i :1
(volume:volume) ratio. In an alternative embodiment of the invention the
solvent may
comprise propylene glycol.
In one embodiment of the invention the salt of niclosamide may comprise a non-
metal
salt. In one preferred embodiment of the invention the salt comprises the
meglumine
salt of niclosamide. Other non-metal salts of niclosamide such as the
piperazine salt
and the ethanolamine salt are well known.
In an alternative embodiment of the invention the salt of niclosamide may
comprise a
metal salt. The metal salt may comprise a tin salt. Preferably however, the
salt com-
prises a metal salt selected from the group consisting of an alkali metal salt
and an
alkali earth metal salt. In the preferred embodiment of the invention the
metal salt
comprises the sodium salt of niclosamide.
The dissolved salt of niclosamide in the organic solvent is preferably formed
in situ.
This may be achieved by dissolving a base suitable for forming a salt of
niclosamide in
the solvent and adding niclosamide to the solvent. Preferably the base is
first dissolved
in the solvent and the niclosamide is subsequently added. Stirring and/or
heating may
be used to assist dissolution of the compounds in the solvent. The solution
may also
be filtered.
In one preferred embodiment of the invention sodium hydroxide is dissolved in
the
solvent and thereafter niclosamide is added to the solution. In this way a
stable solu-
tion is formed.
The anthelmintic composition may in addition also contain additional active
ingredi-
ents. Such ingredients may be aimed at extending the therapeutic spectrum of
the
formulation.
Thus, for example, the composition may contain levamisole either as a base or
as hy-
drohalogen salt, e.g. the hydrochloride or as phosphate salt as a
supplementary active
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ingredient so that the resultant combination formulation would be effective
against
both Cestode and Conical Fluke infestations (due to the presence of
niclosamide] and
against round worms against which levamisole is known to be effective.
An anti-oxidant may also be included in the solution and preferably it is
added at the
time the base is added to the solvent. The anti-oxidant may comprise sodium
metabi-
sulfite.
Other adjuvants such as suitable preservatives and flavourants may also be
added.
The composition of the present invention may be used as an anthelmintic for
veteri-
nary or human use. It may be administered orally [either as a liquid, or a
liquid in a
capsule or in the form of a granulate or tablet made by using the
aforementioned so-
lution].
According to another aspect of the present invention there is provided a
method of
forming an antheimintic composition in the form of a solution comprising
- providing a pharmacologically acceptable organic solvent; and
- dissolving niclosamide in the solvent by forming a pharmacologically accept-
able dissolved salt of niclosamide in the solvent.
The niclosamide may be dissolved in the solvent by providing a
pharmacologically
acceptable salt of niclosamide and dissolving said salt in the organic
solvent.
Alternatively and preferably the dissolved salt of niclosamide is formed in
situ. Pref
erably the dissolved salt of niclosamide is formed in situ as described
hereinabove.
The process is preferably carried out under anhydrous conditions.
The invention will now be further illustrated by way of example without
thereby limit-
ing the scope as envisa?ed above to the illustrated embodiment.
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Example I
Propylene glycol based solution of niclosamide as its sodium salt
0.5 j Ground [i.e. powdered) NaOH and 0.1 g ground sodium metabisulfite was
dis-
solved in 100 ml propylene glycol with stirring.
Mild heating of the propylene glycol may be necessary to aid the dissolution
of these
substances. To the solution was slowly added 4 ~ of powdered [passed through
an
80 mesh screen] anhydrous niclosamide with stirring until dissolved to form a
4% (g
niclosamide/100 ml propylene glycol) solution of niclosamide. The resultant
solution
was filtered and introduced into sealed bottles. Care should be taken not to
introduce
water into the solution as this causes deterioration of the final product as
evidenced
by a browning of the otherwise clear solution.
The solution was tested by way of initial trial work on lambs using the 4%
solution
against Cestode and Conical Fluke infections. Initial results indicated that
less
niclosamide according to the present solution was as effective as more
niclosamide
provided in conventional niclosamide suspensions.
Example 2
Efficacy evaluation of oral formulations of Niclosamide against a confirmed
natural infestation of IVIoniezia exnansa in lambs
The efficacy of a 4% niclosamide solution according to the invention, prepared
as
described in E~:ample 1 ["The Test Article"], was tested at various dosage
rates
against a commercially available niclosamide formulation made up as a 20% (g
niclosamide/100 ml carrier) suspension ["The Standard"] for the control of
Moniezia
expansa. The Standard was administered at the prescribed dosage rate of 50
m~/k~.
The trial was conducted on the applicant's farm "Rondebult" in the Bapsfontein
district in South Africa.
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Examination of the ingests and staining and identification of the Moniezia
expansa
was done in the laboratory. Dorper lamps of approximately two months of age
were
utilized during the trial. The lambs were housed in a kraal for the duration
of the trial
S and fed Lucerne with water available on tap.
The cestocides were tested in naturally infested lambs which was confirmed on
the
trial premises. Moniezia expansa is readily diagnosed in the live animal.
Diagnosis was
done using egg morphology and excreted strobilae although these may be
digested
with corresponding difficulty of identification. The trial was done on the
lines of a
staggered critical control test.
The animals were divided in groups and within each of the groups, and on three
con-
secutive days, some animals were treated with The Test Article (various dosage
rates)
I S some with The Standard (prescribed dosa?e rate of 50 mg/kg) and some were
un-
treated controls ["The Controls"] for comparison.
The animals involved in each stagger were eduipped with faecal collection bags
for
one day pre-treatment and three days post-treatment. The faeces thus collected
were
examined for the presence of strobilae.
The animals involved in each stagger were slaughtered four days post-treatment
foI-
lowing the procedure hereunder:
1. Animals were euthanased, skinned and the abdominal cavity opened. The gas-
tro-intestinal tract was removed and from this the small intestine and
caecum/colon was recovered. These were labeled with the animal's number.
2. Intestines were placed in a bucket. Water was added to both ends of the
intes-
tine allowing filling at each end to approximately 1-2 meters.
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3. The water was allowed to flow through the intestine from both ends until a
loop was formed at the bottom end located in the bucket.
4. One end of the intestine was released and the water was forced from the
intes-
tine by sliding the organ gently between the fingers.
5. The organ was then opened along its entire len~h using a pair of bowel scis-
sots after which the wall was thoroughly washed under a stream of water. The
intestine was then sealed in a glass jar after the addition of formalin for
preser-
vation. This was done in case later examination might be required.
6. Ingesta was recovered, sluiced through an Endecotts sieve and stored in
glass
jars for examination in the laboratory under direct sunlight in the plastic
pans.
The results were as follows:
Number of animalsRemedy Dose Rate Animals infested
at
Post Mortem
7 Test Article 6 mj/kg 2
7 Test Article 8 mg/kg 2
7 Test Article 10 mj/kg 0
5 Test Article 20 mg/kg 0
3 Test Article 40 mg/kg 0
9 Standard 50 mg/kg 0
5 Control - 5
The results indicate that The Test Article is as effective as The Standard at
a dosage
rate as low as 10 m~/kg compound to the dosage rate of 50 m~/k~ of The
Standard.
It will be appreciated that many variations in detail are possible without
thereby de-
parting from the scope and spirit of the invention.
