Note: Descriptions are shown in the official language in which they were submitted.
CA 02220103 1997-10-31
WO 96J34b~05 PCT/EP96J01881
Composition comprising Amoxycillin and Clavulanic acid
This invention relates to a method of treating paediatric bacterial infections
using a combination of the antibiotic amoxycillin and the beta-lactamase
inhibitor
potassium clavulanate, to pharmaceutical formulations for use in such method
and to
methods for the manufacture of such formulations.
The combination of the antibiotic amoxycillin, as amoxycillin trihydratc:, and
potassium clavulanate, is a well known and widely used oral medicament for
bacterial
infections, marketed by SmithKline Beecham in many countries under the trade
mark
A,ugmentin.
Regulatory approval has been obtained, for instance in the UK and U'S, for
W blets containing amoxycillin (250mg) and potassium clavulanate (125mg)
(ratio
2:1), in a three times daily dosing schedule (tid), so that the daily dose of
am.oxycillin
and potassium clavulanate is 750mg and 375mg respectively (the weights being
expressed as the free parent acids amoxycillin and clavulanic acid, this
manner of
expression being used throughout). In severe infections, the ratio is changed
to 4:1,
so that the daily doses of amoxycillin and potassium clavulanate are 1500mg
and
375mg respectively. In other countries such as Italy and Spain, tablets
containing
amoxycillin (875mg) and potassium clavulanate (125mg) (ratio 7:1) are approved
for
twice daily dosing (bid). In France, sachets comprising amoxycillin ( 1000m.g)
and
potassium clavulanate ( 125mg) (ratio 8:1 ) are marketed, for reconstitution
witt:~ water
prior to use, as an individual dosage for adults.
For children, it is preferred to provide the combination as a powder which is
reconstituted prior to use as a liquid aqueous suspension. The usual
recommended
daily dosage is 20/Smg/kg/day (LTK and USA) or 3017.5mg/kg/day (Continental
>=;urope) amoxycillin/potassium clavulanate (ratio 4:1), in divided doses
every eight
hours. For more severe infections such as otitis media, sinusitis and lower
mspiraotory tract infections, the recommended dose is 40/lOmg/kg/day (UK and
LJSA) or 60/lSmg/kg/day (Continental Europe), in three divided doses. For
convenience, the powders are provided in amounts which are made up into a
range of
volumes of suspension so that a small volume, typically about Sml, contains a
unit
dosage. In other countries such as Italy, approval has also been given for
using the
higher strength paediatric formulation on a twice a day (bid) dosing schedule.
Although it is recognised to be more convenient to be able to recommend a
bid dosing schedule for paediatric formulations, to avoid having to give
medicine
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WO 96/34605 PCT/EP96/01881
during the middle of the day when the child may be at school, not all drug
substances
have pharmocokinetics which are compatible with such a regimen.
In addition, gastric intolerance, manifested in symptons such as loose stools,
is
perceived in some countries to be a side effect associated with the use of
amoxycillin/potassium clavulanate in the present tid dosage regimes.
Accordingly,
any measures, such as revised dosage regimes, which can mitigate this would be
advantageous.
The present invention therefore provides a method of treating bacterial
infections in paediatric patients which method comprises administering to a
patient in
need thereof, preferably as a liquid aqueous suspension, amoxycillin
trihydrate and
potassium clavulanate in combination, in a weight ratio of between 6:1 and
8:1,
preferably about 6.5:1 to 7.5:1, more preferably about 7:1 (the weights being
expressed as the free parent acids amoxycillin and clavulanic acid), such
administration being twice daily (bid) and at a dosage of between 15 and
80mg/kg/day, preferably 20 and 75mg/kg/day, more preferably 20 and
70mg/kg/day,
suitably 40 and 70mg/kg/day, of amoxycillin and pro rata amounts of clavulanic
acid.
The term 'paediatric' as used herein means children in the age range from 0 to
about 12 years.
The method is suitable for all infections for which the combination of
amoxycillin trihydrate and potassium clavulanate is normally prescribed, for
instance
infections of the upper and lower respiratory tract, urinary tract, skin and
skin
structures, for example otitis media.
Suitabably the twice daily (bid) administration is at 12 hour intervals,
although a greater or lesser interval between administrations may be used.
Representative daily amounts of amoxycillin/potassium clavulanate include
25/3.6, 35/5, 45/6.4 and 70/10~10%mg/kg/day.
In a further aspect, the present invention provides for pharmaceutical
compositions for use in the aforementioned method of treatment, these
compositions
being distinguishable over previously available compositions on account of the
different ratio of amoxycillin trihydrate:potassium clavulanate used and the
differing
amounts of amoxycillin trihydrate and potassium clavulanate per unit dose, to
achieve
the higher daily dosage regime.
The invention therefore provides a pharmaceutical formulation suitable for
paediatric oral bid administration, comprising amoxycillin trihydrate and
potassium
clavulanate in combination, in a weight ratio of between 6:1 and 8:1,
preferably about
6.5:1 to 7.5:1, more preferably about 7:1 (the weights being expressed as the
free
parent acids amoxycillin and clavulanic acid), and in quantities such as to
provide
between between 15 and 80mg/kg/day, preferably 20 and 75mg/kg/day, more
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R'O 96/346ID5 PCT/EP96/01881
preferably 20 and 70mg/kg/day, suitably 40 and 7Umg/kg/day, of amoxyciitlin
and pro
rata amounts of clavulanic acid.
Formulations according to the present invention are preferably provided in the
form of a dry powder or granule formulation for reconstitution into an aqueous
S suspension with water or other suitable aqueous media, shortly before
administration.
'lChe present invention covers such dry powder and granule formulations as
well as
liquid aqueous preparations.
Such dry formulations may be provided in a substantially air-tight c:on,tainer
such as a bottle or sachet, and this container may suitably include a
desiccant to
F~rotect the potassium clavulanate from degradation by atmospheric water
vapour.
Potassium clavulanate is highly moisture sensitive, and the formulations of
this
invention should be made under conditions of relative humidty (RH) as lour as
possible, preferably 30% RH or less.
The formulation of this invention is provided for bid administration, which
ideally may comprise two administrations at 12 hour dosage intervals, although
a
greater or lesser interval between administrations may be used.
Suitably, formulations according to the present invention are provided in
amounts such that the liquid aqueous suspension contains in a convenient
volume,
typically within the range 2 to IOmI, preferably about Sml, of suspension, a~
unit
dosage of amoxycillin and potassium clavulanate. The volume may be measured by
any conventional measuring device such as a spoon, syringe or graduated
measuring
cup. Unit dosages typically lie within the range 50 to 800mg of amoxycillin
plus pro
rata amounts of potassium clavulanate. It will be appreciated that the
appropriate
unit dosage will be at the discretion of the physician and will depend inter
alia upon
tile age and weight of the patient and the nature and severity of the
infection to be
~-ea.ted.
It is found to be convenient to provide paediatric formulations in a lower
(for
mild-moderate infections) and a higher strength (for severe infections). The
suitable
formulations, when made up as aqueous liquid suspensions, will contain from
100 to
400mg, or 200 to 800mg amoxycillin per Sml of suspension plus pro rata amounts
of
potassium clavulanate. Representative examples include:
amoxycillin potassium clavulanate
200 28.515m1 suspension
400 57;
v~rithin a tolerance of ~10%. .
Accordingly, in a further aspect, the present. invention provides a
pharmaceutical formulation adapted for reconstitution as a liquid aqueous
suspension
comprising amoxycillin trihydrate and potassium clavulanate and which, when
rE:consituted, comprises amoxycillin in an amount 200~10% and clavulanic acid
in an
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WO 96/34605 PCT/EP96/01881
amount 28.5'10% or amoxycillin in an amount 400~10% and clavulanic acid in an
amount 57~10% mg/Sml of liquid aqueous suspension.
In a representative example, for a unit dosages of Sml, the suspension is made
up to a total volume of 100m1. It will however be appreciated that a range of
total
volumes may be used, to adjust the amount in a unit dose to an amount
appropriate
for the individual patient. It will be appreciated that it may also be
convenient to
provide a higher strength formulation to a patient with a larger body weight,
so that
the unit volume is kept reasonable.
The formulation of this invention will normally comprise, in addition to its
active materials amoxycillin trihydrate and potassium clavulanate, excipients
which
are standard in the field of paediatric pharmaceutical oral suspensions. These
will be
used in generally standard proportions, and at generally standard particle
sizes and
grades etc.. Such excipients may comprise suspending aids, glidants (to aid
filling),
diluents, bulking agent, flavours, sweeteners, stabilisers, and, in the case
of dry
formulations for make-up to an aqueous suspension, an edible desiccant to
assist
preservation of the potassium clavulanate against hydrolysis by atmospheric
moisture
on storage. Potassium clavulanate is normally supplied in admixture with
silicon
dioxide as diluent. Suitable excipients for use include xanthan gum
(suspension aid),
colloidal silica (glidant), succinic acid (stabiliser), aspartame (sweetener),
hydroxypropylmethylcellulose (suspension aid) and silicon dioxide (desiccant,
diluent
for potassium clavulanate and bulking agent. Flavours may comprise common
flavours such as orange, banana, raspberry and golden syrup, or mixtures
thereof, to
suit local requirements.
Mannitol is often used in pharmaceutical formulations as an excipient. It is
however recognised to have, at least at certain levels, a diuretic effect. It
has found to
be advantageous to avoid the use of excessive amounts of mannitol in
formulations
comprising amoxycillin/potassium clavulanate, as it is thought that this may
be
associated with reduced levels of gastric irntancy. Accordingly, the present
invention
provides for a pharmaceutical formulation as hereinbefore defined and which is
substantially mannitol-free.
Generally the proportion of active materials amoxycillin trihydrate and
potassium clavulanate in a dry formulation for make-up with aqueous media into
a
suspension formulation of the invention may be around 35-60, e.g. 35-50 wt%.
The formulation of the invention may be manufactured using techniques
which are generally conventional in the field of manufacture of paediatric
suspension
formulations and manufacture of dry formulations for reconstitution into such
suspensions. For example a suitable technique is that of mixing dry powdered
or
granulated ingredients for loading into a suitable container.
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The present invention therefore provides a process for manufacture of a
formulation as described above.
The invention also provides for the use of amoxycillin trihydrate and
potassium clavulanate as described above in the manufacture of a medicament
which
is provided for paediatric oral BID administration for use in the treatment of
bacterial
' infections.
The invention will now be described by way of non-limiting example only.
E:~ample 1
Two formulations of this invention having a composition as listed below were
prepared using conventional techniques as dry powder mixtures. The proportions
of
ingredients are expressed as mg/Sml dose of reconstituted aqueous suspension:
Ingredient mg/Sml mg/Sml
annoxycillin trihydrate*408.0 204.0
potassium clavulanate*61.56 30.78
xaalthan gum 12.5 12.5
colloidal silica 25.0 25.0
succinnic acid 0.84 '0.84
orange flavour 26.25 26.25
golden syrup flavour 23.75 23.75
aspartame 12.50 12.50
h5~droxypropylmethylcellulose79.65 79.65
silicon dioxide to 885.5 to 537.5
* expressed as free acid equivalent.
The above two formulations were manufactured in 100 kg batches.
Cliinical Trial - A
In a multicentre randomized trial, the safety and efficacy in the treatment of
aicute
Oaitis Media in children of formulations according to the present invention
and
comprising amoxycillin/potassium clavulanate in a ratio of 7: l, at a level of
4E5/6.4
mg/kg/day (ratio 7:1) and in divided doses ql2h (BID) were compared with au
currently approved US formulation comprising amo~;ycillin/potassium
clavulanate in
a lratio 4:1 administered at a level of 40/lOmg/kg/day amoxycillin/potassium
cl;avulanate acid in divided doses q 8h (TID). 287 children received the BID
rel;imen
for 10 days and 288 children received the TID regimen for 10 days. The
forrnulations
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according to the present invention were mannitol-free whilst the currently
approved
US formulation contained mannitol.
The BID regimen was shown to be as safe as the TID regimen. Standard diary
cards
were used to assess the incidence of incidence of protocol-defined diarrhoea
(i.e. 3 or
more watery stools in one day, or 2 watery stools per day for two consecutive
days.
This was found to be significantly lower for the BID regimen (7.9%) when
compared
with the TID regimen (22.2%) [95% CI: (-20.5%, -8.1%) ]. Similar trends were
observed for withdrawals due to diarrhoea (2.8% and 7.6% respectively; p =
0.009),
confirming improved patient tolerance compared with the current regimen.
The per protocol clinical success rates at the end of therapy (days 12 to 14)
were
equivalent for the BID regimen (86.5%) and the TID regimen (78.88%). Similar
trends in efficacy were noted at follow-up (days 32 to 38).
Formulations used
Ingredient bid bid tid tid
mg/Sml mg/5ml mg/Sml mg/Sml
amoxycillin trihydrate*408.0 204.0 130.00 260.00
potassium clavulanate*61.56 30.78 35.00 70.00
xanthan gum 12.5 12.5 15.00 15.00
sodium saccharin 4.00 4.00
colloidal silica 25.0 25.0 25.00 25.00
succinnic acid 0.84 0.84 0.85 0.85
banana flavour 20.00
orange flavour 26.25 26.25 23.00
golden syrup flavour 23.75 23.75
aspartame 12.50 12.50
hydroxypropylmethylcellulose79.65 79.65
silicon dioxide to 885.5 to 537.5 82.30 39.70
mannitol to 900.00to 1200.00
* expressed as free acid equivalent.
Clinical trial - B
In a multicentre randomized trial, the safety and efficacy in the treatment of
acute
Otitis Media in children of formulations according to the present invention
and
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WO 96/34b05 PCTIEP96/01881
comprising amoxycillin/potassium clavulanate in a ratio of 7:1, at a level of
7~D/lOmglkg/day (ratio 7:1) and in two divided doses (BID) were compared with
a
ci.~iTently approved European formulation comprising amoxycillin/potassium~
cl:av~ulanate in a ratio 4:1 administered at a level of 60/lSmg/kg/day
vnoxycillin/potassium clavulanate acid in three divided doses ('ITD).
Childt~en aged
from 2-12 years were randomised to 10 days treatment, with 231 children
receiving
tt~e BID regimen and 232 children receiving the TID regimen.
The BID regimen was shown to be as safe as the TID regimen. Standard diary
cards
were used to assess the incidence of protocol-defined diarrhoea (i.e. 3 or
more watery
stools in one day, or 2 watery stools per day for two consecutive days). The
overall
incidence was found to be low, with a lower incidence in the BID group (6.T%)
than
in the TID group (10.3%) although this was not statistically significant
[difff;rence -
3.6%; 95% CI (-8.72%, 1.58%)].
Clinical success rates at the end of therapy were 91.8% for the BID regimen
and
9~D.5% for the T'ID regimen [difference 1.3%,: 95% CI (-3.92%, 6.43%)] and at
follow-up were 80.1% for the BID group and 77.6% for the TID group [difference
2..5%; 95% CI (-4.94%, 9.94%)].
More patients in the BID group (81.3%) than in the TID group (72.8%) had at
least
8~0% compliance over a 7-10 day treatment period [difference 10.3%; 95% C:I
(:?.78%, 17.76%)].
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WO 96/34605 PCT/EP96/01881
Formulations used
Ingredient bid formulationtid formulation
mg/Sml mg/Sml
amoxycillin trihydrate*400.0 250.00
x
potassium clavulanate*59.85 65.63
xanthan gum 12.50 12.50
colloidal silica 25.00 25.00
succinnic acid 0.84 0.84
orange flavour 26.25 26.25
raspberry flavour 22.50
golden syrup flavour 23.75 23.75
aspartame 12.50 12.50
hydroxypropylmethylcellulose79.65 150.00
silicon dioxide to 885.5 125.00
* expressed as free acid equivalent.
_g_
