Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
DESC~IPTIO~'
"NEW INJECTABLE COMPOSITIONS"
This invention relates ~o liquid compositions
comprising 1~(2-hydroxyethyl)-2-methyl-5-nitroimidazole.
1-(2-Hydroxyethyl~-2-methyl-5-nitroimidazole
(hereinafter referred to as 'metronidazole') i6 a well
known agent used for combatting amoebal and
trichomonal infections and infections caused by
anaerobic bacteria.
In order to establish effective tissue levels
of metronidazole by parenteral administration which
are maintained for a reasonable length of time, e.g.
up to eight hours, it is frequently necessary to
administer relatively large amounts of metronidazole,
e.g. up to 500mg. Metronidazole is relatively
insoluble in water, having a solubility of
approximately 0.8% w/v (weight/volume) at room
temperature, necessitating the administration of 100ml
of an 0.5% w/v ~olution to give a dose of 500mg, which
requires intravenous infusion of the solution, the
volume in question being much eoo large to be
administered by intramuscular or subcutaneous
injection. This is relatively inconvenient and there
is a need for more concentrated in~ectable
compositions containing metronidazole, particularly
for veterinary use, and more especially for a
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composition which would permit the administration of a
dose of metronidazole which is effective for up to 24
hours, i.e. 1500mg, in a single injection of
relatively ~mall volume, e.g. 3 to 5 ml.
Aqueous solutions contsining metronidazole in
very much higher concentrations, e.g. 50~/O w/v ~nd
above, than are obtainable using metronidazole itself,
may be obtained by using salts of metronidazole which
are highly soluble in water, for example potassium
metronidazole phosphate. Such concentrated solutions
are, however, hypertonic, that i5 to say possess a
high osmotic pressure relative to body fluids and
cause pain and local intolerance on injection.
Satisfactory suspensions for injection
containing high levels ~f solids, e.g. in excess of
20% w~v, are often difficult to prepare, have
unsatisfactory stora~e lives and often cause pain and
local intolerance at the site of injection.
It is, furthermore, gener~lly recommended
that solid materials for injection should be in the
form of very fine particles, typically particles
havin~ a median maximum dimension of 10 microns or
less, and preferably less than 5 microns.
It is slso well ~nown that it is normally
necessary to include wetting and suspending sgents in
suspensions of fine particles for injection, in order
' ' 3L f~.
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to give a suspension with sufficient mobility and, if
the particles 6eparate out from the liguid medium,
resuspendability, to permit easy and accurate
withdrawal of the reguired dose from the container
into the hypodermic ~yringe and injection into the
body.
Attempts to prepare injectable concentrated,
i~e. up to 50iO w/v, aqueous ~uspensions of fine
particles of metronidazole, i.e. particles having a
median maximum dimension of lO microns or even 5
microns or less, have proved unsuccessful, since the
suspensions have an unacceptably high viscosity, which
renders them dif~icult to draw into or expel from a
hypodermic ~yringe, even when wetting and suspending
agents commonly ~sed in injectable suspensions are
present.
It has now been found that ~atisfactory
aqueous suspensions containing up to approximately 80%
w/v of metronida201e ran be prepared by using
particle5 of metronidazole having a median maximum
dimension in excess of lO microns, the aforesaid
par~icles having a median maximum dimension of from 15
to 30 microns, and containing not more than about 10%
by weight of particles of lO microns or less
maximum dimension and not more thaD about 10% by
weight of particles of 80 microns, and preferably 60
microns, or more maximum dimension, percentages by
weight of particles bein~ measured by a laser
4 --
light-scattering method. These injectable ~4ueous
suspensions of metronidazole do not cause pain on
intramuscular inJection and/or local intolerance and
the release rate of metronidazole from the site of
injection into the body tissues is ~uch that the
required level of metronidazole in the body tissues
may be maintained by a single daily injection.
It is also well known that solids in the
presence of their ~aturated ~olutions undergo an
increase in particle ~ize by an Ostwald ripenin~ or
solution/recrystallisation process whereby larger
particles grow at the expense of smaller particles.
It has been found that this occurs with concentrated
suspensions of metronidazole in water after a few,
~5 e.g. five, days~ This increase in the size of the
metronidazole particles in the suspension is
undesirable9 since excessive growth may produce large
crystals, which will block the Deedle of a hypodermic
needle or interfere with the flow of the aqueous
s~spension through the needle and may adversely affect
the resuspendability of the metronidazole particles in
the suspension medium, such that a given volume of
~uspension will not eontain the expected amount of
~etronidazole. Many particle growth regulants, i.e.
agents which suppress or control the growth of ~olid
particles in contact with their saturated ~olutions,
~%~
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are known, e.g. Tweens, poly(v;nylpyrrolidone~),
lecithin, sodium carboxymethylcellulose, hydroxypropyl-
methylcellulose and mixtures o these regulants. Of
these various par~icle growth re~ulants, hydroxypropyl-
methylcellulose has been found to be effective inpreventin~ thP grow~h of metronidazole particles in
aqueous ~uspensions of metronidazole according to the
present invention, suitably at a concentration of from
0.4 ts 5.0% w/v.
Accordingly, if it i6 desired to prepare an
injectable aqueous suspension of metronidazole
according to the present invention which can be kept
for a period of from a few days up to one month
without unacceptable increase in the particle ~ize of
the metronidazole, this csn be achieved by
incorporating an effective proportion of hydroxypropyl-
me~hylcellulose and more especially hydroxypropyl-
methylcellulose the vi~cosity of a 2% w/v aqueous
solution of which is from 2 to 8 ~entipoi6es at 20~C,
for example the product which is eommercially
available under the Trade Mark "Pharmacoat" 606, in
the suspension. The hydroxypropylmethylcellulose
also serves as a suspending agent retaining the
metronidazole particles in suspension and facilitating
the resuspension of metronidazole particles which
separate out from the suspension. However, if the
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injec~able aqueous su6pension of metronidazole is
intended to be administered i~mediately or very ~oon
after preparation~ i.e. before growth o the
metronidazole particles can occur, oeher ~uspending
agen~s may be used which do not inhibit the growth of
the metronidazole particles, e.g. products of
ethoxylation of castor oil and hydrogenated castor
oil, including those product6 which are commercially
available under the Tr~de Marks "Cremophor" RH410, EL,
10 ~H60 and RH40, "Arlatone" 285 and 164, polypropylene
oxide ethoxylated to varying degrees, including those
products which are commercially avail~ble under the
Trade Marks "Pluronic" L62, F68 and 108, ~orbitan
fatty acid ethoxylates, including those products which
are commercially available under the Trade Mark
"Tween"J poly(vinylpyrrolidones), lecithin, sodium
carboxymethylcelluloses ~nd C~rbomer BP (a synthetic
high molecular weight polymer of acrylic acid
cross-linked with allyl sucrose and containing 56 to
68% of carboxylic acid groups~.
It will be appreciated that ~ince the agueous
suspensions of metronidazole particles are intended to
be administered by injection, they will be prepared
from ~terile materials ~r ~terilised after preparation
~nd 6tored under sterile conditions or contain
preservatives to prevent microbial contamination.
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When the injectable aqueous suspension of
metronidazole is to be stored in a multi-dose
container from which the appropriate quantity of
suspension for a ~ingle dose will be withdrawn as and
when required over a period of time ranging from
several dsys to one month, a preservative should be
incorporated~ The preservative should be compatible
with the particle growth regulant and/or su6pending
agent(s). Benzyl alcohol has been found to be
compatible with hydroxypropylmethylcellulose and is
preferred as the preservative. If hydroxypropylmethyl-
cellulose is not present and other suspending agents
as hercinbefore described are used, other
preservatives, e.g. cresol or ortho-chlorocresol, may
be used.
If desired, conventional agents, for example
sodium chloride, may be incorporated in the injectable
aqueous suspensions according to the present invention
eo render them isotonic with respect to body fluids,
and pharmaceutically-acceptable acids and bases, e.g.
phosphate buffers, may be added, if desired, to render
the æuspension substantially neutral.
Accordingly, the present invention provides
sterile, substantially neutral aqueous injectable
suspensions comprising up to approximately 80~ w/v of
metronidazole, the metronidazole being in the form
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of particles having a median maximum dimension of from
15 to 30 microns ~nd containing not more than about
102 by weight of particles of 10 microns or les~
maximum dimension ~nd not more than about 10% by
weight of particles of 80 microns, and preerably 60
microns, or more maximum dimen~ion, and optionally an
effective amount of a particle growth regulant,
preferably hydroxypropylmethylcellulose, or suspending
agent and optionally one or more agents, for example
~o sodium chloride, which render the aqueous suspension
isotonic to body fluids, and optionally
pharmaceutically-acceptable acids and bases, e.g.
phosphate buffers, to render the suspension
substantially neutral and optionally one or more
preservatives,
According to a preferred feature of the
present invention, there are provided sterile,
~ubstantially neutral aqueous injectable suspensions
which are isotonic in respect of body fluids and
comprise from 1 to 80%, and preferably from 1 to 60%,
w/v of metronidazole, the metronidazole being in the
form of particles having a median maximum dimension of
~rom 15 to 30 microns, and containing not more ~han
~bout 10% by weight of particles of 10 microns or less
maximum dimension and not more than about 10% by
weight of particles of 80 microns, and prefersbly
60 microns, or more maximum dimension, from 0.4
to 5.0~ wlv of hydroxypropylmethylcellulose,
~ 7
and more especially hydroxypropylmethylcellulose the
viscosity of ~ 2h w/v aqueous ~olution of which is
from 2 to 8 centipoises at 20QC, from n. 5 to 1.~% v/v
~volume/volume) of benzyl ~lcohol~ and, optionally,
one or more agents, for example 60dium chloride, which
render the aqueous suspension i~otonic to body fluids
and optionally pharmaceutically-acceptable acids and
bases, e.g. phosphate buffers, to render the
suspensian sub6tantially neutral.
Sterile, ~ubstantially neutral aqueous
injectable ~uspensions according to the present
invention may be prepared by mixing, if necessary with
agi~ation, the appropriate amount of sterile
metronidazole in powder form of the hereinbefore
~pecified particle size ~ith a solution in ~terile
water of the other hereinbefore specified ingredien~s
or by mixing a ~terile suspension as hereinbefore
defined but which contains in excess of 80% w/v of
metronidazole, e.g. up to approximately 902 w/v of
metronidazole, and which requires dilution to give a
~uspensi~n suitable for inject;on (~uch suspensions
containin~ in excess of 80% w/v of metronidazole form
a further feature of the present invention), with
sterile water. The metronidazole may be ~terilised by
gamma radiation or by passage of an aqueous solution
of metronidazole through an ~nti-bacterial filter and
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crystallisation ~d milling under aseptic conditions.
For convenience, the metronidazole in powder form or a
~terile 6uspension as hereinbefore defined but which
contains in excess of 80% wJv of metronidazole ~nd
~terile water or a 601ution in ~terile water of the
other hereinbefore 6pecified ingredients,
respectively, may be provided separately in suitable
container6> for example glass bottles, and combined,
if necessary with agitation, at the time of use. In
the case of 6uspensions according to the present
invention which contain a particle growth regulant and
which may be stored for several days to about one
month, for example in a multi-dose container from
which single doses are removed as and when reguired,
any metronidazole particles which ~eparate from the
~uspensi~n may be resuspended by agitation.
Metronidazole in the form of particles having
a median maximum dimension of from 15 to 30 microns
~nd containing not more than about 10% by weight of
particles of 10 microns or less maximum dimension and
not more than about 10~ by weight of particles of B0
microns, and preferably 60 microns, or more maximum
dimension forms a further feature of the present
invention, and may be prepared by milling
metronidazole powder of greater median particle
dimension in a suitable mill, e.~. a pin disc mill.
The following non-limitative Examples
illustrate the present invention.:-
72~7
EXAMPLE 1
Metronidazole powder having ~ median particlesize of 8D microns with 10% by weight of particles
having a maximum dimension of greater than 200 microns
was milled in ~ Minikek pin disc mill set up with 174
pins until metronidazole in the form of particles
having a median maximum dimension of from 15 to 30
microns with not more than 10% by weight of particles
of 10 microns or less maximum dimension and not more
than about lO~J~ by weight of particles of 60 to 80
mierons or greater maximum dimension9 was obtained,
which was then sterilised by ga~ma radiation.
EXAMPLE 2
Benzyl slcohol ~lOml) and Pharmacoat 606 ~5g)
were added, with stirring, to a solution of sodium
chloride (3.5g) in sterile water ~500ml). Sterile
metronidazole (400g) in the form of particles having a
median maximum dimension of from 15 to 30 microns with
not more than about 10% by weight of particles of 10
- microns or less maximum dimension and not more than
~bout 10% by weight of particles of 60 to 80 microns
or ~reater maximum dimension, (prepared as described
in Example 1) was then added, with stirring, ~o the
~olution thus obtained. Further ~terile water was
then added to a final volume of lOOOml to give a
sterile substantially neutral aqueous injection
su6pension which is isotonic i~ respect of body fluids
containing 40% w/v of metronidazole and which is
stable for up to one month.
:~L2~ 7;27
EXAMPLE 3
_
Benzyl slcohol (lml) end Pharmacoat 606
(0.5g) were added, with ~tirring, to ~ ~olution of
sodium chloride (0.35g) in 6terile water ~60ml). The
~olution thus obtained was placed under ~terile
conditions in 8 150ml glass bottle and sealed.
Sterile metronidazole ~40~) in the form of particles
having a median maximum dimension of frQm 15 to 30
microns with not more than about 10h by weight of
particles of 10 microns or less maximum dimension snd
not more than about 10~ by weight of particles of 60
to 80 microns or greater maximum dimension (prepared
as described in Example 1) W8S placed under sterile
conditions in a 200ml glass bottle. The contents of
the two bottles may be mixed to give lOOml of a
~5 sterile ~ubstantially neutr~l ~q~eou~ injection
suspension which is isotonic in respect of body fluids
containing 40V~ w~v of metronidazole, which may be
~dministered immediately or over a period of up to one
month.
EXAMPLE 4
The proceedure described in Example 3 wa~
repeated but replacing the Pharmaco~t 606 by
poly(vinylpyrrolidone) to give a ~terile ~ubstantially
neutral aqueous injection ~uspension which i~ i~otonic
in respect of body fluids containing 40% w/v of
metronidazole suit~ble for immediate injection.
