Amoxicillin tablet manufacturing process
Amoxicillin tablet manufacturing process
This invention
relates to a novel formulation comprising using amoxicillin and potassium
clavulanate and the use thereof in treating bacterial infections.
Amoxicillin and
potassium clavulanate are respectively a known β-lactam antibiotic and a known
β-lactamase inhibitor. Products comprising amoxicillin and potassium
clavulanate are marketed under the trade name “Augmentin” by SmithKline
Beecham. Such products are particularly effective for treatment of community
acquired infections, in particular upper respiratory tract infections in adults
and otitis media in children.
Various tablet
formulations of amoxicillin and potassium clavulanate have been approved for
marketing, comprising various different weights and ratios of amoxicillin and
potassium clavulanate, for instance, conventional swallow tablets comprising
250/125, 500/125, 500/62.5, and 875/125 mg amoxicillin/clavulanic acid (in the
form of potassium clavulanate). Such tablets comprise amoxicillin and
clavulanic acid in the ratio 2:1, 4:1, 8:1 and 7:1, respectively. The 875/125
mg tablet was developed to provide a tablet formulation which could be
administered in a bid (twice daily) dosage regimen. It is also marketed for tid
(three times daily) dosing, in Italy and Spain. The 500/62.5 mg tablet was also
developed to provide a tablet formulation which could be administered in a bid
dosage regimen, two such tablets being taken every 12 h, in preference to a
single 1000/125 mg tablet. A 1000/125 mg single dosage is also available, in
France, but as a single dosage sachet rather than a tablet. Typically, the
approved regimens provides a single dosage of 125 mg of potassium clavulanate.
In addition, WO 97/09042 (SmithKline Beecham) describes tablet formulations
comprising amoxicillin and clavulanic acid in a ratio in the range 12:1 to
20:1, preferably 14:1. WO 94/16696 (SmithKline Beecham) discloses generally
that clavulanic acid may unexpectedly enhance the efficacy of amoxicillin
against microorganisms having a resistant mechanism which is not β-lactamase mediated.
Existing
marketed tablet formulations of amoxicillin and potassium clavulanate are
conventional in that they provide immediate release of the active ingredients
once the tablet reaches the stomach. There has also been some interest in
developing formulations in which the release profile is modified, to allow for
a longer interval between dosages, for instances, every 12 hours (bid, q12 h),
rather than every 8 hours (tid, q8 h).
Thus, for
instance, WO 95/20946 (SmithKline Beecham) describes layered tablets comprising
amoxicillin and, optionally, potassium clavulanate, having a first layer which
is an immediate release layer and a second layer which is a slow release layer.
The broadest ratio of amoxicillin to clavulanic acid is 30:1 to 1:1, with a preferred
range of 8:1 to 1:1. Amoxicillin is suitably in the form of amoxicillin
trihydrate. Examples provided in WO 95/20946 of such bilayered tablets have
amoxicillin trihydrate in the immediate release layer and amoxicillin plus
clavulanate in the slow release layer. Multi-layered tablets are described more
generically in WO 94/06416 (Jagotec AG). Further bilayered tablets comprising
clavulanic acid and amoxicillin are described in WO 98/05305 (Quadrant Holdings
Ltd). In such tablets, a first layer comprises amoxicillin and a second layer
comprises clavulanate and the excipient trehalose, to stabilise the clavulanate
component.
In addition, WO
95/28148 (SmithKline Beecham) describes amoxicillin/potassium clavulanate
tablet formulations having a core containing amoxicillin and potassium
clavulanate coated with a release retarding agent and surrounded by an outer
casing layer of amoxicillin and potassium clavulanate. The release retarding
agent is an enteric coating, so that there is an immediate release of the
contents of the outer core, followed by a second phase from the core which is
delayed until the core reaches the intestine. Furthermore, WO 96/04908
(SmithKline Beecham) describes amoxicillin/potassium clavulanate tablet
formulations which comprise amoxicillin and potassium clavulanate in a matrix,
for immediate release, and granules in a delayed release form comprising
amoxicillin and potassium clavulanate. Such granules are coated with an enteric
coating, so release is delayed until the granules reach the intestine. WO
96/04908 (SmithKline Beecham) describes amoxicillin/potassium clavulanate
delayed or sustained release formulations formed from granules which have a
core comprising amoxicillin and potassium clavulanate, surrounded by a layer
comprising amoxicillin. WO 94/27557 (SmithKline Beecham) describes controlled
release formulations of amoxicillin and clavulanic acid prepared using a
hydrophobic waxy material which is then subjected to thermal infusion.
Controlled
release formulations comprising amoxicillin have been described by several
groups. Thus, Arancibia et al ((Int J of Clin Pharm, Ther and Tox, 1987, 25,
97-100) describe the pharmacokinetic properties and bioavailability of a
controlled release formulation comprising 500 mg of amoxicillin. No further
details of the formulation are provided. The formulation was however designed
to release 21 to 35% during the first 60 minutes, 51 to 66% at 4 hours, 70 to
80% at 6 hours, 81 to 90% at 8 hours and more than 94% at 12 hours. They
however found little, if any, correlation between the in vitro dissolution rate
and the pharmacokinetic behaviour in the body. Hilton et al (International
Journal of Pharmaceutics, 1992, 86, 79-88) described an alternative controlled
release tablet having a hydrophilic polymer matrix and a gas release system, to
provide intra-gastric buoyancy, to enhance gastric retention time. This showed
no advantage over a conventional capsule formulation, with bioavailability
being diminished. In contrast, Hilton et al (Journal of Pharmaceutical
Sciences, 1993, 82, 737-743) described a 750 mg controlled release tablet
incorporating the enteric polymer hydroxypropylmethyl cellulose acetate
succinate. This however failed to show any advantage over a conventional
capsule. In particular, the bioavailability was reduced to 64.6% compared with
the same dosage provided in a capsule. More recently, Hoffman et al (Journal of
Controlled Release, 1998, 54, 29-37 and WO 98/22091) have described a tablet
comprising 500 mg of amoxicillin in a matrix comprising hydroxypropyl methyl
cellulose, designed to release 50% of its contents in the first three hours and
complete the drug release process over eight hours. The time above MIC was
found to be significantly extended, compared to a capsule formulation, but not
enough for a 12 h dosing interval. The discussion is in the context of a
theoretical MIC of 0.2 μg/ml.
Part of the
challenge in providing formulations of amoxicillin in which the drug release is
effectively modified (and a ready explanation for the lack of success in the
studies already referenced) is the relatively narrow window for absorption of
the drug in the small intestine and the relatively short elimination half life
of the drug. Furthermore, the rapid elimination of amoxicillin (half-life is
about 1.3 hours) makes it difficult to maintain serum levels as clearance from
the body is very rapid. Absorption over a prolonged period is therefore
required to maintain adequate circulating concentrations of amoxicillin.
In existing
tablet formulations comprising amoxicillin and potassium clavulanate,
amoxicillin is present in the form amoxicillin trihydrate, as the use of this
form provides tablets with greater storage stability than those in which
amoxicillin is present as sodium amoxicillin (see GB 2 005 538, Beecham Group
Ltd). Sodium amoxicillin is, however, used as the amoxicillin component in
existing formulations of amoxicillin and potassium clavulanate adapted for i.v.
administration. The form of sodium amoxicillin used is a spray-dried form. In
addition, EP 0 131 147-A1 (Beecham Group plc) describes a further form of
sodium amoxicillin, so-called “crystalline sodium amoxicillin”. A further
process for preparing salts of amoxicillin, including sodium amoxicillin, is
described in WO 99/62910 (SmithKline Beecham). Sodium amoxicillin is relatively
water soluble in comparison to amoxicillin trihydrate.
Formulations comprising clavulanic acid and a pharmaceutically acceptable organic acid or a salt-like derivative thereof, for example calcium citrate, have been described in WO 96/07408 (SmithKline Beecham). In such formulations, it is postulated that the presence of the calcium citrate would help suppress the gastro-intestinal intolerance associated with oral dosing of clavulanate-containing products.
For β-lactams,
including amoxicillin, it is recognised that the time above minimum inhibitory
concentration (T>MIC) is the pharmacodynamic parameter most closely related
to efficacy. For amoxicillin/clavulanate, killing was observed when serum
concentrations exceeded the MIC for only 30% of the dosing interval (Craig and
Andes, Ped Inf Dis J, 1996, 15, 255-259).
A further
parameter which may be of importance is the ratio of the maximum plasma
concentration (Cmax) to the MIC value, as this may be related to the potential
to select for resistance. Too low a ratio may encourage the development of
resistant strains. Preferably, the plasma Cmax value is well
above the MIC value, for instance, at least two times, more preferably at least
three times, most preferably at least four times, the MIC value.
PCT/IB00/00992
describes a new modified release formulation of amoxicillin and clavulanate,
comprising for instance, a 1000/62.5 mg bilayer tablet which has an immediate
release layer comprising about 563 mg amoxicillin and 62.5 mg clavulanate and a
slow release layer comprising about 483 mg of sodium amoxicillin in combination
with citric acid and xanthan gum as release modifying excipients. In addition,
this application describes a BID dosage regimen using two of these tablets,
every 12 hours, for treating bacterial infections, which regimen provides a
T>MIC of at least 4.8 h, for an MIC of 4 μg/ml and a T>MIC of about 4.8
h, for an MIC of 8 μg/ml. Such a regimen is particularly useful for treating
penicillin resistant S. pneumoniae (PRSP). Penicillin
resistance in S. pneumoniae can be assessed according to
criteria developed by the National Committee for Clinical Laboratory Standards
(NCCLS), as follows: susceptible strains have MICs of <0.06 μg/ml,
intermediate resistance is defined as an MIC in the range 0.12 to 1.0 μg/ml
whilst penicillin resistance is defined as an MIC of ≧2 μg/ml.
There still
however remains an unmet need to provide new formulations of
amoxicillin/clavulanate which are effective against a higher target MIC, to
provide continuing clinical efficacy against more resistant Drug/Penicillin
Resistant S pneumoniae (D/PRSP).
Accordingly, in
a first aspect, the present invention provides for a pharmaceutical formulation
to provide a unit dosage of amoxicillin and potassium clavulanate which
comprises from 100 to 150 mg of potassium clavulanate and from 1700 to 2500 mg
of amoxicillin; which formulation is a modified release formulation comprising
an immediate and a slow release phase and in which all of the potassium
clavulanate and from 0 to 50% of the amoxicillin is in an immediate release
phase and from 50 to 100% of the amoxicillin is in a slow release phase; such
that the mean T>MIC is at least 4 h for an MIC of 8 μg/ml.
Typically, the
unit dosage comprises about 125 mg of potassium clavulanate.
Preferably, the
unit dosage comprises from 1900 to 2250, typically about 2000 mg of
amoxicillin.
Preferably, the
slow release phase comprises from 60 to 90, more preferably 70 to 90, yet more
preferably 76 to 90% of the total amoxicillin content.
Preferably, the
mean T>MIC is at least 4.2, 4.4, 4.6, 4.8 h.
Representative
unit dosages include 1750/125, 2000/125, and 2250/125 mg of amoxicillin and
potassium clavulanate, respectively. A preferred dosage is 12000/125 mg of
amoxicillin and potassium clavulanate.
The unit dosage
of a modified release formulation according to the present invention may
conveniently be provided as a number of swallow tablets or capsules, for
instance two, three or four, some of which may be the same and some of which
may comprise amoxicillin only and no potassium clavulanate. Thus, for instance,
a dosage of 2000 mg amoxicillin and 125 mg potassium clavulanate may be
provided by two tablets each comprising 1000/62.5 mg amoxicillin/potassium
clavulanate, one tablet comprising 1000 mg of amoxicillin and one tablet
comprising 1000/125 mg amoxicillin/potassium clavulanate, two tablets each
comprising 500 mg amoxicillin and one tablet comprising 1000/125 mg
amoxicillin/potassium clavulanate or four tablets each comprising tablet
500/32.25 mg amoxicillin/potassium clavulanate. In addition, a dosage of 1750
mg amoxicillin and 125 mg potassium clavulanate may be provided by two tablets
each comprising 875/62.5 mg amoxicillin/potassium clavulanate or one tablet
comprising 875 mg of amoxicillin and one tablet comprising 875/125 mg
amoxicillin/potassium clavulanate.
The dosage in a
modified release formulation may be may also provided as a single tablet.
Because of the quantities of drug substance being used, this would preferably
be other than a swallow tablet, for instance a dispersible tablet or a chewable
tablet which may also be effervescent and/or dispersible. The unit dosage may
also be conveniently provided as a single dosage sachet or as granules, for
direct ingestion, for instance on a spoon or after sprinkling on food. It will
be appreciated that the unit dosage may also be provided as a number of smaller
non-swallow tablets or sachets, for instance 2×1000/62.5 mg or 4×500/32.25 mg
amoxicillin/potassium clavulanate.
The unit dosage
of the present invention is typically provided either as two smaller units each
of which provides half the unit dosage or a single formulation which provides
the whole of the unit dosage. Accordingly, in a further aspect, the present
invention provides a pharmaceutical formulation of amoxicillin and potassium
clavulanate which comprises from 50 to 75 mg of potassium clavulanate and from
850 to 1250 mg of amoxicillin or from 100 to 150 mg of potassium clavulanate
and from 1700 to 2500 mg of amoxicillin; which formulation is a modified
release formulation comprising an immediate and a slow release phase and in
which all of the potassium clavulanate and from 0 to 60% of the amoxicillin is
in an immediate release phase and from 40 to 100% of the amoxicillin is in a
slow release phase; such that the parameter mean T>MIC is at least 4 h for
an MIC of 8 μg/ml.
Typically, the
formulation comprises about 62.5 mg of potassium clavulanate and from 950 to
1125, typically about 1000 mg of amoxicillin; or about 125 mg of potassium
clavulanate and from 1900 to 2250, typically about 2000 mg of amoxicillin.
Preferably, the
slow release phase comprises from 60 to 90, more preferably 70 to 90, yet more
preferably 76 to 90% of the total amoxicillin content.
Preferably,
T>MIC is at least 4.2, 4.4, 4.6, 4.8 h.
It will be
appreciated that the smaller (half) units will typically be a swallow tablet
whilst the larger units will typically be a chewable or dispersible tablet or a
single dose sachet.
Preferably, the
mean plasma concentration of amoxicillin and the mean maximum plasma
concentration of amoxicillin are measured after oral administration of a
formulation comprising amoxicillin at the start of a meal.
The term
“amoxicillin” is used generically to refer to amoxicillin or an alkaline salt
thereof, in particular amoxicillin trihydrate and (crystallised) sodium amoxicillin,
without distinction and unless otherwise indicated.
Unless
otherwise indicated, weights of amoxicillin and (potassium) clavulanate refer
to the equivalent weights of the corresponding free acids. In addition, it will
be appreciated that in practice, weights of amoxicillin and clavulanate to be
incorporated into a formulation will be further adjusted, in accord with
conventional practice, to take account of the potency of the amoxicillin and
clavulanate.
As used herein,
the term “immediate release” refers to the release of the majority of the
active material content within a relatively short time, for example within 1
hour, preferably within 30 minutes, after oral ingestion. Examples of such
immediate release formulations include conventional swallow tablets,
dispersible tablets, chewable tablets, single dose sachets and capsules.
As used herein,
the term “slow release” refers to the gradual but continuous or sustained
release over a relatively extended period of the active material content (in
this case amoxicillin) after oral ingestion and which starts when the
formulation reaches the stomach and starts to disintegrate/dissolve. The
release will continue over a period of time and may continue through until and
after the formulation reaches the intestine. This can be contrasted with the
term “delayed release” in which release of the active does not start
immediately the formulation reaches the stomach but is delayed for a period of
time, for instance until when the formulation reaches the intestine when the
increasing pH is used to trigger release of the active from the formulation.
Preferably, the
modified release formulation has a biphasic profile in vivo with respect to
amoxicillin, that is an initial burst from the immediate release phase to provide
an acceptable Cmax value, supplemented by a further
contribution from the slow release phase, to extend the T>MIC parameter to
an acceptable value.
Preferably, the
modified release formulation provides an “Area Under the (plasma concentration
versus time) Curve” (AUC) value which is substantially similar to, for instance
at least 80%, preferably at least 90%, more preferably about 100%, of that of
the corresponding dosage of amoxicillin taken as a conventional (immediate
release) formulation, over the same dosage period, thereby maximising the
absorption of the amoxicillin component from the slow release component.
The
pharmcokinetic profile for a dosage of the present invention may be readily
determined from a single dosage bioavailability study in human volunteers.
Plasma concentrations of amoxicillin may then be readily determined in blood
samples taken from patients according to procedures well known and documented
in the art.
Preferably, the
modified release formulations of the present invention are formulated such that
the release of amoxicillin is effected predominantly through the stomach and
small intestine, so that absorption through the specific amoxicillin absorption
site in the small intestine is maximised. Preferably, the amoxicillin release profile
is made up of a contribution from an immediate release component which is then
complemented and extended by an on-going contribution from a slow release
component. Preferably, potassium clavulanate is released substantially
immediately from the formulation, when the formulation reaches the stomach and
is absorption begins immediately, thereby minimising the risk of degradation
from prolonged exposure to the stomach. Such formulations are preferably
formulated such that the release of amoxicillin and potassium clavulanate
occurs predominantly within 3 hours of ingestion of the formulation.
Preferably, the
modified release formulation is a tablet. Representative modified release
tablets comprise about 62.5 mg of potassium clavulanate in the immediate release
phase, from 0 to 500 mg amoxicillin in the immediate release phase and from 500
to 1000 mg amoxicillin in the slow release phase, for instance:
(a) a tablet
comprising 1000 mg amoxicillin and 62.5 mg potassium clavulanate, in which the
immediate release phase comprises 62.5 mg±5% of potassium clavulanate and 250
mg±5% amoxicillin and the slow release phase comprises 750 mg±5% of
amoxicillin; or
(b) a tablet
comprising 875 mg amoxicillin and 62.5 mg potassium clavulanate, in which the
immediate release phase comprises 62.5 mg±5% of potassium clavulanate and 275
mg±5% amoxicillin, and the slow release phase about 600 mg of amoxicillin.
It will be
appreciated that when the unit dose is provided as a single unit, for instance
a chewable tablet or a single dose sachet, such unit will comprise twice the
above quantities.
For a tablet
formulation, the immediate and slow release phases may be provided in a number
of different formats.
In a preferred
aspect, the immediate and slow release phases are provided as separate layers
of a layered tablet.
Accordingly, in
a further aspect, the present invention provides for a layered tablet
formulation comprising potassium clavulanate and amoxicillin in an immediate
release layer phase and amoxicillin in a slow release layer. The layered tablet
may have two layers, or two layers plus one or more barrier layer, as well as a
coating layer. As used herein, the term “bilayer” tablet refers to a tablet
consisting of an immediate release and a slow release layer, optionally with a
coating layer.
An immediate
release layer may be, for example, a layer which disintegrates immediately or
rapidly and has a composition similar to that of known tablets which
disintegrate immediately or rapidly. For example, the layer may comprise, in addition
to the active material content, excipients including diluents such as
microcrystalline cellulose; disintegrants such as cross-linked
polyvinylpyrrolidone (CLPVP), sodium starch glycollate; compression aids such
as colloidal silicon dioxide and microcrystalline cellulose; and lubricants
such as magnesium stearate. Such an immediate release layer may comprise around
60 to 85% (all percentages given herein are on a weight percentage basis unless
otherwise stated), preferably 70 to 85%, of active material content, around 10
to 30%, preferably 10 to 20% of fillers/compression aids, and conventional
amounts of disintegrants and lubricants, typically about 0.5 to 3%, etc.
An alternative
type of immediate release layer may be a swellable layer having a composition
which incorporates polymeric materials which swell immediately and extensively
in contact with water or aqueous media, to form a water permeable but
relatively large swollen mass. Active material content may be immediately
leached out of this mass.
Slow release
layers have a composition which comprises amoxicillin together with a release
retarding excipient which allows for slow release of amoxicillin. Suitable
release retarding excipients include pH sensitive polymers, for instance
polymers based upon methacrylic acid copolymers such as the Eudragit (trade
mark) polymers, for example Eudragit L (trade mark) which may be used either
alone or with a plasticiser; release-retarding polymers which have a high
degree of swelling in contact with water or aqueous media such as the stomach
contents; polymeric materials which form a gel on contact with water or aqueous
media; and polymeric materials which have both swelling and gelling
characteristics in contact with water or aqueous media.
Release
retarding polymers which have a high degree of swelling include, inter alia,
cross-linked sodium carboxymethylcellulose, cross-linked
hydroxypropylcellulose, high-molecular weight hydroxypropylmethylcellulose,
carboxymethylamide, potassium methacrylatedivinylbenzene co-polymer,
polymethylmethacrylate, cross-linked polyvinylpyrrolidone, high-molecular
weight polyvinylalcohols etc.
Release
retarding gellable polymers include methylcellulose, carboxymethylcellulose,
low-molecular weight hydroxypropylmethylcellulose, low-molecular weight
polyvinylalcohols, polyoxyethyleneglycols, non-cross linked
polyvinylpyrrolidone, xanthan gum etc.
Release
retarding polymers simultaneously possessing swelling and gelling properties
include medium-viscosity hydroxypropylmethylcellulose and medium-viscosity
polyvinylalcohols.
A preferred release-retarding polymer is xanthan gum, in particular a fine mesh grade of xanthan gum, preferably pharmaceutical grade xanthan gum, 200 mesh, for instance the product Xantural 75 (also known as Keltrol CR, Trade Mark, Monsanto, 800 N Lindbergh Blvd, St Louis, Mo. 63167, USA). Xanthan gum is a polysaccharide which upon hydration forms a viscous gel layer around the tablet through which the active has to diffuse. It has been shown that the smaller the particle size, the slower the release rate. In addition, the rate of release of drug substance is dependent upon the amount of xanthan gum used and can be adjusted to give the desired profile. Controlled release formulations comprising from 7.5 to 25% xanthan gum are described in EP 0 234 670-A (Boots Co plc). The preferred embodiment is a tablet comprising ibuprofen as the drug substance and 15-20% xanthan gum, which is taken once daily.
Other known
release-retarding polymers which may be incorporated include hydrocolloids such
as natural or synthetic gums, cellulose derivatives other than those listed
above, carbohydrate-based substances such as acacia, gum tragacanth, locust
bean gum, guar gum, agar, pectin, carageenin, soluble and insoluble alginates,
carboxypolymethylene, casein, zein, and the like, and proteinaceous substances
such as gelatin.
Such a slow
release layer may contain polymers which immediately swell in contact with
water or aqueous media so that they form a relatively large swollen mass which
is not immediately discharged from the stomach into the intestine.
The slow
release layer may also include diluents such as lactose; compression aids such
as microcrystalline cellulose; and lubricants such as magnesium stearate. The
slow release layer may further comprise disintegrants, such as cross-linked
polyvinylpyrrolidone (CLPVP) and sodium starch glycollate; binders such as
povidone (polyvinylpyrrolidone); desiccants, such as silicon dioxide; and
soluble excipients such as mannitol or other soluble sugars. Typically, the
slow release layer comprises from about 60 to 80% by weight of amoxicillin;
from 10 to 20% by weight of diluent/compression aid and from 1 to 2.5% by
weight of lubricant.
When xanthan
gum is used as release-retarding polymer, the layer contains from 60 to 80% of
amoxicillin, from 4 to 25%, preferably 4 to 15%, more preferably 5 to 15%,
typically about 6 to 10%, of xanthan gum, from 10 to 30%, preferably 10 to 20%
of fillers/compression aids, and conventional quantities of lubricants, all %
being by weight of the layer. In a preferred embodiment, the slow release layer
comprises from 70 to 80% of amoxicillin, from 5 to 10%, of xanthan gum, from 10
to 20% of microcrystalline cellulose, and from 1 to 2.5% of magnesium stearate,
all % being by weight of the layer.
When
release-retarding polymers other than xanthan gum are used, the slow release
layer may contain around 30 to 70%, preferably from 40 to 60%, of amoxicillin,
from 15 to 45% of release-retarding polymer, from 0 to 30% of
fillers/compression aids, conventional quantities of lubricants, and from 5 to
20% of soluble excipients, all % being by weight of the layer.
A further release retarding excipient for use when the amoxicillin in the slow release layer is in the form of a soluble salt thereof, such as sodium or potassium amoxicillin, is an organic acid.
It is believed
that intimate contact between the organic acid and the salt of amoxicillin in
the pharmaceutical formulation, for instance as a consequence of compacted
granule formation or direct compression in a tablet, causes some form of
interaction which modifies the release of the amoxicillin component from the
formulation.
Soluble
pharmaceutically acceptable salts of amoxicillin include alkali metal salts
such as sodium and potassium; alkaline earth metal salts such as magnesium and
calcium, and acid salts such as amoxicillin hydrochloride. Preferably, the salt
is sodium amoxicillin, more preferably crystallised sodium amoxicillin.
As used herein,
the term “pharmaceutically acceptable organic acid” refers to organic acids
which are without pharmacological effect per se, have acceptable organo-leptic
properties, have acceptable density, do not have an extreme pH and are
preferably solid. Examples thereof include mono-carboxylic acids and
poly-carboxylic acids having from 2 to 25, preferably from 2 to 10, carbon
atoms; monocyclic and polycyclic aryl acids such as benzoic acid; as well as
monohydrogen, dihydrogen etc metal salts of multi-valent acids. A single
pharmaceutically acceptable organic acid may be used, or two or more of such
may be used in combination. Preferably, the organic acid is a C(2-10)alkyl-
or alkenyl-carboxylic acid having from one, two or three carboxylic acid
groups, and optionally with one or more hydroxy substituents or an additional
CO group in the carbon chain, for instance malonic acid, succinic acid, fumaric
acid, maleic acid, adipic acid, lactic acid, levulinic acid, sorbic acid or a
fruit acid such as tartaric acid, malic acid, ascorbic acid or citric acid, or
an acidic salt thereof, more preferably citric acid, in particular anhydrous
citric acid.
The organic
acid may be used alone or in combination with a release retarding polymer as
hereinbefore described. A preferred combination comprises citric acid and a
release retarding gellable polymer, in particular xanthan gum. In the presence
of the organic acid, for instance citric acid, xanthan gum may be used at a
lower level then when included on its own, for instance, from 0.5 to 8%,
preferably 1 to 5%, typically about 2%, by weight of the slow release layer.
When an organic
acid is used as a release-retarding excipient, the slow release layer contains
from 60 to 80% of a soluble salt of amoxicillin, from 10 to 30%, preferably 10
to 20% of fillers/compression aids, and conventional quantities of lubricants,
all % being by weight of the layer. In a preferred embodiment, the slow release
layer comprises from 60 to 70% of a soluble salt of amoxicillin, from 10 to 20%
of microcrystalline cellulose, and from 1 to 2.5% of magnesium stearate, all %
being by weight of the layer.
In a
representative example, a layered tablet comprises in the slow release layer
crystallised sodium amoxicillin and citric acid, in a molar ratio of about 50:1
to 1:2, preferably 20:1 to 1:2, more preferably 2:1 to 1:1.2, yet more
preferably about 1:1. In a representative embodiment, the slow release layer comprises
750 mg±5% crystallised sodium amoxicillin, and about 134 mg±10% citric acid.
In a
representative layered tablet comprising 1000 mg amoxicillin and 62.5 mg
potassium clavulanate, the immediate release layer comprises 250 mg±5%
amoxicillin, preferably amoxicillin trihydrate, and about 62.5 mg±5% of
potassium clavulanate and the slow release layer 750 mg±5% of amoxicillin,
preferably crystallised sodium amoxicillin, and 134 mg±10% citric acid.
The tablet
formulations of the invention may also include one or more barrier layers,
which may be located between the respective first and second layers, and/or on
one or more of the outer surfaces of the first and second layers, for example
the end faces of the layers of a substantially cylindrical tablet. Such barrier
layers may, for example, be composed of polymers which are either substantially
or completely impermeable to water or aqueous media, or are slowly erodable in
water or aqueous media or biological liquids and/or which swell in contact with
water or aqueous media. Suitably the barrier layer should be such that it
retains these characteristics at least until complete or substantially complete
transfer of the active material content to the surrounding medium.
Suitable
polymers for the barrier layer include acrylates, methacrylates, copolymers of
acrylic acid, celluloses and derivatives thereof such as ethylcelluloses,
cellulose acetate propionate, polyethylenes and polyvinyl alcohols etc. Barrier
layers comprising polymers which swell in contact with water or aqueous media
may swell to such an extent that the swollen layer forms a relatively large
swollen mass, the size of which delays its immediate discharge from the stomach
into the intestine. The barrier layer may itself contain active material content,
for example the barrier layer may be a slow or delayed release layer. Barrier
layers may typically have an individual thickness of 2 mm to 10 microns.
Suitable
polymers for barrier layers which are relatively impermeable to water include
the Methocel (trade mark) series of polymers mentioned above, for example
Methocel K100M, Methocel K15M, Methocel E5 and Methocel E50, used singly or
combined, or optionally combined with an Ethocel (trade mark) polymer. Such
polymers may suitably be used in combination with a plasticiser such as
hydrogenated castor oil. The barrier layer may also include conventional
binders, fillers, lubricants and compression acids etc such as Polyvidon K30
(trade mark), magnesium stearate, and silicon dioxide, e.g. Syloid 244 (trade mark).
The tablet
formulation of the invention may be wholly or partly covered by a coating
layer, which may be a protective layer to prevent ingress of moisture or damage
to the tablet. The coating layer may itself contain active material content,
and may, for example, be an immediate release layer, which immediately
disintegrates in contact with water or aqueous media to release its active
material content, for example amoxicillin and potassium clavulanate. Preferred
coating materials comprise hydroxypropylmethylcellulose and polyethylene
glycol, with titanium dioxide as an opacifying agent, for instance as described
in WO 95/28927 (SmithKline Beecham).
As well as
active material content etc, the tablet of the invention may also include a pH
modifying agent, such as a pH buffer, which may be contained in either the
immediate-, or slow-release layers, or in a coating around all or part of the
tablet. A suitable buffer is calcium hydrogen phosphate.
In a tablet
without a barrier layer, the immediate release layer comprises from 50 to 60%
and the slow release layer comprises from 40 to 50% of the overall tablet
weight. When a barrier layer is present, the immediate release layer typically
comprises from 40 to 50%, the slow release layer comprises from 35 to 45%, and
the barrier layer comprises from 5 to 20% of the overall tablet weight.
It is found
that a satisfactory pharmacokinetic profile may be obtained from a bilayered
tablet of the present invention without the need to include a barrier layer.
Accordingly, a bi-layer tablet is preferred. This also reduces the complexity
of the manufacturing process.
It will be
appreciated that layered tablets having an immediate release layer and a slow
release layer as hereinbefore described are novel. Accordingly, in a further
aspect, the present invention provides for a pharmaceutical layered tablet
formulation comprising an immediate release layer and a slow release layer and
comprising from 700 to 1250 mg, typically 1000 mg, amoxicillin, and from 50 to
75 mg, typically 62.5 mg, potassium clavulanate, such that all the potassium
clavulanate and from 0 to 60% of the amoxicillin is in the immediate release
layer and from 40 to 100% of the amoxicillin is in the immediate release layer,
in combination with pharmaceutically acceptable excipients or carriers.
Preferably, the layered tablet is a bi-layered tablet.
Suitably the
tablet formulations of the invention may be formed by known compression
tabletting techniques, for example using a known multi-layer tabletting press.
Preferably, in a preliminary step, slugging or roller compaction is used to
form granulates. Lubricants and compression aids (if used) are then added, to
form a compression blend for subsequent compaction.
Representative
bilayer tablets of the present invention may be made by a process which
comprises, as an early phase, the formation of slow release compacted granules,
comprising the steps of milling sodium amoxicillin, a portion of the
diluent/compression aid such as microcrystalline cellulose (typically about
30%), a portion of the lubricant (typically about 70%) and a pharmaceutically
acceptable organic acid such as a fruit acid, for instance citric acid, and
then blending with a release retarding polymer such as xanthan gum, if present,
and a compression aid such as colloidal silicon dioxide, compacting the blend,
for instance in a roller compactor or by slugging, and then milling, to form
slow release granules. Preferably such granules have a size in the range 100 to
1000 microns. The incorporation of xanthan gum appears to also have an
unexpected benefit on processability.
Alternatively,
slow release granules in which amoxicillin is present as amoxicillin trihydrate
and the release modifying excipient is xanthan gum may be prepared by a similar
process.
Such slow
release compacted granules may then be blended with other excipients such as
the remaining magnesium stearate and microcrystalline cellulose, to form a slow
release compression blend.
In addition,
amoxicillin trihydrate, potassium clavulanate (preferably as 1:1 blend with
microcrystalline cellulose), microcrystalline cellulose (a portion of total
used), are milled and blended with a lubricant such as magnesium stearate
(preferably about 50% of the total), and then compacted, for instance in a
roller compactor or by slugging, and milled to form immediate release compacted
granules. These immediate release compacted granules may then be blended with
other excipients such as the remaining magnesium stearate and microcrystalline
cellulose (about 13%), a compression aid such as colloidal silica, and a
disintegrant such as sodium starch glycollate, to form an immediate release
compression blend.
The immediate
release and slow release compression blends may then be compressed as separate
layers on a bilayer tablet press, to form bilayer tablets.
Such slow
release granules are novel. Accordingly, in a further aspect, the present
invention provides for compacted granules comprising a soluble salt of
amoxicillin, for instance sodium amoxicillin, a diluent/compression aid, and an
organic acid or a release retarding polymer or a mixture thereof, as
hereinbefore defined. In a yet further aspect, the present invention also
provides for compacted granules comprising amoxicillin, for instance
amoxicillin trihydrate or sodium amoxicillin, a diluent/compression aid, and a
release retarding polymer, for instance xanthan gum.
Alternatively,
a dry densification process may be used, e.g. briquetting. Typically the active
material content, pH modifiers, buffers, fillers and/or diluent, release
retarding agents, disintegrants and binders, when used are mixed, then
lubricants and compression aids are added. The complete mixture may then be
compressed under high pressure in the tablet press. A wet granulation process
may be also be used, for instance with isopropanol as the solvent and Polyvidon
K-30 (trade mark) as the wet granulating aid.
A barrier
layer, if present, may typically be made up by a wet granulation technique, or
by dry granulation techniques such as roller compaction. Typically the barrier
material, e.g. Methocel (trade mark) is suspended in a solvent such as ethanol
containing a granulation acid such as Ethocel or Polyvidon K-30 (trade mark),
followed by mixing, sieving and granulation. Typically a first layer may be
formed, then a barrier layer deposited upon it, e.g. by compression, spraying
or immersion techniques, then the second layer may be formed so that the
barrier layer is sandwiched between the first and second layers. Additionally,
or alternatively, the first and second layers may be formed and a barrier layer
may then be formed, for instance by compression, spraying or immersion, on one
or more of the end faces of the tablet.
A process for
the preparation of crystallised sodium amoxicillin is described in EP-A-0 131
147 (Beecham Group plc).
Potassium
clavulanate is known to be extremely water sensitive. Therefore tablet
formulations which contain potassium clavulanate should be made up in dry
conditions, preferably at 30% relative humidity or less, and the ingredients of
the formulation should be pre-dried where appropriate. Tablet formulations of
the invention should be stored in containers which are sealed against the
ingress of atmospheric moisture.
Tablet cores
may then be coated with a coating layer which may be applied form an aqueous or
an organic solvent system, preferably an aqueous solvent system, to provide
film coated tablets.
The invention
also provides a method for the manufacture of a tablet formulation as described
above comprising the steps of forming said first and second layers, and any
barrier layers and coating layer(s) which may be present.
In addition to
the layered tablet approach hereinbefore described, other types of tablet may
be used to provide an immediate release phase and a slow release phase, using
the excipients hereinbefore described but providing the phases in different
formats. Thus, the slow release phase may form the core of a tablet which is then
surrounded by an outer casing forming the immediate release phase, optionally
with an intermediate coating layer around the core and/or a final coating layer
around the outer casing (see WO 95/28148, SmithKline Beecham). The slow release
phase may also be provided as granules which are dispersed in a matrix of
amoxicillin and potassium clavulanate, the matrix forming the immediate release
phase (see WO 96/04908, SmithKline Beecham).
In a further
variant, a monolith modified release tablet may be prepared from slow release
compacted granules comprising amoxicillin, a diluent/compression aid such as
microcrystalline cellulose, and a pharmaceutically acceptable organic acid such
as a fruit acid, for instance citric acid (if amoxicillin is present as a soluble
salt thereof), or a release retarding polymer such as xanthan gum or a mixture
thereof, preferably a release retarding polymer (as hereinbefore described);
and immediate release compacted granules comprising amoxicillin and potassium
clavulanate (as hereinbefore described) or immediate release compacted granules
comprising amoxicillin and potassium clavulanate, for instance in a 2:1 ratio,
and further immediate release compacted granules comprising amoxicillin (as
described in WO 98/35672, SmithKline Beecham Laboratoires Pharmaceutiques), the
granules being combined with extragranular excipients to form tablets. Such
granules may also be processed into other pharmaceutical formulations, for
instance single dosage sachets, capsules or chewable tablets comprising a unit
dosage as hereinbefore described.
Chewable
tablets according to the present invention typically comprise a chewable base
formed from, for instance, mannitol, sorbitol, dextrose, fructose or lactose
alone or in combination. A chewable tablet may also comprise further
excipients, for instance, disintegrants, lubricants, sweetening agents,
colouring and flavouring agents. Such further excipients together will
preferably comprise from 3 to 10%, more preferably 4 to 8%, yet more preferably
4 to 7% by weight of the tablet. Disintegrants may be present in from 1 to 4%,
preferably from 1 to 3%, more preferably from 1 to 2% by weight of the tablet.
Representative disintegrants include crospovidone, sodium starch glycollate,
starches such as maize starch and rice strach, croscarmellose sodium and
cellulose products such as microcrystalline cellulose, microfine cellulose, low
substituted hydroxy propyl cellulose, either used singly or in admixture.
Preferably, the disintegrant is crospovidone. Lubricants may be present in from
0.25 to 2.0%, preferably from 0.5 to 1.2% by weight of the tablet. Preferred
lubricants include magnesium stearate. Preferably, the sweetening agent is an
artificial sweetening agent such as sodium saccharin or aspartame, preferably aspartame,
which may be present in from 0.5 to 1.5% by weight of the tablet. Preferably, a
tablet of the present invention is substantially free of sugar (sucrose).
Preferred flavouring agents include fruit flavours which may be natural or
synthetic, for instance peppermint, cherry and banana, or a mixture thereof.
Single dose
sachets according to the present invention comprise, in addition to the drug
substance, excipients typically included in a sachet formulation, such as a
sweetener, for instance aspartame, flavourings, for instance fruit flavours,
optionally a suspending agent such as xanthan gum, as well as silica gel, to
act as a desiccant.
Capsules
according to the present invention comprise, in addition to the drug substance,
excipients typically included in a capsule, for instance starch, lactose,
microcrystalline cellulose, magnesium stearate. It will be appreciated that due
to the hygroscopic nature of clavulanate, the use of materials such as gelatin
for forming the capsules should be avoided. Preferably, capsules are prepared
from materials such as HPMC or a gelatin/PEG combination.
In a further
embodiment, the slow release phase may be provided as a separate component, for
instance as a separate tablet, so that the unit dosage is provided as a combination
of a conventional component in which amoxicillin and potassium clavulanate are
released immediately, optionally with a conventional amoxicillin formulation
such as a tablet, and a further formulation, for instance a tablet, comprising
amoxicillin (and no potassium clavulanate) from which amoxicillin is released
slowly. The weight of potassium clavulanate and the combined weights of
amoxicillin in the conventional and slow release formulations will provide the
overall unit dosage. Thus, for instance a dosage of 2000/125 mg may be provided
by a combination of an existing 250/125 mg amoxicillin/potassium clavulanate
tablet and in combination with 2 slow release tablet comprising 875 mg of
amoxicillin, respectively. Furthermore, a dosage of 1750/125 mg may be provided
by an existing 875/125 mg tablet (as described in WO 95/28927, SmithKline
Beecham) in combination with a slow release tablet comprising 875 mg of
amoxicillin. Accordingly, in a further aspect, the present invention provides
for a kit comprising a conventional (immediate release) tablet comprising
amoxicillin and potassium clavulanate, optionally with a conventional
(immediate release) tablet comprising amoxicillin, and a slow release tablet
comprising amoxicillin (and no potassium clavulanate).
Representative
slow release amoxicillin tablets are described in PCT/IB00/00992.
Preferably, the
unit dosage forms of the present invention are packaged in containers that
inhibit the ingress of atmospheric moisture, for instance blister packs, tightly
closed bottles or desiccated pouch packs etc which are conventional in the art.
Preferably, bottles also include a desiccating material, to preserve the
clavulanate. Preferred bottles include HDPE bottles. Preferred blister packs
include cold-formed blister packs in which each blister may contain one tablet,
or two tablets, where the unit dosage is two tablets, for instance 2×1000/62.5
mg tablets, to improve patient compliance. Formulations of the present
invention are of use in treating bacterial infections. Accordingly, in a
further aspect, the present invention provides for a method of treating a
bacterial infection in a patient in need thereof which method comprises
administering an effective amount of a formulation as hereinbefore defined, to
a patient in need thereof, once daily, preferably about every 24 h.
Infections
amenable to treatment by the present method include those caused by the
commonly occurring β-lactamase producing respiratory pathogens, most
notably H influenzae and M catarrhalis, such
as respiratory tract infections, including community acquired pneumoniae (CAP),
acute exacerbations of chronic bronchitis (AECB) and acute bacterial sinusitis
(ABS). In addition, the present invention will be useful for treating
infections caused by S pneumoniae (including resistant S
pneumoniae). Most outpatient respiratory infections are caused by
either S pneumoniae and/or the β-lactamase producing bacteria
and are treated empirically so there is a continuing need for a method of
treatment, such as the present invention, that provides a spectrum of activity
that covers all such pathogens. The duration of therapy will generally between
7 and 14 days, typically 7 days for indications such as acute exacerbations of
chronic bronchitis but 10 days for acute bacterial sinusitis. Typically, the
dosages regimens are designed for adult patients, rather than paediatric
patients.
The modified
release formulations of the present invention are intended for use in a bid
dosing regimen. It will be appreciated that whilst such a bid dosing regimen is
recognised to offer the advantage of greater convenience and therefore likely
greater compliance, in some instances, it may be preferred to use administer
the same total daily dosage but in a tid regimen, that is in equally divided
doses every 8 hours, rather than every 12 hours.
Accordingly, in
a further aspect, the present invention provides a unit dosage of amoxicillin
and potassium clavulanate which comprises from 100 to 150 mg of potassium
clavulanate and from 1200 to 1700 mg of amoxicillin; which formulation is a
modified release formulation comprising an immediate and a slow release phase
and in which all of the potassium clavulanate and from 0 to 50% of the
amoxicillin is in an immediate release phase and from 50 to 100% of the
amoxicillin is in a slow release phase; such that the mean T>MIC is at least
2.6 h for an MIC of 8 μg/ml.
Typically, the unit dosage comprises about 125 mg of potassium clavulanate.
Representative
unit dosages include 1350/125, and 750/125 mg of amoxicillin and potassium
clavulanate, respectively. A preferred dosage is 675/125 mg of amoxicillin and
potassium clavulanate.
Such a dosage
may be provided by one or two modified release pharmaceutical formulations, in
particular two bilayer or monolith swallow tablets each comprising half the
dosage (for instance, 600 to 850 mg amoxicillin, more preferably 625 to 750 mg
amoxicillin, and 62.5 mg potassium clavulanate) or a larger chewable tablet or
single dose sachet comprising the entire unit dosage (for instance, 1200 to
1700 mg amoxicillin, more preferably 1250 to 1500 mg amoxicillin, and 125 mg
potassium clavulanate), by appropriate adjustment to the corresponding
formulations hereinbefore described. A representative tablet comprises 750 mg
of amoxicllin and 62.5 mg of potassium clavulanate, having a nominal ratio of
amoxicllin:potassium clavulanate of 12:1. Such a tablet may comprise from 300
to 450 mg of amoxicillin in the immediate release phase and from 300 to 450 mg
of amoxicllin in the slow release phase, to make a total of 750 mg amoxicillin.
A further representative tablet comprises 675 mg of amoxicllin and 62.5 mg of
potassium clavulanate. Such a tablet may comprise from 250 to 400 mg of
amoxicillin in the immediate release phase and from 250 to 400 mg of amoxicllin
in the slow release phase, to make a total of 675 mg amoxicillin.
It will be appreciated that the methods and formulations hereinbefore described for amoxicillin and clavulanate are also applicable to amoxicillin alone, with no clavulanate, particularly for treating infections where β-lactamase producing pathogens are not implicated, for instance infections caused by the organism Streptococcus pyogenes, such acute bacterial tonsillitis and/or pharyngitis. The present invention also all such uses and formulations of amoxicillin as the sole agent.
All
publications and references, including but not limited to patents and patent
applications, cited in this specification are herein incorporated by reference
in their entirety as if each individual publication or reference were
specifically and individually indicated to be incorporated by reference herein
as being fully set forth. Any patent application to which this application
claims priority is also incorporated by reference herein in its entirety in the
manner described above for publications and references.
EXAMPLE 11000
mg Monolith Tablet
mg/tablet % Crystallised
Sodium Amoxicillin1 824.2 51.51 Amoxicillin
Trihydrate2 290.7 18.17 Clavulanate Potassium3 76.2 4.76 Dried
Microcrystalline Cellulose 165.9 10.37 Magnesium
Stearate 23.0 1.44 Sodium Starch
glycollate 80.0 5.00 Colloidal silicon
dioxide 6.3 0.39 Citric
acid 133.7 8.36 Total 1600 100.0 1adjusted
for potency of the amoxicillin component and corresponding to 750 mg of
amoxicillin 2adjusted for potency of the amoxicillin component
and corresponding to 250 mg of amoxicillin 3adjusted for
potency of the clavulanate potassium component and corresponding to 62.5 mg of
clavulanate potassium
In further
detail, immediate release granules were prepared thus: containers were charged
with dried microcrystalline cellulose (1), amoxicillin trihydrate (2)
and (5) (in 1:1 ratio), a potassium clavulanate/dried microcrystalline
cellulose blend (1:1) and magnesium stearate (about 50% of total) (4).
The contents of containers (1) and (2) were passed through a
mesh, milled in a “Fitzmill” operating at 1500 rpm and blended with the
contents of container (3). The contents of container (4) were
then screened and milled and blended with the initial blend and then blended
with the contents of container (5) which had gone through a preliminary
screening and milling step. This blend was then subjected to roller compaction
using a Chilsonator operating at a pressure of 1000 psi±200 psi and the product
milled and screened through a vibratory screen with 14 and 80 meshes, to
provide immediate release granules.
The immediate
release and slow release granules were blended with the remaining excipients
(magnesium stearate, dried microcrystalline cellulose) and then compressed into
a monolith tablet on a standard tabletting machine.
Finally, the
tablet cores were coated with an aqueous film coating in a 60 inch coating pan,
operating on a 300 kg sub-batch. The pan was equipped with 4 spray guns and
rotated at 3 to 5 rpm. The inlet air was dehumidified with the temperature in
the range 56 to 60° C. whilst the exhaust air humidity was in the range 4 to
12% and the temperature in the range 43 to 50° C. The spray rate was 80 to 120
ml/min/spray gun.
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