U.S. patent application number 11/614479 was filed with the patent office on 2007-05-10 for compositions and methods of treatment comprising amoxicillin and potassium clavulante with xanthan.
This patent application is currently assigned to Beecham Pharmaceuticals (pte) Limited. Invention is credited to Creighton P. Conley, John A. Roush, Kevin H. Storm.
Application Number | 20070104784 11/614479 |
Document ID | / |
Family ID | 32913310 |
Filed Date | 2007-05-10 |
United States Patent
Application |
20070104784 |
Kind Code |
A1 |
Storm; Kevin H. ; et
al. |
May 10, 2007 |
COMPOSITIONS AND METHODS OF TREATMENT COMPRISING AMOXICILLIN AND
POTASSIUM CLAVULANTE WITH XANTHAN
Abstract
Bacterial infections may be treated using a high dosage regimen
of amoxicillin and potassium clavulanate. Preferably, the dosage is
provided by a bilayer tablet.
Inventors: |
Storm; Kevin H.; (Bristol,
TN) ; Conley; Creighton P.; (Bristol, TN) ;
Roush; John A.; (Kingsport, TN) |
Correspondence
Address: |
GLAXOSMITHKLINE;Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
Beecham Pharmaceuticals (pte)
Limited
|
Family ID: |
32913310 |
Appl. No.: |
11/614479 |
Filed: |
December 21, 2006 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10870818 |
Jun 17, 2004 |
|
|
|
11614479 |
Dec 21, 2006 |
|
|
|
09971560 |
Oct 5, 2001 |
6783773 |
|
|
10870818 |
Jun 17, 2004 |
|
|
|
09689483 |
Oct 12, 2000 |
|
|
|
09971560 |
Oct 5, 2001 |
|
|
|
09544019 |
Apr 6, 2000 |
6878386 |
|
|
09689483 |
Oct 12, 2000 |
|
|
|
60129074 |
Apr 13, 1999 |
|
|
|
60150727 |
Aug 25, 1999 |
|
|
|
60159813 |
Oct 15, 1999 |
|
|
|
Current U.S.
Class: |
424/464 ;
424/468; 514/192; 514/210.09 |
Current CPC
Class: |
A61K 9/209 20130101;
A61K 9/2866 20130101; A61K 31/407 20130101; A61K 9/2013 20130101;
A61K 31/43 20130101; A61K 45/06 20130101; A61K 9/205 20130101; A61K
31/43 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/464 ;
424/468; 514/192; 514/210.09 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 9/22 20060101 A61K009/22; A61K 31/43 20060101
A61K031/43; A61K 31/407 20060101 A61K031/407 |
Claims
1 to 22. (canceled)
23. A composition comprising amoxicillin and potassium clavulanate
in a dosage of 2000 mg of amoxycillin and 125 mg of potassium
clavulanate, wherein the composition is in a solid form and
comprises a first release phase and a second release phase; the
first release phase comprising potassium clavulanate and a first
part of amoxicillin; and the second release phase comprising a
second amount of amoxicillin in the form of a soluble salt at about
60-80% of the second phase a pharmaceutically acceptable organic
acid in a molar ratio of 50:1 to 1:5 (amoxicillin to organic acid,
and a reduced amount of pharmaceutically acceptable release
retarding polymer which is xanthan gum at about 1-5% of the second
phase; wherein the composition provides a mean maximum plasma
concentration (Cmax) of amoxicillin of at least 12 .mu.g/ml.
24-68. (canceled)
69. A composition according to claim 23 wherein the xanthan gum is
pharmaceutical grade xanthan gum, 200 mesh.
70. A composition according to claim 23 wherein the amoxicillin in
the first release phase is amoxicillin trihydrate.
71. A composition according to claim 23 wherein the soluble salt of
amoxicillin in the second release phase is sodium amoxicillin.
72. A composition according to claim 71 wherein the sodium
amoxicillin is crystallized sodium amoxicillin.
73. A composition according to claim 23 wherein the composition
provides an Area under the Curve (AUC) value of amoxicillin which
is at least 80% of that of the same amount if taken as an immediate
release formulation over the same dosage period.
74. A composition according to claim 23 wherein the composition
provides a mean plasma concentration of amoxicillin of at least 4
.mu.g/ml for at least 4.4 hours
75. A composition according to claim 23 wherein the ratio of
amoxicillin in the first and second release phases is from 3:1 to
1:3.
76. A composition according to claim 23 wherein the ratio of
amoxicillin in the first and second release phases is from 3:1 to
2:3.
77. A composition according to claim 23 wherein the ratio of
amoxicillin in the first and second release phases is from 2:1 to
2:3.
78. A composition according to claim 23 wherein the ratio of
amoxicillin in the first and second release phases is from 3:2 to
1:1.
79. A composition according to claim 23 wherein the solid form is a
tablet.
80. A composition according to claim 79 wherein the tablet is a
bilayer tablet.
81. A composition according to claim 23 wherein the first release
phase comprises essentially all the potassium clavulanate.
82. A composition according to claim 23 wherein the release of
amoxicillin has a biphasic profile.
83. A method for treating a bacterial infection in a patient in
need thereof comprising administering to said patient an effective
amount of a formulation according to claim 23.
84. A method according to claim 83 in which the bacterial infection
is caused by at least one of the organisms S. pneumoniae, H.
influenzae, and M. catarrhalis.
85. A method according to claim 84 wherein the S. pneumoniae are
Drug Resistant S. pneumoniae and Penicillin Resistant S. pneumoniae
organisms.
86. A method according to claim 83 wherein the bacterial infection
is a respiratory tract infection.
87. A method according to claim 86 wherein the respiratory tract
infection is community acquired pneumoniae (CAP), acute
exacerbation of chronic bronchitis (AECB), or acute bacterial
sinusitis (ABS).
88. A method according to claim 83 wherein the formulation is
administered over 7 to 14 days.
89. The composition of claim 23 wherein the pharmaceutically
acceptable organic acid is in a molar ratio of 20:1 to 1:2
(amoxicillin to organic acid).
90. The composition of claim 23 wherein the pharmaceutically
acceptable organic acid is selected from mono-carboxylic acids and
poly-carboxylic acids having from 2 to 25 carbon atoms, monocyclic
and polycyclic aryl acids, and monohydrogen, dihydrogen metal salts
of multi-valent acids.
91. The composition of claim 90 wherein the pharmaceutically
acceptable organic acid is selected from 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, and citric acid.
92. The composition of claim 91 wherein the pharmaceutically
acceptable organic acid is citric acid.
93. The composition of claim 92 wherein the sodium amoxicillin and
citric acid are in a molar ratio of 20:1 to 1:2.
94. The composition of claim 93 wherein the sodium amoxicillin is
about 438 mg.+-.5%, citric acid is about 78 mg.+-.10%, and xanthan
gum is about 2% by weight.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a novel method of treatment using
amoxicillin and potassium clavulanate and for novel formulations,
in particular tablet formulations, for use in such methods.
BACKGROUND OF THE INVENTION
[0002] Amoxicillin and potassium clavulanate are respectively a
known .beta.-lactam antibiotic and a known .beta.-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.
[0003] 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 12h, 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.
[0004] 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. Furthermore, it
is suggested that the preferred dosage of 1750/125 mg may be
provided as two tablets, the first comprising 875/125 mg
amoxicillin and clavulanic acid and the second 875 mg amoxicillin.
The 14:1 ratio is said to be useful for the empiric treatment of
bacterial infection potentially caused by drug resistant S
pneumoniae (DRSP). This patent application also describes
paediatric formulations comprising amoxicillin and clavulanate in a
14:1 ratio, for administering amoxicillin dosages of 90 mg/kg/day.
Data suggest that such a dosage may provide antibiotic
concentrations sufficient to eradicate DRSP with
amoxicillin+/-clavulanic acid MICs .ltoreq.4 .mu.g/ml (Bottenfield
et al, Pediatr Infect Dis J, 1998, 17, 963-8).
[0005] 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 .beta.-lactamase mediated.
[0006] 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).
[0007] 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 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.
[0008] 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.
[0009] 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 intragastric 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 .mu.g/ml.
[0010] It has therefore, been determined that there is a continuing
need to provide new dosage regimens for amoxicillin/clavulanate
which are effective against more resistant bacteria.
SUMMARY OF THE INVENTION
[0011] The present invention relates to a method of treating
bacterial infections in humans which comprises administering
thereto a therapeutically effective amount of amoxicillin and
potassium clavulanate such that the amount of amoxicillin is in the
range 1900 to 2600 mg and the amount of potassium clavulanate is
such that the weight ratio of amoxicillin to clavulanate is from
about 2:1 to 20: 1, an at a dosage regiment/interval of about 12
hours. Suitably, the infection is caused by the organisms S
pneumoniae (including Drug Resistant and Penicillin Resistant S
pneumoniae), H influenzae and/or M catarrhalis.
[0012] The present invention also relates to a modified release
pharmaceutical formulation comprising amoxicillin and potassium
clavulanate in the ratio from 2:1 to 20:1 in which all of the
potassium clavulanate and a first part of amoxicillin are
formulated with pharmaceutically acceptable excipients which allow
for immediate release of the potassium clavulanate and the first
part of amoxicillin, to form an immediate release phase, and
further comprising a second part of amoxicillin formulated with
pharmaceutically acceptable excipients which allow for slow release
of the second part of amoxicillin, to form a slow release
phase.
[0013] The present invention also relates to an immediate release
pharmaceutical tablet formulation comprising 1000 mg.+-.5%
amoxicillin and 62.5 mg.+-.5% potassium clavulanate, in a nominal
ratio of about 16:1, in combination with pharmaceutically
acceptable excipients or carriers.
[0014] The present invention also relates to an immediate release
pharmaceutical formulation in the form of a single dose sachet
comprising 2000, 2250 or 2500 mg.+-.5% amoxicillin and 125 mg.+-.5%
potassium clavulanate, in a nominal ratio of about 16:1, 18:1 or
20:1, respectively, or the corresponding half quantities thereof,
in combination with pharmaceutically acceptable excipients or
carriers.
[0015] Other suitable modified or immediate release formulations
are described herein in greater detail.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 shows the structure of various types of layered
tablets of the present invention, in particular the structure of
substantially cylindrical compressed tablets are shown in
longitudinal section. In
[0017] FIG. 1A, shows a tablet comprising a first layer (1) and a
second layer (2), without any barrier layer or coating layer.
[0018]
[0019] FIG. 1B, shows a tablet comprising a first layer (1), a
second layer (2), and a barrier layer (3) sandwiched between the
first and second layers (1) and (2).
[0020]
[0021] FIG. 1C, shows a tablet comprising a first layer (1), a
second layer (2), and a barrier layer (3) located on the end face
of the second layer (2).
[0022] FIG. 1D, shows a tablet comprising a first layer (1), a
second layer (2), a barrier layer (3) sandwiched between the first
and second layers (1) and (2), and a coating layer (4) which partly
covers the tablet. The dotted line shows the possibility of the
coating layer (4A) covering the entire tablet.
[0023] FIG, 1E, shows a tablet comprising a first layer (1) a
second layer (2), and a third layer (3) intermediate between the
first and second layers (1) and (2). All three of these layers (1),
(2) and (3) include active material content.
[0024] FIG. 2 demonstrates modified release tablets prepared
according to the process flow diagram shown in FIG. 2. In brief,
immediate and modified release blends are prepared which involve
initial sieving and milling, as indicated, before roller compaction
in a Chilsonater and further milling, sieving and blending.
[0025] FIG. 3 demonstrates the dissolution profile for tablets of
Examples 1 and 2.
[0026] FIG. 4 demonstrate the pharmacokinetic profiles of Study
A
[0027] FIG. 5 demonstrates the pharmacokinetic profile for
amoxicillin plasma concentration for Study B (in which A is
formulation V, B is formulation VI, D is formulation VIII).
DETAILED DESCRIPTION OF THE INVENTION
[0028] 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 half life of
the drug. Furthermore, the rapid elimination of amoxicillin
(excretion half-life is 1.3 hours) makes it difficult to maintain
serum levels as clearance from the body is very rapid.
[0029] 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 IV 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.
[0030] 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.
[0031] Furthermore, U.S. Pat. No. 5,051,262 (Elan Corp) describes
the incorporation of an organic acid into a modified release
formulation, to provide a microenvironment in which the locally
modified pH helps to protect the active ingredient from
degradation.
[0032] Of concern is the increasing resistance of pathogenic
organisms, such as those found in respiratory tract infections, to
anti-infective agents such as amoxicillin/potassium clavulanate, in
particular drug resistant S pneumoniae. Increased resistance to
penicillin of S pneumoniae (due to modified penicillin binding
proteins) is developing around the world and is affecting clinical
outcomes (see for instance Applebaum P C, Ped Inf Dis J, 1996, 15
(10), 932-9). These penicillin resistant S pneumoniae (PRSP) have
also been termed "DRSP" as they often exhibit decreased
susceptibility not only to penicillin but also to a wider range of
antimicrobial classes, including macrolides, azalides,
beta-lactams, sulfonamides and tetracyclines. Amoxicillin (with or
without clavulanate), along with some of the newer quinolones, has
remained among the most active oral drugs against the increasingly
resistant isolates of S pneumoniae, based on both MIC levels and
pharmacokinetic properties of these compounds. Resistance rates
(and MICs) have however continued to increase. 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
.ltoreq.0.06 .mu.g/ml, intermediate resistance is defined as an MIC
in the range 0.12 to 1.0 .mu.g/ml whilst penicillin resistance is
defined as an MIC of .gtoreq.2 .mu.g/ml. Furthermore, it is found
that some 10% of pneumococci now have an amoxicillin MIC of 2
.mu.g/ml.
[0033] There is consequently a need to provide new formulations of
amoxicillin/clavulanate that combine the known safety profile and
broad spectrum with improved activity against DRSP, including PRSP,
with higher MICs in empiric treatment of respiratory infections
where S pneumoniae, H influenzae and M catarrhalis are likely
pathogens.
[0034] For .beta.-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
a variety of .beta.-lactams, a bacteriological cure rate of 85 to
100% is achieved when serum concentrations exceed the MIC for more
than about 40% of the dosing interval (Craig and Andes, Ped Inf Dis
J, 1996, 15, 255-259). For a 12 hour dosing interval, this is about
4.8 hours.
[0035] 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 C.sub.max 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.
[0036] In a clinical study using the existing Augmentin 875/125 mg
tablet, it was found that, when dosed at 12 hour intervals, the
time above MIC was about 40% for an MIC of 2 .mu.g/ml but only
about 30% for an MIC of 4 .mu.g/ml. The existing Augmentin 875/125
mg tablet has a C.sub.max value of 11.6.+-.2.8 .mu.g/ml (Physicians
Desk Reference, Medical Economics Co, 52 edition, 1998, 2802).
[0037] Based on the foregoing considerations, there is a continuing
need to provide new dosage regimens for amoxicillin/clavulanate
giving optimised pharmacokinetic profiles for amoxicillin whilst
not compromising the bioavailability of clavulanate, so that
therapy is maximised, particularly against more resistant bacteria
whilst the (further) development of resistance is minimised. It has
now been found that such can be achieved using higher dosages of
amoxicillin than previously contemplated.
[0038] Accordingly, in a first aspect, the present invention
provides for a method of treating bacterial infections in humans
which comprises orally administering thereto a therapeutically
effective amount of amoxicillin and potassium clavulanate such that
the amount of amoxicillin is in the range 1900 to 2600 mg,
preferably 1950 to 2550 mg, and the amount of potassium clavulanate
is such that the weight ratio of amoxicillin to clavulanate is from
2:1 to 20:1, preferably 7:1 to 20:1, more preferably 14:1 to 20:1,
at intervals of about 12 hours (hereinafter "h").
[0039] Preferably, the dosage regimen provides a mean plasma
concentration of amoxicillin of 4 .mu.g/mL for at least 4.4 h,
preferably at least 4.6 h, more preferably at least 4.8 h, most
preferably for about 6 h or longer.
[0040] More preferably, the dosage regimen provides a mean plasma
concentration of amoxicillin of 8 .mu.g/ml for at least 4.4 h, more
preferably at least 4.6 h, most preferably at least 4.8 h.
[0041] Preferably, the dosage regimen provides a mean maximum
plasma concentration (C.sub.max) of amoxicillin which is at least 8
.mu.g/mL, preferably at least 12 .mu.g/mL, yet more preferably at
least 14 .mu.g/mL, most preferably at least 16 .mu.g/mL.
[0042] 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 light meal.
[0043] In a further aspect, the present invention provides for a
method of treating bacterial infections in humans which comprises
administering thereto a therapeutically effective amount of
amoxicillin and potassium clavulanate such that the amount of
amoxicillin is in the range 1400 to 1900 mg, preferably 1500 to
1900 mg, and the amount of potassium clavulanate is such that the
weight ratio of amoxicillin to clavulanate is from 2:1 to 14:1,
preferably 7:1 to 14:1, more preferably 12:1 to 14:1, at intervals
of about 12 h, such that the dosage regimen provides a mean plasma
concentration of amoxicillin of 4 .mu.g/mL for at least 4.4 h,
preferably at least 4.6 h, more preferably at least 4.8 h, most
preferably for about 6 h or longer; more preferably, a mean plasma
concentration of amoxicillin of 8 .mu.g/ml for at least 4.4 h, more
preferably at least 4.6 h, most preferably at least 4.8 h, and a
mean maximum plasma concentration (C.sub.max) of amoxicillin which
is at least 8 .mu.g/mL, preferably at least 12 .mu.g/mL, yet more
preferably at least 14 .mu.g/mL, most preferably at least 16
.mu.g/mL.
[0044] Bacterial infections amenable to the present invention
include infections caused by the organisms S pneumoniae (including
Drug Resistant S pneumoniae (DRSP), for instance Penicillin
Resistant S pneumoniae (PRSP)), and/or the .beta.-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), where the
higher break points achievable through the improved pharmacokinetic
profile will be especially advantageous compared to existing
antibacterial agents. Most outpatient respiratory infections are
caused by either S pneumoniae and/or the .beta.-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.
[0045] 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.
[0046] 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.
[0047] In a first embodiment, a dosage of amoxicillin of from 1900
to 2600 mg and a corresponding amount of potassium clavulanate may
delivered from an immediate release formulation. Accordingly, in a
further aspect, the present invention provides for method of
treating bacterial infections in humans which comprises
administering thereto a therapeutically effective amount of
amoxicillin and potassium clavulanate such that the amount of
amoxicillin is in the range 1900 to 2600, preferably 1950 to 2550
mg, and the amount of potassium clavulanate is such that the weight
ratio of amoxicillin to clavulanate is from 2:1 to 20:1, preferably
7:1 to 20:1, more preferably 14:1 to 20:1, at intervals of about 12
h, wherein the dosage is delivered from an immediate
formulation.
[0048] 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.
[0049] Representative dosages include 2000/125, 2250/125 and
2500/125 mg of amoxicillin and potassium clavulanate, respectively.
A preferred dosage is 2000/125 mg of amoxicillin and potassium
clavulanate.
[0050] The dosage in an immediate release formulation may be
provided as a single tablet, for instance a dispersible tablet, a
chewable tablet which may also be, effervescent and/or dispersible,
a single dose capsule or a single dosage sachet, comprising, for
instance, 2000, 2250 or 2500 mg amoxicillin and 125 mg potassium
clavulanate. Alternatively, the dosage may be made up of a number
of smaller tablets or capsules, for instance, 2, 3 or 4, some of
which may be the same and some of which may comprise amoxicillin
only and no potassium clavulanate. Representative such smaller
tablets include swallow tablets, dispersible tablets and chewable
tablets which may also be effervescent and/or dispersible. Thus,
for instance, a dosage of 2000 mg amoxicillin and 125 mg potassium
clavulanate may be provided by a combination of three tablets each
comprising 500 mg amoxicillin and one tablet comprising 500 mg
amoxicillin and 125 mg potassium clavulanate. Alternatively, such a
dosage may be provided by two tablets each comprising 1000/62.5 mg
amoxicillin/potassium clavulanate. In addition, a dosage of 2250 mg
amoxicillin and 125 mg potassium clavulanate may be provided by a
combination of four tablets comprising 500 mg amoxicillin and one
tablet comprising 250 mg amoxicillin and 125 mg potassium
clavulanate or two tablets comprising 875 mg amoxicillin and one
tablet comprising 500 mg amoxicillin and 125 mg potassium
clavulanate. Furthermore, a dosage of 2500 mg amoxicillin and 125
mg potassium clavulanate may be provided by a combination of four
tablet comprising 500 mg amoxicillin and one tablet comprising 500
mg amoxicillin and 125 mg potassium clavulanate. Tablets comprising
500 and 875 mg amoxicillin and 250/125, 500/125 and 875/125 mg
amoxicillin/potassium clavulanate are already commercially
available.
[0051] It will be appreciated that immediate release tablets
comprising 1000/62.5 mg are novel. Accordingly, in a further
aspect, the present invention provides for an immediate release
pharmaceutical tablet formulation comprising 1000 mg.+-.5%
amoxicillin and 62.5 mg.+-.5% potassium clavulanate, in a nominal
ratio of about 16:1, in combination with pharmaceutically
acceptable excipients or carriers. Immediate release tablets
comprising 1000/62.5 mg can be readily prepared by adapting
compositions previously described for 875/125 and 1000/125 mg
tablets (see for instance, WO 95/28927 and WO 98/35672, SmithKline
Beecham).
[0052] It will also be appreciated that immediate release single
dosage sachets comprising 2000/125 mg, 2250/125 mg or 2500/125 mg,
or the corresponding half quantities thereof, are novel.
Accordingly, in a further aspect, the present invention provides
for an immediate release pharmaceutical formulation in the form of
a single dose sachet comprising 2000, 2250 or 2500 mg.+-.5%
amoxicillin and 125 mg.+-.5% potassium clavulanate, in a nominal
ratio of about 16:1, 18:1 or 20:1, respectively, or the
corresponding half quantities thereof, in combination with
pharmaceutically acceptable excipients or carriers. Such sachets
can be readily prepared by adapting compositions previously
described for 875/125 and 1000/125 mg sachets (see for instance, WO
92/19277 and WO 98/35672, SmithKline Beecham).
[0053] It will be further appreciated that immediate release
chewable tablets comprising 2000, 2250 or 2500/125 mg are novel.
Accordingly, in a further aspect, the present invention provides
for an immediate release pharmaceutical formulation in the form of
a chewable, optionally effervescent, tablet comprising 2000, 2250,
or 2500 mg amoxicillin and 125 mg.+-.5% potassium clavulanate, in a
nominal ratio of about 16:1, 18:1 or 20:1, respectively, or the
corresponding half quantities thereof, in combination with a
chewable base and, if effervescent, an effervescent couple, and
other pharmaceutically acceptable excipients or carriers. Such
chewable tablets can be readily prepared by adapting compositions
previously described for chewable tablets comprising amoxicillin
and potassium clavulanate (see for instance, EP-A-0 396 335,
Beecham Group and WO 98/35672, SmithKline Beecham).
[0054] In a second embodiment, a dosage of amoxicillin of from 1900
to 2600 mg and a corresponding amount of potassium clavulanate may
be delivered from a modified release formulation. Accordingly, in a
further aspect, the present invention provides for method of
treating bacterial infections in humans which comprises
administering thereto a therapeutically effective amount of
amoxicillin and potassium clavulanate such that the amount of
amoxicillin is in the range 1900 to 2600 mg, preferably 1950 to
2550 mg, and potassium clavulanate is present in a pro rata amount
such that the weight ratio of amoxicillin to potassium clavulanate
is from 2:1 to 20:1, preferably 7:1 to 20:1, more preferably 14:1
to 20:1, at intervals of about 12 h, in which the dosage is
delivered from a modified release formulation.
[0055] In a third embodiment, a dosage of amoxicillin of from 1400
to 1900 mg and a corresponding amount of clavulanate may be
delivered from the modified release formulation. Accordingly, in a
further aspect, the present invention provides for method of
treating bacterial infections in humans which comprises
administering thereto a therapeutically effective amount of
amoxicillin and potassium clavulanate such that the amount of
amoxicillin is in the range 1400 to 1900 mg, preferably 1500 to
1900 mg, and potassium clavulanate is present in a pro rata amount
such that the weight ratio of amoxicillin to clavulanate is from
2:1 to 14:1, preferably 7:1 to 14:1, more preferably 12:1 to 14:1,
at intervals of about 12 h, in which the dosage is delivered from a
modified release formulation.
[0056] As used herein, the term "modified release" refers to a
release of drug substance from a pharmaceutical formulation which
is at a slower rate than from an immediate release formulation such
as a conventional swallow tablet or capsule and may include an
immediate release phase and a slow release phase. Modified release
formulations are well known in the art, see for instance Remington:
The Science and Practice of Pharmacy, Nineteenth Edn, 1995, Mack
Publishing Co, Pennsylvania, USA.
[0057] 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
absorbed therefrom, 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.
[0058] Typically, a dosage will provide 125 mg of potassium
clavulanate, the amount approved in existing regimens where a
lesser amount of amoxicillin is administered.
[0059] Representative modified release dosages include 1500/125,
1750/125 and 2000/125 mg of amoxicillin and potassium clavulanate,
respectively. A preferred dosage is 2000/125 mg of amoxicillin and
potassium clavulanate.
[0060] The dosage in a modified release formulation 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. A preferred tablet
comprises 1000/62.5 mg amoxicillin/potassium clavulanate.
[0061] The dosage in an 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 or a dispersible
tablet. A single unit dosage may also be conveniently provided as a
single dosage sachet. It will be appreciated that the dosage may
also be provided as a number of smaller non-swallow tablets or
sachets, for instance 2.times.1000/62.5 mg or 4 .times.500/32.25 mg
amoxicillin/potassium clavulanate.
[0062] Preferably, in the modified release formulation, all the
potassium clavulanate is provided in an immediate release phase
whilst amoxicillin is provided in both an immediate release and a
slow release phase.
[0063] Accordingly, in a further aspect, the present invention
provides for a modified release pharmaceutical formulation
comprising amoxicillin and potassium clavulanate in the ratio from
2:1 to 20:1, preferably 7:1 to 20:1, more preferably 12:1 to 20:1,
most preferably 14:1 to 16:1 in which all of the potassium
clavulanate and a first part of amoxicillin are formulated with
pharmaceutically acceptable excipients which allow for immediate
release of the potassium clavulanate and the first part of
amoxicillin, to form an immediate release phase, and further
comprising a second part of amoxicillin formulated with
pharmaceutically acceptable excipients which allow for slow release
of the second part of amoxicillin, to form a slow release
phase.
[0064] 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.
[0065] Preferably, the modified release formulation has an in vitro
dissolution profile in which 45 to 65%, preferably 45 to 55% of the
amoxicillin content is dissolved within 30 min; further in which 50
to 75%, preferably 55 to 65% of the amoxicillin content is
dissolved within 60 min; further in which 55 to 85%, preferably 60
to 70% of the amoxicillin content is dissolved within 120 min;
further in which 70 to 95%, preferably 75 to 85% of the amoxicillin
content is dissolved within 180 min; and further in which 70 to
100%, preferably 75 to 100% of the amoxicillin content is dissolved
within 240 min. In comparison, a conventional, immediate release
amoxicillin tablet dissolves essentially completely within 30
minutes. The dissolution profile may be measured in a standard
dissolution assay, for instance <711 > Dissolution Test,
Apparatus 2, provided in USP 23, 1995, at 37.0.+-.0.5.degree. C.,
using deionised water (900 mL) and a paddle speed of 75 rpm.
[0066] 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
C.sub.max value, supplemented by a further contribution from the
slow release phase, to extend the T>MIC parameter to an
acceptable value.
[0067] Preferably, the modified formulation provides an "Area Under
the 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.
[0068] 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.
[0069] Representative modified release formulations include a
tablet, including swallow tablets, dispersible tablets, chewable
tablets which may also be effervescent and/or dispersible and, a
capsule, granules or a sachet, typically a swallow tablet.
[0070] Representative modified release formulations having an
immediate and a slow release phase provide a unit dosage in the
range 700 to 1300 mg, preferably, 950 to 1300 mg, amoxicillin, for
instance unit dosages of 1000, 875 and 750/62.5 mg
amoxicillin/clavulanate. Alternatively, and where the physical size
of the dosage form is not a problem, the unit dosage may provide
the whole dosage, for instance a single dosage sachet, chewable
tablet or dispersible tablet may comprise 1400 to 2600 mg,
preferably, 1900 to 2600 mg, amoxicillin, for instance unit dosages
of 2000, 1750 and 1500/125 mg amoxicillin/clavulanate. It will be
appreciated that such 1000, 875 and 750/62.5 mg formulations are
novel.
[0071] Accordingly, in a further aspect, the present invention
provides for a pharmaceutical formulation having an immediate
release phase and a slow release phase and comprising:
[0072] (a) a unit dosage in the range 700 to 1300 mg, preferably,
950 to 1300 mg, amoxicillin, and a corresponding amount of
potassium clavulanate, in a nominal ratio of about 16:1, 14;1 or
12:1, for instance unit dosages of 1000, 875 or 750 mg.+-.5%
amoxicillin and 62.5 mg.+-.5% potassium clavulanate, respectively,
or
[0073] (b) a unit dosage in the range 1400 to 2600 mg, preferably,
1900 to 2600 mg, amoxicillin, and a corresponding amount of
potassium clavulanate, in a nominal ratio of about 16:1, 14;1 or
12:1, for instance unit dosages of 2000, 1750 or 1500 mg.+-.5%
amoxicillin and 62.5 mg.+-.5% potassium clavulanate, respectively,
in combination with pharmaceutically acceptable excipients or
carriers.
[0074] Preferably, the ratio of amoxicillin in the immediate and
slow release phases is from 3:1 to 1:3, more preferably, from 2:1
to 2:3, yet more preferably 3:2 to 1:1. Representative ratios
include about 2:1, 9:7 or 1:1. It is found useful to employ an
excess of amoxicillin in the immediate release phase, to ensure an
adequate C.sub.max value.
[0075] In the modified release formulations of the present
invention, the portion of amoxicillin which is released immediately
may be provided as amoxicillin trihydrate or an alkaline salt
thereof, for instance potassium or sodium amoxicillin, preferably,
(crystallised) sodium amoxicillin or a mixture thereof, preferably
amoxicillin trihydrate; whilst the portion of amoxicillin which is
released slowly is provided as amoxicillin trihydrate or an
alkaline salt thereof, for instance potassium or (crystallised)
sodium amoxicillin or a mixture thereof, preferably (crystallised)
sodium amoxicillin.
[0076] Preferably, the modified release formulation is a tablet. In
a preferred modified release tablet comprising 1000 mg amoxicillin
and 62.5 mg potassium clavulanate, the immediate release phase
comprises about 563 mg.+-.5% amoxicillin trihydrate and about 62.5
mg.+-.5% of potassium clavulanate and the slow release phase about
438 mg.+-.5% of amoxicillin, preferably as (crystallised) sodium
amoxicillin.
[0077] In a representative modified release tablet of the present
invention, the immediate release phase comprises about 438 mg
amoxicillin, preferably amoxicillin trihydrate and about 62.5 mg of
potassium clavulanate and the slow release phase about 438 mg of
amoxicillin, preferably (crystallised) sodium amoxicillin,
providing overall an 875/62.5 mg (14:1) tablet.
[0078] In a further representative tablet of the present invention,
the immediate release phase comprises about 500 mg amoxicillin and
about 62.5 mg of potassium clavulanate and the slow release phase
about 250 mg of amoxicillin, preferably (crystallised) sodium
amoxicillin, providing overall a 750/62.5 mg (12:1) tablet.
[0079] It will be appreciated that the use of a mixture of
amoxicillin trihydrate and sodium amoxicillin is more generally
applicable to other pharmaceutical formulations comprising
amoxicillin and potassium clavulanate.
[0080] Accordingly, in a further aspect, the present invention
provides for a pharmaceutical formulation comprising amoxicillin
and potassium clavulanate in a ratio of from 1:1 to 30:1,
preferably 2:1 to 20:1, more preferably 12:1 to 20:1, yet more
preferably 14:1 to 16:1, in which amoxicillin is provided as a
mixture of amoxicillin trihydrate and sodium amoxicillin in a ratio
of from 3:1 to 1:3, more preferably from 2:1 to 2:3, yet more
preferably 3:2 to 1:1. Preferably, sodium amoxicillin is
crystallised sodium amoxicillin. Representative formulation types
include tablets, including immediate release and modified release
tablets as herein described, as well as other solid dosage forms
such as capsules, single dosage sachets and granules.
Representative tablets include those comprising 1000, 875, 500 and
250 mg amoxicillin and a corresponding weight of potassium
clavulanate. Representative ratios include 4:1, 7:1, 8:1, 14:1, and
16:1 (amoxicillin :clavulanate). Preferably, in modified release
formulations of the present invention, the amoxicillin in the
immediate release phase consists essentially of amoxicillin
trihydrate and the amoxicillin of the slow release phase consists
essentially of sodium amoxicillin.
[0081] For a tablet formulation, the immediate and slow release
phases may be provided in a number of different formats.
[0082] In a preferred aspect, the immediate and slow release phases
are provided as separate layers of a layered tablet.
[0083] 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.
[0084] 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.
[0085] 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.
[0086] 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.
[0087] 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.
[0088] Release retarding gellable polymers include methylcellulose,
carboxymethylcellulose, low-molecular weight
hydroxypropylmethylcellulose, low-molecular weight
polyvinylalcohols, polyoxyethyleneglycols, non-cross linked
polyvinylpyrrolidone, xanthan gum etc.
[0089] Release retarding polymers simultaneously possessing
swelling and gelling properties include medium-viscosity
hydroxypropylmethylcellulose and medium-viscosity
polyvinylalcohols.
[0090] 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.
[0091] Examples of other polymers which may be used include
Methocel K4M (Trade Mark), Methocel E5 (Trade Mark), Methocel
E5(Trade Mark), Methocel E4M (Trade Mark), Methocel K15M (Trade
Mark) and Methocel K100M (Trade Mark). An example of a suitable
polymer mixture is a mixture of Methocel E5 and K4M, for example
1:1, w:w.
[0092] 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.
[0093] 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.
[0094] 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.
[0095] When xanthan gum is used as release-retarding polymer, the
layer contains from 60 to 80% of amoxicillin, 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 4 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.
[0096] 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.
[0097] It has also been surprisingly found that when the
amoxicillin in the slow release layer is in the form of a soluble
salt thereof, such as sodium amoxicillin, then the release thereof
may be retarded by the inclusion of an organic acid.
[0098] Accordingly, in a further aspect, the present invention
provides for the use of a pharmaceutically acceptable organic acid
as a release retarding excipient in a formulation comprising a
pharmaceutically acceptable soluble salt of amoxicillin, for
instance sodium or potassium amoxicillin, preferably sodium
amoxicillin.
[0099] It will be appreciated that the use of an organic acid as a
release retarding excipient is more generally applicable beyond the
particular formulations hereinbefore described.
[0100] Accordingly, the present invention further provides for a
pharmaceutical formulation comprising a pharmaceutically acceptable
soluble salt of amoxicillin, for instance sodium amoxicillin, in a
slow release phase which further comprises a release retarding
excipient which is a pharmaceutically acceptable organic acid
present in a molar ratio of from 100:1 to 1:10, preferably 50:1 to
1:5, more preferably 20:1 to 1:2 (amoxicillin to organic acid).
[0101] 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.
[0102] 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 crystalline sodium amoxicillin.
[0103] As used herein, the term "pharmaceutically acceptable
organic acid" refers to organic acids which are without
pharmacological effect per se, have acceptable organoleptic
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.sub.(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.
[0104] 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.
[0105] 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.
[0106] 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 preferred embodiment, the slow release layer comprises about
438 mg.+-.5% crystallised sodium amoxicillin, about 78 mg.+-.10%
citric acid and about 2% by weight of xanthan gum.
[0107] In a preferred layered tablet comprising 1000 mg amoxicillin
and 62.5 mg potassium clavulanate, the immediate release layer
comprises about 563 mg.+-.5% amoxicillin, preferably amoxicillin
trihydrate, and about 62.5 mg.+-.5% of potassium clavulanate and
the slow release layer about 438 mg.+-.5% of amoxicillin,
preferably crystallised sodium amoxicillin, about 78 mg.+-.10%
citric acid and about 2% by weight of xanthan gum.
[0108] 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.
[0109] 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.
[0110] 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).
[0111] 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).
[0112] 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.
[0113] 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.
[0114] 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.
[0115] It will be appreciated that 1000, 875 and 750/62.5 mg
layered tablets having an immediate release layer and a slow
release layer 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 amoxicillin and a
pro rata amount of potassium clavulanate, preferably 1000, 875 or
750 mg.+-.5% amoxicillin and 62.5 mg.+-.5% potassium clavulanate,
in a nominal ratio of about 16:1, 14:1 or 12:1, respectively, in
combination with pharmaceutically acceptable excipients or
carriers. Preferably, the layered tablet is a bi-layered
tablet.
[0116] 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.
[0117] Preferred 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 processibility.
[0118] 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.
[0119] In addition, amoxicillin trihydrate, potassium clavulanate
(preferably as 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% f 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.
[0120] The immediate release and slow release compression blends
may then be compressed as separate layers on a bilayer tablet
press, to form bilayer tablets.
[0121] 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 trihydrate, a diluent/compression aid, and a release
retarding polymer, as hereinbefore defined 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.
[0122] 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.
[0123] A process for the preparation of crystallised sodium
amoxicillin is described in EP-A-0 131 147 (Beecham Group plc).
[0124] 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.
[0125] 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.
[0126] 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.
[0127] 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).
[0128] 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.
[0129] 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.
[0130] 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.
[0131] 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.
[0132] 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 500/125 mg amoxicillin/potassium clavulanate tablet
and a 500 mg amoxicillin tablet in combination with a slow release
tablet comprising 1000 mg of amoxicillin. 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. In addition,
a dosage of 1500/125 mg may be provided by an existing 500/125 mg
tablet and an existing 500 mg tablet of amoxicillin in combination
with a slow release tablet comprising 500 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).
[0133] In a further aspect, the present invention provides for a
pharmaceutical formulation, preferably a tablet, comprising
amoxicillin (as the sole active ingredient) formulated with a
release retarding excipient which causes a slow release of the
amoxicillin from the formulation, and excluding; tablets which
comprise 750 mg or less of amoxicillin in which the amoxicillin is
present essentially as amoxicillin trihydrate; or tablets
comprising from 400 to 500 mg amoxicillin in which amoxicillin is
present as a mixture comprising at least 70% amoxicillin trihydrate
and up to 30% sodium amoxicillin in combination with hydroxypropyl
methylcellulose as a release retarding excipient.
[0134] Such formulations may comprise from 100 to 1250 mg
amoxicillin which may be amoxicillin trihydrate or (crystallised)
sodium amoxicillin or a mixture thereof, for instance 500, 875 or
1000 mg amoxicillin. Suitable excipients for slow release are those
hereinbefore described for slow release layers. The formulation may
comprise from 4 to 25%, preferably from 4 to 15%, more preferably 4
to 10% of xanthan gum, or from 10 to 25, preferably 15 to 20% of a
hydroxypropyl-methylcellulose, for instance Methocel K100LV or
Methocel K4M. Alternatively, such formulations may comprise citric
acid, optionally with xanthan gum, as hereinbefore described.
[0135] 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 for a method of treating bacterial infections in humans
which comprises orally administering thereto a therapeutically
effective amount of amoxicillin and potassium clavulanate such that
the amount of amoxicillin is in the range 1250 to 1750 mg,
preferably 1300 to 1700 mg, and the amount of potassium clavulanate
is such that the weight ratio of amoxicillin to clavulanate is from
2:1 to 20:1, preferably 7:1 to 20:1, more preferably 14:1 to 20:1,
at intervals of about 8 h, in which the dosage is delivered from a
modified release formulation.
[0136] Preferably, the dosage regimen provides a mean plasma
concentration of amoxicillin of 4 .mu.g/mL for at least. 3.0 h,
preferably at least 3.2 h, more preferably at least 3.6 h, most
preferably for about 4 h or longer.
[0137] More preferably, the dosage regimen provides a mean plasma
concentration of amoxicillin of 8 .mu.g/ml for at least 3.0 h, more
preferably at least 3.2 h, most preferably at least 3.6 h.
[0138] Preferably, the dosage regimen provides a mean maximum
plasma concentration (Cmax) of amoxicillin which is at least 8
.mu.g/mL, preferably at least 12 .mu.g/mL, yet more preferably at
least 14 .mu.g/mL, most preferably at least 16 .mu.g/mL.
[0139] A preferred dosage is in the range 1300 to 1700 mg
amoxicillin and 125 mg potassium clavulanate, more preferably 1400
to 1600 mg amoxicillin and 125 mg potassium clavulanate.
[0140] 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, 650
to 850 mg amoxicillin, more preferably 700 to 800 mg amoxicillin,
and 62.5 mg potassium clavulanate) or a larger chewable tablet or
single dose sachet comprising the entire unit dosage (for instance,
1300 to 1700 mg amoxicillin, more preferably 1400 to 1600 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.
[0141] It will be further 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 .beta.-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.
[0142] 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.times.1000/62.5 mg tablets,
to improve patient compliance.
[0143] 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. The invention will now be described by
way of example.
EXAMPLES
[0144] The foregoing examples describe tablet formulations which
comprise potassium clavulanate. This is known to be extremely water
sensitive. Therefore such tablet formulations 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.
Example 1
1000/62.5 mg Modified Release Tablet
[0145] TABLE-US-00001 Ingredient mg/tablet % w/w Immediate Release
Layer Amoxicillin Trihydrate (ERH <40%) 654.1* 40.88 Potassium
Clavulanate 76.2# 4.76 Microcrystalline Cellulose 136.4 8.52 Sodium
Starch Glycollate 18.0 1.12 Colloidal Silicon Dioxide 6.3 0.39
Magnesium Stearate 9.0 0.56 Total (Immediate Release Layer) 900.0
56.23 Slow Release Layer Crystallised Sodium Amoxicillin 480.8**
30.05 Microcrystalline Cellulose 113.2 7.08 Xanthan Gum 14.0 0.87
Citric Acid 78.0 4.87 Colloidal Silicon Dioxide 1.50 0.08 Magnesium
Stearate 14.0 0.87 Total (Sustained Release Layer) 700.0 43.74 Film
coat Opadry YS-1-7700 - Composition: Hydroxypropylmethylcellulose
2910 6 cp 11.6 Hydroxypropylmethylcellulose 2910 15 cp 3.9 Titanium
dioxide 15.1 Polyethylene Glycol 3350 2.3 Polyethylene Glycol 8000
2.3 Total weight of coated tablet 1635.2 *Equivalent to 562.5 mg of
amoxicillin based on an assay of 86.0% #Equivalent to 62.5 mg of
clavulanic acid based on an assay of 82.0% **Equivalent to 437.5 mg
amoxicillin based on an assay of 91.0%
Example 2
[0146] 1000/62.5 mg modified release tablet The immediate release
layer and film coat are as for the tablet of Example 1
TABLE-US-00002 Ingredient mg/tablet % w/w Slow Release Layer
Crystallised Sodium Amoxicillin 480.8** 30.05 Microcrystalline
Cellulose 127.2 7.95 Citric Acid 78.0 4.87 Colloidal Silicon
Dioxide 1.5 0.09 Magnesium Stearate 14.0 0.87 Total (Slow Release
Layer) 700.0 43.74 Total Weight of coated tablet 1635.2
**Equivalent to 437.5 mg amoxicillin based on an assay of 91.0%
Preparation of Modified Release Tablets
[0147] Modified release tablets were prepared according to the
process flow diagram shown in FIG. 2. In brief, immediate and
modified release blends are prepared which involve initial sieving
and milling, as indicated, before roller compaction in a
Chilsonater and further milling, sieving and blending. The two
containers comprising amoxicillin trihydrate and the two containers
comprising sodium amoxicillin comprise about equal weights of
amoxicillin trihydrate and sodium amoxicillin, respectively.
[0148] For the IR blend, the Chilsonator settings were: roll size,
width=4 inches, diam=10 inches; hydraulic pressure=900-1100 psi,
air pressure=25-35 psi, roll speed=15-25 rpm, horizontal auger
speed=15-30 rpm, vertical auger speed=300-350 rpm.
[0149] For the SR blend, the Chilsonator settings were: roll size,
width=4 inches, diam=10 inches; hydraulic pressure=500-700 psi, air
pressure=15-20 psi, roll speed=15-25 rpm, horizontal auger
speed=30-35 rpm, vertical auger speed=300-350 rpm.
[0150] The two blends were then compressed as separate layers in a
bilayer tablet press equipped with punches measuring 0.0406 inches
by 0.8730 inches and having a modified capsule shape. For the first
(immediate release)layer, there was no pre-compression, and a main
compression of less than 10 KN. For the second layer, there was a
pre-compression of less than 20 KN, and a main compression of less
than 60 KN. The tablets thus produced had a total weight of 1600
mg.+-.48 mg, a hardness in the range 8 to 18 SCU and a friability
of less than 0.5%.
[0151] Finally, the tablet cores were coated with an aqueous film
coating, using a 15% solids aqueous suspension, in a 60 inch
coating pan which could accommodate up to 300 kg charge of tablets.
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.degree. C. whilst the exhaust air humidity was in the range 4
to 12% and the temperature in the range 43 to 50.degree. C. The
spray rate was 80 to 120 ml/min/spray gun.
Example 3
Slow Release Tablet (875 mg)
[0152] TABLE-US-00003 mg/ta (a) Sodium Amoxicillin Tablet
Crystallised Sodium Amoxicillin 91%* 961 73 Dried Microcrystalline
Cellulose 273 21 Magnesium Stearate 1 1 Xanthan gum 200 mesh** 5 4
Total 1 (b) Sodium Amoxicillin Tablet with citric acid Crystallised
Sodium Amoxicillin 91%* 961 66 Dried Microcrystalline Cellulose 288
19 Magnesium Stearate 14 1 Citric acid 10 Xanthan gum 200 mesh** 2
2 Total 1 (c) Amoxicillin Trihydrate Tablet Amoxicillin Trihydrate
86%* 101 78 Dried Microcrystalline Cellulose 21 16 Magnesium
Stearate 1 1 Xanthan Gum, 200 mesh** 5 4 Total 1 *adjusted for the
potency of the amoxicillin component and corresponding to 875 mg
amoxicillin, **Xantural 75
Example 4
875/62.5 mg Modified Release Tablet
Slow Release Layer
[0153] This may be formed using half the quantities given above,
for a slow release layer comprising about 438 mg amoxicillin.
TABLE-US-00004 Immediate release layer - 1 Amoxicillin trihydrate
507 mg (equiv to amoxicillin free acid) (438) Potassium clavulanate
71.8 (equivalent to clavulanic acid) (62.5) Microcrystalline
cellulose (Avicel PH102) 125 Sodium starch glycollate (Explotab) 26
Magnesium stearate 6.5
[0154] The immediate release layer comprises nominally 438/62.5 mg
amoxicillin/clavulanate. TABLE-US-00005 Immediate release layer - 2
Amoxicillin trihydrate 507 mg (equiv to amoxicillin free acid)
(438) Potassium clavulanate 71.8 (equivalent to clavulanic acid)
(62.5) Microcrystalline cellulose (Avicel PH102) 135 Sodium starch
glycollate (Explotab) 34 Talc 67 Magnesium stearate 25 Silica
(Syloid) 17
The immediate release layer comprises nominally 438/62.5 mg
amoxicillin/clavulanate. Barrier Layers
[0155] Barrier layers and methods for their preparation are
described in WO 95/20946 (SmithKline Beecham) whose disclosure is
incorporated herein by reference in its entirety.
Preparation of Tablets
[0156] The active ingredients, fillers and diluents
(microcrystalline cellulose), release controlling agents (if
present), disintegrants (crospovidone, sodium starch glycollate)
etc are mixed. Lubricants (talc, Mg-stearate) and colloidal silicon
dioxide (Syloid 244) are added, and mixing is continued for another
minute. The complete mixture is slugged on a tablet press or roller
compacted (briquetting step), followed by size reduction (Apex,
Fitzmill, Frewitt) and passage through an oscillatory sieve or
particle size classifier (Kason, Sweco). If the flow properties are
unsatisfactory, the briquetting step is repeated. Separate
compressed blends are prepared for the immediate and slow release
layers, and barrier layer, if present.
[0157] In some cases, where the bulk density is rather low, a
densifying step (pre-tabletting and sieving as in the briquetting
method) may be required in order to achieve the nominal weight of a
particular layer.
[0158] The blends are then compressed as separate layers on a layer
tablet press to form bilayered tablets. Tablets may then be coated
with a white opaque coating, for instance the product Opadry,
Opaspray (Colorcon).
Example 5
[0159] TABLE-US-00006 mg/tablet % Crystallised Sodium
Amoxicillin.sup.1 824.2 51.51 Amoxicillin Trihydrate.sup.2 290.7
18.17 Clavulanate Potassium.sup.3 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 .sup.1adjusted for potency of the
amoxicillin component and corresponding to 750 mg of amoxicillin
.sup.2adjusted for potency of the amoxicillin component and
corresponding to 250 mg of amoxicillin .sup.3adjusted for potency
of the clavulanate potassium component and corresponding to 62.5 mg
of clavulanate potassium
[0160] Two separate batches of granules, the first, immediate
release granules, comprising amoxicillin and potassium clavulanate
and the second, slow release granules, comprising sodium
amoxicillin and citric acid, were prepared by roller compaction, as
described in Example 2, and then combined with the remaining
excipients, blended and formed into tablets in a tablet press.
Example 6
1000 mg Monolith Tablet
[0161] A tablet similar to the tablet of Example 5 may be prepared
in which the ratio of amoxicillin trihydrate to sodium amoxicillin
is adjusted from 1:3 to 9:7 (563/438 mg)
Example 7
875 mg Slow Release Tablet
[0162] TABLE-US-00007 Ingredient mg/tablet % w/w Sodium Amoxicillin
961.5 73.96 Microcrystalline Cellulose 218.5 16.81 Xanthan gum 97.5
7.50 Colloidal Silicon Dioxide 3.0 0.23 Magnesium Stearate 19.5
1.50 Total 1300.0 100.00 **Equivalent to 875 mg amoxicillin based
on an assay of 91.0%
[0163] Slow release tablets were prepared from slow release
granules using the process described above in Example 1. The
granules were then blended with the remaining ingredients and
compressed in a tablet press into tablets.
Example 8
875 mg Slow Release Tablet
[0164] A tablet similar to the tablet of Example 7 was prepared in
which the level of xanthan gum was increased to 195 mg (15%), with
a corresponding reduction in the weight of microcrystalline
cellulose.
Example 9
875 mg Slow Release Tablet
[0165] A tablet similar to the tablet of Example 7 was prepared in
which the sodium amoxicillin was replaced by an equivalent amount
of amoxicillin trihydrate (1017.4 mg, 78.26%) with a corresponding
reduction in the weight of microcrystalline cellulose
Example 10
Dissolution Testing Methods
[0166] The release of amoxicillin and clavulanate from tablets into
static media was measured using the <711 > Dissolution Test,
Apparatus 2, provided in USP 23, 1995.
[0167] Test Specifications: TABLE-US-00008 Temperature: 37.0 .+-.
0.5.degree. C. Medium: Deionized water, 900 mL Paddle speed 75
rpm
Method
[0168] Aliquots of medium were removed for assay after 15, 30, 45,
60, 90, 120, 150, 180, 240, 300 360, 420 and 480 min, each aliquot
being replaced simultaneously by an equal volume of medium to
maintain constant volume. The amount of drug substance was
determined by UV spectrometry, at 272 nM. The resulting dissolution
profile for the tablets of Example 1 and 2 are shown as FIG. 3.
in vivo Pharmacokinetic Evaluation of Formulations
[0169] The bioavailability of dosages according to the present
invention were evaluated in two human volunteer studies, Study A
and Study B. These were open, randomised, crossover studies in
healthy volunteers. Each dosage was administered with the aid of
approximately 200 mL water, at the start of a light breakfast and
after an overnight fast. Blood samples were collected into tubes
containing EDTA at nominal times of pre-dose and 0.5, 1, 1.5, 2, 3,
4, 5, 6, 7, 8, 10 and 12 h after start of dosing, for assay of
plasma levels of amoxicillin and clavulanate. Samples were cooled
in an ice-bath awaiting further processing. Plasma was separated by
refrigerated centrifugation at 4.degree. C. and transferred to
appropriately labelled polypropylene specimen containers and stored
frozen at approximately -70.degree. C. until assayed.
[0170] Samples were assayed for amoxicillin using a method based on
protein precipitation with acetonitrile. Amoxicillin was extracted
from human plasma (50 .mu.L) by means of protein precipitation,
using acetonitrile containing the internal standard and quantified
by LC/MS/MS. Specifically, human plasma (50 .mu.L) was pipetted
into a 1.5 mL Eppendorf tube followed by the addition of
acetonitrile containing the internal standard
([.sup.13C.sub.6]-amoxicillin, 200 .mu.L). The tube was capped,
vortex mixed and shaken for approximately 15 minutes. After
centrifuging the sample (approximately 11,000.times.g, for 15
minutes), the supernatant was transferred to a silanised 1.1 mL
tapered autosampler vial containing 200 .mu.L of 5 mM ammonium
acetate solution. An aliquot of extract was injected onto the
HPLC/MS/MS system for analysis. The mass spectrometer was operated
in positive ion mode, employing a Turbo IonSpray interface.
Multiple reaction monitoring (MRM) was used to detect the
components, amoxicillin and [.sup.13C.sub.6]-amoxicillin. The MRM
procedure involves (1) mass selection of a characteristic ion of
the required drug or internal standard in the first quadrupole mass
analyser (2) fragmentation of the selected ion in the instrument's
collision cell (3) detection of a fragment ion which is
characteristic of the compound of interest. Quantification is
performed by comparison of the chromatographic peak areas of the
drug relative to the area of the internal standard. Linear
responses in the analyte/internal standard peak area ratios were
observed for analyte concentrations ranging from 0.05 pg/mL (lower
limit of quantification; LLQ) to 10 .mu.g/mL (upper limit of
quantification: ULQ).
[0171] Samples were assayed for clavulanate using a method based on
protein precipitation with acetonitrile. Clavulanate was extracted
from human plasma by means of liquid/liquid using internal standard
and quantified by LC/MS/MS. Specifically, human plasma (50 pL) was
pipetted into a 1.5 mL Eppendorf tube followed by 0.2 mM ammonium
acetate (200 .mu.L) before addition of acetonitrile containing the
internal standard (6-aminopenicillanic acid, 400 .mu.L). The tube
was capped, vortex mixed and shaken for approximately 20 minutes.
After centrifuging the sample (approximately 14,500.times.g, for 15
minutes), the supernatant was transferred to a clean eppendorf tube
and dichloromethane added. After further mixing and centrifugation
(approximately 14, 500.times.g for 10 minutes) supernatent (no more
than 150 uL) was transferred to a tapered 1.1 mL autosampler vial
and left uncapped for at least 20 minutes to allow any traces of
dichloromethane to evaporate. An aliquot of the extract was
injected onto the HPLC/MS/MS system for analysis. The mass
spectrometer was operated in positive ion mode, employing a Turbo
IonSpray interface. Multiple reaction monitoring (MRM) was used to
detect the components, clavulanate and 6-aminopenicillanic acid.
The MRM procedure involves (1) mass selection of a characteristic
ion of the required drug or internal standard in the first
quadrupole mass analyser (2) fragmentation of the selected ion in
the instrument's collision cell (3) detection of a fragment ion
which is characteristic of the compound of interest. Quantification
is performed by comparison of the chromatographic peak areas of the
drug relative to the area of the internal standard. Linear
responses in the analyte/internal standard peak area ratios were
observed for analyte concentrations ranging from 0.05 .mu.g/mL
(lower limit of quantification; LLQ) to 10 .mu.g/mL (upper limit of
quantification: ULQ).
[0172] QC samples were assayed with each batch of samples against
separately prepared calibration standards. The results of the QC
samples were used to assess the day-to-day performance of the
assay.
[0173] Plasma concentration-time data for each subject in each
regimen were analysed by non-compartmental methods using the
non-compartmental pharmacokinetic analysis program WinNonlin
Professional Version 1.5. All calculations were based on actual
sampling times. Pharmacokinetic parameters determined included
maximum observed plasma concentration (Cmax) and time to reach
maximum plasma concentration (Tmax). The apparent terminal
elimination rate constant (lz) was derived from the log-linear
disposition phase of the concentration-time curve using linear
least-squares regression with visual inspection of the data to
determine the appropriate number of points to calculate lz. The
apparent terminal elimination half-life (T1/2) was calculated as
ln(2)/lz.
[0174] Area under the plasma concentration-time curve from time
zero to the last quantifiable plasma concentration [AUC(0-t)] was
determined using the linear trapezoidal rule for each incremental
trapezoid and the log trapezoidal rule for each decremental
trapezoid [Chiou W L., J. Pharmacokinet. Biopharm., 1978, 6,
539-547]. The area under the plasma concentration-time curve
extrapolated to infinity [AUC(0-inf)] was calculated as the sum of
AUC(0-t) and C(t)/lz, where C(t) was the predicted concentration
from the log-linear regression analysis at the last measurable time
point.
[0175] The time above the minimum inhibitory plasma concentration
(T>MIC) was calculated manually by graphical interpolation,
where the minimum inhibitory plasma concentrations was defined as 4
ug/mL for amoxicillin.
[0176] The mean concentration-time profiles for amoxicillin and for
clavulanate were derived at each nominal sampling time for each
formulation. In cases where a post-dose value was not quantifiable,
a value of 1/2 the LLQ (0.050 ug/mL) was assigned to determine the
mean value. Where the calculated mean value was less than the LLQ
or was based on greater than 50% NQ values, a value of NQ was
assigned for that sampling time.
[0177] Log.sub.e-transformed Cmax and untransformed T>MIC for
each of the formulations were analysed using Analysis of Covariance
(ANCOVA) fitting a single term for formulation and fitting the data
from the reference formulation as a co-variate. The 95% confidence
intervals for the means of each formulation were constructed using
the residual variance from the model. For Cmax, the confidence
interval estimates on the log scale were then back-transformed to
obtain the 95% confidence intervals of the geometric mean. These
results were displayed graphically.
[0178] Assumptions underlying the analyses were assessed by
inspection of residual plots. Homogeneity of variance was assessed
by plotting the studentised residuals against the predicted values
from the model, while normality was assessed using normal
probability plots. Particular attention was paid to any outlying
values observed with the reference formulation.
Study A
[0179] The first study compared three modified release dosages of
1750/125 mg (formulations I to III) and a fourth modified release
dosages of 1500/125 mg (formulation IV) against an immediate
release dosage of 1750/125 mg (formulation V), as follows: [0180]
(a) a dosage of 1750/125 mg amoxicillin/potassium clavulanate, made
up of a combination of one modified release tablet comprising
875/125 mg amoxicillin trihydrate/clavulanate and 4% xanthan gum
and one immediate release tablet comprising 875 mg amoxicillin
trihydrate (formulation I); [0181] (b) a dosage of 1750/125 mg
amoxicillin/potassium clavulanate, made up of a combination of one
modified release tablet comprising 875/125 mg crystallised sodium
amoxicillin/clavulanate and 4% xanthan gum and one immediate
release tablet comprising 875 mg amoxicillin trihydrate
(formulation II); [0182] (c) a dosage of 1750/125 mg
amoxicillin/potassium clavulanate, made up of a combination of one
modified release tablet comprising 875/125 mg crystallised sodium
amoxicillin/clavulanate, citric acid (156 mg) and 2% xanthan gum
and one immediate release tablet comprising 875 mg amoxicillin
trihydrate (formulation III); [0183] (d) a dosage of 1500/125 mg
amoxicillin/potassium clavulanate (made up of a modified release
tablet comprising 500/125 mg crystallised sodium
amoxicillin/potassium clavulanate and two immediate release tablet
comprising 500 mg amoxicillin trihydrate (Amoxyl, SmithKline
Beecham) (formulation IV); and [0184] (e) a dosage of 1750/125 mg
amoxicillin/potassium clavulanate, made up of a combination of one
immediate release tablet comprising 875/125 mg amoxicillin
trihydrate/clavulanate (Augmentin, SmithKline Beecham) and one
immediate release tablet comprising 875 mg amoxicillin trihydrate
(Amoxyl, SmithKline Beecham) (formulation V).
[0185] Results TABLE-US-00009 Formulation n Cmax.sup.1 T >
MIC.sup.1,2 AUC.sup.1,3 I 8 12.75 (4.96 4.5 (1.8) 47.83 II 8 18.56
(4.72 4.4 (1.0) 57.46 III 8 13.03 (2.34 5.73 (2.54) 54.93 IV 8
17.33 (4.66 4.8 (0.9) 56.71 V 40 20.21 (6.09 4.2 (0.9) 56.33 ( )
standard deviation .sup.1arithmetic mean value .sup.2T > MIC is
the time (h) above an amoxicillin concentration of 4 .mu.g/ml
.sup.3Area under the curve (0 to 12 h, .mu.g h/mL)
[0186] The pharmacokinetic profile is shown in FIG. 4.
Study B
[0187] The second study investigated two different modified release
dosages of 2000/125 mg (formulations VI and VII) against an
immediate release dosage of 2000/125 mg (formulation VIII), as
follows: [0188] (a) a dosage of 2000/125 mg amoxicillin/potassium
clavulanate, made up of two bilayer tablets according to Example 1
(formulation VI); [0189] (b) a dosage of 2000/125 mg
amoxicillin/potassium clavulanate, made up of two bilayer tablets
according to Example 2 (formulation VII); [0190] (c) a dosage of
2000/125 mg amoxicillin/potassium clavulanate, made up of a
combination of three tablets each comprising 500 mg amoxicillin
(Amoxyl, SmithKline Beecham) and one tablet comprising 500 mg
amoxicillin and 125 mg potassium clavulanate (Augmentin, SmithKline
Beecham) (formulation VIII).
[0191] Results TABLE-US-00010 Formulation N Cmax.sup.1 T >
MIC.sup.1,2 T > MIC.sup.1,3 AUC.sup.1,4 VI 7 17.41 (1.93 6.0
(1.3) 4.8 (1.2) 74.9 VII 8 17.46 (6.02 5.9 (1.3) 4.0 (1.3) 71.5
VIII 12 23.75 (5.73 4.9 (1.1) 3.5 (1.0) 69.2 ( ) standard deviation
.sup.1arithmetic mean value .sup.2T > MIC is the time (h) above
an amoxicillin concentration of 4 .mu.g/ml .sup.3T > MIC is the
time (h) above an amoxicillin concentration of 8 .mu.g/ml
.sup.4Area under the curve (0 to 12 h, .mu.g h/mL).
[0192] Comparison of the AUC values for formulations VI and VII
(bilayer tablets) against VIII (immediate release tablets) shows
that the absorption of the amoxicillin component has not been
compromised by formulating a part of it in a slow release layer.
This means that there is no extra, unabsorbed amoxicillin which may
otherwise cause problems further down in the GI tract, for instance
due to a lack of absorption and destruction of symbiotic
bacteria
[0193] It was also found that for formulation VI, there was less
inter-subject variability in the amoxicillin plasma concentrations
than for formulation VII. These formulations were the same, except
that formulation VI also comprised xanthan gum (2%) in the slow
release layer.
[0194] The pharmacokinetic profile for amoxicillin plasma
concentration is shown in FIG. 5 (in which A is formulation VI, B
is formulation VII, D is formulation VIII).
[0195] The pharmacokinetic profile for the clavulanate component
was substantially the same for the bilayer tablets and the
immediate release tablets, showing that the bioavailability thereof
was not compromised by incorporation into the immediate release
layer of a bilayer tablet.
Study C
[0196] In a further study, the pharmacokinetic profile of the
following dosage regimens was determined: [0197] (a) 2000/125 mg,
using two monolith tablets of Example 5 (Formulation IX); [0198]
(b) 2000/125 mg, using an 875 mg tablet of Example 7 in combination
with an 875 mg tablet of amoxicllin and a 250/125 mg tablet of
amoxicillin/clavulanate (Formulation X); [0199] (c) 2000/125 mg,
using an 875 mg tablet of Example 8 in combination with an 875 mg
tablet of amoxicllin and a 250/125 mg tablet of
amoxicillin/clavulanate (Formulation XI); and [0200] (d) 2000/125
mg, using an 875 mg tablet of Example 9 in combination with an 875
mg tablet of amoxicillin and a 250/125 mg tablet of
amoxicillin/clavulanate (Formulation XII).
[0201] Results TABLE-US-00011 Formulation N Cmax.sup.1 T >
MIC.sup.1,2 T > MIC.sup.3 AUC.sup.1,4 IX 11 20.84 (8.23) 5.95
(1.23) 4.8 79.9 (26.5) X 11 18.73 (5.57) 5.14 (1.28) 3.5 64.8
(21.1) XI 11 18.73 (4.55) 5.47 (1.16) 3.5 69.2 (18.6) XII 11 16.67
(4.04) 6.01 (1.62) 3.1 65.2 17.4) ( ) standard deviation
.sup.1arithmetic mean value .sup.2T > MIC is the time (h) above
an amoxicillin concentration of 4 .mu.g/ml .sup.3T > MIC is the
time (h) above an amoxicillin concentration of 8 .mu.g/ml
.sup.4Area under the curve (0 to 12 h, .mu.g h/mL).
[0202] The present invention also extends to formulations which are
bioequivalent to the tablets of formulations VI and VII, in terms
of both rate and extent of absorption, for instance as defined by
the US Food and Drug Administration and discussed in the so-called
"Orange Book" (Approved Drug Products with Therapeutic Equivalence
Evaluations, US Dept of Health and Human Services, 19th edn,
1999).
REFERENCE DATA
[0203] The existing Augmentin 875/125 mg tablet has a C.sub.max
value of 11.6.+-.2.8 .mu.g/ml (Physicians Desk Reference, Medical
Economics Co, 52 edition, 1998, 2802). The time above MIC was about
40% of the 12 hour dosing interval for an MIC of 2 .mu.g/ml and
about 30% for an MIC of 4 .mu.g/ml (SmithKline Beecham data).
* * * * *