U.S. patent application number 10/681055 was filed with the patent office on 2004-04-08 for novel method of treatment.
This patent application is currently assigned to Beecham Pharmaceuticals (Pte) Limited. Invention is credited to Conley, Creighton P., Roush, John A., Storm, Kevin H..
Application Number | 20040067925 10/681055 |
Document ID | / |
Family ID | 27494778 |
Filed Date | 2004-04-08 |
United States Patent
Application |
20040067925 |
Kind Code |
A1 |
Conley, Creighton P. ; et
al. |
April 8, 2004 |
Novel method of treatment
Abstract
Bacterial infections may be treated using a high dosage regimen
of amoxycillin. Preferably, the dosage is provided by a bilayer
tablet.
Inventors: |
Conley, Creighton P.;
(Bristol, TN) ; Roush, John A.; (Kingsport,
TN) ; Storm, Kevin H.; (Bristol, 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: |
27494778 |
Appl. No.: |
10/681055 |
Filed: |
October 7, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10681055 |
Oct 7, 2003 |
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09911905 |
Jul 24, 2001 |
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6660299 |
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09911905 |
Jul 24, 2001 |
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09544417 |
Apr 6, 2000 |
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6294199 |
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60129074 |
Apr 13, 1999 |
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60150727 |
Aug 25, 1999 |
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60159813 |
Oct 15, 1999 |
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60159838 |
Oct 15, 1999 |
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Current U.S.
Class: |
514/192 |
Current CPC
Class: |
A61K 9/2866 20130101;
A61P 31/04 20180101; A61K 9/209 20130101; A61K 31/43 20130101; A61K
9/2013 20130101; A61K 9/205 20130101; A61K 31/43 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
514/192 |
International
Class: |
A61K 031/43 |
Claims
What is claimed is:
1. A method of treating a bacterial infection in a human in need
thereof which method comprises administering to said human a dosage
of a therapeutically effective amount of amoxycillin in the range
of 1900 to 2600 mg, at a dosage regimen interval of about 12 h.
2. The method according to claim 1 in which the dosage regimen
provides a mean plasma concentration of amoxycillin of 4 .mu.g/mL
for at least 4.4 h and a mean maximum plasma concentration
(C.sub.max) of amoxycillin of at least 12 .mu.g/mL.
3. The method according to claim 1 in which the dosage regimen
provides a mean plasma concentration of amoxycillin of 4 .mu.g/mL
for at least 4.8 h and a mean maximum plasma concentration
(C.sub.max) of amoxycillin of at least 16 .mu.g/mL.
4. The method according to claim 1 in which the dosage regimen
provides a mean plasma concentration of amoxycillin of 8 .mu.g/mL
for at least 4.4 h.
5. The method according to claim 1 in which the dosage is delivered
from an immediate release formulation.
6. The method according to claim 5 in which the dosage is 2000,
2250 or 2500 mg of amoxycillin.
7. The method according to claim 6 in which the dosage is provided
as a single tablet, or as a number of smaller tablets, may be the
same or different.
8. The method according to claim 1 in which the dosage is delivered
from a modified release formulation.
9. The method according to claim 8 in which the dosage is provided
as a number of tablets, which may be the same or different.
10. The method according to claim 8 in which the dosage is 2000,
2250 or 2500 mg of amoxycillin.
11. The method according to claim 1 in which the infection is
caused by the organisms S pneumoniae (including Drug Resistant and
Penicillin Resistant S pneumoniae), H influenzae , M catarrhalis
and/or S pyogenes.
12. A method of treating a bacterial infection in a human in need
thereof which method comprises administering to said human a dosage
of a therapeutically effective amount of amoxycillin in the range
1400 to 1900 mg, at dosage regimen interval of about 12 h, such
that the dosage regimen provides a mean plasma concentration of
amoxycillin of 4 .mu.g/mL for at least 4.4 h, and a mean maximum
plasma concentration (Cmax) of amoxycillin of at least 12
.mu.g/mL.
13. The method according to claim 12 in which the dosage regimen
provides a mean plasma concentration of amoxycillin of 4 .mu.g/ml
for at least 4.8 h and a mean maximum plasma concentration (Cmax)
of amoxycillin of at least 16 .mu.g/ml.
14. The method according to claim 12 in which the dosage is
delivered from a modified release formulation.
15. The method according to claim 12 in which the dosage is 1500 or
1750 mg of amoxycillin.
16. The method according to claim 12 in which the infection is
caused by the organisms S pneumoniae (including Drug Resistant and
Penicillin Resistant S pneumoniae), H influenzae, M catarrhalis
and/or S pyogenes.
17. An immediate release pharmaceutical formulation comprising from
950 to 1300 or 1900 to 2600 mg amoxycillin, in combination with
pharmaceutically acceptable excipients or carriers.
18. An immediate release pharmaceutical tablet formulation
according to claim 17 comprising 1000 mg.+-.5% amoxycillin in
combination with pharmaceutically acceptable excipients or
carriers.
19. An immediate release pharmaceutical formulation according to
claim 17 in the form of a single dose sachet comprising 2000, 2250
or 2500 mg.+-.5% amoxycillin or the corresponding half quantities
thereof, in combination with pharmaceutically acceptable excipients
or carriers.
20. An immediate release formulation according to claim 17 in the
form of a dispersible tablet or a chewable tablet effervescent
dispersible or effervescent chewable tablet comprising 2000, 2250,
or 2500 mg amoxycillin or the corresponding half quantities
thereof, in combination with a chewable base and, if effervescent,
an effervescent couple, and other pharmaceutically acceptable
carrier or excipient.
21. A modified release pharmaceutical formulation comprising an
immediate release phase and a slow release phase; the immediate
release phase comprising a first part of amoxycillin formulated
with pharmaceutically acceptable excipients which allows for
immediate release of the first part of amoxycillin, to form an
immediate release phase, and the slow release phase comprising a
second part of amoxycillin formulated with a release modifying
pharmaceutically acceptable excipient, to form a slow release
phase.
22. The modified release formulation according to claim 21 which
has a biphasic profile with respect to amoxycillin.
23. The modified release formulation according to claim 21 which
has an AUC value which is at least 80% of that of the corresponding
dosage of amoxycillin taken as a conventional (immediate release)
tablet(s), over the same dosage period.
24. The pharmaceutical formulation according to claim 21 in which
the ratio of amoxycillin in the immediate and slow release phases
is from 3:1 to 1:3.
25. The pharmaceutical formulation according to claim 21 comprising
a unit dosage in the range 700 to 1300 mg amoxycillin or 1400 to
2600 mg.
26. The pharmaceutical formulation according to claim 25 in which
the unit dosage is: 1000, 875 or 750 mg +5% amoxycillin; or 2000,
1750 or 1500 mg.+-.5% amoxycillin, in combination with
pharmaceutically acceptable excipients or carriers.
27. The pharmaceutical formulation according to claim 26 which is a
tablet formulation.
28. The pharmaceutical tablet according to claim 27 comprising 1000
mg.+-.5% amoxycillin in which the immediate release phase comprises
about 563 mg .+-.5% amoxycillin and the slow release phase
comprises about 438 mg.+-.5% of amoxycillin.
29. The pharmaceutical formulation according to claim 21 in which
the amoxycillin of the slow release phase consists essentially of
crystallised sodium amoxycillin.
30. The pharmaceutical formulation according to claim 21 which is a
layered tablet comprising an immediate release layer comprising
amoxycillin and a slow release layer comprising amoxycillin and a
release retarding excipient which tablet: (a) is a bilayered
tablet; (b) comprises at least three layers, including an immediate
release and a slow release layer, and comprising at least 275 mg of
amoxycillin in the immediate release layer phase; (c) comprises at
least three layers, including an immediate release and a slow
release layer, and in which the release retarding excipient in the
slow release layer comprises xanthan gum and/or a pharmaceutically
acceptable organic acid, or (d) comprises at least three layers,
including an immediate release and a slow release layer, and in
which the amoxycillin is provided as a mixture of amoxycillin
trihydatre and sodium amoxycillin, in a ratio of 3:1 to 1:3.
31. The layered tablet according to claim 30 in which the slow
release layer comprises a release retarding excipient which is
selected from a pH sensitive polymers; a release-retarding polymer
which has a high degree of swelling in contact with water or
aqueous media; a polymeric material which forms a gel on contact
with water or aqueous media; a polymeric material which has both
swelling and gelling characteristics in contact with water or
aqueous media; a hydrocolloid; carbohydrate-based substances,
proteinaceous substances, or a mixture thereof.
32. The layered tablet according to claim 31 in which the release
retarding gellable polymer is selected from methylcellulose,
carboxymethylcellulose, low-molecular weight
hydroxypropylmethylcellulose- , low-molecular weight
polyvinylalcohols, polyoxyethyleneglycols, and non-cross linked
polyvinylpyrrolidone, or xanthan gum.
33. The layered tablet according to claim 31 in which the release
retarding excipient is xanthan gum.
34. The layered tablet according to claim 33 in which the xanthan
gum is present in from 1 to 25% by weight of the layer.
35. The layered tablet according to claim 30 in which the slow
release layer comprises from 70 to 80% of amoxycillin, from 1 to
25% of xanthan gum, from 10 to 20% of fillers/compression aids, and
a conventional quantity of a lubricant.
36. The layered tablet according to claim 30 in which the slow
release phase comprises sodium amoxycillin and in which the slow
release layer comprises a pharmaceutically acceptable organic acid
present in a molar ratio of from 100: 1 to 1:10 (amoxycillin salt
to organic acid).
37. The layered tablet according to claim 36 in which the
pharmaceutically acceptable acid is citric acid present in a molar
ratio of about 50:1 to 1:2.
38. The layered tablet according to claim 37 further comprising a
release retarding gellable polymer.
39. The layered tablet according to claim 38 in which the release
retarding gellable polymer is xanthan gum.
40. The layered tablet according to claim 39 in which xanthan gum
is present in from 0.5 to 8% by weight of the slow release
layer.
41. The layered tablet according to claim 36 which comprises 1000
mg.+-.5% of amoxycillin and which comprises in the slow release
layer about 438 mg.+-.5% of crystallised sodium amoxycillin, about
78 mg.+-.10% of citric acid and about 2% by weight of xanthan
gum
42. The pharmaceutical formulation according to claim 21 in which
the immediate release phase is formed from immediate release
granules comprising amoxycillin and the slow release phase is
formed from slow release granules comprising amoxycillin.
43. The pharmaceutical formulation according to claim 42 which is a
single dose sachet, a capsule, a monolith tablet, a dispersible
tablet, a chewable tablet, effervescent chewable tablet, or an
effervescent dispersible tablet.
44. A pharmaceutical formulation comprising 1000 mg.+-.5%
amoxycillin, in combination with pharmaceutically acceptable
excipients or carriers.
45. The pharmaceutical formulation according to claim 44 in which
the amoxycillin is present as a mixture of amoxycillin trihydrate
and sodium amoxycillin in a ratio of 3:1 to 1:3.
46. A pharmaceutical formulation comprising amoxycillin in which
amoxycillin is provided as a mixture of amoxycillin trihydrate and
sodium amoxycillin in a ratio of from 3:1 to 1:3.
47. The pharmaceutical formulation according to claim 46 in which
the ratio of amoxycillin trihydrate and sodium amoxycillin is from
3:2 to 2:3.
48. A pharmaceutical formulation comprising a pharmaceutically
acceptable soluble salt of amoxycillin 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 (amoxycillin salt to organic acid).
49. The pharmaceutical formulation according to claim 48 in which
the molar ratio, is 50:1 to 1:5.
50. The pharmaceutical formulation according to claim 48 in which
the organic acid is citric acid.
51. The pharmaceutical formulation according to claim 48 in which
the soluble salt of amoxycillin is, sodium amoxycillin.
52. A kit comprising an immediate release formulation comprising
amoxycillin, and a slow release formulation comprising amoxycillin
(and no potassium clavulanate).
53. Compacted granules for use in a pharmaceutical formulation
comprising amoxycillin, a diluent/compression aid, and an organic
acid (if amoxycillin is present as a soluble salt thereof) or a
release retarding polymer or a mixture thereof.
54. Compacted granules for use in a pharmaceutical formulation
comprising sodium amoxycillin, microcrystalline cellulose, and an
organic acid or a release retarding polymer or a mixture
thereof.
55. The process for preparing compacted granules according to claim
54 which process comprises the steps of blending together sodium
amoxycillin, microcrystalline cellulose, and organic acid or
release retarding polymer or mixture thereof, compacting the blend
and then milling.
56. The pharmaceutical formulation according to claim 42 comprising
slow release compacted granules comprising amoxycillin, a
diluent/compression aid, and an organic acid (if amoxycillin is
present as a soluble salt thereof) or a release retarding polymer
or a mixture thereof, , and further immediate release compacted
granules comprising amoxycillin.
57. The formulation according to claim 21 having an AUC, C.sub.max,
and t.sub.max substantially according to FIG. 4 (formulation VI or
VII).
58. A formulation which is bioequiivalent to the formulation of
claim 57.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a novel method of treatment using
amoxycillin and for novel formulations, in particular tablet
formulations, for use in such methods.
BACKGROUND OF THE INVENTION
[0002] Amoxycillin is a well known .beta.-lactam antibiotic which
has been available for many years. Despite the suspectibility of
amoxycillin to inhibition by .beta.-lactamases produced by
resistant organisms, amoxycillin still enjoys widespread usage as a
broad spectrum antibiotic for the treatment of commonly occurring
bacterial infections. In particular, amoxycillin is particularly
effective in treating sore throats--acute bacterial tonsillitis
and/or pharyngitis where the causative organism is almost
exclusively Streptococcus pyogenes.
[0003] Amoxycillin is available commercially in a variety of
formulations, for instance as capsules containing either 250 or 500
mg amoxycillin, as tablets comprising 500 or 875 mg amoxycillin, as
chewable tablets comprising either 125 or 250 mg amoxycillin and as
dry powder formulation, for reconstitution into an oral suspension.
Other formulation types include dispersible tablets providing. 500
mg amoxycillin, chewable effervescent tablets, comprising 125, 250
or 500 mg amoxycillin and single dose sachets comprising 750 or
3000 mg amoxycillin. The standard adult dosage is 250 mg. three
times daily (tid), increasing to 500 mg tid for more severe
infections. In addition, the 875 mg tablet is intended for dosing
twice daily (bid), as an alternative to the dosage regimen of 500
mg tid. Recently, a 1000 mg chewing tablet has been advertised as
being under development (AC Pharma, see SCRIP No 2472 Sep. 15th
1999, page 11). A high dosage of 3 g, bid, is recommended in
appropriate cases for the treatment of severe or recurrent purulent
infection of the respiratory tract. For short course therapy, in
simple urinary tract infections, two 3g doses, at an interval of
10-12 hours, are given while for a dental abscess, the dosage is
two 3 g doses at an interval of 8 h and for gonorrhoea, a single
dose of 3 g. Furthermore, the use of 1 g of amoxycillin, bid, is
used as one arm of a combination therapy, for eradication of
Helicobacter pylori in peptic ulcer disease.
[0004] In addition, amoxycillin is provided in combination with the
.beta.-lactamase inhibitor potassium clavulanate. in various tablet
formulations of amoxycillin and potassium clavulanate comprising
various different weights and ratios of amoxycillin and potassium
clavulanate, for instance, conventional swallow tablets comprising
250/125, 500/125, 500/62.5, and 875/125 mg amoxycillin/clavulanic
acid (in the form of potassium clavulanate). Such tablets comprise
amoxycillin 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 regimen
provides a single dosage of 125 mg of potassium clavulanate.
[0005] In addition, WO 97/09042 (SmithKline Beecham) describes
tablet formulations comprising amoxycillin 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
amoxycillin and clavulanic acid and the second 875 mg amoxycillin.
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 amoxycillin and clavulanate in a
14:1 ratio, for administering amoxycillin dosages of 90 mg/kg/day.
Data suggest that such a dosage may provide antibiotic
concentrations sufficient to eradicate DRSP with amoxycillin +/-
clavulanic acid MICs.ltoreq.4 .mu.g/ml (Bottenfield et al, Pediatr
Infect Dis J, 1998, 17, 963-8).
[0006] Existing marketed tablet formulations of amoxycillin 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, q12h), rather than
every 8 hours (tid, q8h).
[0007] Thus, for instance, WO 94/06416 (Jagotec AG) describes
multi-layered tablets comprising 500 mg of amoxycillin distributed
equally between an immediate release and a slow release layer.
Furthermore, WO 95/20946 (SmithKline Beecham) describes inter alia
a layered tablet comprising about 500 mg amoxycillin having a first
layer which is an immediate release layer and a second layer which
is a slow release layer, the ratio of amoxycillin between the two
layers being about 1:2.6, as well as an intermediate barrier layer.
Further bilayered tablets comprising clavulanic acid and
amoxycillin are described in WO 98/05305 (Quadrant Holdings Ltd).
In such tablets, a first layer comprises amoxycillin and a second
layer comprises clavulanate and the excipient trehalose, to
stabilise the clavulanate component.
[0008] In addition, WO 95/28148 (SmithKline Beecham) describes
inter alia tablet formulations comprising amoxycillin and,
optionally, clavulanate having a core comprising amoxycillin coated
with a release retarding agent and surrounded by an outer casing
layer of amoxycillin and potassium clavulanate. The release
retarding agent is an enteric coating, so that there is a 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
inter alia tablet formulations comprising amoxycillin in a matrix,
for immediate release, and granules in a delayed release form
comprising amoxycillin. Such granules are coated with an enteric
coating, so release is delayed until the granules reach the
intestine. WO 96/04908 (SmithKline Beecham) describes inter alia
delayed or sustained release formulations of amoxycillin formed
from granules which have a core comprising amoxycillin and
surrounded by a layer comprising amoxycillin.
[0009] In addition, WO 94/27557 (SmithKline Beecham) describes
controlled release formulations of amoxycillin and clavulanic acid
prepared using a hydrophobic waxy material which is then subjected
to thermal infusion.
[0010] Further controlled release formulations comprising
amoxycillin 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 amoxycillin. 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 amoxycillin 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.
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 amoxycillin in the
range 1900 to 2600 mg, at a dosage regimen/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 M catarrhalis and/or S Pyogenes.
[0012] The present invention also relates to a modified release
pharmaceutical formulation comprising amoxycillin in which a first
part of amoxycillin are formulated with pharmaceutically acceptable
excipients which allow for immediate release of the first part of
amoxycillin, to form an immediate release phase, and further
comprising a second part of amoxycillin formulated with
pharmaceutically acceptable excipients which allow for slow release
of the second part of amoxycillin, to form a slow release
phase.
[0013] The present invention also relates to an immediate release
pharmaceutical tablet formulation comprising 1000 mg.+-.5%
amoxycillin 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% amoxycillin, 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] 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).
[0019] 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).
[0020] 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.
[0021] 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.
[0022] FIG. 2 demonstrates the dissolution profile for tablets of
Examples 1 and 2.
[0023] FIG. 3 demonstrate the pharmacokinetic profiles of Study
A
[0024] FIG. 4 demonstrates the pharmacokinetic profile for
amoxycillin plasma concentration for Study B (in which A is
formulation V, B is formulation VI, D is formulation VIII).
DETAILED DESCRIPTION OF THE INVENTION
[0025] Part of the challenge in providing formulations of
amoxycillin 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 amoxycillin
(excretion half-life is 1.3 hours) makes it difficult to maintain
serum levels as clearance from the body is very rapid.
[0026] In existing tablet formulations comprising amoxycillin,
amoxycillin is present in the form amoxycillin trihydrate, as the
use of this form provides tablets with greater storage stability
than those in which amoxycillin is present as sodium amoxycillin
(see GB 2 005 538, Beecham Group Ltd). Sodium amoxycillin is
however used as the amoxycillin component in existing formulations
of amoxycillin and potassium clavulanate adapted for IV
administration. The form of sodium amoxycillin used is a
spray-dried form. In addition, EP 0 131 147-A1 (Beecham Group plc)
describes a further form of sodium amoxycillin, so-called
"crystalline sodium amoxycillin". A further process for preparing
crystalline salts of amoxycillin, including sodium amoxycillin, is
described in WO 99/62910 (SmithKline Beecham). Sodium amoxycillin
is relatively water soluble in comparison to amoxycillin
trihydrate.
[0027] 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 gastrointestinal intolerance associated with oral
dosing of clavulanate-containing products.
[0028] 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.
[0029] Of concern is the increasing resistance of pathogenic
organisms, such as those found in respiratory tract infections, to
anti-infective agents such as amoxycillin, 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. Amoxycillin, 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 <0.06 .mu.g/ml, intermediate resistance is defined as an
MIC in the range 0.12 to 1.0 .mu.g/ml while 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 amoxycillin MIC of 2
.mu.g/ml.
[0030] There is consequently a need to provide new formulations of
amoxycillin 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, as
well as S pyogenes.
[0031] For .beta.-lactams, including amoxycillin, 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.
[0032] A further parameter which may be of importance is the ratio
of the maximum plasma concentration (Cmax) to the MIC value, as
this may be related to the potential to select for resistance. Too
low a ratio may encourage the development of resistant strains.
Preferably, the plasma Cmax value is well above the MIC value, for
instance, at least two times, more preferably at least three times,
most preferably at least four times, the MIC value.
[0033] In a clinical study of an Amoxil 875 mg tablet (SmithKline
Beecham), the mean amoxycillin pharmacokinetic parameters were
shown to be: AUC.sub.0-.infin.=35.4 .+-.8.1 .mu.g.hr/mL;
C.sub.max=13.8 .+-.4.1 .mu.g.hr/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).
[0034] Based on the foregoing considerations, there is a continuing
need to provide new dosage regimens for amoxycillin giving
optimised pharmacokinetic profiles for amoxycillin, so that therapy
is maximised, particularly against more resistant bacteria while
the (further) development of resistance is minimised. It has now
been found that such can be achieved using higher dosages of
amoxycillin than previously contemplated.
[0035] 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 amoxycillin in the range 1900 to 2600 mg,
preferably 1950 to 2550 mg, at intervals of about 12 h.
[0036] Preferably, the dosage regimen provides a mean plasma
concentration of amoxycillin 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.
[0037] More preferably, the dosage regimen provides a mean plasma
concentration of amoxycillin 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.
[0038] Preferably, the dosage regimen provides a mean maximum
plasma concentration (C.sub.max) of amoxycillin 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.
[0039] Preferably, the mean plasma concentration of amoxycillin and
the mean maximum plasma concentration of amoxycillin are measured
after oral administration of a formulation comprising amoxycillin
at the start of a light meal.
[0040] 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
amoxycillin in the range 1400 to 1900 mg, preferably 1500 to 1900
mg, at intervals of about 12 h, such that the dosage regimen
provides a mean plasma concentration of amoxycillin of 4 .mu.g/mL
for at least 4.4 h, preferably at least 4.6 h, more preferably at
least 4.8h, most preferably for about 6h or longer; more
preferably, a mean plasma concentration of amoxycillin 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 amoxycillin 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.
[0041] 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 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. Further
bacterial infections amenable to the present invention include
infections caused by the organism Streptococcus pyogenes, for
instance acute bacterial tonsillitis and/or pharyngitis. The
duration of therapy will generally between 7 and 14 days, typically
7 days for most indications but 10 days for acute bacterial
sinusitis.
[0042] The term "amoxycillin" as used herein shall mean amoxycillin
or an alkaline salt thereof, in particular amoxycillin trihydrate
and (crystallised) sodium amoxycillin, without distinction and
unless otherwise indicated.
[0043] Unless otherwise indicated, weights of amoxycillin refer to
the equivalent weight of the corresponding free acid. In addition,
it will be appreciated that in practice, weights of amoxycillin to
be incorporated into a formulation will be further adjusted, in
accord with conventional practice, to take account of the potency
of the amoxycillin.
[0044] In a first embodiment, a dosage of amoxycillin of from 1900
to 2600 mg may be 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 amoxycillin in the range 1900 to 2600, preferably 1950 to 2550
mg, at intervals of about 12 h, wherein the dosage is delivered
from an immediate formulation.
[0045] As used herein, the term "immediate release" shall mean 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, chewable
tablets, dispersible tablets, single dose sachets and capsules.
[0046] Representative dosages include 2000, 2250 and 2500 mg of
amoxycillin. A preferred dosage is 2000 mg of amoxycillin.
[0047] 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 amoxycillin. Alternatively, the
dosage may be made up of a number of smaller tablets or capsules,
for instance, 2, 3 or 4, which may be the same or different.
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 amoxycillin maybe provided by a combination of four tablets
each comprising 500 mg amoxycillin or two tablets each comprising
1000 mg amoxycillin. In addition, a dosage of 2250 mg amoxycillin
may be provided by a combination of four tablets comprising 500 mg
amoxycillin and one tablet comprising 250 mg amoxycillin or two
tablets comprising 875 mg amoxycillin and one tablet comprising 500
mg amoxycillin. Furthermore, a dosage of 2500 mg amoxycillin may be
provided by a combination of five tablet comprising 500 mg
amoxycillin. Tablets comprising 500 and 875 mg amoxycillin are
already commercially available.
[0048] It will be appreciated that immediate release tablets, in
particular swallow tablets or dispersible tablets, comprising 1000
mg are novel. Accordingly, in a further aspect, the present
invention provides for an immediate release pharmaceutical tablet
formulation comprising 1000 mg.+-.5% amoxycillin, in a nominal
ratio of about 16:1, in combination with pharmaceutically
acceptable excipients or carriers. Immediate release tablets
comprising 1000 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).
[0049] It will also be appreciated that immediate release single
dosage sachets comprising 2000 mg, 2250 mg or 2500 mg amoxycillin,
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%
amoxycillin, 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 of amoxycillin/potassium clavulanate (see for instance, WO
92/19277 and WO 98/35672, SmithKline Beecham).
[0050] 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 tablet which may be effervescent and/or dispersible
comprising 2000, 2250, or 2500 mg amoxycillin, 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 amoxycillin (see for instance, EP-A-0
396 335, Beecham Group and WO 98/35672, SmithKline Beecham).
[0051] In a second embodiment, a dosage of amoxycillin of from 1900
to 2600 mg amoxycillin 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 amoxycillin in the range 1400 to 2600 mg,
preferably 1900 to 2600 mg, more preferably 1950 to 2550 mg, at
intervals of about 12 h, in which the dosage is delivered from a
modified release formulation.
[0052] As used herein, the term "modified release" shall mean 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 portion or phase and a slow release portion or
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.
[0053] Preferably, the modified release formulations of the present
invention are formulated such that the release of amoxycillin is
effected predominantly through the stomach and small intestine, so
that absorption through the specific amoxycillin absorption site in
the small intestine is maximised. Preferably, the amoxycillin
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. Such
formulations are preferably formulated such that the release of
amoxycillin occurs predominantly within 3 hours of ingestion of the
formulation.
[0054] Representative modified release dosages include 1500, 1750
and 2000 mg of amoxycillin. A preferred dosage is 2000 mg of
amoxycillin.
[0055] 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 which may be the same or
different. Thus, for instance, a dosage of 2000 mg amoxycillin may
be provided by two tablets each comprising 1000 mg amoxycillin, two
tablets each comprising 500 mg amoxycillin and one tablet
comprising 1000 mg amoxycillin or four tablets each comprising 500
mg amoxycillin. In addition, a dosage of 1750 mg amoxycillin may be
provided by two tablets each comprising 875 mg amoxycillin. A
preferred tablet comprises 1000 mg amoxycillin.
[0056] 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 or 4.times.500 mg
amoxycillin.
[0057] Preferably, in the modified release formulation, the
amoxycillin is provided in both an immediate release and a slow
release phase.
[0058] Accordingly, in a further aspect, the present invention
provides for a modified release pharmaceutical formulation
comprising amoxycillin in which a first part of amoxycillin is
formulated with pharmaceutically acceptable excipients which allow
for immediate release of the first part of amoxycillin, to form an
immediate release phase, and further comprising a second part of
amoxycillin formulated with pharmaceutically acceptable excipients
which allow for slow release of the second part of amoxycillin, to
form a slow release phase.
[0059] As used herein, the term "slow release" shall mean the
gradual, but continuous or sustained release, over a relatively
extended period of the active material content (in this case
amoxycillin) 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.
[0060] Preferably, the modified release formulation has an in vitro
dissolution profile in which 45 to 65%, preferably 45 to 55% of the
amoxycillin content is dissolved within 30 min; further in which 50
to 75%, preferably 55 to 65% of the amoxycillin content is
dissolved within 60 min; further in which 55 to 85%, preferably 60
to 70% of the amoxycillin content is dissolved within 120 min;
further in which 70 to 95%, preferably 75 to 85% of the amoxycillin
content is dissolved within 180 min; and further in which 70 to
100%, preferably 75 to 100% of the amoxycillin content is dissolved
within 240 min. In comparison, a conventional, immediate release
amoxycillin 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.
[0061] Preferably, the modified release formulation has a biphasic
profile in vivo with respect to amoxycillin, 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.
[0062] 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 amoxycillin
taken as a conventional (immediate release) formulation, over the
same dosage period, thereby maximising the absorption of the
amoxycillin component from the slow release component.
[0063] 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
amoxycillin may then be readily determined in blood samples taken
from patients according to procedures well known and documented in
the art.
[0064] 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.
[0065] 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, more preferably
850 to 1250 mg, amoxycillin, for instance unit dosages of 1000, 875
and 750 mg amoxycillin. 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 or
dispersible tablet may comprise 1400 to 2600 mg, preferably, 1900
to 2600 mg, amoxycillin, for instance unit dosages of 2000, 1750
and 1500 mg amoxycillin. It will be appreciated that such 1000, 875
and 750 mg formulations are novel.
[0066] Accordingly, in a further aspect, the present invention
provides for a pharmaceutical formulation having an immediate
release portion or phase and a slow release portion or phase
comprising:
[0067] (a) a unit dosage in the range 700 to 1300 mg, preferably,
950 to 1300 mg, amoxycillin, for instance unit dosages of 1000, 875
or 750 mg.+-.5% amoxycillin, or
[0068] (b) a unit dosage in the range 1400 to 2600 mg,
preferably1700 to 2600 mg, more preferably 1900 to 2600 mg,
amoxycillin, for instance unit dosages of 2000, 1750 or 1500
mg.+-.5% amoxycillin,
[0069] in combination with pharmaceutically acceptable excipients
or carriers.
[0070] Preferably, the ratio of amoxycillin 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 amoxycillin in the immediate release phase, to ensure an
adequate C.sub.max value.
[0071] In the modified release formulations of the present
invention, the portion of amoxycillin which is released immediately
may be provided as amoxycillin trihydrate or an alkaline salt
thereof, for instance potassium or sodium amoxycillin, preferably,
(crystallised) sodium amoxycillin or a mixture thereof, preferably
amoxycillin trihydrate; while the portion of amoxycillin which is
released slowly is provided as amoxycillin trihydrate or an
alkaline salt thereof, for instance potassium or (crystallised)
sodium amoxycillin or a mixture thereof, preferably (crystallised)
sodium amoxycillin.
[0072] Preferably, the modified release formulation is a tablet. In
a preferred modified release tablet comprising 1000 mg amoxycillin,
the immediate release phase comprises about 563 mg.+-.5%
amoxycillin trihydrate and the slow release phase about 438 mg
.+-.5% of amoxycillin, preferably as (crystallised) sodium
amoxycillin.
[0073] In a representative modified release tablet of the present
invention, the immediate release phase comprises about 438 mg
amoxycillin, preferably amoxycillin trihydrate lanate and the slow
release phase about 438 mg of amoxycillin, preferably
(crystallised) sodium amoxycillin, providing overall an 875 mg
(14:1) tablet.
[0074] In a further representative tablet of the present invention,
the immediate release phase comprises about 500 mg amoxycillin and
the slow release phase about 250 mg of amoxycillin, preferably
(crystallised) sodium amoxycillin, providing overall a 750 mg
(12:1) tablet.
[0075] It will be appreciated that the use of a mixture of
amoxycillin trihydrate and sodium amoxycillin is more generally
applicable to other pharmaceutical formulations comprising
amoxycillin.
[0076] Accordingly, in a further aspect, the present invention
provides for a pharmaceutical formulation comprising amoxycillin in
which amoxycillin is provided as a mixture of amoxycillin
trihydrate and sodium amoxycillin in a ratio of from 3:1 to 1:3,
more preferably 7:3 to 1:3, yet more preferably from 2:1 to 2:3,
most preferably 3:2 to 1:1. Preferably the formulation comprises
more than 500 mg amoxycillin, more preferably at least 600 mg, most
preferably at least 700 mg amoxycillin. Preferably, sodium
amoxycillin is crystallised sodium amoxycillin. 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 amoxycillin. Preferably, in modified release
formulations of the present invention, the amoxycillin in the
immediate release phase consists essentially of amoxycillin
trihydrate and the amoxycillin of the slow release phase consists
essentially of sodium amoxycillin.
[0077] For a tablet formulation, the immediate and slow release
phases may be provided in a number of different formats.
[0078] In a preferred aspect, the immediate and slow release phases
are provided as separate layers of a layered tablet.
[0079] Accordingly, in a further aspect, the present invention
provides for a layered tablet comprising an immediate release layer
comprising amoxycillin and a slow release layer comprising
amoxycillin and a release retarding excipient which tablet:
[0080] (a) is a bilayered tablet;
[0081] (b) comprises at least three layers, including an immediate
release and a slow release layer, and comprising at least 275 mg of
amoxycillin in the immediate release layer phase;
[0082] (c) comprises at least three layers, including an immediate
release and a slow release layer, and in which the release
retarding excipient in the slow release layer comprises xanthan gum
and/or a pharmaceutically acceptable organic acid; or
[0083] (d) comprises at least three layers, including an immediate
release and a slow release layer, and in which the amoxycillin is
provided as a mixture of amoxycillin trihydatre and sodium
amoxycillin, in a ratio of 3:1 to 1:3.
[0084] 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.
[0085] 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.
[0086] 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.
[0087] Slow release layers have a composition which comprises
amoxycillin together with a release retarding excipient which
allows for slow release of amoxycillin. 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.
[0088] 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.
[0089] Release retarding gellable polymers include methylcellulose,
carboxymethylcellulose, low-molecular weight
hydroxypropylmethylcellulose- , low-molecular weight
polyvinylalcohols, polyoxyethyleneglycols, non-cross linked
polyvinylpyrrolidone, xanthan gum etc.
[0090] Release retarding polymers simultaneously possessing
swelling and gelling properties include medium-viscosity
hydroxypropylmethylcellulose and medium-viscosity
polyvinylalcohols.
[0091] 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 diffuise.
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.
[0092] Examples of other polymers which may be used include
Methocel K4M (Trade Mark), Methocel E5 (Trade Mark), Methocel E50
(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.
[0093] 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.
[0094] 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.
[0095] 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 amoxycillin; from 10 to 20% by weight
of diluent/compression aid and from 1 to 2.5% by weight of
lubricant.
[0096] When xanthan gum is used as the release-retarding polymer,
the layer contains from 60 to 80% of amoxycillin, from 1 to 25%,
preferably 2 to 15%, more preferably 4 to 15% 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 amoxycillin, 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.
[0097] 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 amoxycillin, 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.
[0098] It has also been surprisingly found that when the
amoxycillin in the slow release layer is in the form of a soluble
salt thereof, such as sodium amoxycillin, then the release thereof
may be retarded by the inclusion of an organic acid.
[0099] 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 amoxycillin, for
instance sodium or potassium amoxycillin, preferably sodium
amoxycillin.
[0100] 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.
[0101] Accordingly, the present invention further provides for a
pharmaceutical formulation comprising a pharmaceutically acceptable
soluble salt of amoxycillin, for instance sodium amoxycillin, 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 (amoxycillin to organic acid).
[0102] It is believed that intimate contact between the organic
acid and the salt of amoxycillin 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 amoxycillin component from the
formulation.
[0103] Soluble pharmaceutically acceptable salts of amoxycillin
include alkali metal salts such as sodium and potassium; alkaline
earth metal salts such as magnesium and calcium, and acid salts
such as amoxycillin hydrochloride. Preferably, the salt is sodium
amoxycillin, more preferably crystallised sodium amoxycillin.
[0104] As used herein, the term "pharmaceutically acceptable
organic acid" shall mean 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 anhydrous citric acid.
[0105] 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.
[0106] 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 amoxycillin, 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 amoxycillin, from 10 to 20% of microcrystalline
cellulose, and from 1 to 2.5% of magnesium stearate, all % being by
weight of the layer.
[0107] In a representative example, a layered tablet comprises in
the slow release layer crystallised sodium amoxycillin 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 amoxycillin, about 78 mg +10%
citric acid and about 2% by weight of xanthan gum.
[0108] In a preferred layered tablet comprising 1000 mg
amoxycillin, the immediate release layer comprises about 563
mg.+-.5% amoxycillin, preferably amoxycillin trihydrate, and the
slow release layer about 438 mg.+-.5% of a soluble salt of
amoxycillin, preferably crystallised sodium amoxycillin, about 78
mg.+-.10% citric acid and about 2% by weight of xanthan gum.
[0109] 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.
[0110] 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.
[0111] 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).
[0112] 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 amoxycillin 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).
[0113] 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.
[0114] In a tablet without a barrier layer, the immediate release
layer comprises form 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.
[0115] 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.
[0116] It will be appreciated that 1000, 875 and 750 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 amoxycillin, preferably 1000, 875 or 750
mg.+-.5% amoxycillin, in combination with pharmaceutically
acceptable excipients or carriers. Preferably, the layered tablet
is a bi-layered tablet.
[0117] 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.
[0118] 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
blending together sodium amoxycillin, a diluent/compression aid
such as microcrystalline cellulose, a portion of the lubricant
(between 40 and 60%, typically about 50%) and a pharmaceutically
acceptable organic acid such as a fruit acid, for instance citric
acid, or a release retarding polymer such as xanthan gum or a
mixture thereof, 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.
[0119] Such slow release compacted granules may then be blended
with other excipients such as magnesium stearate, to form a slow
release compression blend.
[0120] In addition, amoxycillin trihydrate, microcrystalline
cellulose, a disintegrant such as sodium starch glycollate and a
lubricant such as magnesium stearate, are blended together,
compacted, for instance in a roller compactor or by slugging, and
then milled to form immediate release compacted granules. These
immediate release compacted granules may then be blended with other
excipients such as magnesium stearate and colloidal silica, to form
an immediate release compression blend.
[0121] The immediate release and slow release compression blends
may then be compressed as separate layers on a bilayer tablet
press, to form bilayer tablets.
[0122] Such slow release granules are novel. Accordingly, in a
further aspect, the present invention provides for compacted
granules comprising a soluble salt of amoxycillin, for instance
sodium amoxycillin, 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
amoxycillin trihydrate, a diluent/compression aid, and a release
retarding polymer, as hereinbefore defined.
[0123] 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.
[0124] 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.
[0125] Tablet cores may then be coated with a coating layer which
may be applied from 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 amoxycillin, 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
amoxycillin, a diluent/compression aid such as microcrystalline
cellulose, and a pharmaceutically acceptable organic acid such as a
fruit acid, for instance citric acid (if amoxycillin 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 amoxycillin (as hereinbefore
described) 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 , 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. Preferably, capsules are prepared from
materials such as HPMC or gelatin/PEG combination.
[0132] A process for the preparation of crystallised sodium
amoxycillin is described in EP-A-0 131 147 (Beecham Group plc).
[0133] 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 amoxycillin is released
immediately, and a further formulation, for instance a tablet,
comprising amoxycillin from which amoxycillin is released slowly.
The combined weights of amoxycillin in the conventional and slow
release formulations will provide the overall unit dosage. Thus,
for instance a dosage of 2000 mg may be provided by a combination
of two existing 500 mg amoxycillin tablets in combination with a
slow release tablet comprising 1000 mg of amoxycillin. Furthermore,
a dosage of 1750 mg may be provided by an existing 875 mg tablet
(SmithKline Beecham) in combination with a slow release tablet
comprising 875 mg of amoxycillin. In addition, a dosage of 1500 mg
may be provided by two existing 500 mg tablets of amoxycillin in
combination with a slow release tablet comprising 500 mg of
amoxycillin. Accordingly, in a further aspect, the present
invention provides for a kit comprising a conventional (immediate
release) tablet comprising amoxycillin, and a slow release tablet
comprising amoxycillin.
[0134] In a further aspect, the present invention provides for a
slow release pharmaceutical formulation, preferably a tablet,
comprising amoxycillin (as the sole active ingredient) formulated
with a release retarding excipient which causes a slow release of
the amoxycillin from the formulation, and excluding; tablets which
comprise 750 mg or less of amoxycillin in which the amoxycillin is
present essentially as amoxycillin trihydrate; or tablets
comprising from 400 to 500 mg amoxycillin in which amoxycillin is
present as a mixture comprising at least 70% amoxycillin trihydrate
and up to 30% sodium amoxycillin in combination with hydroxypropyl
methylcellulose as a release retarding excipient.
[0135] Such formulations may comprise from 100 to 1250 mg
amoxycillin which may be amoxycillin trihydrate or (crystallised)
sodium amoxycillin or a mixture thereof, for instance 500, 875 or
1000 mg amoxycillin. Suitable excipients for slow release are those
hereinbefore described for slow release layers. The formulation may
comprise from 1 to 25%, preferably from 2 to 15%, more preferably 4
to 10% of xanthan gum, or from 10 to 25, preferably 15 to 20% of a
hydroxypropylmethylcellulose, for instance Methocel K100LV or
Methocel K4M. Alternatively, such formulations may comprise citric
acid, optionally with xanthan gum, as hereinbefore described.
[0136] 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.
[0137] It will be appreciated that the present application relates
to inventions in which the drug substance consists essentially of
amoxycillin and does not extend inventions in which the drug
substance is amoxycillin in combination with potassium
clavulanate.
[0138] The invention will now be described by way of example only
with reference to the accompanying drawings, in which:
[0139] 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 FIG. 1A, the tablet comprises a first
layer (1) and a second layer (2), without any barrier layer or
coating layer. In FIG. 1B, the tablet comprises a first layer (1),
a second layer (2), and a barrier layer (3) sandwiched between the
first and second layers (1) and (2). In FIG. 1C, the tablet
comprises a first layer (1), a second layer (2), and a barrier
layer (3) located on the end face of the second layer (2). In FIG.
1D, the tablet comprises 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. In FIG. 1E, the tablet comprises 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.
[0140] All publications and references, including but not limited
to patents and patent applications, cited in this specification are
herein incorporated by reference in their entirety as if each
individual publication or reference were specifically and
individually indicated to be incorporated by reference herein as
being fully set forth. Any patent application to which this
application claims priority is also incorporated by reference
herein in its entirety in the manner described above for
publications and references.
EXAMPLE 1
1000 mg Modified Release Tablet
[0141]
1 % Name of Ingredient mg/tablet w/w Immediate Release Layer
Amoxycillin Trihydrate 654.1* 40.88 Microcrystalline Cellulose
216.6 13.28 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 Sodium Amoxycillin
480.8** 30.05 Microcrystalline Cellulose 113.2 7.08 Xanthan Gum
14.0 0.87 Citric Acid (anhydrous) 78.0 4.87 Colloidal Silicon
Dioxide 1.5 0.09 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
amoxycillin based on an assay of 86.0% **Equivalent to 437.5 mg
amoxycillin based on an assay of 91.0%
EXAMPLE 2
1000/62.5 mg Modified Release Tablet The immediate release layer
and film coat are as for the tablet of Example 1
[0142]
2 Name of Ingredient mg/tablet % w/w Slow Release Layer Sodium
Amoxycillin 480.8** 30.05 Microcrystalline Cellulose 127.2 7.95
Citric Acid (anhydrous) 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
amoxycillin based on an assay of 91.0%
Preparation of Modified Release Tablets
[0143] Amoxycillin trihydrate and microcrystalline cellulose (about
90% of the total) were milled and screened and then blended with
magnesium stearate. This blend was roller compacted, using a
Chilsonater, and milled to form immediate release granules. The
remaining magnesium stearate and microcrystalline cellulose, sodium
starch glycollate and colloidal silicon dioxide were then milled
and screened and added to these granules and blended to form the
immediate release compression blend.
[0144] Crystallised sodium amoxycillin microcrystalline cellulose
(about 70% of the total) and anhydrous citric acid were milled and
blended with xanthan gum (if applicable), magnesium stearate (about
70% of the total) and colloidal silicon dioxide. This blend was
then roller compacted in a Chilsonator, and milled to form slow
release granules. The remaining magnesium stearate and
microcrystalline cellulose were added to these granules and blended
to form the slow release compression blend.
[0145] 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.
[0146] Finally, the tablet cores were coated with an aqueous film
coating, using a 15% solids aqueous suspension, in a 60 inch
coating equipped with 4 spray guns.
EXAMPLE 3
Slow Release Tablet (875 mg)
[0147]
3 mg/tablet % (a) Sodium Amoxycillin Tablet Crystallised Sodium
Amoxycillin 961.54 73.96 91%* Dried Microcrystalline Cellulose
273.46 21.04 Magnesium Stearate 13.0 1.00 Xanthan gum 200 mesh**
52.0 4.00 Total 1300 100 (b) Sodium Amoxycillin Tablet with citric
acid Crystallised Sodium Amoxycillin 961.54 66.31 91%* Dried
Microcrystalline Cellulose 288.96 19.92 Magnesium Stearate 14.50
1.00 Citric acid (anhydrous) 156 10.75 Xanthan gum 200 mesh** 29.0
2.00 Total 1450 100 (c) Amoxycillin Trihydrate Tablet Amoxycillin
Trihydrate 86%* 1017.4 78.26 Dried Microcrystalline Cellulose 217.6
16.74 Magnesium Stearate 13.0 1.00 Xanthan Gum, 200 mesh** 52.0
4.00 Total 1300 100 *adjusted for the potency of the amoxycillin
component and corresponding to 875 mg amoxycillin, **Xantural
75
EXAMPLE 4
875 mg Modified Release Tablet
Slow Release Layer
[0148] This may be formed using half the quantities given above,
for a slow release layer comprising about 438 mg amoxycillin.
4 Immediate release layer - 1 Amoxycillin trihydrate 507 mg (equiv
to amoxycillin free acid) (438) Microcrystalline cellulose (Avicel
PH102) 196.8 Sodium starch glycollate (Explotab) 26 Magnesium
stearate 6.5 Immediate release layer - 2 Amoxycillin trihydrate 507
mg (equiv to amoxycillin free acid) (438) Microcrystalline
cellulose (Avicel PH102) 206 Sodium starch glycollate (Explotab) 34
Talc 67 Magnesium stearate 25 Silica (Syloid) 17
Barrier Layers
[0149] Barrier layers and methods for their preparation are
described in WO 95/20946 (SmithKline Beecham).
Preparation of Tablets
[0150] 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.
[0151] In some cases, where the bulk density is rather low, a
densifying step (pretabletting and sieving as in the briquetting
method) may be required in order to achieve the nominal weight of a
particular layer.
[0152] 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
Dissolution Testing Methods
[0153] The release of amoxycillin from tablets into static media
was measured using the <711>Dissolution Test, Apparatus 2,
provided in USP 23, 1995.
5 Test specifications: Temperature: 37.0 .+-. 0.5.degree. C.
Medium: Deionized water, 900 mL Paddle speed 75 rpm
Method
[0154] 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 272nM. The resulting dissolution
profile for the tablets of Example 1 and 2 are shown as FIG. 2.
In vivo Pharmacokinetic Evaluation of Formulations
[0155] The bioavailability of dosages comprising amoxycillin and
potassium clavulante were evaluated in two human volunteer studies,
Study A and Study B. It was not anticipated that the presence of
potassium clavulanate would affect the performance of the
amoxycillin component.
[0156] The two studies 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 amoxycillin 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.
[0157] Samples were assayed for amoxycillin using a method based on
protein precipitation with acetonitrile. Amoxycillin 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]-amoxycillin, 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 5mM 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, amoxycillin and [.sup.13C.sub.6]-amoxycillin. The NRM
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). 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.
[0158] 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 (C.sub.max) 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 halflife (T1/2) was calculated as
ln(2)/lz.
[0159] 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 WL., 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.
[0160] 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
.mu.g/mL for amoxycillin.
[0161] The mean concentration-time profiles for amoxycillin was
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 .mu.g/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.
[0162] 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.
[0163] 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.
[0164] Study A
[0165] 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:
[0166] (a) a dosage of. 1750/125 mg amoxycillin/potassium
clavulanate, made up of a combination of one modified release
tablet comprising 875/125 mg amoxycillin trihydrate/clavulanate and
4% xanthan gum and one immediate release tablet comprising 875 mg
amoxycillin trihydrate (formulation I);
[0167] (b) a dosage of 1750/125 mg amoxycillin/potassium
clavulanate, made up of a combination of one modified release
tablet comprising 875/125 mg crystallised sodium
amoxycillin/clavulanate and 4% xanthan gum and one immediate
release tablet comprising 875 mg amoxycillin trihydrate
(formulation II);
[0168] (c) a dosage of 1750/125 mg amoxycillin/potassium
clavulanate, made up of a combination of one modified release
tablet comprising 875/125 mg crystallised sodium
amoxycillin/clavulanate, citric acid (156 mg) and 2% xanthan gum
and one immediate release tablet comprising 875 mg amoxycillin
trihydrate (formulation III);
[0169] (d) a dosage of 1500/125 mg amoxycillin/potassium
clavulanate (made up of a modified release tablet comprising
500/125 mg crystallised sodium amoxycillin/potassium clavulanate
and two immediate release tablet comprising 500 mg amoxycillin
trihydrate (Amoxyl, SmithKline Beecham) (formulation IV); and
[0170] (e) a dosage of 1750/125 mg amoxycillin/potassium
clavulanate, made up of a combination of one immediate release
tablet comprising 875/125 mg amoxycillin trihydrate/clavulanate
(Augmentin, SmithKline Beecham) and one immediate release tablet
comprising 875 mg amoxycillin trihydrate (Amoxyl, SmithKline
Beecham) (formulation V).
Results
[0171]
6 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 amoxycillin concentration of 4 .mu.g/ml .sup.3Area under the
curve (0 to 12 h, .mu.g.h/mL)
[0172] The pharmacokinetic profile is shown in FIG. 3.
[0173] Study B
[0174] 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:
[0175] (a) a dosage of 2000/125 mg amoxycillin/potassium
clavulanate, made up of two bilayer tablets according to Example 1
(formulation VI);
[0176] (b) a dosage of 2000/125 mg amoxycillin/potassium
clavulanate, made up of two bilayer tablets according to Example 2
(formulation VII);
[0177] (c) a dosage of 2000/125 mg amoxycillin/potassium
clavulanate, made up of a combination of three tablets each
comprising 500 mg amoxycillin (Amoxyl, SmithKline Beecham) and one
tablet comprising 500 mg amoxycillin and 125 mg potassium
clavulanate (Augmentin, SmithKline Beecham) (formulation VII).
Results
[0178]
7 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 amoxycillin concentration
of 4 .mu./ml .sup.3T > MIC is the time (h) above an amoxycillin
concentration of 8 .mu./ml .sup.4Area under the curve (0 to 12 h,
.mu.g.h/mL).
[0179] Comparison of the AUC values for formulations VI and VII
(bilayer tablets) against VIII (immediate release tablets) shows
that the absorption of the amoxycillin component has not been
compromised by formulating a part of it in a slow release layer.
This means that there is no extra, unabsorbed amoxycillin which may
otherwise cause problems further down in the GI tract, for instance
due to a lack of absorption and destruction of symbiotic
bacteria
[0180] It was also found that for formulation VI, there was less
inter-subject variability in the amoxycillin 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.
[0181] The pharmacokinetic profile for amoxycillin plasma
concentration is shown in FIG. 4 (in which A is formulation VI, B
is formulation VII, D is formulation VIII).
[0182] 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
[0183] 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).
* * * * *