U.S. patent application number 13/074944 was filed with the patent office on 2011-07-21 for composition.
This patent application is currently assigned to SmithKline Beecham Limited. Invention is credited to Shing Yue CHAN, Timothy James GRATTAN, Bounkhiene SENGMANEE.
Application Number | 20110177168 13/074944 |
Document ID | / |
Family ID | 9890126 |
Filed Date | 2011-07-21 |
United States Patent
Application |
20110177168 |
Kind Code |
A1 |
CHAN; Shing Yue ; et
al. |
July 21, 2011 |
COMPOSITION
Abstract
A pharmaceutical composition comprising an immediate release
phase and a sustained release phase of paracetamol is described
which has a unique in vitro dissolution profile resulting in
advantageous pharmacokinetic properties.
Inventors: |
CHAN; Shing Yue;
(Parsippany, NJ) ; GRATTAN; Timothy James;
(Weybridge, GB) ; SENGMANEE; Bounkhiene;
(Ermington, AU) |
Assignee: |
SmithKline Beecham Limited
|
Family ID: |
9890126 |
Appl. No.: |
13/074944 |
Filed: |
March 29, 2011 |
Current U.S.
Class: |
424/472 ;
514/629 |
Current CPC
Class: |
A61P 29/00 20180101;
A61K 31/167 20130101; A61K 9/209 20130101; A61P 25/00 20180101 |
Class at
Publication: |
424/472 ;
514/629 |
International
Class: |
A61K 9/24 20060101
A61K009/24; A61K 31/167 20060101 A61K031/167; A61P 25/00 20060101
A61P025/00 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 19, 2000 |
GB |
0009522.4 |
Claims
1. A pharmaceutical composition comprising a bilayer tablet having
an immediate release phase of paracetamol and a sustained release
phase of paracetamol for oral administration every 8 hours wherein,
the immediate release phase being in one layer and comprising from
about 10 to 45% by weight of the total paracetamol; and the
sustained release phase being in the other layer, and the sustained
release layer comprising paracetamol comprising from about 55% to
90% by weight of the total paracetamol in admixture with a matrix
forming water soluble polymer which is selected from two different
viscosities of hydroxypropylmethylcellulose present in an amount
from 0.5 to 10% by weight of the sustained release phase and
wherein the hydroxypropylmethylcellulose is present as a low
viscosity hydroxypropylmethylcellulose and a high viscosity
hydroxypropylmethylcellulose in a ratio of about 1:2; said
composition comprising from 600 to 700 mg of paracetamol per unit
dose and a pharmaceutically acceptable carrier, characterized in
having an in vitro paracetamol dissolution profile (as determined
by the USP type III apparatus, reciprocating basket, with 250 ml of
0.1M HCl at 37 C set at a cycle speed of 15 strokes/min) with the
following constraints: 30 to 48% released after 15 minutes 56 to
75% released after 60 minutes >85% released after 180
minutes.
2. The composition according to claim 1 in which the in vitro
dissolution profile has the following constraints: 35 to 47%
released after 15 minutes 58 to 73% released after 60 minutes
>90% released after 180 minutes.
3. The composition according to claim 1 in which the in vitro
dissolution profile has the following constraints: 38 to 44%
released after 15 minutes 62 to 70% released after 60 minutes
>95% released after 180 minutes.
4. The composition according to claim 1 in which the paracetamol is
present in an amount of 630 to 680 mg per unit dose.
5. The composition according to claim 4 in which the paracetamol is
present in an amount of 650 to 667 mg per unit dose.
6. The composition according to claim 1 in which the matrix forming
polymer is present in an amount from 1 to 6% by weight of the
sustained release phase.
7. The composition according to claim 6 in which the matrix forming
polymer is present in an amount from 2 to 4% by weight of the
sustained release phase.
8. The composition according to claim 1 in which the sustained
release phase comprises from 65 to 75% by weight of the total
paracetamol.
9. The composition according to claim 8 in which the immediate
release phase comprises from 25 to 35% by weight of the total
paracetamol.
10. A composition according to claim 1 in which the sustained
release phase comprises from 60 to 80% by weight of the total
paracetamol, and the immediate release phase comprises from 20 to
40% by weight of the total paracetamol.
Description
RELATED APPLICATION INFORMATION
[0001] This application is a continuation of application Ser. No.
10/257,077, filed 6 Jun. 2003, (allowed) which is a .sctn.371
national stage entry of International Application No.
PCT/EP01/04302, filed 12 Apr. 2001, which claims the benefit of
priority from GB 0009522.4, filed 19 Apr. 2000.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to pharmaceutical compositions
containing N-acetyl-p-aminophenol, known by the generic names
paracetamol, acetaminophen and APAP (hereinafter referred to as
paracetamol). In particular, the invention relates to a sustained
release paracetamol formulation having an advantageous
pharmacokinetic profile.
[0003] Paracetamol is an analgesic and antipyretic agent which is
widely used in prescription and non-prescription medicines, often
in combination with other biologically active compounds.
[0004] The elimination half-life of paracetamol is reported to be
in the range of 1.9-2.5 hours. Its absorption following oral doses
of conventional immediate release tablets is characterised by
passive absorption with high bioavailability (80%) and rapidly
occurring maximum plasma concentration (t.sub.max 30-90 min). These
characteristics determine the conventional dosage regimen of 1000
mg every 4 to 6 hours for the drug. Although this regimen is
acceptable in the short-term treatment of acute pain, it becomes
inconvenient in the context of long-term treatment of sub-chronic
or chronic pain. Therefore, extended release paracetamol may
improve patient's quality of life by reducing the number of doses
to be taken and providing steadier levels of the drug in the blood
as determined by plasma or serum drug concentrations.
[0005] A paracetamol product designed for tid oral dosing should
contain enough paracetamol to give close to the maximum daily dose
when two tablets are taken three times daily, ie about 600 mg to
667 mg per tablet.
[0006] Such a product is described in EP-A-305051 (McNeil Inc)
which discloses a sustained release bilayer tablet containing
either 650 or 667 mg of paracetamol. Such prior disclosed tablets
contain equal amounts of paracetamol in an immediate release layer
and a sustained release layer. The sustained release layer is
provided by a matrix comprising a mixture of hydroxyethylcellulose
and polyvinyl-pyrrolidone. McNeil Inc markets such a bilayer tablet
as Tylenol.RTM. Extended Relief in the US.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1 shows the mean pharmacokinetic profiles of Tablet A,
Tablet B and a 500 mg immediate release paracetamol tablet.
[0008] FIG. 2 shows mean pharmacokinetic profiles as described
therein.
[0009] FIG. 3 shows mean plasma paracetamol concentrations versus
time as described therein.
[0010] FIG. 4 shows the fluctuation index for an SR and an IR
product as described therein.
DESCRIPTION OF THE INVENTION
[0011] A sustained release paracetamol oral dosage form designed
for tid dosing should also provide all the benefit of immediate
release paracetamol plus a sustained action. Therefore an ideal
sustained release paracetamol product for oral administration
should be suitable for treating both acute pain such as dental pain
or headache and chronic pain, such as the pain associated with
arthritis.
[0012] One potential disadvantage concerning a formulation
containing more than the standard dose of paracetamol (500 mg) is
accidental or intentional overdose. In such circumstances more
paracetamol will be ingested from an extended release formulation
compared to a conventional immediate release formulation for any
given number of unit doses such as tablets. This could have serious
consequences for an overdose patient, especially if a large amount
of the dose is absorbed before rescue therapy could be initiated.
It would therefore be preferable if the unit dose (such as a
tablet) was designed to limit the amount of paracetamol absorbed in
the first few hours following dosing. An advantageous sustained
release formulation should therefore demonstrate a lower mean
C.sub.max (preferably at least 20% lower) than a conventional
immediate release formulation which would be indicative of a lower
initial exposure.
[0013] One possible consequence of formulating an orally
administered paracetamol product designed to have a lower C.sub.max
and slower rate of absorption, is that the extent of absorption may
also be decreased, this could then lead to sub-therapeutic systemic
levels of drug 6-8 hours following dosing thus leading to premature
onset of pain before administration of a further dose.
[0014] One further advantage for a product designed to have a lower
C.sub.max and slower rate of absorption where the extent of
absorption is essentially complete (as demonstrable by an
equivalent dose corrected AUC compared to immediate release
tablets) is that it should have the advantage of maintaining
therapeutic levels of paracetamol in plasma for extended periods
following dosing and hence provide analgesia for longer than a
conventional immediate release tablet or capsule. Furthermore as a
result of a reduced C.sub.max, systemic levels of paracetamol are
likely to remain at more constant levels, thus benefiting the
patient.
[0015] Whilst such a formulation should have a lower C.sub.max
compared to a conventional immediate formulation, it is still
desirable to have a fast onset of action, therefore initial levels
of drug in plasma should be rapidly attained (preferably within 30
minutes) and maintained at therapeutic levels of >3 mcg/ml for
at least 1.3 hours and preferably 1.5 hours longer than a standard
immediate release tablet or capsule. In addition the extent of
absorption should be equivalent to a conventional immediate release
formulation.
[0016] Furthermore, upon multiple dosing of a sustained release
formulation the steady state plasma levels of paracetamol should be
more constant than those achieved following multiple dosing of a
conventional immediate release formulation. A convenient measure of
the fluctuation in plasma concentrations is the fluctuation index
(FI) which is defined as (C.sub.max-C.sub.min)/C.sub.average. A low
FI number (ie <1) is considered to be advantageous as it
suggests a reduction in the variability of plasma concentrations
indicative of a safer product.
[0017] In summary, an advantageous sustained release paracetamol
product for oral administration should possess the following
pharmacokinetic attributes:
[0018] (1) therapeutically active drug plasma concentrations should
be attained rapidly.
[0019] (2) the mean maximum plasma concentration (C.sub.max) should
be at least 20% lower compared to standard immediate release
formulation;
[0020] (3) a mean plasma concentration of at least 3 mcg/ml should
be maintained for at least 1.3 hours longer (preferably 1.5 hours
longer) than a standard immediate release formulation;
[0021] (4) the extent of absorption should be equivalent to a
conventional immediate release paracetamol;
[0022] (5) plasma levels of paracetamol following multiple dosing
should be more constant compared to multiple dosing of an immediate
release formulation as measured by a reduction in the fluctuation
index.
[0023] Surprisingly it has now been discovered that such an
advantageous pharmacokinetic profile can be provided by a two phase
(immediate release and sustained release) formulation of
paracetamol which satisfies a unique in vitro dissolution
profile.
[0024] Accordingly, in a first aspect the present invention
provides a pharmaceutical composition, having an immediate release
phase and a sustained release phase of paracetamol, said
composition comprising from 600 to 700 mg of paracetamol per unit
dose and a pharmaceutically acceptable carrier, characterised in
having an in vitro paracetamol dissolution profile (as determined
by the USP type III apparatus, reciprocating basket, with 250 ml of
0.1M HCl at 37 C set at a cycle speed of 15 strokes/min) with the
following constraints: [0025] 30 to 48% released after 15 minutes
[0026] 56 to 75% released after 60 minutes [0027] >85% released
after 180 minutes.
[0028] Preferably the in vitro dissolution profile has the
following constraints: [0029] 35 to 47% released after 15 minutes
[0030] 58 to 73% released after 60 minutes [0031] >90% released
after 180 minutes.
[0032] Most preferably the in vitro dissolution profile has the
following constraints: [0033] 38 to 44% released after 15 minutes
[0034] 62 to 70% released after 60 minutes [0035] >95% released
after 180 minutes.
[0036] Suitably paracetamol is present in an amount of 630 to 680
mg per unit dose, more preferably in an amount of 650 to 667 mg per
unit dose and more preferably in an amount of 665 mg per unit dose,
so that a tid dosage regimen will deliver a maximum daily dose of
about 4 g of paracetamol when two unit doses are taken three times
daily.
[0037] Preferred unit dose forms include tablets or capsules.
[0038] The immediate release phase and the sustained release phase
both contain paracetamol and a pharmaceutically acceptable carrier
and are suitably combined together into a unit dose form. For
example the immediate release phase and the sustained release phase
can be separate blends, granules or pellets which can be mixed
together before being compressed into a tablet or being filled into
a capsule. A preferred unit dose form is a bilayer tablet having an
immediate release layer of paracetamol and a sustained release
layer of paracetamol.
[0039] Suitably the sustained release phase comprises a
matrix-forming polymer to provide a sustained release of
paracetamol.
[0040] Examples of matrix-forming polymers include both water
soluble and water insoluble polymers or mixtures thereof, with
soluble polymers being preferred. Examples of water soluble
polymers include hydroxypropylmethylcellulose,
hydroxyethylcellulose, carboxymethylcellulose, sodium
carboxymethylcellulose, methacrylate hydrogels, polyethylene
glycols and xanthan gum. An example of a water insoluble polymer is
ethylcellulose. A preferred matrix-forming polymer is
hydroxypropylmethylcellulose.
[0041] The amount of matrix-forming polymer in the sustained
release phase and the relative amounts of paracetamol in the
sustained release and immediate release phases are selected so as
to provide the desired in vitro dissolution rate as herein before
described.
[0042] Thus, the matrix-forming polymer is suitably present in an
amount from 0.5 to 10%, preferably from 1 to 6%, and more
preferably from 2 to 4% by weight of the sustained release
phase.
[0043] Suitably the sustained release phase comprises from 55 to
90% by weight of the total paracetamol, and the immediate release
phase comprises from 10 to 45% by weight of the total paracetamol.
Preferably the sustained release phase comprises from 60 to 80% by
weight of the total paracetamol, and the immediate release phase
comprises from 20 to 40% by weight of the total paracetamol. More
preferably the sustained release phase comprises from 65 to 75% by
weight of the total paracetamol, and the immediate release phase
comprises from 25 to 35% by weight of the total paracetamol.
[0044] Compositions of the present invention will generally contain
at least one pharmaceutically acceptable carrier conventionally
used in the art of tablet and/or capsule formulation. Suitable
carriers which may be incorporated include lubricants, for example
magnesium stearate and stearic acid; disintegrants, for example
cellulose derivatives and starches; binders, for example modified
starches, cellulose derivatives and polyvinylpyrrolidone; glidants,
for example colloidol silicas; compression aids, for example
cellulose derivatives; as well as preservatives, suspending agents,
wetting agents, flavouring agents, bulking agents, adhesives,
colouring agents, sweetening agents appropriate to their form.
[0045] In addition to paracetamol, compositions of the invention
may also contain other pharmaceutically active agents, for example
other analgesics, anti-inflammatory analgesic agents,
decongestants, antihistamines, antitussive agents, etc.
Compositions may also contain a pharmaceutically acceptable
analgesic adjuvant, for example caffeine. The compositions of the
present invention can be formulated by conventional methods of
admixture such as granulating, blending, filling and
compressing.
[0046] For example tablets can be produced by a wet granulation
process, where the immediate release phase and sustained release
phase are separately prepared. Suitably, for either the immediate
release or sustained release phase, the active drug substance and
excipients are screened and mixed in a high shear mixer granulator
or fluid bed dryer. The blend is granulated by the addition of a
granulating solution (typically purified water, disintegration
agent dissolved/dispersed in purified water, or drug
dissolved/dispersed in purified water or a suitable solvent)
sprayed into the high shear mixer granulator or fluid bed dryer. If
desired wetting agents e.g. surfactants can be added. The resulting
granules (optionally pelletised) are dried usually with residual
moisture of 1-5% by tray, fluid bed or microwave drying techniques.
The dried granules are milled to produce a uniform particle size,
the granules are blended with extragranular excipients as
necessary, typically a lubricant and glidant (e.g. magnesium
stearate, silicon dioxide). The separately prepared immediate
release and sustained release granules can then be compressed
together using a rotary tablet press (such as a bilayer tablet
press) typically in the range of 600 to 750 mg. The resulting
tablets can be coated in a pan coater typically with a 1-5% aqueous
film coat, followed by a wax polishing.
[0047] Alternatively tablets can be produced by a direct
compression process. Suitably the active drug substance and
excipients for the immediate release and sustained release phases
are separately screened and mixed in a suitable blender e.g. a
cone, cube or V-blender. Other excipients are added as necessary,
and further blended. The separately prepared immediate release and
sustained release phases can be combined and compressed together
using a rotary tablet press as hereinbefore described. The
resulting tablets can be coated in a pan coater.
[0048] Tablets can also be prepared by using both methods of wet
granulation and direct compression. For example the sustained
release phase can be prepared by wet granulation as hereinbefore
described, whilst the immediate release phase can be prepared by
blending the excipients for direct compression. Furthermore
commercially available blends of immediate release paracetamol are
also available for direct compression such as DC90 paracetamol
supplied by Rhone Poulenc. The two phases can then be combined and
compressed together as hereinbefore described.
[0049] Suitably capsules can be produced by separately preparing
the immediate release and sustained release phases by screening and
mixing the active drug substance and excipients in a suitable
blender e.g. a cone, cube or V-blender. Other excipients are added
as necessary, typically a lubricant and glidant, and the mixture
blended. The separately prepared immediate release and sustained
release phased can then be blended and filled into capsules with a
fill weight typically ranging from 600 to 750 mg using a standard
capsule filling machine.
[0050] The following Examples illustrate the advantageous
properties of the compositions of the present invention.
Example 1
[0051] This Example compares the properties of a commercially
available immediate release 500 mg paracetamol tablet with two
prototype sustained release bilayer tablets (Formulations A and B)
which both have an in vitro dissolution profile outside the scope
of the present invention.
[0052] These prototype tablets containing a total of about 650 mg
of paracetamol were prepared from the following ingredients:
TABLE-US-00001 Tablet Formulation A Tablet Formulation B Ingredient
mg/tablet % w/w mg/tablet % w/w Sustained Release Layer Paracetamol
264.08 34.75 403.39 52.10 High viscosity HPMC 18.96 2.49 28.96 3.74
Pregelatinised Starch 21.05 2.77 32.15 4.15 Polyvinylpyrrolidone
5.88 0.77 8.98 1.16 Low viscosity HPMC 5.09 0.67 7.77 1.00
Magnesium Stearate 0.95 0.12 1.45 0.19 Immediate Release Layer
Directly compressible 436.00 57.36 283.5 36.62 paracetamol
granulation DC90# (Paracetamol content in (389.80) (51.28) (260.00)
(33.58) DC90) Film and Wax Coating 8.05 1.06 8.05 1.04 Total 760.05
100.000 774.25 100.00 % w/w SR:IR APAP 41.1:59.9 60.5:39.5 # DC90
is a commercially available directly compressible paracetamol
granulation containing about 90% by weight of paracetamol together
with pregelatinised starch, croscarmellose sodium,
polyvinylpyrrolidone and stearic acid.
[0053] The release profiles of test formulations A and B were
characterised using the USP type III apparatus (reciprocating
basket) with 250 ml 0.1M HCl at 37 C set at a cycle speed of 15
strokes/min. Both formulations comprised an immediate release
component which released within the first fifteen minutes and a
sustained release component that released slowly after 15 minutes
as detailed in table 1.
TABLE-US-00002 TABLE 1 Dissolution profiles for tablets A and B %
paracetamol released Time in Prototype A Paracetamol Prototype B
Paracetamol minutes 650 mg Sustained Release 650 mg Sustained
Release 15 minutes 51.3 39.1 60 minutes 71.2 54.7 120 minutes 87.0
68.7 180 minutes 99.3 79.4 240 minutes 103.7 89.4 300 minutes 96.0
360 minutes 97.3
[0054] The two prototype formulae were assessed in a
pharmacokinetic study in healthy fasted volunteers. The study
design was three-way crossover involving six volunteers, using
paracetamol 500 mg immediate release tablets as a control. The mean
pharmacokinetic profiles are shown in FIG. 1.
[0055] The results from the biostudy demonstrated that neither
formulation A or B met the criteria of achieving a mean paracetamol
plasma concentration of 3 mcg/ml for at least 1.5 hours longer than
the immediate release tablet, with levels of >3 mcg/ml only
being maintained for approximately 5.4 hours for formulation A and
5.8 hours for formulation B, compared to 4.6 hours for the
reference formula (500 mg immediate release paracetamol
tablets).
[0056] The mean C.sub.max values for Formulation A and formulation
B were 15.0 and 9.6 mcg/ml respectively compared to 17.3 mcg/ml for
the 500 mg immediate release tablet and the mean dose corrected AUC
values were 45.9 mcg hr/ml for formulation A, 40.1 mcg hr/ml for
formulation B and 49.3 mcg hr/ml for the 500 mg immediate release
tablet. The lower AUC value observed for Formulation B was
indicative of a reduced extent of absorption.
Example 2
[0057] This Example compares the properties of a commercially
available immediate release 500 mg paracetamol tablet with a
sustained release bilayer tablet (Formulation C) having an in vitro
dissolution profile falling within the scope of the present
invention.
[0058] This advantageous bilayer tablet containing a total of 666.6
mg of paracetamol was prepared from the following ingredients:
TABLE-US-00003 Tablet Formulation C Ingredient mg/tablet % w/w
Sustained Release Layer Paracetamol 473.57 64.39 High viscosity
HPMC 15.43 2.10 Pregelatinised Starch 5.14 0.70
Polyvinylpyrrolidone 10.28 1.40 Low viscosity HPMC 8.23 1.12
Magnesium Stearate 1.54 0.21 Immediate Release Layer Directly
compressible 214.92 29.22 paracetamol granulation DC90 (Paracetamol
content in (193.43) (26.30) DC90) Film and Wax Coating 6.305 0.86
Total 735.42 100.00 % w/w SR:IR APAP 71:29
[0059] The release profile of test formulation C was characterised
using the USP type III apparatus (reciprocating basket) as
hereinbefore described and was found to have the following
dissolution rate as detailed in table 2.
TABLE-US-00004 TABLE 2 Dissolution Profile for Formulation C Time
In-vitro release Results (minutes) (% paracetamol released) 15
39.4% 60 64.4% 120 89.0% 180 101.8%
[0060] Formulation C was assessed in a pharmacokinetic study. The
study design was a four-way crossover, using a panel of 26 healthy
volunteers which compared the pharmacokinetics of paracetamol in
serum in both fed and fasted states following a two tablet dose of
the formula C and a two tablet dose of a currently marketed
standard immediate release paracetamol 500 mg tablet. The mean
pharmacokinetic profiles are shown in FIG. 2.
[0061] Formulation C met all of the pharmacokinetic criteria
outlined above for an ideal sustained release paracetamol tablet.
The pharmacokinetic analysis demonstrated that the C.sub.max was
significantly lower for formulation C (mean value 10.1 mcg/ml)
compared to the reference immediate release product (mean value
18.7 mcg/ml) (in the fasted state). In addition therapeutic serum
concentrations were rapidly attained and mean serum levels of 3 mcg
were maintained until 7.4 hours post dose compared to only 5.3
hours post dose for the 500 mg immediate release tablet. The two
formulae were bioequivalent with respect to AUC indicating that the
extent of absorption was the same for formulation C as for
conventional immediate release paracetamol.
[0062] These advantageous properties of formulation C are
particularly surprising when compared with the plasma
concentrations described in Example 1 of EP-A-305051 which suggests
that the C.sub.max of the prior disclosed sustained release
paracetamol formulation is as high as that observed for an
immediate release formulation
Example 3
[0063] This Example compares the properties of a commercially
available immediate release 500 mg paracetamol tablet with another
sustained release bilayer tablet (Formulation D) having an in vitro
dissolution profile falling within the scope of the present
invention.
[0064] The bilayer tablet of Formulation D was essentially similar
to Formulation C but contained a total of 665 mg of paracetamol and
had a slightly different ratio of sustained release to immediate
release paracetamol (% w/w SR:IR APAP was 69:31).
[0065] The release profile of test formulation D was characterised
using the USP type III apparatus (reciprocating basket) as
hereinbefore described and was found to have the following
dissolution rate as detailed in table 3.
TABLE-US-00005 TABLE 3 Dissolution Profile for Formulation D Time
In-vitro release Results (minutes) (% paracetamol released) 15
40.8% 60 65.0% 120 90.2% 180 101.8%
[0066] Formulation D was assessed in a further biostudy which
involved 27 subjects. The study was an open multiple dose crossover
in healthy subjects. There were two study sessions each consisting
of two days of dosing with a 24 hour blood sampling on the second
day. The study sessions were separated by 48 hours.
[0067] The two study treatments were as follows: [0068] 2 bilayer
sustained release (SR) tablets of formulation D each containing 665
mg given three times per day (every 8 hours). [0069] 2 immediate
release (IR) paracetamol 500 mg tablets given four times per day
(every 6 hours).
[0070] Pharmacokinetic analysis was conducted for the period of 24
hours-48 hours following commencement of the dosing schedule. The
results showed that the two treatments were bioequivalent with
respect to AUC.sub.24-48 and the SR formulation provided a lower
C.sub.max a higher C.sub.min and a substantially lower fluctuation
index (FI) compared to the immediate release formulation. The
values for FI were 0.957 for the SR tablet and 1.388 for the
immediate release paracetamol tablet. The difference was highly
significant (P<0.001). Mean plasma paracetamol concentrations
versus time are shown in FIG. 3.
[0071] The substantially lower FI for the SR product is surprising
considering previous reports for a steady state biostudy conducted
with a 650 mg bilayer tablet (Tylenol Extended Relief) which showed
that the SR product had a numerically higher FI (of 1.49) compared
to a reference 500 mg IR tablet (of 1.44) as illustrated in FIG. 4.
Furthermore, Paracetamol plasma levels were maintained
substantially above 3 mcg/ml for the entire study period, which is
in contrast to the steady state study reported for Tylenol.RTM.
Extended relief.
[0072] The low FI number of <1 found for formulation D, is
particularly advantageous for a sustained release formulation as it
indicates a reduction in the variability of plasma concentration
suggesting a much safer and more reliable product.
Example 4
[0073] This example compares the clinical properties of a
commercially available paracetamol 500 mg immediate release (IR)
tablet with a sustained release (SR) bilayer tablet of Formulation
D.
[0074] The study was a multicentre, single dose, double-blind,
double dummy, two armed parallel group efficacy study involving 510
patients with post-surgical dental pain following third molar
extraction under general anesthesia to compare the efficacy of a 2
tablet dose of either a sustained release tablet containing 665 mg
paracetamol per tablet (252 patients) or a 2 tablet dose of a
commercially available tablet containing 500 mg of immediate
release paracetamol per tablet (258 patients).
[0075] Patients were randomised to receive one of the two
treatments following surgery, when post-surgical dental pain had
reached moderate/severe intensity, defined by a recording of 30 mm
on a visual analogue scale. Patients remained in the clinic for 4
hours after receiving study medication and completed pain
assessments at intervals up to and including 4 hours when a global
assessment of pain relief was made. Patients were discharged from
the clinic and continued to complete pain assessments at home for 4
hours. If additional analgesia was taken during the 8 hour
evaluation period (re-medication), the patient was considered to
have completed the study.
[0076] Parameters measured during the study were as follows:
Primary Parameter
[0077] Overall pain relief: measured on a 5-point verbal scale
(poor, fair, good, very good and excellent) 4 hours following
treatment.
Secondary Parameters
[0078] Other pain assessments were made 0, 0.5, 1, 1.5, 2, 3, 4, 5,
6, 7, and 8 hours after treatment (see below). The results provided
information on pain relief and pain intensity over time. In
addition, time to re-mediation was measured.
[0079] Pain relief: based on a 5-point visual rating scale [no
relief (0), a little relief (1), some relief (3), a lot of relief
(4), complete relief (5)]. The following calculations were made:
peak pain relief, time to peak pain relief and total pain relief
(at 1, 4, 6 and 8 hours).
[0080] Pain intensity difference: based on a 4-point visual rating
scale [none (0), mild (1), moderate (2) and severe (3)].
Differences from baseline were calculated. The following
calculations were made: peak pain intensity difference, time to
peak pain intensity difference and summed pain intensity
differences (at 4, 6 and 8 hours).
[0081] Pain analogue intensity difference: based on a visual
analogue scale from 0 (no pain) to 100 (unbearable pain). Summed
pain analogue intensity differences (from baseline) were calculated
at 4, 6 and 8 hours.
Results
[0082] Based on the patient global assessment at 4 hours, the
extended release product was shown to be equivalent or better than
the immediate release product. A successful response was defined as
a `very good` or `excellent` rating: 88 of 252 (35.1%) patients
treated with the SR paracetamol formulation gave a successful
response compared with 71 of 258 (27.7%) patients treated with
standard IR paracetamol. Equivalence was concluded from the 90%
confidence interval of the treatment difference (7.3% in favour of
SR paracetamol) between the two formulations.
[0083] There was no significant difference between SR paracetamol
and standard IR paracetamol in either development of analgesia
(time to peak pain relief, time to peak pain intensity difference,
total pain relief 1 hour after treatment) or peak analgesic effect
(peak pain relief, peak pain intensity difference), However, the SR
tablet was significantly more effective than standard IR
paracetamol for the summed pain analogue intensity difference at 6
hours (p=0.0344) and 8 hours (p=0.0500). Furthermore, the median
time to re-medication was longer for SR paracetamol (245 mins)
compared with standard IR paracetamol (190 mins). Although this was
not statistically significant, it was clear from the separation of
the two curves on the Kaplan-Meier plot that a smaller proportion
of patients treated with SR paracetamol re-medicated between
approximately 3 and 6 hours compared with standard IR
paracetamol.
[0084] These results indicated that the SR tablet gave rapid
analgesia which was maintained for up to eight hours following
dosing and the SR tablet had a longer duration of action than IR
paracetamol.
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