Note: Descriptions are shown in the official language in which they were submitted.
zo~~ma~
Prolonged release composition based on
trimebutine and process for the preparation thereof
Trimebutine is 2-dimethylamino-2-phenyl-1-
butyl 3,4,5-trimethoxybenzoate of the formula:
OCN3
_ Ei
~CH2-0-C \ ~ OCN3
\ /
ne'~ne OCH3
and has the property of intervening in the organisation
of the regulating mechanisms of digestive function.
Either as the compound itself or as its malefic
acid salt, its use was proposed in around 1970,
in the galenic forms conventionally used in the
pharmaceutical industry, for the gastro-enterological
treatment of spasmodic and painful symptoms of
transit disorders and functional colopathies.
thus, the product was indicated in cases of oesophagitis,
gastritis, gastroduodenitis, dyspepsia, biliary
dyskinesia and also in the case of gastrooesophageal
reflux (RGO) and duodeno-gastric reflux.
In addition, attempts were made to propose
drug preparations of the product which could be
administered by oral route with the aim of affecting
the speed of release by means of the galenic form
proposed, and consequently influencing and/or modifying
its speed and/or duration of effect.
Thus, European Patent Nos. 76515 and 99109
describe microcapsules in which the product is
inside the device and is coated with a membrane
containing ethylcellulose in the composition of
the outer casing of the system. The microcapsules
obtained have good flow properties which are favourable
~UOf~184
- 2 -
to the preparation of various galenic forms and,
in addition, they permit remarkably rapid release
of the product in the body.
On the other hand, European Patent No. 169821
describes a device which aims to achieve controlled
and programmed release of various active agents
according to a kinetic system of the order zero,
i.e: at a constant speed over time until the product
contained in the device has disappeared. In the
general manner described, this comprises:
- a central reservoir nucleus consisting of
an insoluble and non-gelatinisable polymer matrix
which contains in its pores the active agent together
with an additive for dissolving having a negative dissolu-
tion heat which may be a polyol or citric acid
and also, if necessary, a buffer substance which
promotes the dissolution of the active agent in the
fluid in question;
- a first coating for the nucleus which has
the function of regulating diffusion of the product,
solubilised in the fluid, out of the system. This
coating is provided in a homogeneous and continuous
manner by means of a film of polymer which is both
insoluble and permeable to the fluid in question.
The regulating effect can be modified depending on
the thickness of the film, which may be calculated,
depending on the speed of release desired, on the
basis of physico-chemical parameters applying to
the active agent, the coating polymer and the dimensions
of the device;
- a second protective coating which is soluble
and which also consists of a polymer film which may
contain a fraction of the active agent, with the
aim of ensuring rapid effect.
This coating technique is intended particularly
for medicinal active agents and therefore attempts
have been made, without making use of the preceding
calculations, to apply this device to trimebutine
~UUG184
_ 3 _
in Examples 5 and 6, using citric acid as the main
dissolving agent contained in the central reservoir
portion.
The effectiveness of the products obtained
is evaluated by tests of dissolution "in vitro"
in which the quantity of trimebutine released is
determined at different times over a total period
of about 6 hours.
The end product of Example S releases trimebutine
irregularly at levels which may vary from one amount
to double that amount (12 mg between the first
and second hours, 23 mg between the fourth and
fifth hours), whilst the end product of Example
6 exhibits, in the course of this test, a rate
of release of trimebutine which decreases significantly
and rapidly after the first hour.
Clearly, the results of these tests do not
show, for trimebutine, a release kinetic which
is controlled or prolonged, regular and close to
the order zero.
Moreover, owing to the presence of three
constituents necessary for its operation, this
device is tricky to use, requires suitable equipment
and is therefore expensive.
According to the invention, a pharmaceutical
composition has now been found which is simple
and economical to prepare and which contains, as
active agent, trimebutine or one of the pharma-
ceutically acceptable acid addition salts thereof,
particularly trimebutine maleate, which can be
used to obtain products with prolonged release of
the active agent, the latter being released according
to a kinetic system of the order zero, whilst the
bioavailability is equal to that of a conventional
tablet.
The invention t:~erefore relates to a pha~.wr~aceutical com
position in the fornn of a taalet wivnout any ccat'ng ~~' c°;'~'rising.
2UU(~~.~4
g
as active agent, 2-dimethylamino-2-phenyl-1-butanol
3,x,5-trimethoxybenzoate of the formula:
OCH3
_ Ct -
OCH3
\ / CH2-0-C ~ /
h~~he OCH3
or a pharmaceutically acceptable acid addition
salt thereof, characterised in that the active
agent, which represents 35 to 45$ by weight of
the composition, is homogeneously dispersed in
a porous hydrophilic matrix of hydroxypropylmethyl-
cellulose which represents from 15 to 20~ by Weight
of the composition and it further comprises 20
to 25$ by weight of a water-soluble diluent and
from 10 to 20$ by weight of tartaric acid.
In vitro tests show that a composition according
to the invention does not adhere to the punch of
s
a machine for producing tablets having a hardness
of at least 7.5 Kgf, whereas the same composition
without any tartaric acid adheres to the punch
of a tablet making machine and the replacement
of tartaric acid by citric acid, which is convention-
ally used in tablets, produces a tablet of insufficient
hardness. Tests also show that tartaric acid has
the effect of ensuring that the tablet remains
whole when placed in an aqueous liquid and prevents
it from breaking up, a phenomenon which, when it
occurs, considerably modifies the surface area
in contact with the fluid and causes random and
uncontrolled celease of the active substance.
Surprisingly, _in vivo tests show that compositions
tested _in vitro have an unacceptable bioavailability
and that only those compositions containing the
diluent in addition to the tartaric acid and in
which the constituents satisfy the proportions
2006~.8~
- 5 -
required according to the invention result in a
bioavailability of the active agent which is comparable
with that of a conventional tablet.
The hydroxypropylmethylcellulose (HPMC) used
may be any of those which are commercially available,
particularly under the brand names "Metholoses"
(made by Shin Etsu Chemical) and "Methocels" (made
by Dow Chemical Company). These HPMC's differ
from one another in their degree of etherification
(expressed as a percentage of methoxy groups and
hydroxypropoxy groups) and also in their molecular
masses. They are normally characterised by the
nominal viscosity of their aqueous solutions determined
under certain conditions. For the purposes of
the invention, the HPMC's with a viscosity of between
3000 and 5000 mPa.s are particularly preferred.
As diluents it is possible to use water-soluble
carbohydrates, e.g. sugars such as mannitol and
saccharose, lactose being particularly preferred.
A dispersing agent may be added to the diluent,
in which case the proportion of diluent also includes
the quantity of dispersing agent added to it.
It is also possible to use small amounts
of inert water-insoluble charges such as cellulose
or calcium phosphates, of which dicalcium phosphate
is preferred, and, in small amounts excipients
conventionally used in tablet making such as magnesium
stearate, silica gel, polyvinylpyrrolidone, etc.
Preferably, each tablet contains from 175
to 325 mg of active agent. Tablets containing
200 to 300 mg of trimebutine maleate per unit,
when subjected to a dissolution test in vitro,
release from 45 to 65%, more particularly from
50 to 60%, of active agent in 8 hours according
to a kinetic system close to the order zero, within
a period of time ranging from 30 minutes to 8 hours.
When administered to man, they ensure prolonged release
2006184
-s-
of the product over a period of 9 to 15 hours,
with a bioavailability which is comparable to that
of the product administered in the form of conventional
tablets.
Apart from the advantages usually attributed
to prolonged release preparations, the compound according
to the invention meets the needs of certain complaints
treated with trimebutine, particularly in view
of its usefulness in treating gastrooesophageal
reflux (RGO) which is often characterised by chronic
symptoms of pain after meals and at night.
The invention also relates to a process for
preparing a composition according to the invention,
characterised in that it consists of mixing the
active agent, hydroxypropylmethylcellulose, the
diluent and tartaric acid and compressing the mixture
to form a tablet.
The experiments carried out to determine
the composition of the invention are described
hereinafter. Generally and unless otherwise specified,
the operations required to carry them out are familiar
to those skilled in the art and are described succinctly
in the Examples which illustrate the methods of
preparation used.
' ' The tablets obtained from the compositions
prepared are subjected to the following tests and
measurements:
- their hardness is measured in a Schleuniger
apparatus. The hardness must be more than 7.5 Rgf.
The measurement consists in exerting a pressure
on a tablet, using a mechanical apparatus, until
the tablet breaks. This pressure is measured and
expressed in Rgf and must be sufficient to enable
the tablets prepared to be subjected to various
packaging processes without physical damage.
- test of dissolution of the active agent,
which is carried out with the apparatus described
a
~O~el8~
_ 7 _
in method 2 of USP XXI, using as the dissolution
medium 1 litre of demineralised water maintained
at 37°C, whilst stirring is carried out at a speed
of SO rpm throughout the experiment. The dissolution
S liquid is continuously sampled using a peristaltic
pump and the product released is assayed after
15, 30 and 60 minutes and then every hour until
8 hours after the start of the experiment. Measurement
is carried out using spectrophotometry at a wavelength
of 290 nm, at which Beer Lambert's law is verified
for trimebutine solutions at concentrations ranging
from 0 to 350 mg ner litre. Using the results,
the order of the kinetics of dissolution is evaluated
at between t = 30 minutes and t = 8 hours and,
in the case of the order zero, the coefficient
of regression of the line r is calculated for this
interval. The period between t 0 and 30 minutes
which corresponds to the phases of hydration and
gelatinisation of the system is not taken into
account for this kinetic evaluation.
During the test, and irrespective of the
dissolution of'the active agent, the appearance
and wholeness of the gelatinised matrix are observed.
By virtue of the very agent of the apparatus, the
matrix should be virtually unchanged after its
gelatinisation; appreciable breakdown indicates
an unsuitable composition which must be avoided,
whilst any erosion or change in appearance should
be recorded and may provide an indication of the
quality of the formulation being tested.
More precisely, during the dissolution test
carried out with a tablet in one litre of solution
as described hereinbefore the appearance of the
liquid and the tablet are carefully monitored.
In the event of any break-up, irregular fragmentation
of the tablet is observed which may possibly be
accompanied by the appearance of fine particles
2006184
-s-
which are insoluble in the liquid, whereas, in
the event of erosion, the tablet being tested retains
its initial shape overall but erodes during the
test, causing insoluble matter to appear progressively
in the liquid, zn the case of a suitable formulation,
the tablet maintains its appearance and the liquid
stays clear throughout the test.
TESTS
Test series A
These tests are designed to determine the
ingredients necessary to achieve the desired effect
of delayed release. These tests coded A-1 to A-4
include in their constitution an identical quantity
of hydroxypropylmethylcellulose having a stated
viscosity of 4000 mPa.s and adjuvants consisting
of polyvinylpyrrolidone, magnesium stearate and
silica gel, also in constant amounts. The procedure
consists of:
- wetting the mixture of trimebutine maleate,
lactose, polyvinylpyrrolidone and optionally the
acidic agent with an alcoholic solution, then granu-
lating the mixture and drying and calibrating the
granules obtained:
- then adding the hydroxypcopylmethylcellulose
followed by the silica gel and magnesium stearate,
- and finally compressing the mixture obtained
on a rotary machine fitted with flat tablet punches
14 mm in diameter.
In these tests, which are summarised in Table
1 which follows, the effects are studied of
- an excess of lactose in test (A-2), which
should promote the dissolution ~in vitro" of the
active agent,
- and the addition of citric acid (A-3) or
tartaric acid (A-4), which should also promote
this dissolution, by comparison with that observed in (A.1).
CA 02006184 1999-08-20
- g _
Table 1: - Tests A 1 to A 4 and rP~"1rc
TEST - Ref. A.1- A.2- A.3- A.4-
Com~osition wt% . mg/un wt% . m %
g/un wt% . mg/un wto . mg/un
M.Trimebut. 47.84 . 300.040.16 . 300.040.16 . 300.040.16 . 300.0
BFMC~1~ 19.14 . 120.016.06 . 120.016.06 . 120.016.06 . 120.0
Lactose 28.71 : 130.040.16 : 300.024.09 : 180.024.09 . 180.0
Citric Acid 16.06 : 120.0
Tartaric acid 16.06 . 120.0
PVP 25~z~ 1.92 . 12.0 1.60 . 12.0 1.60 . 12.0 1.60 . 12.0
Mg Stear. 1.20 . 7.5 1.00 . 7.5 1.00 . 7.5 1.00 . 7.5
Silica gel 1.20 . 7.5 1.00 . 7.5 1.00 . 7.5 1.00 . 7.5
Total . 627.0 . 747.0 . 747.0 . 747.0
Compression
Hardess 7.5 Kgf 7.8 Kgf 6.0 Kgf 9.0 Kgf
Remarks Sticking Sticking Insufficient Normal
hardess
Dissolution
% after 8h 46.5% (5.3) 73.4% (8.2) 56.1% (3.8) 52.3% (3.2)
Order 0 (r) Yes r=0.9980NO Yes r=0.9996 Yes r=0.9995
Appearance Unpleasant Unpleasant Suitable Suitable
(1) Hydroxypropylmethylcellulose 4.000 mPa.s
(2) Polyvinylpyrrolidone of molecular weight 25,000
X006184
- io -
These tests make it possible:
- to eliminate straight away the composition
of test (A-2), for which the tablets obtained,
subjected to the dissolution test, release the
active agent according to kinetics other than Zero
order, starting from a gelatinised matrix which
breaks up substantially in the course of the test,
- to find that the tablets prepared from
compositions (A-1) and (A-3) release about 50%
of the active agent during the test according to
the desired kinetics of the order zero but that
these compositions are not suitable for compression.
Thus, the granules of composition (A-1) result
in the phenomenon of adhesion to the tablet punches
which means that the operation has to be interrupted
frequently. As ~or the granules of composition
(A-3), they do not produce tablets of suitable
hardness, no matter how the machine is regulated,
- to select, as the preferred composition
in this series, the composition of test (A-4) which
in every step behaves satisfactorily and produces
matrices which behave correctly in the dissolution
test, releasing about 50% of active agent after
8 hours according to zero order kinetics.
Thus, this latter formulation which contains
tartaric acid is unexpectedly found to be favourably
distinguished from the others. In fact, contrary
to what is stated in the prior art, in which the
property nut forward for acids including tartaric
acid is that they promote the release of active
agents which are not readily soluble in a medium
having a pH close to neutrality, tartaric acid
in this case appears not only as such "in vitro"
but also as making it possible to obtain a composition
Which is suitable for compression and for obtaining
tablets of suitable hardness and also for achieving
~OOf 18~
good cohesion of the gelatinised matrix during
the dissolution test. The role of tartaric acid
in this composition is unexpected.
Test series B
The compositions of tests (B-1) to (B-4) are derived
from the preferred composition (A-4) of the A series
of tests described hereinbefore. The modifications
concern:
- the quantity of HPMC used, in order to
determine its importance on the prolonged release
effect observed in the dissolution test,
- the qualitative nature of the diluent product,
by adding dicalcium phosphate (which is insoluble)
to the water-soluble lactose.
In addition, composition (B-2) which is identical
to composition (A-4) provides a means of checking
the properties found earlier.
The steps carried out are identical to those
carried out in the tests of series A. The compositions
and the results of tests (B-1) to (B-4) are reported
in Table 2 which follows.
CA 02006184 1999-08-20
- 12 -
Table 2 - Tests B 1 to B 4 and results
TEST - Ref. B.1- B.2- B.3- B.4-
ComDOSition wt% . mg/unwt% . mg/unwt% . mg/unwt% . mg/un
M.Trimebut. 37.12 . 300.040.16 . 300.038.90 : 300.039.40 : 300.0
BFMC~1~ 22.27 : 180.016.06 . 120.015.50 : 120.07.90 . 60.0
Lactose 22.27 . 180.024.09 : 180.021.00 : 162.023.60 : 180.0
Dicalcium 2.30 . 18.07.90 . 60.0
phosphate
Tartaric acid14.85 : 120.016.06 . 120.016.00 : 124.316.00 : 121.9
PVP 25~z~ 1.48 . 12.01.60 . 12.0 2.80 . 21.61.20 . 9.4
Mg Stear. 1.00 . 8.1 1.00 . 7.5 1.00 . 7.4 1.00 . 7.3
Silica gel 1.00 . 8.1 1.00 . 7.5 0.20 . 1.5 0.20 . 1.5
Talc 3.00 . 22.33.00 . 22.3
Total . 808.2 . 747.0 . 771.1 . 762.4
Compression
Hardess 8.7 Kgf 9.2 Kgf 8.0 Kgf 8.0 Kgf
Dissolution
% after 8h 39.4% (4.5) 55.0% (2.9) 50.1% (6.7) 85.8% (8.6)
Order 0 (r) Yes 0.9992Yes 0.9990 Yes 0.9997Yes 0.9993
r= r= r= r=
Appearance Suitable Suitable Suitable Suitable
(1)(2) See Table 1
~aaaa.~4
- 13 -
The results of this study show that the modified
parameters do not affect the operation of compression
nor the properties of the tablets and matrices
obtained after gelatinisation.
Variation in the quantity of HPMC results
in a change in the speed of dissolution and a release
within 8 hours which is greater, the smaller the
quantity of HPMC in the composition.
These tests and the results of the in vitro
tests of series A and B make it possible to demonstrate
that:
- the quantity of HPMC is the chief factor
in modifying the release of active substance from
the matrix and
- in a manner which is surprising and peculiar
to these formulations, tartaric acid is necessary
in order to obtain compositions which are compressible
under suitable conditions in order to obtain, after
this operation, matrices which are stable in their
behaviour after gelatinisation.
Thus, the formulations of tests B.1 to 8.4
comply with the'aims of the invention both during
their use and during tests to which the tablets
are subjected. The tablets in tests B-I, B-2,
B-4 and A-1 are used in a pharmacokinetic study
in man and their effect is compared with that of
the standard tablet which is marketed and contains
a dosage of 100 mg of active substance per unit.
The study consists of determining the pharmaco-
kinetic parameters after voluntary test subjects
have taken either a 300 mg tablet of the different
forms prepared or three standard tablets each containing
100 mg, in a random cross-over treatment.
In the experiment, after tablets have been
given to the test subjects on an empty stomach,
blood samples are taken at predetermined times
over a total period of 48 hours. After separation,
~00~18~
- 14 -
the plasma from the samples is stored at -20°C
until it can be analysed, which consists of measuring
not the trimebutine. which is rapidly absorbed
and immediately metabolised, but its immediate
metabolite which is representative of it and which
is N-monodesmethyltrimebutine.
The method of analysis used consists, after
taking suitable extracts from the sample, of assaying
the metabolite by high performance liquid chromatography
(HPLC) using a silica column grafted for reverse
phase and an eluant mixture consisting of methanol
and O.OSM acetate buffer. The separated compounds
are detected and assayed by absorption spectrophotometry
at 265 nm.
-The pharmacokinetic parameters were determined
by means of the PHAkM programme (R. Gomeni: An
interactive graphic program for individual and
population pharmacokinetic parameter estimations.
In Medinfo 83 - Ed. by J.H. Van Bemmel - Elsevier
- Amsterdam; 1983 p. 1022 - 1025). The curves
of the plasma levels of metabolite were analysed
according to a model with one or two compartments
with absorption, the choice of the model being
determined as a function of the statistical methods
included in the programme.
The following were determined:
- t 1/2 form. (h) which is the half life
of formation of the metabolite and is itself a
function of the half life of absorption of the
precursor trimebutine.
- C max (ng/ml) which is the maximum plasma
concentration obtained at T max (h).
- t 1/2 elim. which is the half life of elimin-
ation of the metabolite.
- AUCo - 7 ~ (ng.h/ml) which is the area under
the curve of the plasma levels of the metabolite
assayed as a function of time. It is calculated
20i~G184
- 1S
by the trapezium rule of time 0 with extrapolation
to infinity by the formula:
AUCo - ~ ~ - AUCo - ) t + Ct/B
where Ct is the last plasma concentration measured
at time t and S is the gradient of the elimination
phase. This value corresponds in fact to the relative
bioavailability of the product from the galenic
form under consideration.
- F rel. which is the relative bioavailability
of the prolonged release form, compared with the
relative bioavailability demonstrated by the standard
tablet taken as a control. This coefficient is
calculated by the formula:
F. rel. - AUCo --) a'° (FLC)
AUCo --j oo (tablet standard)
- MRT which is the average residence time
of the metabolite in the body. This parameter
takes account of the dissolution times of the active
agent starting from the tablet, then its absorption
and elimination. The results of the study are
shown in Tablet 3.
CA 02006184 1999-08-20
- 16 -
Table 3: Results of the ~harmacokineric study
(300 mg preparations)
Formulation
Parameter Standard
B.1 B.2 B.4 A.1
table*
C max. 2053 (305)486 (125) 724 (285) 1440 (500) 500 (204)
T max. 1.13 (0.31)3.17 (0.98)3.00 (1.76)2.80 (1.10)2.25 (1.04)
t ~ form. 0.12 (0.06)0.96 (0.42)0.68 (0.34)0.80 (0.32)1.02 (0.47)
t ~ elim. 7.59 (3.82)11.29(2.71)10.45(3.63)5.25 (1.51)10.32(4.09)
MRT 5.38 (0.95)12.99(1.16)13.47(3.13)7.03 (2.37)14.20(4.05)
AUCo - -) 8007 (2228)5600 (1798)7384 (2311)8925 (2357)5199 (1575)
~
F rel. 1 0.73 0.94 1.11 0.65
* Composition of a standard tablet:
- trimebutine maleate 100.0 mg
- excipients: lactose, mannitol, crystalline
saccharose, polyethylene glycol, gelatine,
corn starch, magnesium stearate, silica gel.
~00~184
The results show:
- that the tablets of compositions (B-1),
(B-2) and (A-1) have an average retention time
of the metabolite measured of around 12 hours,
S which corresponds to the objective of the invention,
whereas for composition (B-4) this time is significantly
less,
- the tablets of compositions (B-2) and (B-4)
have a measurement of the area under the curve
extrapolated to infinity (AUCo - ~ ~ ) of the same
order as that of the standard tablet.
These unexpected findings relating to the
essential parameters lead one to prefer composition
(B-2) which, both by its duration of activity and
its suitable relative bioavailability, meets the
requirements of the invention and satisfies good
practice in the pharmaceutical industry.
This choice is confirmed by a similar study
reported in Table 4, which shows the effect of
tablets of compositions (C-2) containing 200 mg
of trimebutine maleate, compared with the effect
of 2 standard tablets each containing 100 mg of
product.
20f~~~184
- la -
Table 4 . Results of the pharmacokinetic study
(formula containing 200 mg)
. Compositions
Stan dard C
2
'
. Parameter tabl et ' .
~
C. max. 1571 (658) . 484 (241)
.
T. max. 1,35 (0,63) . 2,79(1,29)
.
. t form. . 0,28(0,20) . 0,70 (0,23)
1/2 .
. t slim. . 6,16(3,16) . 11,52 (3,58)
1/2 .
HRT . 4,83(1,17) . 13,35 (2,82)
.
. AUCo--> . 5565(2373) . 4852 (1960)
.
F rel. . 1 . 0,89
~oooa.a~
- 19 -
As an illustration the Examples which follow
describe the preferred compositions of the invention,
their preparation and their formulation as tablets.
Examples 1 to 3 make use of the so-called "moist
granulation" method whilst Example 4 uses the technique
known as "direct compression". The characteristics
of the urolonged release tablets and the results
of the dissolution tests carried out are given.
Example 1 (Preferred composition 8.2)
- 1500.0 g of trimebutine maleate
- 900.0 g of lactose
- 600.0 g of tartaric acid
are placed in a vortex-type mixer and, with stirring,
200.0 ml of a 30% (by volume) ethanolic solution
of polyvinylpyrrolidone is added to the mixture
of powders then mixing is continued for 5 minutes.
.The granules obtained are dried at 50°C in
a fluidised bed using an "aeromatic" type apparatus
h
until the granules have a residual moisture content
equivalent to 0.6%, measured by a thermobalance.
The granules are. then calibrated by passing them
over an oscillating granulator fitted with a grid
with a mesh size of 1 mm and then introduced into
a biconical-type mixer. 600.0 g of hydroxypropyl-
methyicellulse 4000 mPa.s are added, the mixture
is agitated for 5 minutes then 37.5 g of silica
gel and 37.5 g of magnesium stearate are added
and mixing is continued for 10 minutes.
The powder obtained is subjected to compression
on a rotary machine fitted with flat chamfered
tablet punches 14 mm in diameter. The operation
is carried out without incident and more particularly
without any sticking or jamming.
- Characteristics of the tablets
* Average weight 749.8 mg - theory 747.0 mg
* Hardness 8.2 Rgf
-- Dissolution test (USP XXI method no. 2; demineralised
;~~1(~t~l~?~.
- 20 -
water 1 litre v = 50 rpm; t = 37°C)
* Active agent dissolved after 8 hours: 55.08
* Apparent kinetics of dissolution (t 30 min./8h):
order zero; r = 0.9990
* Appearance of the matrix after 8 hours: coherent
and unchanged
- Dosage
* Trimebutine maleate by theoretical weight of
the tablet: 294.1 mg - theory 300.0 mg
Example 2 (Preferred composition C.2)
In accordance with the operations described
in Example 1 and using:
- 2600.0 g of trimebutine maleate,
- 1560.0 g of lactose,
- 1040.0 g of tartaric acid,
- 104.0 g of polyvinylpyrrolidone 25,
- 1170.0 g of hydroxypropylmethylcellulose
4000 mPa.s
- 65.0 g of silica,
- 65.0 g of magnesium stearate,
a mixture is obtained which is subjected to compression
on an alternating machine fitted with chamfered
tablet punches 12 mm in diameter to obtain tablets
with a theoretical weight of 508.0 mg and a unit
composition:
. mg/tablet : in t
. - Trimebutine maleate . 200.0 . 39.37 .
. - laetose . 120,0 . 23,62 .
- - tartaric acid . 80,0 . 15.75 .
. - PYP 25 . 8.0 . 1,57 .
. - NPMC d000 mPa.s . 90.0 . 17,72 .
. - silica gel . 5,0 . 0.98 .
- magnesium stearate . S.0 . 0,98 .
~UUf 184
- 21 -
The operation of compression of the powder is carried
out without incident.
- Characteristics of the tablets
* Average weight 506.1 mg theory 508.0 mg
* Hardness 9.1 Kgf.
- Dissolution test (USP XXI method no. 2; demineralised
water 1 litre; v = SO rnm; t = 37°C)
* Active agent dissolved after 8 hours: 51.9$
* Apparent kinetics of dissolution (t 30 min.
/8 hours): order zero; r = 0.9968
* Appearance of the matrix after 8 hours:
coherent and unchanged
- Dosage
* trimebutine maleate by theoretical weight
of tablet: 193.7 mg theory 200.0 mg
Example 3 (Composition B.3)
The following are intimately mixed for 10 minutes:
- 500.0 g of trimebutine maleate,
t
- 270.0 g of lactose,
E
- 30.0 g of dicalcium phosphate,
- 200.0 g of hydroxypropylmethylcellulose 4000 mPa.s.
The powder is wetted in a planetary kneader,
by adding 420.0 ml (357 g) of an 80$ aqueous ethanolic
solution containing 10$ of polyvinylpyrrolidone
25 in batches over a period of about 5 minutes.
The mixture is dried in a drying cupboard
at 40°C until a residual moisture content of 2$
is achieved, measured by means of a thermobalance,
then calibrated on an oscillating granulator fitted
with a grid with a mesh size of 1 mm.
750 g of the granules obtained are placed
in a mixer and the following are added successively:
- 150.0 g of tartaric acid,
- 9.0 g of magnesium stearate,
- 27.0 g of talc,
_ 1.8 g of silica.
After 10 minutes' mixing, the product is compressed
~oos~~~
- 22 -
in an alternating machine fitted with flat punches
12 mm in diameter. The operation is carried out
without any particular problems.
- Characteristics of the tablets
* Average weight 769.0 mg theory 777.1 mg
* Hardness 8.0 Kgf.
- Dissolution test (USP XXI method no. 2; deminecalised
water, 1 litre; v = 50 rpm; t = 37°C)
* Active agent dissolved after 8 hours: 50.1%
l0 * Apparent dissolution kinetics (t 30 min./8h):
order zero; r = 0.9997
* Appearance of the matrix after 8 hours:
coherent and unchanged
- Dosage
* Trimebutine maleate by theoretical weight
of tablets: 289.9 mg theory 300.0 mg
Example 4
In a so-called "free fall" mixer are placed
the following:
- 150.0 g of trimebutine maleate,
- 30.0 g of lactose,
- 50.0 g of tartaric acid,
- 120.0 g of hydroxypropylmethylcellulose 4000 mPa.s,
- 3.5 g of magnesium stearate,
- 0.35 g of silica,
after stirring for 20 minutes at a speed of 42 rpm
the mixture is compressed in an alternating machine
fitted with 12 mm punches, regulated so as to produce
tablets with a theoretical unit weight of 707.7 mg
containing 300.0 mg of active agent.
- Characteristics of the tablets
* Average weight 705.0 mg theory 707.7 mg
* Hardness 8.0 Kgf.
- Dissolution test (USP XXI method no. 2; demineralised
water, 1 litre; v = 50 rpm; t = 37°C)
* Active agent dissolved after 8 hours: 45.5%
* Apparent dissolution kinetics it 30 min./8h):
20(~~18~
- 23 -
order zero; r ~ 0.9973
* Appearance of the matrix after 8 hours:
coherent - very slightly eroded
- Oosage
* Trimebutine maleate by theoretical weight
of tablets: 302.1 mg theory 300.0 mg
