Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
lQS'~S67
This invention relates to sulphonamides and pharma-
ceutical formulations thereof, particularly those suited
for oral administration.
Sulphonamides are well-known inhibitors of ~acterial
organisms by interfering with the metabolic pathway by
which bacteria reproduce. This metabolic pathway includes
the synthesis of folinic acid from ~-aminobenzoic acid via
folic acid and the sulphonamides act by preventing the con-
version of ~-aminobenzoic acid to folic acid.
In view of their wide therapeutic utility, sulphona-
mides are formulated in many ways depending on the type of
infection being ~reated and the route of administration
which is desired. However, the most preferred and usual
formulation is that of a tablet which is suited for oral
administration.
Present marketed tablets normally contain from about
100 to lQOO mg of the sulphonamide, e.g. 500 mg, and this
usually represents a proportion of the tablet not higher
than 85% (w/w), frequently between 75 and 85~ (w/w). The
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rema~nder of the tablet is usually taken up with conven-
` tional excipients such as a disintegrating agent, a granu-
lating or binding agent, a lubricating agent and an inert
filler.
~ fortunately, these marketed tablets often encounter
administration problems, particularly with regard to
,~ children and old people, when the size of the tablet makes
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it very difficult to swallow. Moreover, these problems are
augmented as the content of sulphonamide in a single tab-
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let is increased to, for example, above 500 mg. Accordingly,
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t~ere is little doubt that it would be highly desirable to
reduce the overall size of the tablet without altering the
content of sulphonamide present.
However, an increase in the proportion of sulphonamide,
thereby reducing the overall size of the tablet, has hither-
to resulted in poor tablet characteristic, such as a high
disintegration time or dissolution time, a high friability
value or a low hardness value. These characteristics
obviously assume the utmost importance primarily for the
reason that they may not comply with certain medical stan~
dards required by the Health Authorities in many countries.
For instance, poor tablet characteristics may well result
in abrasion or fragmentation of the tablets during trans-
portation~and the patient would not therefore rec~ive the
required amount of active ingredient.
It has now been found that a tablet having excellent
. .,
characteristics can be achieved with a higher proportion
of sulphonamide present than has hitherto been obtained.
In fact, the tablet can be manufactured to contain a pro-
portion as high as 95% (w/w) or even higher. This is made
possible by using a sulphonamide, which has a particle
size, as hereinafter defined, of less than 40 ~m. Since
a reduction in the proportion of excipients is obviously
concomitant with the use of a high proportion or sulphona~ -
mide, the resulting tablet possess economic benefits over
and above previous tablets.
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It has also been found that the inci.usion of a
disintegrating agent having a swelling capacity, as
hereinafter defined, greater than 5ml/g imparts an eve~
greater improvement in these characteristics. In -
.; particular, surprisingly low disintegration times are now
also possible for tab].ets having a high content, for example
95% (w/w), of sulphonamide and, at the same time, a high
hardness value, such as 12kg.
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Accordingly, the present invention provides a tablet,
) which comprises from 80 to 98~ (w/w! of a sulphonamide, a
disintegrating agent and a granulating agent, the total
amount of both agents being from 2 to 20% (w/w), wherein the
particle size, as hereinafter ~efined, of the sulphonamide is
'1
;~ less than 40~m and the disintegrating ag~nt has a swelling
~j capacity, as hereinafter defined, greater than 5ml/g.
i~ In particular, the tablet comprises at least 85% (W/W~,
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preferably at least ~7.5% (w/w), more pxeferably at least
~?
~,~, 90~ (W/W), and m~st preferably at least 92.5~ (W/W), of the
sulphonamide, the particle size of which is ad~antageously
.3 below 30~" desirably below 20~m, and most desirably about
~ lO~m.
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.~ Moreover, a tablet comprising from 1 to 5% (w/w) of a
granulating agent and rrom 1 to 5% (w,/w) of a disintegrating
agent is further preferred.
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A tablet containing from 100 to lOOOmg of a
sulphonamide~ for example about 500mg, constitutes an even
further preferred aspect of this invention.
As used herein, the part~cle size of the sulphonamide
is defined in terms of the "weight median diameter"
hereinafter referred to as W.M.D. Thus, each particle is
,~, considered as a sphere having a volume identical with the
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;~ actual particle and the W.M.D. is that 'diameter', wherein
- 50% (by weight~ of these hypothetical spheres have a larger
3 diameter than that figure and 50% (by weight) a smaller
. . .
diameter than that figure. The W~MoD~ may be determined
using a Coulter counter in which the sulphon2mide is
~ dispersed in an electrolyte comprising an aqueous solution-
,. . .
~A'., ' of~ for example, sodium chloride saturated with -the
j sulphonamide, is passed through a small orifice in a tube
,~ on either side of which is immersed an electrode. The
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~' changes in resistance as particles pass through the orifice
`~ ~enerate voltage pulses whose amplitudes are proportional
to the volwnes of the particles. The pulses are amplified,
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~3 and the numbers counted at different threshold levels.
From this data the size distribution of the suspended
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particles and hence the W~M.D. may be determined.
The particular particle size of the sulphon~nide which
is to be used with the present invention, will depelld upon
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the envisaged content thereof in the resulting tablet.
If, for example, 85% (w/w) of sulphonamide is required,
than the particle size could be, for instance, between
20 and 30 ~m. On the other hand, if a 95% (w/w) content
of sulphonamide is required, it would be advisable to use
an even lover particle size, for example, less than 15 ~m,
preferably about 10 ~m
The particle size of the sulphonamide may readily be
reduced by precipitation techniques or by grinding the
particles with any apparatus or by any other method kn0wn
in the art suitable for such purpose. In particular, the
,.
hammer ~ill, which can be used with either the rigid or the
swing-hammer type and is conveniently combined with a fan
and a cyclone for collecting the material, is pr~ferred.
As used ~erein, the ~welling capacity of a disinte-
grating ~gent is defined as the volume (ml) to which 1 g
of a tablet containing 95~ (w/w) of the dry, disintegrating
agent and 5% (w/w) of polyvinylpyrrollidone (K30) will
swell when in contact with an excess of water at a tempera-
tureOf 21C. It is determined by granulating the disin-
tegrating agent (2 g) with 10% polyvinylpyrrolidone (K30)
. .
(1 ml) and drying the resultant granules at 60C. Com-
pression of the granules to a hardness value of 12 kg pro-
vides tablets having a diameter of 15 m~ and a weight of
approximately 900 mg. Each tablet is then accurately
weigh~d and placed on the bottom of a 25 ml measur~ng cy-
linder. A nylon disc of 8 mm thickness and having two
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grooves provides a close, but sliding, fit in the measur-
ing cylinder, resting on the top of the tablet. The
grooves are disposed opposite each other on the circumfer-
ence of the disc in a direction at right angles to the
plane thereof and allow for a thin hypodermio needle to be
inserted between the disc and the glass wall of the measu-
ring cylinder. A 5 g weight is placed on the nylon disc and
water injected through one of the grooves into the space
surrounding the tablet; the other groove allowing for air
to be displaced~ When the water level is above the top
of the disc, the needle can be removed and water added un-
til it is in excess, e.g. 25 ml. The volume under the
disc is then noted at periodic intervals until there is no ;
further increase in absorption. In some cases, disintegra-
ti~ agents absorb water to form viscous gels, and this
slows down the rate of absorption necessitating a longer
interval, such as 48 hours, before maximum swelling is
achieved.
On completion of swelling, the final volume is read
and corrected to the corresponding value for 1 g of the
tablet, i.e. the value for the swelling capacity. The
whole operation should preferably be ~erf~rmed at an ap-
proximately constant room temperature, for example 21C.
Disintegrating agents which have a swelling capacity
greater than 5 ml/g and which therefoDe may be used in the
present invention include calcium carboxy methyl culluloses,
such as E.C.G~505*, low~iscosity sodium carboxy methyl
celluloses, such as Copagel* and Nymcel*, guar based vegetable
gums, such as Supercol U* and Supercol N~-l*, a sodium alg-
inate,
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such as Alginate IZ*, and sodium starch glycolates, such
as Primojel*. The most preferred disintegrating agent
is Primojel*.
While it is essential that the disintegrating agent
used in the present invention has a swelling capacity greater
than 5ml/g there does not seem to be a maximum value although
it would not be expected to find a disintegrating agent
having a swelling capacity much greater than about 60ml~g.
Granulating agents which may be employed in the present
invention include starch in the form of mucilage, starch
derivatives, such as atarch 'Snow Flake' cellulose derivatives
such as methylcellulose, gelatin and preferably polyvinyl-
pyrrolidone.
Sulphonamides which may be employed in the present
invention include those embraced by formula (I),
2 ~ S2 - NH r~Q ( I)
wherein Q is a substituted or unsubstituted pyrimidin-2-yl,
pyrimidin-4-yl, a quinoxalinyl group, an acyl group or
preferably a substituted DD unsubstituted isoxazolyl group.
Examples of preferred sulphonamides which fall within
formula (III) include sulphamethoxazole {3-(4-aminobenzene-
sulphonamido)-5-methylisoxazole~ , sulphadimethoxine ~6-(4-
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lOS'~S67
aminobenzenesulphonamido) -2,4-dimethoxypyrimidine),
sulphadiazine f 2-(4-aminobenzenesulphonamido)pyrimidineJ,
sul~hadoxine ~4-(4-aminobenzenesulphonamido)-5,6-dimethoxy-
pyrimidine~, sulPhaquinoxaline ~12-sulphonamido-auinoxalin~ ,
sulphadimidine~2-(4-aminobenzenesulphonamido-4,6-
dimethylpvrimidine~ ,sulphafurazole ~5-(4-aminobenzene-
sulphonamido)-3,4-dimethylisoxazol~ , sulphacetamide
N-sulphanilylacetamide , sulphaguanidine N-amidinosul-
phanilamide} and sulphamethoxydiazine. The especiallv
preferred sulphonamide is sulphamethoxaæole.
Sulphonamides may be prepared by any one of a number,
of su~table methods described in the art, for example,
sulphamethoxazole can be prepared by~the process disclosed
in U.K. Pate~t Specification No. 814 276.
It may also be desirable to include a small proportion
of a suitable lubricant, such as magnesium sterate, in the
tablet so that the tablet is thereb~ prevented from adhering
to the punches and dies of the automatic tableting equipment.
Also dyes and preservatives may be added, if required.
; In anothér aspect of thç invention, there is provided
a method of preparing a tablet, which comprises the compresion
on standard mach~nery of a formula~mon containing from 80
to 93~ (w/w) of a sulphonamide, a disintegrating agent and
a granulating agent, the total amount of both agents not being
more than 20$ (w/w) of the formulation, wherein the particle
si~e of the sulphonamide is less than 40 ym and the disinte-
grating
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agent has a swelling capacity greater than 5ml/g.
The sulphonamide and disintegrating agent are mixed
in a dry state at slow speed, for example around 15 ~ev/min,
in a planetary mixer, followed by wet mixing for up to about
30 minutes with a granulating solution, together with addi-
tional solvent, if necessary, for maintaining the consistency
of the mass. The material can then be milled and either
tray-dried or dried in a fluidised bed. The dry material
is sifted and a lubricant is added to the granules provided
in this manner. Compression of the granules on standard
machinery to the specified har~ness then gives tablets of
the ~equired size and shape.
As used herein, the term (w/w) is used to denote the
ratio of the weight of specified excipient or sulphonamide
to the total weight of the tablet.
It should be noted th~t the advantageous characteristics
of a tablet made in accordance with the present invention
are primarily due to the interactions that exist between the
disintegrating agent and each Dr one of the sulphonamide and
the granulating agent.
The disintegrating time may be determined by the method
described in British Pharmacopoeia 1968 which involves the
rapid movement of the tablet in water under standardised
conditions, until there are no fr~gments remaining above a
supporting wire guage tvide pages 1366 to 1367).
The British Pharmacopoeia 1968 that the disintegration
time for any tablet must not exceed 15 minutes but desirably
this time should be less than 10 minutes, especially below
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minutes, for safety reasons in view of inevitable variations
from tablet to tablet. In addition to this essential
requirement it is generally recommended that the moisture
content of the granule from which the tablet is produced
should be below 2%.
The"hardness" of a tablet is the amount of force
required to shatter it or is more correctly the crushing
strength, and although this may be measured accurately
according to various standards, the Monsanto method is
convenient and suitable for testing the tablet produced in
accordance with the ~resent invention. Basically the method
involves the use of a Monsanto Tablet Hardness Tester, which
is a spring-loaded device capable of exerting radial pres-
sure on an edge of the tablet, the shattering force being
read from a scale on the sleeve of the device. In this
respect the pres~nt invention is especially suitable for
tablets which are compressed to a hardness value of 6 to
15kg,pre~erably, 11-13kg.
T~e~fria-b~ ity of a tablet is a measure of the loss of
weight suffered by a tablet from abrasion or shock and may
be tested by a "Roche" Friabilator in which a weighe~
sample of tablets, such as 6g, is subjected in the apParatUs
for a length of time, such as 4 minutes, to abrasion caused
by a tu~ling action, comparable to tablets rubbing one
another or being shaken against the walls of their container
in general use, and to shock resulting from a free-fall of
six inches, such as mi~ht be encountered during various
steps
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in packaging, handling and transport.
The dissolution time of a tablet may, for instance, he
determined according to the ~.S.P. XVIII by usinS an
apparatus comprising a cylindrical basket of 1680~m
stainless steel mesh, a covered 1000m1 glass vessel, a
constant-temperature water bath, and a variable-speed motor.
The dissolution meai.um, which may ke for example 0.6~
hydrochloric acid, p~ 1.2, is poured into the vessel which
has been previously immersed in the constant-temperature ~ath
and the medium is allowed to come to a temperature of 37C.
A tablet is placed in the basket and the apparatus assembled
such that the basket is fully immersed in the medium. The
basket is rotated at, for example, 1~0 rev/min. and samples
are withdrawn at inter~als with a syringe and assayed, for
instance, by U.V. absorbance. ~ -
Further advantages of the present invention will. now
become apparent from the following description of embodiments
of the invention, which embodiments do not limit this invention
iD any way.
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xample 1
The swelling capacity of a variety of disintegrating
agents was determined according to the method hereinbefore
described at a temperature of 21C. Each disintegrant tested
was then included in the following formulation:-
Weight/g
Sulphamethoxazole 800.0
D-sin*egrant 19.0
Polyvinylpyrrolidone K.30 20.8
Dioctyl Sodium Sulphosuccinate 0.8
Magnesium stearate 10.0
850.6
Sulphamethoxazole having a particule size of 10 ~m was
mixed with the disintegrant in a Morton mixer for ten minutes.
Dioctyl sodium sulphosuccinate was dissolved in 260ml of
8~ polyvinylpyrrolidone K30 in a 50/50 (v/v) solution of
alcohol in purified water and the resulting solution was
used to granulate the mixture of sulphamethoxazole and dis-
integrant by wet-m~xing the materials for 10 minutes. The
wet-mass was then passed through a 1200um metal screen and
subsequently dried overnight in an oven at 50C. The dried
granules were passed through a lOOOum screen and mixed with
magnesium stearate which ha~ previously been sifted through
a l50 um screen. The resultant mixture was compressed on
a ~anesty D3 rotary machine to provide tablets having hard-
, ness value of 12.Okg.
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The characteristics, in particular the disintegrationtime, were then examined for each tablet formulation:
DISINTEGRATING AGENT SWELLING CAPACIT-~ DISINTEGRATING
(mltg3 TIME (min. sec.)
Supercol NG-l* 43.6 0.50
Nymcel ZSB-10* 19.4 0.50
E.C.G 505* 6.0 0.53
Primojel* 14.8 1.07
Supercol U* 23.1 2.05 ~-
Alginate -~Z 10.2 2.10
Copagel PB25* 5.2 2.35
Texamid S058* 4.6 11.30
Cepo* Cellulose Flour4.8 >15
Veegum R~gular~ 2.3 ~15
Crodamix U.35* 1.6 >15
Maize Starch 1.3 >15
Protein S~ 0 ~15
These results establish that the use of a disintegra-
ting agent having swelling capacity greater than 5ml/g in
a formulation provides a tablet with superior characteristics
particularly with regard to its disintegration time.
Example 2
Sulphamethoxazole (880g) having a par~icle size of lOum
and Primojel* (20.9g) were mixed in the dry state for 10
minutes in a Z-bla~e mixer. A solution containing poly-
vinyl-
*Trademark
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pyrrolidone (18.4g), dioctylsodium sulphosuccinate (0,77g)
and purified water (230g) was prepared. The solution was
wet-mixed with the powders for 10 minutes using a slow
speed. The wet mass was passed through a lOOOum metal
screen. The granules were dried in a fluidised be~ at 60 C
for 30 minutes to a moisture content of 0.8%. The dr~ed
granules were sifted through a 1000 um screen and magnesium
stearate (llg), sifted 125um, was blended with the granules.
The granules were then compressed on a Manesty D3 Rotary
machine to provide tablets having a hardness value of 12.2
kg (Monsanto) a disintegration time of 3 min. 30 sec., and
a friability value of 0.43~. Each *ablet ha~ a thickness
of 5.22mm, a weight of 423.3 mg, a diameter of 10.2mm and
contained 400mg of a sulphamethoxazole.
Example 3
Phthalysulphathazole (480g) having a particle size of
22.5um and Primojel (24g) were mixed in the dry state for
10 minutes in a Z-blade mixer. A solution containing gelatin
(16g), Dioctylsodium Sulphosuccinate (lg), Alcohol (93g)
and Purified Water (130g) was prepared. The solution was
wet mixed with the powders for 10 minutes, using a slow
speed. The wet mass was passed through a lOOOum screen.
The granules obtained were dried in a fluidised bed at 60 C
for 30 minutes. The dried granules were sifted through a
lOOOum screen and Magnesium Stearate (4.8g), sifted 150um,
was blend~d with the granules. The granules were compressed
on a Manesty D3 Rotary machine to provide tablets havinghardness
value of 12.7kg (Mon anto), a disintegration time of 1 min.
40 sec. and a
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friability value of ~ 0.1~. Each tablet had a thickne~s
of 5.7 min, a weight of 548mg a diameter of 11.8~n and
contained 500mg of Phthalysu]phatlla~ole.
Example 4
Sulph~d midine (480g) having a particle size of 38.7~m,
Primojel (40g) and Lactose (30g) were granulated as in
Exa~.ple 1. After sifting lOOO~m, Magnesium Stearate (4.8g),
Sifted 150~m, was blended with the granules. The granules
were compressed on a Manesty D3 Rotary machine to provide
tablets havillg a hardness value of 13.8kg., a disintegration
time of 2 min. 45 sec. and a friability value of <0.1%. Each
tablet had a thickness of 5.7 mm, a weight of 596mg, a
diameter of 11.8mm and contained 500mg of Sulphadimidine.
Example 5
Sulphaguanidine (480g) having a particle size of 10.8~m.,
Pre-gelled Starch (96g) and Primojel (16g) were mixed in the
dry state for 10 minutes in a Z-blade rnixer. Purified Water
(220g) was wet mixed with the powders for 10 minutes. Tne
granules were prepared as in Example 1. The granules were
compressed on a ~anesty D3 Rotary machine to provide tablets
having a hardness value of 13.Okg, a disintegration time o~
2 min. 03 sec. and a friability of <0.1%. Each tablet hacl
a thickness of 5.~mm, a weight of 622mg, a diameter of 11.0
and contained 500mg of Sulphasuanidine.
Example 6
Sulphamethoxydia~ine (480g) having a par~icle size of
17~m and ~rimojel (32g) were mixed in ihe dry state for 10
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minutes. ~ solution containing Polyethylene Glycol 6000
(28g) and Purified ~1ater ~122g) was wet mixed with the
powders for 10 minutes. The granules were prepared as in
Example 1. Tablets were prepared on a Manesty D3 Rotary
machine. Each tablet had a hardness value of 15kg, a
disintegration time of 6 min. 40 sec. and a friability of
~0.2~. Tablcts had a thickness oi 4.9mm, a weight of 568mg,
a diameter of ll.Omm and contained SOOmg of Sulphamethoxydiazine. :
Example 7
Sulphafurazole (480g) having a particle size of 39.6~m
and Primojel (11.4g) were mixed in the dry state for 10
minutes in a Z-blade mixer. A sol~tion containing Polyvir.yl-
pyrrolidcne, K30 (12.5g), Alcohol (58g) and Purif-ed Water
(72g) was prepared. The solution was wet-mixed with the
powders for 10 minutes using a s]ow speed. The granules were
prepared as in Example 1. The granules were compressed on a
Manesty D3 Rotary machine to provide tablets having a hardness
v~lue of 6.1kg, a disintegration time of 4 min. 45 sec. and
a friability value of 0.8~. Each tablet had a thickness of
5.2mm, a ~7eight of 532mg, a diameter of 11.8mm and conta ned
SOOmg o f Sulphafuraz~le.
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