Note: Descriptions are shown in the official language in which they were submitted.
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Chewable Tablet With Effervescent Action
The invention relates to a chewable tablet or
lozenge with an effervescent action. Such tablets .have been
S developed in order to generate a pleasant fizzy feeling in the
mouth with the saliva during dissolution. Similar tablets are
described, for example, in European Patents 525,388 and
494,972 (WO 91/04757).
However, the inventors have now set themselves the
object of providing a tablet for pharmaceutical formulations
which can be both taken directly orally as a chewable tablet
or lozenge. with a slight effervescent effect and therefore
pleasant fizzy feeling in the mouth, and dissolved or
suspended in water (preferably 50-100 ml), in particular in
_15 less than 2 min, with effervescence. It is desirable to have a
tablet which generates a pleasant fizzy feeling on chewing or
sucking but which, if required, can be dissolved in a small
amount of water if the patient prefers to drink a solution.
The tablets mentioned at the outset are however unsuitable for
dissolution in water before being taken: the tablet according
to E.P. 525,388 has insufficient effervescent base for this
purpose since up to two-thirds of the effervescent components
have already reacted, i.e. only a single carboxyl group of the
citric acid may be free; all tablets according to the examples
of WO 91/04757 have dissolution times of well over 5 minutes
in fresh water.
As the inventors of the present application have
surprisingly found, this is due, inter alia, to three aspects
of the formulation which had not been taken into account by
the inventors of WO 91/04757 because they were concerned only
with a chewable tablet or lozenge, which, according to the
description, was to dissolve in water at 37° C. in less than
10 minutes. The stated relevant lower limit of 30 seconds
cannot be achieved with the formulation of WO 91/04757.
A first reason for this is the use of a lubricant
for tabletting, which is essential according to the
description. Even a relatively low content of lubricant makes
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the individual components hydrophobic, and thus contributes
very substantially to poorer dissolution behaviour of the
tablet in water.
A second reason is the encapsulation or coating of
S the particles of the active substance. The coating material
penetrates into the voids during compression and thus also
blocks access to the effervescent particles. The effervescent
particles then react much more slowly with the water, thus
impeding dissolution of the tablets.
A third reason is the use of relatively large
amounts of rapidly soluble substances as fillers, such as, for
example, sorbitol alone or as a mixture with a sucrose which
is formulated as a tabletting assistant and in turn contains
lubricant although only in small amounts.
Surprisingly, it has been found that relatively
rapidly soluble fillers in a tablet having a relatively low
content of effervescent base (owing to any direct oral intake
of the tablet, the effervescent effect must not be too great,
otherwise it will be found to be unpleasant) prolong the
dissolution time of the tablet. The reason for this is that,
on introduction of the tablet into water, the amounts of
rapidly soluble fillers, which are large in comparison with
the amount of the effervescent base, very rapidly form a
locally very highly concentrated solution in which the
dissolution and reaction of the effervescent components and
hence the disintegration of the tablet take place only slowly.
On the other hand, if the lubricant and/or the
encapsulation of the active substance are omitted, an
unpleasantly strong effervescent effect may be achieved in the
mouth if the tablet is to be chewed or sucked, even with small
amounts of effervescent components which are required for the
dissolution of the tablet in fresh water.
Attempts to achieve the object described at the
outset by means of a disintegrating effervescent material
doped with a small amount of effervescent base, for example
according to European Patent 501,985, also failed since the
disintegrating agents always left behind a sandy, rough
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impression during chewing or sucking, which was found to be
unpleasant.
The inventors have demonstrated this on the basis of
the examples and have mitigated the stated problems as
described herein. A tablet with an effervescent action
formulated according to this invention comprises a
pharmaceutically-active substance, acid particles and/or
carbonate particles of an effervescent base that are coated
with a soluble hydrocolloid and/or wherein the pharmaceutical
substance is free of encapsulating substances and/or the
tablet mixture is free of lubricants.
In accordance with this invention a chewable tablet with
an effervescent action and a tablet weight of less than 3 g,
contains at least one pharmaceutically-active substance, 15 to
50 percent by weight of an effervescent base comprising a
solid, edible organic acid and an alkali metal and/or alkaline
earth metal carbonate and/or bicarbonate, and 30 to 85% by
weight of a soluble filler. The acid particles and/or the
carbonate particles of the effervescent base are coated with a
hydrocolloid, or the active substance is free of any coating
material and/or the tablet contents are free of lubricants.
The small amounts of water in the saliva, in which indeed
other substances are also dissolved, do not dissolve a
hydrocolloid coating on the effervescent components so rapidly
that an undesirably strong effervescent action would occur.
Even small amounts of the hydrocolloid thus slow down the
reaction of the effervescent components with one another in
the mouth quite dramatically, while the hydrocolloid (in
particular a readily soluble one, such as, for example,
maltodextrin, polyvinylpyrrolidone or guar gum) dissolves in
the water very rapidly and prolongs the dissolution time of
the tablet only to an insignificant extent.
Example 1:
This Example corresponds to the prior art; Example
1 of W091/04757 was reworked, with the following variations:
a. Acetaminophen encapsulated, with lubricant (Mg
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stearate)
b. Acetaminophen encapsulated, without lubricant
c. Acetaminophen unencapsulated, with lubricant (Mg
stearate)
d. Acetaminophen unencapsulated, without lubricant
e. Placebo (without active substance), with lubricant
(Mg stearate)
f. Placebo (without active substance), without
lubricant
Four different fillers were alternatively added
to these six systems:
a. 400 mg each of Comprizucker and sorbitol
(corresponding exactly to Example l of W091/04757)
b. 800 mg of Comprizucker~ alone
c. 800 mg of sorbitol alone
d. 400 mg each of sorbitol and mannitol.
Acetaminophen Acetaminophen Placebo
(without
encapsulated unencapsulated active
substance)
a) with b} with- c) with d) with- e) with f) with-
Mg out Mg Mg out Mg Mg out Mg
stearate stearate stearate stearate stearatestearate
a) Compri-after after after Dissolu- after Dissolu-
5 5 5 5
zucker min, the min, the min, the tion min, tion
3/4
(400 mg) tablet tablet tablet time 140 of the time 140
+
sorbitol has has is still sec tablet sec
(400 mg) prac- prac- virtual- has dis-
tically tically ly whole solved
not dis- not dis-
solved solved
at all at all
b) Sorbi- after after after Dissolu- after Dissolu-
5 5 5 5
tol (800 min, the min, the min, the tion min, tion
3/4
mg) tablet tablet tablet time 160 of the time 170
has has is still sec tablet sec
prac- prac- virtual- has dis-
tically tically ly whole solved
not dis- not dis-
solved solved
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Acetaminophen Acetaminophen Placebo
(without
encapsulated unencapsulated active
substance)
a) with b) with- c) with d) with-e) with f) with-
Mg out Mg Mg out Mg Mg out Mg
stearate stearate stearate stearatestearate stearate
c) Compri-after after after Dissolu-after Dissolu-
5 5 5 5
zucker min, the min, the min, the tion min, 3/4 tion
(800 mg) tablet tablet tablet time of the time 100
135
is still is still is still sec tablet sec
virtual- virtual- virtual- has dis-
ly whole ly whole ly whole solved
d) Manni- after after after Dissolu-after Dissolu-
5 5 5 5
tol (400 min, the min, the min, 1/2 tion min, the tion
mg) + tablet tablet the time tablet time 95
sorbitol is still is still tablet 125 sec has vir- sec
(400 mg) virtual- virtual- has dis- tually
ly whole ly whole solved dis-
solved
As is evident from the table, with encapsulated
active substance and lubricant, the tablet has in each
case practically not dissolved at all or only
5 superficially dissolved 5 minutes after introduction
into 100 ml of fresh water.
Even with unencapsulated active substance, but
with lubricant, the tablet has practically not
dissolved or only half dissolved 5 minutes after
introduction into 100 ml of fresh water. Only with
unencapsulated active substance and without lubricant
is the dissolution time - depending on the filler used
- still 135 to 165 sec and only when half the sorbitol
is replaced by mannitol is it then 120 sec.
However, even the placebo variant shows how
troublesome the proposed fillers Comprizucker~ and
sorbitol are. In summary, both the active substance
encapsulation and the lubricant have a disadvantageous
effect on the dissolution behaviour; moreover,
replacing the Comprizucker~ by mannitol is sufficient
to have a positive effect, and dissolution times as
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long as 2 minutes are achieved, which however is still
too high for practice.
Examx~ 1 a 2
An effervescent base is first prepared as
follows: 86 parts of citric acid powder, 8.3 parts of
malic acid, 95 parts of sodium bicarbonate, 13.8 parts
of sodium carbonate < 0.1 mm, 5.5 parts of sodium
cyclamate, 1.1 parts of saccharin sodium and 0.3 part
of aspartame are mixed in a vacuum vessel heated to
60°C. In addition, a solution of 60 parts of
maltodextrin, 12 parts of trisodium citrate dehydrate
in 27 parts of water is prepared. 4.5 parts of this
solution (corresponding to 1.3 parts of maltodextrin,
relative to effervescent base - the coating results in
citric acid not being found so acidic during sucking
but the tablet dissolving sufficiently rapidly) are
sprayed in 5 cycles onto the powder mixture in the
vacuum vessel and distributed uniformly with vibratory
mixing, granulation taking place at the same time.
After each cycle, drying is carried out in vacuo and
the material is then discharged through a 2 mm sieve.
Expediently, another 5 parts by weight of maltodextrin
are applied to the resulting granules after the final
cycle and prior to drying and are distributed uniformly
with stirring and - preferably in vacuo - dried with
slow stirring.
180 parts of the effervescent base thus
prepared are mixed with 720 parts of mannitol, 100
parts of acetylsalicylic acid < 0.3 mm and 0.3 part of
docusate sodium aerosol OTB powder and 0.5 part of
polyvinylpyrrolidone K25, 3.0 parts of vanilla flavour
and 0.3 part of menthol and the mixture is compressed
to give tablets of 1 gram each. On direct oral intake,
the tablets produce a pleasant fizzy feeling in the
mouth or dissolve in 100 ml of water at 15-20°C in 55
seconds.
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The maltodextrin can also be replaced by
another hydrocolloid, such as, for example,
polyvinylpyrrolidone, guar gum or dextrin (the latter
is, however, more poorly soluble), less preferably by
tragacanth (because it froths too strongly) and causes
the effervescent components to undergo a slightly
slowed-down "soft" reaction in the mouth without
however seriously slowing down the dissolution in water
- owing to its good solubility. This measure has a
particularly advantageous effect in the case of citric
acid but is expediently also used in the case of malic
acid, tartaric acid, adipic acid and ascorbic acid.
Theoretically, rapidly soluble fillers could
also be coated with hydrocolloid, but this is a
technologically complicated step since the water
introduced by the solution of the hydrocolloid into the
mixture must be removed again by drying , and the type
and amount of hydrocolloid are difficult to optimize
with regard to the dissolution rate.
A mixture with the same ratios in which only
the citric acid is completely replaced by malic acid
gives completely analogous results.
Example 3:
Mixtures are prepared with 250 mg each of the
effervescent base prepared according to Example 2 and
10 mg each of nifedipine per tablet and are compressed
to give tablets, the type of filler (750 mg each) being
varied: all tablets dissolve in 100 ml of fresh water
at 16°C with little or no residue and exhibit good to
very good behaviour on direct oral intake as a chewable
tablet.
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Filler (750 mg each) Hardness Dissolution time
a. Mannitol 5.8 45"
b~ Maltisorb~ (_ 6.2 45"
hydrogenated maltitol)
c. Fructose 6.1 125"
d. Xylitol 6.0 60"
e. Lactose 6.3 40"
f. Sucrose 5.9 75"
g. Glucose 5.9 105"
h. Sorbitol instant 5.9 180"
It can clearly be seen that the rapidly soluble
fillers glucose, fructose and especially sorbitol
dramatically prolong the dissolution time (for the
reasons stated at the outset). The substances used had
the following sieve analysis:
by MannitolMalti- Lactose Fructose SorbitolXylitol
weight sorb~
Particle
size
(mm)
> 0.5 2.5
> 0.4 5.5 0.85 5.4
> 0.315 4.3 9.0 33.2
> 0.2 2.3 2.8 29.2 48.1 60.2
> 0.1 27.5 12.5 5.5 30.5 33.0 1.5
> 0.05 36.5 51.6 29.6 22.4 8.5
> 0.05 33.7 32.7 64.5 5.6 1.0
The more slowly soluble first three fillers can
be used as fine particles without seriously prolonging
the dissolution time; the more rapidly soluble last
three fillers must be used in the form of coarser
particles, sorbitol still being unsatisfactory with a
dissolution time of three minutes, as can be seen.
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Examble 4:
Mixtures are prepared analogously to Example 3,
except that - for different active substances - the
fillers are varied in type and amount depending on the
active substance and are made up with the effervescent
base to 1000 mg per tablet in each case. All mixtures
were compressed to give tablets having a hardness of
4.5 - 6.0; they dissolve in 100 ml of fresh water (15-
20°C) with little or no residue (with the exception of
any suspended particles or slight turbidity in the case
of insoluble or poorly soluble active substances) and
exhibit good to very good behaviour on direct oral
intake as a chewable tablet:
Active substanceFillers) Effervescenttdise
(mg) (mg) base (sec)
(mg)
a) 100 acetyl- 700 mannitol 190 55
salicylic acid 110 (flavour,
(corresponding sweeteners, PVP,
to etc.)
Example 2)
b) 10 nifedipirie 720 mannitol 240 50
40 (flavour,
sweeteners, PVP,
etc.)
c) 100 Allopurinol 500 xylitol 480 75
20 (flavour,
sweeteners, PVP,
etc.)
d) 40 Furosemide 720 mannitol, 10 240 100
PVP
e) 10 cisapride 740 mannitol 240 60
20 (flavour,
sweeteners, PVP,
etc.)
f) 10 loratadine 90 lactose 260 90
540 mannitol
110 (flavour,
sweeteners, PVP,
etc.)
g) 45 multivitamin 440 xylitol 150 60
mixture 390 mannitol
20 (flavour,
sweeteners, PVP,
etc.)
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Example 5:
A mixture of different fillers is often desired
for reasons relating to taste. Example 3 was repeated,
different filler mixtures being used. Under certain
5 circumstances, such mixtures also permit the use of
more rapidly soluble fillers, at least in part:
a. Mannitol (500 mg)/ 4.0 70"
sorbitol (250 mg)
b. Mannitol (500 mg)/ 4.0 75"
fructose (250 mg)
c. Xylitol (375 mg)/ 4.5 45"
lactose (375 mg)
d. Xylitol (525 mg)/ 4.0 45"
lactose (225 mg)
e. Fructose (375 mg)/ 4.5 55"
lactose (375 mg)
f. Fructose (600 mg)/ 4.5 95"
lactose (150 mg)
g. Glucose (375 mg)/ 5.5 70"
lactose (375 mg)
h. Glucose (600 mg)/ 4.5 95"
lactose (150 mg)
Example 6:
10 The mixture of Example 4 g) is repeated, except
that only mannitol is used as the filler, but in
changing amounts or ratios to the effervescent base.
It is found that both the dissolution time in the water
and the action as a chewable tablet in the mouth can be
classed as good to very good at effervescent base
mannitol ratios - 15:85 to 30:70. At a ratio of
35-40 . 65-60, on the other hand, the dissolution time
is of course gratifyingly low but the effervescent
action in the mouth is already found to be too strong
or the taste too acidic:
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Effervescent Filler Chewable Hardness Dissolution
base tablet time
(parts by weight)
15 85 mannitol very good 5.0 65"
20 80 mannitol very good 5.5 55"
25 75 mannitol good 5.5 45"
30 70 mannitol good 5.0 40"
35 65 mannitol initially 5.5 35"
acidic
40 60 mannitol too acidic 5.0 35"
EXamDla 7:
The mixtures of Example 5 g) and 5 h) were
repeated, with further variation of the mixing ratio
between glucose and lactose on the one hand and the
hardness of the compressed tablets on the other hand;
as can be seen, a still acceptable dissolution time is
obtained even at relatively great tablet hardness;
these tablets, too, were readily or very readily
chewable or suckable on direct oral intake:
Filler (mg) Hardness (kp) Dissolution Residue
time (s)
Glucose 750 5.9 105
none
Glucose 562 5.9 70
none
Lactose 188
Glucose 375 6.3 70 trace
Lactose 375
Glucose 188 6.4 65 trace
Lactose 562
Lactose 750 6.3 40 slight
EXamtJ 1 a $ ( n cra t- i va axa mr~ l c 1
Sorbitol alone is so rapidly soluble, in
particular coarse-particled sorbitol instant, which
however is porous owing to the spray drying, that - as
already mentioned - tablets produced with sorbitol
alone as filler have an undesirably long dissolution
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time, this being dependent on the particle size:
Filler (mg) Hardness (kp) Dissolution Residue
time (s)
Sorbitol 6.5 150 none
instant
Sorbitol P300 6.5 150 none
Sorbitol 60W 6.5 160 none
(c stalline)
Examx~ 1 a 9
468 g of citric acid powder, 312 g of fine
citric acid granules and 150 g of sodium cyclamate are
introduced into a heatable vessel and heated to 60°C
with stirring. At 60°C, 420 g of sodium bicarbonate
are added. The mass is heated to 60°C again with
stirring.
In addition, 90 ml of a solution of 60 g of
maltodextrin, 12 g of trisodium citrate dehydrate and
59 g of water are prepared. 9 ml of this solution are
now sucked in and allowed to react; 19 g of sodium
carbonate are then added at 100 mbar and drying is
carried out with slow stirring to 20 mbar. After
drying, heating is carried out again to 60°C and a
second granulation is effected with 9 ml of the
solution. The mass is dried to 100 mbar with slow
stirring, whereupon a further 77 g of sodium carbonate
are added. The product is then dried to 15 mbar and
sieved to 1.6 mm. This effervescent base is then mixed
with 2784 g of mannitol, 600 g of xylitol, 1200 g of
lactose, 120 g of flavour and 135 g of isosorbide 5-
mononitrate (90~ lactose trituration) and compressed to
give tablets of 1.05 g each.
F.~xa~nx~ 1 a 10
The procedure is analogous to that of Example
2, except that tartaric acid is used instead of citric
acid and, instead of acetylsalicylic acid, a standard
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multivitamin mixture, such as, for example, 50~ of the
RDA (= Recommended Daily Allowance) according to US
standard, of vitamin E acetate (tocopheryl acetate),
thiamine mononitrate, pyridoxine HCl, riboflavin
phosphate sodium, nicotinamide, folic acid, biotin,
calcium pantothenate, vitamin D3 100CwS, vitamin B12
0.1~ and vitamin A palmitate CWS, so that the prepared
tablet has the following composition (in mg):
Tartaric acid powder 86.00
Malic acid 8.30
Sodium bicarbonate 95.00
Anhydrous sodium carbonate 13.80
Sodium cyclamate 5.50
Saccharin sodium 1.10
Aspartame 0.30
Trisodium citrate dihydrate 0.95
Maltodextrin 1.00
Mannitol 700.00
Multivitamin mixture 45.50
Flavour 20,00
977.45
The tablet exhibits satisfactory behaviour in
the mouth and dissolves in a glass of water in less
than 60 sec.
The invention can be used with many active
substances, the dose of which may be up to about
200 mg. Active substances whose dose is only up to
100 mg are particularly advantageous since a small
tablet is more suitable than a larger one for sucking
or chewing.
