Note: Descriptions are shown in the official language in which they were submitted.
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A PROCBSS FOR THE PRBPARATION OF A GRANULATB SUITABLg TO
THE PREPARATION OF RAPIDLY DISINTEGRABj.B MOUTH-SOLUBLE
TABLBTS
Field of the invention
The invention relates to a process for the
preparation of a granulate suitable to the preparation
of rapidly disintegrable mouth-soluble tablets.
5. Technological backaround
One of the changes occurring in modern society is
the progressive ageing of population. Such a phenomenon
is accompanied by the onset of degenerative pathologies
involving difficulties in coordination and in swallowing
the traditional oral forms such as tablets or capsules.
Said problems are also present, although for opposite
causes, in other population groups, such as children.
On the other hand, the need for solid
pharmaceutical forms capable of making the medicament
available within a short time from the administration is
particularly felt even for those patients who do not
have any swallowing problems.
In some fields of therapy, such as that relating
analgesia, fast acting medicaments to be administered by
the oral route are nowadays particularly required.
The conventional solution to such a problem is
usually provided by water-soluble effervescent tablets.
In this case, the patient ingests the aqueous
solution resulting from the disintegration of the tablet
in water so that the active ingredient already dissolved
or dispersed in water is in a highly bio-available form.
A number of methods for the preparation of granu-
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2
lates suitable to the preparation of effervescent
tablets are known. One of said methods, so-called
"single phase", consists in keeping in suspension, in an
air stream, the effervescent mixture and optionally any
excipients and in granulating said mixture using water
and/or a binding polymer. The mass, after the
granulation phase, is dried, sieved and collected in a
single operation.
The effervescent tablets, however, in order to be
administered, have to be dispersed in a carrier, since
they cannot be ingested directly. This is in many cases,
above all for the above mentioned population groups, a
restriction to the use of such a pharmaceutical
formulation.
Therefore, tablets to dissolve in the mouth,
suitable to the oral or sublingual administration, have
been suggested.
The buccal tablets are intended for disintegration
in the mouth, the patient placing them in the buccal
cavity, on the tongue or between cheeks and gums,
thereby allowing a slow dissolution, which usually
requires 30 to 60 minutes (E. Rotteglia "Compresse
farmaceutiche", SocietA Editoriale Farmaceutica, Milan,
Italy, 1966).
On the contrary, sublingual tablets are intended to
be placed under the tongue, wherein the active substance
can be directly absorbed through the mucosa. These forms
are provided with slow-disintegration formulations as
well (E. Rotteglia, ibid. and S. Casadio, Tecnologia
Farmaceutica II Ed., Cisalpina Goliardica, Milan,
Italy).
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This type of prolonged release is hardly suitable
for formulating active ingredients, such as analgesics,
which have to exert an immediate effect.
Such a requirement can be met by freeze-dried
sublingual tablets such as those prepared according to
the Zydis(R) procedure (Manufacturing Chemist, 36-37,
February 1990).
However, such formulations are very expensive and
require sophisticated technologies and methods from the
production point of view. These products are
substantially freeze-dried products, the pharmaceutical
formulation being therefore difficult to handle (due to
its high friability and fragility) and requiring
specific packaging. A problem connected with this type
of formulation is the impossibility to effect any taste-
masking on the active ingredient.
WO 8808298 (Fuisz Technologies, 3-11-1988)
discloses rapid-dissolution pharmaceutical compositions
in which the active ingredient is included in fibres of
a water-soluble carrier obtained through a specific
preparation process which requires a specific, expensive
plant. Moreover, the resulting compositions exhibit
friability problems and must always be handled and
packed with particular precautions (use of dehydrating
-25 agents, humidity-tight packages, controlled-humidity
work environment and so on).
EP-A-494972 (Cima Labs Inc.; 22-7-1992) describes
effervescent tablets suitable to the direct oral
administration, i.e. without a previous development of
the effervescence in water, consisting of microcapsules
containing the active ingredients and an amount of
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4
effervescent agents sufficient to promote the release of
the microgranules when ingested and to give a "fizzing"
sensation when in contact with the buccal mucosa of the
patient.
The amount of effervescent agents, typically citric
acid and a carbonate or a bicarbonate, ranges from 5 to
50% by weight compared with the composition total
weight, preferably from 15 to 30%. Dissolution times in
the mouth range from 30 seconds to 5-7 minutes.
In this case also, notwithstanding the presence of
amounts of effervescent agents lower than in
conventional formulations (60% by weight compared with
the composition total), the typical cautions used for
the effervescent tablets should be taken.
Further drawbacks are the friability of the tablets
and the use of microcapsules. In fact, the preparation
technique described in EP-A-494972 does not envisage the
humid granulation, i.e. using a solvent, but the direct
mixing of the powders and the subsequent compression.
Such a preparation technique yields tablets having
friability values higher than those involving the humid
granulation of the mixture to be pressed.
Summary of the invention
Now it has been found that mouth-soluble, rapidly
disintegrating tablets can be prepared by fluidized bed
granulating an aqueous solution of a water-soluble or
water-dispersible polymer in a polyalcohol, optionally
in mixture with other solid components.
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4a
In one particular embodiment there is provided a
process for the preparation of a granulate for use in
the preparation of mouth-soluble, rapidly disintegrating
tablets, which comprises granulating in a fluidizing
bed, a bed of solids consisting of:
- a polyalcohol,
- from 1 to 30% of an edible acid or an effervescent
mixture of acids and bases for alimentary use in
amount lower than 20% by weight on the total
composition
- optionally other solid components
with an aqueous granulating liquid containing an amount
of water-soluble or water-dispersible polymer ranging
from 1 to 10% by weight on the total composition.
The granulate obtained according to the invention,
characterized by a high porosity and a low apparent
density, allows to prepare tablets rapidly disinte-
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grating in contact with saliva in times ranging, for
example, from 30" to 3', even without the aid of
effervescent agents.
If desired, however, the effervescent agents can be
5 present in the granulate composition in order to promote
further the disintegration of the tablets. For this
purpose, markedly lower amounts of effervescent agents
than those usually employed in the conventional
effervescent compositions. About 20% by weight of
effervescent agents on the basis of the total tablet
assures for example an exceedingly rapid dissolution,
but even lower amounts, for example lower than 5%,
provide similar disintegration times.
Moreover, it has surprisingly been found that
substantially the same disintegrating effect can also be
obtained using the only acid component of the
effervescent couple.
The compositions obtainable according to the
invention, in addition to disintegration times lower or
anyhow comparable to those of the traditional
effervescent formulations, have the following further
advantages:
- high stability;
- very good organoleptic characteristics;
- handling and packaging without need for the
cautions and measures required for the effervescent
formulations.
Detailed disclosure of the 'nv ntion
The method according to the invention consists in
the fluidized bed granulation in a water-soluble or
water-dispersible polymer a diluent of the class of
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polyalcohols and optionally other solid components such
as active ingredients, flavors, sweetening agents,
surfactants, disintegration agents.
The polyalcohols which can be used according to the
invention are those usable for alimentary purposes and
are preferably selected from mannitol, xylitol,
sorbitol, maltitol, erythritol and lactitol.
Particularly preferred are sorbitol or xylitol which
have high water-solubility a negative heat of
dissolution, capable of giving a pleasant feeling of
freshness. The polyalcohol will be from about 50 to
about 90% by the total weight of the tablet obtained by
compression of the granulate.
Water-soluble or water-dispersible polymers are
selected from those conventionally used in the
pharmaceutical field. Examples of said polymers comprise
polyethylene glycols, sodium carboxymethyl cellulose,
hydroxypropylmethyl cellulose, xanthan gum, polyethylene
oxide (Polyox (R)), ethoxylated polyoxypropylene
(Pluronic(R)), acrylic and methacrylic acid polymers
(Eudragit(R)), carrageenin, ethyl cellulose
(AcquacoatR), polyvinyl alcohol. The amount of the
polymer dissolved or dispersed in water varies from 1 to
10% by weight on the total composition.
The fluidized bed granulation is usually carried
out adjusting the operative conditions, so that the
temperature of the inlet air is from 30 to 50 C and the
temperature of the outlet air is from 25 to 45 C. The
flow of the distributed solution will depend of course
on the size and type of the plant. In principle, for a
pilot plant of the type Niro Aereomatic Strea 1 flows
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ranging between 10 and 15 ml/min of polymer solution or
dispersion will be used.
In addition to the polyalcohol, the solid phase can
contain all of the other components (active ingredient,
flavors, sweeteners, and the like) or some thereof can
be mixed with the granulate before compression. Such an
alternative can be suitable in the case of highly
thermo-sensitive components or in the case of excipients
such as lubricants, flavours, disintegrating agents.
When present, the effervescent mixture can consist
of acids and bases for alimentary use.
The acid source can consist of citric, tartaric,
malic, fumaric, adipic, succinic, alginic acids,
anhydrides and acid salts such as dihydrogen phosphate,
disodium dihydrogen phosphate, citric acid salts.
The bases can be: solid carbonates of salts such as
sodium carbonate, sodium bicarbonate, potassium
bicarbonate, potassium carbonate, magnesium carbonate,
sodium glycine carbonate, L-lysine carbonate, arginine
carbonate and amorphous calcium.
The amount of effervescent mixture or of the acid
only is preferably lower than 20% by weight on the basis
of the total composition, most preferably lower than 5%.
Alternatively, the compositions of the invention
can contain only the acid component, particularly citric
acid, in weight percentages from 1 to 4% on the total.
The compositions obtainable according to the
process of the invention are suitable for the
administration of any active ingredient which can be
administered orally and capable of being absorbed by the
buccal mucosa and/or by the gastrointestinal tract. If
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desired, the active ingredients may be previously
coated.
Moreover, the compositions obtainable according to
the process of the invention are particularly suitable
for the administration of vitamins, mineral salts,
dietary supplements, vegetable extracts and mixtures
thereof.
Examples of active ingredients which can be used in
the process of the invention comprise: antitussives,
anthistamines, decongestants, antacids, analgesics,
anti-inflammatories, antibiotics, anticholesterol
agents, antiarrhythmics, antiepileptics, anorexizants,
expextorants, antianxiety agents, antiulcer drugs,
coronary dilators, psychotropics, antipsychotics,
antineoplastics, antiemetics, hypnotics, antikynetosic
agents, muscle relaxants, neuromuscular agents,
hypoglycemic agents, hyperglycemic agents, thyroid
suppressors and stimulants, diuretics, antispasmodics,
uterine relaxants, anabolic agents and combinations
thereof.
Examples of vitamins comprise Vitamin C, Vitamin E,
Vitamin D, Vitamin K, Vitamin A, Vitamin B complex,
folic acid, choline, carnitine, carnosine, carotenoids,
lycopene, optionally in the form of coenzymes.
Examples of mineral salts comprise salts of
essential elements such as calcium, magnesium, iron,
zinc, selenium, copper, iodine, phosphorous, chromium,
cobalt, manganese, optionally in mixtures thereof.
Examples of dietary supplements comprise amino-
acids, proteins, vegetable or fish oils, ginseng, bran,
honey, royal jelly, meals and the like.
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Examples of derivatives or extracts of natural
origin comprise green tea, Ginseng, Guarany, Ginkgo
biloba, bilberry extracts, proanthocyanosides, grape-
seed extracts and the like.
The flavor, which is an important feature of this
type of pharmaceutical formulations, can be included in
the outer phase during the final mixing with other
excipients or, making use of the fluidized bed
granulation technique, it can be sprayed on the
granulate and then on the active ingredient, exploiting
in some cases the capability of taste-masking of the
flavor on the active ingredient.
The flavors can be selected from synthetic or
natural flavors, extracts from plants or flowers, alone
or in a combination thereof, essential oils such as
cinnamon, peppermint, clove, anise, eucalyptus, thyme,
cedar, chamomile oils. Other flavors useful are fruits
essences such as apple, peach, strawberry, raspberry,
orange, apricot, cherry, plum, pineapple, bubble gum
alone or in a combination thereof.
The amount of flavor used can vary, depending on a
number of factors such as the intensity of the desired
organo3.eptic effect: the amount can anyhow vary from 0.5
to 3.0% on the basis of the composition total weight.
.25 The compositions of the invention can moreover
contain disintegration agents such as microcrystalline
cellulose coated with arabic gum; potato or maize
starches, modified starches, polyvinylpyrrolidone,
cross-povidone, alginic acid, starch sodium glycolate,
agar, in amount ranging from 2 to 10% on the basis of
the composition total weight.
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The compositions can optionally contain coloring
agents such as titanium dioxide, acceptable natural or
synthetic coloring agents, which can be sprayed during
the granulation phase.
5 The lubricants and surfactants can be added to the
granulate both during the final mixing phase before
compression and during the granulation.
Among the traditional solid lubricants, Ca, Mg, Zn
of stearic acid salts, partially hydrogenated vegetable
10 oils, polyethylene glycols, polyoxyethylene
monostearate, talc, sodium benzoate, sodium
laurylsuifate, magnesium oxide can be used.
The amount of lubricant to be added can vary from
0.2% to 1.0% of the total composition.
In all of the excipient mixtures, the poured
apparent density before and after the granulation has
been evaluated.
Before the granulation, the density varies from 0.6
to 0.8 g/ml, after the granulation process in the
conditions defined above the density decreases to 0.3 -
0.5 g/ml.
These data confirm the capability of this method of
producing low-density, and therefore high-porosity,
granulates.
This porous structure is maintained even after
compression of the granulate, thereby obtaining tablets
with a variable hardness of 6-7 Kp which disintegrate in
a time ranging between 30" and 120".
In order to increase the disintegration rate, the
granulate obtained according to the invention can be
compressed to a form so as to increase the tablet
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surface, for example in a circular form with a
substantially toroidal section, as shown in Figures la
(plant view) and in Figures lb (sectional view).
The following examples illustrate the invention in
greater detail.
Example 1
Nimesulide mouth-soluble tablets (100 mg of
Nimesulide for 1.0 g tablet, diameter 16 mm)
Amount x Amount batch
1000 mg 500 g (500 tbl)
1 Nimesulide 100.0 mg 50.0 g
2 Citric acid
crystals 19.0 mg 9.5 g
3 Sodium bicarbonate 19.0 mg 9.5 g
4 Sorbitol 820.0 mg 410.0 g
5 Aspartame 4.0 mg 2.0 g
6 PEG 6000 20.0 mg 10.0 g
7 Strawberry flavor 15.0 mg 7.5 g
8 Magnesium stearate 3.0 mg 1.5 g
TOTAL 1000.0 mg 500.0 g
Preparation method
The components 1, 2, 3, 4 e 5, previously weighed e
sieved, were transferred to a fluidized bed (Niro
Aeromatic Strea 1). The granulation was carried out with
a PEG 6000 aqueous solution in 50 ml of water with a 10
ml/minute flow (peristaltic pump) and with inlet air
temperature of 40 C.
The resulting granulate, after drying, cooling and
sieving, was mixed with the components 7 and 8.
The mixture obtained was tabletted with a 16 mm
diameter punch.
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.xamp e-2
Nimesulide mouth-soluble tablets (100 mg of
Nimesulide per 1.0 g tablet, diameter 16 mm)
Amount x Amount per batch
1000 mg tbl 500 g tbl (500 tbl)
1 Nimesulide 100.0-mg 50.0 g
2 Citric acid
crystals 38.0 mg 19.0 g
3 Sorbitol 820.0 mg 410.0 g
4 Aspartame 4.0 mg 2.0 g
5 PEG 6000 20.0 mg 10.0 g
6 Strawberry
flavor 15.0 mg 7.5 g
7 Magnesium
stearate 3.0 mg 1.5 g
TOTAL 1000,0 mg 500.0 g
Preparation method
The components 1, 2, 3 and 4, previously weighed
and sieved, were transferred to a fluidized bed (Niro
Aeromatic Strea 1). The granulation was carried out with
a PEG 6000 aqueous solution in 50 ml of water with a 10
ml/minute flow (peristaltic pump) and with inlet air
temperature of 50 C.
The resulting granulate, after drying, cooling and
sieving, was mixed with the components 6 and 7.
The mixture obtained was tabletted with a 16 mm
diameter punch.
Example 3
Mouth-soluble multi-vitamin tablet (1.0 g tablets,
diameter 16 mm).
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Amount x Amount x batch
1000 mg tbl 600 g tbl (600 tbl)
1 Vitamin B12 0.1% 1.4 mg 0.840 g
2 Vitamin B2 5
phosph. Na 2 H20 1.9 mg 1.140 g
3 Vitamin A palmi-
tate 250 cws 8.33 mg 4.988 g
4 Vitamin B1 mono-
nitrate 1.10 mg 0.660 g
5 Vitamin B6 HC1 1.61 mg 0.966 g
6 Vitamin C 56.25 mg 33.750 g
7 Vitamin D3
100 cws 5.0 mg 3.000 g
8 Vitamin E 50%
acetate 23.99 mg 14.394 g
9 Folic acid 0.134 mg 0.081 g
10 Biotin 0.036 mg 0.021 g
11 Vitamin PP 33
1/3 rocoat 42.90 mg 25.740 g
12 Carotene (tab
10% And) 15.0 mg 9.000 g
13 Sorbitol 761.35 mg 456.810 g
14 Citric acid 38.0 mg 22.800 g
15 Aspartame 5.0 mg 3.000 g
16 PEG 6000 20.0 mg 12.000 g
17 Orange flavor 15.0 mg 9.000 g
18 Magnesium
stearate 3.0 mg 1.800 g
TOTAL 1000,0 mg 600.000 g
Pregaration method.
The components 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 13
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and 15, previously weighed and sieved, were transferred
to a fluidized bed (Niro Aeromatic Strea 1). The
granulation was carried out with a PEG 6000 aqueous
solution in 60 ml of water with a 8 ml/minute flow
(peristaltic pump) and with inlet air temperature of
35 C.
The resulting granulate, after drying, cooling and
sieving, was mixed with the remaining components.
The mixture obtained was tabletted with a 16 mm
diameter punch.
Example 4
Acetylsalicylic acid mouth-soluble tablets (300 mg
of acetylsalicylic acid for 1.1 g tablet, diameter 16
mm)
Am. x tbl Am. x a batch
1100 mg 220 g (200 tbl)
1 Sorbitol 745 mg 149.0 g
2 Aspartam 4.0 mg 0.8 g
3 PEG 6000 20.0 mg 4.0 g
4 Acetylsalicylic
acid 300.0 mg 60.0 g
5 Strawberry flavor 25.0 mg 5.0 g
6 Magnesium stearate 6.0 mg 1.2 g
TOTAL 1100.0 mg 220 g
Preparation method
The components 1 and 2, previously weighed and
sieved, were transferred to a fluidized bed (Niro
Aeromatic Strea 1). The granulation was carried out with
a PEG 6000 aqueous solution in 50 ml of water with a 10
ml/minute flow (peristaltic pump) and with inlet air
temperature of 45 C.
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The resulting granulate, after drying, cooling and
sieving, was mixed with the components 4, 5 and 6.
The mixture obtained was tabletted with a 16 mm
diameter punch.
5 Example 5
Paracetamol (Pharmazome I.R.) mouth-soluble tablets
(500 mg of paracetamol for 2.0 g tablet, diameter 19 mm)
Am. x tbl Am. x a batch
2000 mg 500 g (500 tbl)
10 1 Paracetamol
Ph.z. I.R. 750.0 mg 225.0 g
2 Mannitol 280.0 mg 84.0 g
3 Xylitol 841.0 mg 525.3 g
4 Citric acid crystals 40.0 mg 12.0 g
15 5 Sodium bicarbonate 40.0 mg 12.0 g
6 Aspartame 4.0 mg 1.2 g
7 PEG 6000 20.0 mg 6.0 g
8 Orange flavor 20.0 mg 6.0 g
9 Magnesium stearate 5.0 mg 1.5 g
TOTAL 2000.0 mg 600.0 g
Preparat i on method
The components 1, 2, 3, 4, 5 and 6, previously
weighed and sieved, were transferred to a fluidized bed
(Niro Aeromatic Strea 1). The granulation was carried
out with a PEG 6000 aqueous solution in 60 ml of water
with a 10 ml/minute flow (peristaltic pump) and with
inlet air temperature of 50 C.
The resulting granulate, after drying, cooling and
sieving, was mixed with the components 8 and 9.
The mixture obtained was tabletted with a 19 mm
diameter punch.
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Fxa le 6
Green tea mouth-soluble tablets (50 mg of Green tea
for 1.8 g tablet, diameter 19 mm)
Am. x tbl Am. x a batch
1500 mg 750 g (500 tbl)
1 Green tea 50.0 mg 25.00 g
2 Sorbitol 1337.0 mg 668.50 g
3 Citric acid
crystals 40.0 mg 20.00 g
4 Sodium bicarbonate 20.0 mg 10.00 g
5 Aspartame 9.0 mg 4.50 g
6 PEG 6000 15.0 mg 7.50 g
7 Berry flavor 25.0 mg 12.50 g
8 Magnesium stearate 4.0 mg 2.00 g
TOTAL 1500.0 mg 750.00 g
Preparation method
The components 1, 2, 3, 4 and 5, previously weighed
and sieved, were transferred to a fluidized bed (Niro
Aeromatic Strea 1). The granulation was carried out with
a PEG 6000 aqueous solution in 50 ml of water with a
11.2 ml/minute flow (peristaltic pump) and with inlet
air temperature of 50 C.
The resulting granulate, after drying, cooling and
sieving, was mixed with the components 7 and 8.
The mixture obtained was tabletted with a 19 mm
diameter punch.
Examble 7
Cimetidine mouth-soluble tablets (50 mg of
Cimetidine for 1.0 g tablet, diameter 16 mm)
Am. x tbl Am. x a batch
1000 mg 700 g (700 tbl)
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1 Cimetidine 50.0 mg 35.000 g
2 Xylitol 7.5 mg 5.250 g
3 Aerosil 2000 3.0 mg 2.100 g
4 Monoammonium
glycyrrhizinate 0.3 mg 0.210 g
5 Aspartame 4.0 mg 2.800 g
6 Eudragit L30D55 10.0 mg 7.000 g
7 Talc 5.08 mg 3.556 g
8 Simethicone antifoam 0.12 mg 0.084 g
9 Triethyl citrate 1.0 mg 0.700 g
10 Xylitol 831.0 mg 581.700 g
11 PEG 6000 20.0 mg 14.000 g
12 Citric acid
crystals 19.0 mg 13.300 g
13 Sodium bicarbonate 19.0 mg 13.300 g
14 Raspberry flavor 25.0 mg 17.500 g
15 Magnesium stearate 5.0 mg 3.500 g
TOTAL 1000,0 mg 700.000 g
Prepara#;ion method
The components 1, 2 and 3, previously weighed and
sieved, were transferred to a fluidized bed. First a
solution of the components 4 and 5 in 50 ml of water
was sprayed, then a dispersion of the components 6, 7, 8
and 9 in 20 ml of water. After drying, the components
_25 10, 12 and 13 and were added, granulating with a
solution of PEG 6000 in 60 ml of water, using a 10
mi/minute flow (peristaltic pump) and with inlet air
temperature of 50 C.
The resulting granulate, after drying, cooling and
sieving, was mixed with the components 14 and 15.
The mixture obtained was tabletted with a 16 mm
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diameter punch.
Example 8
Ibuprofen mouth-soluble tablets (100 mg of
Ibuprofen for 1.0 g tablet, diameter 16 mm)
Am. x tbl Am. x a batch
1000 mg 500 g (500 tbl)
1 Ibuprofen 100.0 mg 50.0 g
2 Xylitol 10.0 mg 5.0 g
3 Eudragit L30D 55 20.0 mg 10.0 g
4 Talc 10.6 mg 5.3 g
5 Simethicone
antifoam 0.24 mg 0.12 g
6 Triethyl citrate 2.0 mg 1.0 g
7 Liquid flavor 0.0001 mg 0.00005 g
8 Cremophor RH40 0.0001 mg 0.00005 g
9 Xylitol 751.5598 mg 375.7799 g
10 Citric acid
crystals 50.0 mg 25.0 g
11 Aspartame 10.0 mg 5.0 g
12 Polyoxylresin
WRSN10 6.6 mg 3.3 g
13 Mint flavor 5.0 mg 2.5 g
14 Orange flavor 30.0 mg 15.0 g
15 Magnesium stearate 4.0 mg 2.0 g
TOTAL 1000,0 mg 500.0 g
Preparation method
The components 1 and 2, previously weighed and
sieved, were transferred into a fluidized bed. First a
solution of the components 3, 4, 5 and 6 in 11.5 ml of
water was sprayed, and then a solution of the components
7 and 8 in 25 ml of water. After drying, the components
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9, 10 and 11 were added, granulating with a solution of
12 in 50 ml of water, using a 10 ml/minute flow
(peristaltic pump) and with inlet air temperature of
40 C.
The resulting granulate, after drying, cooling and
sieving, was mixed with the components 13, 14 and 15.
The mixture obtained was tabletted with a 16 mm
diameter punch.
Example 9
N-Acetyl-cysteine month-soluble tablets (200 mg of
N-Acetyl-cysteine for 1.2 g tablet, diameter 16 mm).
Am. x tbl Am. x. a
1200 mg Batch 600 g
1 N-Acetyl-cysteine 200 mg 100.0 g
2 Citric acid 21.8 mg 10.9 g
3 Mannitol 476.0 mg 238.0 g
4 Sorbitol 221.0 mg 110.5 g
5 Polyplasdone CL 60.0 mg 30.0 g
6 PEG 6000 15.0 mg 7.5 g
7 Magnesium Stearate 8.0 mg 4.0 g
8 Aspartame 10.0 mg 5.0 g
9 Sodium Bicarbonate 98.2 mg 49.1 g
10 Avicel CE 15 60.0 mg 30.0 g
11 Lemon Flavor 15.0 mg 7.5 g
12 Tangerine Flavor 15.0 mg 7.5 g
TOTAL 1200 mg 600.0 g
Pre ap ration Method
The components 1, 2, 3, 4 and 5, previously weighed
and sieved, were transferred to a fluidized bed (Niro
Aeromatic Strea 1). The granulation was carried out with
a PEG 6000 aqueous solution in 50 ml of water with a
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11.2 mi/minute flow (Peristaltic pump) and with inlet
air temperature of 50 C.
The resulting granulate, after drying, cooling and
sieving, was mixed with the component 7, 8, 9, 10, 11
5 and 12.
The mixture obtained was tabletted with 16 mm
diameter punch.
In the following table, the results of the physical
controls carried out on the preparations of Examples 1-9
10 are listed.
20
30
CA 02298487 2000-01-24
WO 99/04758 _ PCT/EP98/04514
21
LO
O o
rn n Ln o 0
= ko N = O
O O c-I .-1 l~ kO
l- O
t'- O N
00 = = tt7 O = O
O O .-1 .-1 t0 tD
OD O O
c- LO 0 n o
= %D O = o
o O= .=-4 r-i V-i
M w o
ko ~ ~ o O o
= = o~ ~r; = ~r
o a r-q
N 0 0
Ln l- LO 0
O O
= d1 O = O
O O= r-1 N c=i
O e==I 0
ko 0 O
= tp .-! = O
O O .-1 c-I tD M
O O O
O O O
= = ~O O = N
O O e-I .-1 t~ e- I
O t+ O
N t~- d+ O d~
t0 O = O
O 0 r-; r-I t~ cr)
'd' O O
r-i [" LO 0 0 L[1
= = kD 0 = N
O O e-i .-I t~ .-I
.-~ .~
r-1 r{
1 1
~71 Cf1 ~
~
+j
p to -'-I O '-1 p
O M 4-4 O
4J
ro O 10
.P vl m
~n nl m 0 vl a)
N *-I N =i-J -P -P N -P
I
o a a~ o w ro ~ ~ ~
W
a .ca FG ~~ ~ e-+ ca ~ x r~ --
