Note: Descriptions are shown in the official language in which they were submitted.
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I
PHARMACEUTICAL COMPOSITION AND PROCESS FOR PREPARING THE
SAME
The present invention relates to a homogenizate
comprising piroxicam as active ingredient, to a process
for preparing the same and a process for the preparation
of capsule or tablet from the said homogenizate.
More particularly, the invention relates to a powder
homogenizate comprising N-(2-piridyl)-2-methyl-4-hydroxy-
-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (further
on piroxicam) as active ingredient together with carriers,
further to capsules or tablets prepared from the said
homogenizate.
Piroxicam has been described first by US patent
specification No. 3,591,584, the examples of which suggest
the following compounds to incorporate into tablets or
capsules:
tablets: piroxicam, sodium citrate, alginic acid, polyvinyl
pyrrolidone, magnesium stearate;
capsules: piroxicam, calcium carbonate, polyethylene glycol.
The said patent specification does not disclose any
specific data, e.g. breaking rigidity, resistance to
abrasion, fluidity, disintegration time, mass density,
active ingredient dissolution, being characteristic for
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the tablets or the capsules.
European patent specification No. 66,459 relates to
the preparation of piroxicam ethylenediamine and mono-
or diethanaolamine salts having enhanced dissolving
ability. The examples of this reference describe the
following compositions of tablets and capsules, but the
qualitative properties and dissolution curves are not
taught:
Tablet:
piroxicam ethylenediamine salt 5.88 mg
corn starch USP 34.00 mg
magnesium stearate 1.04 mg
Tablets with 10, 25 and 50 mg active ingredient
content can be prepared similarly, taking the proportional
amounts of the ingredients.
Capsule:
piroxicam monoethanolamine salt 59.21 mg
anhydrous dicalcium phosphate 230.10 mg
corn starch 32.50 mg
sodium lauryl sulfate 0.32 mg
magnesium stearate 2.07 mg
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Tablet:
piroxicam monoethanolamine salt 23.92 mg
microcrystalline cellulose 311.03 mg
modified, pregelatinized starch 84.00 mg
5 magnesium stearate , 0.945 mg
sodium lauryl sulfate 0.105 mg
Tablet:
piroxicam monoethanolamine salt 23.69 mg
anhydrous dicalcium phosphate 113.37 mg
polyvinyl pyrrolidone 50.00 mg
modified, pregelatinized starch 10.0 mg
magnesium stearate 2.65 mg
sodium lauryl sulfate 0.294 mg
When a pharmaceutical composition comprising piroxicam
as active ingredient is prepared, the following problems
arise:
a) Piroxicam is poorly soluble in aqueous medium,
therefore in order to eliminate this disadvantage European
patent specification No. 66,459 suggests the use of a salt
of piroxicam.
b) In the course of a wet granulation process the
composition gets coloured due to the effect of the aqueous
or hydroxyl-group-containing granulating liquid, thus the
composition does not meet the international standard.
c) The adsorption of the active ingredient from the
pharmaceutical formulation is a very important characteristic,
which can be measured by expensive biological tests; thus
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it is preferred if the different dosage forms have the
same composition.
d) When the composition is formulated by wet
granulation technique, the homogeneous distribution of
the ingredients is assured, while when dry homogenization
is applied, in case of non-properly selected excipients,
especially in the course of tabletting, sorting owing to
the gravitational filling uneven distribution of the active
agent may occur which may result in non-admitted scatter-
ing of the active ingredient.
The aim of the invention was to prepare a homogenizate
1) which is suitable for preparing tablets and capsules of
the same composition,
- 2) in which, independently from the crystal form of the
15active ingredient, the dissolution values and qualitative
parameters of the capsule and tablet are suitable,
3) in which the scattering of the active ingredient content
is in accordance with the standards,
4) which can be in dry medium.
20No composition meeting the above requirements can
be found in the prior art.
In the course of our experiments it was found that
with the composition comprising piroxicam as active
ingredient according to USP XXI the desired in vitro dis-
solution level could not be achieved. This dissolutionrate would be obtained if at least 75% by mass of the active
ingredient content were dissolved out from the composition
within 45 minutes.
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According to our measurements, from the standard
composition comprising piroxicam as active ingredient
42 to 45% by mass of the active ingredient content were
dissolved out within 45 minutes at a temperature of 37 C,
at a stirring rate of 50 revolution/minute, by using
artificial gastric juice under the prescriptions of USP XXI
in a rotating dissolving equipment.
The scattering of the active ingredient content in
pharmaceutical formulations comprising piroxicam as active
ingredient may be RSD = 6.0% according to USP XXI.
Now it has been found that if piroxicam crystals are
micronized below a particle size of 30 /um, preferably below
10 /um, and if possibly mannitol and silica are added, the
composition comprising the micronized piroxicam crystals
assures the desired dissolution values and these values
can safely be maintained.
Based on the above, the homogenizate according to
the invention is composed of
1 part by weight of N-(2-piridyl)-2-methyl-4-hydroxy-2H-
-1,2-benzothiazine-3-carboxamide-1,1-dioxide as
active ingredient which at least in 90% by mass has
a particle size of at most 30 /um, preferably 10 /um,
if desired, 0.1 to 5.0 parts by mass, preferably 1 part
by mass, of mannitol optionally of the same particle
size,
if desired, 0.005 to 0.15 parts by mass, preferably 0.06 to 0.1
parts by mass, of silica optionally of the same
particle size,
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5 to 25 parts by mass, preferably 8 to 18 parts by mass,
of spray-dried lactose which at least in 80% by
mass has a particle size of 80 to 200 /um,
if desired, 0.5 to 6.0 parts by mass, preferably 1.5 to
4.0 parts by mass, of a disintegrant, preferably
corn starch,
if desired, 0.005 to 0.05 parts by mass, preferably 0.01
to 0.02 parts by mass,of a surface active agent,
preferably sodium lauryl sulfate, and
if desired, 0.05 to 0.5 parts by mass, preferably 0.1 to
0.2 parts by mass,of a lubricant, preferably
magnesium stearate.
The lactose has preferably a surface pore size of
10 to 20 /um.
The homogenizate according to the invention is
prepared by
micronizing 1 part by mass of N-(2-piridyl)-2-
methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-
dioxide as active ingredient with or without 0.1 to 5.0
parts by mass, preferably 1 part by mass of mannitol and
0.005 to 0.15 parts by mass, preferably 0.06 to 0.1 parts by
mass, of silica in such a manner that at least 90% by mass
of the mixture have a particle size of at most 30 /um,
preferably at most 10 /um, or if mannitol and silica have
not been micronized together with the active ingredient,
if desired, adding mannitol and/or silica in the above
amounts to the mixture after micronization,
then homogenizing the mixture thus obtained with
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the partial or complete mixture of 5 to 25 parts by mass,
preferably 8 to 18 parts by mass of spray-dried lactose
which at least in 80% by mass has a particle size of 80 to
200 /um, a disintegrant such as corn starch in an amount
of 0.5 to 6.0 parts by mass, preferably 1.5 to 4.0 parts
by mass, a surface active agent such as sodium lauryl
sulfate in an amount of 0.005 to 0.05 parts by mass, prefer-
ably 0.01 to 0.02 parts by mass, a lubricant such as
magnesium stearate in an amount of 0.05 to 0.5 parts by
mass, preferably 0.1 to 0.2 parts by mass, and
if desired, filling the thus-obtained homogenizate
into capsules or pressing it into tablets.
The composition according to the invention has anti-
rheumatic and antiinflammatory activity.
The piroxicam capsules according to the invention
show the following dissolution data:
Dissolution of the active ingredient
5 minutes 15 minutes 45 minutes
69% 86% 92%
The suitably low scattering of the active ingredient
content of the tablet or capsule and the high and safe
dilution of the homogenizate could be achieved by mixing
the piroxicam with spray-dried lactose of a surface pore
size of 10 to 20 /um which at least in 80% by weight has a
particle size of 80 to 200 /um. Thus a so-called "arranged"
mixture could be achieved, in which the micronized piroxicam
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particles are adhered into the pores of the lactose, while
the preferable flowing characteristics of lactose are
maintained, enabling the easy preparation of the homogenizate
and the easy formulation of tablets or capsules from the
homogenizate.
The scattering of the active ingredient content in
the capsules is about RS0 = 2.0%, while in the tablets is
about RSD = 2.5%.
The invention is further illustrated by the follow-
ing, non-limiting examples.
Example 1
Micronizing
The particle size distribution of piroxicam of a
quality according to USP XXI measured by microscope:
maximal size:500 /um
above 100 /um:15 %
below 100 /um:85 %
below 50 /um:50 %
20 below 20 /um: 30 %
below 10 /um:10 %
below 5 /um: 5 %.
The micronizing is carried out in a Fryma JM-80 air-
jet mill.
300 9 of piroxicam, 300 9 of mannitol and 18 9 of
~erosil 200 (SiO2) are charged into the mixer and the
components are mixed. The powdering is carried out by adjust-
ing the charger and the air valve to 6 bar.
* trade-mark
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The particle size of the micronized powder mixture
is as follows:
90% by weight under 10 /um,
10% by weight between 10 and 30 /um.
The bulk density of the micronized powder mixture is
as follows:
loose 3.12 ml/g
compacted 2.81 ml/g.
Example 2
Trituration
1800 9 of lactose (DCL 11) and 3.6 9 of sodium
lauryl sulfate are homogenized according to the rules of
triturate preparation. A bronze sieve cloth of 250 /ummesh size
is used in the course of the process. The triturate is
prepared in 40 minutes.
Example 3
Homogenization
The homogenization is carried out in a homogenizator
of Lodige FM-50 type. 3582 9 of lactose (DCL 11) and 1160.4 9
of corn starch are charged into the equipment and the
micronizate and triturate prepared according to Examples
1 and 2 are added. The equipment is closed and the powder
mixture is homogenized for 19 minutes by moving the plough
arms. Then 0.3 9 of magnesium stearate is added and the
mixture is further homogenized for 1 minute. The complete
homogenization time is one hour.
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The bulk density of the homogenized powder mixture
is as follows:
loose 1.56 ml/g
compacted 1.20 ml/g
Mass density: 0.72 g/ml.
Flowability: 2.85 ml/sec.
The sieve analysis of the homogenized powder mixture
is as follows:
between 0.32 to 0.20 mm:6 to 15%,
between 0.20 to 0.10 mm:35 to 45%,
below 0.10 mm: 45 to 55%.
Example 4
Capsulation and tabletting
Preparation of capsules and tablets of 10 mg
From the homogenizate according to Example 3 capsules
and tablets of 10 mg are prepared with the following composi-
tion:
Capsule Tablet
piroxicam USP XXI 10.00 mg 10.00 mg
mannitol 10.00 mg 10.00 mg
aerosil 200 (colloidal SiO2)0.60 mg0.60 mg
sodium lauryl sulfate 0.12 mg 0.12 mg
lactose (DCL 11) 179.40 mg 179.40 mg
corn starch 38.68 mg 38.68 mg
magnesium stearate 1.20 mg 1.20 m~
240.00 mg 240.00 mg
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The capsulation is carried out in a capsule filling
machine of Zanasi LZ-64 type.
Mass of the capsule filling: 240 mg
Type and size of the capsule: Capsugel Coni-snap, 2-s
Maroon op/Buff op,
33/35 or
White L 500-Pink L 770
The homogenizate according to Example 3 is directly
tabletted. The tabletting is carried out on a tabletting
machine of Erweka E XI by using a flat, flanged pressing
tool of 9 mm.
The characteristic properties of the capsules are
as follows:
Disintegration time: 3 minutes
Dissolution of the active ingredient from the capsule:
5 minutes 15 minutes 45 minutes
69% 86% 92%
Scattering of the active ingredient: RSD = 1.8%.
The characteristic properties of the tablets are
20 as follows:
Tabletting Pressing power
10 kN 15 kN 20 kN
breaking resistance 43.2 N 67.7 N 86.5 N
abrasion loss at a 0.43 % 0.44 % 0.74 %
25 rate of 4 minutes/100
revolution
disintegration time 1.6 min. 1.5 min. 2.6 min.
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Dissolution of the active ingredient from the
tablet prepared with 20 kN pressing power:
15 minutes 30 minutes 45 minutes
83% 87.5% 88.5%
Scattering of the active ingredient: RSD = 2.5 %.
Preparation of capsules and tablets of 20 mg
Tablets and capsules containing 20 mg of piroxicam
are similarly prepared. The composition of the tablets
and capsules is as follows:'
Capsule Tablet
piroxicam USP XXI 20.00 mg 20.00 mg
mannitol 20.00 mg 20.00 mg
aerosil 200 (colloidal SiO2) 1.20 mg 1.20 mg
sodium lauryl sulfate0.24 mg 0.24 mg
lactose (DCL 11) 162.00 mg 162.00 mg
corn starch 36.36 mg 36.36 mg
magnesium stearate 1.20 m~ 1.20 mg
240.00 mg 240.00 mg
The characteristics of the capsule are as follows:
Active ingredient dissolution: 100% within 45 minutes.
Scattering of the active ingredient: RSD = 2.1 %.
The characteristics of the tablet are as follows:
Active ingredient dissolution: 100% within 10 minutes.
Scattering of the active ingredient: RSD = 2.5 %.
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Example 5
Preparation of capsules and tablets of 10 mg or
20 mg mass
The process of Examples 1 to 4 is followed except
that the micronizing of piroxicam according to Example 1
is carried out without mannitol or without mannitol and
silica.
The composition of capsules and tablets of 10 mg
without mannitol and silica is as follows:
Capsule Tablet
piroxicam USP XXI 10.00 mg10.00 mg
sodium lauryl sulfate 0.12 mg 0.12 mg
lactose (DCL 11) -190.00 mg190.00 mg
corn starch 38.68 mg38.68 mg
magnesium stearate 1.20 mg 1.20 mg
240.00 mg240.00 mg
The composition of capsules and tablets of 20 mg
without mannitol is as follows:
Capsule Tablet
piroxicam USP XXI 20.00 mg20.00 mg
aerosil 200 (colloidal SiO2)1.20 mg1.20 mg
sodium lauryl sulfate 0.24 mg 0.24 mg
lactose (DCL 11) 162.00 mg 162.00 mg
corn starch 36.36 mg 36.36 mg
magnesium stearate 1.20 mg 1.20 mg
220.00 mg 220.00 mg
