Note: Descriptions are shown in the official language in which they were submitted.
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CONTROLLED RELEASE PHARMACEUTICAL COMPOSITIONS OF
TAMSULOSIN
Field of the Invention
The technical field of the invention relates to controlled release
pharmaceutical
compositions of tamsulosin or pharmaceutically acceptable salts thereof. More
particularly, the invention relates to a controlled release individual unit or
multiple unit
formulation comprising a spherical core obtained by adding a release
controlling agent to a
mixture of tamsulosin and a spheronizing agent. The invention also relates to
methods of
preparing such formulations.
Bacl~~round of the Invention
The need to improve the clinical results of modified release formulations is
well
documented in the prior art. This is particularly important for drugs that
have short half
lives, region specific absorption, produce gastric irntation, or have other
side effects at
high plasma concentrations. One of the most common methods of achieving
modified
drug release involves the use of monolithic systems designed to have modified
release
characteristics. These monolithic systems vary from osmotic drug delivery
systems to
bioerodible or non-erodible matrix based systems.
Although a major portion of the modified release formulations currently
prescribed
are monolithic systems, they nonetheless suffer from a few serious drawbacks.
Intentional
or accidental breakdown of the delivery system is one of the limitations that
may cause
dose dumping. Dose dumping may lead to toxic or fatal effects, depending on
the
pharmaceutical compound. Further, the gastric emptying of the comparatively
large
monolithic systems is variable and is dependent on the presence or absence of
food, as
well as the type of food talcen by the patient.
These disadvantages have prompted a shift in modified release technology from
the use of monolithic systems to multiple unit systems, wherein each
individual unit is
formulated with modified release characteristics. The final dosage form
consists of a
collection of the multiple units, compressed into a tablet, or filled into a
capsule or sachet.
When administered, the individual units are dispersed freely into the
gastrointestinal
contents, avoiding the high local concentration of drug which may lead to
irritation of
gastrointestinal mucosa. Also, the performance of the dosage form is
independent of inter-
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and intra-patient variability in gastric emptying time because of the small
size of the
individual units that malce up the system.
Multiple unit dosage forms possess large surface area, which promotes complete
and mliform absorption, minimize peals plasma fluctuations and thus reduce the
potential
for systemic side effects. Further advantages of these dosage forms are that
high local
concentrations of the active substance in the gastrointestinal system is
avoided, due to the
units being distributed freely throughout the tract, less variation in
absorption is observed
and there is reproducibility in the dissolution characteristics.
Drug release from such extended release multiple units is controlled either by
diffusion of a coating or by erosion of the coating by a process dependent on
enzymes or
pH. The erodible coatings involve the use of enteric polyners, which rapidly
erode in the
intestines.
There are a number of methods available for manufacturing these multiple
units,
which include:
(a) Extrusion-spheronization
(b) Wet granulation
(c) Dry granulation: There are two main processes for dry granulation:
1. Slugging
2. Roller compaction
Extrusion/spheronization is a multistep process used to make uniformly sized
particles. It is used primarily to produce multiparticulates for controlled or
sustained
release applications. Tlus process is also used to increase the bulk density,
improve flow
properties and reduces the problem of dust usually encountered with low-
density, finely
divided active and excipient powders. The general process involves separate
processes of
wet massing, followed by extrusion of this wet mass into cylindrical segments
and
subsequent spheronization of these segments to round off these cylindrical
segments into
spherical particles. Extrusion involves forcing the wet mass through dies and
shaped into
cylindrical particles with uniform diameter. The extrudate particles break at
similar
lengths. These particles are rounded off into spherical particles in an
apparatus, which
consists of a bowl with fixed sidewalls and rapidly rotating bottom plate or
disc. The
rounding off is dependent on frictional forces generated by particle-particle
and particle-
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equipment collisions. This process of rounding off constitutes spheronization.
Tlus process
requires the incorporation of an agent that aids in the rounding off of the
particles which is
known as rounding or spheronizing agent.
Tamsulosin, 5-[(2R)-2-[[2-(2-ethoxy-phenoxy) ethyl] amino] propyl]-2-methoxy
benzene sulfonamide, is an al-adrenoceptor blocking agent, exhibiting
selectivity for al-
receptors in the human prostate. It is disclosed in EP 34432 and U.S. Patent
No.
4,731,478 as a pharmaceutically active substance having alpha-adrenergic
blocking
activity that is useful for treatment of cardiac insufficiencies and benign
prostatic
hyperplasia.
The pharmacokinetic studies of tamsulosin show that it is absorbed from the
intestine and is almost completely bioavailable.
U.S. Patent No. 4,772,475 discloses an oral pharmaceutical controlled release
multiple unit formulation in which the individual units comprise a granulation
product of a
release controlling agent, physiologically active substance and units-forming
substance (s).
The patent emphasizes that the unit-forming substance (crystalline cellulose)
should at
least be 50% by weight. The drug containing units of this invention have high
mechanical
strength and can control dissolution rate without enteric coating.
However, since tamsulosin is absorbed from the intestine, the object should be
to
develop a composition, which releases the drug gradually in the intestine
where it is
completely absorbed.
The inventors have now discovered that enteric-coated, controlled release
formulation of tamsulosin provides release at the desired site. The controlled
release
formulation can be prepared with less than 50% w/w of a spheronizing agent.
Summary of the Invention
In one general aspect there is provided a controlled release pharmaceutical
composition of tamsulosin that includes a spheroid core. The core includes
tamsulosin,
about 10% to about 45% w/w of a spheronizing agent and one or more rate
controlling
polymers; and an outer enteric coating layer. The enteric coating is placed
over the core.
The core may include one or more of sugar, a non-pared seed, microcrystalline
cellulose, celphere, sand silicon dioxide, glass, plastic, polystyrene,
hydroxypropyl
methylcellulose. The sugar may include one or more of glucose, mannitol,
lactose, xylitol,
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dextrose, and sucrose. The core may include one or more of an insoluble
material, a
soluble material, and a swellable material.
Embodiments of the pharmaceutical composition are prepared by a
spheronization process. The spheronizing agent may be microcrystalline
cellulose. The
tamsulosin may include one or more of free base, pharmaceutically acceptable
salts and
isomers of tamsulosin. The pharmaceutically acceptable salts of tamsulosin may
be one or
more of hydrochloride, hydroiodide, hydrobromide, hydrogen fuxnaxate, and the
like. For
example, the pharmaceutically acceptable salt of tamsulosin may be
hydrochloride. The
pharmaceutical composition may contain a concentration of from about 0.03% to
about
0.33% by weight of tamsulosin.
The rate controlling polymer may include one or more of enteric polymers,
water
insoluble polymers, water-soluble polymers, alkaline metal salts of a higher
fatty acid,
waxes, and mixtures thereof. The rate controlling polymer may be present in
the
pharmaceutical composition at a concentration of from about 20% to about 90%
by
weight.
The enteric polymer may include one or more of hydroxylpropylmethyl cellulose
phthalate, cellulose acetate phthalate, methacrylic acid, and ethyl acrylate
copolymer.
In particular, the enteric polymer may include one or more of methacrylic acid
and ethyl
acrylate copolymer.
The wax may include one or more of hydrogenated vegetable oils, esters of long
chain fatty acids, long chain fatty acids, and mixtures thereof. The wax may
include one
or more of glyceryl monostearate and stearic acid.
The water soluble polymer may include one or more of polyvinylpyrrolidone,
hydroxypropyl cellulose, carboxymethylcellulose sodium, hydroxypropylmethyl
cellulose,
hydroxyethyl cellulose, methyl cellulose, and mixtures thereof.
The water insoluble polymer may include one or more of ethyl cellulose,
cellulose
acetate, methacrylic acid-acrylic acid copolymers with quaternary ammonium
groups, and
mixtures thereof.
The alkaline metal salts of higher fatty acid may include one or more of
magnesium stearate, zinc stearate, calcium stearate, and mixtures thereof. In
particular,
the allcaline metal salt of higher fatty acid may include magnesium stearate.
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The spheroid core may include one or more of pharmaceutically acceptable
excipients. The pharmaceutically acceptable excipients may include one or more
of
plasticizers, diluents, colorants and flavoring agents.
The enteric coating may include one or more of hydroxypropyl methylcellulose
phthalate, polyvinyl phthalate, cellulose acetate phthalate, copolymers of
acrylic and
methacrylic acid and mixtures thereof. The enteric coating may also have one
or more of
allcalizing agents, plasticizes, tack-modifiers and opacifiers.
The pharmaceutical composition may be fornulated into capsules, sachets, and
tablets.
In another general aspect there is provided a process for the preparation of a
controlled release pharmaceutical composition of tamsulosin. The process
includes
providing spherical cores that includes tamsulosin, a spheronizing agent and
one or more
of rate controlling polymers; and coating the spheroid cores with an enteric
polymer. The
core may be prepared by extrusion-spheronization. The extrusion-spheronization
process
may include granulating tamsulosin, spheronizing agent and one or more rate
controlling
polymers, extruding the granulated mixture to obtain extrudates, spheronizing
the
extrudates to obtain spherical cores, drying the spheroid cores; and coating
the spheroid
cores with an enteric polymer.
The tamsulosin may include one or more of free base, pharmaceutically
acceptable salts and isomers of tamsulosin. The pharmaceutically acceptable
salts of
tamsulosin may be one or more of hydrochloride, hydroiodide, hydrobromide,
hydrogen
fumarate, and the like. In one embodiment, the pharmaceutically acceptable
salt of
tamsulosin may be hydrochloride. The pharmaceutical composition may contain a
concentration of from about 0.03% to about 0.33% by weight of tamsulosin.
The rate controlling agent may include one or more of enteric polymers, water
insoluble polymers, water-soluble polymers, alkaline metal salts of a higher
fatty acid,
waxes, and mixtures thereof at a concentration of from about 20% to about 90%
by weight
of the composition.
The enteric polyner may include one or more of hydroxylpropylmethyl cellulose
phthalate, cellulose acetate phthalate, methacrylic acid, and ethyl acrylate
copolymer.
In particular, the enteric polymer may include one or more of methacrylic acid
and ethyl
acrylate copolymer.
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The wax may include one or more of hydrogenated vegetable oils, esters of long
chain fatty acids, long chain fatty acids, and mixtures thereof. In
particular, the wax may
include one or more of glyceryl monostearate and stearic acid.
The water soluble polymers may include one or more of polyvinylpyrrolidone,
hydroxypropyl cellulose, carboxymethylcellulose sodium, hydroxypropylmethyl
cellulose,
hydroxyethyl cellulose, methyl cellulose, and mixtures thereof.
The water insoluble polymers may include one or more of ethyl cellulose,
cellulose
acetate, methacrylic acid-acrylic acid copolymers with quaternary ammonium
groups, and
mixtures thereof.
The alkaline metal salts of higher fatty acid may include one or more of
magnesium stearate, zinc stearate, calcium stearate and mixtures thereof. In
particular, the
alkaline metal salt of higher fatty acid may include magnesium stearate.
The spheroid core may include one or more of pharmaceutically acceptable
excipients. The pharmaceutically acceptable excipients may include one or more
of
plasticizers, diluents, colorants and flavoring agents.
The enteric coating may include one or more of hydroxypropyl methylcellulose
phthalate, polyvinyl phthalate, cellulose acetate phthalate, copolymers of
acrylic and
methacrylic acid and mixtures thereof. The enteric coating may also have one
or more of
allcalizing agents, plasticizer, tack-modifiers and opacifiers.
The pharmaceutical-composition may be formulated into capsules, sachets, and
tablets.
In another general aspect there is provided a process for the preparation of a
controlled release pharmaceutical composition of tamsulosin. The process
includes
granulating tamsulosin and spheronizing agent with dispersion of one or more
of rate
controlling polyners, extruding the granulates to form extrudates using an
extruder,
spheronizing the extrudates until spherical cores are formed; and coating the
spheroid
cores with an enteric polymer.
The tamsulosin may include one or more of free base, pharmaceutically
acceptable salts and isomers of tamsulosin. The pharmaceutically acceptable
salts of
tamsulosin may be one or more of hydrochloride, hydroiodide, hydrobromide,
hydrogen
fumarate, and the like. In one embodiment, the pharmaceutically acceptable
salt of
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tamsulosin may be hydrochloride. The pharmaceutical composition may contain a
concentration of from about 0.03% to about 0.33% by weight of tamsulosin.
The rate controlling agent may include one or more of enteric polymers, water
insoluble polymers, water-soluble polymers, alkaline metal salts of a higher
fatty acid,
waxes, and mixtures thereof at a concentration of from about 20% to about 90%
by weight
of the composition.
The enteric polymer may include one or more of hydroxylpropylmethyl cellulose
phthalate, cellulose acetate phthalate, methacrylic acid, and ethyl acrylate
copolymer.
In particular, the enteric polymer may include one or more of methacrylic acid
and ethyl
acrylate copolymer.
The wax may include one or more of hydrogenated vegetable oils, esters of long
chain fatty acids, long chain fatty acids, and mixtures thereof. In
particular, the wax may
include one or more of glyceryl monostearate and stearic acid.
The water soluble polymers may include one or more of polyvinylpyrrolidone,
hydroxypropyl cellulose, carboxymethylcellulose sodium, hydroxypropylmethyl
cellulose,
hydroxyethyl cellulose, methyl cellulose, and mixtures thereof.
The water insoluble polymers may include one or more of ethyl cellulose,
cellulose
acetate, methacrylic acid-acrylic acid copolymers with quaternary ammonium
groups, and
mixtures thereof.
The alkaline metal salts of higher fatty acid may include one or more of
magnesium stearate, zinc stearate, calcium stearate and mixtures thereof. In
particular, the
alkaline metal salt of higher fatty acid may include magnesium stearate.
The spheroid core may include one or more of pharmaceutically acceptable
excipients. The pharmaceutically acceptable excipients may include one or more
of
plasticizers, diluents, colorants and flavoring agents.
The enteric coating may include one or more of hydroxypropyl methylcellulose
phthalate, polyvinyl phthalate, cellulose acetate phthalate, copolymers of
acrylic and
methacrylic acid and mixtures thereof. The enteric coating may also have one
or more of
allcalizing agents, plasticizes, tack-modifiers and opacifiers.
The pharmaceutical composition may be formulated into capsules, sachets, and
tablets.
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In another general aspect, a method for preparing a controlled release
pharmaceutical composition includes providing a core having a coating, forming
individual units, and forming the dosage form by combining one or more
individual units.
Embodiments of the method of preparing a controlled release multiple unit
dosage
form may include one or more of the following features, including any one or
more of the
features described above. Combining one or more individual units may include
filling the
individual units into a capsule or sachet or compressing the individual units
into a tablet.
In another general aspect there is provided a method of treating symptoms of
benign prostatic hyperplasia. The method includes administering a controlled-
release
pharmaceutical composition of tamsulosin, which includes a spheroid core. This
core
includes tamsulosin, about 10% to about 45% w/w of a spheronizing agent, and
one or
more ratecontrolling polymers. The core is then coated by an enteric coating.
Embodiments of the method may contain any one or more features described
above. The details of one or more embodiments of the inventions are set forth
in the
description below. Other features, objects and advantages of the inventions
will be
apparent from the description and claims.
Detailed Description of the Invention
The present invention relates to controlled release individual unit or
multiple unit
formulation comprising an enteric coated spherical core, wherein the core
comprises
tamsulosin, about 10% to about 45% w/w of a spheronizing agent and rate
controlling
polymers.
The term spheroid is conventional in the pharmaceutical art and means a
spherical
granule having a diameter of between about O.lmm and 2.Smm.
Tamsulosin may comprise free base, pharmaceutically acceptable salts or
isomers
of tamsulosin thereof. The pharmaceutically acceptable salts may include
hydrochloride,
hydroiodide, hydrobromide, hydrogen fumarate, and the like. Tamsulosin
constitutes about
0.03 to about 0.33% by weight of the formulation.
The spheroiuzing agent may comprise any pharmaceutically acceptable material,
which may be spheronized together with the active ingredient to form spheroid
cores. The
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most commonly used spheronizing agent is microcrystalline cellulose. The
microcrystalline cellulose employed may be, for example, Avicel~ PH 101 or
Avicel~
PH 102 commercially available from FMC Corporation. The spheronizing agent may
be
present in an amount ranging from about 10% to about 45% by weight of the
formulation.
The rate controlling agent may include one or more of enteric polymers, water
insoluble polymers, water-soluble polymers, alkaline metal salts of a higher
fatty acid,
waxes, and mixtures thereof.
Suitable enteric polymers include those lrnown in the art, such as
hydroxypropyl
methyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate
succinate,
polyvinyl acetate phthalate, polyrnethylacrylates and copolymers of acrylic
and
methacrylic acid (commercially available under the trade name of Eudragit~),
for
example, Eudragit L30D-55 (anionic aqueous polymer dispersion of methacrylic
acid -
ethyl acrylate copolymer), Eudragit L100-55 (Spray-dried Eudragit L30D-55
which can be
reconstituted as aqueous dispersion), Eudragit L100 (anionic polymer powder
solubilizing
above pH 6.0) and Eudragit S 100 (anionic polymer powder solubilizing above pH
7.0).
Suitable waxes include one or more of hydrogenated vegetable oils, esters of
long
chain fatty acids, long chain fatty acids such as stearic acid and oleic acid,
and mixtures
thereof.
Suitable water-insoluble polyners include one or more of ethyl cellulose,
cellulose
acetate, copolymers of polyethylene and vinyl acetate, methacrylic acid methyl
methacrylate copolymers with quaternary ammonimn groups such as those sold
under the
trade name Eudragit~ RL, Eudragit~ RS and Eudragit~ NE, and the lilce.
Suitable examples of the alkaline metal salts of a higher fatty acid include
one or
more of magnesium stearate, zinc stearate, calcium stearate, and the lilce.
Suitable water-soluble polymers may include one or more of
polyvinylpyrrolidone,
carboxymethylcellulose sodium, hydroxylpropyl cellulose, hydroxypropyl
methylcellulose, hydroxyethyl cellulose, methylcellulose, and mixtures
thereof.
The rate controlling polymers may comprise about 20 to about 90% by weight of
the formulation. The rate controlling polymers in accordance with this
invention may also
act as binder and may be added as such or dissolved or dispersed in an
appropriate solvent
system and the resulting solution or dispersion is then used to granulate the
active agent.
The resulting granulated mass may then be subjected to extrusion and
spheronization.
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This method of incorporation allows the rate controlling polymers to more
effectively
retard drug release.
Optionally, in addition to the active ingredient, spheronizing agent and rate
controlling polymers, the spheroid cores may also contain other
pharmaceutically
acceptable excipients. The other pharmaceutically acceptable excipients as
used herein
include plasticizers, diluents, colorants, and flavoring agents.
Suitable diluents include one or more of lactose, starch, sugar alcohols,
sucrose and
mixtures thereof.
The controlled release composition according to this invention may be prepared
by:
a. granulating tamsulosin, spheronizing agent and rate controlling polymers
with
water,
b. extruding the granulated mixture to give extrudates; and
c. spheronizing the extrudates until spherical cores are formed.
Alternatively, granulation according to step a) may be carried out with a
dispersion
of rate controlling polymers.
Extrusion may be carried out in any of the extruders such as screw-feed
extruders
and gravity-feed extruders such as cylindrical roll or gear roll and piston-
feed extruders.
The pharmaceutical composition according to the present invention further
includes an enteric coating over the spheroid core. This coating will
substantially
eliminate dissolution in the acidic environment of the stomach but will
dissolve
sufficiently to permit release in a controlled manner over an extended period
in the
intestine.
Examples of enteric coatings include one or more of neutralized hydroxypropyl
methylcellulose phthalate (HPMCP) coating, beeswax, glyceryl monostearate,
shellac and
cellulose, shellac and stearic acid; neutral copolymer of methacrylic acid and
methacrylic
acid methyl ester (Eudragit~) or a neutral copolymer of polymethacrylic acid
esters
containing metallic stearates.
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The other enteric coating polymers known in the art may also be employed,
including one or more of polyvinyl acetate phthalate, cellulose acetate
phthalate, cellulose
acetate succinate and the like.
Most of the enteric coating materials are acidic in nature and hence may cause
chemical instability when in contact with active ingredient. However, this can
be avoided
by using suitable alkalizing agents like sodium hydroxide, potassium
hydroxide, calcium
carbonate, sodium carboxymethylcellulose, magnesium oxide and magnesium
hydroxide.
The enteric coating may also contain a plasticizer, which may be one or more
of citrate,
triacetin, diethyl phthalate, dibutyl phthalate, polyethylene glycol,
propylene glycol,
glycerol, tributyl citrate, and the like. The enteric coating may also include
anti-adherent
or tack-modifiers as an inert aid in the stability of coating process.
Suitable tack-modifier
may include one or more of talc, kaolin or colloidal anhydrous silica. The
coating may
also include an opacifier such as titanium dioxide.
The enteric coating layer can be formed on the surface of the spheroid cores,
using
conventional coating methods, such as fluidized or pan coating.
The compositions prepared according to the invention may be filled into
capsules,
sachets or compressed into tablets using conventional pharmaceutical
tech~iiques.
The improved, multiple unit systems described above are further illustrated by
the
following examples. Although these examples are illustrative of the
techniques,
compositions, and concepts described herein, they are not intended to be
limiting.
EXAMPLE 1
In redients M /ca sine
Core Tamsulosin hydrochloride _
0.4
Microcrystalline cellulose 126
Magnesium stearate 20
Starch 64.6
Methacrylic acid-ethyl acrylate copolymer79.0
dis ersion
Purified water q.s.
Enteric Methacrylic acid ethyl acrylate copolymer6.59
coat
Sodium hydroxide 0.08
Triacetin 0.99
Talc 1.31
Titanium dioxide 0.11
Purified water q,s
li
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EXAMPLE 2
In redients M /ca rule
Core Tamsulosin hydrochloride 0.4
Microcrystalline cellulose 126
Glyceryl mono stearate 20
Starch 64.6
Methacrylic acid-ethyl acrylate co olymer79.0
dispersion
Purified water Qs
Enteric Same as for example 1
coat ~
EXAMPLE 3
In redients M /ca sule
Core Tamsulosin hydrochloride 0.4
Microcrystalline cellulose 118
Stearic acid 1 g
Starch 60.6
Methacrylic acid-ethyl acrylate copolymer74
dispersion
Povidone 5
Purified water Qs
Enteric Same as for Example 1
coat
Process:
1. Tamsulosin hydrochloride is dissolved in water and the solution is used to
granulate
microcrystalline cellulose, in a mixer.
2. Granulate of step 1 is dried in a fluidized bed dryer at 60°C and
sieved to a particle size
of less than about 600 ~..
3. Magnesium stearate/ glyceryl mono stearate/ stearic acid and starch are
sieved to a
particle size of less than about 600 ~ and mixed with granulate of step 2 in a
mixer.
4. The blend of step 3 is granulated with the dispersion of methacrylic acid-
ethyl acrylate
copolymer (Eudragit L30D 55) in a rotary mixer grinder. In Example 3, same
blend is further granulated by 10°fo solution of povidone in water.
5. Granulate of Step 4 is extruded through a bore of inner diameter of lmm.
6. The extrudates of step 5 are spheronized-using spheronizer fitted with
plate of 3.25
mm pitch.
7. Spherical cores obtained in step 6 are dried in fluidized bed dryer at
60°C for one hour.
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8. Enteric coating dispersion of Eudragit L100: 55 is prepared by dispersing
enteric
coating materials in water.
9. The spherical cores of step 7 are coated with the dispersion of step 8, to
a weight gain
of about 3.33% w/w.
10. The coated cores of step 9 are filled in capsules.
The resulting capsules of Example 1 were compared with FLOMAX capsules
(containing 0.4mg tamsulosin marketed by Boehringer Ingelheim) for in vitro
release of
tamsulosin. The dissolution studies were performed using USP Apparatus II at
50 rpm in
SOOmI phosphate buffer pH 6.8. The results are shown in Table 1.
Table 1: Comparative in vitro release data of tamsulosin from capsules (of
Example
1) and FLOMAX capsules (of Boehringer Ingelheim) using USP dissolution
apparatus II/ 500 ml/ pH 6.8 phosphate buffer/ 50 rpm
Time (hrs) Percent tamsulosin released
(%)
from Capsules of Example from FLOMAX capsules
1
1 45 39
71 61
4 90 90
6 94 107
While several particular forms of the invention have been illustrated and
described,
it will be apparent that various modifications and combinations of the
invention detailed in
the text can be made without departing from the spirit and scope of the
invention. Further,
it is contemplated that any single feature or any combination of optional
features of the
inventive variations described herein may be specifically excluded from the
claimed
invention and be so described as a negative limitation. Accordingly, it is not
intended that
the invention be limited, except as by the appended claims.
13
