Note: Descriptions are shown in the official language in which they were submitted.
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EXTENDED RELEASE PHARMACEUTICAL COMPOSITION CONTAINING
FESOTERODINE AND PROCESS FOR THE PREPARATION THEREOF
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an improved extended release dosage form, and
in particular to a
pharmaceutical composition for oral administration comprising a
therapeutically effective
quantity of fesoterodine or a pharmaceutically acceptable salt, metabolite, or
derivative thereof,
as an active ingredient, and an effective quantity of glycerol dibehenate as
stabilizing agent in
order to prevent the degradation of said active ingredient, and a process for
the preparation
thereof.
BACKGROUND OF THE INVENTION
Fesoterodine is a muscarinic receptor antagonist used for the treatment of
overactive bladder
syndrome including urinary incontinence. Fesoterodine's chemical name is [2-
[(1R)-3-
(Di(propan-2-yl)amino)-1-phenylpropy11-4-(hydroxymethyl)phenyl]2-
methylpropanoate) and its
chemical structure is presented by the following Formula I.
C1113
nac 0
0 CH6
H
HO N 'CHt3,
CI-13
Formula I
Fesoterodine is rapidly hydrolyzed in vivo into its active metabolite 5-
hydroxy methyl
tolterodine, which binds and inhibits muscarinic receptors on the bladder
detrusor muscle,
thereby preventing bladder contractions or spasms caused by acetylcholine.
This results in the
relaxation of bladder smooth muscle and greater bladder capacity, in addition
to a reduction in
involuntary muscle contractions and involuntary loss of urine.
Said conversion of fesoterodine into 5-hydroxymethyltolterodine under humid
environment and
at increased temperature is undesirable in the pharmaceutical formulation.
Therefore, there is a
need to provide a pharmaceutical composition comprising fesoterodine that is
stable against
fesoterodine degradation over an extended period of time.
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Furthermore, the dissolution profile of extended release pharmaceutical
compositions containing
fesoterodine or a pharmaceutical acceptable salt, derivative and metabolite
thereof can also be
influenced by the selection of the excipients, as the drug release rate is
dependent from the
gastrointestinal pH-value and/or ionic strength. It is favorable for an
extended release
formulation to possess drug release rates, independent or less dependent from
the ionic strength
and/or pH of the environment through out the whole gastrointestinal tract in
order to achieve
better treatment to a patient.
Various methods are already known for the industrial preparation of extended
release oral
dosage forms comprising Fesoterodine or a pharmaceutical acceptable salt,
derivative and
metabolite thereof as an active ingredient due to its useful therapeutical
properties. However, the
prior art has encountered substantial difficulties in the production of a
stable extended release
and bioavailable fesoterodine composition of a desirable dissolution profile
and a cost effective
manufacturing process.
EP-B-2029134 discloses a pharmaceutical granulate comprising fesoterodine or a
pharmaceutically acceptable salt or solvate thereof and a pharmaceutically
acceptable stabilizer
against hydrolysis, such as sorbitol, xylitol, polydextrose, isomalt, dextrose
or combinations
thereof. Further, said fesoterodine and stabilizer granulate is embedded in a
gel matrix formed by
a water swellable sustained release agent such as hydroxypropyl
methylcellulose. According to
said document, fesoterodine is more stable in a composition comprising sugar
alcohols and in the
presence of water e.g. by wet granulation. Dry granulation or direct
compression resulted in
higher amounts of undesirable degradation products.
EP-A-2508175 discloses a microencapsulated fesoterodine composition which is
composed of a
particle containing fesoterodine and a shell surrounding the fesoterodine-
containing particle,
wherein the shell comprises a hydrophobic polymer as rate-controlling agent,
such as acrylate-
based polymers, acrylates or methylacrylates and a pore-forming agent, such as
water soluble
polymer or water soluble salt. According to said document, in order to prevent
degradation of
fesoterodine, the proposed composition requires a complex-structured
pharmaceutical
composition.
Although each of the above patents represents an attempt to achieve a
desirable release rate for
once a day administration and to overcome the stability problems of the active
ingredient
associated with pharmaceuticals compositions comprising fesoterodine, there
still exists a need
for improving fesoterodine's stability of such pharmaceutical compositions in
a less complicated
production approach.
SUMMARY OF THE INVENTION
It is, therefore, an object of the present invention to provide an improved
sustained release solid
dosage composition for oral administration containing fesoterodine or
pharmaceutical acceptable
salt, derivative or metabolite thereof as an active ingredient, which
overcomes the deficiencies of
the prior art.
It is another, object of the present invention to provide a stable sustained
release solid
pharmaceutical composition for oral administration containing fesoterodine or
pharmaceutical
acceptable salt, derivative or metabolite thereof as an active ingredient,
which is safe and
effective with sufficient shelf-life and good pharmacotechnical properties.
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Moreover, it is another object of the present invention to provide a suitable
process for the
preparation of an extended release pharmaceutical composition for oral
administration
.. comprising a therapeutically effective quantity of fesoterodine or a
pharmaceutically acceptable
salt, derivative or metabolite thereof as an active ingredient, which is cost
effective and
reproducible.
In accordance with the above objects of the present invention, an extended
release
pharmaceutical composition for oral administration is provided comprising a
therapeutically
effective quantity of fesoterodine or a pharmaceutically acceptable salt,
metabolite or derivative
thereof, as an active ingredient and an effective quantity of glycerol
dibehenate as a stabilizing
agent in order to prevent the degradation and improve the physicochemical
stability of the active
ingredient in the finished dosage form.
According to another embodiment of the present invention, a process for the
preparation of an
extended release pharmaceutical composition for oral administration comprising
a
therapeutically effective quantity of fesoterodine or a pharmaceutically
acceptable salt,
metabolite or derivative thereof as an active ingredient, and an effective
quantity of glycerol
dibehenate as a stabilizing agent in order to prevent the degradation of said
active ingredient is
provided, wherein said process comprises following steps:
A. Dispensing: Weight individually the active ingredient and pass it through
appropriate sieve.
B. Melting: Weight individually the stabilizing agent Glycerol Dibehenate and
melt it at 85 C.
C. Melt Mixing (melt granulation): Add sieved active ingredient from step A to
the molten liquid
obtained from step B, mix for proper time and allow the granules to cool down
D. Sizing: Pass the granules from step C to an appropriate sieve
E. Pre- Mixing: Mix the sieved extragranular excipients (Lactose,
microcrystalline cellulose,
Hydroxypropyl methylcellulose, Talc, colloidal silicon dioxide) and lubricant
(Glycerol
Dibehenate) for appropriate time.
F. Mixing - Lubrication: Mix the powder resulting from step D with the mixture
from step E for
appropriate time.
.. G. Compression: Compress the powder resulting from step F into tablets in a
rotary compression
machine using appropriate punches.
H. Coating: Prepare an aqueous solution/suspension of OpadryTM and coat the
tablets from step
G.
Other objects and advantages of the present invention will become apparent to
those skilled in
the art in view of the following detailed description.
Date Regue/Date Received 2022-12-01
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BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows dissolution profiles of fesoterodine containing pharmaceutical
composition
according to the present invention (composition 1)
DETAILED DESCRIPTION OF THE INVENTION
For the purposes of the present invention, a pharmaceutical composition
comprising fesoterodine
or salts, metabolites or derivatives thereof is considered to be "stable" if
said ingredient
degradates less or more slowly than it does on its own and/or in known
pharmaceutical
compositions during storage.
An excipient is considered to be "incompatible" with fesoterodine or salts,
metabolites or
derivatives thereof if it promotes the degradation of said active ingredient,
that is to say, if said
active ingredient degrades more or faster in the presence of said excipient
when compared with
the degradation of said active ingredient on its own. The terms
"incompatibility", "compatible"
and "compatibility" are defined accordingly.
The active ingredient contained in a dosage form is "bioavailable", if when
administered in a
dosage form is released from the dosage form, absorbed and reaches, at least
the same,
concentration levels in plasma as any of the marketed products containing the
same quantity of
the same active ingredient and intended for the same use.
Although the pharmaceutical composition may be in various forms, the preferred
solid forms are
tablets, capsules and caplets.
One of the main disadvantages of fesoterodine or salts, metabolites or
derivatives thereof is the
fact that, it is very labile and consequently many limitations concerning the
choice of excipients
are raised.
It has been surprisingly found that the object of the present invention is
achieved by employing a
glycerol dibehenate as stabilizing agent, in order to prevent the degradation
and improve the
physicochemical stability of the active ingredient in the finished dosage
form.
Further, it has been found that Fesoterodine or salts, metabolites or
derivatives thereof
comprising glycerol dibehenate as stabilizing agent have very good stability
and dissolution
characteristics.
Glycerol dibehenate is a glyceride with a high melting point used as a
modified release agent,
lubricant in tablets, as stabilizer in lipid coating technologies and as lipid
carrier for
nanoparticles. Glycerol dibehenate is prepared by the esterification of
glycerin with behenic acid
(C22 fatty acid) without the use of catalysts. In the case of Compritol 888
ATO (Gattefosse), raw
materials used are of vegetable origin, and the esterified material is
atomized by spraycooling.
Glycerol dibehenate is inert. It does not react with active pharmaceutical
ingredients (API) or
other excipients. Its inertness is explained by its chemical nature and robust
production process:
= It is a lipid excipient with less than 1% of water
= It does not have reactive groups
= It has very low level of impurity:- low peroxide value, low iodine value
As molten lipid excipient in hot melt coating it comes in effect with the
solid drug particles in a
suitable coating device, it produces a thin, homogeneous film coating that
acts as an effective
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barrier against water vapor protecting substrate-API from relative
humidity/degradation and
resolving API compatibility problems. The mechanism of melt granulation is
analogous to wet
granulation. The initial particle-particle bonds are formed by the surface
tension of liquid
(molten hot-melt lipid excipient). On subsequent cooling, the molten lipid
excipient solidifies
forming solid bridges that permanently bind the particles together.
The weight ratio of fesoterodine fumarate to glycerol dibehenate in the solid
composition
according to the present invention may be selected from 1:0.5 to 1:40.
The pharmaceutical compositions of the present invention may also contain one
or more
additional formulation ingredients selected from a wide variety of excipients.
According to the
desired properties of the composition, any number of ingredients may be
selected, alone or in
combination, based upon their known uses in preparation of solid dosage form
compositions
(tablet/capsule compositions).
Such ingredients include, but are not limited to, diluents, binders, rate
controlling agents,
compression aids, glidants, lubricants, water scavengers, colorants, coating
agents and
preservatives.
The optional excipients must be compatible with fesoterodine or salt,
metabolite or derivative
thereof so that it does not interfere with it in the composition.
Moreover, any excipient may optionally be added to the above composition,
provided that they
are compatible with the active ingredient of the composition, in order to
overcome problems
associated with unfavorable pharmacotechnical characteristics of these
substances, and in order
to increase the stability of the drug and the shelf-life of the pharmaceutical
product, and provide
a product exhibiting excellent bioavailability.
The composition of the present invention may include further additives (alone
or in a
combination) such as absorbents, acids, adjuvants, anticaking agents,
glidants, antitacking
agents, antifoamers, anticoagulants, antimicrobials, antiseptics, diluents,
binders, chelating
agents, sequestrants, coating agents, colorants, dyes, pigments, complexing
agents, softeners,
crystal growth regulators, denaturants, desiccants, dehydrating agents,
dispersants, solubilizers,
emollients, emulsifiers, fillers, flavor masking agents, gelling agents,
humectants, lubricants,
moisturizers, bufferants, p1-1 control agents, plasticizers, retarding agents,
stabilizers, suspending
agents, thickening agents, surfactants, opacifiers, coloring agents,
preservatives, antigellants,
rheology control agents, tonicifiers etc.
Diluents may be selected from calcium carbonate, calcium phosphate dibasic,
calcium phosphate
tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline
silicified cellulose,
powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose
anhydrous, lactose
monohydrate, lactose dihydrate, lactose trihydrate, mannitol, sorbitol,
starch, pregelatinized
starch, sucrose, talc, xylitol, maltose, isomalt, maltodextrin, maltitol and
the like. Diluents may
be in the range of 10-90 weight % of the total weight of the composition.
Binders may be selected from acacia, alginic acid, carbomer,
carboxymethylcellulose calcium,
carbomethylcellulose sodium, microcrystalline cellulose, powdered cellulose,
ethyl cellulose,
gelatin liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl
cellulose,
hydroxypropyl methyl cellulose, maltodextrin, methylcellulose, polydextrose,
polyethylene
=
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oxide, sodium alginate, starch paste, pregelatinized starch, sucrose,
tragacanth, low-substituted
hydroxypropyl cellulose, glucose, sorbitol. Binders may be in the range of 1-
40 weight % of the
total weight of the composition.
Rate controlling agents may be selected from one or more polymers/copolymers
of cellulose or
its derivatives such as hydroxypropylmethyl cellulose, hydroxyethyl cellulose,
hydroxypropyl
cellulose, hydroxyethyl methyl cellulose, methylcellulose,
carboxymethylcellulose and its salts;
polyacrylates, methylacrylates, polyethylene oxides, polyethylene glycols,
gums, chitosan, starch
derivatives, polyurethanes, galactomannans, polysaccharides, polyalcohols,
acrylic acid or its
derivatives, ethyl cellulose, glycerol palmitostearate, beeswax, glycowax,
carnaubawax,
hydrogenated vegetable oil, glycerol monostearate, stearylalcohol, glycerol
dibehenate,
polyanhydrides, methylacrylates, polyamides, polycarbonates, polyalkylene,
polyalkylene
glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols,
polyvinyl ethers,
polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes,
polyurethanes,
polystyrene, polymers of acrylic and methacrylic esters, polylactides,
poly(butyric acid),
poly(valeric acid), poly(lactide-co-glycolides), polyanhydrides,
polyorthoesters, poly(fumaric
acid), poly(maleic acid), cellulose acetate, cellulose propionate, cellulose
acetate butyrate,
cellulose acetate phthalate, carboxymethylcellulose, cellulose triacetate,
cellulose sulfate sodium
salt, poly(methylmethacrylate), poly(ethylmethacrylate),
poly(butylmethacrylate), poly(isobutyl-
methacrylate), poly(hexylmethacrylate), poly(isodecylmethacrylate),
poly(lauryl-methacrylate),
poly(phenylmethacrylate), poly(methylacrylate), poly (isopropyl-methacrylate)
and the like. Rate
controlling agents may be in the range of 1-95 weight % of the total weight of
the composition.
Glidants may be selected from calcium silicate, powdered cellulose, starch,
talc, colloidal silicon
dioxide and the like. Glidants may be in the range of 0.01-5 weight % of the
total weight of the
composition.
Lubricants may be selected from magnesium stearate, stearic acid, sodium
stearyl fumarate,
magnesium lauryl sulphate, talc, polyethylene glycol, glycerol dibehenate and
the like.
Lubricants may be in the range of 0.01-5 weight % of the total weight of the
composition.
All percentages stated herein are weight percentages based on total
composition weight, unless
otherwise stated.
Another embodiment of the present invention is the use of a hot melt
granulation process for the
preparation of solid dosage forms for oral administration containing
fesoterodine or salt,
metabolite or derivative thereof. The steps in this technique may be as
follows:
A. Dispensing: Weight individually the active ingredient and pass it through
appropriate sieve.
B. Melting: Weight individually the stabilizing agent Glycerol Dibehenate and
melt it at 85 C.
C. Melt Mixing (melt granulation): Add sieved active ingredient from step A to
the molten liquid
obtained from step B, mix for proper time and allow the granules to cool down
D. Sizing: Pass the granules from step C to an appropriate sieve
E. Pre- Mixing: Mix the sieved extragranular excipients (Lactose,
microcrystalline cellulose,
Hydroxypropyl methylcellulose, Talc, colloidal silicon dioxide) and lubricant
(Glycerol
Dibehenate) for appropriate time.
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F. Mixing - Lubrication: Mix the powder resulting from step D with the mixture
from step E for
appropriate time.
G. Compression: Compress the powder resulting from step F into tablets in a
rotary compression
machine using appropriate punches.
H. Coating: Prepare an aqueous solution/suspension of opadryTm and coat the
tablets from step
G.
The extended release pharmaceutical composition of the present invention
comprising
Fesoterodine fumarate as an active ingredient has been compared to extended
release reference
product Toviairm consisting of fesoterodine fumarate with the following
excipients xylitol,
Lactose monohydrate, Microcrystalline cellulose, Hypromellose,
Glyceroldibehenate (as
lubricant), Talc, and as film-coating comprising Poly(vinyl alcohol), Titanium
dioxide,
Macrogol, Talc, Soya lecithin and indigo carmine aluminium lake.
The pharmaceutical compositions according to the present invention are
characterized by
.. excellent pharmacotechnical properties, such as homogeneity, flowability
and compressibility.
Thanks to these properties, the solid dosage forms prepared by the process
according to the
present invention exhibit excellent technical characteristics including
dissolution rate, hardness,
and stability.
One of the most critical pharmacotechnical tests is the Dissolution test as it
is strongly correlated
with the bioavailability of the product. For the dissolution method a Paddle
Apparatus was used
at rotation speed 75rpm, in aqueous dissolution medium with pH 6.8.
TABLE 1: Dissolution profile of Composition 1
% Dissolved at p11,6.8
Time (hrs) Composition 1
1 14,8
2 28,2
4 49,0
6 64,1
8 72,7
12 85,6
16 91,5
20 94,9
As it is shown in Table 1, composition 1 according to the present invention
shows an extended
release of Fesoterodine as depicted in Fig. 1.
One of the main objects of the present invention was to prepare a product with
acceptable
stability. For this reason composition I was exposed to accelerated (40 C 2
C/75%- 5% RH)
stability studies according to the current ICH guidelines.
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The stability results are shown in TABLE 2 below.
TABLE 2: Stability results of Composition 1 directly after preparation and
after 1 month of
storage in aluminium blisters at accelerated conditions
Impurities 0 Month 1 Month Accelerated
Dial 0.09 0.27
Total 0.15 0.36
The results showed that the stability of the present invention was good.
The selection of appropriate materials (excipients, reagents etc.) should be
done carefully in
order to avoid any incompatibility problems or non-compliance with European
Pharmacopoeia
and FDA guidelines for inactive ingredients.
The tablets may be film coated with functional or non-functional coating.
The following examples illustrate preferred embodiments in accordance with the
present
invention without limiting the scope or spirit of the invention.
EXAMPLES
Example 1: Fesoterodine fumarate Composition 1 according to the present
invention
Composition 1 of the present invention is illustrated in TABLE 3 below.
TABLE 3: Fesoterodine fumarate Composition 1
Ingredients Composition 1 mg/tab
Fesoterodine Fumarate 8.00
Glycerol dibehenate 36.00
Hydroxypropyl 92.00
methylcellulose
MicroceLacTM 100 162.30
Aerosil TM 200 3.20
Talc 8.50
Glycerol dibehenate 10.00
Tab Total 320.00
Coating 19.00
Total 339.00 =
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Example 2: Fesoterodine fumarate Compositions 2, 3 and 4 according to the
present invention
Compositions 2, 3 and 4 of the present invention, as illustrated in TABLE 4
below, with
different quantities of Glycerol Dibehenate were tested.
Composition 2 comprises Fesoterodine fumarate and Glycerol Dibehenate as
stabilizing agent
wherein the weight ratio of Fesoterodine fumarate to Glycerol Dibehenate is
1:9.
Composition 3 comprises Fesoterodine fumarate and Glycerol Dibehenate as
stabilizing agent
wherein the weight ratio of Fesoterodine fumarate to Glycerol Dibehenate is
1:4.5.
Composition 4 comprises of Fesoterodine fumarate and Glycerol Dibehenate as
stabilizing agent
wherein the weight ratio of Fesoterodine fumarate to Glycerol Dibehenate is
1:18.
TABLE 4: Fesoterodine fumarate Composition 2, 3 and 4
Ingredients Composition 2 Composition 3
Composition 4
mg/tab mg/tab mg/tab
Intra - granular
Fesoterodine Fumarate 8.0 8.0 8.0
Glycerol dibehenate 72.0 36.0
144.0
Extra - granular
Hydroxypropyl 144 0 144.0
144.0
.
methylcellulose
MicroceLacTM 100 74.3 110.3 2.3
Aerosil TM 200 3.2 3.2 3.2
Glidant - Lubricant
Talc 8.5 8.5 8.5
Glycerol dibehenate 10.0 10.0
10.0
Purified water qs qs qs
Tab Weight (mg) 320.0 320.0
320.0
Opadry TM 16.0 16.0 16.0 ,
Tablets of fesoterodine fumarate of the above Compositions 2, 3 and 4 were
prepared according
to the following manufacturing process:
At a first stage, fesoterodine fumarate was weighted individually and passed
through appropriate
sieve. Glycerol dibehenate as stabilizing agent was weighted individually and
then, melted at
85 C. The sieved fesoterodine fumarate was added in the molten liquid of the
stabilizing agent
and mixed for appropriate time until the agglomerates cool down and the melt
granulation
process is completed with the solidification of the molten stabilizing agent.
Subsequently, the
obtained granules were passed through an appropriate sieve.
At a second stage, a mixture of the sieved extragranular excipients was formed
by mixing for
appropriate time MicroceLacTM 100 as diluent, Hydroxypropyl methylcellulose,
as rate
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controlling agent, Talc and colloidal silicon dioxide (Aerosilml 200), as
glidants and the quantity
of Glycerol Dibehenate, as lubricant.
The powder obtained from the first stage was mixed with the mixture of the
second stage until ,
complete homogeneity. The resulting powder was compressed into tablets in a
rotary
compression machine using appropriate punches. Then, the tablets were coated
with an aqueous
solution/suspension of OpadryTm, that was prepared.
Another object of the present invention was to prepare a pharmaceutical
composition that is
stable for a long period of storage time. Therefore, tablets of Compositions
2, 3 and 4 in closed
High-density polyethylene (HDPE) vials were exposed to accelerated (40 C 2
C/75%5% RH)
stability studies according to the current ICH guidelines.
The stability results of Compositions 2, 3 and 4 at accelerated conditions, in
comparison to the
reference product, Toviaz are shown in TABLE 5 below.
TABLE 5: Comparative stability results of Compositions 2, 3 and 4 vs reference
product
Toviaz
Impurities 1Month
Reference Composition Composition Composition
Closed HDPE
Product 2 3 4
Accelerated
0.97/1.92 0.62/1.32 0.31/0.54
0.48/0.70
(Diol/Total) 0/0
The results showed that the stability of Compositions 2, 3 and 4 of the
present invention was
improved compared to reference product Toviaz . Particularly, diol content of
Compositions 2,
3 and 4 was 0.62%, 0.31% and 0.48%, respectively, compared to reference
product wherein diol
impurity was 0.97% and total impurities of Compositions 2, 3 and 4 were 1.32%,
0.54% and
0.70%, respectively, compared to reference product wherein total impurities
were 01.92%.
In addition, as shown in Fig. 1, Fesoterodine Composition 1 showed extended
release of the
active ingredient for a time period more than 20h.
Consequently, a novel improved extended release composition of fesoterodine
fumarate has been
achieved comprising fesoterodine, or a pharmaceutically acceptable salt or
solvate thereof, and a
pharmaceutically acceptable stabilizing agent, wherein said stabilizing agent
is glycerol dibehenate. The
use of glycerol dibehenate is able to improve the physicochemical stability of
the active ingredient
in the finished dosage form by protecting said active ingredient from
degradation, and
maintaining an extended release profile of said active ingredient.
The stability of the product as well as the simple and economic manufacturing
process indicates
the advantages of the present invention relative to the commonly used method
and excipients for
the formulation of fesoterodine.
While the present invention has been described with respect to the particular
embodiments, it
will be apparent to those skilled in the art that various changes and
modifications may be made
in the invention without departing from the spirit and scope thereof, as
defined in the appended
claims.
