Note: Descriptions are shown in the official language in which they were submitted.
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NOVEL ORAL CONTROLLED RELEASE
PHARMACEUTICAL FORMULATIONS
FIELD OF THE INVENTION
The present invention relates to controlled release beads comprising a
pharmaceutically active ingredient, to a formulation containing the controlled
release beads, and to a method of preparing the controlled release beads. In
particular, the invention relates to controlled release beads comprising
tolterodine or
a pharmaceutically acceptable salt thereof.
BACKGROUND OF THE INVENTION
There exist many types of oral dosage formulations which are directed to
controlled release of a pharmaceutically active ingredient, including many
types of
multi-layered controlled release beads. Indeed, these beads generally consist
of an
inert core, a first layer of polymer (i.e. a "seal-coat") applied onto the
inert core, a
layer containing the pharmaceutically active ingredient (i.e. a drug-
containing
layer), and an outer layer for controlling the release rate of the drug
contained from
the drug-containing layer. Examples of such controlled release beads can be
seen in
the following references: United States Patent Nos. 5,783,215, 6,630,162,
6,770,295,
and 6,911,217 (corresponds to Canadian Patent No. 2,350,061), International
Patent
Application WO 2004/105735, and Canadian Patent Application No. 2,472,237.
United States Patent No. 5,783,215 (Arwiddson et al., issued July 21, 1988) is
directed to a controlled release bead comprising a core around which is a drug-
containing layer (in this case, the drug was furosemid) dispersed into a
hydrophilic
polymer, an optional second layer of hydrophilic polymer, and an outer
membrane
layer effective for controlled release of the active ingredient.
United States Patent Nos. 6,630,162 (Nilvebrant et al., issued October 7,
2003)
and 6,770,295 (KreilgArd, et al., issued August 3, 2004), do not claim
controlled
release beads, but are related to various controlled release formulations
containing
such beads. For example, U.S. Patent No. 6,630,162 discloses controlled-
release
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beads comprising: (i) a core unit of a substantially water-soluble or water
swellable
inert material; (ii) a first layer on the core unit of a substantially water-
insoluble
polymer; (iii) a second layer covering the first layer and containing an
active
ingredient; and (iv) a third layer on the second layer of polymer effective
for
controlled release of the active ingredient.
U.S. Patent No. 6,770,295 discloses controlled-release beads comprising: (i) a
core unit of a water-soluble, water-swellable or water-insoluble inert
material; (ii) a
first layer on the core of a substantially water-insoluble polymer (this layer
may
optionally be omitted in the case of an insoluble core); (iii) a second layer
of a water-
soluble polymer having an active ingredient dissolved or dispersed therein;
and (iv)
a third polymer layer effective for controlled release of the active
ingredient.
Canadian Patent Application No. 2,472,237 is directed to a controlled-release
oral preparation characterized in that release of granules from matrix and
drug
release from the granules are conducted in stepwise way, wherein the
preparation
comprises:
1. granules comprising a drug and a carrier material in size of 0.1 - 1 mm,
said carrier material is hydrophobic material in case of drug with water-
solubility of 1 mg/ml or more and said carrier material is hydrophilic
material in case of drug with water-solubility of less than 1 mg/ml;
2. a matrix in which said granules are embedded, comprising swelling and
erodible polymer and swelling-regulating material; and
3, a release-modifying layer comprising hydrophobic release-modifying
polymer, hydrophilic release-modifying polymer, pH-dependent release-
modifying polymer or a mixture thereof.
U.S. Patent No. 6,911,217 (Gren et al., issued on June 28, 2005) is directed
to a
controlled release bead comprising: (i) a core unit of a substantially water
soluble or
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water swellable inert material; (ii) a first layer on the core unit of a
substantially
water-insoluble polymer; (iii) a second layer covering the first layer and
containing
an active ingredient; and (iv) a third layer of polymer on the second layer
effective
for controlled release of the active ingredient, wherein the first layer is
adapted to
control water penetration into the core. In this connection, it is not
uncommon to
apply a "seal-coat" (usually consisting of a water insoluble polymer) between
the
inert core and the layer containing the active ingredient, tolterodine, in
controlled
release beads. Such is done to isolate the drug from the core surface and to
avoid
any potential drug-core chemical interactions.
International Patent Application W02004/105,735 (published December 9,
2004) describes a controlled release pharmaceutical composition of
tolterodine,
wherein each coated unit contained therein comprises: (a) a core; (b) a first
layer
surrounding at least a portion of the core, the first layer comprising
tolterodine and
one or more hydrophilic polymers; and (c) a second layer surrounding at least
a
portion of the first layer and comprising one or more polymers effective for
controlled release of the tolterodine from the first layer.
As it can also be noted, United States Patent No. 6,911,217 and International
Patent Application W02004/105,735 also disclose the possibility of applying a
tolterodine containing layer coat directly onto the inner core. However, as
noted in
International Patent Application W02007/122,015, such a strategy would fail to
maintain the desired zero-order release rate after two hours, thus releasing
tolterodine too quickly.
The inventors of International Patent Application W02007/122,015 attempted
to resolve this problem by inventing controlled release beads formed of a
sugar core,
an innermost layer comprising hydroxyproplylmethyl cellulose (HPMC), a
tolterodine drug layer and an outermost control release layer. The thickness
of the
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hydrophilic HPMC seal-coat layer can allegedly be used to help modulate the
release of the tolterodine drug.
However, there is a need to vary the coating levels of HPMC layer from 5-
15% in order to modify the release profiles to get desired dissolution
profiles.
Indeed, it is stated that the HPMC seal coat is desired to cooperate with
and/or
modify the release profile of the drug in terms of both the rate of
penetration of
water from the outer environment into the core and the osmotic pressure in the
core
that helps the release of the drug out of the bead. This modulation of release
properties is generally achieved by using a layer which has a thickness
greater than
that of a conventional seal coat layer of HPMC.
According to the present invention, it has now surprisingly been found that
by coating the core with a first layer containing a substantially water-
soluble
polymer, improved drug release profiles are obtained with the controlled
release
beads of the present invention.
Additionally by replacing conventional sugar cores with microcrystalline
cellulose cores, and applying a coating onto the core, the present invention
provides
the beneficial advantage of smoothing the inert core's surface thereby
providing a
more consistent surface area, which consequently allows for improved coating
quality when the drug layer and the controlled release membrane layers are
applied
thereon and also allows for easier manufacturing.
SUMMARY OF THE INVENTION
According to an aspect of the present invention, there is provided a
controlled-release bead containing a pharmaceutically active ingredient, the
controlled-release bead comprising:
(i) a core made of a substantially water-insoluble inert material;
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(ii) a first layer disposed over the core, the first layer comprising a
substantially water-soluble polymer;
(iii) a second layer disposed over the first layer, the second layer
containing
the pharmaceutically active ingredient and a polymer; and
(iv) a third layer disposed over the second layer, the third layer comprising
a
controlling release polymeric system.
Preferably, the controlling release polymeric system comprises a water
insoluble polymer or a combination of a water insoluble polymer and a water
soluble polymer.
In a further embodiment, the core is made of materials which are
substantially water insoluble, such as microcrystalline cellulose. Also
preferably, the
core has a diameter ranging from about 0.05 to about 2 mm.
Preferably, the amount of water-soluble polymer in the first layer ranges from
about 2% to about 30% (w/w) of the controlled-release bead. Preferably, the
second
layer constitutes from about 0.1 to about 30% (w/w) of the controlled release
bead.
Preferably, the third layer constitutes from about 5% to about 30% (w/w) of
the
controlled release bead.
Preferably, the pharmaceutically active ingredient is selected from the group
consisting of: tolterodine, the 5-hydroxymethyl metabolite of tolterodine, the
(S)-
enantiomer of tolterodine, the 5-hydroxymethyl metabolite of the (S)-
enantiomer of
tolterodine, the racemate of tolterodine, its prodrug forms and
pharmacologically
acceptable salts thereof. Even more preferably, the pharmaceutically active
ingredient is tolterodine or a pharmacologically acceptable salt thereof.
In the most preferred embodiment, the present invention provides for a
controlled-release bead containing a pharmaceutically active ingredient
wherein the
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pharmaceutically active ingredient released in in vitro USP dissolution
testing is not
more than about 30% after 1 hour, from about 30% to about 60% (preferably from
about 30% to about 50%, and more preferably about 30% to about 40%) after 3
hours,
and not less than about 60% to about 90% after 7 hours.
Preferably, the water-soluble polymer of the first layer is selected from the
group consisting of: cellulose ethers, povidone, and copovidone.
Preferably, the polymer in the second layer is selected from the group
consisting of: cellulose ethers, povidone and copovidone.
Preferably, the controlling release polymeric system in the third layer is
selected from the group consisting of: ethyl cellulose, ammonialkyl
methacrylate
copolymers, methacrylate copolymers, and combinations thereof.
Preferably, the water-insoluble polymer in the third layer is applied in the
form of an aqueous dispersion or in the form of a solution. Preferably, the
water-
soluble polymer in third layer is selected from the group consisting of:
cellulose
ethers, povidone, copovidone, and combinations thereof.
In another aspect of the present invention, there is provided a multiple unit
formulation comprising the controlled release beads according to the present
invention. Preferably, the multiple unit formulation is in the form of a
capsule or a
tablet.
In a further aspect of the present invention, there is provided a method of
producing a controlled release bead containing a pharmaceutically active
ingredient,
which method comprises the steps of:
a) providing a core of a substantially water-insoluble inert material;
b) applying a first layer of a substantially water-soluble polymer to the
core;
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c) applying a second layer onto the first layer, the second layer comprising
an
pharmaceutically active ingredient and a polymer; and
d) applying a third layer onto the second layer, the third layer comprising a
controlling release polymeric system.
Preferably, the controlling release polymeric system comprises a water
insoluble polymer or a combination of a water insoluble polymer and a water
soluble polymer.
The preparation of the multiple unit formulation comprises the additional
step of transforming the beads manufactured according to the present invention
into
a pharmaceutical formulation, such as by filling a predetermined amount of the
beads into a capsule, or compressing the beads into tablets.
The layering or coating operations are preferably performed by spraying a
solution or dispersion of the respective layer materials onto the core,
preferably in a
fluid bed coating apparatus.
After the final coating step, the beads are optionally "cured", usually in a
fluid bed system or in a tray dryer system, by heating to a temperature of
about 30-
80 oC for 30 to 180 minutes, for example. Suitably, the beads are then cooled
below
about 35 C before stopping the process.
The pharmaceutical formulations according to the invention are intended for
oral administration.
By using the process and/or formulation of the present invention, several
advantages present themselves, for example:
(1) the particular choice of MCC beads in the present invention provides
attractive physical-chemical properties, such as low friability and is a good
choice of
core unit on which other substrates can be applied thereon;
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(2) by applying a seal coat onto the core, the present invention provides a
uniform surface on which other layers can be applied thereon. Such can be, for
example, achieved by applying a water soluble coat containing
hydroxypropylcellulose (i.e. a choice of film forming polymer). By applying a
seal
coat onto the MCC core, problems of drug adsorption can be avoided; and
(3) pharmaceutically active ingredient having varying aqueous solubility
can be formulated using the manufacturing described hereinabove.
DETAILED DESCRIPTION OF THE INVENTION
As aforesaid, the present invention is directed to a controlled-release bead
containing a pharmaceutically active ingredient. In a preferred embodiment,
the
beads comprise:
(i) a core made of substantially water-insoluble inert material;
(ii) a first layer disposed over the core, the first layer comprising a
substantially water-soluble polymer, wherein the first layer constitutes
more than about 2%, and more preferably, from about 2% to about 30%
w/w of the final bead composition;
(iii) a second layer disposed over the first layer, the second layer
containing
the pharmaceutically active ingredient and a polymer, wherein the
second layer constitutes from about 0.05% to about 60%, and more
preferably, from about 0.1 % to 30% w/w of the final bead composition;
(iv) a third layer disposed over the second layer, the third layer comprising
a
controlling release polymeric system, wherein the third layer constitutes
from about 1% to about 50%, more preferably from about 5% to about
30% w/ w of the final bead composition; and
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(v) the remaining weight percentage composition of the beads is attributed
to the cores, which are preferably microcrystalline cellulose (MCC)
spheres.
The cores typically have a diameter ranging from about 0.05 to about 2 mm.
The cores comprise a water-insoluble inert material, and may be any such
material
that is conventionally used as cores or any other pharmaceutically acceptable
water-
insoluble material made into beads or pellets. Conventional beads are known to
be
in the shape of spheres and are made of extruded spheres typically comprised
of
excipients such as MCC.
The substantially water-soluble material in the first layer can be selected
from
the group consisting of: cellulose ethers, povidone, copovidone, polyvinyl
alcohol,
polyethylene glycol graft polymers, polyethylene oxide, and combinations
thereof.
In a preferred embodiment, the second layer containing the pharmaceutically
active ingredient (i.e. the drug-containing layer) comprises the
pharmaceutically
active ingredient and a polymer. The polymer can be either a water-soluble or
water-insoluble polymer. Exemplary polymers that can be used in the second
layer
include cellulose ethers, povidone, copovidone, or any other pharmaceutically
acceptable polymer.
Suitable polymers for use in the third layer for controlling the drug release
may be selected from water-insoluble polymers or water-soluble polymers, or a
combination thereof. Examples of water-insoluble polymers include, but are not
limited to, ethyl cellulose, ammonia-alkyl methacrylate copolymer,
methacrylate
copolymers, and mixtures thereof. Other components that can be included in the
third layer (i.e. the controlled release layer), include mixtures of polyvinyl
acetate
with povidone and sodium lauryl sulphate.
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A wide variety of pharmaceutically active ingredients may be used in
conjunction with the present invention. While the active ingredient usually is
a low
or medium dose drug, also high-dose drugs may be contemplated for use in the
present invention. An exemplary class of compounds which may be used as active
ingredients in the present invention include any active ingredient listed in
the
Compendium of Pharmaceuticals and specialties ("CPS"), in particular
tolterodine,
their pharmaceutically acceptable salts with physiologically acceptable acids
and,
when the compounds can be in the form of optical isomers, the racemic mixture
and
the individual enantiomers.
It is of course to be understood herein that any salt, ester, analog, and pro-
drugs of a pharmaceutically acceptable active ingredient may be used in
accordance
with the present invention.
A pro-drug is to be understood herein as being a pharmacological substance
(e.g. drug) which is administered in an inactive (or significantly less
active) form.
Once administered, the pro-drug is metabolized in the body (in vivo) into the
active
compound. In other words, a pro-drug is an inactive (or significantly less
active)
precursor of a drug, converted into an active form in the body by normal
metabolic
processes.
As used herein, the term "pharmaceutically acceptable salt" refers to salts of
an active ingredient that are physiologically tolerated by a user.
In a preferred embodiment, the pharmaceutically active ingredient is
tolterodine, i.e. (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-
phenylpropanamine, as well as the corresponding (S)-enantiomer, the racemate
and
the active 5-hydroxymethyl metabolites, prodrug forms and pharmaceutically
acceptable salts thereof. Useful analogues to the above compounds are
disclosed in,
for example, International Patent Application W098/43942 (published October 8,
1998).
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A wide variety of pharmaceutically active ingredients may be used in
conjunction with the present invention. While the active ingredient usually is
a low
or medium dose drug, also high-dose drugs may be contemplated for use in the
present invention. An exemplary class of compounds which may be used as active
ingredients in the present invention include any active ingredient listed in
the
Compendium of Pharmaceuticals and specialties ("CPS"), in particular
tolterodine,
their pharmaceutically acceptable salts with physiologically acceptable acids
and,
when the compounds can be in the form of optical isomers, the racemic mixture
and
the individual enantiomers.
It is of course to be understood herein that any salt, ester, analog, and
prodrugs of a pharmaceutically acceptable active ingredient may be used in
accordance with the present invention.
A prodrug is to be understood herein as being a pharmacological substance
(e.g. drug) which is administered in an inactive (or significantly less
active) form.
Once administered, the prodrug is metabolized in the body (in vivo) into the
active
compound. In other words, a prodrug is an inactive (or significantly less
active)
precursor of a drug, converted into an active form in the body by normal
metabolic
processes.
As used herein, the term "pharmaceutically acceptable salt" refers to salts of
an active ingredient that are physiologically tolerated by a user.
In a preferred embodiment, the pharmaceutically active ingredient is
tolterodine, i.e. (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-
phenylpropanamine, as well as the corresponding (S)-enantiomer, the racemate
and
the active 5-hydroxymethyl metabolites, prodrug forms and pharmaceutically
acceptable salts thereof. Useful analogues to the above compounds are
disclosed in,
for example, International Patent Application WO98/43942 (published October 8,
1998).
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Specifically, the beads and multiple unit formulation, respectively, according
to the present invention can be suitable for administering the above-mentioned
drug
tolterodine, and would likewise be suitable for its related compounds, for
example:
= the major, active metabolite of tolterodine, i.e. (R)-N,N-diisopropyl-3-
(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropanamine;
= the corresponding (S)-enantiomer to tolterodine, i.e. (S)-N,N-
diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine;
= the 5-hydroxymethyl metabolite of the (S)-enantiomer, i.e. (S)-N,N-
diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-
phenylpropanamine;
= the corresponding racemate to tolterodine, i.e. (R,S)-N,N-diisopropyl-
3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine; and
= prodrug forms and pharmacologically acceptable salts thereof.
When tolterodine is selected as the pharmaceutically active ingredient in the
controlled release bead, the fraction of active ingredient that is released in
vitro is
preferably not more than about 30% after 1 hour, from about 40 to about 85%
after 3
hours, and not less than about 80% after 7 hours.
Administration of the controlled release formulation according to the present
invention allows for a well controlled release of tolterodine, and thereby a
substantially constant serum level of active moiety or moieties to be
maintained in
the patient for up to 24 hours.
Formulations according to the present invention are intended for once daily
or twice daily oral administration, depending on the desired drug release
profiles.
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By the term "active moiety or moieties" is meant, in the case of tolterodine
and its related compounds, the sum of free or unbound (i.e. not protein bound)
concentrations of (i) tolterodine and active metabolite thereof, when
tolterodine (or
prodrug form) is administered; (ii) tolterodine and active metabolite thereof
and/or
(S)-enantiomer to tolterodine and active metabolite thereof, when the
corresponding
racemate (or prodrug form) is administered; (iii) active metabolite, when the
(R)-5-
hydroxymethyl metabolite of tolterodine (or prodrug form) is administered;
(iv) (S)-
enantiomer to tolterodine and active metabolite thereof, when the (S)-
enantiomer (or
prodrug) is administered; or (v) active (S)-metabolite, when the (S)-5-
hydroxymethyl
metabolite is administered.
An example of making tolterodine and its corresponding (S)-enantiomer and
racemate and the preparation thereof are described in, for example, United
States
Patent No. 5,382,600 (Jonsson et al., issued January 17, 1995). United States
Patent
No. 5,559,269 (Johansson, et al. issued September 24, 1996) describes an
active (R)-5-
hydroxymethyl metabolite of tolterodine (as well as the (S)-5-hydroxymethyl
metabolite). The (S)-enantiomer, its non-cholinergic spasmolytic activity and
use in
the treatment of urinary and gastrointestinal disorders are described in
International
laid open application WO 98/03067 (published January 29,1998).
In the preferred embodiment, the ratio of pharmaceutically active ingredient
(i.e. drug) to polymer in the second layer of the controlled release beads is
generally
in the range of from about 1:100 to 100:1 w/w of drug to polymer. In a more
preferred embodiment, the ratio of pharmaceutically active ingredient to
polymer in
the second layer of the controlled release beads is in the range of from about
1:5 to
about 1:10.
The preparation of the multiple unit formulation comprises the additional
step of transforming the beads manufactured according to the present invention
into
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a pharmaceutical formulation, such as by filling a predetermined amount of the
beads into a capsule, or compressing the beads into tablets.
The layering or coating operations are preferably performed by spraying a
solution or dispersion of the respective layer materials onto the core,
preferably in a
fluid bed coating apparatus.
After the final coating step, the beads are optionally "cured", usually in a
fluid bed system or in a tray dryer system, by heating to a temperature of
about 30-
80 C for 30 to 180 minutes, for example. Suitably, the beads are then cooled
below
about 35 C before stopping the process.
The pharmaceutical formulations according to the invention are intended for
oral administration.
It is to be understood that while the invention has been described in
conjunction with the preferred specific embodiments thereof, the description
above
as well as the examples which follow are intended to illustrate and not limit
the
scope of the invention. Other aspects, advantages and modifications within the
scope of the invention will be apparent to persons skilled in the art to which
the
invention pertains.
EXAMPLES
All of the percentages given hereinabove and below are percentages by
weight.
Example 1
A bead according to a preferred embodiment of the present invention
containing tolterodine L-tartrate as the pharmaceutical active ingredient has
the
following components:
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Core - MCC spheres (manufactured by Celphere ) comprising about 70%
w/w of the final bead. These MCC spheres are used as substrate on which
further
coatings can be applied.
First layer - comprises a water soluble polymer and comprises about 5% w/w
of the final bead. Since MCC is known to adsorb drug on its surface, it is
important
to provide a seal coat on the MCC spheres which also provides a uniform
surface to
undergo further processing (coating). This is achieved by providing a water
soluble
coat using hydroxypropylcellulose (HPC) as the film forming polymer.
Second layer - a pharmaceutically acceptable active ingredient, in this case,
tolterodine L-tartrate, combined with a polymer, such as for example HPC. The
second layer comprises about 12.2 % w/w of the final bead. The w/w ratio of
active
ingredient to polymer is about 1:5. The purpose of this second layer is to act
as a
drug supply.
Third layer - combination of ethylcellulose and HPC. The third layer
comprises about 13% w/w of the final bead. The w/w ratio of ethylcellulose to
HPC is about 90:10. The purpose of this third layer is to achieve drug release
rate
control.
Table I - Composition of the First Layer
Serial no. Ingredients Amount
(grams)
1. Microcr stalline cellulose spheres 2000
2. H drox ro l cellulose 140
3. Purified water* 2500
*the purified water is removed during the drying process.
Table II - Composition of the Second Layer
Serial no. Ingredients Amount (grams)
1. Coated beads of First Layer 2000
2. Tolterodine L-Tartrate 56
3. H drox ro l cellulose 280
4. Purified water* 5000
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*the purified water is removed during the drying process.
Table III - Composition of the Third Layer
Serial no. Ingredients Amount ( rams)
1. Coated beads of Second Layer (i.e. the 600
drug aining beads)
2. Aqueous ethylcellulose dispersion 323
(Containing 25% Ethylcellulose)
3. H drox ro l cellulose 9
4. Purified water* 150
*the purified water is removed during the drying process.
Manufacturing Process of First Layer:
Approximately 140 grams of HPC was added into 2500 grams of purified
water. This mixture was continuously mixed until a clear solution was obtained
(solution #1). This solution #1 was sprayed onto about 2000 grams of MCC
spheres
(also known as beads) using a fluid bed bottom spray unit.
Manufacturing Process of Second Layer:
56 grams of a pharmaceutical active ingredient, in this case tolterodine L-
tartrate, was added to about 4000 grams of purified water. This mixture is
continuously mixed until a clear solution is obtained (solution #2). In a
separate
solution (solution #3), 280 grams of HPC is added to about 1000 grams of
purified
water. This mixture is continuously mixed until a clear solution is obtained
(solution
#3). Solution #2 and solution #3 were then mixed together for at least 30
minutes,
thereby forming solution #4. Solution #4 was sprayed on to about 2000 grams of
MCC coated spheres of the first layer using a fluid bed coater equipped with
bottom
spray unit.
Manufacturing Process of Third Layer:
9 grams of HPC was added to about 150 grams of purified water. This
mixture was continuously mixed until a clear solution is obtained (solution
#5).
Approximately, 323 grams of an aqueous ethylcellulose dispersion was added to
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solution #5, thereby forming solution #6. This mixture (solution #6) is
continuously
mixed for at least 30 minutes before undergoing spraying. Solution #6 was then
sprayed on to about 600 grams of the coated beads of the second layer using,
once
again, fluid bed coater equipped with bottom spray unit.
Example 2 - Dissolution Study of Dosage Form of the Formulation of Example 1
A dissolution study was performed using USP apparatus I, paddle speed @
100 rpm, media volume - 900ml, change over media, 1hr, 2hr time points in 0.1N
HCL and 3, 4, 6, 8, 9 hrs and an infinity time point in pH 6.8 phosphate
buffer.
Results are set out in Table IV. The dissolution is performed using 6 tablets
in the
dissolution medium.
Table IV - Dissolution of Tablets Made in Accordance with the Preferred
Embodiment (Example 1)
Time (hrs) Formulation
of Example 1
(% dissolved)
1 3
2 25
3 39
4 51
6 67
8 75
9 77
ITP 85
ITP - infinity time point
Example 3 - Formulation of Tolterodine Tartrate 4 mg Capsules
The following tables set out the formulation of tolterodine tartrate 4 mg
capsules according to an embodiment of the present invention.
Table V - Composition of First Layer
Item Description Qty to weigh (g)
1. MCC-Spheres 2000.0
2. HPC-L 140.0
3. Colloidal silicon dioxide 60.0
4. Dehydrated alcohol" 1500
Sub-total 2200.0
AMENDED SHEET
PCT/CA2009/000418
CA 02718753 2010-09-15 09 February 2010 09-02-2010
-17-
*lost during the manufacturing process.
Table VI - Composition of Second Layer
Item Description Qty to weigh (g)
First Layer beads 1000.0
1. Tolterodine tartrate 40.0
2. HPC-L 280.0
3. Colloidal silicon dioxide 84.0
4. Purified water' 4000.0
Sub-total 1404.0
*the purified water is removed during the drying process.
Table VII - Composition of Third Layer
Item Description Qty to weigh (g)
Second Layer Beads 800.0
1. Ethylcellulose 20c s 62.60
2. Colloidal silicon dioxide 16.11
3. HPC-L 9.353
4. Tri-ethyl citrate 7.94
5. Dehydrated alcohol" 1800
Total 896.0
*lost during the manufacturing process.
Manufacturing Process of First Layer:
Approximately 140 grams of HPC was added into 2500 grams of purified
water. This mixture was continuously mixed until a clear solution was obtained
(solution #1). This solution #1 was sprayed onto about 2000 grams of MCC
spheres
(also known as beads) using a fluid bed bottom spray unit.
Manufacturing Process of Second Layer:
40 grams of a pharmaceutical active ingredient, in this case tolterodine L-
tartrate, was added to about 3000 grams of purified water. This mixture is
continuously mixed until a clear solution is obtained (solution #2). In a
separate
solution (solution #3), 280 grams of HPC and colloidal silicon dioxide is
added to
about 1000 grams of purified water. This mixture is continuously mixed until a
clear
solution is obtained (solution #3). Solution #2 and solution #3 were then
mixed
together for at least 30 minutes, thereby forming solution #4. Solution #4 was
AMENDED SHEET
PCT/CA2009/000418
CA 02718753 2010-09-15 09 February 2010 09-02-2010
-18-
sprayed on about 1000 grams of MCC coated spheres of the first layer using a
fluid
bed coater equipped with bottom spray unit.
Manufacturing Process of Third Layer:
9.353 grams of HPC was added to about 1800 grams of purified water. This
mixture was continuously mixed until a clear solution is obtained (solution
#5).
62.60 grams of ethylcellulose 20cps, 16.11 grams of colloidal silicon dioxide
and 7.94
grams of triethyl citrate was added to solution #5, thereby forming solution
#6. This
mixture (solution #6) is continuously mixed for at least 30 minutes before
undergoing spraying. Solution #6 was then sprayed on to about 800 grams of the
coated beads of the second layer using, once again, fluid bed coater equipped
with
bottom spray unit.
Example 4 - Dissolution Study of Formulation Prepared According to Example 3
Dissolution was performed using USP apparatus I, paddle speed @ 100 rpm,
media volume - 900m1, change over media, lhr, 2hr time points in 0.1N HCL and
3,
4, 6, 8, 9 hrs and an infinity time point in pH 6.8 phosphate buffer. Results
are given
in the table below.
Table VIII - Dissolution of Formulation Made in Accordance with the Example 3
Time (hrs) Formulation of
Example 3 (%
dissolved)
1 1
2 4
3 9
4 14
6 24
8 33
9 38
ITP 60
ITP = infinity time point
AMENDED SHEET
PCT/CA2009/000418
CA 02718753 2010-09-15 09 February 2010 09-02-2010
-19-
Example 5 - Formulation of Tolterodine Tartrate 4 mg Capsules
TABLE IX - Composition of First Layer
Item Description Qty to weigh (g)
1. MCC-Spheres 2000.0
2. HPC-L 140.0
3. Colloidal silicon dioxide 60.0
4. Dehydrated alcohol* 1500.0
Sub-total 2200.0
*lost during the manufacturing process.
Table X - Composition of Second Layer
Item Description Qty to weigh (g)
First Layer beads 500.0
1. Tolterodine tartrate 20.0
2. HPC-L 140.0
3. Colloidal silicon dioxide 42.0
4. Purified water* 2000
Sub-total 702.0
*the purified water is removed during the drying process.
Table XI - Composition of Third Layer
Item Description Qty to weigh (g)
Second layer beads 500.0
1. Ethylcellulose 20cps 26.08
2. Colloidal silicon dioxide 6.72
3. HPC-L 3.90
4. Tri-ethyl citrate 3.308
5. Dehydrated alcohol" 1000.0
Total 540.0
*lost during the manufacturing process.
Manufacturing Process of First Layer:
Approximately 140 grams of HPC was added into 2500 grams of purified
water. This mixture was continuously mixed until a clear solution was obtained
(solution #1). This solution #1 was sprayed onto about 2000 grams of MCC
spheres
(also known as beads) using a fluid bed bottom spray unit.
AMENDED SHEET
PCT/CA2009/000418
CA 02718753 2010-09-15 09 February 2010 09-02-2010
-20-
Manufacturing Process of Second Layer:
40 grams of a pharmaceutical active ingredient, in this case tolterodine L-
tartrate, was added to about 3000 grams of purified water. This mixture is
continuously mixed until a clear solution is obtained (solution #2). In a
separate
solution (solution #3), 140 grams of HPC and colloidal silicon dioxide is
added to
about 1000 grams of purified water. This mixture is continuously mixed until a
clear
solution is obtained (solution #3). Solution #2 and solution #3 were then
mixed
together for at least 30 minutes, thereby forming solution #4. Solution #4 was
sprayed on about 1000 grams of MCC coated spheres of the first layer using a
fluid
bed coater equipped with bottom spray unit.
Manufacturing Process of Third Layer:
3.90 grams of HPC was added to about 1000 grams of purified water. This
mixture was continuously mixed until a clear solution is obtained (solution
#5).
26.08 grams of ethylcellulose 20cps, 6.72 grams of colloidal silicon dioxide
and 3.308
grams of triethyl citrate was added to solution #5, thereby forming solution
#6. This
mixture (solution #6) is continuously mixed for at least 30 minutes before
undergoing spraying. Solution #6 was then sprayed on to about 500 grams of the
coated beads of the second layer using, once again, fluid bed coater equipped
with
bottom spray unit.
Example 6 - Dissolution Study of Formulation Prepared According to Example 5
Dissolution was performed using USP apparatus I, paddle speed @ 100 rpm,
media volume - 900m1, change over media, lhr, 2hr time points in 0.1N HCL and
3,
4, 6, 8, 9 hrs and an infinity time point in pH 6.8 phosphate buffer. Results
are given
in the table below.
AMENDED SHEET
PCT/CA2009/000418
CA 02718753 2010-09-15 09 February 2010 09-02-2010
-21-
Table XII - Dissolution of Formulation Made in Accordance with the Preferred
Embodiment (Example 5)
Time (hrs) Formulation
of Example 5
(% dissolved)
1 2
2 15
3 32
4 43
6 58
8 69
9 74
ITP 77
ITP = infinity time point
All of the percentages given hereinabove are percentages by weight.
While the invention has been described above with reference to specific
embodiments thereof, it is not intended to be restricted thereto in any way
whatsoever. On the contrary, as will be understood by persons skilled in the
art,
various changes, modifications, substitutions and omissions can be made
without
departing from the basic concept of the invention as defined in the claims
which
follow.
AMENDED SHEET
