Note: Descriptions are shown in the official language in which they were submitted.
CA 02795893 2012-11-16
CONTROLLED RELEASE FORMULATIONS OF TOLTERODINE
AND PROCESS OF MANUFACTURING
FIELD OF THE INVENTION
The present invention relates to the field of pharmaceuticals, and
specifically to pharmaceutical
formulations comprising a controlled release multiple unit pharmaceutical
composition and a
process of manufacturing a controlled release composition. In particular, the
multiple unit
pharmaceutical compositions comprise tolterodine, or a pharmaceutically
acceptable salt thereof, as
an active ingredient.
BACKGROUND OF THE INVENTION
Tolterodine, (R)-N,N-diisopropy1-3-(2-hydroxy-5-methylpheny1)-3-
phenylpropanamine, is an
antimuscarinic drug that is used to treat urinary incontinence.
HO IP C H 3
lN..........õ a Fi, : cH,
H3c-------CH3
CH3
Tolterodine, and its pharmaceutically acceptable salts, is administered as a
tablet and an extended-
release capsule to relieve urinary difficulties, including frequent urination
and inability to control
urination. It works by preventing bladder contraction. Tolterodine is
presently being sold in a
number of different countries under the brand name Detrol or Detrositol .
In order to maximize patient compliance, it is desirable to reduce the
frequency of dosing to obtain
effective therapy, while at the same time providing an oral dosage form which
is palatable to the
patient.
One method of accomplishing this goal is the use of controlled release
formulations. The intention
of controlled release formulations is to provide an extended duration of the
pharmacological
response after administration of the dosage form; generally providing a
constant concentration of
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CA 02795893 2012-11-16
the active substance in body fluids for a certain period of time. The extended
release dosage form
may be in the form of a single unit or a multiple unit formulation. Single
unit controlled release
dosage forms of drugs have known disadvantages. For example, dosage forms may
either pass
undisintegrated through the gastrointestinal tract thus not releasing the
active ingredient or release
the entire drug load in a burst (referred to as dose dumping). These dosage
forms are also heavily
dependent upon gastric emptying rates and transit times, as well as intra and
inter-individual
variations. Multiple unit dosage forms may take the shape of a variety of
forms, including a
multiplicity of individual units contained within a rapidly dissolving capsule
or compressed into a
tablet. Soon after ingestion of the formulations, individual units are
directly available in the
gastrointestinal tract.
Extended-release capsules of tolterodine are usually taken once a day to
maintain a therapeutic
serum level of tolterodine and to minimize the effects of missed doses of the
drug caused by lack of
patient compliance.
Several advantages of multiple unit dosage forms have previously been
disclosed. It is, for
example, possible to obtain reproducible results in regards to the emptying of
the units from the
stomach into the small intestine when the particles are less than 1-2 mm.
Dispersion over a large
area in drugs with the decreased plasma concentrations defined by the
decreased peak plasma
concentration (CmAx) and/or area under the curve (AUC) due to increase of the
gastric pH and
consequently impaired in vivo dissolution are for example poorly-water soluble
weakly basic
drugs.
Decreased or increased as used above relates to values compared to the ones
obtained by
administering the drugs to patients having normal stomach and gastrointestinal
pH. Elevated
gastric pH might also change the pharmacokinetic properties of the coated
formulations, because
the pH in the stomach changed as a result of the use of food to the values
that are characteristic for
the small intestine, thus the release of the drug may begin already in the
stomach, resulting in
shorter TMAX (time to reach maximum concentration) and increased CmAx.
The high probability of impaired gastric pH associated with diseases and
conditions selected form
different groups, particularly urinary diseases, thus requires that drugs used
for the manufacturing
of the medicament for treatment of above diseases and/or conditions are
formulated into a
pharmaceutical composition exhibiting predictable pH dependant dissolution
characteristics.
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There exist many types of oral dosage formulations which are directed to the
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.
For example, Canadian Patent No. 2,350,061 (issued May 17, 2005) discloses a
formulation of
tolterodine which is composed of three-layered coated multiparticulates. The
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 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. A method of producing the controlled release bead
is also disclosed.
PCT Publication No. W02004/105735 (published December 9, 2004) discloses a
controlled release
pharmaceutical composition of tolterodine that includes one or more coated
units. Each unit has a
core, a first layer and a second layer. The first layer surrounds the core and
includes tolterodine
and one or more hydrophilic polymers. The second layer includes one or more
polymers effective
for controlled release of the tolterodine from the first layer.
PCT Publication No. W02004/012700 (published February 12, 2004) discloses a
dosage form
comprising of a high dose, high solubility active ingredient as modified
release and a low dose
active ingredient as immediate release where the weight ratio of immediate
release active
ingredient and modified release active ingredient is from 1:10 to 1:15000 and
the weight of
modified release active ingredient per unit is from 500 mg to 1500 mg; a
process for preparing the
dosage form.
PCT Publication No. W02007/011131 (published January 25, 2007) discloses a
novel
pharmaceutical composition which is capable of improving the stability over
time of a drug pellet
during storage and distribution of the pellet having controlled release
properties. More specifically,
the present invention provides a novel pharmaceutical composition which is
capable of preventing
moisture-induced changes in a drug release rate during storage and
distribution of a drug pellet,
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via coating of a controlled-release pellet, particularly sustained-release
pellet, comprising
tolterodine, a tolterodine compound or a pharmaceutically acceptable salt
thereof as a drug, with a
dimethylaminoethyl methacrylate/ methyl methacrylate copolymer (Eudragit E) or
polyvinylacetal
diethylaminoacetate ("AEA") which is insoluble at a pH of 5.5 or higher.
PCT Publication No. W02009/003724 (published January 8, 2009) discloses a
controlled release
bead comprising: a microcrystalline cellulose core unit; a water soluble coat
surrounding said core
comprising a vinyl pyrrolidone polymer; a drug layer comprising tolterodine or
a pharmaceutically
acceptable salt and a pharmaceutical acceptable binder; and a controlled
release layer comprising a
pH independent polymer, preferably a polyacrylate, and a process for preparing
these beads, to a
pharmaceutical dosage form, and to their use.
Canadian Patent Application No. 2,693,166 (published January 29, 2009)
discloses a drug
composition comprising a coated bead that is used in the manufacture of
immediate release and/or
controlled release drug compositions. In a specific embodiment, the bead
includes an inert core of
a water-soluble or water-swellable material, which has been coated with a seal
layer formed from a
non-polymeric hydrophobic material. The immediate and/or controlled release
beads may be used
to form tablets or capsules. A method of making the beads by sequential
deposition of multiple
layers on the inert cores is also described.
Similarly, Canadian Patent Application No. 2,693,163 (published January 29,
2009) discloses a
pharmaceutical composition containing tolterodine L-tartrate stabilized
against degradation with
an acid. Acid-stabilized tolterodine L-tartrate may be used to make various
types of immediate
release and controlled release dosage forms.
The Applicant's international application, PCT Publication No. W02009/121178
(Canadian Patent
Application No. 2,718,753), also relates to a controlled-release bead
containing a pharmaceutically
active ingredient. The controlled-release bead comprises a core made of a
substantially water-
insoluble inert material. A first layer is disposed over the core, with the
first layer comprising a
substantially water-soluble polymer. A second layer disposed over the first
layer, the second layer
containing the pharmaceutically active ingredient and a polymer. Finally, a
third layer is disposed
over the second layer, with the third layer comprising a controlling release
polymeric system. The
application also discloses dosage forms, such as tablets and capsules,
comprising the controlled-
release beads, and methods of manufacturing the controlled-release beads.
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Some more references for pharmaceutical composition contains coated beads of
Tolterodine are
known to exist in prior art as: PCT Publication No. W02011/013082 (published
February 3, 2011);
Canadian Patent Application No. 2,637,444 (published July 26, 2007)
(W02007/082770); Canadian
Patent No. 2,311,755 (issued March 23, 2010) (W02000012069); Canadian Patent
Application No.
2,647,765 (published October 11, 2007) (W02007113207); PCT Publication No.
W02007/122015
(published November 1, 2007); PCT Publication No. W02009/140557 (published
November 19,
2009); and PCT Publication No. W02003/053428 (published July 3, 2003).
Several advantages have been disclosed in the prior art regarding multiple
unit dosage forms of the
extended release formulation of tolterodine, or a pharmaceutically acceptable
salt. However, given
the different mechanism of action, as well as effect of food intake on the
pharmacokinetics, of the
known extended release formulations, there is a need for improved formulations
of tolterodine (or
a pharmaceutically acceptable salt thereof) comprising a controlled release
multiple unit
pharmaceutical composition.
SUMMARY OF THE INVENTION
One aspect of the present invention is to address existing disadvantages by
developing a unique
controlled release tolterodine formulation which can be used for the treatment
of urinary
incontinence due to overactive bladder.
A further aspect of the present invention is to provide tolterodine controlled
release beads and
formulations which provide substantially uniform bioavailability, regardless
of the fasted or fed
state of the patient being treated (i.e. the food effect).
Another aspect of the present invention is to provide a tolterodine controlled
release composition
that is bioequivalent to DETROL LA and different compositions of tolterodine
extended release
capsules.
A further aspect of the present invention provides a process for making this
product with more
conventional manufacturing process by preparing multiple unit controlled
release tolterodine
formulation, which is simple, therapeutically effective and less expensive.
An aspect of the present invention provides a controlled-release composition
for oral
administration, comprising:
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(i) an inert core;
(ii) a first layer disposed over the inert core, the first layer comprises a
hydrophilic film
coating polymer and at least one pharmaceutically acceptable excipient;
(iii ) a second layer disposed over the first layer, the second layer
comprises an active
pharmaceutical ingredient and at least one pharmaceutically acceptable
excipient;
(iv) a third layer, disposed over the second layer, the third layer comprises
a pH-
independent control release polymer and at least one pharmaceutically
acceptable excipient;
and
(v) a fourth layer disposed over the third layer, the fourth layer comprises
an enteric
polymer and at least one pharmaceutically acceptable excipient,
wherein said composition diminishes the food effect when administered to a
patient that has eaten,
i.e. administration of the composition to a human patient allows for
relatively constant
bioavailability of the active pharmaceutical ingredient, regardless of the
fasted or fed state of said
patient.
Preferably, the active pharmaceutical 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.
And more preferably, the active ingredient is tolterodine tartrate.
In another aspect of the present invention, the controlled-release composition
has an in vitro
dissolution profile of the said composition provides from about 80% to about
90 % of the active
ingredient released after 11 hours, as measured by USP Type 1 Apparatus
(rotating basket), with
900 ml of pH 6.8 phosphate buffer, at 37 C, at a basket speed of 100 rpm.
In a further aspect, the controlled-release composition is suitable for use in
the treatment of a
disorder selected from the group consisting of: overactive urinary bladder,
including urinary
incontinence, nocturia and gastrointestinal disorders.
In a preferred embodiment, the administration of the controlled-release
compositions of the present
invention to a patient provides maximum plasma concentrations (Cmax) T/R ratio
from about 50%
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to about 135% and AUCt T/R ratio from about 60 % to about 125% (with 90 %
confidence interval)
in bioequivalence studies comparing the composition to a reference product, in
particular,
DETROL LA , and said composition diminishes the food effect when administered
to a patient
that has eaten.
Further aspect of the present invention there is provided a controlled-release
composition for oral
administration, wherein the pharmaceutically active ingredient exhibits an in
vitro dissolution
profile such that:
= from about 1% to about 20% of the pharmaceutically active ingredient is
released after 1
hour;
= from about 20% to about 50% of the pharmaceutically active ingredient is
released after 3
hours;
= from about 50% to about 80% of the pharmaceutically active ingredient is
released after 7
hours, and
= from about 80% to about 90 % of the pharmaceutically active ingredient is
released after 11
hours, as measured by USP Type 1 Apparatus (rotating basket), with 900 ml of
pH 6.8
phosphate buffer at 37 C, at a basket speed of 100 rpm.
In a further aspect of the present invention, a bioequivalence study of the
controlled-release
composition exhibits a value of maximum plasma concentrations (Cmax) T/R ratio
from about 250%
when there is no enteric coat to about 50% achieved when said composition
comprises about 6% of
enteric coat.
Another aspect of the present invention provides that in bioequivalence study
conducted against
DETROL LA , the controlled-release composition exhibits a value of a maximum
plasma
concentration (Cmax) T/R ratio from about 250% when there is no enteric coat
to about 135%
achieved when said composition comprises about 4.2% of enteric coat.
Preferably, the controlled-release composition provides that administration of
a 4 mg dose of the
said pharmaceutical composition to human patient results in a tolterodine Cmax
ranging from about
1200 pg/ml to about 5000 pg/ml. More preferably, a tolterodine Cmax ranging
from about 1200
pg/ml to about 2600 pg/ml.
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Another aspect of the present invention provides the controlled-release
composition in which the
AUCt T/R ratio of unbound pharmaceutically active ingredient exhibits a value
as follows: from
about 140% when there is no enteric coat to about 60 % when said composition
comprises about 6%
w/w of enteric coat over the third layer.
Another aspect of the present invention provides the controlled-release
composition in which the
AUCt T/R ratio of unbound pharmaceutically active ingredient exhibits a value
from about 140%
when there is no enteric coat to about 125% when said composition comprises
about 4% w/w of
enteric coat over the third layer.
Preferably, the tolterodine area under the curve from time 0 to the last
measured time (AUCt) after
administration of a 4 mg dose of the pharmaceutical composition to a human
patient ranges from
about 15000 pg hr/ml to about 32000 pg hr/ml. More preferably, the tolterodine
area under the
curve from time 0 to the last measured time (AUCt) after administration of a 4
mg dose of the
pharmaceutical composition ranges from about 15000 pg hr/ml to about 24000 pg
hr/ml.
Also preferably, the tolterodine area under the curve from time 0 to time
infinity (AUCO-inf) after
administration of a 4 mg dose of the pharmaceutical composition to a human
patient ranges about
15000 pg=hr/m1 to about 32000 pg hr/ ml. More preferably, the tolterodine area
under the curve from
time 0 to time infinity (AUCO-inf) after administration of a 4 mg dose of the
pharmaceutical
composition ranges about 15000 pg fir/m1 to about 24000 pg hr/ml.
Preferably, the Tmax ranges from about 4 to about 8 hours after administration
of 4 mg dose of the
pharmaceutical composition to a human patient.
Preferably, the water insoluble inert core of the present pharmaceutical
composition is
microcrystalline cellulose.
Preferably, the hydrophilic film coating polymer in the first layer of the
said pharmaceutical
composition is hydroxypropyl cellulose. Also preferably, the amount of the
hydrophilic film
coating polymer in the first layer ranges from about 2% to about 20 % w/w of
the controlled-
release composition. More preferably, the amount of the hydrophilic film
coating polymer in the
first layer ranges from about 2% to about 5 % w/w of the controlled-release
composition.
Preferably, the active ingredient, such as tolterodine tartrate, is present at
a weight to weight ratio
to binder in the second layer from about 1:5 to about 1:10.
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Further, the second layer comprises a binder which is hydroxypropyl cellulose.
More preferably,
the amount of the binder in the second layer ranges from about 20% to about
30% w/w of the
controlled-release composition.
Preferably, the pH-independent control release polymer of the third layer is
selected from the
group consisting of: ethyl cellulose, ammonialkyl methacrylate copolymers,
methacrylate
copolymers, and combinations thereof.
Preferably, the control release polymer of the third layer is ethyl cellulose
and the amount of said
polymer in the third layer ranges from about 3% to about 15% w/w of the
controlled-release
composition. More preferably, the amount of said polymer in the third layer
ranges from about 3%
to about 5% w/w of the said composition.
Preferably, the hydrophilic polymer in the third layer is hydroxypropyl
cellulose and the amount
of hydrophilic polymer in the third layer ranges from about 0.4% to about 2%
w/w of the
controlled-release composition. More preferably, the amount of hydrophilic
polymer in the third
layer ranges from about 0.4% to about 0.6% w/w of the said composition.
Preferably, the enteric coating polymer of the fourth layer is selected from
the group consisting of:
ammonialkyl methacrylate copolymers, methacrylate copolymers, and combinations
thereof. More
preferably, the enteric coating polymer of the fourth layer is an aqueous
dispersion of anionic
polymers with methacrylic acid as a functional group (e.g., Eudragit0 L30 D-
55), and the amount
of the enteric coating polymer in the fourth layer ranges from about 0.5 % to
about 5% w/w of the
controlled-release composition.
Preferably, the third and fourth layers comprise a plasticizer, and more
preferably, the plasticizer is
triethyl citrate. More preferably, the amount of the plasticizer in the third
layer ranges from about
0.4% to about 0.6% w/w and in the fourth layer ranges from about 0.2% to about
2% w/w of the
controlled-release composition.
Preferably, the process used for the preparation of a controlled-release
pharmaceutical composition
is a drug layering process which results in an unique controlled release
dosage form of tolterodine
extended release capsules which is used for the treatment of urinary
incontinence due to overactive
bladder.
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Yet another aspect of the present invention is to provide a method of
producing of a controlled-
release pharmaceutical composition which comprises:
a) providing an inert core;
b) applying a first layer comprising hydrophilic film coating polymer and at
least one
pharmaceutically acceptable excipient onto the inert core;
c) applying a second layer comprising an active ingredient, a binder and at
least one
pharmaceutically acceptable excipient onto the first layer;
d) applying a third layer comprising a pH-independent controlled release
polymer and at least one
pharmaceutically acceptable excipient onto the second layer; and
e) applying a fourth layer comprising an enteric coating polymer and at least
one pharmaceutically
acceptable excipient onto the third layer;
wherein said composition diminishes the food effect when administered to a
patient that has eaten.
Preferably, the water insoluble inert core according to the process is
microcrystalline cellulose.
More preferably, providing a method of manufacturing of 1st layer by adding
hydroxypropyl
cellulose into purified water, continuously mixing mixture until a clear
solution is obtained, and
then spraying obtained solution onto about microcrystalline cellulose spheres
using a fluid bed
bottom spray unit.
Also preferably, providing a method of manufacturing of 2nd layer by adding
tolterodine L- tartrate
to purified water and continuously mixing mixture until a clear solution is
obtained (#1); then
adding hydroxypropyl cellulose and colloidal silicon dioxide to purified water
in a separate
solution (#2), continuously mixing mixture until a suspension is obtained
(#2); then mixing
solution (#1) and suspension (#2) together for at least 30 minutes, thereby
forming suspension (#3),
and spraying obtained mixture (#3) on MCC coated spheres of the 1st layer
using a fluid bed coater
equipped with bottom spray unit.
Also preferably, providing a method of manufacturing of 3rd layer by adding
hydroxypropyl
cellulose to dehydrated alcohol and continuously mixing mixture until a clear
solution is obtained
(#1); then adding ethyl cellulose 20cps, colloidal silicon dioxide and
triethyl citrate to solution (#1),
thereby forming suspension (#2), which is mixing continuously for at least 30
minutes, and
spraying suspension (#2) on coated beads of the 2nd layer using, fluid bed
coater equipped with
bottom spray unit.
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CA 02795893 2012-11-16
More preferably, providing a method of manufacturing of 4th layer by adding
Triethylcitrate to talc
and continuously mixing mixture until a suspension is obtained (#1); then
adding Eudragit L3OD
55@ to suspension (#1) and continuously stirring, thereby forming suspension
(#2) and spraying
obtained mixture (#2) on coated beads of the 3td layer using, fluid bed coater
equipped with bottom
spray unit.
The present invention is further related to a process for the preparation of a
controlled-release
pharmaceutical composition, wherein by introducing the fourth layer of
Eudragit L3OD 55 over
the third layer with ethyl cellulose coated beads the effect of food was
diminished when
administered to a patient that has eaten.
Preferably, the present invention related to a process for the preparation of
a controlled-release
pharmaceutical composition, wherein by introducing the fourth layer of
Eudragit L3OD 558 over
the third layer with ethyl cellulose coated beads, the effect of food was
diminished, and exhibits
maximum concentrations (Cmax) T/R ratio about 50% and AUCr T/R ratio about 60%
(with 90%
confidence interval).
The present invention is further related to use of a therapeutically effective
amount of tolterodine
or pharmacologically acceptable salt thereof, for the preparation of a
pharmaceutical controlled
release composition which diminishes the food effect when administered to a
patient that has eaten
in the treatment of a disorder selected from the group consisting of:
overactive urinary bladder,
including urinary incontinence, nocturia and gastrointestinal disorders,
wherein said composition
exhibits an in vitro release of active ingredient, ranging from about 80% to
about 90% after 11 hours,
as measured by USP Type 1 Apparatus (rotating basket), with 900 ml of pH 6.8
phosphate buffer at
37 C at a basket speed of 100 rpm., and said composition exhibits maximum
plasma concentrations
(Cmax) T/R ratio about 50% and AUCr T/R ratio about 60% (with 90 % confidence
interval).
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a controlled-release pharmaceutical
composition for oral
administration comprising a multiple unit formulation, using a drug layering
process which allows
one to obtain an unique controlled release dosage form of tolterodine extended
release capsules
which is suitable for the treatment of urinary incontinence due to overactive
bladder. Futhermore,
the compositions of the present invention diminishes the food effect when
administered to a
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CA 02795893 2012-11-16
patient that has eaten, i.e. the bioavailability of the oral dosage form is
relatively uniform,
regardless of the fed or fasted state of the patient.
The term "controlled release pharmaceutical composition", as referred to
herein, is defined to mean
oral pharmaceutical compositions which when administered releases the active
ingredient at a
relatively constant rate and provide plasma concentrations of the active
ingredient that remain
substantially invariant over a period of time within the therapeutic range of
the active ingredient
over a 24-hour period and encompasses "prolonged release", "extended release",
"modified
release", "delayed release", "long acting" and "sustained release"
compositions.
The compositions according to the present invention deliver a therapeutically
effective amount of
tolterodine to a patient for 24 hours following a once-daily administration.
The term "therapeutically effective amount" intends to describe an amount of
the active agent
which stops or reduces the progress of the condition to be treated or which
otherwise completely or
partly cures or acts palliative on the condition.
The term "active ingredient" and "active pharmaceutical ingredient" refers to
an Active
Pharmaceutical Ingredients (API) which are active chemicals used in the
manufacturing of drugs.
The active agent can be a therapeutic, a prophylactic, or a diagnostic agent.
The term "food effect", as used herein, means a significant difference in the
bioavailability of a
drug in a patient when the drug is administered in a fasted state compared to
a fed state.
"Diminished food effect" means that there is no significant difference in the
bioavailability of a
drug in a patient when the drug is administered in a fasted state compared to
a fed state, i.e. the
bioavailability is relatively uniform (there is no significant difference)
regardless of the fed or
fasted state of the patient.
Drug release and drug release profiles are measures or representations of the
manner and timing
by which a formulation releases or delivers active ingredients (drug) to a
receiving environment
(e.g. the stomach, intestines, etc.) upon administration. Various methods are
known for evaluating
drug release and producing release profiles, including in vitro tests which
model the in vivo
behavior of a formulation. These include USP dissolution testing for immediate
release and
controlled release solid dosage forms.
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Drug release profiles are distinct from plasma profiles. A plasma profile is a
measure or
representation of the dose or level of active ingredient (drug) in the
bloodstream of a mammal, e.g.
a patient receiving a drug formulation. Upon release of a drug from a
formulation, e.g. into the gut
of a mammal, the amount of drag that is present in the bloodstream over time
can be determined.
A drug release profile may be designed to produce a desired or targeted plasma
profile. Often, but
not necessarily, a plasma profile will mimic a release profile. For example,
it might be expected that
a sustained release of drug is more likely to produce a sustained dose in the
plasma, or that a
pulsed release would produce a pulsed (peak and valley) plasma profile. This
is not necessarily so,
however. For example, the half-life of the drug in the blood stream (its rate
of decay) may be such
that a sustained or continuous plasma profile could result from a pulsed
delivery profile. Other
factors may also play a role, such as bio- absorption, bioavailability, and
first pass effect. The
plasma profile produced by a particular release profile may also vary from
patient to patient.
Measures of bioavailability are well known in the art and include the area
under the plasma
concentration-time curve (AUC), the concentration maximum (Cmax), and the time
to C. AUC is
a measurement of the area under the plasma concentration-time curve, and is
representative of the
amount of drug absorbed following administration of a single dose of a drug
(for example, see
Remington: The Science and Practice of Pharmacy, (Alfonso R. Gennaro ed.
2000), page 999).
Cmax is the maximum plasma concentration achieved after oral administration of
a drug
(Remington, page 999). An oral drug administration results in one Cmax, but
may result in greater
than one "peak plasma concentration" or "plasma concentration peak" (for
example, following the
administration of a pulsed dose formulation).
Tnax is the amount of time necessary to achieve the Cmax after oral drug
administration, and is
related to the rate of absorption of a drag (Remington, page 999).
T/R ratio refers to the Test/Reference ratio. Bioequivalence is the absence of
a significantly
different rate and extent of absorption in the availability of the active
ingredient when
administered at the same dose under similar conditions. Bioequivalence can be
measured by
pharmacokinetic parameters such as, for example, AUC and Cmax.
A controlled release pharmaceutical composition means a pharmaceutical
composition including
an active pharmaceutical ingredient which is formulated with pharmaceutically
acceptable film
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forming polymers and optionally with pharmaceutically acceptable excipients,
wherein the
pharmaceutical composition shows a pH-dependent or a pH-independent
reproducible release
profile.
Examples of controlled release pharmaceutical compositions include immediate
release
pharmaceutical compositions, enteric coated pharmaceutical compositions,
pulsed release
pharmaceutical compositions or sustained release pharmaceutical compositions.
Controlled release of a pharmaceutical composition may be achieved by
different means.
Previously described in the art controlled release was mostly obtained using a
hydrophilic matrix
agent or a combination of hydrophilic and lipophilic or inert matrix agents.
More commonly, the
controlled release was obtained using a coating comprising a combination of
water non-dispersible
and/or water dispersible polymer.
According to the present invention, the controlled release is achieved by
composition containing:
(i) an inert core;
(ii) a first layer disposed over the inert core, wherein the first layer
comprises a hydrophilic
film coating polymer and at least one pharmaceutically acceptable excipient;
(iii) a second layer disposed over the first layer, wherein the second layer
comprises an
active pharmaceutical ingredient or a pharmaceutically acceptable salt
thereof, and at least
one pharmaceutically acceptable excipient;
(iv) a third layer, disposed over the second layer, wherein the third layer
comprises a pH-
independent control release polymer and at least one pharmaceutically
acceptable
excipient; and
(v) a fourth layer disposed over the third layer, wherein the fourth layer
comprises an
enteric polymer and at least one pharmaceutically acceptable excipient.
The present invention provides an advantage for preparing a unique controlled
release
pharmaceutical formulation of tolterodine (extended release) capsules from a
drug layering process
which allows one to obtain an unique controlled release dosage form which is
suitable for the
treatment of urinary incontinence due to overactive bladder and diminishes the
food effect when
administered to a patient that has eaten.
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CA 02795893 2012-11-16
Furthermore, the present invention particularly provides a more conventional
manufacturing
process, which is less time consuming, is very simple and can be easily
transferred to commercial
manufacturing.
The pharmaceutical composition according to the present invention comprises: a
water insoluble
inert core, which is preferably microcrystalline cellulose, and a first layer
disposed over the inert
core comprising a hydrophilic film coating polymer which is selected from the
group consisting of:
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose ethers,
povidone, and
copovidone or a combination comprising at least one of the foregoing polymers.
Preferably, the hydrophilic film coating polymer in the first layer of the
said pharmaceutical
composition is hydroxypropyl cellulose.
Also preferably, the amount of the film coating polymer in the first layer
ranges from about 2% to
about 20% w/w of the controlled-release composition. More preferably the
amount of the film
coating polymer in the first layer ranges from about 2% to about 5% w/w of the
controlled-release
composition.
Preferably, the active pharmaceutical 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.
And more preferably, the active ingredient is tolterodine tartrate.
Preferably, the active ingredient, such as tolterodine or a pharmaceutically
acceptable salt thereof,
is present in a weight to weight ratio to binder in the second layer from
about 1:5 to about 1:10.
The pharmaceutical composition of the present invention, in addition to the
active ingredient,
contains pharmaceutically acceptable excipients added to the composition for a
variety of
purposes. At least one pharmaceutically acceptable excipient may be present in
the composition of
the present invention, such as for example diluents, binders, lubricants,
disintegrants, glidants, and
acidifying agents. As understood by a person skilled in the art, these
excipients are conventional
excipients which are well known in the pharmaceutical art.
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CA 02795893 2012-11-16
Preferably, the binder in the second layer is selected from the group
consisting of: hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl
cellulose, hydroxyethyl
cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose,
polyvinyl pyrrolidone,
polyethylene glycol, polyvinyl alcohol, polymethacrylates, and a combination
thereof.
More preferably, the binder in the second layer is hydroxypropyl cellulose and
the amount of the
binder in the second layer ranges from about 20% to about 30% w/w of the
controlled-release
composition.
The pharmaceutical composition according to the present invention comprises a
pH-independent
control release polymer in the third layer which is selected from the group
consisting of: ethyl
cellulose, ammonialkyl methacrylate copolymers, methacrylate copolymers, and
combinations
thereof.
Preferably, the pH-independent control release polymer of the third layer is
ethyl cellulose, and the
amount of the control release polymer in the third layer ranges from about 3%
to about 15% w/w
of the controlled-release composition. More preferable the amount of ethyl
cellulose ranges from
about 3% to about 5% w/w of the said composition.
In addition to the control release polymer, the third layer of the said
pharmaceutical composition
contains at least one pharmaceutically acceptable excipient. Preferably, at
least one
pharmaceutically acceptable excipient is selected from the group consisting
of: hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, methyl
cellulose, hydroxyethyl
cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose,
polyvinyl pyrrolidone,
polyethylene glycol, polyvinyl alcohol, polymethacrylates, and a combination
thereof.
More preferably, the hydrophilic polymer in the third layer is hydroxypropyl
cellulose and the
amount of said excipient ranges from about 0.4% to about 2% w/w of the
controlled-release
composition. More preferably, the amount of hydroxypropyl cellulose in the
third layer ranges
from about 0.4% to about 0.6% w/w of the said composition.
The pharmaceutical composition according to the present invention comprises an
enteric coating
polymer in the fourth layer which is selected from the group consisting of:
ammonialkyl
methacrylate copolymers, methacrylate copolymers, and combinations thereof.
Preferably, the
enteric coating polymer of the fourth layer is Eudragit L3OD 55 . More
preferably, the amount of
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CA 02795893 2012-11-16
the enteric coating polymer in the fourth layer ranges from about 0.5% to
about 5% w/w of the
controlled-release composition.
Preferably, the third and fourth layers comprise a plasticizer, and more
preferably, the plasticizer is
selected from the group consisting of: diethyl phthalate, dibutyl
phthalate,dibutyl sebacate,
tributyl citrate, triethyl citrate, acetyl tributyl citrate, castor oil,
mineral oil, glyceryl monostearate,
and a combination thereof.
More preferably, the plasticizer in the third and in the forth layers is
triethyl citrate and wherein
the amount of the plasticizer in the third layer ranges from about 0.4% to
about 2% w/w and in the
fourth layer ranges from about 0.2% to about 2% w/w of the controlled-release
composition.
Oral dosage forms which may be employed with the present invention include
granules, spheroids
or pellets in a capsule or in any other suitable solid form. Preferably,
however the oral dosage form
is a capsule.
In a preferred embodiment of the invention, the oral controlled release
composition comprises
contains a 4 mg dose of tolterodine tartrate.
The controlled release composition can be manufactured in accordance with
conventional
techniques in which the first layer of hydrophilic polymer is applying to non
pareils (MCC beads),
then applying onto first layer, a second layer comprising the active
ingredient, such as tolterodine
tartrate, and hydroxypropyl cellulose as binder; then applying onto the second
layer, a third pH-
independent polymer layer effective for controlled release of the active
ingredient, wherein the
polymer used is to control the release is ethylcellulose; and applying over
the third layer, a fourth
layer effective for controlled release of the active ingredient, herein the
polymer used is to control
the release is Eudragit 30D 55 .
According to an aspect of the present invention, the process for the
manufacturing of a controlled-
release pharmaceutical composition comprising: an inert core, an active
ingredient, a hydrophilic
film coating polymer, a pH-independent controlled release polymer, an enteric
coating polymer
and at least one pharmaceutically acceptable excipient, wherein said process
comprises following
steps:
1. Manufacturing process of 1st layer:
a) adding hydroxypropyl cellulose into purified water;
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CA 02795893 2012-11-16
b) mixing continuously the prepared mixture until a clear solution is
obtained;
c) spraying obtained solution over microcrystalline cellulose spheres (also
known as beads)
using a fluid bed bottom spray unit.
2. Manufacturing process of 2nd layer:
a) adding the active ingredient, such as Tolterodine L- Tartrate, to purified
water
b) mixing continuously prepared mixture until a clear solution is obtained
solution (#1);
c) adding hydroxypropyl cellulose and colloidal silicon dioxide to purified
water in a
separate suspension ( #2);
d) mixing mixture until a suspension is obtained (#2).
e) mixing solution (#1) and suspension (#2) together for at least 30 minutes,
thereby
forming mixture (#3).
f) spraying mixture (#3) over MCC coated spheres of the 1st layer using a
fluid bed coater
equipped with bottom spray unit.
3. Manufacturing Process of 3rd layer
a) adding hydroxypropyl cellulose to dehydrated alcohol.
b) mixing continuously mixture until a clear solution is obtained (#1);
c) adding ethylcellulose 20cps, colloidal silicon dioxide and triethyl citrate
to solution (#1),
thereby forming suspension (#2);
d) mixing suspension (#2) continuously for at least 30 minutes;
e) spraying suspension (#2) over the coated beads of the 2nd layer using,
fluid bed coater
equipped with bottom spray unit.
4. Manufacturing Process of 4th layer
a) adding Triethylcitrate to talc to purified water while continuously mixing;
b) mixing continuously mixture until a clear solution is obtained (#1);
c) adding Eudragit L3OD 55 to mixture (#1)
d) continuously stirring, thereby forming mixture (#2);
e) spraying mixture (#2) over the coated beads of the 3rd layer using, fluid
bed coater
equipped with bottom spray unit.
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CA 02795893 2012-11-16
The following examples illustrate the preferred embodiments and various
aspects of the present
invention and are not be considered as limiting the invention in any way.
Example 1. FORMULATION AND METHOD OF PRODUCING A CONTROLLED-RELEASE
COMPOSITION FOR TOLTERODINE EXTENDED RELEASE CAPSULES.
Manufacturing process of 1st layer:
The required quantity of hydroxypropyl cellulose is added into purified water
and continuously
mixed until a clear solution is obtained (solution #1). This solution (#1) is
sprayed onto
microcrystalline cellulose spheres (also known as beads) using a fluid bed
bottom spray unit.
Manufacturing process of 2nd layer:
The required quantity of Tolterodine L-Tartrate is added to purified water and
continuously mixed
until a clear solution is obtained (solution #1). Preparing binding solution
adding hydroxypropyl
cellulose and colloidal silicon dioxide to purified water, continuously mixing
until a suspension is
obtained (suspension #2). Solution (#1) and suspension (#2) are then mixed
together for at least 30
minutes, thereby forming mixture (#3). Mixture #3 is sprayed onto the MCC
coated spheres of the
1st layer using a fluid bed coater equipped with bottom spray unit.
Manufacturing Process of 3rd layer:
The required quantity of hydroxypropyl cellulose is added to dehydrated
alcohol and continuously
mixed until a clear solution is obtained (solution #1). Ethylcellulose 20cps,
colloidal silicon dioxide
and triethyl citrate are added to solution (#1), thereby forming suspension
(#2), which is
continuously mixed for at least 30 minutes before using it. Suspension (#2) is
then sprayed onto
coated beads of the 2nd layer using fluid bed coater equipped with bottom
spray unit.
Manufacturing Process of 4th layer:
The required quantity of triethylcitrate is added to talc and continuously
mixed with purified water
until a clear solution is obtained (solution #1). Eudragit L3OD 55 is added
to solution (#1) while
continuously stirring, thereby forming suspension (#2). Suspension (#2) is
then sprayed onto
coated beads of the 3rd layer using, fluid bed coater equipped with bottom
spray unit.
The formulation of Example 1 is set out in Table 1 below.
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CA 02795893 2012-11-16
Table 1. The formulation of Example 1 for a controlled-release composition.
1st LAYER COMPOSITION: seal coating-performed on non pareils (MCC beads)
No. Description mg/capsules
A (w/w)
1 MCC-Spheres 72.73
53.76
2 Hydroxypropylcellulose-Type-L 5.09
3.76
3 Colloidal Silicon Dioxide 2.18
1.61
4 Dehydrated alcohol -
-
Sub-total 80.0
-
2nd LAYER COATING: drug layering performed on 1st layer coated beads
No. Description mg/capsules
%(w/w)
1 Tolterodine-L-Tartrate 4.0
2.96
2 Hydroxypropyl cellulose- Type- 28.0
20.7
L
3 Colloidal silicon dioxide 8.4
6.21
- 4 Purified water -
-
Sub-total 120.4
-
3rd LAYER COATING: controlled release coating- performed on 2nd layer coated
beads
No. Description mg/capsules
4)/0(w/w)
1 Ethylcellulose 20cps 5.50
4.07
2 Colloidal Silicon dioxide 1.41
1.04
3 Hydroxypropyl Cellulose Type- 0.82
0.61
L
4 Tr-ethyl Citrate 0.69
0.51
5 Dehydrated Alcohol -
-
Sub-total 128.82
-
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CA 02795893 2012-11-16
4th LAYER COATING: enteric polymer coating-coating performed on 3rd layer
coated beads.
No. Description mg/capsules "/0(w/w)
1 Methacrylic acid Copolymer 3.169 2.34
2 Triethyl citrate 0.381 0.28
3 Talc LM 2.898 2.14
4 Purified water
S.Total 135.27 100
6 Capsules size 3 white opaque 48.0
Total 183.27
DISSOLUTION DATA FOR EXAMPLE 1
The pharmaceutical composition obtained from above mentioned Example 1 was
subsequently
tested for in vitro dissolution rate, measured by USP Type 1 Apparatus
(rotating basket), using the
5 following parameters:
Basket speed - 100 rpm
Media - pH 6.8 phosphate buffer
Dissolution medium - 900m1
Temperature - 37 C
Time -1, 3, 7 and 11 hrs.
The dissolution results are set out in Table II below.
Table II. DISSOLUTION DATA
No. Time (hrs) Example 1 (%)
1 1 5
2 3 40
3 7 78
4 11 90
Example 2. THE FORMULATION FOR A CONTROLLED-RELEASE COMPOSITION.
The procedure of the above Example 1 is followed in this example, wherein the
present example is
controlled-release pharmaceutical composition of tolterodine without the 4th
enteric polymer
coating.
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CA 02795893 2012-11-16
The formulation of Example 2 is set out in Table III below.
TABLE III: Example 2
1st LAYER COMPOSITION: seal coating-performed on non pareils (MCC beads)
No. Description mg/capsules %(w/w)
1 MCC-Spheres 72.73 53.76
2 Hydroxypropylcellulose-Type-L 5.209 3.76
3 Colloidal Silicon Dioxide 2.18 1.61
4 Dehydrated alcohol - -
Sub-total 80.0 -
2" LAYER COATING: drug layering performed on 1st layer coated beads
No. Description mg/capsules %(w/w)
1 Tolterodine-L-Tartrate 4.0 2.96
2 Hydroxypropyl cellulose- Type- 28.0 20.70
L
3 Colloidal silicon dioxide 8.4 6.21
4 Purified water - -
Sub-total 120.38 -
3rd LAYER COATING: controlled release coating- performed on 2nd layer coated
beads
No. Description mg/capsules %(w/w)
1 Ethylcellulose 20cps 5.50 4.07
2 Colloidal Silicon dioxide 1.41 1.04
3 Hydroxypropyl Cellulose Type- 0.82 0.61
L
4 Tr-ethyl Citrate 0.69 0.51
5 Dehydrated Alcohol - -
Sub-total 128.80 -
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CA 02795893 2012-11-16
4th LAYER COATING: enteric polymer coating-coating performed on 3rd layer
coated beads.
No. Description mg/capsules /0(w/w)
1 Methacrylic acid Copolymer
2 Triethyl citrate
3 Talc LM
4 Purified water
Capsules size 3 white opaque
Total 128.80
The pharmaceutical composition obtained from above mentioned Example 2(without
enteric
polymer coating) was subsequently tested in a bioequivalence study performed
against DETROL
LA , wherein said composition provides maximum plasma concentrations (Cmax)
T/R ratioof
about 246% and AUCt T/R ratio of about 140.8 % (with 90 % confidence
interval).
The bioequivalence study data of Example 2 is set out in Table IV below.
Table IV. BIOEQUIVALENCE FED STUDY DATA - T/R RATIOS
No. DESCRIPTION NO ENTERIC COAT
1 Cmax 246.2%
2 AUCt 140.8%
Example 3. FORMULATION FOR A CONTROLLED-RELEASE COMPOSITION OF
TOLTERODINE CAPSULES.
The procedure of manufacturing of the above Example 1 is followed in this
example, wherein the
present example is controlled-release pharmaceutical composition of
tolterodine tartrate coated
with about 6 % w/w enteric polymer coating performed on 3rd layer coated
beads.
The formulation of Example 3 is set out in Table V below.
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CA 02795893 2012-11-16
TABLE V: Example 3.
1st LAYER COMPOSITION: seal coating-performed on non pareils (MCC beads)
No. Description mg/capsules A (w/w)
1 MCC-Spheres 72.73 53.76
2 Hydroxypropylcellulose-Type-L 5.209 3.76
3 Colloidal Silicon Dioxide 2.18 1.61
4 Dehydrated alcohol - -
Sub-total 80.0 -
2" LAYER COATING: drug layering performed on 1st layer coated beads
No. Description mg/capsules 1)/0(w/w)
1 Tolterodine-L-Tartrate 4.0 2.96
2 Hydroxypropyl cellulose- Type-28.0 20.70
L
3 Colloidal silicon dioxide 8.4 6.21
4 Purified water - -
Sub-total 120.38 -
3rd LAYER COATING: controlled release coating- performed on 2nd layer coated
beads
No. Description mg/capsules A (w/w)
1 Ethylcellulose 20cps 5.50 4.07
2 Colloidal Silicon dioxide 1.41 1.04
3 Hydroxypropyl Cellulose Type-0.82 0.61
L
4 Tr-ethyl Citrate 0.69 0.51
Dehydrated Alcohol - -
Sub-total 128.80 -
4th LAYER COATING: enteric polymer coating-coating performed on 3rd layer
coated beads.
No. Description mg/capsules A (w/w)
1 Eudragit L3OD 558 5.42 3.97
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CA 02795893 2012-11-16
4th LAYER COATING: enteric polymer coating-coating performed on 3rd layer
coated beads.
No. Description mg/capsules (w/w)
2 Triethyl citrate 1.65 1.20
3 Talc LM 0.65 0.47
4 Purified water
Total 136. 52
The pharmaceutical composition obtained from above mentioned Example 3 (with
about 6 % w/w
enteric polymer coating performed on 3rd layer coated beads) was subsequently
tested in a
bioequivalence study performed against DETROL LA , wherein said composition
provides
maximum plasma concentrations (Cmax) T/R ratio about 51% and AUCt T/R ratio
about 63.8 %
(with 90 % confidence interval).
The bioequivalence study data of Example 3 is set out in Table VI below.
Table VI. BIOEQUIVALENCE FED STUDY DATA - T/R RATIOS
No. Description About 6% (w/w) enteric coat
I.Cmax 51.0%
2 AUCt 63.8%
Example 4 FORMULATION FOR A CONTROLLED-RELEASE COMPOSITION OF
TOLTERODINE CAPSULES.
The procedure of manufacturing of the above Example 1 is followed in this
example, wherein the
present example is controlled-release pharmaceutical composition of
Tolterodine tartrate coated
with about 4 % w/w enteric polymer coating performed on 3rd layer coated
beads.
The formulation of Example 4 is set out in Table VII below.
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CA 02795893 2012-11-16
TABLE VII: Example 4.
1st LAYER COMPOSITION: seal coating-performed on non pareils (MCC beads)
No. Description mg/capsules % (w/w)
1 MCC-Spheres 72.73 53.76
2 Hydroxypropylcellulose-Type-L 5.209 3.76
3 Colloidal Silicon Dioxide 2.18 1.61
4 Dehydrated alcohol
Sub-total 80.0
2nd LAYER COATING: drug layering performed on 1st layer coated beads
No. Description mg/capsules %(w/w)
1 Tolterodine-L-Tartrate 4.0 2.96
2 Hydroxypropyl cellulose- Type-28.0 20.70
3 Colloidal silicon dioxide 8.4 6.21
4 Purified water
Sub-total 120.38
3rd LAYER COATING: controlled release coating- performed on 2nd layer coated
beads
No. Description mg/capsules % (w/w)
1 Ethylcellulose 20cps 4.48 3.38
2 Colloidal Silicon dioxide 1.15 0.87
3 Hydroxypropyl Cellulose Type-0.67 0.50
4 Tr-ethyl Citrate 0.56 0.42
Dehydrated Alcohol
Sub-total 127.24
5
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CA 02795893 2012-11-16
4th LAYER COATING: enteric polymer coating-coating performed on 3rd layer
coated beads.
No. Description mg/capsules (w/w)
1 Eudragit L3OD 55 2.138 1.61
2 Triethyl citrate 2.949 2.22
3 Talc LM 0.257 0.19
4 Purified water
Total 132.584
The pharmaceutical composition obtained from above mentioned Example 4 (with
about 4 % w/w
enteric polymer coating performed on 3rd layer coated beads) was subsequently
tested in
Bioequivalence study performed against DETROL LA , wherein said composition
provides
maximum plasma concentrations (Cmax) T/R ratio about 135 % and AUCt T/R ratio
about 129 %
(with 90 % confidence interval).
The bioequivalence study data of Example 4 is set out in Table VIII below.
Table VIII. BIOEQUIVALENCE FED STUDY DATA - T/R RATIOS
No. Description About 4 A (w/w) enteric coat
Cmax 135.0 %
2 AUCt 129.0 %
Example 5 FORMULATION FOR A CONTROLLED-RELEASE COMPOSITION OF
TOLTERODINE LA CAPSULES - COMPARATIVE STUDY
The procedure of manufacturing of the above Example 1 is followed in all these
examples, wherein
the present example is comparative study of the controlled-release
pharmaceutical composition of
tolterodine tartrate capsules (4mg).
The results of comparative study on those formulations are set out in Table IX
below.
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CA 02795893 2012-11-16
TABLE IX: Example 5.
1st LAYER COMPOSITION: seal coating-performed on non pareils (MCC beads)
No. Description No enteric coat, 6% (w/w) enteric 4.2 % (w/w)
enteric
mg/caps. coat, mg/caps. coat, mg/caps.
1 MCC-Spheres 72.73 72.73 72.73
2 Hydroxypropylcellulose-Type- 5.209 5.209 5.209
3 Colloidal Silicon Dioxide 2.18 2.18 2.18
4 Dehydrated alcohol
Sub-total 80.0 80.0 80.0
2nd LAYER COATING: drug layering performed on 1st layer coated beads
No. Description No enteric coat, 6% (w/w) enteric 4.2
/0(w/w)enteric
mg/ caps. coat, mg/caps. coat, mg/caps.
1 Tolterodine-L-Tartrate 4.0 4.0 4.0
2 Hydroxypropylcellulose-Type- 28.0 28.0 28.0
3 Colloidal silicon dioxide 8.4 8.4 8.4
4 Purified water
Sub-total 120.38 120.38 120.38
3rd LAYER COATING: controlled release coating- performed on 2nd layer coated
beads
No. Description No enteric coat, 6%(w/w) enteric 4.2 A) (w/w)
enteric
mg/ caps. coat, mg/caps. coat, mg/caps.
1 Ethylcellulose 20cps 5.5 5.5 4.48
2 Colloidal Silicon dioxide 1.41 1.41 1.15
3 itlydroxypropylcellulose Type- 0.82 0.82 0.67
4 Tr-ethyl Citrate 0.69 0.69 0.56
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CA 02795893 2012-11-16
3rd LAYER COATING: controlled release coating- performed on 2nd layer coated
beads
No. Description No enteric coat, 6 /0(w/w) enteric 4.2 % (w/w)
enteric
mg/caps. coat, mg/caps. coat, mg/caps.
Dehydrated Alcohol
Sub-total 128.80 128.80 127.24
4th LAYER COATING: enteric polymer coating-coating performed on 3rd layer
coated beads.
No. Description No enteric coat, 6% (w/w) enteric 4.2 % (w/w)
enteric
mg/caps. coat, mg/caps. coat, mg/caps.
1 Eudragit L3OD 55 5.42 2.138
2 Triethyl citrate 1,65 2. 949
3 Talc LM 0.65 0. 257
4 Purified water
Total 128.80 136.52 132. 584
The pharmaceutical composition obtained from above mentioned Examples was
subsequently
5 tested in a bioequivalence study performed against DETROL LA , wherein
said composition
provides maximum plasma concentrations (Ct.) T/R ratio from about 50% to about
135% and
AUCt T/R ratio from about 60 % to about 125 % (with 90 % confidence interval).
The bioequivalence comparative study data is set out in Table X below.
Table X. BIOEQUIVALENCE COMPARATIVE FED STUDY DATA - T/R RATIOS
No. Description No enteric coat 6% (w/w). 4.2%(w/w)*
enteric coat enteric coat
1 Cmax 246.2% 51.0% 135%
2 AUCt 140.8% 63.8% 129%
"Along with percentage change, the coating compositions were also different.
The bioequivalence summary of main study results on Tolteraodine L-Tartrate
extended release
capsules 4 mg (Fed) is set out in Table XI below.
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CA 02795893 2012-11-16
Table XI. SUMMARY OF THE MAIN STUDY RESULTS ON BIOEQUIVALENCE
TOLTERODINE L-TARTRATE LA CAPSULES 4 MG (FED)
PARAMETER MEAN TEST C.V. (%) MEAN C.V.
CYOREFERENCE
Cmax (pg/mL) 2864.583 41.3
2077.000 22.0
in (Cmax) 7.960 3.7 7.639
3.1
Tmax (hours) * 4.50 12.5
5.00 27.6
AUCT (pg h/mL) 28215.213 50.0
24964.825 51.8
In (AUCT) 10.248 3.9
10.125 3.9
AUCF (pg =h/mL) 28423.363 49.6
25477.133 49.6
In (AUC.) 10.255 3.9
10.146 3.9
AUCT/ E (%) 99.110 0.5
96.819 5.3
Kei (hours-1) 0.132 23.5
0.123 24.6
Ty,ei (hours) 5.467 22.7
5.945 26.2
* median is presented
30
