Note: Descriptions are shown in the official language in which they were submitted.
CA 02524422 2005-10-25
TITLE: A GASTRIC RETENTION DRUG DELIVERY SYSTEM
The present invention relates to a gastric retention drug delivery system
(i.e. a
controlled release drug dosage form ) which is formulated so as to promote
retention
of the dosage form in the upper gastrointestinal tract and in particular the
stomach.
Such a dosage form may be useful for many medicinal products, for example for
site
specific delivery in the upper gut to treat local pathology in the stomach
and/or to
allow a less frequent administration: i.e. once a day instead of twice a day,
or twice a
day instead of 3 times a day.
Gastro-retentive dosage forms are known for releasing a drug into for example
at least
a portion of a region defined by the stomach and the upper gastrointestinal
tract. It is
generally known that the location of an orally administered controlled drug
delivery
system in the stomach and the gastrointestinal tract as well as the rate at
which a
controlled drug delivery system moves from the stomach to the colon may be
factors
that need to be considered in the design of an oral controlled drug delivery
system. It
is thus known that a prolonged period of retention of the system in the
stomach for
example may be beneficial for various types of drugs, i.e. gastric retention
systems
may for example be beneficial when the drug to be administered is most
effectively
absorbed locally in the stomach.
One known approach that has been suggested for achieving gastric retention
involves
using a composition containing highly swellable polymers (i.e. swellable
matrices) in
admixture with a gas-generating agent to form in situ (i.e. in the stomach), a
system
that is large in size as well as capable of floating on gastric fluids (see
for example
Canadian patent application no. 2452738, the entire contents of which is
incorporated
herein by reference). Dosage forms containing swellablc polymers in admixture
with
a gas-generating agent will float on gastric fluids because the gas generated
and
entrapped within the dosage form decreases the density of the dosage form. It
is also
known to manipulate the initial size and as well as the composition of an
expandable
drug dosage form so that it is able to swell in the stomach to a larger size,
the larger
size being a size which will promote the desired retention of the system in
the
stomach; such systems should be capable of retaining this size in the gastric
fluids for
sufficiently long periods under agitation conditions created by gastric
motility. (see
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CA 02524422 2005-10-25
also U.S. Pat. No. 5,232,704; U.S. Pat. No. 6,120,803; U.S. Pat. No.
4,996,058;
and U.S. Pat. No. 5,972,389: the entire contents of all of which are
incorporated
herein by reference).
It is in particular also known to use hydroxypropyl cellulose (HPC) and
hydroxypropyl methylcellulose (HPMC) as components for various types of dosage
forms; see for example, US Pat. No 4871548, US Pat. No 6861072, US Pat. No
6077538, US Pat. No 4915952, US Pat. No 6090411, US Pat. No 5593694 as
well as US Pat. No 6861072and Canadian Patent Application no. 2464322; the
entire
contents of all of which are incorporated herein by reference.
Notwithstanding the known gastric retention systems, such as those described
in the
above mentioned patent documents, it would be advantageous to have an
alternative
means of administering a therapeutically effective amount of a drug(s) to a
patient in
need thereof, in a gastric retained dosage form. Thus, the search still goes
on for
alternate swellable matrices comprising a gas generating component for use as
part of
gastro-retentive dosage forms; in particular swellable matrices comprising a
gas
generating component which have good swelling characteristics e.g. a good
sweallable matrix is one which is able to swell to up to 140 % or more of its
original
volume within one-half hour after administration, and maintain and/or increase
such
swelled volume (as well as its integrity) for a desired or necessary time
period
thereafter (for 2 to 4 hours thereafter or longer).
SUMMARY OF THE INVENTION
Thus, in general the present invention provides a dosage form which comprises
a
hydrophilic swellable matrix component which is intermingled with both a
pharmaceutically active component and a pharmaceutically acceptable gas
generating
component (i.e. a gas component able to generate a pharmaceutically acceptable
gas
in the stomach).
The present invention in particular relates to dosage forms that are
relatively easy to
manufacture and that are able to deliver a pharmaceutically active component
(e.g.
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CA 02524422 2005-10-25
one or more drugs and/or pro-drugs) in a controlled release manner to the
upper
gastrointestinal tract and in particular the stomach. A pro-drug is a
pharmacological
substance (e.g. drug) which is administered in an inactive (or significantly
less active)
form; once administered, the pro-drug is metabolised in the body (in vivo)
into the
active compound. Stated in another way, a pro-drug is an inactive precursor of
a
drug, converted into an active form in the body by normal metabolic processes.
The present invention more particularly relates to the realisation that a
satisfactory
controlled release dosage form may be formulated by exploiting a gas
generating
component in conjunction with a swellable matrix component provided that two
conditions are met. Firstly, the swellable matrix component must be a
combination of
only hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC).
Secondly, the swellable matrix must comprise specific amounts of hydroxypropyl
cellulose (HPC) and of hydroxypropyl methylcellulose (HPMC) relative to each
other; in particular, the matrix component weight ratio of HPC to HPMC must be
such
that neither the weight amount of HPC nor that of HPMC is below 20% by weight
of
the matrix component as a whole. Thus HPC may make up from 80 to 20 % by
weight of the matrix component while conversely HPMC may make up from 20 to
80% by weight of the matrix component; e.g. if HPC represents 80% by weight of
the
matrix component HPMC represents 20% by weight of the matrix component; if HPC
represents 60% by weight of the matrix component HPMC represents 40% by weight
of the matrix component; if HPC represents 40% by weight of the matrix
component
HPMC represents 60% by weight of the matrix component; if HPC represents 20%
by
weight of the matrix component HPMC represents 80% by weight of the matrix
component; etc..
Accordingly, the present invention provides an oral controlled release
pharmaceutical
dosage form, for releasing a pharmaceutically active component (e.g. a drug)
into the
stomach, said dosage form comprising a combination of
a solid hydrophilic swellable matrix component, and
said pharmaceutically active component intermingled with (i.e. associated
with) said matrix component,
characterized in that
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CA 02524422 2005-10-25
said matrix component consists of a combination of hydroxypropylcellulose and
hydroxypropylmethylcellulose, the weight ratio of hydroxypropylcellulose to
hydroxypropymethylcellulose being from 80:20 to 20:80, (e.g. 70:30 to 30:70,
preferably 60:40 to 40:60), and
said dosage form further comprises a pharmaceutically acceptable gas
generating
component (e.g. a carbon dioxide gas generating component) intermingled with
said
matrix component,
wherein the matrix component and the gas generating component are each
respectively present in an amount whereby upon contact with gastric fluid said
matrix component is able to swell to a larger size for promoting retention of
the
dosage form in the stomach and said gas generating component is able to
generate
sufficient gas (i.e. gas bubbles, e.g. carbon dioxide bubbles ) to promote
flotation of
the dosage form in the stomach for promoting such retention.
The present invention in one aspect provides an oral controlled release
pharmaceutical
dosage form, for releasing a pharmaceutically active component (e.g. a drug )
into the
stomach, said dosage form consisting of a combination of
a solid hydrophilic swellable matrix component, and
said pharmaceutically active component intermingled with (i.e. associated
with) said matrix component,
characterized in that
said matrix component consists of a combination of hydroxypropylcellulose and
hydroxypropylmethylcellulose, the weight ratio of hydroxypropylcellulose to
hydroxypropymethylcellulose being from 80:20 to 20:80,
said dosage form further comprises a pharmaceutically acceptable gas
generating
component (e.g. a carbon dioxide gas generating component) intermingled with
said
matrix component,
and optionally (i.e. as necessary or desired), said dosage form may further
comprise a
pharmaceutically acceptable additive component comprising one or more members
selected from the group consisting of pharmaceutically acceptable lubricants,
diluents,
binders, disintegrants, and glidants,
wherein the matrix component and the gas generating component are each
respectively present in an amount whereby upon contact with gastric fluid said
matrix
component is able to swell to a larger size for promoting retention of the
dosage form
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CA 02524422 2005-10-25
in the stomach and said gas generating component is able to generate
sufficient gas
(i.e. bubbles, e.g. carbon dioxide bubbles) to promote flotation of the dosage
form in
the stomach for promoting such retention.
In accordance with the present invention, the expression "consisting of' is to
be
understood as characterising a component or combination of components (e.g.
the
dosage form itself, the pharmaceutically active component, the matrix
component,
the pharmaceutically active component etc.) as comprising only the specified
element(s) of the combination or component; but does not exclude the possible
presence of minor amounts of another impurity material(s) which may have been
initially associated with one or more starting materials used to formulate the
dosage
form (e.g. tablet) or component thereof. Thus a dosage form or a component
thereof
characterised by the above expression may comprise one or more materials which
may be considered as pharmaceutically acceptable impurities, the impurity(ies)
being
of a kind and being present in an amount(s) which still provides a
pharmaceutical
acceptable drug form or component thereof, i.e. the presence of such other
material(s)
do(es) not adversally affect the function of the drug form components nor the
end use
of the drug form. In other words, a dosage form or a component thereof
characterised
by the above expression is one which conforms to acceptable drug formulation
practice(s), e.g. the above expression characterizes a dosage form or
component
thereof as being at least substantially of the specified materials.
In accordance with the present invention the matrix component of the dosage
form
may comprise a solid monolithic matrix component associated with a
pharmaceutically active (i.e. drug) component and a gas generating component
intermingled therewith. In accordance with the present invention the dosage
form
may have the form of a mono-form body. Thus the dosage form may be a mono-
form (i.e. a monolithic) tablet (e.g. a controlled-release oral drug dosage
form) for
releasing a drug into the stomach.
It is to be understood herein that a mono-form body may be a solid dosage form
such
as a for example a tablet made from a simple blend of components or a tablet
made
from a mixture of granules and non-matrix and non-drug components, the
granules
containing the matrix component, drug component and a gas generating
component.
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It is also to be understood herein that a mono-form body (i.e. tablet) as
contemplated
by the present invention is, a form which is monolithic in nature, i.e. of
essentially
uniform but not necessarily homogeneous make-up or composition. A mono-form
body may thus be a body obtained by compression of a simple powder mixture
comprising a matrix component, a pharmaceutically active component and a gas
generating component in dry powder form or a body obtained by compression of a
mixture of components wherein the mixture comprises granules as well as non-
matrix
and non-drug components in dry powder form, the granules having been obtained
from the dry granulation, wet granulation, compaction or extrusion of a simple
mixture of a matrix component, a pharmaceutically active component and a gas
generating component (e.g. the mono-form body may be a tablet made-up of a
single
essentially uniform body (e.g. single layer)).
It is to be understood herein that a mono-form body, such as for example a
(mono-
form) tablet, as contemplated by the present invention is, unless otherwise
indicated,
a dosage form which is free or essentially free of a (known) functional or non-
functional coating or layer-(i.e. the dosage form is an uncoated or single
layered
dosage form). A functional coating may for example be one which also comprises
an
active pharmaceutical component (i.e. drug).
It is to be understood herein, that if a "class", "range", "group of
substances", etc. is
mentioned with respect to a particular characteristic (e.g., temperature,
weight ratio,
concentration, time, (number average) molecular weight, viscosity, and the
like) of the
present invention, the present invention relates to and explicitly
incorporates herein
each and every specific member and combination of sub-classes, sub-ranges or
sub-
groups therein whatsoever. Thus, any specified class, range or group is to be
understood as a shorthand way of referring to each and every member of a
class,
range or group individually as well as each and every possible sub-class, sub-
range or
sub-group encompassed therein; and similarly with respect to any sub-class,
sub-
ranges or sub-groups therein. Thus, for example, as mentioned herein
- with respect to the weight ratio of HPC:HPMC, the mention of the range of
80:20 to 20:80, is to be understood herein as specifically incorporating each
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CA 02524422 2005-10-25
and every sub-range as well as each individual weight ratio of HPC:HPMC
such as, for example, 70:30 to 30:70, 70:30 to 35:65, 70:30 to 45:55, 65:35
to 35:65, 60:40 to 40:60, 32:68, 45:55, 70:30, etc.;
- the mention that the matrix component comprises from 40% to 98% by
weight of the dosage form is to be understood herein as specifically
incorporating each and every sub-range as well as each individual weight
amount such as for example 45% to 80%, 50 % to 75%, 40%, 49.5%, 50%,
90% etc.;
- mention that the weight ratio of the pharmaceutically active component to
the dosage form (e.g. tablet) may be from 0.05:99.95 to 60:40 is to be
understood herein as specifically incorporating each and every sub-range as
well as each individual weight ratio such as for example ; in particular
1:1.24.
- mention that the gas generating component which comprises at least one
carbon dioxide-generating agent may be present in an amount of from 0.5 to
3% by weight of the dosage form is to be understood herein as specifically
incorporating each and every sub-range as well as each individual weight;
- mention that hydroxypropyl cellulose having a viscosity of from 2
centipoise (cps) to 4000 centipoise(cps) is to be understood herein as
specifically incorporating each and every sub-range as well as each individual
viscosity,
and similarly with respect to any other parameters whatsoever (for example,
molecular weight), etc..
It is in particular to be understood herein that for any group or range, no
matter how
defined, a reference thereto is a shorthand way of mentioning and including
herein
each and every individual member described thereby as well as each and every
possible class or sub-group or sub-class of members whether such class or sub-
class is
defined as positively including particular members, as excluding particular
members
or a combination thereof; for example an exclusionary definition for a formula
may
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CA 02524422 2005-10-25
read as follows: "provided that when one of A and B is -X and the other is Y, -
X may
not be Z".
MATRIX COMPONENT
The weight ratio of hydroxypropylcellulose to hydroxypropymethylcellulose for
the
swellable matrix component may, as mentioned, be from 80:20 to 20:80; in other
words the swellable matrix must contain a minimum amount of each of
hydroxypropylcellulose and hydroxypropymethylcellulose. The weight ratio of
hydroxypropylcellulose to hydroxypropymethylcellulose may, for example, be
from
70:30 to 30:70, from 70:30 to 35:65, and more particularly from 60:40 to
40:60.
The matrix component itself may comprise from 40% to 98% (e.g. 49.5%) by
weight
of the dosage form.
The hydrophilic polymers which are suitable for forming a swellable
hydrophilic
polymer matrix may be chosen from:
hydroxypropyl cellulose having a viscosity of from 2 centipoise (cps) to
4000 centipoise(cps), (e.g. from 2 to 500 cps, from 150 to 400
cps, from 6 to 10 cps) measured as a 2% by weight solution in water 20 C;
hydroxypropyl methylcellulose having a viscosity of from 2.4 centipoise
(cps) to 120,000 centipoise(cps) , (e.g. from 50 to 120,000 cps, from 4000
to 120,000 cps, from 80,000 to 120,000 cps, 100000cps) measured as a 2%
by weight solution in water 20 C;
hydroxypropyl cellulose having a molecular weight (weight averaged) of
from 80,000 to 10,000,000 daltons, (e.g. a molecular weight of from 80,000
to 1,150,000);
hydroxypropyl methylcellulose having a number average molecular weight
(weight averaged) of 10,000 to 1,500,000;
etc..
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The release of pharmaceutically active component (e.g. drug) may be
facilitated by
the use of a relatively low molecular weight hydroxypropylcellulose and
hydroxypropylmethylcellulose provided that the minimum amounts of each of
these
cellulose ethers as specified herein is respected.
HPC grades of varying viscosity and degree of substitutions of hydroxypropyl
groups
may be used. Some representative examples are as follows:
= Different grades of HPC (klucel ) are available from Herculis Incorporatedd
USA with molecular weights of about 80,000 to about 1,150,000; Nisso
HPC types -SSL, -SL, -L, -M, -H with viscosity ranges between 2 to 4000
mPa.s (viscosity of aqueous solution containing 2% by weight of dry HPC at
C) and other commercially available grades.
15 = Hydroxy propyl cellulose - low substituted of different grades such as LH-
11,
LH-21, LH-3 1, LH-22, LH-32, LH-20, LH-30 and other available commercial
grades from Shin-Etsu Chemicals Japan.
=
HPMC grades of varying viscosities and degree of substitution such as HPMC-
2208,
20 HPMC-2906, HPMC-2910. Some representative examples include Methocel from
Dow Chemicals USA with viscosity ranges between about 4 to 120000 mPa.s
(viscosity of 2% w/v aqueous solution at 20 C)
GAS GENERATING COMPONENT
A gas generating component may be intermingled with the matrix component in
any
manner whatsoever keeping in mind the purpose thereof (i.e. a gas generating
component may, for example, be dispersed in the matrix component). As
mentioned
the gas generating component is present in an amount whereby upon contact with
gastric fluid said gas generating component is able to generate sufficient gas
(i.e. gas
bubbles, e.g. carbon dioxide bubbles ) to promote flotation of the dosage form
in the
stomach for promoting retention of the dosage form in the stomach. The
function of
the gas generating component is thus to form gas in situ (i.e. in the stomach)
in the
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CA 02524422 2005-10-25
form of gas bubbles in the dosage form (i.e. relative to the matrix
component). These
gas bubbles contribute toward the expansion of the matrix component by gas
inflation.
These gas bubbles also contribute toward the flotation of and then maintenance
of the
dosage form at the surface of the liquids contained in the stomach. The
floatation of
the dosage form may thus increase the gastric residence time (i.e. promote
residence
in the stomach) of the dosage form (e.g. tablet) and result in a relatively
prolonged
release of the drug in the acidic environment. In addition, the floatability
of the
dosage form may enhance the total mean gastrointestinal residence time and
allow for
increased drug bioavailability.
A gas generating component may comprise at least one gas generating agent.
Such
agents, including mixtures of agents, may, for example, be selected from among
substances capable of releasing pharmaceutically acceptable gases such as for
example carbon dioxide or nitrogen; gas generating agents may for example be
selected from among pharmaceutically acceptable mono- and di-basic salts of
carbonic acid, ammonium carbonate and sodium azide.
A gas generating component which is suitable in a pharmaceutical composition
according to the invention may for example comprise at least one carbon
dioxide-
generating agent. The carbon dioxide-generating agent(s) may be an alkali
metal
carbonate, an alkaline-earth metal carbonate, (such as calcium carbonate), or
an alkali
metal bicarbonate (preferably sodium bicarbonate).
In accordance with the present invention, the amount of intermingled gas
generating component (i.e. intermingled with any of the other dosage form
materials
including any granules thereof) is to be chosen keeping in mind the purpose of
the
dosage form herein, namely, to provide an oral controlled release
pharmaceutical
dosage form, for releasing a drug into the stomach. A gas generating component
may
comprise, for example, from 0.5 to 3% by weight of the dosage form; the dosage
form
may comprise lesser or greater amounts of gas generating component depending
on
the amount and/or nature of the other dosage form components and may be
determined empirically keeping in mind the purpose thereof. In particular a
gas
generating component may be one which comprises at least one carbon dioxide-
CA 02524422 2005-10-25
generating agent which may be present in an amount of from 0.5 to 3% by weight
of
the dosage form.
In accordance with the present invention all of the gas generating component
may be intermingled with the matrix component and the pharmaceutically active
component (along with any other desired or necessary materials), i.e. for
example,
from 0.5 to 3% by weight (of the dosage form) of gas generating component may
be
intermingled with the matrix component and the pharmaceutically active
component
(along with any other desired or necessary materials), and the obtained blend
compressed into tablets.
As an alternative, (i.e. as desired or necessary) a portion of the gas
generating
component may be intermingled (i.e. as an intragranule addition) with the
matrix
component and the pharmaceutically active component (along with any other
desired
or necessary intragranule materials) to form an intermediate blend; granules
may be
formed from the intermediate blend; and the remaining portion of the gas
generating
component may be intermingled (i.e. as an extragranule addition) with such
granules
(along with any other desired or necessary materials) to form a further blend
which
may then be compressed to form tablets. In accordance with this alternative
approach, the amount of the portion of gas generating component used as an
intragranule addition and as an extragranule addition is to be chosen keeping
in mind
the purpose of the dosage form herein, namely, to provide an oral controlled
release
pharmaceutical dosage form, for releasing a drug into the stomach. Thus, for
example, a minimum of 0.1% by weight (of the dosage form) of the gas
generating
component may be added as an intragranule adddition (i.e. while mfg.
granules). In
particular, the gas generating component may, for example be subdivided into
0.5 to
2.0% by weight (of the dosage form) as an intragranule addition and 1.0 to
2.5% by
weight (of the dosage form) as an extragranule addition.
As a further alternative, (i.e. as desired or necessary) the matrix component
and the
pharmaceutically active component (along with any other desired or necessary
intragranule materials) may be intermingled to form an intermediate (non-gas
generating) blend; granules may be formed from the intermediate (non-gas
generating) blend; and the gas generating component may be intermingled (i.e.
as an
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CA 02524422 2005-10-25
extragranule addition) with such granules (along with any other desired or
necessary
materials) to form a further blend which may then be compressed to form
tablets.
If the active drug component is of basic nature, it may, if possible, be
necessary to
adjust the acidic content of the dosage form to facilitate in situ gas
generation. Thus,
a gas generating component may additionally comprise at least one acidic
compound
chosen from the group consisting of monocarboxylic acids, polycarboxylic acids
as
well as partial salts of polycarboxylic acids. Such acidic compounds include
lactic
acid, tartaric acid, maleic acid, malonic acid, malic acid, fumaric acid,
succinic acid,
tartaric acid, ascorbic acid, adipic acid and citric acid and partial salts
thereof, such as
monosodium citrate.
The gas generating component may further include other types of substances
used in
effervescent mixtures. The gas generating component may thus, for example,
comprise sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium
tartrate, sodium ascorbate or sodium citrate. Yeasts which are likewise
capable of
generating carbon dioxide gas (e.g. baker's yeast) may also be used as a gas
source;
in this case the gas generating component may additionally comprise the
necessary
nutrients, for example glucose.
PHARMACEUTICALLY ACTIVE (e.g. DRUG) COMPONENT
The weight ratio of the pharmaceutically active component to the dosage fornl
as a
whole (e.g. tablet form) may be from 0.05:99.95 (for low drug loading
medicaments)
to 60:40 (high drug loading medicaments; for example the weight ratio of
pharmaceutically active component (i.e. drug) to tablet in particular may be
from
1:1.24 to 1:1.5 (e.g. the weight ratio of drug to tablet may be 40:60).
As mentioned above, the pharmaceutically active component is intermingled with
the
matrix component (i.e. the pharmaceutically active component may be dispersed
in
the matrix component). In relation to the matrix component itself, the weight
ratio of
the pharmaceutically active component to the matrix component may be from
0.1:99.9
to 70:30. In particular the weight ratio of drug: matrix component may be
44.6:55.4
(this is same as the ratio of 1:1.24 mentioned above in relation to the tablet
weight).
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In accordance with the present invention a pharmaceutically active component
(e.g. a
drug) is any substance that may be used in the diagnosis of, treatment of,
relief of a
symptom of, or prevention of, an illness, disease or injury, including any
substance
that may be used to modify a chemical process or processes in the body (e.g. a
mammalian body, in particular a human being's body).
The pharmaceutically active component may comprise one or more drugs and/or
one
or more pro-drugs with respect to which it is desired to facilitate retention
in the
gastrointestinal tract e.g. for drug absorption. The dosage form may, for
example, be
used beneficially with any drug having a significant absorption in the upper
gastrointestinal tract. A gastric retained dosage form may be particularly
beneficial
for delivery of a drug wherein the preferred region of absorption is in the
upper
gastrointestinal tract (e.g. in the stomach).
The pharmaceutically active component may, for example, comprise one or more
drugs selected from the group consisting of gabapentin, metformin
hydrochloride,
losartan potassium, sodium valproate, valproic acid, ciprofloxacin base,
ciprofloxacin
hydrochloride, captopril, ranitidine hydrochloride, diltiazem hydrochloride,
acyclovir
etc.; additional representative example drugs may be found in US 6261601, the
entire
contents of which is incorporated herein by reference.
In particular, U.S. Pat. No. 4,087,544, for example, discloses gabapentin (1-
(aminomethyl) cyclohexane acetic acid) and various analogs thereof. Gabapentin
pro-drugs are also described in U.S. Pat. No. 6,683,112. The entire contents
of
these two U.S. patents are incorporated herein by reference.
The gastric retention delivery system of the present invention may be used for
the
delivery of a drug which may have anticonvulsant activity such as, for
example,
gabapentin, an analogue thereof, a pro-drug thereof or a pharmaceutically
acceptable
salt thereof. As used herein, the term "pharmaceutically acceptable salt"
refers to
salts that are physiologically tolerated by a user.
Gabapentin, a water soluble compound is one of the most widely used
antiepileptic
agents used for adjuvant therapy in the treatment of partial seizures with and
without
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secondary generalization in adults with epilepsy. It is absorbed by an active
and
saturable transport system. Therefore, its oral bioavailability is not dose
proportional
i.e. as dose increased, bioavailability decreases. Its bioavailability
decreases from
60% to 34% upon increase in the dose from 900 to 2400 mg/day given in 3
divided
doses. Because of its multiple administrations per day, a missed dose can
result in
fluctuations in plasma levels of gabapentin, which is very critical for any
antiepileptic
drug. Therefore, it is a very good candidate for sustained release dosage form
with
once or twice a day administration.
Gabapentin has appreciable absorption in the upper gastrointestinal tract. A
dosage
form retainable in the stomach may thus be particularly beneficial for
delivery of
gabapentin, i.e. the dosage form would be able to maintain a sustained
presence in the
preferred region of absorption (e.g. in the stomach).
Gabapentin may be used in the free amphoteric form. Pharmaceutically
acceptable
salt forms that retain the biological effectiveness and properties of
gabapentin and are
not biologically or otherwise undesirable may also be used. As used herein,
the term
"gabapentin" if used alone (there being no direct or indirect indication to
the contrary)
is intended to include the compound itself, pro-drugs thereof as well as its
pharmaceutically acceptable salts.
Pharmaceutically acceptable salts may be amphoteric and may be present in the
form
of internal salts. Gabapentin may form acid addition salts and salts with
bases.
Exemplary acids that can be used to form such salts include, by way of example
and
not limitation, mineral acids such as hydrochloric, hydrobromic, sulfuric or
phosphoric acid or organic acids such as organic sulfonic acids and organic
carboxylic
acids. Salts formed with inorganic bases include, for example, the sodium,
potassium,
lithium, ammonium, calcium, and magnesium salts. Salts derived from organic
bases
include, for example, the salts of primary, secondary and tertiary amines,
substituted
amines including naturally-occurring substituted amines, and cyclic amines,
including
isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine,
ethanolamine, 2-dimethyl aminoethanol, tromethamine, lysine, arginine,
histidine,
caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,
glucosamine, N-
alkylglucamines, theobromine, purines, piperazine, piperidine, N-
ethylpiperidine,
14
CA 02524422 2005-10-25
fumarate, maleate, succinate, acetate and oxalate.
Herein after reference will be made to "gabapentin" by way of example only.
ANCILLARY ADDITIVE(S)
Pharmaceutically acceptable glidants, lubricants and other additives such as
are well
known to those of skill in the art, may also be included in the gastric
retained dosage
form, i.e. any such additive(s) may for example be included in the formulation
in an
amount of from 0.01% to 10% of the weight of the dosage form. For example a
glidant is a substance added to the granulation in order for the granules to
flow from a
hopper onto a tablet press to the dies and for consistent and uniform fill. As
used
herein, in relation to other additives, the term "pharmaceutically acceptable"
characterises the additive compounds as compounds that are compatible with the
other
ingredients in a pharmaceutical formulation and not injurious to the subject
when
administered in therapeutically effective amounts.
A dosage form of the present invention (i.e. a sustained release tablet) may
for
example optionally contain a pharmaceutically acceptable additive component
comprising one or more members selected from the group comprising (e.g.
consisting
of)
a lubricant or anti-adherent (such as, for example, magnesium stearate sodium
stearyl fumarate, zinc stearate, stearic acid, glyceryl behanate, glyceryl
monostearate,
etc.);
a glidant (such as, for example, talc, colloidal silicon dioxide, or any other
silica etc).;
a binder (such as, for example, polyvinylpyrrolidone (PVP), starch, gelatine,
ethyl celluose sodium carboxy methyl cellulose ) ;
a diluent (such as, for example, lactose, microcrystalline cellulose,
dicalcium
phosphate, sugars such as mannitol, sorbitol etc.) ; and
a disintegrant (such as, for example, Croscarmalose sodium, sodium starch
glycolate, cross linked PVP, starch etc.).
CA 02524422 2005-10-25
In any event, it is to be kept in mind that any such ancillary additive(s), if
present,
is/are of course to be chosen and to be incorporated into the dosage form in
amounts,
keeping in mind the purpose of the dosage form herein, namely, to provide an
oral
controlled release pharmaceutical dosage form, for releasing a drug into the
stomach.
NON-FUNCTIONAL COATING:
The dosage form (i.e. tablet) may be uncoated or may be coated with commonly
used
non-functional aqueous or non-aqueous coating compositions. Examples of
commercially available aqueous coating formulations include Opadry , Opadry II
,
Opadry-AMB etc. (from Colorcon USA) As a representative example, qualitative
composition of Opadry II white YS-22-18096 is provided along with. Opadry II
white
YS-22-18096 contains titanium dioxide, polydextrose, HPMC 2910 (3cP), HPMC
2910 (6cP), HPMC 2910 (50cP), triethyl citrate and PEG 8000. A representative
example of non-aqueous coating composition is as follows: HPC-L, PEG-400,
talc,
titanium dioxide and ethanol. Any pharmaceutically acceptable solvent can be
used in
the non-aqueous coating composition.
DOSAGE FORM PREPARATION
The pharmaceutically active component may for example comprise 40% by weight
of
the dosage form.
A typical dosage form may provide for a drug delivery profile such that
pharmaceutically active component may for example be delivered for at least 2
to 8
hours, and typically over a time period of about 2 to 24 hours. In order to
provide for
sustained delivery, the dosage form may, for example, be formulated such that
at
least 30 to 40 wt % of pharmaceutically active component is retained in the
dosage
form after 1 hour and after about 6-12 hours 40 to 100 wt % of
pharmaceutically
active component has been administered. The dosage form may of course be
formulated for any other desired or necessary drug delivery profile.
The dosage form (e.g. tablet) of the invention may be produced in the
following way:
powders and/or granules are mixed together using the current production
techniques
16
CA 02524422 2005-10-25
Thus as mentioned above a dosage form may be obtained by compression of a
simple
powder mixture comprising a matrix component and a pharmaceutically active
component in dry powder form. A dosage form may as well be obtained by
compression of a mixture of components wherein the mixture comprises non-
matrix
and non-drug components in dry powder form and granules, the granule having
been
obtained from the dry granulation, wet granulation, compaction or extrusion of
a
simple mixture of a matrix component and a pharmaceutically active component
in
dry powder form (e.g _the mono-form body may be a tablet made-up of a single
essentially uniform body (e.g. layer)).
An example composition of a dosage form in accordance with the present
invention
made by wet granulation may be as shown in Table A below:
Table A
Ingredient % Mg/tab
Gabapentin 40 400
H droxy ro l cellulose (LH11) 28.22 282.2
H droxy ro l methyl cellulose K100M CR 21.28 212.8
Povidone K-90 7 70
Sodium bicarbonate 1.5 15
Talc 1 10
Magnesium stearate 1 10
Total 100 1000
Povidone K-90 (PVP): as Binder; Talc: as Glidant & lubricant; Magnesium
stearate:
as Lubricant; LH11 from Shin-Etsu Chemicals Japan and K100M CR from Dow
Chemicals USA
In the drawings which illustrate example embodiments of the present invention
:
Figure 1 is a graph illustrating the dissolution profile of ineformun IR and
SR tablets.
For the following Gabapentin was used in the base form and was from Zambon
Group SpA . Metformin hydrochloride was from Ferico Labs. The
hydroxypropylcellulose (HPC) used here in after was mfg. by Nippon Soda Co.
Ltd.
Based in Japan, namely L-HPC and has viscosity range of 6 to 10 mPa s./ cps
(2%
solution at 20C). The hydroxypropylmethylcellulose used here in after was from
Dow Chemicis Inc. The hydroxypropylmethylcellulose (HPMC) used in was
Methocel K 100M (HPMC chemically) with a nominal viscosity of 100,000 and
range
17
CA 02524422 2005-10-25
of 80,000 to 120,000 mPa.s or centipoises for 2% concentration at 20C Other
grades
available have viscosity range of 2.4 to 120,000 mPa s.
The tablets for the trials reported below in table 1 and identified by lot
numbers 049,
050, 051, 078, 079, 132 were formulated by a dry blend process, namely a
direct
compression. The dry blend process (direct compression process) comprised the
following steps:
1. Gabapentin, HPMC, HPC and sodium bicarbonate were passed through a
no. 20 mesh (US) screen and the obtained screened material was mixed in a
polyethylene bag;
2. Colloidal Si02 was mixed with part of the blend from step 1 and passed
through a no. 20 mesh (US) screen. The obtained screened material was added to
the
blend of step 1 and the whole was mixed in the polyethylene bag;
3. Mg stearate was passed through no. 40 mesh (US)screen, and the obtained
screened material was added to the blend of step 2 and mixed in the
polyethylene bag
to obtain a final blend ready for compression; and
4. The obtained final blend was then compressed into tablets.
The results of swelling studies in Table 1 a suggest that direct compression
process can
be used for preparing Gabapentin SR tablets (herein the initials SR means
"sustained
release").
Table 1: Ratio of HPC: HPMC used in different lots:
Composition (% Lot 049 Lot 050 Lot 051 Lot 078 Lot 079 Lot 132
w t. of tablet)
Gabapentin 40 40 40 40 40 40
L-HPC (Nisso) 50.85 42.37 32.2 42.37 32.2 --
M-HPC (Nisso) -- -- -- -- -- 22.6
HPMC K 100 5.65 14.13 24.3 -- -- 33.9
MCR
HPMC K15 -- -- -- 14.13 24.3 --
MCR
Sodium 1.5 1.5 1.5 1.5 1.5 1.5
bicarbonate
Colloidal Si02 1 1 1 1 1 1
Mg stearate 1 1 1 1 1 1
18
CA 02524422 2005-10-25
HPC: HPMC 90:10 75:25 57:43 75:25 57:43 40:60
ratio
Tablet hardness 7-8.5 kp 7-9 kp 7-8.5 kp 7-9 kp 10 kp 10-12 kp
Table 1 a
Swelling
(% vol. Increase)
0 100% 100% 100% 100% 100% 100%
30 min 112% 145% 151% 123% 142% 152%
2 h 99% 169% 200% 165% 190% 193%
4 h 98.2% 152% 241% 156% 232% 247%
HPC from Nippon Soda, Japan; HPMC from Dow Chemicals USA
As may be seen from the above, the lot 049 wherein the weight ratio of
hydroxypropylcellulose to hydroxypropylmethylcellulose is 90:10 does not
provide a
satisfactory swellable dosage form.
Tablets for a lot no. 155, having the formulation set forth in Table 2 below,
were
made by a Dry granulation process. In the Dry granulation process, a blend of
gabapentin, L-HPC, HPMC K100 MCR, and one third part of the sodium
bicarbonate,
and one half part of the talc and Mg stearate were passed through a roller
compactor
to obtain sheets or ribbons. The sheets or ribbons were passed through a Comil
to
obtain granules; Comil being the brand name of the equipment manufactured by
Quadro Engineering, Canada. The granules had a particle size distribution as
set forth
in Table B below wherein the percentages (unless otherwise indicated) specify
the
percentage by weight of the granules retained on the specified U.S. sieve no.:
Table B:
Sieve NO. (US) % w/w retained
20 3.1%
40 10%
60 3.9%
100 6.8%
200 26.3%
Sieve base (undersize fines) 49.9%
19
CA 02524422 2005-10-25
Extragranular ingredients (i.e. the remaining part of the sodium bicarbonate,
talc and
Mg stearate) were then admixed with the granules in a polyethylene bag or
appropriate blender and the obtained blend compressed by rotary tablet press
to obtain
tablets. More particularly, the Dry granulation process comprised:
step 1. Mix intragranular components viz. gabapentin, L-HPC (LH-11),
HPMC K100MCR, sodium bicarbonate (0.5% by weight of the tablet), talc (0.5% by
weight of the tablet) & Mg stearate (0.5% by weight of the tablet) in a
polyethylene
bag. Pass this mix through the rollar compactor to obtain the sheets or
ribbons.
step 2. Pass the sheets obtained in above step 1 through a Comil
(Quadro Engineering, Canada) to obtain the granules.
Step 3. Pass extragranular components viz, talc (0.5% by weight of the
tablet) and Mg stearate (0.5% by weight of the tablet) each individually
through a no.
40 mesh sieve (US standard) manually.
Step 4. to the granules obtained at step 2, add sodium bicarbonate
(1% by weight of the tablet) and the talc of above step 3, and mix for about 2
min.
Step 5. Add Mg stearate of step 3 to the blend of step 4, and mix
for a short time (e.g. about 30 sec.) to obtain final blend ready for
compression.
The swelling characteristics for the tablets of lot 155 were determined and
are set
forth in Table 2a below.
Table 2
Composition
(% wgt. of tablet)
Gabapentin 40
L-HPC (LH 11) 32.2
HPMC K100 MCR 24.3
Sodium bicarbonate 1.5
Talc 1
Mg stearate 1
HPC: HPMC ratio 57:43
Tablet hardness 6-8 kp
Table 2a
Swelling
(% vol. Increase)
CA 02524422 2005-10-25
0 100%
30 min 158%
2 h 188%
4h 215%
The above results shown in Table 2a of swelling studies of the tablets
prepared by
roller compaction indicate that dry granulation process can also be used to
prepare
gabapentin SR tablets.
Dissolution:
A) Dissolution of gabapentin SR Tablets:
Dissolution test was carried out with Gabapentin tablets made by a wet
granulation process (see below) and which had the composition as set forth in
Table
2b below:
Table 2b
Gabapentin SR tablet
Composition % wgt
of tablet
Gabapentin 40
HPC 28.2
HPMC 21.3
PVP 7
Sodium bicarbonate 1.5
Talc 1
Mg stearate 1
Dissolution method details :
Apparatus - USP apparatus 2 (paddles) from Varian, USA
RPM - 50
Medium - 0.1N HCl
Dissolution results are reported in table 3 below which specifies the
percentage by weight (w/w) of the initial amount of gabapentin released after
the
specified time period:
Table 3
Time % gabapentin released
(h) Gabapentin SR tablet
21
CA 02524422 2005-10-25
1 23
4 50
8 70
B) Dissolution comparison of gabapentin tablets using an alternate dissolution
method:
Dissolution method details:
Apparatus - USP apparatus 1 (baskets) from Varian, USA
RPM - 100
Medium - Deionized water
Dissolution results using alternate dissolution method are given in table 4
below which specifies the percentage by weight (w/w) of the initial amount of
gabapentin released after the specified time period:
Table 4
Time % gabapentin released
(h) Gabapentin SR tablet
1 19
4 38
6.5 48
8 --
Particle size distribution:
Gabapentin SR tablets were made in two lots identified as lots 327 and 332,
each lot
having the formulation set forth in Table 2a above. Each lot was made by a wet
granulation method (see below) using granules having the particle size
distribution set
forth in table 5 below wherein the percentages (unless otherwise indicated)
specify the
percentage by weight of the granules retained on the specified U.S. sieve no.:
22
CA 02524422 2005-10-25
Table 5
U.S. Sieve no (& size) 327 332
# 20 (850 pm) 32.3% 23.5%
# 40 (425 pm) 26.6% 27.1%
# 60 250 m 12.5% 15.2%
# 80 180 m 3.6% 9.8%
# 100 (150 m) 2.0% 3.5%
Sieve base (undersized 22.9% 20.9%
fines)
Particle size distribution may have some impact on the floating behaviour of
tablets;
keeping in mind the purpose of the dosage form herein, namely, to provide an
oral
controlled release pharmaceutical dosage form, for releasing a drug into the
stomach,
the desired or necessary particle size distribution may be determined on an
empirical
basis. In case of lot 327, 3 out of 5 tablets float immediately in 0.1N HCI,
while
remaining 2 tablets float in 5 min. In case of lot 332, all tablets float
immediately in
0.1N HCI.
Exploitation of dosage form using alternate drug, namly, Metformin SR tablets,
500
mg:
Tablets were prepared (by wet granulation method - see below) using metformin
hydrochloride as a the pharmaceutically active component. The 500 mg strength
of
metformin was selected to prepare sustained release (SR) tablets. The weight
ratio of
HPC: HPMC was maintained at 53:47 (same as used for Gabapentin SR). Also the
process as well as tablet weight was kept similar for Gabapentin SR viz. 1000
mg.
The composition of inetformin SR tablets is as follows in Table 6:
Table 6
Composition (% METSRT/001
wgt. of tablet)
Metformin HCl 50
L-HPC (LH11) 23.9
HPMC K100 MCR 18.1
Sodium bicarbonate 1.5
Colloidal Si02 0.5
Mg stearate 1
HPC: HPMC ratio 57:43
Tablet hardness 9-12 kp
23
CA 02524422 2005-10-25
Floating behaviour of the above metformin SR tablets was studied in 0.1N HCI.
2 out
of 5 tablets started floating immediately, additional 2 tablets started
floating in 5 min
and all 5 tablets were floating in 10 min. This indicates that the floating
behaviour is
retained irrespective of the drug used (metformin or gabapentin). The
dissolution of
metformin SR tablets was compared with metformin IR tablets (also prepared by
wet
granulation process - analogous to the process referred to below), i.e. 500 mg
metformin; the initials IR herein mean immediate release. The metformin IR
tablets
had the composition as set forth in table 7 below:
Table 7
Composition (% P-0190
wgt of tablet
Metformin HCL 90.9
Pregelatinized starch 1.0
Croscarmalose 1.0
sodium
Microcrystalline 3.9
cellulose
PVP 1.8
M stearate 1.0
Colloidal Si02 0.4
The details of the dissolution method are as follows:
Medium: pH 6.8 phosphate buffer
Apparatus: USP apparatus 1 (basket)
RPM: 100
The results of dissolution tests for the metformin SR tablets and the
metformin IR
tablets are shown below in Table 8 which specifies the percentage by weight
(w/w) of
the initial amount of metformin dissolved after the specified time period
Table 8:
Metformin IR tablets, 500 mg Metformin SR tablets, 500 mg
Lot no: P-0190 Lot no: METSRT/001
Time min.) % dissolved Time (min) % dissolved
0 0 0 0
10 42.92 60 38
15 73.25 120 53
90.58 240 72
99.83 480 91
45 101.13 620 99
24
CA 02524422 2005-10-25
The dissolution profile of ineformun IR and SR tablets is set forth in Figure
1
The dissolution results show that combination of HPC & HPMC significantly
slowed
the dissolution of metformin providing sustained release behaviour.
Results of biostudy:
The bioavailability of gabapentin SR tablets, 400 mg, made by wet granulation
process (see below) was evaluated in healthy human volunteers. The
pharmacokinetic
parameters for this Study were as follows:
Parameter Mean CV
Cmax 2859 ng/ml 16%
Tmax 6 h 24%
AUCo-48 42397 11%
AUCo_- 42592 11%
wherein
CV = coefficient of variance
Cmax = Peak plasma concentration;
Tmax = Time required to reach peak plasma concentration;
AUCo_48 = the area under the curve in the graph of plasma drug concentration
Versus
Time; The 0-48 signifies the time scale in the graph i.e. 0 to 48 hours;
AUCo- = the area under the plasma concentration versus time curve where the
curve
is
extrapolated to the infinity time point;
Css = Steady state plasma concentration.
The above mentioned pharmacokinetic parameters were compared for immediate
release (IR) Gabapentin tablets, 600 mg; gabapentin capsules, 400 mg; and
gabapentin
SR tablets, 400 mg; slower and sustained plasma levels were estimated.
CA 02524422 2005-10-25
The composition of Gabapentin 400 mg SR tablets, is as given in Table A above;
the
tablets were made by wet granulation process (see below).
The Gabapentin 600 mg IR tablets were made by Wet granulation process
(analogous
to the wet process described below). The composition for 600 mg gabapentin IR
tablets (lot no. P-744) was as follows:
Composition % w/w
Gabapentin 75%
Pregelatinized starch 3%
Croscarmalose sodium 2%
Microcrystalline cellulose 13%
Colloidal Si02 2.5%
PVP 3%
Mg stearate 1.5%
The gabapentin 400 mg capsules were made by Direct blending and filling into
capsules. The composition of gabapentin 400 mg capsules was as follows:
Composition %w/w
Gabapentin 75.2%
Lactose 16.9%
Corn starch 4.9%
Talc 3%
The comparison of pharmacokinetic parameters are shown in Table 9 below:
Table 9
r Dose Dosing Estimated Average Cmax T,,,ax (h) AUC;,,f
interval CSS (ng/ml) (ng/ml) (ng*h/ml)
26
CA 02524422 2005-10-25
400 mg 12 h 3549 2569 6 42592
gabapentin SR
tablets
600 mg 8 h 5280 4178 3 42243
gabapentin IR
tablets
400 mg 8 h 4252 3190 3.42 34023
gabapentin
capsules
These results show that gabapentin SR tablets significantly increased the
T,,,a, of
gabapentin as compared to immediate release tablets and capsule, suggesting
prolonged retention of gabapentin SR tablets in stomach. Also, the AUC for
sustained
release tablets was found to be higher than immediate release tablets and
capsules.
Tablets prepared by Wet granulation Process using isopropyl alcohol
The process involved following steps:
1. Prepare the granulating solution of povidone K-90 in isopropyl alcohol
(6.25%
w/w of PVP K-90 in isopropanol).
2. In a high shear granulator (T.K. fielder from Aeromatic Fielder Ltd. UK),
add
gabapentin, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose
(HPMC) and sodium bicarbonate (1% by weight of the tablet) and perform
granulation using the granulating solution of step 1.
3. Dry the granules of step 2 in fluid bed dryer (from O'Hara Technologies,
Canada) followed by sizing using comil.
4. Mix the extragranular components (i.e. remaining sodium bicarbonate (0.5%
by weight of the tablet) and the talc and magnesium stearate) with the dried
granules of step 3 to obtain the final blend.
5. Compress the final blend of above step on a rotary tablet press (Type-
Colton,
from Vector Corporation USA) with the target weight of 1000 mg and target
hardness of 12 kp.
27
CA 02524422 2005-10-25
Tablets prepared by above Wet process float immediately on water or 0.1 N HCI.
Further the combination of HPMC and HPC-L swells rapidly in 0.1N HCl
increasing
to 150% and 230% of its original size in 30 min and 2 hr, respectively. This
may
prevent escape of tablet through pyloric sphincter, which has a diameter of
12.8 7
mm.
An example composition of a dosage form in accordance with the present
invention
made by the above mentioned wet granulation process may be as follows:
Ingredient % wgt. of Mg/tab
tablet
Gaba entin (base) 40 400
Hydroxy rop l cellulose (LH11) 28.22 282.2
H drox ro l methyl cellulose K100M CR 21.28 212.8
Povidone K-90 7 70
Sodium bicarbonate 1.5 15
Talc 1 10
Magnesium stearate 1 10
Total 100 1000
Povidone K-90 (PVP): as Binder; Talc: as Glident & lubricant; Magnesium
stearate:
as Lubricant; Gabapentin (base) from Zambon Group SpA; Hydroxypropyl cellulose
(LH11) from Dow Chemicals USA; Hydroxypropyl methyl cellulose K100M CR
from Shin-Etsu chemicals, Japan
28
