Note: Descriptions are shown in the official language in which they were submitted.
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RAPIDLY EXPANDING COMPOSITION FOR GASTRIC RETENTION
AND CONTROLLED RELEASE OF THERAPEUTIC AGENTS,
AND DOSAGE FORMS INCLUDING THE COMPOSITION
CROSS-REFERENCE TO RELATED APPLICATIONS
This invention claims the benefit under 35 U.S.C. 119(e) of provisional
applications Serial No. 60/213,832, filed June 23, 2000; Serial No.
60/217,110, filed July
10, 2000 and Serial No. 60/223,212, filed August 4, 2000.
FIELD OF THE INVENTION
The present invention relates to orally administered gastric retention systems
and
to pharmaceutical dosage forms that use them to release a drug in a patient's
stomach.
BACKGROUND OF THE INVENTION
~ After the discovery of a new drug for treatment of a human disease, further
investigation is undertaken to determine if the drug is most effectively
administered to a
patient intravenously, transdennally, subcutaneously or orally. Orally
administered
drugs are often favored whenever an oral route is feasible.
Pharmacokinetic studies can yield important information about how to get an
optimum therapeutic response from a drug. For some drugs, maintaining a
constant
bloodstream and tissue concentration throughout the course of therapy is the
most
desirable mode of treatment. Immediate release of these drugs can cause blood
levels to
peak above the level required to elicit the desired response, which wastes the
drug and
may cause or exacerbate toxic side effects.
Many drugs provide better therapy when they are delivered in a controlled
release
manner. There are known dosage forms that are capable of sustaining or
delaying
release of a drug. In some sustained release dosage forms, the active
ingredient is
embedded in a matrix that slowly erodes to release the active ingredient.
Other sustained
and delayed release dosage forms have a coating. The coating on a sustained
release
dosage form may be semipermeable to the drug and thereby slow its release. The
coating on some conventional delayed release dosage forms is impermeable to
the drug
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and dissolves slowly in gastrointestinal fluid, thereby delaying release of
the active
ingredient until dissolution of the coating allows gastrointestinal fluid to
contact the
drug. However, semipermeable and impermeable coatings and conventional
erodible
matrices are often ineffective for sustained and delayed release of drugs with
site specific
absorption.
Many orally-administered drugs are most readily absorbed by the jejunum and
duodenum. Other drugs are most readily absorbed through the stomach wall. Few
drugs
are efficiently absorbed by the colon. The residence time of a conventional
dosage form
in the stomach is 1 to 3 hours on average. After transiting the stomach, there
is an
' approximately 3 to 5 hour window of bioavailablity before the dosage form
reaches the
colon. Sustained or delayed release vehicles that are not retained in the
stomach before
and during release of the drug may release a significant portion of the drug
after the
window of bioavailablity has passed. However, if the dosage form is retained
in the
stomach, the active ingredient will be released upstream of the small
intestine and will
enter the intestine in solution, a state in which it can be readily absorbed.
Gastric
retention dosage forms, i. e., dosage forms that are designed to be retained
in the
stomach for a prolonged period of time, can increase the bioavailability of
drugs that are
most readily absorbed by the upper gastrointestinal tract.
Another important application of gastric retention dosage forms is to improve
the
bioavailablity of a drug that is unstable to the basic conditions of the
intestine. A
composition that is formulated ~to dissolve upon contact with any aqueous
solution will at
least partially dissolve in the stomach because it reaches the stomach before
it reaches
the intestine. However, unless the drug is very rapidly absorbed, or the
residence time is
increased, some of the drug will pass into the intestine. An unstable drug
will at least
partially decompose to a product compound that either is not absorbed or, if
absorbed,
may not exert the desired therapeutic effect. Accordingly, decomposition of a
base
sensitive drug that passes into the intestine reduces the effectiveness of the
dosage and
introduces an uncontrollable factor that is detrimental to accurate dosing.
Another important application of gastric retention is to deliver drugs to the
active
site for treatment of local disorders of the stomach, such as peptic ulcers.
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For the foregoing reasons, pharmaceutical formulation specialists have
developed
strategies to increase the residence time of oral dosage forms in the stomach.
One of the
general strategies is intragastric expansion, wherein expansion of the dosage
form
prevents it from passing through the pylorus. The diameter of the pylorus
varies
between individuals from about 1 to about 4 cm, averaging about 2 cm. An
expanding
gastric retention .dosage form must expand to at least 2 cm x 2 cm in two
dimensions to
cause gastric retention, though a size of 2.5 cm x 2 cm is more desirable.
One type of intragastric expanding dosage form uses hydrogels to expand the
dosage form upon contact with gastric fluid to sufficient size to prevent its
passage
through the pylorus. An example of such a dosage form is described in U.S.
Patent No.
4,434,153. The '153 patent discloses a device for executing a therapeutic
program after
oral ingestion, the device having a matrix formed of a non-hydrated hydrogel
and a
plurality of tiny pills containing a drug dispersed throughout the matrix.
As noted in Hwang, S. et al. "Gastric Retentive Drug-Delivery Systems,"
Critical
Reviews i~ Ther°apeutic Drug Ca~~ie~ Systems, 1998, I5, 243-284, one of
the major
problems with intragastric expanding hydrogels is that it can take several
hours for the
hydrogel to become fully hydrated and to expand to sufficient size to cause it
to be
retained in the stomach. Since non-expanding dosage forms remain in the
stomach on
average for about 1 to 3 hours, there is a high probability that known
expanding dosage
forms like that of the '153 patent will pass through the pylorus before
attaining a
sufficient size to obstruct passage. The rate-limiting factor in the expansion
of ordinary
hydrogels is the rate of diffusion of water to non-surfacial hydrogel material
in the
dosage form. Conventional hydrogels are not very porous when they are dry, so
transport of water into the hydrogel can be slow. In addition, a low
permeability
gelatinous layer forms on the surface of wetted hydrogel, which further slows
transport
of water into the hydrogel.
One approach to solving the problem of slow expansion has been the
development of superporous hydrogels. Superporous hydrogels have networks of
pores
of 100 ~ diameter or more. At that diameter, the pores are able to rapidly
transport water
deep into the superporous hydrogel by capillary action. Water reaches the non-
surfacial
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hydrogel material quickly resulting in a rapid expansion of the superporous
hydrogel to
its full extent. Superporous hydrogels are still under development and have
not been
approved for pharmaceutical use by the U.S. Food and Drug Administration.
There are
also shortcomings attendant to the use of superporous hydrogels. They tend to
be
structurally weak and some are unable to withstand the mechanical stresses of
the natural
contractions that propel food out of the stomach and into the intestine. The
superporous
hydrogels tend to break up quickly into particles too small to be retained.
Chen, J. and Park, K. Journal of Controlled Release 2000, 65, 73-82, describes
a
superporous hydrogel whose mechanical strength is improved by the
polymerization of
precursor hydrogel monomers in the presence of several superdisintegrants. The
result
of the polymerization described by Chen and Park is a new substance having
interconnecting cross-linking networks of polyacrylate and, e.g., cross-linked
carboxymethyl cellulose sodium. Such interconnecting networks are not expected
to
have the same physical properties as conventional hydrogels made from the same
precursor hydrogel monomers.
Another general strategy for retaining dosage forms in the stomach is
intragastric
floatation, as exemplified in U.S. PatentNos. 4,140,755 and 4,167,558.
Intragastric
floatation systems are less dense than gastric fluid and avoid passage through
the pylorus
by floating on top of the gastric fluid. These systems generally take one of
three forms.
Hydrodynamically balanced floating systems comprise capsules of the active
ingredient
and a hydrogel that forms a gelatinous coating upon contact with water that
slows further
uptake of water. In one example of such a system, a capsule containing the non-
hydrated
hydrogel and an active ingredient dissolves upon contact with gastric fluid.
The
hydrogel then comes into contact with gastric fluid and forms a gelatinous
coating on the
surface. The gelatinous coating traps air inside the hydrogel thereby making
the mass
buoyant. Expansion of the hydrogel also makes it less dense and therefore more
buoyant. Another form of intragastric floatation system is a gas generating
system,
which evolves gas upon contact with water. Gas bubbles trapped in the dosage
form
make it buoyant. Another variation on the intragastric floatation systems are
low density
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core systems, wherein the active ingredient is coated over a low density
material like
puffed rice.
The floating dosage forms and expanding dosage forms previously described
operate by different gastric retention mechanisms, each with its own
requirements to be
effective. A floatation system must remain buoyant even while absorbing
gastric fluid.
An expanding system must be capable of expansion to a size sufficient to
obstruct transit
into the intestine and yet be small enough in its non-hydrated state to be
swallowed. The
present invention includes embodiments that expand as well as embodiments that
expand
and generate gas.
There is a particular need for an effective gastric retention system for
treatment of
Parkinson's disease with levodopa. Parkinson's disease is a degenerative
condition
associated with reduced dopamine concentrations in the basal ganglia region of
the brain.
The deficiency is considered to be caused by oxidative degradation of
dopaminergic
neurons in the substantia nigra. The preferred course of therapy is to restore
dopamine
concentration in the brain by administration of levodopa, a metabolic
precursor of
dopamine that, unlike dopamine, is able to cross the blood-brain barrier. The
metabolic
transformation of levodopa to dopamine is catalyzed by the aromatic L-amino
acid
decarboxylase enzyme. This enzyme is found throughout the body including
gastric
juices and the mucosa of the intestine. Treatment with levodopa alone requires
administration of large doses of the drug due to extracerebrial metabolism by
this
enzyme. The resulting high concentration of extracerebrial dopamine causes
nausea in
some patients. To overcome this problem, levodopa is usually administered with
an
inhibitor of the aromatic L-amino decarboxylase enzyme such as carbidopa.
Levodopa eases the symptoms of Parkinsonism by temporarily boosting
dopamine concentration in the central nervous system, but it is not a cure.
During
prolonged treatment of the disease with levodopa, the body typically becomes
less
sensitive to levodopa concentration in the brain. The body requires more
frequent dosing
to suppress the manifestations of the disease: tremor, muscular rigidity, lack
of facial
expression, and altered gait. As the blood plasma concentration drops, the
return of
disease manifestations in the so-called "off state," signals the need for
immediate
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administration of another dose. There is, unfortunately, a delay between
ingestion of
levodopa and a return to the "on state" suppression of the disease symptoms.
Aggressive administration of levodopa to circumvent off state symptoms of
rigidity and
akinesia, can lead to equally disabling involuntary motions called
dyskinesias.
From the foregoing, it will be appreciated that it is highly desirable to be
able to
administer levodopa as a sustained release oral dosage form capable of
stabilizing the
serum level of levodopa in a patient. Levodopa/carbidopa is currently
available in
Sinamet~ CR controlled release tablets (DuPont Pharma) that slowly erode to
release the
actives. According to the Physician's Desk Reference, 54th ed., the tablets
use a
polymeric based drug delivery system. Prolonged suppression of disease
manifestations
with these tablets is limited by the mechanism of absorption of levodopa from
the
gastrointestinal tract. Levodopa is absorbed by the active transport mechanism
for
amino acids, which is most active in the duodenum region of the small
intestine.
Sustained release is therefore limited by the transit time of the dosage form
through the
stomach and duodenum which, though highly variable from individual-to-
individual and
dependent upon nutritional state, typically takes only about 3 to 4 hours.
Levodopa
released after the 3-4 hour therapeutic window has passed is not bioavailable.
Sinemet~
CR controlled release tablets have about 75% of the bioavailability of
Sinemet~
conventional release tablets. Physicians Desk Reference, 54th edition (Medical
Economics Co., publisher, 2000) at p. 979.
Another problem in Parkinson's disease therapy that could be addressed with an
improved controlled release levodopa delivery vehicle is the reduction in
plasma
levodopa concentration that occurs while a patient is sleeping. Parkinson's
patients
usually awaken in the morning in the off state and must wait for a morning
dose of
levodopa to take effect before they can function comfortably. It would be
highly
desirable if a Parkinson's disease patient could take levodopa in the evening,
while under
the therapeutic effect of a previous dose, and wake up in the morning without
the
manifestations of the disease. For such purpose, the drug delivery vehicle
ideally would
not only extend the release of levodopa over time, but would also delay
release of
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levodopa until the early morning hours before the patient awakens so that the
patient
would awaken when the therapeutic effect of the dose is near its maximum.
Therefore, there is a need for a controlled release levodopa oral dosage form
that
is able to deliver levodopa to a patient's bloodstream over a longer time
period than is
currently possible without resort to a regimen of frequent dosing, and the
fluctuations in
plasma levodopa levels that occur with frequent dosing. Further, there is a
need for
improvement in controlled-release forms that improves the bioavailability of
levodopa as
well as lowers the dosage frequency.
There is also a particular need for an effective gastric retention system for
use in
treatment of children with hyperactivity and attention deficit disorder.
Methylphenidate,
the mainstay in treatment of hyperactivity, has a short half life in the human
body and,
so, frequent dosing (about every four hours) is required. Children therefore
need to take
the drug when they are in school. This poses administrative problems for
schools that
are asked to see that a child takes his medication. Sustained release
formulations of
methylphenidate have been developed. Methylphenidate is currently available in
Ritalin°-SR sustained-release tablets (Novartis). According the
Physician's Desk
Reference, 54th ed., Ritalin~-SR tablets contain cellulose compounds and
povidone.
Another sustained release formulation of methylphenidate is proposed in U.S.
Patent
5,874,090. Unfortunately, patients become tolerant to a sustained high blood
level of
methylphenidate and require more medication to suppress their hyperactivity or
distractibility.
U.S. Patent 6,034,101 (and WO 98114168) discloses a methylphenidate dosage
form that is designed to overcome the development of tolerance within a single
dosage
interval. This dosage form delivers methylphenidate in pulses of ascending
intensity.
However, the dosage form is not a gastric retention form. Therefore, while the
first pulse
of drug is released in the stomach, subsequent pulses are delivered in the
jejunum, ileum,
and/or colon. Methylphenidate is more readily absorbed by the stomach than by
the
intestine. Consequently, the pulses that are designed to be the most intense
are the least
bioavailable because they are released downstream of the stomach. Another
dosage form
for delivering methylphenidate in pulses is described in U.S. Patent
5,837,284. In
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addition to the mismatch between the ascending dose profile and the descending
bioavailability as the dosage form passes through the GI tract, these pulsed
methods have
the drawback that the higher dosages can increase the severity and occurrence
of the side
effects experienced with the drug, especially sleep disturbance.
Allowing a sufficiently long drug-free interval between doses of
methyhphenidate
is a more preferred approach to avoid acute tolerance than using an ascending
drug
profile. However, the pulse delivery systems used to deliver methyhphenidate
over
greater periods of time suffer the same bioavailability problems as the pulsed
dosage
forms with ascending profiles. Thus, there is a need for a gastric retention
pulsed
delivery system that can deliver methylphenidate in pulses with consistent
bioavailability.
There is clearly a need for improvement in gastric retention-controlled
release
technology and a particular need for improved gastric retention dosage forms
of
hevodopa and methylphenidate.
BRIEF DESCRIPTION OF THE FIGURES
Fig. 1 is a plot showing the blood level concentration of levodopa and
carbidopa
in a beagle dog over time after.administration of a delayed release levodopa
and
carbidopa dosage form of this invention.
OBJECTS AND SUMMARY OF THE INVENTION
We have now discovered a composition that expands rapidly in the gastric
juices
of a patient, thereby increasing the likelihood that the composition will be
retained in the
stomach for a prolonged period of time. This composition is a blend of a
superdisintegrant, tannic acid and one or more hydrogehs. The composition is
useful in
gastric retention dosage forms because it increases the likelihood that an
active
ingredient carried by the form will be released in the stomach. A dosage form
of the
present invention expands rapidly, at a rate not previously attainable with
known
expanding hydrogel formulations, yet because it does not contain a superporous
hydrogel, it avoids the mechanical strength problems associated with
superporous
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hydrogels. An additional advantage of using conventional hydrogels in the
inventive
composition and dosage forms is that the degradation/erosion rates of these
hydrogels are
well studied.
The present invention provides a pharmaceutical composition for use in an
orally
administered pharmaceutical product that expands upon contact with gastric
fluid to
promote retention of a dosage form in the patient's stomach for a prolonged
period of
time. The composition comprises a non-hydrated hydrogel, a superdisintegrant
and
tannic acid, preferably in amounts, exclusive of any other excipients that may
be present,
of from about 20 wt. % to about 70 wt. % hydrogel, from about 10 wt. % to
about 75 wt.
% superdisintegrant and from about 2 wt. % to about 12 wt. % tannic acid.
In one embodiment, the pharmaceutical composition comprises from about 10
wt. % to about 20 wt. % hydroxypropyl methylcellulose ("HPMC"), from about 45
wt.
to about 50 wt. % hydroxypropyl cellulose ("HPC"), about 25 wt. % to about 35
wt.
sodium starch glycolate and about 4 wt. % to about 6 wt. % tannic acid. A
second
embodiment of the pharmaceutical composition comprises from about 10 wt. % to
about
30 wt. % hydroxypropyl methylcellulose, from about 40 wt. % to about 60 wt.
hydroxypropyl cellulose, about 7 wt. % to about 35 wt. % sodium crosscannelose
and
about 4 wt. % to about 12 wt. % tannic acid. These compositions can expand in
volume
five fold or more within about fifteen minutes by imbibing water from gastric
fluid.
The present invention further provides orally administered pharmaceutical
dosage
forms containing a therapeutic agent and the pharmaceutical composition. The
forms
can be used to deliver the therapeutic agent to the stomach of the patient in
an immediate
or controlled release manner. For instance, in one of the dosage forms, the
therapeutic
agent is provided as coated particles which are dispersed throughout a matrix
comprising
the pharmaceutical composition of the present invention. This form is well
suited for
delayed and pulsed delivery of the therapeutic agent. In another dosage form
embodiment, the therapeutic agent is contained in a sustained release
reservoir embedded
in a shell comprising the composition of the present invention. The shell
promotes
retention of the dosage form in the patient's stomach while the therapeutic
agent is
released in a sustained manner from the reservoir.
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The present invention further provides dosage forms for controlled gastric
release
of levadopa and controlled gastric release of methylphenidate. These dosage
forms are
adapted to address problems with current therapies that use these drugs. The
present
invention therefore further provides methods of treating diseases with these
drugs, and
other drugs, by administering the dosage forms and compositions of this
invention.
DETAILED DESCRIPTION OF THE INVENTION
The terms "drug," "actives," "active ingredient," "therapeutically beneficial
agent" and "therapeutic agent" are all used interchangeably in this disclosure
and mean a
compound that exerts a therapeutically beneficial effect on a patient and
prodrugs,
solvates, molecular complexes and pharmaceutically acceptable salts and
derivatives of
the compound.
The term "gastric fluid" means the endogenous fluid medium of the stomach,
including water and secretions, or simulated gastric fluid. "Simulated gastric
fluid"
means any fluid that is generally recognized as providing a useful substitute
for authentic
gastric fluid in experiments designed to assess the chemical or biochemical
behavior of
substances in the stomach. One such simulated gastric fluid is USP Gastric
Fluid TS,
without enzymes. United States Pharmacopeia and National Formulary 24/19 p.
2235
(1999). Thus, it will be understood that throughout this disclosure and in the
claims
"gastric fluid" means authentic gastric fluid or simulated gastric fluid.
"Immediate release" means that release of the active ingredient is not
significantly delayed by means of a protective coating or embedding in a
matrix. The
excipients used to achieve immediate release typically dissolve or disperse
rapidly in
gastric fluid. "Sustained release" means release of the active ingredient from
the dosage
form over a longer period of time than the immediate release time for the same
quantity
of the same active ingredient from an equivalent dosage in an immediate
release
formulation. "Delayed release" means that there is a period of time after the
dosage
form contacts gastric fluid during which the active ingredient either is not
released or is
released at a rate that is not therapeutically effective for the purpose that
the drug has
been administered to the patient. "Burst release" means release of most of the
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ingredient over a short period of time, typically less than 30 minutes.
"Pulsed release"
means release of the active ingredient over two or more time periods separated
by a
period of time in which either the active ingredient is not release or is
released at a rate
that is not therapeutically effective for the purpose that the drug has been
administered to
the patient. Burst release, pulsed release and sustained release may be
coupled with
delayed release so that release of the active ingredient according to that
profile begins
after a delay period in which the active ingredient either is not released or
is released at a
rate that is not therapeutically effective for the purpose that the drug has
been
administered to the patient. The term "controlled release" is used inclusively
to mean
, delayed release; sustained release, including delayed sustained release;
burst release,
including delayed burst release; pulsed release, including delayed pulsed
release; and any
release other than immediate release.
The present invention provides a gastric retention composition that expands
rapidly upon contact with the gastric juices of a patient. The expanding
composition is
advantageously used as a gastric retention delivery system ("GRDS") in an
orally
administered pharmaceutical dosage form to increase the likelihood that the
dosage form
will be retained in a patient's stomach for a prolonged period of time.
After the expanding composition is hydrated and expanded, it allows
solubilized
substances inside the expanded composition to diffuse into the surrounding
fluid
environment. Thus, the expanding composition is well suited for use in a
delayed, burst
and/or pulsed release dosage form. The expanding composition is also well
suited for
use with a reservoir designed to deliver a drug in a sustained release manner.
The
reservoir may be a sustained release core embedded in the expanding
composition; it
may be a tablet enclosed within a capsule along with the expanding composition
or it
may be a layer of a multi-layer construction in which the reservoir layer
contains the
active ingredient and is provided with means for releasing the active
ingredient in a
sustained manner and the other layer contains the expanding composition. The
expanding composition is also well adapted for use with sustained release
particles in
which a coating is applied to the particle which slows the release of the
active ingredient
or with sustained release particles in which the active ingredient is
dispersed in a particle
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matrix that slows release of the active ingredient. The expanding composition
also may
be used to slow the release of the active ingredient.
The composition's rapid rate of expansion has clinical implications. There is
a
chance that any expanding gastric retention dosage form will pass through the
stomach
before it has expanded sufficiently to be retained. If the drug happens to be
administered
to a patient shortly before peristalsis, the dosage form may pass out of the
stomach in
much less time than the average residence time. After an incompletely expanded
dosage
form is passed into the intestine, further expansion may cause blockage of the
patient's
intestine for a period of time. The window of bioavailability also may be
missed,
I O especially if the active ingredient is most readily absorbed in the
stomach or is unstable
to basic conditions. The likelihood that an expanding dosage form will pass
through the
stomach before it attains a size sufficient to block passage through the
pylorus depends
upon many factors such as the fasting or fed state of the patient and the
gastric motility
of the patient. In a fasting state, conventional oral dosage forms are emptied
from the
stomach about every one hundred minutes by gastric peristalsis. Another factor
over
which the present invention gives the clinician control is the relationship
between
amount of time required for the dosage form to expand and the time it takes
for gastric
emptying. Thus, it will be appreciated that a rapid rate of expansion is a
significant
advantage of the present invention.
Another aspect of the invention provides dosage forms containing the expanding
composition of the present invention. Dosage forms according to this invention
are
retained in the stomach for an extended period of time by expansion of the
composition
and, optionally, by floatation. In an embodiment that uses floatation for
improved
gastric retention, the dosage form contains a substance that effervesces on
contact with
aqueous or aqueous acidic solution. The expanded composition traps some of the
bubbles given off by the effervescent substance thereby making the dosage form
buoyant. Gastric retention causes the active ingredient to be released
upstream of the
jejunum and duodenum, which are the two segments of the GI tract which most
actively
absorb many drugs. Over time the expanded dosage form degrades or erodes into
particles that are sufficiently small to pass through the pylorus.
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Rapid expansion of the composition and dosage forms containing it is achieved
with a novel combination of hydrogel, superdisintegrant and tannic acid.
Hydrogels are polymers that axe hydrophilic but insoluble in water. In their
hydrated condition they swell to an equilibrium volume, are elastically
deformable but
virtually immune to plastic deformation. In their dry state, hydrogels may be
structurally
rigid. The preferred hydrogel of the expanding composition is hydroxypropyl
methylcellulose, either alone or in combination with hydroxypropyl cellulose.
and/or a
cross-linked acrylate polymer. Preferably, the HPMC has a molecular weight of
from
about 4000 to about 100,000 a.u. and a viscosity grade of about 8000 mPa~s or
less.
HPMC is commercially available under the trade name Methocel~ from Dow
Chemical
Co.
Hydroxypropyl cellulose used in the expanding composition preferably has a
molecular weight in the range of from about 80,000 to about 1.2 million, more
preferably
from about 1.0 million to about 1.2 million. HPC is commercially available
under the
trade name Klucel~ from Hercules Inc.
Suitable cross-linked acrylate polymers include polyacrylic acid crosslinked
with
allyl sucrose commercially available under the trade name Carbopolm (BF
Goodrich
Chemical Ltd.) and polyacrylic acid cross linked with divinyl glycol.
The most preferred hydrogel of the present invention is a combination of
hydroxypropyl methylcellulose and hydroxypropyl cellulose in a weight ratio of
from
about 1:3 to about 5:3.
The expanding composition also includes a superdistintegrant.
Superdisintegrants are disintegrants that expand upon contact with water.
Preferred
superdisintegrants of the present invention expand to at least double their
non-hydrated
volume on contact with water. Exemplary of these superdisintegrants are cross-
linked
carboxymethyl cellulose sodium (a.k.a. croscarmellose sodium), sodium starch
glycolate
and cross-linked polyvinyl pyrollidone (a.k.a. crospovidone). Croscarmellose
sodium is
commercially available from FMC Corp. under the tradename Ac-Di-Sol~ and from
Avebe Corp. under the tradename Primellose~. Sodium starch glycolate is
commercially
available from Penwest Pharmaceuticals Co. under the tradename Explotab~ and
from
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Avebe Corp.wnder the tradename Primojel~. Crospovidone is commercially
available
from BASF Corp. under the tradename I~ollidon~ CL and from International
Specialty
Chemicals Core. under the tradename Polyplasdone~. The most preferred
superdisintegrant is croscarmellose sodium.
The expanding composition further includes tannic acid. Tannic acid, also
called
tannin, gallotannin and gallotannic acid, is a naturally occurring constituent
of the bark
and fruit of many trees. The term "tannins" conventionally refers to two
groups of
compounds, "condensed tannins" and "hydrolyzable tannins." Merck Index
monograph
No. 8828 (9th ed. 1976). The hydrolyzable tannins are sugars that are
esterified with one
or more (polyhydroxylarene) formic acids. One common polyhydroxylarene formic
acid
substituent of tannic acid is galloyl (i. e. 3,4,5-trihydroxybenzoyl). Another
common
polyhydroxylarene formic acid substituent of tannic acid is meta-digallic
acid. A
common sugar moiety of tannic acid is glucose. Preferably, USP grade tannic
acid is
used.
The expanding composition comprises a hydrogel, preferably hydroxypropyl
methylcellulose optionally in combination with other hydrogel polymers, a
superdisintegrant and tannic acid, preferably in an amount, exclusive of any
other
excipients that may be present, of from about 20 wt. % to about 70 wt. %
hydrogel, from
about 10 wt. % to about 75 wt. % superdisintegrant and from about 2 wt. % to
about 12
wt. % tannic acid. An especially preferred expanding composition comprises
from about
wt. % to about 55 wt. % superdisintegrant, about 5 wt. % (~ 2 wt. %) tannic
acid, plus
an amount of hydrogel sufficient to bring the total to 100 wt. %.
As previously mentioned, a preferred hydrogel for the expanding composition is
hydroxypropyl methylcellulose, optionally in combination with hydroxypropyl
cellulose
25 or a cross-linked acrylate polymer. An expanding composition in which a
preferred
hydrogel is used preferably comprises from about 10 wt. % to about 30 wt.
hydroxypropyl methylcellulose, from about 40 wt. % to about 60 wt. %
hydroxypropyl
cellulose, from about 7 wt. % to about 35 wt. % croscarmellose sodium and from
about 4
wt. % to about 12 wt. % tannic acid.
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A second preferred embodiment of the expanding composition in which the
preferred hydrogel is used comprises from about 10 wt. % to about 20 wt.
hydroxypropyl methylcellulose, from about 45 wt. % to about 50 wt. %
hydroxypropyl
cellulose, about 25 wt. % to about 35 wt. % sodium starch glycolate and about
4 wt. % to
about 6 wt. % tannic acid.
Within these ranges, there are preferred formulations in dosage forms designed
for particular applications, as described in detail below. In particular, a
matrix type
dosage form for delayed release of levodopa or a mixture of levodopa and
carbidopa is
provided. An especially preferred expanding composition for the matrix of a
delayed
release levodopa/carbidopa dosage form contains from about 10 wt. % to about
14 wt.
HPMC, from about 42 wt. % to about 47 wt. % HPC, from about 7 wt. % to about
12 wt
croscarmellose sodium, from about 6 to about 9 wt. % tannic acid, from about
18 wt.
to about 22 wt. % levodopa from about 3 wt. % to about 6 wt. % carbidopa and
from
about 0.3 wt. % to about 1 wt. % tablet lubricant such as magnesium stearate.
' An especially preferred formulation of the expanding composition for use as
a
shell in a reservoir dosage form of levodopa, levidopalcarbidopa,
methylphenidate or
alendronate comprises from about 10 wt. % to about 20 wt. % HPMC, from about
50 wt.
to about 60 wt. % HPC, from about 12 wt. % to about 25 wt. % croscarmellose
sodium, from about 8 wt. % to about 12 wt. % tannic acid and from about 0.5
wt. % to
about 1 wt. % of a tablet lubricant such as magnesium stearate.
The novel expanding composition of the invention can be prepared
conventionally by dry blending, dry granulation or wet granulation.
In dry granulation, the composition is blended dry and then compacted into a
slug
or a sheet and then comminuted into compacted granules. It will be appreciated
that the
processes of slugging or roller compaction, followed by comminution and
recompression
render the hydrogel, superdisintegrant and tannic acid intragranular in the
final dosage
form. The active ingredient of the pharmaceutical may also be provided
intragranularly
by blending it with the expanding composition prior to compaction.
Alternatively, the
active ingredient, hydrogel, superdisintegrant or tannic acid may be added
after
comminution, which results in that (or those) ingredients) being
extragranular. The
CA 02412490 2002-12-20
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granulate may be used to prepare a dosage form by any of the methods described
below
or any other means.
In wet granulation, the excipients may be granulated using a water:alcohol
mixture or an alcohol as a granulation solvent by standard granulation
techniques known
in the art. The granulate may then be dried and optionally milled and sieved.
The
hydrogel, superdisintegrant, tannic acid or active ingredient may be added to
one or more
of the wet granulated ingredients either before or after compaction, in which
case an
ingredient added after granulation would be extragranular in the final dosage
form. After
drying, the granulate prepared by wet granulation may be used to prepare a
dosage form
I O by any of the methods described below or any other means.
The composition may be compacted following conventional compression and
direct compression techniques. Direct compression produces a more uniform
tablet
without granules. Thus the hydrogel, superdisintegrant, tannic acid, the
active
ingredients) and any other desired excipients are blended with the composition
prior to
direct compression tableting. Such additional excipients that are particularly
well suited
for direct compression tableting include microcrystalline cellulose, spray
dried lactose,
dicalcium phosphate dehydrate and colloidal silica. The proper use of these
and other
excipients in direct compression tableting is known to those in the art with
experience
and skill in the particular formulation challenges of direct compression
tableting.
In some dosage forms, controlled release of the active ingredient may be
provided by applying a coating to the active ingredient. Thus, where the
foregoing
description of the present invention has described mixing, blending,
granulating,
compressing, etc. of the active ingredient, it will be appreciated by those
skilled in the art
that the active ingredient may previously be coated with a coating.
The preceding description is intended to highlight variations of compounding
techniques already well known in the art. However, the composition can be used
with
any chemically compatible drug in any manufacturing process. Specific novel
and
therapeutically useful gastric retention dosage forms are disclosed below.
The pharmaceutical dosage forms of the present invention comprise an active
ingredient and a drug delivery vehicle comprising the expanding composition of
the
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invention and any other desired pharmaceutical excipients. Pharmaceutical
dosage forms
of this invention can be retained in the stomach for three hours or more, more
preferably
about five hours or more. The dosage forms of the present invention are
capable of
expanding in volume by a factor of about three or more, about five or more if
an
expanding composition according to the preferred embodiments is used and ,
about eight
or more if an expanding composition according to the most preferred
embodiments is
used. Expansion occurs within about fifteen minutes of contacting gastric
fluid, within
about five minutes when formulated according to the preferred embodiments.
Further improvement in gastric residence time may be realized by adding an
effervescent compound that produces gas when contacted with gastric fluid,
such as
sodium bicarbonate. In a dry granulation process, the effervescent compound
may be
introduced into the dosage form by blending it into the expanding composition
before or
after first compaction. In a wet granulation process, it may be provided as an
extragranular constituent after wet granulation. Further the effervescent
compound may
be a constituent of a reservoir in reservoir-type dosage form. The
effervescent
compound is preferably used at low concentration, i. e. from about 0.5 wt % to
about 5
wt. % of the dosage form. In addition to sodium bicarbonate, effervescent
compounds
include, for example, other alkali and alkaline-earth metal carbonates and
bicarbonates.
Mucoadhesive substances also may be added to enhance gastric retention of
dosage forms prepared according to the present invention.
One gastric retention dosage form embodiment is a tablet which may be prepared
by compacting the expanding composition, active ingredients) and, optionally,
other
excipients, as a powder blend or granulate in any type of tableting equipment
known to
the pharmaceutical arts. Another dosage form is a capsule, which may be
prepared by
filling a conventional capsule shell (e.g., gelatin) with a powder blend,
granulate or tablet
containing the expanding composition, active ingredients) and, optionally,
other
excipients.
Dosage forms of the present invention may be made in any shape desired. Ovoid
or elliptical shaped dosage forms are well retained after expanding to their
full extent.
An ovoid or elliptical dosage form preferably is sized at between about 4 mm
and 10 mm
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in two dimensions and between about 10 mm and 20 mm in the third dimension,
more
preferably 6x6x16 mm ~2 mm.
There is a wide variety of dosage forms and ways to use the expanding
composition in the dosage forms of the present invention.
Dosage forms may be a matrix type in which the active ingredients(s) are
particles uniformly dispersed throughout the expanding composition. In a
matrix
construction, the particles of active ingredients) may be a milled powder or
granulate.
The particles also may be pre-formulated beads, pills, pellets, microcapsules,
microspheres, microgranules, nanocapsules or nanospheres and the like
containing or
having on their surface the active ingredient. These preformulated particles
are dispersed
in the matrix.
A pre-formulated particle may contain the powdered active ingredient in a
natural, semi-synthetic or synthetic polymer matrix. Representative matrices
for
dispersed particles are polysaccharides, agar, agarose, sodium alginate,
carrageenan, gum
arabic, tragacanth gum, locust bean gum, pectin, amylopectin, gelatin, starch,
microcrystalline cellulose and hydrogels. Further particle matrices can
include
crosslinked gelatin, crosslinked albumin, crosslinked sodium alginate,
crosslinked
carboxymethylcellulose, crosslinked polyvinyl alcohol and crosslinked chitin
as
described in U.S. Patent No. 5,007,790.
The active ingredients) may be contained in coated particles, e.g., beads,
tiny
pills, microspheres, nanospheres and microgranules that have been coated with
a
substance or substances that are impermeable or semipermeable to the active
ingredient
and/or slowly dissolve in gastric fluid. A coating may be used to slow the
release of the
active ingredient or to delay the release of the active ingredient. A delay
release coating
is impermeable to the active ingredient until the coating is breached by the
gastric fluid.
Dosage forms of the matrix type may be formulated for delayed release using
coated
particles. The expanding composition will retain the dosage forms in the
stomach until
the delay time has passed, whereupon the drug is released.
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Particles may be coated with known film coating agents such as water soluble
resins, such as arabinogalactan, carboxymethylcellulose, gelatin, gum arabic,
hydroxyethylcellulose, methylcellulose, polyvinyl alcohol, polyacrylic acid,
and starch;
water insoluble resins, such as cellulose nitrate, ethyl cellulose, e.g.,
EthocelTM;
cellulose nitrate, polyamide, polyethylene, polyethylene-vinyl acetate),
poly(lactide-co-
glycolide), polymethacrylate, e.g., EudragitTM NE, EudragitTM RS, Eudragit~
RL,
EudragitTM L and EudragitTM S and silicones; waxes and lipids such as
paraffin, carnauba.
wax, spermaceti, beeswax, stearic acid stearyl alcohol and glyceryl stearates;
and enteric
resins such as cellulose acetate phthalate, polyvinyl acetate and
hydroxypropyl
methylcellulose acetate. The glyceryl esters may be mixed with a wax as
previously
described in U.S. Patent No. 4,764,380, which is incorporated by reference in
its entirety.
Such a coating may be made from triglyceryl esters like glyceryl distearate,
glyceryl
tristearate, glyceryl monostearate, glyceryl dipalmitate, glyceryl
tripalmitate, glyceryl
monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl
monodocosanoate, glyceryl monocaprate, glyceryl dicaprate, glyceryl
tricaprate, glyceryl
monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl
monodecenoate,
glyceryl didecenoate and glyceryl tridecenoate. Waxes that may be used include
beeswax, cetyl palmitate, spermacetic wax, carnauba wax, cetyl myristate,
cetyl
palmitate, ceryl cerotate, stearyl palmitate, stearyl myristate and lauryl
laurate. Particles
coatings may also be from other polymeric coating substances which include
methylcellulose phthalate, poly(alkyl methacrylates), poly(alkyl
cyanoacrylates),
polyglutaraldehyde, poly(lactide-glycolide) and albumin. Additional coating
materials
that may be used are disclosed in U.S. Patents Nos. 4,434,153; 4,721,613;
4,853,229;
2,996,431; 3,139,383 and 4,752,470, which are hereby incorporated by reference
in their
entirety.
Particles coated with delayed release coatings may be advantageously used to
produce a dosage form for pulsed release of the active ingredient(s). For
example, one
could deliver two, three (or more) timed doses in a pulse fashion while the
patient needs
to take the dose only once. The three doses would mimic taking multiple doses
of the
drug at the prescribed times, with the drug being absorbed from the stomach or
upper
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intestine with each dose. Such dosing allows for improved compliance to dosage
schedules and in many cases will lead to improved therapy. Delayed dosage
forms that
do not include gastric retention will deliver each such dose in a different
part of the GI
tract with different absorption profiles for each of the doses. Such therapy
would not be
equivalent to taking three doses of the drug at the prescribed times, wherein
the drug
would have been absorbed from the stomach or upper intestine in each case. For
this
purpose, particles may be provided with coatings of different thicknesses.
Alternatively,
the particles may be coated with different substances having different
dissolution rates in
gastric fluid.
Gastric fluid rapidly penetrates the expanding dosage form because of the
hydrophilicity and porosity of the expanding composition. Consequently, the
coated
particles contact gastric fluid approximately simultaneously regardless of
their proximity
to the outer surface of the dosage form. The coatings of a certain proportion
of particles,
either those with a thin coating or a relatively soluble coating, are breached
nearly
simultaneously. This causes release of the active ingredients(s) from those
particles over
a short time period, i. e., in a pulse. A second pulse occurs when the coating
of particles
having either a thicker coating or a coating of a slower dissolving substance
is breached.
The timing and intensity of the pulses can be determined by the formulator
using
knowledge available about the dissolution rates of coating substances and by
routinely
selecting the proportion of each type of coated particle to match the
intensity of the pulse
desired.
A pulsed release may be used to deliver one, two or more active ingredients at
different times after the patient has swallowed the dosage form.
In a coated pulsed release dosage form, the core of the particle preferably
can be
either one or more active ingredients or a mixture of the active ingredients)
with
excipients that do not retard release of the active ingredient(s). Even if the
particle core
contains excipients that in certain applications retard release of actives,
such as high
molecular weight polyvinyl pyrollidone, rapid release may occur nevertheless
due to the
small volume and relatively large surface area of the particles.
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In a hydrated state, the expanding compositions of this invention do not
necessarily limit diffusion of a solubilized active ingredient into the
gastric environment.
Therefore, the pulsed release of active ingredient inside of the expanded
dosage form
may translate into pulsed release into the gastric fluid.
The composition is also suited for the retention of drugs in the stomach when
such drugs are contained in tablets that are either partially embedded in the
expanding
composition or attached thereto by an adhesive. These tablets can be of a slow
release
nature giving slow or controlled release for an extended period of time in the
stomach.
These tablets can further be of a delayed pulse release nature. The expanding
composition of this invention will retain these forms in the stomach until the
delay time
has passed whereupon the drug will be released in a burst or pulse fashion.
Attaclung, or
partially embedding, several such tablets, each timed with a different delay
to release, to
the composition of this invention, allows versatile dosing schemes from one
taken dose.
For example one could deliver three (or more) timed doses in a pulse fashion
while the
patient needs to take the dose only once. The three doses would mimic taking
three
doses of the drug at the prescribed times, with the drug being absorbed from
the stomach
with each dose. Such dosing allows for improved compliance to dosage schedules
and in
many cases will lead thereby to improved therapy. Delayed dosage forms that
are not
coupled to gastric retention will deliver each such dose in a different part
of the GI tract
with different absorption profiles for each of the doses. Such therapy would
not be
equivalent to taking three doses of the drug at the prescribed times, wherein
the drug
would have been absorbed from the stomach in each case.
Dosage forms may be a reservoir (depot) type. Reservoir forms contain the
active ingredient in a reservoir that is embedded in a shell of any desired
thickness that
does not cause the dosage form to be too large to be swallowed by the patient.
Embedded tablets and tablets with cores are examples of reservoir type of
dosage forms.
A reservoir type further includes capsule forms, multilayer forms and other
forms
wherein the active ingredient is separated from the expanding composition. The
reservoir may be fully embedded in a shell of the expanding composition or it
may be
partially embedded so that a portion of the surface of the reservoir is
exposed. A
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reservoir may be a tablet enclosed within a capsule along with a tablet
containing the
expanding composition. These types of products may be manufactured using
methods
known in the art.
The reservoir may be formulated to be either immediate release or controlled
release. The release profile of the dosage form may be made to approximate the
release
profile of the reservoir (even when the reservoir is completely embedded in
the
expanding composition) because the hydrated and expanded composition does not
necessarily inhibit diffusion of solubilized substances into the gastric
environment. For
example, an immediate release reservoir may be prepared by blending an active
ingredients) with microcrystalline cellulose, lactose and magnesium stearate
and
compressing the blend into a compacted reservoir. For another example, a
sustained
release reservoir may be prepared by direct compression of the active with
about 5-75
hydroxypropyl methylcellulose, such as Methocel~ K15M, Kl00LV, K4M, K100M,
E4M and ElOM, lactose and magnesium stearate.
~ The reservoir may also be attached to the expanding composition with an
adhesive. The expanding composition is compacted into a tablet ("GRDS
tablet"). The
reservoir can be attached by adhesive during manufacture by depositing a drop
of
adhesive on a GRDS tablet as it leaves the punch station in the tableting
machine and
having a device push the reservoir, e.g., another tablet, containing the drug
against the
deposited adhesive.
More preferably, the drug containing reservoir can be adhered to the GRDS
tablet
in situ the 'stomach by coating the GRDS tablet with an aqueous based adhesive
that does
not interfere with its swelling properties and loading the GRDS tablet and one
or more
drug reservoirs(s) into an appropriately sized gelatin capsule where the GRDS
tablet is
physically in contact with the drug reservoirs) to be adhered to it. When
water enters the
capsule, the adhesive is wetted and adheres the drug reservoirs) due to their
proximity in
the capsule prior to the GRDS system's rapid swelling. The tablets remain
adhered to
each other after the swelling. Preferred water based adhesives for this use
are protein
adhesives such as gelatin, egg albumin, and casein their salts and derivatives
and
polysaccharide adhesives such as starch, modified starches, and other
polysaccharide
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derivatives known in the art as glues. The most preferred adhesive for in situ
adhesion
of the drug reservoir to the GRDS unit is sodium caseinate available
commercially as
Emulac~ 50.
A reservoir may be coated with a conventional sustained release coating. Such
coating materials include polymethacrylate, e.g., EudragitTM NE, EudragitTM
RS,
EudragitTM RL, EudragitTM L, EudragitTM S, and mixtures of hydrophilic and
hydrophobic film forming agents. Hydrophilic film forms include methyl
cellulose,
hydroxypropyl methylcellulose, cellulose phthalate, cellulose acetate
phthalate and
polyvinyl alcohol. Hydrophobic film forming agents include ethyl cellulose,
cellulose
acetate, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol malefic
anhydride
copolymers, (3-pinene polymers rosin, partially hydrogenated rosin and
glycerol esters of
rosin. A sustained release coating may be applied by methods known in the art
such as
by fluid bed or pan coating techniques.
In addition to being of an immediate release or sustained release nature, the
reservoir can further be of a delayed pulse release nature or a delayed
sustained release
nature.
Dosage forms of the present invention may also have a layered construction
wherein the actives, alone or in mixture with any other excipients, form a
layer that is
bonded, e.g., by compression, to another layer containing the expanding
composition.
Preferred dimensions for a layered dosage form are about 14x8 mm ~2 mm. A
layered
construction may be prepared by conventional multilayer compression
techniques. A
layered dosage form comprising two or more layers, one comprising the
expanding
composition and another comprising the actives and any other desired
excipients, may be
made to delay release of the actives by coating only the actives-containing
layer with a
conventional coating resistant to gastric fluids. A further method of
achieving a delay in
the release is to formulate the drug-containing layer as a matrix that delays
diffusion and
erosion or by incorporating the active substances in microcapsules or coated
beads
within the drug-containing layer.
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One preferred active ingredient for use in the dosage forms of the present
invention is methylphenidate. Especially preferred dosage forms for pulsed
delivery of
methylphenidate are the following tablet and capsule forms.
One preferred pulsed release methylphenidate tablet contains coated particles
or
multiple coated reservoirs dispersed in a matrix or shell comprising the
expanding
composition. In each case, the particle or reservoir is coated with a suitable
coating as
previously described. In such methylphenidate tablets containing particles, a
portion of
the plurality of particles may be uncoated for immediate release. A second
proportion of
the particles is coated to release a second pulse (after the irmnediate pulse)
of
methylphenidate preferably from about 3 to about 5 h after the tablet is
administered to
the patient. There may also be a third proportion of particles that is coated
to release
about 4 h after the second pulse. Timing the pulses about 4 h apart provides
an interval
of low methylphenidate concentration in the bloodstream that resists
development of
acute tolerance. In reservoir-containing tablets, the number of reservoirs
corresponds to
the number of pulses desired, typically two or three. One of the reservoirs
may be
uncoated for immediate release while the others are coated so as to release
the
methylphenidate within the same time ranges specified above as preferred
release times
from particles.
An especially preferred capsule dosage form for pulsed delivery of
methylphenidate contains two tablets (reservoirs) containing the drug and
coated for
timed delay of release. These two tablets are placed in contact with a coated
GRDS tablet
that has an adhesive such as sodium caseinate and an immediate release dose of
methylphenidate as its coating. When the capsule enters the stomach, the
gelatin capsule
dissolves, the adhesive coating on the GRDS is wetted and causes adhesion of
the drug
containing tablets to the GRDS tablet, the immediate dose of methylphenidate
is released
and the GRDS tablet swells for gastric retention. The three tablet ensemble is
retained in
the stomach for an extended period. At the predetermined time, e.g. 4 hours,
the second
dose is released. The third dose is released at the second predetermined time
e.g. 8 hours.
In a methylphenidate pulsed release capsule, one tablet may be an immediate
release formulation and the second tablet may be a delayed release
formulation, though
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both may be delayed release. There will be some delay in release from an
immediate
release tablet due to the time required to dissolve the capsule. An immediate
release
formulation may be a tablet prepared as described by any of the methods above,
or other
method, in which the methylphenidate is dispersed as a powder, or as an
ingredient of a
particle, throughout the tablet matrix. A delayed release tablet is preferably
a matrix
type with a delayed release coating around the tablet. Such a tablet,
therefore, may
contain methylphenidate dispersed as a powder or as an ingredient of an
immediate
release particle. Two or more delayed release tablets may be provided in the
capsule,
which have coatings of different substances, or of different thicknesses so as
to release
the methylphenidate at different times. The preferred release time for a first
delayed
release tablet is from about 4 h to about 5 h after the drug is administered
to a patient.
Successive delayed-release pulses from additional delayed release tablets that
may be
provided in the capsule preferably occur in intervals of about 4 to about 5 h.
Whether a pulsed release methylphenidate dosage form is in a tablet, capsule
or
other form, each pulse preferrably releases from about 2 to about 15 mg of
methylphenidate, more preferrably from about 5 to about 10 mg of
methylphenidate.
Another preferred active ingredient for use in the dosage forms of the present
invention is levodopa, optionally, in combination with an inhibitor of the
aromatic L-
amino decarboxylase enzyme such as carbidopa. The most preferred mode for
treating
Parkinson's patients is a formulation where the levodopa and carbidopa are
uniformly
dispersed in the gastric retention delivery system. A most preferred
formulation for the
GRDS with levodopa and carbidopa homogeneously mixed in the matrix comprises
about 10 wt. % to about 14 wt. % HPMC, from about 42 wt. % to about 47 wt. %
HPC,
from about 7 wt. % to about 12 wt. % croscarmellose sodium, from about 6 wt. %
to
about 9 wt. % tannic acid, from about 18 wt. % to about 22 wt. % levodopa ,
from about
3 wt. % to about 6 wt. % carbidopa, and, optionally, from about 0.3 wt. % to
about 1.0
wt. % of a tablet lubricant such as magnesium stearate. This formulation can
be
administered every 8 hours and is a distinct improvement over current dosing.
A second most preferred mode for treating Parkinson's patients is nighttime
dosing of levodopa so that the patient wakes in an "on" state. In this case a
slow release
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tablet of levodopalcarbidopa is embedded in the expanding composition so that
a delay
of drug release is obtained while the delivery system remains in the stomach.
A slow
release tablet based on HPMC, for example as is known in the art, is embedded
, using a
I~ilian RUD press coat machine or equivalent, in the expanding composition.
The most
preferred formulation for this use is from about 10 wt. % to about 20 wt. %
HPMC, from
about 50 wt. % to about 60 wt. % HPC, from about 12 wt. % to about 25% wt.
croscarmellose sodium, from about 8 wt. % to about 12 wt. % tannic acid and
from about
0.5 wt. % to about 1 wt. % tablet lubricant such as magnesium stearate. This
tablet
would be taken at night before sleep, will delay release until the early
morning hours,
and will then slowly release the drug.
The levodopa dose is preferrably from about 150-250 mg, more preferrably about
200 mg, in the most preferred dosage forms for delivery of levodopa,
optionally in
combination with an amino decarboxylase enzyme inhibitor.. When carbidopa is
used,
the carbidopa dose is preferrably from about 25 to about 100 mg, more
preferrably about
50 mg, in the most preferred dosage forms for delivery of levodopa and an
amino
decarboxylase enzyme inhibitor.
The dosage forms of the present invention are useful for administration of a
wide
variety of active ingredients. The dosage forms are particularly valuable for
delayed,
sustained and pulsed delivery of drugs that have a narrow window of
bioavailability due
to slow absorption or selective absorption by the stomach, duodenum or
jejunum. The
dosage forms may be used to administer drugs that are best absorbed through
the lining
of the stomach, duodenum or jejunum and drugs intended to have a local effect
in these
regions. Drugs intended to have a local effect in the stomach include
antipeptic ulcer
drugs, antacids, drugs for treating gastritis and esophagitis, and drugs to
reduce risk of
gastric carcinoma. As previously discussed, dosage forms made according the
present
invention have distinct therapeutic advantages for treatment of attention
deficit disorder
and hyperactivity in children with methylphenidate, treatment of Parkinson's
disease
with levodopa and treatment of bone loss with alendronate and other bis-
phosphonates.
Other active ingredients that may be administered in the drug delivery
vehicles of
the present invention include adrenergic receptor agonists and antagonists;
muscarinic
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receptor agonists and antagonists; anticholinesterase agents; neuromuscular
blocking
agents; ganglionic blocking and stimulating agents; sympathomimetic drugs;
serotonin
receptor agonists and antagonists; central nervous system active drugs such as
psychotropic drugs, antipsychotic drugs, antianxiety drugs, antidepressents,
antimanic
drugs, anesthetics, hypnotics, sedatives, hallucinogenic drugs and
antihallucinogenic
drugs; antiepileptic drugs; antimigraine drugs; drugs for treatment of
Parkinson's,
Alzheimer's and Huntington's disease; analgesics; antitussive agents;
antihistaminic
drugs; HI, H2, and H3 receptor antagonists; bradykinin receptor antagonists;
antipyretic
agents; antiinflammatory agents; NSAIDs; diuretics; inhibitors of Nay-Cl-
symport;
vasopressin receptor agonists and antagonists; ACE inhibitors; angiotensin II
receptor
antagonists; renin inhibitors; calcium channel blockers; (3-adrenergic
receptor
antagonists; antiplatelet agents; antithrombic agents; antihypertensive
agents;
vasodialators; phosphodiesterase inhibitors; antiarrhythmic drugs; HMG CoA
reductase
inhibitors; H+, K+-ATPase inhibitors; prostaglandins and prostaglandin
analogs;
laxatives; antidiarrheal agents; antiemetic agents; prokinetic agents;
antiparasitic agents
such as antimalarial agents, antibacterial agents, drugs for treatment of
protozoal
infections and antihelmintic drugs; antimicrobial drugs such as sulfonamides,
quinolones, ~3-lactam antibiotics, aminoglycosides, tetracyclines,
chloramphenicol and
erythromycin; drugs for treatment of tuberculosis, drugs for treatment of
leprosy;
antifungal agents; antiviral agents; immunomodulators; hematopoietic agents;
growth
factors; vitamins; minerals; anticoagulants; hormones and hormone antagonists
such as
antithyroid drugs, estrogens, progestins, androgens, adrenocortical steroids
and
adrenocortical steroid inhibitors; insulin; hypglycemic agents; calcium
resorption
inhibitors; clucocorticoids; retinoids and heavy-metal antagonists. The active
ingredient
in the dosage form may be a pharmaceutically acceptable salt, prodrug or
derivative of
the agent that exerts a therapeutic effect in the patient.
In addition to the above-described excipients, the drug delivery vehicle may
further include one or more other excipients that may be added to the vehicle
for a
variety of purposes. It will be understood by those in the art that some
substances serve
more than one purpose in a dosage form. For instance, some substances are
binders that
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help hold a tablet together after compression, yet are disintegrants that help
break the
tablet apart once it reaches a patient's stomach. It will be further
understood that the
hydrogel, superdisintegrant and tannic acid of the expanding composition may
serve to
perform additional functions in the dosage form, which functions may already
be known
to those skilled in the art.
Diluents increase the bulk of a solid pharmaceutical product and may make it
easier for the patient and care giver to handle. Diluents include, for
example,
microcrystalline cellulose (e.g., Avicel~), microfine cellulose, lactose,
starch,
pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates,
dextrin,
dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate,
kaolin,
magnesium carbonate, magnesium oxide, maltodextrin, mannitol,
polymethacrylates
(e.g., Eudragit~), potassium chloride, powdered cellulose, sodium chloride,
sorbitol and
talc.
Compacted dosage forms like those of the present invention may include
excipients whose functions include helping to bind the active ingredient and
other
excipients together after compression. Binders for solid pharmaceutical
compositions
include, but are not limited to, acacia, alginic acid, carbomer (e.g.,
carbopol),
carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, glucose,
guar gum,
hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose
(e.g.,
Klucel~), hydroxypropyl methylcellulose (e.g., Methocel~), liquid glucose,
magnesium
aluminum silicate, maltodextrin, methylcellulose, polymethacrylates,
polyvinylpyrrolidone (e.g., Kollidon~, Plasdone~), starch, pregelatinized
starch, sodium
alginate and alginate derivatives.
The dissolution rate of a compacted dosage form in the patient's stomach also
may be adjusted by the addition of a disintegrant or second superdistegrant to
the dosage
form, in addition to the superdisintegrant of the present inventive
composition. Such
additional disintegrants include, but are not limited to, alginic acid,
carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac-Di-
Sol~,
Primellose~), colloidal silicon dioxide, croscarmellose sodium, crospovidone
(e.g.,
Kollidon~, Polyplasdone~), guar gum, magnesium aluminum silicate, methyl
cellulose,
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microcrystalline cellulose, polacrilin potassium, powdered cellulose,
pregelatinized
starch, sodium alginate, sodium starch glycolate (e.g., Explotab~) and starch.
Glidants can be added to improve the flow properties of a solid composition
and
improve the accuracy of dosing. Excipients that may function as glidants
include, but
are not limited to, colloidal silicon dioxide, magnesium trisilicate, powdered
cellulose,
starch, talc and tribasic calcium phosphate.
When a dosage form such as a tablet is made by compaction, a composition is
subjected to pressure from a punch and dye. Some excipients and active
ingredients
have a tendency to adhere to the surfaces of the punch and dye, which can
cause the
product to have pitting and other surface irregularities. A lubricant can be
added to the
composition to reduce adhesion and ease release of the product from the dye.
Lubricants
include, but are not limited to, magnesium stearate, calcium stearate,
glyceryl
monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated
vegetable
oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate,
sodium
steaxyl fumarate, stearic acid, surfactants, talc, waxes and zinc stearate.
Flavoring agents and flavor enhancers make the dosage form more palatable to
the patient. Common flavoring agents and flavor enhancers for pharmaceutical
products
that may be included in the drug delivery vehicle of the present invention
include, but are
not limited to, maltol, vanillin, ethyl vanillin, menthol, citric acid,
fiunaric acid ethyl
maltol, and tartaric acid.
The dosage forms may also be colored using any pharmaceutically acceptable
colorant to improve their appearance and/or facilitate patient identification
of the product
and unit dosage level.
Having thus described the present invention with reference to certain
preferred
embodiments, the following examples are provided to further illustrate the
invention.
EXAMPLES
Materials:
The HPMC used was Methocel~ I~-15PM, available from Dow Chemical Co.
The hydroxypropyl cellulose used was Klucel~ HF NF, available from Hercules,
except
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where otherwise indicated. The croscarmellose sodium used was Ac-Di-Sol~
available
from Avebe Corp. The crosslinked polyacrylic acid was Carbopol~ 974P available
from
B.F. Goodrich Chemical Ltd. Tannic Acid was purchased from Merck. All
materials
were pharmaceutical grade.
EXAMPLE 1
Preparation of Tablets
The compositions of each of the tablets prepared in Example 1 are summarized
in Table 1. All the compositions contain hydroxypropyl methylcellulose, tannic
acid, a
superdisintegrant and 1 % magnesium stearate. All of the excipients, except
for
magnesium stearate, were mixed simultaneously and thoroughly blended by hand.
Magnesium stearate was then added at a level of 1 % w/w and the blend was
further
mixed by hand until the magnesium stearate was uniformly distributed
throughout the
composition. The amount of each composition needed to produce a 5 mm thick
tablet
was determined and then that amount was compressed into 5 mm thick tablets on
a
Manesty f3 single punch tableting machine with a 10 mm diameter punch and die.
Tablets ranged in weight from 350 - 400 mg and each had a hardness within the
range of
5-7 KP as tested in an Erweka hardness tester.
Table 1
Formulation
No.
(wt.
%)
Excipient 1 2 3 4 5 6 7 8
Hydroxypropyl methylcellulose23.832.7 30.3 23.8 26.7 38.5 34.8 15.9
Hydroxypropyl cellulose 0.0 0.0 0.0 0.0 16.0 19.2 0.0 47.6
Cross-linked polyacrylic0.0 0.0 0.0 0.0 0.0 0.0 8.7 0.0
acid
Total hydrogel 23.832.7 30.3 23.8 42.7 57.7 43.5 63.5
Sodium starch glycolate 71.4 65.4 60.6 0.0 53.3 38.5 52.231.7
Croscarmellose sodium 0.0 0.0 0.0 71.4 0.0 0.0 0.0 0.0
Tannic acid 4.8 2.0 9.1 4.8 4.0 3.8 4.3 4.8
Total 100 100 100 100 100 100 100 100
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Expansion Tests
The tablets were added to 40 ml of simulated gastric fluid (0.1M HCl)
contained
in a 50 ml beaker and maintained at 372°C. The tablets were removed
after fifteen
minutes with a tweezers and measured with a caliper. Gel strength was assessed
qualitatively with the tweezers.
The results of the expanding tests are summarized in Table 2. Expansion of the
hydrogel was enhanced using either croscarmellose sodium or sodium starch
glycolate.
The formulation can optionally and advantageously contain a mixture of two
hydrogel
polymers as demonstrated by the incorporation hydroxypropyl cellulose and
Carbopol~
in the formulations of Examples 5, 6 and 8. The tablet that expanded the most
(36 fold)
contained about 5 wt. % tamiic acid and croscarmellose sodium as the
superdisintegrant.
The tablet with the second highest expansion (18 fold) also contained about 5
wt.
tannic acid but used sodium starch glycolate as the superdisintegrant. Both of
those gels
(Examples 1 and 4) were qualitatively weak compared to those of examples 5-8.
The
best performing tablets in terms of a high degree of expansion and good
mechanical
strength are those of Examples 5 and 8, which contained 5 wt. % tannic acid
and used
both hydroxypropyl methylcellulose and hydroxypropyl cellulose hydrogel
polymers.
Table 2
Formulation No. Degree of Expansions Strength
1 18.1 moderate
2 12.7 moderate
3 7.2 moderate
4 36.0 moderate
5 10.4 strong
6 2.0 strong
7 4.5 strong
8 9.7 strong
a ratio of hydrated tablet volume to dry tablet volume
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EXAMPLE 2
Rate and Degree of Swelling of Placebo Formulations
The formulations in Table 3, below, were prepared by first dry mixing the
powdered ingredients, except the magnesium stearate, for 5 minutes. Magnesium
stearate was then added and blended in over 2 minutes. The formulation was
pressed
into oval tablets of dimensions 17 x 9 x 8.5 mm using a Manesty f3 single
punch tablet
press where the 8.5 is the tablet thickness or height in the dimension of
compression.
Table 3
Formulations of Placebo GRDS
Formulation No. (wt. %)
Ingredient I 0 I 1 12
HPMC I~15 16 15.7 13.4
HPC 48 47.2 45
Croscarmellose sodium 31.9 31.4 29.1
Tannic acid 3.1 4.7 I2
Magnesium stearate 1 1 0.5
The tablets were immersed in 450 ml of USP Gastric TS buffer (pH=1.2)
without enzymes at 37°C in a USP type II dissolution bath with the
paddles set at the top
of the buffer so as not to hit the expanding tablets. The solution was stirred
at 50 RPM.
The tablets were removed from the buffer at 15 minutes, 1 and 3 hours, gently
blotted
dry with paper, and measured using a calibrated caliper. The two major
dimensions,
length and height, were measured. The third dimension expanded from 9 mm to
about
14 mm in all of the cases. Results of the measurements are shown in Table 4.
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Table 4
Expansion of the Placebo GRDS tablets in USP Gastric TS buffer
Formulation No.: 10 11 12
Time (hours) Size (mm x Size (mm x Size (mm x
mm) mm) mm)
0 17x8.5 17x8.5 17x8.5
0.25 21 x 15 25 x 21 25 x 18
1 21x15 32x24 27x19
3 21 x 15 32x24 27x20
Most of the expansion occurred in the first 15 minutes. One can see that the
degree of expansion was greatest in the dimension of compression. This
dimension
expanded between 1.8 and 2.8 times its size. In length, the tablet grew from
1.2 to 1.9
times its size.
EXAMPLE 3
Method
Gel strength was measured by the weight needed to deflect the expanded gel by
4
mm. The gels were removed from the Gastric TS buffer, blotted dry with paper,
and
placed on a flat surface on a top loading balance. A plastic cylinder was
placed on the
gel and water was added slowly to the cylinder until the gel was compressed
downward
by 4 mm. The weight required for 4 mm deflection was recorded.
Effect of Tannic Acid Content on Gel Strength
Formulations were prepared as in Example 2 with varying amounts of tannic
acid. Tablets were pressed and immersed in simulated gastric fluid as
described in
Example 2. All the tablets swelled to at least 25 x 22 mm in 15 minutes. '
Results of the
measurement of gel strength are found in Table 5.
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Table 5
Strength of Expanded Gels as a Function of Tannic Acid Content
Formulation % Tannic Acid Strength (g)
13 4.2 27
14 4.7 51
6 90
16 7 147
Raising the percent of tannic acid from 4.2 to 7 percent dramatically
increased
10 the strength the expanded gel. In experiments not reported in Table 5 it
was discovered
that increasing the percent of tannic acid from 7 and 12 % resulted in little
further
increase in gel strength.
Effect of Superdisinte.grant Content on Gel Strength
15 Formulations were prepared as described in Example 2 with varying amounts
of
croscarmellose sodium. Tablets were pressed and the tablets were immersed in
simulated gastric fluid as described in Example 2. All the tablets swelled to
at least 23 x
18 mm in 15 minutes. The formulations tested and the results of the
measurement of gel
strength are provided in Table 6.
Table 6
Strength of Expanded Gels as a Function of Croscarmellose Sodium Content
Formulation No. %)
(wt.
Ingredient 17 18 19
HPC 46.6 50 55.9
Croscarmellose sodium 31 26 21.4
HPMC K15 15.5 15 15.7
Tannic acid 5.9 6 6
Magnesium stearate 1 1 1
Weight required to deflect 90 116 157
gel by 4 mm (g)
As can be seen in Table 6, lowering the percent of the superdisintegrant in
the
formulation tended to increase the gel strength.
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EXAMPLE 4
Stren hgt of Expanded Gel of Tablets Containing Levodopa/Carbidona
The formulations in Table 7, containing 200 mg levodopa and SO mg carbidopa,
were prepared as follows. Drug granulate: a solution of 0.75% w/v Klucel LF in
ethanol
S was used as a binding solution for a mixture of 4:1 levodopa:carbidopa. The
granulation
was carried out in a Zanchetta Rotolab one pot granulator. The granulate was
either
dried under vacuum in the granulator or air dried at room temperature
protected from
light. The final composition of the granulate was levodopa 80.5 %, Garbidopa
19.9%,
Klucel LF 0.6%. A drug granulate containing levodopa was prepared by the same
method. Final composition: 99.4% levodopa, 0.6% Klucel LF.
The dried granulate was milled through a 0.63 mm sieve and then mixed with the
other powders and tablets pressed as described in Example 2. The drug
granulate was
dispersed uniformly throughout the expanding composition. The tablets were
swelled
and the strength measured as in Example 3. All the formulations swelled to at
least 2S x
1 S 22 mm in 1 S minutes. The formulations tested and the strength of the
expanded gel
measured are given in Table 7.
Table 7
Strength of Expanded Gels as a Function of Croscarmellose Sodium
Content for Levodopa/Carbidopa GRDS Formulations
Formulation %)
(wt.
Ingredient 20 21 22 23 24
I~PMC 12.7 12.7 17.7 12.7 13.4
2S HPC 38.4 43.4 38.4 45.9 48.4
Croscarmellose sodium 16.8 11.8 11.8 9.3 9.8
Tannic acid 7.6 7.6 7.6 7.6 8
Levodopalcaxbidopa granulate 24.1 24.1 24.1 24.1 ---
Levodopa granulate --- --- --- --- 20
Magnesium stearate 0.4 0.4 0.4 0.4 0.4
Weight required to deflect 100 162 168 282 298
gel
by 4 mm (g)
As can be seen in Table 7, lowering the superdisntegrant content of the
3S formulation has a strong influence on tablet strength as was found with the
placebo
3S
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formulations. Whether the amount of croscarmellose was replaced with HPC as in
Formulation No. 21 or with HPMC as in Formulation No. 22.had no effect on the
gel
strength.
EXAMPLE 5
Release of Drugs Homogeneously Dispersed in the GRDS Formulation
Formulations of different drugs, or drug granulates, were prepared by direct
compression techniques where the drug is uniformly dispersed in the powder
mixture
and tablets were pressed as described in the previous examples. The release of
the drug
was measured in 900 ml USP Gastric TS in a USP type II dissolution apparatus
at 37°C
and 50 RPM with the paddle in the standard position. The swollen tablets,
which were of
neutral density, were occasionally hit by the paddle during the release
experiments. The
tablets were strong enough not to be deformed by such battering.
Levodopa and Carbidopa Tablets
The release of the drugs from Formulations 23 and 24 described above in
Example 4 was measured. The cumulative amount of drug released was measured by
HPLC using the following conditions:
Column: Merck Lichrosphere 60 RP-Select B Sym 125 x 4 mm
Mobile phase: 94:4 Phosphate buffer (pH= 2.3 ):Acetonitrile
Flow rate: 1 ml/ min
Detector: UV at 280 mn
Retention times: Levodopa 5 minutes; Carbidopa 13 minutes
Levodopa and carbidopa are released from the GRDS system at about the same
rate of ~ 8 %/hour. Formulations 23 and 24 afford an extended controlled
relase of the
two drugs. The release rate data is provided in Table 8.
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Table 8
Cumulative Release of Levodopa and Carbidopa
Homogeneously Dispersed in the GRDS
Formulation No.: 23 24
Time (h) Levodopa (%) Carbidopa (%) Levodopa (%)
1 9 8.5 11.4
2 21.4 18.1 26.1
3 30.8 26.4 33
4 37.6 33.4 39.1
5 44.5 39.6 ---
6 52.8 53.5 48.8
7 58.1 56.9 ---
8 64 62 54.6
12 --- --- 67.9
18 ___ ___ 78.5
24 --- --- 92.4
Acetaminophen Tablets
Diffused tablets of acetaminophen at dose levels of 200 mg and 10 mg per
tablet
were prepared with the tablet weight being 1 gram. The formulations are given
in Table
9.
Table 9
Formulations of GRDS with Acetaminophen
Homogeneously Dispersed in the Tablet
Formulation (wt.
%)
Ingredient 25 26
HPMC 16.7 13
HPC 56.3 46
Croscarmellose sodium 15 10
Tannic acid 1 10
Acetaminophen 1 20
Magnesium stearate 1 1
The release of the drug was measured in Gastric TS as described above and the
cumulative drug release measured by HPLC using the following conditions:
Column: Hypersyl ODS 250 x 4.6 mm, 5 micron
Mobile phase: 75:25 water:methanol
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Flow rate: 1.S ml / min
Detector: UV at 243 nm
Retention times: 3.S minutes
S The results of the drug release are shown in Table 10. One sees an extended
controlled release of this soluble drug.
Table 10
Cumulative Release of Acetaminophen
Homogeneously Dispersed in the GRDS
Percent Release
Time (h) 2S 26
1 11.8 16.0
2 20.2 25.0
1 S 3 28.0 32.6
4 34.9 39.2
86.1 91.5
20 Alendronate Tablets
Sodium Alendronate monohydrate was dispersed in the GRDS tablet at a weight
equivalent to 10 mg alendronic acid per tablet. The formulation is given in
Table 11 and
the release profile in Table 12. Alendronate concentrations were measured
using HPLC
on the FMOC (9-Fluroneylmethylchloroformate) derivative using the following
2S conditions:
Column: Hamilton PRP-1, 2S0 x 4.1 mm, S micron
Mobile phase: 7S: 20 : S Citrate+Phosphate buffer (pH=8):Acetonitrile:methanol
Flow rate: 1.0 ml/ min
Detector: UV at 266 nm
Retention time: S.6 minutes
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Table 11
Formulation of Alendronate Homogeneously Dispersed in the GRDS
Formulation No.
Ingredient 27 (wt. %)
HPMC 16.7
HPC 56.6
Croscarmellose sodium 14
Tannic acid 10
Sodium alendronate monohydrate 1.67
Magnesium stearate 1
Table 12
Cumulative Release of Alendronate
Homogeneously Dispersed in the GRDS
Time (h) % Release
1 2.5
2 3.1
3 5
~ 5 7
8 12.6
24 45
EXAMPLE 6
Release of Levodopa and Carbidopa from an Embedded Reservoir in the GRDS
A 275 mg reservoir tablet containing 200 mg levodopa and 50 mg carbidopa
unformly dispersed in an HPC matrix was formed. This reservoir slowly erodes
to
release the drugs over about two hours. This reservoir was embedded in 725 mg
of the
GRDS formulation of Table 13 and compressed into an oval tablet of dimensions
17 x 9
x 8.5 mm.
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Table 13
Ingredient Formulation No. 28 (wt. %)
HPC 50.3
HPMC 16.7
Croscarmellose sodium 22
Tannic acid 10
Magnesium steaxate 1
The cumulative release of the two drugs, measured as above in Example 5, is
given in Table 14.
Table 14
Cumulative Release of Levodopa and Carbidopa
from a Tablet Embedded in the GRDS
Time (h) ' Levodopa Carbidopa
(%) (%)
1 1.1 0.9
2 2 1.5
3 3.1 3
4 5.1 5.9
5 16.4 16.9
6 69.7 73.7
Both drugs show an initial delay in release followed, several hours later, by
the
two drugs being released in parallel. The inner eroding tablet was designed
for a short
controlled release. This example shows the feasibility of giving the GRDS
levodopa/carbidopa at night for a delayed delivery in the stomach in the early
morning.
This tablet also could be designed to give a more extended release profile.
Release of Alendronate from a Reservoir Partially Embedded in the GRDS
Two different formulations of an inner tablet of alendronate, Formulations 29
and
30, were prepared and embedded in the GRDS formulation such that one face of
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embedded tablet was partially exposed to the surface. The GRDS formulation
used was:
Table 15
GRDS of Formulations
Ingredient Nos. 29 & 30 (wt. %)
HPC 57.3
HPMC 16.7
Croscarmellose sodium 15
Tannic acid 10
Magnesium stearate 1
The inner core for Formulation No. 29 was formed by wet granulation of sodium
alendronate monohydrate and urea with 50% aqueous ethanol, drying, milling and
mixing the powder with magnesium stearate. The tablets pressed were of 5 mm
diameter, weighed 50 mg /tablet and contained 11.6 mg of the sodium
alendronate
monohydrate, 37.9 mg urea and 0.5 mg magnesium stearate per tablet.
The inner core of Formulation No. 30 was formed by mixing the alendronate salt
and Avicel, adding magnesium stearate and mixing for a few minutes and again
pressing
50 mg tablets of 5 mm diameter that contain 11.6 mg sodium alendronate
monohydrate,
37.9 mg Avicel and 0.5 mg magnesium stearate per tablet.
The release of alendronate was measured as described in Example 5 and the
results of those measurements axe provided in Table 16. As can be seen from
the
cummulative release over 21 h, partially embedded tablets axe another means of
achieving extended controlled release from the GRDS system in a patient's
stomach.
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Table 16
Cumulative Release of Alendronate
from Partially Embedded Tablets
Cumulative Percent
Release
Time (h) Form. 29 Form. 30
1 16 7
2 23.7 18
3 27.8 31
4 31.6 41
6 44.2 53
21 79.6 -
EXAMPLE 7
In Vivo Release of LevodopalCarbido~a in a Bea._1~ a Dog
Levodopa, the mainstay of treatment for Parkinson's disease, would benefit
from
an extended drug release profile. However, conventional extended release
formulations
cannot be used for this drug because it is absorbed in the duodenum only and
not in the
distal small intestine nor in the colon. The residence time of a drug in the
duodenum is
very short, on the order of minutes. Any extended delivery of levodopa must be
in the
stomach from where the drug will transfer to the duodenum, its site of
absorption.
Therefore, a gastric retention extended delivery vehicle will greatly enhance
levodopa's
efficacy in treating Parkinson's disease. The drug is also an excellent
indicator of gastric
retention. Shortly after gastric emptying the drug is no longer absorbed.
Levodopa also
has a short half life in the blood. All extended absorption found in an in
vivo trial is
indicative of gastric retention with duodenal absorption.
Methods
Blood Sampling for Pharmacokinetic Evaluation
Prior to the study, an adequate amount (5-10 ml) of whole blood was drawn from
the dog to prepare a standard calibration reference curve.
In addition, four labeled Eppendorf microcentrifuge tubes were prepared for
each
sampling time (i. e., hourly intervals from 0-12 hours). To each of the
prepared
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microcentrifuge tubes was added 50 ~,L of water plus 300 ~,L of an extraction
mixture.
The extraction mixture consists of 25.5 ml 70% perchloric acid, 2.5 grams
sodium
metabisulfite, 2.5 grams sodium lauryl sulfate, 0.25 grams disodium EDTA, 2.5
ml TEA,
50 ml Ethanediol, and 1.25 grams Tween 20, up to a total volume of S00 ml,
adjusting to
volume with water.
At the study, the foreleg (right or left, as deemed appropriate by the animal
handler), was shaved using an electric shaver, and the area cleansed with a
chlorhexidine
swab. A permanent in-dwelling polyethylene catheter using a 23 gauge needle
was
inserted in the cephalic vein in the foreleg of each dog and taped in place to
allow for
periodic blood sampling over 12 hours. A plastic bonnet was placed around the
head of
each dog to ensure that the dog's mouth could not reach the catheter site.
At each time point, 2.0 ml blood was removed by syringe and then placed into
the
pre-labeled heparinized test tube. The test-tube, was shaken vigorously by
hand. Then,
four aliquots, each containing 250 ~,L of whole blood, were withdrawn from the
test-tube
by pipette and immediately added to one of the four labeled Eppendorf
microcentrifuge
tubes, for that sampling time point.
The Eppendorf microcentrifuge tubes were vortexed and then immediately
transferred to a deep freezer where the samples were maintained at -
70°C.
The aliquot tubes were weighed and 25 ~.L of 1M Na2HP04 solution containing
NazSz05 (10% w/v) were added to the tubes. The tubes were then centrifuged at
13000 g
for about 15 minutes at 4°C. The supernatant from each sample was
filtered through a
0.2 ~,m syringe filter. The residual supernatants were stored frozen at -
70°C in labeled
vials in case sample dilution was required.
HPLC AnalySlS
The levels of levodopa and carbidopa in whole blood were determined by
reversed phase high performance liquid chromatography (RP-HPLC) with
electrochemical detection.
The HPLC column was a Licrosphere 60RP select B, S~,m, 250 x 4.0 mm,
(Merck, #1.50214) with a Licrocart 4-4 cartridge 60RP select B, 5 Vim, 4.0 x
4.0 mm
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(Merck, No. 1.50963). The injection volume was 10,1, with a sample temperature
of 5°C
and a flow rate of 1.3 ml/min.-'; The column temperature was 50°C, with
a run time of
about 10 minutes. The electrochemical detector (Coulochem II 5200-A ESA
Huntingdon, UK, Model 5010; Analytical Cell = Model 5021) had the following
parameters: Potential El=-350 mV; Potential EZ =+250 mV; Guard Potential E=-50
mV;
Rise Time - 5 seconds, and Gain - 1 ~.A.
The lower limits of detection (LLD) for both levodopa and carbidopa were 12.5
ng/ml.
The Study
The dog was fasted overnight for a period of at least 12 hours at which time
he
received a single mixed meal of solid food and liquid nutrients. 250 grams of
bite-size
commercial dog chow (Bonzo Feed) were measured and placed in a feeding dish.
The
dog was allowed to eat over %2 hour, at which time the dish was removed. The
food
remaining in the dish was measured and the difference from the original 250
grams was
recorded as the amount of food consumed. Additionally, 250 calories of liquid
nutrients
(Ensure , 237 ml) were administered via a gastroesophageal feeding tube. No
additional
food was allowed for the duration of the study, but water was provided ad
libitum from a
tap in the dog's cage during the study.
Within two hours following the meal, the dog was prepared for catheter
insertion
and a "pre-dosing" "0" hour blood sample was drawn. The blood was drawn and
the
sample handled as described above ("Blood Sampling for Pharmacokinetic
Evaluation").
Two hours after the meal, after the "pre-dosing" blood sample was taken, the
dog
was dosed with Formulation 23 (Example 4, Table 7) with the following
composition:
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Formulation
23
Ingredient wt. % wt. (mg)
HPMC 12.7 132
HPC 45.9 476
Croscarmellose sodium 9.3 96
Tannic acid 7.6 79
Levodopa 19.3 200
Carbidopa 4.8 50
Magnesium stearate 0.4 4
Total 100 1037
After administering the test hydrogel, 300 mg of pH regulated (pH of 2.0)
water was
administered, via flexible tubing to the stomach.
Every hour following dosing, up to 12 hours, a blood sample (2 ml) of whole
blood was withdrawn from the catheter and placed in a heparinized glass test-
tube, from
which 4 individual aliquots (250 ~1) were removed and each aliquot placed into
a labeled,
prepared Eppendorf microcentrifuge tube. The microcentrifuge tubes were
vortexed
(Vortex-2 Genie; Scientific Industries Model G-560E) for a few seconds and
then
immediately placed in a deep freezer, where the samples were maintained at -
70°C until
analysis.
For each sampling time, four aliquots were prepared and frozen. Replicate
samples were assayed over the next few days for levodopa and carbidopa levels,
while
the remaining two aliquots were stored in the deep freezer for future
analysis.
Results
The Results of the in vivo release of levodopa/carbidopa are shown in Table
17.
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Table 17
In Vivo Release of Levodopa/Carbidopa in a Beagle Dog
Blood Concentration (ng
ml- )
Time (h) Levodopa Carbidopa
0 0.0 0
1 96.5 0
2 104.1 32.5
3 574.3 52.8
4 653.1 ' 86.3
5 387.4 75.0
6 1008.7 119.2
7 1934.8 337.0
8 1783.1 661.8
9 371.1 226.7
10 214.0 145.7
11 202.3 174.0
12 96.5 70.9
The release of the two drugs is delayed and quite extended. There are
significant
levels of levodopa for at least 6 hours and the peak is delayed, indicating
that the delivery
system was in the stomach for many hours releasing the drugs. The data of
Table 17 is
also presented graphically in Fig. 1.
EXAMPLE 8
Gastric Retention Deliver~ystem with In Situ External Tablet Adhesion
One method of obtaining pulsed delivery of a drug in the stomach is to attach
tablets with predetermined delays before disintegration to the gastric
retention delivery
system (GRDS) tablet. Such attachment can be through partial embedding of the
tablet in
the GRDS matrix or by adhering it externally to the GRDS. In this example we
show the
feasibility of such external adhesion.
The GRDS formulation was that shown in Table 13 of Example 6. The powders,
except the lubricant, were mixed for five minutes. Magnesium stearate was then
added
and the powders mixed for one minute more. The blend was pressed into
rectangular
(truncated oval) tablets of 10 x 7 x 7 mm in a Manesty f3 single punch
tableting
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machine.
An adhesive solution was prepared as follows. Sodium caseinate (EmolacTM 50,
15 g) was dissolved in 100 ml water by stirring overnight at room temperature.
500 ml of
ethanol was added with stirring to obtain an emulsion of 2.5% sodium caseinate
in
water:ethanol.
The tablets were then coated with the adhesive. The emulsion was spray coated
on
the tablets in a pan coater at a rate of 4 ml /min with the product
temperature between
30-40°C to a coating weight of between 5 and 14 mg. The tablets were
air dried in the
coating pan to give GRDS tablets coated with the adhesive.
Placebo tablets based on microcrystalline cellulose were prepared (5 x 5 x 5
mm
rectangular) and coated with Eudragit TM S to make them impervious to acid
conditions.
The tablets were loaded into a gelatin #00 capsule in a stack such that a GRDS
ablet was
in between two placebo tablets. The contact between the tablets was on the 7 x
7 mm
face of the GRDS tablet which is perpendicular to the compression axis.
The gelatin capsules were placed in 0.1 N HCl in a USP type II dissolution
bath
at 37°G and stirred at 50 RPM. The capsule dissolved and the three
tablet stack adhered
to one another in situ. Within 15 minutes the GRDS tablet had swollen to 13 x
22 mm
from 10 x 7 mm (the swelling being mostly along the compression axis). At two
hours
the GRDS tablet had swollen to 14 x 25 mm. The placebo tablets remained
attached to
the GRDS tablet, despite its swelling, for over 12 hours in the dissolution
bath. In order
to test the viability of the adherence under more vigorous conditions of flow,
the stack
was placed in 0.1 N HCl at 37°C in a disintegration tester at 50
strokes per minute. The
flows on the tablets in a disintegration tester are considerably stronger than
in the
dissolution tester. The three tablets remained adhered to one another for 10
hours.
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EXAMPLE 9
Timed Pulsed Delivery of Methylphenidate
Methylphenidate disintegrating tablets of the formulation shown in Table 18
were
prepared.
Table 18
Ingredient Percent
Methylphenidate 10
HPC (I~lucel LF) 5
Starch 25
Microcrystalline cellulose (Avicel) 49
Sodium starch glycolate 10
Magnesium stearate 1
The preparation of the tablets was as follows. Two parts methylphenidate were
granulated with one part HPC and five parts starch by adding two parts water
and mixing
in a Zanchetta Rotolab one pot granulator. The granulate was dried in a
fluidized bed
drier at 45°C, and milled through a 0.63 mm sieve. The granulate was
mixed with
microcrystalline cellulose and sodium starch glycolate for five minutes,
magnesium
stearate added and the mixing continued for 1 minute. The blend was pressed
into 5 mm
tablets of 100 mg each in a Manesty f3 single punch tableting machine.
A coating solution was prepared by dissolving 5 grams of ethylcellulose, 0.75
grams urea, and 0.5 grams triethylcitrate in ethanol for a total weight of 100
grams. This
solution was sprayed on the tablets in a pan coater with the tablet bed kept
at 30-40°C.
Different weights of coating were sprayed on the tablets. The tablets were
tested for
delay in burst drug release in a USP type II dissolution apparatus in O.1N HCl
at 37°C
and 50 RPM. The results of the burst delay as a function of coating level is
shown in '
Table 19.
Table 19
Coating level (mg/tablet) Burst Time (h)
4 2
6 5
8 12
Tablets of this type can be adhered to GRDS tablets to afford extended
residence
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in the stomach and burst release of methylphenidate.
Having thus described the invention with reference to certain preferred
embodiments, other embodiments will become apparent to one skilled in the art
from
consideration of the specification and examples. It is intended that the
specification,
including the examples, is exemplary only, with the scope and spirit of the
invention
being defined by the claims which follow.
49
