Note: Descriptions are shown in the official language in which they were submitted.
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MODIFIED RELEASE TICLOPIDINE COMPOSITIONS
Cross-Reference to Related Applications
This application claims the benefit of U.S. Provisional Application No.
60/686,931, filed June
12, 2005, and is a continuation-in-part of U.S. Application No. 11/372,857,
filed March 10, 2006,
which is a continuation-in-part of U.S. Application No. 10/827,689, filed
April 19, 2004, which is a
continuation of U.S. Application No. 10/354,483, filed January 30, 2003, now
U.S. Pat. No.
6,793,936, which in turn is a continuation of U.S. Application No. 10/331,754,
filed December 30,
2002, now U.S. Pat. No. 6,902,742, which in turn is a continuation of U.S.
Application No.
09/850,425, filed May 7, 2001, now U.S. Pat. No. 6,730,325, which in turn is a
continuation of U.S.
Application No. 09/566,636, filed May 8, 2000, now U.S. Pat. No. 6,228,398,
which in turn is a
continuation of PCT Application No. PCT/US99/25632, filed November 1, 1999,
which claims the
benefit of U.S. Provisional Application No. 60/106,726, filed November 2,
1998, all of which are
herein incorporated by reference in their entireties.
Field of the Invention
The present invention relates to novel compositions and dosage forms for
patients in need of
platelet aggregation inhibition therapy. In particular, the present invention
relates to novel
compositions and dosage forms for the delivery of ticlopidine and to methods
of treatment and
suppression using the same.
Background of the Invention
Ticlopidine is known as (5-[(2-chlorophenyl)methyl]-4,5,6,7-
tetrahydrothieno[3,2-c]pyridine).
Ticlopidine hydrochloride, the hydrochloride salt of ticlopidine, has a
molecular weight of 300.25 and
is a white, crystalline solid. It is soluble in water and self-buffers to a pH
of about 3.6. It dissolves in
methanol, is sparingly soluble in methylene chloride and ethanol, slightly
soluble in acetone and
insoluble in a buffer solution of pH 6.3.
The structural formula of the hydrochloride salt of ticlopidine is shown
below:
,, - t~l ~a
:, 1 <r~r
~H"
.HC1
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Ticlopidine belongs to the thieneo-pyridine class of compounds and is used as
a platelet
aggregation inhibitor. Ticlopidine causes a time and dose-dependent inhibition
of ADP-induced
platelet-fibrinogen binding as well as prolongation of bleeding time. The
effect on platelet function is
irreversible for the life of the platelet, as shown both by persistent
inhibition of fibrinogen binding
after washing platelets ex vivo and by inhibition of platelet aggregation
after resuspension of platelets
in buffered medium. The reduction of fibrinogen in plasma has the effects of
lowering the blood
viscosity and improving the plasticity of the red blood cells. In view this
activity in preventing
excessive blood clotting, ticlopidine is used to reduce the risk of stroke,
particularly in patients who
have previously had a stroke or who have experienced transient ischemic
attacks (TIAs or "mini-
strokes").
Conventional tableted ticlopidine hydrochloride is marketed by Roche
Laboratories (Nutley,
New Jersey) under the trade name Ticlid . In addition to 250 mg of ticlopidine
hydrochloride, these
film-coated tablets also contain citric acid, magnesium stearate,
microcrystalline cellulose, povidone,
starch and stearic acid. Ticlopidine hydrochloride tablets, such as Ticlid ,
have a half-life of about
12.6 hours, and are administered orally two or more times a day.
Upon oral administration of a single 250-mg dose, ticlopidine hydrochloride is
rapidly
absorbed with peak plasma levels occurring at approximately 2 hours after
dosing and is extensively
metabolized. Absorption is greater than 80%. Administration after meals
results in a 20% increase in
the AUC of ticlopidine. Ticlopidine hydrochloride displays nonlinear
pharmacokinetics and
clearance decreases markedly on repeated dosing. In older volunteers the
apparent half-life of
ticlopidine after a single 250-mg dose is about 12.6 hours; with repeat dosing
at 250 mg bid, the
terminal elimination half-life rises to 4 to 5 days and steady-state levels of
ticlopidine hydrochloride
in plasma are obtained after approximately 14 to 21 days.
Ticlopidine hydrochloride binds reversibly (98%) to plasma proteins, mainly to
serum
albumin and lipoproteins. The binding to albumin and lipoproteins is
nonsaturable over a wide
concentration range. Ticlopidine also binds to alpha-1 acid glycoprotein. At
concentrations attained
with the recommended dose, only 15% or less ticlopidine in plasma is bound to
this protein.
Ticlopidine hydrochloride is metabolized extensively by the liver; only trace
amounts of intact
drug are detected in the urine. Following an oral dose of radioactive
ticlopidine hydrochloride
administered in solution, 60% of the radioactivity is recovered in the urine
and 23% in the feces.
Approximately 1/3 of the dose excreted in the feces is intact ticlopidine
hydrochloride, possibly
excreted in the bile. Ticlopidine hydrochloride is a minor component in plasma
(5%) after a single
dose, but at steady-state is the major component (15%). Approximately 40% to
50% of the
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radioactive metabolites circulating in plasma are covalently bound to plasma
proteins, probably by
acylation.
Ticlopidine compounds have been disclosed in U.S. Pat. Nos. 4,051,141 to
Castaigne, entitled
"Thieno[3,2-c]pyridine derivatives"; 4,591,592 to Chowhan, entitled "Acid
stabilized composition of
thieno-pyridine derived compounds"; and 5,520,928 to Sherman, entitled
"Pharmaceutical
composition of ticlopidine hydrochloride" each of which is hereby incorporated
by reference in its
entirety.
The effectiveness of pharmaceutical compounds in the prevention and treatinent
of disease
states depends on a variety of factors including the rate and duration of
delivery of the compound
from the dosage form to the patient. The combination of delivery rate and
duration exhibited by a
given dosage form in a patient can be described as its in vivo release profile
and, depending on the
pharmaceutical compound administered, will be associated with a concentration
and duration of the
pharmaceutical compound in the blood plasma, referred to as a plasma profile.
As pharmaceutical
compounds vary in their pharmacokinetic properties such as bioavailability,
and rates of absorption
and elimination, the release profile and the resultant plasma profile become
important elements to
consider in designing effective drug therapies.
The release profiles of dosage forms may exhibit different rates and durations
of release and
may be continuous or pulsatile. Continuous release profiles include release
profiles in which one or
more pharmaceutical compounds are released continuously, either at a constant
or variable rate, and
pulsatile release profiles include release profiles in which at least two
discrete quantities of one or
more pharmaceutical compounds are released at different rates and/or over
different time frames. For
any given pharmaceutical compound or combination of such compounds, the
release profile for a
given dosage form gives rise to an associated plasma profile in a patient.
Similar to the variables
applicable to the release profile, the associated plasma profile in a patient
may exhibit constant or
variable blood plasma concentration levels of the pharmaceutical compounds in
the dosage form over
the duration of action and may be continuous or pulsatile. Continuous plasma
profiles include plasma
profiles of all rates and duration which exhibit a single plasma concentration
maximum. Pulsatile
plasma profiles include plasma profiles in which at least two higher blood
plasma concentration
levels of pharmaceutical compound are separated by a lower blood plasma
concentration level.
Pulsatile plasma profiles exhibiting two peaks may be described as "bimodal."
When two or more components of a dosage form have different release profiles,
the release
profile of the dosage form as a whole is a combination of the individual
release profiles. The release
profile of a two-component dosage form in which each component has a different
release profile may
described as "bimodal." For dosage forms of more than two components in which
each component
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has a different release profile, the resultant release profile of the dosage
form may be described as
"multimodal." Depending on, at least in part, the pharmacokinetics of the
pharmaceutical compounds
that are used as well as the specific release profiles of the components of
the dosage form, a bimodal
or multimodal release profile may result in either a continuous or a pulsatile
plasma profile in a
patient.
Conventional frequent dosage regimes in which an immediate release (IR) dosage
form is
administered at periodic intervals typically gives rise to a pulsatile plasma
profile. In such cases, a
peak in the plasma drug concentration is observed after administration of each
IR dose with troughs
(regions of low drug concentration) developing between consecutive
administration time points.
Such dosage regimes (and their resultant pulsatile plasma profiles) can have
particular
pharmacological and therapeutic effects associated with them that are
beneficial for certain drug
therapies. For example, the wash out period provided by the fall off of the
plasma concentration of
the active ingredient between peaks has been thought to be a contributing
factor in reducing or
preventing patient tolerance to various types of drugs.
Many controlled release drug formulations are aimed at producing a zero order
release of the
drag compound. Indeed, it is often a specific object of these formulations to
minimize the peak to
trough variation in plasma concentration levels associated with conventional
frequent dosage regimes.
For certain drugs, however, some of the therapeutic and pharmacological
effects intrinsic in a
pulsatile system may be lost or diminished as a result of the constant or
nearly constant plasma
concentration levels achieved by zero order release drug delivery systems.
Thus, modified release
compositions or formulations which substantially mimic the release of frequent
IR dosage regimes,
while reducing the need for frequent dosing, is desirable. Similarly, modified
release compositions or
formulations which combine the benefits of at least two different release
profiles to achieve a
resultant plasma profile exhibiting pharmacokinetic values within
therapeutically effective parameters
is also desirable.
A typical example of a drug which may produce tolerance in patients is
methylphenidate.
Methylphenidate, or a-phenyl-2-piperidine acetic acid methyl ester, is a
stimulant affecting the
central nervous and respiratory systems and is primarily used in the treatment
of attention deficit
hyperactivity disorder (ADHD). After absorption from the gastrointestinal
tract (GIT), drag effects
persist for 3-6 hours after oral administration of conventional IR tablets or
up to about 8 hours after
oral administration of extended release formulations. The total dosage is
typically in the range of 5-30
mg per day, in exceptional cases rising to 60 mg/day. Under conventional
dosage regimes,
methylphenidate is given twice daily, typically with one dose given before
breakfast and a second
dose given before lunch. The last daily dose is preferably given several hours
before retiring. Adverse
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effects associated with methylphenidate treatment include insomnia and the
development of patient
tolerance.
WO 98/14168 (Alza Corp.) teaches a dosage form and a method of administering
methylphenidate in a sustained and constantly ascending rate. The dosage form
disclosed comprises a
plurality of beads comprising a hydrogel matrix with increasing amounts of the
active ingredient
therein, coated with varying amounts of a release rate controlling material.
Appropriate combinations
of the active ingredient dose and the number and thickness coating layers can
be selected to give an
ascending release profile in which the plasma concentration of the active
ingredient continually
increases over a given period of time. An object of WO 98/14168 is to release
a dosage form at a
constantly ascending rate specifically to avoid uneven blood levels
(characterized by peaks and
troughs) associated with conventional treatments using immediate release
dosage formulations. As a
result, this formulation does not deliver the active ingredient in either a
pulsatile or a bimodal manner.
WO 97/03672 (Chiroscience Ltd.) discloses that methylphenidate exhibits a
therapeutic effect
when administered in the form of a racemic mixture or in the form of a single
isomer (such as the RR
d-threo enantiomer). Further, WO 97/03763 (Chiroscience Ltd.) discloses a
sustained release
formulation containing d-threo methylphenidate (dtmp). This disclosure teaches
the use of a
composition comprising a coating through which the dtmp passes in order to
attain sustained release
and achieve serum levels (of the active ingredient) of at least 50% cmax over
a period of at least 8
hours. As above, this formulation does not deliver the active ingredient in
either a pulsatile or a
bimodal manner.
Shah et al., J Cont. Rel. (1989) 9:169-175 purports to disclose that certain
types of
hydroxypropyl methylcellulose ethers compressed into a solid dosage form with
a therapeutic agent
may produce a bimodal release profile. However, it is noted that while
polymers from one supplier
yielded a bimodal profile, the same polymers with almost identical product
specifications obtained
from a different source gave non-bimodal release profiles.
Giunchedi et al., Int. J. Pharm (1991) 77:177-181 discloses the use of a
hydrophilic matrix
multiple-unit formulation for the pulsed release of ketoprofen. Giunchedi et
al. teach that ketoprofen
is rapidly eliminated from the blood after dosing (plasma half-life 1-3 hours)
and consecutive pulses
of drug may be more beneficial than constant release for some treatments. The
multiple-unit
formulation disclosed comprises four identical hydrophilic matrix tablets
placed in a gelatin capsule.
Although the in vivo studies show two peaks in the plasma profile there is no
well defined wash out
period and the variation between the peak and trough plasma levels is small.
Conte et al., Drug Dev. Ind. Pharm, (1989) 15:2583-2596 and EP 0 274 734
(Pharmidea Srl)
teach the use of a three layer tablet for delivery of ibuprofen in consecutive
pulses. The three layer
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tablet is made up of a first layer containing the active ingredient, a barrier
layer (the second layer) of
semi-permeable material which is interposed between the first layer and a
third layer containing an
additional amount of active ingredient. The barrier layer and the third layer
are housed in an
impermeable casing. The first layer dissolves upon contact with a dissolving
fluid while the third
layer is only available after dissolution or rupture of the barrier layer. In
such a tablet the first portion
of active ingredient must be released instantly. This approach also requires
the provision of a
semi-pemieable layer between the first and third layers in order to control
the relative rates of
delivery of the two portions of active ingredient. Additionally, rupture of
the semi-permeable layer
leads to uncontrolled dumping of the second portion of the active ingredient
which may not be
desirable.
U.S. Pat. No. 5,158,777 (E. R. Squibb & Sons Inc.) discloses a formulation
comprising
captopril within an enteric or delayed release coated pH stable core combined
with additional
captopril which is available for immediate release following administration.
In order to form the pH
stable core, chelating agents such as disodium edetate or surfactants such as
polysorbate 80 are used
either alone or in combination with a buffering agent. The compositions have
an amount of captopril
available for immediate release following oral administration and an
additional amount of pH
stabilized captopril available for release in the colon.
U.S. Pat. Nos. 4,728,512, 4,794,001 and 4,904,476 (American Home Products
Corp.) relate to
preparations providing three distinct releases. The preparation contains three
groups of spheroids
containing an active medicinal substance: the first group of spheroids is
uncoated and rapidly
disintegrates upon ingestion to release an initial dose of medicinal
substance; the second group of
spheroids is coated with a pH sensitive coat to provide a second dose; and the
third group of
spheroids is coated with a pH independent coat to provide to third dose. The
preparation is designed
to provide repeated release of medicinal substances which are extensively
metabolized
presystemically or have relatively short elimination half-lives.
U.S. Pat. No. 5,837,284 (Mehta et al) discloses a methylphenidate dosage form
having
immediate release and delayed release particles. The delayed release is
provided by the use of
ammonio methacrylate pH independent polymers combined with certain fillers.
Accordingly, it is an object of the present invention to provide a
multiparticulate modified
release composition comprising at least two populations of active ingredient-
containing particles
which, upon administration to a patient, exhibits a bimodal or multimodal
release profile.
It is another object of the invention to provide a multiparticulate modified
release composition
comprising at least two populations of active ingredient containing particles
which, upon
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administration to a patient, exhibits a bimodal or multimodal release profile
that results in a plasma
profile within therapeutically effective pharmacokinetic parameters.
It is a further object of the invention to provide a multiparticulate modified
release
composition comprising at least two populations of active ingredient
containing particles which, upon
administration to a patient, exhibits a pulsatile release profile.
It is yet another object of the invention to provide a multiparticulate
modified release
composition comprising at least two populations of active ingredient
containing particles which, upon
administration to a patient, results in a pulsatile plasma profile.
It is still another object of the invention to provide a multiparticulate
modified release
composition comprising at least two populations of active ingredient
containing particles which, upon
administration to a patient, produces a plasma profile substantially similar
to the plasma profile
produced by the administration of two or more IR dosage forms given
sequentially.
It is yet a further object of the invention to provide a multiparticulate
modified release
composition comprising at least two populations of active ingredient
containing particles which, upon
administration to a patient, substantially mimics the pharmacological and
therapeutic effects produced
by the administration of two or more IR dosage forms given sequentially.
It is still a further object of the invention to provide a multiparticulate
modified release
composition comprising at least two populations of active ingredient
containing particles in which the
amount of the one or more active ingredients in the first population of
particles is a minor portion of
the amount of the one or more active ingredients in the composition, and the
amount of the one or
more active ingredients in the one or more additional population of particles
is a major portion of the
amount of the one or more active ingredients in the composition.
It is yet a further object of the invention to provide a solid oral dosage
form comprising the
multiparticulate modified release composition of the present invention.
Still other objects and advantages of the present invention will become
readily apparent to
those skilled in the art from the following detailed description, wherein the
preferred embodiments of
the invention are shown and described, simply by way of illustration of the
best mode contemplated
of carrying out the invention. As will be realized, the invention is capable
of other and different
embodiments, and its several details are capable of modifications in various
obvious respects, all
without departing from the invention.
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Summary of the Invention
The above objects are realized by a multiparticulate modified release
composition having a
first component comprising a first population of active ingredient-containing
particles and at least a
second component comprising a second population of active ingredient-
containing particles, wherein
each component has a different rate and/or duration of release and wherein at
least one of said
components comprises ticlopidine. The particles of the at least second
component are provided in a
modified release (MR) form such as, for example, coated with a modified
release coating or
comprising or incorporated in a modified release matrix material. Upon oral
administration to a
patient, the composition releases the one or more active ingredients in a
bimodal or multimodal
manner.
The first component of the multiparticulate modified release composition may
exhibit a
variety of release profiles including profiles in which substantially all of
the active ingredient
contained in the first component is released rapidly upon administration of
the dosage form, released
rapidly but after a time delay (delayed release), or released slowly over
time. In one embodiment, the
active ingredient contained in the first component of the dosage form is
released rapidly upon
administration to a patient. As used herein, "released rapidly" includes
release profiles in which at
least about 80% of the active ingredient of a component of the dosage form is
released within about
an hour after administration, the term "delayed release" includes release
profiles in which the active
ingredient of a component of the dosage form is released (rapidly or slowly)
after a time delay, and
the terms "controlled release" and "extended release" include release profiles
in which at least about
80% of the active ingredient contained in a component of the dosage form is
released slowly.
The second component of the multiparticulate modified release composition may
also exhibit
a variety of release profiles including an immediate release profile, a
delayed release profile or a
controlled release profile. In one embodiment, the second component exhibits a
delayed release
profile in which the active ingredient of the component is released after a
time delay. In another
embodiment, the second component exhibits a controlled release profile in
which the active
ingredient of the component is released over a period of about 12 to about 24
hours after
administration.
In two-component embodiments in which the components exhibit different release
profiles,
the release profile of the active ingredients from the composition is bimodal.
In embodiments in
which the first component exhibits an immediate release profile and the second
component exhibits a
delayed release profile, there is a lag time between the release of active
ingredient from the first
component and the release of the active ingredient from the second component.
The duration of the
lag time may be varied by altering the amount and/or composition of the
modified release coating or
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by altering the amount and/or composition of the modified release matrix
material utilized to achieve
the desired release profile. Thus, the duration of the lag time can be
designed to mimic a desired
plasma profile.
In embodiments in which the first component exhibits an immediate release
profile and the
second component exhibits a controlled release profile, the active ingredients
in the first and second
components are released over different time periods. In such embodiments, the
immediate release
component serves to hasten the onset of action by minimizing the time from
administration to a
therapeutically effective plasma concentration level, and the one or more
subsequent components
serve to minimize the variation in plasma concentration levels and/or maintain
a therapeutically
effective plasma concentration throughout the dosing interval. In one such
embodiment, the active'
ingredient in the first component is released rapidly and the active
ingredient in the second
component is released within a period of about 12 hours after administration.
In another such
embodiment, the active ingredient in the first component is released rapidly
and the active ingredient
in the second component is released within a period of about 24 hours after
administration. In yet
another such embodiment, the active ingredient in the first component is
released rapidly and the
active ingredient in the second component is released over a period of about
12 hours after
administration. In still another such embodiment, the active ingredient in the
first component is
released rapidly and the active ingredient in the second component is released
over a period.of about
24 hours after administration. In yet another such embodiment, the active
ingredient in the first
component is released rapidly and the active ingredient in the second
component is released over a
period of at least about 12 hours after administration. In still another such
embodiment, the active
ingredient in the first component is released rapidly and the active
ingredient in the second
component is released over a period of at least about 24 hours after
administration.
The plasma profile produced by the administration of dosage forms of the
present invention
which comprise an immediate release component and at least one modified
release component can be
substantially similar to the plasma profile produced by the administration of
two or more IR dosage
forms given sequentially; or to the plasma profile produced by the
administration of separate IR and
MR dosage forms. The modified release composition of the present invention is
particularly useful
for administering ticlopidine which is normally administered two or three
times daily. In one
embodiment of the present invention, the composition delivers the ticlopidine
in a bimodal manner.
Upon administration, such a composition produces a plasma profile which
substantially mimics that
obtained by the sequential administration of two IR doses of ticlopidine in
accordance with a typical
treatment regimen. In another embodiment, the composition delivers the
ticlopidine in a trimodal
manner. Upon administration, such a composition produces a plasma profile
which substantially
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mimics that obtained by the sequential administration of three IR doses of
ticlopidine in accordance
with a typical treatment regimen.
According to another aspect of the present invention, the composition can be
designed to
produce a plasma profile that minimizes or eliminates the variations in plasma
concentration levels
associated with the administration of two or more IR dosage forms given
sequentially. In such
embodinients, the composition may be provided with an immediate release
component to hasten the
onset of action by minimizing the time from administration to a
therapeutically effective plasma
concentration level, and at least one modified release component to maintain a
therapeutically
effective plasma concentration level throughout the dosing interval.
The present invention also provides solid oral dosage forms made from the
composition of the
invention, and for methods for treating an animal, particularly a human, in
need of treatment,
comprising administering a dosage form comprising a therapeutically effective
amount of the
composition of the invention to provide bimodal or multimodal release of the
active ingredient
contained therein.
Advantages of the present invention include reducing the required dosing
frequency while still
maintaining the benefits derived from a bimodal or multimodal plasma profile.
It is also advantageous
in terms of patient compliance to have a formulation which may be administered
at reduced
frequency.
Detailed Descri.ption of the Invention
The term "particulate" as used herein refers to a state of matter which is
characterized by the
presence of discrete particles, pellets, beads or granules irrespective of
their size, shape or
morphology. The term "multiparticulate" as used herein means a plurality of
discrete or aggregated
particles, pellets, beads, granules, or mixtures thereof, irrespective of
their size, shape or morphology.
The term "modified release" as used herein includes a release which is not
immediate and
includes controlled release, extended release, sustained release and delayed
release.
The term "time delay" as used herein refers to the period of time between the
administration
of a dosage form comprising the composition of the invention and the release
of the active ingredient
from a particular component thereof.
The term "lag time" as used herein refers to the time between the release of
the active
ingredient from one component of the composition and the release of the active
ingredient from
another component of the composition.
The term "erodable" as used herein refers to formulations which may be worn
away,
diminished, or deteriorated by the action of substances within the body.
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The term "diffusion controlled" as used herein refers to formulations which
may spread as the
result of their spontaneous movement, for example, from a region of higher to
one of lower
concentration.
The term "osmotic controlled" as used herein refers to formulations which may
spread as the
result of their movement through a semi-permeable membrane into a solution of
higher concentration
that tends to equalize the concentrations of the formulation on the two sides
of the membrane.
The term "ticlopidine" as used herein includes ticlopidine, its
pharmaceutically acceptable
salts, acids, esters, metabolites, complexes or other derivatives and thereof,
and each of their
respective stereoisomers including mixtures, racemic or otherwise, of two or
more such
stereoisomers.
The active ingredients in each component may be the same or different. For
example, the
composition may comprise components comprising only ticlopidine as the active
ingredient.
Alternatively, the composition may comprise a first component comprising
ticlopidine and at least
one subsequent component comprising an active ingredient other than
ticlopidine suitable for
coadministration therewith, or a first component containing an active
ingredient other than ticlopidine
and at least one subsequent component comprising ticlopidine. Indeed, two or
more active
ingredients may be incorporated into the same component when the active
ingredients are compatible
with each other. An active ingredient present in one component of the
composition may be
accompanied by, for example, an enhancer compound or a sensitizer compound in
another component
of the composition, in order to modify the bioavailability or therapeutic
effect thereof.
As used herein, the term "enhancer" refers to a compound which is capable of
enhancing the
absorption and/or bioavailability of an active ingredient by promoting net
transport across the GIT in
an animal, such as a human. Enhancers include but are not limited to medium
chain fatty acids; salts,
esters, ethers and derivatives thereof, including glycerides and
triglycerides; non-ionic surfactants
such as those that can be prepared by reacting ethylene oxide with a fatty
acid, a fatty alcohol, an
alkylphenol or a sorbitan or glycerol fatty acid ester; cytochrome P450
inhibitors, P-glycoprotein
inhibitors and the like; and mixtures of two or more of these agents.
In those embodiments in which more than one a ticlopidine-containing component
is present,
the proportion of ticlopidine contained in each component may be the same or
different depending on
the desired dosing regime. The ticlopidine present in the first component and
in subsequent
components may be any amount sufficient to produce a therapeutically effective
plasma concentration
level. In one embodiment, the ticlopidine is present in the composition in an
amount of from about
0.1 to about 500 mg. In another embodiment, the ticlopidine is present in the
composition in an
amount of from about 0.1 to about 250 mg.
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In embodiments which comprise one or more additional active ingredients,
suitable additional
active ingredients include any active ingredient for which it is useful to
combine the advantages of the
release profiles and their associated plasma profiles that are achieved by the
compositions of the
present invention in order to reduce the dosing frequency may be used in
practice of the present
invention. Exemplary active ingredients include but are not limited to drug
compounds acting on the
central nervous system such as psychostimulants and cerebral stimulants, for
example
methylphenidate; aldosterone inhibitors such as spironolactone, eplerenone and
analogs thereof;
alkaloids; alpha/beta-blockers such as labetalol, carvedilol and analogs
thereof; analgesics such as
acetaminophen, tramadol and opioids such as morphine, codeine, thebaine,
heroin, oxycodone,
hydrocodone, dihydrocodiene, hydromorphone, oxymorphone, buprenorphine,
etorphine, naloxone,
nicomorphine, methadone, pethidine, fentanyl, alfentanil, sufentanil,
remifentanil, carfentanyl,
pentazocine, phenazocine, butorphanol, levorphanol and analogs thereof;
anesthetics such as
lidocaine and bupivacaine and analogs thereof; anorectics such as
benzphetamine, diethylproprion,
mazindol, phendimetrazine, and phentermine; anti-adrenergic agents such as
centrally and
peripherally acting anti-adrenergic agents and analogs thereof; anti-allergic
agents; anti anginal
agents such as nitroglycerine and analogs thereof; anti-arrythmic agents such
as moricizine, ibutilide,
quinidine, procainamide, disopyramide, lidocaine, tocainide, flecainide,
mexiletine, propafenone,
bretylium, amiodarone, adenosine, dofetilide and analogs thereof; anti-
asthmatic agents such as
salbutamol and analogs thereof; antibiotics such as aminosalicylic acid,
amoxicillin, amoxicillin and
potassium clavulanate, ampicillin, ampicillin and sulbactam, azithromycin,
bacampicillin,
carbenicillin, carbenicillin indanyl sodium, capreomycin, cefadroxil,
cefazolin, cefcapene pivoxil,
cephalexin, cephalothin, cephapirin, cephacelor, cefprozil, cephadrine,
cefamandole, cefonicide,
ceforanide, cefuroxime, cefixime, cefoperazone, cefotaxime, cefpodoxime,
ceftaxidime, ceftibuten,
ceftizoxime, ceftriaxone, cefepime, cefinetazole, cefotetan, cefoxitin,
ciprofloxacine, clarithromycin,
clindamycin, clofazimine, cloxacillin, cotriamoxazole, cycloserine,
dicloxacillin, dirithromycin,
erythromycin, ethambutol, ethionamide, fosfomycin, imipenem, isoniazide,
levofloxacine,
lomefloxacine, loracarbef, methicillin, methenamine, metronidazole,
metoclopramide, mezlocillin,
nafcillin, nalidixic acid, nitrofurantoin, norfloxacin, novobiocin, ofloxacin,
oxacillin, penicillin,
pentamidine, piperacillin, piperacillin and tazobactam, sparfloxacin,
sulphacytine, sulphamerazine,
sulphamethazine, sulphamethixole, sulphasalazine, sulphisoxazole,
sulphapyrizine, sulphadiazine,
sulphmethoxazole, sulphapyridine, ticarcillin, ticarcillin and potassium
clavulanate, trimethoprime,
trimetrexate, troleanomycin, vancomycin, verapamil and analogs thereof; anti-
cancer agents; anti
coagulant agents such as heparin, hirudin and analogs thereof; anti-
convulsants such as
carbamazepine, levetiracetam, topiramate and analogs thereof; anti-depressant
agents such as
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amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine,
doxepin, escitalopram,
fluoxetine, fluvoxamine, imipramine, maprotiline, mirtazapine, nefazodone,
nortriptyline, paroxetine,
phenelzine, protriptyline, sertraline, tranylcypromine, trazodone,
trimipramine, venlafaxine, and
analogs thereof; anti-diabetic agents; anti-diarrheal agents such as
loperamide and analogs thereof;
anti emetic agents such as scopolamine, ondansetron, domperidone,
metoclopramide and analogs
thereof; anti-epileptic agents; anti-fungal agents such as acylanilide and
analogs thereof
antihistamines such as terfenadine and analogs thereof; anti-hypertensive
agents; anti-inflammatory
agents; anti migraine agents such as sumatriptan, ergot alkaloids and analogs
thereof; anti neoplastics
such as fluorouracil, bleomycin and analogs thereof; anti-parkinsonian agents
other than carbidopa,
levodopa or entacapone; anti-psychotic agents such as acetophenazine,
aripiprazole, chlorprothixene,
droperidol, olanzapine, promazine, quetiapine, risperidone, sulpiride,
triflupromazine, ziprasidone,
and analogs thereof; anti-rheumatic agents such as fentiazac and analogs
thereof; anti-thrombic
agents; anti-tussive agents; anti-ulcer agents such as 5-asa, cimetidine,
famotidine, lansoprazole,
omeprazole, ranitidine and analogs thereof; anti-viral agents such as
acyclovir, famciclovir,
ganciclovir, zidovudine and analogs thereof; anxiolytic agents such as
alprazolam, buspirone,
clonazepam, clorazepate, chlordiazepoxide, diazepam, hydroxyzine, lorazepam,
meprobamate,
oxazepam, and analogs thereof; ARB blockers, such as irbesartan, candesartan,
losartan, valsartan,
telmisartan, eprosartan and analogs thereof; beta-blockers, such as
acebutolol, atenolol, betaxolol,
bisoprolol, esmolol, metoprolol, carteolol, nadolol, penbutolol, pindolol,
propanolol, sotalol, timolol,
labetalol and analogs thereof; blood lipid-lowering agents such statins such
as simvastatin and
analogs thereof; calcium channel blockers such as nifedipine, verapamil,
diltiazem, nicardipine,
nisoldipine, nimodipine, isradipine, bepridil, felodipine, amlodipine and
analogs thereof;
cardiovascular agents, anti hypertensive agents and vasodilators such as
benazepril, captopril,
clonidine, enelapril, fosinopril, isosorbide dinitrate, isosorbide 5
mononitrate, hydralizine, lisinopril,
moexipril, pentoxifylline, perindopril, prazosine, quinapril, quinidine,
ramipril, trandolapril, nitrates,
peripheral vasodilators and analogs thereof; chelating agents such as
deferoxamine and analogs
thereof; chemotherapy agents such as vincristine and analogs thereof;
contraceptives; diuretic agents
such as loop diuretics, acetazolamide, amiloride, bendroflumethiazide,
bumetanide, chlorthalidone,
chlorothiazide, dichlorphenamide, ethacrynic acid, furoseamide,
hydrochlorothiazide,
hydroflumethiazide, indapamide, mannitol, methazolamide, methyclothiazide,
metolazone, naturetin,
polythiazide, spironolactone, triameterene, triamterene, trichlormethiazide,
triamterene, torsemide,
and analogs thereof; fertility promoters; hypnotic agents such as amobarbital,
butabarbital, chloral
hydrate, estazolam, flurazepam, mephobarbital, paraldehyde, pentobarbital,
phenobarbital, quazepam,
secobarbital, temazepam, triazolam, zaleplon, zolpidem and analogs thereof;
inducers and inhibitors
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of uterine labor; inotropic agents such as digoxin and analogs thereof;
narcotic antagonists; NSAIDs
such as celecoxib, etoricoxib, rofecoxib, valdecoxib, diclofenac, diflunisal,
etodolac, fenoprofen,
flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamate,
mefenamic acid,
meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac,
tolmetin, tiaprofenic
acid, salicylates such as acetylsalicylic acid, choline magnesium salicylate,
choline salicylate,
magnesium salicylate, and sodium salicylate, and analogs thereof; neuroleptic
agents; synthetic and
naturally occurring peptides, proteins or hormones such as desmopressin,
vasopressin, insulin,
calcitonin, calcitonin gene regulating protein, atrial natriuretic protein,
colony stimulating factor,
betaseron, erythropoietin (EPO), interferons such as a, 0 or y interferon,
somatropin, somatotropin,
somastostatin, insulin like growth factor (somatomedins), luteinizing hormone
releasing hormone
(LHRH), tissue plasminogen activator (TPA), growth hormone releasing hormone
(GHRH),
oxytocin, estradiol, growth hormones, leuprolide acetate, factor VIII,
interleukins such as interleukin
2 and analogs thereof; prostaglandins and analogs thereof; sedatives such as
benzodiazepines,
phenothiozines and analogs thereof; and vasoprotective agents.
It will be understood that suitable additional active ingredients also include
all
pharmaceutically acceptable salts, acids, esters, complexes or other
derivatives of the active
ingredients recited above, and may be present either in the form of one
stereoisomer or as a mixture,
racemic or otherwise, of stereoisomers.
The time release characteristics for the delivery of ticlopidine from each of
the components
may be varied by modifying the composition of each component, including
modifying any of the
excipients and/or coatings which may be present. In particular, the release of
ticlopidine may be
controlled by changing the composition and/or the amount of the modified
release coating on the
particles, if such a coating is present. If more than one modified release
component is present, the
modified release coating for each of these components may be the same or
different. Similarly, when
modified release is facilitated by the inclusion of a modified release matrix
material, release of the
active ingredient may be controlled by the clloice and amount of modified
release matrix material
utilized. The modified release coating may be present, in each component, in
any amount that is
sufficient to yield the desired delay time for each particular component. The
nlodified release coating
may be preset, in each component, in any amount that is sufficient to yield
the desired time lag
between components.
The lag time and/or time delay for the release of ticlopidine from each
ticlopidine-containing
component may also be varied by modifying the composition of each of the
components, including
modifying any excipients and coatings which may be present. For example, the
first component may
be an immediate release component wherein the ticlopidine is released
immediately upon
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administration. Alternatively, the first component may be, for example, a time-
delayed immediate
release component in which ticlopidine is released substantially in its
entirety imnlediately after a
time delay. The second and subsequent component may be, for example, a time-
delayed immediate
release component as just described or, alternatively, a time-delayed
sustained release or extended
release component in which ticlopidine is released in a controlled fashion
over an extended period of
time.
As will be appreciated by those skilled in the art, the exact nature of the
plasma concentration
curve will be influenced by the combination of all of these factors just
described. In particular, the lag
time between the delivery (and thus also the onset of action) of ticlopidine
in each ticlopidine-
containing component may be controlled by varying the composition and coating
(if present) of each
of the components. Thus by variation of the composition of each component
(including the amount
and nature of the active ingredient(s)) and by variation of the lag time,
numerous release and plasma
profiles may be obtained. Depending on the duration of the lag time between
the release of ticlopidine
from each such component and the nature of the release of ticlopidine from
such each component (i.e.
immediate release, sustained release etc.), the plasma profile may be
continuous (i.e., having a single
maximum) or pulsatile in which the peaks in the plasma profile may be well
separated and clearly
defined (e.g. when the lag time is long) or superimposed to a degree (e.g.
when the lag time is short).
The plasma profile produced from the administration of a single dosage unit
coniprising the
composition of the present invention is advantageous when it is desirable to
deliver two or more
pulses of active ingredient without the need for administration of two or more
dosage units.
Additionally, in the case of treating viral infections, it is particularly
useful to have such a multimodal
plasma profile. For example, typical ticlopidine treatment regimes consists of
the administration of
either two doses of an immediate release dosage formulation given twelve hours
apart or three doses
of an immediate release dosage formulation given eight hours apart for a
period of seven days. These
types of regimes have been found to be therapeutically effective and are
widely used.
Any coating material which modifies the release of ticlopidine in the desired
manner may be
used. In particular, coating materials suitable for use in the practice of the
present invention include
but are not limited to polymer coating materials such as cellulose acetate
phthalate, cellulose acetate
trimaletate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate
phthalate,
ammoniomethacrylate copolymers such as those sold under the trademark Eudragit
RS and RL, poly
(acrylic acid) and polyacrylate and methacrylate copolymers such as those sold
under the trademark
Eudragit S and L, polyvinyl acetaldiethylamino acetate,
hydroxypropylmethylcellulose acetate
succinate, shellac, hydrogels and gel-forming materials such as carboxyvinyl
polymers, sodium
alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch,
polyvinyl alcohol,
CA 02611938 2007-12-11
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hydroxyethylcellulose, methylcellulose, gelatin, starch, and cellulose based
cross-linked polymers--in
which the degree of crosslinking is low so as to facilitate adsorption of
water and expansion of the
polymer matrix, hydoxypropylcellulose, hydroxypropyl-methylcellulose,
polyvinylpyrrolidone,
crosslinked starch, microcrystalline cellulose, chitin, aminoacrylmethacrylate
copolymer (Eudragit
RS-PM, Rohm & Haas), pullulan, collagen, casein, gum arabic, sodium
carboxymethylcellulose,
(swellable hydrophilic polymers) poly(hydroxyalkyl methacrylate) (mol. wt. -5k-
5,000k),
polyvinylpyrrolidone (mol. wt. -10k-360k), anionic and cationic hydrogels,
polyvinyl alcohol having
a low acetate residual, a swellable mixture of agar and
carboxymethylcellulose, copolymers of maleic
anhydride and styrene, ethylene, propylene or isobutylene, pectin (mol. wt. -
30k-300k),
polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar,
polyacrylamides, Polyox
polyethylene oxides (mol. wt. -100k-5,000k), AquaKeep acrylate polymers,
diesters of polyglucan,
crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, sodium starch
glucolate (e.g.
Explotab ; Edward Mandell C. Ltd.); hydrophilic polymers such as
polysaccharides, methylcellulose,
sodium or calcium carboxymethylcellulose, hydroxypropylmethylcellulose,
hydroxypropylcellulose,
hydroxyethylcellulose, nitrocellulose, carboxymethylcellulose, cellulose
ethers, polyethylene oxides
(e.g. Polyox , Union Carbide), methylethylcellulose,
ethylhydroxyethylcellulose, cellulose acetate,
cellulose butyrate, cellulose propionate, gelatin, collagen, starch,
maltodextrin, polyvinyl pyrrolidone,
polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters,
polyacrylamide, polyacrylic acid,
copolymers of methacrylic acid or methacrylic acid (e.g. Eudragit , Rohm and
Haas), other acrylic
acid derivatives, sorbitan esters, natural gums, lecithins, pectin, alginates,
ammonia alginate, sodium,
calcium, potassium alginates, propylene glycol alginate, agar, and gums such
as arabic, karaya, locust
bean, tragacanth, carrageens, guar, xanthan, scleroglucan and mixtures and
blends thereof. As will be
appreciated by the person skilled in the art, excipients such as plasticisers,
lubricants, solvents and the
like may be added to the coating. Suitable plasticisers include for example
ac,etylated
monoglycerides; butyl phthalyl butyl glycolate; dibutyl tartrate; diethyl
phthalate; dimethyl phthalate;
ethyl phthalyl ethyl glycolate; glycerin; propylene glycol; triacetin;
citrate; tripropioin; diacetin;
dibutyl phthalate; acetyl monoglyceride; polyethylene glycols; castor oil;
triethyl citrate; polyhydric
alcohols, glycerol, acetate esters, gylcerol triacetate, acetyl triethyl
citrate, dibenzyl phthalate, dihexyl
phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate,
dioctyl azelate, epoxidised
tallate, triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl
phthalate, di-i-octyl phthalate, di-i-
decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-
ethylhexyl trimellitate, di-2-
ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl
sebacate.
When the modified release component comprises a modified release matrix
material, any
suitable modified release matrix material or suitable combination of modified
release matrix materials
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may be used. Such materials are known to those skilled in the art. The term
"modified release matrix
material" as used herein, includes hydrophilic polymers, hydrophobic polymers
and mixtures thereof
which are capable of modifying the release of ticlopidine dispersed therein in
vitro or in vivo.
Modified release matrix materials suitable for the practice of the present
invention include but are not
limited to microcrystalline cellulose, sodium carboxymethylcellulose,
hydroxyalkylcelluloses such as
hydroxypropylmethylcellulose and hydroxypropylcellulose, polyethylene oxide,
alkylcelluloses such
as methylcellulose and ethylcellulose, polyethylene glycol,
polyvinylpyrrolidone, cellulose acteate,
cellulose acetate butyrate, cellulose acteate phthalate, cellulose acteate
trimellitate, polyvinylacetate
phthalate, polyalkylmethacrylates, polyvinyl acetate and mixture thereof.
A modified release composition according to the present invention may be
incorporated into
any suitable dosage form which facilitates release of the active ingredient in
a pulsatile manner. In
one embodiment, the dosage form comprises a blend of different populations of
active ingredient-
containing particles which make up the immediate release and the modified
release components, the
blend being filled into suitable capsules, such as hard or soft gelatin
capsules. Alternatively, the
different individual populations of active ingredient-containing particles may
be compressed
(optionally with additional excipients) into mini-tablets which may be
subsequently filled into
capsules in the appropriate proportions. Another suitable dosage form is that
of a multilayer tablet. In
this instance the first component of the modified release composition may be
compressed into one
layer, with the second component being subsequently added as a second layer of
the multilayer tablet.
The populations of ticlopidine-containing particles making up the composition
of the invention may
further be included in rapidly dissolving dosage forms such as an effervescent
dosage form or a fast-
melt dosage form.
In one embodiment, the composition and the solid oral dosage forms containing
the
composition release ticlopidine such that substantially all of the ticlopidine
contained in the first
component is released priox to release of ticlopidine from the at least one
second component. When
the first component comprises an IR component, for example, it is preferable
that release of
ticlopidine from the at least one second component is delayed until
substantially all ticlopidine in the
ZR component has been released. Release of ticlopidine from the at least one
second component may
be delayed as detailed above by the use of a modified release coatings and/or
a modified release
matrix material.
When it is desirable to minimize patient tolerance by providing a dosage
regime which
facilitates wash-out of a first dose of ticlopidine from a patient's system,
release of ticlopidine from
subsequent components may be delayed until substantially all of the
ticlopidine contained in the first
component has been released, and further delayed until at least a portion the
ticlopidine released from
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the first component has been cleared from the patient's system. In one
embodiment, the release of
ticlopidine from subsequent components of the composition is substantially, if
not completely,
delayed for a period of at least about six hours after administration of the
coinposition. In another
embodiment, the release of ticlopidine from subsequent components of the
composition is
substantially, if not completely, delayed for a period of at least about
twelve hours after
administration of the composition.
As described hereinbelow, the present invention also includes various types of
modified
release systems by which ticlopidine may be delivered in either a pulsatile or
continuous manner.
These systems include but are not limited to: films with ticlopidine in a
polymer matrix (monolithic
devices); ticlopidine contained by the polymer (reservoir devices); polymeric
colloidal particles or
microencapsulates (microparticles, microspheres or nanoparticles) in the form
of reservoir and matrix
devices; ticlopidine contained by a polymer containing a hydrophilic and/or
leachable additive e.g., a
second polymer, surfactant or plasticizer, etc. to give a porous device, or a
device in which the release
of ticlopidine may be osmotically controlled (both reservoir and matrix
devices); enteric coatings
(ionizable and dissolve at a suitable pH); (soluble) polymers with
(covalently) attached pendant drug
molecules; and devices where release rate is controlled dynamically: e.g., the
osmotic pump.
The delivery mechanism of the present invention can control the rate of
release of ticlopidine.
While some mechanisms will release ticlopidine at a constant rate, others will
vary as a function of
time depending on factors such as changing concentration gradients or additive
leaching leading to
porosity, etc.
Polymers used in sustained release coatings are necessarily biocompatible, and
ideally
biodegradable. Examples of both naturally occurring polymers such as Aquacoat
(FMC
Corporation, Food & Pharmaceutical Products Division, Philadelphia, USA)
(ethylcellulose
mechanically spheronised to sub-micron sized, aqueous based, pseudo-latex
dispersions), and also
synthetic polymers such as the Eudragit (Rohm Pharma, Weiterstadt) range of
poly(acrylate,
methacrylate) copolymers are known in the art.
In one approach, a modified release is achieved by encapsulation or
containment of the drug
entirely (e.g., as a core) within a polymer film or coat (i.e., microcapsules
or spray/pan coated cores).
The various factors that can affect the diffusion process may readily be
applied to reservoir devices
(e.g., the effects of additives, polymer functionality (and, hence, sink-
solution pH) porosity, film
casting conditions, etc.) and, hence, the choice of polymer must be an
important consideration in the
development of reservoir devices. Modeling the release characteristics of
reservoir devices and
monolithic devices in which the transport of the drug is by a solution-
diffusion mechanism therefore
typically involves a solution to Fick's second law (unsteady-state conditions;
concentration
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dependent flux) for the relevant boundary conditions. When the device contains
dissolved active
agent, the rate of release decreases exponentially with time as the
concentration (activity) of the
agent (i.e., the driving force for release) within the device decreases (i.e.,
first order release). If,
however, the active agent is in a saturated suspension, then the driving force
for release is kept
constant until the device is no longer saturated. Alternatively the release-
rate kinetics may be
desorption controlled, and a function of the square root of time.
Transport properties of coated tablets, may be enhanced compared to free-
polymer films, due
to the enclosed nature of the tablet core (the permeant) which may enable the
internal build-up of an
osmotic pressure which will then act to force the permeant out of the tablet.
The effect of de-ionized water on salt containing tablets coated in
poly(ethylene glycol)
(PEG)-containing silicone elastomer, and also the effects of water on free
films has been
investigated. The release of salt from the tablets was found to be a mixture
of diffusion through water
filled pores, formed by hydration of the coating, and osmotic pumping. KCl
transport through films
containing just 10% PEG was negligible, despite extensive swelling observed in
similar free films,
indicating that porosity was necessary for the release of the KC1 which then
occurred by trans-pore
diffusion. Coated salt tablets, shaped as disks, were found to swell in de-
ionized water and change
shape to an oblate spheroid as a result of the build-up of internal
hydrostatic pressure: the change in
shape providing a means to measure the force generated. As might be expected,
the osmotic force
decreased with increasing levels of PEG content. The lower PEG levels allowed
water to be imbibed
through the hydrated polymer, while the porosity resulting from the coating
dissolving at higher
levels of PEG content (20 to 40%) allow the pressure to be relieved by the
flow of KCI.
Methods and equations have been developed, which by monitoring (independently)
the
release of two different salts (e.g., KCl and NaCI) allowed the calculation of
the relative magnitudes
that both osmotic pumping and trans-pore diffusion contributed to the release
of salt from the tablet.
At low PEG levels, osmotic flow was increased to a greater extent than was
trans-pore diffusion due
to the generation of only a low pore number density: at a loading of 20%, both
mechanisms
contributed approximately equally to the release. The build-up of hydrostatic
pressure, however,
decreased the osmotic inflow, and osmotic pumping. At higher loadings of PEG,
the hydrated film
was more porous and less resistant to outflow of salt. Hence, although the
osmotic pumping
increased (compared to the lower loading), trans-pore diffusion was the
dominant release
mechanism. An osmotic release mechanism has also been reported for
microcapsules containing a
water soluble core.
Monolithic (matrix) devices, where the active agent is provided within a
polymer matrix, are
commonly used for controlling the release of drugs. Such devices are typically
fonned by the
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compression of a polymer/drug mixture or by dissolution or melting. In
contrast to reservoir devices,
the danger of an accidental high dosage that could result from the rupture of
the membrane of a
reservoir device is not present in the monolithic device.
The release properties of monolithic devices may be dependent upon a variety
of factors
including whether the drug is dispersed or dissolved in the polymer, the
solubility of the drug in the
polymer matrix and, in the case of porous matrices, the solubility in the sink
solution within the
particle's pore network and the tortuosity of the network. For low loadings of
drug, (0 to 5% w/v) the
drug will be released by a solution-diffusion mechanism (in the absence of
pores). At higher loadings
(5 to 10% w/v), the release mechanism will be complicated by the presence of
cavities formed near
the surface of the device as the drug is lost: such cavities fill with fluid
from the environment
increasing the rate of release of the drug.
It is common to add a plasticizer (e.g., a poly(ethylene glycol)), a
surfactant, or adjuvant (i.e.,
an ingredient which increases effectiveness), to monolithic devices and
reservoir devices as a means
to enhance the permeability (although, in contrast, plasticizers may be
fugitive, and simply serve to
aid film formation and, hence, decrease permeability - a property normally
more desirable in polymer
paint coatings). It has been noted that the leaching of PEG increased the
permeability of (ethyl
cellulose) films linearly as a function of PEG loading by increasing the
porosity, however, the films
retained their barrier properties, not permitting the transport of
electrolyte. It was deduced that the
enhancement of their permeability was as a result of the effective decrease in
thickness caused by the
PEG leaching. This was evidenced from plots of the cumulative permeant flux
per unit area as a
function of time and film reciprocal thickness at a PEG loading of 50% w/w:
plots showing a linear
relationship between the rate of permeation and reciprocal film thickness, as
expected for a (Fickian)
solution-diffusion type transport mechanism in a homogeneous membrane.
Extrapolation of the
linear regions of the graphs to the time axis gave positive intercepts on the
time axis: the magnitude
of which decreased towards zero with decreasing film thickness. These changing
lag times were
attributed to the occurrence of two diffusional flows during the early stages
of the experiment (the
flow of the drug and also the flow of the PEG), and also to the more usual lag
time during which the
concentration of permeant in the film is building-up. Caffeine, when used as a
penneant, showed
negative lag times. No explanation of this was forthcoming, but it was noted
that caffeine exhibited a
low partition coefficient in the system, and that this was also a feature of
aniline permeation through
polyethylene films which showed a similar negative time lag.
The effects of added surfactants on hydrophobic matrix devices has been
investigated. It was
thought that surfactant may increase the drug release rate by three possible
mechanisms: (i) increased
solubilization, (ii) improved "wettability" to the dissolution media, and
(iii) pore formation as a result
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of surfactant leaching. For the system studied (Eudragit RL 100 and RS 100
plasticized by sorbitol,
flurbiprofen as the drug, and a range of surfactants) it was concluded that
improved wetting of the
tablet led to only a partial improvement in drug release (implying that the
release was diffusion,
rather than dissolution, controlled), although the effect was greater for
Eudragit RS than Eudragit
RL, while the greatest influence on release was by those surfactants that were
more soluble due to the
formation of disruptions in the matrix allowing the dissolution medium access
to within the matrix.
This is of obvious relevance to a study of latex films which might be suitable
for pharmaceutical
coatings, due to the ease with which a polymer latex may be prepared with
surfactant as opposed to
surfactant-free. Differences were found between the two polymers with only the
Eudragit RS
showing interactions between the anionic/cationic surfactant and drug. This
was ascribed to the
differing levels of quatemary ammonium ions on the polymer.
Composite devices consisting of a polymer/drug matrix coated in a polymer
containing no
drug also exist. Such a device was constructed from aqueous Eudragit
lattices, and was found to
provide a continuous release by diffusion of the drug from the core through
the shell. Similarly, a
polymer core containing the drug has been produced and coated with a shell
that was eroded by
gastric fluid. The rate of release of the drug was found to be relatively
linear (a function of the rate
limiting diffusion process through the shell) and inversely proportional to
the shell thickness,
whereas the release from the core alone was found to decrease with time.
Methods for the preparation of hollow microspheres have been described. Hollow
microspheres were formed by preparing a solution of ethanol/dichloromethane
containing the drug
and polymer. On pouring into water, an emulsion is formed containing the
dispersed
polymer/drug/solvent particles, by a coacervation-type process from which the
ethanol rapidly
diffused precipitating polymer at the surface of the droplet to give a hard-
shelled particle enclosing
the drug dissolved in the dichloromethane. A gas phase of dichloromethane was
then generated
within the particle which, after diffusing through the shell, was observed to
bubble to the surface of
the aqueous phase. The hollow sphere, at reduced pressure, then filled with
water which could be
removed by a period of drying. No drug was found in the water. Highly porous
matrix-type
microspheres have also been described. The matrix-type microspheres were
prepared by dissolving
the drug and polymer in ethanol. On addition to water, the ethanol diffused
from the emulsion
droplets to leave a highly porous particle. A suggested use of the
microspheres was as floating drug
delivery devices for use in the stomach.
Pendent devices for attaching a range of drugs such, as for example,
analgesics and
antidepressants, etc., by means of an ester linkage to poly(acrylate) ester
latex particles prepared by
aqueous emulsion polymerization has been developed. These lattices, when
passed through an ion
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exchange resin such that the polymer end groups were converted to their strong
acid form, could self-
catalyze the release of the drug by hydrolysis of the ester link.
Drugs have been attached to polymers, and also monomers have been synthesized
with a
pendent drug attached. Dosage fomzs have been prepared in which the drug is
bound to a
biocompatible polymer by a labile chemical bond e.g., polyanhydrides prepared
from a substituted
anhydride (itself prepared by reacting an acid chloride with the drug:
methacryloyl chloride and the
sodium salt of methoxy benzoic acid) were used to form a matrix with a second
polymer (Eudragit
RL) which released the drug on hydrolysis in gastric fluid. The use of
polymeric Schiff bases suitable
for use as carriers of pharmaceutical amines has also been described.
Enteric coatings and films consist of pH sensitive polymers. Typically the
polymers are
carboxylated and interact very little with water at low pH, while at high pH
the polymers ionize
causing swelling or dissolving of the polymer. Coatings and films can
therefore be designed to
remain intact in the acidic environment of the stomach, protecting either the
drug from this
environment or the stomach from the drug, but to dissolve in the more alkaline
environment of the
- 15 intestine.
Osmotically controlled devices such as an osmotic pump are similar to a
reservoir device but
contain an osmotic agent (e.g., the active agent in salt form) which acts to
imbibe water from the
surrounding medium via a semi-permeable membrane. Such a device, called an
elementary osmotic
pump, has been described. Pressure is generated within the device which forces
the active agent out
of the device via an orifice of a size designed to minimize solute diffusion,
while preventing the
build-up of a hydrostatic pressure head which can have the effect of
decreasing the osmotic pressure
and changing the dimensions of the device. While the internal volume of the
device remains
constant, and there is an excess of solid or saturated solution in the device,
then the release rate
remains constant delivering a volume equal to the volume of solvent uptake.
Monolithic devices have been prepared using polyelectrolyte gels which swell
when, for
example, an external electrical stimulus is applied causing a change in pH.
The release may be
modulated by changes in the applied current to produce a constant or pulsatile
release profile.
In addition to their use in drug matrices, hydrogels find use in a number of
bioniedical
applications such as, for example, soft contact lenses, and various soft
implants, and the like.
According to another aspect of the present invention, there is provided a
method for treating a
patient in need of platelet aggregation inhibition therapy, comprising the
step of administering a
therapeutically effective amount of the composition of the present invention
in solid oral dosage
form. Advantages of the method of the present invention include a reduction in
the dosing frequency
required by conventional multiple IR dosage regimes while still maintaining
the benefits derived
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from a pulsatile plasma profile or eliminating or minimizing the variations in
plasma concentration
levels. This reduced dosing frequency is advantageous in term.s of patient
compliance and the
reduction in dosage frequency made possible by the method of the present
invention would
contribute to controlling health care costs by reducing the amount of tizne
spent by health care
workers on the administration of drugs.
In the following examples, all percentages are weight by weight unless
otherwise stated. The
term "purified water" as used throughout the Examples refers to water that has
been purified by
passing it through a water filtration system. It is to be understood that the
examples are for illustrative
purposes only, and should not be interpreted as restricting the spirit and
breadth of the invention as
defined by the scope of the claims that follow.
EXAMPLE 1
A multiparticulate modified release composition according to the present
invention
comprising an immediate release component and a modified release component
each containing
ticlopidine is prepared as follows.
(a) Immediate Release Component
A solution of ticlopidine is prepared according to any of the formulations
given in Table 1.
The ticlopidine solution is then coated onto nonpareil seeds to a level of
approximately 16.9% solids
weight gain using, for example, a Glatt GPCG3 (Glatt, Protech Ltd., Leicester,
UK) fluid bed coating
apparatus to form the IR particles of the immediate release component.
TABLE 1
Immediate release component solutions
Amount (% (w/w)) Amount (% (w/w))
Ingredient (i) (ii)
Ticlopidine 13.0 13.0
Polyethylene Glycol 6000 0.5 0.5
Polyvinylpyrrolidone 3.5
Purified Water 83.5 86.5
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(b) Modified Release Component
Delayed release particles containing ticlopidine are prepared by coating
immediate release
particles prepared according to Example 1(a) above with a modified release
coating solution as
detailed in Table 2. The immediate release particles are coated to varying
levels up to approximately
to 30% weight gain using, for example, a fluid bed apparatus.
TABLE 2
Modified release component coating solutions
Amount, % (w/w)
Ingredient (i) (ii) (iii) (iv) (v) (vi) (vii) (viii)
Eudragit 49.7 42.0 47.1 53.2 40.6 -- -- 25.0
RS 12.5
Eudragit -- -- -- -- -- 54.35 46.5 --
S 12.5
Eudragit -- -- -- -- -- -- 25.0 --
L 12.5
Polyvinyl- -- -- -- 0.35 0.3 -- -- --
pyrrolidone
Diethyl- 0.5 0.5 0.6 1.35 0.6 1.3 1.1 --
phthalate
Triethyl- -- -- -- -- -- -- -- 1.25
citrate
Isopropyl 39.8 33.1 37.2 45.1 33.8 44.35 49.6 46.5
alcohol
Acetone 10.0 8.3 9.3 -- 8.4 -- -- --
Talcl -- 16.0 5.9 -- 16.3 -- 2.8 2.25
Talc is simultaneously applied during coating for formulations in colunm (i),
(iv) and (vi).
(c) Encapsulation of Immediate and Delayed Release Particles.
The immediate and delayed release particles prepared according to Example 1(a)
and (b)
above are encapsulated in size 2 hard gelatin capsules to an overall 20 mg
dosage strength using, for
example, a Bosch GKF 4000S encapsulation apparatus. The overall dosage
strength of 20 mg of
ticlopidine was made up of 10 mg from the immediate release component and 10
mg from the
modified release component.
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EXAMPLE 2
A multiparticulate modified release composition according to the present
invention
comprising an immediate release component and a modified release component
comprising a
modified release matrix material is prepared according to the formulations
shown in Table 3(a) and
(b).
TABLE 3 (a)
100 mg of IR component is encapsulated with 100 mg of modified
release (MR) component to give a 20 mg dosage strength product
% (w/w)
IR component:
Ticlopidine 10
Microcrystalline cellulose 40
Lactose 45
Povidone 5
MR component
Ticlopidine 10
Microcrystalline cellulose 40
Eudragit RS 45
Povidone 5
TABLE 3 (b)
50 mg of IR component is encapsulated with 50 mg of modified
release (MR) -component to give a 20 mg dosage strength product.
% (w/w)
IR component
Ticlopidine 20
Microcrystalline cellulose 50
Lactose 28
Povidone 2
MR component
Ticlopidine 20
Microcrystalline cellulose 50
Eudragit RS 28
Povidone 2
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It will be apparent to those skilled in the art that various modifications and
variations can be
made in the methods and compositions of the present inventions without
departing from the spirit or
scope of the invention. Thus, it is intended that the present invention cover
the modification and
variations of the invention provided they come within the scope of the
appended claims and their
equivalents.
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