Note: Descriptions are shown in the official language in which they were submitted.
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Delayed Release or Extended-Delayed Release Dosage Forms of Pramipexole
Reference to Related Application
This application claims the benefit of the filing date of U.S. Provisional
Application
Serial No. 60/693,602, entitled "IMPROVED DOSAGE FORMS FOR MOVEMENT
DISORDER TREATMENT," and filed on June 23, 2005. The teachings of the entire
referenced application are incorporated herein by reference.
Background of the Invention
A movement disorder is a neurological disturbance that involves one or more
muscles
or muscle groups. Movement disorders affect a significant portion of the
population, causing
disability as well as distress. Movement disorders include Parkinson's
disease, Huntington's
chorea, progressive supranuclear palsy, Wilson's disease, Tourette's syndrome,
epilepsy,
tardive dyskinesia, and various chronic tremors, tics and dystonias. Different
clinically
observed moveinent disorders can be traced to the same or similar areas of the
brain. For
example, abnormalities of basal ganglia (a large cluster of cells deep in the
hemispheres of
the brain) are postulated as a causative factor in diverse movement disorders.
Parlcinson's disease (PD) is a common disabling disease of old age affecting
about one
percent of the population over the age of 60 in the United States. The
incidence of
Parlcinson's disease increases witli age and the cumulative lifetime risk of
an individual
developing the disease is about 1 in 40. It is a progressive neurodegenerative
disorder of the
extra pyramidal nervous system, and is associated with the depletion of
dopamine from cells
in the corpus striatum. The disease affects the mobility and control of the
skeletal muscular
system. Its characteristic features include resting tremor, bradykinetic
movements, rigidity
and postural change. A perceived pathophysiological cause of Parkinson's
disease is
progressive destruction of dopamine-producing cells in the basal ganglia which
comprise the
pars compartum of the substantia nigra, basal nuclei located in the brain
stem. Loss of
dopamineric neurons results in a relative excess of acetylcholine. See
Jellinger, PostMortefn
Studies in Parlcinson.s Disease - Is It Possible to Detect Brain Areas For
Specific SyfnptoTns?
J. Neural. Transna. 56(Supp): 1-29:1999. Parlcinson's disease often begins
with mild limb
stiffness and infi equent tremors and progresses over a period of ten or more
years to frequent
tremors and memory impairment, to uncontrollable tremors and dementia.
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The management of early Parkinson's disease must employ strategies that slow
or halt
the progression of the disease and reduce the risk of eventual motor
complications.
Continuous dopaminergic stimulation early in the disease is the therapeutic
goal for treatment
of patients with Parkinson disease. Pramipexole is a non-ergot potent dopamine
receptor
agonist and has been shown to be clinically effective in treating Parkinson's
patients in early
PD. It has preferential affinity for D3 receptor within the D2 subfamily of
dopamine
receptors and inhibits dopamine synthesis and release. It has been found
effective as a
monotherapy as well as an adjunct to levodopa therapy in patients with advance
disabilities.
Pramipexole is marketed as immediate release tablets by Pfizer under the trade
name
MIRAPEX .
Tardive Dyskinesia (TD) is a chronic disorder of the nervous system,
characterized by
involuntary, irregular rhythmic movements of the mouth, tongue, and facial
muscles. The
upper extremities also may be involved. These movements may be accompanied, to
a
variable extent, by other involuntary movements and movement disorders. These
include
rocking, writhing, or twisting movements of the trunk (tardive dystonia),
forcible eye closure
(tardive blepharospasm), an irresistible impulse to move continually (tardive
akathisia),
jerking movements of the neck (tardive spasmodic torticollis), and disrupted
respiratory
movements (respiratory dyskinesia). The vast majority of TD cases are caused
by the
prolonged use of antipsychotic drugs (neuroleptics). A relatively small number
are caused by
the use of other medications, such as metoclopramide, that, like neuroleptics,
block dopamine
receptors. TD often manifests or worsens in severity after neuroleptic drug
therapy is
discontinued. Resumption of neuroleptic therapy will temporarily suppress the
involuntary
movements, but may aggravate them in the long run.
TD affects approximately 15-20% of patients treated with neuroleptic drugs
(Khot et
al., Neui oleptics and Classic Tardive Dyskinesia, in Lang AE, Weiner WJ
(eds.): Drug
Induced Movenzent Disorders, Futura Publishing Co., 1992, pp 121-166).
Therefore, the
condition affects hundreds of thousands of people in the United States alone.
The cumulative
incidence of TD is substantially higher in women, in older people, and in
those being treated
with neuroleptics for conditions other than schizophrenia, such as bipolar
disorder (manic-
depressive illness) (see, e.g., Hayashi et al., Clin. Neuropharmacol. 19: 390,
1996; Jeste et
al., Arch. Gen. Psychiatiy 52: 756, 1995). Unlike the acute motor side effects
of neuroleptic
drugs, TD does not respond in general to antiparkinson drugs (Decker et al.,
New Eng. JMed.
Oct. 7, p. 861, 1971).
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Focal Dystonias (FD) are a class of related movement disorders involving the
intermittent sustained contraction of a group of muscles. The prevalence of
focal dystonias in
one US county was estimated as 287 per million (Monroe County Study); this
suggests that at
least 70,000 people are affected in the US alone. The spasms of focal dystonia
can last many
seconds at a time, causing major disruption of the function of the affected
area. Some of the
focal dystonias are precipitated by repetitive movements; writer's cramp is
the best known
example. Focal dystonia can involve the face (e.g., blepharospasm, mandibular
dystonia), the
neck (torticollis), the limbs (e.g., writer's cramp), or the trunk. Dystonia
can occur
spontaneously or can be precipitated by exposure to neuroleptic drugs and
other dopamine
receptor blockers (tardive dystonia). No systemic drug therapy is generally
effective, but
some drugs give partial relief to some patients. Those most often prescribed
are
anticholinergics, baclofen, benzodiazepines, and dopamine agonists and
antagonists. The
most consistently effective treatment is the injection of botulinum toxin into
affected
muscles.
The various focal dystonias tend to respond to the same drugs (Chen, Cliya.
Ortliop.
June 102-6, 1998; Esper et al., Tenn. Med. 90: 18-20, 1997; De Mattos et aL,
Arq
Neuropsiquiatr 54: 30-6, 1996) This suggests that a new treatment helpful for
one focal
dystonia would be likely to be helpful for another. Furthenmore, the common
symptoms,
signs, and responses to medication of spontaneous (idiopathic) dystonia and
neuroleptic-
induced dystonia suggest that an effective treatment for a drug-induced focal
dystonia will be
effective for the same dystonia occurring spontaneously.
A tic is an abrupt repetitive movement, gesture, or utterance that often
mimics a
normal type of behavior. Motor tics include movements such as eye blinking,
head jerks or
shoulder shrugs, but can vary to more complex purposive-appearing behaviors
such as facial
expressions of emotion or meaningful gestures of the arms and head. In extreme
cases, the
movement can be obscene (copropraxia) or self-injurious. Phonic or vocal tics
range from
throat clearing sounds to complex vocalizations and speech, sometimes with
coprolalia
(obscene speech) (Leckman et al., supra). Tics are irregular in time, though
consistent
regarding the muscle groups involved. Characteristically, they can be
suppressed for a short
time by voluntary effort.
Tics are estimated to affect 1% to 13% of boys and 1% to 11% of girls, the
male-
female ratio being less than 2 to 1. Approximately 5% of children between the
ages of 7 and
11 years are affected with tic behavior (Leckman et al., Neuropsychiatry of
the Bas. Gang
20(4): 839-861, 1997). The estimated prevalence of multiple tics with
vocalization, e.g.,
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Tourette's syndrome, varies among different reports, ranging from 5 per 10,000
to 5 per
1,000.
Gilles de la Tourette syndrome (TS) is the most severe tic disorder.
Tourette's
syndrome is 3-4 times more common in boys than girls and 10 times more common
in
children and adolescents than in adults (Leckman et al., Neuropsychiatzy of
the Bas. Gang
20(4): 839-861, 1997; Esper et al., Tenn. Med. 90: 18-20, 1997). Patients with
TS have
multiple tics, including at least one vocal (phonic) tic. TS becomes apparent
in early
childhood with the presentation of simple motor tics, for example, eye
blinking or head jerks.
Initially, tics may come and go, but in time tics become persistent and
severe, and begin to
have adverse effects on the child and the child's family. Phonic tics
manifest, on average, 1 to
2 years after the onset of motor tics. By the age of 10, most children have
developed an
awareness of the premonitory urges that frequently precede a tic. Such
premonitions may
enable the individual to voluntary suppress the tic, yet premonition
unfortunately adds to the
discomfort associated witli having the disorder. By late adolescence/early
adulthood, tic
disorders can improve significantly in certain individuals. However, adults
who continue to
suffer from tics often have particularly severe and debilitating symptoms.
(Leckman et al.,
Neuropsychiatry of the Bas. Gang 20(4): 839-861, 1997).
Although the present'day pharmacopeia offers a variety of agents to treat
movement
disorders, none of these agents can prevent or cure these conditions. Many
treatments focus
on eliminating or at least alleviating certain symptoms of the disorder.
Furthermore, the most
effective treatments are often associated with intolerable side effects.
For example, in the case of Parkinson's Disease, pramipexole therapy is
usually
associated with a number of undesirable side effects, and patient compliance
is a significant
obstacle for effective treatment.
Specifically, the majority of the patients taking MIR.APEX are middle-aged
and
quite active. MIRAPEX tablets often have to be given three times a day in
equally divided
doses. Therefore, compliance is a major problem with patients.
A second problem for the multiple dose regimen is that the daily "peak and
trough"
blood levels produced by multiple daily doses result in fluctuating
stimulation of the
dopaminergic neurons. These fluctuations may contribute to the pathogenesis of
the motor
complications in Parkinson disease. Commonly occurring adverse effects
associated with
MIRAPEX include nausea, vomiting / emesis, weakness, dizziness, fainting,
agitation,
confusion, hallucinations, muscle twitching, uncontrollable movements, a
tingling sensation,
chest pain, insomnia, somnolence, decreased appetite, dry mouth, sweating,
headache,
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constipation and gastric intestinal complications. Episodes of sudden
uncontrollable
somnolence have been reported in 22% of PD patients receiving pramipexole in a
dose
related manner. Other side effects of pramipexole have been reported to
include orthostatic
hypotension, the incidence of which is dose- and peak-related. There are also
reports of
subjects on pramipexole medication experiencing increased somnolence, in
particular "sleep
attacks." Such attacks involve a subject falling asleep while engaged in
activities of daily
living, including operation of a motor vehicle, sometimes resulting in
accidents. In addition,
compulsive gambling behaviors (see Dodd et al., Patliological Gasnblitzg
Caused by Drugs
Used to Treat Parkinson Disease, Archives of Neurology vol. 62, Sept. 2005;
Driver-
Dunckley et al., Pathological Ganzbling Associated Witla Doparnine Agonist
Therapy in
Parkinson's Disease, Neurology, Vol. 61, August 2003), excessive shopping,
overeating, and
hypersexuality have also been linked to MIR.APEX treatment.
Although the main indication of MIRAPEX is PD treatment, MIRAPEX is also
used in lower doses to treat other movement disorders such as restless legs
syndrome (e.g.,
0.125 mg daily versus 4.5 mg daily for Parkinson's). It is also being used off-
label to treat
depression as well as some sleep disorders.
Thus, the currently available immediate release pramipexole formulation is not
ideal
as it is associated with poor patient compliance as well as treatment-emergent
side effects that
lead to poor patient tolerance. Therefore, there remains a clear-cut need for
new treatments
and improved dosage forms for various movement disorders, such as using
pramipexole in
alleviating at least one adverse effect associated with the treatment of
Parkinson's disease.
Summary of the Invention
The pharmacokinetics of pramipexole is linear, with plasma concentrations
increasing
proportionate with increase in dosage. Pramipexole is rapidly absorbed,
reaching peak
concentration in approximately 2 hours. The absolute bioavailability of
pramipexole is
greater than 90%. It undergoes little presystemic metabolism and is excreted
virtually
unchanged in the urine. However, it is difficult to reach the upper limit of
the dose range
using the currently available immediate release forrnulation. This is partly
because both
gastrointestinal and CNS side effects are more frequent during the initial
ascending phase of
the plasma profile. Nausea was primarily reported at the moment of peak
pramipexole plasma
levels, and increased with increase in dose. Data from other studies suggest
that pramipexole
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may induce a locally mediated nausea via gastric irritation as rapid onset of
the nausea was
observed prior to achieving peak plasma levels.
The present invention is directed to pramipexole pharmaceutical compositions
that
allow for highly controlled, delayed administration, preferably once-daily
administration that
release pramipexole over an extended period of time. The delayed / extended
xelease dosage
form is preferably at least equivalent in effectiveness to the conventional
immediate release,
three-time daily regimen, and provides average steady-state blood levels of
pramipexole over
a course of treatment. A delayed and/or once-a-day administration of
pramipexole is
advantageous over thrice-a-day administration in terms of patient compliance
and reduced
adverse events, thus providing better treatment of the conditions for which
the pramipexole is
indicated.
In one aspect, the invention provides an oral delayed immediate release (DIR
or DR)
or delayed extended release (DXR) dosage form that provides continuous and
stable delivery
of pramipexole over extended duration and maintains the desired therapeutic
effects, while
minimizing, if not eliminating, the undesired side effects and with improved
patient
compliance.
Preferably, pramipexole and/or its prodrug(s) and/or stereoisomers are
released at a
rate that results in reduction in the frequency or severity of at least one
adverse effect
associated with pramipexole therapy. In certain embodiments, the dosage form
releases
pramipexole and/or its prodrug and/or stereoisomer at a rate that results in
reduction in the
frequency or severity of at least one adverse event associated with current
pramipexole
therapies, or allows for a more convenient dosing regimen than current
therapies.
Thus one aspect of the invention provides a delayed-release (DR) pramipexole
pharmaceutical composition in an orally deliverable form, comprising an
enteric coating, a
pramipexole core, and one or more pharmaceutically acceptable carriers and
excipients,
wherein the enteric coating reduces or substantially eliminates the release
and/or absorption
of pramipexole in the upper gastrointestinal (GI) tract.
In certain embodiments, pramipexole is first released and/or absorbed in
intestine.
In certain embodiments, the enteric coating delays the release of pramipexole
by at
least about 1.5 - 2 hours, or 2-3 hours after ingestion.
In certain embodiments, the enteric coating is selected from: cellulose
acetate
phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl
acetate
phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS),
cellulose
acetate trimellitate, liydroxypropyl methylcellulose succinate, cellulose
acetate succinate,
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cellulose acetate hexahydrophthalate, cellulose propionate phthalate,
copolymer of
methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate,
methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and
maleic
anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-
chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein,
shellac and
copal collophorium, carboxymethyl ethylcellulose, Spheromer III (dopa-
functionalized
poly(butadiene-co-maleic acid), Spherics, Inc.), Spheromer IV (carbidopa-
functionalized
poly(butadiene-co-maleic acid), Spherics, Inc.), co-polymerized methacrylic
acid /
methacrylic acid methyl esters selected from: EUDRAGIT L12.5, L100, EUDRAGIT
S12.5, S100, EUDRAGIT L30D55, EUDRAGIT FS30D, EUDRAGIT L100-55,
EUDRAGIT S100 (Rohm Pharma), KOLLICOAT MAE30D and 30DP (BASF),
ESTACRYL 30D (Eastman Chemical), AQUATERIC and AQUACOAT CPD30
(FMC)), Acryl-EZETM White, or equivalents thereof.
In certain embodiments, the enteric coating becomes soluble at above pH 4.5,
such as
around pH 5.5-6.8.
In certain embodiments, the pramipexole pharmaceutical composition comprises
one
or more pramipexole salts, derivatives and/or stereoisomers.
In certain embodiments, the pramipexole salt is pramipexole dihydrochloride
monohydrate.
In certain embodiments, the pramipexole core is formulated as an immediate
release
(IR) composition.
In certain embodiments, the pramipexole core is formulated as an extended
release
(XR) composition.
In certain embodiments, the .XR composition is prepared by coating pramipexole-
layered inert pellets with a release-controlling polymer.
In certain embodiments, the release-controlling polymer is ethylcellulose-
based.
In certain embodiments, the release-controlling polymer is selected from:
EUDRAGIT RL; EUDRA.GIT RS; cellulose derivatives selected from:
ethylcellulose
aqueous dispersions (AQUACOAT , SURELEASEO), hydroxyethyl cellulose,
hydroxypropyl cellulose, or hydroxypropyl methylcellulose;
polyvinylpyrrolidone;
polyvinylpyrrolidone / vinyl acetate copolymer; OPADRY , or equivalents
thereof.
In certain embodiments, the delayed-release pramipexole pharmaceutical
composition
is formulated to provide an effective dose over at least 4 - 24 hours after
administration to the
patient.
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In certain embodiments, the delayed-release pramipexole pharmaceutical
composition
is formulated to provide an effective plasma level over at least 8 - 16 hours
after
administration to the patient.
In certain embodiments, the effective plasma level at a 0.375 mg dose is about
50 -
400 pg/mL for Parkinson's Disease treatment. The effective plasma levels may
increase with
an increase in dose levels, such as to 800-1800 pg/mL or even 400-4000 pg/mL.
In certain embodiments, the pramipexole core comprises an XR portion and an IR
portion.
In certain embodiments, the XR portion and the IR portion are both present as
multiparticulate beads / pellets embedded within an inactive dissolvable /
disintegratable
matrix.
In certain embodiments, the XR portion and the IR portion are each present as
a
section of the pramipexole core.
In certain embodiments, the XR portion is partially or completely covered by a
rate-
controlling coating that controls the release rate of the XR portion.
In certain embodiments, the delayed-release pramipexole pharnlaceutical
coinposition
is formulated as a once-a-day coniposition.
In certain embodiments, the once-a-day composition contains about 0.375 mg,
0.5
mg, 1.0 mg, 1.5 mg, 3.0 mg, or 4.5 mg of prainipexole dihydrochloride
monohydrate, or
equivalent thereof.
In certain embodiments, the delayed-release pramipexole pharmaceutical
composition
further comprises a bioadhesive layer that adheres to the lower GI tract.
In certain embodiments, the bioadhesive layer comprises polymeric materials
selected
from polyamides, polyalkylene glycols, polyalkylene oxides, polyvinyl
alcohols,
polyvinylpyrrolidone, polyglycolides, polyurethanes, polymers of acrylic and
methacrylic
esters, polylactides, poly(butyric acid), polyanhydrides, polyorthoesters,
poly(fumaric acid),
poly(maleic acid), polycarbonates, polyalkylenes, polyalkylene terephthalates,
polyvinyl
alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides,
polysiloxanes, polystyrene,
poly(lactide-co-glycolide), chitosan, chitin, hyaluronic acid, hyaluronan,
Carbopols, Corplex
polymers, Polycarbophils-Cysteine (Thiomers), Chitosan-Thioglycolic acid
copolymers,
poly(methacrylic acid-grafted-ethylene glycol), poly (methyl vinyl ether-co-
malic anhydride),
cholestyramine (Duolite AP- 143), sucralfate, gliadin, blends and copolymers
thereof.
In certain embodiments, the delayed-release pramipexole pharmaceutical
composition, upon administration to an individual, reduces or eliminates at
least one
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undesirable side-effect selected from: nausea, emesis, insomnia,
hallucination, somnolence,
constipation, and gastric and./or intestinal complication as compared to
treatment with a
thrice-daily immediate release composition of the same overall dosage.
In certain embodiments, the nausea or emesis results from a locally mediated
gastric
irritation.
In certain embodiments, the delayed-release pramipexole pharmaceutical
composition
provides substantially the same bioavailability and/or maximum blood
concentration (Ciõa,,)
compared to an immediate-release pramipexole pharmaceutical composition of the
same
dosage without the enteric coating.
In certain einbodiments, the delayed and/or extended release pharmaceutical
composition provides a substantially reduced degree of fluctuation in plasma
levels compared
to an immediate release pharmaceutical composition of the pramipexole of the
same dose
administered three tiines daily.
In certain embodiments, the delayed and/or extended release pharmaceutical
composition is associated with reduced side effects (e.g., nausea, vomiting)
compared to an
immediate release pharmaceutical composition of the pramipexole of the same
dose
administered tliree times daily.
In certain embodiments, the delayed-release pramipexole pharmaceutical
composition
is suitable for human treatment, or for veterinary treatment of a non-human
mammal.
Another aspect of the invention provides a method of preparing a pramipexole
pharmaceutical composition, comprising coating a fonnulation comprising
pramipexole with
an enteric coating that reduces or substantially eliminates the release and/or
absorption of
pramipexole in the upper gastrointestinal (GI) tract.
Another aspect of the invention provides a method of treating Parkinson's
Disease in
an individual, comprising administering to the individual a delayed-release
pramipexole
pharmaceutical composition as set forth above.
Enibodiments described herein are contemplated to be combined with each other
embodiments as appropriate. Embodiments described in detail under one aspect
of the
invention may be equally applicable for the other aspects of the invention.
Brief Description of the Drawings
Figures 1 A -1J are schematic drawings (not to scale) illustrating cross-
sectional
views of exemplary designs for the subject delivery device.
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Figure 2 shows the results of an exemplary experiment comparing concentration
of
MIRAPEX 0.125 mg tablets over time in fed and fasted Beagle dogs.
Figure 3 shows the results of an exemplary experiment comparing enteric-coated
MIRAPEX 0.125 mg tablets and plain MIR.APEX 0.125 mg tablets in fasted
Beagle dogs.
Figure 4 shows the dissolution profile of pramipexole 0.375 mg Extended-
Release
(ER) and delayed extended release (DER) formulations.
Figure 5 shows the results of comparing pramipexole 0.375 mg Extended Release
(ER) and Delayed Extended Release (DER) formulations in fasted Beagles.
Figure 6 shows the results of comparing pramipexole 0.375 mg Extended Release
multiparticulate-based capsules and matrix-based tablet formulations, with
0.375 mg
MIRAPAX Tablets Given in a Three-In-a-Day (TID) Dosing Regimen (0.125 mg x 3)
in
fed Beagles.
Figure 7 shows dissolution profiles of pramipexole 0.375 mg Delayed Extended-
Release formulations in phosphate buffer pH = 6.8 using USP II apparatus.
Figure 8 shows a comparison between pramipexole 0.375 mg Extended Release
Multiparticulate-based capsules formulations vs. 0.375mg Mirapex tablets given
in a TID
dosing regimen (0.125 mg x 3) in beagles.
Figures 9A-C show the mean human pramipexole plasma concentration comparing
pramipexole 0.375 mg extended release multiparticulate formulations with
MirapexOO tablets,
0.375 mg (0.125 mg x 3).
Figure l0A is the in vitro dissolution profile of pramipexole extended release
tablet
formulation, 0.375 mg [5% coating (80 parts Surelease and 20 parts OPADRY),
obtained
using a USP II apparatus.
Figure 10B shows the in vivo PK performance of a pramipexole extended release
tablet, 0.375 mg [5% coating (80 parts Surelease + 20 parts OPADRY)] and
pramipexole
extended release capsules, 0.375mg [8.3 % Ethocel and 5% Spheromer III coated)
in fasted
beagle dogs.
Figure 11 is a comparison of pramipexole ER Formulations with Mirapex (0.125)
mg
tablets administered in three times a day dosing regimen.
Figure 12 is a schematic drawing (not to scale) illustrating a cross-sectional
view of
one design of the subject delivery device.
Figure 13 is a schematic drawing (not to scale) illustrating a cross-sectional
view of
one design of the subject delivery device.
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.Figure 14 is a schematic drawing (not to scale) illustrating a cross-
sectional view of
one design of the subject delivery device.
Figure 15 is a schematic drawing (not to scale) illustrating a cross-sectional
view of
one design of the subject delivery device.
Detailed Description of Invention
1. Overview
In general, the present invention relates to pharmaceutical compositions and
methods
for the treatrnent of disorders for which pramipexole is administered. Such
disorders include
some sleep disorders and certain movement disorders (such as Parkinson's
disease and
restless legs syndrome, etc.). The present invention also relates to the
methods for protecting
neural cells. The pharmaceutical compositions and methods of the invention
relate to the use
of pramipexole either alone or in combination with other active agents or
pharmaceutical
compositions suitable for the treatment of such diseases or the prevention or
inhibition of
diseases using pramipexole as a neuroprotectant.
In certain embodiments, the invention relates to particular pramipexole dosage
fonns
(e.g., a delayed release, preferably once-a-day dosage form) that provide
release profiles that
are effective for the intended therapeutic use (e.g., ameliorating or
overcoming symptoms of
a movement disorder, such as Parkinson's disease), while reducing or avoiding
at least one
undesirable side-effect associated with conventional pramipexole treatment.
While not wishing to be bound by any particular theory, it is believed that
releasing
pramipexole in the upper GI tract may cause local irritation and lead to at
least one
undesirable side effect of pramipexole treatment, including emesis and nausea.
Thus,
according to one aspect of the invention, one or more undesirable side effects
traditionally
associated with administering pramipexole to an individual can be alleviated
or even
eliminated by delaying the release of pramipexole until the drug is in the
lower GI tract, such
as in the intestine (e.g., the small intestine, the colon, and/or the rectum).
Also according to
the instant invention, one way to reduce or eliminate the release of
pramipexole in the
stomach is to utilize an enteric coating, such that pramipexole is not
substantially released in
the acidic environment of the stomach. Once inside the intestine, where the
local pH
environment based on the fed or fasted states varies between 4.5 and 7.4,
pramipexole is
released either as an immediate release (IR) dosage form or as an extended
release (XR)
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dosage form, or a mixture thereof. Since such dosage forms are also delayed-
release dosage
forms, they are referred to as delayed immediate release (DIR or DR) or
delayed extended
release (DXR) dosage forms, respectively.
In a preferred embodiment, the DXR dosage form achieves the therapeutic
benefit of
the conventional thrice-a-day pramipexole regimen and yet is administered as a
single daily
administration, e.g., which contains substantially the same total dosage of
pramipexole, yet
releases the drug in a controlled manner and over an extended period of time,
thus improving
patient compliance, and alleviating and/or eliminating the undesirable daily
"peak and
trough" blood levels produced by multiple daily doses, and the associated
fluctuating
stimulation of the dopamiiiergic neurons.
In certain embodiments, the dosage form may include bioadhesive layers that
adhere
to the lower GI tract, such as intestinal walls, to prolong the release of
pramipexole in the
lower GI tract. The bioadhesive layer may be inside or outside the enteric
coating. In the
former case, the presence of the bioadhesive layer (e.g., as a partial coating
that is continuous
or discontinuous) preferably does not substantially impede the release of
pramipexole. In the
latter case, the presence of the bioadhesive layer (e.g., as a partial coating
that is continuous
or discontinuous) does not substantially impede the degradation of the enteric
layer in the
neutral pH environment of the intestine.
Pramipexole is not acid-sensitive, and thus need not be protected from the
relative
acidic environment of the upper GI tract per se. Indeed, in certain
embodiments, pramipexole
needs to be delivered to the lower GI tract, for example, for targeted
treatment of certain
colon diseases. However, the present invention is based in part on the
unexpected discovery
that by by-passing the release of pramipexole in the upper GI tract (e.g., the
stomach) it is
possible to avoid one or more undesirable side effects typically associated
with pramipexole
treatments, such as nausea and/or emesis.
The compositions of the present invention may be in the form of, among others,
a
granule, tablet (including matrix or osmotic), pellet, powder, sachet,
capsule, gel, dispersion,
solution or suspension. The only requirement is that the dosage forms be
composed in such a
manner as to achieve the profiles set forth herein.
Iba vivo profiles for pramipexole that provide the appropriate blood (or, more
particularly, plasma) concentration levels over time in order to meet the
therapeutic
requirements for once daily administration were provided in the present
invention. These
profiles are such that the mean blood pramipexole levels provide an effective
amount of the
drug for the treatment of such conditions as PD or other related movement
disorders, yet
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below levels that induce adverse side effects typically associated with spikes
in the plasma
concentration that follow the multiple administration of fast / immediate
release formulations.
In addition, by-passing the release of pramipexole in the upper GI tract, such
as in the
stomach, avoids side effects such as nausea and/or emesis.
Thus, with the present invention, it was found that an effective blood
pramipexole
concentration at relatively steady state could be achieved by formulating
pramipexole in
several inventive dosage forms. These dosage forms are in the form of a
delayed release, an
immediate release, an extended release, or combination thereof.
Another aspect of the invention provides a method for making the
phannaceutical
compositions with one or more features as described above.
Another aspect of the invention provides a method for using the pharmaceutical
compositions with one or more features as described above, in treating a
movement disorder,
such as Parkinson's disease.
Another aspect of the invention provides the use of a pharmaceutical
composition
with one or more features as described above in manufacturing medicaments for
the
treatment of a movement disorder, such as Parkinson's disease.
The subject preparations and methods can be used as part of treatments for
human
and/or other animal subjects. In addition to humans, other animal subjects to
which the
invention is applicable extend to both domestic animals and livestock, raised
either as
laboratory ariimals, pets or zoo animals, or for coinmercial purposes.
Exainples are rodents
such as mice, rats, hamsters, or rabbits; dogs; cats; cattle; horses; sheep;
hogs; and goats.
Certain general features of the invention are further elaborated in the
sections below.
II. Definitions
For convenience, certain terms employed in the specification, examples, and
appended claims are collected here. All other terms have their ordinary
meanings as
understood by a skilled artisan.
As used herein, "about" means within the pharmaceutically acceptable limits
found in
the United States Pharmacopeia (USP-NF 21), 2003 Annual Edition, or available
at the USP
website, for amount of active pharmaceutical ingredients. With respect to
blood levels,
"about" means within FDA acceptable guidelines.
The term "water-soluble" herein means having solubility of at least about 10
mg/ml.
Unless otherwise specified, "solubility" herein means solubility in water at
20-25 C at any
physiologically acceptable pH, for example at any pH in the range of about 4
to about 8. In
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the case of a salt, reference herein to solubility in water pertains to the
salt, not to the free
base form of pramipexole.
"Solid fraction" is the ratio of absolute to apparent density of a compact of
the starch.
A "compact" herein is a compressed tablet, prepared for example on a tablet
press, consisting
only of a sample of starch for which it is desired to measure tensile
strength. A "solid fraction
representative of the tablet" is a solid fraction selected to be similar to
the solid fraction of
tablets prepared according to the invention. Typically a solid fraction of
about 0.75 to about
0.85, illustratively 0.8, will be selected.
The tenn "orally deliverable" herein means suitable for oral, including
peroral and
intra-oral (e.g., sublingual or buccal) administration, but tablets of the
present invention are
adapted primarily for peroral administration, i.e., for swallowing, typically
whole (or, in
certain embodiments, broken), with the aid of water or other drinkable fluid.
A"subject" herein is an animal of any species, preferably mammalian, most
preferably human. Conditions and disorders in a subject for which a particular
agent is said
herein to be "indicated" are not restricted to conditions and disorders for
which the agent has
been expressly approved by a regulatory authority, but also include other
conditions and
disorders known or believed by a physician to be amenable to treatment with
the agent.
"Treatment" herein embraces prophylactic treatment unless the context requires
otherwise.
The term. "adrenergic" refers to neurotransmitters or neuromodulators
chemically
related to adrenaline (epinephrine) or to neurons which release such
adrenergic mediators.
Examples are dopamine, norepinephrine, and epinephrine. Such agents are also
referred to as
catecholamines, which are derived from the amino acid tyrosine.
As used herein "catechol moiety" refers to a moiety with the following generic
structure:
HO
HO
In certain embodiments of the invention, a polymer may be functionalized by
covalently attaching catechol moieties or compounds comprising catechol
moieties.
Alternatively, a compound comprising a catechol moiety may be blended with a
polymer to
form a simple mixture with no covalent association between the catechol
moieties and the
polymer.
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The term "catecholamines" refers to neurotransmitters that have a catechol
ring (e.g.,
a 3, 4-dihydroxylated benzene ring). Examples are dopamine, norepinephrine,
and
epinephrine.
The term "cholinergic" refers to neurotransmitters or neuromodulators
chemically
related to choline or to neurons which release such cholinergic mediators.
The term "dopaminergic" refers to neurotransmitters or neuromodulators
chemically
related to dopamine or to neurons which release such dopaminergic mediators.
The term "dopamine" refers to an adrenergic neurotransmitter, as is known in
the art.
The term "ED50" means the dose of a drug which produces 50% of its maximum
response or effect.
An "effective amount" of, e.g., a movement disorder pharmaceutical
composition,
with respect to the subject method of treatment, refers to an amount of the
pharmaceutical
composition in a preparation which, when applied as part of the subject dosage
regimen
brings about the desired correction / suppression of the movement disorder
(e.g., dyskinesis
and/or bradykinesis) according to clinically acceptable standards.
The term "LD50" means the dose of a drug which is lethal in 50% of test
subjects.
The term "lethal therapeutic index" refers to the therapeutic index of a drug
defined as
LD50/ED50.
The term "metabolites" refers to active derivatives produced upon introduction
of a
compound into a biological milieu, such as a patient.
A"patient," "individual," or "subject" to be treated by the subject method can
mean
either a human or non-human animal.
The term "prevent," "preventing," or "prevention" as used herein means
reducing the
probability / risk of developing a condition in a subject (e.g., a human), or
delaying the onset
of a condition in the subject, or lessening the severity of one or more
symptoms of a
condition (e.g., a movement disorder) that may develop in the subject, or any
combination
thereof.
The term "prodrug" is intended to encompass compounds which, under physiologic
conditions, are converted into the therapeutically active agents of the
present invention. A
common method for making a prodrug is to include one or more selected moieties
which are
hydrolyzed under physiologic conditions to reveal the desired molecule. In
other
embodiments, the prodrug is converted by an enzymatic activity of the host
animal.
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The phrase "protecting group" as used herein means temporary substituents
which
protect a potentially reactive functional group from undesired chemical
transfonnations.
Examples of such protecting groups include esters of carboxylic acids, silyl
ethers of
alcohols, and acetals and ketals of aldehydes and ketones, respectively. The
field of
protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M.
Protective
Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991).
The term "SeD50" means the dose of a drug which is produces a particular side-
effect
in 50% of test subjects.
The term "side-effect-therapeutic index" refers to the therapeutic index of a
drug
defined as SeD50/ED50=
The term "statistically significant" as used herein means that the obtained
results are
not likely to be due to chance fluctuations at the specified level of
probability. The two most
commonly specified levels of significance are 0.05 (p=0.05) and 0.01 (p=0.01).
The level of
significance equal to 0.05 and 0.01 means that the probability of error is 5
out of 100 and 1
out of 100, respectively.
The term "treat," "treating," or "treatment" as used herein means to
counteract a
medical condition (e.g., a movement disorder) to the extent that the medical
condition is
improved according to clinically acceptable standard(s). For example, "to
treat a movement
disorder" means to improve the movement disorder or relieve symptoms of the
particular
movement disorder in a patient, wherein the improvement and relief are
evaluated with a
clinically acceptable standardized test (e.g., a patient self-assessment
scale) and/or an
empirical test (e.g., PET scan).
The term "Cmax" as used herein means maximum plasma concentration of
pramipexole achieved by the ingestion of the composition of the invention or
the t.i.d
comparator (Mirapex IR tablets).
The teim "Cmin" as used herein means minimum plasma concentration of
pramipexole achieved by the ingestion of the composition of the invention or
the t.i.d
comparator (Mirapex IR tablets).
The term "Cavg" as used herein means average plasma concentration of
pramipexole
achieved by the ingestion of the composition of the invention or the t.i.d
comparator
(Mirapex IR tablets). Cavg is calculated by AUC over a 24 hours intervals
divided by 24.
The term "Tmax" as used herein means the time to achieve maximum plasma
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concentrations produced by uigestion of of the composition of the invention or
the t.i.d
comparator (Mirapex IR tablets).
The term "AUC" as used herein means the area under the plasma concentration-
time
curve, as calculated by the trapezoidal rule over the 24 hour interval for all
the formulations.
The term "Degree of Fluctuation (DFL)" as used herein is expressed as
DFL = (Cmax - Cmin)/Cavg
produced by ingestion of the-the composition of the invention or the t.i.d
comparator
(Mirapex IR tablets).
As used in this application, the term "Cmin" and "trough levels" should be
considered
synonyms. Likewise, "Cmax" and "peak levels" should be considered synonyms.
III. Dosage Forins
The effective ingredient of the various dosage forms of the invention is
pramipexole.
Pramipexole (formula I below) is a dopamine D2 receptor agonist useful in
treatment of
Parkinson's disease and complications associated therewith. Pramipexole as its
dihydrochloride salt is commercially available in the United States as MIRAPEX
tablets of
Pharmacia & Upjohn / Pfizer. These are marketed as immediate-release tablets
in 0.125 mg,
0.25 mg, 0.5 mg, 1.0 mg and 1.5 mg strengths, designed for thrice-a-day oral
administration
of a single tablet each to provide a daily dose of 0.375 to 4.5 mg. See
Physiciaras' Desk
Reference 57th edition (2003), 2768-2772. Doses herein are expressed in
amounts of
pramipexole dihydrochloride monohydrate unless otherwise specified; e.g., 1.0
mg
pramipexole dihydrochloride monohydrate is equivalent to about 0.7 mg
pramipexole base.
Other salt forms can be readily converted from the amount of pramipexole base
contained
therein.
H2N~ ..o%- \ = 2 HCI -H20
H
pramipexole (C10H17N3S 2 HCl H20)
It should be understood that mention of pramipexole or a salt thereof herein
embraces
racemates, enantiomers, polymorphs, hydrates and solvates thereof, Pramipexole
(I) is used
preferably in the form of its S-enantiomer, (S)-2-amino-4,5,6,7-tetrahydro-6-
(propylamino)-
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benzothiazole. A preferred salt of pramipexole is the dihydrochloride salt,
most preferably in
the form of the monohydrate. Pramipexole compositions of the invention are
preferably
suitable for administration no more than once daily. Such compositions are
useful in
treatment of any CNS condition or disorder for which pramipexole has
therapeutic utility, but
especially Parkinson's disease and complications associated therewith.
Pramipexole and its salts useful herein can be prepared by processes known per
se,
including processes disclosed in patents and other literature pertaining to
pramipexole.
The amount of the pramipexole salt present in a composition of the invention
is
sufficient to provide a daily dose in one to a small plurality, for example
one to about 4, of
tablets to be administered at one time. Preferably the full daily dose is
delivered in a single
tablet. An amount of pramipexole salt, expressed as pramipexole
dihydrochloride
monohydrate equivalent, of about 0.1 to about 10 mg per tablet, or about 0.05%
to about 5%
by weight of the composition, will generally be suitable. Preferably an amount
of about 0.2 to
about 6 mg, more preferably an amount of about 0.3 to about 5 mg, per tablet
is present.
Although many examples of this application use 0.3 75 mg pramipexole
dihydrochloride
monohydrate for Beagle dogs, specific dosage amounts per tablet contemplated
herein
include about 0.375, 0.5, 0.75, 1.0, 1.5, 3.0 and 4.5 mg pramipexole
dihydrochloride
monohydrate.
A. Immediate Release (IR) Composition
By "immediate release composition" is meant a dosage form that is formulated
to
release substantially all the active ingredient on administration with no
enhanced, delayed or
extended release effect. Such a composition may be in the form of a pellet (a
term used
interchangeably with "bead" or "beadlet" herein). The immediate release pellet
can serve as a
precursor to an extended or delayed release pellet, or be used with an
extended or delayed
release pellet.
The non-active ingredients and processes for preparing such immediate release
pellets
are well known in the art, and the present invention is not limited in these
respects. See, for
example, Remington's Pharmaceutical Sciences, 18th Edition, A. Gennaro, Ed.,
Mack Pub.
Co. (Easton, Pa. 1990), Chapters 88-91, the entireties of which are hereby
incorporated by
reference.
For instance, an immediate release pellet can be prepared by mixing
pramipexole with
a bulking agent. Additionally, one can add disintegrating agents,
antiadherents and glidants to
the formulation.
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Bulking agents employable in these compositions may be chosen from, among
others:
microcrystalline cellulose, for example, AVICELO (FMC Corp.) or EMCOCEL
(Mendell
Inc.), which also has binder properties; dicalcium phosphate, for example,
EMCOMPRESS
(Mendell Inc.); calcium sulfate, for example, COMPACTROL (Mendell Inc.); and
starches,
for example, Starch 1500; and polyethylene glycols (CARBOWA) ). Such bulking
agents
are typically present in the range of about 5% to about 75% (w/w), with a
preferred range of
about 25% to about 50% (w/w).
Suitable disintegrants include, but are not limited to: crosslinked sodium
carboxymethyl cellulose (AC-DI-SOL ), sodium starch glycolate (EXPLOTAB ,
PRIMOJEL ) and crosslinked polyvinylpolypyrrolidone (PLASONE-XL ).
Disintegrants are
used to facilitate disintegration of the pellet upon administration and are
typically present in
an amount of about 3% to about 15% (w/w), with a preferred range of about 5%
to about
10% (w/w).
Antiadherents and glidants employable in such formulations can include talc,
cornstarch, silicon dioxide, sodium lauryl sulfate, colloidal silica dioxide,
and metallic
stearates, among others.
In addition, the imnlediate release composition may contain one or more
binders to
give the pellets cohesiveness. Such binders are well known in the art, and
include such
substances as microcrystalline cellulose, polyvinyl pyrrolidone, starch,
maltrin,
methylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose,
sucrose solution,
dextrose solution, acacia, tragacanth and locust bean gum, which may be
applied wet. The
binding agent may be present in the composition in an amount of from about 0.2
wt % to
about 40 wt %, preferably from about 5 wt % to about 30 wt %, or from about 10
wt % to
about 15 wt %.
The pellets can be made by, for example, simple granulation such as wet
granulation
or dry granulation, followed by sieving; extrusion and marumerization
(spheronization);
rotogranulation; or any agglomeration process that results in a pellet of
reasonable size and
robustness. For extrusion and marumerization, the drug and other additives are
granulated by
addition of a binder solution. The wet mass is passed through an extruder
equipped with a
certain size screen, and the extrudates are spheronized in a marumerizer. The
resulting pellets
are dried and sieved for further applications.
One may also use high-shear granulation, wherein the drug and other additives
are
dry-mixed and then the mixture is wetted by addition of a binder solution in a
high shear-
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granulator/mixer. The granules are kneaded after wetting by the combined
actions of mixing
and milling. The resulting granules or pellets are dried and sieved for
further applications.
Alternatively, and preferably, the immediate release beadlets or pellets are
prepared
by solution or suspension layering, whereby a drug solution or dispersion,
with or without a
binder and optionally an anti-tacking agent such as talc, is sprayed onto a
core or starting
seed (either prepared or a commercially available product) in a fluid bed
processor or other
suitable equipment. The cores or starting seeds can be, for example, sugar
spheres or spheres
made from microcrystalline cellulose. The binder in the formula can be present
in amounts
ranging from about 0% to about 5% by weight, and preferably about 0.5% to
about 2% by
weight. The amount of anti-tacking agent used can be from about 0% to about
5%, preferably
about 0.5% to about 2% by weight. The drug thus is coated on the surface of
the starting
seeds. The drug may also be layered onto the drug-containing pellets described
above, if
desired. Following drug layering, the resulting drug-loaded pellets are dried
for further
applications.
A protective layer, or overcoating, may be desired to ensure that the drug-
loaded
pellets do not aggregate during processing or upon storage. The protective
coating layer may
be applied immediately outside the core, either a drug-containing core or a
drug-layered core,
by conventional coating techniques such as pan coating or fluid bed coating
using solutions
of polymers in water or suitable organic solvents or by using aqueous polymer
dispersions.
OPADRY , OPADRY II (Colorcon) and corresponding color and colorless grades
from
Colorcon can be used to protect the pellets from being tacky and provide
colors to the
product. Different anhydride-based polymers (e.g., sebacic/fumaric copolymers
such as
Spheromer I or Spheromer II from Spherics, Inc.) may also be used as
protective layer. The
suggested levels of protective or color coating are from about 1% to about 6%,
preferably
about 2% to about 3% (w/w). In certain embodiments, many ingredients can be
incorporated
into the overcoating formula, for example to provide a quicker immediate
release, such as
plasticizers: acetyltriethyl citrate, triethyl citrate, acetyltributyl
citrate; dibutylsebacate,
triacetin, polyethylene glycols, propylene glycol and the others; lubricants:
talc, colloidal
silica dioxide, magnesium stearate, calcium stearate, titanium dioxide,
magnesium silicate,
and the like.
In certain embodiments, the immediate release composition may be prepared as
an
uncoated tablet, or a tablet core prior to coating, comprising starch and a
hydrophilic polymer
acting as a matrix for a water-soluble drug or prodrug requires to have a
certain minimum
hardness in order to be able to resist breakage and/or attrition due to
mechanical stresses
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imposed during a high-speed tableting operation (including all steps up to and
including
filling of the tablets into containers). The minimum acceptable hardness will
depend on a
number of factors, including the severity of the mechanical stresses, but is
typically at least
about 20 SCU, preferably at least about 22 SCU, more preferably at least about
24 SCU
(about 17 kp).
Hardness can be increased by increasing the compression force applied by the
tablet
press, but only up to a certain level. At least in the case of tablets as
described herein, above a
certain compression force, further increases in compression force give little
or no further
increase in tablet hardness. There is, in other words, a maximum hardness
achievable by
compression of a particular starch / hydrophilic polymer / active agent
composition. A starch
providing a maximum hardness inadequate to withstand the mechanical stresses
of a high-
speed tableting operation is unsuitable for the present purpose. Certain
pregelatinized starches
provide a maximum hardness of 20 SCU or less; these are starches having low
tensile
strength (0.1 kN cm Z or less). Even if a maximum hardness of at least about
20 SCU is
achievable, with a starch of low tensile strength it may be achievable only by
use of
extremely high compression forces. A requirement for such forces reduces speed
and
efficiency and increases cost of a tableting operation and is undesirable for
these reasons.
The immediate release pellets are contemplated as being used in combination
with
extended release pellets and/or delayed release pellets in a single dosage
form, and/or being
modified to generate extended release (XR) pellets, delayed release (DR)
pellets, and/or
delayed and extended release (DXR) pellets in a single dosage form.
B. Delayed Release Composition (DR)
The delayed-release component has a coat applied to the surface of the active
pellet
that delays the release of the drug from the pellet after administration for a
certain period of
time. This delayed release can be accomplished by applying a coating of
enteric materials.
"Enteric materials" are polymers that are substantially insoluble in the
acidic
environinent of the stomach, but are predominantly soluble in intestinal
fluids at various
specific pH's, such as pH 4.5 or higher. The enteric materials are non-toxic,
pharmaceutically
acceptable polymers, and include, for example, cellulose acetate phthalate
(CAP),
hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate
(PVAP),
hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate
trimellitate,
hydroxypropyl methylcellulose succinate, cellulose acetate succinate,
cellulose acetate
hexahydrophthalate, cellulose propionate phthalate, copolymer of
methylmethacrylic acid and
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methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and
methacrylic
acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series),
ethyl
methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate
copolymer,
natural resins such as zein, shellac and copal collophorium, carboxymethyl
ethylcellulose,
Spheromer III, Spheromer IV, co-polymerized methacrylic acid/methacrylic acid
methyl
esters such as, for instance, materials known under the trade name EUDRAGIT
L12.5,
L100, or EUDRAGIT S 12.5, S 100, and several commercially available enteric
dispersion
systems (e.g., EUDRAGIT L30D55, EUDRAGIT FS30D, EUDRAGIT L100-55,
EUDRAGIT S100 (Rohm Pharma), KOLLICOAT MAE30D and 30DP (BASF),
ESTACRYL 30D (Eastman Chemical), AQUATERIC and AQUACOAT CPD30
(FMC)), Acryl-EZETM White, etc.
The foregoing is merely a list of possible enteric coating materials, but one
of skill in
the art would appreciate that there are other such materials that would meet
the objectives of
the present invention of providing for a delayed release profile, including
tailoring release
based on the ambient pH environment, temporal considerations and/or other
factors.
These coating materials can be employed in coating the surfaces in a range of
from
about 1.0% (w/w) to about 50% (w/w) of the pellet composition. Preferably,
these coating
materials are in the range of from about 10-20% (w/w). The pellets may be
coated in a
fluidized bed apparatus or pan coating, for example, in a conventional manner.
With the enteric-coated pellets, there is no substantial release of
pramipexole in the
acidic stomach environment of below about pH 4.5. The pramipexole becomes
available
when the pH-sensitive enteric layer dissolves at a higher pH in the GI tract,
after a certain
delayed time, or after the unit passes through the stoxnach. The preferred
delay time is in the
range of about 0.5 to about 6 hours, but more preferable is about 0.5 to about
4 hours.
For example, certain DR pellets may be coated with EUDRAGIT L30D-55, which
dissolves at about pH 5.5-6.0, i.e., in the upper intestines. In other
embodiments, the DR
pellets may be coated with EUDRAGIT FS30D, which dissolves at about pH 7.0,
i.e., in the
lower intestine and colon.
As a variation of this embodiment, the XR pellet described above may be
additionally
coated with the enteric material to generate delayed and extended release
(DXR) pellets. Such
a dosage form is delayed release until the drug reaches non-acidic
environment, such as the
upper and/or lower intestine,-and thereupon releasing drugs over an extended
period of time.
C. Extended Release Composition (XR)
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Pramipexole extended release pellets can be prepared in many different ways to
achieve an extended release profile.
For example, in certain embodiments, the subject pramipexole XR pellets can be
prepared by coating drug layered inert pellets with release-controlling
polymers. First, the
inert pellet is coated with the drug layer, or a drug loaded granule is
prepared, as described
above. Then the active (drug loaded) pellet is coated with a release-
controlling polymeric
membrane. The release-controlling coating layer may be applied immediately
outside the
core (such as a drug-containing core or a drug-layered core), by conventional
coating
techniques, such as pan coating or fluid bed coating, using solutions of
polymers in water or
suitable organic solvents, or by using aqueous polymer dispersions. As an
alternative
embodinient, the release controlling membrane can separate additional drug
layers on the
core; for instance, after coating with the release controlling substance,
another drug layer can
be applied, which is followed by another release controlling layer, etc.
Suitable materials for
the release-controlling layer include EUDRA.GIT RL, EUDRAGIT RS, cellulose
derivatives such as ethylcellulose aqueous dispersions (AQUACOAT , SURELEASE
),
hydroxyethyl cellulose, hydroxypropyl cellulose, liydroxypropyl
methylcellulose,
polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolyrner, OPADRY ),
and the
like. The thickness of the coating affects the release profile, and so this
parameter can be used
to customize the profile. The suggested coating levels are from about 1% to
about 40%, about
5% to about 30% (w/w), or about 20% or about 25% in other embodiments.
For example, for pramipexole salts of high water solubility as specified
herein, a
hydrophilic polymer matrix core can be inadequate to provide sustained release
of
sufficiently long duration to permit once daily administration. It is believed
that such salts are
readily leached out of the hydrophilic matrix when contacted by an aqueous
medium such as
gastrointestinal fluid. Thus in certain embodiments, it is desirable to
further slow the process
of drug release by providing a release-controlling coating around the tablet
to produce an
extended-release (XR) tablet. Such a coating may coinprise a hydrophobic or
water-insoluble
polymer component such as ethylcellulose together with a hydrophilic or water-
soluble pore-
forming component such as HPMC. In addition, where tablets are to be subjected
to an
additional process step after compression, in particular a coating step,
exposure to mechanical
stresses is also greatly increased.
Where a starch is used having a tensile strength of at least about 0.151cN
crri 2,
preferably at least about 0.175 kN cm -2, more preferably at least about 0.2
kN cm 2, at a solid
fraction representative of the tablet (e.g., about 0.75 to about 0.85), the
composition is found
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to be especially suited to a high-speed tableting operation that includes a
step of coating the
tablet with a release-controlling layer.
Alternatives to ethylcellulose and HPMC as components of a release coating
layer
include other cellulosic polymers (e.g., methylcellulose,
hydroxypropylcellulose,
hydroxyethylcellulose, carboxymethylcellulose sodium, cellulose esters such as
cellulose
acetate, etc.), polyvinyl acetate, polyvinyl pyrrolidone, polymers and
copolymers of acrylic
acid and methacrylic acid and esters thereof, polyethylene glycol, carrageenan
and other
gums, etc.
A release-controlling layer, if present, typically constitutes about 1% to
about 15%,
preferably about 2.5% to about 10%, by weight of the tablet as a wliole. The
hydrophobic or
water-insoluble component, preferably comprising ethylcellulose, typically
constitutes about
1% to about 10%, preferably about 2% to about 7%, by weight of the tablet as a
whole. The
pore-forming component, preferably comprising HPMC, is typically present in an
amount of
about 5% to about 50%, preferably about 10% to about 40%, by weight of the
water-
insoluble or hydrophobic component.
The coating, if present, can optionally contain additional pharmaceutically
acceptable
excipients such as plasticizers, dyes, etc. Illustratively, a release-
controlling layer in an
amount of about 2.5% to about 5% by weight of the tablet core (i.e., the
tablet weight
excluding the coating) comprises an ethylcellulose-based material (e.g.,
SURELEASE of
Colorcon) and an HPMC-based pore-forming material (e.g., OPADRY of Colorcon)
in a
weight ratio of about 3:1 to about 4:1. A release-controlling layer or coating
is preferably
applied at a relatively uniform thickness to provide even control of release
rate of the
pramipexole.
Alternatively or in addition, the sustained-release tablet of the invention
comprises a
nonfunctional coating. A nonfunctional coating can comprise a polymer
component, for
example HPMC, optionally with other ingredients, for example one or more
plasticizers,
colorants, etc. The term "nonfunctional" in the present context means having
no substantial
effect on release properties of the tablet, and does not imply that the
coating serves no useful
purpose. For example, such a coating can impart a distinctive appearance to
the tablet,
provide protection against attrition during packaging and transportation,
improve ease of
swallowing, and/or have other benefits. A nonfunctional coating should be
applied in an
amount sufficient to provide.complete coverage of the tablet. Typically an
amount of about
1% to about 10%, more typically an amount of about 2.5% to about 5%, by weight
of the
tablet as a whole, will be found suitable.
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Uncoated tablets and cores of coated tablets of the invention can optionally
contain
one or niore pharmaceutically acceptable excipients in addition to the starch
and hydrophilic
polymer components described above. Such excipients include without limitation
glidants
and lubricants. Other conventional excipients known in the art can also be
included. A glidant
can be used to improve powder flow properties prior to and during tableting
and to reduce
caking. Suitable glidants include colloidal silicon dioxide, magnesium
trisilicate, powdered
cellulose, starch, talc, tribasic calcium phosphate and the like. In certain
embodiments,
colloidal silicon dioxide is included as a glidant in an amount up to about
2%, preferably
about 0.2% to about 0.6%, by weight of the tablet. A lubricant can be used to
enhance release
of a tablet from apparatus on which it is formed, for exaniple by preventing
adherence to the
face of an upper punch ("picking") or lower punch ("sticking"). Suitable
lubricants include
magnesium stearate, calcium stearate, canola oil, glyceryl palmitostearate,
hydrogenated
vegetable oil, magnesium oxide, mineral oil, poloxamer, polyethylene glycol,
polyvinyl
alcoliol sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate,
stearic acid, talc,
hydrogenated vegetable oil, zinc stearate and the like. In certain
embodiments, magnesium
stearate is included as a lubricant in an amount of about 0.1 % to about 1.5%,
preferably about
0.3 % to about 1%, by weight of the tablet.
In another embodiment, the coated extended-release (XR) tablets of pramipexole
dihydrochloride of the invention are prepared using the composition shown in
the table
below:
Composition of coated tablets
Ingredient Amount (mg)
Pramipexole dihydrochloride monohydrate 0.375
HPMC type 2208, 4000 rnPa s 140.0
Pregelatinized starch 206.5
Colloidal silicon dioxide 1.41
Magnesium stearate 1.75
Total core 350
Ethylcellulose-based coating material (SURELEASE ) 14.0
HPMC-based coating material (OPADRY ) 3.5
Total coating 17.5
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Tablet cores were prepared as following: all ingredients except the lubricant
(magnesium stearate) were screened to remove lumps and were blended thoroughly
in a low-
shear mixer operating at 24 rpm for 10-30 minutes. The lubricant was then
screened into the
mixer and the materials were blended for a further 2-5 minutes. The resulting
lubricated
mixture was compressed into 350 mg tablets using a GlobePharma Manual Tablet
Compaction Machine.
In an alternative embodiment, pramipexole was layered onto the lactose
particles to
achieve its uniform dispersion.
A coating solution was prepared as follows: OPADRY HPMC-based material in an
amount of 8.002 g was added to 171.735 g water and mixed for 45 minutes to
provide an
HPMC mixture. Next, 128.032 g SURELEASE ethylcellulose-based material was
added to
the HPMC mixture and mixed for an additional 30 minutes to provide a coating
solution.
Coating to a 5% total weight gain and curing of the coated tablets were
performed as
following: the coating solution was applied to the tablet cores in an amount
providing a 5%
weight gain. The resulting coated tablets were cured using a 12 inch (about 30
cm) Vector
LCDS or 24 inch (about 60 cm) Thomas Accela-Coata coating pan for about 15
minutes at a
bed temperature of at least about 70 C. After curing, temperature was ramped
down over a
period of about 8 minutes to an exhaust temperature of about 45 C.
The extended release pellets typically contain the same amount of total
pramipexole
used for thrice-a-day conventional treatment, e.g., about 0.375 mg for the
0.125 mg regimen.
IV. Exemplary Delivery Devices
A. General Considerations
As noted previously herein, the compositions of the present invention can be
in a
number of different forms, such as tablets, powders, suspensions, solutions,
etc. The
composition is preferably in pellet/beadlet form, which can be incorporated
into hard gelatin
or other kinds of capsules, either with additional excipients, or alone.
The dosage formulations described herein, e.g., the cores of tablets and drug
eluting
devices of the invention, may contain one or more excipients, carriers or
diluents. These
excipients, carriers or diluents can be selected, for example, to control the
disintegration rate
of a tablet or drug eluting device to fit the desired release profile
according to the instant
invention. In addition, the one or more carriers (additives) and/or diluents
may be
pharmaceutically acceptable.
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The phrase "pharmaceutically acceptable carrier" as used herein means a
pharmaceutically acceptable material, composition or vehicle, such as a liquid
or solid filter,
diluent, excipient, solvent or encapsulating material, involved in carrying or
transporting the
subject regulators from one organ, or portion of the body, to another organ,
or portion of the
body. Each carrier must be "acceptable" in the sense of being compatible with
the other
ingredients of the formulation and not injurious to the patient. Some examples
of materials
which can serve as pharmaceutically acceptable carriers include (1) sugars,
such as lactose,
glucose and sucrose; (2) starches, such as corn starch and potato starch; (3)
cellulose, and its
derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and
cellulose acetate; (4)
powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as
cocoa butter and
suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower
oil, sesame oil, olive
oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11)
polyols, such as
glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters such as
ethyl oleate and ethyl
laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and
aluminum
hydroxide; (15) alginic acid; '(16) pyrogen-free water; (17) isotonic saline;
(18) Ringer's
solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other
non-toxic
compatible substances employed in pharmaceutical formulations.
Typical excipients to be added to a capsule formulation include, but are not
limited to:
fillers such as microcrystalline cellulose, soy polysaccharides, calcium
phosphate dihydrate,
calcium sulfate, lactose, sucrose, sorbitol, or any other inert filler. In
addition, there can be
flow aids such as fumed silicon dioxide, silica gel, magaesium stearate,
calcium stearate or
any other materials that impart good flow properties. A lubricant can also be
added if desired,
such as polyethylene glycol, leucine, glyceryl behenate, magnesium stearate or
calcium
stearate.
The formulations can conveniently be presented in unit dosage form and can be
prepared by any of the methods well known in the art of pharmacy. All methods
include
bringing into association the drug with the carrier or diluent which
constitutes one or more
accessory ingredients. In general, the formulations are prepared by uniformly
and intimately
bringing into association the agent with the carriers and then, if necessary,
dividing the
product into unit dosages thereof. It will be understood by those skilled in
the art that any
vehicle or carrier conventionally employed and which is inert with respect to
the active agent,
and preferably does not interfere with bioadhesion in embodiments ensploying a
bioadhesive
coating, may be utilized for preparing and administering the pharmaceutical
compositions of
the present invention. Illustrative of such vehicles and carriers are those
described, for
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example, in Remington's Pharnzaceutical Sciences, 18th ed. (1990), the
disclosure of which is
incorporated herein by reference.
Examples of carriers and diluents include pharmaceutically accepted liydrogels
such
as alginate, chitosan, methylmethacrylates, cellulose and derivatives thereof
(microcrystalline
cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,
carboxymethylcellulose,
ethylcellulose), agarose and POVIDONETM, leaolin, magnesium stearate, starch,
lactose,
sucrose, density-controlling agents such as barium sulfate and oils,
dissolution enhancers
such as aspartic acid, citric acid, glutamic acid, tartartic acid, sodium
bicarbonate, sodium
carbonate, sodium phosphate, glycine, tricine, Tromethamine, and TRIS.
The excipients, carriers or diluents can also be selected to control the time
until a
dosage form detaches from a mucosal membrane. In particular, the addition of
one or more
disintegrating agents will reduce the time until a tablet or drug eluting
device detaches.
Alternatively or in combination with the disintegrating agents, an agent that
interferes with
the mucosa-tablet / device adhesion can be used to control the time until
detaclnnent occurs.
As set out above, certain components, such as pramipexole, of the present
pharmaceutical compositions may contain a basic functional group, such as
amino or
alkylamino, and are thus capable of forming pharmaceutically acceptable salts
with
pharmaceutically acceptable acids. The term "pharmaceutically acceptable
salts" in this
respect, refers to the relatively non-toxic, inorganic and organic acid
addition salts of
compounds of the present invention. These salts can be prepared in situ during
the final
isolation and purification of the compounds of the invention, or by separately
reacting a
purified compound of the invention in its free base form with a suitable
organic or inorganic
acid, and isolating the salt thus formed. Representative salts include but are
not limited to
following: 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 3-hydroxy-2-
naphthoate, 3-
phenylpropionate, acetate, adipate, alginate, amsonate, aspartate,
benzenesulfonate, benzoate,
besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium
edetate, camphorate,
camphorsulfonate, camsylate, carbonate, citrate, clavulariate,
cyclopentanepropionate,
digluconate, dodecylsulfate, edetate, edisylate, estolate, esylate,
ethanesulfonate, fumarate,
gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate,
glycollylarsanilate,
hemisulfate, heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate,
hydrabamine,
hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, iodide,
isothionate, lactate,
lactobionate, laurate, laurylsulphonate, malate, maleate, mandelate, mesylate,
methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate,
naphthylate,
napsylate, nicotinate, nitrate, N-methylglucaniine ammonium salt, oleate,
oxalate, palmitate,
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pamoate, pantothenate, pectinate, persulfate, phosphate,
phosphate/diphosphate, picrate,
pivalate, polygalacturonate, propionate, p-toluenesulfonate, salicylate,
stearate, subacetate,
succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate,
thiocyanate, tosylate,
triethiodide, undecanoate, and valerate salts, and the like. (See, for
example, Berge et aL,
"Pharmaceutical Salts", J. Plaarm. Sci. 66: 1-19, 1977).
In certain embodiments, the pharmaceutically acceptable salts of compounds,
such as
pramipexole, include the conventional non-toxic salts of the compounds, e.g.,
from non-toxic
organic or inorganic acids. Particularly suitable are salts of weak acids. For
example, such
conventional non-toxic salts include those derived from inorganic acids such
as hydrochloric,
hydrobromic, hydriodic, cinnamic, gluconic, sulfuric, sulfamic, phosphoric,
nitric, and the
like; and the salts prepared from organic acids sucll as acetic, propionic,
succinic, glycolic,
stearic, lactic, maleic, tartaric, citric, ascorbic, palmitic, maleic,
hydroxymaleic, phenylacetic,
glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric,
toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
In other cases, the components of formulations of the present invention may
contain
one or more acidic functional groups and, thus, are capable of forming
pharmaceutically
acceptable salts with pharmaceutically acceptable bases. The term
"pharmaceutically
acceptable salts" in these instances refers to the relatively non-toxic,
inorganic and organic
base addition salts of compounds of the present invention. These salts can
likewise be
prepared in situ during the final isolation and purification of the compounds,
or by separately
reacting the purified compound in its free acid form with a suitable base,
such as the
hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal
cation, with
ammonia, or with a pharmaceutically acceptable organic primary, secondary or
tertiary
amine. Representative alkali or alkaline earth salts include the lithium,
sodium, potassium,
calcium, and magnesium salts and the like. Representative organic amines
useful for the
formation of base addition salts include ethylamine, diethylamine,
ethylenediamine,
tromethamin, ethanolaniine, diethanolamine, piperazine and the like. (See, for
example,
Berge et al., supra).
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and
magnesium stearate, as well as coloring agents, release agents, coating
agents, sweetening,
flavoring and perfiiming agents, preservatives and antioxidants can also be
present in the
compositions.
Pharmaceutically acceptable antioxidants may also be included. Examples of
pharmaceutically acceptable antioxidants include: (1) water soluble
antioxidants, such as
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ascorbic acid, cysteine nyctrocntonde, sodium bisulfate, sodium metabisulfite,
sodium sulfite
and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate,
butylated
hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl
gallate, alpha-
tocopherol, and the like; and (3) metal chelating agents, such as citric acid,
ethylenediamine
tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the
like.
In certain embodiments, the disintegration time of a coinposition (e.g., XR or
DXR)
may be formulated to effect a substantially zero-order release, over a period
of 2, 4, 6, 8, 12,
or 24 hours, for instance.
In certain embodiments, multiparticulate capsules are preferred because they
provide
an increased surface area as opposed to a tablet or matrix, and thus allow for
better release
profiles and bioavailability.
However, the pellets described above can be incorporated into a tablet, in
particular
by incorporation into a tablet matrix, which rapidly disperses the particles
after ingestion. In
order to incorporate these particles into such a tablet, a filler/binder must
be used in the
tableting process that will not allow the destruction of the pellets during
the tableting process.
Materials that are suitable for this purpose include, but are not limited to,
microcrystalline
cellulose (AVICEL ), soy polysaccharide (EMCOSOY ), pre-gelatinized starches
(STARCH 1500, NATIONAL 1551), and polyethylene glycols (CARBOWAX ). These
materials should be present in the range of about 5%-75% (w/w), and preferably
between
about 25%-50% (w/w).
In addition, disintegrants may be added to the tablets in order to disperse
the beads
once the tablet is ingested. Suitable disintegrants include, but are not
limited to: crosslinked
sodium carboxymetliyl cellulose (AC-DI-SOL ), sodium starch glycolate
(EXPLOTAB ,
PRIMOJEO), and crosslinked polyvinylpolypyrrolidone (Plasone-XL). These
materials
should be present in the range of about 3%-15% (w/w), with a preferred range
of about 5%-
10% (w/w).
Lubricants may also be added to assure proper tableting, and these can
include, but
are not limited to: magnesium stearate, calcium stearate, stearic acid,
polyethylene glycol,
leucine, glyceryl behenate, and hydrogenated vegetable oil. These lubricants
should be
present in amounts from about 0.1%-10% (w/w), witli a preferred range of about
0.3%-3.0%
(w/w).
Tablets are formed, fbr example, as follows. The pellets are introduced into a
blender
along with AVICEL , disintegrants and lubricant, mixed for a set number of
minutes to
provide a homogeneous blend which is then put in the hopper of a tablet press
with which
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tablets are compressed. The compression force used is adequate to form a
tablet; however, it
is not sufficient to fracture the beadlets or coatings.
The subject once-a-day dosage forms of pramipexole typically contain the same
total
amount of therapeutically effective amount of pramipexole that is administered
to a patient
during a conventioiial pramipexole treatment. For example, for the treatment
of PD, one
conventional thrice-a-day regimen comprises 3 times a day of 0.125 mg
pramipexole each
(other dosages are available as 0.5, 0.75, 1.0, 1.5, 3.0, and 4.5 mg, etc.).
Thus for this
embodiment, the total amount of pramipexole for PD treatment is about 0.375
ing (3 x 0.125
mg) in the subject once-a-day dosage forms. However, in certain embodiments,
the total
amount of pramipexole used may be adjusted upward or downward by, for example,
5-30%,
or 10-20%, etc., depending on specific patient's age, weight, gender, race,
health condition,
and other considerations.
In certain embodiments, the subject pharmaceutical composition is formulated
for
variable dosing, such as customized dosing for individual patients.
In addition, more than one type of drugs can be present in a tablet or a drug
eluting
device of the invention, e.g., for combination therapy with other
pharmaceutical compositions
effective for treating PD or other movement disorders (see below). The drugs
can be evenly
distributed throughout a medicament or can be heterogeneously distributed in a
medicament,
such that one drug is fully or partially released before a second drug. See
different
embodiments of the drug devices and/or layering in other parts of this
specification.
Dosage forms of the invention typically weigh at least about 50 mg. Dosage
forms
(such as the various shell designs of the invention) can also weigh at least
100 mg, at least
150 mg, at least 250 mg, at least 500 mg, or at least 1000 mg, etc.
Dosage forms of the invention typically measure at least 2 mm in one
direction. For
example, dosage forms can measure at least 5 mm, at least 10 mm, at least 15
n1m or at least
20 mm in one direction. Typically, the diameter of the dosage forms is 2 to 40
mm,
preferably 10 to 30 mm such as 20 to 26 mm. Mini-tablets have a diameter of 2
mm to about
mm. Such dosage forms can measure at least 2 mm, at least 5 mm, at least 10
mm, at least
mm or least 20 mm in a second direction and, optionally, a third direction.
Preferably, the
dosage form is of a size that facilitates swallowing by a subject.
The volume of a typical dosage form of the invention is at least 0.008 mL, at
least
0.01 mL, at least 0.05 mL, at least 0.1 mL, at least 0.125 mL, at least 0.2
mL, at least 0.3 mL,
at least 0.4 mL or at least 0.5 mL.
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Dosage forms of the invention may be a tablet that can be of any suitable size
and
shape, for example, round, oval polygonal or pillow-shaped, and optionally
bear
nonfunctional surface markings. Especially in the case of coated tablets, they
are preferably
designed to be swallowed whole and are therefore typically not provided with a
breaking
score. Tablets of the invention can be packaged in a container, e.g.,
accompanied by a
package insert providing pertinent information such as, for example, dosage
and
administration information, contraindications, precautions, drug interactions
and adverse
reactions.
To produce a dosage form that can release at least two or three drugs at two
or three
different rates, and with preprogrammed delays, special dosage forms are used.
For example,
in the embodiments of the invention wherein different dosage forms of
pramipexole (e.g., IR,
DR, XR, DXR, etc.) are designed to be released concomitantly, the drugs may be
formulated
as bilayer (or other multilayer) tablets or shells (e.g., stacked layer of
cakes, each may
represent an independent formulation). Alternatively, the drugs may be
formulated as a tablet
within a tablet or bead (not limited to two nested layers). Optionally, a
bioadhesive layer may
be coated over part or all of a gel capsule (or other forms of delivery
device) to enhance the
stay of the device within a certain area of the GI tract, such as the
intestine.
B. Exemplary Delivery Devices / Forms
In certain embodiments, the drugs may be formulated into a core tablet held in
a
recessed fashion within an annular ring of drug material. Such a dosage form
is described in
U.S. patent application Ser. No. 10/419,536 entitled "Dosage Form with a Core
Tablet of
Active Ingredient Sheathed in a Compressed Angular Body of Powder or Granular
Material,
and Process and Tooling for Producing It," filed on Apr. 21, 2003 and Ser. No.
10/379,338
entitled "Controlled Release Dosage Forms," filed on Mar. 3, 2003 and are
incorporated
herein by reference. This design may be used for many embodiments of the
subject dosage
forms. For example, the outer annular ring is formulated for either immediate
release (IR) or
extended release (XR) delivery for a desired amount of time. The inner core(s)
of the dosage
form may be released after a delay which may be formulated for the desired
release profile.
The enteric coating covers the tablet to delay drug delivery until the tablet
enters a non-acidic
environment.
Other embodiments of the invention use the dosage form described in U.S.
patent
application Ser. No. 10/191,298 entitled "Drug Delivery System for Zero-order,
Zero-Order
Biphasic, Ascending or Descending Drug Delivery," filed on Jul. 10, 2002,
incorporated
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herein by reference. The dopamine transport inhibitor may be formulated in the
tablet mantle
and released at the desired rate after a delay. The pramipexole composition
may be
formulated in the expanding plug and released at the desired rate upon entry
into the intestine.
Another embodiment of this invention rnay be achieved by formulating each of
the
drugs as pellets / beads, each with its own release profile and delay where
applicable, and
delivering the mixture of the pellets (e.g., IR, DR, DXR, etc.) in a shell
using methods
commonly known in the art. Furthermore, the proportions of the different types
of pellets /
beads may be altered or customized by a skilled artisan (e.g., qualified
physician or
pharmacologist), based on an individual patient's characteristics, such as
weight, age, gender,
ethnicity, and/or specific genetic backgrounds. Such customization may be
effected with the
aid of, or automatically executed by a computer program based on relevant
parameters such
as those described above.
In certain embodiments, the drug-releasing beads are characterized by a
dissolution
profile wherein 0 to 20% (e.g., 1-20%) of the beads undergo dissolution and
release the drug
in 0 to 2 hours, 20 to 40% uridergo dissolution and release the drug in 2 to 4
hours, 40 to 60%
exliibit dissolution and release in 4 to 6 hours, 60 to 80% in 6 to 8 hours,
and 80 to 100% in 8
to 10 hours or longer. The drug-releasing beads can include a central
composition or core
comprising a drug and pharmaceutically acceptable composition forming
ingredients
including a lubricant, antioxidant, and buffer. The beads comprise increasing
doses of drug,
for example, 0.1 mg, 0.2 mg, 0.5 mg, and so forth to a high dose. For
sustained release
embodiments, the beads may be coated with a release rate-controlling polymer
that can be
selected utilizing the dissolution profile disclosed above. The manufacture of
the beads can
be adapted from, for example, Liu et al., IiateJ . J. of Pharfia. 112: 105-
116, 1994; Liu et al.,
Iftter. J. ofPlzarm. 112: 117-124, 1994; Pharm. Sci., by Remington, 14th Ed.
pp. 1626-1628
(1970); Fincher et al., J. Pharni. Sci. 57: 1825-1835, 1968; and U.S. Pat. No.
4,083,949.
Certain embodiments of the subject beads or pellets are described in more
detail
below.
Some specific tablets or gel capsules designed are described below for
illustration
purpose. These designs are by no means limiting, and a skilled artisan can
readily envision
other equivalent designs based on the general teachings described herein.
In one example, as shown in the schematic drawing of Figure 1 A (not
necessarily to
scale), the tablet is a longitudinally compressed tablet. The core of the
tablet is a slow-
eroding active core 1 with pramipexole and other pharmaceutical excipients.
The side of the
core is coated with a bioadhesive polymer layer 4, while the two ends of the
core are coated
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with an insoluble plug 2 and an enteric polymer plug 3, respectively. The
enteric polymer
plug 3 will only dissolve in a relatively higher pH environment (e.g., about
pH 4.5 and
higher), such as those found in intestine or colon. Once the enteric polymer
layer 3 is
dissolved, the active core 1 starts to release its contents. The bioadhesive
layer 4 is selectively
adhesive to intestine or colon, such that the content of the active core 1 may
be released over
a prolonged period of time.
Figure 1B shows a slight variation of the device depicted in Figure IA, in
that the
insoluble plug 2 in replaced by a second enteric polymer plug 2. According to
this
embodiment, both enteric polymer plugs 2 will dissolve in relatively higher pH
environments,
either substantially simultaneously, or at different time, such that the rate
of release from the
slow-eroding active core 1 may be regulated.
Figure 1 C shows yet another alternative embodiment, in that the slow eroding
active
core 1 in Figure tA becomes two consecutive layers - an immediate release
active core layer
2, followed by a slow-eroding active core layer 1. As a result, once the
enteric polymer plug 4
is dissolved, the immediate release layer 2 provides a rapid drug release,
which is maintained
by more sustained drug release from the slow-eroding active core 1.
Figure 1D shows a schematic (not necessarily to scale) drawing of another
embodiment of the delivery device containing multiparticulate beads / pellets.
The
multiparticulate dosage form combines two types of pellets - the immediate
release pellets 1
and the controlled release active pellets (DR or XR) 2- both embedded in an
appropriate
matrix of excipients (e.g.,- HPMC, MCC, lactose). The matrix is inside a hard
gelatin capsule
3, which in turn is coated by enteric material 4. This type of dosage fomi
will provide
niultiple pulses of drug release, with the effect being a more or less
sustained blood level of
drug within the acceptable range. The release is delayed by the enteric
coating 4 in order to
by-pass the upper GI tract.
With this coinbination, the IR pellets are designed to provide an effective
blood level
soon after the start of the drug release, which is subsequently maintained by
the DR and/or
XR combinations. The DR portion provides an immediate release after a delay.
If XR pellets
are also used, the XR portion provides an extended release profile that
maintains the effective
blood level of pramipexole throughout the remaining course of the day. The
total dose of
pramipexole in this composition is usually no greater than 0.3 75 mg. The IR
pellets may
comprise 1/3 (or 0.125 mg) of the total, while the remaining 2/3 is provided
by the DR and/or
XR.
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A similar effect may be achieved by a device as depicted in Figure 1E, where
an
enteric coating 3 covers an inner core with two (asymmetric) portions - the
immediate release
active layer (IR)1 and the controlled release active layer (DR or XR) 2. The
ratio of IR to DR
/ XR may be anywhere between 1:10 to 2:1. In a preferred embodiment, the ratio
may be 1:2.
In Figure 1F, the complex core of Figure 1E is replaced with a uniform slow-
eroding
or non-eroding active matrix core 1, from which pramipexole is released after
the enteric
coating 2 is dissolved.
Figure 1 G presents yet another embodiment, wherein an enteric coating 4
delays the
release its drug contents. Upon degradation of the enteric coating 4, the
immediate release
active core 1 is quickly dissolved, effectively splitting the core into two
halves of controlled-
release active core 2, each coated by a layer of rate-controlling coating 3 at
surfaces not in
contact with the immediate release active core 1. Thus the release of the drug
content from
the controlled-release active core 2 is only through the rate-controlling
coating 3
(comparatively slow) before the immediate release active core 1 is dissolved.
The rate
gradually increases as the immediate release active core 1 dissolves, exposing
more surface
area of the two controlled-release active cores 2 not coated by the rate-
controlling coating 3.
Release profile may be controlled by, for example, the amount of the immediate
release
active core 1, the thickness and material of the rate-controlling coating 3,
the geometric shape
/ surface area of the controlled-release active core 2 directly in contact
with the immediate
release active core 1, etc.
In Figure 1H, the active core 1 is substantially covered by a layer of semi-
permeable
coating 3, which contains one or more small openings / orifices 2. The
outermost portion of
the whole device is further coated with a layer of delayed-release coating /
enteric coating 4.
Once coating 4 is dissolved, the orifice(s) is exposed, allowing direct
release of the active
core 1 tlirough the orifice(s) 2. Different release profiles may be obtained,
for example, by
controlling the number and/or size of the orifice(s) 2, the thickness and/or
material of the
semi-permeable coating 3.
An alternative embodiment is shown in Figure 11. Although the enteric coating
outside the semi-permeable coating 5 is not shown, the enteric coating may be
added in
certain embodiments. For the depicted embodiment in Figure 11, the core
comprises three
layers, with the middle layer being the active core 1. Underneath the active
core 1 is a push
layer 2 that will swell after the tablet comes into contact with body fluid
and when the fluid
enter the tablet through the semi-permeable coating 5. Above the active core
is a delayed-
release layer 3 having access to one or more orifice(s) for drug release. The
swelling push
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layer 2 will cause first the delayed-release layer 3, and then the active core
1 to be released
through the orifice 4. The delayed release layer may also have the IR
component or an
immediate release component in between the delayed release and slow release
core layer.
In yet another embodiment (Figure 1J), the immediate release beads / pellets 1
and the
controlled-release (XR and/or DR and/or DXR) beads / pellets 2 are embedded
within the
enteric polymer material 3 as multiparticulate beads / pellets. The enteric
polymer material 3
may additionally comprise compression enhancers or fillers, or any other
materials described
herein that are customarily used in tablet production.
Alternatively, the IR portion of the dosage form is formulated as a matrix for
embedding one or more other portions of the same dosage form (DR, XR, DXR,
etc.). The IR
may be coated by enteric layer to avoid release in upper GI tract. Each
controlled release
portion (DR, XR, DXR, etc.) is optionally coated by a bioadhesive coat and/or
a delayed
release coat. Each CR portion may be formed as microparticles (e.g., beads)
suspended in the
first portion (e.g., IR portion) matrix. The disintegration of the matrix
leads to the release of
the embedded microparticles, which may re-adhere to the gut or other tissues
(if coated by
bioadhesive layer), and provided for sustained release.
Figure 12 features yet another configuration of the delivery device, in which
a drug
portion 1201 is sandwiched between two adhesive layers 1202 (e.g., a layered
cross section)
or inside one continuous adhesive layer 1202 (e.g., configured as a filled
tube).
SPHEROMERTM I[p(FASA)] and SPHEROMERTM III are exemplary such bioadhesive
layers. The portion / layer can (but need not) be substantially flat. In
certain embodiments,
there are two substantially flat adhesive layers 1202 sandwiching one drug
layer 1201.
Components of the drug can be either released from surfaces not in contact
with the adhesive
parts 1202, and/or through the adhesive materials if such materials are at
least partially
permeable.
In certain embodiments, an immediate release portion IR 1203 may be present,
and is
coated over all or a part of the adhesive layer 1202. In certain embodiments,
the rapid
dissolution of the IR portion exposes a drug surface not in contact with the
adhesive material.
In another embodiment, the dissolution of the IR portion does not
substantially change the
release rate of the drug portion. This multilayer configuration is finally
applied with an
enteric or delayed release coating.
Figure 13 features yet another configuration of the subject delivery device,
which
may be used in general to deliver any kind of drugs (or prodrugs/metabolic
precursors
thereof, etc.). It should be understood that the subject delivery devices
(such as the one
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described in Figure 13), dosage form, and methods of making and using are not
limited to
these specific exemplary drug compositions described herein.
Thus according to this aspect of the invention, any drug to be delivered
(e.g.,
pramipexole), optionally including a bioadhesive polymer composition, and/or
pharmaceutically acceptable excipients, may be formulated using the subject
granulation-
extrusion-spheronization process into multiparticulate pellets, which in turn
may be dispersed
in certain matrix materials, or simply encapsulated in capsules, e.g.,
according to the various
embodiments disclosed above.
Specifically, appropriate amounts of the different ingredients are first
weighed and
mixed.
Suitable excipients for use in the subject granulation-extrusion-
spheronization process
include: Starcap-1500, starch-1500, and glycerine monostearate. In certain
embodiments, the
mixture is substantially free of microcrystalline cellulose.
In an exemplary embodiment, about 30-90%, about 40-85%, or about 50-80% (v/v)
of
the mixture (and the pellets formed therefrom) is effective ingredient (e.g.,
drug
composition), rather than excipients or polymers. Such loadings can be
achieved using any
drug or combination of drugs that are suitably cohesive, plastic, and engage
in hydrogen
bonding. Pramipexole is an example of such drugs, though others will be known
to or can be
easily identified by those of skill in the art.
These different ingredients can then be blended together in any suitable
device, such
as a planetary type mixer (e.g., Hobart Mixer with a 5-qt mixing bowl,
operating at the speed
setting #1, for about 5-15 min.). Optionally, the blending process is done in
small volume to
reduce any possible loss of the ingredients due to their non-specific
adherence to the blending
device. The blending step is typically done to ensure the formation of a
uniform dry mix of
the ingredients, typically over a period of, e.g., 5-15 min.
The dry mix is then granulated, e.g., under low shear with a granulation
fluid, so as to
form a wet granulation. Granulation fluids may be purified water, an aqueous
solution of a
mineral or organic acid, an aqueous solution of a polymeric composition, a
pharmaceutically
acceptable alcohol, a ketone or a chlorinated solvent, a hydro-alcoholic
mixture, an alcoholic
or hydro-alcoholic solution of a polymeric composition, a solution of a
polymeric
composition in a chlorinated *solvent or in a ketone, etc. or any suitable
mixture thereof
In certain embodiments, the granulation process is conducted in a small
volume, such
as in a 500-mL cylindrical vessel.
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In certain embodiments, the granulation process is conducted with manual
mixing, or
conducted mechanically, e.g., in a planetary type mixer (such as a Hobart
Mixer with a 5-qt
mixing bowl). If the Hobart Mixer is used, it can be operated at its speed
setting #1,
depending on the batch size. Other types of mechanical mixers may also be
used, with their
respective appropriate settings, to achieve substantially the same result.
Once the wet granulation is formed, it is extruded through the screen of a
screen-type
extruder. In certain embodiments, a Caleva Model 20 (or Model 25) Extruder may
be used,
operating at 10-20 rpm, and forming breakable wet strands ("the extrudate").
The screen
aperture may be set at 0.8, 1, or 1.5 mm. Other types of extruders may be used
to achieve
substantially the same result.
The extrudate is then spheronized in a spheronizer. For example, a Caleva
Model 250
spheronizer equipped with a 2.5-mm spheronization plate may be used, which may
be
operated at a speed of about 1000-2000 rpm, typically for 5-10 min., in order
to form
spheronized pellets. Other types of spheronizer may be used to achieve
substantially the same
result.
The spheronized pellets are then dried. The drying may be conducted in a
fluidized
bed drier, such as a Vector MFL.01 Micro Batch Fluid Bed System. If the Vector
drier is
-used, it may be operated at an inlet air flow rate of 100-300 lpm (liters per
minute) and an
inlet air temperature of about 50 C. Alternatively, the pellets may be dried
in an ACT
(Applied Chemical Technology) fluidized bed drier, operating at an inlet air
flow rate of 140-
150 fpm (foot per minute) and an inlet air temperature of 104 F. Other types
of driers may
also be used to achieve substantially the same result. Depending on the
specific type of drugs
/ compositions, the drying temperature for a drier similar to the Vector drier
may be between
35-70 C, or 40-65 C, or 45-60 C, or 45-55 C, etc. The drying temperature
for a drier similar
to the ACT drier may be between 70-140 F, or 80-130 F, or 90-120 F, or 100-
110 F, etc.
In yet another embodiment, the spheronized pellets may be dried in an oven,
such as a
Precision gravity oven, operating at about 50 C, for 4-48 hrs, or 8-24 hrs.
Depending on the
specific type of drugs / compositions, the oven drying tenlperature for a
drier similar to the
Precision gravity oven may be between 35-70 C, or 40-65 C, or 45-60 C, or 45-
55 C, etc.
The dried pellets are then screened and/or classified. This can be done by
using a
stack of sieves, such as stainless steel sieves U.S. standard mesh sizes 8,
10, 12, 14, 16, 18,
20, 25, 30, 40, 45, or 60, etc., and using a mechanical sieve shalcer (e.g.,
W.S. Tyler Sieve
Shaker Ro-Tap Rx-29, operated for 5 min.). Particle size and distribution of
pellet
formulations can then be analyzed, and the classified pellets ranging from
0.25 mm (mesh #
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60) to 2 mm (mesh # 10) may be selected for use or future formulation, such as
additional
film coating or other experimentation.
In certain embodiments, the selected pellets may be film-coated, e.g., with a
delayed-
release coating (such as an entaric coating), a controlled-release (CR)
coating, a bioadhesive
polymeric composition, and/or a dispersion-promoting coating, etc.
For example, the pellet core may be optionally surrounded by a CR coating,
such as
polymeric substance based on acrylates and/or methacrylates, e.g., a
EUDRAGITTM polymer
(sold by Rohm America, Inc:). Specific EUDRAGITTM polymers can be selected
having
various permeability and water solubility, which properties can be pH
dependent or pH
independent. For example, EUDRAGITTM RL, EUDRAGITTM NE, and EUDRAGITTM RS
are acrylic resins comprising copolymers of acrylic and methacrylic acid
esters with a low
content of quatemary ammonium groups, which are present as salts and give rise
to the
permeability of the lacquer films. EUDRAGITTm RL is freely permeable and
EUDRAGITTm
RS is slightly permeable, independent of pH. In contrast, the permeability of
EUDRAGITTM
L is pH dependent. EUDRAGITTM L is an anionic polymer synthesized from
methacrylic
acid and methacrylic acid methyl ester. It is insoluble in acids and pure
water, but becomes
increasingly soluble in a neutral to weakly alkaline solution by forming salts
with alkalis.
Above pH 5.0, the polymer becomes increasingly permeable. If desired, two or
more types of
polymeric substances may be mixed for use as the CR coating. Other polymers
suitable for
CR coatings, such as ethyl cellulose and cellulose acetate, can also be used
in the CR coating.
In certain embodiments, the CR coating may comprise one or more suitable
polymers, such
as a combination of two or more of the polymers discussed above.
Optionally, the pellets may also be coated by a bioadhesive polymeric
composition.
The adhesive material may facilitate the adhesion of the pellets to a desired
surface, such as a
preferred GI tract surface. For example, the pellets / beads may be coated by
a top-layer of a
bioadhesive polymer such as SPHEROMERTM I [p(FASA)], SPHEROMERTM II,
SPHEROMERTM III, SPHEROMERTM IV, or mixtures thereof.
In certain embodiments, the functions of a CR coating and bioadhesive coating
can be
combined in a single layer by using a mixture of polymers including a
bioadhesive polymer
and a polymer suitable for controlled release, i.e., a single layer may be
both the CR layer and
the bioadhesive layer of a particle.
Optionally, the pellets can also be film-coated with an additional layer of a
so-called
"non-functional polymer," such as OPADRYTM II, EUDRAGITTM E, AcryIEZETM,
hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol,
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polyvinylacetate, polyanhydride, etc. This layer may serve as a dispersion-
promoting coating
that inhibits clumping and aggregation of the particles during dispersion. In
embodiments
wherein the pellets are further compressed with excipients to form tablets,
this layer is
preferably sufficiently strong or resilient to remain substantially intact
during the
compression process. This layer may also be protected by including a
cushioning material
among the excipients of the tablet matrix.
The coating material (such as bioadhesive polymers and/or functional /
nonfunctonal
polymers) may be dissolved in an appropriate solvent, such as methylene
chloride (e.g., for
SPHEROMERTM I), methanol (e.g., for SPHEROMERTM III), a binary mixture of
methanol
and methylene chloride (e.g., for SPHEROMERTM I and SPHEROMERTM III), methanol
or a
binary mixture of ethanol and water (3:1 v/v) (e.g., for SPHEROMERTM IV), or
methanol,
ethanol, or isopropanol, or their binary mixture with acetone (e.g.,
functional or non-
functional polymer).
The film coating may be performed in a fluidized bed coater, such as a Vector
MFL.01 Micro Batch Fluid Bed System, equipped with a Wurster insert, operating
at an inlet
air flow rate of 100-300 lpm (liters per minute), and an inlet air temperature
of about 25-45
C, or about 30-40 C, depending on the specific drugs and coatings (e.g., 25-
30 C for
SPHEROMERTM I-coated pramipexole; about 35 C for SPHEROMERTM III-coated
pramipexole, etc.). If the Vector System is used, the pellets may be pre-
warmed at 35 C for
2-5 min., and after film-coating, post-dried at about 30 C for about 15-30
min.
Alternatively, pellets may be coated in a fluid bed processor, such as a Fluid
Air
Model 5 fluid bed processor equipped with a Wurster insert, operating at an
inlet air flow rate
of about 70 cfm (cubic foot per minute) and an inlet air temperature of about
35 C. For this
type of fluid bed processor, the pellets may be pre-warmed at 40 C for 5-7
min., and after
film-coating, post-dried at about 35 C for about 30 min.
Other types of coaters may also be used to achieve substantially the same
result.
Different lots of the same pellets produced using the subject method may
optionally
be mixed, e.g., by using a blender (such as a GlobePharma Maxiblend Blender
equipped with
an 8-qt stainless steel V-shell).
In certain embodiments, different types of pellets may be mixed. For example,
some
pellets may have no coating other than a core comprising the effective
ingredients. Other
pellets, such as those identically made, may have additionally been coated by
one or more
types of coatings, e.g., bioadhesive coating, delayed-release coating,
controlled-release
coating, and/or dispersion-promoting coating, etc.
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In certain embodiments, pellets produced using the methods of the invention
may be
encapsulated in capsules, such as hard gelatin capsules or pullulan capsules
(NPcapsTM), each
with a predetermined amount of effective ingredients.
In certain embodiments, pellets produced using the methods of the invention
may be
dispersed in a matrix material to assist the delivery of the effective
ingredients of the pellets.
There are at least two preferred configurations according to this embodiment
of the invention.
Figure 13 shows a schematic drawing (not to scale) of one such configuration.
In
Figure 19, the active comporients 1301 (such as the pellets produced using the
subject
method, which are not necessarily round in shape) are embedded / dispersed
within an
inactive material or carrier matrix 1302. The carrier matrix 1302 can rapidly
disintegrate, e.g.,
dissolve substantially completely (superdisintegrant) within about 15 minutes,
10 minutes, 8
minutes, 7 minutes, 6 minutes, 5 minutes, 3 minutes, 2 minutes, or about 1
minute or less.
The inactive materia11302 may additionally comprise one or more cushioning
material(s) dispersed throughout, e.g., sufficient to protect the active
components 1301 when
preparing the delivery device, by substantially absorbing the impact of
compacting, and/or
reducing friction on the surface of the particles 1301 (to prevent danlaging
the substructure of
the particles, see below).
The particles 1301 may be in any suitable size and shape (rods, beads, or
other regular
or irregular shapes). In certain embodiments, the particles are beads with a
diameter of less
than about 2 mm, about 1.5 mm, about 1 mm, about 0.8 mm, about 0.5 mm, about
0.3 mm, or
about 0.1 mm. In certain embodiments, for pellets with pramipexole as
effective ingredient,
the pellet size is about 0.8 - 1 mm. Particles are formulated to these sizes
in order to enable
high drug loading when needed.
As described above, particles 1301 may have substructures, such as various
coating
layers surrounding a drug / prodrug core. Although the following describes the
substructures
using a bead with pramipexole as effective ingredient, it is an illustrative
example only, and
the description also applies to other shapes of particles with other effective
ingredients.
The core by itself may be an immediate release portion, or may have release-
controlling components (e.g., CR portion), and preferably, the core is made by
extrusion,
such as the granulation-extrusion-spheronization process. The core is
optionally surrounded
by a CR coating, such as polymeric substance based on acrylates and/or
methacrylates, e.g., a
EUDRAGITTM polymer (sold by Rohm America, Inc.). Specific EUDRAGITTM polymers
can be selected having various permeability and water solubility, which
properties can be pH
dependent or pH independent. For example, EUDRAGITTM RL, EUDRAGITTM NE, and
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EUDRAGITTM RS are acrylic resins comprising copolymers of acrylic and
methacrylic acid
esters with a low content of quatemary ammonium groups, which are present as
salts and
give rise to the permeability of the lacquer films. EUDRAGITTM RL is freely
permeable and
EUDRAGITTM RS is slightly permeable, independent of pH. In contrast, the
permeability of
EUDRAGITTM L is pH dependent. EUDRAGITTM L is an anionic polymer synthesized
from
methacrylic acid and methacrylic acid methyl ester. It is insoluble in acids
and pure water,
but becomes increasingly soluble in a neutral to weakly alkaline solution by
forming salts
with alkalis. Above pH 5.0, the polymer becomes increasingly permeable. If
desired, two or
more types of polymeric substances may be mixed for use as the CR coating.
Other polymers
suitable for CR coatings, such as ethyl cellulose and cellulose acetate, can
be used in the CR
coating. The CR coating may comprise one or more suitable polymers, such as a
combination
of two or more of the polymers discussed above.
Optionally, the CR coating is itself coated by a layer of adhesive material
that
facilitates the adhesion of the particles / beads to a desired surface, such
as a preferred GI
tract surface. Various suitable adhesive materials are described herein above.
For example,
the pellets / beads may be coated by a top-layer of a bioadhesive polymer such
as
SPHEROMERTM I [p(FASA)], SPHEROMERTM III, SPHEROMERTM IV, or mixtures
thereof. In certain embodiments, the functions of a CR coating and bioadhesive
coating can
be combined in a single layer by using a mixture of polymers including a
bioadhesive
polyiner and a polymer suitable for controlled release, i.e., a single layer
may be both the CR
layer and the bioadhesive layer of a particle.
Optionally, pellets can be further film-coated with an additional layer of a
so-called
"non-functional polymer" such as OPADRYTM II, EUDRAGITTM E, AcryloezeTM,
hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol,
polyvinylacetate, polyanhydride, etc. This layer may serve as a dispersion-
promoting coating
that inhibits clumping and aggregation of the particles during dispersion. In
embodiments
wherein the pellets are further compressed with excipients to form tablets,
this layer is
preferably sufficiently strong or resilient to remain substantially intact
during the
compression process. This layer may also be protected by including a
cushioning material
among the excipients of the tablet matrix.
Optionally, an IR portion is included in the particle, such as over the
dispersion-
promoting coating, or between the dispersion-promoting coating and the
adhesive layer, etc.
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In an alternative embodiment, particles 1301 are not embedded within the
inactive
materia11302, but are instead disposed loose in a capsule that dissolves and
releases the
particles in the GI tract.
Figure 14 features yet another embodiment of the delivery device, in which
particles
described herein above (e.g., with respect to Figure 19) are embedded within a
slow eroding
material 1401 (e.g., that gradually erodes over 30 minutes, 45 minutes, 1 hr,
2 hrs, 4 hrs, 6
hrs, or longer). At least a portion of the eroding material 1401 is covered by
an IR portion
1402, which disintegrates relatively rapidly to expose a surface of eroding
material 1401. A
portion of the slow eroding material 1401 is also optionally covered by a
passive polymer
support layer and/or an adhesive material 1403 as described herein above. In
certain
embodiments, the IR portion 1402 may be disposed on the adhesive layer 1403
instead of the
eroding material 1401 as depicted.
According to a related aspect of the invention, any drug to be delivered
(e.g.,
pramipexole), optionally including a bioadhesive polymer composition, and/or
pharmaceutically acceptable excipients, may also be formulated as a multilayer
tablet.
Specifically, different ingredients (such as those described above) are
weighed and
mixed. These ingredients, possibly with the exception of any lubricants, can
then be blended
together in any suitable device, such as an end-over-end ATR rotator (e.g.,
model RKVS), or
a planetary type mixer (e.g., Hobart Mixer). Optionally, the blending process
is done in small
volume to reduce any possible loss of the ingredients due to their non-
specific adherence to
the blending device. The blending step is typically done to ensure the
formation of a uniform
dry mix of the ingredients, typically over a period of, e.g., 5-15 min.
The dry mix is then granulated, e.g., under low shear with a granulation
fluid, so as to
form a wet granulation. Granulation fluids may be purified water, an aqueous
solution of a
mineral or organic acid, an aqueous solution of a polymeric composition, a
pharmaceutically
acceptable alcohol, a ketone or a chlorinated solvent, a hydro-alcoholic
mixture, an alcoholic
or hydro-alcoholic solution of a polymeric composition, a solution of a
polymeric
composition in a chlorinated solvent or in a ketone, etc.
In certain embodiments, the granulation process is conducted in a small
volume, such
as in a 500-mL cylindrical vessel.
In certain embodiments, the granulation process is conducted with manual
mixing, or
conducted mechanically, e.g., in a planetary type mixer (such as a Hobart
Mixer with a 5-qt
mixing bowl). If the Hobart Mixer is used, it can be operated at its speed
setting #1,
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depending on the batch size. Other types of mechanical mixers may also be
used, with their
respective appropriate settings, to achieve substantially the same result.
Once the wet granulation is formed, it is dried. In certain embodiments, the
wet
granulation is dried in an oven (e.g., a Precision gravity oven, operating at
about 50 C, for 8-
24 hrs; or similar appropriate conditions for other types of ovens).
Altexnatively, the
granulation may be dried in a fluidized bed drier, such as a Vector MFL.01
Micro Batch
Fluid Bed System, operating at an inlet air flow rate of 100-3001pm (liters
per minute) and an
inlet air temperature of about 50 C. The drying temperature is generally
around 50 C.
However, depending on different types of drugs / compositions, the temperature
may be 35-
70 C, or 40-65 C, or 45-60 C, or 45-55 C, etc.
The dried granulation is then grinded, e.g., by using a pestle in a mortar,
optionally
followed by sieving the ground material, e.g., through an appropriate-sized
screen (such as a
U.S. Std. mesh # 60 screen), depending on the desired size of the granules.
At this point, the sieved granulation may be blended with a lubricant. In
certain
embodiments, the blending is conducted using an end-over-end ATR rotator
(e.g., model
RKVS). In certain embodiments, the blending is conducted using a planetary
type mixer (e.g.,
Hobart Mixer, operating at the speed setting #1, for 5-15 min.). As a result,
a uniformly
lubricated dry mix is formed, which is then ready for compression.
Optionally, before compression, the lubricated dry mix may be passed through a
sieve
or screen, e.g., a U.S. Std. mesh # 60 screen.
Different components of the pharmaceutical composition (e.g., the effective
ingredients, any bioadhesive polymers, or other coatings, etc.) may be
prepared as a mixture
or separately using the subject methods. Once the dry mixes are formed, they
can be
compressed into single layer or multilayer tablets. For example, the
lubricated dry mix may
be pressed into tablets, such as by using a single-station manual tablet press
(e.g.,
GlobePharma Manual Tablet Compaction Machine MTCM-I, equipped with adequate
die
and punch set). If the G1obePharma machine is used, tablets may be prepared,
e.g., at a
pressure ranging from 250 to 4000 pounds per square inch (psi), and a
compression time of,
e.g., 1 to 4 seconds. Other machines may also be used to achieve substantially
the same
result.
Alternatively, in certain embodiments, tablets may be produced with wet
granulation
of active ingredients followed by direct compression.
In certain embodiments, multilayer tablets may be produced, with each layer
comprising a different ingredient. In these embodiments, a single-station
manual tablet press
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WO 2007/002518 PCT/US2006/024665
(e.g., GlobePharma Manual Tablet Compaction Machine MTCM-I, equipped with
adequate
die and punch set) may be used in several steps to produce the multilayer
tablets. For
example, for a bilayer tablet, the compression process may include:
(1) adding the first layer blend into the die cavity, optionally followed by
manually tapping it using a stainless steel spatula;
(2) adding the second layer blend into the die cavity;
(3) pre-compressing the two layers together, e.g., at a pressure ranging from
250
to 500 pounds per square inch (psi) and a compression time of, e.g., 1 to 5
seconds.
(4) compressing the pre-compacted layers together, e.g., at a pressure ranging
from 1000 to 4000 pounds per square inch (psi) and a compression time of,
e.g., 1 to 4
seconds.
The process can be repeated or modified if more than two layers of ingredients
are to
be used.
In certain embodiments, the tablet can be made with a pre-compressed insert
with
effective ingredients. Such pre-compressed inserts may be produced witli
direct compression.
The same press machine may be used for this process. For example, if using the
GlobePliarma Manual Tablet Compaction Machine MTCM-I machine, tablet inserts
may be
prepared, e.g., at a pressure ranging from 500 to 1000 pounds per square inch
(psi), and a
compression time of, e.g., 1 to 2 seconds. Other machines may also be used to
achieve
substantially the same result. The pre-compressed insert may be used as one of
the layers
(e.g., the second layer) in the tablet, or embedded in the middle of another
layer (e.g., the
second layer).
Optionally, the tablets may be coated with one or more coating compositions,
such as
in the form of successive layers. The coating compositions may. include
bioadhesive layers,
delayed release layers, controlled-release layers, and/or other functional /
non-functional
polymers etc. (supra). For example, tablets may be film-coated for this
purpose, using a pan
coater (e.g., O'Hara Labcoat, operating at an inlet air flow rate of about 60
cfin (cubic foot
per minute) and an inlet air temperature of about 35 C). The tablets may be
pre-warmed at
35 C for 5-10 inin., and after film coating, may be post-dried at about 30 C
for about 15-30
min. Other coaters may also be used to achieve substantially the same result.
Figure 15 features yet another embodiment of the delivery device, in which
particles
1500 described herein above (e.g., with respect to Figure 13) are disposed on
the surface of a
bioadhesive film 1501. The film may optionally be dried or cured, e.g.,
without disrupting the
particle adhesion. The film may then be folded and placed in a capsule 1502
for
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WO 2007/002518 PCT/US2006/024665
administration to a patient. If needed the capsule containing the active
containing bioadhesive
film is coated with delayed release coating to allow the film to adhere to the
proximal part of
the GI tract. If needed, the film may first be folded or cut to a suitable
shape or size. Once
administered to a patient, the capsule releases the film, which then
rehydrates (if necessary)
and adheres to a mucosal surface, allowing the particles spreaded and adhered
thereto to
release the active components.
Additional details of the granulation-extrusion-spheronization process are
described
(with examples) in the co-pending U.S. application entitled "IMPROVED DOSAGE
FORMS FOR
MOVEMENT DISORDER TREATMENT," filed on June 23, 2006 (the teachings of the
entire
referenced application are incorporated herein by reference).
These various embodiments are only a sample of numerous possible
configurations to
deliver the subject dosage forms. Other variations may be readily envisioned
based on the
principals and teachings of the instant specification. For example, various
other drug-eluting
devices are described in U.S. Patent Nos. 4,290,426, 5,256,440, 5,378,475,
5,773,019 and
6,797,283, the contents of which are incorporated herein by reference.
In these and other embodiments of the invention, the various bioadhesive
coatings
that can be used are described in detail in the section below.
Many of the different embodiments described above may be implemented by using
rechargeable or biodegradable devices. Various slow release polymeric devices
have been
developed and tested in vivo in recent years for the controlled delivery of
drugs. A variety of
biocompatible polymers (including hydrogels), including both biodegradable and
non-
degradable polymers, can be used to form an implant for the sustained release
of a subject
pharmaceutical composition at a particular target site. The biodegradable
polymers undergo
chemical decomposition to form soluble monomers or soluble polymer units. The
biodegradation of polymers usually involves chemically or enzymatically
catalyzed
liydrolysis. Representative biodegradable polymers comprise a member selected
from
biodegradable poly(amides), poly(amino acids), poly(esters), poly(lactic
acid), poly(glycolic
acid), poly(orthoesters), poly(anhydrides), biodegradable poly(dehydropyrans),
and
poly(dioxinones). The polymers are known to the art in Controlled Release of
Drugs, by
Rosoff, Ch. 2, pp. 53-95 (1989); and in U.S. Pat. Nos. 3,811,444; 3,962,414;
4,066,747;
4,070,347; 4,079,038; and 4,093,709.
In certain embodiments, representative dosage forms include hydrogel matrix
containing a plurality of tiny pills or other particles. The hydrogel matrix
comprises a
hydrophilic polymer, such as selected from a polysaccharide, agar, agarose,
natural gum,
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alkali alginate including sodium alginate, carrageenan, fucoidan, furcellaran,
laminaran,
hypnea, gum arabic, gum ghatti, gum karaya, gum tragacanth, locust bean gum,
pectin,
amylopectin, gelatin and a hydrophilic colloid. The hydrogel matrix comprises
a plurality of
tiny pills or particles (such as 4 to 50), each tiny pill or particle may
comprise a different
portion of the subject pramipexole compositions (e.g., IR, XR, DR, DXR, etc.).
Representative of wall-forming materials include a triglyceryl ester selected
from glyceryl
tristearate, glyceiyl monostearate, glyceryl dipalmitate, glyceryl laureate,
glyceryl
didecenoate and glyceryl tridecenoate. Other wall forming materials comprise
polyvinyl
acetate phthalate, methylcellulose phthalate, and microporous vinyl olefins.
Procedures for
manufacturing tiny pills are disclosed in U.S. Pat. Nos. 4,434,153; 4,721,613;
4,853,229;
2,996,431; 3,139,383 and 4,752,470, which are incorporated by reference
herein.
In still other embodiments, the invention employs a dosage fonn comprising a
polymer that releases a drug by diffusion, flux through pores, or by rupture
of a polymer
matrix. The dosage form matrix can be made by procedures known to the polymer
art. An
example of providing a dosage fonn comprises blending a pharmaceutically
acceptable
carrier, like polyethylene glycol, with a known dose of the subject
pharmaceutical
composition, and adding it to a silastic medical grade elastomer with a cross-
linking agent,
like stannous octanoate, followed by casting in a mold. The step is repeated
for each
successive layer. The system is allowed to set, e.g., for 1 hour, to provide
the dosage form.
Representative polymers suitable for manufacturing the dosage form include
olefin and vinyl
polyiners, condensation polymers, carbohydrate polymers, and silicon polymers
as
represented by poly(ethylene), poly(propylene), poly(vinyl acetate),
poly(methyl acrylate),
poly(isobutyl methacrylate), poly(alginate), poly(amide), and poly(silicone).
The polymers
and manufacturing procedures are known in Polymers, by Coleman et al., Vol.
31, pp. 1187-
1230 (1990); Drug Carriet= Systerns, by Roerdink et al., Vol. 9, pp. 57-109
(1989); Adv. Drug
Deliveiy Rev., by Leong et al., Vol. 1, pp. 199-233 (1987); Handbook of Common
Polymers,
Compiled by Roff et al., (1971) published by CRC Press; and U.S. Pat. No.
3,992,518.
V. Contbinatiort Tlterapy
In a further embodiment, a coniposition of the invention is administered in
combination therapy with one or more additional drugs or prodrugs. The term
"combination
therapy" herein means a treatment regimen wherein the agent provided by the
composition of
the invention and a second agent are administered individually or together,
sequentially or
simultaneously, in such a way as to provide a beneficial effect from co-action
of these
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therapeutic agents. Such beneficial effect can include, but is not limited to,
pharmacokinetic
or pharmacodynamic co-action of the therapeutic agents. Combination therapy
can, for
example, enable administration of a lower dose of one or both agents than
would normally be
administered during monotherapy, thus decreasing risk or incidence of adverse
effects
associated with higher doses. Alternatively, combination therapy can result in
increased
therapeutic effect at the normal dose of each agent in monotherapy.
Compositions of the invention can be especially suited to combination
therapies,
particularly where the second agent is one that is, or can be, administered
once daily. There
are significant advantages in patient convenience and compliance where both
components of
a combination therapy can be administered at the same time and with the same
frequency.
This is especially true in the case of geriatric patients or those suffering
memory impairment.
When administered simultaneously, the two components of the combination
therapy
can be administered in separate dosage forms or in coformulation, i.e., in a
single dosage
form, When administered sequentially or in separate dosage fornzs, the second
agent can be
administered by any suitable route and in any pharmaceutically acceptable
dosage form, for
example by a route and/or in a dosage form other than the present composition.
In a preferred
embodiment, both components of the combination therapy are formulated together
in a single
dosage form.
The second components of the subject combination therapy, e.g., drugs useful
for the
treatment Parkinson's disease and other movement disorders, include L-dopa,
selegiline,
apomorphine and anticholinergics. L-dopa (levo-dihydroxy-phenylalanine) is a
dopamine
precursor which can cross the blood-brain barrier and be converted to dopamine
in the brain.
Unfortunately, L-dopa has a short half life in the body and it is typical
after long use (i. e.,
after about 4-5 years) for the- effect of L-dopa to become sporadic and
unpredictable,
resulting in fluctuations in motor function, dyskinesias and psychiatric side
effects.
Additionally, L-dopa can cause B vitamin deficiencies to arise. The
gastrointestinal
absorption of orally administered levodopa depends on the gastrointestinal
transit rates as
absorption occurs primarily in the proximal third of the intestine
(duodenum/jejunum) and
not in the stomach (Rivera-Calimlim et al. Europ. J. Clin. Invest. 1, 1313-
1320, 1971).
Therefore a delayed release dosage form containing levodopa/carbidopa or
levodopa/carbidopa/entacapone with pramipexole will allow the levodopa to be
released in
the target proximal intestine region and release levodopa is a sustained
manner similar to
enteral infusion of levodopa.
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Selegiline (Deprenyl, Eldepryl) has been used as an alternative to L-dopa, and
acts by
reducing the breakdown of dopamine in the brain. Unfortunately, selegiline
becomes
ineffective after about nine months of use. Apomorphine, a dopamine receptor
agonist, has
been used to treat Parkinson's disease, although is causes severe vomiting
when used on its
own, as well as skin reactions, infection, drowsiness and some psychiatric
side effects.
Systemically administered anticholinergic drugs (such as benzhexol and
orphenedrine) have also been used to treat Parkinson's disease and act by
reducing the
amount of acetylcholine produced in the brain and thereby redress the
dopamine/acetylcholine imbalance present in Parkinson's disease.
Unfortunately, about 70%
of patients taking systemically administered anticholinergics develop serious
neuropsychiatric side effects, including hallucinations, as well as dyskinetic
movements, and
other effects resulting from wide anticholinergic distribution, including
vision effects,
difficulty swallowing, dry mouth, and urine retention. See e.g. Playfer,
PaYkinson's Disease,
Postgrad Med J73: 257-264, 1997 and Nadeau, PaNkinson's Disease, JAna Ger Soc
45: 233-
240, 1997.
Newer drug refinements and developments include direct-acting dopamine
agonists,
slow-release L-dopa formulations, inhibitors of the dopamine degrading enzymes
catechol-O-
methyltransferase (COMT) and monoamine oxidase B (MAO-B), and dopamine
transport
blockers. These treatments enhance central dopaminergic neurotransmission
during the early
stages of Parkinson's disease, ameliorate symptoms associated with Parkinson's
disease, and
temporarily improve the quality of life. However, despite improvements in the
use of L-dopa
for treating Parkinson's disease, the benefits accorded by these dopaminergic
therapies are
temporary, and their efficacy declines with disease progression. In addition,
these treatments
are accompanied by severe adverse motor and mental effects, most notably
dyskinesias at
peak dose and "on-off' fluctuations in drug effectiveness (Poewe and Granata,
in Moveinent
Disorders. Neurological Pf=inciples and Practice (Watts and Koller, eds)
McGraw-Hill, New
York, 1997; and Marsden and Parkes, Lancet 1: 345-349, 1977). No drug
treatments are
currently available that lessen the progressive pace of nigrostriatal
degeneration, postpone the
onset of illness, or that substantively slow disability (Shoulson, supra).
Other methods for the treatment of Parkinson's disease involve neurosurgical
intervention, such as thalamotomy, pallidotomy, and deep brain stimulation.
The thalamic
outputs of the basal ganglia are an effective lesion target for the control of
tremor (i.e.,
thalamotonly). Thalamotomy destroys part of the thalamus, a brain region
involved in
movement control. Unilateral stereotactic thalamotomy has proven to be
effective for
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controlling contralateral tremor and rigidity, but carries a risk of
hemiparesis. Bilateral
thalamotomy carries an increased risk of speech and swallowing disorders
resulting.
Stereotactic pallidotomy, surgical ablation of part of the globus pallidus (a
basal
ganglia), has also be used with some success. Pallidotomy is performed by
inserting a wire
probe into the globus pallidus and heating the probe to destroy nearby tissue.
Pallidotomy is
most useful for the treatment of peak-dose diskinesias and for dystonia that
occurs at the end
of a dose.
Aside from surgical resection, deep brain stimulation, high frequency
stimulating
electrodes placed in the ventral intermedialis nucleus, has been found to
suppress abnormal
movements in some cases. A variety of techniques exist to permit precise
location of a probe,
including computed tomography and magnetic resonance imaging. Unfortunately,
the
akinesia, speech and gait disorder symptoms of Parkinson's disease are little
helped by these
surgical procedures, all of which result in destructive brain lesions. Despite
the development
of modem imaging and surgical techniques to improve the effectiveness of these
neurosurgical interventions for the treatment of Parkinson's disease tremor
symptoms, the use
of neurosurgical therapies is not widely applicable. For example, thalamotomy
does not
alleviate the akinetic symptoms which are the major functional disability for
many people
suffering from Parkinson's disease (Marsden et al., Adv. Neurol. 74: 143-147,
1997).
Therapeutic methods aimed at controlling suspected causative factors
associated with
Parkinson's disease (e.g., therapies which control oxidative stress and
excitotoxicity) have
also been developed. Clinical trials have shown that administration of
antioxidative agents
vitamin E and deprenyl provided little or no neuroprotective function
(Shoulson et al., Ann.
Neurol. 43: 318-325, 1998). Glutamate-receptor blockers and neuronal nitric
oxide synthase
(NOS) inhibitors have been proposed as therapies for Parkinson's disease;
however, no
experimental results from human studies have yet been published (Rodriguez,
Ann. Neurol.
44: S 175-S 188, 1998).
The use of neurotrophic factors to stimulate neuronal repair, survival, and
growth in
Parkinson's disease has also been studied, particularly the use of glial cell
line-derived
neurotrophic factor (GDNF). Although GDNF protein protects some dopamine
neurons from
death, it is difficult to supply GDNF protein to the brain. Furthermore, the
use of such protein
therapies in general is problematic, since protein molecules show rapid in
vivo degradation,
are unable to penetrate the blood-brain barrier, and must be directly injected
into the
ventricles of the patient's brain (Palfi et al., Soc. Neurosci. Abstr. 24: 41,
1998; Hagg, Exp.
Neurol. 149: 183-192) 1998; and Dunnett and Bjorklund, supra). Other
neurotrophic factors
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which may have therapeutic value have been proposed based on in vitro and
animal model
systems, including neurturin, basic fibroblast growth factor (bFGF), brain-
derived
neurotrophic factor (BDNF), neurotrophins 3 and 415, ciliary neurotrophic
factor and
transforming growth factor B (TGF-B). However, the effectiveness of these
therapies in
humans remains unknown. At present, no single chemical compound or peptide has
been
reported to completely protect dopamine neurons from death by tropic factor
withdrawal or
neurotoxin exposure.
Cell replacement therapies have also received much attention as potential
methods for
treating Parkinson's disease (Freed et al., Arch. Neurol. 47: 505-512, 1990;
Freed et al., N.
Engl. J. Med. 327: 1549-1555, 1992; Lindvall et al., Science 247: 574-577,
1990; Spencer et
al., N. Engl. J. Med. 327: 1541-1548, 1992; Widner et al., N. Engl. J. Med.
327: 1556-1563,
1992; Lindvall, NeuroReport 8: iii-x, 1997; Olanow et al., Adv. Neurol. 74:
249-269, 1997;
and Lindvall, Nature Biotechn. 17: 635-636, 1999). These neural grafting
therapies use
dopamine supplied from cells implanted into the striatum as a substitute for
nigrostriatal
dopaminergic neurons that have been lost due to neurodegeneration. Although
animal models
and preliminary human clinical studies have shown that cell replacement
therapies may be
useful in the treatment of Parkinson's disease, the failure of the
transplanted neurons to
survive in the striatum is a major impediment in the development of cell
replacement
therapies.
Various sources of dopaminergic neurons for use in the transplantation process
have
been tried in animal experiments, including the use of mesencephalic dopamine
neurons
obtained from human embryo cadavers, immature neuronal precursor cells (i.e.,
neuronal
stem cells), dopamine secreting non-neuronal cells, terminally differentiated
teratocarcinoma-
derived neuronal cell lines (Dunnett and Bjorkland, supra), genetically
modified cells
(Raymon et al., Exp. Neurol. 144: 82-91, 1997; and Kang, Mov. Dis. 13: 59-72,
1998), cells
from cloned embryos (Zawada et al., Nature Medicine 4: 569-573, 1998) and
xenogenic cells
(Bjorklund et al., Nature 298: 652-654, 1982; Huffaker et al., Exp. Brain Res.
77: 329-336,
1989; Galpem et al., Exp. Neurol. 140: 1-13, 1996; Deacon et al., Nature Med.
3: 350-353,
1997; and Zawada et al., Nature Med. 4: 569-573, 1998). Nonetheless, in
current grafting
protocols, no more than 5-20% of the transplanted dopamine neurons survive.
Additional therapies are also available, such as physical therapy,
occupational
therapy, or speech / language therapy. Exercise, diet, nutrition,
patient/caregiver education,
and psychosocial interventions have also been shown to have a positive effect
on the mental
and/or physical state of a person suffering from Parkinson's disease.
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Various methods of evaluating Parkinson's disease in a patient include Hoehn
and
Yahr Staging of Parkinson's Disease, Unified Parkinson Disease Rating Scale
(UPDRS), and
Schwab and England Activities of Daily Living Scale.
A person suffering from Parkinson's disease should avoid contraindicated and
potentially contraindicated drugs such as antipsychotic drugs, Haloperidol
(Haldol),
Perphenazine (Trilafon), Chlorpromazine (Thorazine), Trifluoperazine
(Stelazine),
Flufenazine (Prolixin, Permitil) Thiothixene (Navane), Thioridazine
(Mellaril);
antidepressant drug, combination of Perphenazine and Amitriptyline (Tiiavil);
anti-vomiting
drugs, Prochlorperazine (Compazine), Metoclopramide (Reglan, Maxeran),
Thiethylperazine
(Torecan), Reserpine (Serpasil), Tetrabenazine (Nitoman); blood pressure drug,
Alpha-
methyldopa (Aldomet); anti-seizure drug, Phenytoin (Dilantin); mood
stabilizing drug,
lithium; and anti-anxiety drug, Buspirone (Buspar).
In certain embodiments, the method includes administering, conjointly with the
subject pharmaceutical composition, one or more of other therapeutic
compositions useful for
the treatment of diseases, for which pramipexole is indicated for. For
exaniple, in the case of
treating Parkinson's Disease and certain movement disorders, pramipexole may
be co-
administered with a dopamine precursor, a dopaminergic agent, a dopaminergic
and anti-
cholinergic agent, an anti-cholinergic agent, a dopamine agonist, a MAO-B
(monoamine
oxidase B) inhibitor, a COMT (catechol 0-methyltransferase) inhibitor, a
muscle relaxant, a
sedative, an anticonvulsant agent, a dopamine reuptake inhibitor, a dopamine
blocker, a,6-
blocker, a carbonic anhydrase inhibitor, a narcotic agent, a GABAergic agent,
or an alpha
antagonist.
In certain embodiments, the subject packages, preparations, pharmaceutical
compositions, and methods for the treatment of movement disorders further
comprise one or
more therapeutic agents for treating Parkinson's disease selected from a
dopamine precursor,
such as L-dopa; a dopaminergic agent, such as Levodopa-carbidopa (SINEMET ,
SINEMET
CR ) or Levodopa-benserazide (PROLOPA , MADOPAR , MADOPAR HBS ); a
dopaminergic and anti-cholinergic agent, such as amantadine (SYMMETRYL ,
SYMADINE ); an anti-cholinergic agent, such as trihexyphenidyl (ARTANE ),
benztropine
(COGENTIN ), ethoproprazine (PARSITAN ), or procyclidine (KEMADRIN ); a
dopamine agonist, such as apomorphine, bromocriptine (PARLODEL ), cabergoline
(DOSTINEX ), lisuride (DOPERGINE ), pergolide (PERMAX ), or ropinirole (REQUIP
);
a MAO-B (monoamine oxidase B) inhibitor, such as selegiline or deprenyl
(ATAPRYL ,
CARBEX , ELDEPRYL ); a COMT (catechol 0-methyltransferase) inhibitor, such as
CGP-
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28014, tolcapone (TASMAR ) or entacapone (COMTAN ); or other therapeutic
agents, such
as baclofen (LIORESAL ), domperidone (MOTILIUM ), fludrocortisone (FLORINEF ),
midodrine (AMATINE ), oxybutynin (DITROPANO), propranolol (INDERAL , INDERAL-
LA ), clonazepam (RIVOTRIL ), or yohimbine.
US20030045539 (incorporated herein by reference) discloses a combination
treatment
of cabergoline and pramipexole provided concurrently to a patient suffering
from various
central nervous system diseases, and in particular for the treatment of
Parkinson's Disease
(PD). The initial dose of cabergoline is administered to the patient at a dose
of 0.5 to 1
mg/patient/day and is adjusted upward at weekly intervals to a therapeutic
dosage of 2, 4, 6, 8
or 10 mg/patient/day and where the initial dose of pramipexole is started at
0.375
mg/patient/day and is adjusted upward every 5 to 7 days to a therapeutic
dosage of 3, 4, 5, 6,
or 7 mg/patient/day. At least one portion of the subject pharmaceutical
composition may
additional comprises cabergoline and pramipexole for treating Parkinson's
disease.
US20040166159 (incorporated herein by reference) discloses a pharmaceutical
dosage forms having immediate and controlled release properties that contain
an aromatic
amino acid decarboxylase (AAAD) inhibitor (such as carbidopa), levodopa, and
optionally a
catechol-O-methyltransferase (COMT) inhibitor, for the treatment of medical
conditions
associated with reduced dopamine levels in a patient's brain. The dosage form
may comprise
up to about 1000 mg, or about 20-500 mg, about 50-500 mg, or about 100-200 mg
of COMT
inhibitor. The COMT inhibitor may be contained only within the immediate
release
component, or only within the sustained release component, or both. The COMT
inhibitor
may be CGP-28014, entacapone, or tolcapone. The dosage form may further
comprise one or
more drugs such as anti-cholinergics, beta 2-agonists, cyclooxygenase-2 (COX-
2) inhibitors,
dopamine receptor agonists, monoamine oxidase (MAO) inhibitors, opiate delta
receptor
agonists, opiate delta receptor antagonists, and N-methyl-D-aspartate (NMDA)
antagonists.
The dosage form may further comprise one or more drugs selected from
albuterol, alpha-
lipoic acid, amantadine, andropinirole, apomorphine, baclofen, biperiden,
benztropine,
bromocriptine, budipine, cabergoline, clozapine, deprenyl, dextromethorphan,
dihydroergokryptine, dihydrolipoic acid, eliprodil, eptastigmine, ergoline,
formoterol,
galanthamine, lazabemide, lysuride, mazindol, memantine, mofegiline,
orphenadrine,
pergolide, pirbuterol, propentofylline, procyclidine, rasagiline, remacemide,
riluzole,
rimantadine, ropinirole, salmeterol, selegiline, spheramine, terguride, and
trihexyphenidyl.
Similarly, other movement disorders may also be treated with similar methods
and
suitable pharmaceutical compositions, such as the ones described below.
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Fox example, in certain embodiments of the packages, preparations,
compositions, and
methods for the treatment of a movement disorder, the invention further
comprises one or
more therapeutic agents for treating dystonia selected from an anti-
cholinergic agent, such as
trihexyphenidyl (ARTANE ), benztropine (COGENTIN'), ethoproprazine (PARSITAN
),
or procyclidine (KEMADRIN ); a dopaminergic agent, such as Levodopa-carbidopa
(SINEMET , SINEMET CR ) or Levodopa-benserazide (PROLOPA , MADOPAR ,
MADOPAR HBS ); a muscle relaxant, such as baclofen (LIORESAL ); a sedative,
such as
Clonazepam (RIVOTRIL"); an anticonvulsant agent, such as carbamazepine
(TEGRETOL );
a dopamine reuptake inhibitor, such as tetrabenazine (NITOMAN ); or a dopamine
blocker,
such as haloperidol (HA.LDOL ).
In certain embodiments of the packages, preparations, compositions, and
methods for
the treatment of a movement disorder, the invention further comprises one or
more
therapeutic agents for treating tremor selected from a0-blocker, such as
propranolol
(INDERAL , INDERAL-LA ); an anticonvulsant agent, such as primidone (MYSOLINE
);
or a carbonic anhydrase inhibitor, such as acetalzolamide (DIAMOX~) or
methazolamide
(NEPTAZANE ).
In certain embodiments of the packages, preparations, compositions, and
methods for
the treatment of a movement disorder, the invention further comprises one or
more
therapeutic agents for treating myoclonus selected from a sedative, such as
clonazepam
(RIVOTRIL ); or an anticonvulsant agent, such as valproic acid (EPIVAL ).
In certain embodiments of the packages, preparations, compositions, and
methods for
the treatment of a movement disorder, the invention further comprises one or
more
therapeutic agents for treating chorea selected from a dopamine blocker, such
as haloperidol
(HALDOL ); or a dopamine reuptake inhibitor, such as tetrabenazine (NITOMAN ).
In certain embodiments of the packages, preparations, compositions, and
methods for
the treatment of a movement disorder, the invention further comprises one or
more
therapeutic agents for treating restless leg syndrome selected from a
dopaminergic, such as
Levodopa-carbidopa (SINEMET , SINEMET CR ) or Levodopa-benserazide (PROLOPA~),
MADOPAR , MADOPAR HBS ); a sedative, such as clonazepam (RIVOTRIL'); a
dopamine agonists, such as bromocriptine (PARLODEL ), pergolide (PERMAX ), or
ropinirole (REQUIP ); a narcotic agent, such as codeine (TYLENOL # 3 ); or a
GABAergic
agent, such as gabapentin (NEURONTIN ).
In certain embodiments of the subject paclcages, preparations, compositions,
and
methods for the treatment of movement disorders, the invention further
comprises one or
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more therapeutic agents for treating tics selected from a sedative, such as
clonazepam
(RIVOTRIL ); an alpha antagonist, such as clonidine (CATAPRESS ); a dopamine
reuptake
inhibitor, such as tetrabenazine (NITOMANO); or a dopamine blocker, such as
haloperidol
(HALDOL ) or perphenazine.
In certain embodiments, the method includes administering, conjointly with the
pharmaceutical composition, one or more of physical therapy, occupational
therapy, or
speech/language therapy.
An agent to be administered conjointly with a subject compound may be
formulated
together with a subject compound as a single pharmaceutical preparation, e.g.,
as a pill or
other medicament including both agents, or may be administered as a separate
pharmaceutical preparation.
Another aspect of the invention provides a packaged pharmaceutical
composition,
comprising the subject pharmaceutical composition in an ainount sufficient to
treat or prevent
a movement disorder in a patient, which may additionally include a
pharmaceutically
acceptable carrier, and instructions (written and/or pictorial) describing the
use of the
formulation for treating the patient, wherein the patient suffers from ataxia,
corticobasal
ganglionic degeneration (CBGD), dyskinesia, dystonia, tremors, hereditary
spastic
paraplegia, Huntington's disease, multiple system atrophy, myoclonus,
Parkinson's disease,
progressive supranuclear palsy, restless legs syndrome, Rett syndrome,
spasticity,
Sydenham's chorea, other choreas, athetosis, ballism, stereotypy, tardive
dyskinesia/dystonia,
tics, Tourette's syndrome, olivopontocerebellar atrophy (OPCA), diffuse Lewy
body disease,
hemibalismus, hemi-facial spasm, restless leg syndrome, Wilson's disease,
stiff man
syndrome, akinetic mutism, psychomotor retardation, painful legs moving toes
syndrome, a
gait disorder, a drug-induced movement disorder, or other movement disorder.
In certain preferred embodiments, the movement disorder is Parkinson's
disease.
VI. Exeinplaiy Uses of the Dosage Fortns
In various embodiments, the present invention contemplates modes of treatment
and/or prophylaxis (e.g., treating or preventing the development of symptoms
in high-risk
populations), which utilize one or more of the subject dosage forms for
decreasing or
overcoming the defects in a movement disorder patient. The improvement andlor
restoration
of mental or physical state in an organism has positive behavioral, social,
and psychological
consequences.
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For example, Parkinson's disease is the second most common neurodegenerative
disorder, affecting nearly 1 million people in North America. The disease is
characterized by
symptoms such as muscle rigidity, tremor and bradykinesia. Early studies of
Parkinson's
disease showed unusual inclusions in the cytoplasm of neurons (i.e., Lewy
bodies), occurring
predominantly in the substantia nigra, which innervate the striatal region of
the forebrain.
Although Lewy bodies were also found in other neurodegenerative conditions,
the presence
of Lewy bodies in Parkinson's disease is accompanied by cell loss in the
substantia nigra.
This cell loss is considered to be the defining pathological feature of
Parkinson's disease.
Epidemiological studies have reported geographic variation in Parkinson's
disease
incidence, leading to the search for environmental factors (Olanow and Tatton,
Ann. Rev.
Neurosci. 22: 123-144, 1998). The recent discovery that 1-methyl-4-phenyl-
1,2,3,6-
tetrahydropyridine (MPTP) toxin causes a Parkinson's-like syndrome
indistinguishable from
the idiopathic disease suggests that Parkinson's disease may be caused by
environmental
factors (e.g., toxins and causative agents). (See e.g., Langston, Ann. Neurol.
44: S45-S52,
1998).
Recent research has also identified genes associated with Parkinson's disease
(Mizuno
et al., Bioined. Plaannaacother. 53(3): 109-116, 1999; Dunnett and Bjorklund,
Nature 399
(6738 Suppl): A32-A39, 1999); namely, the a-synuclein gene (Polymeropouos et
al., Science
276: 2045-2047, 1997), the parkin gene (Kitada et al., Nature 392: 605-608,
1998), and the
UCH-L1 thiol protease gene (Leroy et al., Nature 395: 451-452, 1998). Although
additional
chromosomal loci associated with the disease state have been identified, these
chromosomal
loci have not been analyzed at the molecular level. At present, the
biocheinical roles played
by these gene products in both normal cells and in diseased neurons remain
anlbiguous, and
no gene therapy protocols involving their use have been developed.
Furthermore, Parkinson's disease is associated with the progressive loss of
dopamine
neurons in the ventral mesencephalon of the substantia nigra (Shoulson,
Science 282: 1072-
1074, 1998), which innervates the major motor-control center of the forebrain,
the striatum.
Although a gradual decline in the number of neurons and dopamine content of
the basal
ganglia is normally associated with increasing age, progressive dopamine loss
is pronounced
in people suffering from Parkinson's disease, resulting in the appearance of
symptoms when
about 70-80% of striatal dopamine and 50% of nigral dopamine neurons are lost
(Dunnett and
Bjorklund, supra). This loss of dopamine-producing neurons resulting in a
dopamine
deficiency is believed to be responsible for the motor symptoms of Parkinson's
disease.
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Although the cause of dopaminergic cell death remains unknown, it is believed
that
dopaminergic cell death is affected by a combination of necrotic and apoptotic
cell death.
Mechanisms and signals responsible for the progressive degeneration of nigral
dopamine
neurons in Parkinson's disease have been proposed (Olanow et al., Ann. Neurol.
44: S1-S196,
1998), and include oxidative stress (from the generation of reactive oxygen
species),
mitochondrial dysfunction, excitotoxicity, calcium imbalance, inflammatory
changes and
apoptosis as contributory and interdependent factors in Parkinson's disease
neuronal cell
death.
Apoptosis (i.e., programmed cell death) plays a fundamental role in the
development
of the nervous system (Oppenheim, Ann. Rev. Neurosci. 14: 453-501, 1991), and
accelerated
apoptosis is believed to underlie many neurodegenerative diseases, including
Parkinson's
disease (Barinaga, Science 281: 1303-1304, 1998; Mochizuki et al., .I. Neurol.
Sci. 137: 120-
123, 1996; and Oo et al., Neuroscience 69: 893-901, 1995). In living systems,
apoptotic death
can be initiated by a variety of external stimuli, and the biochemical nature
of the intracellular
apoptosis effectors is at least partially understood.
VII. Controlled Release /Bioadlaesive Layer
According to the instant invention, the subject dosage form is administered
orally to
the lower gastrointestinal (GI) tract. Thus, it is desirable that the subject
drug delivery system
adhere to the lining of the appropriate viscus, such that its contents can be
delivered as a
function of proximity and duration of contact.
An orally ingested product can adhere to either the epithelial surface or the
mucus
lining of the GI tract. For the delivery of bioactive substances, it can be
advantageous to have
a polymeric drug delivery device adhere to the epithelium or to the mucous
layer.
Bioadhesion in the GI tract may proceed in two stages: (1) viscoelastic
defonnation at the
point of contact of the synthetic material into the mucus substrate, and (2)
formation of bonds
between the adhesive synthetic material and the mucus or the epithelial cells.
In general,
adhesion of polymers to tissues may be achieved by (i) physical or mechanical
bonds, (ii)
primary or covalent chemical bonds, and/or (iii) secondary chemical bonds
(e.g., ionic).
Physical or mechanical bonds can result from deposition and inclusion of the
adhesive
material in the crevices of the mucus or the folds of the mucosa. Secondary
chemical bonds,
contributing to bioadhesive properties, consist of dispersive interactions
(e.g., van der Waals
interactions) and stronger specific interactions, which include hydrogen
bonds. The
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hydrophilic functional groups primarily responsible for forming hydrogen bonds
are the
hydroxyl and the carboxylic groups.
"Bioadhesion" is defined as the ability of a material to adhere to a
biological tissue for
an extended period of time. Bioadhesion is one solution to the problem of
inadequate
residence time resulting from intestinal peristalsis, and froxn displacement
by ciliary
movement. For sufficient bioadhesion to occur, an intimate contact must exist
between the
bioadhesive and the receptor tissue, the bioadhesive must penetrate into the
crevice of the
tissue surface and/or mucus, and mechanical, electrostatic, or chemical bonds
must form.
Polycarbophils and acrylic acid polymers usually have the best adhesive
properties. Duchene
et al., in Drug Dev. Ind. Plzarin., 14:283-318, 1988, reviewed the
pharmaceutical and medical
aspects of bioadliesive systems for drug delivery (incorporated herein by
reference). These
bioadhesive systems may be adapted for use in the instant invention. Other
bioadhesive
systems that may be adapted for use in the instant application are described
in WO 93/21906;
Smart et al., J. Plaaryia. Pharnaacol. 36: 295-299, 1984; Gurney et al.,
Biomaterials 5: 336-
340, 1984; Park et al., "Alternative Approaches to Oral Controlled Drug
Delivery:
Bioadhesives and In-Situ Systems," in J. M. Anderson and S. W. Kim, Eds.,
"Recelat
Advances in Drug Delivery," Plenum Press, New York, 1984, pp. 163-183; Mikos
et al., J.
Colloid Intesface Sci. 143: 366-373, 1991; and Lelir et al., J. Controlled
Rel. 13: 51-62, 1990,
all incorporated herein by reference.
In certain embodiments, the subject dosage forms having increased lower
gastrointestinal retention time. For purposes of this invention, intestinal
residence time is the
time required for a dosage form to transit through the intestine to the
pyloric sphincter. For
example, a dosage form of the invention has an intestinal residence tiine of
at least 3 hours, at
least 4 hours, at least 6 hours, at least 8 hours or at least 12 hours. The
dosage forms of the
invention may have an increased retention time in the small and/or large
intestine, or in the
area of the gastrointestinal tract that absorbs the drug contained in the
dosage form. For
example, dosage forms of the invention can be retained in the small intestine
(or one or two
portions thereof, selected from the duodenum, the jejunum and the ileum) for
at least 6 hours,
at least 8 hours or at least 12 hours, such as from 16 to 18 hours.
Certain polymers for use in the subject invention are described in more
details below.
Polymers
Suitable bioadhesive polymeric coatings are disclosed in U.S. Patent Nos.
6,197,346,
6,217,908 and 6,365,187 (the contents of which are incorporated herein by
reference), and
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include soluble and insoluble, biodegradable and nonbiodegradable polymers.
These can be
hydrogels or thermoplastics, homopolymers, copolymers or blends, and/or
natural or
synthetic polymers. The preferred polymers are synthetic polymers, with
controlled synthesis
and degradation characteristics. Particularly preferred polymers are anhydride
copolymers of
fumaric acid and sebacic acid (P(FA:SA)), which have exceptionally good
bioadhesive
properties when administered to the GI tract. Examples of P(FA:SA) copolymers
include
those having a 1:99 to 99:1 ratio of fumaric acid to sebacic acid, such as
5:95 to 75:25, for
example, 10:90 to 60:40 or at least 15:85 to 25:75. Specific examples of such
copolymers
have a 20:80 or a 50:50 ratio of fumaric acid to sebacic acid.
Polymers used in dosage forms of the invention produce a bioadhesive
interaction
(fracture strength) of at least 100 N/mz (10 mN/cm2) when applied to the
mucosal surface of
rat intestine. The fracture strength of the dosage forms is advantageously at
least 250 N/mZ, at
least 500 N/m2 or at least 1000 N/m2. For example, the fracture strengtli of a
polymer-
containing dosage form can be from 100 to 500 N/m2. The forces described
herein refer to
measurements made upon rat intestinal mucosa, unless otherwise stated. The
same adhesive
measurements made on a different species of animal will differ from those
obtained using
rats. This difference is attributed to both compositional and geometrical
variations in the
mucous layers of different animal species as well as cellular variations in
the mucosal
epithelium. However, the data shows that the same general trends prevail no
matter what
animal is studied (i.e., P(FA: SA) produces stronger adhesions than polylactic
acid (PLA) in
rats, slleep, pigs, etc.). For example, the fracture strength of dosage forms
of the invention on
rat intestine is generally at least 125 N/m2, such as at least 150 N/mz, at
least 250 N/mz, at
least 500 N/m2 or at least 1000 N/ma.
The fracture strength of a dosage fornl can be measured according to the
methods
disclosed by Duchene et al. Briefly, the dosage form is attached on one side
to a tensile tester
and is contacted with a testing surface (e.g., a mucosal membrane) on the
opposite surface.
The tensile tester measures the force required to displace the dosage form
from the testing
surface. Common tensile testers include a Texture Analyzer and the Instron
tensile tester.
In the preferred method for mucoadhesive testing, dosage forms are pressed
using
flat-faced tooling, 0.3750" (9.525 mm) in diameter. Dosage form weight will
depend on
composition; in most cases, the dosage forms have a final weight of 200 mg.
These dosage
forms are then glued to a plastic 10 mm diameter probe using a common, fast-
drying
cyanoacrylate adhesive. Once the dosage forms are firmly adhered to the probe,
the probe is
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attached to the Texture Analyzer. The Texture Analyzer is fitted with a 1 kg
load cell for
maximum sensitivity. The following settings are used:
Pre-Test Speed 0.4 mm / sec Stop Plot At Final Position
Test Speed 0.1 mm / sec Tare Mode Auto
Post-Test Speed 0.1 mm / sec Delay Ac uisition Off
Applied Force 20.00 Advanced On
Options
Return Distance 0 mm Pro ortional Gain 0
Contact Time 420 s Inte ral Gain 0
Trigger Type Auto Differential Gain 0
Trigger Force 0.5 g Max. Tracking 0 mm / sec
Speed
The Test aiid Post-Test Speeds are as low as the instrument will allow, to
ensure a
maximum number of data points captured. The Pre-Test speed is used only until
the probe
encounters the Trigger Force; i.e., prior to contacting the tissue.
The Proportional, Integral, and Differential Gain are set to 0. These
settings, when
optimized, maintain the system at the Applied Force for the duration of the
Contact Time.
With soft tissue as a substrate, however, the probe and dosage form are
constantly driven into
the deformable surface. This results in visible damage to the tissue. Thus,
the probe and
dosage form are allowed to relax gradually from the Applied Force by setting
these
parameters to 0. The tracking speed, which is a measure of how rapidly the
feedback is
adjusted, is also set to 0.
The tissue on which the dosage forms are tested is secured in the Mucoadhesive
Rig;
the rig is then completely immersed in a 600 mL Pyrex beaker containing 375 mL
of PBS.
The tissue is maintained at approximately 37 C for the duration of the test;
no stirring is used
as the machine can detect the oscillations from the stir bar.
In the past, two classes of polymers have shown useful bioadhesive properties,
hydrophilic polymers and hydrogels. In the large class of hydrophilic
polymers, those
containing carboxylic groups (e.g., poly[acrylic acid]) exhibit the best
bioadhesive properties.
It is thus expected that polymers with the highest concentrations of
carboxylic groups are
preferred materials for bioadhesion on soft tissues. In other studies, the
most promising
polymers were sodium alginate, carboxymethylcellulose, hydroxymethylcellulose
and
methylcellulose. Some of these materials are water-soluble, while others are
hydrogels.
Rapidly bioerodible polymers such as poly[lactide-co-glycolide],
polyanhydrides, and
polyorthoesters, whose carboxylic groups are exposed on the external surface
as their smooth
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surface erodes, are suitable for bioadhesive drug delivery systems. In
addition, polymers
containing labile bonds, such as polyanhydrides and polyesters, are well known
for their
hydrolytic reactivity. Their hydrolytic degradation rates can generally be
altered by simple
changes in the polymer backbone.
Representative natural polymers suitable for the present invention include
proteins
(e.g., hydrophilic proteins), such as zein, modified zein, casein, gelatin,
gluten, serum
albumin, or collagen, and polysaccharides such as cellulose, dextrans,
polyhyaluronic acid,
polymers of acrylic and methacrylic esters and alginic acid. These are
generally less suitable
for use in bioadhesive coatings due to higher levels of variability in the
characteristics of the
final products, as well as in degradation following administration.
Synthetically modified
natural polymers include alkyl celluloses, hydroxyalkyl celluloses, cellulose
ethers, cellulose
esters, and nitrocelluloses.
Representative synthetic polymers for use in bioadhesive coatings include
polyphosphazines, poly(vinyl alcohols), polyamides, polycarbonates,
polyalkylenes,
polyacrylamides, polyalkylene glycols, polyalkylene oxides, polyalkylene
terephthalates,
polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone,
polyglycolides,
polysiloxanes, polyurethanes and copolymers thereof. Other polymers suitable
for use in the
invention include, but are not limited to, methyl cellulose, ethyl cellulose,
hydroxypropyl
cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose,
cellulose acetate,
cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate,
carboxymethyl
cellulose, cellulose triacetate, cellulose sulfate sodium salt, poly(methyl
methacrylate),
poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl
methacrylate), poly(hexyl
methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate),
poly(phenyl
methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl
acrylate),
poly(octadecyl acrylate) polyethylene, polypropylene, poly(ethylene glycol),
poly(ethylene
oxide), poly (ethylene terephthalate), poly(vinyl acetate), polyvinyl
chloride, polystyrene,
polyvinyl pyrrolidone, and polyvinylphenol. Representative bioerodible
polymers for use in
bioadhesive coatings include polylactides, polyglycolides and copolymers
thereof,
poly(ethylene terephthalate), poly(butyric acid), poly(valeric acid),
poly(lactide-co-
caprolactone), poly[lactide-co-glycolide], polyanhydrides (e.g., poly(adipic
anhydride)),
polyorthoesters, chitosan, chitin, hyaluronic acid, hyaluronan, Carbopols,
Corplex polymers,
Polycarbophils-Cysteine (Thiomers), Chitosan-Thioglycolic acid copolymers,
poly(methacrylic acid-grafted-ethylene glycol), poly (methyl vinyl ether-co-
malic anhydride),
cholestyramine (Duolite AP-143), sucralfate and gliadin blends and copolymers
thereof.
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Polyanhydrides are particularly suitable for use in bioadhesive delivery
systems
because, as hydrolysis proceeds, causing surface erosion, more and more
carboxylic groups
are exposed to the external surface. However, polylactides erode more slowly
by bulk
erosion, which is advantageous in applications where it is desirable to retain
the bioadhesive
coating for longer durations. In designing bioadhesive polymeric systems based
on
polylactides, polymers that liave high concentrations of carboxylic acid are
preferred. The
high concentrations of carboxylic acids can be attained by using low molecular
weight
polymers (MW of 2000 or less), because low molecular weight polymers contain a
high
concentration of carboxylic acids at the end groups.
The polymers listed above can be obtained from sources such as Sigma Chemical
Co.,
St. Louis, Mo., Polysciences, Warrenton, Pa., Aldrich, Milwaukee, Wis., Fluka,
Ronkonkoma, N.Y., and BioRad, Richmond, Calif., or can alternatively be
synthesized from
monomers obtained from these suppliers using standard techniques.
When the bioadhesive polymeric coating is a synthetic polymer coating, the
synthetic
polymer is typically selected from polyamides, polycarbonates, polyalkylenes,
polyalkylene
glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols,
polyvinyl
ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone,
polyglycolides,
polysiloxanes, polyurethanes, polystyrene, polymers of acrylic and methacrylic
esters,
polylactides, poly(butyric acid), poly(valeric acid), poly(lactide-co-
glycolide),
polyanhydrides, polyorthoesters, poly(fumaric acid), poly(maleic acid), and
blends and
copolymers of thereof. Preferably, the synthetic polymer is poly(fumaric-co-
sebacic)
anhydride.
Another group of polymers suitable for use as bioadhesive polymeric coatings
are
polymers having a hydrophobic backbone with at least one hydrophobic group
pendant from
the backbone. Suitable hydrophobic groups are groups that are generally non-
polar. Examples
of such hydrophobic groups include alkyl, alkenyl and alkynyl groups.
Preferably, the
hydrophobic groups are selected to not interfere and instead to enhance the
bioadhesiveness
of the polymers.
A further group of polymers suitable for use as bioadhesive polymeric coatings
are
polymers having a hydrophobic backbone with at least one hydrophilic group
pendant from
the backbone. Suitable hydrophilic groups are groups that are capable of
hydrogen bonding to
another functional group. Example of such hydrophilic groups include
negatively charged
groups such as carboxylic acids, sulfonic acids and phosponic acids,
positively charged
groups such as (protonated) amines and neutral, polar groups such as amides
and imines.
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Preferably, the hydrophilic groups are selected to not interfere and instead
to enhance the
bioadhesiveness of the polymers. The hydrophilic groups can be either directly
attaclled to a
hydrophobic polymer backbone or attached through a spacer group. Typically, a
spacer group
is an alkylene group, particularly a C1-C8 alkyl group such as a C2-C6 alkyl
group. Preferred
compounds containing one or more hydrophilic groups include amino acids (e.g.,
phenyalanine, tyrosine and derivatives thereof) and amine-containing
carbohydrates (sugars)
such as glucosamine.
Polymers can be modified by increasing the number of carboxylic groups
accessible
during biodegradation, or on the polymer surface. The polymers can also be
modified by
binding amino groups to the polymer. The polymers can be modified using any of
a number
of different coupling chemistries available in the art to covalently attach
ligand molecules
with bioadhesive properties to the surface-exposed molecules of the polymeric
microspheres.
The attachment of any positively charged ligand, such as polyethyleneimine or
polylysine, to a polymer may improve bioadhesion due to the electrostatic
attraction of the
cationic groups coating the beads to the net negative charge of the mucus. The
mucopolysaccharides and mucoproteins of the mucin layer, especially the sialic
acid residues,
are responsible for the negative charge coating. Any ligand with a high
binding affinity for
mucin could also be covalently linked to most polymers with the appropriate
chemistry, such
as with carbodiimidazole (CDI), and be expected to influence the binding to
the gut. For
example, polyclonal antibodies raised against components of mucin or else
intact mucin,
when covalently coupled to a polymer, would provide for increased bioadhesion.
Similarly,
antibodies directed against specific cell surface receptors exposed on the
lumenal surface of
the intestinal tract would increase the residence time when coupled to
polymers using the
appropriate chemistry. The ligand affinity need not be based only on
electrostatic charge, but
other useful physical parameters such as solubility in mucin or specific
affinity to
carbohydrate groups.
The covalent attachment of any of the natural components of mucin in either
pure or
partially purifled form to the -polymers would increase the solubility of the
polymer in the
mucin layer. The list of useful ligands would include but not be limited to
the following:
sialic acid, neuraminic acid, n-acetyl-neuraminic acid, n-glycolylneuraminic
acid, 4-acetyl-n-
acetylneuraminic acid, diacetyl-n-acetylneuraminic acid, glucuronic acid,
iduronic acid,
galactose, glucose, mannose, fucose, any of the partially purified fractions
prepared by
chemical treatment of naturally occurring mucin, e.g., mucoproteins,
mucopolysaccharides
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and mucopolysaccharide-protein complexes, and antibodies immunoreactive
against proteins
or sugar structure on the mucosal surface.
The attachment of polyamino acids containing extra pendant carboxylic acid
side
groups, such as polyaspartic acid and polyglutamic acid, may also increase
bioadhesiveness.
The polyanzino chains would increase bioadhesion by means of chain
entanglement in mucin
strands as well as by increased carboxylic charge.
Polymer-Metal Conaplexes
As disclosed in U.S. Patent Nos. 5,985,312, 6,123,965 and 6,368,586, the
contents of
which are incorporated herein by reference, polymers, such as those named
above, having a
metal compound incorporated therein have a further improved ability to adhere
to tissue
surfaces, such as mucosal meinbranes. The metal compound incorporated into the
polymer
can be, for example, a water-insoluble metal oxide. The incorporation of metal
compounds
into a wide range of different polymers, even those that are not normally
bioadhesive,
improves their ability to adhere to tissue surfaces such as mucosal membranes.
Metal compounds which can be incorporated into polymers to improve their
bioadhesive properties preferably are water-insoluble metal compounds, such as
water-
insoluble metal oxides and metal hydroxides, which are capable of becoming
incorporated
into and associated with a polymer to thereby improve the bioadhesiveness of
the polymer.
As defined herein, a water-insoluble metal compound is defined as a metal
compound with
little or no solubility in water, for example, less than about 0.0 to 0.9
mg/ml.
The water-insoluble metal compounds can be derived from a wide variety of
metals,
including, but not limited to,.calcium, iron, copper, zinc, cadmium, zirconium
and titanium.
The water insoluble metal compound preferably is a metal oxide or hydroxide.
Water
insoluble metal compounds of multivalent metals are preferred. Representative
metal oxides
suitable for use in the compositions described herein include cobalt (I) oxide
(CoO), cobalt
(II) oxide (CoZ03), selenium oxide (Se02), chromium (IV) oxide (Cr02),
manganese oxide
(Mn02), titanium oxide (TiO2), lanthanum oxide (La203), zirconium oxide
(Zr02), silicon
oxide (SiOZ), scandium oxide (Sc203), beryllium oxide (BeO), tantalum oxide
(Ta205),
cerium oxide (CeO2), neodymium oxide (Nd203), vanadium oxide (V2.05),
molybdenum
oxide (Mo203), tungsten oxide (WO), tungsten trioxide (WO3), samarium oxide
(Sm203),
europium oxide (Eu203), gadolinium oxide (Gd2O3), terbium oxide (Tb407),
dysprosium
oxide (Dy203), holmium oxide (Hoz03), erbiunl oxide (Er203), thulium oxide
(Tm203),
ytterbium oxide (Yb203), lutetium oxide (Lu203), aluminum oxide (A1203),
indium oxide
(InO3), germanium oxide (Ge02), antimony oxide (Sb203), tellurium oxide
(TeOZ), nickel
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oxide (NiO), and zinc oxide (ZnO). Other oxides include barium oxide (BaO),
calcium oxide
(CaO), nickel oxide (III) (NiZO3), magnesium oxide (MgO), iron (II) oxide
(FeO), iron (III)
oxide (Fe203), copper oxide (II) (CuO), cadmium oxide (CdO), and zirconium
oxide (Zr02).
Preferred properties defining the metal compound include: (a) substantial
insolubility
in aqueous environments, such as acidic or basic aqueous environments (such as
those
present in the gastric lumen); and (b) ionizable surface charge at the pH of
the aqueous
environment.
The water-insoluble metal compounds can be incorporated into the polymer by
one of
the following mechanisms: (a) physical mixtures which result in entrapment of
the metal
compound; (b) ionic interaction between metal compound and polymer; (c)
surface
modification of the polymers which would result in exposed metal compound on
the surface;
and (d) coating techniques such as fluidized bed, pan coating, or any similar
methods known
to those skilled in the art, which produce a metal compound enriched layer on
the surface of
the device. In certain embodiments, nanoparticles or microparticles of the
water-insoluble
metal compound are incorporated into the polymer.
In certain embodiments, the metal compound is provided as a fine particulate
dispersion of a water-insoluble metal oxide which is incorporated throughout
the polymer or
at least on the surface of the polymer which is to be adhered to a tissue
surface. The metal
compound also can be incorporated in an inner layer of the polymer and exposed
only after
degradation or else dissolution of a"protective" outer layer. For example, a
tablet core
containing a polymer and metal may be covered with an enteric coating designed
to dissolve
when exposed to intestinal fluid. The metal compound-enriched core then is
exposed and
become available for binding to GI mucosa.
Fine metal oxide particles can be produced for example by micronizing a metal
oxide
by mortar and pestle treatment to produce particles ranging in size, for
example, from 10.0 to
300 nm. The metal oxide particles can be incorporated into the polymer, for
example, by
dissolving or dispersing the particles into a solution or dispersion of the
polymer.
Advantageously, metal compounds which are incorporated into polymers to
improve
their bioadhesive properties can be metal compounds which are already approved
by the FDA
as either food or pharmaceutical additives, such as zinc oxide.
Suitable polymers which can be used and into which the metal compounds can be
incorporated include soluble and water-insoluble, and biodegradable and
nonbiodegradable
polymers, including hydrogels, thermoplastics, and homopolymers, copolymers
and blends of
natural and synthetic polymers, provided that they have the requisite fracture
strength when
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mixed with a metal compound. In additional to those listed above,
representative polymers
which can be used in conjunction with a metal compound include hydrophilic
polymers, such
as those containing carboxylic groups, including polyacrylic acid. Bioerodible
polymers
including polyanhydrides, poly(hydroxy acids) and polyesters, as well as
blends and
copolymers thereof also can be used. Representative bioerodible poly(hydroxy
acids) and
copolymers thereof which can be used include poly(lactic acid), poly(glycolic
acid),
poly(hydroxy-butyric acid), poly(hydroxyvaleric acid), poly(caprolactone),
poly(lactide-co-
caprolactone), and poly(lactide-co-glycolide). Polymers containing labile
bonds, such as
polyanhydrides and polyorthoesters, can be used optionally in a modified form
with reduced
hydrolytic reactivity. Positively charged hydrogels, such as chitosan, and
thermoplastic
polymers, such as polystyrene also can be used.
Representative natural polymers which also can be used include proteins, such
as
zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, and
polysaccharides
such as dextrans, polyhyaluronic acid and alginic acid. Representative
synthetic polymers
include polyphosphazenes, polyamides, polycarbonates, polyacrylamides,
polysiloxanes,
polyurethanes and copolynlers thereof. Celluloses also can be used. As defined
herein the
term "celluloses" includes naturally occurring and synthetic celluloses, such
as alkyl
celluloses, cellulose ethers, cellulose esters, hydroxyalkyl celluloses and
nitrocelluloses.
Exemplary celluloses include ethyl cellulose, methyl cellulose, carboxymethyl
cellulose,
hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl
cellulose,
hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate,
cellulose acetate
butyrate, cellulose acetate phthalate, cellulose triacetate and cellulose
sulfate sodium salt.
Polymers of acrylic and methacrylic acids or esters and copolymers thereof can
be
used. Representative polymers which can be used include poly(methyl
methacrylate),
poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl
methacrylate), poly(hexyl
methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate),
poly(phenyl
methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl
acrylate), and
poly(octadecyl acrylate).
Other polymers which can be used include polyalkylenes such as polyethylene
and
polypropylene; polyarylalkylenes such as polystyrene; poly(alkylene glycols),
such as
poly(ethylene glycol); poly(alkylene oxides), such as poly(ethylene oxide);
and poly(alkylene
terephthalates), such as poly(ethylene terephthalate). Additionally, polyvinyl
polymers can be
used, which, as defined herein includes polyvinyl alcohols, polyvinyl ethers,
polyvinyl esters
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and polyvinyl halides. Exemplary polyvinyl polymers include poly(vinyl
acetate), polyvinyl
phenol and polyvinylpyrrolidone.
Water soluble polymers can also be used. Representative examples of suitable
water
soluble polymers include polyvinyl alcohol, polyvinylpyrrolidone, methyl
cellulose,
hydroxypropyl cellulose, hydroxypropylmethyl cellulose and polyethylene
glycol,
copolymers of acrylic and methacrylic acid esters, and mixtures thereof. Water
insoluble
polymers also can be used. Representative examples of suitable water insoluble
polymers
include ethylcellulose, cellulose acetate, cellulose propionate (lower, medium
or -higher
molecular weight), cellulose acetate propionate, cellulose acetate butyrate,
cellulose acetate
phtlialate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl
methacrylate),
poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl
methacrylate),
poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl
methacrylate),
poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate),
poly(octadecyl
acrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene) high
density,
poly(propylene), poly(ethylene oxide), poly(ethylene terephthalate),
poly(vinyl isobutyl
ether), poly(vinyl acetate), poly(vinyl chloride), polyurethanes, and mixtures
thereof. In
certain embodiments, a water insoluble polymer and a water soluble polymer are
used
together, such as in a mixture. Such mixtures are useful in controlled drug
release
formulations, wherein the release rate can be controlled by varying the ratio
of water soluble
polymer to water insoluble polymer.
Polymers varying in viscosity as a function of temperature or shear or other
physical
forces also may be used. Poly(oxyalkylene) polymers and copolymers such as
poly(ethylene
oxide)-poly(propylene oxide) (PEO-PPO) or poly(ethylene oxide)-poly(butylene
oxide)
(PEO-PBO) copolyiners, and copolymers and blends of these polymers with
polymers such
as poly(alpha-hydroxy acids), including but not limited to lactic, glycolic
and hydroxybutyic
acids, polycaprolactones, and polyvalerolactones, can be synthesized or
commercially
obtained. For example, polyoxyalkylene copolymers are described in U.S. Patent
Nos.
3,829,506, 3,535,307, 3,036,118, 2,979,578, 2,677,700 and 2,675,619.
Polyoxyalkylene
copolymers are sold, for example, by BASF under the trade name PLURONICSTM.
These
materials are applied as viscous solutions at room temperature or lower which
solidify at the
higher body temperature. Other materials with this behavior are lrnown in the
art, and can be
utilized as described herein. These include KLUCELTM (hydroxypropyl
cellulose), and
purified konjac glucomannan gum.
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Other suitable polymers are polymeric lacquer substances based on acrylates
and/or
methacrylates, commonly called EUDRAGITTM polymers (sold by Rohm America,
Inc.).
Specific EUDRAGITTM polymers can be selected having various permeability and
water
solubility, which properties can be pH dependent or pH independent. For
example,
EUDRAGITTM RL and EUDRAGITTM RS are acrylic resins comprising copolymers of
acrylic and methacrylic acid esters with a low content of quaternary ammonium
groups,
which are present as salts and give rise to the permeability of the lacquer
films, whereas
EUDRAGITTM RL is freely permeable and EUDRAGITTM RS is slightly permeable,
independent of pH. In contrast, the permeability of EUDRAGITTM L is pH
dependent.
EUDRAGITTM L is an anionic polymer synthesized from methacrylic acid and
methacrylic
acid methyl ester. It is insoluble in acids and pure water, but becomes
increasingly soluble in
a neutral to weakly alkaline solution by forming salts with alkalis. Above pH
5.0, the polymer
becomes increasingly permeable.
Polymer solutions that are liquid at an elevated temperature but solid or
gelled at body
temperature can also be utilized. A variety of thermoreversible polymers are
known,
including natural gel-forming materials such as agarose, agar, furcellaran,
beta-carrageenan,
beta-1,3-glucans such as curdlan, gelatin, or polyoxyalkylene containing
compounds, as
described above. Specific examples include thermosetting biodegradable
polymers for in vivo
use described in U.S. Patent No. 4,938,763, the contents of which are
incorporated herein by
reference.
Polymer Blends with Monotnef s and/or Oli og mers
Polymers with enhanced bioadhesive properties are provided by incorporating
anhydride monomers or oligomers into one of the polymers listed above by
dissolving,
dispersing, or blending, as taught by U.S. Patent Nos. 5,955,096 and
6,156,348, the contents
of which are incorporated herein by reference. The polymers may be used to
form drug
delivery systems which have improved ability to adhere to tissue surfaces,
such as mucosal
membranes. The anhydride oligomers are formed from organic diacid monomers,
preferably
the diacids normally found iri the Krebs glycolysis cycle. Anhydride oligomers
which
enhance the bioadhesive properties of a polymer have a molecular weight of
about 5000 or
less, typically between about 100 and 5000 Daltons, or include 20 or fewer
diacid units
linked by anhydride linkages and terminating in an anhydride linkage with a
carboxylic acid
monomer.
The oligomer excipients can be blended or incorporated into a wide range of
hydrophilic and hydrophobic polymers including proteins, polysaccharides and
synthetic
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biocompatible polymers, including those described above. In certain
embodiments, anhydride
oligomers may be combined with metal oxide particles, such as those described
above, to
improve bioadhesion even more than with the organic additives alone. Organic
dyes, because
of their electronic charge and hydrophobicity or hydrophilicity, can either
increase or
decrease the bioadliesive properties of polymers when incorporated into the
polymers.
As used herein, the term "anhydride oligomer" refers to a diacid or polydiacid
linked
by anhydride bonds, and having carboxy end groups linked to a monoacid such as
acetic acid
by anhydride bonds. The anhydride oligomers have a molecular weight less than
about 5000,
typically between about 100 and 5000 Daltons, or are defined as including
between one to
about 20 diacid units linked by anhydride bonds. In certain embodiments, the
diacids are
those normally found in the Krebs glycolysis cycle. The anhydride oligomer
compounds have
high chemical reactivity.
The oligomers can be formed in a reflux reaction of the diacid with excess
acetic
anhydride. The excess acetic anhydride is evaporated under vacuum, and the
resulting
oligomer, which is a mixture of species which include between about one to
twenty diacid
units linked by anhydride bonds, is purified by recrystallizing, for example,
from toluene or
other organic solvents. The oligomer is collected by filtration, and washed,
for example, in
ethers. The reaction produces anhydride oligomers of mono and poly acids with
terminal
carboxylic acid groups linked to each other by anhydride linkages.
The anhydride oligomer is hydrolytically labile. As analyzed by gel permeation
chromatography, the molecular weight may be, for example, on the order of 200-
400 for
fumaric acid oligomer (FAPP) and 2000-4000 for sebacic acid oligomer (SAPP).
The
anhydride bonds can be detected by Fourier transform infrared spectroscopy by
the
characteristic double peak at 1750 cm"1 and 1820 cm"1, with a corresponding
disappearance of
the carboxylic acid peak normally at 1700 crn 1.
In certain embodiments, the oligomers may be made from diacids described for
example in U.S. Patent Nos. 4,757,128, 4,997,904 and 5,175,235, the
disclosures of which
are incorporated herein by reference. For example, monomers such as sebacic
acid, bis(p-
carboxy-phenoxy)propane, isophathalic acid, fumaric acid, maleic acid, adipic
acid or
dodecanedioic acid may be used.
Organic dyes, because of their electronic charge and hydrophilicity or
hydrophobicity,
may alter the bioadhesive properties of a variety of polymers when
incorporated into the
polymer matrix or bound to the surface of the polymer. A partial listing of
dyes that affect
bioadhesive properties include, but are not limited to: acid fuchsin, alcian
blue, alizarin red s,
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auramine o, azure a and b, Bismarck brown y, brilliant cresyl blue ald,
brilliant green,
carmine, cibacron blue 3GA, congo red, cresyl violet acetate, crystal violet,
eosin b, eosin y,
erythrosin b, fast green fcf, giemsa, hematoylin, indigo carmine, Janus green
b, Jenner's stain,
malachite green oxalate, methyl blue, methylene blue, methyl green, methyl
violet 2b, neutral
red, Nile blue a, orange II, orange G, orcein, paraosaniline chloride,
phloxine b, pyronin b
and y, reactive blue 4 and 72, reactive brown 10, reactive green 5 and 19,
reactive red 120,
reactive yellow 2,3, 13 and 86, rose bengal, safranin, Sudan III and IV, Sudan
black B and
toluidine blue.
Polymers Furactioraalized with Hydroxy-Substituted Arofiaatic Groups
Polymers having an aromatic group which contains one or more hydroxyl groups
grafted onto them or coupled to individual monomers are also suitable for use
in the
bioadhesive coatings of the invention. Such polymers can be biodegradable or
non-
biodegradable polymers. The polymer can be hydrophobic. Preferably, the
aromatic group is
catechol or a derivative thereof and the polymer contains reactive functional
groups.
Typically, the polymer is a polyanhydride and the aromatic compound is the
catechol
derivative DOPA. These materials display bioadhesive properties superior to
conventional
bioadhesives used in therapeutic and diagnostic applications.
The molecular weight of the suitable polymers and percent substitution of the
polymer
with the aromatic group may vary greatly. The degree of substitution varies
based on the
desired adhesive strength, it may be as low as 10%, 25% or 50%, or up to 100%
substitution.
Generally, at least 50% of the monomers in the polymeric backbone are
substituted with at
least one aromatic group. Preferably, about 100% of the monomers in the
polymeric
backbone are substituted with at least one aromatic group. The resulting
polymer has a
niolecular weight ranging from about 1 to 2,000 kDa.
The polymer that forms that backbone of the bioadhesive material can be a
biodegradable polymer. Examples of preferred biodegradable polymers include
synthetic
polymers such as poly hydroxy acids, such as polymers of lactic acid and
glycolic acid,
polyanhydrides, poly(ortho)esters, polyesters, polyurethanes, poly(butyric
acid), poly(valeric
acid), poly(caprolactone), poly(hydroxybutyrate), poly(lactide-co-glycolide)
and poly(lactide-
cocaprolactone), and natural polymers such as alginate and other
polysaccharides, collagen
and chemical derivatives thereof (substitutions, additions of chemical groups,
for example,
alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely
made by those
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skilled in the art), albumin and other hydrophilic proteins, zein and other
prolamines and
hydrophobic proteins, copolymers and mixtures thereof. In general, these
materials degrade
either by enzymatic hydrolysis or exposure to water in vivo and by surface or
bulk erosion.
The foregoing materials may be used alone, as physical mixtures (blends), or
as co-polymers.
Suitable polymers can formed by first coupling the aromatic compound to the
monomer and then polymerizing. In this example, the monomers may be
polymerized to form
a polymer backbone, including biodegradable and non-biodegradable polymers.
Suitable
polymer backbones include, but are not limited to, polyanhydrides, polyamides,
polycarbonates, polyalkylenes, polyalkylene oxides such as polyethylene
glycol,
polyalkylene terephthalates such as poly(ethylene terephthalate), polyvinyl
alcohols,
polyvinyl ethers, polyvinyl esters, polyethylene, polypropylene, poly(vinyl
acetate),
poly(vinyl chloride), polystyrene, polyvinyl halides, polyvinylpyrrolidone,
polyhydroxy
acids, polysiloxanes, polyurethanes and copolymers thereof, alkyl cellulose,
hydroxyalkyl
celluloses, cellulose ethers, cellulose esters, nitrocellulloses, polymers of
acrylic and
methacrylic esters, methyl cellulose, ethyl cellulose, hydroxypropyl
cellulose, hydroxy-
propyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate,
cellulose
propionate, cellulose acetate butyrate, cellulose acetate phthalate,
carboxylethyl cellulose,
cellulose triacetate, cellulose sulfate sodium salt, and polyacrylates such as
poly(methyl
methacrylate), poly(ethylmethacrylate), poly(butylmethacrylate),
poly(isobutylmethacrylate),
poly(hexylmethacrylate), poly(isodecylmethacrylate), poly(lauryl
methacrylate), poly(phenyl
methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl
acrylate),
poly(octadccyl acrylate).
A suitable polymer backbone can be a known bioadhesive polymer that is
hydrophilic
or hydrophobic. Hydrophilic polymers include CARBOPOLTM, polycarbophil,
cellulose
esters, and dextran.
Non-biodegradable polymers, especially hydrophobic polymers are also suitable
as
polymer backbones. Exainples of preferred non-biodegradable polymers include
ethylene
vinyl acetate, poly(methacrylic acid), copolymers of maleic anhydride with
other unsaturated
polymerizable monomers, poly(butadiene maleic anhydride), polyamides,
copolymers and
mixtures thereof and dextran, cellulose and derivatives thereof.
Hydrophobic polymer backbones include polyanhydrides, poly(ortho)esters, and
polyesters such as polycaprolactone. Preferably, the polymer is sufficiently
hydrophobic that
it is not readily water soluble, for example the polymer should be soluble up
to less than
about 1% w/w in water, preferably about 0.1 /o w/w in water at room
temperature or body
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temperature. In the most preferred embodiment, the polymer is a polyanhydride,
such as a
poly(butadiene maleic anhydride) or another copolymer of maleic anhydride.
Polyanhydrides
may be formed from dicarboxylic acids as described in U.S. Patent No.
4,757,128 to Domb et
al., incorporated herein by reference. Suitable diacids include aliphatic
dicarboxylic acids,
aromatic dicarboxylic acids, aromatic-aliphatic dicarboxylic acid,
combinations of aromatic,
aliphatic and aromatic-aliphatic dicarboxylic acids, aromatic and aliphatic
heterocyclic
dicarboxylic acids, and aromatic and aliphatic heterocyclic dicarboxylic acids
in combination
with aliphatic dicarboxylic acids, aromatic-aliphatic dicarboxylic acids, and
aromatic
dicarboxylic acids of more than one phenyl group. Suitable monomers include
sebacic acid
(SA), fumaric acid (FA), bis(p-carboxyphenoxy)propane (UP), isophthalic acid
(IPh), and
dodecanedioic acid (DD).
A wide range of molecular weights are suitable for the polymer that forms the
backbone of the bioadhesive material. The molecular weight may be as low as
about 200 Da
(for oligomers) up to about 2,000 kDa. Preferably the polymer has a molecular
weight of at
least 1,000 Da, more preferably at least 2,000 Da, most preferably the polymer
has a
molecular weight of up to 20 kDa or up to 200 kDa. The molecular weight of the
polymer
may be up to 2,000 kDa.
The range of substitution on the polymer varies greatly and depends on the
polymer
used and the desired bioadhesive strength. For example, a butadiene maleic
anhydride
copolymer that is 100% substituted with DOPA will have the same number of DOPA
molecules per chain length as a 67% substituted ethylene maleic anhydride
copolymer.
Typically, the polymer has a percentage substitution ranging from 10% to 100%,
preferably
ranging from 50% to 100%.
The polymers and copolymers that form the backbone of the bioadhesive material
include reactive functional groups that interact with the functional groups on
the aromatic
compound.
It is desirable that the polymer or monomer that forms the polymeric backbone
contains accessible functional groups that easily react with molecules
contained in the
aromatic compounds, such as amines and thiols. In a preferred embodiment, the
polymer
contains amino reactive moieties, such as aldehydes, ketones, carboxylic acid
derivatives,
cyclic anhydrides, alkyl halides, aryl azides, isocyanates, isothiocyanates,
succinimidyl esters
or a combination thereof.
Preferably, the aromatic compound containing one or more hydroxyl groups is
catechol or a derivative thereof. Optionally, the aromatic compound is a
polyhydroxy
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aromatic compound, such as a trihydroxy aromatic compound (e.g.,
phloroglucinol) or a
multihydroxy aromatic compound (e.g., tannin). The catechol derivative may
contain a
reactive group, such as an amino, thiol, or halide group. The preferred
catechol derivative is
3,4-dihydroxyphenylalanine (DOPA), which contains a primary amine. Tyrosine,
the
immediate precursor of DOPA, which differs only by the absence of one hydroxyl
group in
the aromatic ring, can also be used. Tyrosine is capable of conversion (e.g.,
by hydroxylation)
to the DOPA form. A particularly preferred aromatic compound is an amine-
containing
aromatic compound, such as an amine-containing catechol derivative (e.g.,
dopamine).
Two general methods are used to form the polymer product. In one example, a
compound containing an aromatic group which contains one or more hydroxyl
groups is
grafted onto a polymer. In this example, the polymeric backbone is a
biodegradable polymer.
In a second example, the aromatic compound is coupled to individual monomers
and then
polymerized.
Any chemistry which allows for the conjugation of a polymer or monomer to an
aromatic compound containing one or more hydroxyl groups can be used, for
example, if the
aromatic compound contains an amino group and the monomer or polymer contains
an amino
reactive group, this modification to the polyiner or monomer is performed
through a
nucleophilic addition or a nucleophilic substitution reaction, such as a
Michael-type addition
reaction, between the amino group in the aromatic compound and the polymer or
monomer.
Additionally, other procedures can be used in the coupling reaction. For
example,
carbodiimide and mixed anhydride based procedures form stable amide bonds
between
carboxylic acids or phosphates and amino groups, bifunctional aldehydes react
with primary
amino groups, bifunctional active esters react with primary amino groups, and
divinylsulfone
facilitates reactions with amino, thiol, or hydroxy groups.
The aromatic compounds are grafted onto the polynler using standard techniques
to
form the bioadhesive material. In one example, L-DOPA is grafted to maleic
anhydride
copolymers by reacting the free amine in L-DOPA with the maleic anhydride bond
in the
copolymer.
A variety of different polymers can be used as the backbone of the bioadhesive
material, as described above. Additional representative polymers include 1:1
random
copolynlers of maleic anhydride with ethylene, vinyl acetate, styrene, or
butadiene. In
addition, a number of other compounds containing aromatic rings with hydroxy
substituents,
such as tyrosine or derivatives of catechol, can be used in this reaction.
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In another embodiment, the polymers are prepared by conjugate addition of a
compound containing an aromatic group that is attached to an amine to one or
more
monomers containing an amino reactive group. In a preferred method, the
monomer is an
acrylate or the polymer is acrylate. For example, the monomer can be a
diacrylate such as
1,4-butanediol diacrylate, 1,3-propanediol diacrylate, 1,2-ethanediol
diacrylate, 1,6-
hexanediol diacrylate, 2,5-hexanediol diacrylate or 1,3-propanediol
diacrylate. In an example
of the coupling reaction, the monomer and the compound containing an aromatic
group are
each dissolved in an organic solvent (e.g., THF, CH2C12, methanol, ethanol,
CHC13, hexanes,
toluene, benzene, CC14, glyme, diethyl ether, etc.) to form two solutions. The
resulting
solutions are combined, and the reaction mixture is heated to yield the
desired polymer. The
molecular weight of the synthesized polyiner can be controlled by the reaction
conditions
(e.g., temperature, starting materials, concentration, solvent, etc.) used in
the synthesis.
For example, a monomer, such as 1,4-phenylene diacrylate or 1,4-butanediol
diacrylate having a concentration of 1.6 M, and DOPA or another primary amine
containing
aromatic molecule are each dissolved in an aprotic solvent such as DMF or DMSO
to form
two solutions. The solutions are mixed to obtain a 1:1 molar ratio between the
diacrylate and
the amine group and heated to 56 C to form a bioadhesive material.
Bioadhesive Polynaer Blerads
Hydrophobic polyiners, such as polyesters, poly (anhydrides), ethyl cellulose,
even if
possibly non-adhesive on their own, may nevertheless be made bioadhesive
simply by
physically mixing the hydrophobic polymers with one or more suitable compounds
(such as
catechols or derivatives L-DOPA, D-DOPA, dopamine, or carbidopa, etc.) to
create
"bioadhesive compositions." Similarly, metal oxides may also be used for this
purpose.
The molecular weight of the bioadhesive polymers and percent substitution of
the
polymers with residues of the compounds disclosed may vary greatly. The degree
of
substitution varies based on the desired adhesive strength, it may be as low
as 10%, 20%,
25%, 50%, or up to 100% substitution. On average, at least 50% of the repeat
units in the
polymeric backbone are substituted with at least one residue. In one
particular embodiment,
75-95% of the residues in the backbone are substituted with at least one
residue. In another
particular embodiment, on average 100% of the repeat units in the polymeric
backbone are
substituted with at least one residue. The resulting bioadhesive polymer
typically has a
molecular weight ranging from about 1 to 2,0001cDa, such as 1 to 1,000 kDa, 10
to 1,000
kDa or 100 to 1,000 kDa. Polymers used in bioadhesive compositions typically
have the same
range of molecular weights.
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Unlike the bioadhesive polymers described above, there is typically no
covalent bond
formed between the compounds and the polymer in the bioadhesive compositions
(i.e., the
polymer does not chemically react with the conlpound, although hydrogen bonds,
ionic bonds
and/or van der Waals interactions can occur).
Suitable polymers for use in bioadhesive compositions are described above.
Typically, the polymer itself may not be bioadhesive, but the polymer can be
bioadhesive
(e.g., a polymer with hydrogen bond-forming pendant groups). Preferably, the
polymer is a
hydrophobic polymer such as a poly(lactone), e.g., poly(caprolactone).
To form the bioadhesive compositions of the invention, typically a polymer and
a
suitable compound are dissolved in a compatible solvent and mixed together.
The solvent is
then evaporated, preferably at a controlled temperature and rate of removal.
Alternatively or
in combination with general evaporation, the bioadhesive composition can be
spray dried or
dried at room temperature.
In another example, a mixture of a polymer and a suitable compound are melted
at or
slightly above the melting point of the polymer, typically while being mixed.
Both the
polymer and the suitable compound should be selected such that they are
chemically stable
(e.g., do not decompose, do riot become oxidized) at the melting point
temperature. After the
composition has re-solidified, it can be milled in order to obtain particles
of the desired size.
The subject bioadhesive compositions can also be prepared by dry mixing of a
polymer and a suitable compound, provided that the suitable compound is
sufficiently
distributed throughout the composition.
In each of the above methods, additional components can be added to the
mixture
prior to dissolution, melting and/or mixing. The additional components are
preferably stable
under the conditions the mixture is exposed to. In particular, active agents
should be stable at
the melting point temperature if that method is employed.
The weight ratio of polymer to the suitable compound in a bioadhesive
composition
can be selected to give the desired amount of bioadhesion. Typically, the
weight ratio of
polymer to compound is 9:1 to 1:9, such as 3:1 to 1:3 or 2:1 to 1:2. For
example, when the
polymer is predominant component, the weight ratio is 9:1 to 1:1, 3:1 to 1:1
or 2:1 to 1:1.
In the subject methods and pharmaceutical compositions, the suitable compounds
(such as L-DOPA, D-DOPA, dopamine, or carbidopa, etc.) may be used as agents
to render
the hydrophobic polymers bioadhesive, and/or be used as active ingredients in
the
pharmaceutical composition to be delivered to the patient. Thus, in certain
embodiments, if
carbidopa is used as part of the bioadhesive layer (for example, as the
bioadhesive material
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on the shell of Figure 5, or as the layer to coat the core comprising the
second zero-order
release portion), the total carbidopa dosage may be adjusted to account for
the release of
carbidopa from the bioadhesive material.
Similarly, in certain embodiments, when L- or D-dopa is used as the suitable
coinpound to render the hydrophobic polymer bioadhesive, the dosage of total
levodopa or
precursor thereof may be adjusted elsewhere in, for example, the relevant
portion or sub-
portions of the IR or CR (controlled release, e.g., zero-order release rate
portion).
In certain embodiments, a higher proportion of L-dopa (or D-Dopa) may be used
to
achieve a significant amount of release (e.g., more or less immediate release)
from the
polymers. In other embodiments, L- or D-Dopa may be used such that the polymer
is still
adhesive, but the release of L- or D-Dopa from the bioadhesive polymer is less
significant
compared to the levodopa or precursors thereof in IR, and/or one or more other
portions or
sub-portions of the subject dosage form.
Coatings
Preferred bioadhesive coatings do not appreciably swell upon hydration, such
that
they do not substantially inhibit or block movement (e.g., of ingested food)
through the
gastrointestinal tract, as compared to the polymers disclosed by Duchene et
al. Generally,
polymers that do not appreciably swell upon hydration include one or more
hydrophobic
regions, such as a polymethylene region (e.g., (CH2)n, where n is 4 or
greater). The swelling
of a polymer can be assessed by measuring the change in volume when the
polymer is
exposed to an aqueous solution. Polymers that do not appreciably swell upon
hydration
expand in volume by 50% or less when fully hydrated. Preferably, such polymers
expand in
volume by less than 25%, less than 20%, less than 15%, less than 10% or less
than 5%. Even
more preferably, the bioadhesive coatings are mucophilic. A polymer that does
not
appreciably swell upon hydration can be mixed with a polymer that does swell
(e.g.,
CARBOPOLTM, poly(acrylic acid), provided that the amount of swelling in the
polymer does
not substantially interfere with bioadhesiveness.
In certain embodiments, the bioadhesive polymeric coating consists of two
layers, an
inner bioadhesive layer that does not substantially swell upon hydration and
an outer
bioadhesive layer that is readily hydratable and optionally bioerodable, such
as one
comprised of CARBOPOLTM
The bioadhesive polymers discussed above can be mixed with one or more
plasticizers or thernloplastic polymers. Such agents typically increase the
strength and/or
reduce the brittleness of polymeric coatings. Examples of plasticizers include
dibutyl
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sebacate, polyethylene glycol, triethyl citrate, dibutyl adipate, dibutyl
fumarate, diethyl
phthalate, ethylene oxide-propylene oxide block copolymers such as PLURONIC'
F68 and
di(sec-butyl) fumarate. Examples of thermoplastic polymers include polyesters,
poly(caprolactone), polylactide, poly(lactide-co- glycolide), methyl
methacrylate (e.g.,
EUDRAGITTM), cellulose and derivatives thereof such as ethyl cellulose,
cellulose acetate
and hydroxypropyl methyl cellulose (HPMC) and large molecular weight
polyanhydrides.
The plasticizers and/or thermoplastic polymers are mixed with a bioadhesive
polymer to
achieve the desired properties. Typically, the proportion of plasticizers and
thermoplastic
polymers, when present, is from 0.5% to 40% by weight.
In certain embodiments, the bioadhesive polymer coating, in a dry packaged
form of a
tablet, is a hardened shell.
A tablet or a drug eluting device can have one or more coatings in addition to
the
bioadhesive polymeric coating. These coatings and their thickness can, for
example, be used
to control where in the gastrointestinal tract the bioadhesive coating becomes
exposed. In one
example, the additional coating prevents the bioadhesive coating from
contacting the mouth,
esophagus, and stomach. In another example, the additional coating remains
intact until
reaching the small intestine (e.g., an enteric coating).
Examples of coatings include methylmethacrylates, zein, cellulose acetate,
cellulose
phthalate, HMPC, sugars, enteric polymers, gelatin and shellac. Premature
dissolution of a
tablet in the mouth can be prevented with hydrophilic polymers such as HPMC or
gelatin.
Coatings used in tablets of the invention typically include a pore former,
such that the
coating is permeable to the drug. Exemplary pore formers include: sugar,
mannitol, HPC
(hydroxypropyl cellulose), HPMC, dendrites, NaCl, etc.
Tablets and drug eluting devices of the invention can be coated by a wide
variety of
methods. Suitable methods include compression coating, coating in a fluidized
bed or a pan,
enrobing, and hot melt (extrusion) coating, etc. Such methods are well lcnown
to those skilled
in the art.
All the above compositions, derivatives, precursors, additional components
that can
be used with the subject pramipexole compositions, dosage forms, methods of
making and
using, etc., are adaptable or directly useable with the instant invention, and
are thus expressly
incorporated herein by reference.
Examples:
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Having 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. The invention is further defined by reference to the following
examples
describing in detail the preparation of the composition and methods of use of
the invention. It
will be apparent to those skilled in the art that many modifications, both to
materials and
methods, may be practiced without departing from the scope of the invention.
Example 1 Plaartfzacokirzetic Studies foN Mirapex Tablets
Preliminary pharmacokinetic studies were conducted in beagle dogs to evaluate
the
performance of MIRAPEX tablets. The purpose of these studies was to determine
the
performance and limitations of MIRAPEX tablets.
The results showed that the pharmacokinetic (PK) performance of MIR.APEX
0.125
mg tablets in fed and fasted beagles was identical, and food intake did not
affect the
bioavailability of pramipexole (see Figure 2 and Table 1). These results were
in accordance
to those reported for humans.
However, all six fasted dogs had emesis within 1 hour of dosing, while no
emesis was
observed in fed dogs. Emesis was mainly attributed to rapid dissolution of
tablets with an
immediate release of pramipexole, triggering a locally mediated nausea via
gastric irritation.
Table 1: Pliamiacokinetic Performance of MIRAPEX 0.125 mg Tablets
in Fed and Fasted Beagle Dogs
Formulation/State Eniesis AUC" C. (nblmL) T,,,;.,,(hrs)
(n=6) (ng/mLxhr) MIRA.PEX Tablets, none 8.55 ~ 1.85 1.75 4- 0.26 2.0 0.4
0.125 mg (Fed)
MIRAPEX Tablets, All within '1 hr 11.05 ~ 2.89 1.85 0.44 1.7:1: 0.3
0.125 mg (Fasted) of dosing
Example 2 Prah tipexole Delayed Release (DR) Tablets
Based on the PK data above, it was determined that an effective formulation of
pramipexole with reduced peak plasma levels, and a lag time should reduce the
adverse
effects.
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An additional study was performed to evaluate the performance of MIRAPEX
0.125
mg tablets, plain, as well as MIRAPEX 0.125 mg tablets, coated with an
enteric polymer,
EUDRAGIT L 100 in fasted dogs. In this experiment, MIRAPEX 0.125 mg tablets
were
enteric-coated manually to produce the enteric polymer-coated MIRAPEX 0.125
mg tablets.
Specifically, tablets were hand-dipped using forceps in 10% w/v coating
solution of
EUDRAGIT L 100 in acetone, so as to achieve a final weight gain of 5-20% w/w.
The results of one exemplary experiment are shown in Figure 3 and Table 2.
Table 2: PK Performance and Emesis Response of Enteric-Coated MIRAPEX 0.125
mg
Tablets and Plain MIRA.PEX 0.125 mg Tablets in Fasted Beagle Dogs
F'or-mulation Emesis AUC Cll,ax T,,,a, (hrs)
(n=5) (ng/mL*hr) (ug/?ntI.,)
Enteric-Coated
MIRAPEX Tablets, None 10.24 1.86 1.45 0.24 3.4+0.4
0.125 mg
MIRAPEX Tablets, All (Within 1 11.05 2.89 1.85 0.44 1.7 0.1
0.125 mg hr of dosing)
The experiments showed that the enteric-coated MIRAPEX tablets remained
intact
in the gastric pH of the stomach and did not release the drug. The time to
achieve maximum
plasma concentration (T,,,aX) was increased by about 1.5 - 2 hours without
affecting the extent
of absorption. Importantly, none of the dogs involved in this study showed
emesis,
demonstrating that the modified delayed-release tablets substantially
eliminates one side-
effect associated with the conventional pramipexole treatment.
Example 3: Pliarmacokitzetic evaluation ofMirapex 0.125 nzg Tablet
adrrzinistered iu
three tiynes a day dosing reginzen
This examples describes pharmacokinetic data for MIRAPEX (pramipexole
dihydrochloride) tablets 0.125 mg; (lot#511-047) to be dosed at the 0, 8, and
16 hour time
poiiit (Lot# 511-047) in the fed state of the dog model.
Previously, PK studies in beagle dogs have been conducted with single dose of
Mirapex 0.125 mg tablet, and this dose has been well tolerated by the beagle
dog model. The
subject pramipexole extended release capsule formulation contains 0.375 mg of
pramipexole.
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This study was conducted to compare the bioavailability of a commercially
available
immediate release formulation to the subject ER formulation containing
equivalent amount of
the active drug.
Table 3: PK Performance of MIRAPEX 0.125 mg Tablets three times a day in
Beagle Dogs
Formulatiou AUC Cmax T,,,,, (hrs)
(nghnL*har) (ng/mL)
MIRAPEX Tablets, 58.05 4.61 3.43 0.16 11.3~2.8
0.125 mg (three times a day)
Example 4A Preparation of the Pranzipexole Extended Release (YR) Fornzulation
Based on the above results, Applicants produced pramipexole extended release
(XR)
forrnulation, which contains multiparticulate beads containing 0.375 mg of
pramipexole
encased in an enteric-coated capsule. Pramipexole was initially layered on
placebo core
pellets (1.1- 1.4 mm) using Vector Mini Fluid Bed Drier (Mfl.01) with OPADRY
Clear as a
binder.
The placebo core pellets were prepared using low shear granulation, extrusion
and
spheronization techniques. Following is the composition used for preparing
placebo core
pellets.
Components Weight (mg) % w/w
Microcrystalline Cellulose (Emcocel 90M),
SP/NF 60.0 30.0
Mannitol (Mannogem Powdered), USP/NF 130.0 65.0
Hydroxypropylcellulose (HPC SSL), USP/NF 10.0 5.0
Purified Water, USP/NF * *
* Evaporated during drying process.\
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The placebo pellets were dried in oven at 50 C for 17 hours to achieve a
desired
moisture level of 0.3% w/w. These pellets were then screened through size 10,
12, 14, 16 and
18 mesh sieves. The particles retained on screen 14 and 16 were used for
subsequent
pramipexole layering process.
Pramipexole layered pellets were subsequently coated in Vector Mini Fluid Bed
Drier
(Mfl.0 1) with rate controlling polymer composition containing ethylcellulose
(ETHOCEL
cps.) to achieve a final weight gain of 8.3% w/w and over coated with
bioadhesive
polyiner SPHEROMERTM III polymer (5.3%). These pellets were then encapsulated
in a size
1 gelatin capsule and tested for release profile in USP lI dissolution
apparatus. The pellets
were also evaluated for their in vivo performance in beagle dogs (see Figure
5).
The following is the unit dose composition used for preparing pramipexole
extended
release capsule.
Unit Dose Composition of Pramipexole Extended Release Capsule
Components Weight (mg) %w/w
Pramipexole Dihyhrochloride Monohydrate 0.375 0.19
Microcrystalline Cellulose (EMCOCEL 90M) 28.13 14.60
Mannitol (Mannogem Powder) 60.93 31.62
Hydroxypropyl Cellulose (HPC SSL) 4.69 2.43
OPADRY Clear (YS- 1 - 1 9025-A) 5.63 2.92
Ethylcellulose (Ethocel 10 cps) 8.28 4.30
Dibutyl Sebacate 0.25 0.13
Poloxamer (LUTROL F 68) 0.27 0.14
SPHEROMER III 5.14 2.67
Gelatin Capsule 79 41.00
Ethanol* - .-
Methyl Alcohol*
Purified Water*
Total 192.7 100
* evaporated during processing
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Example 4B Prepat=atiosa of the Prantipexole Extended Release (XR)
Foriraulation
Based on the above results, Applicants produced a pramipexole extended release
(XR)
fonnulation, which contains multiparticulate beads containing 0.375 mg of
pramipexole
encased in an enteric-coated capsule. Pramipexole was initially layered on
placebo core
pellets (1.1- 1.4 mm) using Vector Mini Fluid Bed Drier (Mfl.01) with OPADRY
Clear as a
binder.
The placebo core pellets were prepared using low shear granulation, extrusion
and
spheronization techniques. Following is the composition used for preparing
placebo core
pellets.
Components Weight (mg) % w/w
Microcrystalline Cellulose (Emcoce190M),
SP/NF 60.0 30.0
Mannitol (Mannogem Powdered), USP/NF 130.0 65.0
Hydroxypropylcellulose (HPC SSL), USP/NF 10.0 5.0
Purified Water, USP/NF * *
* Evaporated during drying process.
The placebo pellets were dried in oven at 50 C for 17 hours to achieve a
desired
moisture level of 0.3% w/w. These pellets were then screened through size 10,
12, 14, 16 and
18 mesh sieves. The particles retained on screen 14 and 16 were used for
subsequent
pramipexole layering process.
Pramipexole layered pellets were subsequently coated in a Vector Mini Fluid
Bed
Drier (Mfl.01) with a rate controlling polymer composition containing
ethylcellulose
(ETHOCEO 10 cps.) to achieve a final weight gain of 8.3% w/w
These pellets were then encapsulated in a size 1 gelatin capsule and tested
for release
profile in USP II dissolution apparatus. The pellets were also evaluated for
their in vivo
performance in beagle dogs (See Figure 6).
The following is the unit dose composition used for preparing pramipexole
extended
release capsule.
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Unit Dose Composition of Spherics' Pramipexole Multiparticulates Coated with
8.3%
Ethylcellulose.
Components Weight (mg) %w/w
Pramipexole Dihydrochloride
Monohydrate 0.375 0.2
Microcrystalline Cellulose
(Emcocel 90M) 28.13 15.27
Mannitol (Mannogem Powder) 60.93 33.06
Hydroxypropyl Cellulose 4.69
(HPC SSL) 2.55
Opadry Clear (YS-1-19025-A) 5.63 3.05
Ethylcellulose (Ethocel 10 cps) 8.28 4.49
Dibutyl Sebacate 0.25 0.13
Gelatin Capsule 76.00 41.24
Ethanol* = - -
Methyl Alcohol* - -
Purified Water* - -
Total 184.3 100.0
* evaporate during processing
Example 5 Preparation of the Pramipexole Delayed and Extended Release
Formulation
Extended release capsules from Example 4A were further coated with an enteric
coating composition, Acryl-EZETM White in a pan coater (O'Hara). Specifically,
about 10%
w/v solution of Acryl-EZETM White was prepared in ethanol and sprayed on
pramipexole
extended release (XR) capsule so as to achieve a final weight gain of 12% w/w.
These
delayed extended release (DYR) capsules were then tested for release profile
in USP II
dissolution apparatus, and were also evaluated for their in vivo performance
in beagle dogs.
The following is the unit dose composition of pramipexole Delayed Extended
Release
(DXR) capsule.
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Unit Dose Composition of the Pramipexole Delayed Extended Release Capsule
Components Weight %w/w
(mg)
Pramipexole Dihyhrochloride Monohydrate 0.375 0.17
Microcrystalline Cellulose (EMCOCEL 90M) 28.13 13.03
Mannitol (Mannogem Powder) 60.93 28.23
Hydroxypropyl Cellulose (HPC SSL) 4.69 2.17
OPADRY Clear (YS-1-19025-A) 5.63 2.61
Ethylcellulose (Ethocel 10 cps) 8.28 3.84
Dibutyl Sebacate 0.25 0.12
Poloxamer (LUTROL F 68) 0.27 0.13
SPHEROMER7 III 5.14 2.38
Acryl-EZET' White (93018509) 23.12 10.71
Gelatin Capsule 79.00 36.61
Ethanol* - -
Methyl Alcohol* - -
Purified Water* - -
Total 215.81 100.0
* evaporate during processing
The enteric-coated pramipexole capsules were tested for dissolution profiles
using
USP II apparatus. Initially, the dissolution was performed in 0.1 N HCL media,
pH = 1.2 for
2 hours, followed by phosphate buffer pH = 6.8 for 22 hours.
As shown in Figure 4, enteric-coated pramipexole delayed extended release
(DXR)
capsule showed a two hour delay in acidic environment, followed by a slower
release of
pramipexole at pH 6.8.
Example 6: Pranaipexole ER, 0.375 nzg Tablets [5 % coating (80 parts Surelease
+ 20
parts OPADRY ) Formulation
An extended release matrix dosage form according to the International
Publication
No. WO 2004/010999A1 (Lee et al., the entire contents of which is incorporated
herein by
reference) was prepared as a'comparator formulation. The pramipexole matrix
based
controlled release formulation given in Example 5 of WO 2004/010999A1
(incorporated
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herein by reference) was prepared according to the process disclosed therein,
with the
exception that pramipexole was layered onto the lactose particles to achieve
its uniform
dispersion. The in vitro release rate of the assembled formulation in
phosphate buffer (pH
6.8) using the USP Apparatus II at 50 rpm was similar to that disclosed in
Lee.
A study was conducted in fed beagle dogs to evaluate the perfonnance of: (1)
extended release multiparticulate-based capsule formulation, (2) matrix-based
tablet
formulation, both containing 0.375 mg pramipexole administered as a single
dose, and (3)
MIRAPEX tablets (0.125 mg) administered in three-times-a-day dosing regimen.
As shown in Figure 6, immediate release MIRAPEX tablets exhibited rapid
initial
absorption of pramipexole and dramatic fluctuations in pramipexole
concentration, while the
extended release formulations resulted in a lag time, followed by extended
absorption up to
16 hours.
As shown in Table 4 below, the bioavailability estimate of the extended
release
capsule formulation was about 50% when compared to MIRAPEX tablets given in a
repeated manner. The bioavailability of Lee matrix formulation was even lower
than the
multiparticulate-based system. Although in the preliminary study in beagle
dogs, decreased
bioavailability was observed for the extended release formulation, this can be
primarily
attributed to short residence time in GI tract. Since there are known
differences between
humans and dogs in terms of motility, bacterial metabolism and GI transit
time, the above
extended release formulation is expected to show higher extent of absorption
in humans, as
the half life of prainipexole is longer in humans.
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Table 4: MIR.APEX tablets, 0.375 mg (0.125 mg X 3) vs. Pramipexole 0.375 mg
Extended
Release Multiparticulate and Matrix Based Fonnulations
Formulation AUC Cmax Tmax
(ng/mL*hr) (ng/mL) (hrs)
MIRAPEX 0.375 mg
(0.125 mg X 3) tablets 58.05 4.61 3.43 1.56 11.3 2.8
Pramipexole Multiparticulate Extended Release
28.2~:5.26 1.88 0.29 9.3f1.7
Capsule Formulation (0.375 mg) [Example 4]
Pramipexole Matrix-Based Extended Release Tablet
Formulation (0.375 mg) [Example 6] 18.1 4.22 1.5210.26 10.0 1.0
Example 7: PNasnipexole Delayed and Extended Release Capsule Formulations
Applicants have conducted a human pharmacokinetic study to evaluate three
subject
pramipexole extended release capsules (known as "Type A," "Type B" and "Type
C"
formulations) against the approved reference product Mirapex tablets
(manufactured and
marketed by Boehringer Ingelheim Pharmaceuticals, Inc., and marketed by
Pfizer) listed in
the FDA's Approved Drug Products with Therapeutic Equivalence Evaluations 25th
Edition,
2005.
Three formulations of pramipexole extended release capsule, Type A, Type B and
Type C, are provided for clinical testing. These formulations are once daily
extended release
(XR) pramipexole formulations containing multiparticulates encapsulated in
enteric coated
gelatin capsules. These formulations are similar with respect to the active
substance to the
existing formulation for Mirapex tablets, e.g., pramipexole dihydrochloride
monohydrate is
the active substance in all the formulations. However, the dose levels are
different. Each
Mirapex tablet contains 0.125 mg of pramipexole dihydrochloride monohydrate,
and is
dosed three times a day with a total drug substance level of 0.375 mg (0.125mg
x 3). The
currently available immediate release pramipexole formulation (e.g., Mirapex )
is not ideal,
as it is associated with poor patient compliance as well as treatment-emergent
side effects that
lead to poor patient tolerance.
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The subject formulations contain 0.375 mg of active substance, and are
suitable for
once-daily administration. They are delayed, extended release oral dosage
forms that will
maintain effective plasma pramipexole levels to produce a therapeutic effect
over
approximately 24 hours when administered to patients in need, and should
result in
diminished incidence and decreased intensity of pramipexole's unwanted side
effects.
The pramipexole extended release capsules, Type A, Type B and Type C, use
0.375
mg of pramipexole dihydrochloride monohydrate as their active ingredient. The
level used is
within the limits specified in FDA's Approved Drug Products with Therapeutic
Equivalence
Evaluations 25th Edition, 2005, (Orange book). All excipients utilized in
these formulations
are within or below the listed levels for orally administered products.
The subject extended release formulation was conceptualized for once-daily
administration with improved bioavailability, patient compliance and
tolerability. It was to
provide a lag time with slow absorption followed by steady plasma levels over
an extended
duration. The objectives of subject formulation approach were to slow down or
delay the
rapid absorption of pramipexole that has been correlated with the major
adverse effects of
Mirapex tablets, while maintaining the effective plasma concentration over a
24 hours
period. An enteric polymer coating was applied on the capsule not to allow the
drug to get
released in the stomach.
The pramipexole extended release capsules, Type A, Type B and Type C,
described
below differ either in the level of the rate controlling polymer,
ethylcellulose, or bioadhesive
coating composition containing Spheromer III. Typically, the manufacture of
pramipexole
multiparticulate extended release capsules Type A, Type B and Type C involves
the
following steps.
1. Manufacture of placebo core pellets.
2. Manufacture of pramipexole extended release pellets Type A, Type B and
Type C.
3. Manufacture of the enteric coated pramipexole extended release capsules
Type
A, Type B and Type C.
A brief description of the typical manufacturing process and in-process
controls are
detailed below.
1. Preparation of Placebo Core Pellets:
- Mannitol and microcrystalline cellulose are blended with hydroxypropyl
cellulose in a blender.
- The dry blend is granulated with purified water using a low shear mixer.
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- The granules are extruded in a double roller extruder using a 1.5 mm screen
and the moisture content measured.
- The extrudate is spheronized in an extruder.
- The pellets are dried in a dryer until the desired moisture content is
achieved.
- The dried pellets are checked for size distribution. The placebo core
pellets are
tested for appearance, moisture content and particle size distribution.
2. Preparation of Pramipexole XR Pellets for Types A, B and C
- The placebo core pellets are coated with a solution of OPADRY Clear (YS-
1-19025-A) and pramipexole in the fluidized bed coater until the target weight
gain is
achieved.
- The pramipexole layered pellets are film coated with a polymer solution
comprised of Ethocel 10 cps and dibutyl sebacate in the fluidized bed coater
until the target
weight gain is achieved. The target weight gain is 8.3% w/w for Type A and
Type B and
12% w/w of the original pramipexole mannitol pellets for formulation Type C.
- The resulting extended release Type B pellets are film coated with a coating
solution of SPHEROMERTM III and Poloxamer 188 (Lutrol F68) in the fluidized
bed coater
until the target weight gain of 5.3% w/w is achieved. The pellets are then
tested for
appearance, identification, content assay, residual solvent and in vitro
dissolution.
3. Encapsulation and Enteric coating of Drug Product for Types A, B and C
- Gelatin capsules are manually filled with pramipexole extended release
pellets
for either Type A, Type B and Type C.
- The resulting capsules are applied with a gelatin band at the seam and
coated
with Acryl-EzeTM White (93018509) enteric coating in the pan coater until the
target weight
gain is attained. The pellets are then tested for appearance, identification,
content uniformity,
content assay, impurities and dissolution.
Specifically, pramipexole delayed and extended release (XR) formulation
containing
nlultiparticulate beads containing 0.375 mg of pramipexole encased in an
enteric coated hard
gelatin capsule was formulated. Pramipexole was initially layered on placebo
core pellets
(1.1- 1.4 mm) using Vector Mini Fluid Bed Drier (Mfl.01) with OPADRY Clear as
a
binder.
The placebo core pellets were prepared using low shear granulation, extrusion
and
spheronization technique. Following is the compo,sition used for preparing
placebo core
pellets.
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Components Weight (g) % w/w
Microcrystalline Cellulose
(Emcoce190M), USP/NF 60.0 30.0
Mannitol (Mannogem Powdered), USP/NF 130.0 65.0
Hydroxypropylcellulose
(HPC SSL), USP/NF 10.0 5.0
Purified Water, USP/NF * *
Total 200.0 100.0
* Evaporated during drying process.
The placebo pellets were dried in oven at 50 C for 12-17 hours to achieve a
desired
moisture level of 1% w/w. These pellets were then screened through size 10,
12, 14, 16 and18
mesh sieves and the particles retained on screen 14 and 16 were used for
subsequent
pramipexole layering process. pramipexole layered pellets were subsequently
coated in
Vector Mini Fluid Bed Drier (Mfl.0 1) with rate controlling polymer
composition containing
ethylcellulose (Ethocel 10 cps.) to achieve a final weight gain of 8.3% w/w.
These pellets
were then encapsulated in a size 2 gelatin capsule. These capsules were sealed
at the junction
of cap and body using an aqueous gelatin solution and later on coated with 1.6
% OPADRY
Clear (YS-1 -1 9025-A). These OPADRY coated capsules were later on coated with
an enteric
coating composition, Acryl-EZe White in a pan coater (O'Hara). 10% w/v
solution of
Acryl-EZETT" White was prepared in ethanol and water (90:10) and sprayed on
pramipexole
extended release capsule so as to achieve a final weight gain of 12% w/w.
These delayed
extended release capsules were then tested for release profile in USP II
dissolution apparatus
and were also evaluated for their in vivo performance in beagle dogs.
Following is the unit
dose composition used for preparing pramipexole delayed extended release
capsules Type A,
Type B and Type C.
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Unit Dose Composition of the Pramipexole Delayed Extended Release Capsule,
Type A,
0.375 mg
Components Weight (mg) %w/w
Pramipexole Dihydrochloride Monohydrate 0.375 0.13
Microcrystalline Cellulose (Emcocel 90M) 28.13 10.10
Mannitol (Mannogem Powder) 60.93 21.87
Hydroxypropyl Cellulose (HPC SSL) 4.69 1.68
OPADRY Clear (YS-1-19025-A) 8.80 3.16
Ethylcellulose (Ethocel 10 cps) 8.28 2:97
Dibutyl Sebacate 0.25 0.09
Acryl-EZE White (93018509) 23.12 8.30
Gelatin capsule 144.00 51.69
Ethanol* - -
Methyl Alcohol* - -
Purified Water* - -
Total 278.58 100.0
* evaporate during processing
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Unit Dose Composition of the Pramipexole Delayed Extended Release Capsule,
Type B,
0.375 mg
Components Weight (mg) %w/w
Pramipexole Dihydrochloride Monohydrate 0.375 0.13
Microcrystalline Cellulose (Emcocel 90M) 28.13 9.90
Mannitol (Mannogem Powder) 60.93 21.45
Hydroxypropyl Cellulose (HPC SSL) 4.69 1.65
OPADR Clear (YS-1-19025-A) 8.90 3.13
Ethylcellulose (Ethocel 10 cps) 8.28 2.91
Poloxamer (Lutrol F 68) 0.27 0.10
SPHEROMER III 5.14 1.81
Dibutyl Sebacate 0.25 0.09
Acryl-EZE White (93018509) 23.12 8.14
Gelatin Capsules 144.00 50.69
Ethanol* - -
Methyl Alcohol* - -
Purified Water* - -
Total 284.09 100.0
* evaporated during processing
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Unit Dose Composition of the Pramipexole Delayed Extended Release Capsule,
Type C,
0.375 mg
Components Weight (mg) %w/w
Pramipexole Dihydrochloride Monohydrate 0.375 0.20
Microcrystalline Cellulose (Enlcocel 90M) 28.13 14.89
Mannitol (Mannogem Powder) 60.93 32.25
Hydroxypropyl Cellulose (HPC SSL) 4.69 2.48
OPADRY Clear (YS-1-19025-A) 8.90 4.71
Ethylcellulose (Ethocel 10 cps) 11.97 6.33
Dibutyl Sebacate 0.36 0.19
Acryl-EZE White (93018509) 23.60 12.49
Gelatin Capsule ' 50.00 26.46
Ethanol - -
Methyl Alcohol - -
Purified Water - -
Total 188.96 100.0
Iri vitro dissolution Profile of Pramipexole Formulations
The enteric-coated pramipexole capsules were tested for dissolution profiles
using
USP II apparatus. Initially, the dissolution was performed in 0.1 N HCL media,
pH = 1.2 for
2 hours and later on in phosphate buffer at pH = 6.8 for 24 hours.
No drug was released from the three enteric coated pramipexole Formulations in
0.1
N HCL. Mirapex0 tablets dissolved in 10 minutes in phosphate buffer pH 6.8.
Figure 7
shows the dissolution profile of the three enteric coated praniipexole
formulations in
phosphate buffer at pH 6.8.
Pharmacokinetic Evaluation of Pramipexole Formulations in Beagles:
A study was conducted in fasted beagle dogs to evaluate the performance of
0.375 mg
pramipexole delayed and extended release multiparticulate based capsule
formulations
(Types A, B and C) administered as a single dose and Mirapex tablets, (0.125)
mg
administered in three times a day dosing regimen. As shown in Figure 8,
immediate release
Mirapex tablets exhibited rapid initial absorption of pramipexole, while the
extended release
formulation resulted in a lag time, followed by extended absorption up to 16
hours. As
shown in Table 5, the bioavailability estimate of the extended release capsule
formulations
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was about 50% when compared to Mirapex tablets given in a repeated manner.
Although in
the preliminary study in beagle dogs decreased bioavailability was observed
for the extended
release formulation, this can be primarily attributed to short residence time
in beagle GI tract.
There are known differences between humans and dogs in terms of motility,
bacterial
metabolism and GI transit time.
Table 5: Mirapex tablets, 0.375 mg (0.125 mg X 3) vs. Pramipexole 0.375 mg
Extended Release Multiparticulate Formulations
Formulation AUCo-48 Cmaa Tmax
(ng/mL*hr) , _ . (ag/mL). (hrs),Type A 22.18 3.35 1.76 0.11 9.2:L0.8
Type B 25.48 3.50 1.73 0.22 14.33 1.19
Type C 15.03 3.70 1.28 0.17 9.3 1.8
Pilot Sinae-dose Pharmacokinetic Study Comparing 0.375 mg Prami exole
Extended/Delayed Release Multiparticulate Formulations with Mirapex tablets,
0.375 mg
(0.125 mg X 3) in Humans
A single-dose, crossover study comparing the pharmacokinetics and tolerability
of
comparing pramipexole 0.375 mg extended release multiparticulate forniulations
with
MirapexOO tablets, 0.375 mg (0.125 mg X 3) in 12 healthy volunteers was
carried out. Each
subject received a single dose of each of the formulations in random order
under the fasted
conditions (a light breakfast was given 60 minutes after the dosing) and
plasma levels of
pramipexole were measured using LC/MS/MS. The LC-MS/MS method employed
injection
of plasma samples diluted 1:1 with dichloroacetic acid containing an internal
standard (that
was not observed in the dog plasma blank sample) at a concentration of 20
ng/mL. The
amount of pramipexole was calculated using a weighted calibration curve. The
linearity curve
was obtained using pramipexole standards ranging from 100 pg/mL to 25 ng/mL.
All
standards were prepared in Harlan Dog plasma. In order to assure accuracy
throughout the
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experiment, quality control (QC) samples were injected every 12 samples. The
QC standards
were prepared in dog plasma at known concentrations of -1.0 ng/mL and -10.0
ng/mL.
The doses were separated by 1-week washout periods. Figures 9A-C represent the
pramipexole plasma concentration vs. time graph. The area under the plasma
pramipexole vs.
time curve (AUC), maximum concentration (Cmax), time to maximum concentration
(Tmax)
were calculated and are indicated in Table 6.
Table 6: PK parameters comparing different 0.375 mg Pramipexole Delayed
Extended
Release Multiparticulate Formulations with Mirapex tablets, 0.375 mg (0.125
mg X 3)
Formulation A:UCQ_oo C,,a,; Tmax
(ng/mL*hr) (Pg/mL) (hrs)
Mirapex 0.375 mg
(0.125 mg X 3) tablets 7.14 1.6 390.83 105.22 17.0+5.3
Type A(Example 7) 6.96 2.4 424.08 389.31* 12.7+4.9
Type B(Example 7) 7,07+2.4 241.75 78.57 16.8 5.2
Type C(Example 7) 5.66 2.1 176.25 60.97 18.5 10.8
* One of the subjects in Type A testing showed a Cmax of about 1650 pg/mL vs.
the average
Cmax of 424 pg/mL
Example 8: Prauiipexole ER, 0.375 yng Tablets [5 % coating (80 parts Surelease
+ 20
parts OPADRY ) Fornzulation in Fasted condition
This example describes pharmacokinetic data for pramipexole 0.375 mg Tablet
(Lot
#509-060) coated with OPADRY / Surelease in beagle dogs under fasted
condition.
Pramipexole was layered on sugar spheres and compressed into a tablet along
with
otlier excipients as listed below. A pharmacokinetic study was performed
earlier in the fed
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conditions using the same formulation; however this study was done under
fasted conditions.
The data obtained from this study can be used to compare against the subject
pramipexole
extended release formulations which contain 0.375 mg of pramipexole
dihydrochloride.
Pramipexole ER, 0.375 mg Tablets coated with 80 parts Surelease + 20 parts
OPADRY
Ingredients % Per Tablet Wt. Per Tablet (mg)
Pramipexole layered
38.13 0.375
on sugar spheres
HPMC 2208 4000cps 24.77 140
Pregelatinized starch 36.54 206.5
Colloidal Silicon
0.25 1.4
Dioxide
Magnesium Stearate 0.31 1.75
Total 100 350.25
Lot# 509-060 tablets were coated with 80% Surelease and 20% OPADRY until a
weight gain
of 5% w/w was achieved.
Figure l0A shows the in vitro dissolution profile obtained using USP II
apparatus. For
the above formulation, the dissolution was performed in phosphate buffer pH
6.8 for 24
hours. The Sureleasee coated tablets formulated in house show an identical
profile to the
innovator's sustained release formulation.
Figure 10 B is the comparison of above example with Pramipexole Delayed
Extended Release Capsule, Type B, 0.375mg described in example 5. Both the
formulations
demonstrate a similar extent of absorption.
Figure 11 is the coinparison of pramipexole ER Formulations witli Mirapex
(0.125)
mg tablets administered in three times a day dosing regimen.
Pramipexole multiparticulates from Example 7 (Type A, Type B or Type C) were
fed
to beagle dogs in order to evaluate their pharmacokinetic performance and were
later on
compared to Mirapex 0.125 mg tablets administered in three times a day dosing
regimen and
Pramipexole ER, 0.375 mg tablets (Example 8). Mirapex (0.125) mg tablets
administered in
three times a day dosing regimen exhibited rapid initial absorption of
pramipexole, whereas
pramipexole ER formulations showed an extended absorption with just once a day
administration. The bioavailability estimate of the extended release
formulations was about
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50% when compared to Mirapex tablets given in a repeated manner. Although in
the
preliminary study in beagle dogs decreased bioavailability was observed for
the extended
release formulation, this can be primarily attributed to short residence time
in GI tract. There
are known differences between humans and dogs in terms of motility, bacterial
metabolism
and GI transit time. The above extended release formulation is expected to
show higher
extent of absorption in humans as the half life of pramipexole is longer in
humans.
Example 9 Preparation of Pranzipexole Extended-Release Pellet FoNmulation, Lot
#
601-048
An extended-release pellet formulation of pramipexole was prepared to be
combined
with an immediate- and controlled-release multiparticulate formulation of
levodopa-
carbidopa. Pramipexole was initially layered on placebo core pellets (1.1-1.4
mm dia.) with
Opadry Clear as a binder using a Vector MFL.01 Micro Batch Fluid Bed System,
equipped
with a Wurster insert.
The placebo core pellets were prepared using low-shear granulation, extrusion
and
spheronization technique. The following table provides the weight and
composition of
placebo core pellets.
Weight and Composition of Placebo Core Pellets
Ingredients Weight (%) Weight (g)
Microcrystalline Cellulose (Emcocel 90M), NF 30.0 60.0
Mannitol (MannogemTM Powdered), USP 65.0 130.0
Hydroxypropylcellulose (HPC-SSL), NF 5.0 10.0
Purified Water, USP * *
Total 100.0 200.0
* Evaporated during drying process.
The placebo pellets were dried in an oven at 50 C to achieve a desired
moisture level
of 1%(w/w). These pellets were then screened through size 10, 12, 14, 16 and
18 mesh
sieves and the particles retained on screen size 14 and 16 were used for
subsequent
pramipexole layering process.
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Pramipexole layered pellets were subsequently coated in the Vector MFL.01
Micro
Batch Fluid Bed System, equipped with a Wurster insert, with a release rate-
controlling
polymer composition containing ethylcellulose to achieve a weight gain of 8.3%
(w/w), and
then coated with bioadhesive Spheromer III polymer to a weight gain of 5.3%
(w/w).
The unit dose composition of a pramipexole 0.375 mg extended-release pellet
formulation is given below.
Unit Dose Composition of Pramipexole 0.375 mg Extended-Release Pellet
Formulation
Components Weight (%) Weight (mg)
Pramipexole Dihydrochloride Monohydrate, USP 0.33 0.375
Mannitol (MannogemTM Powdered), USP 53.44 60.93
Microcrystalline Cellulose (Emcocel 90M), NF 24.67 28.13
Ethylcellulose (Ethocel'"' Std 10 FP Premium), NF 7.26 8.28
Opadry Clear (YS-1-19025-A) 4.94 5.63
SpheromerT"' III 4.78 5.45
Hydroxypropyl Cellulose (HPC-SSL), NF 4.11 4.69
Poloxamer 188 (Lutrol F 68), NF 0.25 0.29
Dibutyl Sebacate, NF 0.22 0.25
Total 100.00 114.025
The bioadhesive pramipexole pellets may be optionally top-coated with
bioadhesive
Spheromer"" I polymer, a hypromellose polymer, a hydroxypropylcellulose
polymer, or a
polyvinyl alcohol polymer to a weight gain of 2-5% (w/w).
Example 10 Pz=oduction ofLevodopa, Carbidopa, and Levodopa-Carbidopa Pellets
witlz
Graizulatiozz-Extrusiou-Sphez=ouizatiou and Fluid Bed Dzying
Levodopa, carbidopa, and levodopa-carbidopa pellets were produced with
granulation-extrusion-spheronization and fluid bed drying. The production
processes
included the following:
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(1) Weighing levodopa or carbidopa, or both levodopa and carbidopa, optionally
a
bioadhesive polymer composition, and pharmaceutically acceptable excipients.
(2) Blending levodopa or carbidopa, or both levodopa and carbidopa, and
optionally a
bioadhesive polymer composition, with pharmaceutically acceptable excipients
in a
planetary type mixer, Hobart Mixer with a 5-qt mixing bowl, operating at the
speed
setting #1, for 5-15 niin, forming a dry mix.
(3) Granulating the dry mix from step (2) under low shear with a granulation
fluid,
forming a wet granulation. The granulation fluids were mainly selected from a
group
consisting of purified water, an aqueous solution of a mineral or organic
acid, an
aqueous solution of a polymeric composition, a pharmaceutically acceptable
alcohol,
a ketone or a chlorinated solvent, a hydro-alcoholic mixture, an alcoholic or
hydro-
alcoholic solution of a polymeric composition, a solution of a polymeric
composition
in a chlorinated solvent or in a ketone.
(4) Extruding the wet granulation from step (3) through the screen of a screen-
type
extruder, Caleva Model 20 (or Model 25) Extruder, operating at 10-20 rpm, and
forming breakable wet strands, the extrudate. The screen aperture was 0.8, 1,
or 1.5
mm.
(5) Spheronizing the extrudate from step (4) in a spheronizer, Caleva Model
250,
equipped with a 2.5-mm spheronization plate, operating at 1000-2000 rpm for 5-
10
min, and forming spheronized pellets.
(6) Drying the spheronized pellets froin step (5) in a fluidized bed drier,
Vector MFL.01
Micro Batch Fluid Bed System, operating at an inlet air flow rate of 100-300
lpm
(liters per minute) and an inlet air temperature of 50 C. Alternatively,
pellets were
dried either in an ACT (Applied Chemical Technology) fluidized bed drier or in
a
conventional Precision oven. The ACT fluidized bed drier was operated at an
inlet air
flow rate of 140-150 fpm (foot per minute) and an inlet air temperature of 104
F. The
oven was set at 50 C.
(7) Screening and classifying the dried pellets from step (6) through a stack
of stainless
steel sieves, U.S. standard mesh sizes 8, 10, 12, 14, 16, 18, 20, 25, 30, 40,
45, and 60
using a mechanical sieve shaker, W.S. Tyler Sieve Shaker Ro-Tap Rx-29,
operated
for 5 min. The particle size and distribution of pellet formulations were
analyzed, and
classified pellets ranging from 0.25 mm (mesh # 60) to 2 mm (mesh # 10) were
selected for future film coating or other experimentation.
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Levodopa, carbidopa, and levodopa-carbidopa pellets were produced with
granulation-extrasion-spheronization and oven drying. The production processes
included the
steps 1 to 5 and 7 of Example 1 but the spheronized pellets were dried in a
Precision gravity
oven, operating at 50 C, for 8-24 h.
Example 11 Production of Levodopa Pellets witla Granulation-Extrusion-
Splzeroni.zation,
Lot # 510-095
Three identical sub-lots of levodopa pellets (sub-lots # 511-068, 511-069, and
511-
070) were prepared in accordance with the method described in Example 1. The
weight and
composition of pellets of the sub-lot # 511-068 are given in the following
table. Levodopa
was blended with inactive excipients for 5 min. The levodopa-excipients blend
was then
granulated by spraying purified water while mixing at low shear. The
granulation was
blended for an additional 5 min and then extruded through a 1.5 mm screen of a
Caleva
extruder, mode125, operating at 15 rpm. The extrudate was spheronized in a
Caleva
spheronizer, mode1250, operating at 1000 rpm for 5 min. The spheronized
pellets were dried
in an ACT (Applied Cheinical Technology) fluidized bed drier at 104 F14 F for
75 min. The
dried pellets were screened and particles with diameters ranging from 1 mm to
2 mm were
selected for future experimentation. The screened pellets of the three sub-
lots were blended in
a GlobePharma Maxiblend Blender equipped with an 8-qt stainless steel V-shell.
Weight and Composition of Levodopa Pellets, Sub-lot # 511-068
Ingredients Weight % Weight (g)
Levodopa, USP 50.0 300
Microcrystalline cellulose (Emcocel 90 M), NF 25.0 150
Mannitol (MannogemTM Powdered), USP 14.0 84
Hydroxypropylcellulose (HPC-SSL), NF 5.0 30
Croscarmellose sodium (Ac-Di-Sol ), NF 5.0 30
Citric acid, anhydrous, USP 1.0 6
Total 100.0 600
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Example 12 Filsiz coating of Levodopa-Carbidopa Pellets with Bioadlzesive
Polytner,
SpkeronterTMlll, Lot # 510-098
Levodopa, carbidopa, and levodopa-carbidopa pellets were film-coated with a
bioadhesive polymeric composition, SpheromerTM III. Bioadhesive SpheromerTM
III and
optionally a functional polymer, or a non-functional polymer, and optionally
pharmaceutically acceptable excipients, were dissolved in methanol. The film
coating was
performed in a fluidized bed coater, Vector MFL.01 Micro Batch Fluid Bed
System,
equipped with a Wurster insert, operating at an inlet air flow rate of 100-
3001pm (liter per
minute) and an inlet air temperature of 35 C:L2 C. The pellets were pre-warmed
at 35 C for
2-5 min and after film-coating were post-dried at 30 C for 15-30 inin.
Alternatively, pellets
were coated in a Fluid Air Mode15 fluid bed processor, equipped with a Wurster
insert,
operating at an inlet air flow rate of 70 cfin (cubic foot per minute) and an
inlet air
temperature of 35 C. The pellets were pre-warmed at 40 C for 5-7 min and after
film-coating
were post-dried at 35 C for 30 min.
Composition of SpheromerTM III Coating Solution, Lot # 511-098
Ingredients Weight % Weight (g)
SpheoromerTM III 94.7 71
Poloxamer 188 (Lutrol F68), NF 5.3 4
Methyl alcohol, NF * (1,500 mL)
Total 100.0 150
a. Methyl alcohol is removed during the coating/drying process.
Example 13 Film coating ofLevodopa Pellets witl: Bioadlaesive Polytraer,
SpheroftzerTM
III, aud Hydroxypropylcellulose (HPC-SSL), Lot # 511-092
One thousand grams of levodopa pellets, lot # 510-095, were film-coated in a
Fluid
Air Mode15 fluid bed processor, equipped with a Wurster insert, in accordance
with the
method described in Example 12. The composition of the coating solution is
given below.
SpheromerTM III and Hydroxypropylcellulose (HPC-SSL) were dissolved in
methanol and
sprayed onto the fluidized pellets to obtain a 12% weight gain on pellets.
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Composition of SpheromerTM III/Hydroxypropylcellulose (HPC-SSL) Coating
Solution, Lot
# 511-092
Ingredients Weight % Weight (g)
SpheoromerTM III 80.0 120
Hydroxypropylcellulose (HPC SSL), NF 20.0 30
Methyl alcohol, NF* - (3,000 mL)
Total 100.0 150
* Methyl alcohol is removed during the coating/drying process.
Example 14 Production of Carbidopa Granules with Low Shear Granulation, Lot #
511-
101
Carbidopa granules were produced with low shear granulation method consisting
of
the following processes:
(1) Weighing carbidopa, optionally a bioadhesive polymer composition, and
pharniaceutically acceptable excipients.
(2) Blending carbidopa, and optionally a bioadhesive polymer composition, with
pharmaceutically acceptable excipients in a planetary type mixer, Hobart
Mixer,
operating at the speed setting #1, for 5-15 inin, forming a dry mix.
(3) Granulating the dry mix from step (2) under low shear with a granulation
fluid,
forming a wet granulation. The granulation fluid was mainly selected from
purified
water, an aqueous solution of a mineral or organic acid, an aqueous solution
of a
polymeric composition, an alcohol, a hydro-alcoholic mixture, or an alcoholic
or
hydro-alcoholic solution of a polymeric composition.
(4) Drying the granulation from step (3) in a fluidized bed drier, Vector
MFL.0 1 Micro
Batch Fluid Bed System, operating at an inlet air flow rate of 100-3001pm
(liters per
minute) and an inlet air temperature of 50 C. Alternatively, the granulation
from step
(3) was dried in a Precision gravity oven, operating at 50 C, for 8-24 h.
(5) Screening and classifying the dried granules from step (4) through a stack
of stainless
steel sieves, U.S. standard mesh sizes 20 and 60, using a mechanical sieve
shaker,
W.S. Tyler Sieve Shaker Ro-Tap Rx-29, operated for 5 min. Particle size and
distribution of granular formulations were analyzed, and classified granules
ranging
from 0.25 mm (mesh # 60) to 0.85 mm (mesh # 20) were selected for future
experimentation.
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The weight and composition of granules are given below. Carbidopa was blended
with inactive excipients for 5 min. The carbidopa-excipients blend was then
granulated by
spraying purified water while mixing at low shear. The granulation was blended
for an
additional 5 min and then dried in a Precision gravity oven at 50 C for 8 - 48
hours. The dried
granules were screened and particles smaller than 0.85 mm were selected for
future
experimentation.
Weight and Composition of Carbidopa Granules, Lot # 511-101
Ingredients Weight % Weight (g)
Carbidopa monohydrate, USP 52.0 104
Microcrystalline cellulose (Emcocel 90 M), NF 23.5 47
Mannitol (MannogemTM Powdered), USP 13.5 27
Hydroxypropylcellulose (HPC-SSL), NF 5.0 10
Croscarmellose sodium (Ac-Di-Sol ), NF 5.0 10
Citric acid, anhydrous, USP 1.0 2
Total 100.0 200
Example 15 Preparation of Levodopa-Carbidopa 200 sng/50 ing MultipaNticulate
Capsules, Lots # 510-099 & 510-100
Levodopa pellets (lot # 510-095), SpheromerTM III-coated levodopa-carbidopa
pellets
(lot # 510-098), HPC-SSL/SpheromerTM III-coated levodopa pellets (lot # 511-
092), and
carbidopa granules (lot # 511-101) were encapsulated in 00-size hard gelatin
capsules. Each
capsule contained 200 mg levodopa and 50 mg carbidopa anhydrous. The
composition of
multiparticulates in each capsule formulation is given below.
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Composition (mg) of Multiparticulate Capsule Formulations, Lot # 510-099 & 510-
100
Components Lot # 510-099 510-100
Levodopa Pellets 510-095 80 80
Spheromer III-coated Levodopa-Carbidopa Pellets 510-098 340 255
HPC-SSL/SpheromerTM III-coated Levodopa 511-092 - 90
Carbidopa Granules 511-101 20 40
Total (mg per capsule) - 440
Example 16 Preparation of Combined PNamipexole 0.375 mg Extended-Release
Pellets
and Levodopa-CaNbidopa 200 rng/50 mg Immediate/Cotztrolled-Release
Multipas=ticulates
as a Delayed-Release Capsule Formulatioii
Pramipexole extended-release pellets, lot # 601-048 (from Example 9),
containing
0.375 mg pramipexole, and levodopa-carbidopa immediate/controlled-release
multiparticulates, lot # 510-099 (from Example 15), containing 200 mg levodopa
and 50 mg
carbidopa, were co-encapsulated in two-piece hard gelatin capsules. These
capsules were
sealed at the junction of cap and body using an aqueous gelatin solution and
then coated with
1.6% (w/w) Opadry Clear (YS-1-19025-A). The Opadry-coated capsules were top-
coated
with an enteric coating composition, Acryl-EZE"" White, in a pan coater
(O'Hara
Technologies Labcoat System). The capsules were sprayed with a 10% (w/v)
solution of
Acryl-EZr White in ethanol and water mixture (90:10 v/v) so as to achieve a
final weight
gain of 5-12% (w/w).
The bioadhesive pramipexole and levodopa-carbidopa pellets may be optionally
top-
coated with bioadhesive Spheromer I polymer, a hypromellose polymer, a
hydroxypropylcellulose polymer, or a polyvinyl alcohol polymer to a weight
gain of 2-5%
(w/w).
Example 17 Preparation of Prafnipexole 0.375 mg DelayedlExtended-Release
Capsule
Forznaulatioia, Lot # 601-056
Pramipexole extended-release pellets, lot # 601-048 (from Example 9)
containing
0.375 mg pramipexole were encapsulated in a size 2 hard shell gelatin capsule.
These
capsules were sealed at the junction of cap and body using an aqueous gelatin
solution and
coated with 1.6 % Opadry Clear (YS-1-19025-A). The Opadry-coated capsules were
then
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coated with an enteric coating composition, Acry1-EZE7 White, in a pan coater
(O'Hara
Technologies Labcoat System). ). The capsules were sprayed with a 10% (w/v)
solution of
Acryl-EZE7 White in ethanol and water mixture (90:10 v/v) so as to achieve a
final weight
gain of 5-12% (w/w).
The unit dose composition of a pramipexole 0.375 mg delayed/extended-release
capsule formulation is given below.
Unit Dose Composition of Pramipexole 0.375 mg Delayed/Extended-Release Capsule
Formulation
Components Weight (%) Weight (mg)
Pramipexole Dihydrochloride Monohydrate, USP 0.13 0.375
Mannitol (MannogemTM Powdered), USP 21.45 60.93
Microcrystalline Cellulose (Emcocel 90M), NF 9.90 28.13
Acryl-EZE'f" White (93018509) 8.14 23.12
Opadry Clear (YS-1-19025=A) 3.13 8.90
Ethylcellulose (Ethocel' ' Std 10 FP Premium), NF 2.91 8.28
Spheromer III 1.81 5.14
Hydroxypropyl Cellulose (HPC-SSL), NF 1.65 4.69
Poloxamer 188 (Lutrol F 68), NF 0.10 0.27
Dibutyl Sebacate, NF 0.09 0.25
Gelatin Capsule, Size 2 50.69 144.00
Total 100.00 284.085
Example 18 PNeparatiou of Combiued Pranaipexole 0.375 mg Delayed/Extended-
Release
Pellets and Levodopa-Carbidopa 200 mg/50 mg Ifizsizediate/Coutrolled-Release
Multiparticulates as a Capsule Fornzulatiou
Pramipexole delayed/extended-release pellets, lot # 601-056 (from Example 17),
containing 0.375 mg pramipexole, and levodopa-carbidopa iminediate-controlled-
release
multiparticulates, lot # 510-099 (from Example 15), containing 200 mg levodopa
and 50 mg
carbidopa, were co-encapsulated in two-piece hard gelatin capsules.
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The bioadhesive pramipexole and levodopa-carbidopa pellets may be optionally
top-
coated with bioadhesive Spheromer'h' I polymer, a hypromellose polymer, a
hydroxypropylcellulose polymer, or a polyvinyl alcohol polymer to a weight
gain of 2-5%
(w/w).
Eguivalents
Those skilled in the art will recognize, or be able to ascertain using no more
than
routine experimentation, many equivalents to the specific embodiments of the
invention
described herein. Such equivalents are intended to be enconipassed by the
following claims.
All patents, publications, and other references cited above are hereby
incorporated by
reference in their entirety.
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