U.S. patent application number 16/268373 was filed with the patent office on 2019-08-15 for composition and method for treating neurological disease.
The applicant listed for this patent is Osmotica Kereskedelmi es Szolgaltato Korlatolt Felelossegu Tarsasag. Invention is credited to Marcelo Fernando BEFUMO, Joaquina FAOUR, Glenn A. MEYER, Ana Cristina PASTINI.
Application Number | 20190247331 16/268373 |
Document ID | / |
Family ID | 67540667 |
Filed Date | 2019-08-15 |
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United States Patent
Application |
20190247331 |
Kind Code |
A1 |
MEYER; Glenn A. ; et
al. |
August 15, 2019 |
COMPOSITION AND METHOD FOR TREATING NEUROLOGICAL DISEASE
Abstract
The present disclosure is directed to methods of treating
neurological disorders in a patient such as Parkinson's disease,
drug-induced extrapyramidal reactions, and/or levodopa-induced
dyskinesia comprising administering to the patient once daily in
the morning a pharmaceutical composition comprising about 50 mg to
about 400 mg of extended-release amantadine or a pharmaceutically
acceptable salt thereof.
Inventors: |
MEYER; Glenn A.;
(Wilmington, NC) ; FAOUR; Joaquina; (Ciudad
Autonoma de Buenos Aires, AR) ; PASTINI; Ana Cristina;
(Ciudad Autonoma de Buenos Aires, AR) ; BEFUMO; Marcelo
Fernando; (Ciudad Autonoma de Buenos Aires, AR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Osmotica Kereskedelmi es Szolgaltato Korlatolt Felelossegu
Tarsasag |
Budapest |
|
HU |
|
|
Family ID: |
67540667 |
Appl. No.: |
16/268373 |
Filed: |
February 5, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16241631 |
Jan 7, 2019 |
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16268373 |
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15898143 |
Feb 15, 2018 |
10213393 |
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16241631 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2886 20130101;
A61K 31/13 20130101; A61K 9/0004 20130101; A61K 9/20 20130101; A61P
25/16 20180101; A61K 45/06 20130101 |
International
Class: |
A61K 31/13 20060101
A61K031/13; A61K 9/00 20060101 A61K009/00; A61P 25/16 20060101
A61P025/16; A61K 9/20 20060101 A61K009/20; A61K 45/06 20060101
A61K045/06 |
Claims
1. A solid oral dosage form comprising i) amantadine or a
pharmaceutically acceptable salt thereof in an extended release
form, and ii) amantadine or a pharmaceutically acceptable salt
thereof in an immediate release form, wherein said solid oral
dosage form comprises about 258 mg of amantadine free base
equivalent, wherein at least about 50% of amantadine or a
pharmaceutically acceptable salt thereof is in an extended release
form, and wherein said solid oral dosage form has one or more of
the, following dimensions: (a) a volume of about 0.2 mL to about
0.6 mL; (b) a wall height of about 3 mm to about 6 mm; and (c) the
largest dimension of said solid oral dosage form is about 8 mm to
about 15 mm.
2. The solid oral dosage form of claim 1, wherein said solid oral
dosage form has a volume of about 0.24 mL to about 0.56 mL.
3. The solid oral dosage form of claim 2, wherein said solid oral
dosage form has a volume of about 0.4 mL.
4. The solid oral dosage form of claim 1, wherein said solid oral
dosage form has a wall height of about 3.5 mm to about 5 mm.
5. The solid oral dosage form of claim 4, wherein said solid oral
dosage form has a wall height of about 4 mm.
6. The solid oral dosage form of claim 1, wherein the largest
dimension of said solid oral dosage form is about 11 ruin to about
14 mm.
7. The solid oral dosage form of claim 6, wherein the largest
dimension of said solid oral dosage form is about 11.2 mm.
8. The solid oral dosage form of claim 1, wherein said solid oral
dosage form has a volume of about 0.4 mL, a wall height of about 4
mm, and the largest dimension of said solid oral dosage form is
about 11.2 mm.
9. A solid oral dosage form comprising i) amantadine or a
pharmaceutically acceptable salt thereof in an extended release
form, and ii) amantadine or a pharmaceutically acceptable salt
thereof in an immediate release form, wherein said solid oral
dosage form comprises about 193 mg of amantadine free base
equivalent, wherein at least about 50% of amantadine or a
pharmaceutically acceptable salt thereof is in an extended release
form, and wherein said solid oral dosage form has one or more of
the following dimensions: (a) a volume of about 0.1 mL to about 0.5
mL; (b) a wall height of about 3 mm to about 6 mm; and (c) the
largest dimension of said solid oral dosage form is about 8 mm to
about 14 mm.
10. The solid oral dosage form of claim 9, wherein said solid oral
dosage form has a volume of about 0.18 mL to about 0.42 mL.
11. The solid oral dosage form of claim 10, wherein said solid oral
dosage form has a volume of about 0.30 mL.
12. The solid oral dosage form of claim 9, wherein said solid oral
dosage form has a wall height of about 3.5 mm to about 5 mm.
13. The solid oral dosage form of claim 12, wherein said solid oral
dosage form has a wall height of about 4 mm.
14. The solid oral dosage form of claim 9, wherein the largest
dimension of said solid oral dosage form is about 10 mm to about 13
mm.
15. The solid oral dosage form of claim 14, wherein the largest
dimension of said solid oral dosage form is about 10.2 mm.
16. The solid oral dosage form of claim 9, wherein said solid oral
dosage form has a volume of about 0.3 mL, a wall height of about 4
mm, and the largest dimension of said solid oral dosage form is
about 10.2 mm.
17. A solid oral dosage form comprising i) amantadine or a
pharmaceutically acceptable salt thereof in an extended release
form, and ii) amantadine or a pharmaceutically acceptable salt
thereof in an immediate release form, wherein said solid oral
dosage form comprises about 129 mg of amantadine free base
equivalent, wherein at least about 50% of amantadine or a
pharmaceutically acceptable salt thereof is in an extended release
form, and wherein said solid oral dosage form has one or more of
the following dimensions: (a) a volume of about 0.1 mL to about 0.4
mL; (b) a wall height of about 3 mm to about 6 mm; and (c) the
largest dimension of said solid oral dosage form is about 6 mm to
about 10 mm.
18. The solid oral dosage form of claim 17, wherein said solid oral
dosage form has a volume of about 0.12 mL to about 0.28 mL.
19. The solid oral dosage form of claim 8, wherein said solid oral
dosage form has a volume of about 0.20 mL.
20. The solid oral dosage form of claim 17, wherein said solid oral
dosage form has a wall height of about 3.5 mm to about 5 mm.
21. The solid oral dosage form of claim 20, wherein said solid oral
dosage for has a wall height of about 4 mm.
22. The solid oral dosage form of claim 17, wherein the largest
dimension of said solid oral dosage form is about 8 mm to about 10
mm.
23. The solid oral dosage form of claim 22, wherein the largest
dimension of said solid oral dosage form is about 8.1 mm.
24. The solid oral dosage form of claim 17, wherein said solid oral
dosage form has a volume of about 0.2 mL, a wall height of about 4
mm, and the largest dimension of said solid oral dosage form is
about 8.1 mm.
25. The solid oral dosage form of claim 1, wherein the dosage form
is a tablet.
26. The solid oral dosage form of claim 1, wherein the dosage form
is a capsule.
27. The solid oral dosage form of claim 9, wherein the dosage form
is a tablet.
28. The solid oral dosage form of claim 9, wherein the dosage form
is a capsule.
29. The solid oral dosage form of claim 17, wherein the dosage form
is a tablet.
30. The solid oral dosage form of claim 17, wherein the dosage form
is a capsule.
Description
FIELD OF THE INVENTION
[0001] This invention relates to compositions and methods for
treating neurological disorders, such as Parkinson's disease,
drug-induced extrapyramidal reactions, and levodopa-induced
dyskinesia.
BACKGROUND OF THE INVENTION
[0002] A neurological disorder is any disorder of the nervous
system, which can be categorized according to the primary location
affected, the primary type of dysfunction involved, or the primary
type of cause. The broadest division is between central nervous
system disorders and peripheral nervous system disorders. Movement
disorder is one of the sub-categories that involves the disorder of
the central and/or peripheral nervous system such as Parkinson's
disease, secondary Parkinsonism, essential tremor, amyotrophic
lateral sclerosis. Tourette's Syndrome, multiple sclerosis,
extrapyramidal movement disorders, and various types of Peripheral
Neuropathy.
[0003] Among the various neurological disorders, Parkinson's
Disease (PD) is a progressive, chronic, neurodegenerative disease
characterized by impairment or death of neurons in the substantia
nigra pars compacta. This neuronal deficit leads to motor symptoms
including muscle rigidity, postural instability, tremor, akinesia
or bradykinesia. In addition to the motor symptoms, most patients
develop other health problems related to PD. These symptoms are
diverse but are collectively known as non-motor symptoms and can
likewise be troublesome and disabling. The average age of onset of
PD is approximately 60 years. Parkinson's disease is the second
most common neurodegenerative disease after Alzheimer's disease
with an incidence of up to 1/1,000 person-years. The prevalence of
PD in the United States (US) is 0.3%, which increases to 4-5% among
people aged 85 years. Approximately 1,000,000 people in the US have
PD. Levodopa is the most common drug prescribed to relieve the
symptoms of PD. However, it is associated with motor and
psychiatric side-effects. Consequently, interest has turned to
alternative drugs with improved side-effect profiles to replace or
augment levodopa. Amantadine, originally used as an antiviral drug,
has been shown to improve the symptoms of PD.
[0004] Levodopa-induced dyskinesia is a form of dyskinesia
associated with levodopa, used to treat Parkinson's disease. It
often involves hyperkinetic movements, including chorea, dystonia,
and athetosis. In the context of PD, dyskinesia is often the result
of long-term dopamine therapy. These motor fluctuations occur in up
to 80% of PD patients after 5-10 years of levodopa treatment, with
the percentage of affected patients increasing over time.
Amantadine has also been shown to improve levodopa-induced
dyskinesia.
[0005] Drug-induced extrapyramidal reactions, also referred to as
drug-induced extrapyramidal symptoms or drug-induced extrapyramidal
side effects, are drug-induced movement disorders that include
acute and tardive symptoms. These symptoms include dystonia
(continuous spasms and muscle contractions), akathisia (motor
restlessness), parkinsonism (characteristic symptoms such as
rigidity), bradykinesia (slowness of movement), tremor, and tardive
dyskinesia (irregular, jerky movements). Several types of drugs may
cause drug-induced extrapyramidal reactions, such as
antipsychotics, neuroleptic agents, antiemetics, and
antidepressants. Levodopa has been previously tested for use in the
treatment of drug-induced extrapyramidal syndrome but with a
disappointing therapeutic response.
[0006] Amantadine hydrochloride, a noncompetitive NMDA receptor
antagonist, is currently approved both as an immediate release
product and as an extended release product in the US. The first New
Drug Application for amantadine in the US was approved 40 years
ago, with an indication for idiopathic PD and other forms of
symptomatic parkinsonism. Amantadine has been shown in clinical
studies to be an effective treatment to reduce motor fluctuations
in patients with advanced PD. Amantadine has also been effective in
treating drug-induced extrapyramidal reactions caused by
administration of, for example, antipsychotics or drugs to slow the
progression of PD. However, treatment with amantadine has
previously been only with immediate release ("IR") amantadine as
tablets, capsules or oral liquid or syrup. Administration of the IR
form raised issues with patient compliance, because of the number
of dosages required per day, and the negative side effects from use
of the IR dosage form throughout the day.
[0007] To address the ongoing challenge of balancing the efficacies
with the relative risk of adverse events, the inventors have
developed a novel extended-release (ER) dosage form of amantadine.
The extended-release dosage form and once daily morning dosing
schedule were developed to provide more consistent levels of
amantadine throughout the day and to enhance patient compliance by
reducing administration from two or more times a day to once daily
in the morning.
BRIEF SUMMARY OF THE INVENTION
[0008] The present disclosure provides a solid oral dosage form
comprising i) amantadine or a pharmaceutically acceptable salt
thereof in an extended release form, and ii) amantadine or a
pharmaceutically acceptable salt thereof in an immediate release
form, wherein said solid oral dosage form comprises about 258 mg of
amantadine free base equivalent, wherein at least about 50% of
amantadine or a pharmaceutically acceptable salt thereof is in an
extended release form, and wherein said solid oral dosage form has
one or more of the following dimensions: [0009] (a) a volume of
about 0.2 mL to about 0.6 mL; [0010] (b) a wall height of about 3
mm to about 6 mm; and [0011] (c) the largest dimension of said
solid oral dosage form is about 8 mm to about 15 mm.
[0012] In some embodiments, the solid oral dosage form has a volume
of about 0.24 mL to about 0.56 mL. In other embodiments, the solid
oral dosage form has a volume of about 0.4 mL.
[0013] In some embodiments, the solid oral dosage form has a wall
height of about 3.5 mm to about 5 mm. In another embodiment the
solid oral dosage form has a wall height of about 4 mm.
[0014] In some embodiments, the largest dimension of the solid oral
dosage form is about 11 mm to about 14 mm. In other embodiments,
the largest dimension of the solid oral dosage form is about 11.2
mm.
[0015] In some embodiments, the solid oral dosage form has a volume
of about 0.4 mL, a wall height of about 4 mm, and the largest
dimension of the solid oral dosage form is about 11.2 mm.
[0016] The present disclosure also provides a solid oral dosage
form comprising i) amantadine or a pharmaceutically acceptable salt
thereof in an extended release form, and ii) amantadine or a
pharmaceutically acceptable salt thereof in an immediate release
form, wherein said solid oral dosage form comprises about 193 mg of
amantadine free base equivalent, wherein at least about 50% of
amantadine or a pharmaceutically acceptable salt thereof is in an
extended release form, and wherein said solid oral dosage form has
one or more of the following dimensions: [0017] (a) a volume of
about 0.1 mL to about 0.5 mL; [0018] (b) a wall height of about 3
mm to about 6 mm; and [0019] (c) the largest dimension of said
solid oral dosage form is about 8 mm to about 14 mm.
[0020] In some embodiments, the solid oral dosage form has a volume
of about 0.18 mL to about 0.42 mL. In other embodiments, the solid
oral dosage form has a volume of about 0.30 mL.
[0021] In some embodiments, the solid oral dosage form has a wall
height of about 3.5 mm to about 5 mm. In other embodiments, the
solid oral dosage form has a wall height of about 4 mm.
[0022] In some embodiments, the largest dimension of the solid oral
dosage form is about 10 mm to about 13 mm. In other embodiments,
the largest dimension of the solid oral dosage form is about 10.2
mm.
[0023] In some embodiments, the solid oral dosage form has a volume
of about 0.3 mL, a wall height of about 4 mm, and the largest
dimension of the solid oral dosage form is about 10.2 mm.
[0024] The present disclosure also provides a solid oral dosage
form comprising amantadine or a pharmaceutically acceptable salt
thereof in an extended release form, and ii) amantadine or a
pharmaceutically acceptable salt thereof in an immediate release
form, wherein said solid oral dosage form comprises about 129 mg of
amantadine free base equivalent, wherein at least about 50% of
amantadine or a pharmaceutically acceptable salt thereof is in an
extended release form, and wherein said solid oral dosage form has
one or more of the following dimensions: [0025] (a) a volume of
about 0.1 mL to about 0.4 mL; [0026] (b) a wall height of about 3
mm to about 6 mm; and [0027] (c) the largest dimension of the solid
oral dosage form is about 6 mm to about 10 mm.
[0028] In some embodiments, the solid oral dosage form has a volume
of about 0.12 mL to about 0.28 mL. In other embodiments, the solid
oral dosage form has a volume of about 0.20 mL.
[0029] In some embodiments, the solid oral dosage form has a wall
height of about 3.5 mm to about 5 mm. In other embodiments, the
solid oral dosage for has a wall height of about 4 mm.
[0030] In some embodiments, the largest dimension of the solid oral
dosage form is about 8 mm to about 10 mm. In other embodiments, the
largest dimension of the solid oral dosage form is about 8.1
mm.
[0031] in some embodiments, the solid oral dosage form has a volume
of about 0.2 mL, a wall height of about 4 mm, and the largest
dimension of the solid oral dosage form is about 8.1 mm.
[0032] In some embodiments, the solid oral dosage form in a form of
a tablet. In sonic other embodiments, the tablet is an osmotic
device.
[0033] The present disclosure also provides a method of treating a
patient with Parkinson's disease, the method comprising
administering to the patient a pharmaceutical composition
comprising amantadine, or a pharmaceutically acceptable salt
thereof, in an extended release form, and amantadine, or a
pharmaceutically acceptable salt thereof, in an immediate release
form. In some embodiments, the patient is an adult.
[0034] The present disclosure also provides a method of treating
drug-induced extrapyramidal reactions in a patient, the method
comprising administering to the patient a pharmaceutical
composition comprising amantadine, or a pharmaceutically acceptable
salt thereof, in an extended release form, and amantadine, or a
pharmaceutically acceptable salt thereof, in an immediate release
form. In some embodiments, the patient is an adult.
[0035] The present disclosure also provides a method of treating
levodopa-induced dyskinesia in a patient, the method comprising
administering to the patient a pharmaceutical composition
comprising amantadine, or a pharmaceutically acceptable salt
thereof, in an extended release form, and amantadine, or a
pharmaceutically acceptable salt thereof, in an immediate release
form. In some embodiments, the patient is an adult.
[0036] The present disclosure also provides a method of treating
one or more of Parkinson's disease, drug-induced extrapyramidal
reactions, and levodopa-induced dyskinesia in a patient, the method
comprising administering to the patient a pharmaceutical
composition comprising amantadine, or a pharmaceutically acceptable
salt thereof, in an extended release form, and amantadine, or a
pharmaceutically acceptable salt thereof, in an immediate release
form. In some embodiments, the patient is an adult.
[0037] The present disclosure also provides a method of treating
one or more of Parkinson's disease, drug-induced extrapyramidal
reactions, and levodopa-induced dyskinesia in a patient, the method
comprising administering to the patient a solid oral dosage form
comprising of about 258 mg of amantadine free base equivalent,
wherein said solid oral dosage form has one or more of the
following dimensions: [0038] (a) a volume of about 0.2 mL to about
0.6 mL; [0039] (b) a wall height of about 3 mm to about 6 mm; and
[0040] c) the largest dimension of the solid oral dosage form is
about 8 mm to about 15 mm;
[0041] In some embodiments, the solid oral dosage form has a volume
of about 0.24 mL to about 0.56 mL. In other embodiments, the solid
oral dosage form has a volume of about 0.4 mL.
[0042] In some embodiments, the solid oral dosage form has a wall
height of about 3.5 mm to about 5 mm. In another embodiment the
solid oral dosage form has a wall height of about 4 mm.
[0043] In some embodiments, the largest dimension of the solid oral
dosage form is about 11 mm to about 14 mm. In other embodiments,
the largest dimension of the solid oral dosage form is about 11.2
mm.
[0044] In some embodiments, the solid oral dosage form has a volume
of about 0.4 mL, a wall height of about 4 mm, and the largest
dimension of the solid oral dosage form is about 11.2 mm.
[0045] The present disclosure also provides a method of treating
one or more of Parkinson's disease, drug-induced extrapyramidal
reactions, and levodopa-induced dyskinesia in a patient, the method
comprising administering to the patient a solid oral dosage form
comprising of about 193 mg of amantadine free base equivalent,
wherein said solid oral dosage form has one or more of the
following dimensions: [0046] (a) a volume of about 0.1 mL to about
0.5 mL; [0047] (b) a wall height of about 3 mm to about 6 mm; and
[0048] (c) the largest dimension of the solid oral dosage form is
about 8 mm to about 14 mm.
[0049] In some embodiments, the solid oral dosage form has a volume
of about 0.18 mL to about 0.42 mL. In other embodiments, the solid
oral dosage form has a volume of about 0.30 mL.
[0050] In some embodiments, the solid oral dosage form has a wall
height of about 3.5 mm to about 5 mm. In other embodiments, the
solid oral dosage form has a wall height of about 4 mm.
[0051] In some embodiments, the largest dimension of the solid oral
dosage form is about 10 mm to about 13 mm. In other embodiments,
the largest dimension of the solid oral dosage form is about 10.2
mm.
[0052] In some embodiments, the solid oral dosage form has a volume
of about 0.3 mL, a wall height of about 4 mm, and the largest
dimension of the solid oral dosage form is about 10.2 mm.
[0053] The present disclosure also provides a method of treating
one or more of Parkinson's disease, drug-induced extrapyramidal
reactions, and levodopa-induced dyskinesia in a patient, the method
comprising administering to the patient a solid oral dosage form
comprising of about 129 mg of amantadine free base equivalent,
wherein said solid oral dosage form has one or more of the
following dimensions: [0054] (a) a volume of about 0.1 mL to about
0.4 mL; [0055] (b) a wall height of about 3 mm to about 6 mm; and
[0056] (c) the largest dimension of the solid oral dosage form is
about 6 mm to about 10 mm.
[0057] In some embodiments, the solid oral dosage form has a volume
of about 0.12 mL to about 0.28 mL. In other embodiments, the solid
oral dosage form has a volume of about 0.20 mL.
[0058] In some embodiments, the solid oral dosage form has a wall
height of about 3.5 mm to about 5 mm. In other embodiments, the
solid oral dosage for has a wall height of about 4 mm.
[0059] In some embodiments, largest dimension of the solid oral
dosage form is about 8 mm to about 10 mm. In other embodiments, the
largest dimension of the solid oral dosage form is about 8.1
mm.
[0060] In some embodiments, the solid oral dosage form has a volume
of about 0.2 mL, a wall height of about 4 mm, and the largest
dimension of the solid oral dosage form is about 8.1 mm.
[0061] In some embodiments, the pharmaceutical composition
comprises about 50 mg to about 400 mg of amantadine or a
pharmaceutically acceptable salt thereof. In some embodiments, the
amantadine or a pharmaceutically acceptable salt thereof in an
extended release form is from about 70 mg to about 300 mg. In some
embodiments, the amantadine or a pharmaceutically acceptable salt
thereof in an immediate release form is from about 40 mg to about
70 mg.
[0062] In some embodiments, at least about 50% of amantadine or a
pharmaceutically acceptable salt thereof is in an extended release
form. In one embodiment, between about 60% and about 82% of
amantadine or a pharmaceutically acceptable salt thereof is in an
extended release form.
[0063] In some embodiments, the composition is administered once
daily in the morning.
[0064] In some embodiments, the pharmaceutical composition
comprises about 129 mg to about 258 mg of amantadine free base
equivalent.
[0065] In some embodiments, the pharmaceutical composition is a
dosage form comprising 129 mg, 193 mg, or 258 mg of amantadine free
base equivalent.
[0066] In some embodiments, the pharmaceutical composition is a
dosage form comprising about 48 mg of amantadine free base
equivalent, in an immediate release form.
[0067] In some embodiments, the pharmaceutically acceptable salt
thereof is amantadine
[0068] In some embodiments, the pharmaceutical composition is a
dosage form comprising 160 mg, 240 mg, or 320 mg of amantadine
HCl.
[0069] In some embodiments, the dC/dT values of the pharmaceutical
composition of the invention and the immediate release form are
measured in the same pharmacokinetic study.
[0070] In some embodiments, the method comprises: i) administering
to the patient a pharmaceutical composition comprising about 160 mg
of amantadine or a pharmaceutically acceptable salt thereof for at
least one week; and increasing the dose of amantadine or a
pharmaceutically acceptable salt thereof to a maximum daily dose of
about 320 mg. In some embodiments, the dose is increased to about
240 mg of amantadine or a pharmaceutically acceptable salt thereof.
In some embodiments, the dose increase is weekly. In one
embodiment, each of the pharmaceutical compositions comprises an
extended release component comprising amantadine or a
pharmaceutically acceptable salt thereof; and an immediate release
component comprising about 60 mg amantadine or a pharmaceutically
acceptable salt thereof.
[0071] In some embodiments, the method comprises: i) administering
to the patient a pharmaceutical composition comprising about 129 mg
of amantadine free base equivalent for at least one week; and ii)
increasing the dose of amantadine free base equivalent to a maximum
daily dose of about 322 mg. In one embodiment, the maximum daily
dose of about 322 mg comprises a pharmaceutical composition
comprising about 129 mg of amantadine free base equivalent and a
pharmaceutical composition comprising about 193 mg of amantadine
free base equivalent. In some embodiments, the dose is increased to
about 193 mg of amantadine free base equivalent. In some
embodiments, the dose increase is weekly. In one embodiment, each
of the pharmaceutical compositions comprises an extended release
component comprising amantadine or a pharmaceutically acceptable
salt thereof; and an immediate release component comprising about
48 mg amantadine free base equivalent.
[0072] In some embodiments, the method comprises: i) administering
to the patient a pharmaceutical composition comprising about 129 mg
of amantadine free base equivalent for at least one week;
increasing the dose of amantadine by administering to the patient a
pharmaceutical composition comprising about 193 mg of amantadine
free base equivalent. In some embodiments, each of the
pharmaceutical compositions comprises an extended release component
comprising amantadine free base equivalent; and an immediate
release component comprising about 48 mg of amantadine free base
equivalent. In some embodiments, the pharmaceutical composition is
administered once daily in the morning.
[0073] In some embodiments, the method comprises: i) administering
to the patient a pharmaceutical composition consisting essentially
of about 129 mg of amantadine free base equivalent for at least one
week; ii) increasing the dose of amantadine by administering to the
patient a pharmaceutical composition consisting essentially of
about 193 mg of amantadine free base equivalent. In some
embodiments, each of the pharmaceutical compositions consists of an
extended release component consisting essentially of amantadine
free base equivalent and an immediate release component consisting
essentially of about 48 mg of amantadine free base equivalent. In
some embodiments, the pharmaceutical composition is administered
once daily in the morning.
[0074] In some embodiments, the method comprises: i) administering
to the patient a pharmaceutical composition comprising about 129 mg
of amantadine free base equivalent for at least one week; ii)
increasing the dose of amantadine by administering to the patient a
pharmaceutical composition comprising about 193 mg of amantadine
free base equivalent for at least one week; iii) increasing the
dose of amantadine by administering to the patient a pharmaceutical
composition comprising about 258 mg of amantadine free base
equivalent.
[0075] In some embodiments, each of the pharmaceutical compositions
comprises i) an extended release component comprising amantadine
free base equivalent; and ii) an immediate release component
comprising about 48 mg of amantadine free base equivalent. in some
embodiments, the pharmaceutical compositions are administered once
daily in the morning. In some embodiments, the method further
comprises: iv) decreasing the dose of amantadine by administering
to the patient a pharmaceutical composition comprising about 193 mg
of amantadine free base equivalent for at least one week; and v)
decreasing the dose of amantadine by administering to the patient a
pharmaceutical composition comprising about 129 mg of amantadine
free base equivalent for at least one week,
[0076] In some embodiments, the pharmaceutical composition provides
a mean change in amantadine plasma concentration as a function of
time (dC/dT) that is between about 40% and about 70% of the dC/dT
provided by the same quantity of amantadine or a pharmaceutically
acceptable salt thereof in an immediate release form, wherein the
dC/dT values are measured in a single dose human pharmacokinetic
study over the time period between 0 and 4 hours after
administration.
[0077] In some embodiments, the T.sub.max of the pharmaceutical
composition after a single-dose administration is between about 5
and about 12 hours.
[0078] In some embodiments, the median T.sub.max of the
pharmaceutical composition after a single-dose administration is
about 7.5 hours.
[0079] In some embodiments, the mean C.sub.max of the
pharmaceutical composition after a single-dose administration is
between about 540 and about 895 ng/ml.
[0080] In some embodiments, the mean C.sub.max of the
pharmaceutical composition after a single-dose administration is
between about 370 and about 550 ng/ml.
[0081] In some embodiments, the mean C.sub.max of the
pharmaceutical composition after a single-dose administration is
between about 265 and about 390 ng/ml.
[0082] In some embodiments, the mean AUC.sub.0-.infin. of the
pharmaceutical composition after a single-dose administration is
between about 12,000 and about 26,000 ng.h/mL.
[0083] In some embodiments, the mean AUC.sub.0-.infin. of the
pharmaceutical composition after a single-dose administration is
between about 8,000 and about 20,000 ng.h/mL.
[0084] In some embodiments, the mean AUC.sub.0-.infin. of the
pharmaceutical composition after a single-dose administration is
between about 6,000 and about 12,000 ng.h/mL.
[0085] In some embodiments, the mean AUC.sub.0-.infin. of the
pharmaceutical composition after a single-dose administration is
between about 6,900 and about 11,000 ng.h/mL.
[0086] In some embodiments, the mean AUC.sub.0-.infin. of the
pharmaceutical composition after a single-dose administration is
between about 10,000 and about 40,000 ng.h/mL.
[0087] In some embodiments, the pharmaceutical composition has an
in vitro dissolution profile ranging between about 0.1% to about
50% in about 0.5 hour. about 20% to about 80% in about 2.5 hours,
about 40% to about 90% in about 4 hours, and no less than about 85%
in about 8 hours as measured in water using a USP type II (paddle)
dissolution system at 50 rpm, at a temperature of 37.+-.0.5 C.
[0088] In one embodiment, the pharmaceutical composition has an in
vitro dissolution profile ranging between about 28% to about 48% in
about 0.5 hour, about 39% to about 63% in about 2.5 hours, about
61% to about 85% in about 4 hours, and no less than about 85% in
about 8 hours as measured in water using a USP type II (paddle)
dissolution system at 50 rpm, at a temperature of 37.+-.0.5 C.
[0089] In another embodiment, the pharmaceutical composition has an
in vitro dissolution profile ranging between about 15% to about 35%
in about 0.5 hour, about 29% to about 53% in about 2.5 hours, about
53% to about 77% in about 4 hours, and no less than about 85% in
about 8 hours as measured in water using a USP type II (paddle)
dissolution system at 50 rpm, at a temperature of 37.+-.0.5 C.
[0090] In yet another embodiment, the pharmaceutical composition
has an in vitro dissolution profile ranging between about 9% to
about 29% in about 0.5 hour, about 37% to about 62% in about 2.5
hours, about 59% to about 83% in about 4 hours, and no less than
about 85% in about 8 hours as measured in water using a USP type II
(paddle) dissolution system at 50 rpm, at a temperature of
37.+-.0.5 C.
[0091] In some embodiments, the method improves dyskinesia in a
patient with levodopa-induced dyskinesia (LID) as determined by a
reduction in a total Unified Dyskinesia Rating Scale (UdysRS) score
after twelve weeks.
[0092] In some embodiments, the reduction in UdysRS score is
between about -2 and about -7 after twelve weeks, compared to
placebo.
[0093] In some embodiments, the reduction in UdysRS score is about
-5 after twelve weeks, compared to placebo.
[0094] In some embodiments, the reduction in UdysRS score is
between about -9 and about -17 after twelve weeks.
[0095] In some embodiments, the reduction in UdysRS score is about
-13 after twelve weeks.
[0096] In some embodiments, the method increases the number of
awake ON hours without dyskinesia in the patient.
[0097] In some embodiments, the method increases the number of
awake ON hours without dyskinesia in the patient by about 1 to
about 4 hours after twelve weeks.
[0098] In some embodiments, the method increases the number of
awake ON hours without dyskinesia in the patient by about 4 hours
after twelve weeks.
[0099] In some embodiments, the number of awake ON hours without
dyskinesia in the patient is between about 9 and about 14
hours.
[0100] In some embodiments, the methods do not worsen Parkinson's
disease symptoms in the patient.
[0101] In some embodiments, the methods do not worsen drug-induced
extrapyramidal symptoms in the patient.
[0102] In some embodiments, the methods do not worsen
levodopa-induced dyskinesia in the patient.
[0103] In some embodiments, the relative bioavailability of
amantadine or a pharmaceutically acceptable salt thereof is
approximately the same under fed and fasting conditions.
[0104] In some embodiments, the pharmaceutical composition is an
osmotic device.
[0105] In some embodiments, the osmotic device comprises: i) an
extended release component comprising about 70 mg to about 300 mg
of amantadine or a pharmaceutically acceptable salt thereof; and
ii) an immediate release component comprising about 40 to about 70
mg of amantadine or a pharmaceutically acceptable salt thereof. In
one embodiment, the pharmaceutical composition provides a mean
change in amantadine plasma concentration as a function of time
(dC/dT) that is between about 40% and about 70% of the dC/dT
provided by the same quantity of amantadine or a pharmaceutically
acceptable salt thereof in an immediate release form, wherein the
dC/dT values are measured in a single dose human pharmacokinetic
study over the time period between 0 and 4 hours after
administration.
[0106] In some embodiments, the pharmaceutical composition is
administered as a combination with a second agent. In some
embodiments, the second agent further comprises one or more
compounds selected from the group consisting of
aromatic-L-amino-acid decarboxylase inhibitors, dopamine agonists,
COMT (catechol O-methyltransferase) inhibitors, MAO-B (monoamine
oxidase B) inhibitors, anticholinergics, benzodiazepines, SSRIs
(selective serotonin reuptake inhibitors), tricyclic and
tetracyclic antidepressants, nonsteroidal anti-inflammatory agents,
non-narcotic analgesic, narcotic analgesics, ADORA2A (adenosine A2A
receptor) antagonists, anti-epileptic agents, and any combinations
thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0107] FIG. 1 depicts the amantadine plasma concentration-time
(mean) profile following oral administration of one 320-mg
Amantadine HCl ER Tablet under fasting (T1) or fed (T2) condition.
Study III.
[0108] FIG. 2 depicts the mean amantadine plasma concentration-time
profile following oral administration of one 160 mg (Treatment-A).
240 mg (Treatment-B) or 320 mg (Treatment-C) Amantadine HCl ER
Tablet or 160 mg of Amantadine HCl Oral Syrup (Treatment-D) to 23
fasted healthy volunteers, Study II.
[0109] FIG. 3 depicts the amantadine plasma concentration-time
(mean) profile following oral administration of one 320-mg
Amantadine HCl ER Tablet daily (Treatment-A) or 160 mg of
Amantadine HCl Oral Syrup. 50 mg/5 mL twice daily (Treatment-B) for
7 days to fasted healthy volunteers, Study I.
[0110] FIG. 4 depicts the amantadine plasma concentration-time
(mean) profile (semi-logarithmic scale) following oral
administration of one 320-mg Amantadine HCl ER Tablet daily
(Treatment-A) or 160 mg of Amantadine HCl Oral Syrup, 50 mg/5 ml,
twice daily (Treatment-B) for 7 days to fasted healthy volunteers,
Study I.
[0111] FIG. 5 depicts the dissolution profile of Amantadine HCl ER
Tablets, 160 mg in various dissolution media.
[0112] FIG. 6 depicts the dissolution profile of Amantadine HCl ER
Tablets, 240 mg in various dissolution media.
[0113] FIG. 7 depicts the dissolution profile of Amantadine HCl ER
Tablets, 320 mg in various dissolution media.
[0114] FIG. 8 depicts alcohol effect on the dissolution profile of
Amantadine HCl ER 160-mg Tablets in 0.1 N HCl.
[0115] FIG. 9 depicts alcohol effect on the dissolution profile of
Amantadine HCl ER 160-mg Tablets in water.
[0116] FIG. 10 depicts alcohol effect on the dissolution profile of
Amantadine HCl ER 160-mg Tablets (0.1 N HCl media) over two-hour
and eight-hour periods.
[0117] FIG. 11 depicts alcohol effect on the dissolution profile of
Amantadine HCl ER 160-mg Tablets in water media over two-hour and
eight-hour periods.
[0118] FIG. 12 depicts alcohol effect on the dissolution profile of
Amantadine HCl ER 240-mg Tablets in 0.1 N HCl.
[0119] FIG. 13 depicts alcohol effect on the dissolution profile of
Amantadine HCl ER 240-mg Tablets in water.
[0120] FIG. 14 depicts alcohol effect on the dissolution profile of
Amantadine HCl ER 320-mg Tablets in 0.1 N HCl.
[0121] FIG. 15 depicts alcohol effect on the dissolution profile of
Amantadine HCl ER 320-mg Tablets in water.
[0122] FIG. 16 depicts the individual and mean amantadine plasma
concentration 24 hours after dose 5, 6 and 7 of Amantadine HCl ER
Tablets, 320 mg. Study I.
[0123] FIG. 17 depicts the simulated amantadine plasma
concentration-time profiles over a period of 24 hours following
administration of 200 mg amantadine in an immediate release
formulation twice a day (TMT 3) and 400 mg amantadine ((160 mg
tablet+240 tablet administered simultaneously) in a sustained
release formulation once a day (TMT 10).
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0124] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this disclosure belongs. In case
of conflict, the present application including the definitions will
control. Unless otherwise required by context, singular terms shall
include pluralities and plural terms shall include the singular.
All publications, patents and other references mentioned herein are
incorporated by reference in their entireties for all purposes as
if each individual publication or patent application were
specifically and individually indicated to be incorporated by
reference.
[0125] Although methods and materials similar or equivalent to
those described herein can be used in practice or testing of the
present disclosure, suitable methods and materials are described
below. The materials, methods and examples are illustrative only
and are not intended to be limiting. Other features and advantages
of the disclosure will be apparent from the detailed description
and from the claims.
[0126] In order to further define this disclosure, the following
terms and definitions are provided.
[0127] The singular forms "a," "an" and "the" include plural
referents unless the context clearly dictates otherwise. The terms
"a" (or "an"), as well as the terms "one or more," and "at least
one" can be used interchangeably herein. In certain aspects, the
term "a" or "an" means "single." In other aspects, the term "a" or
"an" includes "two or more" or "multiple."
[0128] The term "about" is used herein to mean approximately,
roughly, around, or in the regions of. When the term "about" is
used in conjunction with a numerical range, it modifies that range
by extending the boundaries above and below the numerical values
set forth. In general, the term "about" is used herein to modify a
numerical value above and below the stated value by a variance of
10 percent, up or down (higher or lower).
[0129] The term "and/or" where used herein is to be taken as
specific disclosure of each of the two specified features or
components with or without the other. Thus, the term "and/or" as
used in a phrase such as "A and/or B" herein is intended to include
"A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the
term "and/or" as used in a phrase such as "A, B, and/or C" is
intended to encompass each of the following aspects: A, B, and C;
A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A
(alone); B (alone); and C (alone).
[0130] The term "immediate release" or "IR" as used herein means a
release of an active agent to an environment over a period of
seconds to no more than about 30 minutes once release has begun and
release begins within a second to no more than about 15 minutes
after administration.
[0131] The term "rapid release" as used herein means a release of
an active agent to an environment over a period of 1 minute to one
hour once release has begun and release can begin within a few
minutes after administration or after expiration of a delay period
(lag time) after administration.
[0132] The term "controlled release" as used herein means a release
of an active agent to an environment over a period of about eight
hours up to about 12 hours, 16 hours, 18 hours, 20 hours, a day, or
more than a day. A controlled release can begin within a few
minutes after administration or after expiration of a delay period
(lag time) after administration.
[0133] The term "sustained release" as used herein means a
controlled release of an active agent to maintain a constant drug
level in the blood or target tissue of a subject to which the
device is administered.
[0134] The term "extended release" or "ER" as used herein means a
controlled release of an active agent from a dosage form to an
environment over an extended period of time. As used herein, the
term "extended release" profile assumes the definition as widely
recognized in the art of pharmaceutical sciences. An extended
release dosage form will release drug at substantially constant
rate over an extended period of time or a substantially constant
amount of drug will be released incrementally over an extended
period of time. The term "extended release", as regards to drug
release, includes the terms "prolonged release", "sustained
release", or "slow release", as these terms are used in the
pharmaceutical sciences.
[0135] The term "amantadine" as used herein refers to the free base
or a pharmaceutically acceptable salt form of amantadine.
[0136] The term "free base" as used herein includes, but is not
limited to, the unprotonated form of a therapeutic agent, molecule,
or compound. Additionally, "free base" includes, but is not limited
to, the neutral form of a molecule or compound.
[0137] The term "free base equivalent" as used herein refers to the
salt form of a therapeutic agent, molecule, or compound that has
the same molar quantity as its free base. For example, 60 mg
amantadine HCl salt is 48 mg amantadine free base equivalent. 160
mg amantadine HCl salt is 129 mg amantadine free base equivalent.
240 mg amantadine HCl salt is 193 mg amantadine free base
equivalent. 320 mg amantadine HCl salt is 258 mg amantadine free
base equivalent. All numbers are rounded up to the nearest
integer.
[0138] The term "unitary core" as used herein means the core of an
osmotic device that is not divided into two or more layers or
laminas. The core is considered to be the composition enclosed
within the semipermeable membrane of the osmotic device.
[0139] The term "pharmaceutically acceptable" as used herein refers
to those compounds, materials, compositions, and/or dosage forms
which are, within the scope of sound medical judgment, suitable for
use in contact with the tissues of human beings and animals without
excessive toxicity, irritation, allergic response, or other problem
or complication, commensurate with a reasonable benefit/risk
ratio.
[0140] The term "effective amount" or "pharmaceutically effective
amount" as used herein refers to the amount or quantity of a drug
or pharmaceutically active substance which is sufficient to elicit
the required or desired therapeutic response, or in other words,
the amount which is sufficient to elicit an appreciable biological
response when administered to a patient.
[0141] The term "unit dosage form" or "unit close composition" as
used. herein refers to a device containing a quantity of the
therapeutic compound, said quantity being such that one or more
predetermined units may be provided as a single therapeutic
administration.
[0142] The term "C.sub.max" as used herein refers to the maximum
plasma concentration of a drug after it is administered to a
patient.
[0143] The term "T.sub.max" as used herein refers to the time
required to reach the maximal plasma concentration ("C.sub.max")
after administration of a drug.
[0144] The term "AUC" as used herein refers to the area under the
curve of a plot of plasma concentration versus time following
administration of a drug.
[0145] The term "AUC.sub.0-t" as used herein refers to the area
under the drug concentration-time curve from time zero to the time
of the last measurable concentration (C.sub.t).
[0146] The term "AUC.sub.0-.infin." as used herein refers to the
area under the drug concentration-time curve from time zero to
infinity.
[0147] The term "dC/dT" as used herein refers to the change of
plasma concentration of a drug over a prescribed time.
[0148] The term "steady state" as used herein means that the amount
of the drug reaching the system is approximately the same as the
amount of the drug leaving the system. Thus, at "steady-state," the
patient's body eliminates the drug at approximately the same rate
that the drug becomes available to the patient's system through
absorption into the blood stream.
[0149] The term "LOCF" as used herein refers to last observation
carried forward.
[0150] The term "treating" or "treatment" as used herein refers to
the administration of a composition to a subject for therapeutic
purposes.
[0151] The term "UDysRS" as used herein refers to the Unified
Dyskinesia Ratings Scale.
[0152] The term "awake ON hours" or "awake `ON` hours", as used
herein, refers to time in which the medication has therapeutic
benefits related to mobility, slowness and/or rigidity.
[0153] The term "awake OFF hours" or "awake `OFF` hours" as used
herein refers to time when a medication's therapeutic effect has
diminished or stopped and no longer provides a benefit related to
mobility, slowness and/or stiffness.
[0154] The term "mean" refers to an average value in a patient
population. For example, a "mean Cmax" refers to an average of the
maximum plasma concentrations of a drug in a patient
population.
[0155] The term "adult" refers to a person 18 years of age or
older.
[0156] The term "wall height" refers to the height of a
pharmaceutical tablet at its outer edge.
[0157] The term "largest dimension" refers to the length of the
longest straight line that can be drawn within an object from any
point on the edge of the object, to another point on the edge of
the object . By way of example, the largest dimension of a circle
is its diameter; the largest dimension of a capsule- or oval-shaped
object (also known as an ellipse) is its major axis (also known as
the largest diameter); the largest dimension of a square or a
rectangle is a line drawn between the opposite corners of the
square or the rectangle; etc.
[0158] The term "volume" refers to the amount of space occupied by
a three-dimensional object.
Methods of Treatment
[0159] The present invention relates to a method of treating
Parkinson's disease, comprising administering to the patient a
pharmaceutical composition comprising 100 mg to 400 mg of
amantadine or a pharmaceutically acceptable salt thereof. In some
embodiments, the method comprises treating a patient with
idiopathic Parkinson's disease, symptomatic parkinsonism,
parkinsonism in association with cerebral arteriosclerosis, or any
combination thereof.
[0160] The present invention also relates to a method of treating
drug-induced extrapyramidal reactions in a patient, comprising
administering to the patient a pharmaceutical composition
comprising amantadine, or a pharmaceutically acceptable salt
thereof, in an extended release form, and amantadine, or a
pharmaceutically acceptable salt thereof, in an immediate release
form.
[0161] The drug-induced extrapyramidal reactions may be caused by
the previous or concomitant administration of drugs such as one or
more antipsychotics, antidepressants, or other drugs to treat PD or
symptoms of PD.
[0162] The present invention also relates to a method of treating
levodopa-induced dyskinesia in a patient, comprising administering
to the patient a pharmaceutical composition comprising amantadine,
or a pharmaceutically acceptable salt thereof, in an extended
release form, and amantadine, or a pharmaceutically acceptable salt
thereof, in an immediate release form.
[0163] The present invention also relates to a method of treating
one or more of Parkinson's disease, drug-induced extrapyramidal
reactions, and levodopa-induced dyskinesia in a patient, comprising
administering to the patient a pharmaceutical composition
comprising amantadine, or a pharmaceutically acceptable salt
thereof, in an extended release form, and amantadine, or a
pharmaceutically acceptable salt thereof, in an immediate release
form.
[0164] In some embodiments, the pharmaceutical composition is
administered daily or once daily in the morning. In some
embodiments, the pharmaceutical composition is administered daily
or once daily in the afternoon. In some embodiments, the
pharmaceutical composition is administered daily or once daily in
the evening. In one embodiment, the pharmaceutical composition is
administered more than 4 hours before bedtime.
[0165] In some embodiments, the patient is an adult.
[0166] In some embodiments of the invention, a pharmaceutically
acceptable salt of amantadine is an inorganic acid salt. In some
embodiments, the inorganic salt of amantadine is a mineral acid
salt. In some embodiments, the inorganic salt of amantadine is a
hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a sulfate,
a bisulfate, or a phosphate salt of amantadine. In one embodiment,
the amantadine salt is a hydrochloride salt.
Dosing
[0167] In some embodiments, the amount of amantadine administered
per day is from about 50 mg to about 1000 mg, from about 50 mg to
about 900 mg, from about 50 mg to about 800 mg, from about 50 mg to
about 700 mg, from about 50 mg to about 600 mg, from about 50 mg to
about 500 mg, from about 50 mg to about 400 mg, from about 50 mg to
about 300 mg, from about 50 mg to about 200 mg, or from about 50 mg
to about 100 mg.
[0168] In some embodiments, the amount of amantadine administered
per day is from about 100 mg to about 1000 mg, from about 100 mg to
about 900 mg. from about 100 mg to about 800 mg, from about 100 mg
to about 700 mg. from about 100 mg to about 600 mg, from about 100
mg to about 500 mg, from about 100 mg to about 400 mg, from about
100 mg to about 300 mg, or from about 100 mg to about 200 mg. In
one embodiment, the amount of amantadine administered per day is
from about 100 mg to about 400 mg. In another embodiment, the
amount of amantadine administered per day is from about 160 mg to
about 320 mg.
[0169] In some embodiments, the amount of amantadine free base
equivalent administered per day is from about 100 mg to about 1000
mg, from about 100 mg to about 900 mg, from about 100 mg to about
800 mg, from about 100 mg to about 700 mg, from about 100 mg to
about 600 mg, from about 100 mg to about 500 mg, from about 100 mg
to about 400 mg, from about 100 mg to about 300 mg, or from about
100 mg to about 200 mg. In one embodiment, the amount of
amantadine, free base equivalent administered per day is from about
120 mg to about 300 mg. In another embodiment, the amount of
amantadine free base equivalent administered per day is from about
130 mg to about 250 mg. In some embodiments, the amount of
amantadine free base equivalent administered per day is from about
129 mg to about 258 mg. In some embodiments, the amount of
amantadine free base equivalent administered per day is from. 129
mg to 258 mg.
[0170] In some embodiments, the amount of amantadine administered
per day is from about 100 mg to about 150 mg, from about 150 mg to
about 200 mg, from about 200 mg to about 250 mg, from about 250 mg
to about 300 mg, from about 300 mg to about 350 mg, from about 350
mg to about 400 mg. In one embodiment, the amount of amantadine
administered per day is about 160 mg. In another embodiment, the
amount of amantadine administered per day is about 240 mg. In
another embodiment, the amount of amantadine administered per day
is about 320 mg. In another embodiment, the amount of amantadine
administered per day is 160 mg. In another embodiment, the amount
of amantadine administered per day is 240 mg. In yet another
embodiment, the amount of amantadine administered per day is 320
mg. In one embodiment, the amount of amantadine free base
equivalent administered is 129 mg or about 129 mg. In one
embodiment, the amount of amantadine free base equivalent
administered per day is 129 mg or about 129 mg. In another
embodiment, the amount of amantadine free base equivalent
administered is 193 mg or about 193 mg. In another embodiment, the
amount of amantadine free base equivalent administered per day is
193 mg or about 193 mg. In yet another embodiment, the amount of
amantadine free base equivalent administered is 258 mg or about 258
mg. In yet another embodiment, the amount of amantadine free base
equivalent administered per day is 258 mg or about 258 mg.
[0171] In some embodiments, the pharmaceutical composition
comprises an. extended release component comprising amantadine or a
pharmaceutically acceptable salt thereof and an immediate release
component comprising amantadine or a pharmaceutically acceptable
salt thereof.
[0172] In some embodiments, the amount of amantadine in an extended
release form administered per day is from about 50 mg to about 500
mg, from about 50 mg to about 400 mg, from about 50 mg to about 300
mg, from about 50 mg to about 200 mg, or from about 50 mg to about
100 mg.
[0173] In some embodiments, the amount of amantadine in the
extended release form administered per day is from about 50 mg to
about 500 mg, from about 50 mg to about 400 mg, from about 50 mg to
about 300 mg, or from about 50 mg to about 200 mg. In one
embodiment, the amount of amantadine in the extended release form
administered per day is from about 70 mg to about 300 mg.
[0174] In some embodiments, the amount of amantadine in the
extended release form administered per day is from about 50 mg to
about 100 mg, from about 100 mg to about 150 mg, from about 150 mg
to about 200 mg, from about 200 mg to about 250 mg, or from about
250 mg to about 300 mg. In one embodiment, the amount of amantadine
in the extended release form administered per day is about 100 mg.
In another embodiment, the amount of amantadine in the extended
release form administered per day is about 180 mg, In another
embodiment, the amount of amantadine in the extended release form
administered per day is about 260 mg. In one embodiment, the amount
of amantadine in the extended release form administered per day is
about 81 mg of amantadine free base equivalent. In another
embodiment, the amount of amantadine in the extended release form
administered per day is about 145 mg of amantadine free base
equivalent. In another embodiment, the amount of amantadine in the
extended release form administered form per day is about 210 mg of
amantadine free base equivalent.
[0175] In some embodiments, the amount of amantadine in the
immediate release form administered per day is from about 20 mg to
about 100 mg, from about 20 mg to about 90 mg, from about 20 mg to
about 80 mg, from about 20 mg to about 70 mg, from about 20 mg to
about 60 mg, from about 20 mg to about 50 mg, from about 20 mg to
about 40 mg, or from about 20 mg to about 30 mg.
[0176] In some embodiments, the amount of amantadine in the
immediate release form administered per day is from about 40 mg to
about 100 mg, from about 40 mg to about 90 mg, from about 40 mg to
about 80 mg, from about 40 mg to about 70 mg, or from about 40 mg
to about 60 mg. In one embodiment, the amount of amantadine in the
immediate release form administered per day is from about 40 mg to
about 70 mg.
[0177] In some embodiments, the amount of amantadine in the
immediate release form administered per day is from about 10 mg to
about 20 mg, from about 20 mg to about 30 mg, from about 30 mg to
about 40 mg, from about 40 mg to about 50 mg, from about 50 mg to
about 60 mg, from about 60 mg to about 70 mg, from about 70 mg to
about 80 mg, from about 80 mg to about 90 mg, or from about 90 mg
to about 100 mg. In one embodiment, the amount of amantadine in the
immediate release form administered per day is about 60 mg. In one
embodiment, the amount of amantadine in the immediate release form
administered per clay is about 48 mg of amantadine free base
equivalent.
[0178] In some embodiments, the amantadine administered is
amantadine HCl. in one embodiment, the amount of amantadine HCl
administered per day is about 160 mg, wherein the 160 mg amantadine
HCl comprises about 100 mg amantadine HCl in the extended release
form and about 60 mg amantadine HCl in the immediate release form.
In another embodiment, the amount of amantadine HCl administered
per day is about 240 mg, wherein the 240 mg amantadine HCl
comprises about 180 mg amantadine HCl in the extended release form
and about 60 mg amantadine HCl in the immediate release form. In
another embodiment, the amount of amantadine HCl administered per
day is about 320 mg, wherein the about 320 mg amantadine HCl
comprises about 260 mg amantadine HCl in the extended release form
and about 60 mg amantadine HCl in the immediate release form.
[0179] In some embodiments, the pharmaceutical composition is a
dosage form comprising from about 100 mg to about 300 mg of
amantadine free base equivalent. In one embodiment, the
pharmaceutical composition is a dosage form comprising about 129 mg
of amantadine free base equivalent (which equals about 160 mg of
amantadine HCl). In another embodiment, the pharmaceutical
composition is a dosage form comprising about 193 mg of amantadine
free base equivalent (which equals about 240 mg of amantadine HCl).
In one embodiment, the pharmaceutical composition is a dosage form
comprising about 258 mg of amantadine free base equivalent (which
equals about 320 mg of amantadine HCl).
[0180] In one embodiment, the pharmaceutical composition is a
dosage form comprising about 81 mg of amantadine free base
equivalent in extended release form and about 48 mg of amantadine
free base equivalent in immediate release form. In another
embodiment, the pharmaceutical composition is a dosage form
comprising about 145 mg of amantadine free base equivalent in
extended release form and about 48 mg of amantadine free base
equivalent in immediate release form. In yet another embodiment,
the pharmaceutical composition is a dosage form comprising about
210 mg of amantadine free base equivalent in extended release form
and about 48 mg of amantadine free base equivalent in immediate
release form.
[0181] In some embodiments, the pharmaceutical composition is a
dosage form comprising about 258 mg of amantadine free base
equivalent and is in the form of a tablet. In some other
embodiments, the pharmaceutical compositions is a dosage form in
the form of a capsule. In some embodiments, the largest dimension
of the tablet or a capsule is about 8 mm to about 15 mm. In other
embodiments, the largest dimension of the tablet or a capsule is
about 9 mm to about 14 mm. In other embodiments, the largest
dimension of the tablet or a capsule is about 10 mm to about 13 mm.
In other embodiments, the largest dimension of the tablet or a
capsule is about 10 mm to about 12 mm. In other embodiments, the
largest dimension of the tablet or a capsule is about 10 mm to
about 14 mm. In other embodiments, the largest dimension of the
tablet or a capsule is about 11 mm to about 14 mm. In other
embodiments, the largest dimension of the tablet or a capsule is
about 11 mm to about 13 mm. In other embodiments, the largest
dimension of the tablet or a capsule is about 11 mm to about 12 mm.
In other embodiments, the largest dimension of the tablet or a
capsule is about 11 mm. In other embodiments, the largest dimension
of the tablet or a capsule is about 11.2 mm. In other embodiments,
the largest dimension of the tablet or a capsule is about 11.5 mm.
In other embodiments, the largest dimension of the tablet or a
capsule is about 12 mm. In other embodiments, the largest dimension
of the tablet or a capsule is about 12.5 mm. In other embodiments,
the largest dimension of the tablet or a capsule is about 13 mm. In
other embodiments, the largest dimension of the tablet or a capsule
is about 13.4 mm. in other embodiments, the largest dimension of
the tablet or a capsule is about 13.5 mm. In other embodiments, the
largest dimension of the tablet is about 14 mm.
[0182] In some embodiments, the pharmaceutical composition is a
dosage form comprising about 258 mg of amantadine free base
equivalent and is in the form of a tablet or a capsule, wherein the
tablet or a capsule has a volume of about 0.2 mL. to about 0.6 mL.
In other embodiments, the tablet or a capsule has a volume of about
0.24 mL to about 0.56 mL. In other embodiments, the tablet or a
capsule has a volume of about 0.3 mL to about 0.5 mL. In other
embodiments, the tablet or a capsule has a volume of about 0.3 mL
to about 0.6 mL. In other embodiments, the tablet or a capsule has
a volume of about 0.4 mL to about 0.6 mL. In other embodiments, the
tablet or a capsule has a volume of about 0.4 mL to about 0.5 mL.
In other embodiments, the tablet or a capsule has a volume of about
0.4 mL. In other embodiments, the tablet or a capsule has a volume
of about 0.45 mL. In other embodiments, the tablet or a capsule has
a volume of about 0.5 mL. In other embodiments, the table has a
volume of about 0.55 mL. In other embodiments, the tablet or a
capsule has a volume of about 0.56 mL. In other embodiments, the
tablet or a capsule has a volume of about 0.6 mL.
[0183] In some embodiments, the pharmaceutical composition is a
dosage form comprising about 258 mg of amantadine free base
equivalent and is in the form of a tablet, wherein the tablet has a
wall height of about 3 min to about 6 mm. In other embodiments, the
tablet has a wall height of about 3.5 mm to about 5 mm. In other
embodiments, the tablet has a wall height of about 4 mm to about 6
mm. In other embodiments, the tablet has a wall height of about 4
mm to about 5 mm. In other embodiments, the tablet has a wall
height of about 4 mm. In other embodiments, the tablet has a wall
height of about 4.5 mm. In other embodiments, the tablet has wall
height of about 4.6 mm. In other embodiments, the tablet has a wall
height of about 5 mm. In other embodiments, the tablet has a wall
height of about 5.5 mm. In other embodiments, the tablet has a wall
height of about 5.6 mm. In other embodiments, the tablet or a
capsule has a wall height of about 6 mm.
[0184] In some embodiments, the pharmaceutical composition is a
dosage form comprising about 193 mg of amantadine free base
equivalent and is in the form of a tablet. In some other
embodiments, the pharmaceutical compositions is a dosage form in
the form of a capsule. In some embodiments, the largest dimension
of the tablet or a capsule is about 8 mm to about 14 mm. in other
embodiments, the largest dimension of the tablet or a capsule is
about 9 mm to about 13 mm. In other embodiments, the largest
dimension of the tablet or a capsule is about 10 mm to about 13 mm.
In other embodiments, the largest dimension of the tablet or a
capsule is about 10 mm to about 12 mm. In other embodiments, the
largest dimension of the tablet or a capsule is about 10 mm to
about 11 mm. In other embodiments, the largest dimension of the
tablet or a capsule is about 10 mm to about 14 mm. In other
embodiments, the largest dimension of the tablet or a capsule is
about 10 mm. In other embodiments, the largest dimension of the
tablet or a capsule is about 10.2 mm. In other embodiments, the
largest dimension of the tablet or a capsule is about 10.5 mm. In
other embodiments, the largest dimension of the tablet or a capsule
is about 11 mm. In other embodiments, the largest dimension of the
tablet or a capsule is about 11.5 mm. In other embodiments, the
largest dimension of the tablet or a capsule is about 12 mm. In
other embodiments, the largest dimension of the tablet or a capsule
is about 12.2 mm. In other embodiments, the largest dimension of
the tablet or a capsule is about 12.5 mm. In other embodiments, the
largest dimension of the tablet or a capsule is about 13 mm. In
other embodiments, the largest dimension of the tablet or a capsule
is about 13.5 mm. In other embodiments, the largest dimension of
the tablet or a capsule is about 14 mm.
[0185] In some embodiments, the pharmaceutical composition is a
dosage form comprising about 193 mg of amantadine free base
equivalent and is in the form of a tablet or a capsule, wherein the
tablet or a capsule has a volume of about 0.1 mL to about 0.5 mL.
In other embodiments, the tablet or a capsule has a volume of about
0.18 mL to about 0.42 mL. In other embodiments, the tablet or a
capsule has a volume of about 0.2 mL to about 0.4 mL. In other
embodiments, the tablet or a capsule has a volume of about 0.3 mL
to about 0.5 mL. In other embodiments, the tablet or a capsule has
a volume of about 0.3 mL to about 0.4 mL. In other embodiments, the
tablet or a capsule has a volume of about 0.3 mL. In other
embodiments, the tablet or a capsule has a volume of about 0.35 mL.
In other embodiments, the tablet or a capsule has a volume of about
0.4 mL. In other embodiments, the tablet or a capsule has a volume
of about 0.42 mL. In other embodiments, the tablet or a capsule has
a volume of about 0.45 mL. In other embodiments, the tablet or a
capsule has a volume of about 0.5 mL.
[0186] In some embodiments, the pharmaceutical composition is a
dosage form comprising about 193 mg of amantadine free base
equivalent and is in the form of a tablet that has a wall height of
about 3 mm to about 6 mm. In other embodiments, the tablet has a
wall height of about 3.5 mm to about 5 mm. In other embodiments,
the tablet has a wall height of about 4 mm to about 6 mm. In other
embodiments, the tablet has a wall height of about 4 mm to about 5
mm. In other embodiments, the tablet has a wall height of about 4
mm. In other embodiments, the tablet has a wall height of about 4.5
mm, In other embodiments, the tablet has a wall height of about 4.6
mm. In other embodiments, the tablet has a wall height of about 5
mm. In other embodiments, the tablet has a wall height of about 5.6
mm. In other embodiments, the tablet has a wall height of about 6
mm.
[0187] In some embodiments, the pharmaceutical composition is a
dosage form comprising about 129 mg of amantadine free base
equivalent and is in the form of a tablet. In some other
embodiments, the pharmaceutical compositions is a dosage form in
the form of a capsule, in some embodiments, the largest dimension
of the tablet or a capsule is about 6 mm to about 10 mm. In other
embodiments, the largest dimension of the tablet or a capsule is
about 7 mm to about 9 mm. In other embodiments, the largest
dimension of the tablet or a capsule is about 8 to about 10 mm. In
other embodiments, the largest dimension of the tablet or a capsule
is about 8 mm to about 9 mm. In other embodiments, the largest
dimension of the tablet or a capsule is about 8.1 mm. In other
embodiments, the largest dimension of the tablet or a capsule is
about 8 mm. In other embodiments, the largest dimension of the
tablet or a capsule is about 8.5 mm, In other embodiments, the
largest dimension of the tablet or a capsule is about 9 mm. In
other embodiments, the largest dimension of the tablet or a capsule
is about 9.5 mm. In other embodiments, the largest dimension of the
tablet or a capsule is about 9.72 mm. In other embodiments, the
largest dimension of the tablet or a capsule is about 10 mm.
[0188] In some embodiments, the pharmaceutical composition is a
dosage form comprising about 129 mg of amantadine free base
equivalent and is in the form of a tablet or a capsule, wherein the
tablet or a capsule has a volume of about 0.1 mL to about 0.4 mL.
In other embodiments, the tablet or a capsule has a volume of about
0.12 mL to about 0.28 mL. In other embodiments, the tablet or a
capsule has a volume of about 0.2 mL to about 0.3 mL. In other
embodiments, the tablet or a capsule has a volume of about 0.2 mL
to about 0.4 mL. In other embodiments, the tablet or a capsule has
a volume of about 0.2 mL. In other embodiments, the tablet or a
capsule has a volume of about 0.25 mL. In other embodiments, the
tablet or a capsule has a volume of about 0.28 mL. In other
embodiments, the tablet or a capsule has a volume of about 0.3 mL.
In other embodiments, the tablet or a capsule has a volume of about
0.35 mL. In other embodiments, the tablet or a capsule has a volume
of about 0.4 mL.
[0189] In some embodiments, the pharmaceutical composition is a
dosage form comprising about 129 mg of amantadine free base
equivalent and is in the form of a tablet that has a wall height of
about 3 mm to about 6 mm. In other embodiments, the tablet has a
wall height of about 3.5 mm to about 5 mm. in other embodiments,
the tablet has a wall height of about 4 mm to about 6 mm. In other
embodiments, the tablet has a wall height of about 4 mm to about 5
mm. In other embodiments, the tablet has a wall height of about 4
mm. In other embodiments, the tablet has a wall height of about 4.5
mm. In other embodiments, the tablet has a wall height of about 4.6
mm. In other embodiments, the tablet has a wall height of about 5
mm. In other embodiments, the tablet has a wall height of about 5.6
mm. In other embodiments, the tablet has a wall height of about 6
mm.
Dosing Frequency and Dose Escalation
[0190] According to the present invention, a subject (e.g., human)
having or at risk of having PD, is administered any of the
pharmaceutical compositions described herein. In addition,
according to the present invention, a subject (e.g., human) having
or at risk of having a drug-induced extrapyramidal reaction, is
administered any of the pharmaceutical compositions described
herein.
[0191] In addition, according to the present invention, a subject
(e.g., human) having or at risk of having levodopa-induced
dyskinesia, is administered any of the pharmaceutical compositions
described herein.
[0192] In some embodiments, the pharmaceutical compositions are
administered at a constant, therapeutically-effective dose from the
onset of therapy. For example, a pharmaceutical composition
containing an extended release component and an immediate release
component of amantadine may be administered three times per day,
twice per day, or once per day in a unit dose comprising a total
daily amantadine dose of about 50 mg, about 100 mg, about 200 mg,
about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700
mg. or about 800 mg. In one embodiment, the pharmaceutical
composition is administered once daily. In one embodiment, the
pharmaceutical composition is administered in the morning. In one
embodiment, the pharmaceutical composition is administered in the
afternoon. In one embodiment, the pharmaceutical composition is
administered in the evening. In one embodiment, the pharmaceutical
composition is administered more than 4 hours before bedtime. In
some embodiments, a pharmaceutical composition containing an
extended release component and an immediate release component of
amantadine HCl may be administered twice per day or once per day in
a unit dose comprising a total daily amantadine dose, or
pharmaceutically acceptable salt thereof, of about 160 mg, about
240 mg, or about 320 mg.
[0193] In some embodiments, the pharmaceutical compositions are
administered in a dose-escalating fashion. In some embodiments, the
method of treatment comprises a Titration Period (the initial
dose), a Maintenance Period, and/or a Taper Period.
[0194] In some embodiments, the Titration Period is in weekly
intervals, from about one week to about four weeks, from about one
week to about three weeks, from about one week to about two weeks,
from about two weeks to about four weeks, from about two weeks to
about three weeks, or from about three weeks to about four weeks.
In some embodiments, the Titration Period is about one week, about
two weeks, about three weeks, or about four weeks. In one
embodiment, the Titration Period is about one week. In another
embodiment, the Titration Period is about two weeks. In one
embodiment, the Titration Period is one week. In another
embodiment, the Titration Period is two weeks. In one embodiment,
the patient is observed for the occurrence of hallucinations
throughout treatment, especially at initiation and after dose
increases. In some embodiments, the treatment should not be
discontinued abruptly. The dose should be reduced gradually from
higher doses to 129 mg daily for 1 to 2 weeks before
discontinuing.
[0195] In some embodiments, the amount of amantadine administered
per day is from about 50 mg to about 500 mg, from about 50 mg to
about 400 mg, from about 50 mg to about 300 mg, or from about 50 mg
to about 200 mg during the Titration Period. In one embodiment, the
amount of amantadine administered per day is about 160 mg, or about
240 mg during the Titration Period. In another embodiment, the
amount of amantadine administered is about 160 mg per day for one
week, and then about 240 mg per day for one week, during the
Titration Period. In one embodiment, the amount of amantadine free
base equivalent administered per day is about 129 mg, or about 193
mg during the Titration Period. In another embodiment, the amount
of amantadine administered is about 129 mg per day for one week,
and then about 193 mg per day for one week, during the Titration
Period, In one embodiment, the pharmaceutical composition is
administered in the morning. In one embodiment, the pharmaceutical
composition is administered in the afternoon. In one embodiment,
the pharmaceutical composition is administered in the evening. In
one embodiment, the pharmaceutical composition is administered more
than 4 hours before bedtime.
[0196] In some embodiments, the Maintenance Period is from about 10
weeks to about 100 weeks, from about 10 weeks to about 70 weeks,
from about 10 weeks to about 50 weeks, from about 10 weeks to about
30 weeks, from about 10 weeks to about 25 weeks, front about 10
weeks to about 20 weeks. In some embodiments, the Maintenance
Period is at least 10 weeks. In some embodiments, the Maintenance
Period is at least more than 10 weeks. In some embodiments, the
Maintenance Period is at least 30 weeks, In one embodiment, the
Maintenance Period is about 12 weeks. In another embodiment, the
Maintenance Period is about 22 weeks.
[0197] In some embodiments, the amount of amantadine administered
per day is from about 50 mg to about 500 mg, from about 50 mg to
about 400 mg, from about 50 mg to about 300 mg, or from about 50 mg
to about 200 mg during the Maintenance Period. In one embodiment,
the amount of amantadine administered per day is about 160 mg,
about 240 mg, or about 320 mg during the Maintenance Period. In
another embodiment, the amount of amantadine free base equivalent
administered per day is about 129 mg, about 193 mg, or about 258 mg
during the Maintenance Period.
[0198] In some embodiments, the Taper Period is from about one week
to about four weeks, from about one week to about three weeks, from
about one week to about two weeks, from about two weeks to about
four weeks, from about two weeks to about three weeks, or from
about three weeks to about four weeks. In some embodiments, the
Taper Period is about one week, about two weeks, about three weeks,
or about four weeks. In one embodiment, the Taper Period is about
one week. In another embodiment, the Taper Period is about two
weeks.
[0199] In some embodiments, the amount of amantadine administered
per day is from about 20 mg to about 300 mg, from about 20 mg to
about 250 mg, from about 20 mg to about 200 mg, or from about 20 mg
to about 100 mg during the Taper Period. In one embodiment, the
amount of amantadine administered per day is about 160 mg, or about
240 mg during the Taper Period. In another embodiment, the amount
of amantadine administered is about 240 mg per day for one week,
and then about 160 mg per day for one week, during the Taper
Period. In one embodiment, the amount of amantadine free base
equivalent administered per day is about 129 mg, or about 193 mg
during the Taper Period. In another embodiment, the amount of
amantadine free base equivalent administered is about 193 mg per
day for one week, and then about 129 mg per day for one week,
during the Taper Period. In one embodiment, the pharmaceutical
composition is administered in the morning. In one embodiment, the
pharmaceutical composition is administered in the afternoon. In one
embodiment, the pharmaceutical composition is administered in the
evening. In one embodiment, the pharmaceutical composition is
administered more than 4 hours before bedtime.
Pharmaceutical Compositions
[0200] Another aspect of the present disclosure relates to a
pharmaceutical composition comprising amantadine. In some
embodiments, the pharmaceutical composition is an oral dosage form.
The present disclosure is not limited to a particular oral dosage
form, and any dosage form capable of delivering amantadine to a
patients is suitable for the present invention, so long as the
dosage form achieves pharmacokinetic and therapeutic effects
described in the present disclosure. Oral dosage forms are
recognized by those skilled in the art to include, but are not
limited to, liquid formulations, tablets, capsules, and gelcaps. In
one embodiment, the pharmaceutical composition is a tablet. In some
embodiments, the tablets of the invention can be round, biconvex,
and white, green or blue coated tablets.
[0201] In some embodiments, the present disclosure provides a
pharmaceutical composition comprising about 50 mg to about 400 mg
of amantadine or a pharmaceutically acceptable salt thereof. In
some embodiments, the pharmaceutical composition is suitable for
oral administration.
[0202] In some embodiments, the pharmaceutical composition
comprises an adsorbent, antioxidant, buffering agent, colorant,
flavorant, sweetening agent, antiadherent, binder, diluent, direct
compression excipient, disintegrant, glidant, lubricant, opaquant
and/or polishing agent.
[0203] As used herein, the term "adsorbent" is intended to mean an
agent capable of holding other molecules onto its surface by
physical or chemical (chemisorption) means. Such compounds include,
by way of example and without limitation, powdered and activated
charcoal and other materials known to one of ordinary skill in the
art.
[0204] As used herein, the term "antioxidant" is intended to mean
an agent that inhibits oxidation and thus is used to prevent the
deterioration of preparations by the oxidative process. Such
compounds include, by way of example and without limitation,
ascorbic acid, ascorbylpalmitate, butylated hydroxyanisole,
butylated hydroxytoluene, hypophosphorous acid, monothioglycerol,
propyl gallate, sodium ascorbate, sodium bisulfite, sodium
formaldehyde sulfoxy late and sodium metabisulfite and other
materials known to one of ordinary skill in the art.
[0205] As used herein, the term "buffering agent" is intended to
mean a compound used to resist change in pH upon dilution or
addition of acid or alkali. Such compounds include, by way of
example and without limitation, potassium metaphosphate, potassium
phosphate, monobasic sodium acetate and sodium citrate anhydrous
and dihydrate and other materials known to one of ordinary skill in
the art.
[0206] As used herein, the term "sweetening agent" is intended to
mean a compound used to impart sweetness to a preparation. Such
compounds include, by way of example and without limitation,
aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol
and sucrose and other materials known to one of ordinary skill in
the art.
[0207] As used herein, the term "antiadherent" is intended to mean
an agent that prevents the sticking of tablet formulation
ingredients to punches and dies in a tableting machine during
production. Such compounds include, by way of example and without
limitation, magnesium stearate, talc, calcium stearate, glyceryl
behenate, PEG, hydrogenated vegetable oil, mineral oil, stearic
acid and other materials known to one of ordinary skill in the
art.
[0208] As used herein, the term "binder" is intended to mean a
substance used to cause adhesion of powder particles in tablet
granulations. Such compounds include, by way of example and without
limitation, Copovidone (Kollidon VA-64) NF, alginic acid,
carboxymethylcellulose sodium, poly(vinylpyrrolidone), compressible
sugar (e.g., NuTab.TM.), ethylcellulose, gelatin, liquid glucose,
methylcellulose, povidone and pregelatinized starch and other
materials known to one of ordinary skill in the art.
[0209] When needed, a binder may also be included in the present
compositions. Exemplary binders include acacia, tragacanth,
gelatin, starch, cellulose materials such as methyl cellulose and
sodium carboxy methyl cellulose, alginic acids and salts thereof,
polyethylene glycol, guar gum, polysaccharide, bentonites, sugars,
invert sugars, poloxamers (PLURONIC F68, PLURONIC F127), collagen,
albumin, gelatin, cellulosics in nonaqueous solvents, combinations
thereof and others known to those of ordinary skill. Other binders
include, for example, polypropylene glycol,
polyoxyethylenepolypropylene copolymer, polyethylene ester,
polyethylene sorbitan ester, polyethylene oxide, combinations
thereof and other materials known to one of ordinary skill in the
art.
[0210] As used herein, the term "diluent" or "filler" is intended
to mean an inert substance used as filler to create the desired
bulk, flow properties, and compression characteristics in the
preparation of tablets and capsules. Such compounds include, by way
of example and without limitation, dibasic; calcium phosphate,
kaolin, lactose, sucrose, mannitol, microcrystalline cellulose
(e.g., Microcrystalline Cellulose PH101 NF, and Microcrystalline
Cellulose PH200 NF), powdered cellulose, precipitated calcium
carbonate, sorbitol, and starch and other materials known to one of
ordinary skill in the art.
[0211] As used herein, the term "direct compression excipient" is
intended to mean a compound used in direct compression tablet
formulations. Such compounds include, by way of example and without
limitation, dibasic calcium phosphate (e.g., Ditab) and other
materials known to one of ordinary skill in the art.
[0212] As used herein, the term "glidant" is intended to mean
agents used in tablet and capsule formulations to promote the
flowability of a granulation. Such compounds include, by way of
example and without limitation, colloidal silica, colloidal silicon
dioxide NF, cornstarch, talc, calcium silicate, magnesium silicate,
colloidal silicon, silicon hydrogel and other materials known to
one of ordinary skill in the art. In some embodiments, the
pharmaceutical composition further comprises a granulation solvent,
e.g., purified water USP.
[0213] As used herein, the term "lubricant" is intended to mean
substances used in tablet formulations to reduce friction during
tablet compression. Such compounds include, by way of example and
without limitation, magnesium stearate NF, calcium stearate,
magnesium stearate, mineral oil, stearic acid, and zinc stearate
and other materials known to one of ordinary skill in the art.
[0214] As used herein, the term "opaquant" is intended to mean a
compound used to render a capsule or a tablet coating opaque. May
be used alone or in combination with a colorant. Such compounds
include, by way of example and without limitation, titanium dioxide
and other materials known to one of ordinary skill in the art.
[0215] As used herein, the term "polishing agent" is intended to
mean a compound used to impart an attractive sheen to coated
tablets. Such compounds include, by way of example and without
limitation, carnauba wax, and white wax and other materials known
to one of ordinary skill in the art.
[0216] As used herein, the term "disintegrant" is intended to mean
a compound used in solid dosage forms to promote the disruption of
the solid mass into smaller particles which are more readily
dispersed or dissolved. Such disintegrants include, by way of
example and without limitation, starches such as corn starch,
potato starch, pre-gelatinized and modified starches thereof,
sweeteners, clays, such as bentonite, microcrystalline cellulose
(e.g., Avicel), carboxymethylcellulose calcium, cellulose
polyacrilin potassium (e.g. Amberlite), alginates, sodium starch
glycolate, gums such as agar, guar, locust bean, karaya, pectin,
tragacanth and other materials known to one of ordinary skill in
the art.
[0217] As used herein, the term. "colorant" is intended to mean a
compound used to impart color to solid (e.g., tablets)
pharmaceutical preparations. Such compounds include, by way of
example and without limitation, FD&C Red No. 3, FD&C Red
No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green
No, 5, D&C Orange No, 5, D&C Red No. 8, caramel, and ferric
oxide, red, other F.D. & C. dyes and natural coloring agents
such as grape skin extract, beet red powder, beta-carotene, annato,
carmine, turmeric, paprika, and other materials known to one of
ordinary skill in the art. The amount of coloring agent used varies
as desired.
[0218] As used herein, the term "flavorant" is intended to mean a
compound used to impart a pleasant flavor and often odor to a
pharmaceutical preparation. Exemplary flavoring agents or
flavorants include synthetic flavor oils and flavoring aromatics
and/or natural oils, extracts from plants, leaves, flowers, fruits
and so forth and combinations thereof. These may also include
cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay
oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of
nutmeg, oil of sage, oil of bitter almonds and cassia oil. Other
useful flavors include vanilla, citrus oil, including lemon,
orange, grape, lime and grapefruit, and fruit essences, including
apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple,
apricot and so forth. Flavors which have been found to be
particularly useful include commercially available orange, grape,
cherry and bubble gum flavors and mixtures thereof. The amount of
flavoring may depend on a number of factors, including the
organoleptic effect desired. Flavors will be present in any amount
as desired by those of ordinary skill in the art. Particularly
preferred flavors are the cherry flavors and citrus flavors such as
orange.
[0219] In some embodiments, the pharmaceutical composition
comprises an internal layer, e.g., a core, and an external layer,
e.g., a coat. In some embodiments, the amantadine in the core is in
an extended release form and the amantadine in the external coat is
in an immediate release form, hi some embodiments, the total amount
of amantadine in the pharmaceutical composition ranges from about
65 mg to about 320 mg. In one embodiment, the total amount of
amantadine is about 160 mg. In another embodiment, the total amount
of amantadine is about 240 mg. In another embodiment, the total
amount of amantadine is about 320 mg. The amount of amantadine in
the core generally exceeds the amount present in the external coat.
In some embodiments, the amount of amantadine in the core ranges
from about 50% to about 85% of the total amount present in the
pharmaceutical composition. In some embodiments, the amount of
amantadine in the core ranges from about 60% to about 82% of the
total amount present in the pharmaceutical composition. In one
embodiment, the amount of amantadine in the core is about 62% of
the total amount present in the pharmaceutical composition. In
another embodiment, the amount of amantadine in the core is about
75% of the total amount present in the pharmaceutical composition.
In another embodiment, the amount of amantadine in the core is
about 81% of the total amount present in the pharmaceutical
composition.
[0220] In some embodiments of the present invention, the
pharmaceutical composition is an osmotic device. In some
embodiments, the osmotic device comprises an active ingredient
(drug) and an osmotic salt (osmotic agent) in the core, hi these
embodiments, amantadine release from the extended release core of a
dosage form of the present disclosure invention is controlled by an
osmotic pump system. For example, an osmotic pump system may
comprise of a drug core contained within a semipermeable polymer
membrane that is permeable to water molecules but not to the drug.
In some embodiments, the osmotic device further comprises an
immediate release layer comprising amantadine or a pharmaceutically
acceptable salt thereof. Amantadine release from the osmotic device
is driven by the existence of an osmotic gradient between the
contents of the drug core and the fluid in the gastrointestinal
tract. Since the osmotic gradient remains constant, drug delivery
remains essentially constant after the immediate-release layer
dissolves. The biologically inert components of the osmotic device
remain intact during gastrointestinal transit and are eliminated in
the stool as a tablet shell. In some embodiments, the osmotic
device comprises a unitary core enclosed with a semipermeable
membrane optionally having at least one preformed passageway there
through. In some embodiments, the unitary core comprises a mixture
of amantadine salt, osmotic salt and one or more pharmaceutical
excipients. In some embodiments, the release rate of the active
ingredient is reduced and the release profile of the active
ingredient is modified by increasing the amount of the osmotic salt
in the core. In some embodiments, the osmotic salt is an organic
salt. In some embodiments, the osmotic salt is an inorganic salt.
In some embodiments, the osmotic salt and the amantadine salt have
an ion in common. Having an "ion in common" means that amantadine
salt and the osmotic salt each have ions of the same identity. It
is not meant that amantadine salt and the osmotic salt actually
share the same ion. In some embodiments, the inorganic osmotic salt
is a metal halide. In some embodiments, the inorganic osmotic salt
is an alkali metal halide or an earth metal halide. In one
embodiment, the inorganic osmotic salt is a sodium chloride. By way
of example and without limitation, amantadine HCl and NaCl have the
chloride ion in common.
[0221] In some embodiments, the osmotic device is capable of
providing a sigmoidal, pseudo-zero order or zero order release of
amantadine or a pharmaceutically acceptable salt thereof. In some
embodiments, the sigmoidal, pseudo-zero order, or zero order
release is from the core of the device, once the immediate-release
layer is dissolved. In one particular embodiment, the release is a
zero order release. In another embodiment, the release is
pseudo-zero order. In some embodiments, the release of amantadine
or a pharmaceutically acceptable salt thereof is essentially
constant.
[0222] In some embodiments, the unitary core comprises a
heterogeneous mixture. In some embodiments, the unitary core
comprises a homogeneous mixture. A homogeneous mixture is one
wherein all of the ingredients have been thoroughly mixed such that
the composition of the formulation is substantially the same
throughout different portions of the core, The combined step of
mixing and directly compressing the ingredients of the core
generally provides a homogeneous mixture. A heterogeneous mixture
is one wherein the ingredients of the core are divided into two or
more groups that are processed separately to form two or more
respective blends, at least one of which contains drug and at least
one of which contains the osmotic salt. The blends are then mixed
together and compressed to form the unitary core, A heterogeneous
mixture can be obtained by wet granulation, dry granulation,
pelleting or combinations thereof.
[0223] In some embodiments, the osmotic device has a semipermeable
membrane. The semipermeable membrane of the osmotic device is
formed of a material that is substantially permeable to the passage
of fluid from the environment of use to the core and substantially
impermeable to the passage of active agent from the core. In some
embodiments, the semipermeable membrane comprises a laser drilled
orifice for drug delivery. Many common materials that form a
semipermeable wall which are known by those of ordinary skill in
the art of pharmaceutical sciences are suitable for this
purpose.
[0224] In some embodiments, the semipermeable membrane comprises at
least one film forming polymer. In one embodiment, the
semipermeable membrane comprises at least two film-forming
polymers. In other embodiments, the semipermeable membrane
comprises a plasticizer. Examples of film-forming polymers include,
but are not limited to, cellulose esters, cellulose ethers,
cellulose esters-ethers, cellulose acylate, or any combinations
thereof In one embodiment, the film-forming polymer is Cellulose
Acetate NF (CA-320S), Cellulose Acetate NF (CA-398-10), or a
combination thereof In another embodiment, the film-forming polymer
is Opadry Yellow. Examples of plasticizers include, but are not
limited to, polyethylene glycol, propylene glycol, polyesters (e.g.
poly (lactic acid), and poly(lactide-co-glycolide)),
polyesteramides, diesters/triesters of acids, and
diesters/triesters of alcohols.
[0225] In one embodiment, the semipermeable membrane comprises
cellulose acetate (CA) and poly(ethylene glycol) (PEG). In one
embodiment, the PEG is PEG 400. The ratio of CA:PEG generally
ranges from about 50-99% by weight of CA: about 50-1% by weight of
PEG, and about 95% by weight of CA: about 5% by weight of PEG. The
ratio can be varied to alter permeability and ultimately the
release profile of the osmotic device. In some embodiments, the
cellulose acylate is cellulose acetate, cellulose diacetate,
cellulose triacetate or any combinations thereof. Many suitable
polymers, including those disclosed in Argentine Patent No.
199,301, U.S. Pat. No. 6,004,582 and other references cited herein,
are hereby incorporated by reference.
[0226] In some embodiments, the semipermeable membrane comprises at
least two different grades of cellulose acetate. Grade 1 cellulose
acetate has a higher viscosity, a higher percentage of hydroxyl
groups, and a lower percentage of acetyl groups than does grade 2,
meaning that grade 2 has a lower viscosity, lower percentage of
hydroxyl groups and higher percentage of acetyl groups than does
grade 1. In some embodiments, the two different grades of cellulose
acetate are Cellulose Acetate NF (CA-320S) and Cellulose Acetate NF
(CA-398-10).
[0227] In some embodiments, the semi-permeable membrane further
comprises a coating solvent. Examples of coating solvents include,
but are not limited to, ethylcellulose, ethanol, acetone,
dichloromethane, isopropanol, and other materials known to one of
ordinary skill in the art, In one embodiment, the coating solvent
is acetone . In another embodiment, the coating solvent is water.
In yet another embodiment, the semi-permeable membrane comprises
acetone and purified water USP.
[0228] In some embodiments, the osmotic device comprises a water
soluble and/or erodible coating, which covers and surrounds the
semipermeable membrane and plug any preformed passageway in the
membrane if the passageway had been formed prior to addition of the
coating. The water soluble and/or erodible coating is described in
detail above.
[0229] In some embodiments, the osmotic device comprises a color
separation coating over the semi-permeable membrane. The color
separating coating can comprise a film forming polymer, a coating
solvent, or a combination thereof.
[0230] In some embodiments, the osmotic device further comprises an
IR layer comprising amantadine or a pharmaceutically acceptable
salt thereof. In some embodiment, the IR layer further comprises a
film forming polymer. In another embodiment, the IR layer comprises
a coating solvent. Examples of film-forming polymers and coatings
solvents are listed above and can also include other materials
known to one of ordinary skill in the art.
[0231] In some embodiments, the osmotic device further comprises an
aesthetic coating comprising a film forming polymer and a coating
solvent. Examples of film-forming polymers and coatings solvents
are listed above and can also include other materials known to one
of ordinary skill in the art. In one embodiment, the film for wing
polymer is Opadry White (Y-30-18037), Opadry Green (15B110000),
Opadry Blue (15B105001), or any combinations thereof In one
embodiment, the coating solvent is purified water.
[0232] In some embodiment, the osmotic device further comprises a
printing. In one embodiment, the printing is ink (e.g., Opacode AVE
NS-78-17821 Black).
[0233] Method of Preparation of the Pharmaceutical Compositions
[0234] The pharmaceutical compositions can be prepared according to
the methods disclosed herein or those well known in the art.
[0235] In the embodiment related to an osmotic device, the active
agent and excipients that comprise the core are mixed in solid,
semisolid or gelatinous form, then moistened and sieved through a
specified screen to obtain a granulate. The granulate is then dried
in a dryer and compressed, for example, by punching to form
uncoated cores. The compressed and uncoated cores are then covered
with a solution of suitable materials that comprise the wall.
Subsequently, the wall surrounding each core is perforated with,
for example, laser equipment to form the preformed passageway in
the manner previously described. In some embodiments, a
drug-containing external coat is applied to cover the wall as a
sprayed coating or a compression coating. In some embodiments, the
osmotic device is coated with a finish coat as is commonly done in
the art to provide the desired shine, color, taste or other
aesthetic characteristics. Materials suitable for preparing the
finish coat are well known in the art and found in the disclosures
of many of the references cited and incorporated by reference
herein.
Combination Therapy
[0236] Amantadine may be administered as a combination with a
second agent for treatment of
[0237] Parkinson's Disease. Amantadine may also be administered as
a combination with a second agent for treatment of drug-induced
extrapyramidal reactions. Additionally, amantadine may be
administered as a combination with a second agent for treatment of
levodopa-induced dyskinesia. In some embodiments, the second agent
comprises one or more compounds selected from the group consisting
of levodopa and/or another drug selected from the group consisting
of an aromatic-L-amino-acid decarboxylase inhibitor such as
carbidopa or benserezide; dopamine agonists such as apomorphine,
bromocriptine, cabergoline, lisuride, pergolide, pramipexole,
ropinirole, and rotigotine; COMT (catechol O-methyltransferase)
inhibitors such as entacapone, tolcapone and BIA 9-1067
(opicapone): MAO-B (monoamine oxidase B) inhibitors such as
selegiline, rasagiline and safinamide; anticholinergics such as
trihexyphenidyl, benztropine, orphenadrine, procyclidine,
ethopropazine, and glycopyrrolate; benzodiazepines such as
alprazolam, lorazepam, diazepam, clonazepam; SSRIs (selective
serotonin reuptake inhibitors) such as fluoxetine, sertraline,
paroxetine and fluvoxamine; tricyclic and tetracyclic
antidepressants such as mirtazapine, doxepin, imipramine,
desipramine, trazodone, and nortriptyline; nonsteroidal
anti-inflammatory agents such as minocycline and COX-2
(cyclooxygenase-2) inhibitors; non-narcotic analgesic such as
acetaminophen, aspirin, diclofenac, diflusinal, etodolac, fenbufen,
flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen,
ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen,
oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin, tramadol
and zomepiracadenosine; narcotic analgesics such as codeine,
dihydrocodeine, hydrocodone, hydromorphone, levorphanol, morphine,
oxycodone and tapentadol; ADORA2A (adenosine A2A receptor)
antagonists such as preladenant, tozadenant, DT-1133 and DT1687;
anti-epileptic agents selected from the group consisting of RMPA
antagonists, Benzodiazepines, Barbiturates, Valproates, GABA
analogs, Iminostilbenes, Hydantoins, NMDA antagonists, Sodium
channel blockers, Carboxylic acids, oxazolidinediones,
succinimides, pyrrolidines, sulphonamides, aminobutyric acids,
sulfamate-substituted monosaccharides, carboxamides, aromatic
allylic alcohols, ureas, phenyltriazines, carbamates, pyrrolidines,
losigamone, retigabine, rufinamide, acetazolamide, clomthiazole
edisilate, zonisamide, felbamate, topiramate, tiagabine,
levetiracetatn, briveracetam, SPD 421 (DP-VPA), T-2000, XP-13512,
GSK-362115, GSK-406725, ICA-69673, CBD cannabis derivative,
isovaleramide (NPS-1776), carisbamate, safinamide, seletracetatn,
soretolide, stiripentol, and valiocemide; lacosamide, gabapentin,
indomethacin, steroids, fluorocortisone, desmopressin, oxybutynin,
tolterodine, hyoscyamine, midodrine, phenylephrine,
phenylpropanolamine, baclofen, dantrolene, domperidone, mosapride,
tegaserod, donepezil, memantine, riluzole, rivastigmine, coenzyme
Q10, vitamin E, vitamin C, creatine, ginkgo biloba, nicotinamide,
carnitine, piribedil, buspirone, clozapine, quetiapine, olanzapine,
risperidone, aripiprazole, methylphenidate, modafinil,
dipraglurant, fipamezole, AFQ056, AQW-051, Neu-120, olesoxime,
17-B-hydroxyepiandrosterone, (+)-phenserine, clavulanic acid,
HE-3286, YM-50018, MCD-386, AV-101, SUVN-502, EVP-0334, V-81444,
SCH-900800, ADX-88178, NNZ-2591, AEOL-11207, Proximagen, IC-200214,
SIG-1012, ADL-5510, TrkB PAM, and G-79.
[0238] In some embodiments, the second agent is present in an
amount known to be therapeutically (clinically) effective for the
treatment of a target condition, disease or disorder, such as those
described herein, when a unit dose of the pharmaceutical
composition is administered to a subject in need thereof. Guidance
as to the therapeutically effective amount of each previously
marketed second agent can be obtained from the Food and Drug
Administration (USA, www.fda.gov), European Medicines Agency
(Europe, ema.europa.eu), National Institute of Health Sciences
(Japan, www.nihs.go.jp), and National Administration of Drugs,
Food, and Medical Technology (Administracion Nacional de
Medicamentos, Alimentos y Tecnologia Medica, Argentina,
www.anmat.gov.ar), the disclosures of which are incorporated herein
by reference in their entirety. For example, the package insert for
any approved drug includes dosage and administration information,
which can be used to determine the proper amount of each drug to be
included in a pharmaceutical composition of the invention. The
amounts for a particular drug combination in accordance with this
invention can be determined employing routine experimental testing.
If the drugs are present in such a weight ratio that a
super-additive or synergistic therapeutic effect is observed upon
administration to the patients, the overall administered dose may
be lowered, so that fewer undesired side-effects will occur.
[0239] In some embodiments, the pharmaceutical composition
comprises a combination of amantadine and one or more other drugs,
and may contain an excess of amantadine, an excess of the one or
more other drugs, or equivalent amounts of amantadine and the one
or more other drugs. The weight ratio of amantadine to the one or
more other drugs can range from about 100:1 to 1:100. In one
embodiment, the one or more other drugs are administered to the
subject, sequentially or concomitantly, in another dosage form such
that the subject receives a dose of the one or more other drugs in
the pharmaceutical composition and a dose of the one or more other
drugs in another dosage form. The dosing regimen for the one or
more other drugs can thus be the same as or different than the
dosing regimen for amantadine.
[0240] In some embodiments, the pharmaceutical composition
comprises an external coat comprising a second active agent for
immediate release of the drug. In some embodiments, the osmotic
device comprises a coat external to the semipermeable membrane. The
external coat can be a rapid release coat. In some embodiments, the
second active ingredient in the external rapid release coat is
selected from the group consisting of amantadine, cabergoline,
pergolide, selegiline, rasagiline, trihexyphenidyl, benztropine,
donepezil, fluoxetine, sertraline, paroxetine, fluvoxamine,
mirtazapine, doxepin, desipramine, clozapine, olanzapine,
risperidone, aripiprazole, fludrocortisone, safinamide, and
smilagenin. In some embodiments, the osmotic device comprises a
non-absorbable shell.
In vitro Assays
[0241] The pharmaceutical compositions prepared according to
certain embodiments of the present invention preferably exhibit the
following dissolution profile when tested in a USP Type II
dissolution apparatus (paddles), using water or in 0.1N HCl as a
dissolution media, with a fixed agitation rate of 50 revolutions
per minute, maintained at a temperature of about 37.+-.0.5.degree.
C. In some embodiments, the pharmaceutical composition has an in
vitro dissolution profile ranging between about 0.1% to about 50%
in about 0.5 hour, about 20% to about 80% in about 2.5 hours, about
40% to about 90% in about 4 hours, and no less than about 85% in
about 8 hours using water as a dissolution media. hi one
embodiment, the pharmaceutical composition has an in vitro
dissolution profile ranging between about 28% to about 48% in about
0.5 hour, about 39% to about 63% in about 2.5 hours, about 61% to
about 85% in about 4 hours, and no less than about 85% in about 8
hours using water as a dissolution media. In another embodiment,
the pharmaceutical composition has an in vitro dissolution profile
ranging between about 15% to about 35% in about 0.5 hour, about 29%
to about 53% in about 2.5 hours, about 53% to about 77% in about 4
hours, and no less than about 85% in about 8 hours using water as a
dissolution media. In another embodiment, the pharmaceutical
composition has an in vitro dissolution profile ranging between
about 9% to about 29% in about 0.5 hour, about 37% to about 62% in
about 2.5 hours, about 59% to about 83% in about 4 hours, and no
less than about 85% in about 8 hours using water as a dissolution
media. in one embodiment, the pharmaceutical composition has an in
vitro dissolution profile ranging between about 0.1% to about 10%
in about 1 hour, about 20% to about 60% in about 2.5 hours, about
40% to about 80% in about 4 hours, about 70% to about 95% in about
6 hours, and no less than about 85% in about 8 hours. In another
embodiment, the pharmaceutical composition has an in vitro
dissolution profile in water ranging between about 0.1% to about
10% in about 1 hour, about 5% to about 50% in about 2.5 hours,
about 40% to about 80% in about 4 hours, about 70% to about 95% in
about 6 hours, and no less than about 85% in about 8 hours. In
another embodiment, the pharmaceutical composition has an in vitro
dissolution profile in water ranging between about 0.1% to about
10% in about 1 hour, about 5% to about 60% in about 2.5 hours,
about 40% to about 90% in about 4 hours, about 80% to about 97% in
about 6 hours, and no less than about 95% in about 8 hours. In some
embodiments, an extended release pharmaceutical composition
comprising amantadine has an in vitro dissolution profile in a
solution with a neutral pH (e.g., water) that is substantially the
same as its dissolution profile in an acidic dissolution
medium.
Pharmacokinetics
[0242] Amantadine in an extended release form is released into a
subject sample at a slower rate than observed for an immediate
release formulation of the same quantity of amantadine, such that
the rate of change in the biological sample is measured as the
dC/dT over a defined period.
[0243] In some embodiments, the dC/dT of amantadine is less than
about 80%, about 70%, about 60%, about 50%, about 40%, about 30%,
or about 20% of the dC/dT provided by the same quantity of
amantadine in an immediate release form, when the dC/dT is measured
between 0 and 4 hours after administration. In some embodiments,
the dC/dT of amantadine is greater than about 30%, about 40% and
about 50% of the dC/dT provided by the same quantity of amantadine
in an immediate release form, when the dC/dT is measured between 0
and 4 hours after administration. In one embodiment, the dC/dT of
amantadine is greater than about 50% of the dC/dT provided by the
same quantity of amantadine in an immediate release form, when the
dC/dT is measured between 0 and 4 hours after administration.
[0244] In some embodiments, the dC/dT of amantadine is from about
40% to about 70%, from about 40% to about 60%, from about 40% to
about 50%, from about 50% to about 60%, from about 50% to about
70%, from about 60% to about 70% of the dC/dT provided by the same
quantity of amantadine in an immediate release form, when the dC/dT
is measured between 0 and T.sub.max for the IR formulation after
administration. In one embodiment, the dC/dT of amantadine is about
45% of the dC/dT provided by the same quantity of amantadine in an
immediate release form, when the dC/dT is measured between 0 and
for the IR formulation after administration. In another embodiment,
the dC/dT of amantadine is about 55% of the dC/dT provided by the
same quantity of amantadine in an immediate release form, when the
dC/dT is measured between 0 and T.sub.max for the IR formulation
after administration. In another embodiment, the dC/dT of
amantadine is about 70% of the dC/dT provided by the same quantity
of amantadine in an immediate release form, when the dC/dT is
measured between 0 and T.sub.max for the IR formulation after
administration.
[0245] In some embodiments, amantadine is formulated to release at
a rate that is significantly reduced over an immediate release
dosage form, with an associated delay in the mean In some
embodiments, the pharmaceutical composition is formulated to
provide a shift in T.sub.max by about 16 hours, about 14 hours,
about 12 hours, about 10 hours, about 9 hours, about 8 hours, about
7 hours, about 6 hours, about 5 hours, about 4 hours, about 3
hours, about 2 hours, or about 1 hour.
[0246] In some embodiments, the T.sub.max of the pharmaceutical
composition is between about 5 and about 12 hours, between about 5
and about 10 hours, between about 5 and about 8 hours, between
about 5 and about 6 hours, between about 6 and about 12 hours,
between about 6 and about 10 hours, between about 6 and about 8
hours, between about 7 and about 12 hours, between about 7 and
about 10 hours, between about 7 and about 8 hours, between about 8
and about 12 hours, between about 8 and about 10 hours, between
about 9 and about 12 hours, between about 9 and about 10 hours, or
between about 10 and about 12 hours. In one embodiment, the median
T.sub.max of the pharmaceutical composition is about 7.5 hours.
[0247] In some embodiments, the pharmaceutical composition
comprising an extended release amantadine reduces the dC/dT of the
drug, and not only increases mean T.sub.max, but also reduces mean
C.sub.max (the drug concentration at T.sub.max) and reduces the
C.sub.max/C.sub.mean ratio providing a more constant amount of drug
to the subject being treated over a given period of time, enabling
increased dosages for appropriate indications. In some embodiments,
the mean C.sub.max of the pharmaceutical composition after a
single-dose administration is between about 200 and about 1000
ng/ml, between about 200 and about 900 ng/ml, between about 200 and
about 800 ng/ml, between about 200 and about 700 ng/ml, between
about 200 and about 600 ng/ml, between about 200 and about 500
ng/ml, between about 200 and about 400 ng/ml, between about 200 and
about 300 ng/ml, between about 300 and about 1000 ng/ml, between
about 300 and about 900 ng/ml, between about 300 and about 800
ng/ml, between about 300 and about 700 mg/ml, between about 300 and
about 600 mg/ml, between about 300 and about 500 ng/ml, between
about 300 and about 400 ng/ml, between about 400 and about 1000
ng/ml, between about 400 and about 900 ng/ml, between about 400 and
about 800 ng/ml, between about 400 and about 700 mg/ml, between
about 400 and about 600 ng/ml, between about 400 and about 500
ng/ml, between about 500 and about 1000 ng/ml, between about 500
and about 900 ng/ml, between about 500 and about 800 ng/ml, between
about 500 and about 700 ng/ml, between about 500 and about 600
ng/ml.
[0248] In some embodiments, the mean C.sub.max of the
pharmaceutical composition after a single-dose administration is
between about 540 and about 895 ng/ml. In one embodiment, the
pharmaceutical composition comprises about 320 mg amantadine. In
some embodiments, the mean C.sub.max of the pharmaceutical
composition after a single-dose administration is between about 370
and about 550 ng/ml. In one embodiment, the pharmaceutical
composition comprises about 240 mg amantadine, In some embodiments,
the mean C.sub.max of the pharmaceutical composition after a
single-dose administration is between about 265 and about 390
ng/ml. In one embodiment, the pharmaceutical composition comprises
about 160 mg amantadine. In some embodiments, after a single oral
administration of the 129 mg amantadine free base equivalent, the
mean (CV %) C.sub.max is 328 ng/ml (18%). C.sub.max with other dose
levels of the pharmaceutical composition increases
proportionally.
[0249] Another PK parameter of interest is the resulting area under
the plasma concentration-time curve (AUC.sub.0-.infin.), calculated
to the last measured concentration (AUC.sub.0-T) and extrapolated
to infinity (AUC.sub.t-.infin.), for extent of absorption of
amantadine. In some embodiments, the mean AUC.sub.0-.infin. of the
pharmaceutical composition after a single-dose administration is
between about 6,000 and about 24.000 ng.h/mL, between about 6,000
and about 20,000 ng.h/mL, between about 6.000 and about 16,000
ng.h/mL, between about 6,000 and about 12,000 ng.h/mL, between
about 6,000 and about 10,000 ng.h/mL, between about 6,000 and about
8,000 ng.h/mL, between about 8,000 and about 24.000 ng.h/mL between
about 8,000 and about 20,000 ng.h/mL, between about 8,000 and about
16,000 ng.h/mL, between about 8,000 and about 12,000 ng.h/mL,
between about 8,000 and about 10,000 ng.h/mL, between about 10,000
and about 24,000 ng.h/mL, between about 10,000 and about 20,000
ng.h/mL, between about 10,000 and about 16,000 ng.h/mL, between
about 10,000 and about 12,000 ng.h/mL, between about 12,000 and
about 24,000 ng.h/mL, between about 12,000 and about 20,000
ng.h/mL, between about 12,000 and about 16,000 ng.h/mL, between
about 16,000 and about 24,000 ng.h/mL, between about 16,000 and
about 20,000 ng.h/mL, or between about 20,000 and about 24,000
ng.h/mL.
[0250] In some embodiments, the mean AUG.sub.0-.infin. of the
composition after a single-dose administration is between about
12,000 and about 26,000 ng.h/mL. In some embodiments, the mean of
the composition after a single-dose administration is between about
12,500 and about 23,500 ng.h/mL. In one embodiment, the
pharmaceutical composition comprises about 320 mg amantadine HCl.
In some embodiments, the mean AUC.sub.0-.infin. of the composition
after a single-dose administration is between about 8,000 and about
20,000 ng.h/mL. In some embodiments, the mean AUC.sub.0-.infin. of
the composition after a single-dose administration is between about
10,400 and about 15,900 ng.h/mL. In one embodiment, the
pharmaceutical composition comprises about 240 mg amantadine HCl.
In some embodiments, the mean AUC.sub.0-.infin. of the composition
after a single-dose administration is between about 6,000 and about
26,000 ng.h/mL. In some embodiments, the mean AUC.sub.O-.infin. of
the composition after a single-dose administration is between about
6,900 and about 10,300 ng.h/mL. the mean AUC.sub.0-.infin. of the
composition after a single-dose administration is between about
6,000 and about 12,000 ng.h/mL. In one embodiment, the
pharmaceutical composition comprises about 160 mg amantadine HCl.
In some embodiments, after a single oral administration of the 129
mg amantadine free base equivalent, the mean AUC.sub.0-.infin. is
about 8580 ng.h/mL with other dose levels of the pharmaceutical
composition increasing proportionally.
[0251] In some embodiments, the relative bioavailability of
amantadine or a pharmaceutically acceptable salt thereof is
approximately the same under fed and fasting conditions.
Efficacy
[0252] In the present invention, treatment of patients with an
extended release amantadine dosage form of the present invention
improves symptoms of PD, extrapyramidal reactions, and/or
levodopa-induced dyskinesia.
[0253] In some embodiments, treatment of patients with an extended
release amantadine dosage form of the present invention improves
dyskinesia in a patient with levodopa-induced dyskinesia (LID) as
determined by a reduction in a total Unified Dyskinesia Rating
Scale (UdysRS) score after twelve weeks. In some embodiments, the
treatment increases the number of awake ON hours without dyskinesia
in the patient.
[0254] In some embodiments, the reduction in UdysRS score is
between about -2 and about -7, between about -2 and about -6.
between about -2 and about -5. between about -2 and about -4,
between about -2 and about -3, between about -3 and about -7,
between about -3 and about -6, between about -3 and about -5,
between about -3 and about -4, between about -4 and about -7,
between about -4 and about -6, between about -4 and about -5,
between about -5 and about -7, between about -5 and about -6, or
between about -6 and about -7. after twelve weeks, compared to
placebo. In one embodiment, the reduction in UdysRS score is about
-5 after twelve weeks, compared to placebo.
[0255] In some embodiments, the reduction in UdysRS score is
between about -9 and about -17, between about -9 and about -16,
between about -9 and about -15, between about -9 and about -14,
between about -9 and about -13, about -9 and about -12, about -9
and about -11, about -9 and about -10, between about -10 and about
-17, between about -10 and about -16, between about -10 and about
-15. between about -10 and about -14, between about -10 and about
-13. about -10 and about -12, about -10 and about -11, between
about -11 and about -17. between about -11 and about -16, between
about -11 and about -15, between about -11 and about -14, between
about -11 and about -13, about -11 and about -12, between about -12
and about -17, between about -12 and about -16, between about -12
and about -15, between about -12 and about -14, between about -12
and about -13, between about -13 and about -17, between about -13
and about -16. between about -13 and about -15, between about -13
and about -14, between about -14 and about -17, between about -14
and about -16, between about -14 and about -15, between about -15
and about -17, between about -15 and about -16, or between about
-16 and about -17, after twelve weeks. In one embodiment, the
reduction in UdysRS score is about -13 after twelve weeks.
[0256] In some embodiments, the method increases the number of
awake ON hours without dyskinesia in the patient by about 1 to
about 4 hours, by about 1 to about 3 hours, by about 1 to about 2
hours, by about 2 to about 4 hours, by about 2 to about 3 hours, or
by about 3 to about 4 hours after twelve weeks. In one embodiment,
the method increases the number of awake ON hours without
dyskinesia in the patient by about 4 hours after twelve weeks.
[0257] In some embodiments, the number of awake ON hours without
dyskinesia in the patient is between about 9 and about 14 hours,
between about 9 and about 13 hours, between about 9 and about 12
hours, between about 9 and about 11 hours, between about 9 and
about 10 hours, between about 10 and about 14 hours, between about
10 and about 13 hours, between about 10 and about 12 hours, between
about 10 and about 11 hours, between about 11 and about 14 hours,
between about 11 and about 13 hours, between about 11 and about 12
hours, between about 12 and about 14 hours, between about 12 and
about 13 hours, or between about 13 and about 14 hours.
[0258] In some embodiments, MDS-UPDRS (Movement Disorder
Society-Unified Parkinson's Disease Rating Scale) Part II and III
is used to assess any potential worsening of PD symptoms. In some
embodiments, the method does not worsen Parkinson's disease
symptoms in the subjects (patients).
Indications
[0259] The pharmaceutical compositions of the present invention are
suitable for the treatment of diseases, disorders and/or symptoms
that are therapeutically or clinically responsive to amantadine
therapy. In some embodiments, diseases, disorders and/or symptoms
that are responsive to amantadine therapy include, but are not
limited to, Parkinson's disease, parkinsonism, drug-induced
extrapyramidal reactions (including, for example, akathisia,
dystonia or dyskinesia), levodopa-induced dyskinesia, viral
infection, and signs and symptoms of infection caused by various
strains of influenza A virus, especially for high-risk patients
such as those in critical public-service positions,
immunosuppressed patients, nursing home residents, contacts of
high-risk patients, and those with severe influenza A viral
infection.
[0260] The pharmaceutical compositions of the present invention can
be administered for the treatment of elderly patients believed to
develop Parkinsonism in association with or as a result of cerebral
arteriosclerosis or another neurodegenerative disease, dementia in
Parkinson's disease, fatigue associated with multiple, reducing
relapses in multiple sclerosis, improving symptoms of attention
deficit hyperactivity disorder (ADHD), SSRI-induced sexual
dysfunction, management of addictions and substance dependence,
resistant unipolar depression, bipolar disorders, Alzheimer's
Disease, senile dementia, Huntington's disease, neuropathic pain,
postoperative pain, refractory absence seizures, brain injury, and
traumatic brain injury.
[0261] In some embodiments, the pharmaceutical compositions of the
present invention are suitable for the treatment of a disease or a
disorder selected from the group consisting of Parkinson's disease,
drug-induced extrapyramidal reactions, levodopa-induced dyskinesia,
and any combinations thereof.
[0262] In some embodiments, the pharmaceutical compositions of the
present invention are suitable for the treatment of Parkinson's
disease.
[0263] In another embodiment, the pharmaceutical compositions of
the present invention are suitable for the treatment of
drug-induced extrapyramidal reactions.
[0264] In another embodiment, the pharmaceutical compositions of
the present invention are suitable for the treatment of
levodopa-induced dyskinesia.
[0265] In some embodiments, the drug-induced extrapyramidal
reactions include, but are not limited to, dystonia (continuous
spasms and muscle contractions), akathisia (motor restlessness),
parkinsonism (characteristic symptoms such as rigidity),
bradykinesia (slowness of movement), tremor, tardive dyskinesia
(irregular, jerky movements), and other side effects caused by
antipsychotics.
[0266] In some embodiments, the drug-induced extrapyramidal
reactions are caused by, but not limited to, antipsychotic drugs,
such as haloperidol, fluphenazine, thilthixene, trifluoroperazine,
acetophenazine, prochlorperazine, perphenazine, loxapine,
chlorpromazine, triflupromazine, molindone, mesoridazine,
chlorprothixene, thioridazine, clozapine; other anti-dopaminergic
drugs, such as antiemetic metoclopramide, trimethobenzamide (e.g.,
Tigan.RTM.) and metoclopramide (e.g., Reglan.RTM.), other
substituted benzamides; antidepressants, such as selective
serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine
reuptake inhibitors (SNRI), and norepinephrine-dopamine reuptake
inhibitors (NDRI), desipramine (e.g., Norpramin.RTM.),
protriptyline (e.g., Vivactil.RTM.). duloxetine, sertraline,
escitalopram, fluoxetine, and bupropion; concomitantly using
neuroleptics and lithium; anticonvulsant agents such as phenytoin
(e.g., Dilantin.RTM.) and carbamazepine (e.g., Tegretol.RTM.); and
oral contraceptives.
[0267] In a specific embodiment, the patient has Parkinson's
disease, which, as used herein, also encompasses a diagnosis of
parkinsonism. In one embodiment, the patient has early stage
Parkinson's disease, and the pharmaceutical composition of the
present invention is administered as a monotherapy or in
combination with a MAO-B inhibitor without concomitant use of
levodopa. In another embodiment, the patient has late stage
Parkinson's disease and the patient takes levodopa in addition to
the pharmaceutical composition of the present invention. In another
embodiment, the patient has multiple sclerosis and the
pharmaceutical composition of the present invention is used for the
treatment of walking impairment (that is, improve walking mobility,
distance and speed), and to reduce or to relieve fatigue.
[0268] The pharmaceutical compositions of the present invention are
also suitable for the treatment of diseases, disorders and/or
symptoms that are responsive to a combination of amantadine and a
second drug. In some embodiments, the invention includes an osmotic
device for the combined administration of amantadine in a
controlled release manner and an antidepressant in an immediate or
rapid release manner, e.g., the combination of amantadine and
citalopram, fluoxetine, paroxetine, sertraline, fluvoxamine or
escitalopram. In some embodiments, the invention also includes an
osmotic device for the combined administration of amantadine in a
controlled release manner and an anxiolytic agent in an immediate
or rapid release manner, e.g., amantadine and buspirone or
trazodone, for the amelioration of undesired tremors, akinesia,
dyskinesia, or bradykinesia associated with one or more different
disorders or diseases. In some embodiments, the invention also
includes an osmotic device for the combined administration of
amantadine and a second anti-Parkinsonian drug in a controlled
release manner from the core, e.g., amantadine and ropinirole, or
selegiline, or levodopa-carbidopa. The term "anti-Parkinsonian
drug" means a drug known in the art for use in treating Parkinson's
disease.
[0269] In some embodiments, amantadine is combined with an active
agent selected from narcotic analgesics, gabapentin and/or
lacosamide to control a patient's pain. Examples of medical
conditions and/or types of pain that can be treated with such an
osmotic device include acute inflammatory pain; acute pain;
alcoholism-associated or alcoholism-induced neuropathic pain;
allodynia (occurring independently or as a symptom of another
condition); arthritic conditions; back pain; cancer-related
neuropathic pain, e.g., painful compression by tumor growth of
adjacent nerves, the brain or the spinal cord; central neuropathic
pain; chronic headache; chronic inflammatory pain; chronic pain;
chronic pain due to peripheral nerve injury; diabetes-associated or
diabetes-induced neuropathic pain; diabetic pain; diabetic distal
sensory neuropathy; diabetic distal sensory polyneuropathy;
fibromyalgia; headache; hyperalgesia (occurring independently or as
a symptom of another condition); hyperesthesia; hyperpathia;
migraine, including classical migraine and common migraine;
myalgia; myofascial pain syndrome; neuralgia; neuroma;
non-inflammatory musculoskeletal pain; non-inflammatory
osteoarthritic pain; non-neuropathic inflammatory pain; neuropathic
pain; pain associated with or induced by chemotherapy or radiation
therapy; pain associated with or induced by traumatic nerve injury
or compression or by traumatic injury to the brain or spinal cord;
painful diabetic neuropathy; peripheral neuropathic pain;
persistent clinical pain; phantom pain; rheumatoid arthritis pain;
secondary inflammatory osteoarthritic pain; trigeminal neuralgia;
and vascular headache.
EXAMPLES
Example 1
Amantadine Tablet Formulation
[0270] Amantadine HCl Extended Release (ER) Tablets, 160, 240 and
320 mg (each tablet contains 129 mg, 193 mg, or 258 mg amantadine
fee base equivalent, respectively) were manufactured as described
herein. The tablets contain an extended release core and an
immediate release layer.
[0271] Amantadine release from the extended release core is
controlled by an osmotic pump system. The osmotic pump system
consists of a drug core contained within a semipermeable polymer
membrane that is permeable to water molecules but not to the drug
with a laser drilled orifice for drug delivery. Amantadine release
is driven by the existence of an osmotic gradient between the
contents of the drug core and the fluid in the gastrointestinal
tract. Since the osmotic gradient remains constant, drug delivery
remains essentially constant after the immediate-release layer
dissolves. The biologically inert components of the tablet remain
intact during gastrointestinal transit and are eliminated in the
stool as a tablet shell.
[0272] Amantadine HCl core was coated with a semi-permeable
membrane (Coating A) and laser drilled to provide an orifice. The
extended release core was coated with the following 3 additional
coatings: a color separation coating (Coating B), an amantadine HCl
immediate release layer (Coating C), and a non-performance color
coating (Coating D) with black imprinting.
[0273] The formulation was designed to provide for once-a-day
dosing; the immediate release component was included to eliminate a
lag time. The core composition is the same for all three tablet
strengths, the weight of the core increases dose proportionally
with increasing dose. The unit-dose composition for Amantadine HCl
ER Tablets, 160, 240 and 320 mg is provided in Table 1. Parameters
for the 160, 240, and 320 mg tablets are provided in Table 1A.
TABLE-US-00001 TABLE 1 Summary of Unit-Dose Amantadine HCl ER
Tablet Composition by Tablet Strength 160 mg 240 mg 320 mg
Ingredient mg/tablet % w/w mg/tablet % w/w mg/tablet % w/w Tablet
Core Amantadine Hydrochloride 100.00 30-50 180.00 35-55 260.00
40-60 USP (Active) Osmotic Agent 4-9 2-3 9-14 2-4 13-20 2-5 Binder
4-10 2-4 10-16 2-5 15-24 2-5 Filler 1 23-29 8-12 40-54 10-14 54-72
10-16 Filler 2 6-10 2-4 11-18 2-5 16-26 3-5 Glidant 0.5-0.8 0.2-0.3
0.5-2 0.2-0.4 1-2 0.2-0.5 Lubricant 1-1.5 0.4-0.6 1-3 0.2-1 2-4
0.4-0.8 Granulation Solvent 25-35 44-64 63-83 Final Core weight
(mg) 120-180 210-330 310-470 Osmotic Coating (Coating A) Film
forming polymer 1 6-10 2-4 8-15 2-4 8-15 1-3 Film forming polymer 2
6-10 2-4 8-15 2-4 8-15 1-3 Plasticizer 0.5-1 0.2-0.5 0.8-2 0.2-0.6
0.8-2 0.1-0.5 Coating Solvent 1 200-300 300-400 300-400 Coating
Solvent 2 30-50 50-70 50-70 Osmotic Coating weight 12-21 20-30
20-30 (mg) Coated Tablet weight (mg) 130-200 230-360 330-500 Color
Separation Coating (Coating B) Film forming polymer 4-6 1.5-2.5
7-11 1.8-3 9-15 1.8-3 Coating Solvent 38-54 64-98 85-130 Coated
Tablet weight (mg) 135-205 235-365 342-512 IR Layer (Coating C)
Active 60.00 18-30 60.00 12-18 60.00 8-14 Film forming polymer
11-18 4-8 11-18 3-5 11-18 2-3.5 Coating Solvent 300-500 300-500
300-500 IR Layer weight (mg) 60-90 60-90 60-90 IR Coated Tablet
weight 200-300 300-450 400-600 (mg) Aesthetic Coating (Coating D)
Film forming polymer 1 6-9 2.5-3.5 Film forming polymer 2 -- 9-14
2.5-3.5 Film forming polymer 3 -- 10-20 2-4 Coating Solvent 50-80
80-130 100-170 Coated Tablet weight (mg) 200-300 300-500 400-600
Printing (Optional) Ink Total Tablet weight (mg) 200-300 100.00%
300-500 100.00% 400-600 100.00% .sup.1Removed during manufacturing
process
TABLE-US-00002 TABLE 1A Summary of Amantadine HCl ER Tablet
Dimensions by Tablet Strength 160 mg 240 mg 320 mg Largest
dimension (mm) 8.1 10.2 11.2 Average Thickness (mm) 5.2 5.5 5.7
Average Wall Height (mm) 4.0 4.0 4.0 Average Volume (mL/Tablet) 0.2
0.3 0.4
Example 2
Biopharmaceutic Studies and Associated Analytical Methods
2.1 Background and Overview.
[0274] Three clinical studies were conducted to compare relative
bioavailability of Amantadine HCl ER Tablets, 160 mg, 240 mg and
320 mg, and an immediate release amantadine oral syrup formulation,
Amantadine ER Tablets were manufactured as described in Example 1.
Amantadine HCl syrup, 50 mg/5 mL (amantadine HCl oral solution,
USP), ANDA 075060, was the approved immediate-release product
(Reference Listed Drug, RLD) and used as reference product in the
comparative bioavailability studies.
[0275] The three bioavailability studies were carried out in
healthy volunteers: [0276] 1. Study 1 compared the steady-state
bioavailability of amantadine from one Amantadine HCl ER 320 mg
Tablet administered orally once daily to 160 mg amantadine HCl
syrup, 50 mg/5 mL administered orally twice daily for 7 days;
[0277] 2. Study II compared the single-dose bioavailability and
pharmacokinetics of Amantadine MCI ER Tablets, at 160 mg, 240 mg,
and 320 mg to a single oral 160 mg dose of amantadine HCl syrup, 50
mg/5 mL; and [0278] 3. Study III evaluated the effect of a high-fat
meal on amantadine bioavailability for Amantadine HCl ER Tablets,
at 320 mg.
[0279] 2.2 Summary of Results of Individual Studies
2.2.1 Study III (Relative Bioavailability of Amantadine MCI ER
Tablet, 320 mg Under Fasting and Fed Conditions)
[0280] Study III was an open-label, balanced, randomized,
two-period, two-sequence, single dose, bioavailability study under
fasting and fed conditions of Amantadine HCl 320 mg ER Tablets in
normal, healthy, adult male and female volunteers.
[0281] In each study period, 22 blood samples (4 mL each),
including one pre-dose blood sample were collected from each
subject. There were 7 days between dosing periods. The following 2
treatments were administered: Amantadine HCl 320 mg ER tablets
given under fasting conditions (Test-T1, Fasted), and Amantadine
HCl 320 mg ER tablets given under fed conditions (Test T2 Fed).
Dosing Under Fasting Conditions
[0282] After an overnight fast of at least 10 hours, a single oral
dose (320 mg) of the test product was administered to the subjects
with 240 mL of drinking water at ambient temperature in sitting
posture.
Dosing Under Fed Conditions
[0283] After an overnight fast of at least 10 hours, the subjects
were served a high fat meal, which they consumed within 30 minutes.
A single oral close (320 mg) of the test product was administered
to the subjects at 30 minutes after serving the high fat meal. The
standard high fat meal consisted of: 2 eggs fried in butter, 2
strips of bacon, 2 slices of toast with butter, 4 ounces of hash
brown potatoes, and 8 fluid ounces (.about.240 mL) of whole milk
The test product was administered in sitting posture with 240 mL of
drinking water at ambient temperature.
[0284] The dosing activity was followed by a mouth and hands check
to assess the compliance to dosing. The test product administration
was as per the randomization schedule and under open-label
conditions.
Results:
[0285] Subjects enrolled and completed both treatment periods. The
mean age was 40.8 years, and the mean BMI was 26.75 kg/m.sup.2.
Pharmacokinetic Results:
[0286] A summary of the descriptive statistics for the amantadine
pharmacokinetic parameter values are summarized in Table 2.
TABLE-US-00003 TABLE 2 Descriptive Statistics of Treatment Mean
Pharmacokinetic Values for Amantadine HCl ER Tablets Administered
Under Fed and Fasting Conditions, Study III Mean .+-. SD
(Un-transformed data) Test-T2 Test-T1 Parameters (Units) (under fed
condition) (under fasting condition) T.sub.max (h)* 9.009
(5.000-10.067) 9.000 (5.000-10.000) C.sub.max (ng/mL) 726.500 .+-.
168.3258 667.406 .+-. 124.7239 AUC.sub.0-t (ng h/mL) 16689.043 .+-.
4142.8550 17736.805 .+-. 4550.6428 AUC.sub.0-.infin. (ng h/mL)
17379.367 .+-. 4644.9896 18481.399 .+-. 5015.5387 .lamda..sub.z
(1/h) 0.053 .+-. 0.0113 0.053 .+-. 0.0110 t1/2 (h) 13.564 .+-.
2.9835 13.577 .+-. 3.0546 AUC_% 3.509 .+-. 2.7670 3.625 .+-. 2.7349
Extrap_obs (%) T.sub.lag (h)* 0.000 (0.000-0.667) 0.000
(0.000-0.333) *T.sub.max and T.sub.lag are represented as median
(min-max) value.
Conclusions:
[0287] Amantadine bioavailability following oral administration of
320-mg Amantadine HCl ER Tablets under fed (Test) and fasted
(Reference) conditions are equivalent. See mean profile in FIG. 1
for the relative bioavailability under fed and fasted
conditions.
2.2.2 Study II (Relative Bioavailability of a Single Dose
Amantadine HCl ER Tablets, 160 mg, 240 mg, and 320 mg Compared to
Syrup Dose Form Study)
[0288] Study II was a single center, randomized,
laboratory-blinded, four-treatment, four-period, four-sequence,
single oral dose crossover design study in healthy male and female
volunteers.
[0289] The primary study objectives were to evaluate dose
proportionality between Amantadine HCl ER Tablets, 160 mg, 240 mg,
and 320 mg and to determine the relative bioavailability of
Amantadine HCl ER Tablets 160 mg compared to a reference
formulation of 160 mg of Amantadine HCl syrup (50 mg/5 mL) in
healthy volunteers of both genders after single dose administration
under fasting conditions.
[0290] Subjects received the following treatments: Amantadine HCl
160-mg ER Tablet (Treatment A), Amantadine HCl 240-mg ER Tablet
(Treatment B), Amantadine HCl 320-mg ER Tablet (Treatment C), and
160 mg Amantadine HCl 50 mg/5 mL syrup (Treatment D).
[0291] Following a 10-hour fast, subjects were orally administered
their assigned treatment with 240 mL water. During each treatment
period, 28 blood samples (4 mL each) were collected from each
subject at predetermined times, pre-dose and through 72 hours
post-dose.
Results:
[0292] As shown in FIG. 2 and Table 3, longer T.sub.max and
decreased C.sub.max values confirmed slower rate of amantadine
absorption from the Amantadine HCl ER Tablet; T.sub.max occurred
much later (approximately 9.00 hours post dose) for the Amantadine
HCl ER Tablet compared to 3.00 hours for the oral amantadine HCl
syrup; C.sub.max value for the 160-mg Amantadine HCl ER Tablet was
81.05% of that following administration of oral syrup.
[0293] The extent of amantadine absorption from the 160-mg
Amantadine HCl ER Tablet was equivalent to that from 160 mg
amantadine HCl syrup.
[0294] Plasma amantadine exposure (C.sub.max, AUC.sub.inf) after
single oral doses (160 mg, 240 mg, 320 mg) of Amantadine HCl ER
Tablets increased proportionally with increasing dose.
TABLE-US-00004 TABLE 3 Summary of Mean Pharmacokinetic Parameter
Values (CV %) of Amantadine Following Oral Administration of one
160 mg, 240 mg or 320 mg Amantadine HCl ER Tablet or 160 mg of
Amantadine HCl Oral Syrup to Fasted Healthy Volunteers, Study II
Treatment A Treatment B Treatment C Treatment D PARAMETER (160 mg
tablet) (240 mg tablet) (320 mg tablet) (160 mg syrup) (units) Mean
(% CV) Mean (% CV) Mean (% CV) Mean (% CV) C.sub.max (ng/mL) 328.21
(18.2) 459.56 (19.0) 629.52 (20.9) 403.54 (16.2) T.sub.max
(hours).sup.a 9.00 (5.50-10.00) 9.00 (6.00-12.00) 9.50 (5.00-12.00)
3.00 (1.50-8.50) AUC.sub.0-T 8263.28 (17.9) 12397.98 (17.6)
16931.18 (19.9) 8686.33 (15.9) (ng h/mL) AUC.sub.0-.infin. 8580.45
(19.0) 13123.64 (20.4) 17705.51 (21.3) 9007.72 (17.8) (ng h/mL)
.lamda..sub.z (hours.sup.-1) 0.0524 (19.8) 0.0501 (28.1) 0.0515
(20.5) 0.0533 (22.2) T.sub.half (hours) .sup.b 13.2 13.8 13.5 13.0
.sup.aMedian range), .sup.b harmonic mean T.sub.half = 0.693/mean
.lamda..sub.z
[0295] 2.2.3 Study I (Relative Bioavailability of Amantadine HCl ER
Tablets Compared to Amantadine HCl Syrup at Steady State)
[0296] Study I was a single center, laboratory-blinded, randomized,
two-treatment, two-period, two-sequence, multiple oral dose
crossover design study with a two-day titration period in healthy
male and female volunteers.
[0297] The primary objective of the study was to determine the
steady-state relative bioavailability after multiple closing of
Amantadine HCl ER Tablets, 320 mg once a day compared to the plasma
profiles and pharmacokinetics parameters of an equivalent daily
dose of 320 mg Amantadine HCl Oral syrup (50 mg/5mL) divided into
two equal doses in healthy volunteers of both genders under fasting
conditions.
[0298] In each 9-day study period, a once daily dose of 160 mg
amantadine HCl oral syrup, 50 mg/5 mL (16 mL) was administered for
2 days (titration period). Thereafter, 320 mg daily doses (one
320-mg Amantadine HCl ER Tablet once daily [Treatment A]; or 160 mg
amantadine HCl oral syrup twice daily [Treatment B]) were
administered for 7 consecutive days. There was at least a
7-calendar day washout period between the last morning dose of the
first period and the first dose of the second period.
[0299] During each treatment period, 31 blood samples (4 mL each)
were collected from each subject, for pharmacokinetic analysis at
predetermined times: pre-dose and through 72 hours post-dose on Day
7.
[0300] Result: Following multiple-dose oral administration of
160-mg amantadine HCl syrup twice daily, plasma concentrations
increased rapidly with a median T.sub.max value of 2.00 to 3.00
hours postdose (T.sub.max0-12 and T.sub.max12-24 was 3.00 and 14.00
hours, respectively) and thereafter declined in a log-linear manner
with a terminal phase harmonic mean half-life of 13.7 hours, see
FIGS. 3 and 4.
[0301] Following multiple-dose oral administration of Amantadine
HCl ER 320-mg Tablets once daily, amantadine plasma concentration
increased slowly with a median T.sub.max0-24 value of 7.50 hours
and thereafter declined in a log-linear manner with a terminal
phase harmonic mean half-life of 13.3 hours, see FIGS. 3 and 4.
[0302] Longer T.sub.max values confirmed slower rate of amantadine
absorption from Amantadine HCl ER Tablets; T.sub.max0-24 value was
much later (7.50 hours postdose) for Amantadine HCl ER Tablets
compared to 2.00 to 3.00 hours post dose for amantadine MCI oral
syrup.
[0303] Both formulations achieved steady-state when evaluation was
based on the -24, 0 and 24 hour concentrations for Day 7, thereby
confirming that steady state was achieved by Day 6 (-24 hours),
Mean 12-hour AUC values following the morning (11656.41 ng h/mL)
and evening (11506.74 ng h/mL) syrup doses on Day 7 were similar,
further suggesting steady state was achieved prior to Day 7.
[0304] At steady state, systemic exposure of amantadine from the
once daily Amantadine HCl ER Tablet was similar to the twice daily
syrup, further supporting bioequivalence of the formulations.
[0305] The mean C.sub.avg value for 320-mg Amantadine HCl ER Tablet
administered once daily (947.40 ng/mL) was similar (98% to 99%) to
the mean C.sub.avg value of 160 mg amantadine HCl syrup
administered in the morning (971.37 ng/mL) and evening (958.90
ng/mL). The extent of amantadine absorption from the once-daily
Amantadine HCl ER Tablet as reflected by AUC.sub.0-24 was 97.48% of
that of amantadine HCl syrup. Inspection of amantadine HCl syrup
C.sub.max values for each 12-hour dosing interval and for the
24-hour sample interval revealed that C.sub.max values for twice
daily administration of 160-mg immediate-release amantadine HCl
syrup, 50 mg/5 mL were comparable to that for once daily
administration of 320-mg Amantadine HCl ER Tablets, see Table
4.
[0306] The C.sub.min value following oral administration of one
Amantadine HCl ER Tablet daily was slightly lower than that
following twice daily administration of amantadine HCl syrup; the
geometric least squares mean values were 565.68 and 695.90,
respectively.
Bioequivalence
[0307] At steady state, the 320-mg Amantadine HCl ER Tablet is
bioequivalent to 320 mg/day amantadine HCl syrup (160 mg twice
daily).
Conclusion:
[0308] Amantadine is slowly absorbed from 320-mg Amantadine HCl ER
Tablets. Steady state is achieved by the 6th day of multiple dose
administration of 320-mg Amantadine HCl ER Tablets once daily and
160 mg amantadine HCl oral syrup, 50 mg/5 mL twice daily. At steady
state, 320-mg Amantadine HCl ER Tablets are bioequivalent to 320
mg/day amantadine HCl oral syrup, 50 mg/5 mL (160 mg administered
twice daily).
TABLE-US-00005 TABLE 4 Mean Pharmacokinetic Parameter Values (CV %)
of Amantadine Following Oral Administration of One 320-mg
Amantadine HCl ER Tablet Daily (Treatment-A) or 160 mg Amantadine
HCl Oral Syrup Twice Daily (Treatment-B) to Fasted Healthy
Volunteers, Study I PA- Treatment-A.sup.a Treatment-B.sup.b RAMETER
MEAN C.V. (%) MEAN C.V. (%) C.sub.min0-12 NC NC 747.53 (27.0)
(ng/mL) C.sub.min0-24 612.19 (39.5) 724.34 (28.8) (ng/mL)
C.sub.max0-12 NC NC 1129.02 (19.6) (ng/mL) C.sub.max12-24 NC NC
1140.03 (19.2) (ng/mL) C.sub.max0-24 1275.01 (21.6) 1165.90 (18.9)
(ng/mL) T.sub.max0-12 NC NC 3.00 (2.00-7.50) (hours).sup.c
T.sub.max12-24 NC NC 14.00.sup.e (14.00-20.00) (hours).sup.c
T.sub.max0-24 7.50 (5.00-11.95) 14.00.sup.e (2.00-20.00)
(hours).sup.c AUC.sub.0-12 NC NC 11656.41 (21.8) (ng h/mL)
AUC.sub.12-24 NC NC 11506.74 (22.5) (ng h/mL) AUC.sub.0-24 22737.52
(24.7) 23163.15 (22.0) (ng h/mL) C.sub.avg0-12 NC NC 971.37 (21.8)
(ng/mL) C.sub.avg12-24 NC NC 958.90 (22.5) (ng/mL) C.sub.avg0-24
947.40 (24.7) 965.13 (22.0) (ng/mL) C.sub.pd(-48) 609.08 (36.5)
692.18 (26.2) (ng/mL) C.sub.pd(-24) 662.28 (35.4) 750.17 (26.7)
(ng/mL) C.sub.pd(0) 634.58 (39.6) 736.85 (27.8) (ng/mL) C.sub.24
(ng/mL) 662.70 (33.6) 762.75 (29.8) .lamda..sub.z (hours.sup.-1)
0.0521 (27.6) 0.0505 (27.3) T.sub.half (hours).sup.d 13.3 NA 13.7
NA NA = not applicable; NC = not calculated .sup.aTreatment-A =
Amantadine HCl 320 mg ER tablet once daily .sup.bTreatment-B =
Amantadine HCl 160 mg dose oral solution twice daily, 50 mg/5 mL
.sup.cMedian (range) .sup.dharmonic mean half-life (T.sub.half =
0.693/mean .lamda..sub.z) .sup.e14.00 hours is 2.00 h postdose
Example 3
In Vitro Dissolution
[0309] Amantadine HCl ER Tablets were analyzed in various media to
confirm the extended release of amantadine HCl from Amantadine HCl
ER Tablets. Three Amantadine HCl ER Tablets were manufactured as
described in Example 1 and the dissolution profile data are
presented in FIGS. 5-7. The dissolution profiles of extended
release cores for each of the three strengths (160 mg, 240 mg, and
320 mg) have also been characterized in the following four
dissolution media: 1) water (drug product test method) 2) 0.1 N
HCl, 3) pH 4.5 acetate buffer and 4) pH 6.8 phosphate buffer.
[0310] All 3 strengths (160 mg, 240 mg, and 320 mg of amantadine
HCl) are soluble in 250 mL water, and sink conditions
(concentration is less than 20% of solubility of amantadine
HCl).
3.1 Dissolution in Water
[0311] The dissolution test method for Amantadine MCI ER Tablets is
summarized in Table 5.
[0312] In vitro dissolution data revealed slow release of
amantadine HCl from Amantadine HCl ER Tablets, 160 mg, 240 mg and
320 mg. Slow release of amantadine HCl from Amantadine HCl ER
Tablets was reflected in the relatively long T.sub.max values (9
hours) in the bioavailability studies which confirmed slow
absorption of amantadine after oral administration of Amantadine
HCl ER Tablets, 160 mg, 240 mg and 320 mg.
TABLE-US-00006 TABLE 5 Summary of Dissolution Test Method for
Amantadine HCl ER Tablets, 160 mg, 240 mg and 320 mg Apparatus USP
Apparatus 2 Paddles Temperature 37.0 .+-. 0.5.degree. C. Speed 50
rpm Volume 900 mL Dissolution medium Purified water Draw volume 9
mL Offset.sup.1 3 mL Flush time.sup.1 1 time Flush volume.sup.1 10
mL (recycle Option - ON) Pull times 0.5 hour, 2.5 hour, 4 hour, and
8 hour Analytical method HPLC Test method reference AP-0057
.sup.1Auto-sampler parameters for Distek Evolution 4300 Dissolution
Auto-sampler.
[0313] A summary of the dissolution profiles for the amantadine
extended release tablet cores in water is shown in Table 6.
TABLE-US-00007 TABLE 6 Summary of Dissolution of the Extended
Release Core of Amantadine HCl ER Tablets, 160 mg, 240 mg and 320
mg Strength 320 mg % Dissolved at Time 1 h 3 9 6 5 (Hr) (1-4).sup.1
(4-10) (5-8) (2-7) Mean 2.5 h 27 43 43 39 (Min-Max) (21-36).sup.1
(31-55) (40-47) (29-46) 4 h 55 67 68 66 (47-63).sup.1 (56-78)
(66-71) (58-71) 6 h 79 86 88 88 (73-85).sup.1 (80-93) (87-91)
(83-91) 8 h 92 94 96 95 (88-94).sup.1 (91-97) (95-97) (94-98)
Strength 240 mg % Dissolved at Time 1 h 1 2 1 1 (Hr) (0-3)
(1-5).sup.1 (1-3) (0-2) Mean 2.5 h 16 23 23 22 (Min-Max) (5-32)
(13-45).sup.1 (12-36) (11-31) 4 h 54 54 56 55 (43-71) (45-73).sup.1
(45-67) (42-63) 6 h 85 82 84 84 (76-92) (76-91).sup.1 (77-91)
(75-88) 8 h 96 92 93 94 (99-92) (89-97).sup.1 (91-96) (91-97)
Strength 160 mg % Dissolved at Time (Hr) 1 h 1 2 3 Mean (0-3) (1-3)
(2-8) (Min-Max) 2.5 h 25 24 31 (8-40) (13-34) (18-56) 4 h 65 62 68
(54-74) (49-72) (60-86) 6 h 90 89 91 (86-93) (84-91) (88-96) 8 h 96
96 97 (95-98) (95-97) (95-99) .sup.1Did not meet dissolution
criteria.
Dissolution in Various Media
[0314] The effect of dissolution media on drug release from
Amantadine HCl ER Tablets was also examined. A comparison of the
profiles by strength is provided in FIG. 5 through FIG. 7. As
expected, the dissolution profile of these osmotic pump tablets is
relatively insensitive to the dissolution media. The dissolution
profiles were comparable (f.sub.2.gtoreq.50) in water vs 0.1 N HCl
and pH 4.5 buffer. The profiles were also comparable in 0.1 N HCl
vs pH 6.8 buffer, but they were not considered comparable
(f.sub.2<50) in water or pH 4.5 vs pH 6.8.
[0315] The dissolution profile of Amantadine HCl ER Tablets, 160
mg, 240 mg and 320 mg in water (QC dissolution medium) for each of
the three registration batches was similar with each other.
[0316] After release of the 60-mg immediate-release portion of the
tablet, the release rate of amantadine HCl from Amantadine HCl ER
Tablets in 0.1 N HCl, pH 4.5 acetate buffer, or pH 6.8 phosphate
buffer was similar for all three strengths.
[0317] The dissolution of these osmotic pump tablets is relatively
insensitive to the dissolution media.
3.3 Ethanol Dissolution
[0318] In vitro drug dissolution studies (using 12 tablets) were
conduct to evaluate the potential of alcohol induced dose dumping.
Drug release for all product strengths at ethanol levels of 0%, 5%,
20% and 40% in 0.1N HCl (pH 1.2) and in water (media of the drug
product [QC] dissolution method) were measured employing the
chromatographic parameters. Table 5.
3.3.1 Ethanol impact on Amantadine HCl Immediate-Release
Portion
[0319] All tablet strengths contained 60 mg amantadine HCl in an IR
layer which was coated onto the extended-release tablet core; 60 mg
is 38%, 25% and 19% of the label claim (LC) for the 160-mg, 240-mg
and 320-mg ER tablets, respectively. The amount of ethanol in water
or 0.1N HCl did not affect the amount released in 30 minutes for
any of the strengths; mean amount released values ranged from 53 to
70 mg amantadine HCl.
3.3.2 Impact on Extended Release Properties
3.3.2.1 160 mg ER Tablets
[0320] As shown in, FIG. 8 and FIG. 9, levels of ethanol up to 20%
in acidic and QC media did not affect the release profile of the
160-mg tablets, f.sub.2 values were greater than 50, see Table
7.
TABLE-US-00008 TABLE 7 Summary of Comparison of Amantadine HCl
Dissolution Profiles for 160-mg Amantadine HCl ER Tablets in Acidic
(0.1N HCl) or QC (Water) Media Containing 0%, 5%, 20% and 40%
Ethanol Amount Amount dissolved dissolved (mg) in (% LC) in
Dissolution Media f.sub.2 value 2 hours 2 hours 0% EtOH/0.1N HCl NA
69 mg 43% 5% EtOH/0.1N HCl 90 70 mg 44% 20% EtOH/0.1N HCl 65 83 mg
52% 40% EtOH/0.1N HCl 46 101 mg 63% 0% EtOH/water NA 69 mg 43% 5%
EtOH/water 77 77 mg 48% 20% EtOH/water 57 90 mg 56% 40% EtOH/water
42 106 mg 66%
[0321] Compared to 0% ethanol, the amount released over the 2-hour
period in 40% ethanol increased by only 32 mg and 37 mg in 0.1 N
HCl and water, respectively (32% and 37% of the 100 mg amantadine
HCl in the extended-release tablet core of 160-mg ER tablet).
Inspection of the dissolution profiles revealed that the Amantadine
HCl ER 160-mg Tablets maintained their extended-release properties.
The profile maintained its pseudo-zero order characteristic; the
release profile was linear from 30 minutes to 120 minutes.
Moreover, the maximum amount released in 2 hours was only 101 mg or
106 mg amantadine HCl, approximately one-half of an amantadine HCl
oral solution dose of 200 mg.
[0322] These results confirm that Amantadine HCl ER 160-mg Tablets
do not dose dump in ethanol solutions containing up to 40% ethanol,
as shown in Table 8 and Table 9.
TABLE-US-00009 TABLE 8 160-mg Amantadine HCl ER Tablets--Mean
Amount Amantadine HCl Released in 0.1N HCl and 0%, 5%, 20% and 40%
Ethanol Over a Two-Hour Period Mean Amount Released (% Label Claim)
by Sample Time (minutes) % 15 30 45 60 75 90 105 120 Ethanol min
min min min min min min min 0 35 38 38 38 39 40 41 43 5 33 36 37 37
38 40 42 44 20 32 35 37 39 41 45 49 52 40 30 35 39 45 50 55 59 63
Mean Amount Released (mg) by Sample Time (minutes) % 15 30 45 60 75
90 105 120 Ethanol min min min min min min min min 0 56 61 61 61 62
64 66 69 5 53 58 59 59 61 64 67 70 20 51 56 59 62 66 72 78 83 40 48
56 62 72 80 88 94 101
TABLE-US-00010 TABLE 9 160-mg Amantadine HCl ER Tablets--Mean
Amount Amantadine HCl Released in Water and 0%, 5%, 20% and 40%
Ethanol Over a Two-Hour Period Mean Amount Released (% Label Claim)
by Sample Time minutes) % 15 30 45 105 120 Ethanol min min min 60
min 75 min 90 min min min 0 34 36 36 37 38 39 41 43 5 35 38 38 39
40 42 44 48 20 31 35 37 40 43 47 52 56 40 30 35 41 47 52 58 62 66
Mean Amount Released (mg) by Sample Time (minutes) % 15 30 45 105
120 Ethanol min min min 60 min 75 min 90 min min min 0 54 58 58 59
61 62 66 69 5 56 61 61 62 64 67 70 77 20 50 56 59 64 69 75 83 90 40
48 56 66 75 83 93 99 106
[0323] Characterization of the profile for 8 hours was performed
for the 160-mg tablets. The impact of ethanol on the dissolution
profile was examined further for the 160-mg Amantadine HCl ER
Tablets as this strength was affected the most in the 2-hour
studies. FIG. 10 and FIG. 11 include data from both the 2-hour and
8-hour alcohol interaction studies, and show that levels of ethanol
up to 20% in both acidic and QC media did not affect the release
profile of the 160-mg tablets over the 8 hour period, f.sub.2
values were greater than 50. In 40% ethanol, the f.sub.2 values
were below 50 for both the acidic (f.sub.2=43) and QC media
(f.sub.2=46), but inspection of the dissolution profiles and the
amount of amantadine HCl released confirm that the Amantadine HCl
ER 160-mg Tablets do not dose dump in ethanol solutions containing
up to 40% ethanol.
3.3.2.2 240 mg ER Tablets
[0324] The dissolution study of 240 mg ER Tablets was conducted
using the same test method as shown in Table 5 and in the same
media as 160 mg ER tablets. FIG. 12 and FIG. 13 show the result of
the dissolution study. These results confirmed that Amantadine HCl
ER 240-mg tablets, similar to the 160 mg tablets, do not dose dump
in ethanol solutions containing up to 40% ethanol.
[0325] 3.3.2.3 320 mg ER Tablets
[0326] The dissolution study of 320 mg ER Tablets was conducted
using the same test method as shown in Table 5 and in the same
media as 160 mg ER tablets. FIG. 14 and FIG. 15 show the result of
the dissolution study. These results confirmed that the Amantadine
HCl ER 320-mg tablets, similar to the 160 mg tablets, do not dose
dump in ethanol solutions containing up to 40% ethanol.
3.3.3 Conclusions
[0327] Examination of amantadine HCl dissolution profiles in 40%
ethanol in acidic (0.1 N HCl) or QC (water) media revealed that
Amantadine HCl ER 160-mg, 240-mg, and 320-mg tablets maintained
their extended-release properties. The profile maintained its
pseudo-zero order characteristic; the release profile was linear
from 30 minutes to 120 minutes. The maximum increase in amantadine
HCl release induced by the addition of up to 40% ethanol was only
37%, 34% and 16% of the amount of amantadine HCl in the extended
release tablet core for the 160-mg, 240-mg and 320-mg ER Tablets,
respectively. Moreover, the maximum amount released in 2 hours for
the 160-mg, 240-mg and 320-mg ER Tablets was only 53%, 66% and 87%
of the dose of a 200-mg immediate-release amantadine HCl oral
solution dose.
[0328] Further examination of amantadine HCl dissolution profiles
for 160-mg Amantadine HCl ER Tablets in up to 40% ethanol for 8
hours confirmed the absence of dose dumping.
[0329] Dissolution media containing up to 40% ethanol does not
compromise the release-rate controlling mechanism of the
extended-release tablet core of Amantadine HCl ER Tablets.
Amantadine HCl ER Tablets do not dose dump in ethanol solutions
containing up to 40% ethanol.
Example 4
Study to Confirm Extended Release for Amantadine HCl ER Tablets
[0330] Amantadine HCl immediate-release products (tablet, capsule,
syrup (solution)) are administered twice daily. Amantadine HCl ER
Tablets have been developed for once daily administration. All
three strengths (160 mg, 240 mg, and 320 mg) of Amantadine HCl ER
Tablets provide 60 mg as an immediate-release dose, and the
remainder of the amantadine HCl dose is contained in the
extended-release tablet core.
[0331] In vitro dissolution studies confirm that amantadine HCl is
slowly released over 8 hours from Amantadine HCl ER Tablets, see
FIGS. 5-7.
[0332] The 3 bioavailability studies in Example 2 were also
conducted to further characterize the extended-release properties
of Amantadine HCl ER Tablets.
[0333] The reference material for these bioavailability studies was
Amantadine HCl Oral Syrup, 50 mg/5 nL, an approved drug product
solution, of the active ingredient (amantadine
[0334] Longer T.sub.max values in Study II revealed that amantadine
is slowly absorbed following single oral dose administration of
Amantadine HCl ER Tablets, 160 mg, 240 mg or 320 mg. Amantadine
plasma exposure (C.sub.max, AUC.sub.0-.infin.) increased dose
proportionally following oral administration of single doses of
160-mg, 240-mg, and 320-mg Amantadine HCl ER Tablets. The extent of
amantadine absorption (AUC) from the 160-mg ER tablet is equivalent
to that from 160 mg Amantadine HCl Oral Syrup, 50 mg/5 mL.
[0335] Furthermore, following multiple-dose, once-daily, steady
state administration in Study I, Amantadine HCl ER Tablets 320 mg
were bioequivalent to 320 mg Amantadine HCl Oral Syrup (160 mg
twice daily). Thereby confirming that the drug product's
steady-state performance is equivalent to a currently marketed
non-extended-release drug product that contains the same active
drug ingredient or therapeutic moiety and that is subject to an
approved full new drug application. Inspection of individual and
mean subject data following once-daily oral administration of
Amantadine HCl ER Tablets for 7 days revealed that the amantadine
plasma concentration values 24 hours after dose 5, 6 and 7
administration were consistent, see FIG. 16.
[0336] Study III revealed that amantadine bioavailability following
oral administration of 320-mg, Amantadine HCl ER Tablets with a
high fat meal (fed, Test) is equivalent to fasted (Reference). No
significant food effect was observed, thereby ruling out the
occurrence of any dose dumping.
Example 5
Pharmacokinetics
[0337] Four different formulations were used in this example: 160
mg amantadine HCl syrup (50 mg of amantadine HCl/5 ml, administered
16 ml), in immediate release form; and Amantadine ER 160, 240, 320
mg tablets, manufactured as described in Example 1.
5.1 Absorption, Distribution, and Elimination
Absorption
[0338] Following oral administration of Amantadine ER, the peak
concentration of amantadine was observed in a median time of 7.5
hours (range 5.5 to 12 hours). After a single oral administration
of the Amantadine ER 160 mg tablet (129 mg dose in terms of
amantadine freebase), the mean (CV %) Cmax and AUC were 328 ng/ml
(18%) and 8263 ng.h/ml (18%) respectively. Cmax and AUC with other
dose levels of Amantadine ER increase proportionally.
Effect of Food
[0339] Food does not affect the rate or the extent of absorption of
Amantadine ER.
Distribution
[0340] Amantadine is 67% bound to plasma proteins over a
concentration range of 0.1 to 2.0 .mu.g/mL. The volume of
distribution after intravenous administration is 3-8 L/kg,
suggesting potential extravascular distribution.
Elimination
[0341] Amantadine is mainly eliminated renally, and approximately
85% of the administered dose is excreted unchanged in urine. After
oral administration of a single Amantadine ER 160 mg tablet (129 mg
dose in terms of amantadine free base), the apparent oral clearance
was approximately 11 L/h. The half-life was approximately 16 hours.
Coadministration of quinine or quinidine with amantadine was shown
to reduce the renal clearance of amantadine by about 30%.
Metabolism
[0342] Metabolism accounts for only 5-15% of the total clearance
for amantadine. Eight metabolites of amantadine have been
identified in human urine. One metabolite, an N-acetylated
compound, was quantified in human urine and accounted for 0-15% of
the administered dose in multiple studies. The contribution of this
metabolite to efficacy or toxicity is not known.
Excretion
[0343] Amantadine is primarily excreted by glomerular filtration
and tubular secretion. The pH of the urine has been reported to
influence the excretion rate of amantadine.
5.2 Steady State Pharmacokinetic Simulations
[0344] Using the formulations described above, the amantadine
plasma concentration over a period of 24 hours was simulated using
the pharmacokinetic software, NONMEM 7, PDx-POP 5.2 following the
administration of either 200 mg amantadine in an immediate release
formulation bid. (twice per day) or 400 mg amantadine in a
sustained release formulation q.d. (160 mg tablet+240 tablet
administered simultaneously, once per day). As shown in FIG. 17,
the initial slope of the dC/dT for the sustained release
formulation is less than the slope determined for the immediate
release formulation. As shown in FIG. 17 and Table 10, the
sustained release formulation exhibits slightly higher plasma
concentration peaks and longer T.sub.max and T.sub.last compared
with the immediate release formulation. In addition, the sustained
release formulation indicates higher exposures (AUC.sub.0-t)
compared with the immediate release formulation.
TABLE-US-00011 TABLE 10 Amantadine steady state pharmacokinetic
parameters Dose C.sub.max T.sub.max T.sub.last C.sub.last
AUC.sub.0-.tau. cav TMT Regimen ng/mL h h ng/mL h ng/mL ng/mL ER
160 mg + 1532 7.5 24 857 28838 1202 240 mg q24h IR 200 mg q12h 1342
3 12 1002 14413 1201
Example 6
Pharmacokinetics in Special Populations
6.1 Effect of Age
[0345] The apparent oral plasma clearance of amantadine is reduced,
and the plasma half-life and plasma concentrations are increased in
healthy elderly individuals age 60 and older. After single dose
administration of 25 to 75 mg to 7 healthy, elderly male
volunteers, the apparent plasma clearance of amantadine was
0.10.+-.0.04 L/h/kg (range 0.06 to 0.17 L/h/kg) and the half-life
was 29.+-.7 hours (range 20 to 41 hours). Whether these changes are
due to decline in renal function or other age related factors is
not known.
[0346] In clinical studies with Amantadine ER tablets, patients 65
to 85 years of age on average had higher plasma amantadine
concentrations than younger patients.
6.2 Effect of Gender
[0347] In a study of young healthy subjects (n=20), mean renal
clearance of amantadine, normalized for body mass index, was 1.5
fold higher in males compared to females (p<0.032).
6.3 Effect of Renal Impairment
[0348] Compared with otherwise healthy adult individuals, the
clearance of amantadine is significantly reduced in adult patients
with renal insufficiency. The elimination half-life increases two
to three fold or greater when creatinine clearance is less than 40
mL/min/1.73m.sup.2 and averages eight days in patients on chronic
maintenance hemodialysis. Amantadine is removed in negligible
amounts by hemodialysis.
[0349] Renal Impairment--Amantadine ER
[0350] A summary of plasma C.sub.max, T.sub.max, AUC.sub.0-.infin.,
terminal elimination half-life (T-half), apparent clearance (CL/F),
and apparent volume of distribution (Vd/F) following a single
160-mg dose of Amantadine ER in subjects with normal renal function
compared with subjects with moderate and severe renal impairment is
provided in Table 11.
TABLE-US-00012 TABLE 11 Summary of Amantadine ER Pharmacokinetic
Parameters in Patients with Renal Impairment and Control Subjects
with Normal Renal Function C.sub.max T.sub.max
AUC.sub.(0-0-.infin.) T-half CL/F Vd/F (ng/mL) (h) (ng h/mL) (h)
(L/h) (L) Mean Median Mean Mean Mean Mean Renal Function (% CV)
(range) (% CV) (% CV) (% CV) (% CV) Moderate Impairment.sup.1 N 8 8
8 8 8 8 eGFR 30-59 mL/min/1.73 380.0 11.5 33066.1 47.2 5.5 344.8
m.sup.2 (21.4) (9.0-24.0) (31.6) (31.4) (45.2) (26.5) Severe
Impairment.sup.1 N 8 8 8 8 8 8 eGFR <30 mL/min/1.73 344.9 11.0
39031.7 116.3 4.6 799.8 m.sup.2 (22.8) (6.0-14.0) (39.9) (46.6)
(29.9) (68.8) Normal.sup.2 N 8 8 8 8 8 8 281.3 11.0 10108.7 18.5
17.4 448.2 CrCl >89 mL/min (26.4) (8.0-12.2) (260) (13.2) (40.3)
(27.3) .sup.1eGFR estimated by the Modification of Diet in Renal
Disease equation .sup.2CrCl estimated by the Cockcroft-Gault
equation
[0351] The mean renal amantadine clearance was 11 L/h (% CV 41.3),
3.5 L/h (% CV 47.0), and 2.6 L/h (% CV 34.5) in subjects with
normal renal function, moderate, and severe renal impairment,
respectively.
Dosing in Patients with Renal Impairment
[0352] There are no modifications for the recommended initial and
maximum dosage in patients with renal impairment; however,
modifications are contemplated for the titration interval and
frequency of dosing in patients with moderate and severe renal
impairment. Renal Function is estimated by Modification of Diet in
Renal Disease (MDRD) method, expressed as Estimated GFR
(mL/min/1.73 m.sup.2). For Mild renal impairment (60 to 89), the
minimum titration interval is to increase every week and frequency
of dosing regimen is one dose every 24 hours. For Moderate renal
impairment (30 to 59), the minimum titration interval is to
increase every 3 weeks and frequency of dosing regimen is one dose
every 48 hours. For Severe renal impairment (15 to 29), the minimum
titration interval is to increase every 4 weeks and frequency of
dosing regimen is one dose every 96 hours. For End-Stage renal
impairment (below 15), minimum titration interval and frequency of
dosing regimen is contraindicated. It is recommended to monitor
patients with renal impairment for change in renal function,
especially in those with severe renal impairment receiving the
maximum daily dosage of 322 mg.
Example 7
Clinical Studies: Primary and Secondary Efficacy Analysis
[0353] Amantadine HCl ER Tablets as described in Example 1 were
used in Phase 3 clinical studies.
7.1 Overview
[0354] Two randomized, double-blind, placebo-controlled Phase 3
studies (Study A and Study B) evaluated the efficacy and safety of
Amantadine HCl ER Tablets at dosages of 240 mg/day and 320 mg/day
for the treatment of Parkinson's disease (PD) patients with
LID.
7.2 Study Designs--Phase 3 Clinical Studies
Study A
[0355] Study A was a Phase 3, randomized, double-blind,
placebo-controlled, parallel-group, 3-arm, multicenter study. This
was a fixed-dose trial (after a Titration Period) that compared the
efficacy and safety of Amantadine HCl ER tablets with placebo in
subjects 30 to 85 years of age with PD who had LID. Subjects
diagnosed with secondary PD or had a history of pallidotomy or
other ablative surgery for treatment of PD, or had been implanted
with a uni- or bilateral deep brain stimulator, were excluded from
participation in the study.
[0356] Eligible subjects were randomized in a 1:1:1 manner into one
of three treatment groups: Amantadine HCl ER 320 mg, Amantadine HCl
ER 240 mg, or Placebo.
[0357] Subjects assigned to the Amantadine HCl ER 320 mg group
underwent a 2-week dose titration beginning with a 160 mg QD dose
for 1 week, then a 240 mg QD dose for 1 week, and then a 320 mg QD
dose for 12 weeks followed by a dose-taper for 2 weeks. Subjects
assigned to the Amantadine HCl ER 240 mg group underwent a 2-week
dose titration beginning with placebo QD dose for 1 week, then a
160 mg QD close for 1 week, and then a 240 mg QD dose for 12 weeks
followed by a dose-taper for 2 weeks. Subjects assigned to the
Placebo group took placebo tablets QD for 16 weeks.
Study B
[0358] Study B was a Phase 3, randomized, double-blind,
placebo-controlled, parallel-group, 3-arm, multicenter study. This
was a fixed-dose trial (after a Titration Period) that compared the
efficacy and safety of Amantadine HCl ER tablets with placebo in
subjects 30 to 85 years of age with PD who had LID. Subjects
diagnosed with secondary PD or had a history of pallidotomy or
other ablative surgery for treatment of PD, or had been implanted
with a uni- or bilateral deep brain stimulator were excluded from
participation.
[0359] Eligible subjects were randomized in a 1:1:1 manner into one
of three treatment groups: Amantadine HCl ER 320 mg, amantadine HCl
ER 240 mg, or Placebo.
[0360] Subjects assigned to the Amantadine HCl ER 320 mg group
underwent a 2-week dose titration beginning with a 160 mg QD (every
day) dose for 1 week, then a 240 mg QD dose for 1 week, and then a
320 mg QD dose for 22 weeks followed by a dose-taper for 2 weeks.
Subjects assigned to the Amantadine HCl ER 240 mg group underwent a
2-week close titration beginning with placebo QD dose for 1 week,
then a 160 mg QD dose for 1 week, and then a 240 mg QD dose for 22
weeks followed by a dose-taper for 2 weeks. Subjects assigned to
the Placebo group took placebo tablets QD for 26 weeks.
[0361] Study A and Study B were almost identical; the primary
difference between the two studies was the duration of treatment.
The duration of treatment was 16 and 26 weeks for Study A and Study
B, respectively.
Unified Dyskinesia Rating Scale (UDysRS)
[0362] Overview: The Unified Dyskinesia Rating Scale (UDysRS) is
developed to evaluate involuntary movements often associated with
treating Parkinson's disease. There are two primary sections:
[0363] On-Dyskinesia refers to the choreic and dystonic movements
described to the patient as "jerking or twisting movements that
occur when your medicine is working."
[0364] Off-Dystonia were described to the patient as "spasms or
cramps that can be painful and occur when your Parkinson's disease
medications are not taken or are not working."
7.3 Efficacy Results--Pooled Analysis of Phase 3 Studies (Study A
and Study B)
[0365] Table 12 summarizes subject disposition for the Phase 3
Study Population. The Phase 3 Study Population included subjects
from the two Phase 3 studies (Study A and Study B).
TABLE-US-00013 TABLE 12 Subject Disposition by Treatment Group -
Study A and Study B - Phase 3 Study Population Amantadine HCl ER
Amantadine All Subjects 320 mg HCl ER 240 mg Placebo Combined n (%)
n (%) n (%) n (%) Screened 348 Randomized Population 75 75 72 222
ITT Population 75 (100.0) 75 (100.0) 72 (100.0) 222 (100.0)
Completed the Study 46 (61.3) 44 (58.7) 43 (59.7) 133 (59.9)
Discontinued Study by Reason 29 (38.7) 31 (41.3) 29 (40.3) 89
(40.1) Adverse Event 13 (17.3) 8 (10.7) 6 (8.3) 27 (12.2) Lack of
Efficacy 0 (0.0) 0 (0.0) 1 (1.4) 1 (0.5) Lost to Follow-up 0 (0.0)
0 (0.0) 1 (1.4) 1 (0.5) Non-Compliance with Study Drug 0 (0.0) 0
(0.0) 1 (1.4) 1 (0.5) Physician Decision 0 (0.0) 2 (2.7) 1 (1.4) 3
(1.4) Protocol Violation 1 (1.3) 2 (2.7) 1 (1.4) 4 (1.8) Trial
Screen Failure* 0 (0.0) 0 (0.0) 1 (1.4) 1 (0.5) Study Terminated by
Sponsor 8 (10.7) 11 (14.7) 8 (11.1) 27 (12.2) Withdrawal by Subject
6 (8.0) 8 (10.7) 8 (11.1) 22 (9.9) Other 1 (1.3) 0 (0.0) 1 (1.4) 2
(0.9) The denominator for calculating percentages is the number of
subjects in the Randomized Population. *Subject 002-003 was
randomized to study A in error with high serum creatinine levels.
As the subject neared completion of the study, the high serum
creatinine levels were noted and the investigator removed the
subject from the study on Study Day 139 with the reason for
discontinuation recorded as "trial screen failure". ER =
extended-release; ITT = Intention-to-Treat.
[0366] Table 13 presents the results for mean change in Total
UDysRS score from baseline to Day 98 (Visit 7) using stable dose
LOCF for the Phase 3 Intent To Treat ("ITT") Population. The mean
reduction from baseline to Day 98 using stable dose LOCF was 13.5
for the Amantadine HCl ER 320 mg group, 16.5 for the Amantadine HCl
ER 240 mg group, and 9.3 for the Placebo group.
TABLE-US-00014 TABLE 13 Mean Change in Total UDysRS Score from
Baseline to Day 98 Using Stable Dose LOCF - Study A and Study B -
Phase 3 ITT Population Amantadine Amantadine HCl ER HCl ER Visit
320 mg 240 mg Placebo Statistic (N = 75) (N = 75) (N = 72) Visit 2
(Baseline) n 74 74 72 Mean (SD) 37.4 (12.21) 43.3 (13.74) 39.9
(12.94) Visit 7 (Day 98)/Stable Dose LOCF [1] n 66 66 62 Mean (SD)
24.0 (13.03) 26.9 (15.89) 30.3 (13.19) Change from Baseline -13.5
(11.88) -16.5 (15.86) -9.3 (12.39) (SD) The analysis visit window
for Day 98 (Visit 7) for the primary endpoint used stable dose last
observation carried forward (last data point collected after Day 39
and before Day 102). n is the number of subjects with values at
each time point. ER = extended-release; LOCF = last observation
carried forward; SD = standard deviation; UDysRS = Unified
Dyskinesia Rating Scale.
[0367] Table 14 presents the treatment comparisons of the
Amantadine HCl ER 320 mg group and the Amantadine HCl ER 240 mg
group with placebo for mean change in Total UDysRS score from
baseline to Day 98 using stable dose LOU for the Phase 3 ITT
Population. Treatment with Amantadine HCl ER 320 mg resulted in a
significantly larger reduction in Total UDysRS score than placebo
(&42 5.2; p=0.017). Treatment with Amantadine HCl ER 240 mg
also resulted in a significantly larger reduction in Total UDysRS
score than placebo (-5.5; p=0.012).
TABLE-US-00015 TABLE 14 Analysis of Mean Change in Total UDysRS
Score from Baseline to Day 98 Using Stable Dose LOCF - Studies A
and B - Phase 3 ITT Population Treatment Difference (Amantadine HCl
ER vs. Placebo) 95% CI of Treatment Group LS Mean (SE) Difference
Difference P-value Amantadine HCl ER -14.7 (1.51) -5.2 (-9.5, -0.9)
0.017 320 mg Amantadine HCl ER -15.1 (1.52) -5.5 (-9.8, -1.2) 0.012
240 mg Placebo -9.5 (1.55)
7.5.4 Secondary Efficacy Analysis--Change in the Number of Awake
"ON" Hours Without Troublesome Dyskinesias from Baseline to Day 98
Using Stable Dose LOCF
[0368] Table 15 presents the results for mean change in number of
awake "ON" hours without troublesome dyskinesia (without dyskinesia
and with non-troublesome dyskinesia) from baseline to Day 98 using
stable dose LOCF for the Phase 3 ITT Population.
[0369] The mean increase from baseline to Day 98 using stable dose
LOCF was 3.7 hours for the Amantadine HCl ER 320 mg group, 2.3
hours for the Amantadine HCl ER 240 mg group, and 1.5 hours for the
Placebo group.
TABLE-US-00016 TABLE 15 Mean Change in Number of Awake "ON" Hours
Without Troublesome Dyskinesias from Baseline to Day 98 Using
Stable Dose LOCF - Study A and Study B - Phase 3 ITT Population
Amantadine Amantadine Visit HCl ER HCl ER Statistic 320 mg 240 mg
Placebo Visit 2 (Baseline) n 72 72 62 Mean (SD) 9.7 (3.48) 10.0
(3.73) 9.5 (3.51) Visit 7 (Day 98)/Stable Dose LOCF [1] n 75 75 72
Mean (SD) 13.5 (4.50) 12.2 (4.04) 11.3 (3.66) Change from Baseline
(SD) 3.7 (4.40) 2.3 (3.47) 1.5 (3.49) The analysis visit window for
Day 98 (Visit 7) for the secondary endpoint used stable dose last
observation carried forward (last data point collected after Day 39
and before Day 102). n is the number of subjects with values at
each time point.
[0370] Table 16 presents the treatment comparisons of the
Amantadine HCl ER 320 mg group and the Amantadine HCl ER 240 mg
group with placebo for mean change in number of awake "ON" hours
without troublesome dyskinesia from baseline to Day 98 using stable
dose LOCF for the Phase 3 ITT Population.
[0371] Treatment with Amantadine HCl ER 320 mg resulted in a
significantly larger increase in number of awake "ON" hours without
troublesome dyskinesia than placebo (2.3 hours; p<0.001). The
treatment comparison of Amantadine HCl ER 240 mg with placebo was
not statistically significant (p=0.119).
TABLE-US-00017 TABLE 16 Analysis of Mean Change in Number of Awake
"ON" Hours Without Troublesome Dyskinesias from Baseline to Day 98
Using Stable Dose LOCF - Study A and Study B - Phase 3 ITT
Population Treatment Difference (Amantadine HCl ER vs. Placebo) 95%
CI of Treatment Group LS Mean (SE) Difference Difference P-value
Amantadine HCl ER 3.67 (0.42) 2.3 (1.1, 3.5) <0.001 320 mg
Amantadine HCl ER 2.36 (0.42) 1.0 (-0.3, 2.2) 0.119 240 mg Placebo
1.39 (0.45)
7.5.5 Exploratory Efficacy Analyses
[0372] 7.5.5.1 Change in the Number of Awake "OFF" Hours from
Baseline to Day 98 Using Stable Dose LOCF
[0373] Table 17 presents the results for mean change in number of
awake "OFF" hours from baseline to Day 98 using stable dose LOCF
for the Phase 3 ITT Population. The changes in awake "OFF" hours
over time for all treatment groups were small with no meaningful
trends observed.
TABLE-US-00018 TABLE 17 Number of Awake "OFF" Hours from Baseline
to Day 98 Using Stable Dose LOCF - Study A and Study B - Phase 3
ITT Population Amantadine Amantadine Visit HCl ER HCl ER Statistic
320 mg 240 mg Placebo Visit 2 (Baseline) n 68 68 58 Mean (SD) 3.7
(2.45) 3.4 (2.03) 4.2 (2.11) Visit 7 (Day 98)/Stable Dose LOCF [1]
n 72 74 69 Mean (SD) 3.4 (2.45) 3.6 (2.36) 3.7 (2.05) Change from
Baseline (SD) -0.3 (2.12) 0.3 (2.34) -0.3 (2.25) The analysis visit
window for Day 98 (Visit 7) for the primary endpoint used stable
dose last observation carried forward (last data point collected
after Day 39 and before Day 102). n is the number of subjects with
values at each time point.
[0374] Table 18 presents the treatment comparisons of the
Amantadine HCl ER 320 mg group and the Amantadine HCl ER 240 mg
group with placebo for mean change in number of awake "OFF" hours
from baseline to Day 98 using stable dose LOCF for the Phase 3 ITT
Population. No statistically significant treatment differences were
observed.
TABLE-US-00019 TABLE 18 Analysis of Mean Change in Number of Awake
"OFF" Hours from Baseline to Day 98 Using Stable Dose LOCF - Study
A and Study B - Phase 3 ITT Population Treatment Difference
(Amantadine HCl ER vs. Placebo) 95% CI of Treatment Group LS Mean
(SE) Difference Difference P-value Amantadine HCl ER -0.29 (0.244)
-0.26 (-0.97, 0.45) 0.472 320 mg Amantadine HCl ER 0.12 (0.245)
0.15 (-0.57, 0.87) 0.680 240 mg Placebo -0.03 (0.266)
7.5.5.2 Change in the Sum of MDS-UPDRS Parts II and III from
Baseline to Day 98 Using Stable Dose LOCF
[0375] The MDS-UPDRS is a validated scale used to evaluate
different neurological aspects of parkinsonian subjects and is
composed of 4 parts: Part I (non-motor experiences of daily
living), Part II (motor experiences of daily living). Part III
(motor examination) and Part IV (motor complications). The
MDS-UPDRS Parts II and III were completed at screening (Visit 1),
at baseline (Visit 2), at the end of the Titration Period (Visit
4), during the Maintenance Period (Visits 5, 6, and 7) or at the
Premature Termination Visit.
[0376] The MDS-UPDRS Part II score and the MDS-UPDRS Part III score
were derived. The MDS-UPDRS Part II score was calculated as the sum
of the individual scores for Part II (score range is from 0 to 52).
The MDS-UPDRS Part III score was calculated as the sum of the 33
individual scores for Part III (score range is from 0 to 132).
[0377] For the integrated/pooled analysis, the change from baseline
in the sum of MDS-UPDRS Part II and Part III score was analyzed at
Day 98 (Visit 7).
[0378] Table 19 presents the results for mean change in the sum of
MDS-UPDRS Parts II and III from baseline to Day 98 using stable
dose LOCF for the Phase 3 ITT Population. The mean change in the
sum of MDS-UPDRS Parts II and III was -4.3 for the Amantadine HCl
ER 320 mg group, -5.9 for the Amantadine HCl ER 240 mg group, and
-8.3 for the Placebo group.
TABLE-US-00020 TABLE 19 Mean Change in the Sum of MDS-UPDRS Parts
II and III from Baseline to Day 98 Using Stable Dose LOCF - Study A
and Study B - Phase 3 ITT Population Amantadine Amantadine Visit
HCl ER HCl ER Statistic 320 mg 240 mg Placebo Visit 2 (Baseline) n
75 75 72 Mean (SD) 37.3 (17.91) 42.3 (19.52) 42.3 (19.75) Visit 7
(Day 98)/Stable Dose LOCF [1] n 67 66 62 Mean (SD) 34.4 (17.01)
37.3 (18.74) 34.1 (17.85) Change from Baseline (SD) -4.3 (13.65)
-5.9 (14.76) -8.3 (14.61) The analysis visit window for Day 98
(Visit 7) for the primary endpoint used stable dose last
observation carried forward (last data point collected after Day 39
and before Day 102). n is the number of subjects with values at
each time point.
[0379] Table 20 presents the treatment comparisons of the
Amantadine HCl ER 320 mg group and the Amantadine HCl ER 240 mg
group with placebo for mean change in the sum of MDS-UPDRS Parts II
and III from baseline to Day 98 using stable dose LOCF for the
Phase 3 ITT Population. No statistically significant treatment
differences were observed.
TABLE-US-00021 TABLE 20 Analysis of Mean Change in the Sum of
MDS-UPDRS Parts II and III from Baseline to Day 98 Using Stable
Dose LOCF - Study A and Study B - Phase 3 ITT Population Treatment
Difference (Amantadine HCl ER vs. Placebo) 95% CI of Treatment
Group LS Mean (SE) Difference Difference P-value Amantadine HCl ER
-5.3 (1.56) 2.7 (-1.8, 7.1) 0.235 320 mg Amantadine HCl ER -5.3
(1.57) 2.7 (-1.8, 7.1) 0.237 240 mg Placebo -7.9 (1.62)
7.5.5.3 Change in Total UDysRS Score from Baseline to Day 42 and
Day 70
[0380] Table 21 presents the results for mean change in Total
UDysRS score from baseline to Day 42 and Day 70 for the Phase 3 ITT
Population. From baseline to Day 42 and Day 70, respectively, the
mean reduction in the Total UDysRS score was 14.0 and 14.8 for the
Amantadine HCl ER 320 mg group, 16.9 and 17.5 for the Amantadine
HCl ER 240 mg group, and 8.2 and 9.9 for the Placebo group. At both
time points, there were larger reductions in the Total UDysRS score
in the Amantadine HCl ER 320 mg and Amantadine HCl ER 240 mg groups
compared with placebo.
TABLE-US-00022 TABLE 21 Mean Change in Total UDysRS Score from
Baseline to Day 42 and Day 70 - Study A and Study B - Phase 3 ITT
Population Amantadine Amantadine Visit HCl ER HCl ER Statistic 320
mg 240 mg Placebo Visit 2 (Baseline) n 74 74 72 Mean (SD) 37.4
(12.21) 43.3 (13.74) 39.9 (12.94) Visit 5 (Day 42) n 63 69 60 Mean
(SD) 24.2 (13.01) 26.9 (14.16) 30.3 (13.39) Change from Baseline
-14.0 (11.03) -16.9 (14.59) -8.2 (11.25) (SD) Visit 6 (Day 70) n 58
55 54 Mean (SD) 22.4 (12.58) 25.6 (14.12) 28.9 (14.16) Change from
Baseline -14.8 (11.27) -17.5 (14.45) -9.9 (12.23) (SD) n is the
number of subjects with values at each time point.
[0381] Table 22 presents the treatment comparisons of the
Amantadine HCl ER 320 mg group and the Amantadine HCl ER 240 mg
group with placebo for mean change in Total UDysRS score from
baseline to Day 42 and Day 70 for the ITT Population.
[0382] Treatment with Amantadine HCl ER 320 mg and 240 mg both
resulted in a significantly larger reduction in Total UDysRS score
than placebo from baseline to Day 42 and Day 70.
TABLE-US-00023 TABLE 22 Analysis of Mean Change in Total UDysRS
Score from Baseline to Day 42 and Day 70-Study A and Study B-Phase
3 ITT Population Treatment Difference (Amantadine HCl ER vs.
Placebo) LS P-value Visit Treatment Mean 95% CI of versus (Day)
Group N (SE) Difference Difference Placebo Visit 5 Amantadine 63
-15.0 -6.4 (-10.2, 0.001 HCl ER (1.37) 2.5) (Day 42) 320 mg
Amantadine 69 -15.3 -6.6 (-10.5, 0.001 HCl ER (1.33) -2.8) 240 mg
Placebo 60 -8.6 (1.39) Visit 6 Amantadine 58 -16.1 -5.8 (-10.0,
0.007 (Day 70) HCl ER (1.49) 1.6) 320 mg Amantadine 55 -16.2 -5.9
(-10.1, 0,007 HCl ER (1.50) -1.6) 240 mg Placebo 54 -10.3 (1.53) A
mixed effect repeated measure analysis was performed on change from
baseline values with treatment group, visit, and treatment
group-by-visit interaction as fixed effects, patient as a random
effect and baseline score as a covariate.
Overall Conclusions
[0383] The pooled results from two Phase 3 randomized,
double-blind, placebo-controlled studies designed to evaluate the
efficacy and safety of Amantadine HCl ER Tablets with placebo in
subjects with PD who had LID were analyzed. The primary efficacy
endpoint in these studies was the change from baseline to Day 98 in
the Total UDysRS score. The pooled analysis of these Phase 3
studies demonstrated that Amantadine HCl ER tablets, at both 320 mg
and 240 mg administered once daily in the morning, improved
dyskinesia in PD subjects with LID as determined by statistically
significant and clinically meaningful reductions in Total UDysRS
scores.
[0384] The Phase 3 studies enrolled male and female subjects 30 to
85 years of age who had been diagnosed with idiopathic PD who had
levodopa-induced predictable peak-effect dyskinesia considered by
the subject to be problematic and/or disabling. UDysRS and
MDS-UPDRS were administered within 3 hours of the last dose of
levodopa to allow for consistent assessment of peak dose
dyskinesia. The two Phase 3 studies randomized 222 subjects: 75
subjects were randomized to Amantadine HCl ER 320 mg, 75 subjects
to Amantadine HCl ER 240 mg, and 72 subjects to placebo. One
hundred thirty-three subjects completed the respective studies.
[0385] Subjects recruited for the Phase 3 studies were typical of a
population with PD who had LID. To enter the studies all subjects
were required to be currently treated with levodopa. The baseline
mean dose of levodopa was 735 mg. For all subjects, the mean
baseline Total UDysRS score was 40. Across all treatment groups,
the mean Hoehn & Yahr Stage was 2.
[0386] The primary analysis window was Day 98 (Visit 7) using
stable dose LOCF, which included the last data point collected
after Day 39 and before Day 102. The LS mean reduction in Total
UDysRS score was 14.7 for the Amantadine HCl ER 320 mg group, 15.1
for the Amantadine HCl ER 240 mg group, and 9.5 for the Placebo
group. From baseline to Day 98 with stable dose LOCF, treatment
with Amantadine HCl ER 320 mg resulted in a significantly larger
reduction in Total UDysRS score than placebo (-5.2; p=0.017).
Treatment with Amantadine HCl ER 240 mg also resulted in a
significantly larger reduction in Total UDysRS score than placebo
(-5.5; p=0.012) from baseline to Day 98 with stable dose LOCF.
[0387] A key secondary endpoint in the Phase 3 trials was the
change in the number of awake "ON" hours without troublesome
dyskinesia from baseline to Day 98 using stable dose LOGE,
Treatment with Amantadine HCl ER 320 mg resulted in a larger
increase in the number of awake "ON" hours without troublesome
dyskinesia than placebo (2.3 hours; p<0.001). Treatment with
Amantadine HCl ER 240 mg resulted in a mean increase in the number
of awake "ON" hours without troublesome dyskinesia, however, the
treatment difference was not statistically significant compared
with placebo (1.0 hours; p=0.119).
[0388] MDS-UPDRS Part II and III was used to assess any potential
worsening of PD symptoms during the study. There was little change
in the sum of MDS-UPDRS Parts II and III compared with placebo at
both dose levels of Amantadine HCl ER, which suggests that
treatment with Amantadine HCl ER did not worsen PD symptoms.
[0389] In the analysis of the primary and secondary efficacy
parameters by subgroups, there were larger mean reductions in Total
UDysRS score observed in subjects who had more severe LID (baseline
Total UDysRS scores>median) compared to subjects with less
severe LID (baseline Total UDysRS scores median). There were larger
mean reductions in Total UDysRS observed in the subgroup of
subjects enrolled outside the US compared to those subjects
enrolled at sites in the US. There were no noteworthy trends in
mean change in Total UDysRS scores or in mean change in awake "ON"
hours without troublesome dyskinesia from baseline to Day 98 using
stable dose LOCF based on subpopulations of age, race, gender, or
baseline levodopa dose categories (.ltoreq.median vs. >median
dose).
[0390] In the pooled efficacy analysis from Study A and Study B,
treatment with Amantadine HCl ER 320-mg and 240-mg tablets for 12
weeks was effective in improving dyskinesia in PD subjects with LID
as measured by objective and subjective measures. Both doses
produced statistically significant reductions in Total UDysRS
score, and Amantadine HCl ER 320 mg was associated with a
statistically significant increase in awake "ON" hours without
troublesome dyskinesia.
Example 8
Safety
[0391] The safety of Amantadine ER tablets, prepared according to
Example 1, was evaluated in two placebo-controlled clinical studies
in the U.S., Canada, and Europe. Adverse events were consistent and
no new or unexpected safety issues were reported. Throughout the
study, the most frequently reported Treatment-emergent adverse
events (TEAEs) by preferred term were hallucinations (8.1%),
increased dyskinesia (8.1%), fall (7.2%), nausea (7.2%), dry mouth
(5.4%), peripheral edema (5.0%), urinary tract infection (5.0%),
and somnolence (5.0%).
Example 9
Clinical Trials on Patients with Drug-Induced Extrapyramidal
Reactions
[0392] A clinical trial on the effects of amantadine on
drug-induced extrapyramidal reactions is conducted. Inclusion
criteria include patients, both male and female, who are 18 years
old of age and older and who suffer from drug-induced
extrapyramidal reactions. The patients exhibit at least one of the
following symptoms: dystonia (continuous spasms and muscle
contractions), akathisia (motor restlessness), parkinsonism
(characteristic symptoms such as rigidity), bradykinesia (slowness
of movement), tremor, and tardive dyskinesia (irregular, jerky
movements).
[0393] Studies are conducted to evaluate the efficacy and safety of
Amantadine HCl ER Tablets at dosages of 160 mg/day, 240 mg/day and
320 mg/day for the treatment of patients with drug-induced
extrapyramidal reactions.
Study C and D
[0394] These two studies are two fixed-dose trials (after a
Titration Period) that compare the efficacy and safety of
Amantadine HCl ER tablets with placebo in subjects 18 to 85 years
of age with drug-induced extrapyramidal reactions. Eligible
subjects are randomized in a 1:1:1:1 manner into one of four
treatment groups: Amantadine HCl ER 320 mg, Amantadine HCl ER 240
mg, Amantadine HCl ER 160 mg, or Placebo.
[0395] Subjects assigned to the Amantadine HCl ER 320 mg group
undergo a 2-week dose titration beginning with a 160 mg QD dose for
1 week, then a 240 mg QD dose for 1 week, and then a 320 mg QD dose
for 12 weeks or 22 weeks followed by a dose-taper for 2 weeks.
Subjects assigned to the Amantadine HCl ER 240 rng group undergo a
2-week dose titration beginning with placebo QD dose for 1 week,
then a 160 mg QD dose for I week, and then a 240 mg QD dose for 12
weeks or 22 weeks followed by a dose-taper for 2 weeks. Subjects
assigned to the Amantadine HCl ER 160 mg group begin with placebo
QD dose for 1 week, and then a 160 mg QD dose for 15 weeks or 25
weeks. Subjects assigned to the Placebo group take placebo tablets
QD for 16 weeks or 26 weeks.
[0396] During the Titration Period, patients randomized to the
Amantadine ER 240 mg treatment group receive placebo daily for one
week, then Amantadine ER 160 mg daily for one week, before
increasing to the 240 mg once daily maintenance dose. Patients in
the Amantadine ER 320 mg treatment group receive Amantadine ER 160
mg daily for one week, then Amantadine ER 240 mg daily for one
week, before increasing to the 320 mg once daily maintenance dose.
The 2-week dose controlled Taper Period follows the 12-week and
26-week Maintenance Periods, respectively. During the Taper Period,
patients receiving Amantadine ER 240 mg daily are withdrawn from
study medication by receiving Amantadine ER 160 mg daily for 1
week, then placebo for 1 week. Patients receiving Amantadine ER 320
mg daily are withdrawn from study medication by receiving
Amantadine ER 240 mg daily for 1 week, then Amantadine ER 160 mg
for 1 week.
[0397] Study C and Study D are almost identical; the primary
difference between the two studies is the duration of treatment.
The duration of treatment is 16 and 26 weeks for Study C and Study
D, respectively.
[0398] For efficacy assessments, the patients are assessed with the
following rating scales that are commonly used to assess the
severity of movement disorders: Simpson-Angus Scale (SAS), Barnes
Akathisia Rating Scale (BARS), Abnormal Involuntary Movement Scale
(AIMS), and Extrapyramidal Symptom Rating Scale (ESRS).
* * * * *
References