U.S. patent application number 14/863051 was filed with the patent office on 2016-09-15 for amantadine compositions and methods of use.
The applicant listed for this patent is Adamas Pharmaceuticals, Inc.. Invention is credited to Michael Coffee, Gangadhara Ganapati, Ashok Katdare, Gayatri Sathyan, Efraim Shek, Kavita Vermani, Gregory T. Went.
Application Number | 20160263054 14/863051 |
Document ID | / |
Family ID | 44115504 |
Filed Date | 2016-09-15 |
United States Patent
Application |
20160263054 |
Kind Code |
A1 |
Went; Gregory T. ; et
al. |
September 15, 2016 |
AMANTADINE COMPOSITIONS AND METHODS OF USE
Abstract
Methods of nighttime administration of amantadine to reduce
sleep disturbances in patient undergoing treatment with amantadine
are described, as well as compositions of extended release
amantadine that are suitable for nighttime administration.
Inventors: |
Went; Gregory T.; (Mill
Valley, CA) ; Sathyan; Gayatri; (Bangalore, IN)
; Vermani; Kavita; (Fremont, CA) ; Ganapati;
Gangadhara; (Palo Alto, CA) ; Coffee; Michael;
(Tiburon, CA) ; Shek; Efraim; (Pleasanton, CA)
; Katdare; Ashok; (Berkeley, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Adamas Pharmaceuticals, Inc. |
Emeryville |
CA |
US |
|
|
Family ID: |
44115504 |
Appl. No.: |
14/863051 |
Filed: |
September 23, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14523565 |
Oct 24, 2014 |
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14863051 |
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14267597 |
May 1, 2014 |
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14523565 |
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12959321 |
Dec 2, 2010 |
8741343 |
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14267597 |
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61266053 |
Dec 2, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/14 20130101; A61K
9/5026 20130101; A61K 9/0053 20130101; A61K 9/5047 20130101; A61K
31/198 20130101; A61K 9/4891 20130101; A61K 9/5078 20130101; A61P
25/16 20180101; A61K 9/5015 20130101; A61P 25/20 20180101; A61P
25/14 20180101; A61K 9/4808 20130101; A61K 9/48 20130101; A61K
9/0004 20130101; A61K 9/50 20130101; A61K 31/13 20130101; A61K
9/0002 20130101; A61P 25/00 20180101; A61P 25/28 20180101 |
International
Class: |
A61K 31/13 20060101
A61K031/13; A61K 9/50 20060101 A61K009/50; A61K 9/00 20060101
A61K009/00 |
Claims
1. A pharmaceutical composition consisting of (i) 110 mg to 445 mg
of a drug selected from the group consisting of amantadine and
pharmaceutically acceptable salts thereof and (ii) at least one
excipient, wherein the composition is suitable for once daily, oral
administration to a human subject at a time such that the drug does
not interfere with sleep, wherein at least one of said excipients
modifies the release of the drug to provide an extended release
form, and wherein administration of the composition provides a Tmax
of 6 to 18 hours as measured in a single dose human pharmacokinetic
study and once daily administration provides a C-ave-day to
C-ave-night ratio of 1.1 to 1.9 as determined in a multiple dose
human pharmacokinetic study.
2. The composition of claim 1, wherein administration of the
composition provides a Tmax of 6 to 9 hours as measured in a single
dose human pharmacokinetic study.
3. The composition of claim 1, wherein administration of the
composition provides a Tmax of 8 to 18 hours as measured in a
single dose human pharmacokinetic study.
4. The composition of claim 3, wherein the composition is suitable
for administration is 0 to 4 hours before bedtime.
5. The composition of claim 1, wherein administration of the
composition provides a Cmax of 1.0 to 2.8 ng/ml per mg amantadine
and an AUC0-inf of 40 to 75 ng*hr/ml per mg amantadine as
determined in a single dose human pharmacokinetic study.
6. The composition of claim 1, wherein once daily administration of
the composition provides a steady state plasma concentration
profile characterized by a Cmax of 2.4 to 4.2 ng/ml per mg of
amantadine as determined in a multiple dose human pharmacokinetic
study.
7. The composition of claim 1, wherein once daily administration of
the composition provides a steady state plasma concentration
profile characterized by a Cmin of 1.1 to 2.6 ng/ml per mg of
amantadine as determined in a multiple dose human pharmacokinetic
study.
8. The composition of claim 1, wherein once daily administration of
the composition provides a steady state plasma concentration
profile characterized by an AUC0-24 of 44 to 83 ng*hr/ml per mg of
amantadine as determined in a multiple dose human pharmacokinetic
study.
9. The composition of claim 1, wherein at least some of the drug is
in an immediate release form.
10. The composition of claim 1, wherein at least 50% of the drug is
in the extended release form.
11. The composition of claim 1, wherein at least 75% of the drug is
in the extended release form.
12. The composition of claim 1, wherein at least 90% of the drug is
in the extended release form.
13. The composition of claim 1, wherein administration of the
composition provides a single dose AUC0-inf per mg amantadine that
is equivalent to that of a 100 mg tablet of an immediate release
formulation of amantadine HCl.
14. The composition of claim 1, wherein once daily administration
of the composition maximizes the daytime plasma exposure to
amantadine while minimizing night plasma exposure at steady
state.
15. The composition of claim 1, wherein once daily administration
of the composition provides maximum benefit in morning hours.
16. The composition of claim 1, wherein the composition is
therapeutically effective for the treatment of Parkinson's
disease.
17. The composition of claim 1, wherein the human subject has been
diagnosed with Parkinson's disease.
18. The composition of claim 1, wherein the human subject suffers
from dyskinesia.
19. The composition of claim 18, wherein the dyskinesia is levodopa
induced dyskinesia.
20. The composition of claim 18, wherein the composition reduces
the frequency or severity of dyskinesia.
21. The composition of claim 1, wherein the extended release form
is an osmotic dosage form.
22. The composition of claim 1, wherein the amantadine or a
pharmaceutically acceptable salt thereof is 220 to 445 mg.
23. The composition of claim 1, wherein the drug is 40% to 65% of
the composition.
Description
CROSS-REFERENCE
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/523,565, filed Oct. 24, 2014, which is a
continuation of U.S. patent application Ser. No. 14/267,597, filed
May 1, 2014, which is a continuation of U.S. patent application
Ser. No. 12/959,321, filed Dec. 2, 2010, now U.S. Pat. No.
8,741,343, which claims benefit of U.S. Provisional Application No.
61/266,053, filed Dec. 2, 2009, all of which applications are
incorporated herein by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] The field of the invention is extended release compositions
of amantadine and uses thereof.
[0003] Amantadine is indicated for various conditions that can be
treated by NMDA receptor antagonists including the treatment of
idiopathic Parkinson's disease (Parlysis Agitans), postencephalitic
Parkinsonism, and symptomatic Parkinsonism which may follow injury
to the nervous system by carbon monoxide intoxication. Amantadine
also has activity as a viral M2 channel inhibitor and is used for
the prophylaxis and treatment of infection of viral diseases,
especially influenza A virus.
[0004] Currently marketed forms of amantadine are immediate release
formulations that are typically administered two or more times a
day. Amantadine's use is limited by dose related CNS side effects
including dizziness, confusion, hallucinations, insomnia and
nightmares (Gracies J M, Olanow C W; Current and Experimental
Therapeutics of Parkinson's Disease; Neuropsychopharmacology: the
Fifth Generation of Progress, p. 1802; American College of
Neuropsychopharmacology 2002), which can be particularly
exacerbated when amantadine is administered at night.
[0005] It is known that immediate release amantadine can act as a
stimulant, causing insomnia and sleep disturbance. Therefore, the
last dose is typically administered no later than 4 pm in order to
minimize these side effects. Such dosing of amantadine results in
peak plasma amantadine concentrations occurring in the evening or
night, and very low plasma concentrations in the morning.
[0006] Extended release forms of amantadine have been described in
the art. U.S. Pat. No. 5,358,721, to Guittard et al., and U.S. Pat.
No. 6,217,905, to Edgren et al., each disclose an oral osmotic
dosage form comprising an antiviral or anti-Parkinson's drug,
respectively, where in each case amantadine is listed as a possible
drug to be utilized in the dosage form. U.S. Pat. No. 6,194,000, to
Smith et al., discloses analgesic immediate and controlled release
pharmaceutical compositions utilizing NMDA receptor antagonists,
such as amantadine, as the active agent. U.S. Patent Appl.
Publication Nos. US 2006/0252788, US 2006/0189694, US 2006/0142398,
and US 2008/0227743, all to Went et al., each disclose the
administration of an NMDA receptor antagonist, such as amantadine,
optionally in controlled release form.
SUMMARY OF THE INVENTION
[0007] The inventors have identified a need in the art for improved
formulations of amantadine that result in a patient having higher
plasma concentrations of amantadine upon waking in the morning
without adversely affecting sleep. Further, the inventors have
identified a need in the art for a method of administering
amantadine in the late afternoon or evening, e.g. after 4 pm, which
reduces side effects of insomnia and sleep disturbance and provides
effective plasma concentrations of amantadine upon waking.
[0008] Therefore, there exists a need in the art for improved
methods of amantadine therapy which can be administered to a
patient shortly before they wish to sleep (e.g., at bedtime)
without causing insomnia or sleep disturbance. In addition, there
is a need for an amantadine therapy which can be taken by the
patient before they go to sleep and then provides a suitable plasma
concentration of amantadine when they wake up, e.g. in the morning,
after a full night's sleep.
[0009] In addition, many Parkinson's disease patients have
difficulty swallowing and are on multiple medications. Hence there
is a need for amantadine therapy that delivers a therapeutically
effective dose of the drug, can be administered once daily and is
in an oral dosage form that is small in size and does not unduly
increase the pill burden.
[0010] One aspect of the invention is a method of administering
amantadine to a patient in need thereof, said method comprising
orally administering an extended release (ER) composition
comprising amantadine, or a pharmaceutically acceptable salt
thereof, less than three hours before bedtime (i.e. the time at
which the subject wishes to go to sleep for the night). This aspect
also includes the use of such compositions and the use of
amantadine for the manufacture of a medicament as described below.
Alternatively, the composition is administered less than about 4
hours before bedtime.
[0011] In a second aspect, the invention provides a method of
reducing sleep disturbance in a human subject undergoing treatment
with amantadine, said method comprising administering an extended
release (ER) composition comprising amantadine, or a
pharmaceutically acceptable salt thereof, less than about three
hours before bedtime (i.e. the time at which the subject wishes to
go to sleep for the night). This aspect also includes the use of
such compositions and the use of amantadine for the manufacture of
a medicament as described below. Alternatively, the composition is
administered less than about 4 hours before bedtime.
[0012] In a third aspect, the invention provides a method of
treating levodopa induced dyskinesia, or fatigue, or dementia, or
any other symptom of Parkinson's disease, said method comprising
administering an extended release (ER) composition comprising
amantadine, or a pharmaceutically acceptable salt thereof, less
than about three hours before bedtime (i.e. the time at which the
subject wishes to go to sleep for the night). This aspect also
includes the use of such compositions and the use of amantadine for
the manufacture of a medicament as described below.
[0013] In a fourth aspect, the invention provides a method of
treating brain injury, brain trauma, dementia, Alzheimer's disease,
stroke, Huntington's disease, ALS, Multiple Sclerosis,
neurodegenerative diseases, dementias, cerebrovascular conditions,
movement disorders, cranial nerve disorders, neuropsychiatric
disorders, said method comprising administering an extended release
(ER) composition comprising amantadine, or a pharmaceutically
acceptable salt thereof, less than about three hours before bedtime
(i.e. the time at which the subject wishes to go to sleep for the
night). This aspect also includes the use of such compositions and
the use of amantadine for the manufacture of a medicament as
described below.
[0014] In one embodiment of any of the above aspects,
administration occurs less than two and a half, less than two, less
than one and a half, less than one or less than half hour before
bedtime (i.e. the time at which the subject wishes to go to sleep
for the night).
[0015] In one embodiment of any of the above aspects the patient
has been diagnosed with Parkinson's disease.
[0016] In one embodiment of any of the above aspects, the
composition is administered once daily. In another aspect, the
daily dose exceeds 200 mg, and is given in 1, 2 or 3 capsules of
size 0, 1 or 2.
[0017] In one embodiment of any of the above aspects,
administration of the composition to a Parkinson's disease patients
results in a significant reduction in levodopa induced dyskinesia
(LID). In a specific embodiment, administration of the composition
results in about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,
55%, 60%, 65%, 70%, 75% or 80% reduction in levodopa induced
dyskinesia. In further embodiments, the reduction in levodopa
induced dyskinesia is measured on a numeric scale that is used by
the FDA to evaluate effectiveness of drugs indicated to reduce LID.
In further specific embodiments, the scale used in measuring the
reduction in LID could be UDysRS, UPDRS Part IV (subscores 32, 33),
Dyskinesia Rating Scale (DRS), Abnormal Involuntary Movement Scale
(AIMS), or other scales developed for this purpose.
[0018] In one embodiment of any of the above aspects,
administration of the composition to a Parkinson's disease patients
results in a significant reduction in Parkinson's disease fatigue.
In a specific embodiment, administration of the composition results
in about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or
60% reduction in Parkinson's disease fatigue. In further specific
embodiments, the reduction in fatigue is measured on a numeric
scale that is used by the FDA to evaluate effectiveness of drugs
indicated to reduce fatigue. In further specific embodiments, the
scale used in measuring the reduction in fatigue could be the
Fatigue Severity Scale (FSS).
[0019] In one embodiment of any of the above aspects,
administration of the composition to a Parkinson's disease patients
results in a significant reduction in Parkinson's disease symptoms.
In a specific embodiment, administration of the composition results
in about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% reduction in
Parkinson's symptoms. In further specific embodiments, the
reduction in Parkinson's symptoms is measured on a numeric scale
that is used by the FDA to evaluate effectiveness of drugs
indicated to reduce Parkinson's symptoms. In further specific
embodiments, the scale used in measuring the reduction in
Parkinson's symptoms could be the Unified Parkinson's Disease
Rating Scale (UPDRS).
[0020] In one embodiment of any of the above aspects, the
composition is added to food, and in a more specific embodiment to
a small amount of soft food (e.g. applesauce or chocolate pudding),
prior to administration. Addition to food may involve a capsule
being opened and the contents sprinkled over the patient's food.
This is advantageous if the patient is unable or unwilling to
swallow the composition.
[0021] In one embodiment of any of the above aspects, there is no
increase in plasma concentration of amantadine for at least one
hour after the administration at steady state plasma
concentrations.
[0022] In one embodiment of any of the above aspects, there is no
increase in the plasma concentration of amantadine for at least two
hours after the administration at steady state plasma
concentrations.
[0023] In one embodiment of any of the above aspects, the
administration of the composition to a human subject at steady
state amantadine plasma concentrations increases the amantadine
plasma concentration by less than 5%, 10%, 15%, 20% or 25% at 1, 2,
2.5 or 3 hours following such administration. For example,
administration of the composition to a human subject at steady
state amantadine plasma concentrations increases the amantadine
plasma concentration by less than 5% at 1, 2, 2.5 or 3 hours
following such administration; or by less than 10% at 1, 2, 2.5 or
3 hours following such administration; or by less than 15% at 1, 2,
2.5 or 3 hours following such administration; or by less than 20%
at 1, 2, 2.5 or 3 hours following such administration; or by less
than 25% at 1, 2, 2.5 or 3 hours following such administration.
[0024] In one embodiment of any of the above aspects the amantadine
has a single dose Tmax of 9 to 15 hours. In a more specific
embodiment, the amantadine has a single dose Tmax of 10 to 14 hours
after administration. In another more specific embodiment, the
amantadine has a single dose Tmax of 11 to 13 hours after
administration.
[0025] In one embodiment of any of the above aspects the amantadine
has a steady state Tmax of 7 to 13 hours. In a more specific
embodiment, the amantadine has a steady state Tmax of 8 to 12 hours
after administration. In another more specific embodiment, the
amantadine has a steady state Tmax of 9 to 11 hours after
administration.
[0026] In one embodiment of any of the above aspects peak plasma
concentration of amantadine is achieved between 6 and 16 hours
after administration of a single dose of the composition. In a more
specific embodiment, peak amantadine plasma concentration is
achieved 8 to 14 hours after administration of a single dose of the
composition. In another more specific embodiment, peak amantadine
plasma concentration is achieved 10 to 12 hours after
administration of a single dose of the composition. In additional
specific embodiments, peak amantadine plasma concentration is
achieved between 6, 7, 8, 9, 10, 11 or 12 hours to about 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours after
administration of a single dose of the composition.
[0027] In one embodiment of any of the above aspects, a once daily
oral administration of the composition to a human subject provides
a steady state plasma concentration profile characterized by a
concentration increase of amantadine of less than 25% at three
hours after the administration. In a more specific embodiment, the
steady state plasma concentration profile is characterized by a
concentration increase of amantadine of less than 25% at four hours
after the administration.
[0028] In one embodiment of any of the above aspects, the
composition is administered once a day and the ratio of Cmax to
Cmin at steady state is 1.5 to 2.0, or, more specifically, 1.7 to
1.9, or, more specifically, about 1.8.
[0029] In one embodiment of any of the above aspects, the steady
state plasma concentration profile following multiple
administrations to a human subject of the composition at bedtime is
characterized by an average plasma concentration during the day
("C-ave-day", defined as the average day time amantadine plasma
concentration as measured in a human PK study) that is 1.1 to 2.0
times the average plasma concentration during the night
("C-ave-night", defined as the average night time amantadine plasma
concentration as measured in a human PK study). In more specific
embodiments the C-ave-day is the average amantadine plasma
concentration as measured between the hours of 5 am, 6 am, 7 am, 8
am or 9 am to the hours of 4 pm, 5 pm, 6 pm, 7 pm or 8 pm; for
example, between the hours of 6 am and 4 pm, between the hours of 7
am and 6 pm, or between the hours of 7 am and 5 pm. The C-ave-night
is the average amantadine plasma concentration as measured between
the hours of 4 pm, 5 pm, 6 pm, 7 pm, 8 pm, 9 pm, 10 pm or 11 pm to
the hours of 5 am, 6 am, 7 am, 8 am or 9 am; for example, between
the hours of 10 pm and 6 am, between the hours of 7 pm and 6 am, or
between the hours of 8 pm and 6 am.
[0030] In one embodiment of any of the above aspects, the steady
state plasma concentration profile following multiple
administrations to a human subject of the composition at bedtime is
characterized by an average plasma concentration during the morning
("C-ave-morning", defined as the average amantadine plasma
concentration as measured in a human PK study during the morning
hours) that is 1.1 to 2.0 times the average plasma concentration
during the night. In one embodiment the C-ave-morning is the
average amantadine plasma concentration as measured between the
hours of 5 am, 6 am, 7 am, 8 am or 9 am to the hours of 11 am,
11:30 am, 12 pm, 12:30 pm or 1:00 pm; for example, between the
hours of 5 am and 11 am, or between the hours of 7 am and 12 pm.
More preferably, the ratio of C-ave-morning/C-ave-night at steady
state is 1.2 to 1.6.
[0031] In one embodiment of any of the above aspects, the steady
state plasma concentration profile following daily administration
of the composition is characterized by an average plasma
concentration during the period 8 hours to 12 hours after
administration ("C-ave-8-12 hrs") that is 1.1 to 2.0 times the
average plasma concentration during the first 8 hours after
administration ("C-ave-0-8 hrs"). More preferably, the ratio of
C-ave-8-12 hrs/C-ave-0-8 hrs at steady state is 1.2 to 1.6.
[0032] In one embodiment of any of the above aspects,
administration of a single dose of the composition to a human
subject provides a plasma concentration profile characterized by: a
fractional AUC from 0 to 4 hours that is less than 5%, and
preferably less than 3% of AUC.sub.0-inf; a fractional AUC from 0
to 8 hours that is about 5 to 15%, and preferably about 8 to 12% of
AUC.sub.0-inf; a fractional AUC from 0 to 12 hours that is about 10
to 40%, and preferably about 15 to 30% of AUC.sub.0-inf; a
fractional AUC from 0 to 18 hours that is about 25 to 60%, and
preferably about 30 to 50% of AUC.sub.0-inf; and a fractional AUC
from 0 to 24 hours that is about 40 to 75%, and preferably about 50
to 70% of AUC.sub.0-inf.
[0033] In one embodiment of any of the above aspects, a once daily
oral administration of the composition to a human subject provides
a steady state plasma concentration profile characterized by: a
fractional AUC from 0 to 4 hours that is about 2 to 25%, and
preferably about 5 to 20% of AUC.sub.24; a fractional AUC from 0 to
8 hours that is about 15 to 50%, and preferably about 20 to 40% of
AUC.sub.24; a fractional AUC from 0 to 12 hours that is about 30 to
70%, and preferably about 40 to 60% of AUC.sub.24: and a fractional
AUC from 0 to 18 hours that is about 60 to 95%, and preferably
about 75 to 90% of AUC.sub.24.
[0034] In one embodiment of any of the above aspects, a once daily
oral administration of the composition to a human subject provides
a steady state plasma concentration profile characterized by: a
fractional AUC from 0 to 8 hours that is about 15 to 40%, and
preferably about 20 to 32% of AUC.sub.24; a fractional AUC from 8
to 16 hours that is about 30 to 50%, and preferably about 35 to 45%
of AUC.sub.24; and a fractional AUC from 16 to 24 hours that is
about 20 to 35%, and preferably about 25 to 33% of AUC.sub.24.
[0035] In one embodiment of any of the above aspects the amantadine
is administered as a pharmaceutically acceptable salt. In a more
specific embodiment, the amantadine is administered as
hydrochloride or amantadine sulfate.
[0036] In one embodiment of any of the above aspects, a total daily
dose of 50 mg to 600 mg of amantadine, or a pharmaceutically
acceptable salt thereof is administered to a patient. More
specifically the daily dose of amantadine or pharmaceutically
acceptable salt thereof administered may be in the range of 100 to
440 mg. In another specific embodiment, the daily dose of
amantadine or pharmaceutically acceptable salt thereof maybe in the
range of 260 to 420 mg. In another embodiment, the daily dose of
amantadine or pharmaceutically acceptable salt thereof administered
exceeds 300 mg per day. In various specific embodiments, the daily
dose of amantadine or pharmaceutically acceptable salt thereof may
be 50 to 75 mg, 70 to 95 mg, 90 to 115 mg, 110 to 135 mg, 130 to
155 mg, 150 to 175 mg, 170 to 195 mg, 190 to 215 mg, 210 to 235 mg,
230 to 255 mg, 250 to 275 mg, 270 to 295 mg, 290 to 305 mg, 300 to
315 mg, 310 to 325 mg, 320 to 335 mg, 330 to 345 mg, 340 to 355 mg,
350 to 365 mg, 360 to 375 mg, 370 to 385 mg, 380 to 395 mg, 390 to
405 mg, 400 to 415 mg, 410 to 425 mg, 420 to 435 mg, 430 to 445 mg
or 440 to 455 mg.
[0037] In one embodiment of any of the above aspects, the
composition comprises 50 mg to 600 mg of amantadine, or a
pharmaceutically acceptable salt thereof. More specifically, the
composition may comprise 100 mg to 450 mg of amantadine, or a
pharmaceutically acceptable salt thereof. Still more specifically,
the composition may comprise 130-210 mg of amantadine, or a
pharmaceutically acceptable salt thereof. In various specific
embodiments, a dosage form containing the composition comprises 50
to 75 mg, 70 to 95 mg, 90 to 115 mg, 110 to 135 mg, 130 to 155 mg,
150 to 175 mg, 170 to 195 mg, 190 to 215 mg, 210 to 235 mg, 230 to
255 mg, 250 to 275 mg, 270 to 295 mg, 290 to 305 mg, 300 to 315 mg,
310 to 325 mg, 320 to 335 mg, 330 to 345 mg, 340 to 355 mg, 350 to
365 mg, 360 to 375 mg, 370 to 385 mg, 380 to 395 mg, 390 to 405 mg,
400 to 415 mg, 410 to 425 mg, 420 to 435 mg, 430 to 445 mg or 440
to 455 mg of amantadine, or a pharmaceutically acceptable salt
thereof. In a more specific embodiment, the composition comprises
about 110, 120, 130, 140, 150, 160 170, 180, 190, 210, or 220 mg
amantadine, or a pharmaceutically acceptable salt thereof. In
another more specific embodiment, the composition comprises 110 mg
amantadine hydrochloride. In another more specific embodiment, the
composition comprises 130 mg amantadine hydrochloride. In another
more specific embodiment, the composition comprises 170 mg
amantadine hydrochloride. In another more specific embodiment, the
composition comprises 210 mg amantadine hydrochloride.
[0038] In one embodiment of any of the above aspects, the
composition is administered as one, two, three or four unit dosage
forms each comprising 100 to 175 mg amantadine, or a
pharmaceutically acceptable salt thereof. In a more specific
embodiment, the composition is administered as two unit dosage
forms each comprising 100 to 175 mg amantadine, or a
pharmaceutically acceptable salt thereof.
[0039] In one embodiment of any of the above aspects, the
composition is administered as one, two, or three unit dosage forms
each comprising 50 to 250 mg amantadine, or a pharmaceutically
acceptable salt thereof. In a more specific embodiment, the
composition is administered as one or two unit dosage forms each
comprising 65 to 220 mg amantadine, or a pharmaceutically
acceptable salt thereof.
[0040] In one embodiment of any of the above aspects, oral
administration of a single dose of the composition to a human
subject in a fasted state provides a maximum plasma concentration
(Cmax) of 1.0 to 2.8 ng/ml per mg of amantadine. In a more specific
embodiment, oral administration of a single dose of the composition
to a human subject in a fasted state provides a maximum plasma
concentration (Cmax) of 1.6 to 2.4 ng/ml per mg of amantadine and
an AUC.sub.0-inf (Area under the concentration-curve curve from t=0
to t=infinity) of 40 to 75 ng*h/mL per mg of amantadine.
[0041] In one embodiment of any of the above aspects, the daily
oral administration of a dose of the composition to a human subject
provides a steady state plasma concentration profile characterized
by at least one of: (i) a Cmax of 2.4 to 4.2 ng/ml per mg of
amantadine, (ii) a Cmin of 1.1 to 2.6 ng/ml per mg of amantadine,
and (iii) an AUC.sub.0-24 of 44 to 83 ng*h/mL per mg of amantadine.
In a more specific example, all three criteria of (i), (ii) and
(iii) are met.
[0042] In a more specific embodiment, the steady state plasma
concentration profile is further characterized by: (iv) no increase
in concentration of amantadine for at least one hour after the
administration; and (v) Cmax/Cmin ratio of 1.5 to 2.0. In a more
specific embodiment, both criteria of (iv) and (v) are met.
[0043] In another more specific embodiment, the steady state plasma
concentration profile is further characterized by at least one of:
(iv) no increase in plasma concentration of amantadine for at least
two hours after the administration; and (v) a Cmax/Cmin ratio of
1.7 to 1.9. In a more specific embodiment, both criteria of (iv)
and (v) are met.
[0044] In one embodiment of any of the above aspects the
composition has an in vitro dissolution profile of amantadine which
shows at least one of (i) not more than 25% dissolution at 2 hours,
(ii) not more 55-85% dissolution at 6 hours, and (iii) at least 80%
dissolution at 12 hours, using a USP Apparatus II (Paddles) at 50
rpm with 500 ml water at 37.degree. C. as the dissolution medium.
In a more specific embodiment two of criteria (i), (ii) and (iii)
are met. In a more specific embodiment, all three of criteria (i),
(ii) and (iii) are met.
[0045] In one embodiment of any of the above aspects the
composition has an in vitro dissolution profile of amantadine which
shows at least one of (i) not more than 25% dissolution at 2 hours,
(ii) not more than 25-55% dissolution at 6 hours, and (iii) at
least 80% dissolution at 12 hours, using a USP Apparatus II
(Paddles) at 50 rpm with 500 ml water at 37.degree. C. as the
dissolution medium. In a more specific embodiment two of criteria
(i), (ii) and (iii) are met. In a more specific embodiment, all
three of criteria (i), (ii) and (iii) are met.
[0046] In one embodiment of any of the above aspects the
composition has an in vitro dissolution profile of amantadine which
shows at least one of (i) not more than 20% dissolution at 1 hour,
(ii) about 25-45% dissolution at 2 hours, (iii) not more than
50-80% dissolution at 4 hours, and (iv) at least 80% dissolution at
8 hours, using a USP Apparatus II (Paddles) at 50 rpm with 500 ml
water at 37.degree. C. as the dissolution medium. In a more
specific embodiment two of criteria (i), (ii), (iii) and (iv) are
met. In a more specific embodiment, all four of criteria (i), (ii),
(iii) and (iv) are met.
[0047] In one embodiment of any of the above aspects the in vitro
dissolution profile of amantadine is further characterized by
release of amantadine of: (i) not more than 10% at 1 hour, or (ii)
30-50% at 4 hours, or (iii) at least 90% at 12 hours using a USP
Apparatus II (Paddles) at 50 rpm with 500 ml water at 37.degree. C.
as the dissolution medium. In a more specific embodiment two of
criteria (i), (ii) and (iii) are met. In a more specific
embodiment, all three criteria of (i), (ii) and (iii) are met.
[0048] In another aspect, the present invention provides a
pharmaceutical composition comprising or consisting of a
pellet-in-capsule, wherein a pellet comprises a core that comprises
a core seed with a mixture of amantadine and a binder coated onto
the core seed, and an extended release coating surrounding the core
comprising ethyl cellulose, a pore forming agent such as
hydroxypropyl methyl cellulose or povidone, and a plasticizer.
[0049] In another aspect, the present invention provides a
pharmaceutical composition for use in the methods of the aspects
described above, wherein said composition is for oral
administration and comprises a capsule for oral administration,
said capsule comprising a plurality of pellets, each pellet
comprising: (a) a pellet core comprising amantadine, or a
pharmaceutically acceptable salt thereof, and (b) an extended
release coating surrounding the pellet core.
[0050] In one embodiment, the extended release coating comprises
ethyl cellulose and at least one of povidone and hydroxypropyl
methyl cellulose, and a plasticizer. In a more specific embodiment,
the extended release coating comprises ethyl cellulose, povidone,
and a plasticizer.
[0051] In one embodiment, the pellet core comprises amantadine and
a binder coated onto a core seed. In one embodiment, the core seed
is a sugar sphere (nonpareil) or microcrystalline cellulose seed
(e.g. Celphere.RTM.). In a more specific embodiment, the core seed
is a microcrystalline cellulose core. In another specific
embodiment, the core seed has a diameter in the range of 100
microns to 1,000 microns. In additional specific embodiments, the
core seed has a diameter of 100, 200, 300, 400, 500, 600 or 700
microns. In preferred specific embodiments, the core seed has a
diameter of less than 500 microns.
[0052] In one embodiment, based on the combined weight of the
pellet core and extended release coating, the amantadine, or a
pharmaceutically acceptable salt thereof, is present in amounts
from 20 to 80 wt %, with a bulk density of 0.3 to 1.2
g/cm.sup.3.
[0053] In one embodiment, based on the combined weight of the
pellet core and extended release coating, the amantadine, or a
pharmaceutically acceptable salt thereof, is present in amounts
from 40 to 60 wt %, with a bulk density of 0.5 to 1.2
g/cm.sup.3.
[0054] In one embodiment, based on the combined weight of the
pellet core and extended release coating, the amantadine, or a
pharmaceutically acceptable salt thereof, is present in amounts
from 60 to 80 wt %, with a bulk density of 0.5 to 1.2
g/cm.sup.3.
[0055] In one embodiment, based on the combined weight of the
pellet core and extended release coating, the binder is present in
amounts from 8 to 25 wt %.
[0056] In one embodiment, based on the combined weight of the
pellet core and extended release coating, the core seed is present
in amounts from 8 to 25 wt %.
[0057] In one embodiment, based on the combined weight of the
pellet core and extended release coating, the ethyl cellulose is
present in amounts from 10 to 20 wt %.
[0058] In one embodiment, based on the combined weight of the
pellet core and extended release coating, the povidone is present
in amounts from 1 to 4 wt %.
[0059] In one embodiment, based on the combined weight of the
pellet core and extended release coating, and the plasticizer is
present in amounts from 1 to 4 wt %.
[0060] In one embodiment, the coated pellet has a diameter in the
range of 200 microns to 1700 micros. In additional specific
embodiments, the coated pellet has a diameter of 200, 300, 400,
500, 600, 700, 800, 900, 1000, 1100, 1200, 1300 or 1500 microns. In
certain specific embodiments, the coated pellet has a diameter of
less than 1000 microns, e.g., from 500 to 1000 microns.
[0061] In one embodiment, based on the combined weight of the
pellet core and extended release coating, the binder is present in
amounts from 5 to 25 wt %.
[0062] In one embodiment, based on the combined weight of the
pellet core and extended release coating, the core seed is present
in amounts from 1 to 15 wt %.
[0063] In one embodiment, based on the combined weight of the
pellet core and extended release coating, the ethyl cellulose is
present in amounts from 5 to 20 wt %.
[0064] In one embodiment, based on the combined weight of the
pellet core and extended release coating, the povidone is present
in amounts from 0.25 to 4 wt %.
[0065] In one embodiment, based on the combined weight of the
pellet core and extended release coating, and the plasticizer is
present in amounts from 0.25 to 4 wt %.
[0066] In one embodiment, the pellet further comprises a seal
coating between the pellet core and the extended release coating.
In some embodiments, an inert coating can be applied to the inert
core prior to drug coating or on drug-coated pellets or on
controlled release coated pellets. In another embodiment, an
enteric coating can be applied to the drug coated pellets or
controlled release pellets.
[0067] In one embodiment, the pellet core comprises a binder,
selected from the group consisting of hydroxypropyl methyl
cellulose, copovidone, and mixtures thereof.
[0068] In one embodiment, the above composition is provided in a
size 3, size 2, size 1, size 0 or size 00 capsule.
[0069] In one embodiment, the therapeutically effective daily dose
of the above composition is administered in no more than two
capsules. In another embodiment, the therapeutically effective
daily dose of the composition is administered in no more than three
size 1 capsules. In another embodiment, the therapeutically
effective daily dose of the composition is administered in no more
than two size 0 capsules. In a still more preferred embodiment, the
therapeutically effective daily dose of the composition is
administered in no more than two size 1 capsules. In another
embodiment, the therapeutically effective daily dose of the
composition is administered in no more than three size 2
capsules.
[0070] In a preferred embodiment, the above composition is provided
in an amount of 50 to 110 mg of amantadine or a pharmaceutically
acceptable salt thereof in a size 2 capsule, and in the amount of
110 mg to 210 mg of amantadine or a pharmaceutically acceptable
salt thereof in a size 1 capsule. In additional embodiments, the
above composition comprises coated pellets of diameter 300 to 1000
microns, with amantadine or pharmaceutically acceptable salt
thereof content of 40-80% wt % and at a bulk density of 0.5-1.2
g/cm.sup.3. In a further preferred embodiment, the above
composition has an in vitro dissolution profile of amantadine which
shows at least one of (i) not more than 25% dissolution at 2 hours,
(ii) not more than 55-85% dissolution at 6 hours, and (iii) at
least 80% dissolution at 12 hours, using a USP Apparatus II
(Paddles) at 50 rpm with 500 ml water at 37.degree. C. as the
dissolution medium. In a more specific embodiment two of criteria
(i), (ii) and (iii) are met. In a more specific embodiment, all
three of criteria (i), (ii) and (iii) are met.
[0071] In one embodiment, the plasticizer is selected from the
group consisting of medium chain triglycerides, diethyl phthalate,
citrate esters, polyethylene glycol, glycerol, acetylated
glycerides, and castor oil. In a more specific embodiment, the
plasticizer is medium chain triglycerides, e.g. Miglyol 812 N.
[0072] In another aspect, the present invention provides method of
administering amantadine, or a pharmaceutically acceptable salt
thereof, to a human subject in need thereof, said method comprising
orally administering a composition of any of the above aspects.
[0073] In another aspect, the present invention provides a method
of treating Parkinson's disease in a human subject in need thereof,
said method comprising orally administering a composition of any of
the above aspects. In a preferred aspect, the present invention
provides a method of treating disease in a human subject in need
thereof, said method comprising orally administering a composition
of any of the above aspects once daily at nighttime, administering
1, 2 or 3 capsules.
[0074] References to administering amantadine to a subject in need
thereof include treating a patient with a disease or condition
which may be treated, prevented or cured by a NMDA antagonist. More
specifically, administering amantadine to a subject in need thereof
includes treating a patient with Parkinson's Disease, brain injury,
brain trauma, dementia, Alzheimer's disease, stroke, Huntington's
disease, ALS, Multiple Sclerosis, neurodegenerative diseases,
dementias, cerebrovascular conditions, movement disorders, cranial
nerve disorders, neuropsychiatric disorders.
BRIEF DESCRIPTION OF THE DRAWINGS
[0075] FIG. 1 shows the dissolution profiles for three amantadine
ER formulations, A, B, C referred to in Example 3.
[0076] FIGS. 2A and 2B show the mean plasma concentration-time
curves after administration of amantadine IR twice daily (A) and
amantadine ER once daily (B) to healthy, adult, male and female
subjects under fasting conditions on days 1 and 9.
[0077] FIG. 3 shows a plot of mean plasma concentration of
amantadine versus time curves after administration of amantadine IR
twice daily and amantadine ER once daily to healthy, adult, male
and female subjects under fasting conditions on day 9.
[0078] FIG. 4 shows the simulated mean plasma concentration of
amantadine versus time curves following multiple dose
administration of various strengths of immediate release amantadine
dosed twice or thrice daily and various strengths of amantadine ER
administered once daily.
[0079] FIG. 5 shows a plot of mean (SD) plasma amantadine
concentrations versus scheduled time for four (4) amantadine
treatments.
[0080] FIG. 6 shows a semi-logarithmic mean (SD) plasma amantadine
concentrations versus scheduled time for four (4) amantadine
treatments.
[0081] FIG. 7 shows simulated steady state plasma concentration
time profiles for the ER amantadine formulations as described in
Example 12. The ER amantadine formulation 2, administered once
daily at night, results at steady state in about 4 hour delay in
achieving peak plasma concentration relative to formulation 1.
DETAILED DESCRIPTION OF THE INVENTION
[0082] The invention provides a method of reducing sleep
disturbances in a patient undergoing treatment with amantadine. The
method comprises administering amantadine to a patient in need
thereof, such that the amantadine does not interfere with sleep,
yet provides maximum benefit in morning hours when often needed
most by many patients who take amantadine and further, provides
nighttime coverage of symptoms of Parkinson's disease if needed.
Nighttime coverage includes providing benefit if the patient wakes
up and wishes to return to sleep.
[0083] The method of the invention comprises orally administering
to the patient an extended release (ER) amantadine composition
designed for nighttime administration. The composition is taken
less than three hours before bedtime, and preferably less than two
and a half, less than two, less than one and a half, or less than
one hour before bedtime. Most preferably the ER amantadine
composition is taken less than half hour before bedtime (i.e. the
time at which the subject wishes to go to sleep for the night). As
used herein, a reference to amantadine is intended to encompass
pharmaceutically acceptable salts thereof (e.g. amantadine
hydrochloride, amantadine sulfate, etc.). Alternatively, the
composition is administered less than about 4 hours before
bedtime.
[0084] As used herein, "extended release" includes "controlled
release", "modified release", "sustained release", "timed release",
"delayed release", and also mixtures of delayed release, immediate
release, enteric coated, etc. with each of the above.
[0085] The patient may be diagnosed with any disease or disorder
for which amantadine is prescribed, such as Parkinson's disease,
multiple sclerosis, drug-induced extrapyramidal reactions,
levodopa-induced dyskinesia, and viral diseases (e.g. influenza,
HBV, and HCV). 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 amantadine is used as a
monotherapy or in combination with a monoamine oxidase type B
(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 amantadine. In another
embodiment, the patient has multiple sclerosis and the amantadine
is used for the treatment of fatigue. In other embodiments, the
patient has a brain injury, brain injury, brain trauma, dementia,
Alzheimer's disease, stroke, Huntington's disease, ALS, Multiple
Sclerosis, neurodegenerative diseases, dementias, cerebrovascular
conditions, movement disorders, cranial nerve disorders,
neuropsychiatric disorders.
[0086] An ER amantadine composition for use in the invention is
adapted for nighttime administration by providing a plasma
concentration profile that does not interfere with the subject's
sleep. The composition of the invention will, upon administration
to a human subject, result in a gradual initial increase in plasma
concentration of amantadine such that, at steady state conditions,
administration of a dose of the composition results in an increase
in plasma concentration of amantadine of less than 25% at three
hours after the dose is administered. For example, if a subject's
steady state plasma concentration of amantadine is 500 ng/ml at the
time a dose of the composition is administered, three hours later
the subject's plasma concentration of amantadine will be less than
625 ng/ml. Preferably, the increase in plasma concentration of
amantadine is less than 15%, and most preferably, less than 10%.
Particularly preferred compositions have a plasma concentration
profile further characterized by no increase in amantadine plasma
concentration, or even a decrease (at steady state conditions), for
at least one or, in a preferred embodiment, two hours after the
administration. The composition for use in the invention is further
adapted for bedtime (i.e. the time at which the subject wishes to
go to sleep for the night) administration by providing a maximum
concentration of amantadine (Cmax) in the morning hours. The time
to reach Cmax (Tmax), as measured after single dose administration
in the fasted state, is at least, 8 hours and up to 13, 14, 15, or
16 hours, or at least 9 hours and up to 13, 14, 15, or 16 hours, or
at least 10 hours, and up to 13, 14, 15, or 16 hours. In specific
embodiments, the Tmax is 9 to 15 hours, preferably 10 to 14 hours,
and most preferably 11 to 13 hours. At steady state, with once
daily administration of the composition, the Tmax is 7 to 13 hours,
preferably 8 to 12 hours, and most preferably 9 to 11 hours. A
suitable ER amantadine composition may be further characterized by
having a steady-state Cmax/Cmin ratio of 1.5 to 2.0, and preferably
1.7 to 1.9, resulting in a composition with optimal
fluctuation.
[0087] In more specific, preferred embodiments, the plasma
concentration profile is further characterized by having an AUC
profile after administration of a single dose of the composition
characterized by: a fractional AUC from 0 to 4 hours that is less
than 5%, and preferably less than 3% of AUC.sub.0-inf; a fractional
AUC from 0 to 8 hours that is about 5 to 15%, and preferably about
8 to 12% of AUC.sub.0-inf; a fractional AUC from 0 to 12 hours that
is about 10 to 40%, and preferably about 15 to 30% of
AUC.sub.0-inf; a fractional AUC from 0 to 18 hours that is about 25
to 60%, and preferably about 30 to 50% of AUC.sub.0-inf; and a
fractional AUC from 0 to 24 hours that is about 40 to 75%, and
preferably about 50 to 70% of AUC.sub.0-inf.
[0088] In a further preferred embodiment, the plasma concentration
profile is further characterized by having an AUC profile after
once daily dosing of the composition at steady state conditions
characterized by: a fractional AUC from 0 to 4 hours that is about
2 to 25%, and preferably about 5 to 20% of AUC.sub.24; a fractional
AUC from 0 to 8 hours that is about 15 to 50%, and preferably about
20 to 40% of AUC.sub.24; a fractional AUC from 0 to 12 hours that
is about 30 to 70%, and preferably about 40 to 60% of AUC.sub.24:
and a fractional AUC from 0 to 18 hours that is about 60 to 95%,
and preferably about 75 to 90% of AUC.sub.24.
[0089] In some embodiments of any of the above aspects, the steady
state plasma concentration profile following multiple
administrations to a human subject of the composition at bedtime is
characterized by an average plasma concentration during the day
("C-ave-day", defined as the average day time amantadine plasma
concentration as measured in a human PK study) that is 1.1 to 2.0
times the average plasma concentration during the night
("C-ave-night", defined as the average night time amantadine plasma
concentration as measured in a human PK study). In some
embodiments, the ratio of C-ave-day/C-ave-night at steady state is
within one of the ranges 1.1 to 1.9, 1.1 to 1.8, 1.1 to 1.7, 1.1 to
1.6, 1.1 to 1.5, 1.1 to 1.4, 1.2 to 1.9, 1.2 to 1.7, 1.2 to 1.6,
1.2 to 1.5, 1.3 to 1.9, 1.3 to 1.8, 1.3 to 1.7, 1.3 to 1.6, 1.4 to
1.9, 1.4 to 1.8, 1.4 to 1.7, 1.5 to 1.9, 1.5 to 1.8, 1.5 to 1.7,
1.6 to 1.9, 1.6 to 1.8 or 1.7 to 1.9. In some embodiments, the
ratio of C-ave-day/C-ave-night at steady state is 1.1, 1.15, 1.2,
1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65, 1.7, 1.75, 1.8,
1.85, 1.9, 1.95, or 2.0. In some embodiments, the C-ave-day is the
average amantadine plasma concentration as measured between the
hours of 5 am, 6 am, 7 am, 8 am or 9 am to the hours of 4 pm, 5 pm,
6 pm, 7 pm or 8 pm and the C-ave-night is the average amantadine
plasma concentration as measured between the hours of 4 pm, 5 pm, 6
pm, 7 pm, 8 pm, 9 pm, 10 pm or 11 pm to the hours of 5 am, 6 am, 7
am, 8 am or 9 am. In some embodiments, the C-ave-day is the average
amantadine plasma concentration as measured within any four to
twelve hour period between the hours of 5 am and 8 pm; and the
C-ave-night is the average amantadine plasma concentration as
measured within any four to twelve hour period between the hours of
8 pm and 5 am. In some embodiments, the C-ave-day is the average
amantadine plasma concentration as measured within any four, five,
six, seven, eight, nine, ten, eleven or twelve hour period between
the hours of 5 am and 8 pm; and the C-ave-night is the average
amantadine plasma concentration as measured within any four, five,
six, seven, eight, nine, ten, eleven or twelve hour period between
the hours of 8 pm and 5 am.
[0090] In some embodiments described herein an amantadine
composition is administered to a patient from 0 to 4 hours prior to
bedtime. In some embodiments, the amantadine composition is
administered to a patient from 0 to 3, 0 to 2 or 0 to 1 hours prior
to bedtime. In some embodiments, the amantadine composition is
administered to a patient from 0 to 240 minutes, from 0 to 180
minutes, e.g. from 0 to 120 minutes, from 0 to 60 minutes, from 0
to 45 minutes, from 0 to 30 minutes, from 0 to 15 minutes or from 0
to 10 minutes prior to bedtime. In some embodiments, the amantadine
composition is administered to a patient from 60 to 240 minutes,
from 60 to 180 minutes, from 60 to 120 minutes or from 60 to 90
minutes prior to bedtime.
[0091] It is to be understood that administration to a patient
includes administration by a healthcare professional and self
administration by the patient.
[0092] Unless otherwise specified herein, the term "bedtime" has
the normal meaning of a time when a person retires for the primary
sleep period during a twenty-four hour period of time. While for
the general populace, bedtime occurs at night, there are patients,
such as those who work nights, for whom bedtime occurs during the
day. Thus, in some embodiments, bedtime may be anytime during the
day or night.
[0093] As used herein, unless otherwise indicated, reference to a
plasma concentration profile or a specific pharmacokinetic property
(e.g. Cmax, Cmin, AUC, Tmax, etc.) in a human subject refers to a
mean value obtained from healthy adults s determined in a typical
phase I clinical trial designed to measure pharmacokinetic
properties of a drug (see e.g. Examples 5, 6 and 7, below).
References herein to Tmax refer to values obtained after
administration of a single dose at fasted states, unless otherwise
indicated.
[0094] In some embodiments of the invention, the dose of the
amantadine administered in accordance with the present invention is
within or above the ranges normally prescribed for immediate
release compositions of amantadine. In other embodiments, the doses
of the amantadine administered with the present invention are
higher than the ranges normally prescribed for immediate release
compositions of amantadine. For example, the recommended dose of
amantadine for the treatment of Parkinson's disease is 100 mg
administered twice daily. In limited cases of the patient not
deriving sufficient benefit at that dose and subject to the patient
being able to tolerate such higher dose, the dose may be increased
to 300 mg or 400 mg in divided doses. The most commonly prescribed
doses of amantadine are 100 mg to 200 mg per day, with the latter
administered in divided doses. More than 200 mg (for example 300
mg) is always given in divided doses. For the present invention,
doses of 50 to 600 mg, or more preferably, 200 to 450 mg are
administered for treatment of Parkinson's disease, and the methods
and compositions of the invention may comprise administration of a
dose as defined by any of these ranges. In specific embodiments the
administration of such higher doses may be once daily. In
additional embodiments the administration of such higher doses may
be at night. In additional embodiments the administration of such
higher doses may be in the form of 1, 2 or 3 capsules of size 0, 1
or 2 administered once daily.
[0095] In one embodiment of any of the above aspects the amantadine
is administered as a pharmaceutically acceptable salt. In a more
specific embodiment, the amantadine is administered as
hydrochloride or amantadine sulfate.
[0096] In one embodiment of any of the above aspects, a total daily
dose of 50 mg to 600 mg of amantadine, or a pharmaceutically
acceptable salt thereof is administered to a patient. More
specifically the daily dose of amantadine or pharmaceutically
acceptable salt thereof administered may be in the range of 100 mg
to 440 mg. In another specific embodiment, the daily dose of
amantadine or pharmaceutically acceptable salt thereof maybe in the
range of 260 mg to 420 mg. In another embodiment, the daily dose of
amantadine or pharmaceutically acceptable salt thereof administered
exceeds 300 mg per day. In various specific embodiments, the daily
dose of amantadine or pharmaceutically acceptable salt thereof may
be 50 to 75 mg, 70 to 95 mg, 90 to 115 mg, 110 to 135 mg, 130 to
155 mg, 150 to 175 mg, 170 to 195 mg, 190 to 215 mg, 210 to 235 mg,
230 to 255 mg, 250 to 275 mg, 270 to 295 mg, 290 to 305 mg, 300 to
315 mg, 310 to 325 mg, 320 to 335 mg, 330 to 345 mg, 340 to 355 mg,
350 to 365 mg, 360 to 375 mg, 370 to 385 mg, 380 to 395 mg, 390 to
405 mg, 400 to 415 mg, 410 to 425 mg, 420 to 435 mg, 430 to 445 mg
or 440 to 455 mg.
[0097] In one embodiment of any of the above aspects, the
composition comprises 50 to 600 mg of amantadine, or a
pharmaceutically acceptable salt thereof. More specifically, the
composition may comprise 100 to 450 mg of amantadine, or a
pharmaceutically acceptable salt thereof. Still more specifically,
the composition may comprise 130-210 mg of amantadine, or a
pharmaceutically acceptable salt thereof. In various specific
embodiments, the dosage form comprises 50 to 75 mg, 70 to 95 mg, 90
to 115 mg, 110 to 135 mg, 130 to 155 mg, 150 to 175 mg, 170 to 195
mg, 190 to 215 mg, 210 to 235 mg, 230 to 255 mg, 250 to 275 mg, 270
to 295 mg, 290 to 305 mg, 300 to 315 mg, 310 to 325 mg, 320 to 335
mg, 330 to 345 mg, 340 to 355 mg, 350 to 365 mg, 360 to 375 mg, 370
to 385 mg, 380 to 395 mg, 390 to 405 mg, 400 to 415 mg, 410 to 425
mg, 420 to 435 mg, 430 to 445 mg or 440 to 455 mg of amantadine, or
a pharmaceutically acceptable salt thereof. In a more specific
embodiment, the composition comprises about 110, 120, 130, 140,
150, 160 170, 180, 190, 210, or 220 mg amantadine, or a
pharmaceutically acceptable salt thereof. In another more specific
embodiment, the composition comprises 110 mg amantadine
hydrochloride. In another more specific embodiment, the composition
comprises 130 mg amantadine hydrochloride. In another more specific
embodiment, the composition comprises 170 mg amantadine
hydrochloride. In another more specific embodiment, the composition
comprises 210 mg amantadine hydrochloride.
[0098] In one embodiment of any of the above aspects, the
composition comprises from about 50 mg, 60 mg, 70 mg, 80 mg, 90 mg,
100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180
mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg
of amantadine, or a pharmaceutically acceptable salt thereof to
about 75 mg, 85 mg, 95 mg, 105 mg, 115 mg, 125 mg, 135 mg, 145 mg,
155 mg, 165 mg, 175 mg, 185 mg, 195 mg, 205 mg, 215 mg, 225 mg, 235
mg, 245 mg, 255 mg, 265 mg, 275 mg, 285 mg, 295 mg, 305 mg, 315 mg,
325 mg, 335 mg, 345 mg, 355 mg, 365 mg, 375 mg, 385 mg, 395 mg, 405
mg, 415 mg, 425 mg, 435 mg, 445 mg of amantadine, or a
pharmaceutically acceptable salt thereof.
[0099] In a specific embodiment of the invention, a subject's
entire daily dose of amantadine is administered once, during a
period of less than about three, two or one hours before bedtime
(i.e. the time at which the subject wishes to go to sleep for the
night). In other embodiments, at least one half of the daily dose
of amantadine is taken during said period before bedtime.
Preferably at least 2/3 of the dose of amantadine is taken in said
period before bedtime, with the remainder taken in morning or
afternoon. The morning or afternoon dose of the amantadine may be
provided in a conventional, immediate release dosage form, or in an
extended release form.
[0100] In one embodiment of any of the above aspects,
administration of the composition to a Parkinson's disease patients
results in a significant reduction in levodopa induced dyskinesia.
In a specific embodiment, administration of the composition results
in about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,
65%, 70%, 75% or 80% reduction in levodopa induced dyskinesia. In
further embodiments, the reduction in levodopa induced dyskinesia
is measured on a numeric scale that is used by or accepted by the
FDA or other regulatory agencies to evaluate the effectiveness of
and to approve for licensure drugs for the treatment of LID. In
further specific embodiments, the scale used in measuring the
reduction in LID could be UDysRS, UPDRS Part IV (subscores 32, 33),
Dyskinesia Rating Scale (DRS), Abnormal Involuntary Movement Scale
(AIMS), Rush Dyskinesia Rating Scale, Parkinson Disease Dyskinesia
Scale (PDYS-26), Obeso Dyskinesia Rating Scale (CAPIT), Clinical
Dyskinesia Rating Scale (CDRS), Lang-Fahn Activities of Daily
Living Dyskinesia or other scales developed for this purpose.
[0101] In one embodiment of any of the above aspects,
administration of the composition to a Parkinson's disease patients
results in a significant reduction in Parkinson's disease fatigue.
In a specific embodiment, administration of the composition results
in about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or
60% reduction in Parkinson's disease fatigue. In further specific
embodiments, the reduction in fatigue is measured on a numerical
scale used by or accepted by the FDA or other regulatory agencies
to evaluate the effectiveness of and to approve for licensure drugs
for the treatment of fatigue. In further specific embodiments, the
scale used in measuring the reduction in fatigue could be the
Fatigue Severity Scale (FSS), Fatigue Assessment Inventory,
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT
Fatigue), Multidimensional Fatigue Inventory (MFI-20), Parkinson
Fatigue Scale (PFS-16) and the Fatigue Severity Inventory. In other
specific embodiments, the reduction in fatigue is measured relative
to placebo in a controlled clinical trial. In other embodiments,
the reduction in fatigue is measured relative to baseline in a
controlled clinical trial.
[0102] In one embodiment of any of the above aspects,
administration of the composition to a Parkinson's disease patients
results in a significant reduction in Parkinson's disease symptoms.
In a specific embodiment, administration of the composition results
in about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% reduction in
Parkinson's symptoms. In further specific embodiments, the
reduction in Parkinson's symptoms is measured on a numerical scale
used by or accepted by the FDA or other regulatory agencies to
evaluate the effectiveness of and to approve for licensure drugs
for the treatment of Parkinson's symptoms. In further specific
embodiments, the scale used in measuring the reduction in
Parkinson's symptoms could be the Unified Parkinson's Disease
Rating Scale (UPDRS). Unified Parkinson's Disease Rating Scale
(UPDRS, MDS revision)--Part I: non-motor aspects of experiences of
daily living (13 items), Part II: motor aspects of experiences of
daily living (13 items)--Part III: motor examination (33 scored
items)--Part I: mental status, behavior and mood--Part II:
activities of daily living--Part III: motor examination (27 scored
items) Hoehn and Yahr Staging Scale (Original or Modified).
[0103] In one embodiment of any of the above aspects,
administration of the composition to a Parkinson's disease patients
results in a significant reduction in levodopa induced dyskinesia.
In a specific embodiment, administration of the composition results
in about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%,
65%, 70%, 75% or 80% reduction in levodopa induced dyskinesia. In
further embodiments, the reduction in levodopa induced dyskinesia
is measured on a numeric scale that is used by the FDA to evaluate
effectiveness of drugs indicated to reduce LID. In further specific
embodiments, the scale used in measuring the reduction in LID could
be UDysRS, UPDRS Part IV (subscores 32, 33), Dyskinesia Rating
Scale (DRS), Abnormal Involuntary Movement Scale (AIMS), or other
scales developed for this purpose. In other specific embodiments,
the reduction in LID is measured relative to placebo in a
controlled clinical trial. In other embodiments, the reduction in
LID is measured relative to baseline in a controlled clinical
trial.
[0104] In one embodiment of any of the above aspects,
administration of the composition to a Parkinson's disease patients
results in a significant reduction in Parkinson's disease fatigue.
In a specific embodiment, administration of the composition results
in about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% reduction in
Parkinson's disease fatigue. In further specific embodiments, the
reduction fatigue is measured on a numeric scale that is used by
the FDA to evaluate effectiveness of drugs indicated to reduce
fatigue. In further specific embodiments, the scale used in
measuring the reduction in fatigue could be the Fatigue Severity
Scale (FSS). In other specific embodiments, the reduction in
fatigue is measured relative to placebo in a controlled clinical
trial. In other embodiments, the reduction in fatigue is measured
relative to baseline in a controlled clinical trial.
[0105] In one embodiment of any of the above aspects,
administration of the composition to a Parkinson's disease patients
results in a significant reduction in Parkinson's disease symptoms.
In a specific embodiment, administration of the composition results
in about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% reduction in
Parkinson's symptoms. In further specific embodiments, the
reduction in Parkinson's symptoms is measured on a numeric scale
that is used by the FDA to evaluate effectiveness of drugs
indicated to reduce Parkinson's symptoms. In further specific
embodiments, the scale used in measuring the reduction in
Parkinson's symptoms could be the Unified Parkinson's Disease
Rating Scale (UPDRS). In other specific embodiments, the reduction
in Parkinson's disease symptoms is measured relative to placebo in
a controlled clinical trial. In other embodiments, the reduction in
Parkinson's disease symptoms is measured relative to baseline in a
controlled clinical trial.
Extended Release Formulations
[0106] Extended release amantadine compositions suitable for use in
the method of the invention can be made using a variety of extended
release technologies, such as those described in the patent
publications referenced in the above background section, which
publications are incorporated herein by reference in their
entireties. In some embodiments, the invention is a pellet in
capsule dosage form. In some embodiments, the pellets comprise a
pellet core, which is coated with at least one drug layer and at
least one extended release coating layer. In some embodiments, the
pellets are coated with at least one drug layer, an intermediate
layer such as a seal coat and an extended release coating layer. In
some embodiments, the pellet, the drug layer or both comprise one
or more binders.
[0107] In some embodiments, the dosage unit comprises a plurality
of coated pellets. In some embodiments, the pellets have a diameter
of for example 300 to 1700 microns, in some cases 500 to 1200
microns. The pellets will comprise, for example, inert substrates,
such as sugar spheres, microcrystalline cellulose (MCC) spheres,
starch pellets. In some embodiments, pellets can be prepared by
other processes such as pelletization, extrusion, spheronization,
etc. or combinations thereof. The core pellets will comprise of
amantadine hydrochloride and pharmaceutically acceptable
excipients.
[0108] Coated Pellets
[0109] The pellet cores are coated with the active ingredient,
e.g., amantadine or a pharmaceutically acceptable salt and/or
polymorph thereof. In some embodiments, in addition to the active
ingredient, the pellets also comprise one or more binders, such as
for example hydroxypropyl methyl cellulose, copovidone, povidone,
hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose,
carboxymethyl cellulose etc. In some embodiments, the pellets also
contain one or more additional excipients, such as anti-tack agents
(e.g. talc, magnesium stearate etc.)
[0110] In some embodiments, the pellets cores are coated with a
drug layer comprising active ingredient, and optionally one or more
binders, anti-tack agents and/or solvents by conventional coating
techniques such as fluidized bed coating, pan coating.
[0111] Intermediate Layer Coating
[0112] In some embodiments, the pellets are coated with an
intermediate layer, such as a seal coat. In some embodiments, the
seal coat is adapted to prevent ingredients in the extended release
coating from interacting with ingredients in the pellet core, to
prevent migration of the ingredients in the pellet core from
diffusing out of the pellet core into the extended release layer,
etc. As described herein, the seal coat of the present invention
can comprise one or more film forming polymers including but not
limited to hydroxypropylmethyl cellulose (HPMC), copovidone,
povidone, polyvinyl pyrrolidone, hydroxypropyl cellulose,
hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose
or any combination thereof and the like.
[0113] The seal coat can further comprise other additives like
plasticizers, such as, propylene glycol, triacetin, polyethylene
glycol, tributyl citrate and optionally anti-tacking agents, such
as, magnesium stearate, calcium silicate, magnesium silicate, and
colloidal silicon dioxide or talc.
[0114] Apart from plasticizers and anti-tacking agents as mentioned
above, the seal coat can optionally contain buffers, colorants,
opacifiers, surfactants or bases, which are known to those skilled
in the art.
[0115] Seal coating can be applied to the core using conventional
coating techniques such as fluidized bed coating, pan coating etc.
In some embodiments, the drug coated pellets cores are coated with
a seal coat layer that optionally comprises one or more binders,
anti-tack agents and/or solvents by fluidized bed coating or pan
coating.
[0116] Binders
[0117] In some embodiments, either the pellet cores, the
intermediate coating layer, or both may comprise one or more
binders (e.g., film forming polymers). Suitable binders for use
herein include, e.g.: alginic acid and salts thereof; cellulose
derivatives such as carboxymethylcellulose, methylcellulose (e.g.,
Methocel.RTM.), hydroxypropylmethylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel.RTM.),
ethylcellulose (e.g., Ethocel.RTM.), and microcrystalline cellulose
(e.g., Avicel.RTM.); microcrystalline dextrose; amylose; magnesium
aluminum silicate; polysaccharide acids; bentonites; gelatin;
polyvinylpyrrolidone/vinyl acetate copolymer; crospovidone;
povidone; starch; pregelatinized starch; tragacanth, dextrin, a
sugar, such as sucrose (e.g., Dipac.RTM.), glucose, dextrose,
molasses, mannitol, sorbitol, xylitol (e.g., Xylitab.RTM.), and
lactose; a natural or synthetic gum such as acacia, tragacanth,
ghatti gum, mucilage of isapol husks, polyvinylpyrrolidone (e.g.,
Polyvidone.RTM. CL, Kollidon.RTM. CL, Polyplasdone.RTM. XL-10),
larch arabogalactan, Veegum.RTM., polyethylene glycol, waxes,
sodium alginate, and the like.
[0118] Extended Release Coating
[0119] The pellets are coated with an extended release coating. The
extended release coating is adapted to delay release of the drug
from the coated drug cores for a period of time after introduction
of the dosage form into the use environment. In some embodiments,
the extended release coating includes one or more pH-dependent or
non-pH-dependent extended release excipients. Examples of non-pH
dependent extended release polymers include ethyl cellulose,
hydroxypropylmethyl cellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, carboxymethyl cellulose, copolymer of
ethyl acrylate, methyl methacrylate (e.g. Eudgrait RS) etc.
Examples of pH dependent extended release excipients include
methacrylic acid copolymers, hydroxypropylmethyl cellulose acetate
succinate, hydroxypropylmethyl cellulose phthalate, and cellulose
acetate phthalate etc. The extended release coating may also
include a pore former, such as povidone, polyethylene glycol,
hydroxypropyl cellulose, hydroxypropylmethyl cellulose, etc.,
sugars such as sucrose, mannitol, lactose, and salts, such as
sodium chloride, sodium citrate, etc., a plasticizer, such as
acetylated citrated esters, acetylated glycerides, castor oil,
citrate esters, dibutylsebacate, glyceryl monostearate, diethyl
phthalate, glycerol, medium chain triglycerides, propylene glycol,
polyethylene glycol. The extended release coating may also include
one or more additional excipients, such as lubricants (e.g.,
magnesium stearate, talc etc.).
[0120] Extended release coating can be applied using conventional
coating techniques such as fluidized bed coating, pan coating etc.
The drug coated pellets cores, which optionally comprise a seal
coat, are coated with the extended release coating by fluidized bed
coating.
[0121] Extended Release Excipients (Coating Polymers)
[0122] As described herein, exemplary extended release excipients
include, but are not limited to, insoluble plastics, hydrophilic
polymers, and fatty compounds. Plastic matrices include, but are
not limited to, methyl acrylate-methyl methacrylate, polyvinyl
chloride, and polyethylene. Hydrophilic polymers include, but are
not limited to, cellulosic polymers such as methyl and ethyl
cellulose, hydroxyalkyl celluloses such as hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, and
cross-linked acrylic acid polymers like Carbopol.RTM. 934,
polyethylene oxides and mixtures thereof. Fatty compounds include,
but are not limited to, various waxes such as carnauba wax and
glyceryl tristearate and wax-type substances including hydrogenated
castor oil or hydrogenated vegetable oil, or mixtures thereof.
[0123] In certain embodiments, the plastic material can be a
pharmaceutically acceptable acrylic polymer, including but not
limited to, acrylic acid and methacrylic acid copolymers, methyl
methacrylate, methyl methacrylate copolymers, ethoxyethyl
methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate
copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic
acid alkylamine copolymer poly(methyl methacrylate),
poly(methacrylic acid)(anhydride), polymethacrylate,
polyacrylamide, poly(methacrylic acid anhydride), and glycidyl
methacrylate copolymers.
[0124] In certain other embodiments, the acrylic polymer is
comprised of one or more ammonio methacrylate copolymers Ammonio
methacrylate copolymers are well known in the art, and are
described in NF XVII as fully polymerized copolymers of acrylic and
methacrylic acid esters with a low content of quaternary ammonium
groups.
[0125] In still other embodiments, the acrylic polymer is an
acrylic resin lacquer such as that which is commercially available
from Rohm Pharma under the trade name Eudragit.RTM.. In further
embodiments, the acrylic polymer comprises a mixture of two acrylic
resin lacquers commercially available from Rohm Pharma under the
trade names Eudragit.RTM. RL30D and Eudragit.RTM. RS30D,
respectively. Eudragit.RTM. RL30D and Eudragit.RTM. RS30D are
copolymers of acrylic and methacrylic esters with a low content of
quaternary ammonium groups, the molar ratio of ammonium groups to
the remaining neutral (meth)acrylic esters being 1:20 in Eudragit
RL30D and 1:40 in Eudragit.RTM. RS30D. The mean molecular weight is
about 150,000. Edragit.RTM. S-100 and Eudragit.RTM. L-100 are also
suitable for use herein. The code designations RL (high
permeability) and RS (low permeability) refer to the permeability
properties of these agents. Eudragit.RTM. RL/RS mixtures are
insoluble in water and in digestive fluids. However,
multiparticulate systems formed to include the same are swellable
and permeable in aqueous solutions and digestive fluids.
[0126] The polymers described above such as Eudragit.RTM. RL/RS may
be mixed together in any desired ratio in order to ultimately
obtain an extended release formulation having a desirable
dissolution profile. One skilled in the art will recognize that
other acrylic polymers may also be used, such as, for example,
Eudragit.RTM. L.
Pore Formers
[0127] In some embodiments, the extended release coating includes a
pore former. Pore formers suitable for use in the extended release
coating can be organic or inorganic agents, and include materials
that can be dissolved, extracted or leached from the coating in the
environment of use. Examples of pore formers include but are not
limited to organic compounds such as mono-, oligo-, and
polysaccharides including sucrose, glucose, fructose, mannitol,
mannose, galactose, lactose, sorbitol, pullulan, dextran; polymers
soluble in the environment of use such as water-soluble hydrophilic
polymers, such as povidone, crospovidone, polyethylene glycol,
hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
hydroxyalkyl celluloses, carboxyalkyl celluloses, cellulose ethers,
acrylic resins, polyvinylpyrrolidone, cross-linked
polyvinylpyrrolidone, polyethylene oxide, carbowaxes,
Carbopol.RTM., and the like, diols, polyols, polyhydric alcohols,
polyalkylene glycols, polyethylene glycols, polypropylene glycols,
or block polymers thereof, polyglycols, poly(.alpha.-.OMEGA.)
alkylenediols; inorganic compounds such as alkali metal salts,
lithium carbonate, sodium chloride, sodium bromide, potassium
chloride, potassium sulfate, potassium phosphate, sodium acetate,
sodium citrate, suitable calcium salts, and the like. In certain
embodiments, plasticizers can also be used as a pore former.
[0128] Capsules
[0129] The extended release pellets are introduced into a suitable
capsule by using an encapsulator equipped with pellet dosing
chamber. The capsule sizes may be 00, 0, 0EL, 1, 1EL, 2, 2EL, 3, 4
or 5. A particularly preferred composition that provides ideal
pharmacokinetic properties and plasma concentration profiles is a
pellet-in-capsule composition that comprises a plurality of
pellets, typically having a diameter of about 500 .mu.m to 1.2 mm,
and preferably about 700 .mu.m to 1000 .mu.m, where each pellet
comprises a core comprising amantadine and a binder, and an
extended release coating surrounding the core that extends release
of the amantadine so as to provide the desired pharmacokinetic
properties and amantadine plasma concentration profiles described
above.
[0130] In some embodiments, the pellets in the pellet-in-capsule
are in a size 0 or smaller, preferably a size 1 or smaller capsule.
Mean pellet diameters in some embodiments may be in a range of 500
.mu.m to 1200 .mu.m, e.g. from 500 .mu.m to 1100 .mu.m, from 500
.mu.m to 1000 .mu.m, from 500 .mu.m to 900 .mu.m, from 500 .mu.m to
800 .mu.m, from 500 .mu.m to 700 .mu.m, from 600 .mu.m to 1100
.mu.m, from 600 .mu.m to 1000 .mu.m, from 600 .mu.m to 900 .mu.m,
from 600 .mu.m to 800 .mu.m, from 600 .mu.m to 700 .mu.m, from 700
.mu.m to 1100 .mu.m, from 700 .mu.m to 1000 .mu.m, from 700 .mu.m
to 900 .mu.m, or from 700 .mu.m to 800 .mu.m. In some embodiments
the mean particle diameters are, .+-.10%, e.g.: 500 .mu.m, 550
.mu.m, 600 .mu.m, 650 .mu.m, 700 .mu.m, 750 .mu.m, 800 .mu.m, 850
.mu.m, 900 .mu.m, 950 .mu.m, 1000 .mu.m, 1050 .mu.m, 1100 .mu.m,
1150 .mu.m or 1200 .mu.m.
[0131] One preferred composition of the invention is a
pellet-in-capsule composition wherein each pellet comprises a core
that comprises a core seed with a mixture of amantadine and a
binder coated onto the core seed, and an extended release coating
surrounding the core comprising ethyl cellulose, a pore forming
agent such as hydroxypropyl methyl cellulose or povidone, and a
plasticizer. In some embodiments, the pellets may further comprise
a seal coating between the pellet core and the extended release
coating. The pellets are formulated using methods known in the art,
such as those described in Example 1 below. In a specific
embodiment, based on the combined weight of the pellet core and
extended release coating, the amantadine is present in amounts from
20-80 wt %, 45-70 wt %, 40-50 wt %, 45-55 wt %, 50-60 wt %, 55-65
wt %, 60-70 wt %, 65-75 wt %, 70-80 wt %, or 40 to 60 wt %, the
binder, which is preferably hydroxypropyl methyl cellulose,
copovidone, or mixtures thereof, is present in amounts from 1 to 25
wt %, the core seed, preferably a sugar sphere (nonpareil) or
microcrystalline cellulose seed (e.g. Celphere.RTM.), is present in
amounts from 8 to 25 wt %, the ethyl cellulose is present in
amounts from 10 to 20 wt %, the pore forming agent, preferably
povidone, is present in amounts from 1 to 4 wt %, and the
plasticizer is present in amounts from 1 to 4 wt %. In another
specific embodiment, based on the combined weight of the pellet
core and extended release coating, the amantadine is present in
amounts from 50 to 70 wt %, the binder, which is preferably
hydroxypropyl methyl cellulose, copovidone, or mixtures thereof, is
present in amounts from 1 to 25 wt %, the core seed, preferably a
sugar sphere (nonpareil) or microcrystalline cellulose seed (e.g.
Celphere.RTM.), is present in amounts from 5 to 15 wt %, the ethyl
cellulose is present in amounts from 1 to 15 wt %, the pore forming
agent, preferably povidone, is present in amounts from 0.25 to 4 wt
%, and the plasticizer is present in amounts from 0.25 to 4 wt
%.
[0132] Additional embodiments of the invention are illustrated in
the Table, below, entitled "Various Amantadine ER Capsule Size 1
Formulations". By means of methods and compositions described
herein, formulations can be made that achieve the desired
dissolution characteristics and target pharmacokinetic profiles
described herein. More specifically, therapeutically effective
doses of amantadine can be administered once daily in no more than
two size 1 (or smaller, e.g. size 2 or 3) capsules using the
manufacturing methods and compositions that have been described
herein to achieve these results. In particular, higher drug loading
can be achieved using compositions and manufacturing methods
described herein. In some embodiments, higher drug loading may be
achieved, with the required dissolution profile, using smaller core
pellet sizes and concomitantly increased drug layering on smaller
cores, but with no change in the extended release coat. In some
embodiments, using alternative manufacturing approaches described
herein, e.g. extrusion and spheronization, even higher drug loads
can be achieved to realize the desired dissolution profile,
enabling high amantadine drug loads with suitable pharmacokinetic
profiles, resulting in compositions that are therapeutically more
effective, and at least as well tolerated, and can be filled in
relatively small sized capsules (e.g., size 1, 2 or 3), enabling
ease of administration to patients.
TABLE-US-00001 TABLE Various Amantadine ER Capsule Size 1
Formulations Inert Core Extended AMT Pellet Active Release Bulk %
Fill in AMT Dissolution (%) Strength Manufacture Size Drug Coating
% Density Size 1 (at T (hrs)): (mg) Method (mm) % w/w w/w
(g/cm.sup.3) Capsule 2 hrs 6 hrs 12 hrs 110 mg Fluid bed 0.3-0.5
40-50% 10-30% 0.6-1.0 60-70% <25% 40-80% >80% coating 140 mg
Fluid bed 0.3-0.5 45-50% 10-30% 0.6-1.0 80-90% <25% 40-80%
>80% coating 150 mg Fluid bed 0.3-0.5 50-55% 10-30% 0.6-1.0
80-90% <25% 40-80% >80% coating 170 mg Fluid bed 0.2-0.3
50-55% 10-30% 0.6-1.0 80-90% <25% 40-80% >80% coating 170 mg
Extrusion N/A 55-75% 10-30% 0.6-1.0 65-75% <25% >80%
spheronization, pan or fluidized bed coating 190 mg Extrusion N/A
55-75% 10-30% 0.6-1.0 75-85% <25% 40-80% >80% spheronization,
pan or fluidized bed coating 210 mg Extrusion N/A 55-75% 10-30%
0.6-1.0 80-90% <25% 40-80% >80% spheronization, pan or
fluidized bed coating 230 mg Extrusion N/A 55-75% 10-30% 0.6-1.0
85-95% <25% 40-80% >80% spheronization, pan or fluidized bed
coating
[0133] In some embodiment, the amantadine, or a pharmaceutically
acceptable salt thereof, is present in amounts from 20 to 80 wt %
(based on the combined weight of the pellet core and extended
release coating), with a bulk density of 0.3 to 1.2 g/cm.sup.3. In
some embodiments, the amantadine or pharmaceutically acceptable
salt thereof is present in amounts from 20 to 77.5 wt %, from 20 to
75 wt %, from 20 to 72.5 wt %, from 20 to 70 wt %, from 20 to 67.5
wt %, from 20 to 65 wt %, from 20 to 62.5 wt %, from 20 to 60 wt %,
from 20 to 57.5 wt %, from 20 to 55 wt %, from 20 to 52.5 wt %,
from 20 to 50 wt %, from 20 to 47.5 wt %, from 20 to 45 wt %, from
20 to 42.5 wt %, from 20 to 40 wt %, from 20 to 37.5 wt %, from 20
to 35 wt %, from 20 to 32.5 wt %, from 20 to 30 wt %, from 30 to 80
wt %, from 30 to 77.5 wt %, from 30 to 75 wt %, from 30 to 72.5 wt
%, from 30 to 70 wt %, from 30 to 67.5 wt %, from 30 to 65 wt %,
from 30 to 62.5 wt %, from 30 to 60 wt %, from 30 to 57.5 wt %,
from 30 to 55 wt %, from 30 to 52.5 wt %, from 30 to 50 wt %, from
30 to 47.5 wt %, from 30 to 45 wt %, from 30 to 42.5 wt %, from 30
to 40 wt %, from 40 to 80 wt %, from 40 to 77.5 wt %, from 40 to 75
wt %, from 40 to 72.5 wt %, from 40 to 70 wt %, from 40 to 67.5 wt
%, from 40 to 65 wt %, from 40 to 62.5 wt %, from 40 to 60 wt %,
from 40 to 57.5 wt %, from 40 to 55 wt %, from 40 to 52.5 wt %,
from 40 to 50 wt %, from 40 to 47.5 wt %, from 40 to 45 wt %, from
50 to 80 wt %, from 50 to 77.5 wt %, from 50 to 75 wt %, from 50 to
72.5 wt %, from 50 to 70 wt %, from 50 to 67.5 wt %, from 50 to 65
wt %, from 50 to 62.5 wt %, from 50 to 60 wt %, from 50 to 57.5 wt
%, from 50 to 55 wt %, from 60 to 80 wt %, from 60 to 77.5 wt %,
from 60 to 75 wt %, from 60 to 72.5 wt %, from 60 to 70 wt %, from
60 to 67.5 wt %, from 60 to 65 wt %. In some embodiments, the bulk
density is 0.3 to 1.2 g/cm.sup.3, 0.3 to 1.15 g/cm.sup.3, 0.3 to
1.1 g/cm.sup.3, 0.3 to 1.05 g/cm.sup.3, 0.3 to 1.0 g/cm.sup.3, 0.3
to 0.9 g/cm.sup.3, 0.3 to 0.8 g/cm.sup.3, 0.3 to 0.7 g/cm.sup.3,
0.3 to 0.6 g/cm.sup.3, 0.3 to 0.5 g/cm.sup.3, 0.3 to 0.4
g/cm.sup.3, 0.4 to 1.2 g/cm.sup.3, 0.4 to 1.15 g/cm.sup.3, 0.4 to
1.1 g/cm.sup.3, 0.4 to 1.05 g/cm.sup.3, 0.4 to 1.0 g/cm.sup.3, 0.4
to 0.9 g/cm.sup.3, 0.4 to 0.8 g/cm.sup.3, 0.4 to 0.7 g/cm.sup.3,
0.4 to 0.6 g/cm.sup.3, 0.4 to 0.5 g/cm.sup.3, 0.5 to 1.2
g/cm.sup.3, 0.5 to 1.15 g/cm.sup.3, 0.5 to 1.1 g/cm.sup.3, 0.5 to
1.05 g/cm.sup.3, 0.5 to 1.0 g/cm.sup.3, 0.5 to 0.9 g/cm.sup.3, 0.5
to 0.8 g/cm.sup.3, 0.5 to 0.7 g/cm.sup.3, 0.5 to 0.6 g/cm.sup.3,
0.6 to 1.2 g/cm.sup.3, 0.6 to 1.15 g/cm.sup.3, 0.6 to 1.1
g/cm.sup.3, 0.6 to 1.05 g/cm.sup.3, 0.6 to 1.0 g/cm.sup.3, 0.6 to
0.9 g/cm.sup.3, 0.6 to 0.8 g/cm.sup.3, 0.6 to 0.7 g/cm.sup.3, 0.7
to 1.2 g/cm.sup.3, 0.7 to 1.15 g/cm.sup.3, 0.7 to 1.1 g/cm.sup.3,
0.7 to 1.05 g/cm.sup.3, 0.7 to 1.0 g/cm.sup.3, 0.7 to 0.9
g/cm.sup.3, 0.7 to 0.8 g/cm.sup.3, 0.5 to 1.2 g/cm.sup.3, 0.8 to
1.15 g/cm.sup.3, 0.8 to 1.1 g/cm.sup.3, 0.8 to 1.05 g/cm.sup.3, 0.8
to 1.0 g/cm.sup.3, 0.8 to 0.9 g/cm.sup.3, 0.9 to 1.2 g/cm.sup.3,
0.9 to 1.15 g/cm.sup.3, 0.9 to 1.1 g/cm.sup.3, 0.9 to 1.05
g/cm.sup.3, or 0.9 to 1.0 g/cm.sup.3. In some embodiments, the
composition is in a dosage unit comprising a pellet in capsule
formulation, wherein the capsule size is size 00, size 0, size 1,
size 2 or size 3. In some preferred embodiments, the dosage unit
includes pellets containing from 50 to 250 mg of amantadine in a
size 0, 1, 2 or 3 capsule. In some embodiments, the dosage unit
includes pellets containing from 100 to 250 mg, e.g. 100 to 200 mg
of amantadine in a size 0, 1, 2 or 3 capsule, preferably a size 1,
2 or 3 capsule. In a more specific embodiment, the dosage unit
comprises about 110, 120, 130, 140, 150, 160 170, 180, 190, 210, or
220 mg amantadine, or a pharmaceutically acceptable salt thereof.
In another more specific embodiment, the dosage unit comprises 110
mg amantadine hydrochloride. In another more specific embodiment,
the dosage unit comprises 130 mg amantadine hydrochloride. In
another more specific embodiment, the dosage unit comprises 170 mg
amantadine hydrochloride. In another more specific embodiment, the
dosage unit comprises 210 mg amantadine hydrochloride.
[0134] Suitable plasticizers include medium chain triglycerides,
diethyl phthalate, citrate esters, polyethylene glycol, glycerol,
acetylated glycerides, castor oil, and the like. The pellets are
filled into capsules to provide the desired strength of amantadine.
An advantage of this composition is it provides the desired release
properties that make the composition suitable for administration
during said period before bedtime. A further advantage is that the
extended release coating is sufficiently durable so that the
capsule can be opened and the pellets sprinkled onto food for
administration to patients who have difficulty swallowing pills,
without adversely affecting the release properties of the
composition. When the composition is administered by sprinkling
onto food, it is preferred to use a soft food such as applesauce or
chocolate pudding, which is consumed within 30 minutes, and
preferably within 15 minutes. A yet further advantage of the
above-described composition is that it has very good batch-to-batch
reproducibility and shelf-life stability.
[0135] In some embodiments, the composition of the invention has an
in vitro dissolution profile of amantadine of not more than 25% at
2 hours, 55-85% at 6 hours, and at least 80% at 12 hours, as
measured using a USP Apparatus II (Paddles) at 50 rpm with 500 ml
water at 37.degree. C. as the dissolution medium. More preferably,
the in vitro dissolution is further characterized by release of
amantadine of not more than 10% at 1 hour, 30-50% at 4 hours, and
at least 90% at 12 hours.
[0136] In additional embodiments, 110 mg to 210 mg of ER amantadine
in a size 1 capsule of the composition of the invention has an in
vitro dissolution profile of amantadine of not more than 25% at 2
hours, 55-85% at 6 hours, and at least 80% at 12 hours, as measured
using a USP Apparatus II (Paddles) at 50 rpm with 500 ml water at
37.degree. C. as the dissolution medium. More preferably, the in
vitro dissolution is further characterized by release of amantadine
of not more than 10% at 1 hour, 30-50% at 4 hours, and at least 90%
at 12 hours.
[0137] In one embodiment of any of the above aspects the
composition has an in vitro dissolution profile of amantadine which
shows at least one of (i) not more than 25% dissolution at 2 hours,
(ii) not more than 25-55% dissolution at 6 hours, and (iii) at
least 80% dissolution at 12 hours, using a USP Apparatus II
(Paddles) at 50 rpm with 500 ml water at 37.degree. C. as the
dissolution medium. In a more specific embodiment two of criteria
(i), (ii) and (iii) are met. In a more specific embodiment, all
three of criteria (i), (ii) and (iii) are met.
[0138] In one embodiment of any of the above aspects the
composition has an in vitro dissolution profile of amantadine which
shows at least one of (i) not more than 20% dissolution at 1 hour,
(ii) about 25-45% dissolution at 2 hours, (iii) not more than
50-80% dissolution at 4 hours, and (iii) at least 80% dissolution
at 8 hours, using a USP Apparatus II (Paddles) at 50 rpm with 500
ml water at 37.degree. C. as the dissolution medium. In a more
specific embodiment two of criteria (i), (ii) and (iii) are met. In
a more specific embodiment, all three of criteria (i), (ii) and
(iii) are met.
[0139] A preferred pellet-in-capsule composition of the invention,
in addition to having the above in vitro dissolution properties and
any of the above-described pharmacokinetic properties (e.g. in vivo
release profile, Tmax, Cmax/Cmin ratio, etc) that make the
composition suitable for administration in said period before
bedtime. The composition is further characterized by providing a
Cmax of 1.6-2.4 ng/ml per mg of amantadine and an AUC.sub.0-inf of
40-75 ng*h/mL per mg of amantadine after oral administration of a
single dose of the capsule to a human subject in a fasted state. A
preferred pellet-in-capsule composition is further characterized by
a steady state plasma concentration in which once daily oral
administration of the capsule to a human subject provides a Cmax of
2.4 to 4.2 ng/ml per mg of amantadine, a Cmin of 1.1 to 2.6 ng/ml
per mg of amantadine, and an AUC.sub.0-24 of 48-73 ng*h/mL per mg
of amantadine.
[0140] The above-described pellet-in-capsule compositions may be
provided at a strength suitable for amantadine therapy. Typical
strengths range from at least about 50 mg to about 250 mg. In a
specific embodiment, the capsule strength is 70 mg, 80 mg, 90 mg,
110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 160 mg, 170
mg, 180 mg, 190 mg, 210 mg, and 220 mg, that provides a single dose
AUC.sub.0-inf per mg that is equivalent to a 100 mg tablet of an
immediate release formulation of amantadine HCl (e.g.
Symmetrel.RTM., or other FDA Orange Book reference listed drug).
One, two, or three, of such capsules can be administered to a
subject in the period before bedtime. In a preferred embodiment,
between 220 mg and 650 mg of amantadine is adminstered using 2
capsules of a suitable ER formulations once daily.
[0141] The invention may also be described in terms of the
following numbered embodiments: [0142] 1. An extended release (ER)
composition comprising amantadine, or a pharmaceutically acceptable
salt thereof, for use in a method of administering amantadine to a
subject in need thereof, said method comprising orally
administering said composition less than three hours before bedtime
(i.e. the time at which the subject wishes to go to sleep for the
night). [0143] 2. Use of amantadine, or a pharmaceutically
acceptable salt thereof, in the manufacture of a medicament for the
treatment of a disease mediated by the NMDA receptor to a subject
in need thereof, said medicament being an extended release (ER)
composition, and said treatment comprising orally administering
said composition less than three hours before bedtime (i.e. the
time at which the subject wishes to go to sleep for the night).
[0144] 3. An extended release (ER) composition comprising
amantadine, or a pharmaceutically acceptable salt thereof, for use
in a method of reducing sleep disturbance in a human subject
undergoing treatment with amantadine, said method comprising
administering said composition less than three hours before bedtime
(i.e. the time at which the subject wishes to go to sleep for the
night). [0145] 4. Use of amantadine, or a pharmaceutically
acceptable salt thereof, in the manufacture of a medicament for
reducing sleep disturbance in a human subject undergoing treatment
with amantadine, said medicament being an extended release (ER)
composition and being adapted for administration less than three
hours before bedtime (i.e. the time at which the subject wishes to
go to sleep for the night). [0146] 5. The use or composition of any
one of embodiments 1-4 wherein administration occurs less than 1
hour before bedtime. [0147] 6. The use or composition of any one of
embodiments 1-5, wherein the patient has been diagnosed with
Parkinson's disease. [0148] 7. The use or composition of any one of
embodiments 1-6, wherein the composition is administered once
daily. [0149] 8. The use or composition of any one of embodiments
1-7, wherein the composition is added to food prior to
administration. [0150] 9. The use or composition of any one of
embodiments 1-8, wherein there is no increase in plasma
concentration of amantadine for at least one hour after the
administration at steady state. [0151] 10. The use or composition
of any one of embodiments 1-9, wherein there is no increase in
plasma concentration of amantadine for at least two hours after the
administration at steady state. [0152] 11. The use of composition
of any one of embodiments 1-10, wherein, the amantadine has a
single dose Tmax of 9 to 15 hours and/or a steady state Tmax of 7
to 13 hours after administration. [0153] 12. The use or composition
of any one of embodiments 1-11, wherein the amantadine has a single
dose Tmax of 10 to 14 hours after administration, and/or a steady
state Tmax of 8 to 12 hours after administration. [0154] 13. The
use of composition of any one of embodiments 1-10, wherein, the
amantadine has a single dose Tmax of 9 to 15 hours, and/or a steady
state Tmax of 7 to 13 hours after administration. [0155] 14. The
use or composition of any one of embodiments 1-11, wherein the
amantadine has a single dose Tmax of 10 to 14 hours after
administration, and/or a steady state Tmax of 8 to 12 hours after
administration. [0156] 15. The use of composition of any one of
embodiments 1-10, wherein, the amantadine has a single dose Tmax of
9 to 15 hours, and/or a steady state Tmax of 7 to 13 hours after
administration. [0157] 16. The use or composition of any one of
embodiments 1-11, wherein the amantadine has a single dose Tmax of
10 to 14 hours after administration, and/or a steady state Tmax of
8 to 12 hours after administration. [0158] 17. The use or
composition of any one of embodiments 1-12, wherein the amantadine
has a single dose Tmax of 11 to 13 hours after administration, and
or a steady state Tmax of 9 to 11 hours after administration.
[0159] 18. The use or composition of any one of embodiments 1-13,
wherein a once daily oral administration of the composition to a
human subject provides a steady state plasma concentration profile
characterized by a concentration increase of amantadine of less
than 25% at three hours after the administration. [0160] 19. The
use or composition of any one of embodiments 1-14 having a
Cmax/Cmin ratio of 1.5 to 2.0. [0161] 20. The use or composition of
any one of embodiments 1-15 having a Cmax/Cmin ratio of 1.7 to 1.9.
[0162] 21. The use or composition of any one of embodiments 1-16,
wherein the amantadine is amantadine hydrochloride or amantadine
sulfate. [0163] 22. The use or composition of any one of
embodiments 1-17 wherein the composition comprises 50 to 600 mg of
amantadine, or a pharmaceutically acceptable salt thereof [0164]
23. The use or composition of embodiment 18, wherein the
composition is administered as one, two, or three or four unit
dosage forms each comprising 100 to 175 mg amantadine, or a
pharmaceutically acceptable salt thereof [0165] 24. The use or
composition of any one of embodiments 1-19 wherein the composition
comprises 200 to 420 mg of amantadine, or a pharmaceutically
acceptable salt thereof [0166] 25. The use or composition of
embodiment 20, wherein the composition is administered as two unit
dosage forms each comprising 110 to 175 mg amantadine, or a
pharmaceutically acceptable salt thereof [0167] 26. The use or
composition of any one of embodiments 1 to 17, wherein the
composition comprises 50 to 200 mg amantadine or a pharmaceutically
acceptable salt thereof [0168] 27. The use or composition of
embodiment 22, wherein the composition comprises 100 to 125 mg
amantadine, or a pharmaceutically acceptable salt thereof. [0169]
28. The use or composition of embodiment 23, wherein the
composition comprises 110 mg amantadine hydrochloride. [0170] 29.
The use or composition of any one of embodiments 1-24, wherein oral
administration of a single dose of the composition to a human
subject in a fasted state provides a maximum plasma concentration
(Cmax) of amantadine of 1.6 to 2.4 ng/ml per mg of amantadine and
an AUC.sub.0-inf of 40 to 75 ng*h/mL per mg of amantadine. [0171]
30. The use or composition of any one of embodiments 1-25, wherein
once daily oral administration of a dose of the composition to a
human subject provides a steady state plasma amantadine
concentration profile characterized by: [0172] (i) a Cmax of 2.4 to
4.2 ng/ml per mg of amantadine, [0173] (ii) a Cmin of 1.1 to 2.6
ng/ml per mg of amantadine, and [0174] (iii) an AUC.sub.0-24 of 44
to 83 ng*h/mL per mg of amantadine. [0175] 31. The use or
composition of embodiment 26, wherein the steady state plasma
concentration profile is further characterized by: [0176] (iv) no
increase in plasma concentration of amantadine for at least one
hour after the administration; and [0177] (v) a Cmax/Cmin ratio of
1.5 to 2.0. [0178] 32. The use or composition of embodiment 27,
wherein the steady state plasma concentration profile is further
characterized by: [0179] (iv) no increase in concentration of
amantadine for at least two hours after the administration; and
[0180] (v) a Cmax/Cmin ratio of 1.7 to 1.9. [0181] 33. The use or
composition of any one of embodiments 1-28, wherein the composition
has an in vitro dissolution profile of amantadine of not more than
25% at 2 hours, 55-85% at 6 hours, and at least 80% at 12 hours,
using a USP Apparatus II (Paddles) at 50 rpm with 500 ml water at
37.degree. C. as the dissolution medium. [0182] 34. The use or
composition of embodiment 29, wherein the in vitro dissolution
profile of amantadine is further characterized by release of
amantadine of not more than 10% at 1 hour, 30-50% at 4 hours, and
at least 90% at 12 hours [0183] 35. The use or composition of any
one of embodiments 1-30, wherein the composition has an AUC profile
after administration of a single dose of the composition
characterized by: a fractional AUC from 0 to 4 hours that is less
than 5% of AUC.sub.0-inf; a fractional AUC from 0 to 8 hours that
is about 5 to 15% of AUC.sub.0-inf; a fractional AUC from 0 to 12
hours that is about 10 to 40% of AUC.sub.0-inf; a fractional AUC
from 0 to 18 hours that is about 25 to 60% of AUC.sub.0-inf; and a
fractional AUC from 0 to 24 hours that is about 40 to 75% of
AUC.sub.0-inf. [0184] 36. The use or composition of any one of
embodiments 1-31, wherein the composition has an AUC profile after
once daily dosing of the composition at steady state conditions
characterized by: a fractional AUC from 0 to 4 hours that is about
2 to 25% of AUC.sub.24; a fractional AUC from 0 to 8 hours that is
about 15 to 50% of AUC.sub.24; a fractional AUC from 0 to 12 hours
that is about 30 to 70% of AUC.sub.24: and a fractional AUC from 0
to 18 hours that is about 60 to 95% of AUC.sub.24. [0185] 37. A
pharmaceutical composition as embodied in any one of embodiments 1,
3, or 5 to 32, or the use of any one of embodiments 2, 4 or 5 to
32, wherein said composition is for oral administration and
comprises a capsule for oral administration, said capsule
comprising a plurality of pellets, each pellet comprising: [0186]
(a) a pellet core comprising amantadine, or a pharmaceutically
acceptable salt thereof, and [0187] (b) an extended release coating
surrounding the pellet core. [0188] 38. The use or composition of
embodiment 32, wherein the extended release coating comprises ethyl
cellulose, at least one of povidone and hydroxypropyl methyl
cellulose, and a plasticizer. [0189] 39. The use or composition of
any one of embodiments 33 or 34, wherein the pellet core comprises
amantadine, or a pharmaceutically acceptable salt thereof, and a
binder coated onto a core seed. [0190] 40. The use or composition
of embodiment 35, wherein, based on the combined weight of the
pellet core and extended release coating, the amantadine is present
in amounts from 40 to 60 wt %, the binder is present in amounts
from 8 to 25 wt %, the core seed is present in amounts from 8 to 25
wt %, the ethyl cellulose is present in amounts from 10 to 20 wt %,
the povidone is present in amounts from 1 to 4 wt %, and the
plasticizer is present in amounts from 1 to 4 wt %. [0191] 41. The
use or composition of any one of embodiments 33 to 36, further
comprising a seal coating between the pellet core and the extended
release coating. [0192] 42. The use or composition of any one of
embodiments 35 to 37, wherein the wherein the pellet core comprises
a binder, selected from the group consisting of hydroxypropyl
methyl cellulose, copovidone, and mixtures thereof [0193] 43. The
use or composition of any one of embodiments 18 to 38, wherein the
plasticizer is selected from the group consisting of medium chain
triglycerides, diethyl phthalate, citrate esters, polyethylene
glycol, glycerol, acetylated glycerides and castor oil. [0194] 44.
A composition of any one of embodiments 33 to 39, for use in a
method of treating Parkinson's disease in a human subject in need
thereof, said method comprising orally administering said
composition.
[0195] Some embodiments herein provide a method of administering
amantadine to a subject in need thereof, said method comprising
orally administering an extended release (ER) composition
comprising amantadine, or a pharmaceutically acceptable salt
thereof, less than three hours before bedtime. In some embodiments,
administration occurs less than 1 hour before bedtime. In some
embodiments, the patient has been diagnosed with Parkinson's
disease. In some embodiments, the composition is administered once
daily. In some embodiments, the composition is added to food prior
to administration. In some embodiments, there is no increase in
plasma concentration of amantadine for at least one hour after the
administration. In some embodiments, there is no increase in plasma
concentration of amantadine for at least two hours after the
administration. In some embodiments, the amantadine has a single
dose Tmax of 9 to 15 hours, and/or a steady state Tmax of 7 to 13
hours. In some embodiments, the amantadine has a single dose Tmax
of 10 to 14 hours after administration, and/or a steady state Tmax
of 8 to 12 hours. In some embodiments, the amantadine has a single
dose Tmax of 11 to 13 hours after administration, and/or a steady
state Tmax of 9 to 11 hours. In some embodiments, a once daily oral
administration of the composition to a human subject provides a
steady state plasma concentration profile characterized by a
concentration increase of amantadine of less than 25% at three
hours after the administration. In some embodiments, the PK curve
has a Cmax/Cmin ratio of 1.5 to 2.0. In some embodiments, the PK
curve has a Cmax/Cmin ratio of 1.7 to 1.9. In some embodiments, the
ratio of C-ave-day/C-ave night at steady state is 1.2 to 1.6. In
some embodiments, the ratio of C-ave-morning/C-ave night at steady
state is 1.3 to 1.5. In some embodiments, the average amantadine
plasma concentration during the day (C-ave-day) at steady state is
500-2000 ng/ml. In some embodiments, the average amantadine plasma
concentration in the morning (C-ave-morning) at steady state is
500-2000 ng/ml. In some embodiments, the amantadine is amantadine
hydrochloride or amantadine sulfate. In some embodiments, the
composition comprises 50 to 600 mg of amantadine, or a
pharmaceutically acceptable salt thereof. In some embodiments, the
composition is administered as one, two, or three or four unit
dosage forms each comprising 100 to 175 mg amantadine, or a
pharmaceutically acceptable salt thereof. In some embodiments, the
composition is administered as one or two unit dosage forms each
comprising 130 to 210 mg of extended release amantadine, or a
pharmaceutically acceptable salt thereof. In some embodiments, the
composition is within a capsule of capsule size #1. In some
embodiments, the composition comprises 200 to 350 mg of amantadine,
or a pharmaceutically acceptable salt thereof. In some embodiments,
the composition is administered as two unit dosage forms each
comprising 100 to 175 mg amantadine, or a pharmaceutically
acceptable salt thereof. In some embodiments, the composition
comprises 50 to 200 mg amantadine or a pharmaceutically acceptable
salt thereof. In some embodiments, the composition comprises 100 to
125 mg amantadine, or a pharmaceutically acceptable salt thereof.
In some embodiments, the composition comprises 110 mg amantadine
hydrochloride. In some embodiments, oral administration of a single
dose of the composition to a human subject in a fasted state
provides a maximum plasma concentration (Cmax) of 1.6 to 2.4 ng/ml
per mg of amantadine, and an AUC.sub.0-inf of 40 to 75 ng*h/mL per
mg of amantadine. In some embodiments, once daily oral
administration of a dose of the composition to a human subject
provides a steady state plasma concentration profile characterized
by: (a) a Cmax of 2.4 to 4.2 ng/ml per mg of amantadine; (b) a Cmin
of 1.1 to 2.6 ng/ml per mg of amantadine, and (c) an AUC.sub.0-24
of 44 to 83 ng*h/mL per mg of amantadine. In some embodiments, the
steady state plasma concentration profile is further characterized
by: (d) no increase in plasma concentration of amantadine for at
least one hour after the administration; and (e) a Cmax/Cmin ratio
of 1.5 to 2.0. In some embodiments, the steady state plasma
concentration profile is further characterized by: (f) no increase
in concentration of amantadine for at least two hours after the
administration; and (g) a Cmax/Cmin ratio of 1.7 to 1.9. In some
embodiments, the composition has an in vitro dissolution profile of
amantadine of not more than 25% at 2 hours, 55-85% at 6 hours, and
at least 80% at 12 hours, using a USP Apparatus II (Paddles) at 50
rpm with 500 ml water at 37.degree. C. as the dissolution medium.
In some embodiments, the composition has an in vitro dissolution
profile of amantadine of not more than 25% at 2 hours, 25-55% at 6
hours, and at least 80% at 12 hours, using a USP Apparatus II
(Paddles) at 50 rpm with 500 ml water at 37.degree. C. as the
dissolution medium. In some embodiments, the composition has an in
vitro dissolution profile of amantadine of not more than 20% at 1
hour, 25-45% at 2 hours, 50-80% at 4 hours, and at least 80% at 8
hours, using a USP Apparatus II (Paddles) at 50 rpm with 500 ml
water at 37.degree. C. as the dissolution medium. In some
embodiments, the in vitro dissolution profile of amantadine is
further characterized by release of amantadine of not more than 10%
at 1 hour, 30-50% at 4 hours, and at least 90% at 12 hours. In some
embodiments, the composition has an AUC profile after
administration of a single dose of the composition characterized
by: a fractional AUC from 0 to 4 hours that is less than 5% of
AUC.sub.0-inf; a fractional AUC from 0 to 8 hours that is about 5
to 15% of AUC.sub.0-inf; a fractional AUC from 0 to 12 hours that
is about 10 to 40% of AUC.sub.0-inf; a fractional AUC from 0 to 18
hours that is about 25 to 60% of AUC.sub.0-inf; and a fractional
AUC from 0 to 24 hours that is about 40 to 75% of AUC.sub.0-inf. In
some embodiments, the composition has an AUC profile after once
daily dosing of the composition at steady state conditions
characterized by: a fractional AUC from 0 to 4 hours that is about
2 to 25% of AUC.sub.24; a fractional AUC from 0 to 8 hours that is
about 15 to 50% of AUC.sub.24; a fractional AUC from 0 to 12 hours
that is about 30 to 70% of AUC.sub.24: and a fractional AUC from 0
to 18 hours that is about 60 to 95% of AUC.sub.24.
[0196] Some embodiments herein provide a method of reducing sleep
disturbance in a human subject undergoing treatment with
amantadine, said method comprising administering an extended
release (ER) composition comprising amantadine, or a
pharmaceutically acceptable salt thereof, less than three hours
before bedtime. In some embodiments, administration occurs less
than 1 hour before bedtime. In some embodiments, the patient has
been diagnosed with Parkinson's disease. In some embodiments, the
composition is administered once daily. In some embodiments, the
composition is added to food prior to administration. In some
embodiments, there is no increase in plasma concentration of
amantadine for at least one hour after the administration. In some
embodiments, there is no increase in plasma concentration of
amantadine for at least two hours after the administration. In some
embodiments, the amantadine has a single dose Tmax of 9 to 15
hours, and/or a steady state Tmax of 7 to 13 hours. In some
embodiments, the amantadine has a single dose Tmax of 10 to 14
hours after administration, and/or a steady state Tmax of 8 to 12
hours. In some embodiments, the amantadine has a single dose Tmax
of 11 to 13 hours after administration, and/or a steady state Tmax
of 9 to 11 hours. In some embodiments, a once daily oral
administration of the composition to a human subject provides a
steady state plasma concentration profile characterized by a
concentration increase of amantadine of less than 25% at three
hours after the administration. In some embodiments, the PK curve
has a Cmax/Cmin ratio of 1.5 to 2.0. In some embodiments, the PK
curve has a Cmax/Cmin ratio of 1.7 to 1.9. In some embodiments, the
ratio of C-ave-day/C-ave night at steady state is 1.2 to 1.6. In
some embodiments, the ratio of C-ave-morning/C-ave night at steady
state is 1.3 to 1.5. In some embodiments, the average amantadine
plasma concentration during the day (C-ave-day) at steady state is
500-2000 ng/ml. In some embodiments, the average amantadine plasma
concentration in the morning (C-ave-morning) at steady state is
500-2000 ng/ml. In some embodiments, the amantadine is amantadine
hydrochloride or amantadine sulfate. In some embodiments, the
composition comprises 50 to 600 mg of amantadine, or a
pharmaceutically acceptable salt thereof. In some embodiments, the
composition is administered as one, two, or three or four unit
dosage forms each comprising 100 to 175 mg amantadine, or a
pharmaceutically acceptable salt thereof. In some embodiments, the
composition is administered as one or two unit dosage forms each
comprising 130 to 210 mg of extended release amantadine, or a
pharmaceutically acceptable salt thereof. In some embodiments, the
composition is within a capsule of capsule size #1. In some
embodiments, the composition comprises 200 to 350 mg of amantadine,
or a pharmaceutically acceptable salt thereof. In some embodiments,
the composition is administered as two unit dosage forms each
comprising 100 to 175 mg amantadine, or a pharmaceutically
acceptable salt thereof. In some embodiments, the composition
comprises 50 to 200 mg amantadine or a pharmaceutically acceptable
salt thereof. In some embodiments, the composition comprises 100 to
125 mg amantadine, or a pharmaceutically acceptable salt thereof.
In some embodiments, the composition comprises 110 mg amantadine
hydrochloride. In some embodiments, oral administration of a single
dose of the composition to a human subject in a fasted state
provides a maximum plasma concentration (Cmax) of 1.6 to 2.4 ng/ml
per mg of amantadine, and an AUC.sub.0-inf of 40 to 75 ng*h/mL per
mg of amantadine. In some embodiments, once daily oral
administration of a dose of the composition to a human subject
provides a steady state plasma concentration profile characterized
by: (a) a Cmax of 2.4 to 4.2 ng/ml per mg of amantadine; (b) a Cmin
of 1.1 to 2.6 ng/ml per mg of amantadine, and (c) an AUC.sub.0-24
of 44 to 83 ng*h/mL per mg of amantadine. In some embodiments, the
steady state plasma concentration profile is further characterized
by: (d) no increase in plasma concentration of amantadine for at
least one hour after the administration; and (e) a Cmax/Cmin ratio
of 1.5 to 2.0. In some embodiments, the steady state plasma
concentration profile is further characterized by: (f) no increase
in concentration of amantadine for at least two hours after the
administration; and (g) a Cmax/Cmin ratio of 1.7 to 1.9. In some
embodiments, the composition has an in vitro dissolution profile of
amantadine of not more than 25% at 2 hours, 55-85% at 6 hours, and
at least 80% at 12 hours, using a USP Apparatus II (Paddles) at 50
rpm with 500 ml water at 37.degree. C. as the dissolution medium.
In some embodiments, the composition has an in vitro dissolution
profile of amantadine of not more than 25% at 2 hours, 25-55% at 6
hours, and at least 80% at 12 hours, using a USP Apparatus II
(Paddles) at 50 rpm with 500 ml water at 37.degree. C. as the
dissolution medium. In some embodiments, the composition has an in
vitro dissolution profile of amantadine of not more than 20% at 1
hour, 25-45% at 2 hours, 50-80% at 4 hours, and at least 80% at 8
hours, using a USP Apparatus II (Paddles) at 50 rpm with 500 ml
water at 37.degree. C. as the dissolution medium. In some
embodiments, the in vitro dissolution profile of amantadine is
further characterized by release of amantadine of not more than 10%
at 1 hour, 30-50% at 4 hours, and at least 90% at 12 hours. In some
embodiments, the composition has an AUC profile after
administration of a single dose of the composition characterized
by: a fractional AUC from 0 to 4 hours that is less than 5% of
AUC.sub.0-inf; a fractional AUC from 0 to 8 hours that is about 5
to 15% of AUC.sub.0-inf; a fractional AUC from 0 to 12 hours that
is about 10 to 40% of AUC.sub.0-inf; a fractional AUC from 0 to 18
hours that is about 25 to 60% of AUC.sub.0-inf; and a fractional
AUC from 0 to 24 hours that is about 40 to 75% of AUC.sub.0-inf. In
some embodiments, the composition has an AUC profile after once
daily dosing of the composition at steady state conditions
characterized by: a fractional AUC from 0 to 4 hours that is about
2 to 25% of AUC.sub.24; a fractional AUC from 0 to 8 hours that is
about 15 to 50% of AUC.sub.24; a fractional AUC from 0 to 12 hours
that is about 30 to 70% of AUC.sub.24: and a fractional AUC from 0
to 18 hours that is about 60 to 95% of AUC.sub.24.
[0197] Some embodiments herein provide a method of treating
levodopa induced dyskinesia in a patient with Parkinson's disease,
said method comprising orally administering once daily an extended
release (ER) composition comprising amantadine, or a
pharmaceutically acceptable salt thereof, less than about three
hours before bedtime. In some embodiments, administration occurs
less than 1 hour before bedtime. In some embodiments, the patient
has been diagnosed with Parkinson's disease. In some embodiments,
the composition is administered once daily. In some embodiments,
the composition is added to food prior to administration. In some
embodiments, there is no increase in plasma concentration of
amantadine for at least one hour after the administration. In some
embodiments, there is no increase in plasma concentration of
amantadine for at least two hours after the administration. In some
embodiments, the amantadine has a single dose Tmax of 9 to 15
hours, and/or a steady state Tmax of 7 to 13 hours. In some
embodiments, the amantadine has a single dose Tmax of 10 to 14
hours after administration, and/or a steady state Tmax of 8 to 12
hours. In some embodiments, the amantadine has a single dose Tmax
of 11 to 13 hours after administration, and/or a steady state Tmax
of 9 to 11 hours. In some embodiments, a once daily oral
administration of the composition to a human subject provides a
steady state plasma concentration profile characterized by a
concentration increase of amantadine of less than 25% at three
hours after the administration. In some embodiments, the PK curve
has a Cmax/Cmin ratio of 1.5 to 2.0. In some embodiments, the PK
curve has a Cmax/Cmin ratio of 1.7 to 1.9. In some embodiments, the
ratio of C-ave-day/C-ave night at steady state is 1.2 to 1.6. In
some embodiments, the ratio of C-ave-morning/C-ave night at steady
state is 1.3 to 1.5. In some embodiments, the average amantadine
plasma concentration during the day (C-ave-day) at steady state is
500-2000 ng/ml. In some embodiments, the average amantadine plasma
concentration in the morning (C-ave-morning) at steady state is
500-2000 ng/ml. In some embodiments, the amantadine is amantadine
hydrochloride or amantadine sulfate. In some embodiments, the
composition comprises 50 to 600 mg of amantadine, or a
pharmaceutically acceptable salt thereof. In some embodiments, the
composition is administered as one, two, or three or four unit
dosage forms each comprising 100 to 175 mg amantadine, or a
pharmaceutically acceptable salt thereof. In some embodiments, the
composition is administered as one or two unit dosage forms each
comprising 130 to 210 mg of extended release amantadine, or a
pharmaceutically acceptable salt thereof. In some embodiments, the
composition is within a capsule of capsule size #1. In some
embodiments, the composition comprises 200 to 350 mg of amantadine,
or a pharmaceutically acceptable salt thereof. In some embodiments,
the composition is administered as two unit dosage forms each
comprising 100 to 175 mg amantadine, or a pharmaceutically
acceptable salt thereof. In some embodiments, the composition
comprises 50 to 200 mg amantadine or a pharmaceutically acceptable
salt thereof. In some embodiments, the composition comprises 100 to
125 mg amantadine, or a pharmaceutically acceptable salt thereof.
In some embodiments, the composition comprises 110 mg amantadine
hydrochloride. In some embodiments, oral administration of a single
dose of the composition to a human subject in a fasted state
provides a maximum plasma concentration (Cmax) of 1.6 to 2.4 ng/ml
per mg of amantadine, and an AUC.sub.0-inf of 40 to 75 ng*h/mL per
mg of amantadine. In some embodiments, once daily oral
administration of a dose of the composition to a human subject
provides a steady state plasma concentration profile characterized
by: (a) a Cmax of 2.4 to 4.2 ng/ml per mg of amantadine; (b) a Cmin
of 1.1 to 2.6 ng/ml per mg of amantadine, and (c) an AUC.sub.0-24
of 44 to 83 ng*h/mL per mg of amantadine. In some embodiments, the
steady state plasma concentration profile is further characterized
by: (d) no increase in plasma concentration of amantadine for at
least one hour after the administration; and (e) a Cmax/Cmin ratio
of 1.5 to 2.0. In some embodiments, the steady state plasma
concentration profile is further characterized by: (f) no increase
in concentration of amantadine for at least two hours after the
administration; and (g) a Cmax/Cmin ratio of 1.7 to 1.9. In some
embodiments, the composition has an in vitro dissolution profile of
amantadine of not more than 25% at 2 hours, 55-85% at 6 hours, and
at least 80% at 12 hours, using a USP Apparatus II (Paddles) at 50
rpm with 500 ml water at 37.degree. C. as the dissolution medium.
In some embodiments, the composition has an in vitro dissolution
profile of amantadine of not more than 25% at 2 hours, 25-55% at 6
hours, and at least 80% at 12 hours, using a USP Apparatus II
(Paddles) at 50 rpm with 500 ml water at 37.degree. C. as the
dissolution medium. In some embodiments, the composition has an in
vitro dissolution profile of amantadine of not more than 20% at 1
hour, 25-45% at 2 hours, 50-80% at 4 hours, and at least 80% at 8
hours, using a USP Apparatus II (Paddles) at 50 rpm with 500 ml
water at 37.degree. C. as the dissolution medium. In some
embodiments, the in vitro dissolution profile of amantadine is
further characterized by release of amantadine of not more than 10%
at 1 hour, 30-50% at 4 hours, and at least 90% at 12 hours. In some
embodiments, the composition has an AUC profile after
administration of a single dose of the composition characterized
by: a fractional AUC from 0 to 4 hours that is less than 5% of
AUC.sub.0-inf; a fractional AUC from 0 to 8 hours that is about 5
to 15% of AUC.sub.0-inf; a fractional AUC from 0 to 12 hours that
is about 10 to 40% of AUC.sub.0-inf; a fractional AUC from 0 to 18
hours that is about 25 to 60% of AUC.sub.0-inf; and a fractional
AUC from 0 to 24 hours that is about 40 to 75% of AUC.sub.0-inf. In
some embodiments, the composition has an AUC profile after once
daily dosing of the composition at steady state conditions
characterized by: a fractional AUC from 0 to 4 hours that is about
2 to 25% of AUC.sub.24; a fractional AUC from 0 to 8 hours that is
about 15 to 50% of AUC.sub.24; a fractional AUC from 0 to 12 hours
that is about 30 to 70% of AUC.sub.24: and a fractional AUC from 0
to 18 hours that is about 60 to 95% of AUC.sub.24.
[0198] Some embodiments herein provide a pharmaceutical composition
for any of the methods described herein, wherein said composition
is for oral administration and comprises a capsule for oral
administration, said capsule comprising a plurality of pellets,
each pellet comprising: (a) a pellet core comprising amantadine, or
a pharmaceutically acceptable salt thereof, and (b) an extended
release coating surrounding the pellet core. In some embodiments,
the extended release coating comprises ethyl cellulose, at least
one of povidone and hydroxypropyl methyl cellulose, and a
plasticizer. In some embodiments, the pellet core comprises
amantadine, or a pharmaceutically acceptable salt thereof, and a
binder coated onto a core seed. In some embodiments, based on the
combined weight of the pellet core and extended release coating,
the amantadine is present in amounts from 40 to 60 wt %, the binder
is present in amounts from 8 to 25 wt %, the core seed is present
in amounts from 1 to 25 wt %, the ethyl cellulose is present in
amounts from 10 to 20 wt %, the povidone is present in amounts from
1 to 4 wt %, and the plasticizer is present in amounts from 1 to 4
wt %. In some embodiments, the composition further comprises a seal
coating between the pellet core and the extended release coating.
In some embodiments, the pellet core comprises a binder selected
from the group consisting of hydroxypropyl methyl cellulose,
copovidone, and mixtures thereof. In some embodiments, the
plasticizer is selected from the group consisting of medium chain
triglycerides, diethyl phthalate, citrate esters, polyethylene
glycol, glycerol, acetylated glycerides and castor oil.
[0199] Some embodiments herein provide a method of administering
amantadine, or a pharmaceutically acceptable salt thereof, to a
human subject in need thereof, said method comprising orally
administering a pharmaceutical composition comprising amantadine in
a capsule for oral administration, said capsule comprising a
plurality of pellets, each pellet comprising: (a) a pellet core
comprising amantadine, or a pharmaceutically acceptable salt
thereof, and (b) an extended release coating surrounding the pellet
core. In some embodiments, the extended release coating comprises
ethyl cellulose, at least one of povidone and hydroxypropyl methyl
cellulose, and a plasticizer. In some embodiments, the pellet core
comprises amantadine, or a pharmaceutically acceptable salt
thereof, and a binder coated onto a core seed. In some embodiments,
based on the combined weight of the pellet core and extended
release coating, the amantadine is present in amounts from 40 to 60
wt %, the binder is present in amounts from 8 to 25 wt %, the core
seed is present in amounts from 1 to 25 wt %, the ethyl cellulose
is present in amounts from 10 to 20 wt %, the povidone is present
in amounts from 1 to 4 wt %, and the plasticizer is present in
amounts from 1 to 4 wt %. In some embodiments, the composition
further comprises a seal coating between the pellet core and the
extended release coating. In some embodiments, the pellet core
comprises a binder selected from the group consisting of
hydroxypropyl methyl cellulose, copovidone, and mixtures thereof.
In some embodiments, the plasticizer is selected from the group
consisting of medium chain triglycerides, diethyl phthalate,
citrate esters, polyethylene glycol, glycerol, acetylated
glycerides and castor oil. Some embodiments comprise treating
Parkinson's disease in a human subject in need thereof.
[0200] Some embodiments herein provide a pharmaceutical composition
suitable for once daily oral administration to a patient in need
thereof said composition comprising a therapeutically effective
amount of amantadine or a pharmaceutically acceptable salt thereof
in an extended release form which can be administered as not more
than two size 0 or smaller capsules in a single daily
administration. In some embodiments, the composition comprises
110-220 mg of amantadine or pharmaceutically acceptable salt
thereof. In some embodiments, the composition has an in vitro
dissolution profile of amantadine of not more than 25% at 2 hours,
40-80% at 6 hours, and at least 80% at 12 hours, using a USP
Apparatus II (Paddles) at 50 rpm with 500 ml water at 37.degree. C.
as the dissolution medium. In some embodiments, the composition
comprises a plurality of pellets, each pellet comprising: (a) a
pellet core comprising amantadine, or a pharmaceutically acceptable
salt thereof, and (b) an extended release coating surrounding the
pellet core. In some embodiments, the extended release coating
comprises ethyl cellulose, at least one of povidone and
hydroxypropyl methyl cellulose, and a plasticizer. In some
embodiments, the pellet core comprises amantadine, or a
pharmaceutically acceptable salt thereof, and a binder coated onto
a core seed. In some embodiments, the composition comprises
amantadine and, based on the combined weight of the pellet core and
extended release coating, the amantadine is present in amounts from
40 to 70 wt %. In some embodiments, the pellet core comprises a
core seed comprising sugar or microcrystalline cellulose that is
between 100 and 500 microns in diameter. In some embodiments, the
bulk density is between 0.5 and 1 gm/cm.sup.3. In some embodiments,
the composition comprises a seal coating between the pellet core
and the extended release coating. In some embodiments, the pellet
core comprises a binder selected from the group consisting of
hydroxypropyl methyl cellulose, copovidone, and mixtures thereof.
In some embodiments, the plasticizer is selected from the group
consisting of medium chain triglycerides, diethyl phthalate,
citrate esters, polyethylene glycol, glycerol, acetylated
glycerides and castor oil.
[0201] Some embodiments herein provide a method of treating
Parkinson's disease in a human subject, said method comprising
orally administering a composition comprising a therapeutically
effective amount of amantadine or a pharmaceutically acceptable
salt thereof in an extended release form which can be administered
as not more than two size 0 or smaller capsules in a single daily
administration. In some embodiments, the composition comprises
110-220 mg of amantadine or pharmaceutically acceptable salt
thereof. In some embodiments, the composition has an in vitro
dissolution profile of amantadine of not more than 25% at 2 hours,
40-80% at 6 hours, and at least 80% at 12 hours, using a USP
Apparatus II (Paddles) at 50 rpm with 500 ml water at 37.degree. C.
as the dissolution medium. In some embodiments, the composition
comprises a plurality of pellets, each pellet comprising: (a) a
pellet core comprising amantadine, or a pharmaceutically acceptable
salt thereof, and (b) an extended release coating surrounding the
pellet core. In some embodiments, the extended release coating
comprises ethyl cellulose, at least one of povidone and
hydroxypropyl methyl cellulose, and a plasticizer. In some
embodiments, the pellet core comprises amantadine, or a
pharmaceutically acceptable salt thereof, and a binder coated onto
a core seed. In some embodiments, the composition comprises
amantadine and, based on the combined weight of the pellet core and
extended release coating, the amantadine is present in amounts from
40 to 70 wt %. In some embodiments, the pellet core comprises a
core seed comprising sugar or microcrystalline cellulose that is
between 100 and 500 microns in diameter. In some embodiments, the
bulk density is between 0.5 and 1 gm/cm.sup.3. In some embodiments,
the composition comprises a seal coating between the pellet core
and the extended release coating. In some embodiments, the pellet
core comprises a binder selected from the group consisting of
hydroxypropyl methyl cellulose, copovidone, and mixtures thereof.
In some embodiments, the plasticizer is selected from the group
consisting of medium chain triglycerides, diethyl phthalate,
citrate esters, polyethylene glycol, glycerol, acetylated
glycerides and castor oil.
[0202] Some embodiments herein provide a method of treating
levodopa induced dyskinesia in a human subject, said method
comprising orally administering a composition comprising a
therapeutically effective amount of amantadine or a
pharmaceutically acceptable salt thereof in an extended release
form which can be administered as not more than two size 0 or
smaller capsules in a single daily administration. Some embodiments
herein provide a method of treating traumatic brain injury in a
human subject, said method comprising orally administering a
composition comprising a therapeutically effective amount of
amantadine or a pharmaceutically acceptable salt thereof in an
extended release form which can be administered as not more than
two size 0 or smaller capsules in a single daily administration.
Some embodiments provide a method of treating traumatic brain
injury in a human subject, said method comprising orally
administering a composition comprising a therapeutically effective
amount of amantadine or a pharmaceutically acceptable salt thereof
in an extended release form which can be administered as not more
than two size 0 or smaller capsules in a single daily
administration. Some embodiments provide a method of treating
fatigue in a human subject, said method comprising orally
administering a composition comprising a therapeutically effective
amount of amantadine or a pharmaceutically acceptable salt thereof
in an extended release form which can be administered as not more
than two size 0 or smaller capsules in a single daily
administration. In some embodiments, the composition comprises
110-220 mg of amantadine or pharmaceutically acceptable salt
thereof. In some embodiments, the composition has an in vitro
dissolution profile of amantadine of not more than 25% at 2 hours,
40-80% at 6 hours, and at least 80% at 12 hours, using a USP
Apparatus II (Paddles) at 50 rpm with 500 ml water at 37.degree. C.
as the dissolution medium. In some embodiments, the composition
comprises a plurality of pellets, each pellet comprising: (a) a
pellet core comprising amantadine, or a pharmaceutically acceptable
salt thereof, and (b) an extended release coating surrounding the
pellet core. In some embodiments, the extended release coating
comprises ethyl cellulose, at least one of povidone and
hydroxypropyl methyl cellulose, and a plasticizer. In some
embodiments, the pellet core comprises amantadine, or a
pharmaceutically acceptable salt thereof, and a binder coated onto
a core seed. In some embodiments, the composition comprises
amantadine and, based on the combined weight of the pellet core and
extended release coating, the amantadine is present in amounts from
40 to 70 wt %. In some embodiments, the pellet core comprises a
core seed comprising sugar or microcrystalline cellulose that is
between 100 and 500 microns in diameter. In some embodiments, the
bulk density is between 0.5 and 1 gm/cm.sup.3. In some embodiments,
the composition comprises a seal coating between the pellet core
and the extended release coating. In some embodiments, the pellet
core comprises a binder selected from the group consisting of
hydroxypropyl methyl cellulose, copovidone, and mixtures thereof.
In some embodiments, the plasticizer is selected from the group
consisting of medium chain triglycerides, diethyl phthalate,
citrate esters, polyethylene glycol, glycerol, acetylated
glycerides and castor oil. In some embodiments, the method
comprises administering the composition to a patient less than
three hours before bed time.
[0203] The present invention may be better understood by reference
to the following examples, which are not intended to limit the
scope of the claims.
Example 1
Amantadine Extended Release Coated Pellet Formulations
[0204] Amantadine HCl extended release coated pellet compositions
designed for nighttime administration were prepared using the
components and relative amounts shown in Table 1 below. For each
composition, the drug coating solution was prepared by adding HPMC
5 cps and Copovidone to isopropyl alcohol with continuous stirring.
Purified water was added to this dispersion and stirring continued
until a clear solution is formed. Drug (Amantadine HCl) was then
added to this binder solution and stirring continued until the drug
was completely dissolved. Finally, talc was added and dispersed
uniformly by stirring.
[0205] Celphere beads (screen sizes #35 to #50 i.e. 300 to 500
micron) were loaded in a Wurster coating unit. The drug coating
dispersion was sprayed onto the beads followed by a period of
drying. The resulting drug coated pellets were sieved to retain the
fraction between screens #18 and #24 (approximately 700 .mu.m to 1
mm diameter).
[0206] The seal coating solution was prepared by adding HPMC 5 cps
to isopropyl alcohol with continuous stirring. Purified water was
added to this dispersion and stirring continued until a clear
solution was formed. Talc was added and dispersed uniformly by
stirring. The sieved drug coated pellets were loaded in a Wurster
coating unit. The seal coating dispersion was sprayed over the drug
coated pellets followed by a period of drying to remove the
residual solvent and water in the pellets. The resulting seal
coated pellets were sieved to retain the fraction between screens
#18 and #24.
[0207] The ER coating solution was prepared by dissolving ethyl
cellulose (viscosity 7 cps) in isopropyl alcohol and purified water
and stirring until a clear solution was formed. Povidone K-90 was
then dissolved in this clear solution followed by addition of
plasticizer Miglyol 812N with continuous stirring to form a clear
solution. The sieved seal coated pellets were loaded in a Wurster
coating unit. The ER coating solution was sprayed over the seal
coated pellets followed by a period of drying to affect the ER coat
and remove the residual solvent and water in the pellets. After
drying, magnesium stearate was spread on the top bed of the coated
pellets in the annulus region followed by recirculation of the
pellets in the Wurster unit to blend the magnesium stearate with
the coated pellets. The resulting ER coated pellets were sieved to
retain the fraction between screens #18 and #24.
[0208] The desired weight of the ER coated pellets containing the
unit dose were filled into empty 1 hard gelatin capsule shell (size
1 for 100-140 mg strength) using an encapsulator equipped with
pellet dosing chamber.
TABLE-US-00002 TABLE 1 Composition of amantadine HCl ER capsules
combined w/w Component Function of capsule Pellet Core Amantadine
Active 40-50% Hydrochloride USP Microcrystalline cellulose Core
seeds 10-15% spheres (Celphere .RTM.) Hydroxypropyl methyl Binder
10-15% cellulose 5 cps USP Copovidone Binder 1-5% Talc USP
Anti-tack 1-5% Isopropyl alcohol Solvent --.sup.1 Water Solvent
--.sup.1 Seal Coating (optional) Hydroxypropyl methyl Coating
polymer 5-10% cellulose 3 cps USP Talc USP Anti-tack 0-5% Isopropyl
alcohol Solvent --.sup.1 Water Solvent --.sup.1 Extended Release
Coating Ethyl cellulose Coating polymer 10-20% Povidone Pore former
1-5% Medium chain Plasticizer 1-5% triglycerides Isopropyl alcohol
Solvent --.sup.1 Water Solvent --.sup.1 Magnesium Stearate NF
Lubricant 0-1% Density of pellets 0.6-0.9 gm/cm.sup.3 NF = National
Formulary .sup.1Purified water and isopropyl alcohol are removed
during processing.
[0209] The in vitro dissolution of capsules prepared above was
tested using a USP Apparatus II (Paddles) at 50 rpm with 500 ml
water at 37.degree. C. as the dissolution medium. Capsules meeting
desired dissolution specifications released not more than 25% of
the drug in 2 hours, 40-80% in 6 hours, and at least 80% at 12
hours. In an exemplary dissolution profile, there was 0% drug
release at 1 hour, 12% release at 2 hours, 43% release at 4 hours,
68% release at 6 hours, 83% release at 8 hours, 92% release at 10
hours, and 97% release at 12 hours. Capsules prepared in accordance
with the above method exhibited good shelf-stability, and
batch-to-batch reproducibility upon scale-up.
Example 2
Amantadine Extended Release Coated Pellet Formulation with Higher
Drug Loading
[0210] Amantadine HCl extended release coated pellet compositions
designed for nighttime administration are prepared using the
components and relative amounts shown in Table 2 below and the
manufacturing process described in example 1.
[0211] The diameter of the inert cores is 200-300 microns. The
diameter of the coated pellets is 600-1200 microns. The bulk
density of the coated pellets is 0.7-1.2 g/cm.sup.3.
[0212] The desired weight of the ER coated pellets containing the
unit dose are filled into an empty hard gelatin capsule shell (size
1 for 170 mg strength) using an encapsulator equipped with pellet
dosing chamber.
TABLE-US-00003 TABLE 2 Composition of amantadine HCl ER capsules
combined w/w Component Function of capsule Pellet Core Amantadine
Hydrochloride USP Active 50-65% Microcrystalline cellulose spheres
Core seeds 1-15% (Celphere .RTM.) Hydroxypropyl methyl cellulose
USP Binder 5-25% Copovidone Binder 1-5% Talc USP Anti-tack 1-5%
Isopropyl alcohol Solvent --.sup.1 Water Solvent --.sup.1 Seal
Coating (optional) Hydroxypropyl methyl cellulose USP Coating
polymer 0-10% Talc USP Anti-tack 0-5% Isopropyl alcohol Solvent
--.sup.1 Water Solvent --.sup.1 Extended Release Coating Ethyl
cellulose Coating polymer 10-20% Povidone Pore former 1-5% Medium
chain triglycerides Plasticizer 1-5% Isopropyl alcohol Solvent
--.sup.1 Water Solvent --.sup.1 Magnesium Stearate NF Lubricant
0-1% NF = National Formulary .sup.1Purified water and isopropyl
alcohol are removed during processing.
[0213] The in vitro dissolution of capsules prepared above are
tested using a USP Apparatus II (Paddles) at 50 rpm with 500 ml
water at 37.degree. C. as the dissolution medium and release not
more than 25% of the drug in 2 hours, 40-80% in 6 hours, and at
least 80% at 12 hours.
Example 3
Amantadine Extended Release Coated Pellet Formulations
[0214] Amantadine HCl extended release coated pellet compositions
suitable for nighttime administration were prepared using the
components and relative amounts shown in Table 3 below and the
manufacturing process described in Example 1.
[0215] The desired weight of the ER coated pellets containing the
unit dose was filled into empty #1 hard gelatin capsule shell (100
mg strength) using an encapsulator equipped with pellet dosing
chamber.
TABLE-US-00004 TABLE 3 Composition of amantadine HCl ER capsules
combined w/w of capsule Component Function A B C Pellet Core
Amantadine Active 50.15% 47.94% 45.15% Hydrochloride USP
Microcrystalline Core seeds 14.33% 13.70% 12.90% cellulose spheres
(Celphere .RTM.) Hydroxypropyl methyl Binder 13.37% 12.79% 12.04%
cellulose USP Copovidone Binder 3.34% 3.2% 3.01% Talc USP Anti-tack
2.51% 2.4% 2.26% Isopropyl alcohol Solvent --.sup.1 --.sup.1
--.sup.1 Water Solvent --.sup.1 --.sup.1 --.sup.1 Seal Coating
(optional) Hydroxypropyl methyl Coating 7.61% 7.27% 6.85% cellulose
USP polymer Talc USP Anti-tack 0.76% 0.73% 0.69% Isopropyl alcohol
Solvent --.sup.1 --.sup.1 --.sup.1 Water Solvent --.sup.1 --.sup.1
--.sup.1 Extended Release Coating Ethyl cellulose Coating 6.23%
9.46% 13.53% polymer Povidone Pore 0.85% 1.29% 1.84% former Medium
chain Plasticizer 0.75% 1.13% 1.62% triglycerides Isopropyl alcohol
Solvent --.sup.1 --.sup.1 --.sup.1 Water Solvent --.sup.1 --.sup.1
--.sup.1 Magnesium Stearate NF Lubricant 0.1% 0.1% 0.1% NF =
National Formulary .sup.1Purified water and isopropyl alcohol are
removed during processing.
[0216] The in vitro dissolution of capsules prepared above were
tested using a USP Apparatus II (Paddles) at 50 rpm with 500 ml
water at 37.degree. C. as the dissolution medium. The results are
shown in FIG. 1.
Example 4
Amantadine Extended Release Formulation Made by Extrusion
Spheronization
[0217] Amantadine HCl extended release compositions designed for
nighttime administration are prepared using the components and
relative amounts shown in Table 4 below and the manufacturing
process described below.
[0218] A blend of amantadine HCl, microcrystalline cellulose and
lactose monohydrate was prepared and a wet mass is prepared in a
high shear granulator using an aqueous solution of povidone. The
wet mass is extruded using 1 mm sieve and extruded mass is
spheronized using a spheronizer. The pellets are dried in a tray
drier to yield core pellets. The core pellets are coated with
extended release coating solution in a pan coater. The desired
weight of the ER coated pellets containing the unit dose is filled
into empty 1 hard gelatin capsule shell (170 mg strength) using an
encapsulator equipped with pellet dosing chamber.
TABLE-US-00005 TABLE 4 Composition of amantadine HCl ER capsules
combined w/w Component Function of capsule Pellet Core Amantadine
Hydrochloride USP Active 59.40% Microcrystalline cellulose Diluent
18.67% Lactose monohydrate Diluent 6.15% Povidone Binder 0.64%
Water Solvent --.sup.1 Extended Release Coating Ethyl cellulose
Coating polymer 12.41% Polyethylene glycol Pore former 1.24%
Dibutyl sebacate Plasticizer 1.49% Ethanol Solvent --.sup.1
[0219] The in vitro dissolution of capsules prepared above are
tested using a USP Apparatus II (Paddles) at 50 rpm with 500 ml
water at 37.degree. C. as the dissolution medium and release not
more than 25% of the drug in 2 hours, 40-80% in 6 hours, and at
least 80% at 12 hours.
Example 5
Pharmacokinetic Measurement of Formulations of Amantadine ER
Compared to IR Amantadine
[0220] Objective: The primary objective of the study was to confirm
the PK properties of extended release formulations in example 3, to
determine the pharmacokinetic profiles, safety and tolerability of
three prototype formulations of ER capsules of amantadine HCl
described with different release properties in Example 3 relative
to a 100 mg film-coated IR amantadine HCl tablet (SYMMETREL.RTM.)
given as single doses to healthy adult subjects under fasting
conditions.
[0221] Study design: This was a Phase 1, randomized, single dose,
open-label, four-period, crossover, fasting pharmacokinetic study
in which single 100 mg doses of three formulations of Amantadine ER
capsules with different release properties were compared to single
100 mg doses of marketed amantadine IR tablets (SYMMETREL.RTM.).
The three ER formulations differed in the amantadine release rates
in vitro, as shown in FIG. 1.
[0222] Methods: Subjects were admitted to the unit for the first
period of dosing within 21 days of study screening. Subjects were
dosed on the day after checking into the unit and discharged at 24
hours post dose. Subjects were asked to return after discharge for
follow-up visits at 56 hours and 152 hours after dosing. Each
dosing period was separated by at least 7 day washout.
[0223] After an overnight fast, the formulation was administered to
the subjects while in a sitting position with 240 mL of water.
Blood samples were collected at 0 (pre-dose), 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 24 (discharge), and 56 hours
following each dose. Plasma samples were assayed for amantadine by
a validated liquid chromatography/tandem mass spectroscopy
(LC/MS/MS) method. Pharmacokinetic parameters were calculated using
a non-compartmental analysis with WinNonlin software (version 4.1
or higher; Pharsight Corporation).
[0224] An analysis of variance (ANOVA) was performed on the natural
logarithms of Cmax and AUC0-.infin. determined from the data
following a single dose of study drug using linear mixed effects
model. The model included effects for subject, sequence, period,
and regimen. The effects of sequence, period, and regimen were
fixed, while the effect of subject was random. Ratio of ER to IR
for both AUC (relative bioavailability for ER formulations) and
Cmax was calculated. (Adverse events were monitored throughout the
study. Vital signs (pulse rate, blood pressure and body
temperature), clinical laboratory measures (biochemistry,
hematology, and urinalysis) and ECGs were collected at various
times during the study.
[0225] Results: A total of 20 subjects participated in the study.
The mean age was 25.5 years old (range 20-38 years). The study
consisted of 8 male (40%) and 12 female (60%) subjects with a mean
body mass index (BMI) of 23.6 kg/m2.+-.2.85. The racial makeup was
100% Caucasian. Fifteen subjects received all 4 treatments.
[0226] The PK results from this study showed that all three of the
Amantadine ER formulations reduced the rate of absorption, based on
the reduced values of Cmax and increased Tmax, compared to
SYMMETREL.RTM. (Table 5, FIGS. 5, 6). The IR formulation had the
highest mean Cmax (277.+-.73.9 ng/mL) and shortest median Tmax (4
h) values. Formulations A, B, and C produced progressively lower
Cmax and longer Tmax values. Cmax decreased from 204.+-.61.4 to
166.+-.34.8 to 149.+-.34.4 ng/mL, and median Tmax increased from
7.0, to 11.0, to 14.0 h for formulations A, B, and C, respectively.
Total amantadine exposure, as measured by AUC0-.infin., was
slightly lower in all three Amantadine ER formulations than
SYMMETREL.RTM. but all three formulations had acceptable
bioavailability (85-95%).
TABLE-US-00006 TABLE 5 Single Dose Pharmacokinetic Parameters of
Three Formulations of Amantadine ER (Formulation A, B, and C), as
Compared to SYMMETREL .RTM. (Formulati.sub.on IR) 100 mg 100 mg 100
mg 100 mg Formulation A Formulation B Formulation C
F.sub.ormulation IR Parameter .sup.a (n = 19.sup.) (n = 17) (n =
18) (n = 18) C.sub.max (ng/mL) 204 .sub..+-. 61 166 .+-. 35 149
.+-. 34 277 .+-. 74 T.sub.max (h) [range] 7 [5-11] 11 [5-15] 14
[.sub.9-18] 4 [2-6] A.sub.UC0-last (ng*h.sub./mL) 5064 .+-. 1573
5028 .+-. 2328 4525 .+-. 1268 5488 .+-. 1730 AUC.sub.0-.infin.
(ng*h/mL) 5545 .+-. .sub.1904 5724 .+-. 2369 5652 .+-. 2581 5907
.+-. 1907 t.sub.1/2 (h) 13.9 .+-. 3.0 16.3 .+-. 5.2 18.3 .+-. 7.5
12.3 .+-. 3.5 .sup.a All parameters are reported as the mean .+-.
standard deviation (SD), except t.sub.max which is reported as a
median value (min to max range)
TABLE-US-00007 TABLE 6 Ratio ER/IR for C.sub.max and
AUC.sub.0-.infin. Comparison Variable ER/IR.sup.a A vs. IR
C.sub.max (ng/mL) 66.0% AUC.sub.0-.infin. (ng*h/mL) 85.3% B vs. IR
C.sub.max (ng/mL) 60.9% AUC.sub.0-.infin. (ng*h/mL) 94.6% C vs. IR
C.sub.max (ng/mL) 51.2% AUC.sub.0-.infin. (ng*h/mL) 88.5%
.sup.aPoint estimate of the geometric mean ratio (ER/IR).
Example 6
Food-Effect Evaluation of Amantadine ER
[0227] Objective:
[0228] The primary objective was to demonstrate that the amantadine
ER formulations suitable for nighttime administration exhibit
excellent bioavailability when administered with food. We
determined the pharmacokinetics of a 100 mg capsule of an
amantadine ER formulation (Example 3, Formulation B), when
administered both with a high fat meal and in a fasted state.
[0229] Study Design:
[0230] This was a Phase 1, randomized, single dose, open-label,
two-period, crossover, food-effect study to compare single 100 mg
doses of Formulation 1 in healthy adult (18 to 45 years of age)
male and female subjects in fed and fasted states. The study
consisted of a 21-day to -2 day screening phase (prior to the
scheduled dosing day) and two treatment periods, Period 1 and
Period 2, with an 8-day wash-out period between treatment
periods.
[0231] Methods:
[0232] After an overnight fast, the formulation was administered to
the subjects while in a sitting position with 240 mL of water at
ambient temperature for the fasted condition. For the fed
condition, after the overnight fast, subjects were served a high
fat and high calorie test meal (Guidance for Industry Food-Effect
Bioavailability and Fed Bioequivalence Studies, December 2002) as
breakfast, which they were required to consume completely within 30
minutes before taking the study medication. Subjects were
randomized to one of two sequences, each composed of treatment
administration under fed and fasted conditions separated by an
eight day wash out period.
[0233] For each period, pharmacokinetic blood samples were
collected at pre-dose and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 18, 24, 28, 48, 72, 96 and 144 hours after dosing
in each period. Subjects were housed in the clinical facility at
least 15 hours before investigational product administration and
remained in the clinical facility for at least 28 hours after
administration of the investigational product in each period.
Samples after 28 hours in each period were collected on an
ambulatory basis. Amantadine in plasma was quantified by a
validated LC/MS/MS method. The pharmacokinetic parameters were
calculated from the drug concentration-time profile by
non-compartmental model using WinNonlin Professional
Software-Version 5.0.1 (Pharsight Corporation, USA) for amantadine.
Absence of food effect was defined as met if the point estimates
and 90% confidence intervals (CI) for the ln-transformed C.sub.max,
AUC.sub.last and AUC.sub..infin. fed/fasting ratios of the
population means were entirely within the standard accepted range
of 80% to 125%. All statistical analyses for amantadine were
performed using PROC MIXED of SAS.RTM. Release 9.1.3 (SAS Institute
Inc., USA).
[0234] Routine safety monitoring was conducted during and after
dosing in all subjects.
[0235] Results:
[0236] A total of 26 subjects participated in the study, 19 (73%)
male and 7 (27%) female. The mean age was 26 years (range 19-44)
and the mean BMI was 22.4 kg/m.sup.2 (range 18.1-29.8). The racial
makeup was 100% Asian. All subjects received at least one dose of
study drug and were included in the safety analysis. Twenty-four
(92.3%) subjects completed the study and were included in the
pharmacokinetic analysis. Two subjects (7.7%) were withdrawn prior
to completion of the study due protocol deviations.
[0237] The results of this study (Table 7) indicate that the single
dose pharmacokinetics of Formulation B are not affected by food.
The rate, as measured by C.sub.max, and the extent, as measured by
AUC.sub.0-last and AUC.sub.0-.infin., of absorption of amantadine,
administered with and without food, were equivalent (Table 8).
TABLE-US-00008 TABLE 7 Mean .+-. SD Pharmacokinetic Parameters
after Single Dose Administration of 100 mg of Formulation B in Fed
and Fasted States Mean .+-. SD (Un-transformed data) n = 24
Parameters (Units).sup.a Fasted State Fed State T.sub.max (h) 11.9
.+-. 2.1 (8-15) 9.5 .+-. 2.4 (5-16) C.sub.max (ng/mL) 198.8 .+-.
34.7 219.4 .+-. 41.5 AUC.sub.0-last (ng*h/mL) 5571.2 .+-. 1654.2
5394.4 .+-. 1581.5 AUC.sub.0-.infin. (ng*h/mL) 5663.1 .+-. 1677.4
5476.6 .+-. 1590.7 t.sub.1/2 (h) 11.9 .+-. 2.8 11.5 .+-. 2.0
t.sub.lag (h) 1.0 2.0 .sup.aAll parameters are reported as the mean
.+-. standard deviation (SD). t.sub.max is reported as the mean
.+-. SD (min to max range).
TABLE-US-00009 TABLE 8 Geometric Least Squares Mean, Ratios and 90%
Confidence Interval for Formulation B (n = 24) in Fed and Fasted
States ln-transformed data 90% Geometric Least Squares Mean
Confidence Fed Fasted Ratio Interval Parameters (Units) State State
(Fed/Fasted)% (Parametric) C.sub.max (ng/mL) 215.6 195.8 110.1
104.4-116.2% AUC.sub.0-last (ng*h/mL) 5195.9 5344.2 97.2
91.0-103.8% AUC.sub.0-.infin. (ng*h/mL) 5280.3 5434.7 97.2
90.9-103.8%
[0238] Conclusion:
[0239] The results of this study indicate that the single dose
pharmacokinetics of amantadine ER are not affected by food. The
rate, as measured by C.sub.max, and the extent, as measured by
AUC.sub.0-last and AUC.sub.0-.infin., of absorption of amantadine,
administered with and without food, were equivalent.
Example 7
Pharmacokinetic Study Comparing Once-Daily Administration of
Amantadine HCl ER Capsules with Twice-Daily Administration of
Amantadine HCl IR Tablets in Healthy Adults Under Fasting
Conditions
[0240] Objective: The primary objective of this study was to
measure at steady state under repeat or chronic dosing the
pharmacokinetics of an ER amantadine formulation suitable for
nighttime administration, and enable the calculation of critical PK
parameters for future safety and efficacy studies (i.e.,
Cave-morning, Cave-day, Cave-night) of ER amantadine formulations
administered at night. We compared the single dose and repeat dose
pharmacokinetics of amantadine HCl administered twice daily as a
commercially available immediate release (IR) formulation to a once
daily amantadine extended release (ER) formulation (Example 3,
Formulation B).
[0241] Study Design:
[0242] This was a two period, multiple dose, crossover study. After
a 21 day screening period, 26 healthy male and female subjects were
randomized to receive one of two treatments (amantadine ER 200 mg
once daily or amantadine IR 100 mg twice daily) in Period-I, then
crossed over to receive the other treatment in Period-II.
[0243] Methods:
[0244] Study drug administration started on day 1. Study drug was
not administered on Day 2. Multiple dosing commenced on day 3 and
continued for 7 days (through day 9). A washout period of 8 days
separated the dose administrations. The study drug was administered
with 240 mL of drinking water. No other fluids were allowed within
1 hour of dosing. For each period, pharmacokinetic blood samples
were collected at pre-dose and at 1, 2, 3, 4, 5, 6, 8, 10, 11, 12,
13, 14, 15, 16, 17, 18, 20, 24, 28, 36, and 48 hours after the
first dose. The morning trough (pre-dose) blood samples were
collected on Days 7 and 8. Blood samples were again collected
immediately before the morning dose on Day 9 and at 1, 2, 3, 4, 5,
6, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 24, 28, 48, 72, and
96 hours thereafter. Samples after 28 hours following the morning
dose on day 9 were collected on an ambulatory basis in each period.
Amantadine in plasma was quantified by a validated LC/MS/MS method.
The pharmacokinetic parameters were calculated from the drug
concentration-time profile by non-compartmental model using
WinNonlin Professional Software-Version 5.0.1 (Pharsight
Corporation, USA) for amantadine.
[0245] Statistical analyses were conducted to assess the
pharmacokinetic profile of single dose and repeat dose amantadine
HCl administered twice daily as a commercially available immediate
release (IR) formulation compared to a once daily extended release
(ER) formulation (Formulation B). An analysis of variance (ANOVA)
was performed on the natural logarithms of C.sub.max, C.sub.min,
and AUC.sub.24 determined from the data following the dose of study
drug on study day 9 using linear mixed effects model. The model
included the fixed effects for sequence, period, regimen and a
random subject effect. The confidence intervals were used to
perform the 2 one-sided tests procedure for equivalence assessment.
The confidence intervals were obtained by exponentiating the
endpoints of the confidence intervals for the difference of mean
logarithms obtained within the framework of the ANOVA model. The
upper and lower limits of confidence intervals from the natural-log
transformed data were back-exponentiated to obtain the 90%
confidence interval for the ratio of geometric means. Equivalence
was established if the exponentiated 90% confidence interval fell
entirely within the interval (80.00%, 125.00%).
[0246] Repeated measures ANOVA was carried out for comparison of
C.sub.min for day 7, 8 and 9 at 5% level of significance on both
untransformed and ln-transformed data. Steady state was
demonstrated if the repeated measures ANOVA test was found to be
non-significant. The statistical analysis for amantadine was
performed using PROC MIXED of SAS.RTM. Release 9.1.3 (SAS Institute
Inc., USA).
[0247] Routine safety monitoring was conducted during and after
dosing in all subjects, and at the end of the study.
[0248] Results:
[0249] A total of 26 subjects participated in the study, 22 (84.6%)
male and 4 (15.4%) female. The mean age was 26 years (range 19-42)
and the mean BMI was 22.9 kg/m.sup.2 (range 18.1-28.8). The racial
makeup was 100% Asian. All subjects received at least one dose of
study drug and were included in the safety analysis. Twenty-four
(92.3%) subjects completed the study and were included in the
pharmacokinetic analysis. Two subjects (7.7%) were withdrawn from
the PK analysis prior to completion of the study due to vomiting
within 12 hours of dosing, which was a pharmacokinetic exclusion
criterion.
[0250] As expected from its half-life, once daily administration of
amantadine ER and twice daily dosing of amantadine IR resulted in
accumulation as measured by higher C.sub.max and AUC on Day 9
compared to Day 1 (Table 9 and FIG. 2). Steady state was achieved
by Day 9 for both formulations as demonstrated by similar trough
levels on Days 7, 8 and 9 (data not shown). At steady state (Day 9)
plasma concentrations (FIG. 2, Table 9) and pharmacokinetic
parameters (Table 9) were comparable for both formulations.
Furthermore, the formulations are equivalent in terms of the extent
and the rate of absorption of amantadine as measured by steady
state C.sub.max, C.sub.min and AUC.sub.0-24 (Table 9), where
equivalency is defined by the 90% CIs of the ratio of the least
square means of the test versus reference for steady state
C.sub.max, C.sub.min and AUC.sub.0-24 of Amantadine ER to
Amantadine IR falling within 80%-125%.
TABLE-US-00010 TABLE 9 Mean (.+-.SD) Pharmacokinetic Parameters of
Amantadine after Single and Multiple Dose Administration of IR (100
mg BID) and ER (200 mg QD) Formulations Formulation IR (n = 24) ER
(n = 24) Parameter (Units).sup.a Day 1 Day 9 Day 1 Day 9 t.sub.1/2
(h) 13.2 .+-. 2.8 12.6 .+-. 2.4 13.7 .+-. 3.6 12.8 .+-. 2.2
[9.1-18.8] [9.4-18.1] [9.1-22.7] [9.2-17.4] t.sub.max (h) 14.42
.+-. 0.88 12.6 .+-. 4.5 11.4 .+-. 1.9 10.3 .+-. 2.0 [13-16] [1-15]
[8-18] [8-18] C.sub.max (ng/mL) 530 .+-. 80 728 .+-. 153 431 .+-.
84 665 .+-. 179 [407.5-752.7] [538.4-1101.8] [313.5-559.9]
[444.4-1140.0] AUC.sub.0-last (ng h/mL) 11989 .+-. 2224 23040 .+-.
8273 11171 .+-. 2773 21362 .+-. 8946 [9243-17106] [13133-46446]
[7326-16970] [10821-47134] AUC.sub.0-.infin. (ng h/mL) 13685 .+-.
3324 NA 12900 .+-. 4087 NA [10167-20989] [7817-22153] AUC.sub.0-24
(ng h/mL) 7695 .+-. 1026 13752 .+-. 3586 7173 .+-. 1367 12680 .+-.
3879 [5967-10171] [9085-22519] [5021-9552] [7896-23058] C.sub.min
(ng/mL) -- 412.4 .+-. 142.6 -- 374.9 .+-. 151.7 [218.5-795.2]
[172.2-767.1] .sup.aAll parameters are reported as the mean .+-.
SD, [min to max range] NA = not applicable
[0251] Certain additional PK parameters that are important in
determining the suitability of the ER amantadine formulation for
once daily, night time administration are also reported in Table
10.
TABLE-US-00011 TABLE 10 Additional Steady State PK parameters of
Amantadine ER ER 200 mg QD IR 100 mg BID Cmax/Cmin 1.86 1.68
C-ave-8-16 hrs(ng/ml) 614 586 C-ave-8-12 hrs (ng/ml) 643 510
C-ave-16-24 hrs (ng/ml) 502 569 C-ave-0-8 hrs (ng/ml) 465 586
C-ave-8-16 hrs/C-ave-0-8 hrs 1.32 1.00 C-ave-8-12 hrs/C-ave-0-8 hrs
1.38 0.87 % Change in Plasma 5% 55% Concentration 0-3 hrs % Change
in Plasma 23% 48% Concentration 0-4 hrs AUC 0-4 as % of AUC 24 12%
N/A AUC 0-8 as % of AUC 24 30% N/A AUC 0-12 as % of AUC 24 51%
N/A
[0252] Conclusion: the ER amantadine formulation exhibits the
desired steady state PK properties that would make the same
suitable for administration at night and for achieving desired
efficacy and tolerability benefits. Specifically, the ER amantadine
formulation administered once daily at night results in relatively
slow initial rise in amantadine plasma concentration, higher
average amantadine plasma concentrations 8 to 12 hours after
administration relative to 0-8 hours after administration and thus
if administered at night higher ratios of average day time to night
time amantadine plasma concentrations relative to IR amantadine.
Thus this formulation is well suited for administration at higher
doses than current practice that are expected to be relatively well
tolerated and potentially provide superior efficacy in the
treatment of LID, fatigue and Parkinson's disease.
Example 8
Study Comparing Administration of Amantadine HCl ER Capsules Once
Nightly with Twice-Daily Administration of Amantadine HCl IR
Tablets in Normal Healthy Volunteers
[0253] Objective: The primary objective is to compare the effects
on sleep of amantadine extended release (ER) capsules (Formulation
B) administered once daily at bedtime with amantadine immediate
release (IR) tablets administered twice daily in normal healthy
volunteers. This ER formulation exhibits a Cave, day/Cave,
night=1.30.
[0254] Study Design:
[0255] This is a single-center, double-blind, triple-dummy,
randomized, cross-over study to compare the effects on sleep of
amantadine ER capsules, QHS, amantadine IR tablets BID, and
caffeine caplets (active comparator) in 30 normal healthy
volunteers as assessed by overnight polysomnography (PSG) and
standardized questionnaires (Stanford Sleepiness Scale (SSS);
Modified Epworth Sleepiness Scale (m-ESS)/Karolinska Sleepiness
Scale (KSS); Toronto Hospital Alertness Test (THAT)/ZOGIM Alertness
Scale (ZOGIM-A); Visual analog scale of sleepiness/alertness
(VAS)).
[0256] Study drugs are administered in 3 dosing periods. A single
day's dosage of one drug is administered per dosing period. Each
day of dosing is separated by a washout period of 1 week. A single
day's dosage of amantadine ER (Formulation B) consists of one 220
mg capsule (or 2.times.110 mg capsule) administered at bed time
(QHS; defined as 23:00 h for the purposes of this study). A single
day's dosage of amantadine IR consists of one 100 mg capsule
administered twice a day (BID; defined as 8:00 h and 16:00 h for
the purposes of this study). A single day's dosage of caffeine
consists of one 100 mg capsule administered three times a day (TID;
defined as 8:00 h, 16:00 h, & 23:00 h for the purposes of this
study).
[0257] All subjects are dosed three times a day, at 8:00 h, 16:00
h, & 23:00 h. At each hour of dosing, every subject receives
either the active drug or the matching placebo for each of the 3
treatments. Whether the capsule, tablet, or caplet administered at
a specific hour of dosing contains active study drug or is a
placebo dummy is determined according to the dosing sequence and
period to which the subject is assigned.
[0258] Consented subjects who meet eligibility criteria are
randomized equally to one of 3 treatment sequences (groups), each
comprising 3 single-day treatment periods separated by 1 week
washout periods as described above. Additionally, there is a
one-day, single-blind, placebo run-in prior to each double-blind
dosing day. This is to allow subjects to acclimate to sleeping in
the Clinical Research Unit (CRU) under conditions of PSG recording
and to establish individual baseline (BL) PSG characteristics.
[0259] For each dosing period, subjects are admitted to a CRU
equipped with a sleep laboratory the day before the first day of
dosing with active study drug. They stay in the CRU overnight and
through the entirety of the active drug-dosing day. They again stay
overnight and then are discharged from the CRU the morning of the
following day. For the first dosing period, the day of admission to
the CRU (Day -1) constitutes the last day of the screening phase,
and the day of discharge from the CRU constitutes the first day of
the first washout period (Day 2). For the second dosing period, the
day of re-admission to the CRU (Day 7) constitutes the last day of
the first washout period, and the day of discharge (Day 9) will
constitute the first day of the second washout period. For the
third dosing period, the day of re-admission to the CRU (Day 14)
constitutes the last day of the second washout period, and the day
of discharge (Day 16) constitutes the first day of the follow-up
phase.
[0260] On the day of admission (or re-admission) to the CRU,
subjects undergo routine laboratory and vital sign testing. They
are administered one each of the placebo dummies (for amantadine
ER, amantadine IR, & caffeine) at 16:00 h and at 23:00 h in
single-blind fashion. They are questioned for adverse events (AEs)
and have vital signs checked immediately prior to each dosing.
Blood is drawn for routine laboratory testing and toxicology screen
prior to the 16:00 h dosing. Subjects spend the night in the sleep
lab under conditions of PSG recording.
[0261] On the day of dosing with active study drug, subjects are
awakened at 7:00 h and fill out a battery of sleep and alertness
questionnaires. They receive study drug (active or placebo) at 8:00
h, 16:00, and 23:00 h. They are questioned for AEs and have vital
signs checked immediately prior to each dosing. Blood is drawn to
measure plasma amantadine concentrations prior to the 23:00 h
dosing.
[0262] On the day after dosing with active study drug, subjects are
awakened at 7:00 h and fill out a battery of sleep and alertness
questionnaires. Shortly before 8:00 h, i.e., 9 hours after the last
dosing time, they are questioned for AEs and have vital signs
checked. Also, blood is drawn to measure plasma amantadine
concentrations. Instructions for contacting the site to report any
AEs are reviewed with the subjects prior to their discharge from
the CRU. The schedule for returning to the PSU for the next dosing
period (this applies to returning for Periods 2 & 3) or for
telephone contact (this applies to the follow-up after the third
dosing period) is be reviewed.
[0263] All subjects receive a follow-up telephone call 3 days
following discharge from the CRU (Day 19).
[0264] AEs and concomitant medications are monitored throughout the
study. Blood samples for measurement of blood plasma concentrations
are drawn immediately prior to the 23:00 h dosing time on Days 1,
8, and 15, and at approximately 8:00 h on Days 2, 9, and 16.
[0265] Sleep parameters and measurements of sleepiness and
alertness at each time point are listed by subject. Both composite
scores and scores from the individual components of the PSG and
questionnaires are tabulated and analyzed. For each parameter
measured, descriptive summary statistics are calculated by sequence
and treatment, including means (or medians, as appropriate),
ranges, and standard deviations (SDs).
[0266] Inferential statistics are performed on selected results
wherein the magnitude of the differences between the means across
treatment groups relative to the variance suggests a possible
differential treatment effect. Continuous variable data is analyzed
by parametric statistics (repeated measures analysis of variance
with appropriate supplemental post-hoc analyses and/or paired
t-test). Categorical data and data not conforming to a normal
distribution is analyzed by non-parametric statistics (Wilcoxon
signed rank test). PSG data may also be assessed by multivariate
analyses and/or spectral analyses.
[0267] Results:
[0268] A lack of increase in, or reduction of, sleep disturbances
with QD administration of 220 mg of amantadine ER compared to BID
administration of amantadine IR, as measured by PSG and a
standardized sleep questionnaire (e.g. SSS, m-ESS, KSS, THAT,
ZOGIM-A, or VAS), demonstrates the suitability of amantadine ER for
once daily administration at bedtime.
Example 9
Study Comparing the Effects on Sleep and Efficacy of Amantadine HCl
ER Capsules Administered Once Daily at Night Relative to Amantadine
HCl IR Capsules Administered Twice Daily in Parkinson's
Patients
[0269] Objective: To compare the effects on sleep and efficacy of
amantadine extended release (ER) capsules.
[0270] Study Design:
[0271] This is a Multi-Center, Double-Blind, Randomized Study to
Compare the Effects on Sleep and Efficacy of Amantadine Extended
Release (ER) Capsules in 120 Parkinsons Patients as assessed by
UPDRS (Unified Parkinson's Disease Rating Scale), UPDRS-IV (Unified
Parkinson's Disease Rating Scale Part IV), AIMS (Abnormal
Involuntary Movement Scale), overnight polysomnography (PSG) and
standardized questionnaires (Stanford Sleepiness Scale (SSS);
Modified Epworth Sleepiness Scale (m-ESS)/Karolinska Sleepiness
Scale (KSS); Toronto Hospital Alertness Test (THAT)/ZOGIM Alertness
Scale (ZOGIM-A); Visual analog scale of sleepiness/alertness
(VAS)).
[0272] All study drugs are administered orally. Treatment A
consists of a placebo capsule administered in the morning and two
110 mg capsules of Amantadine (ER) and a placebo capsule
administered at bed time. Treatment B consists of a placebo capsule
administered in the morning and three 110 mg capsules of Amantadine
(ER) administered at bed time. Treatment C consists of a 100 mg
capsule of Amantadine IR administered in the morning and a 100 mg
capsule of Amantadine IR and two placebo capsules administered at
bed time. Treatment D consists of a placebo capsule administered in
the morning and 3 placebo capsules administered at bed time.
[0273] Consented subjects who meet eligibility criteria are
randomized equally to one of 3 treatment groups, each comprising
14-day treatment periods. Additionally, there is a one-day,
single-blind, placebo run-in prior to each double-blind dosing day.
This is to allow subjects to acclimate to sleeping in the Clinical
Research Unit (CRU) under conditions of PSG recording and to
establish individual baseline (BL) PSG characteristics.
[0274] For each dosing period, subjects are admitted to a CRU
equipped with a sleep laboratory the day before the first day of
dosing with active study drug. They stay in the CRU overnight and
through the entirety of the active drug-dosing day. They again stay
overnight and then are discharged from the CRU the morning of the
following day.
[0275] Parkinson's scores are recorded in the mornings on days 1, 7
and 14 using standard scoring methods, including the UPDRS and
AIM.
[0276] AEs and concomitant medications are monitored throughout the
study.
[0277] Sleep parameters and measurements of sleepiness and
alertness at each time point are listed by subject. Both composite
scores and scores from the individual components of the PSG and
questionnaires are tabulated and analyzed. For each parameter
measured, descriptive summary statistics are calculated by sequence
and treatment, including means (or medians, as appropriate),
ranges, and standard deviations (SDs).
[0278] Inferential statistics are performed on selected results
wherein the magnitude of the differences between the means across
treatment groups relative to the variance suggests a possible
differential treatment effect. Continuous variable data is analyzed
by parametric statistics (repeated measures analysis of variance
with appropriate supplemental post-hoc analyses and/or paired
t-test). Categorical data and data not conforming to a normal
distribution is analyzed by non-parametric statistics (Wilcoxon
signed rank test). PSG data may also be assessed by multivariate
analyses and/or spectral analyses.
[0279] Results:
[0280] An improvement in UPDRS, UPDRS-IV, AIM, lack of increase in,
or reduction of, sleep disturbances, as measured by PSG and a
standardized sleep questionnaire (e.g. SSS, m-ESS, KSS, THAT,
ZOGIM-A, or VAS), demonstrates the suitability of amantadine ER for
once daily administration at bedtime.
Example 10
Simulated Pharmacokinetic Characteristics of Higher Strength,
Amantadine ER Formulations Administered at Nighttime
[0281] Objective: The objective is to use the data generated in the
clinical study described in Example 7 to predict steady state
plasma concentration-time profiles of various IR and ER amantadine
regimens at different dose levels to show the benefits of higher
strength amantadine ER formulations administered at nighttime.
[0282] Methodology: Plasma concentration-time profiles from healthy
volunteers that received multiple doses of the ER and IR
formulations of amantadine per study procedures described in
Example 7 (ADS-5101-MD-104) were used to develop a pharmacokinetic
model describing each of the two formulations. This study was an
open-label, randomized, two-treatment, two-period, two-way
crossover study comparing once-daily amantadine ER capsules and
twice-daily amantadine IR tablets in 26 healthy, adult male and
female volunteers. Complete data from 24 individuals were used in
this exercise. Blood samples for pharmacokinetic evaluation were
collected after single dosing on Day 1 and at steady state on Day
9. In the first step of the analysis, WinNonlin 5.2.1 (Pharsight
Corp., Mountain View, Calif.) was used to fit a one-compartment
model with first-order input and first-order output, weighted 1/y
(where y is the amantadine plasma concentration), to each
individual's plasma concentration-time data obtained after single
(Day 1) and repeated (Day 9) dose administration of amantadine IR
and ER; the fitting was done separately for both formulations, but
simultaneously for both days. Modeling assumptions employed include
dose proportionality and constant clearance as a function of
time.
[0283] The model is described by the following equation:
C = FD V ( k a - k ) [ exp ( - k ( t - t lag ) ) ) - exp ( - k a (
t - t lag ) ) ) ] Equation 1 ##EQU00001##
[0284] where C is the plasma concentration, F is the absolute
bioavailability, D is dose, V is the volume of distribution,
k.sub.a is the absorption rate constant, k is the elimination rate
constant, t is time, and t.sub.lag is the lag time of absorption.
The goodness of fit was verified by comparing the individual model
predicted and observed concentration-time data from Study
ADS-5101-MD-104. After Equation 1 was fitted to each individual's
plasma concentration-time data, model parameter estimates of V/F,
k.sub.a, k, and t.sub.lag were obtained for each of the 24
subjects. The goodness of the prediction at steady state was
confirmed by comparing the observed data and predicted steady-state
concentrations of amantadine obtained after daily dosing of 200 mg
as the ER and IR formulations (Day 9).
[0285] In the second step of the analysis, individual model
parameter estimates were used to simulate steady-state
concentration-time profiles for each individual for both
formulations by reinserting the individual parameter estimates into
Equation 1, and summing the contribution of 7 sequential days of
dosing, according to the following dosing regimens: [0286] 1. Once
Daily (QD) dosing of 260, 340, and 420 mg of the ER formulation to
steady state [0287] 2. Three times daily (TID) dosing of 100 mg of
the IR formulation to steady state [0288] 3. Twice daily (BID)
dosing of 100 mg of the IR formulation to steady state
[0289] Results: FIG. 4 shows the simulated steady state plasma
concentration time profiles for various ER amantadine doses along
with various regimes of IR amantadine. Table 11 summarizes values
of the pharmacokinetic parameters that affect the efficacy and
tolerability of ER amantadine when administered at night.
TABLE-US-00012 TABLE 11 PK parameters associated with nighttime
administration - morning peak benefit measured for ER Amantadine
formulation IR 100 IR 100 ER 260 ER 340 ER 420 mg BID mg TID mg QD
mg QD mg QD Cmax (ng/ml) 669 936 834 1091 1348 Cmin (ng/ml) 435 731
461 603 745 Cmax/Cmin 1.54 1.28 1.81 1.81 1.81 C-ave-day 571 845
766 1002 1238 (6 am-4 pm) (ng/ml) C-ave-morn 479 870 824 1078 1332
(6 am-10 am) (ng/ml) C-ave-even 522 852 591 773 955 (4 pm-10 pm)
(ng/ml) C-ave-night 596 843 616 805 995 (10 pm-6 am) (ng/ml)
C-ave-day/C-ave-night 0.96 1.00 1.24 1.24 1.24
C-ave-morn/C-ave-night 0.80 1.03 1.34 1.34 1.34 C-ave-day relative
to 1.00 1.48 1.34 1.76 2.17 100 mg BID IR
[0290] As shown in Table 11 and in the figures, the ER amantadine
formulations administered once daily at night result in higher
ratios of average day time to night time amantadine plasma
concentrations relative to IR amantadine and are predicted to be
relatively well tolerated. The ER formulations also result in
average day time amantadine plasma concentrations that are 1.3 to
2.2 fold that of IR amantadine administered at 100 mg twice daily
and is predicted to result in significantly enhanced efficacy when
administered to patients in the clinical study described in Example
11 below.
Example 11
A Randomized, Double-Blind, Placebo-Controlled Study of the
Efficacy and Safety of Amantadine Extended Release Oral Capsules
for the Treatment of Levodopa-Induced Dyskinesia in Parkinson's
Disease
[0291] Study Objectives: This study is designed to confirm dose
range of Amantadine Extended Release (ER) oral capsules dosed once
daily at nighttime for the treatment of levodopa-induced dyskinesia
(LID) in subjects with Parkinson's Disease (PD). In addition, the
study is designed to demonstrate the safety and tolerability of
Amantadine ER oral capsules dosed once daily for the treatment of
LID in subjects with PD. Finally, to confirm the steady-state
pharmacokinetics of the Amantadine ER dosing regimens in Parkinsons
patients and to correlate C-ave-day, Cave-morning,
C-ave-morning/C-ave-night and C-ave-day/C-ave-night with the
efficacy and tolerability of amantadine.
[0292] Study Design:
[0293] This will be a multi-center, randomized, double-blind,
placebo-controlled, 4-arm parallel group study of Amantadine ER in
subjects with PD and LID/Consenting subjects who meet eligibility
criteria will be randomized 1:1:1:1 to receive one of the following
4 treatments, each administered as once daily, dosed at night, for
8 weeks: [0294] Treatment A: Placebo, [0295] Treatment B: 260 mg
Amantadine ER (ADS-5102), [0296] Treatment C: 340 mg Amantadine ER
(ADS-5102) [0297] Treatment D: 420 mg Amantadine ER (ADS-5102)
[0298] Subjects who are randomized to Treatment C or D (higher dose
amantadine groups) will receive, in double-blind fashion, 260 mg
Amantadine ER once daily during week 1, with an increase to either
340 mg or 420 mg once daily at the beginning of week 2. Dosing will
continue through week 8.
[0299] Following completion of the baseline visit and
randomization, subjects will return to the clinic after 1, 2, 4, 6,
and 8 weeks of dosing, with a follow-up visit 14 days following the
last dose of study drug. Study visits and assessments will be
scheduled during morning hours when possible (9 am through 1 pm). A
set of two 24-hour diaries will be completed during 48 hours prior
to randomization and 48 hours prior to selected study visits. The
diary will be used to score five different conditions in 30-minute
intervals: Sleep, OFF, ON without dyskinesias, ON with
nontroublesome dyskinesias, ON with troublesome dyskinesias.
[0300] Blood samples will be collected at selected study visits for
determination of amantadine plasma concentrations, and evaluation
of steady-state population pharmacokinetics. Subject participation
during the study will be up to 12 weeks and will include a 2-week
(maximum) screening period, 8-week (maximum) treatment period, and
a 2-week follow-up period. Subjects who are unable to tolerate
their assigned study drug assignment will permanently discontinue
study drug and continue to be followed for safety through 2 weeks
following the last dose of study drug.
[0301] Patient Eligibility Criteria:
[0302] Subjects are eligible to take part in the study if they meet
the inclusion and do not meet the exclusion criteria. Selected key
criteria are as follows:
[0303] Inclusion Criteria: [0304] Male or female adults, residing
in the community (i.e. not residing in an institution) [0305]
Between 30 and 75 years of age, inclusive [0306] Ambulatory or
ambulatory-aided (e.g. walker or cane) ability, such that the
subject can come to required study visits [0307] Knowledgeable and
reliable caregiver/study partner, if appropriate, to accompany the
subject to study visits [0308] Signed a current IRB/IEC-approved
informed consent form [0309] Following training, the subject is
willing and able to understand and complete the 24-hour home diary
(caregiver assistance allowed) [0310] Idiopathic Parkinson's
Disease, complicated by dyskinesia (a MDS-UPDRS score will be
determined during screening, but a minimum score is not required)
[0311] On a stable regimen of antiparkinson's medications,
including levodopa, for at least 30 days prior to screening, and
willing to continue that regimen during study participation [0312]
Presence of dyskinesia, defined as a minimum UDysRS score
[0313] Exclusion Criteria: [0314] Presence of other neurological
disease that may affect cognition, including, but not limited to
Alzheimer's dementia, Huntington's disease, Lewy body dementia,
frontotemporal dementia, corticobasal degeneration, or motor or
sensory dysfunction secondary to stroke or brain trauma. [0315]
Presence of cognitive impairment, as evidenced by a Mini-mental
State Examination (MMSE) score of less than 24 during screening.
[0316] Presence of an acute major psychiatric disorder (e.g., Major
Depressive Disorder) according to DSM-IV-TR or symptom (e.g.,
hallucinations, agitation, paranoia) that could affect the
subject's ability to complete study assessments [0317] Presence of
sensory impairments (e.g., hearing, vision) that would impair the
subject's ability to complete study assessments [0318] History of
alcohol or drug dependence or abuse, according to DSM-IV criteria,
within 2 years prior to screening [0319] History of seizures
(excluding febrile seizures of childhood) [0320] History of stroke
or TIA within 2 years prior to screening [0321] History of
myocardial infarction, NYHA Congestive Heart Failure Class 3 or 4,
or atrial fibrillation within 2 years prior to screening [0322]
History of cancer within 5 years prior to screening, with the
following exceptions: adequately treated non-melanomatous skin
cancers, localized bladder cancer, non-metastatic prostate cancer
or in situ cervical cancer (these exceptions must be discussed with
and approved by the Medical Monitor before study entry) [0323] Any
of the following lab abnormalities; Hemoglobin <10 g/dL, WBC
<3.0.times.10.sup.9/L, Neutrophils <1.5.times.10.sup.9/L,
Lymphocytes <0.5.times.10.sup.9/L, Platelets
<100.times.10.sup.9/L, Hemoglobin A1C >9%, or Aspartate
aminotransferase (AST) and/or alanine aminotransferase (ALT) >2
times the upper limit of normal [0324] Estimated GFR <50
mL/min/1.73 m.sup.2 by Modification of Diet in Renal Disease (MDRD)
or Cockcroft-Gault equation [0325] Any clinically significant ECG
abnormalities [0326] Inability to swallow oral capsules, or a
history of gastrointestinal malabsorption that would preclude the
use of oral medication
[0327] Study Endpoints:
[0328] The primary efficacy endpoint will be the change from
baseline to week 8 in the Unified Dyskinesia Rating Scale (UDysRS)
score. Key secondary endpoints will include: [0329] ON time without
troublesome dyskinesia (ON without dyskinesia plus ON with
non-troublesome dyskinesia), based on a standardized PD home diary
[0330] Unified Parkinson's Disease Rating Scale (MDS-UPDRS),
overall score [0331] Fatigue as measured by the Fatigue Severity
Scale (FSS). This scale includes 9 questions that are completed by
the patient using a rating scale from 1 (strongly disagree) to 7
(strongly agree). This fatigue scale is recommended by MDS for both
screening and severity rating (2010) [0332] Safety, including
adverse events, safety-related study drug discontinuations, vital
signs, and laboratory tests.
[0333] The following mixture of traditional and new scales have
been selected for this phase 2 study: [0334] Unified Dyskinesia
Rating Scale (UDysRS) will be used for primary outcome measure.
This scale has four parts, and a total possible score of 104:
[0335] I: Historical Disability (patient perceptions) of
On-Dyskinesia impact [0336] II: Historical Disability (patient
perceptions) of Off-Dystonia impact [0337] III: Objective
Impairment (dyskinesia severity, anatomic distribution, and type,
based on 4 observed activities) [0338] IV: Objective Disability
based on Part III activities [0339] ON time without troublesome
dyskinesia, based on a standardized Parkinson's Disease home diary
(suggest Test Diary II), [33] will be a secondary outcome measure.
This scale has been used in number of studies with mixed success
[34]. However, most KOLs feel that subject-reported dairy data must
be collected, and needs to support the primary outcome measure.
[0340] Unified Parkinson's Disease Rating Scale (UPDRS), part IV,
items 32 (duration of dyskinesias: 0=none, 4=76-100% of the waking
day) and 33 (disability of dyskinesias: 0=not disabling,
4=completely disabling) will be a secondary outcome measure. This
scale is a traditional scale used in PD for many years and these
items have been utilized in most LID studies. [0341] Cognitive
Scales: Global caregiver impression, depression and other scales
will be employed to measure the mental status benefits of ER
amantadine.
Statistical Methods
[0342] Efficacy Analyses: The efficacy analysis population will
include all randomized and dosed subjects who provide at least one
post-baseline efficacy assessment. For the efficacy endpoint of
UDysRS score, the change from baseline to week 8 will be analyzed
using an analysis of covariance (ANCOVA) model with treatment group
as a factor and the UDysRS baseline value as a covariate. The
primary analysis will compare the 260 mg ADS-5102 group to the
placebo group using a two-sided test at the 5% level of
significance. If the primary comparison is statistically
significant (p<0.05), then the 340 mg and 420 mg ADS-5102 groups
will be compared to placebo, also using a two-sided test at the 5%
level of significance.
[0343] The secondary endpoints will be analyzed using the same
types of ANCOVA models as described for the primary endpoint. All
secondary comparisons between treatment groups will be performed
using two-sided tests at the 5% level of significance. A last
observation carried forward (LOCF) approach will be utilized for
missing data. The primary efficacy analysis will be repeated for
the per-protocol population, a subset of the efficacy analysis
population who provide week 8 efficacy assessments.
[0344] Safety Analyses:
[0345] The safety analysis population will include all randomized
subjects who receive at least one dose of study drug. All safety
endpoints will be analyzed from the time of first dose through the
completion of follow-up (or 2 weeks following the last dose of
study drug). A safety analysis will also be done on the safety
reported during the first 2 weeks of study drug treatment, in order
to assess tolerability of initial dosing with ADS-5102 amantadine
ER.
[0346] Results: following improvements are expected from this study
are shown in the table below. Additional endpoints are described
that [0347] Significant (20-60%) reduction in dyskinesia score
measured by acceptable primary endpoint (e.g., UDysRS) [0348]
Increase in ON time without troubling dyskinesia by 20-60% [0349]
Improvement in UPDRS from 5% to 20%. [0350] Improvement in
Parkinson's fatigue (FSS) from 5% to 60%. [0351] Improvement in
mood by PGI from 5% to 20%.
TABLE-US-00013 [0351] % Clinical Instruments for Effect (Placebo -
Dyskinesia Active/Placebo) Range of Scores Unified Dyskinesia 5-60%
0-104 (4 parts, 26 items Rating Scale total, each 0, normal-4,
(UDysRS) severe) Unified Parkinson's 5-20% Disease Rating Scale
(UPDRS, MDS revision) Part IV 5-60% 0-24 (6 items, each 0,
normal-4, severe) Part IV, dyskinesia 5-60% 0-8 (2 dyskinesia
items, 4.1 items only and 4.2, each 0, normal-4, severe)
Parkinson's Disease 5-40% 0-100% (on time without Home Diary
dyskinesia or with (Hauser et al) nontroublesome dyskinesia)
Example 12
Simulated Pharmacokinetic Characteristics of Amantadine ER
Formulations with a Delayed Release Coat Suitable for Night Time
Administration
[0352] Objective: The objective is to evaluate the pharmacokinetic
profile of two alternative ER formulations of amantadine suitable
for nighttime administration--Formulation 1, which is the
formulation tested in Example 7, and Formulation 2, which is the
formulation tested in Example 7, but with a delayed release over
coat on top of the extended release coat.
[0353] Plasma concentration-time profiles from healthy volunteers,
who received multiple doses of the ER and IR formulations of
amantadine per study procedures described in Example 7
(ADS-5101-MD-104), were used to develop a pharmacokinetic model
describing each of the two formulations. This study was an
open-label, randomized, two-treatment, two-period, two-way
crossover study comparing once-daily amantadine ER capsules and
twice-daily amantadine IR tablets in 26 healthy, adult male and
female volunteers. Complete data from 24 individuals were used in
this exercise. Blood samples for pharmacokinetic evaluation were
collected after single dosing on Day 1 and at steady state on Day
9. In the first step of the analysis, WinNonlin 5.2.1 (Pharsight
Corp., Mountain View, Calif.) was used to fit a one-compartment
model with first-order input and first-order output, weighted 1/y
(where y is the amantadine plasma concentration), to each
individual's plasma concentration-time data obtained after single
(Day 1) and repeated (Day 9) dose administration of amantadine IR
and ER; the fitting was done separately for both formulations, but
simultaneously for both days. Modeling assumptions employed include
dose proportionality and constant clearance as a function of
time.
[0354] The model is described by the following equation
C = FD V ( k a - k ) [ exp ( - k ( t - t lag ) ) ) - exp ( - k a (
t - t lag ) ) ) ] Equation 1 ##EQU00002##
[0355] where C is the plasma concentration, F is the absolute
bioavailability, D is dose, V is the volume of distribution,
k.sub.a is the absorption rate constant, k is the elimination rate
constant, t is time, and t.sub.lag is the lag time of absorption.
The goodness of fit was verified by comparing the individual model
predicted and observed concentration-time data from Study
ADS-5101-MD-104. After Equation 1 was fitted to each individual's
plasma concentration-time data, model parameter estimates of V/F,
k.sub.a, k, and t.sub.lag were obtained for each of the 24
subjects. The goodness of the prediction at steady state was
confirmed by comparing the observed data and predicted steady-state
concentrations of amantadine obtained after daily dosing of 200 mg
as the ER and IR formulations (Day 9).
[0356] In the second step of the analysis, individual model
parameter estimates were used to simulate steady-state
concentration-time profiles for each individual for both
formulations by reinserting the individual parameter estimates into
Equation 1, and summing the contribution of 7 sequential days of
dosing, according to the following dosing regimens:
[0357] 1. Once Daily (QD) dosing of 200 mg of the ER Formulation 1
to steady state
[0358] 2. Once Daily (QD) dosing of 200 mg of the ER Formulation 2
to steady state
[0359] Results: FIG. 7 shows the simulated steady state plasma
concentration time profiles for the two ER amantadine formulations.
(Amantadine blood plasma concentrations are shown on the y, time of
day on the x-axis.) As shown in FIG. 7, the ER amantadine
formulation 2 administered once daily at night results in about a 4
hour delay in achieving peak plasma concentration at steady state
relative to formulation 1. Thus, a formulation comprising a delayed
release coat on top of the extended release coat has a very
favorable pharmacokinetic profile in that it maximizes the daytime
plasma exposure to amantadine whilst minimizing night plasma
exposure at steady state.
[0360] While preferred embodiments of the present invention have
been shown and described herein, such embodiments are provided by
way of example only. Numerous variations, changes, and
substitutions will now occur to those skilled in the art without
departing from the invention. It should be understood that various
alternatives to the embodiments of the invention described herein
may be employed in practicing the invention. All references cited
herein are incorporated herein by reference in their entirety.
* * * * *