U.S. patent application number 15/014854 was filed with the patent office on 2017-03-30 for accordion pill comprising levodopa for an improved treatment of parkinson's disease symptoms.
The applicant listed for this patent is INTEC PHARMA LTD.. Invention is credited to Eva Abramov, Giora Carni, David Kirmayer, Elena Kluev, Nadav Navon, Julia Shvetz, Zeev Weiss.
Application Number | 20170087091 15/014854 |
Document ID | / |
Family ID | 45464636 |
Filed Date | 2017-03-30 |
United States Patent
Application |
20170087091 |
Kind Code |
A9 |
Navon; Nadav ; et
al. |
March 30, 2017 |
ACCORDION PILL COMPRISING LEVODOPA FOR AN IMPROVED TREATMENT OF
PARKINSON'S DISEASE SYMPTOMS
Abstract
The invention provides for the use of an accordion pill
comprising levodopa for the treatment of symptoms of Parkinson's
disease in a subject in need thereof over a 24 hour period, to be
administered to the subject in a twice daily administration
regimen, with an interval of about 8 to about I 0 hours between the
first dose and the second dose, and with an interval of about 14 to
about 16 hours between the second dose and the first dose of the
following day. The twice daily administration regimen provides a
stable blood plasma level of levodopa in the subject after multiple
administrations and is effective in treating the symptoms of
Parkinson's disease over a 24 hour period.
Inventors: |
Navon; Nadav; (Jerusalem,
IL) ; Kirmayer; David; (Jerusalem, IL) ;
Shvetz; Julia; (Jerusalem, IL) ; Kluev; Elena;
(Jerusalem, IL) ; Abramov; Eva; (Jerusalem,
IL) ; Weiss; Zeev; (Jerusalem, IL) ; Carni;
Giora; (Jerusalem, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
INTEC PHARMA LTD. |
Jerusalem |
|
IL |
|
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20160220495 A1 |
August 4, 2016 |
|
|
Family ID: |
45464636 |
Appl. No.: |
15/014854 |
Filed: |
February 3, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13882768 |
Sep 9, 2013 |
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PCT/IB2011/002888 |
Nov 1, 2011 |
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15014854 |
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61408985 |
Nov 1, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0065 20130101;
A61K 9/7007 20130101; A61P 25/16 20180101; A61K 9/4808 20130101;
A61K 31/198 20130101 |
International
Class: |
A61K 9/48 20060101
A61K009/48; A61K 9/00 20060101 A61K009/00; A61K 31/198 20060101
A61K031/198 |
Claims
1-24. (canceled)
25. A method for the treatment of symptoms of Parkinson's disease
in a subject in need thereof, comprising: repetitively
administering an accordion pill comprising a therapeutically
effective amount levodopa, to the subject in a twice daily
administration regimen of two doses in a day, as a first dose of
the day and as a second dose of the same day, with an interval of
about 8 to about 10 hours between the first dose of the day and the
second dose of the same day, with the first dose of the following
consecutive day commencing 24 hours after the first dose of the
previous day wherein the accordion pill comprising levodopa is a
multilayered gastroretentive dosage form, folded into a capsule in
undulated form, which unfolds upon contact with gastric fluids.
26. The method according to claim 25, wherein the accordion pill
comprises about 250 mg levodopa, and wherein the repetitive twice
daily administration regimen provides average blood plasma levels
of levodopa of 200-1,000 ng/ml in the subject over a 24 hour period
following administration of the first dose of the day; or wherein
the accordion pill comprises about 375 mg levodopa, and wherein the
repetitive twice daily administration regimen provides average
blood plasma levels of levodopa of 500-1,500 ng/ml in the subject
over a 24 hour period following administration of the first dose of
the day; or wherein the accordion pill comprises about 500 mg
levodopa, and wherein the repetitive twice daily administration
regimen provides average blood plasma levels of levodopa of
700-2,000 ng/ml in the subject over a 24 hour period following
administration of the first dose of the day.
27. The method according to claim 25, wherein the accordion pill
provides absorption of levodopa into the blood plasma of the
subject for about 6 to about 14 hours following administration of
the accordion pill to the subject.
28. The method according to claim 25, wherein the repetitive twice
daily administration regimen further comprises administering to the
subject one or more dosage forms comprising immediate-release or
controlled-release levodopa.
29. The method according to claim 25, wherein the repetitive twice
daily administration regimen provides stable blood plasma levels of
levodopa with an absolute peak-to-trough ratio of levodopa blood
plasma concentrations below 7.
30. The method according to claim 25, wherein the repetitive twice
daily administration regimen reduces peak-to-trough fluctuations in
the blood plasma levels of levodopa in the subject by at least 50%
in comparison to immediate-release formulations of levodopa
comprising daily equal-doses, administered four times a day.
31. The method according to claim 25, wherein the repetitive twice
daily administration regimen shortens or eliminates total OFF time
during waking hours in the subject.
32. The method according to claim 25, wherein the repetitive twice
daily administration regimen allows faster onset of the ON period
in the subject.
33. The method according to claim 25, wherein the repetitive twice
daily administration regimen alleviates or eliminates nightly sleep
disturbances and daytime sleepiness or drowsiness in the
subject.
34. The method according to claim 31, wherein the repetitive twice
daily administration regimen further comprises administering to the
subject one or more add-on dosage forms comprising
immediate-release or controlled-release levodopa.
35. The method according to claim 25, wherein the repetitive twice
daily administration regimen produces significantly high morning
levels of levodopa in the blood plasma of the subject, thereby
allowing faster onset of the ON period or shortening of the OFF
period after the first dose of the day.
36. The method according to claim 35, wherein the repetitive twice
daily administration regimen alleviates or eliminates nightly sleep
disturbances and daytime sleepiness or drowsiness in the
subject.
37. The method according to claim 38, wherein the accordion pill
comprises about 250 mg levodopa and 50 mg of carbidopa, and wherein
the repetitive twice daily administration regimen provides an
average blood plasma level of levodopa of 200-1,000 ng/ml in the
subject over a 24 hour period following administration of the first
dose of the day; or wherein the accordion pill comprises about 375
mg levodopa and 50 mg of carbidopa, and wherein the repetitive
twice daily administration regimen provides an average blood plasma
level of levodopa of 500-1,500 ng/ml in the subject over a 24 hour
period following administration of the first dose of the day; or
wherein the accordion pill comprises about 500 mg levodopa and 50
mg of carbidopa, and wherein the repetitive twice daily
administration regimen provides an average blood plasma level of
levodopa of 700-2,000 ng/ml in the subject over a 24 hour period
following administration of the first dose of the day.
38. The method according to claim 25, wherein the accordion pill
further comprises an amount of carbidopa sufficient to provide
carbidopa blood plasma levels sufficient to adequately prevent
peripheral levodopa side effects in the subject.
39. The method according to claim 25, wherein the repetitive twice
daily administration regimen provides stable blood plasma levels of
levodopa in the subject with values of area-under-the-curve over 24
hours and a relative bioavailability that is not less than 85%
relative to the values obtained from immediate-release formulations
comprising daily equal-doses administered four times a day.
40. (canceled)
41. The method according to claim 26, wherein the accordion pill
comprises about 375 mg levodopa, and wherein the repetitive twice
daily administration regimen provides an average blood plasma level
of levodopa of 500-1,500 ng/ml in the subject over a 24 hour period
following administration of the first dose of the day.
42. The method according to claim 26, wherein the accordion pill
comprises about 375 mg levodopa, and wherein the twice daily
administration regimen after multiple administrations provides an
average blood plasma level of levodopa of 500-1,500 ng/ml in the
subject over a 24 hour period following administration of the first
dose, and wherein the repetitive twice daily administration regimen
reduces total OFF time during waking hours of not less than 50% in
comparison to the total OFF time associated with immediate-release
formulations comprising daily equal-doses of levodopa, administered
four times a day.
43. A method for the treatment of symptoms responsive to levodopa
in a subject in need thereof over a nocturnal period, comprising
administering to said patient an accordion pill comprising
levodopa, wherein said accordion pill is administered to the
subject at or before bedtime; wherein said accordion pill is
administered to the subject no later than 5 hours from the
administration of the last levodopa dose; wherein said
administration provides improvement in sleep quality in said
subject over the night following administration; and wherein the
accordion pill comprising levodopa is a multilayered
gastroretentive dosage form, folded into a capsule in undulated
form, which unfolds upon contact with gastric fluids.
44. The method according to claim 43, wherein said administration
further alleviates or eliminates the symptoms of morning akinesia
or morning dystonia.
45. The method according to claim 38, wherein the accordion pill
comprises about 50 mg to about 75 mg of carbidopa.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a 35 U.S.C. .sctn.371 National Phase
Entry Application of International Application No.
PCT/IB2011/002888 filed on Nov. 1, 2011, which designates the U.S.,
and which claims benefit of 35 U.S.C. .sctn.119(e) of U.S.
Provisional Application No. 61/408,985 filed on Nov. 1, 2010, the
contents of which are incorporated herein by reference in their
entireties.
FIELD OF THE INVENTION
[0002] The present invention relates to the use of multi-layered,
biodegradable, gastroretentive drug formulations, known as the
Accordion Pill, for the controlled release of carbidopa/levodopa in
an improved method of treatment of Parkinson's Disease
symptoms.
BACKGROUND OF THE INVENTION
[0003] Levodopa (LD) is the most effective drug for the symptomatic
treatment of Parkinson's disease (PD). No other medical or surgical
therapy currently available has been shown to provide
anti-Parkinson benefits superior to what can be achieved with LD.
However, following few years of LD treatment, the actions of each
dose tend to wear off in the majority of PD patients. This wearing
off between doses is strongly correlated to the drug's peripheral
pharmacokinetic (PK) profile. The patients may find themselves
during the day in either ON state, when the patients are capable of
normal movement, or in OFF state, wherein the patients suffer from
impaired movement. As the disease progresses, the patients begin to
fluctuate between the two states. These fluctuations are often
accompanied by troublesome diskinesias in ON state and deep OFF
state, wherein movement is severely impaired. Hence, improving
consistency of LD's plasma levels is essential for improving its
anti-Parkinson effects.
[0004] In addition, in current treatment, physicians fractionate LD
doses in an attempt to reduce the pulsed action of fewer, larger
doses, and to stabilize the LD's pharmacokinetic (PK) profile.
Hence, a significant pill burden is another major concern,
associated with LD treatment. Advanced PD patients often take up to
8-10 LD doses a day, trying to stabilize their motor
conditions.
[0005] For these reasons, numerous efforts have been made by many
pharmaceutical companies over the years to develop an effective
long-acting LD. Available controlled-release preparations of LD
currently on the market do not maintain sufficiently high LD plasma
levels. The reason is that in addition to its very short half-life
(90 min), LD is absorbed mainly in the upper part of the GI tract.
Once a typical controlled-release formulation has passed the drug's
narrow absorption window in the upper part of the GI, the drug is
no longer absorbed in the distal intestine, regardless of the
manner it is released from the dosage form.
[0006] Another concern with current LD treatment is that rapid
elimination of LD and lack of means to sustain relevant LD levels
for prolonged time intervals lead to the absence of sufficiently
high LD plasma levels in patients in the morning, causing movement
arrest and necessitating ultra-rapid LD dosage forms, generally
unavailable on the market, or parenteral preparations which are
cumbersome for self administration in deep OFF state.
[0007] The symptoms of PD in patients are frequently expressed as
Unified Parkinson's Disease Rating Scale (UPDRS) score. Most
frequently, so-called "part 3" is used in evaluation by a clinician
of motor abilities/impairment of PD patients. The UPDRS was
recently reviewed and updated, and is regarded as a standard mean
to evaluate PD patients (see Movement Disorders, Vol. 22, No. 1,
2007, pp. 41-47; Movement Disorder Society-Sponsored Revision of
the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process,
Format, and Clinimetric Testing Plan, by Dr. Christopher G. Goetz
et al, doi: 10.1002/mds.21198).
[0008] It is postulated that gastric retention could significantly
prolong the LD's absorption phase, by retaining the drug in
proximity to its absorption site and releasing the drug in a
continuous manner, towards that absorption site. Some examples of
gastroretentive LD delivery systems are disclosed in WO2009/144558
(Intec Pharma), which is herein incorporated by reference in its
entirety. These gastroretentive formulations are also frequently
referred to as "Accordion Pill", or AP. Alternatively, some gastric
retentive pharmaceutical compositions for treatment and prevention
of CNS disorders are disclosed in WO2010/019915 (Depomed).
[0009] Hence, the challenge is to develop an oral, effective
long-acting LD regimen that provides significantly more continuous
and stable relevant LD plasma levels over 24 hours, with reduced
Total OFF Time and significantly reduced doses per day, preferably
a twice-daily dosing.
SUMMARY OF THE INVENTION
[0010] The present invention is directed to overcoming the problems
of the prior art described above.
[0011] Thus, in one embodiment, the invention provides for the use
of an accordion pill comprising levodopa for the treatment of
symptoms of Parkinson's disease in a subject in need thereof over a
24 hour period. The accordion pill comprising levodopa is
administered to the subject in a twice daily administration
regimen, as a first dose and as a second dose, with an interval of
about 8 to about 10 hours between the first dose and the second
dose, and with an interval of about 14 to about 16 hours between
the second dose and the first dose of the following day. In a
preferred aspect of the invention, the twice daily administration
regimen provides a stable blood plasma level of levodopa in the
subject after multiple administrations. In an even more preferred
aspect of the invention, the stable blood plasma levels of levodopa
are effective in treating the symptoms of Parkinson's disease over
a 24 hour period following the administration of the first
dose.
[0012] In one embodiment, the accordion pill comprises about 250 mg
levodopa, and the twice daily administration regimen provides after
multiple administrations average blood plasma levels of levodopa of
200-1,000 ng/ml in the subject over a 24 hour period following
administration of the first dose.
[0013] In a different embodiment, the accordion pill comprises
about 375 mg levodopa, and wherein the twice daily administration
regimen provides after multiple administrations average blood
plasma levels of levodopa of 500-1,500 ng/ml in the subject over a
24 hour period following administration of the first dose.
[0014] In yet another embodiment, the accordion pill comprises
about 500 mg levodopa, and the twice daily administration regimen
provides after multiple administrations average blood plasma levels
of levodopa of 700-2,000 ng/ml in the subject over a 24 hour period
following administration of the first dose.
[0015] In some embodiments, the accordion pill of the twice daily
administration regimen provides absorption of levodopa into the
blood plasma of the subject for about 6 to about 14 hours following
administration of the accordion pill.
[0016] In one aspect of the invention, the twice daily
administration regimen further comprises administering to the
subject one or more dosage forms comprising immediate-release or
controlled-release levodopa.
[0017] In a preferred embodiment, the stable blood plasma level of
levodopa in the subject provides an absolute peak-to-trough ratio
of levodopa blood plasma concentrations below 7.
[0018] In another preferred embodiment, the twice daily
administration regimen reduces peak-to trough fluctuations in the
blood plasma levels of levodopa in the subject by at least 50% in
comparison to immediate-release formulations comprising daily
equal-doses administered four times a day.
[0019] In one aspect of the invention, the twice daily
administration regimen shortens or eliminates total OFF time during
waking hours in the subject. In a different aspect of the
invention, the twice daily administration regimen allows faster
onset of the ON period in the subject.
[0020] In a preferred embodiment, the twice daily administration
regimen alleviates or eliminates nightly sleep disturbances and
daytime sleepiness or drowsiness in the subject.
[0021] In a different aspect of the invention, the twice daily
administration regimen further comprises administering to the
subject one or more add-on dosage forms comprising
immediate-release or controlled-release levodopa.
[0022] In an additional embodiment, the invention provides for the
use of an accordion pill comprising levodopa for the treatment of
symptoms of Parkinson's disease in a subject in need thereof over a
24 hour period. The accordion pill comprising levodopa is
administered to the subject in a twice daily administration
regimen, with an interval of about 8 to about 10 hours between the
first dose and the second dose, and with an interval of about 14 to
about 16 hours between the second dose and the first dose of the
following day.
[0023] Preferably, the twice daily administration regimen provides
a stable blood plasma level of levodopa in the subject after
multiple administrations. In a preferred aspect of the invention,
the stable blood plasma level of levodopa in the subject is
effective in treating the symptoms of Parkinson's disease over a 24
hour period following the administration of the first dose.
[0024] In an even more preferred aspect of the invention, the twice
daily administration regimen of the invention produces
significantly high morning levels of levodopa in the blood plasma
of the subject. Preferably, the significantly high morning levels
of levodopa in the blood plasma of the subject allow faster onset
of the ON period or shorten the OFF period after the first levodopa
administration of the day.
[0025] In one preferred aspect of the invention, the twice daily
administration regimen alleviates or eliminates nightly sleep
disturbances and daytime sleepiness or drowsiness in the
subject.
[0026] In one embodiment, the accordion pill comprises about 250 mg
levodopa, and the twice daily administration regimen provides after
multiple administrations average blood plasma levels of levodopa of
200-1.000 ng/ml in the subject over a 24 hour period following
administration of the first dose.
[0027] In a different embodiment, the accordion pill comprises
about 375 mg levodopa, and wherein the twice daily administration
regimen provides after multiple administrations average blood
plasma levels of levodopa of 500-1,500 ng/ml in the subject over a
24 hour period following administration of the first dose.
[0028] In yet another embodiment, the accordion pill comprises
about 500 mg levodopa, and the twice daily administration regimen
provides after multiple administrations average blood plasma levels
of levodopa of 700-2,000 ng/ml in the subject over a 24 hour period
following administration of the first dose.
[0029] In one aspect of the invention, the accordion pill may
further comprise about 50 mg to about 75 mg of carbidopa. In a
preferred aspect of the invention, the twice daily administration
regimen provides carbidopa blood plasma levels sufficient to
adequately prevent peripheral levodopa side effects in the subject
for a 24 hour period.
[0030] In a preferred aspect of the invention, the stable blood
plasma level of levodopa in the subject after multiple
administrations provides values of area-under-the-curve over 24
hours and a relative bioavailability that is not less than 85%
relative to the values obtained from immediate-release formulations
comprising daily equal doses administered four times a day.
Alternatively, the stable blood plasma levels of levodopa in the
subject after a single administration provides values of
area-under-the-curve extrapolated to infinity and a relative
bioavailability that is not less than 85% relative to the values
obtained from immediate-release formulations comprising equal doses
of levodopa.
[0031] In preferred embodiments, the twice daily administration
regimen of the invention after multiple administrations provides a
reduction of total OFF time during waking hours from about 3 hours
to about 1 hour. Alternatively, the twice daily administration
regimen of the invention after multiple administrations provides a
reduction in total OFF time during waking hours of not less than
50% in comparison to the total OFF time associated with the
administration of optimized prior treatment of the subject with
levodopa.
[0032] In yet a different aspect, the invention provides for the
use of an accordion pill comprising levodopa for the treatment of
symptoms responsive to levodopa in a subjects in need thereof over
a nocturnal period. The accordion pill comprising levodopa is
preferably administered at bed time. In a preferred aspect of the
invention, bed time administration improves sleep quality during
the night following administration. In an even more preferred
aspect of the invention, bed time administration alleviates or
eliminates the symptoms of morning akinesia or morning
dystonia.
[0033] The foregoing general description and the detailed
description are exemplary and explanatory and are intended to
provide further explanation of the invention as claimed. Other
objects, advantages, and novel features will be readily apparent to
those skilled in the art from the following detailed description of
the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] FIG. 1 presents the results of a pharmacokinetic equidose
study in early PD patients with AP CD/LD 50/250 mg, administered
b.i.d vs IR q.i.d.
[0035] FIG. 2 presents the results of a pharmacokinetic equidose
study in advanced PD patients with AP CD/LD 50/375 mg, administered
b.i.d vs IR q.i.d.
[0036] FIG. 3 presents the results of a pharmacokinetic equidose
study in healthy volunteers with AP CD/LD 50/500 mg, administered
qd (once) vs IR b.i.d.
[0037] FIG. 4 presents the levodopa absorption profile as
percentage of total bioavailable dose, as calculated from the data
of the example 2.
[0038] FIG. 5 presents strong correlation between steady LD blood
plasma levels and elevated UPDRS scores of the
patients--AP-CD/LD-50/375 mg.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0039] "Gastroretentive dosage form", or "Accordion Pill", or "AP",
as used interchangeably herein refers to dosage forms with delayed
gastric emptying as compared to food or to regular oral drug
formulations (or retention in the stomach beyond the retention of
food). In particular, the term refers to a multilayered
gastroretentive dosage form, folded into a capsule in undulated
form, which unfolds upon contact with the gastric fluids.
[0040] The term "degradable" as used herein is intended as capable
of being chemically and/or physically reduced, dissolved or broken
down in the body of a patient and within a relevant time
period.
[0041] A "patient" or "subject" as referenced herein is a human or
non-human mammal suffering from symptoms of Parkinson's disease or
of a related disorder.
[0042] "Treating" or "treatment", are used herein to refer to
obtaining a desired pharmacological and physiological effect. The
effect may be prophylactic in terms of preventing or partially
preventing a disease, symptom or pathological condition and/or may
be therapeutic in terms of a partial or complete cure of a disease,
condition, symptom or adverse effect attributed to a pathological
condition. Thus, "treatment" covers any treatment of a disease in a
mammal, particularly a human, and includes: (a) preventing a
pathological condition from occurring in an individual which may be
predisposed to develop a pathological condition but has not yet
been diagnosed as having it, i.e., causing the clinical symptoms of
a pathological condition not to develop in a subject that may be
predisposed to develop the condition but does not yet experience or
display symptoms of the condition; (b) inhibiting, i.e., arresting
or reducing the development of the pathological condition or its
clinical symptoms; or (c) relieving symptoms associating with the
pathological condition. In particular, the term refers to
alleviating symptoms of Parkinson's disease and of related movement
disorders, clinically responsive to levodopa.
[0043] "About" as used herein generally refers to approximate
values. When referred to a dose of LD in milligrams, "about" should
be construed as including the range of a value .+-.50 mg. When
referred to time intervals of dose administration, "about" should
be construed as including the range of a value .+-.1.0 hour. When
referred to pharmacodynamic values of total ON or total OFF time,
during waking hours or over 24 hours, the term should be construed
as including the range of a value .+-.0.15 hour. When referred to
blood plasma levels of LD and other values, the term should be
construed as including the range of a value .+-.15%
[0044] The term "equidose", or "equal-dose", as used
interchangeably herein, refers to as containing the same total dose
of an active material, administered over the dosing regimen,
particularly, over 24 hours periods.
[0045] "Add-on dose", or "rescue dose", as used interchangeably
herein, refer to a medicinal product comprising levodopa. An add-on
dose provides additional levodopa to the regimen of the present
invention. Sometimes add-on doses are taken by the patients to
expedite the arrival to ON state. The term should be construed as
including an immediate-release product comprising levodopa, or a
controlled-release product, comprising levodopa.
[0046] "Effective LD blood plasma levels", as used herein, refer to
LD levels that provide the desired pharmacodynamic effect in a
subject in need of treatment with minimal side effects. For early
non-fluctuating PD patients the effective LD blood plasma levels
are usually not less than about 200 ng/ml at any point of time for
24 hours after administration of a first dose of the regimen. The
effective LD blood plasma levels usually do not exceed about 1000
ng/ml. In more advanced non-fluctuating PD patients, the effective
LD blood plasma levels are usually not less than about 300 ng/ml,
and preferably above about 500 ng/ml, and do not exceed about 1500
ng/ml. In fluctuating PD patients, the effective LD blood plasma
levels are usually greater than about 500 ng/ml, and preferably
greater than about 700 ng/ml, and do not exceed about 2000 ng/ml
over a 24-hours period after administration of a first dose of the
regimen.
[0047] "Significantly High Morning LD levels", as used herein, are
the LD levels achieved by PD patients as a result of multiple
administrations according to the regimen of the invention about 0.5
hour or just prior to administration of the first dose of the
consecutive treatment day. In early non-fluctuating patients these
levels are usually above about 200 ng/ml. In more advanced
non-fluctuating PD patients, the significantly high morning LD
levels are not less than about 300 ng/ml and preferably above about
500 ng/ml. In fluctuating PD patients, the significantly high
morning LD levels are above about 500 ng/ml, and preferably above
about 700 ng/ml. The term is used as opposed to "significantly low
morning LD levels", which should be construed as confined to the
values significantly below the above described.
[0048] "Relevant therapeutic LD levels throughout the night" and
"Significant night levels of LD", as used interchangeably herein,
are effective nocturnal LD blood plasma levels that lead to
significantly high morning LD levels.
[0049] "LD Elimination Half Life", as used herein, is a
pharmacokinetic parameter as known in the art, and represents the
time required for levodopa blood plasma concentration to decrease
to half of its initial value in absence of input of levodopa to the
bloodstream.
[0050] "Short Absorption phase", as used herein, is an absorption
phase having a duration of less than 14 hours, and preferably less
than 6 hours.
[0051] "Long arrival to ON state" and "Long duration of OFF time
upon administration of a subsequent dose", as used interchangeably
herein, relate to the buildup of LD blood plasma levels required
for conventional formulations for arrival usually from
significantly low morning LD levels to effective LD blood plasma
levels, as opposed to the "Quick arrival to ON state" and "Faster
onset of the ON period", as used interchangeably herein, which
refer usually to the arrival from significantly high morning LD
levels to effective LD blood plasma levels, said arrival does not
require significant buildup of LD blood plasma levels. More
specifically, the terms refer to the time intervals required for a
patient to reach ON state following the first administration of LD
of the day.
[0052] "Morning OFF time", as used herein, refers to the time
interval between the administration to a PD subject LD and the
subject's arrival to ON state following the administration. Morning
OFF time is usually associated with significantly low morning LD
blood plasma levels.
[0053] "Repetitive dosing", or "multiple administrations", as used
interchangeably herein, refers to repetitive administration of LD
according to a specified dosing regimen, for period over more than
one day.
[0054] Induce rapidly ON state--as used herein, refers to a process
of rapid arrival to ON state, usually as a consequence of
administration of an add-on dose of levodopa, an immediate-release
dose of levodopa, or prematurely taking a consecutive dose of a
treatment. In the description herein, the term usually refers to
current treatment regimens of levodopa.
[0055] "Peak-to-trough ratio", as used herein, refers to the ratio
between the peak concentration of the regimen (Cmax) and the trough
concentration of the regimen (Cmin) over 24 hours period.
[0056] "Absolute fluctuation", as used herein, refers to the
mathematical difference between the peak concentration of the
regimen (Cmax) and the trough concentration of the regimen (Cmin)
over 24 hours period.
[0057] "Total OFF time", as used herein, refers to the duration of
total of all OFF episodes over a specified time interval, either
during waking hours, or over 24 hours.
[0058] "Total ON time", as used herein, refers to the overall
duration of all ON episodes over a specified time interval, either
during waking hours, or over 24 hours.
[0059] "Significant Reduction", as used herein, refers to a
statistically significant reduction as measured by ANOVA test
(.alpha.=0.05) (P value below 0.05).
[0060] "Better sleep quality", as used herein, refers to improved
sleep quality, defined by fewer mid-night awakenings, increased
total sleep time and extended depth of sleep.
[0061] The Accordion Pill (AP)
[0062] The Accordion Pill (AP) is a dosage form designed to
significantly increase efficacy and/or to reduce adverse drug
reactions (ADRs) and/or frequent daily dosing of drugs that are
characterized by poor absorption in the colon or which absorption
is confined to yet narrower sites. The AP is retained in the
stomach and releases the drug in a predetermined release profile,
enabling a prolonged exposure to the absorption area in the upper
part of the small intestine, hence--to significantly prolong the
actual absorption phase of the drug.
[0063] The Accordion Pill is composed of degradable
pharmaceutically acceptable polymeric films. The films are layered
sandwich style and are folded in an undulated structure, like an
accordion, into a standard capsule. After oral administration, the
capsule dissolves and the dosage form unfolds and is retained in
the stomach. While in the stomach, the Accordion Pill releases the
active ingredients in a predetermined release profile (controlled
release or combination of immediate and controlled release). Once
the AP is expelled from the stomach and reaches the intestines, it
degrades m the higher pH and within a few hours it totally
dissolves.
[0064] Certain delivery systems of AP-CD/LD are disclosed in
WO2009/144558, which is herein incorporated by reference in its
entirety.
[0065] In preferred embodiments, the AP-CD/LD comprises an internal
layer, one or more outer membranes, preferably two, sandwiching
said internal layer, all said layers being ultrasonically welded
together.
[0066] The internal layer comprises levodopa and a polymer,
substantially uniformly distributed throughout the internal layer.
The polymer may be selected from the group consisting of a
degradable hydrophilic polymer which is not instantly soluble in
gastric fluid, a degradable enteric polymer which is substantially
insoluble at pH less than 5.5, a hydrophobic polymer, or mixtures
thereof. Said internal layer may further comprise acceptable
pharmaceutical additives, such as plasticizers, humectants, fillers
and others. Examples of such additives are provided in various
sources in the art, for example in the "Handbook of pharmaceutical
excipients", edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian,
printed by Pharmaceutical Press. Examples of degradable hydrophilic
polymers which are not instantly soluble in gastric fluid suitable
for the invention include but not limited to hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone,
copovidone, polyethylene oxide, poloxamers and methylcellulose.
Examples of the enteric polymers include but not limited to
polymethacrylate copolymers, cellulose acetate phthalate,
hypromelose acetate succinate or hypromellose phthalate. Examples
of hydrophobic polymers include but not limited to ethyl cellulose,
cellulose acetate, cellulose butyrate and polyvinyl acetate. In
further preferred embodiments, the internal layer comprises
levodopa, an enteric polymer, a degradable hydrophilic polymer
which is not instantly soluble in gastric fluid and a plasticizer.
In further preferred embodiments, the enteric polymer is
polymethacrylate copolymer--methacrylic acid copolymer type A or
methacrylic acid copolymer type B, as defined in the United States
Pharmacopea 34/National Formulary 29 (USP/NF). These materials are
also known under newer specifications of the USP/NF as "methacrylic
acid and methyl methacrylate copolymer (1:1)", and "methacrylic
acid and methyl methacrylate copolymer (1:2)", respectively. In
another preferred embodiment, the plasticizer is a mixture of
polyethylene glycol and a poloxamer. In yet further preferred
embodiments, the internal layer provides substantial mechanical
strength.
[0067] Each of the outer membranes of the AP-CD/LD comprises at
least one polymeric combination of a hydrophilic polymer and a
polymer, insoluble in gastric media, and at least one plasticizer.
Examples of hydrophilic polymers include but not limited to
gelatin, hydroxypropylcellulose, hydroxypopyl methycellulose,
pectin, polyethylene oxide, starch, and zein. In preferred
embodiments, the hydrophilic polymer is gelatin. The enteric
polymers suitable for the outer membranes include but not limited
to hypromellose phthalate, hypromellose acetate succinate and
polymethacrylate co-polymers. In preferred embodiments, the enteric
polymer is polymethacrylate copolymer--methacrylic acid copolymer
type A or methacrylic acid copolymer type C, as defined in the
USP/NF, or, under newer definitions, "methacrylic acid and methyl
methacrylate copolymer (1:1)" and "methacrylic acid and ethyl
acrylate copolymer (1:1)". Plasticizers suitable for the outer
membrane include but not limited to glycols, including various MW
polyethylene glycols, glycerin, poloxamers, triethyl citrate, or a
mixture of any of the above. In a preferred embodiment, the
plasticizer is propylene glycol. In another preferred embodiment,
the plasticizer is a mixture of polyethylene glycol and
poloxamer.
[0068] In various embodiments, the outer membranes swell in the
presence of gastric fluid.
[0069] In preferred embodiments, the internal layer and two outer
layers are joined together by ultrasonic welding. The combination
of swelling outer membrane layers with a non-swelling internal
layer having planar accordion geometry causes the internal layer to
undergo an unfolding process once the formulation reaches the
stomach, thus extending gastric residence time and preventing the
drug-containing dosage form from being evacuated until complete
release. In some embodiments the internal layer has a swelling rate
less than the swelling rate of the membrane.
[0070] In some embodiments, the AP-CD/LD comprises an internal
layer and at least two outer membranes as described above, and may
further comprise additionally one or more immediate release layers
covering the outer membranes and comprising the active agent and a
composition that provides for the immediate release of the active
agent. In some embodiments, the additional layer comprises
levodopa. In other embodiments, said additional layer comprises
carbidopa. In preferred embodiments, two additional layers are
provided covering both outer membranes, wherein a first additional
layer comprises levodopa, and a second additional layer comprises
carbidopa. Said composition may comprise soluble polymers, enteric
polymers, plasticizers, disintegrants, surface-active agents and
other pharmaceutical excipients, as described above.
[0071] In several embodiments, the soluble polymers of said
composition for the use in said additional layers include but not
limited to soluble cellulose derivatives, i.e. methyl cellulose,
hydroxypropyl cellulose, hydroxyethyl cellulose, hypromelose,
various grades of povidone, including copovidone, polyvinyl alcohol
and its derivatives, i.e. Kollicoat IR, soluble gums and others.
The composition for the use in said additional layers may further
include surface-active agents, plasticizers and humectants, such as
PEGs, different grades of polysorbates and sodium lauryl sulfate.
In several embodiments, the enteric polymers of said composition
for the use in said additional layers include but not limited to
polymethacrylate copolymers, hypromellose phthalate, hypromellose
acetate succinate, cellulose acetate phthalate, or a mixture
thereof. In preferred embodiments, the polymer is methacrylic acid
copolymer type C, also known as "methacrylic acid and ethyl
acrylate copolymer (1:1)", as described in the USP/NF. In several
preferred embodiments, said composition further comprises a
disintegrant. Disintegrants imbibe water upon contact and swell
rapidly to provide separation of the adjacent parts. The
disintegrant of said composition for the use in said additional
layers is crospovidone, croscarmellose, sodium starch glycolate, or
mixtures of the above. In preferred embodiments, the disintegrant
is sodium starch glycolate.
[0072] In further embodiments, the AP-CD/LD may further comprise an
optional additional layer covering each outer membrane or each
additional layer and comprising a powder or a film. The purpose of
the layer is to avoid adhesion of the folds of the undulated form
of AP-CD/LD upon capsulation, and the adhesion of the folds to the
capsule. In some instances it may be found that the outer layers
stick together in the capsule and do not unfold properly upon
dissolving of the capsule. In preferred embodiments, said optional
layer comprises at least one powder, and optionally at least one
polymer. In other embodiments the preferred polymers are
rapidly-dissolving film formers, which can be selected from but not
limited to soluble cellulose derivatives, i.e. methyl cellulose,
hydroxypropyl cellulose, hydroxyethyl cellulose, hypromelose;
various grades of povidone; polyvinyl alcohol and its derivatives,
i.e. Kollicoat IR; soluble gums and others. The films may further
comprise surface-active agents, plasticizers and humectants. The
powders that may be used in said optional layer include but not
limited to microcrystalline cellulose, talc, silica, colloidal
silicon dioxide, a clay or a mixture of any of the above. In
preferred embodiments, said optional layer comprises
microcrystalline cellulose.
[0073] In all embodiments of the present invention, the AP-CD/LD is
folded into undulated form and compacted into a standard
pharmaceutical capsule.
[0074] The Dosing Regimen
[0075] The present invention provides a twice daily administration
regimen of AP-CD/LD formulations in doses such as, for example, a
50/250 mg dosage form, targeted for early stage PD patients; 50/500
or 50/530 mg dosage forms targeted for advances stage PD patients;
and 50/375 mg or 50/405 mg dosage forms for treatment of both
populations. In preferred embodiments, the twice daily
administration regimen of the AP-CD/LD formulations of the
invention provide effective blood plasma level of levodopa for time
intervals of about 24 hours, due to the absorption phase, provided
by AP-CD/LD, which is between about 6 to about 14 hours. In an even
more preferred embodiment, of the absorption phase, provided by
AP-CD/LD formulations of the invention are longer than 14
hours.
[0076] The length of the absorption phase is exemplified by the
data presented in the examples provided herein. Absorption data may
be obtained from the concentration-vs-time curve by methods known
in the art. These include modeling and de-convolution of functions,
which describe the absorption. One of the approaches is known as
Wagner-Nelson approach. The analysis of the data presented in
Example 2 using Wagner-Nelson approach yields an absorption curve,
which is presented in FIG. 4. The doses were administered at time
0, and after 8 hours. FIG. 4 shows that the major absorption phase
throughout the dosing regimen, for 24 hours, indicating individual
absorption phases of over 6 hours, and over 14 hours, exemplifying
some of the preferred embodiments. Alternatively, the absorption
phase may have duration of 6.5 hours, or 7.0, 7.5, 8.0, 8.5, 9.0,
9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5,
15.0, 15.5, or 16.0 hours.
[0077] In the use of the oral dosage forms of levodopa disclosed in
the invention, said dosage forms are administered twice a day, in a
regimen generally known as b.i.d. regimen. Conventionally, the
b.i.d. regimen is considered as administration every 12 hours. In
some embodiments of the present invention, the two doses are
administered twice daily, every 12 hours. However, in preferred
embodiments of present invention, the two doses of levodopa from
the oral dosage form of the invention are administered as a first
administration of a day and a second administration of the same
day, with an interval of about 8 to about 10 hours between the
first dose administration and the administration of a second dose
of levodopa, and with an interval of about 14 to about 16 hours
between the second dose of the first day and the first dose of the
following consecutive day. Whereas generally the preference is that
the described interval between the first administration and the
second administration is 8 to 10 hours, the second dose can be
administered about 6.0 hours after administration of the first
dose, or 6.5 hours, or 7.0 hours, or 7.5, hours, or 8.0 hours, or
8.5 hours, or 9.0 hours, or 9.5 hours, or 10.0 hours, or 10.5
hours, or 11 hours after administration of the first dose. The
regimen of administration of the two dosage forms according to the
invention provides effective LD blood plasma levels in the subject
for 24 hour consecutive periods. Furthermore, repetitive
administration of LD according to the specified dosing regimen
("repetitive dosing") provides stable effective LD blood plasma
levels in the subject for extended consecutive periods of time and
decreases or prevents fluctuations in the blood plasma level of LD
in the subject. In all aspects and embodiments of the present
invention, the repetitive dosing, or multiple administrations, are
referred to a period having duration of more than one day, for
example, 2 days, 3 days, 4, 5, or 6 days, 1 week, 2 weeks or 3
weeks, 1 month, 1.5 months, 2 months, or 3 months. In principle,
said twice-daily treatment regimen of the present invention may be
continued in the same or varied dosing and intervals for as long as
benefit to a patient is sustained.
[0078] Sleep quality is another major issue in PD. Entering into
OFF state during the sleep leads to awakening of the patients, and
poses a problem to fall asleep again. As shown in the examples of
the present application, the regimen of administration of the two
dosage forms according to the invention results in morning LD
levels in the blood plasma of a patient that are significantly
higher than the morning blood plasma LD levels provided by known
current treatment methods. The significantly high morning blood
plasma LD levels that the invention provides indicate that the
administration regimen of the invention maintains therapeutic LD
levels in the blood plasma of the subject being treated throughout
the night, and leads to clinically relevant, stable concentrations
of LD in the blood plasma of the subject. In turn, the retention of
therapeutic LD levels throughout the night improves quality of
sleep and reduces day time sleepiness in the subject being
treated.
[0079] Normally, LD does not reach continuously effective LD blood
plasma level when administered as immediate or controlled-release
dosage forms, due to LD short elimination half-life and short
absorption phase provided by these dosage forms; the parameters are
not sufficiently increased by conventional controlled-release
dosage forms. As a result, conventional regimens do not afford
significant blood plasma night levels of LD, thereby reducing
quality of sleep, and as a result causing day sleepiness and
drowsiness, as described above. In addition, the lack of
therapeutic LD blood plasma levels throughout the night leads to
low morning LD blood plasma levels, significantly prolongs the
duration of OFF time upon administration of a subsequent dose the
next day, and results in a delayed arrival to the ON state, because
the process requires a large LD blood plasma level buildup to reach
the ON state. Frequently, to overcome the problem, the patients use
high doses of IR levodopa, thus increasing fluctuations of blood
plasma levels of LD.
[0080] The twice daily administration regimen of the invention,
wherein the two LD doses are administered with an interval of about
8 to about 10 hours between the first dose of a day and the second
dose of the same day, and with an interval of about 14 to about 16
hours between the second LD dose of the first day and the first LD
dose of the following consecutive day, affords effective night
levels and thus reduces, alleviates or potentially eliminates
nightly sleep disturbances and daytime sleepiness or drowsiness,
which are major issues in subjects suffering from Parkinson's
disease. Furthermore, the twice daily administration regimen of the
invention produces significantly high morning levels of LD,
shortens or eliminates morning OFF time, and, because of the
significantly high morning levels of LD, results in a quicker
arrival to the ON state upon administration of the first dose in
the consecutive morning, since the process does not require LD
blood plasma level buildup to reach the ON state. Upon a particular
need, regular or reduced doses of LD can be used to arrive quickly
to ON state.
[0081] LD is released from the oral dosage forms administered
according to the regimen of the invention providing relatively
stable LD blood plasma levels in the subjects being treated for
extended periods of time. Surprisingly, the LD blood plasma levels
are sustained for 24 hours in the subject after repetitive dosing
according to the regimen. In one embodiment, the dose of LD in the
oral dosage form is about 250 mg, and under the b.i.d. regimen of
8-10 h, as described above, the blood plasma in the subject being
treated reaches a stable LD level of 200-1,000 ng/ml. The blood
plasma levels of levodopa would be therefore generally more than
about 200 ng/ml, or 180, 200, 220, 240, 250, 260, 280 or 300 ng/ml,
and generally less than 1000 ng/ml, or 980, 950, 925, 900, or 875
ng/ml. In another embodiment, the dose of LD in the oral dosage
form is about 375 to about 405 mg, and the blood plasma of the
subject being treated reaches a stable LD level of about 500-1,500
ng/ml. The blood plasma levels of levodopa would be therefore
generally more than about 500 ng/ml, or 450, 475, 500, 525, 550,
575, 600, 650 or 700 ng/ml, and generally less than 1500 ng/ml, or
1475, 1450, 1425, 1400, 1350, or 1300 ng/ml. In yet another
embodiment, the dose of LD in the oral dosage form is from about
500 to about 530 mg, and the blood plasma of the subject being
treated reaches a stable LD level of about 700-2,000 ng/ml. The
blood plasma levels of levodopa would be therefore generally more
than about 700 ng/ml, or 625, 650, 675, 700, 725, 750, 775, 800,
825 or 850 ng/ml, and generally less than 2000 ng/ml, or 1950,
1925, 1900, 1875, 1850, 1825 or 1800 ng/ml.
[0082] In one aspect of the invention, the two oral dosage forms
administered according to the regimen of the invention contain the
same dose of LD. In alternative embodiments, the doses are
different to accommodate the needs of the patient in either the
first part of the day or the second part of the day. One patient
may require higher levels in the afternoon, whereas another may
require higher levels in the first part of the day. The doses can
be varied by the prescriber to obtain optimal efficacy over 24
hours, according to individual needs of the patients. This gives
rise to asymmetrical regimens, whereby the first dose is not
necessarily equal to the second. In alternating multiple
embodiments, there are many such combinations possible, exemplified
but not limited to 250 mg in the morning and 250 mg in the
afternoon, 250 mg in the morning and 375 mg in the afternoon, 375
mg in the morning and 500 mg in the afternoon, 250 mg in the
morning and 500 mg in the afternoon, or 500 mg in the morning and
375 mg in the afternoon. Any such or similar combination represents
the basal treatment regimen and provide treatment of Parkinson's
disease symptoms over 24 hours, when administered to a patient in
need thereof in an interval of about 8 to 10 hours, after
repetitive dosing, thereby providing stable efficacious blood
plasma levels of LD.
[0083] The treatment provided according to the regimen of the
invention may be optionally enhanced by administration of "add-on"
doses. These comprise dosage forms comprising LD for either
immediate release (IR), or controlled release (CR), or a
combination thereof. The need for these add-on doses arises from
inevitable intra-subject variability, meaning that the same subject
may not react the same way to the same dosage form administered on
a different day. This intra-subject variability in day-to-day
response to LD is well-known in PD treatment. The add-on doses are
vastly used in current treatment schedules to induce rapidly ON
state and to end OFF state. The current regimens overburden the
patients with the doses of LD. The disclosed regimen overcomes this
problem, as it cumulatively requires substantially fewer number of
LD doses per day, than needed with current treatments. Therefore,
in some embodiments, said twice-daily regimen further comprises
administration of one or more add-on LD doses. In some embodiments,
said add-on doses are immediate-release doses. In alternative
embodiments, said add-on doses are controlled release doses. In
other embodiments, said doses comprise mixed immediate-release and
controlled-release doses. In several embodiments, said doses are
administered on the same time every treatment day. Alternatively,
said add-on doses may be administered as needed on varying time
during the treatment day.
[0084] Conventional dosing regimens frequently result in high
fluctuations. The peak-to-trough ratio is usually used to evaluate
the fluctuations of blood plasma levels of a drug. Alternatively,
when comparing dosing regimens, sometimes absolute fluctuation
values are used to express the degree of change that certain dosage
form produces. Fluctuations of levodopa blood plasma levels in
subjects treated with the conventional formulations are very high,
due to rapid elimination and limited absorption window of the
conventional dosage forms.
[0085] The peak-to-trough ratio is calculated as maximal
concentration achieved during the 24-hours period, over minimal
concentration over the same period. Said ratio is 1 for continuous
delivery dosage forms, such as intravenous infusion. Current
treatment of immediate-release presents ratio of over 40. In
several embodiments of the present invention, said ratio is below
about 10, preferably below about 9.5, 9.0, 8.5, 8.0, 7.5, or 7.
Alternatively, the fluctuations may be expressed by comparison to
current treatment, and the fluctuations produced by the twice-daily
regimen of the invention are reduced at least by about 50%, or by
44%, 46%, 48%, 50%, 52%, 54%, 56%, 58%, 62% or 64% in comparison to
conventional daily equal-dose IR treatment four times a day. In
preferred embodiments, said fluctuations are reduced by about
60%.
[0086] The reduction in LD blood plasma fluctuations provided by
the regimen of the invention decreases adverse effects associated
with LD treatment. Most significantly, the total OFF time during
waking hours decreases, and total ON time increases. The side
effects are usually associated with more progressive stage of the
disease. Administration of an oral dosage form of LD comprising
about 375 mg or about 500 mg of LD according to the regimen of the
invention with an interval of 8 to about 10 hours between the first
and the second dose to a patient in need thereof produces a
significant reduction of total OFF time during waking hours.
Alternatively, two dosage forms, with an LD amount of 375 mg and
500 mg, respectively, may be administered to a subject in need
thereof according to the regimen of the invention for the treatment
of symptoms of Parkinson's disease. Such administration leads to a
significant reduction of total OFF time during the subject's waking
hours. Similarly, the reduction of total OFF time in patients in
need thereof can be enhanced by incorporating into said regimen at
least one add-on. Similarly to the described above, said add-on
doses may comprise an IR levodopa dose, a CR levodopa dose, or a
mixture of the IR and CR levodopa dose. The doses may be taken
preferably as fixed-time dose, or alternatively, on "as needed"
basis, as rescue dose for the interruption or alleviation of the
OFF state, thereby enhancing reduction of total OFF time during
waking hours. Alternatively, a method of treatment is provided, for
reduction or alleviation of Parkinson's disease symptoms in
patients in need thereof, said method comprising administration any
of two oral dosage forms, comprising about 375 mg of LD, or about
500 mg of LD each, according to the regimen of the invention, which
method further comprises administration of one or more add-on doses
of IR or CR levodopa.
[0087] The effectiveness of an anti-parkinson treatment is
estimated as reduction in total OFF time, or as reduction of total
OFF time during waking hours, sometimes used interchangeably. The
total OFF time is an important parameter and varies within the
population of PD patients, according to the severity of the
disease. Early patients have very short periods of OFF during the
waking hours, or do not suffer at all from the OFF phenomenon. As
the disease advances, the patients may reach total OFF time of 0.5
hour to over 6.5 hours, and sometimes even to over 8.0 hours. In
yet more advanced stage, the patients reach these "total OFF"
values even being treated adequately by best available regimens.
The treatment provided according to the regimen of the invention
significantly reduces total OFF time. In some embodiments, the
total OFF time during waking hours is reduced by at least about
45%, but can be decreased by 44%, 45%, 46%, 48%, 52%, 54%, 56%,
58%, 60%, 62% or by 64%, versus either baseline values or versus
the optimized LD treatment of a subject. In other preferred
embodiment, the treatment provided according to the regimen of
invention reduces total OFF time by at least 1.2 hours, but can be
decreased by 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5,
1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8,
2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1,
4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or by 5.0 hours. In further
preferred embodiments, the regimen of present invention provides a
reduction in total OFF time during waking hours from 2.9 hours to
1.2 hours, versus optimized levodopa treatment in the subject. In
yet further preferred embodiments, the reduction is obtained by
administering to the patient in need the AP-CD/LD 375 mg twice
daily, according to the regimen of the invention, without or
practically without add-on doses (dosing frequency 2.2.+-.0.2 per
24 hours).
[0088] Conventional regimens of LD treatment do not provide the
subject being treated with significantly high morning levels of LD,
as described above. Moreover, PD patients frequently suffer from
night OFF state, whereby the patients are awakened by their
incapacity to move during their sleep. This sometimes results in
the need to take nocturnal LD doses. These subjects suffer from
drowsiness and daytime sleepiness, as a result of night awakening.
The overall quality of life of these patients may deteriorate.
Taking higher LD doses at bedtime does not solve the problem, as LD
is rapidly removed from the bloodstream and its absorption is
limited to a maximum of two hours of the narrow absorption window.
Moreover, taking overdoses of LD can result in troublesome
diskinesias, expressed by involuntary movements, which further
impede falling asleep and offer no solution. A large number of
subjects affected by PD and facing fluctuations in their blood
plasma LD level are thus compelled to use sleep-inducing medicines,
which further burden the patient with yet a higher pill-load and
increases the risk of drug-to-drug interactions.
[0089] The treatment regimen of the present invention resolves
these issues by providing high blood plasma LD levels in the
morning over 24 hour periods in subjects in need of treatment of
Parkinson's disease symptoms. The twice daily administration
regimen of the invention, wherein the two LD doses are administered
with an interval of about 8 to about 10 hours between the first
dose of a day and the second dose of the same day, and with an
interval of about 14 to about 16 hours between the second,
pre-midnight LD dose of the first day and the first LD dose of the
following consecutive day, provides the subjects being treated with
stable, effective LD blood plasma concentrations for consecutive 24
hour periods, affords effective LD night levels and thus reduces,
alleviates or potentially eliminates nightly sleep disturbances and
daytime sleepiness or drowsiness, and produces significantly high
morning levels of LD. The high morning pre-dose LD blood plasma
levels provided by the treatment regimen of the present invention
alleviate or eliminate symptoms related to degenerative disorders
of the central nervous system, Parkinson's disease in particular,
motor skills, speech and related impairments, prior to the
subsequent administration of the next day consecutive dose. In
addition, the morning high LD blood plasma levels provided by the
treatment regimen of the present invention allow a faster onset of
the ON period and shorten the OFF period after the next day
subsequent administration of the first dose. Moreover, the morning
high LD blood plasma levels provided by the treatment regimen of
the present invention result in better sleep quality throughout the
night and alleviate or eliminate daytime sleepiness and drowsiness
on the subsequent day.
[0090] In some embodiments, there is provided a use of an AP-CD/LD,
administered to a patient in need thereof prior to going to sleep.
Said bedtime, or nocturnal administration provides effective LD
blood plasma levels throughout the night. In some embodiments, the
dose should be administered no later than 3 hours apart from the
last LD dose of the patient, but may be administered 1.25, 1.5,
1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.50,
4.75 or 5.0 hours from the administration of the last LD dose. In
one aspect, the dose of levodopa in AP-CD/LD is about 250 mg. In
another aspect, the dose of levodopa in AP-CD/LD is about 375 mg.
In yet another aspect, the dose of levodopa in AP-CD/LD is about
500 mg. In some embodiments, the nocturnal administration of
AP-CD/LD provides better sleep quality to the patient in need
thereof. In other embodiments, the nocturnal administration
alleviates or eliminates morning akinesia symptoms in patients in
need thereof.
[0091] Levodopa is usually administered with a DOPA-decarboxylaze
inhibitor, such as benserazide or carbidopa. Normally, levodopa is
co-administered with carbidopa. The art discloses several effective
carbidopa/levodopa combinations with different ratios between the
two. There is much reasoning in favor of many ratios. Although
there is a general consensus that the total daily dose of carbidopa
should not exceed 150-200 mg, PD subjects are often treated with a
vast variety of doses of LD that not always have the same
carbidopa/levodopa ratio. Many patients, especially advanced PD
patients, are prone therefore to reach the maximum allowed daily
carbidopa amounts under current treatment schedules. In contrast,
the treatment regimen of the present invention supplies carbidopa
in sufficient quantity to provide a stable CD blood plasma
concentration for 24 hour periods, regardless of the total LD daily
dose administered according to the treatment regimen. Moreover,
even with the supplementation of add-on dosages, the subject being
treated according to the regimen of the invention will not exceed
the maximum allowed daily carbidopa amounts, as the regimen
provides effective amounts of carbidopa to inhibit peripheral
decarboxylaze activity sufficiently over 24 hour periods. Studies
show that peripheral DOPA decarboxylase is saturated by carbidopa
at approximately 70 to 100 mg a day. Therefore in some preferred
embodiments, the oral dosage forms administered according to the
treatment regimen of the invention comprise carbidopa or
pharmaceutically acceptable salt thereof, preferably in an amount
from about 50 mg to about 75 mg of carbidopa each. Carbidopa is
released from the dosage forms. In the treatment regimen of the
present invention, the carbidopa released upon absorption provides
blood plasma levels of carbidopa that are sufficient to adequately
prevent peripheral LD side effects for consecutive 24 hour
periods.
[0092] When designing a treatment regimen, it is compulsory that
the doses of one dosing regimen be easily translated into another.
It is well known in the art that some controlled-release dosage
forms provide lower absolute bioavailability than immediate-release
doses, and therefore also lower relative bioavailability in
reference to the immediate release dose. This usually causes
difficulties in transferring patients from one treatment to
another, as individual responses in patients are often poorly
predictable and one cannot lower bioavailability before trial and
error. By providing stable LD blood plasma concentrations after
repetitive dosing in a subject, the treatment regimen of the
present invention affords a relative bioavailability which is not
less than 95%, preferably not less than 90%, and even more
preferably not less than 89%, 88%, 87%, 86%, or 85%. In preferred
embodiments, the treatment regimen of the present invention
provides an area under concentration-vs-time curve over 24 hour
periods (AUC.sub.0-24), and thus a relative bioavailability (F),
which is not less than 95%, preferably not less than 90%, and even
more preferably not less that 85%, of the relative bioavailability
obtained with an equivalent dose regimen of immediate release
dosage forms. Similarly, the treatment regimen of the present
invention, after a single dose, provides an area under
concentration-vs-time curve extrapolated to infinity
(AUC.sub.0-inf), and consequently, a relative bioavailability (F)
which is not less than 89%, 88%, 87%, 86%, or 85% of the
AUC.sub.0-inf obtained with an equivalent dose regimen of immediate
release dosage forms.
[0093] In further aspect, the administration of said two doses is
not restricted to specific alimentary requirements. Usually,
Parkinson's disease patients are advised to avoid high-protein
food, high acidity food and beverages, and are warned against
delayed gastric emptying that might impede the action of
conventional dosage forms of levodopa. Some levodopa products even
advise taking the medicine on empty stomach. Once the number of
doses to be administered is low, the restriction can be complied
with. At higher dosing frequency, a patient may be required to fast
for a significant portion of a day. Some dosage forms that can
provide benefit at three and more times a day administration,
require the medicine to be taken with a meal, sometimes a meal of
no less than 750 kcal, whereof not less than 40% should be derived
from fat. However, patients normally comply better with medications
that do not require extensive fasting or purposeful excessive
eating.
[0094] In the administration of said two dosages of levodopa
according to the regimen of the present invention, a small meal may
be recommended before the administration. No excessive restrictions
on diet are imposed by said regimen, providing a significant
advantage to the patient. In some embodiments, the meals to
accompany the first dosing of the dosage forms have calorie value
of below 550 kcal, preferably below 540 kcal, or below 530, 500,
450, 400, 350, 300, 250, 200, or 191 kcal. In preferred
embodiments, the meal has calorie value of 191 kcal, with 49% of
calories being derived from fat. In further embodiments, the meals
to accompany the second dosing of the dosage forms have calorie
value of ranging from about 430 kcal, to about 670 kcal, but can
have the calorie value of 450, 475, 500, 525, 550, 575, 600, 625,
650 or 670 kcal. In further embodiments, the calorie value derived
from fat, of said meal accompanying second administration of the
regimen of the invention, comprise about 40%, or about 38%, 36%,
34%, 32%, or 30%. In further preferred embodiments, the amount fat
in the meals is an average amount of fat in alimentary products for
human consumption.
[0095] Whereas levodopa is used vastly and primarily for treatment
of Parkinson's disease symptoms, there arc conditions responsive to
levodopa, such as restless leg syndrome and others, that are not
directly related to Parkinson's disease. All the disadvantages of
conventional regimens as disclosed above are valid for every other
treatment of conditions, responsive to levodopa. The treatment of
night symptoms remains a significant challenge. Therefore, in some
embodiments, there is provided use of an accordion pill comprising
levodopa for the treatment of symptoms responsive to levodopa in a
subject in need thereof over nocturnal period. In further
embodiments, the AP-CD/LD is administered to the subject at or
before bedtime. In yet further embodiments, said administration
provides improvement in sleep quality in said subject over the
night following administration. In various embodiments, the dose of
levodopa in the AP-CD/LD is about 250 mg, or about 375 mg, or about
500 mg. In other embodiments, there is provided use of AP-CD/LD for
alleviating or eliminating the symptoms of morning akinesia or
morning dystonia.
[0096] The present invention, thus generally described, will be
understood more readily by reference to the following examples,
which are provided by way of illustration and are not intended to
be limiting of the present invention.
EXAMPLES
Example 1
Phase IIA Included 12 Early Stage PD Patients
Clinical Study Design:
[0097] A multi center, open, two-way randomized crossover, multiple
dose, active control, pharmacokinetic study in Parkinson's patients
that are not experiencing wearing off, treated with low dose
AP-CD/LD
[0098] The group was crossed over with a daily equidose of
immediate release (IR) preparations of carbidopa/levodopa.
The Objectives
[0099] The primary objective was to evaluate the blood level
profile of the AP-CD/LD relative to that of IR
carbidopa/levodopa.
[0100] Another objective was to monitor the subjects for adverse
events during the study period and to compare the safety of the
test products with the reference products.
The Course of the Study
[0101] Subjects were randomized to start with either AP-CD/LD or
with IR-CD/LD. The AP-CD/LD was dosed at 0 and 8 hrs on each day,
for seven days. The reference product was the commercially
available 25/250 mg Dopicar.RTM. (Teva Pharmaceuticals) CD/LD
immediate-release tablet (IR-CD/LD), which was administered four
times a-day, as a 1/2 tablet (12.5/125) at 0, 4, 8 and 12 hours on
each day, for seven days. Since the amount of CD from the IR-CD/LD
was half of that given by the AP-CD/LD and below the recommended
amount of daily CD (70-100 mg), additional CD was given with each
dose during the pharmacokinetics (PK) evaluation day (day 7 of the
control treatment period). On the PK day Patients were
co-administered an additional 12.5 mg IR CD capsule with each
Dopicar.RTM. dose to provide a total CD dose of 100 mg. The total
daily CD/LD doses for both products were equivalent.
[0102] During days 1-6 of each period, the test and reference
products were self-administered at home every day. On the 7th day
of dosing in each period, patients were dosed in the clinic (PK
day).
[0103] Within 7 days after the last PK day (days 15-22), the
subjects underwent post-study medical evaluation including blood
and urine testing.
[0104] Each group was crossed over with an equal-dose of IR
levodopa in a randomized manner.
AP-CD/LD 50/250 mg, Carbidopa/Levodopa Dosage Form
TABLE-US-00001 [0105] Amount/AP-CD/LD (mg) Immediate Internal layer
Release Outer (sum Controlled Component Layer of two films) release
Carbidopa 25.0 25.0 Levodopa 70.0 180.0 Eudragit S100 47.1 Eudragit
L100 23.5 61.0 Eudragit L100-55 23.5 Fish Gelatin 94.2 Propylene
glycol 94.2 KOH 6.0 Poloxamer 407 32.0 PEG 400 3.1 30.0 Tween 80
11.8 Povidone 90 13.7
Phase IIA, Subjects
TABLE-US-00002 [0106] Duration of Duration of Subject number Gender
Age PD, (years) LD's Treatment H&Y 102 M 68 3 6 months 2 104 M
73 2 9 months 2 106 M 74 2 3 months 2 107 M 65 2 5 months 1.5 113 M
69 2 11 months 2 101 M 67 6 3 years 2 103 M 76 7 7 years 2 105 M 76
9 3 years 2 108 M 71 11 6 years 2 110 M 67 6 3 years 3 111 M 54 4 3
years 2 114 M 59 8 7 months 2
Results:
[0107] The results of primary objective (pharmacokinetic profile)
are presented in FIG. 1. True controlled-release profile of LD has
been accomplished. BID administration of AP-CD/LD provided 15
monitored hours coverage of 400-1,000 ng/ml LD plasma levels, and
in fact 24 hours coverage profile, since significant morning levels
were achieved.
[0108] BID administration of AP-CD/LD provided average plasma
levels within the range that is currently obtained with four times
a-day (equivalent total daily dose) LD formulation that is on the
market, with substantially reduced peaks.
[0109] Morning starting plasma levels of LD from AP product were
significantly higher than these from IR treatment (200 vs 30
ng/ml). This capability of AP-CD/LD can improve morning akinesia,
improve sleep quality and reduce day time sleepiness.
Safety
[0110] No significant adverse effects were reported during the
study.
Example 2
Phase IIB--12 Fluctuating PD Patients
[0111] The purpose of this study was to evaluate the efficacy
(pharmacokinetics and pharmacodynamics) and the safety of AP-CD/LD
50/375 mg, in various groups of advanced PD patients, after
multiple dosing, in comparison to CD/LD formulations, currently on
the market.
Clinical Study Design
[0112] A multi center, open, two-way randomized crossover, multiple
dose, active control, pharmacokinetic and pharmacodynamic study in
patients with wearing off treated with high dose AP-CD/LD.
[0113] The group was crossed over with the patient's current
treatment dose. The study was conducted in three medical
centers.
The Objectives:
[0114] The primary objectives of the study was to evaluate the
pharmacokinetic profile of AP-CD/LD relative to that of IR-CD/LD
and to determine the relative pharmacodynamic profiles of the
AP-CD/LD vs. IR-CD/LD under real conditions of use (i.e. derived
from at-home diary entries). Another objective was to monitor the
subjects for adverse events during the study period and to compare
the safety of the test products with the reference products.
[0115] The secondary objectives of the study was to assess patient
and investigator global evaluation of, and degree of satisfaction
with, AP-CD/LD relative to IR-CD/LD; and to determine the
pharmacodynamic profile of AP-CD/LD relative to that of IR-CD/LD
during the PK day.
Pharmacodynamic Evaluation Methods:
[0116] ON/OFF chart on PK days by subject and investigator;
[0117] UPDRS Motor testing at baseline and at every hour until +16
hours on the PK days;
[0118] Self rating of ON/OFF by patient every 1/2 hour for 16 hours
on days 4, 5 and 6 and on days 11, 12 and 13;
[0119] Total OFF time, total ON time, time to ON, Total time of On
with non-troublesome dyskinesias and of ON with troublesome
dyskinesias;
[0120] Other pharmacodynamic parameters were allowed to be
calculated for exploratory evaluations.
Clinical Study Course
Days 1-6 and 8-13
[0121] Subjects were randomized to start with either AP-CD/LD or
current treatment, taken for 6 days at home.
[0122] Subjects were asked to fill in an ON/OFF diary on days 4, 5
and 6 and on days 11, 12 and 13.
Dosing:
[0123] Test arm: BID administration of AP-CD/LD 50/375 mg (morning
and +8 hours). Due to the individuality and variability of
treatment of the fluctuating Parkinson's patient the subjects were
allowed (if necessary) to take up to 3 daily add-on doses of
IR-CD/LD on days 1-6 or 8-13 of the "at home" treatment. Each
additional "add-on" doses was limited to either 1/2 tablet of
Dopicar (12.5/125 mg CD/LD) or 1/4 tablet of Dopicar (6.25/62.5 mg
CD/LD). All add-on doses were documented in the subject's daily
diary.
[0124] Control arm: The current, individual treatment of each
subject.
[0125] No additional CD/LD was allowed after midnight of days 6 and
13 (prior to the PK day).
Days 7 and 14
[0126] Subjects were confined to the clinic from the previous night
for the duration of the day until the next morning (36 hours).
Dosing:
[0127] Test arm: BID AP-CD/LD, No add-on doses were allowed during
the PK day (during the blood sampling), since they will interfere
with the pharmacokinetic profile. Additional IR-CD/LD was allowed
only after the last blood sample was taken.
[0128] Control arm: 4.times.3/4 tablet of Dopicar (18.75/187.5 mg
CD/LD) at 0, +4, +8, +12 hours.
[0129] On day 7 (at the clinic), pharmacodynamic evaluations were
conducted for the first 16 hours by an assessor using the UPDRS
part III. The patient documented ON/OFF times for 16 hours. The
objective of these UPDRS and ON/OFF evaluations on days 7 and 14
were to evaluate the pharmacokinetics/pharmacodynamic correlation.
Each subgroup was crossed over with an equal-dose of current
individualized levodopa treatment in a randomized manner.
Post Study Medical Evaluation:
[0130] Within 7 days after the last PK day (days 15-22), the
subjects underwent post-study medical evaluation including blood
and urine testing.
AP-CD/LD 50/375 mg, Designed for Advanced Stage PD Patients
TABLE-US-00003 [0131] Amount/AP-CD/LD (mg) Internal layer Outer
(sum of Immediate Release Component Controlled release two films)
capsule coating Layer CD layer Carbidopa 50 Levodopa 375 50
Eudragit S100 52 Eudragit L100 80 26 Eudragit L100-55 26 11 Fish
Gelatin 104 Propylene glycol 104 KOH 6.6 Poloxamer 407 40 5.5 PEG
400 40 3 Titanium Oxide 3 Kollidon VA64 15
Results
Pharmacokinetics (PK)
[0132] Mean LD plasma concentrations are presented in FIG. 2.
[0133] True controlled-release profile of LD has been presented,
with significantly more stable LD levels, during the 16 waking
hours, and in fact 24 hours since significant morning levels were
achieved.
[0134] A clear "flip-flop" kinetics (where Ka is much slower than
Ke, hence the curve reflects the actual Ka) can be seen. LD's
absorption phase was increased by 6 folds and more, by the
AP-CD/LD. BID administration of AP-CD/LD provided 24 hours coverage
of mean LD plasma levels of 522-1,710 ng/ml, in comparison to mean
LD plasma levels of 91 (or 68--see below)--3,377 ng/ml, obtained
with four times a-day administrations of IR-CD/LD, currently on the
market (with equidose total daily LD of 750 mg, in both arms).
[0135] Peak to trough fluctuations (Mean Cmax-Mean Cmin) were
statistically significantly reduced, by the AP-CD/LD, to a half.
Similarly, peak to trough ratio (mean Cmax/mean Cmin) is reduced by
almost sevenfold:
TABLE-US-00004 Least-Squares Means.sup.1 Significance.sup.3 LD
Parameter AP-CD/LD Control Ratio.sup.2 (p < 0.05) Mean Cmax
2,285 3,999 0.571 0.0055 (ng/mL) Mean Cmin 348 90.9 3.830 0.0332
(ng/mL) Absolute Peak-to- 1,937 3,908 0.496 0.0023 Trough
Fluctuation (ng/mL) Peak to trough 6.57 44.00 6.7 ratio
.sup.1Least-squares arithmetic means. .sup.2Ratio calculated as
AP-CD/LD least-squares mean divided by Control least-squares mean.
.sup.3Results of the statistical evaluation by ANOVA (.alpha. =
0.05) for the hypothesis of equal treatment effects
[0136] Mean AUC.sub.0-24, achieved with the AP-CD/LD was 94.6% of
the Mean AUC.sub.0-24 achieved by IR-CD/LD. This calculation is
based on the assumption that LD level at t=24 h is equal to LD
level at t=0, in both arms (whereas current available controlled
release LD products decrease bioavailability to about 75%).
[0137] The LD morning plasma levels achieved with the AP-CD/LD are
statistically significantly higher (p=0.0191) than those achieved
with the commercial IR treatment: 522 ng/ml vs. 91 ng/ml.
Pharmacodynamics
[0138] In 10 patients who completed the study in accordance with
the study protocol, a statistically significant decrease in `OFF
time` and statistically significant reduction in the number of
doses per day were achieved. In 80% of these patients, an average
reduction of about 35% in the OFF time (2.96 hours compared to 4.48
hours with their current treatment) was achieved, which is
statistically significant.
[0139] The number of daily doses in this patient group was reduced
by half, from 6.0 times per day to 3.2 times per day (namely--BID
administration of AP-CD/LD plus 1.2 add-on doses per day), with a
statistically significance. This reduction was obtained due to an
effective long acting AP-CD/LD. This achievement addresses one of
the current unmet needs with respect to PD treatment--the daily
significant pill burden, which is a result of the very short
half-life of LDs preparations currently on the market.
[0140] Both subjects' and investigators' CGI and GSS evaluations
correlated with the improvements demonstrated in the various
pharmacodynamics end-points.
Mean Time to ON after First Dose (Day 7)
Mean Time to ON (Hours) Post Morning Dose on Day 7 (N=6)
TABLE-US-00005 [0141] AP-CD/LD Current Difference Mean Time to 0.64
0.97 -0.33 ON Post Morning Dose
[0142] The shorter Mean Time to On, with AP-CD/LD, was obtained due
to two attributes: [0143] Significantly higher LD plasma levels at
time 0 (7 AM), due to the true-controlled release performances of
the AP-CD/LDs given the day before (522.0 vs 90.9 ng/ml, as
described above); [0144] An efficient IR component of the
AP-CD/LD.
[0145] The significantly higher morning LD plasma levels provide a
very important advantage in the treatment of advanced-stage PD
patients.
PK/PD Correlation (Day 7)
[0146] A strong correlation was demonstrated in day 7 between LD
plasma levels and ON/OFF and UPDRS data, during the 16 hours'
evaluations. This validates the concept of the strong PK/PD
correlation in LD treatment, with respect to the drug's motor
complications, as well as the huge importance of stabilizing the
drug's PK. The graph, presenting the correlation of UPDRS score
with the blood plasma levels of LD is presented in FIG. 5. As can
be seen from the figure, the UPDRS does not go above the baseline
score, meaning steady improvement in PD symptoms over tested
period.
Safety
[0147] No significant adverse effects were reported during the
study.
Subjects Enrolled:
TABLE-US-00006 [0148] Duration of Duration LD's Randomization of
PD, Treatment, Usual Daily Current LD No. Gender Age (years)
(years) H&Y Treatment* 301 F 61 19 16 2.5 Completed the study
not per protocol 303 M 75 10 6 2.5 5 .times. 125 + 100 = 725 mg 304
M 77 10 10 2.5 5 .times. 125 = 625 mg 305 M 84** 12 10 3 4 .times.
125 + 3 .times. 100 + 62.5 = 862.5 mg 306 M 62 6 6 2 5 .times. 125
= 625 mg 307 M 60 11 9 3 200 + 8 .times. 100 = 1,000 mg** 308 M 71
17 15 2.5 5 .times. 125 = 625 mg 309 F 61 Dropped out 310 F 57 13
13 3 6 .times. 125 = 750 mg 311 M 77 9 6 2.5 5 .times. 125 = 625 mg
312 M 64 10 6 2 6 .times. 125 = 750 mg 313 M 61 8 6 2.5 5 .times.
187.5 = 937.5 mg *Subject's usual LD treatment, in addition to
other medications. This was also the control arm's treatment in
days 4-6 and 11-13, for each subject, in general. **Both deviations
above were pre-approved by the IRB.
[0149] Based on examples 1 and 2, the AP-CD/LD has demonstrated its
potential to a significantly improve LD treatment through: [0150]
Reducing the pills burden; [0151] Decreasing wearing OFF; [0152]
Improving patients' compliance with therapy; and [0153] Improving
sleep quality and morning akinesia.
Example 3
Pharmacodynamic Evaluation in Fluctuating Patients
[0154] The purpose of this study was to evaluate pharmacodynamic
changes in fluctuating PD patients upon treatment with AP-CD/LD
50/375 mg, following three weeks treatment.
Study Objectives:
[0155] Primary objectives of the study were to evaluate a change in
the total daily OFF time (hr) from at home ON/OFF diaries, at week
3 of each treatment, between AP-CD/LD and active control; and to
assess patient and investigator global evaluation, and degree of
satisfaction with, AP-CD/LD relative to current levodopa
treatment.
Course of the Study:
[0156] The study included multiple dosing for 21 days with the
AP-CD/LD crossed over with a similar duration of treatment with the
patient's current therapy. Both treatment periods included 21 days
of treatment out of which the first 14 days were for equilibration
(readjusting to the treatment after the crossover) and the last 4
days were for the evaluation (test period).
[0157] Subjects were randomized to start with either AP-CD/LD or
current treatments. There was no washout period between treatment
periods due to the equilibration period prior to the test periods.
The test period included 4 days of treatment. Pharmacodynamics
evaluation was based on ON/OFF home diaries from 3 days prior to
the clinic visit and on UPDRS part III performed every hour for 6
hours during a clinic visit on the last day of each test period
(days 21 and 42).
Results
[0158] In a sub-group of 6 patients the regimen was based on BID AP
CD/LD 50/375 mg. In this group the Total OFF Time was reduced from
2.9 hours with the current treatment to 1.2 hours with the AP
treatment. In addition, a significant reduction (more than
threefold) of LD doses was achieved. The number of LD daily doses
in their current treatment arm was 6.6 times a day.
Example 4
Pharmacokinetic Profile of AP-CD/LD 50/500 mg
[0159] The purpose of the study was to evaluate the pharmacokinetic
parameters of AP-CD/LD 50/500 mg, in healthy volunteers, as single
dose versus IR of 2.times.250 mg LD (Sinemet.RTM. 25/250 mg (Merck
& Co., Inc.)).
Study Objectives:
[0160] The primary objective was to compare the pharmacokinetic
profiles of LD and carbidopa, following oral administration of a
single-dose of a controlled-release gastric retentive formulations,
with that obtained following oral ingestion of two consecutive
doses of the reference product Sinemet.RTM., taken after a
low-medium calorie meal.
[0161] The secondary objective was to monitor the subjects for
adverse events during the study period and to compare the safety of
the test formulation with the reference product.
Study Design:
[0162] Single center, randomized, single-dose, open label, two-way,
comparative crossover study. The wash-out period between study
sessions will be at least 7 days.
Course of the Study:
[0163] Pretreatment--50 mg of carbidopa three times daily on the
three days prior to each dnrug administration was administered to
diminish or avoid the ADRs that were anticipated in LD-naive
patients.
[0164] Dosing--the dosing of either 2.times.Sinemet.RTM. 25/250 mg
or 1.times.AP-CD/LD 50/500 mg was performed in a cross-over manner
with washout period of 1 week.
Formulation of AP-CD/LD 50/500 mg
TABLE-US-00007 [0165] Amount/AP-CD/LD (mg) Internal Outer Immediate
layer (sum of Release Controlled two Levodopa Component release
films) Layer CD layer Carbidopa 50 Levodopa 430.0 70.0 Eudragit
S100 14.3 50.9 Eudragit L100 109.9 Eudragit L100-55 12.7 11 Fish
Gelatin 50.9 Polyox WSR-205 5.9 KOH 2.1 Poloxamer 407 9.5 5.5
Poloxamer 124 62.1 14.9 PEG 400 62.1 35.7 Sodium Starch 50.0
Glycolate
Results:
[0166] The pharmacokinetic profile is presented in FIG. 3.
[0167] The PK parameters are summarized in table below:
TABLE-US-00008 Least-Squares Means .sup.1 90% Confidence Interval
.sup.3 Parameter Test Reference Ratio .sup.2 Lower Upper AUG 0-t
(ng-hr/mL) 10693 14047 0.761* 0.615 0.907 AUCinf (ng-hr/mL) 12426
14123 0.880 0.486 1.274 Cmax (ng/mL) 1951 4062 0.480* 0.153 0.808
Tmax (hour) 4.67 4.83 0.966 -- -- Ke (1/hour) 0.2829 0.4041 0.700
-- -- T1/2 (hour) 5.15 1.76 2.927 -- -- .sup.1 Least-squares
geometric means for In-transformed data. .sup.2 Ratio calculated as
Test least-squares mean divided by the Reference least-squares
mean. .sup.3 Confidence interval on the ratio. *Comparison was
detected as statistically significant by ANOVA (.alpha. =
0.05).
[0168] The results show that high LD concentrations can be reached
with AP-CD/LD 50/500 mg, concentrations sufficient to provide the
need for advanced PD patients.
Example 5
Typical Exemplary Menu Employed in the Examples Above
Version 1
[0169] Breakfast (-30 min) 529 Kcal 51% fat
[0170] 2 slices of bread, butter (40 g), 8 olives, cookies (40 g),
tea (decaffeinated, 1 spoon of sugar).
[0171] Lunch (+5 hours) 530 Kcal 40% fat
[0172] Salami sandwich (one, approx. 50 g), vegetable salad (120
g), fruit salad (1 cup)
[0173] Snack (+7.75 hours) 190 kcal 49% fat
[0174] Plain croissant (50 g)
[0175] Dinner (+12 hours) 525 kcal 34% fat
[0176] Fried breaded chicken breast (100 g), vegetable salad (120
g), rice (1 cup)
Version 2
[0177] Breakfast (-30 min) 529 Kcal 51% fat
[0178] 2 slices of bread, butter (40 g), 8 olives, cookies (40 g),
tea (decaffeinated, 1 spoon of sugar).
[0179] Lunch (+5 hours) 648-670 Kcal 34% fat
[0180] Option 1: Salami sandwiches (two, approx. 100 g), vegetable
salad (120 g), fruit salad (1 cup)
[0181] Option 2: Humus sandwiches (two, approx. 100 g), vegetable
salad (120 g), fruit salad (1 cup)
[0182] Snack (+7.75 hours) 190 kcal 49% fat
[0183] Plain croissant (50 g)
[0184] Dinner (+12 hours) 525 kcal 34% fat
[0185] Fried breaded chicken breast (100 g), vegetable salad (120
g), rice (1 cup)
Version 3
[0186] Snack at arrival 190 kcal 49% fat
[0187] Plain croissant or cookies (50 g), non-caffeinated tea
[0188] Lunch (.about.+5 hours) 648-670 Kcal 34% fat
[0189] Option 1: Salami sandwiches (two, approx. 100 g), vegetable
salad (120 g), fruit salad (1 cup)
[0190] Option 2: Humus sandwiches (two, approx. 100 g), vegetable
salad (120 g), fruit salad (1 cup)
[0191] Snack prior to second dosing of AP 190 kcal 49% fat
[0192] Plain croissant (50 g) or cookies, non-caffeinated tea
Version 4
[0193] Breakfast (-30 min) 529 Kcal 51% fat
[0194] Option 1: 2 slices of bread with butter (40 g) with 1 small
Plain croissant
[0195] Option 2: 2 slices of bread with butter (40 g) with Vanilla
pudding
[0196] Both with tea (decaffeinated, 1 spoon of sugar)
[0197] Lunch (.about.+5 hours) 648-670 Kcal 34% fat
[0198] Option 1: Salami sandwiches (two, approx. 100 g), vegetable
salad (120 g), fruit salad (1 cup)
[0199] Option 2: Humus sandwiches (two, approx. 100 g), vegetable
salad (120 g), fruit salad (1 cup)
Throughout the Day (Optional)
[0200] Cookies and non-caffeinated tea
[0201] Those of skill in the art will recognize that numerous
modifications and changes may be made to the exemplary designs and
embodiments described herein and that the invention is not limited
to such embodiments.
* * * * *