U.S. patent application number 16/693098 was filed with the patent office on 2020-10-22 for compositions and methods for treatment related to fall and fall frequency in neurodegenerative diseases.
The applicant listed for this patent is Neurocea, LLC. Invention is credited to Arasteh Ari AZHIR.
Application Number | 20200330448 16/693098 |
Document ID | / |
Family ID | 1000004930891 |
Filed Date | 2020-10-22 |
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United States Patent
Application |
20200330448 |
Kind Code |
A1 |
AZHIR; Arasteh Ari |
October 22, 2020 |
COMPOSITIONS AND METHODS FOR TREATMENT RELATED TO FALL AND FALL
FREQUENCY IN NEURODEGENERATIVE DISEASES
Abstract
The present disclosure provides methods and compositions for
treating fall-related symptoms in patients with neurodegenerative
diseases such as Parkinson's disease or Parkinson-related diseases.
In some embodiments, the disclosure utilizes nicotine or a salt
thereof in combination of dopaminergic agent treatments for
reducing fall-related symptoms such as reducing frequency of fall,
reducing injuries related to fall, reducing severity of injuries
related to fall, freezing of gait, improving posture stability,
improving locomotion ability, improving balance and gait. In some
embodiments, the methods predict fall frequency and tendency of
recurrent falls in patients with Parkinson's disease, in
particular, patients with typical Parkinson's disease.
Inventors: |
AZHIR; Arasteh Ari; (Los
Altos, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Neurocea, LLC |
Los Altos |
CA |
US |
|
|
Family ID: |
1000004930891 |
Appl. No.: |
16/693098 |
Filed: |
November 22, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16109458 |
Aug 22, 2018 |
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16693098 |
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15853151 |
Dec 22, 2017 |
10292977 |
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16109458 |
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15484960 |
Apr 11, 2017 |
10143687 |
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15853151 |
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62320871 |
Apr 11, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 45/06 20130101;
A61P 25/26 20180101; A61K 31/465 20130101 |
International
Class: |
A61K 31/465 20060101
A61K031/465; A61P 25/26 20060101 A61P025/26; A61K 45/06 20060101
A61K045/06 |
Claims
1-61. (canceled)
62. A kit comprising: (a) one or more starting unit doses of
nicotine or a salt thereof for administration one time to six times
a day for about 1 week to about 4 weeks, wherein no more than 1 mg
of the nicotine or salt thereof is administered at each
administration; (b) one or more first escalating unit doses of the
nicotine or salt thereof for administration one time to six times a
day for about 1 week to about 4 weeks, wherein no more than 2 times
the one or more starting unit doses of the nicotine or salt thereof
is administered at each administration; (c) optionally, one or more
second escalating unit doses of the nicotine or salt thereof for
administration one time to six times a day for about 1 week to
about 4 weeks, wherein no more than 4 times the one or more
starting unit doses of the nicotine or salt thereof is administered
at each administration; (d) optionally, one or more third
escalating unit doses of the nicotine or salt thereof for
administration one time to four times a day for about 1 week to
about 4 weeks, wherein no more than 6 times the one or more
starting unit doses of the nicotine or salt thereof is administered
at each administration; and (e) instructions for dose escalation of
the nicotine or salt thereof; wherein a total dose for
administration is no more than 24 mg per day.
63-77. (canceled)
78. A method of administering nicotine or a salt thereof to a
subject in need thereof, comprising: (a) administering a starting
dose of the nicotine or salt thereof one time to six times a day
for about 1 week to about 4 weeks, wherein the starting dose is
about 1 mg; (b) administering a first escalating dose of the
nicotine or salt thereof one time to six times a day for about 1
week to about 4 weeks, wherein the first escalating dose of the
nicotine or salt thereof is about 2 mg; (c) optionally,
administering a second escalating dose of the nicotine or salt
thereof one time to six times a day for about 1 week to about 4
weeks, wherein the second escalating dose of the nicotine or salt
thereof is about 4 mg; (d) optionally, administering a third
escalating dose of the nicotine or salt thereof one time to four
times a day for about 1 week to about 4 weeks, wherein the third
escalating dose of the nicotine or salt thereof is about 6 mg; and
(e) evaluating one or more parameters; wherein a total dose for
administration is no more than 24 mg per day.
79. The method of claim 78, wherein the one or more parameters is
an adverse event.
80. The method of claim 78, wherein the subject is evaluated for
the one or more parameters using laboratory tests, mental
evaluation tests, or physical evaluation tests.
81. The method of claim 78, wherein the method does not result in
tolerance or dependence on the nicotine or salt thereof.
82. The method of claim 79, wherein the adverse event is selected
from nausea, dizziness, constipation, vomiting, fatigue, pain,
diarrhea, headache, pain in extremity, tremor, nightmare, and
insomnia.
83. The method of claim 78, comprising (c) administering the second
escalating dose of the nicotine or salt thereof one time to six
times a day for about 1 week to about 4 weeks, wherein the second
escalating dose of the nicotine or salt thereof is about 4 mg.
84. The method of claim 83, comprising (d) administering the third
escalating dose of the nicotine or salt thereof one time to four
times a day for about 1 week to about 4 weeks, wherein the third
escalating dose of the nicotine or salt thereof is about 6 mg.
85. The method of claim 84, comprising administering the second
escalating dose of the nicotine or salt thereof one time to six
times a day for about 1 week to about 4 weeks if the subject does
not tolerate the third escalating dose of the nicotine or salt
thereof due to nausea or vomiting, wherein the second escalating
dose of the nicotine or salt thereof is about 4 mg.
86. The method of claim 78, comprising administering the starting
dose of the nicotine or salt thereof four times a day.
87. The method of claim 78, comprising administering the first
escalating dose of the nicotine or salt thereof four times a
day.
88. The method of claim 78, comprising administering the second
escalating dose of the nicotine or salt thereof four times a
day.
89. The method of claim 78, comprising administering the third
escalating dose of the nicotine or salt thereof four times a
day.
90. The method of claim 78, comprising administering the starting
dose of the nicotine or salt thereof four times a day,
administering the first escalating dose of the nicotine or salt
thereof four times a day, administering the second escalating dose
of the nicotine or salt thereof four times a day, and administering
the third escalating dose of the nicotine or salt thereof four
times a day.
91. The method of claim 78, wherein the nicotine or salt thereof is
formulated for oral administration.
92. The method of claim 78, wherein the method reduces falls in the
subject.
93. The method of claim 78, wherein the subject has Parkinson's
disease.
94. The method of claim 93, wherein the subject is on levodopa
treatment.
95. The method of claim 94, wherein the method reduces falls in the
subject.
96. A method of administering nicotine or a salt thereof to a
subject in need thereof, comprising: (a) administering a starting
dose of the nicotine or salt thereof one time to six times a day
for about 1 week to about 4 weeks, wherein the starting dose is no
more than 1 mg; (b) administering a first escalating dose of the
nicotine or salt thereof one time to six times a day for about 1
week to about 4 weeks, wherein the first escalating dose of the
nicotine or salt thereof is no more than 2 times the starting dose;
(c) optionally, administering a second escalating dose of the
nicotine or salt thereof one time to six times a day for about 1
week to about 4 weeks, wherein the second escalating dose of the
nicotine or salt thereof is no more than 4 times the starting dose;
(d) optionally, administering a third escalating dose of the
nicotine or salt thereof one time to four times a day for about 1
week to about 4 weeks, wherein the third escalating dose of the
nicotine or salt thereof is no more than 6 times the starting dose;
and (e) evaluating one or more parameters; wherein a total dose for
administration is no more than 24 mg per day.
Description
CROSS-REFERENCE
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/109,458, filed Aug. 22, 2018, which is a
continuation of U.S. patent application Ser. No. 15/853,151, filed
Dec. 22, 2017, now U.S. Pat. No. 10,292,977, issued May 21, 2019,
which is a continuation-in-part of U.S. patent application Ser. No.
15/484,960, filed Apr. 11, 2017, now U.S. Pat. No. 10,143,687,
issued Dec. 4, 2018, which claims the benefit of U.S. Provisional
Application No. 62/320,871 filed on Apr. 11, 2016, which are
incorporated herein by reference in their entirety.
BACKGROUND
[0002] Parkinson's disease (also known as Parkinson disease,
Parkinson's, idiopathic parkinsonism, primary parkinsonism, PD, or
paralysis agitans) is a degenerative disorder of the central
nervous system. It results from the death of dopamine-containing
cells in the substantia nigra, a region of the midbrain; the cause
of cell-death is unknown. Early in the course of the disease, the
most obvious symptoms are movement- and balance-related, including
shaking, rigidity, falls, freezing of gait, slowness of movement
and difficulty with walking and gait. The main motor symptoms are
collectively called parkinsonism, or a "parkinsonian syndrome". The
pathology of the disease is characterized by the accumulation of a
protein called alpha-synuclein into inclusions called Lewy bodies
in neurons, and from insufficient formation and activity of
dopamine produced in certain neurons of parts of the midbrain.
INCORPORATION BY REFERENCE
[0003] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference.
BRIEF SUMMARY
[0004] Described herein are methods of reducing frequency of falls
in a subject at risk of falling comprising: administering to said
subject nicotine or a salt thereof in an amount no more than 24 mg
per day, whereby the frequency of falls is reduced. The subject at
risk of falling may be elderly or may have a central nervous system
disease or disorder. The central nervous system disease or disorder
may be Parkinson's disease. The nicotine or the salt thereof may be
in a dosage form that delivers an immediate-release dose of
nicotine and a second immediate-release dose of nicotine about 2
hours to about 8 hours after administration. A dose of nicotine of
salt thereof may be administered to the subject one time to six
times a day. The dose may be no more than 1 mg, no more than 2 mg,
no more than 4 mg, no more than 6 mg, or no more than 8 mg. The
administration of the nicotine or salt thereof may result in a
plasma nicotine level below about 7.5 ng/mL about 180 minutes after
administration of the dosage form. The administration of the
nicotine or salt thereof may result in a peak plasma nicotine level
above 10 ng/mL about 25 minutes to about 50 minutes after
administration of the dosage form. The administration of the
nicotine or salt thereof may result in a peak plasma nicotine
levels above 10 ng/mL about 25 minutes to about 50 minutes followed
by a plasma nicotine level of below about 7.5 ng/mL about 180
minutes after administration of the dosage form. The administration
of the nicotine or salt thereof may result in a peak plasma
nicotine levels above 7.5 ng/mL about 25 minutes to about 50
minutes followed by a plasma nicotine level of below about 5 ng/mL
about 180 minutes after administration of the dosage form. The
administration of the nicotine or salt thereof may result in a peak
plasma nicotine level above 5 ng/mL about 25 minutes to about 50
minutes after administration of the dosage form. The administration
of the nicotine or salt thereof may result in a peak plasma
nicotine level above 10 ng/mL about 45 minutes to about 90 minutes
after administration of the dosage form. The administration of the
nicotine of salt thereof may result in a plasma level no more than
1.0 ng/mL about 300 minutes after administration of the dosage
form. The nicotine or salt thereof may be formulated for oral,
topical, buccal, transdermal, or inhalation administration. The
frequency of falls may be reduced by at least 20%. The falls may be
independent of freezing of gait (FOG). The falls may be related to
FOG or levodopa induced dyskinesia (LID). FOG may be reduced.
Dyskinesia, walking, gait, balance, or postural control in the
subject may be improved. Cognitive-related symptoms may be
improved. The cognitive-related symptoms may be related to
dementia. The subject may be evaluated using Falling Unrelated to
Freezing from question 13 from UPDRS Part II (Activities of Daily
Life (ADL)), Freezing When Walking from question 14 from UPDRS Part
II (ADL), ambulation subset from Unified Dyskinesia Rating Scale
(UDysRS), or combinations thereof. The subject may be further
evaluated using Item 30 from UPDRS Part III. The Falling Unrelated
to Freezing from question 13 from UPDRS Part II (Activities of
Daily Life (ADL)) and the Freezing When Walking from question 14
from UPDRS Part II (ADL) may be not changed in the subject, and
ambulation subset from Unified Dyskinesia Rating Scale (UDysRS) may
be improved in the subject.
[0005] Described herein are methods of reducing freezing of gait
(FOG) in a subject comprising: administering to said subject
nicotine or salt thereof in an amount no more than 24 mg per day,
whereby the FOG is reduced. The subject may be elderly or may have
a central nervous system disease or disorder. The central nervous
system disease or disorder may be Parkinson's disease. The nicotine
or the salt thereof may be in a dosage form that delivers an
immediate-release dose of nicotine and a second immediate-release
dose of nicotine about 2 hours to about 8 hours after
administration. The nicotine or salt thereof may be administered to
the subject one time to six times a day. The dose may be no more
than 1 mg, no more than 2 mg, no more than 4 mg, no more than 6 mg,
or no more than 8 mg. The administration of the nicotine or salt
thereof may result in a plasma nicotine level below about 7.5 ng/mL
about 180 minutes after administration of the dosage form. The
administration of the nicotine or salt thereof may result in a peak
plasma nicotine level above 10 ng/mL about 25 minutes to about 50
minutes after administration of the dosage form. The administration
of the nicotine or salt thereof may result in a peak plasma
nicotine levels above 10 ng/mL about 25 minutes to about 50 minutes
followed by a plasma nicotine level of below about 7.5 ng/mL about
180 minutes after administration of the dosage form. The
administration of the nicotine or salt thereof may result in a peak
plasma nicotine levels above 7.5 ng/mL about 25 minutes to about 50
minutes followed by a plasma nicotine level of below about 5 ng/mL
about 180 minutes after administration of the dosage form. The
administration of the nicotine or salt thereof may result in a peak
plasma nicotine level above 5 ng/mL about 25 minutes to about 50
minutes after administration of the dosage form. The administration
of the nicotine or salt thereof may result in a peak plasma
nicotine level above 10 ng/mL about 45 minutes to about 90 minutes
after administration of the dosage form. The administration of the
nicotine or salt thereof may result in a plasma level no more than
1.0 ng/mL about 300 minutes after administration of the dosage
form. The nicotine or salt thereof may be formulated for oral,
topical, buccal, transdermal, or inhalation administration. The FOG
may be reduced by at least 20%. Frequency of falls may be reduced.
Falls may be prevented. Fall-related complications may be
reduced.
[0006] Described herein are methods of improving postural stability
in a subject comprising: administering to said subject nicotine or
a salt thereof in an amount no more than 24 mg per day, whereby
postural stability is improved. The postural stability may be
related to falls, freezing of gait (FOG), or dyskinesia.
[0007] Described herein are methods of reducing frequency of falls
in a subject at risk of falling comprising: administering to said
subject a nicotinic acetylcholine receptor (nAChR) agonist in an
amount no more than 24 mg per day, whereby the frequency of falls
is reduced.
[0008] Described herein are methods of preventing falls in a
subject comprising: administering to said subject nicotine or salt
thereof in an amount no more than 24 mg per day, whereby the falls
are prevented. The subject may be elderly or has a central nervous
system disease or disorder. The central nervous system disease or
disorder may be Parkinson's disease. The nicotine or the salt
thereof may be in a dosage form that delivers an immediate-release
dose of nicotine and a second immediate-release dose of nicotine
about 2 hours to about 8 hours after administration.
[0009] Described herein are methods of treating a cognitive disease
or disorder in a subject comprising: administering to said subject
nicotine or a salt thereof in an amount no more than 24 mg per day.
The method may not result in tolerance or dependence on the
nicotine or salt thereof.
[0010] Described herein are multiparticulate formulations
comprising nicotine or a salt thereof, wherein the formulation
delivers an immediate-release dose of nicotine and a second
immediate-release dose of nicotine about 2 hours to about 8 hours
after administration, wherein a total dosage administered to the
subject is no more than 24 mg per day. The formulation may be
administered to the subject one time to six times a day. The
formulation may deliver no more than 1 mg every 6 hours, no more
than 2 mg every 6 hours, no more than 4 mg every 6 hours, or no
more than 6 mg every 6 hours. Administration of the formulation may
result in a plasma nicotine level below about 7.5 ng/mL about 180
minutes after administration of the formulation. Administration of
the formulation may result in a peak plasma nicotine level above 10
ng/mL about 25 minutes to about 50 minutes after administration of
the formulation. Administration of the formulation may result in a
peak plasma nicotine levels above 10 ng/mL about 25 minutes to
about 50 minutes followed by a plasma nicotine level of below about
7.5 ng/mL about 180 minutes after administration of the
formulation. Administration of the formulation may result in a peak
plasma nicotine levels above 7.5 ng/mL about 25 minutes to about 50
minutes followed by a plasma nicotine level of below about 5 ng/mL
about 180 minutes after administration of the formulation.
Administration of the formulation may result in a peak plasma
nicotine level above 5 ng/mL about 25 minutes to about 50 minutes
after administration of the formulation. Administration of the
formulation may result in a peak plasma nicotine level above 10
ng/mL about 45 minutes to about 90 minutes after administration of
the formulation. The formulation may result in a plasma level no
more than 1.0 ng/mL about 300 minutes after administration of the
formulation.
[0011] Described herein are kits comprising: (a) one or more
starting unit doses of nicotine or a salt thereof for
administration one time to six times a day for about 1 week to
about 4 weeks, wherein no more than 1 mg of the nicotine or salt
thereof is administered at each administration; (b) one or more
first escalating unit doses of the nicotine or salt thereof for
administration one time to six times a day for about 1 week to
about 4 weeks, wherein no more than 2 times the one or more
starting unit doses of the nicotine or salt thereof is administered
at each administration; (c) optionally, one or more second
escalating unit doses of the nicotine or salt thereof for
administration one time to six times a day for about 1 week to
about 4 weeks, wherein no more than 4 times the one or more
starting unit doses of the nicotine or salt thereof is administered
at each administration; (d) optionally, one or more third
escalating unit doses of the nicotine or salt thereof for
administration one time to four times a day for about 1 week to
about 4 weeks, wherein no more than 6 times the one or more
starting unit doses of the nicotine or salt thereof is administered
at each administration; and (e) instructions for dose escalation of
the nicotine or salt thereof, wherein a total dose for
administration is no more than 24 mg per day. The kit may comprise
one or more unit starting doses of the nicotine or a salt thereof
for administration four times a day for four weeks. The kit may
comprise a dosage of the nicotine or salt thereof of 112 mg. The
nicotine or salt thereof may be formulated for oral administration.
The nicotine or salt thereof may be in solution form. The nicotine
or salt thereof may be in solid form. The nicotine or salt thereof
may be in liquid, gel, semi-liquid, semi-solid, or solid form.
[0012] Described herein are kits comprising: (a) one or more unit
doses of a first dose of nicotine or a salt thereof for a first
period of about 1 week to about 4 weeks, wherein the first dose is
about 1 mg; (b) one or more unit doses of a second dose of nicotine
or a salt thereof for a second period of about 1 week to about 4
weeks, wherein the second dose is about 2 mg; (c) optionally, one
or more unit doses of a third dose of nicotine or a salt thereof
for a third period of about 1 week to about 4 weeks, wherein the
third dose is about 4 mg; (d) optionally, one or more unit doses of
a fourth dose of nicotine or a salt thereof for a fourth period of
about 1 week to about 4 weeks, wherein the fourth dose is about 6
mg; and (e) instructions for dose escalation of the nicotine or
salt thereof, wherein a total dose for administration is no more
than 24 mg per day. The first dose may be administered one time to
six times a day. The second dose may be administered one time to
six times a day. The third dose may be administered one time to six
times a day. The fourth dose may be administered one time to four
times a day. Time between the first period and the second period
may be about 1 week to about 4 weeks. Time between the second
period and the third period may be about 1 week to about 4 weeks.
Time between the third period and the fourth period may be about 1
week to about 4 weeks. Time between the first period and the fourth
period may be no more than 10 weeks.
[0013] Described herein are methods of administering nicotine or a
salt thereof to a subject in need thereof, comprising: (a)
administering a starting dose of the nicotine or salt thereof one
time to six times a day for about 1 week to about 4 weeks, wherein
the starting dose is about 1 mg; (b) administering a first
escalating dose of the nicotine or salt thereof one time to six
times a day for about 1 week to about 4 weeks, wherein the first
escalating dose of the nicotine or salt thereof is about 2 mg; (c)
optionally, administering a second escalating dose of the nicotine
or salt thereof one time to six times a day for about 1 week to
about 4 weeks, wherein the second escalating dose of the nicotine
or salt thereof is about 4 mg; (d) optionally, administering a
third escalating dose of the nicotine or salt thereof one time to
four times a day for about 1 week to about 4 weeks, wherein the
third escalating dose of the nicotine or salt thereof is about 6
mg; and (e) measuring one or more parameters; wherein a total dose
for administration is no more than 24 mg per day. The one or more
parameters may be an adverse event. The subject may be measured for
the one or more parameters using laboratory tests, mental
evaluation tests, or physical evaluation tests. The method may not
result in tolerance or dependence on the nicotine or salt
thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] The novel features of the invention are set forth with
particularity in the appended claims. A better understanding of the
features and advantages of the present invention will be obtained
by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the invention
are utilized, and the accompanying drawings of which:
[0015] FIG. 1 illustrates a method for treating and evaluation
fall-related symptoms in subjects with Parkinson's disease.
[0016] FIG. 2 illustrates a timeline of evaluating effectiveness of
nicotine or a salt thereof in treating fall-related symptoms in
subjects with Parkinson's disease.
[0017] FIG. 3 illustrates a pharmacokinetic profile of different
modes of administration of nicotine, including by transdermal patch
(15 mg/16 hr), transbuccal gum (4 mg, assuming hourly
administration), or oral tablet (3 mg, 4 mg, or 6 mg).
[0018] FIG. 4 illustrates a graph of dyskinesia ratings/time point
on a Y axis and time (min) on an X axis in control and nicotine
treated monkeys.
[0019] FIG. 5 illustrates a graph of Parkinsonian ratings on a Y
axis in an OFF L-dopa (left bars on X axis) and ON L-dopa (right
bars on X axis) in control and nicotine treated monkeys.
[0020] FIG. 6A illustrates a schematic of Phase 2 safety and
tolerability study trial design.
[0021] FIG. 6B illustrates a schematic of Phase 2 study
schedule.
[0022] FIG. 7 illustrates a multiparticulate PH independent dosage
form. Coating substrate is shown in white with drug containing
layer. A rate controller polymer is layered on top of the drug
containing layer.
[0023] FIG. 8 illustrates a drug release profile for an immediate
release (triangles), delayed release (squares), and a 2 pulse drug
release profile (circles).
[0024] FIG. 9 illustrates a schematic of PK sampling schedule.
[0025] FIG. 10 illustrates a drug release profile for an immediate
release (triangles) and delayed release (squares).
[0026] FIG. 11A illustrates a graph of single dose nicotine PK
profiles.
[0027] FIG. 11B illustrates a hypothetical nicotine PK profiles
from a 2-pulse modified dosage form.
[0028] FIG. 12 is a graph of a target 2-pulse PK profile from a
nicotine modified-release capsule, 12 mg (6 mg IR and 6 mg DR).
[0029] FIG. 13 illustrates a decision tree for evaluation of in
vitro dissolution performance of nicotine delayed.
[0030] FIG. 14 illustrates activity of seven days including
different types of physical activities.
[0031] FIG. 15 illustrates sedentary and active movements during a
seven day period.
[0032] FIG. 16 illustrates activity levels associated with seven
days including various activities such as light, moderate,
vigorous, and very vigorous activities.
[0033] FIG. 17 illustrates various activities associated with
sleep.
[0034] FIG. 18 illustrates a graph of decrease in falls unrelated
to freezing of gait (FOG) assessed by Part II of Unified Parkinson
Disease Rating Scale (UPDRS) in patients administered NP002 (left
bar) or placebo (right bar) at end of treatment period (week 10, x
axis). Y axis shows percentage (%) of patients experiencing
decrease in falls.
[0035] FIG. 19 illustrates a graph of decrease freezing of gait
(FOG) assessed by Part II of Unified Parkinson Disease Rating Scale
(UPDRS) in patients administered NP002 (left bar) or placebo (right
bar) at end of treatment period (week 10, x axis). Y axis shows
percentage (%) of patients experiencing decrease in FOG.
[0036] FIG. 20 illustrates a graph of decrease in ambulation as
assessed by Unified Parkinson Disease Rating Scale (UPDRS) subtest
in patients administered NP002 (left bar) or placebo (right bar) at
end of treatment period (week 10, x axis). Y axis shows improvement
in ambulation.
DETAILED DESCRIPTION
[0037] As used herein, the term "postural instability" (PI) refers
to impaired balance.
[0038] As described herein, the term "balance" refers to a
multisystem function that strives to keep the body upright while
sitting or standing and while changing posture.
[0039] As used herein, the term "zero-order release" refers to a
uniform or nearly uniform rate of release of a drug from a dosage
form during a given period of release, a rate of release that is
independent of the concentration of drug in the dosage form. A
dosage form with a zero-order release profile is referred to herein
as a "zero-order dosage form." Any zero-order dosage form has the
advantage of providing maximum therapeutic value while minimizing
side effects.
[0040] The term "oral administration," as used herein, refers a
form of delivery of a dosage form of a drug to a subject, wherein
the dosage form is placed in the mouth of the subject and
swallowed.
[0041] The term "orally deliverable" herein means suitable for oral
administration.
[0042] The term "enteric coating," as used herein, refers to a
tablet coating that is resistant to gastric juice, and which
dissolves after a dosage form with the enteric coating passes out
of the stomach, after oral administration to a subject.
[0043] A "therapeutic effect," as that term is used herein,
encompasses a therapeutic benefit and/or a prophylactic benefit. By
therapeutic benefit is meant eradication or amelioration of the
underlying disorder being treated. Also, a therapeutic benefit is
achieved with the eradication or amelioration of one or more of the
physiological symptoms associated with the underlying disorder such
that an improvement is observed in the patient, notwithstanding
that the patient may still be afflicted with the underlying
disorder. For prophylactic benefit, the compositions may be
administered to a patient at risk of developing a particular
disease, or to a patient reporting one or more of the physiological
symptoms of a disease, even though a diagnosis of this disease may
not have been made. A prophylactic effect includes delaying or
eliminating the appearance of a disease or condition, delaying or
eliminating the onset of symptoms of a disease or condition,
slowing, halting, or reversing the progression of a disease or
condition, or any combination thereof.
[0044] The term "excipient," as used herein, means any substance,
not itself a therapeutic agent, used as a carrier or vehicle for
delivery of a therapeutic agent to a subject or added to a
pharmaceutical composition to improve its handling, storage,
disintegration, dispersion, dissolution, release or organoleptic
properties or to permit or facilitate formation of a dose unit of
the composition into a discrete article such as a capsule or tablet
suitable for oral administration. Excipients can include, by way of
illustration and not limitation, diluents, disintegrates, binding
agents, adhesives, wetting agents, lubricants, glidants, substances
added to mask or counteract a disagreeable taste or odor, flavors,
dyes, fragrances, and substances added to improve appearance of the
composition.
[0045] The term "pH independent release" refers to a rate of
release of a drug from a dosage form that does not change when the
pH of the environment in which the dosage form is found is changed,
e.g., from an acidic pH to a higher pH. The term "pH dependent
release" refers to a rate of release of a drug from a dosage form
that changes when the pH of the environment in which the dosage
form is found is changed from, e.g., an acidic pH to a higher
pH.
[0046] The terms "NC001" and "NP002" as used herein refer to
Nicotine Bitartrate and can be used interchangeably.
[0047] The term "about" unless specifically stated or obvious from
context, as used herein, refers to a number or range of numbers is
understood to mean the stated number and numbers +/-10% thereof, or
10% below the lower listed limit and 10% above the higher listed
limit for the values listed for a range.
[0048] In various aspects, the present disclosure relates to
compounds, compositions, and methods for treating fall-related
symptoms of an individual suffering from diseases associated with
neurodegenerative disorders, for example, Parkinson's disease (PD)
and PD-related disorders, Alzheimer's disease (AD), dementias,
amyotrophic lateral disease (ALS) or Lou Gehrig's disease,
Huntington's disease (HD), multiple sclerosis (MS), Spinocerebellar
ataxia (SCA), Spinal muscular atrophy (SMA), motor neuron disease
(MND) and prion disease. In some embodiments, this is accomplished
by administering a therapeutically effective amount of nicotine or
a salt thereof or a nicotinic receptor modulator to an individual
suffering from the diseases. In some embodiments, the present
disclosure also relates to compositions comprising nicotine or a
salt thereof or a nicotinic receptor modulator and a pharmaceutical
carrier formulated for administration to an individual suffering
from the diseases. As disclosed herein, administering the effective
amount of nicotine or a salt thereof or a nicotinic receptor
modulator to a subject with neurodegenerative diseases reduces
fall-related symptoms such as reducing frequency of fall, reducing
frequency of injuries related to fall, and reducing seventy of
injuries related to fall, improving posture stability, improving
static balance, improving locomotor ability, and improving gait. In
some embodiments, the subject has Parkinson's disease (PD) or
PD-related disorders. In some embodiments, the subject has typical
Parkinson's disease. In some embodiments, the subject has
dopaminergic agent treatment.
Fall and Parkinson's Disease
[0049] People with neurodegenerative diseases fall more often.
Falls, especially recurrent falls, are a major cause of disability
in neurodegenerative diseases such as PD (Temlett and Thompson,
"Reasons for admission to hospital for Parkinson's disease", Intern
Med J 36:524-526, Jul. 7, 2006; Johnell et al., "Fracture risk in
patients with parkinsonism: a population-based study in Olmsted
County, Minnesota", Age Aging 21: 32-38, January 1992). Falls occur
because of impaired, slowed, locomotion and impaired postural
stability (balance). Falls, single falls, early in PD (within 1-5
years of after diagnosis), usually occur from impaired, slow
locomotion, and usually respond to dopaminergic drugs (e.g.,
levodopa, dopamine agonists, and monoamine oxidase type B
inhibitors). Falls, recurrent falls, falls with injuries, usually
occur later (5 or more years after diagnosis).
[0050] Falls area major risk for Parkinson's disease (PD) patients.
Falls occur mostly due to impaired, slowed, locomotion and impaired
postural stability or balance. Recent researches show that people
with PD often have single falls or recurrent falls (Lieberman et
al, "Comparison of Parkinson disease patients who fell once with
patients who fell more than once (Recurrent fallers)", J.
Alzheimers Dis Parkinsonism, 4(2), Mar. 15, 2014; doi:
10.4172/2161-0460.1000140). Single falls, such as falls occur once
in a year, in older people may be related to underlying disease or
may be accidental. Recurrent falls, such as falls occur more than
once in a year, are more likely to be related to the underlying
disease. Recurrent falls may also cause injuries or increase the
severity of injuries related to fall.
[0051] Recurrent fallers, known as people who have recurrent falls,
differed significantly from single and non-fallers, known as people
who have single fall or do not fall, in duration and severity of
PD. They also differed significantly from single and non-fallers in
freezing of gait (FOG), postural instability (e.g., the "pull
test") and static balance (e.g., inability to stand on one leg
<3 seconds).
[0052] People with PD fall more often than people without PD.
Single falls are common in people with PD within 1-5 years of
diagnosis. Usually, single falls can be treated with dopaminergic
drugs, for example, levodopa, carbidopa, dopamine agonists,
monoamine oxidase type B inhibitors and amantadine. Recurrent falls
are common in people diagnosed with PD for at least 5 years.
[0053] Falls early in PD, probably arise from impaired, slowed
locomotion. Slowed locomotion is corrected by dopaminergic drugs,
hence falls early in PD are decreased by such drugs. Later in PD (5
or more years after diagnosis) recurrent falls occur despite such
drugs. Falls late in PD occur possibly because of impaired postural
stability, and impaired postural stability does not respond to
dopaminergic drugs or may be made worse by such drugs (Chen R
Paradoxical worsening of gait with levodopa in Parkinson disease
Neurology 2012 78: 446-447, Helv M A, Morris G L, Wayne G J Sydney
Multicenter Study of Parkinson's Disease: Non L-Dopa Responsive
Problems Dominate at 15 Years Movement Disorders 20; 2005:
190-199). In some cases, people fall late in PD have recurrent
falls and occasionally may be made worse by dopaminergic drug
treatments.
[0054] Recurrent fallers have PD longer and are more disabled: they
have higher Unified Parkinson Disease Rating Scale (UPDRS) scores
than single fallers. As a non-limiting example, recurrent fallers
are more likely to be unable to stand on one foot for <3
seconds. In some cases, the ability to stand on one foot for <3
seconds can be used to predict recurrent falls in patients with or
without freezing of gait. Recurrent fallers are more likely to have
freezing of gait, which can serve as a good predictor of recurrent
falls but not as good as an inability to stand on one foot for
<3 seconds. Together, inability to stand on one foot for <3
seconds and freezing of gait are more likely to predict recurrent
falls than the subtests of gait, and postural stability (the "pull
test") of the UPDRS.
[0055] Besides of the stand on one foot <3 seconds test and the
freezing of gait test, the Barrow Neurological Institute balance
scale can be a useful addition to the UPDRS scale especially in
predicting recurrent falls.
[0056] Fall severity can be categorized as falls that require
medical attention or falls that do not require medical attention.
Typically a serious fall is one that requires medical attention,
and can be defined with the following criteria: 1) the person falls
on the floor, without loss of consciousness, all 4 limbs or the
skull hitting the ground; 2) the person needed help in arising; 3)
the person twisted a joint or sustained a fracture. Typically, the
persons with PD may visit an Emergency Room or an Urgent Care
Center.
[0057] A single fall, although serious, may be only partly related
or even unrelated to PD. However some people with PD fall
repeatedly (Lieberman et al, "Comparison of Parkinson disease
patients who fell once with patients who fell more than once
(Recurrent fallers)", J. Alzheimers Dis Parkinsonism, 4(2), Mar.
15, 2014; doi: 10.4172/2161-0460.1000140; Lieberman A, "Falls in
Parkinson disease: the relevance of short steps", J Nov Physiother
4(3), Apr. 18, 2014; doi:10.4172/2165-7025.1000209). In these
studies, the role of impaired postural stability was stressed. The
mechanisms underlying impaired postural stability are not known.
Attention, however, is focused on the central nervous system (CNS)
cholinergic system (Chung K A, Lobb B M, Nutt J G, Horak F B,
"Effects of a central cholinesterase inhibitor on reducing falls in
Parkinson disease", Neurology 2010 75: 1263-1269; Sep. 1,
2010).
[0058] Locomotion, e.g. short steps, is significantly decreased in
recurrent versus single fallers and less decreased in single versus
non-fallers. Impaired balance, not locomotion, is the main cause of
falls in PD. Without being limited by any theory, cholinergic
mechanisms related to cholinergic centers in the basal forebrain
and the pre-peduncular nucleus (PPN) may play a key role in
maintaining postural stability and may play a key role in
preventing or ameliorating falls.
[0059] NP002, a central cholinergic agonist, was recently evaluated
as a possible treatment for levodopa-induced dyskinesias (LIDs) in
PD as disclosed in U.S. patent application Ser. No. 12/901,354,
filed Oct. 8, 2010. NP002 is a small molecule, a usually orally
available nicotinic receptor agonist that has been shown in
preclinical studies to reduce LIDs without affecting Parkinsonian
symptoms. NP002 may also be helpful in PD patients with impaired
postural stability who fall.
Posture Instability and Balance
[0060] Postural instability (PI), or impaired balance, is common in
PD patients such as idiopathic Parkinson's disease (IPD),
especially as the disease severity advances (Bronte-Stewart et al.,
"Postural instability in idiopathic Parkinson's disease: the role
of medication and unilateral pallidotomy", Brain 125: 2100-2114,
September 2002). Faulty balance mechanisms may contribute to
fall-related injuries, restriction of gait patterns and decreased
mobility. These disabilities lead to loss of functional
independence and social isolation.
[0061] Balance is needed to keep the body oriented appropriately
while performing voluntary activity, during external perturbations
and when the support surface or environment changes. Horak et al.
(Horak et al., "Postural inflexibility in parkinsonian subjects", J
Neurol Sci 111: 46-58; 1992) proposed that balance or postural
stability requires three distinct processes: (i) sensory
organization, in which one or more of the orientational senses
(somatosensory, visual and vestibular) are involved and integrated
within the CNS; (ii) a motor adjustment process involved with
executing coordinated and properly scaled neuromuscular responses;
and (iii) the background tone of the muscles, through which changes
in balance are effected.
[0062] Organization of the orientational senses is understood to
bean adaptive hierarchical system. There are two main reference
frames for the sensory representation of the body posture with
respect to space. On a lower level, a weighted combination of
orientational inputs directly mediates the activity of postural
muscles and mainly controls the horizontal centre of gravity (COG)
position (the bottom-up organization). On a higher level,
vestibular inputs provide the orientational reference, against
which conflicts in support surface and visual orientation are
identified and the combination of inputs adapted to the task
conditions (the top-down organization). For postural stability, the
information from the lower level must be coherent with the
inertial-gravitational reference of the higher level, and any
conflicting orientation inputs must be quickly suppressed in favour
of those congruent with the internal reference. Thus, in adults,
the sensory organizational process is context specific due to the
rapid weighting and re-weighting of sensory inputs to/from the
lower level by the higher level adaptive process.
[0063] Clinical measures of postural control in PD are typically
derived from items in standardized clinical rating scales, such as
the Unified Parkinson's Disease Rating Scale (UPDRS) (Fahn S, Elton
R L, members of the UPDRS Development Committee. Unified
Parkinson's Disease Rating Scale. In: Fahn S, Marsden C, Calne D,
editors. Recent developments in Parkinson's disease. Florham Park
(N.J.): Macmillan Healthcare Information; 1987. P. 153-163). The
commonly accepted Postural Instability and Gait Disorder (PIGD)
subscore comprises historical questions relating to falling,
walking and freezing, and objective ratings of the patient's
ability to change posture, walk and maintain equilibrium during a
retropulsive or propulsive pull (Lozano et al., "Effect of GPi
pallidotomy on motor function in Parkinson's disease", Lancet 346:
1383-1387; 1995).
[0064] There are limitations of the MDS-UPDRS motor scale in
evaluating postural stability or balance, only 24 out of 132 points
are devoted to axial or midline testing. As a supplementary
approach, testing which better reflects problems in posture
stability or balance can be further assessed utilizing Romberg
test, Turning test, Standing on one leg test, and Tandem gait
test.
[0065] Postural instability (PI), or impaired balance, is common in
PD patients such as idiopathic Parkinson's disease (IPD),
especially as the disease severity advances (Bronte-Stewart et al.,
"Postural instability in idiopathic Parkinson's disease: the role
of medication and unilateral pallidotomy", Brain 125: 2100-2114,
September 2002). Faulty balance mechanisms may contribute to
fall-related injuries, restriction of gait patterns and decreased
mobility. These disabilities lead to loss of functional
independence and social isolation.
Cognitive Impairment
[0066] The relationship between attention and the control of
posture and gait have been widely described in patients with
Parkinson Disease (PD). There is evidence that cholinergic
mechanisms related to cholinergic centers in the basal forebrain
and the prepeduncular nucleus (PPN) play a key role in maintaining
postural stability. They also play a key role in preventing or
ameliorating falls. Subtle disturbances in gait can be observed in
ageing and in (preclinical) subtypes of dementia that are not known
for prominent motor disturbances, supporting a close relationship
between gait and cognition. Some examples of these dementias are
mild cognitive impairment, Alzheimer's Disease, vascular cognitive
impairment, Subcortical Ischemic Vascular Dementia, Frontotemporal
Mild Cognitive Impairment, and Frontotemporal Dementia.
[0067] Brain neuroimaging findings may link cognition, gait and
fall risk and white matter changes may be linked to postural
instability, gait disturbances and falls in older adults. If
cognitive deficits are in the causal pathway and they exacerbate
the risk of falls or prevent appropriate compensatory mechanisms,
improvement of cognitive abilities, at least certain aspects, may
improve gait and reduce the risk of falls, especially in more
challenging conditions that rely on executive function.
[0068] Many research studies show findings that indicate that all
aspects of balance control deteriorate with increasing severity of
cognitive impairment and that executive function plays an important
role in balance control. It has been established that gait
impairments predict cognition, and cognition impairment is a risk
factor for falls in PD. Several cognitive operations within the
brain are a function of intact neuronal nicotinic acetylcholine
receptors (neuronal nAChRs) localized in discrete neuroanatomical
pathways. Dementia of the Alzheimer's type offers an example of the
correlation between profound cognitive impairment and impaired
neuronal nAChR function. Nicotine regulates ACh release from areas
involved in cognition that are putatively defective in
schizophrenia. There is ample evidence that these receptors are
involved in normal cognitive operations within the brain.
[0069] Nicotine offers the ability to enhance cognition and provide
neuroprotection. nACHR agonists could act as therapeutic agents for
treating cognition impairment in Alzheimer's Disease and
schizophrenia, and most notably in Parkinson's Disease. As PD
progresses, the treatment of non-motor symptoms such as cognitive
impairment takes precedence over the treatment of non-motor
symptoms such as cognitive impairment takes precedence over the
treatment of motor symptoms. The majority of the morbidity and
mortality associated with PD is related to non-motor aspects,
including cognition, and gait and balance. Falls and postural
instability are major problems in Parkinson disease (PD) and,
unlike gait, are largely unresponsive to dopaminergic replacement.
Falls, injuries related to falls and fear of falling pose a major
problem in PD. Improving postural stability and reducing falls
improves the lives of PD patients.
Nicotine
[0070] In one aspect, the present disclosure provides methods and
compositions utilizing nicotine or a salt thereof for treating
fall-related symptoms as well as cognitive symptoms in a subject
with neurodegenerative disease, e.g. Parkinson's disease or
Parkinson-related disease. Details of the disclosure are described
herein.
[0071] Nicotine may be isolated and purified from nature or
synthetically produced in any manner. This term "nicotine" is also
intended to encompass the commonly occurring salts containing
pharmacologically acceptable anions, such as hydrochloride,
hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate
or acid phosphate, acetate, lactate, citrate or acid citrate,
tartrate or bitartrate, succinate, maleate, fumarate, gluconate,
saccharate, benzoate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluene sulfonate, camphorate and pamoate
salts. Nicotine is a colorless to pale yellow, strongly alkaline,
oily, volatile, hygroscopic liquid having a molecular weight of
162.23. The systematic name of nicotine is
(S)-3-[1-methylpyrrolidin-2-yl]pyridine and its structure is:
##STR00001##
[0072] Unless specifically indicated otherwise, the term "nicotine"
further includes any pharmacologically acceptable derivative or
metabolite of nicotine which exhibits pharmacotherapeutic
properties similar to nicotine. Such derivatives, metabolites, and
derivatives of metabolites are known in the art, and include, but
are not necessarily limited to, cotinine, norcotinine, nornicotine,
nicotine N-oxide, cotinine N-oxide, 3-hydroxycotinine and
5-hydroxycotinine or pharmaceutically acceptable salts thereof A
number of useful derivatives of nicotine are disclosed within the
Physician's Desk Reference (most recent edition) as well as
Harrison's Principles of Internal Medicine. Methods for production
of nicotine derivatives and analogues are well known in the art.
See, e.g., U.S. Pat. Nos. 4,590,278; 4,321,387; 4,452,984;
4,442,292; and 4,332,945.
[0073] The compounds of the present invention may have asymmetric
carbon atoms. All isomers, including diastereomeric mixtures such
as racemic mixtures and pure enantiomers are considered as part of
the invention.
[0074] Without being limited to any one theory, one mechanism of
action can be that after a prolong exposure to nicotinic receptor
agonist nicotinic receptors become desensitized and the nicotinic
receptor agonists start working as nicotinic receptor antagonists.
In some embodiments, the nicotinic receptor agonists work as
antagonists to reduce or eliminate a side effect induced by a
dopaminergic agent.
[0075] In some embodiments, the disclosure provides a composition
for administration of nicotine to an animal. In some embodiments,
the disclosure provides a composition for administration of
nicotine to an animal to reduce a symptom of a neurodegenerative
disorder, e.g., for the oral delivery of nicotine, that contain at
least about 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99, 99.5,
99.9, or 99.99% nicotine. In some embodiments, the disclosure
provides a composition for administration of nicotine to an animal
to reduce a side effect of a dopaminergic agent, e.g., for the oral
delivery of nicotine, that contain at least about 1, 5, 10, 20, 30,
40, 50, 60, 70, 80, 90, 95, 99, 99.5, 99.9, or 99.99% nicotine. In
some embodiments, the disclosure provides a composition for the
oral delivery of nicotine that contains no more than about 2, 5,
10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99, 99.5, 99.9, 99.99, or
100% nicotine. In some embodiments, the disclosure provides a
composition that contains about 1-100% nicotine, or about 10-100%
nicotine, or about 20-100% nicotine, or about 50-100% nicotine, or
about 80%-100% nicotine, or about 90-100% nicotine, or about
95-100% nicotine, or about 99-100% nicotine. In some embodiments,
the disclosure provides a composition that contains about 1-90%
nicotine, or about 10-90% nicotine, or about 20-90% nicotine, or
about 50-90% nicotine, or about 80-90% nicotine. In some
embodiments, the disclosure provides a composition that contains
about 1-75% nicotine, or about 10-75% nicotine, or about 20-75%
nicotine, or about 50-75% nicotine. In some embodiments, the
disclosure provides a composition that contains about 1-50%
nicotine, or about 10-50% nicotine, or about 20-50% nicotine, or
about 30-50% nicotine, or about 40-50% nicotine. In some
embodiments, the disclosure provides a composition that contains
about 1-40% nicotine, or about 10-40% nicotine, or about 20-40%
nicotine, or about 30-40% nicotine. In some embodiments, the
disclosure provides a composition that contains about 1-30%
nicotine, or about 10-30% nicotine, or about 20-30% nicotine. In
some embodiments, the disclosure provides a composition that
contains about 1-20% nicotine, or about 10-20% nicotine. In some
embodiments, the disclosure provides a composition that contains
about 1-10% nicotine. In some embodiments, the disclosure provides
a composition that contains about 1, 2, 5, 10, 20, 30, 40, 50, 60,
70, 80, 90, 95, 96, 97, 98, or 99% nicotine.
[0076] In some embodiments, the a concentration of nicotine is less
than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%,
16%, 15%, 14%, 13%, 12%, 11%, 10%, 9, 8%, 7%, 6%, 5%, 4%, 3%, 2%,
1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%,
0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%,
0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%,
0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v or
v/v.
[0077] In some embodiments, a concentration of nicotine is greater
than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%
19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%,
16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%,
14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%,
12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%,
9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%,
7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%,
4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%,
1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%,
0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%,
0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%,
0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or
0.0001% w/w, w/v, or v/v.
[0078] In some embodiments, a concentration of nicotine is in the
range from approximately 0.0001% to approximately 50%,
approximately 0.001% to approximately 40%, approximately 0.01% to
approximately 30%, approximately 0.02% to approximately 29%,
approximately 0.03% to approximately 28%, approximately 0.04% to
approximately 27%, approximately 0.05% to approximately 26%,
approximately 0.06% to approximately 25%, approximately 0.07% to
approximately 24%, approximately 0.08% to approximately 23%,
approximately 0.09% to approximately 22%, approximately 0.1% to
approximately 21%, approximately 0.2% to approximately 20%,
approximately 0.3% to approximately 19%, approximately 0.4% to
approximately 18%, approximately 0.5% to approximately 17%,
approximately 0.6% to approximately 16%, approximately 0.7% to
approximately 15%, approximately 0.8% to approximately 14%,
approximately 0.9% to approximately 12%, approximately 1% to
approximately 10% w/w, w/v or v/v.
[0079] In some embodiments, a concentration of nicotine is in the
range from approximately 0.001% to approximately 10%, approximately
0.01% to approximately 5%, approximately 0.02% to approximately
4.5%, approximately 0.03% to approximately 4%, approximately 0.04%
to approximately 3.5%, approximately 0.05% to approximately 3%,
approximately 0.06% to approximately 2.5%, approximately 0.07% to
approximately 2%, approximately 0.08% to approximately 1.5%,
approximately 0.09% to approximately 1%, approximately 0.1% to
approximately 0.9% w/w, w/v or v/v.
[0080] In some embodiments, the amount of nicotine is equal to or
less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g,
6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5
g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6
g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15
g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g,
0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004
g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006
g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.
[0081] In some embodiments, the amount of nicotine is equal or
greater than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g,
0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g,
0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g,
0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g,
0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04
g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08
g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g,
0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g,
0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g,
4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g,
or 10 g.
Nicotinic Receptor Modulators
[0082] In some embodiments, the disclosure provides compositions
and methods utilizing a nicotinic receptor modulator, e.g., to
reduce or eliminate a side effect associated with dopaminergic
agent treatment. A nicotinic receptor modulator can be an agonist
or it can be an antagonist. Details of the disclosure are described
herein.
[0083] In one aspect, the term "agonist" as used herein refers to a
molecule having the ability to initiate or enhance a biological
function of a target polypeptide. Accordingly, the term "agonist"
is defined in the context of the biological role of the target
polypeptide. While preferred agonists herein specifically interact
with (e.g. bind to) the target, molecules that enhance a biological
activity of the target polypeptide by interacting with other
members of the signal transduction pathway of which the target
polypeptide is a member are also specifically included within this
definition. Agonists, as defined herein, without limitation,
include antibodies, antibody derivatives, antibody fragments and
immunoglobulin variants, peptides, peptidomimetics, simple or
complex organic or inorganic molecule, antisense molecules,
oligonucleotide decoys, proteins, oligonucleotide, vitamin
derivatives, carbohydrates, and toxins.
[0084] The term "antagonist" as used herein refers to a molecule
having the ability to inhibit a biological function of a target
polypeptide. Accordingly, the term "antagonist" is defined in the
context of the biological role of the target polypeptide. While
preferred antagonists herein specifically interact with (e.g. bind
to) the target, molecules that inhibit a biological activity of the
target polypeptide by interacting with other members of the signal
transduction pathway of which the target polypeptide is a member
are also specifically included within this definition. Antagonists,
as defined herein, without limitation, include antibodies, antibody
derivatives, antibody fragments and immunoglobulin variants,
peptides, peptidomimetics, simple or complex organic or inorganic
molecule, antisense molecules, oligonucleotide decoys, proteins,
oligonucleotide, vitamin derivatives, carbohydrates, and
toxins.
[0085] In some embodiments, the nicotinic receptor modulator
modulates a nicotinic receptor in the brain. In some embodiments,
the nicotinic receptor modulator modulates a nicotinic receptor in
the striatum or substantia niagra. In some embodiments, the
nicotinic receptor modulator modulates a nicotinic receptor
comprising at least one .alpha.subunit or a nicotinic receptor
containing at least one .alpha.subunit and at least one .beta.
subunit. In some embodiments, the .alpha.subunit is selected from
the group consisting of .alpha.2, .alpha.3, .alpha.4, .alpha.5,
.alpha.6, .alpha.7, .alpha.8, .alpha.9, and .alpha.10 and the
.beta. subunit is selected from the group consisting of .beta.2,
.beta.3 and .beta.4. In some embodiments, the nicotinic receptor
modulator modulates a nicotinic receptor comprising subunits
selected from the group consisting of .alpha.4.beta.2,
.alpha.6.beta.2, .alpha.4.alpha.6.beta.2,
.alpha.4.beta.3.beta.5.beta.2, .alpha.4.alpha.6.beta.2.beta.3,
.alpha.6.beta.2.beta.3 and .alpha.4.alpha.2.beta.2. In some
embodiments, the nicotinic receptor modulator modulates a nicotinic
receptor comprising at least one a subunit selected from the group
consisting of .alpha.4, .alpha.6, and .alpha.7.
[0086] The nicotinic receptor agonist of the disclosure may be any
ligand that binds to and activates the nicotinic receptor, thereby
resulting in a biological response. The potential of a given
substance to act as a nicotinic receptor agonist may be determined
using standard in vitro binding assays and/or standard in vivo
functionality tests.
[0087] Other nicotinic receptor agonists include choline esterase
inhibitors (e.g., that increase local concentration of
acetylcholine), derivatives of epibatidine that specifically bind
the neuronal type of nicotinic receptors (with reduced binding to
the muscarinic receptor) and having reduced deleterious
side-effects (e.g., Epidoxidine, ABT-154, ABT418, ABT-594; Abbott
Laboratories (Damaj et al. (1998) J. Pharmacol Exp. Then 284:1058
65, describing several analogs of epibatidine of equal potency but
with high specificity to the neuronal type of nicotinic receptors).
Further nicotinic receptor agonists of interest include, but are
not necessarily limited to, N-methylcarbamyl and
N-methylthi-O-carbamyl esters of choline (e.g.,
trimethylaminoethanol) (Abood et al. (1988) Pharmacol. Biochem.
Behay. 30:403 8); acetylcholine (an endogenous ligand for the
nicotinic receptor); and the like.
[0088] Multiple nicotinic acetylcholine receptors (nAChRs) exist
throughout the body. The nAChRs .alpha.1.beta.1, .alpha.3.beta.4
and .alpha.7 nAChRs are the major subtypes in the peripheral
nervous system and .alpha.4.beta.2, .alpha.6.beta.2 and .alpha.7
nAChRs the primary subtypes in the brain. Varenicline, which acts
at all nAChRs, as well as several .beta.2 selective drugs (A-85380,
sazetidine, TC-2696, TI-10165, TC-8831 and TC-10600) may reduce
LIDs. Similarly, other .beta.2 selective agonists such as ABT-089,
a partial .beta.2 nAChR agonist (Ki=17 nM) and the full .beta.2
agonist ABT-894 (Ki=0.3 nM) may decrease LIDs. AZD1446, a .beta.2
nAChR agonist of relatively low affinity (Ki=30 nM) may also reduce
LIDs, while full high affinity .beta.2 nAChR agonists may be more
effective. In addition, .alpha.7 nAChR agonist ABT-107 (Ki=0. 5 nM)
and AQW051 (Ki=27 nM) may also reduce LIDs and the greatest
reduction in LIDs may be associated with higher affinity
(.gtoreq.10 nM) full nAChR agonists such as ABT-894 and ABT-107.
Partial agonists or drugs with lower affinities (such as
varenicline, TC-8831, ABT-089, AZD1446, AQW051) may also be
efficacious. An important consideration is side effects and drugs
such as varenicline and TC-8831 are associated with nausea, and
thus may be less desirable.
The antidyskinetic effect of nicotine may be receptor-mediated via
both .beta.2 and .alpha.7 nAChRs and LIDs may be preferably reduced
with agonists to .beta.2 and .alpha.7 nAChRs. The .beta.2 and
.alpha.7 nAChRs are in some cases paired with other nAChR subunits.
The .beta.2 and .alpha.7 nAChRs agonists are selected from known
agonists, such as 3-Bromocytisine, Acetylcholine, Cytisine,
Epibatidine, A-84,543, A-366,833, ABT-418, Altinicline, Dianicline,
Ispronicline, Pozanicline, Rivanicline, Tebanicline, TC-1827,
Sazetidine A, N-(3-pyridinyl)-bridged bicyclic diamines,
(+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide,
A-582941, AR-R17779, Amyloid beta, TC-1698, TC-5619, EVP-6124,
GTS-21, PHA-543,613, PNU-282,987, PHA-709829, SSR-180,711,
Tropisetron, WAY-317,538, Anabasine, or ICH-3. The .beta.2 and
.alpha.7 nAChRs agonists are also new agonists developed to target
these receptors.
Dopaminergic Agents
[0089] In some embodiments, the disclosure provides compositions
and methods to reduce or eliminate the side effects of a
dopaminergic agent. In some embodiments, the compositions and
methods retain or enhance a desired effect of the dopaminergic
agent, e.g., antiparkinsonian effect. The methods and compositions
of the disclosure apply to any dopaminergic agent for which it is
desired to reduce one or more side effects. In some embodiments,
the compositions and methods of the disclosure utilize a dopamine
precursor. In some embodiments, the compositions and methods of the
disclosure utilize a dopamine agonist. Dopaminergic agents include
a dopamine precursor or a dopamine receptor agonist. Examples of
dopaminergic agents include levodopa, bromocriptine, pergolide,
pramipexole, cabergoline, ropinorole, apomorphine, carbidopa,
dopamine agonists, monoamine oxidase type B inhibitors, amantadine
or a combination thereof.
[0090] In some embodiments, the compositions and methods of the
disclosure utilize one or more agents used in the art in
combination with a dopamine agent treatment to achieve a
therapeutic effect. For instance, in one exemplary embodiment the
compositions and methods of the invention utilize levodopa in
combination with an agent such as carbidopa, which blocks the
conversion of levodopa to dopamine in the blood. In yet another
exemplary embodiment, the compositions and methods of the
disclosure utilize levodopa in combination with a dopaminergic
agonist. In yet another exemplary embodiment, the compositions and
methods of the disclosure utilize levodopa in combination with
monoamine oxidase type B (MAO-B) inhibitor such as selegiline. In
yet another exemplary embodiment, the compositions and methods of
the disclosure utilize levodopa in combination with amantadine. In
yet another exemplary embodiment, the compositions and methods of
the disclosure utilize levodopa in combination with a COMT
Inhibitor, such as entacapone.
Levodopa
[0091] Levodopa, an aromatic amino acid, is a white, crystalline
compound, slightly soluble in water, with a molecular weight of
197.2. It is designated L-3,4-dihydroxyphenylalanine or
(S)-2-amino-3-(3,4-dihydroxyphenyl) propanoic acid. Its structural
formula is:
##STR00002##
[0092] Levodopa is used for the treatment of Parkinson's disease.
Parkinson's disease is a progressive, neurodegenerative disorder of
the extrapyramidal nervous system affecting the mobility and
control of the skeletal muscular system. Its characteristic
features include resting tremor, rigidity, and bradykinetic
movements. Current evidence indicates that symptoms of Parkinson's
disease are related to depletion of dopamine in the corpus
striatum. Administration of dopamine is ineffective in the
treatment of Parkinson's disease apparently because it does not
cross the blood-brain barrier. However, levodopa, the metabolic
precursor of dopamine, does cross the blood brain barrier, and
presumably is converted to dopamine in the brain. This is thought
to be the mechanism whereby levodopa relieves symptoms of
Parkinson's disease.
[0093] However, although initially very effective, long term
treatment with levodopa gives rise to multiple complications.
Levodopa treatment may cause nausea, vomiting, involuntary
movements (e.g. dyskinesias), mental disturbances, depression,
syncope, and hallucinations. The precise pathophysiological
mechanisms of levodopa side effects are still enigmatic, but are
thought to be due to increased brain dopamine following
administration of levodopa. Previous work has shown that levodopa
induced dyskinesias (LIDs) arise due to enhanced intermittent
stimulation of D1, D2 and/or other dopamine receptor subtypes. This
results in an imbalance in activity of the two major striatal
output pathways, possibly through activation of D1 and inhibition
of D2 receptors on the direct and indirect dopaminergic pathways,
respectively, although there is some overlap between striatal
efferents. Recent data suggest that D1 receptors, through enhanced
G-protein coupling, may play a more prominent role in functional
hypersensitivity associated with levodopa-induced dyskinesias,
while D2 receptor activation may be more closely linked to the
anti-parkinsonian action of dopaminergic drugs.
Carbidopa
[0094] Carbidopa is a white, crystalline compound, slightly soluble
in water, with a molecular weight of 244.3. It is designated
chemically as
(-)-L-.alpha.-hydrazino-.alpha.-methyl-.beta.-(3,4-dihydroxybenzene)
propanoic acid monohydrate. Its structural formula is:
##STR00003##
[0095] Carbidopa is a drug given to people with Parkinson's disease
and is used in tandem with levodopa. Administration of carbidopa
with levodopa can increase the plasma half-life of levodopa from 50
minutes to 11/2 hours. Carbidopa typically does not cross the blood
brain barrier and can inhibit peripheral aromatic-L-amino acid
decarboxylase (DOPA Decarboxylase or DDC). Without being bound by
any theory, carbidopa can inhibit peripheral metabolism of
levodopa, prevents the conversion of levodopa to dopamine
peripherally, and allow a greater proportion of peripheral levodopa
to cross the blood brain barrier for central nervous effect,
thereby reducing the side effects caused by dopamine on the
periphery, as well as increasing the concentration of levodopa and
dopamine in the brain.
[0096] Carbidopa is commonly used to inhibit the activity of
dopamine decarboxylase, an enzyme known to break down levodopa in
the periphery and converts it to dopamine. This can results in the
newly formed dopamine being unable to cross the blood brain barrier
and the effectiveness of levodopa treatments is greatly decreased.
Carbidopa can reduce the amount of levodopa required to produce a
given response by about 75% and, when administered with levodopa,
increases both plasma levels and the plasma half-life of levodopa,
and decreases plasma and urinary dopamine and homovanillic acid.
Carbidopa can also eliminate the half-life of levodopa by about 1.5
hours.
[0097] In some cases, carbidopa and levodopa are administered in a
combined composition. Examples commercially available medicament of
the combination of carbidopa/levodopa includes the brand names of
Kinson, Sinemet, Parcopa and Atamet, while Stalevo further
comprises entacapone, which enhances the bioavailability of
carbidopa and levodopa.
Dopamine Agonist
[0098] A dopamine agonist is a compound that activates dopamine
receptors in the absence of that receptor's physiological ligand,
the neurotransmitter dopamine. Dopamine agonists can treat
hypodopaminergic (low dopamine) conditions; they are typically used
for treating Parkinson's disease, attention deficit/hyperactivity
disorder (in the form of stimulants) and certain pituitary tumors
(prolactinoma), and may be useful for restless legs syndrome (RLS).
Both Requip (Ropinirole) and Mirapex (Pramipexole) are FDA-approved
for the treatment of RLS. There is also an ongoing clinical trial
to test the effectiveness of the dopamine agonist Requip
(ropinirole) in reversing the symptoms of SSRI-induced sexual
dysfunction and Post-SSRI sexual dysfunction (PSSD).
[0099] Some drugs can act as dopamine agonist. Typically, there are
two classes of commercially available dopamine agonists, partial
agonist and agonist of full/unknown efficacy. Examples of partial
agonist include, but not limited to, Aripiprazole, Quinpirole, and
Salvinorin. Examples of agonist of full/unknown efficacy include,
but not limited to, apomorphine, bromocriptine, cabergoline,
ciladopa, dihydrexidine, dinapsoline, doxanthrine, epicriptine,
lisuride, pergolide, piribedil, pramipexole, propylnorapomorphine,
quinagolide, ropinirole, rotigotine, roxindole, sumanirole, and
fenoldopam.
Amantadine
[0100] Amantadine, commercially known as Symmetrel (Endo
Pharmaceuticals) is a drug that has the Food and Drug
Administration of the United States approval for use both as an
antiviral and an antiparkinsonian drug. It is the organic compound
1-adamantylamine or 1-aminoadamantane, meaning it consists of an
adamantane backbone that has an amino group substituted at one of
the four methyne positions. Its structural formula is:
##STR00004##
[0101] Rimantadine is a closely related derivative of adamantane
with similar biological properties.
[0102] Amantadine is a weak antagonist of the NMDA-type glutamate
receptor. It can increase dopamine release, block dopamine
reuptake, and can be a therapy for Parkinson's disease. Although,
as an anti-parkinsonian, it can be used as monotherapy, or together
with levodopa to treat levodopa-related motor fluctuations such as
shortening of levodopa duration of clinical effect, and
levodopa-related dyskinesias.
Monoamine Oxidase B Inhibitor
[0103] Monoamine oxidase inhibitors (MAOIs) are chemicals which
inhibit the activity of the monoamine oxidase enzyme family. MAOIs
can prevent the breakdown of monoamine neurotransmitters and can
increase their availability. MAOIs have a long history of use as
medications prescribed for the treatment of depression,
particularly atypical depression, Parkinson's disease and several
other disorders.
[0104] MAOIs such as selegiline is typically used in the treatment
of Parkinson's disease. MAOIs can also be used in the treatment of
Parkinson's disease by targeting MAO-B in particular and affecting
dopaminergic neurons, as well as providing an alternative for
migraine prophylaxis.
[0105] Inhibition of both MAO-A and MAO-B is also used in the
treatment of clinical depression and anxiety. MAOIs appear to be
particularly indicated for outpatients with "neurotic depression"
complicated by panic disorder or hysteroid dysphoria, which
involves repeated episodes of depressed mood in response to feeling
rejected.
[0106] MAOIs have also been found to be effective in the treatment
of panic disorder with agoraphobia, social phobia, atypical
depression or mixed anxiety and depression, bulimia, and
post-traumatic stress disorder, as well as borderline personality
disorder. MAOIs appear to be particularly effective in the
management of bipolar depression according to a recent
retrospective-analysis. In some cases, MAOI may be effective in the
treatment of obsessive-compulsive disorder (OCD), trichotillomania,
dysmorphophobia, and avoidant personality disorder.
[0107] Without being limited to any theory, MAOIs act by inhibiting
the activity of monoamine oxidase, thus preventing the breakdown of
monoamine neurotransmitters and thereby increasing their
availability. There are two isoforms of monoamine oxidase, MAO-A
and MAO-B. MAO-A preferentially deaminates serotonin, melatonin,
epinephrine, and norepinephrine. MAO-B preferentially deaminates
phenylethylamine and trace amines. Dopamine is equally deaminated
by both types.
Side Effects
[0108] The principal adverse reactions of dopaminergic agent
include headache, diarrhea, hypertension, nausea, vomiting,
involuntary movements (e.g. dyskinesias), mental disturbances,
depression, syncope, hallucinations, and abnormal renal
function.
[0109] The disclosure provides compositions and methods utilizing
nicotine or a salt thereof, or a nicotinic receptor modulator that
reduces or eliminates a side effect associated with dopaminergic
agent treatment. In some embodiments, the disclosure provides
compositions and methods utilizing a nicotinic receptor modulator
that reduces or eliminates dyskinesias associated with dopaminergic
agent treatment. Without being limited to any theory, one
possibility is that nicotinic receptor modulator exerts its effect
by acting at nicotinic acetylcholine receptors (nAChR), which are
expressed in the striatum. There is a dense cholinergic innervation
in striatum that closely coincides with dopaminergic neurons. Under
physiological conditions, these cholinergic interneurons tonically
release acetylcholine, which stimulates nicotinic receptors on
dopaminergic nerve terminals to release dopamine. Similarly,
exogenously applied agents such as nicotine result in a release of
dopamine from striatal terminals
Methods of Treatment
[0110] In one aspect, the present disclosure provides for a method
of treating fall-related symptoms in a subject with
neurodegenerative disease comprising administering nicotine or a
salt thereof to the subject. In some embodiments, the nicotine and
salt thereof is administered in dosage form. The administration of
nicotine or a salt thereof can reduce frequency of fall, reduce
frequency of injuries related to fall, and/or reduce severity of
injuries related to fall in a subject with neurodegenerative
diseases, e.g. Parkinson's disease or Parkinson's-related diseases.
In some embodiments, the subject has typical Parkinson's disease.
In some embodiments, the subject has Parkinson's disease but does
not suffer from LIDs. In some embodiments, the subject is diagnosed
for Parkinson's disease for at least 5 years. In some embodiments,
the subject is on dopaminergic agent treatment. In some
embodiments, the subject has fallen or recurrent falls in past
year. In some embodiments, the method does not result in tolerance
or dependence on the nicotine or salt thereof.
[0111] Described herein are methods of administration of a nicotine
dosage form, wherein said administration can result in a
pharmacokinetic profile having plasma nicotine levels below about
7.5 ng/ml at a time point about 120 minutes after administration of
said dosage form. The administration of said dosage form can result
in a pharmacokinetic profile having plasma nicotine levels below
about 7.5 ng/ml at a time point about 180 minutes after
administration of said dosage form. The pharmacokinetic profile can
have plasma nicotine levels below about 5 ng/ml at about 180
minutes after administration. The pharmacokinetic profile can have
plasma nicotine levels below about 5 ng/ml at about 120 minutes
after administration. The pharmacokinetic profile can have plasma
nicotine levels above about 5 ng/ml at about 45 to 90 minutes after
administration. The pharmacokinetic profile can have plasma
nicotine levels above about 15 ng/ml at about 60 minutes after
administration.
[0112] Described herein are methods of treating fall-related
symptoms in a subject with neurodegenerative disease, the methods
may comprise administering to the subject a dosage form comprising
nicotine or a salt thereof. The fall-related symptoms may comprise
fall frequency. A subject treated with the dosage form comprising
nicotine may have a reduced fall frequency. The fall-related
symptoms may be related to freezing of gait (FOG). The fall-related
symptoms may be related to levodopa-induced dyskinesias (LIDs). The
fall-related symptoms may not be related to levodopa-induced
dyskinesias (LIDs). A subject treated with the dosage form
comprising nicotine or a salt thereof can have reduced fall
frequency, reduced freezing of gait (FOG), reduced levodopa-induced
dyskinesias (LIDs), improved postural stability, or combinations
thereof. Falls may be prevented in a subject treated with the
dosage form comprising nicotine or salt thereof. Fall-related
complications may be reduced. A subject treated with the dosage
form comprising nicotine can have reduced fall frequency, reduced
freezing of gait (FOG), and reduced levodopa-induced dyskinesias
(LIDs). The reduced fall frequency may be a reduction by at least
10%. The reduced fall frequency may be a reduction by at least or
about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%,
90%, or more than 90%. The reduced freezing of gait (FOG) can be a
reduction by at least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, 50%, 60%, 70%, 80%, 90%, or more than 90%. The reduced
freezing of gait (FOG) can be a reduction by at least 10%. The
reduced freezing of gait (FOG) can be a reduction by at least or
about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%,
90%, or more than 90%. The reduced levodopa-induced dyskinesias
(LIDs) may be a reduction by at least 10%. The reduced
levodopa-induced dyskinesias (LIDs) may be a reduction by at least
or about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%,
80%, 90%, or more than 90%. The improved postural stability may be
an improvement by at least 10%. The improved postural stability may
be an improvement by at least or about 10%, 15%, 20%, 25%, 30%,
35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more than 90%. The
subject may have at least a 0.5-fold reduction in fall frequency.
The subject may have at least or about a 0.5, 1.0, 1.5, 2.0, 2.5,
3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, or more than 8.0-fold
reduction in fall frequency. The subject may have at least a
0.5-fold reduction in freezing of gait (FOG). The subject may have
at least or about a 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5,
5.0, 6.0, 7.0, 8.0, or more than 8.0-fold reduction in freezing of
gait (FOG). The subject may have at least a 0.5-fold reduction in
levodopa-induced dyskinesias (LIDs). The subject may have at least
or about a 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0,
7.0, 8.0, or more than 8.0-fold reduction in levodopa-induced
dyskinesias (LIDs). The subject may have at least a 0.5-fold
improvement in postural stability. The subject may have at least or
about a 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0,
8.0, or more than 8.0-fold improvement in postural stability.
[0113] Reduction in fall frequency, reduction in freezing of gait
(FOG), reduction in levodopa-induced dyskinesias (LIDs),
improvements in postural stability, or combinations thereof may be
compared to a control. Falls may be prevented in a subject compared
to a control treated with the dosage form comprising nicotine or
salt thereof. Fall-related complications may be reduced in a
subject compared to a control treated with the dosage form
comprising nicotine or salt thereof. The control may be a subject
at baseline or a subject administered placebo. In some instances,
the control has idiopathic Parkinson's disease. The control may
have LIDs. The control may be in a peak "on" state of levodopa.
[0114] The nicotine or a salt thereof may not change dopaminergic
activity. The nicotine or a salt thereof may increase cholinergic
activity. The fall-related symptoms can comprise frequency of
injuries related to fall. A subject treated with the dosage form
comprising nicotine can have reduced frequency of injuries related
to fall. The fall-related symptoms may comprise severity of fall
with injuries. A subject treated with the dosage form comprising
nicotine may have reduced severity of fall with injuries. The
subject may have recurrent falls. The subject may have fallen at
least once in past year. The improvement of symptoms can comprise
utilizing one or more of evaluation tests selected from the group
consisting of: Unified Parkinson's Disease Rating Scale (UPDRS),
Barrow Neurological Institute (BNI) Falls Evaluation, Hoehn &
Yahr Staging System, Romberg test, turning test, standing on one
leg, tandem gait, step length and velocity. The evaluation
utilizing the Unified Parkinson's Disease Rating Scale (UPDRS) can
be selected from the group consisting of: Walking and Balance from
questions 2.12 from Movement Disorder Society Unified Parkinson's
Disease Rating Scale (MDS UPDRS), Freezing of Gait from questions
2.14 from Movement Disorder Society Unified Parkinson's Disease
Rating Scale (MDS UPDRS), Dyskinesias from questions 32-35 from
original Unified Parkinson's Disease Rating Scale (UPDRS), Response
Fluctuation from questions 36-39 from original Unified Parkinson's
Disease Rating Scale (UPDRS), Sleep Disturbance from question 40
from original Unified Parkinson's Disease Rating Scale (UPDRS),
Movement Disorder Society Unified Parkinson's Disease Rating Scale
(MDS UPDRS) 142 points, Axial, Midline part of Movement Disorder
Society Unified Parkinson's Disease Rating Scale (MDS UPDRS), Gait
Subtest from Movement Disorder Society Unified Parkinson's Disease
Rating Scale (MDS UPDRS, Postural Stability Subtest from Movement
Disorder Society Unified Parkinson's Disease Rating Scale (MDS
UPDRS), and Freezing of Gait Subtest (FOG) from Movement Disorder
Society Unified Parkinson's Disease Rating Scale (MDS UPDRS). The
evaluation may comprise Falling Unrelated to Freezing from question
13 from UPDRS Part II (Activities of Daily Life (ADL)), Freezing
When Walking from question 14 from UPDRS Part II(ADL), ambulation
subset from Unified Dyskinesia Rating Scale (UDysRS), or
combinations thereof. The evaluation may comprise Falling Unrelated
to Freezing from question 13 from UPDRS Part II (Activities of
Daily Life (ADL)), Freezing When Walking from question 14 from
UPDRS Part II (ADL), and ambulation subset from Unified Dyskinesia
Rating Scale (UDysRS). The improvement of symptoms may comprise
evaluation utilizing Reason for Fall from the Barrow Neurological
Institute (BNI) Falls Evaluation. The improvement of symptoms can
comprise evaluation utilizing Severity of Fall from the Barrow
Neurological Institute (BNI) Falls Evaluation. Evaluation of a
subject may include laboratory tests, analysis of concomitant
medications, physical examinations, mental evaluations, physical
evaluations, electrocardiograms (ECGs), vital signs, assessments of
impulse control, nicotine withdrawal symptoms, changes in disease
symptoms, Mini Mental State Examination, examinations using the Jay
Midi Scale, UDysRS, Hoehn and Yahr scale, Clinical Global
impression scale, Patient global impression scale, Lang-Fahn daily
activity scale, and Minnesota Nicotine Withdrawal Scale-Revised
(MNWS-R). Laboratory tests include, but are not limited to, urine
analysis, serum cotinine analysis, urine cotinine analysis, serum
nicotine analysis, hematology, chemistry, and pregnancy.
[0115] In various embodiments, the present disclosure provides for
a method of treating fall-related symptoms in a subject with
neurodegenerative disease comprising administering a composition
comprising a nicotinic receptor modulator to the subject. In some
embodiments, the composition is administered in dosage form. In
some embodiments, the nicotinic receptor modulator is a nicotinic
receptor agonist or antagonist. The administration of the
composition can reduce frequency of fall, reduce frequency of
injuries related to fall, and/or reduce severity of injuries
related to fall in a subject with neurodegenerative diseases, e.g.
Parkinson's disease or Parkinson's-related diseases. In some
embodiments, the subject has typical Parkinson's disease. In some
embodiments, the subject does not have LIDs.
[0116] In some embodiments, the present disclosure utilizes a
nicotinic receptor agonist, such as nicotine or a salt thereof for
treatment of fall-related symptoms in a subject with
neurodegenerative diseases. The method comprises administering
nicotine or a salt thereof to a subject in need thereof. The method
may not result in tolerance or dependence on the nicotine or salt
thereof. In some embodiments, the subject has Parkinson's disease
or Parkinson's-related diseases. In some embodiments, the subject
has fallen and recurrent falls in past year. In some embodiments,
the subject has fallen at least 1 time, 2 times, 3 times, 4 times,
5 times, 6 times, or more in past year.
[0117] Described herein are methods of treating posture
instability, static balance, locomotor disability and gait in a
subject with neurodegenerative disease, the methods can comprise
administering to the subject a dosage form comprising nicotine or a
salt thereof. A subject treated with the dosage form comprising
nicotine can have improved posture stability. A subject treated
with the dosage form comprising nicotine can have improved static
balance. A subject treated with the dosage form comprising nicotine
can have improved locomotor ability. A subject treated with the
dosage form comprising nicotine can have improved gait. Improvement
of symptoms may comprise utilizing one or more of evaluation tests
selected from the group consisting of Unified Parkinson's Disease
Rating Scale (UPDRS), BNI Falls Evaluation, Hoehn & Yahr
Staging System, Romberg test, turning test, standing on one leg,
tandem gait, step length and velocity. The evaluation utilizing the
Unified Parkinson's Disease Rating Scale (UPDRS) can be selected
from the group consisting of: Walking and Balance from questions
2.12 from Movement Disorder Society Unified Parkinson's Disease
Rating Scale (MDS UPDRS), Freezing of Gait from questions 2.14 from
Movement Disorder Society Unified Parkinson's Disease Rating Scale
(MDS UPDRS), Dyskinesias from questions 32-35 from original Unified
Parkinson's Disease Rating Scale (UPDRS), Response Fluctuation from
questions 36-39 from original Unified Parkinson's Disease Rating
Scale (UPDRS), Sleep Disturbance from question 40 from original
Unified Parkinson's Disease Rating Scale (UPDRS), Movement Disorder
Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) 142
points, Axial, Midline part of Movement Disorder Society Unified
Parkinson's Disease Rating Scale (MDS UPDRS), Gait Subtest from
Movement Disorder Society Unified Parkinson's Disease Rating Scale
(MDS UPDRS, Postural Stability Subtest from Movement Disorder
Society Unified Parkinson's Disease Rating Scale (MDS UPDRS), and
Freezing of Gait Subtest (FOG) from Movement Disorder Society
Unified Parkinson's Disease Rating Scale (MDS UPDRS). The
evaluation may comprise Falling Unrelated to Freezing from question
13 from UPDRS Part II (Activities of Daily Life (ADL)), Freezing
When Walking from question 14 from UPDRS Part II(ADL), ambulation
subset from Unified Dyskinesia Rating Scale (UDysRS), or
combinations thereof. The evaluation may comprise Falling Unrelated
to Freezing from question 13 from UPDRS Part II (Activities of
Daily Life (ADL)), Freezing When Walking from question 14 from
UPDRS Part II (ADL), and ambulation subset from Unified Dyskinesia
Rating Scale (UDysRS). The subject may have Parkinson's disease.
The subject may have typical Parkinson's disease. The subject may
have Parkinson's disease for at least five years. The subject may
have Parkinson's disease for at least four years. The subject may
have Parkinson's disease for at least three years. The subject may
have Parkinson's disease for at least two years. The subject may
have Parkinson's disease for at least one year. The subject may
have dopaminergic agent treatment. The dopaminergic agent may be
levodopa, carbidopa, dopamine agonist, amantadine, monoamine
oxidase B inhibitor, or combination thereof. The subject may be
evaluated in: an "off" period, wherein the subject may be about 16
hours off dopaminergic agent treatment; The "off" period may about
2, 4, 6, 8, 10, 12, 14, 16, 18, or 24 hours. During the "on" period
the subject may be about 1 hour after usual morning dose of
dopaminergic agent treatment; wherein the dopaminergic treatment
may be levodopa, carbidopa, dopamine agonist, amantadine, monoamine
oxidase B inhibitor, or combination thereof. The "on" period may
about 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, or 24 hours. The
"off" period may be at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30,
35, 40, 45, 50, 55, 60, 65, 70, 75, or more than 75 hours. The
"off" period may be at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45,
50, 55, 60, 65, 70, or 75 hours. The "on" period may be at least or
about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70,
75, or more than 75 hours. The "on" period may be at most 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,
22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 hours.
The subject can have Montreal Cognitive Assessment (MOCA) score of
at least 26. The subject can have Montreal Cognitive Assessment
(MOCA) score of at least or about 20, 25, 30, 35, 40, or more than
40. The subject can be excluded with disorders selected in the
group consisting of: atypical Parkinson, Progressive Supranuclear
Palsy (PSP), Multiple System Atrophy (MSA), Primary Freezing of
Gait (PFG), Corticobasiler Degeneration, dementia with Montreal
Cognitive Assessment (MOCA) score of less than 21, legally blind,
orthopedic problems in hips or knees, hips or knees replacements,
orthostatic hypotension, schizophrenia, schizo-affective disorder,
bipolar disorder, hallucinations, psychoses, delusions, deep brain
stimulation (DBS) intervention, history of recent stroke, and
history of myocardial infarction. The dosage form may comprise a
nicotinic receptor agonist. The dosage form may comprise at least 1
mg to 6 mg of nicotine or a salt thereof for a period of 6 months,
wherein the dosage form may be escalated upward at treatment
intervals. The dosage form may comprise at least or about 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, or more than 12 mg of nicotine or a
salt thereof. The dosage form may comprise about 2, 4, 6, 12, 18,
or 24 mg of nicotine or a salt thereof. The period may be at least
or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more than 12
months. The dosage form may comprise nicotine or a salt thereof may
be escalated upward at two weeks treatment intervals. The dosage
form may comprise nicotine or a salt thereof may be escalated
upward at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more than 12
weeks treatment intervals. The dosage form may be administered for
more than 12 weeks. The dosage form may be administered for 1 week,
2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months,
6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1
year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8
years, or more than 8 years. The dosage form may be used for
chronic treatment. The dosage form may comprise nicotine or a salt
thereof comprises: at least 1 mg every 6 hours; at least 2 mg every
6 hours; at least 4 mg every 6 hours; at least 6 mg every 6 hours;
wherein the dose may be escalated at two weeks treatment intervals;
and wherein the dose may be maintained at 6 mg every 6 hours until
completion of the treatment period of 6 months. The nicotine or a
salt thereof can be administered in an amount less than 24 mg in a
period of 24 hours. The nicotine or a salt thereof can be
administered in an amount of at least or about 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,
25, 30, 35, 40, 45, 50, 55, 60, or more than 60 mg. The nicotine or
a salt thereof may be administered in an amount of about 2, 4, 6,
8, 10, 12, 18, or 24 mg. The nicotine or a salt thereof can be
administered in a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45,
50, 55, 60, or more than 60 hours. The nicotine or a salt thereof
can be administered at least 4 times in a period of 24 hours. The
nicotine or a salt thereof can be administered at least 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more
than 20 times. The nicotine or a salt thereof can be administered
about every 6 hours in a period of 24 hours. The nicotine or a salt
thereof can be administered about every 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 hours in
a period of 24 hours. The treatment period may be more than 12
weeks. The treatment period may be 1 week, 2 weeks, 3 weeks, 1
month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months,
8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years,
4 years, 5 years, 6 years, 7 years, 8 years, or more than 8 years.
The treatment may be a chronic treatment. The therapeutic
effectiveness of the administration can evaluated regularly for a
period of at least 2 to 14 months. The therapeutic effectiveness of
the administration can be evaluated regularly for a period of at
least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, or more
than 60 months. The therapeutic effectiveness of the administration
can be evaluated regularly for a period of at least 6 months. The
evaluation can be performed every 2 months. The evaluation can be
performed every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more than
12 months. Evaluation may include laboratory tests, analysis of
concomitant medications, physical examinations, mental evaluations,
physical evaluations, electrocardiograms (ECGs), vital signs,
assessments of impulse control, nicotine withdrawal symptoms,
changes in disease symptoms, Mini Mental State Examination,
examinations using the Jay Midi Scale, UDysRS, Hoehn and Yahr
scale, Clinical Global impression scale, Patient global impression
scale, Lang-Fahn daily activity scale, and Minnesota Nicotine
Withdrawal Scale-Revised (MNWS-R). Laboratory tests include, but
are not limited to, urine analysis, serum cotinine analysis, urine
cotinine analysis, serum nicotine analysis, hematology, chemistry,
and pregnancy. The dosage form may be formulated for oral,
intravenous, intraarterial, parenteral, buccal, topical,
transdermal, rectal, intramuscular, subcutaneous, intraosseous,
transmucosal, or intraperitoneal administration. The dosage form
may be formulated for oral administration. The dosage form may be
formulated as a unit dosage. The composition may be formulated as a
unit dosage in liquid, gel, semi-liquid, semi-solid, or solid form.
The dosage form may be formulated in a tablet. The dosage form may
be formulated in a capsule. The unit dosage may be formulated as a
food. The unit dosage may be formulated as a beverage. The unit
dosage may be formulated as a dietary supplement. The
administration of said dosage form may result in a pharmacokinetic
profile having plasma nicotine levels below about 7.5 ng/ml at a
time point about 120 minutes after administration of said dosage
form. The administration of said dosage form may result in a
pharmacokinetic profile having plasma nicotine levels below about
7.5 ng/ml at a time point about 180 minutes after administration of
said dosage form. The pharmacokinetic profile may have plasma
nicotine levels below about 5 ng/ml at about 180 minutes after
administration. The pharmacokinetic profile may have plasma
nicotine levels below about 5 ng/ml at about 120 minutes after
administration. The pharmacokinetic profile may have plasma
nicotine levels above about 5 ng/ml at about 45 to 90 minutes after
administration. The pharmacokinetic profile may have plasma
nicotine levels above about 15 ng/ml at about 60 minutes after
administration. Administration of said dosage of nicotine or salt
thereof may not result in tolerance or dependence on the nicotine
or salt thereof.
[0118] In some embodiments, the present disclosure utilizes a
nicotinic receptor agonist, such as nicotine or a salt thereof for
treatment of fall-related symptoms in a subject with
neurodegenerative diseases. The method may comprise administering
nicotine or a salt thereof to a subject in need thereof. In some
embodiments, the subject has Parkinson's disease or
Parkinson's-related diseases. In some embodiments, the subject has
Parkinson's disease but does not have LIDs. In some embodiments,
the subject has increased frequency of fall in past year compared
to the year before. In some embodiments, the frequency of fall is
increased by at least 1 time, 2 times, 3 times, 4 times, 5 times, 6
times, 7 times, 8 times, 9 times, 10 times, 20 times, 50 times, 100
times, 1000 times or more in past year. In some embodiments, the
frequency of fall is increased between about 1 to 1000 times in
past year.
[0119] In some embodiments, the present disclosure utilizes a
nicotinic receptor agonist, such as nicotine or a salt thereof for
treatment of fall-related symptoms in a subject with
neurodegenerative diseases. The method may comprise administering
nicotine or a salt thereof to a subject in need thereof. In some
embodiments, the subject has Parkinson's disease or
Parkinson's-related diseases. In some embodiments, the subject has
Parkinson's disease but does not have LIDs. In some embodiments,
present disclosure provides a method for reducing frequency of fall
in subject with neurodegenerative disease. In some embodiments, the
frequency of fall is reduced by at least 1 time, 2 times, 3 times,
4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 20
times, 50 times, 100 times, 1000 times or more in past year. In
some embodiments, the frequency of fall is increased between about
1 to 1000 times in past year.
[0120] In some embodiments, the present disclosure utilizes a
nicotinic receptor agonist, such as nicotine or a salt thereof for
treatment of fall-related symptoms in a subject with
neurodegenerative diseases. The method may comprise administering
nicotine or a salt thereof to a subject in need thereof. In some
embodiments, the subject has increased frequency of injuries
related to fall in past year compared to the year before. The
frequency of injuries related to fall is by at least 1 to 1000
times. In some embodiments, the frequency of injuries related to
fall is increased between about 1 to 1000 times in past year.
[0121] In some embodiments, the present disclosure utilizes a
nicotinic receptor agonist, such as nicotine or a salt thereof for
treatment of fall-related symptoms in a subject with
neurodegenerative diseases. The method may comprise administering
nicotine or a salt thereof to a subject in need thereof. In some
embodiments, the present disclosure provides a method for reducing
the frequency of injuries related to fall. In some embodiments, the
frequency of injuries related to fall is reduced by at least 1 to
1000 times. In some embodiments, the frequency of injuries related
to fall is increased between about 1 to 1000 times in past
year.
[0122] In some embodiments, the present disclosure utilizes a
nicotinic receptor agonist, such as nicotine or a salt thereof for
treatment of fall-related symptoms in a subject with
neurodegenerative diseases. The method may comprise administering
nicotine or a salt thereof to a subject in need thereof. In some
embodiments, the subject has increased severity of injuries related
to fall in past year compared to the year before. In some
embodiments, the severity of injuries related to fall is increased
by at least 1 to 1000 times. In some embodiments, the severity of
injuries related to fall is increased between about 1 to 1000 times
in past year.
[0123] In some embodiments, the present disclosure utilizes a
nicotinic receptor agonist, such as nicotine or a salt thereof for
treatment of fall-related symptoms in a subject with
neurodegenerative diseases. The method may comprise administering
nicotine or a salt thereof to a subject in need thereof. In some
embodiments, the present disclosure provides a method for reducing
the severity of injuries related to fall. In some embodiments, the
severity of injuries related to fall is reduced by at least 1 time,
2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9
times, 10 times, 20 times, 50 times, 100 times, 1000 times or more
in past year. In some embodiments, the severity of injuries related
to fall is increased between about 1 to 1000 times in past
year.
[0124] In various embodiments, the present disclosure provides for
a method of predicting recurrent falls in in a subject with
neurodegenerative disease comprising administering nicotine or a
salt thereof to the subject. In some embodiments, the nicotine and
salt thereof is administered in dosage form. The administration of
nicotine or a salt thereof can reduce frequency of fall, reduce
frequency of injuries related to fall, and/or reduce severity of
injuries related to fall in a subject with neurodegenerative
diseases, e.g. Parkinson's disease or Parkinson's-related diseases.
In some embodiments, the subject has typical Parkinson's disease.
In some embodiments, the subject is diagnosed for Parkinson's
disease for at least 5 years. In some embodiments, the subject is
on dopaminergic agent treatment. In some embodiments, the subject
has fallen at least once and/or has recurrent falls in past
year.
[0125] In some embodiments, the present disclosure provides for a
method of treating fall-related symptoms in a subject with
Parkinson's disease or Parkinson's-related diseases comprising
administering nicotine or a salt thereof to the subject. The
administration of nicotine or a salt thereof may prevent falls. The
administration of nicotine or a salt thereof may reduce
complications associated with falls. The administration of nicotine
or a salt thereof can reduce frequency of fall, reduce frequency of
injuries related to fall, and/or reduce severity of injuries
related to fall in the subject. In some embodiments, the subject is
on dopaminergic agent treatment. Non limiting examples of
dopaminergic agents includes levodopa, bromocriptine, pergolide,
pramipexole, cabergoline, ropinorole, apomorphine, carbidopa,
dopamine agonists, monoamine oxidase type B inhibitors, amantadine
or a combination thereof. In some embodiments, the subject is on
levodopa, carbidopa, dopamine agonist, amantadine, monoamine
oxidase B inhibitor, or combination thereof.
[0126] In various embodiments, disclosed herein are methods and
compositions for reducing fall-related symptoms in a subject with
Parkinson's disease or Parkinson-related disease and is on
dopaminergic agent treatment, e.g. levodopa/carbidopa, the methods
and compositions comprising administering nicotine or a salt
thereof to the subject. In some embodiments, the subject has fallen
at least or has recurrent falls in past year. The administration of
nicotine or a salt thereof in combination with a dopaminergic agent
can reduce fall-related symptoms, e.g. frequency of fall, frequency
of injuries related to fall, severity of injuries related to fall.
In various embodiments, utilization of the disclosed methods and
compositions reduces side effects related to dopaminergic agent
treatment, for example, reducing dyskinesia and improving response
fluctuations: "wearing off and of off".
[0127] In one aspect, the present disclosure provides for a method
of improving posture stability and gait in a subject with
neurodegenerative disease comprising administering nicotine or a
salt thereof to the subject. In some embodiments, the nicotine and
salt thereof is administered in dosage form. In some embodiments,
administration of nicotine or a salt thereof improves posture
stability, static balance, locomotor ability, and/or gait in a
subject with neurodegenerative diseases, e.g. Parkinson's disease
or Parkinson's-related diseases. In some embodiments, the subject
has typical Parkinson's disease. In some embodiments, the subject
is diagnosed for Parkinson's disease for at least 5 years. In some
embodiments, the subject is on dopaminergic agent treatment. In
some embodiments, the subject has fallen or recurrent falls in past
year.
[0128] In some embodiments, the present disclosure provides for a
method of improving posture stability and gait in a subject with
neurodegenerative disease comprising administering a nicotinic
receptor modulator to the subject. In some embodiments, the
nicotinic receptor modulator is administered in dosage form. In
various embodiments, the nicotinic receptor modulator is a
nicotinic receptor agonist. In various embodiments, the nicotinic
receptor modulator is a nicotinic receptor antagonist. In some
embodiments, administration of the nicotinic receptor modulator
improves posture stability, static balance, locomotor ability,
and/or gait in a subject with neurodegenerative diseases, such as
Parkinson's disease or Parkinson's-related diseases. In some
embodiments, the subject has typical Parkinson's disease. In some
embodiments, the subject is diagnosed for Parkinson's disease for
at least 5 years. In some embodiments, the subject has fallen at
least once or has recurrent falls in past year.
[0129] In some embodiments, the present disclosure provides for a
method of improving posture stability in a subject with
neurodegenerative disease comprising administering nicotine or a
salt thereof to the subject. In some embodiments, the nicotinic
receptor agonist is administered in dosage form. In some
embodiments, administration of nicotine or a salt thereof improves
posture stability by least 1 time, 2 times, 3 times, 4 times, 5
times, 6 times, 7 times, 8 times, 9 times, 10 times, 20 times, 50
times, 100 times, 1000 times or more. In some embodiments, posture
stability of the treated subject is improved by between about 1 to
1000 times.
[0130] In some embodiments, the present disclosure provides for a
method of improving static balance in a subject with
neurodegenerative disease comprising administering nicotine or a
salt thereof to the subject. In some embodiments, the nicotinic
receptor agonist is administered in dosage form. In some
embodiments, administration of nicotine or a salt thereof improves
static balance by least 1 time, 2 times, 3 times, 4 times, 5 times,
6 times, 7 times, 8 times, 9 times, 10 times, 20 times, 50 times,
100 times, 1000 times or more. In some embodiments, static balance
of the treated subject is improved by between about 1 to 1000
times.
[0131] In some embodiments, the present disclosure provides for a
method of improving locomotor abilities in a subject with
neurodegenerative disease comprising administering nicotine or a
salt thereof to the subject. In some embodiments, the nicotinic
receptor agonist is administered in dosage form. In some
embodiments, administration of nicotine or a salt thereof improves
locomotor abilities by least 1 time, 2 times, 3 times, 4 times, 5
times, 6 times, 7 times, 8 times, 9 times, 10 times, 20 times, 50
times, 100 times, 1000 times or more. In some embodiments,
locomotor ability of the treated subject is improved by between
about 1 to 1000 times.
[0132] In some embodiments, the present disclosure provides for a
method of improving gait such as freezing of gait and tandem gait
in a subject with neurodegenerative disease comprising
administering nicotine or a salt thereof to the subject. In some
embodiments, the nicotinic receptor agonist is administered in
dosage form. In some embodiments, administration of nicotine or a
salt thereof improves gait such as freezing of gait and tandem gait
by least 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7
times, 8 times, 9 times, 10 times, 20 times, 50 times, 100 times,
1000 times or more. In some embodiments, gait such as freezing of
gait and tandem gait of the treated subject is improved by between
about 1 to 1000 times.
[0133] In some embodiments, the subject has impaired locomotion,
slowed locomotion, impaired stability, freezing of gait (FOG),
posture instability, static balance problems, loss of balance,
unstable walking, and/or short steps. Administering nicotine or a
salt thereof, or a nicotinic receptor modulator to the subject may
improve locomotion, gait, posture stability, balance and/or
walking. In some embodiments, the subject has improved locomotion,
gait, posture stability, balance and/or walking by at least 1 time,
2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9
times, 10 times, 20 times, 50 times, 100 times, 1000 times, or
more, compared to the past year. In some embodiments, the subject
has improved locomotion, gait, posture stability, balance and/or
walking by between about 1 to 1000 times compared to the past
year.
[0134] In some embodiments, improvements of fall-related symptoms
are evaluated by utilizing standard tests. Exemplary tests are
Unified Parkinson's Disease Rating Scale (UPDRS), Barrow
Neurological Institute (BNI) Falls Evaluation, Hoehn & Yahr
Staging System, Tinetti score, Romberg test, turning test, standing
on one leg, tandem gait, step length and velocity.
[0135] In some embodiments, the present method comprises evaluating
a subject with neurodegenerative disease under dopaminergic agent
treatment, the method comprises: (a) an "off" period when the
subject is about 16 hours off dopaminergic agent treatment, and (b)
an "on" period when the subject is about 1 hour after usual morning
dose of dopaminergic agent treatment. In some embodiments, the
subject is under dopaminergic agent treatment such as levodopa,
carbidopa, dopamine agonists, monoamine type B oxidase inhibitors,
and/or amantadine. In some embodiments, the subject has Parkinson's
disease or Parkinson-related disease.
[0136] In some embodiments, a subject is evaluated using laboratory
tests, analysis of concomitant medications, physical examinations,
mental evaluations, physical evaluations, electrocardiograms
(ECGs), vital signs, assessments of impulse control, nicotine
withdrawal symptoms, changes in disease symptoms, Mini Mental State
Examination, examinations using the Jay Midi Scale, UDysRS, Hoehn
and Yahr scale, Clinical Global impression scale, Patient global
impression scale, Lang-Fahn daily activity scale, and Minnesota
Nicotine Withdrawal Scale-Revised (MNWS-R). Laboratory tests
include, but are not limited to, urine analysis, serum cotinine
analysis, urine cotinine analysis, serum nicotine analysis,
hematology, chemistry, and pregnancy.
[0137] Described herein are methods of treating cognitive-related
symptoms in a subject with neurodegenerative disease, the methods
can comprise administering to the subject a dosage form comprising
nicotine or a salt thereof. The cognitive-related symptoms can be
impairments in visuospatial memory, executive functioning, short
term memory, working memory, long-term memory, attention, language,
abstraction, or spatial orientation. The improvement of symptoms
can comprise utilizing one or more of evaluation tests Montreal
Cognitive Assessment. The subject may have Parkinson's disease. The
subject may have typical Parkinson's disease. The subject may have
subject Parkinson's disease for at least five years. The subject
may have subject Parkinson's disease for at least four years. The
subject may have subject Parkinson's disease for at least three
years. The subject may have subject Parkinson's disease for at
least two years. The subject may have subject Parkinson's disease
for at least one years. The subject may have dopaminergic agent
treatment. The dopaminergic agent may be levodopa, carbidopa,
dopamine agonist, amantadine, monoamine oxidase B inhibitor, or
combination thereof. The subject may be evaluated in: an "off"
period, wherein the subject can be about 16 hours off dopaminergic
agent treatment; an "on" period, wherein the subject can be about 1
hour after usual morning dose of dopaminergic agent treatment;
wherein the dopaminergic treatment can be levodopa, carbidopa,
dopamine agonist, amantadine, monoamine oxidase B inhibitor, or
combination thereof. The "off" period may be at least or about 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or more
than 75 hours. The "off" period may be most 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,
30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 hours. The "on" period
may be at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50,
55, 60, 65, 70, 75, or more than 75 hours. The "on" period may be
most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,
19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or
75 hours. The subject can have Montreal Cognitive Assessment (MOCA)
score of at least 26. The dosage form may comprise a nicotinic
receptor agonist. The dosage form may comprise at least 1 mg to 6
mg of nicotine or a salt thereof for a period of 6 months, wherein
the dosage form can be escalated upward at treatment intervals. The
dosage form may comprise at least or about 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, or more than 12 mg of nicotine or a salt thereof.
The period may be at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, or more than 12 months. The dosage form may comprise
nicotine or a salt thereof can be escalated upward at two weeks
treatment intervals. The dosage form may comprise nicotine or a
salt thereof can be escalated upward at 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, or more than 12 weeks treatment intervals. The dosage
form may comprise nicotine or a salt thereof comprises: at least 1
mg every 6 hours; at least 2 mg every 6 hours; at least 4 mg every
6 hours; at least 6 mg every 6 hours; wherein the dose can be
escalated at two weeks treatment intervals; and wherein the dose
can be maintained at 6 mg every 6 hours until completion of the
treatment period of 6 months. The dosage form may comprise nicotine
or a salt thereof of at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30,
35, 40, 45, 50, 55, 60, or more than 60 mg. The dosage form may
comprise nicotine or a salt thereof administered in a period of 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, or more than 60
hours. The dosage form may be escalated at 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, or more than 12 weeks treatment intervals. The
dosage form may be administered for more than 12 weeks. The dosage
form may be administered for 1 week, 2 weeks, 3 weeks, 1 month, 2
months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months,
9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years,
5 years, 6 years, 7 years, 8 years, or more than 8 years. The
dosage form may be used for chronic treatment. The dose may be
maintained at least or about at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12 or more than 12 mg. The dose may be maintained every 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
23, 24, or more 24 hours. The treatment period may be at least or
about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23, 24, or more than 24 months. The treatment
period may be more than 12 weeks. The treatment period may be 1
week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5
months, 6 months, 7 months, 8 months, 9 months, 10 months, 11
months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7
years, 8 years, or more than 8 years. The treatment may be a
chronic treatment. The nicotine or a salt thereof may be
administered in an amount less than 24 mg in a period of 24 hours.
The nicotine or a salt thereof may be administered at least 4 times
in a period of 24 hours. The nicotine or a salt thereof may be
administered about every 6 hours in a period of 24 hours. The
nicotine or a salt thereof can be administered at least 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more
than 20 times. The nicotine or a salt thereof can be administered
about every 6 hours in a period of 24 hours. The nicotine or a salt
thereof can be administered about every 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 hours in
a period of 24 hours. The therapeutic effectiveness of the
administration can evaluated regularly for a period of at least 2
to 14 months. The therapeutic effectiveness of the administration
can be evaluated regularly for a period of at least 6 months. The
therapeutic effectiveness of the administration can be evaluated
regularly for a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35,
40, 45, 50, 55, 60, or more than 60 months. The evaluation can be
performed every 2 months. The evaluation can be performed every 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more than 12 months.
Evaluation may include laboratory tests, analysis of concomitant
medications, physical examinations, mental evaluations, physical
evaluations, electrocardiograms (ECGs), vital signs, assessments of
impulse control, nicotine withdrawal symptoms, changes in disease
symptoms, Mini Mental State Examination, examinations using the Jay
Midi Scale, UDysRS, Hoehn and Yahr scale, Clinical Global
impression scale, Patient global impression scale, Lang-Fahn daily
activity scale, and Minnesota Nicotine Withdrawal Scale-Revised
(MNWS-R). Laboratory tests include, but are not limited to, urine
analysis, serum cotinine analysis, urine cotinine analysis, serum
nicotine analysis, hematology, chemistry, and pregnancy. The said
dosage form can be formulated for oral, intravenous, intraarterial,
parenteral, buccal, topical, transdermal, rectal, intramuscular,
subcutaneous, intraosseous, transmucosal, or intraperitoneal
administration. The said dosage form can be formulated for oral
administration. The said dosage form can be formulated as a unit
dosage. The said dosage form can be formulated as a unit dosage in
liquid, gel, semi-liquid, semi-solid, or solid form. The said
dosage form can be formulated in a tablet. The said dosage form can
be formulated in a capsule. The said dosage form can be formulated
as a food. The said dosage form can be formulated as a beverage.
The said dosage form can be formulated as a dietary supplement. The
administration of said dosage form can result in a pharmacokinetic
profile having plasma nicotine levels below about 7.5 ng/ml at a
time point about 120 minutes after administration of said dosage
form. The said dosage form can be formulated as a dietary
supplement. The administration of said dosage form can result in a
pharmacokinetic profile having plasma nicotine levels below about
7.5 ng/ml at a time point about 180 minutes after administration of
said dosage form. The pharmacokinetic profile may have plasma
nicotine levels below about 5 ng/ml at about 180 minutes after
administration. The pharmacokinetic profile may have nicotine
levels below about 5 ng/ml at about 120 minutes after
administration. The pharmacokinetic profile may have plasma
nicotine levels above about 5 ng/ml at about 45 to 90 minutes after
administration. The pharmacokinetic profile may have plasma
nicotine levels above about 15 ng/ml at about 60 minutes after
administration. The dosage form may be the multiparticulate
formulation. The dosage form may provide a 1 ng/mL to 20 ng/ml
plasma concentration of nicotine about 2 hours after administration
of a dopaminergic agent. The dosage form may provide a 1 ng/mL to
20 ng/ml plasma concentration of nicotine about 2 hours, 3 hours, 4
hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours
after administration of a dopaminergic agent. The dosage form may
provide a 1 ng/mL to 20 ng/ml plasma concentration of nicotine
about 1 hour to 8 hours, 1 hour to 7 hours, 1 hour to 6 hours, 1
hour to 5 hours, 1 hour to 4 hours, 1 hour to 3 hours, 2 hours to 8
hours, 2 hours to 7 hours, 2 hours to 6 hours, 2 hours to 5 hours,
or 2 hours to 4 hours after administration of a dopaminergic agent.
The dosage form may provide a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, or more than 35
ng/mL plasma concentration of nicotine about 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12 or more than 12 hours after administration of a
dopaminergic agent. The neurodegenerative disease may be selected
from the group consisting of Parkinson's disease, schizophrenia,
mild cognitive impairment, Alzheimer's Disease, vascular cognitive
impairment, Subcortical Ischaemic Vascular Dementia, Frontotemporal
Mild Cognitive Impairment, and Frontotemporal Dementia.
[0138] Described herein are methods of treating fall-related
symptoms in a subject with neurodegenerative disease, the methods
can comprise administering to the subject a dosage form comprising
a nicotinic acetylcholine receptor (nAChR) agonist. The nAChR
agonist may be specific for the .alpha.7, .beta.2, or .alpha.7 and
.beta.2 subunit of the nAChR. The nAChR agonist may be a full
agonist. The nAChR agonist may be selected from Varenicline,
A-85380, sazetidine, TC-2696, TI-10165, TC-8831, TC-10600, ABT-089,
ABT-894, AZD1446, ABT-107, AQW051, ABT-894 and ABT-107,
3-Bromocytisine, Acetylcholine, Cytisine, Epibatidine, A-84,543,
A-366,833, ABT-418, Altinicline, Dianicline, Ispronicline,
Pozanicline, Rivanicline, Tebanicline, TC-1827, Sazetidine A,
N-(3-pyridinyl)-bridged bicyclic diamines,
(+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide,
A-582941, AR-R17779, Amyloid beta, TC-1698, TC-5619, EVP-6124,
GTS-21, PHA-543,613, PNU-282,987, PHA-709829, SSR-180,711,
Tropisetron, WAY-317,538, Anabasine, and ICH-3. The nAChR agonist
may be selected from ABT-894, ABT-107, TC-8831, ABT-089, AZD1446,
and AQW051. The nAChR agonist may be selected from ABT-894 and
ABT-107. The fall-related symptoms may comprise fall frequency. A
subject treated with the dosage form comprising the nAChR agonist
may have a reduced fall frequency. The fall-related symptoms may
comprise frequency of injuries related to fall. A subject treated
with the dosage form comprising the nAChR agonist may have reduced
frequency of injuries related to fall. The fall-related symptoms
may comprise severity of fall with injuries. A subject treated with
the dosage form comprising the nAChR agonist may have reduced
severity of fall with injuries. The subject may have recurrent
falls. The subject may have fallen at least once in past year. The
improvement of symptoms may comprise utilizing one or more of
evaluation tests selected from the group consisting of: Unified
Parkinson's Disease Rating Scale (UPDRS), Barrow Neurological
Institute (BNI) Falls Evaluation, Hoehn & Yahr Staging System,
Romberg test, turning test, standing on one leg, tandem gait, step
length and velocity. The evaluation utilizing the Unified
Parkinson's Disease Rating Scale (UPDRS) may be selected from the
group consisting of: Walking and Balance from questions 2.12 from
Movement Disorder Society Unified Parkinson's Disease Rating Scale
(MDS UPDRS), Freezing of Gait from questions 2.14 from Movement
Disorder Society Unified Parkinson's Disease Rating Scale (MDS
UPDRS), Dyskinesias from questions 32-35 from original Unified
Parkinson's Disease Rating Scale (UPDRS), Response Fluctuation from
questions 36-39 from original Unified Parkinson's Disease Rating
Scale (UPDRS), Sleep Disturbance from question 40 from original
Unified Parkinson's Disease Rating Scale (UPDRS), Movement Disorder
Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) 142
points, Axial, Midline part of Movement Disorder Society Unified
Parkinson's Disease Rating Scale (MDS UPDRS), Gait Subtest from
Movement Disorder Society Unified Parkinson's Disease Rating Scale
(MDS UPDRS, Postural Stability Subtest from Movement Disorder
Society Unified Parkinson's Disease Rating Scale (MDS UPDRS), and
Freezing of Gait Subtest (FOG) from Movement Disorder Society
Unified Parkinson's Disease Rating Scale (MDS UPDRS). The
evaluation may comprise Falling Unrelated to Freezing from question
13 from UPDRS Part II (Activities of Daily Life (ADL)), Freezing
When Walking from question 14 from UPDRS Part II (ADL), ambulation
subset from Unified Dyskinesia Rating Scale (UDysRS), or
combinations thereof. The evaluation may comprise Falling Unrelated
to Freezing from question 13 from UPDRS Part II (Activities of
Daily Life (ADL)), Freezing When Walking from question 14 from
UPDRS Part II(ADL), and ambulation subset from Unified Dyskinesia
Rating Scale (UDysRS). The improvement of symptoms may comprise
evaluation utilizing Reason for Fall from the Barrow Neurological
Institute (BNI) Falls Evaluation. The improvement of symptoms may
comprise evaluation utilizing Severity of Fall from the Barrow
Neurological Institute (BNI) Falls Evaluation.
[0139] Described herein are methods of treating posture
instability, static balance, locomotor disability and gait in a
subject with neurodegenerative disease, the methods may comprise
administering to the subject a dosage form comprising nicotinic
acetylcholine receptor (nAChR) agonist. The nAChR agonist may be
specific for the .alpha.7, .beta.2, or .alpha.7 and .beta.2 subunit
of the nAChR. The nAChR agonist may be a full agonist. The nAChR
agonist may be selected from Varenicline, A-85380, sazetidine,
TC-2696, TI-10165, TC-8831, TC-10600, ABT-089, ABT-894, AZD1446,
ABT-107, AQW051, ABT-894 and ABT-107, 3-Bromocytisine,
Acetylcholine, Cytisine, Epibatidine, A-84,543, A-366,833, ABT-418,
Altinicline, Dianicline, Ispronicline, Pozanicline, Rivanicline,
Tebanicline, TC-1827, Sazetidine A, N-(3-pyridinyl)-bridged
bicyclic diamines,
(+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide,
A-582941, AR-R17779, Amyloid beta, TC-1698, TC-5619, EVP-6124,
GTS-21, PHA-543,613, PNU-282,987, PHA-709829, SSR-180,711,
Tropisetron, WAY-317,538, Anabasine, and ICH-3. The nAChR agonist
may be selected from ABT-894, ABT-107, TC-8831, ABT-089, AZD1446,
and AQW051. The nAChR agonist may be selected from ABT-894 and
ABT-107. A subject treated with the dosage form comprising nicotine
may have improved posture stability. A subject treated with the
dosage form comprising nicotine may have improved static balance. A
subject treated with the dosage form comprising nicotine may have
improved locomotor ability. A subject treated with the dosage form
comprising nicotine may have improved gait. The improvement of
symptoms may comprise utilizing one or more of evaluation tests
selected from the group consisting of: Unified Parkinson's Disease
Rating Scale (UPDRS), BNI Falls Evaluation, Hoehn & Yahr
Staging System, Romberg test, turning test, standing on one leg,
tandem gait, step length and velocity. The evaluation utilizing the
Unified Parkinson's Disease Rating Scale (UPDRS) may be selected
from the group consisting of: Walking and Balance from questions
2.12 from Movement Disorder Society Unified Parkinson's Disease
Rating Scale (MDS UPDRS), Freezing of Gait from questions 2.14 from
Movement Disorder Society Unified Parkinson's Disease Rating Scale
(MDS UPDRS), Dyskinesias from questions 32-35 from original Unified
Parkinson's Disease Rating Scale (UPDRS), Response Fluctuation from
questions 36-39 from original Unified Parkinson's Disease Rating
Scale (UPDRS), Sleep Disturbance from question 40 from original
Unified Parkinson's Disease Rating Scale (UPDRS), Movement Disorder
Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) 142
points, Axial, Midline part of Movement Disorder Society Unified
Parkinson's Disease Rating Scale (MDS UPDRS), Gait Subtest from
Movement Disorder Society Unified Parkinson's Disease Rating Scale
(MDS UPDRS, Postural Stability Subtest from Movement Disorder
Society Unified Parkinson's Disease Rating Scale (MDS UPDRS), and
Freezing of Gait Subtest (FOG) from Movement Disorder Society
Unified Parkinson's Disease Rating Scale (MDS UPDRS). The
evaluation may comprise Falling Unrelated to Freezing from question
13 from UPDRS Part II (Activities of Daily Life (ADL)), Freezing
When Walking from question 14 from UPDRS Part II (ADL), ambulation
subset from Unified Dyskinesia Rating Scale (UDysRS), or
combinations thereof. The evaluation may comprise Falling Unrelated
to Freezing from question 13 from UPDRS Part II (Activities of
Daily Life (ADL)), Freezing When Walking from question 14 from
UPDRS Part II (ADL), and ambulation subset from Unified Dyskinesia
Rating Scale (UDysRS). The subject may have Parkinson's disease.
The subject may have typical Parkinson's disease. The subject may
have Parkinson's disease for at least five years. The subject may
have Parkinson's disease for at least four years. The subject may
have Parkinson's disease for at least three years. The subject may
have Parkinson's disease for at least two years. The subject may
have Parkinson's disease for at least one year. The subject may
have dopaminergic agent treatment. The dopaminergic agent may be
levodopa, carbidopa, dopamine agonist, amantadine, monoamine
oxidase B inhibitor, or combination thereof. The subject may be
evaluated in: an "off" period, wherein the subject can be about 16
hours off dopaminergic agent treatment; an "on" period, wherein the
subject can be about 1 hour after usual morning dose of
dopaminergic agent treatment; "off" wherein the dopaminergic
treatment can be levodopa, carbidopa, dopamine agonist, amantadine,
monoamine oxidase B inhibitor, or combination thereof. The "off"
period may be at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40,
45, 50, 55, 60, 65, 70, 75, or more than 75 hours. The "off" period
may be most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65,
70, or 75 hours. The "on" period may be at least or about 1, 2, 3,
4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,
22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or more
than 75 hours. The "on" period may be most 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,
30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 hours. The subject can
have Montreal Cognitive Assessment (MOCA) score of at least 26. The
subject can have Montreal Cognitive Assessment (MOCA) score of at
least or about 20, 25, 30, 35, 40, or more than 40. The subject may
be excluded with disorders selected in the group consisting of:
atypical Parkinson, Progressive Supranuclear Palsy (PSP), Multiple
System Atrophy (MSA), Primary Freezing of Gait (PFG),
Corticobasiler Degeneration, dementia with Montreal Cognitive
Assessment (MOCA) score of less than 21, legally blind, orthopedic
problems in hips or knees, hips or knees replacements, orthostatic
hypotension, schizophrenia, schizo-affective disorder, bipolar
disorder, hallucinations, psychoses, delusions, deep brain
stimulation (DBS) intervention, history of recent stroke, and
history of myocardial infarction. The dosage form may comprise at
least 1 mg to 6 mg of the nAChR agonist for a period of 6 months,
wherein the dosage form can be escalated upward at treatment
intervals. The dosage form may comprise at least or about 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, or more than 12 mg of nAChR agonist.
The period may be at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, or more than 12 months. The dosage form comprises nAChR
agonist may be escalated upward at two weeks treatment intervals.
The dosage form comprises nAChR agonist may be escalated upward at
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more than 12 weeks
treatment intervals. The dosage form comprising nAChR agonist may
be administered for more than 12 weeks. The dosage form comprising
nAChR agonist may be administered for 1 week, 2 weeks, 3 weeks, 1
month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months,
8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years,
4 years, 5 years, 6 years, 7 years, 8 years, or more than 8 years.
The dosage form comprising nAChR agonist may be used for chronic
treatment. The treatment period may be more than 12 weeks. The
treatment period may be 1 week, 2 weeks, 3 weeks, 1 month, 2
months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months,
9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years,
5 years, 6 years, 7 years, 8 years, or more than 8 years. The
treatment period may be a chronic treatment. The nAChR agonist may
be administered in an amount less than 24 mg in a period of 24
hours. The nAChR agonist can be administered in an amount of at
least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60,
or more than 60 mg. The nAChR agonist can be administered in a
period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, or
more than 60 hours. The nAChR agonist can be administered at least
4 times in a period of 24 hours. The nAChR agonist may be
administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, or more than 20 times. The nAChR
agonist can be administered about every 6 hours in a period of 24
hours. The nAChR agonist can be administered about every 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,
22, or 23 hours in a period of 24 hours. The therapeutic
effectiveness of the administration can be evaluated regularly for
a period of at least 2 to 14 months. The therapeutic effectiveness
of the administration can evaluated regularly for a period of at
least 6 months. The therapeutic effectiveness of the administration
can be evaluated regularly for a period of at least 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, 30, 35, 40, 45, 50, 55, 60, or more than 60 months. The
evaluation can be performed every 2 months. The evaluation can be
performed every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more than
12 months. Evaluation may include laboratory tests, analysis of
concomitant medications, physical examinations, mental evaluations,
physical evaluations, electrocardiograms (ECGs), vital signs,
assessments of impulse control, nicotine withdrawal symptoms,
changes in disease symptoms, Mini Mental State Examination,
examinations using the Jay Midi Scale, UDysRS, Hoehn and Yahr
scale, Clinical Global impression scale, Patient global impression
scale, Lang-Fahn daily activity scale, and Minnesota Nicotine
Withdrawal Scale-Revised (MNWS-R). Laboratory tests include, but
are not limited to, urine analysis, serum cotinine analysis, urine
cotinine analysis, serum nicotine analysis, hematology, chemistry,
and pregnancy. The dosage form can be formulated for oral,
intravenous, intraarterial, parenteral, buccal, topical,
transdermal, rectal, intramuscular, subcutaneous, intraosseous,
transmucosal, or intraperitoneal administration. The dosage form
can be formulated for oral administration. The dosage form can be
formulated as a unit dosage. The composition can be formulated as a
unit dosage in liquid, gel, semi-liquid, semi-solid, or solid form.
The dosage form can be formulated in a tablet. The dosage form can
be formulated in a capsule. The dosage form can be formulated as a
food. The dosage form can be formulated as a beverage. The dosage
form can be formulated as a dietary supplement.
[0140] Described herein are methods of reducing frequency of falls,
the method comprising administering to a subject a dosage form
comprising nicotine or a salt thereof. The subject may be elderly
or have a central nervous system disease or disorder. The central
nervous system disease or disorder may be Parkinson's disease.
Further described herein are methods of reducing freezing of gait
(FOG), the method comprising administering to the subject a dosage
form comprising nicotine or a salt thereof. The number of falls and
FOG may be related to levodopa-induced dyskinesias (LIDs). The
number of falls and FOG may not be related to levodopa-induced
dyskinesias (LIDs). The method may improve postural stability.
Falls may be prevented in a subject treated with the dosage form
comprising nicotine or salt thereof. The frequency of falls may be
reduced by at least 10%. The frequency of falls may be reduced by
at least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,
60%, 65%, 70%, 75%, 80%, 85%, 90%, or more than 90%. The frequency
of falls may be reduced by at least 20%. FOG may be reduced by at
least 10%. FOG may be reduced by at least or about 10%, 15%, 20%,
25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,
90%, or more than 90%. FOG may be reduced by at least 20%. LIDs may
be reduced by at least 10%. LIDs may be reduced by at least or
about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,
70%, 75%, 80%, 85%, 90%, or more than 90%. LIDs may be reduced by
at least 20%. The improved postural stability may be an improvement
by at least 10%. The improved postural stability may be an
improvement by at least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, 50%, 60%, 70%, 80%, 90%, or more than 90%. The subject can
have at least a 0.5-fold reduction in the frequency of falls. The
subject can have at least a 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 4.5,
5-fold reduction in the frequency of falls. The subject can have at
least a 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 4.5, 5-fold reduction in
FOG. The subject can have at least a 0.5, 1.0, 1.5, 2.0, 2.5, 3.0,
4.0, 4.5, 5-fold reduction in levodopa-induced dyskinesias (LIDs).
The subject may have at least a 0.5-fold improvement in postural
stability. The subject may have at least or about a 0.5, 1.0, 1.5,
2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0, or more than
8.0-fold improvement in postural stability. The falls and the FOG
may occur independently. The falls may be associated with FOG.
[0141] Described herein are methods of reducing frequency of falls
in a subject at risk of falling, wherein the subject is
administered nicotine or a salt thereof. The subject at risk of
falling may be elderly or has a central nervous system disease or
disorder. The subject at risk of falling may have Parkinson's
disease.
[0142] Described herein are methods of preventing falls, the method
comprising administering to a subject a dosage form comprising
nicotine or a salt thereof. In some embodiments, the subject is
administered a nAChr agonist or antagonist. For example, methods
for preventing falls reduce an incidence of falls. The incidence of
falls may be reduced by at least or about 10%, 15%, 20%, 25%, 30%,
35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or more
than 90%. The incidence of falls may be reduced by at least
20%.
[0143] Described herein are methods of reducing fall-related
complications, the method comprising administering to a subject a
dosage form comprising nicotine or a salt thereof. In some
embodiments, the subject is administered a nAChr agonist or
antagonist. Fall-related complications include, but are not limited
to, postural instability, abnormal postural balance, delayed
reaction time, impaired gait-dependent activities, impaired daily
activities, and injuries. Fall-related complications may be reduced
by at least 10%. Fall-related complications may be reduced by at
least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,
60%, 65%, 70%, 75%, 80%, 85%, 90%, or more than 90%. Fall-related
complications may be reduced by at least 20%.
[0144] Described herein are methods of improving cognitive-related
symptoms, the method comprising administering to a subject a dosage
form comprising nicotine or a salt thereof. In some embodiments,
the subject is administered a nAChr agonist or antagonist.
Cognitive-related symptoms may be related to a neurodegenerative
disease or disorder. Cognitive-related symptoms may be related to
mild cognitive impairment, Alzheimer's Disease, vascular cognitive
impairment, Subcortical Ischemic Vascular Dementia, Frontotemporal
Mild Cognitive Impairment, or Frontotemporal Dementia.
Cognitive-related symptoms may be improved by at least 10%.
Cognitive-related symptoms may be improved may be reduced by at
least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,
60%, 65%, 70%, 75%, 80%, 85%, 90%, or more than 90%.
Cognitive-related symptoms may be improved may be reduced by at
least 20%.
[0145] Reduction in fall frequency, reduction in freezing of gait
(FOG), reduction in levodopa-induced dyskinesias (LIDs), prevention
of falls, reduction of fall-related complications, improvements in
postural stability, improvements in cognitive-related symptoms, or
combinations thereof may be compared to a control. The control may
be a subject at baseline or a subject administered placebo. In some
instances, the control has idiopathic Parkinson's disease. The
control may have LIDs. The control may be in a peak "on" state of
levodopa. The nicotine or a salt thereof may not change
dopaminergic activity. The nicotine or a salt thereof may not
nicotine or a salt thereof increases cholinergic activity. The
evaluation of the subject may comprise Falling Unrelated to
Freezing from question 13 from UPDRS Part II (Activities of Daily
Life (ADL)), Freezing When Walking from question 14 from UPDRS Part
II (ADL), ambulation subset from Unified Dyskinesia Rating Scale
(UDysRS), or combinations thereof. The dosage form may be
formulated for oral administration. Evaluation may include
laboratory tests, analysis of concomitant medications, physical
examinations, mental evaluations, physical evaluations,
electrocardiograms (ECGs), vital signs, assessments of impulse
control, nicotine withdrawal symptoms, changes in disease symptoms,
Mini Mental State Examination, examinations using the Jay Midi
Scale, UDysRS, Hoehn and Yahr scale, Clinical Global impression
scale, Patient global impression scale, Lang-Fahn daily activity
scale, and Minnesota Nicotine Withdrawal Scale-Revised (MNWS-R).
Laboratory tests include, but are not limited to, urine analysis,
serum cotinine analysis, urine cotinine analysis, serum nicotine
analysis, hematology, chemistry, and pregnancy.
[0146] Methods as described herein may comprise administering a
dose of nicotine or a salt thereof to a subject over a period of
time. In some embodiments, the subject is administered a nAChr
agonist or antagonist. Methods may relate to reducing fall
frequency. Methods may relate to reducing freezing of gait (FOG).
In some embodiments, methods may relate to reducing
levodopa-induced dyskinesias (LIDs). Methods may relate to
prevention of falls. Methods may relate to reduction of
fall-related complications. Methods may relate to improving
postural stability. Methods may relate to improving
cognitive-related symptoms. Methods as described herein may not
result in tolerance or dependence on the nicotine or salt thereof.
The subject may be elderly or has a central nervous system disease
or disorder. The subject may have Parkinson's disease. The subject
may have Parkinson's disease but not LIDs.
[0147] Methods as described herein may comprise administering
nicotine or a salt thereof, wherein an amount of no more than 24 mg
per day of the nicotine or salt thereof is administered. In some
embodiments, the amount or total dose of nicotine or the salt
thereof may be more than 24 mg per day. The amount or total dose of
nicotine or a salt thereof may be no more than about 4 mg per day,
6 mg per day, 8 mg per day, 10 mg per day, 12 mg per day, 14 mg per
day, 16 mg per day, 18 mg per day, 20 mg per day, 22 mg per day, 24
mg per day, 26 mg per day, 28 mg per day, 30 mg per day, 32 mg per
day, 34 mg per day, 36 mg per day, 38 mg per day, 40 mg per day, 42
mg per day, 44 mg per day, 46 mg per day, 48 mg per day, or more
than 48 mg per day. The amount or total dose of nicotine or a salt
thereof may be in a range of about 1 mg per day to 24 mg per day, 2
mg per day to 22 mg per day, 3 mg per day to 20 mg per day, 4 mg
per day to 18 mg per day, 5 mg per day to 16 mg per day, 6 mg per
day to 14 mg per day, or 8 mg per day to 12 mg per day. The amount
or total dose of nicotine or a salt thereof may be in a range of
about 8 mg per day to 24 mg per day.
[0148] In some embodiments, methods for administering nicotine or a
salt thereof comprise a dose of the nicotine or salt thereof
equivalent to an oral dose. For example, the nicotine or salt
thereof is administered as a dose that is equivalent to 24 mg per
day of an oral dose. In some embodiments, the nicotine or salt
thereof is administered as a dose that is equivalent to at least 1
mg per day, 2 mg per day, 4 mg per day, 6 mg per day, 8 mg per day,
10 mg per day, 12 mg per day, 14 mg per day, 16 mg per day, 18 mg
per day, 20 mg per day, 22 mg per day, 24 mg per day, 26 mg per
day, 28 mg per day, 30 mg per day, 32 mg per day, 34 mg per day, 36
mg per day, 38 mg per day, 40 mg per day, 42 mg per day, 44 mg per
day, 46 mg per day, 48 mg per day, or more than 48 mg per day of an
oral dose. In some embodiments, the nicotine or salt thereof is
administered as a dose that is equivalent to about 1 mg per day, 2
mg per day, 4 mg per day, 6 mg per day, 8 mg per day, 10 mg per
day, 12 mg per day, 14 mg per day, 16 mg per day, 18 mg per day, 20
mg per day, 22 mg per day, 24 mg per day, 26 mg per day, 28 mg per
day, 30 mg per day, 32 mg per day, 34 mg per day, 36 mg per day, 38
mg per day, 40 mg per day, 42 mg per day, 44 mg per day, 46 mg per
day, 48 mg per day, or more than 48 mg per day of an oral dose. In
some embodiments, the nicotine or salt thereof is administered as a
dose that is equivalent to at most 1 mg per day, 2 mg per day, 4 mg
per day, 6 mg per day, 8 mg per day, 10 mg per day, 12 mg per day,
14 mg per day, 16 mg per day, 18 mg per day, 20 mg per day, 22 mg
per day, 24 mg per day, 26 mg per day, 28 mg per day, 30 mg per
day, 32 mg per day, 34 mg per day, 36 mg per day, 38 mg per day, 40
mg per day, 42 mg per day, 44 mg per day, 46 mg per day, 48 mg per
day, or more than 48 mg per day of an oral dose. In some
embodiments, the dose of the nicotine or salt thereof is equivalent
to a dose for a different route of administration. For example, the
route of administration may be for intravenous, intraarterial,
oral, parenteral, buccal, topical, transdermal, rectal,
intramuscular, subcutaneous, intraosseous, transmucosal,
inhalation, or intraperitoneal administration. The nicotine or salt
thereof may be administered as a dose that is equivalent to at most
1 mg per day, 2 mg per day, 4 mg per day, 6 mg per day, 8 mg per
day, 10 mg per day, 12 mg per day, 14 mg per day, 16 mg per day, 18
mg per day, 20 mg per day, 22 mg per day, 24 mg per day, 26 mg per
day, 28 mg per day, 30 mg per day, 32 mg per day, 34 mg per day, 36
mg per day, 38 mg per day, 40 mg per day, 42 mg per day, 44 mg per
day, 46 mg per day, 48 mg per day, or more than 48 mg per day of a
dose formulated for intravenous, intraarterial, oral, parenteral,
buccal, topical, transdermal, rectal, intramuscular, subcutaneous,
intraosseous, transmucosal, inhalation, or intraperitoneal
administration.
[0149] In some embodiments, a plurality of doses is administered to
the subject. In some embodiments, 12, 3, 4, 5, 6, 7, 8, 9, or 10
different doses of the nicotine or salt thereof. The dose of the
nicotine or salt thereof may be about 1 mg to about 6 mg. The dose
may be at least or about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg,
8 mg, 9 mg, 10 mg, 11 mg, 12 mg, or more than 12 mg. The dose may
be at least or about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8
mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg,
18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, or more than 24
mg. The dose may be in a range of about 0.1 mg to about 6 mg. The
dose may be in a range of about 0.1 mg to about 1 mg, about 0.1 mg
to about 2 mg, about 0.1 mg to about 2.5 mg, about 0.1 mg to about
3 mg, about 0.1 mg to about 3.5 mg, about 0.1 mg to about 4 mg,
about 0.1 mg to about 4.5 mg, about 0.1 mg to about 5 mg, or about
0.1 mg to about 6 mg. The period of time may be 1 day, 2 days, 3
days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5
weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12
weeks, or more than 12 weeks. The period of time may be 1 month, 2
months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months,
9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years,
5 years, 6 years, 7 years, 8 years, or more than 8 years. The dose
of nicotine or salt thereof may be used for chronic treatment.
[0150] Methods as described herein may comprise providing a dose of
nicotine or a salt thereof over the period of time for
administration at least once a day. Administration may be 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12 more than 12 times a day.
Administration may be every 1 hour, 2 hours, 3 hours, 4 hours, 5
hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12
hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours,
19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours.
[0151] In some embodiments, methods of administering nicotine or a
salt thereof comprises increasing the dose of the nicotine or salt
thereof upward at treatment intervals. The methods may provide a
plurality of doses. The methods may provide 1, 2, 3, 4, 5, 6, 7, 8,
9, or 10 different doses of the nicotine or salt thereof. The dose
of the nicotine or salt thereof may be about 1 mg to about 6 mg.
The dose may be at least or about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6
mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, or more than 12 mg. The
dose may be at least or about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7
mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17
mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, or more than
24 mg. The dose may be escalated upward at two weeks treatment
intervals. The dose may be escalated upward at 1 week to 4 week
treatment intervals. The dose may be escalated upward at 1 day, 2
day, 3 day, 4 day, 5 day, 6 day, 1 week, 2 week, 3 week, 4 week, 5
week, 6 week, 7 week, 8 week, or more than 8 week treatment
intervals. The dose may be escalated until an optimum dose is
determined followed by use of the optimum dose for chronic
treatment.
[0152] Methods as described herein may comprise providing a
starting dose of nicotine or a salt thereof over a period of time,
wherein the starting dose can be escalated upward to a first
escalated dose. The first escalated dose may be 1.5 times, 1.75
times, or 2 times as high as the starting dose. The first escalated
may be 1.5 times, 2 times, 2.5 times, 3.0 times, 3.5 times, 4.0
times, 4.5 times, 5.0 times, 5.5 times, 6.0 times, 6.5 times, 7.0
times, 7.5 times, 8.0 times, 9.0 times, 9.5 times, 10 times, 11
times, or 12 times as high as the starting dose. In some
embodiments, the starting dose is escalated to a second escalated
dose. The second escalated dose may be 2.5 times, 3.0 times, 3.5
times, or 4 times as high as the starting dose. The second
escalated dose may be 2.5 times, 3.0 times, 3.5 times, 4.0 times,
4.5 times, 5.0 times, 5.5 times, 6.0 times, 6.5 times, 7.0 times,
7.5 times, 8.0 times, 9.0 times, 9.5 times, 10 times, 11 times, or
12 times as high as the starting dose. In some embodiments, the
starting dose is escalated to a third escalated dose. The third
escalated dose may be 4.5 times, 5.0 times, 5.5 times, 6.0 times,
or 6.5 times as high the starting dose. The fourth dose may be 4.5
times, 5.0 times, 5.5 times, 6.0 times, 6.5 times, 7.0 times, 7.5
times, 8.0 times, 9.0 times, 9.5 times, 10 times, 11 times, or 12
times as high the starting dose. The kits may provide for a
plurality of escalated doses from a starting dose. The methods may
provide for a plurality of different or non-identical escalated
doses from a starting dose. A number of different or non-identical
escalated doses may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12
escalated doses from a starting dose. The escalated dose may be 1.5
times, 2 times, 2.5 times, 3.0 times, 3.5 times, 4.0 times, 4.5
times, 5.0 times, 5.5 times, 6.0 times, 6.5 times, 7.0 times, 7.5
times, 8.0 times, 9.0 times, 9.5 times, 10 times, 11 times, or 12
times as high the starting dose.
[0153] Methods as described herein may comprise administering a
dose of nicotine or a salt thereof that can be administered at
least once a day. The dose of nicotine or a salt thereof may be
administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or
more than 12 times a day. The dose of nicotine or a salt thereof
may be administered about 1, 2, 3, 4, 5, or 6 times a day. The dose
of nicotine or a salt thereof may be administered once a day. The
dose of nicotine or a salt thereof may be administered twice a day.
A time between administration may be at least 1 hour, 2 hours, 3
hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10
hours, 11 hours, 12 hours, or more than 12 hours. A time between
administration may be in a range of 0 hours to 24 hours, 1 hour to
23 hours, 2 hours to 22 hours, 3 hours to 21 hours, 4 hours to 20
hours, 5 hours to 19 hours, 6 hours to 18 hours, 7 hours to 17
hours, 8 hours to 16 hours, 9 hours to 15 hours, and 10 hours to 12
hours. A time between administration may be in a range of about 1
hour to about 6 hours or about 2 hours to about 6 hours.
Administration may be every 1 hour, 2 hours, 3 hours, 4 hours, 5
hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12
hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours,
19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours.
[0154] In some embodiments, methods as described herein provide a
dosage form of nicotine or salt thereof that delivers an
immediate-release dose of the nicotine or the salt thereof followed
by a second-immediate release dose about 2 hours to 8 hours after
administration. The dosage form may deliver an immediate-release
dose of the nicotine or the salt thereof followed by a
second-immediate release dose about 1 hour to 8 hours, 1 hour to 7
hours, 1 hour to 6 hours, 1 hour to 5 hours, 1 hour to 4 hours, 1
hour to 3 hours, 2 hours to 8 hours, 2 hours to 7 hours, 2 hours to
6 hours, 2 hours to 5 hours, or 2 hours to 4 hours after
administration. In some embodiments, the second-immediate release
dose is followed by a third-immediate release dose about 8 hours to
about 16 hours after administration. In some embodiments, the
third-immediate release dose is followed by a fourth-immediate
release dose about 16 hours to about 24 hours after administration.
The dose of nicotine or the salt thereof may be about 1 mg to about
6 mg over a period of time. For example, the dose of nicotine or
the salt thereof may be about 1 mg to about 6 mg over 6 hours. The
dose may comprise at least or about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6
mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, or more than 12 mg of
nicotine or a salt thereof. The dose may comprise at least or about
1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg,
12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21
mg, 22 mg, 23 mg, 24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg, 36 mg,
38 mg, 40 mg, 42 mg, 44 mg, 46 mg, 48 mg, or more than 48 mg of
nicotine or a salt thereof. The period of time may be 1 hour, 2
hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9
hours, 10 hours, 11 hours, 12 hours, or more than 12 hours. The
dose of nicotine or a salt thereof may be administered at least 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more than 12 times a day.
The dose of nicotine or a salt thereof may be administered about 1,
2, 3, 4, 5, or 6 times a day. The dose of nicotine or a salt
thereof may be administered once a day. The dose of nicotine or a
salt thereof may be administered twice a day. A time between
administration may be at least or within a range spanning 1 hour, 2
hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9
hours, 10 hours, 11 hours, 12 hours, more than 12 hours, or more
than 12 hours. A time between administration may be in a range of 0
hours to 24 hours, 1 hour to 23 hours, 2 hours to 22 hours, 3 hours
to 21 hours, 4 hours to 20 hours, 5 hours to 19 hours, 6 hours to
18 hours, 7 hours to 17 hours, 8 hours to 16 hours, 9 hours to 15
hours, and 10 hours to 12 hours.
[0155] In some embodiments, methods as described herein provide a
dosage form of nicotine or salt thereof that delivers one or more
immediate-release doses of the nicotine or the salt thereof over a
period of time. A number of immediate-release doses of the nicotine
or the salt thereof may be 1, 2, 3, 5, 6, 7, 8, or more than 8
immediate-release doses. A number of immediate-release doses of the
nicotine or salt thereof may be in a range of 1 to 8, 1 to 7, 1 to
6, 1 to 5, 1 to 4, 1 to 3, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4
immediate-release doses. The dosage form may provide an
immediate-release dose about 1 hour to 8 hours, 1 hour to 7 hours,
1 hour to 6 hours, 1 hour to 5 hours, 1 hour to 4 hours, 1 hour to
3 hours, 2 hours to 8 hours, 2 hours to 7 hours, 2 hours to 6
hours, 2 hours to 5 hours, or 2 hours to 4 hours after
administration. The dosage form may provide an immediate-release
dose about 8 hour to 16 hours, 8 hours to 15 hours, 8 hours to 14
hours, or 8 hours to 12 hours after administration. The dosage form
may provide an immediate-release dose about 16 hour to 24 hours, 16
hours to 22 hours, 16 hours to 20 hours, or 16 hours to 18 hours
after administration.
[0156] In some embodiments, the methods provide a dosage form that
delivers a delayed-release pulse of the nicotine or the salt
thereof. The delayed-release pulse of the nicotine or the salt
thereof may be delivered over a period of time. A dose of nicotine
or the salt thereof may be no more than 24 mg per day. In some
embodiments, the dose of nicotine or the salt thereof may be more
than 24 mg per day. The dose may comprise at least or about 1 mg, 2
mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg,
13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22
mg, 23 mg, 24 mg, or more than 24 mg of nicotine or a salt thereof.
The dose may comprise at least or about 1 mg, 2 mg, 3 mg, 4 mg, 5
mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15
mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg,
26 mg, 28 mg, 30 mg, 32 mg, 34 mg, 36 mg, 38 mg, 40 mg, 42 mg, 44
mg, 46 mg, 48 mg, or more than 48 mg of nicotine or a salt thereof.
The period of time may be or within a range spanning 1 hour, 2
hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9
hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours,
16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22
hours, 23 hours, 24 hours, or more than 24 hours.
Unified Parkinson's Disease Rating Scale (UPDRS)
[0157] The Unified Parkinson's Disease Rating Scale (UPDRS) is
typically used to follow the longitudinal course of Parkinson's
disease. In general, the UPDRS is made up of five sections: Part I:
evaluation of mentation, behavior and mood; Part II:
self-evaluation of the activities of daily life (ADLs) including
speech, swallowing, handwriting, dressing, hygiene, falling,
salivating, turning in bed, walking and cutting food; Part III:
clinical-scored monitored motor evaluation; Part IV: Hoehn and Yahr
staging of severity of Parkinson's disease; and Part V: Schwab and
England ADL scale.
[0158] These UPDRS sections are evaluated by interview and clinical
observation. In some cases, a section may require multiple grades
assigned to each extremity. Typically, a clinician or a healthcare
profession, or a researcher would use the UPDRS and the motor
section in particular to follow the progression of a person's
Parkinson's disease. For example, a research may use it to measure
the benefits from a given therapy. As another example, a healthcare
profession may use it in clinical practice to follow the
progression of their patients' symptoms. Following the UPDRS scores
overtime can provide insight into the patient's disease
progression. Typically, the "mentation, behavior and mood" scores
increase later in the disease.
[0159] The Unified Parkinson's Disease Rating Scale (UPDRS) is the
most utilized test for evaluating patients with Parkinson's
disease. The original UPDRS has a question in the activities of
daily living, on falls. This question is absent on the revised
Movement Disorder Society UPDRS (MDS-UPDRS). Both the original
UPDRS and the MDS-UPDRS have only one subtest on balance (postural
instability), known as the "pull test". This subtest makes up only
4 points out of a total of 132 points, which is about 3% of the
motor examination and is a small part for assessing fall in
Parkinson's disease patients.
The Movement Disorder Society revised UPDRS (MDS-UPDRS)
[0160] The Movement Disorder Society (MDS) published a revision of
the UPDRS, known as the MDS-UPDRS. The revision highlights the
limitations of the original UPDRS. Two major limitations include
the lack of consistent anchor among subscales and the low emphasis
on the nonmotor features of PD. The modified UPDRS retains the
four-scale structure with a reorganization of the various
subscales. The scales are titled; (1) nonmotor experiences of daily
living (13 items), (2) motor experiences of daily living (13
items), (3) motor examination (18 items), and (4) motor
complications (six items). Each subscale now has 0-4 ratings, where
0=normal, 1=slight, 2=mild, 3=moderate, and 4=severe.
Tinetti Test (TT)
[0161] The Tinetti Test (TT), also known as Performance Oriented
Mobility Assessment (POMA) is a common clinical test for assessing
a person's static and dynamic balance abilities. The test is in two
short sections, one examining static balance abilities in a chair
and then standing; the other one is gait. In some cases, the two
sections can be used as separate tests.
Barrow Neurological Institute (BNI)
[0162] Unlike the Tinetti score typically used for assessing
balance, the Barrow Neurological Institute (BNI) balance scale
focuses on Parkinson's disease and addresses issues that result in
falls in Parkinson's disease (Lieberman et al., "A quick and
easy-to-use clinical scale to assess balance in Parkinson's
disease", Journal of Parkinsonism & Restless Legs Syndrome, 2:
67-71, Nov. 30, 2012). Non-limited examples of issues result in
falls in Parkinson's disease include, turning, standing on one foot
while reaching or walking up or down stairs, and walking in
confined spaces. In addition, the BNI balance scale does not
duplicate any part of the MDS-UPDRS. As such, the BNI balance scale
can be used as a complement to the MDS-UPDRS.
[0163] The BNI balance scale comprises five subtest under three
major categories for assessing balance and predicting fall. The BNI
balance scale incorporates subtests relevant for Parkinson's
disease that are related to falls, of which turning and standing on
one leg are subtests of the Tinett (item 8 of the balance section)
and Berg (items 11 and 14) scales. Patients are assessed for
turning, standing on one foot and tandem gait. Patient performance
is evaluated by scores with a maximum of 20 points. Details of
assessment are described herein.
[0164] Patients taking the Turning test are asked to turn
360.degree. and assessed for a score system of 8 points (Table 1).
First, patients are asked turn to the right which scores 4 points.
Second, patients are asked to turn to the left which scores 4
points. In general, scoring is similar to the Berg, except 4 is
normal or baseline on the Berg and 0 is normal or the baseline on
the BNI.
TABLE-US-00001 TABLE 1 BNI balance scale Turning test Score
(points) Description 0 Accomplished 360.degree. turn in .ltoreq.4
seconds (usually in four steps) 1 Accomplished 360.degree. turn in
more than 4 seconds (usually in five or six steps) 2 Accomplished
360.degree. turn safely but slowly (usually in seven or eight
steps) 3 Accomplished 360.degree. turn, but patient needs close
(usually in nine or ten steps) 4 Needs assistance in turning (or
can't turn)
[0165] Patients taking the Standing on one foot test are asked to
lift one leg independently and hold for a period of time. First,
patients are asked to stand on right foot alone which scores 4
points. Second, patients are asked to stand on left foot alone
which scores 4 points. The ability of holding a lifted leg is
assessed for a score system of 8 points (Table 2). In general,
scoring is similar to the Berg, except 4 is normal or the baseline
on the Berg and 0 is normal of the baseline on the BNI.
TABLE-US-00002 TABLE 2 BNI balance scale Standing on one foot test
Score (points) Description 0 Able to lift leg independently and
hold for more than 10 seconds (with no assistance or support) 1
Able to lift leg independently and hold for 5-10 seconds (with no
assistance or support) 2 Able to lift leg independently and hold
for .gtoreq.3 seconds (with no assistance or support) 3 Able to
lift leg independently and hold for less than 3 seconds (may
require assistance or support) 4 Unable to try
[0166] In general, the Tandem gait test requires patients to take
ten steps, placing one foot in front of the other, the heel of one
foot touching to toe of the other. Patients are assessed for a
score system of 4 points (Table 3). A score of 0 point is normal or
the baseline.
TABLE-US-00003 TABLE 3 BNI balance scale Tandem gait test Score
(points) Description 0 Can walk ten steps, with no missteps
(deviation from the midline) 1 Can walk ten steps, with one misstep
2 Can walk ten steps, with two, three, or four missteps 3 Can walk
ten steps, with five or more missteps; usually, patient cannot take
five or more consecutive steps 4 Cannot tandem walk
[0167] In some embodiments, improvements of fall-related symptoms
are evaluated by utilizing Reason for Fall from the Barrow
Neurological Institute (BNI) Falls Evaluation. In some embodiments,
improvements of fall-related symptoms are evaluated by utilizing
Severity of Fall from the Barrow Neurological Institute (BNI) Falls
Evaluation.
[0168] In some embodiments, the possibility of fall in a subject
with neurological disease is predicted using the Barrow
Neurological Institute (BNI) balance scale. As a non-limiting
example, patients who have had at least three falls during the
month prior to the test are considered fallers and typically score
at least 3 points on the BNI Standing on one foot test, at least 3
points on the BNI Turning test, and at least 2 points on the BNI
Tandem gait test. As another non-limited example, a patient who
reported balance difficulty on the BNI question may also have a
MDS-UPDRS posture stability (PS) score at least 2 points, the
patient may fall at least three times per month.
[0169] In some embodiments, the present disclosure provides methods
for evaluating fall-related symptoms in a subject with
neurodegenerative disease such as Parkinson's disease or
Parkinson's-related disease utilizing the modified BNI Balance
Scale constituted of the original UPDRS, the MDS-UPDRS, the Romberg
Test, the Turning test, the Standing On One Leg test, and the
Tandem gait test. Exemplary tests include Dyskinesias from
questions 32-35 from original UPDRS, Response fluctuation from
questions 36-39 from original UPDRS, Sleep disturbance from
question 40 from original UPDRS, Hoehn & Yahr Staging System
(0-V), MDS-UPDRS 132 points, Axial, Midline Part of MDS-UPDRS 24
points, Gait Subtest from MDS-UPDRS, Postural Stability, known as
the "pull test", from MDS-UPDRS, and Freezing of Gait (FOG) Subtest
from MDS-UPDRS.
[0170] In some embodiments, the present disclosure provides methods
for evaluating fall-related symptoms in a subject with
neurodegenerative disease such as Parkinson's disease or
Parkinson's-related disease. In some embodiments, the subject is
evaluated by the ability to walk 25 feet or an equivalent of 7.62
meters. The numbers of steps the subject taken to walk 25 feet or
an equivalent of 7.62 meters are counted and timed.
[0171] In some embodiments, the present disclosure provides methods
for evaluating fall-related symptoms in a subject with
neurodegenerative disease such as Parkinson's disease or
Parkinson's-related disease. In some embodiments, the subject is
evaluated for Freezing of Gait in the "on" and "off" state with FOG
questions 2.13 from MDS-UPDRS and the MDS-UPDRS subtest of FOG
(Espay A J, Fasano A, van Nuenen B F L, "On state freezing of gait
in Parkinson's disease: a paradoxical levodopa-induced
complication", Neuerology 78:454-457, Jan. 18, 2012).
[0172] In some embodiments, the present disclosure provides methods
and compositions for treating fall-related symptoms in a subject
with Parkinson's disease or Parkinson-related disease comprising
administering the compositions to the subject and evaluating the
subject's response to the treatment. In some embodiments, the
compositions are administered to the subject over a period of 6
months (Fahn S, Elton R L, Members of the UPDRS Development
Committee Unified Parkinson's Disease Rating Scale, Fahn S, Marsden
C D, Calne D, Goldstein M, "Recent Developments in Parkinson's
Disease", Macmillan Healthcare Information Florham Park N.J., pp
3-163, 1988). The effectiveness of the treatment is evaluated by
the subject's performance on "on off" testing. In some embodiments,
an evaluation is performed every 2 months for up to 6 months. After
completion of the six months period, the subject is administered
with placebo and is evaluated by "on off" testing 2 months after
the cross-over. In some cases, the subject is given two months
after the cross-over for treatment re-titration. After the
cross-over and re-titration period, the subject's performance on
"on off" testing are then evaluated every 2 months for up to 6
months.
[0173] In some embodiments, the present disclosure provides methods
and compositions for treating fall-related symptoms in a subject
with Parkinson's disease or Parkinson-related disease, the methods
comprise administering the compositions comprising nicotine or a
salt thereof to the subject and evaluating the subject's response
to the treatment. In some embodiments, a placebo is administered to
the subject over a period of 6 months. The effectiveness of the
treatment is evaluated by the subject's performance on "on off"
testing. In some embodiments, an evaluation is performed every 2
months for up to 6 months. After six months, the subject is
administered with the compositions comprising nicotine and salt
thereof to serve as his/her own control. Without being limited by
any theory, subjects who are on placebo may not be able to tolerate
full dose of the present compositions, the subject may undergo
another titration period of the treatment. After 2 months of the
cross-over and completion of the re-titration, the treatment
effectiveness is evaluated by the subject's performance on "on off"
testing every 2 months for up to 6 months.
[0174] In some embodiments, the present disclosure provides methods
and compositions for treating fall-related symptoms in a subject
with Parkinson's disease or Parkinson-related disease, the methods
comprise administering the compositions comprising nicotine or a
salt thereof to the subject and evaluating the subject's response
to the treatment. In some embodiments, the present compositions are
administered to the subject over a period of 6 months. The
effectiveness of the treatment is evaluated by the subject's
performance on "on off" testing every 2 months for up to 6 months.
After six months, the subject is administered with placebo to serve
as his/her own control. After 2 months of the cross-over and
completion of the re-titration, the treatment effectiveness is
evaluated by the subject's performance on "on off" testing every 2
months for up to 6 months.
[0175] In some embodiments, the effectiveness of treating
fall-related symptoms in a subject with Parkinson's disease or
Parkinson-related disease is monitored regularly by evaluating the
subject's response to the treatment. The evaluation can be done by
a health professional who provides such as preventive, curative,
promotional or rehabilitative health care services in a systematic
way to people, families or communities. A health professional can
be a health care practitioner. Examples of health care practitioner
include physicians, dentists, pharmacists, physician assistants,
nurses (including advanced practice registered nurses), surgeons,
surgeon's assistant, surgical technologist, midwives (obsterics),
dietitians, therapists, psychologists, chiropractors, clinical
officers, social workers, phlebotomists, physical therapists,
respiratory therapists, occupational therapists, audiologists,
speech pathologists, optometrists, emergency medical technicians,
paramedics, medical laboratory scientists, medical prosthetic
technicians, radiographers and a wide variety of other human
resources trained to provide some type of health care service. They
often work in hospitals, health care centers, and other service
delivery points, but also in academic training research, and
administration. Some provide care and treatment services for
patients in private homes. In some cases, a community health worker
can work outside of formal health care institutions. Health care
practitioners are commonly grouped into a number of professions:
medical (including generalists and specialists); nursing (including
various professional titles); Midwifery (Obstetrics); dentistry;
and other health professions, including occupational therapy,
pharmacy, physical therapy, paramedicine respiratory therapy,
radiographer and many other health specialists.
[0176] In some embodiments, the effectiveness of the treating
fall-related symptoms using the present methods and compositions is
evaluated by monitoring the subject's response to the treatment
such as the subject's performance on "on off" testing. In some
embodiments, the subject is evaluated every 2 months for at least 6
to 14 months. In some embodiments, the subject is evaluated for at
least four times over a period of 6 months. For example, the
subject is evaluated upon receiving treatment, as known as the
initial visit, 2 months after receiving initial treatment; 4 months
after receiving initial treatment; and 6 months after receiving
initial treatment. In various embodiments, the subject undergoes
treatment cross-over and a re-titration period for about 2 months.
The subject is evaluated for performance on "on off" testing. After
completion of the re-titration period, the subject is then
evaluated every 2 months for at least 6. In some embodiments, the
subject is evaluated for at least four times over a period of 6
months after the treatment cross-over and re-titration period. For
example, the subject is evaluated upon completion of the
treatment-cross over and re-titration; 2 months after treatment
cross-over and completion of re-titration; 4 months after treatment
cross-over and completion of re-titration; and 6 months after
treatment cross-over and completion of re-titration.
[0177] The present disclosure also provides methods for evaluating
fall-related symptoms or predicting recurrent falls in a subject
with neurodegenerative disease such as Parkinson's disease or
Parkinson-related diseases. In various embodiments, the subject is
diagnosed with typical Parkinson's disease. The subject can be male
or female between ages of 30 to 83. The subject is in an "on" state
of the Hoehn and Yahr Stage II, III, IV and has Montreal Cognitive
Assessment (MOCA) score .gtoreq.26. In some embodiments, the
subject has fallen at least once in past year. The subject is also
on stable dose of levodopa, dopamine agonist, amantadine, and/or
monoamine oxidase B inhibitor.
[0178] In some embodiments, a subject with neurodegenerative
disease and fall-related symptoms can be treated with the present
methods and compositions. The subject may not have atypical
Parkinson's disease, or disorders that while infrequent, result in
a high number of falls especially early in the disease. These
disorders include Progressive Supranuclear Palsy (PSP), Multiple
System Atrophy (MSA), Primary Freezing of Gait (PFG), and
Corticobasiler Degeneration. The subject may not have Parkinson's
disease and dementia. Excluded are also subjects who are legally
blind, subjects who have major orthopedic problems of their hips or
knees, patients who needed hip or knee replacements. Although
orthostatic hypotension, reflecting involvement of the autonomic
nervous system (ANS), can be part of Parkinson's disease, it can
also result from the use of anti-hypertensives, diuretics, selected
anti-depressants, and dehydration. It is often difficult to
determine if a fall from orthostatic hypotension resulted from
impairment of the ANS or from drugs and dehydration, subjects with
orthostatic hypotension are excluded. Also excluded are subjects
with a history of schizophrenia, schizo-affective disorder, bipolar
disorder, hallucinations, psychoses or delusions, subjects who had
deep brain stimulation (DBS) intervention, and/or subjects with a
history of recent stroke or myocardial infarction.
[0179] In one aspect, the present disclosure provides for a method
of treating cognitive-related symptoms in a subject with
neurodegenerative disease comprising administering nicotine or a
salt thereof to the subject. In some embodiments, the nicotine and
salt thereof is administered in dosage form. The administration of
nicotine or a salt thereof can reduce cognitive impairment in a
subject with a neurodegenerative disease such as Parkinson's
disease, schizophrenia, mild cognitive impairment, Alzheimer's
Disease, vascular cognitive impairment, Subcortical Ischaemic
Vascular Dementia, Frontotemporal Mild Cognitive Impairment, and
Frontotemporal Dementia. In some embodiments, the subject has
typical Parkinson's disease. In some embodiments, the subject is
diagnosed for Parkinson's disease for at least 5 years. In some
embodiments, the subject is on dopaminergic agent treatment. In
some embodiments, the subject has fallen or recurrent falls in past
year.
[0180] In various embodiments, the present disclosure provides for
a method of treating cognitive-related symptoms in a subject with
neurodegenerative disease comprising administering a composition
comprising a nicotinic receptor modulator to the subject. In some
embodiments, the composition is administered in dosage form. In
some embodiments, the nicotinic receptor modulator is a nicotinic
receptor agonist or antagonist. The administration of the
composition can reduce cognitive impairment in a subject with
neurodegenerative diseases such as Parkinson's disease,
schizophrenia, mild cognitive impairment, Alzheimer's Disease,
vascular cognitive impairment, Subcortical Ischaemic Vascular
Dementia, Frontotemporal Mild Cognitive Impairment, and
Frontotemporal Dementia. In some embodiments, the subject has
typical Parkinson's disease.
[0181] In some embodiments, the present disclosure provides for a
method of treating cognitive-related symptoms in a subject with
Parkinson's disease, schizophrenia, mild cognitive impairment,
Alzheimer's Disease, vascular cognitive impairment, Subcortical
Ischaemic Vascular Dementia, Frontotemporal Mild Cognitive
Impairment, or Frontotemporal Dementia comprising administering
nicotine or a salt thereof to the subject. The administration of
nicotine or a salt thereof can reduce cognitive impairments. In
some embodiments, the subject is on dopaminergic agent treatment.
Non limiting examples of dopaminergic agents includes levodopa,
bromocriptine, pergolide, pramipexole, cabergoline, ropinorole,
apomorphine, carbidopa, dopamine agonists, monoamine oxidase type B
inhibitors, amantadine or a combination thereof. In some
embodiments, the subject is on levodopa, carbidopa, dopamine
agonist, amantadine, monoamine oxidase B inhibitor, or combination
thereof.
[0182] In various embodiments, disclosed herein are methods and
compositions for reducing cognitive-related symptoms in a subject
with Parkinson's disease, schizophrenia, mild cognitive impairment,
Alzheimer's Disease, vascular cognitive impairment, Subcortical
Ischaemic Vascular Dementia, Frontotemporal Mild Cognitive
Impairment, or Frontotemporal Dementia and is on dopaminergic agent
treatment, e.g. levodopa/carbidopa, the methods and compositions
comprising administering nicotine or a salt thereof to the subject.
The administration of nicotine or a salt thereof in combination
with a dopaminergic agent can reduce cognitive-related symptoms. In
various embodiments, utilization of the disclosed methods and
compositions reduces side effects related to dopaminergic agent
treatment, for example, reducing dyskinesia and improving response
fluctuations: "wearing off and of off".
Pharmaceutical Composition
[0183] In some embodiments, the present disclosure provides for a
pharmaceutical composition comprising nicotine or a salt thereof
for treating fall-related and cognitive-related symptoms in a
subject with neurodegenerative disease. In some embodiments, the
composition can be any nicotine-containing composition described
herein. In some embodiments, the pharmaceutical composition is
formulated in dosage form for administration. In a related
embodiment, the composition comprises a nicotinic receptor
modulator, such as nicotine or a salt thereof described herein. In
some embodiments, the nicotinic receptor modulator is a nicotinic
receptor agonist. In a related embodiment, the dosage form is a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier, examples of which are described herein.
[0184] Pharmaceutical compositions of the invention suitable for
oral administration can be presented as discrete dosage forms, such
as capsules, cachets, or tablets, or liquids or aerosol sprays each
containing a predetermined amount of an active ingredient as a
powder or in granules, a solution, or a suspension in an aqueous or
non-aqueous liquid, an oil-inwater emulsion, or a water-in-oil
liquid emulsion. Such dosage forms can be prepared by any of the
methods of pharmacy, but all methods include the step of bringing
the active ingredient into association with the carrier, which
constitutes one or more necessary ingredients.
[0185] In some embodiments, the composition comprises nicotine or a
salt thereof at the amount of between about 0.001 to 1000 mg, 0.01
to 100 mg, 0.1 to 200 mg, 3 to 200 mg, 5 to 500 mg, 10 to 100 mg,
10 to 1000 mg, 50 to 200 mg, or 100 to 1000 mg of nicotine or a
salt thereof. In some embodiments, the pharmaceutical composition
comprises about or more than about 0.001 mg, 0.0.1 mg, 0.1 mg, 0.5
mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15
mg, 18 mg, 20 mg, 24 mg, 25 mg, 50 mg, 100 mg, 200 mg, 500 mg, 1000
mg, or more of nicotine or a salt thereof.
[0186] In some embodiments, the composition comprises nicotine or a
salt thereof at the amount of between about 0.1 mg to 5 mg, between
about 1 mg to 3 mg, between about 2 mg to 20 mg, between about 10
mg to 25 mg, between about 15 mg to 50 mg, between about 20 mg to
200 mg, between about 100 mg to 500 mg, between about 150 mg to
1000 mg. In some embodiments, the amount of nicotine or a salt
thereof is between about 1 mg to 24 mg. In some embodiments, the
amount of nicotine or a salt thereof is about 0.001 mg, about 0.01
mg, about 0.1 mg, about 1 mg about 2 mg, about 3 mg, about 4 mg,
about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about
10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, about 20
mg, about 25 mg, about 30 mg, about 50 mg, about 100 mg, about 150
mg, about 200 mg, about 500 mg, about 1000 mg. In some embodiments,
the amount of nicotine or a salt thereof is less than about 0.001
mg, less than about 0.01 mg, less than about 0.1 mg, less than
about 1 mg, less than about 2 mg, less than about 3 mg, less than
about 4 mg, less than about 5 mg, less than about 6 mg, less than
about 7 mg, less than about 8 mg, less than about 9 mg, less than
about 10 mg, less than about 12 mg, less than about 14 mg, less
than about 16 mg, less than about 18 mg, less than about 20 mg,
less than about 25 mg, less than about 30 mg, less than about 50
mg, less than about 100 mg, less than about 150 mg, less than about
200 mg, less than about 500 mg, less than about 1000 mg. In some
embodiments, the nicotine or a salt thereof is present at about 1
mg. In some embodiments, the nicotine or a salt thereof is present
at about 2 mg. In some embodiments, the nicotine or a salt thereof
is present at about 4 mg. In some embodiments, the nicotine or a
salt thereof is present at about 6 mg.
Formulation
[0187] In some embodiments, the composition is formulated for
administering to a subject in need thereof wherein the composition
comprises nicotine or a salt thereof in an amount effective to
reduce fall-related symptoms. The treatment may comprise reducing
fall-related symptoms such as reducing fall frequency, reducing
injuries related to fall, reducing severity of injuries related to
fall, and improving balance, posture stability and gait. The
treatment may also comprise reducing cognitive-related symptoms.
The treatment may also comprise reducing FOG. The treatment may
also comprise reducing LIDs. The composition may be formulated in
dosage form. In some embodiments, the composition is formulated in
dosage form comprising a nicotinic receptor modulator such as a
nicotinic receptor agonist. In various embodiments, the composition
is formulated for administering in combination with a dopaminergic
agent, e.g. levodopa, carbidopa, dopamine agonists, amantadine, and
monoamine oxidase B inhibitor, or combination thereof.
[0188] In various embodiments, the composition comprises between
about 00.001 to 1000 mg, 0.01 to 100 mg, 0.1 to 200 mg, 3 to 200
mg, 5 to 500 mg, 10 to 100 mg, 10 to 1000 mg, 50 to 200 mg, or 100
to 1000 mg of nicotine or a salt thereof. In some embodiments, the
pharmaceutical composition comprises about or more than about 0.001
mg, 0.0.1 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7
mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 2.0 mg, 100 mg,
200 mg, 500 mg, 1000 mg, or more of nicotine or a salt thereof. In
some embodiments, the pharmaceutical composition comprises at least
about 1 mg of nicotine or a salt thereof. In some embodiments, the
pharmaceutical composition comprises at least about 2 mg of
nicotine or a salt thereof. In some embodiments, the pharmaceutical
composition comprises at least about 4 mg of nicotine or a salt
thereof. In some embodiments, the pharmaceutical composition
comprises at least about 6 mg of nicotine or a salt thereof. In
some embodiments, the pharmaceutical composition comprises an
amount between about 1-10 mg of nicotine or a salt thereof.
[0189] In some embodiments, the composition is formulated to
provide a therapeutically effective amount of a compound of the
present disclosure as the active ingredient, or a pharmaceutically
acceptable salt, ester, prodrug, solvate, hydrate or derivative
thereof. Where desired, the pharmaceutical composition contain
pharmaceutically acceptable salt and/or coordination complex
thereof, and one or more pharmaceutically acceptable excipients,
carriers, including inert solid diluents and fillers, diluents,
including sterile aqueous solution and various organic solvents,
permeation enhancers, solubilizers and adjuvants.
[0190] The subject composition disclosed herein can be formulated
for administration via oral, intravenous injection, and/or topical.
In some embodiments, the disclosed pharmaceutical composition is
formulated for topical administration.
[0191] In some embodiments, the composition further comprises a
carrier compatible with intravenous, intraarterial, oral,
parenteral, buccal, topical, transdermal, rectal, intramuscular,
subcutaneous, intraosseous, transmucosal, inhalation, or
intraperitoneal administration.
[0192] In some embodiments, the composition is formulated as a unit
dosage in liquid, gel, semi-liquid, semi-solid, and/or solid
form.
[0193] In some embodiments, the composition is formulated as a
topical cream.
[0194] In some embodiments, the composition is formulated in a
food. In some embodiments, the composition is formulated in a
beverage. In some embodiments, the composition is formulated in a
dietary supplement.
[0195] Described herein are multiparticulate formulations, wherein
the formulation can deliver an immediate-release of nicotine, and a
second immediate-release dose of nicotine about 2 hours to about 8
hours after administration. The formulation can deliver an
immediate-release dose of nicotine at time zero, 1, 2, 3, 4, 5, 6,
7, 8, 9, or 10. The formulation can deliver a second
immediate-release dose of nicotine approximately 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more than 20 hours
after administration. The formulation can deliver an
immediate-release dose of nicotine 1 hour to 8 hours, 1 hour to 7
hours, 1 hour to 6 hours, 1 hour to 5 hours, 1 hour to 4 hours, 1
hour to 3 hours, 2 hours to 8 hours, 2 hours to 7 hours, 2 hours to
6 hours, 2 hours to 5 hours, or 2 hours to 4 hours after
administration. The formulation can deliver a second
immediate-release dose of nicotine 1 hour to 8 hours, 1 hour to 7
hours, 1 hour to 6 hours, 1 hour to 5 hours, 1 hour to 4 hours, 1
hour to 3 hours, 2 hours to 8 hours, 2 hours to 7 hours, 2 hours to
6 hours, 2 hours to 5 hours, or 2 hours to 4 hours after
administration. The multiparticulate formulation may comprise: a
first population of particles coated with a drug layer comprising
nicotine; and a second population of particles coated with the drug
layer comprising nicotine, further coated with a delayed release
coating. The first population of particles may be further coated
with an immediate release coating. The immediate release coating
may be an Opadry coating. The delayed release coating may comprise
a polymer, a plasticizer, and an antitack agent. The polymer, the
plasticizer, and the antitack agent may be present in a ratio of
6:1:3. The polymer may be Eudragit RS and/or Eudragit RL. The
plasticizer may be triethyl citrate. The antitack agent may be
talc. The administration of said multiparticulate formulation may
result in a pharmacokinetic profile having plasma nicotine levels
below about 7.5 ng/ml at a time point about 120 minutes after
administration of said dosage form. The administration of said
multiparticulate formulation may result in a pharmacokinetic
profile having plasma nicotine levels below about 7.5 ng/ml at a
time point about 180 minutes after administration of said dosage
form. The pharmacokinetic profile may have plasma nicotine levels
below about 5 ng/ml at about 180 minutes after administration. The
pharmacokinetic profile may have plasma nicotine levels below about
5 ng/ml at about 120 minutes after administration. The
pharmacokinetic profile may have plasma nicotine levels above about
5 ng/ml at about 45 to 90 minutes after administration. The
pharmacokinetic profile may have plasma nicotine levels above about
15 ng/ml at about 60 minutes after administration.
[0196] Described herein are formulations and methods relating to
use of the formulations comprising nicotine or a salt thereof,
wherein administration can result in a pharmacokinetic profile
having plasma nicotine levels below about 7.5 ng/ml at a time point
about 120 minutes after administration of said dosage form. The
administration of said dosage form can result in a pharmacokinetic
profile having plasma nicotine levels below about 7.5 ng/ml at a
time point about 180 minutes after administration of said dosage
form. The pharmacokinetic profile can have plasma nicotine levels
below about 5 ng/ml at about 180 minutes after administration. The
pharmacokinetic profile can have plasma nicotine levels below about
5 ng/ml at about 120 minutes after administration. The
pharmacokinetic profile can have plasma nicotine levels above about
5 ng/ml at about 45 to 90 minutes after administration. The
pharmacokinetic profile can have plasma nicotine levels above about
15 ng/ml at about 60 minutes after administration.
[0197] Provided herein are formulations and methods relating to use
of the formulations comprising nicotine or a salt thereof. The
formulations and methods as described herein may reduce the
frequency of falls in a subject at risk of falling. The
formulations and methods as described herein may prevent falls. The
formulations and methods as described herein may reduce FOG. In
some embodiments, formulations and methods as described herein
reduce fall-related symptoms. In some embodiments, formulations and
methods as described herein reduce frequency of fall-related
complications. In some embodiments, formulations and methods as
described herein reduce frequency of fall, reduce frequency of
injuries related to fall, reduce severity of injuries related to
fall, improve posture stability, improve static balance, improve
locomotor ability, or improve gait. In some embodiments,
formulations and methods as described herein do not result in
tolerance or dependence on the nicotine or salt thereof. In some
embodiments, the subject has Parkinson's disease (PD) or PD-related
disorders.
[0198] Described herein are formulations and methods relating to
use of the formulations comprising nicotine or a salt thereof,
wherein administration of nicotine or a salt thereof can result in
plasma nicotine levels below about 0.25 ng/mL, 0.5 ng/mL, 1.0
ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0
ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5
ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5
ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL,
17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23
ng/mL, 24 ng/mL, or 25 ng/mL at a time point after administration.
Administration of nicotine or a salt thereof can result in plasma
nicotine levels above about 0.25 ng/mL, 0.5 ng/mL, 1.0 ng/mL, 1.5
ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0 ng/mL, 4.5
ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5 ng/mL, 8.0
ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5 ng/mL, 11
ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL, 17 ng/mL,
18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23 ng/mL, 24
ng/mL, or 25 ng/mL at a time point after administration.
Administration of nicotine or a salt thereof can result in plasma
nicotine levels about 0.25 ng/mL, 0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL,
2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL,
5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL,
8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5 ng/mL, 11 ng/mL,
12 ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL, 17 ng/mL, 18
ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23 ng/mL, 24 ng/mL,
or 25 ng/mL at a time point after administration. Administration of
nicotine or a salt thereof can result in plasma nicotine levels in
a range of about 0 ng/mL to 20 ng/mL, 1.0 ng/mL to 19 ng/mL, 1.5
ng/mL to 18 ng/mL, 2.0 ng/mL to 17 ng/mL, 2.5 ng/mL to 16 ng/mL,
3.0 ng/mL to 15 ng/mL, 3.5 ng/mL to 14 ng/mL, 4.0 ng/mL to 12
ng/mL, 4.5 ng/mL to 11 ng/mL, 5.0 ng/mL to 10 ng/mL, 6.0 ng/mL to 9
ng/mL, 6.5 ng/mL to 8.5 ng/mL, or 7.0 ng/mL to 8.0 ng/mL at a time
point after administration. The time point after administration may
be about or within a range spanning 5 minutes, 10 minutes, 15
minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40
minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65
minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90
minutes, 95 minutes, 100 minutes, 110 minutes, 120 minutes, 130
minutes, 140 minutes, 150 minutes, 160 minutes, 170 minutes, 180
minutes, 190 minutes, 200 minutes, 220 minutes, 240 minutes, 260
minutes, 280 minutes, 300 minutes, 320 minutes, 340 minutes, 360
minutes, 380 minutes, 400 minutes, 420 minutes, 440 minutes, 460
minutes, 480 minutes, 500 minutes, 520 minutes, 540 minutes, 560
minutes, 580 minutes, 600 minutes or more than 600 minutes after
administration.
[0199] In some embodiments, administration of nicotine or a salt
thereof can result in peak plasma nicotine levels below about 0.25
ng/mL, 0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0
ng/mL, 3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5
ng/mL, 7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5
ng/mL, 10.0 ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14
ng/mL, 15 ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL,
21 ng/mL, 22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point
after administration. Administration of nicotine or a salt thereof
can result in plasma nicotine levels above about 0.25 ng/mL, 0.5
ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5
ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0
ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0
ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15
ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL,
22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point after
administration. Administration of nicotine or a salt thereof can
result in plasma nicotine levels about 0.25 ng/mL, 0.5 ng/mL, 1.0
ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0
ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5
ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5
ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL,
17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23
ng/mL, 24 ng/mL, or 25 ng/mL at a time point after administration.
Administration of nicotine or a salt thereof can result in plasma
nicotine levels in a range of about 0 ng/mL to 20 ng/mL, 1.0 ng/mL
to 19 ng/mL, 1.5 ng/mL to 18 ng/mL, 2.0 ng/mL to 17 ng/mL, 2.5
ng/mL to 16 ng/mL, 3.0 ng/mL to 15 ng/mL, 3.5 ng/mL to 14 ng/mL,
4.0 ng/mL to 12 ng/mL, 4.5 ng/mL to 11 ng/mL, 5.0 ng/mL to 10
ng/mL, 6.0 ng/mL to 9 ng/mL, 6.5 ng/mL to 8.5 ng/mL, or 7.0 ng/mL
to 8.0 ng/mL at a time point after administration. The time point
after administration may be about or within a range spanning 5
minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30
minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55
minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80
minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 110
minutes, 120 minutes, 130 minutes, 140 minutes, 150 minutes, 160
minutes, 170 minutes, 180 minutes, 190 minutes, 200 minutes, 220
minutes, 240 minutes, 260 minutes, 280 minutes, 300 minutes, 320
minutes, 340 minutes, 360 minutes, 380 minutes, 400 minutes, 420
minutes, 440 minutes, 460 minutes, 480 minutes, 500 minutes, 520
minutes, 540 minutes, 560 minutes, 580 minutes, 600 minutes or more
than 600 minutes after administration. Following peak plasma
nicotine levels, plasma nicotine levels may be below about, or
about 0.25 ng/mL, 0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5
ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0
ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0
ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13
ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL,
20 ng/mL, 21 ng/mL, 22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a
time point about 30 minutes, 40 minutes, 60 minutes, 75 minutes, 90
minutes, 120 minutes, 140 minutes, 150 minutes, 160 minutes, 180
minutes, 200 minutes, 240 minutes, 270 minutes, 300 minutes, 350
minutes, 400 minutes, 500 minutes, 600 minutes, or more than 600
minutes following reaching the peak plasma level.
[0200] Administration of nicotine or a salt thereof can result in
peak plasma nicotine levels below about 0.25 ng/mL, 0.5 ng/mL, 1.0
ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0
ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5
ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5
ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL,
17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23
ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 25 minutes after
administration. Administration of nicotine or a salt thereof may
result in peak plasma nicotine levels above about 0.25 ng/mL, 0.5
ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5
ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0
ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0
ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15
ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL,
22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 25
minutes after administration. Administration of nicotine or a salt
thereof may result in peak plasma nicotine levels about 0.25 ng/mL,
0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL,
3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL,
7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL,
10.0 ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15
ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL,
22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 25
minutes after administration. The time point may be less than 25
minutes after administration. The time point may be more than 25
minutes after administration. The time point may be in a range of 0
minutes to 25 minutes, 5 minutes to 20 minutes, or 10 minutes to 15
minutes after administration. Following peak plasma nicotine levels
about 25 minutes after administration, plasma nicotine levels may
be below about, or about 0.25 ng/mL, 0.5 ng/mL, 1.0 ng/mL, 1.5
ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0 ng/mL, 4.5
ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5 ng/mL, 8.0
ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5 ng/mL, 11
ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL, 17 ng/mL,
18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23 ng/mL, 24
ng/mL, or 25 ng/mL at a time point about 30 minutes, 40 minutes, 60
minutes, 75 minutes, 90 minutes, 120 minutes, 140 minutes, 150
minutes, 160 minutes, 180 minutes, 200 minutes, 240 minutes, 270
minutes, 300 minutes, 350 minutes, 400 minutes, 500 minutes, 600
minutes, or more than 600 minutes following administration.
[0201] Administration of nicotine or a salt thereof may result in
peak plasma nicotine levels below about 0.25 ng/mL, 0.5 ng/mL, 1.0
ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0
ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5
ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5
ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL,
17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23
ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 60 minutes after
administration. Administration of nicotine or a salt thereof may
result in peak plasma nicotine levels above about 0.25 ng/mL, 0.5
ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5
ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0
ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0
ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15
ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL,
22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 60
minutes after administration. Administration of nicotine or a salt
thereof may result in peak plasma nicotine levels about 0.25 ng/mL,
0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL,
3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL,
7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL,
10.0 ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15
ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL,
22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 60
minutes after administration. The time point may be less than 60
minutes after administration. The time point may be more than 60
minutes after administration. The time point may be in a range of 0
minutes to 60 minutes, 5 minutes to 55 minutes, 10 minutes to 50
minutes, 15 minutes to 45 minutes, 20 minutes to 40 minutes, or 25
minutes to 30 minutes after administration. Following peak plasma
nicotine levels about 60 minutes after administration, the plasma
nicotine levels may be below about, above about, or about 0.25
ng/mL, 0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0
ng/mL, 3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5
ng/mL, 7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5
ng/mL, 10.0 ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14
ng/mL, 15 ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL,
21 ng/mL, 22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point
about 65 minutes, 75 minutes, 90 minutes, 120 minutes, 140 minutes,
150 minutes, 160 minutes, 180 minutes, 200 minutes, 240 minutes,
270 minutes, 300 minutes, 350 minutes, 400 minutes, 500 minutes,
600 minutes, or more than 600 minutes following administration.
[0202] Administration of nicotine or a salt thereof may result in
peak plasma nicotine levels below about 0.25 ng/mL, 0.5 ng/mL, 1.0
ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0
ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5
ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5
ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL,
17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23
ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 90 minutes after
administration. Administration of nicotine or a salt thereof may
result in peak plasma nicotine levels above about 0.25 ng/mL, 0.5
ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5
ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0
ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0
ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15
ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL,
22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 90
minutes after administration. Administration of nicotine or a salt
thereof may result in peak plasma nicotine levels about 0.25 ng/mL,
0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL,
3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL,
7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL,
10.0 ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15
ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL,
22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 90
minutes after administration. The time point may be less than 90
minutes after administration. The time point may be more than 90
minutes after administration. The time point may be in a range of 0
minutes to 90 minutes, 5 minutes to 85 minutes, 10 minutes to 80
minutes, 15 minutes to 75 minutes, 20 minutes to 70 minutes, 25
minutes to 65 minutes, 30 minutes to 60 minutes, 35 minutes to 55
minutes, or 40 minutes to 50 minutes after administration.
Following peak plasma nicotine levels about 90 minutes after
administration, the plasma nicotine levels may be below about,
above about, or about 0.25 ng/mL, 0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL,
2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL,
5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL,
8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5 ng/mL, 11 ng/mL,
12 ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL, 17 ng/mL, 18
ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23 ng/mL, 24 ng/mL,
or 25 ng/mL at a time point about 95 minutes, 100 minutes, 100
minutes, 120 minutes, 140 minutes, 150 minutes, 160 minutes, 180
minutes, 200 minutes, 240 minutes, 270 minutes, 300 minutes, 350
minutes, 400 minutes, 500 minutes, 600 minutes, or more than 600
minutes following administration.
[0203] Administration of nicotine or a salt thereof may result in
peak plasma nicotine levels below about 0.25 ng/mL, 0.5 ng/mL, 1.0
ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0
ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5
ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5
ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL,
17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23
ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 120 minutes
after administration. Administration of nicotine or a salt thereof
may result in peak plasma nicotine levels above about 0.25 ng/mL,
0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL,
3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL,
7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL,
10.0 ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15
ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL,
22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 120
minutes after administration. Administration of nicotine or a salt
thereof may result in peak plasma nicotine levels about 0.25 ng/mL,
0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL,
3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL,
7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL,
10.0 ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15
ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL,
22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 120
minutes after administration. The time point may be less than 120
minutes after administration. The time point may be more than 120
minutes after administration. The time point may be in a range of 0
minutes to 120 minutes, 5 minutes to 115 minutes, 10 minutes to 110
minutes, 15 minutes to 105 minutes, 20 minutes to 100 minutes, 25
minutes to 95 minutes, 30 minutes to 90 minutes, 35 minutes to 85
minutes, 40 minutes to 75 minutes after administration. 45 minutes
to 70 minutes, or 50 minutes to 65 minutes after administration.
Following peak plasma nicotine levels about 120 minutes after
administration, the plasma nicotine levels may be below about,
above about, or about 0.25 ng/mL, 0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL,
2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL,
5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL,
8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5 ng/mL, 11 ng/mL,
12 ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL, 17 ng/mL, 18
ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23 ng/mL, 24 ng/mL,
or 25 ng/mL at a time point about 130 minutes, 140 minutes, 150
minutes, 160 minutes, 180 minutes, 200 minutes, 240 minutes, 270
minutes, 300 minutes, 350 minutes, 400 minutes, 500 minutes, 600
minutes, or more than 600 minutes following administration.
[0204] Administration of nicotine or a salt thereof may result in
peak plasma nicotine levels below about 0.25 ng/mL, 0.5 ng/mL, 1.0
ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0
ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5
ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5
ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL,
17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23
ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 180 minutes
after administration. Administration of nicotine or a salt thereof
may result in peak plasma nicotine levels above about 0.25 ng/mL,
0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL,
3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL,
7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL,
10.0 ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15
ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL,
22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 180
minutes after administration. Administration of nicotine or a salt
thereof may result in peak plasma nicotine levels about 0.25 ng/mL,
0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL,
3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL,
7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL,
10.0 ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15
ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL,
22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 180
minutes after administration. The time point may be less than 180
minutes after administration. The time point may be more than 180
minutes after administration. The time point may be in a range of 0
minutes to 180 minutes, 5 minutes to 175 minutes, 10 minutes to 170
minutes, 15 minutes to 165 minutes, 20 minutes to 160 minutes, 25
minutes to 155 minutes, 30 minutes to 150 minutes, 35 minutes to
145 minutes, 40 minutes to 140 minutes after administration. 45
minutes to 135 minutes, 50 minutes to 130 minutes, 55 minutes to
125 minutes, 60 minutes to 120 minutes, 65 minutes to 115 minutes,
70 minutes to 110 minutes, 75 minutes to 105 minutes, or 80 minutes
to 100 minutes after administration. Following peak plasma nicotine
levels about 180 minutes after administration, the plasma nicotine
levels may be below about, above about, or about 0.25 ng/mL, 0.5
ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5
ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0
ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0
ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15
ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL,
22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 185
minutes, 200 minutes, 240 minutes, 270 minutes, 300 minutes, 350
minutes, 400 minutes, 500 minutes, 600 minutes, or more than 600
minutes following administration.
[0205] Administration of nicotine or a salt thereof may result in
peak plasma nicotine levels below about 0.25 ng/mL, 0.5 ng/mL, 1.0
ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0
ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5
ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5
ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL,
17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23
ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 240 minutes
after administration. Administration of nicotine or a salt thereof
may result in peak plasma nicotine levels above about 0.25 ng/mL,
0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL,
3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL,
7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL,
10.0 ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15
ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL,
22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 240
minutes after administration. Administration of nicotine or a salt
thereof may result in peak plasma nicotine levels about 0.25 ng/mL,
0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL,
3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL,
7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL,
10.0 ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15
ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL,
22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 240
minutes after administration. The time point may be less than 240
minutes after administration. The time point may be more than 240
minutes after administration. The time point may be in a range of 0
minutes to 240 minutes, 5 minutes to 220 minutes, 10 minutes to 200
minutes, 15 minutes to 180 minutes, 20 minutes to 170 minutes, 25
minutes to 160 minutes, 30 minutes to 150 minutes, 35 minutes to
145 minutes, 40 minutes to 140 minutes after administration. 45
minutes to 135 minutes, 50 minutes to 130 minutes, 55 minutes to
125 minutes, 60 minutes to 120 minutes, 65 minutes to 115 minutes,
70 minutes to 110 minutes, 75 minutes to 105 minutes, or 80 minutes
to 100 minutes after administration. Following peak plasma nicotine
levels about 240 minutes after administration, the plasma nicotine
levels may be below about, above about, or about 0.25 ng/mL, 0.5
ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5
ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0
ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0
ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15
ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL,
22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 250
minutes, 270 minutes, 300 minutes, 350 minutes, 400 minutes, 500
minutes, 600 minutes, or more than 600 minutes following
administration.
[0206] Administration of nicotine or a salt thereof may result in
peak plasma nicotine levels below about 0.25 ng/mL, 0.5 ng/mL, 1.0
ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0
ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5
ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5
ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL,
17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23
ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 300 minutes
after administration. Administration of nicotine or a salt thereof
may result in peak plasma nicotine levels above about 0.25 ng/mL,
0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL,
3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL,
7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL,
10.0 ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15
ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL,
22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 300
minutes after administration. Administration of nicotine or a salt
thereof may result in peak plasma nicotine levels about 0.25 ng/mL,
0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL,
3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL,
7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL,
10.0 ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15
ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL,
22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 300
minutes after administration. The time point may be less than 300
minutes after administration. The time point may be more than 300
minutes after administration. The time point may be in a range of 0
minutes to 300 minutes, 5 minutes to 280 minutes, 10 minutes to 260
minutes, 15 minutes to 240 minutes, 20 minutes to 220 minutes, 25
minutes to 200 minutes, 30 minutes to 180 minutes, 35 minutes to
160 minutes, 40 minutes to 140 minutes after administration. 45
minutes to 135 minutes, 50 minutes to 130 minutes, 55 minutes to
125 minutes, 60 minutes to 120 minutes, 65 minutes to 115 minutes,
70 minutes to 110 minutes, 75 minutes to 105 minutes, or 80 minutes
to 100 minutes after administration. Following peak plasma nicotine
levels about 300 minutes after administration, the plasma nicotine
levels may be below about, above about, or about 0.25 ng/mL, 0.5
ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5
ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0
ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0
ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15
ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL,
22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 310
minutes, 320 minutes, 350 minutes, 400 minutes, 500 minutes, 600
minutes, or more than 600 minutes following administration.
[0207] Administration of nicotine or a salt thereof may result in
peak plasma nicotine levels below about 0.25 ng/mL, 0.5 ng/mL, 1.0
ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0
ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5
ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5
ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL,
17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23
ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 360 minutes
after administration. Administration may result in peak plasma
nicotine levels above about 0.25 ng/mL, 0.5 ng/mL, 1.0 ng/mL, 1.5
ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0 ng/mL, 4.5
ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5 ng/mL, 8.0
ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5 ng/mL, 11
ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL, 17 ng/mL,
18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23 ng/mL, 24
ng/mL, or 25 ng/mL at a time point about 360 minutes after
administration. The time point may be less than 360 minutes after
administration. Administration may result in peak plasma nicotine
levels about 0.25 ng/mL, 0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0
ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0
ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5
ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5 ng/mL, 11 ng/mL, 12
ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL,
19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23 ng/mL, 24 ng/mL, or 25
ng/mL at a time point about 360 minutes after administration. The
time point may be less than 360 minutes after administration. The
time point may be more than 360 minutes after administration. The
time point may be in a range of 0 minutes to 360 minutes, 5 minutes
to 320 minutes, 10 minutes to 280 minutes, 15 minutes to 240
minutes, 20 minutes to 200 minutes, 25 minutes to 180 minutes, 30
minutes to 160 minutes, 35 minutes to 150 minutes, 40 minutes to
140 minutes after administration. 45 minutes to 135 minutes, 50
minutes to 130 minutes, 55 minutes to 125 minutes, 60 minutes to
120 minutes, 65 minutes to 115 minutes, 70 minutes to 110 minutes,
75 minutes to 105 minutes, or 80 minutes to 100 minutes after
administration. Following peak plasma nicotine levels about 360
minutes after administration, the plasma nicotine levels may be
below about, above about, or about 0.25 ng/mL, 0.5 ng/mL, 1.0
ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0
ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5
ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5
ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL,
17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23
ng/mL, 24 ng/mL, or 25 ng/mL at a time point about 370 minutes, 380
minutes, 390 minutes, 400 minutes, 500 minutes, 600 minutes, or
more than 600 minutes following administration.
[0208] Provided herein is administration of nicotine or salt
thereof, wherein plasma nicotine levels is a percentage lower than
peak plasma nicotine levels at a particular time. The plasma
nicotine levels may be at least 5%, 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45%, 50%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%
lower than peak plasma nicotine levels. The plasma nicotine levels
may be about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 65%,
70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% lower than peak plasma
nicotine levels. The plasma nicotine levels may be in a range of
5%-100%, 10%-95%, 15%-90%, 20%-85%, 25%-80%, 30%-75%, 35%-70%, or
40%-65% lower than peak plasma nicotine levels. The particular time
may be about or within a range spanning 5 minutes, 10 minutes, 15
minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40
minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 65
minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90
minutes, 95 minutes, 100 minutes, 110 minutes, 120 minutes, 130
minutes, 140 minutes, 150 minutes, 160 minutes, 170 minutes, 180
minutes, 190 minutes, 200 minutes, 220 minutes, 240 minutes, 260
minutes, 280 minutes, 300 minutes, 320 minutes, 340 minutes, 360
minutes, 380 minutes, 400 minutes, 420 minutes, 440 minutes, 460
minutes, 480 minutes, 500 minutes, 520 minutes, 540 minutes, 560
minutes, 580 minutes, 600 minutes or more than 600 minutes. For
example, the plasma nicotine levels may be at least 5%, 10%, 15%,
20%, 25%, 30%, 35%, 40%, 45%, 50%, 65%, 70%, 75%, 80%, 85%, 90%,
95%, 99%, or 100% lower than peak plasma nicotine levels at a time
about 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30
minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55
minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80
minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 110
minutes, 120 minutes, 130 minutes, 140 minutes, 150 minutes, 160
minutes, 170 minutes, 180 minutes, 190 minutes, 200 minutes, 220
minutes, 240 minutes, 260 minutes, 280 minutes, 300 minutes, 320
minutes, 340 minutes, 360 minutes, 380 minutes, 400 minutes, 420
minutes, 440 minutes, 460 minutes, 480 minutes, 500 minutes, 520
minutes, 540 minutes, 560 minutes, 580 minutes, 600 minutes or more
than 600 minutes.
[0209] In some embodiments, plasma nicotine levels at a particular
time after reaching the peak plasma level are at least 5%, 10%,
15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 65%, 70%, 75%, 80%, 85%,
90%, 95%, 99%, or 100% lower than peak plasma nicotine levels. The
plasma nicotine levels at a particular time after reaching the peak
plasma level may be about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, 50%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% lower
than peak plasma nicotine levels. The plasma nicotine levels at a
particular time after reaching the peak plasma level may be in a
range of 5%-100%, 10%-95%, 15%-90%, 20%-85%, 25%-80%, 30%-75%,
35%-70%, or 40%-65% lower than peak plasma nicotine levels. In
certain embodiments, plasma nicotine levels at a particular time
after administration may be at least 5%, 10%, 15%, 20%, 25%, 30%,
35%, 40%, 45%, 50%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%
lower than peak plasma nicotine levels. The plasma nicotine levels
at a particular time after administration are be about 5%, 10%,
15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 65%, 70%, 75%, 80%, 85%,
90%, 95%, 99%, or 100% lower than peak plasma nicotine levels. The
plasma nicotine levels at a particular time after administration
may be in a range of 5%-100%, 10%-95%, 15%-90%, 20%-85%, 25%-80%,
30%-75%, 35%-70%, or 40%-65% lower than peak plasma nicotine
levels. The particular time may be about or within a range spanning
5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30
minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55
minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80
minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 110
minutes, 120 minutes, 130 minutes, 140 minutes, 150 minutes, 160
minutes, 170 minutes, 180 minutes, 190 minutes, 200 minutes, 220
minutes, 240 minutes, 260 minutes, 280 minutes, 300 minutes, 320
minutes, 340 minutes, 360 minutes, 380 minutes, 400 minutes, 420
minutes, 440 minutes, 460 minutes, 480 minutes, 500 minutes, 520
minutes, 540 minutes, 560 minutes, 580 minutes, 600 minutes or more
than 600 minutes after administration. For example, the plasma
nicotine levels may be at least 5%, 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45%, 50%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%
lower than peak plasma nicotine levels at a time about 5 minutes,
10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35
minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60
minutes, 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85
minutes, 90 minutes, 95 minutes, 100 minutes, 110 minutes, 120
minutes, 130 minutes, 140 minutes, 150 minutes, 160 minutes, 170
minutes, 180 minutes, 190 minutes, 200 minutes, 220 minutes, 240
minutes, 260 minutes, 280 minutes, 300 minutes, 320 minutes, 340
minutes, 360 minutes, 380 minutes, 400 minutes, 420 minutes, 440
minutes, 460 minutes, 480 minutes, 500 minutes, 520 minutes, 540
minutes, 560 minutes, 580 minutes, 600 minutes or more than 600
minutes after administration.
[0210] In some embodiments, administration of nicotine or a salt
thereof result in peak plasma nicotine levels and following peak
plasma nicotine levels, the plasma nicotine levels is below about
or more than about 0.25 ng/mL, 0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0
ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0
ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5
ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5 ng/mL, 11 ng/mL, 12
ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL,
19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23 ng/mL, 24 ng/mL, or 25
ng/mL at a time point after administration. Administration of
nicotine or a salt thereof may result in peak plasma nicotine
levels and following peak plasma nicotine levels, the plasma
nicotine levels may be about 0.25 ng/mL, 0.5 ng/mL, 1.0 ng/mL, 1.5
ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0 ng/mL, 4.5
ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5 ng/mL, 8.0
ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5 ng/mL, 11
ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL, 17 ng/mL,
18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23 ng/mL, 24
ng/mL, or 25 ng/mL at a time point after administration. The peak
plasma levels may be below about, above about, or about 0.25 ng/mL,
0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0 ng/mL, 2.5 ng/mL, 3.0 ng/mL,
3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 6.5 ng/mL,
7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5 ng/mL, 9.0 ng/mL, 9.5 ng/mL,
10.0 ng/mL, 10.5 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, 15
ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL, 19 ng/mL, 20 ng/mL, 21 ng/mL,
22 ng/mL, 23 ng/mL, 24 ng/mL, or 25 ng/mL at a time point after
administration. The time point after administration may be about or
within a range spanning 5 minutes, 10 minutes, 15 minutes, 20
minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45
minutes, 50 minutes, 55 minutes, 60 minutes, 65 minutes, 70
minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes, 95
minutes, 100 minutes, 110 minutes, 120 minutes, 130 minutes, 140
minutes, 150 minutes, 160 minutes, 170 minutes, 180 minutes, 190
minutes, 200 minutes, 220 minutes, 240 minutes, 260 minutes, 280
minutes, 300 minutes, 320 minutes, 340 minutes, 360 minutes, 380
minutes, 400 minutes, 420 minutes, 440 minutes, 460 minutes, 480
minutes, 500 minutes, 520 minutes, 540 minutes, 560 minutes, 580
minutes, 600 minutes or more than 600 minutes after
administration.
[0211] In some embodiments, peak plasma nicotine levels vary over
time. For example, administration of the nicotine or salt thereof
may result in a peak plasma nicotine levels above 10 ng/mL about 25
minutes to about 50 minutes followed by a plasma nicotine level of
below about 7.5 ng/mL about 180 minutes after administration. The
administration of the nicotine or salt thereof may result in a peak
plasma nicotine levels above 7.5 ng/mL about 25 minutes to about 50
minutes followed by a plasma nicotine level of below about 5 ng/mL
about 180 minutes after administration. The peak plasma nicotine
levels may vary having any peak plasma nicotine levels as described
herein at any time after administration as described herein.
[0212] In some embodiments, a time from peak plasma nicotine levels
to baseline varies. The time from peak plasma nicotine levels to
baseline may be about or within a range spanning 5 minutes, 10
minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35
minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60
minutes, 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85
minutes, 90 minutes, 95 minutes, 100 minutes, 110 minutes, 120
minutes, 130 minutes, 140 minutes, 150 minutes, 160 minutes, 170
minutes, 180 minutes, 190 minutes, 200 minutes, 220 minutes, 240
minutes, 260 minutes, 280 minutes, 300 minutes, 320 minutes, 340
minutes, 360 minutes, 380 minutes, 400 minutes, 420 minutes, 440
minutes, 460 minutes, 480 minutes, 500 minutes, 520 minutes, 540
minutes, 560 minutes, 580 minutes, 600 minutes or more than 600
minutes. Baseline nicotine may be below about 3 ng/mL. Baseline
nicotine may be about 0.25 ng/mL, 0.50 ng/mL, 0.75 ng/mL, 1.0
ng/mL, 1.25 ng/mL, 1.5 ng/mL, 1.75 ng/mL, 2.0 ng/mL, 2.25 ng/mL,
2.5 ng/mL, 2.75 ng/mL, 3.0 ng/mL, 3.25 ng/mL, 3.5 ng/mL, 3.75
ng/mL, or 4.0 ng/mL. Baseline nicotine may be in a range of 0.1
ng/mL to 3.0 ng/mL, 0.25 ng/mL to 2.75 ng/mL, 0.5 ng/mL to 2.5
ng/mL, 0.75 ng/mL to 2.25 ng/mL, or 1.0 ng/mL to 2 ng/mL.
[0213] A time from a first peak plasma nicotine levels to a second
peak plasma nicotine levels may vary. The first peak plasma
nicotine levels or the second plasma nicotine levels may be below,
above, or about 0.25 ng/mL, 0.5 ng/mL, 1.0 ng/mL, 1.5 ng/mL, 2.0
ng/mL, 2.5 ng/mL, 3.0 ng/mL, 3.5 ng/mL, 4.0 ng/mL, 4.5 ng/mL, 5.0
ng/mL, 6.0 ng/mL, 6.5 ng/mL, 7.0 ng/mL, 7.5 ng/mL, 8.0 ng/mL, 8.5
ng/mL, 9.0 ng/mL, 9.5 ng/mL, 10.0 ng/mL, 10.5 ng/mL, 11 ng/mL, 12
ng/mL, 13 ng/mL, 14 ng/mL, 15 ng/mL, 16 ng/mL, 17 ng/mL, 18 ng/mL,
19 ng/mL, 20 ng/mL, 21 ng/mL, 22 ng/mL, 23 ng/mL, 24 ng/mL, or 25
ng/mL. The time between the first peak plasma nicotine levels to
the second peak plasma nicotine levels may be about or within a
range spanning 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25
minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50
minutes, 55 minutes, 60 minutes, 65 minutes, 70 minutes, 75
minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, 100
minutes, 110 minutes, 120 minutes, 130 minutes, 140 minutes, 150
minutes, 160 minutes, 170 minutes, 180 minutes, 190 minutes, 200
minutes, 220 minutes, 240 minutes, 260 minutes, 280 minutes, 300
minutes, 320 minutes, 340 minutes, 360 minutes, 380 minutes, 400
minutes, 420 minutes, 440 minutes, 460 minutes, 480 minutes, 500
minutes, 520 minutes, 540 minutes, 560 minutes, 580 minutes, 600
minutes or more than 600 minutes. The time between the first peak
plasma nicotine levels to the second peak plasma nicotine levels
may be at least 180 minutes. The time between the first peak plasma
nicotine levels to the second peak plasma nicotine levels may be at
most 600 minutes.
[0214] Peak plasma cotinine levels may vary following
administration of nicotine or a salt thereof. Administration of
nicotine or a salt thereof may result in peak plasma cotinine
levels of below, above, or about 1.0 ng/mL, 2.0 ng/mL, 3.0 ng/mL,
4.0 ng/mL, 5.0 ng/mL, 6.0 ng/mL, 7.0 ng/mL, 8.0 ng/mL, 9.0 ng/mL,
10.0 ng/mL, 12 ng/mL, 14 ng/mL, 16 ng/mL, 18 ng/mL, 20 ng/mL, 22
ng/mL, 24 ng/mL, 26 ng/mL, 28 ng/mL, 30.0 ng/mL, 32 ng/mL, 34
ng/mL, 36 ng/mL, 38 ng/mL, 40 ng/mL, 42 ng/mL, 44 ng/mL, 46 ng/mL,
48 ng/mL, 50 ng/mL, 52 ng/mL, 54 ng/mL, 56 ng/mL, 58 ng/mL, 60
ng/mL at a time point after administration. 10 ng/mL, 20 ng/mL, 30
ng/mL, 40 ng/mL, 50 ng/mL, 60 ng/mL, 70 ng/mL, 80 ng/mL, 90 ng/mL,
100 ng/mL, 160 ng/mL, 180 ng/mL, 200 ng/mL, 220 ng/mL, 240 ng/mL,
260 ng/mL, 280 ng/mL, 300 ng/mL, 32 ng/mL, 340 ng/mL, 360 ng/mL,
380 ng/mL, 400 ng/mL, 420 ng/mL, 440 ng/mL, 460 ng/mL, 480 ng/mL,
500 ng/mL, 520 ng/mL, 540 ng/mL, 560 ng/mL, 580 ng/mL, 600 ng/mL,
640 ng/mL, 700 ng/mL, 750 ng/mL, 800 ng/mL, 850 ng/mL, 900 ng/mL,
1000 ng/mL, 1100 ng/mL, 1200 ng/mL, 1400 ng/mL, 1600 ng/mL, or more
than 1600 ng/mL at a time point after administration.
Administration of nicotine or a salt thereof may result in peak
plasma cotinine levels in a range of about 10 ng/mL to about 50
ng/mL. Administration of nicotine or a salt thereof may result in
peak plasma cotinine levels in a range of about 10 ng/mL to about
1100 ng/mL. Administration of nicotine or a salt thereof may result
in peak plasma cotinine levels in a range of about 30 ng/mL to
about 1200 ng/mL or about 30 ng/mL to about 500 ng/mL. The time
point after administration may be about or within a range spanning
5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30
minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55
minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80
minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 110
minutes, 120 minutes, 130 minutes, 140 minutes, 150 minutes, 160
minutes, 170 minutes, 180 minutes, 190 minutes, 200 minutes, 220
minutes, 240 minutes, 260 minutes, 280 minutes, 300 minutes, 320
minutes, 340 minutes, 360 minutes, 380 minutes, 400 minutes, 420
minutes, 440 minutes, 460 minutes, 480 minutes, 500 minutes, 520
minutes, 540 minutes, 560 minutes, 580 minutes, 600 minutes or more
than 600 minutes after administration.
[0215] In some embodiments, a time from peak plasma cotinine levels
to baseline varies. The time from peak plasma cotinine levels to
baseline may be about or within a range spanning 5 minutes, 10
minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35
minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60
minutes, 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85
minutes, 90 minutes, 95 minutes, 100 minutes, 110 minutes, 120
minutes, 130 minutes, 140 minutes, 150 minutes, 160 minutes, 170
minutes, 180 minutes, 190 minutes, 200 minutes, 220 minutes, 240
minutes, 260 minutes, 280 minutes, 300 minutes, 320 minutes, 340
minutes, 360 minutes, 380 minutes, 400 minutes, 420 minutes, 440
minutes, 460 minutes, 480 minutes, 500 minutes, 520 minutes, 540
minutes, 560 minutes, 580 minutes, 600 minutes or more than 600
minutes. Baseline nicotine may be below about 1 ng/mL. Baseline
nicotine may be about 0.25 ng/mL, 0.50 ng/mL, 0.75 ng/mL, 1.0
ng/mL, 1.25 ng/mL, 1.5 ng/mL, 1.75 ng/mL, or 2.0 ng/mL. Baseline
nicotine may be in a range of 0.1 ng/mL to 1.0 ng/mL.
Pharmaceutical Composition for Oral Administration
[0216] In some embodiments, the disclosure provides a
pharmaceutical composition for oral administration containing a
nicotinic receptor modulator such as nicotine or a salt thereof,
and a pharmaceutical excipient suitable for oral administration.
The composition may be in the form of a solid, liquid, gel,
semi-liquid, or semi-solid. In some embodiments, the composition
further comprises a second agent.
[0217] Pharmaceutical composition of the disclosure suitable for
oral administration can be presented as discrete dosage forms, such
as capsules, cachets, or tablets, or liquids or aerosol sprays each
containing a predetermined amount of an active ingredient as a
powder or in granules, a solution, or a suspension in an aqueous or
non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil
liquid emulsion. Such dosage forms can be prepared by any of the
methods of pharmacy, which typically include the step of bringing
the active ingredient into association with the carrier. In
general, the composition are prepared by uniformly and intimately
admixing the active ingredient with liquid carriers or finely
divided solid carriers or both, and then, if necessary, shaping the
product into the desired presentation. For example, a tablet can be
prepared by compression or molding, optionally with one or more
accessory ingredients. Compressed tablets can be prepared by
compressing in a suitable machine the active ingredient in a
free-flowing form such as powder or granules, optionally mixed with
an excipient such as, but not limited to, a binder, a lubricant, an
inert diluent, and/or a surface active or dispersing agent. Molded
tablets can be made by molding in a suitable machine a mixture of
the powdered compound moistened with an inert liquid diluent.
[0218] This disclosure further encompasses anhydrous pharmaceutical
composition and dosage forms comprising an active ingredient, since
water can facilitate the degradation of some compounds. For
example, water may be added (e.g., 5%) in the pharmaceutical arts
as a means of simulating long-term storage in order to determine
characteristics such as shelf-life or the stability of formulations
overtime. Anhydrous pharmaceutical composition and dosage forms of
the disclosure can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
Pharmaceutical composition and dosage forms of the disclosure which
contain lactose can be made anhydrous if substantial contact with
moisture and/or humidity during manufacturing, packaging, and/or
storage is expected. An anhydrous pharmaceutical composition may be
prepared and stored such that its anhydrous nature is maintained.
Accordingly, anhydrous composition may be packaged using materials
known to prevent exposure to water such that they can be included
in suitable formulary kits. Examples of suitable packaging include,
but are not limited to, hermetically sealed foils, plastic or the
like, unit dose containers, blister packs, and strip packs.
[0219] An active ingredient can be combined in an intimate
admixture with a pharmaceutical carrier according to conventional
pharmaceutical compounding techniques. The carrier can take a wide
variety of forms depending on the form of preparation desired for
administration. In preparing the composition for an oral dosage
form, any of the usual pharmaceutical media can be employed as
carriers, such as, for example, water, glycols, oils, alcohols,
flavoring agents, preservatives, coloring agents, and the like in
the case of oral liquid preparations (such as suspensions,
solutions, and elixirs) or aerosols; or carriers such as starches,
sugars, micro-crystalline cellulose, diluents, granulating agents,
lubricants, binders, and disintegrating agents can be used in the
case of oral solid preparations, in some embodiments without
employing the use of lactose. For example, suitable carriers
include powders, capsules, and tablets, with the solid oral
preparations. If desired, tablets can be coated by standard aqueous
or nonaqueous techniques.
[0220] Binders suitable for use in pharmaceutical composition and
dosage forms include, but are not limited to, corn starch, potato
starch, or other starches, gelatin, natural and synthetic gums such
as acacia, sodium alginate, alginic acid, other alginates, powdered
tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl
cellulose, cellulose acetate, carboxymethyl cellulose calcium,
sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl
cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose,
microcrystalline cellulose, and mixtures thereof.
[0221] Examples of suitable fillers for use in the pharmaceutical
composition and dosage forms disclosed herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch,
and mixtures thereof.
[0222] Disintegrants may be used in the composition of the
disclosure to provide tablets that disintegrate when exposed to an
aqueous environment. Too much of a disintegrant may produce tablets
which may disintegrate in the bottle. Too little may be
insufficient for disintegration to occur and may thus alter the
rate and extent of release of the active ingredient(s) from the
dosage form. Thus, a sufficient amount of disintegrant that is
neither too little nor too much to detrimentally alter the release
of the active ingredient(s) may be used to form the dosage forms of
the compounds disclosed herein. The amount of disintegrant used may
vary based upon the type of formulation and mode of administration,
and may be readily discernible to those of ordinary skill in the
art. About 0.5 to about 15 weight percent of disintegrant, or about
1 to about 5 weight percent of disintegrant, may be used in the
pharmaceutical composition. Disintegrants that can be used to form
pharmaceutical composition and dosage forms of the disclosure
include, but are not limited to, agar-agar, alginic acid, calcium
carbonate, microcrystalline cellulose, croscarmellose sodium,
crospovidone, polacrilin potassium, sodium starch glycolate, potato
or tapioca starch, other starches, pre-gelatinized starch, other
starches, clays, other algins, other celluloses, gums or mixtures
thereof.
[0223] Lubricants which can be used to form pharmaceutical
composition and dosage forms of the disclosure include, but are not
limited to, calcium stearate, magnesium stearate, mineral oil,
light mineral oil, glycerin, sorbitol, mannitol, polyethylene
glycol, other glycols, stearic acid, sodium lauryl sulfate, talc,
hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,
sunflower oil, sesame oil, olive oil, corn oil, and soybean oil),
zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures
thereof. Additional lubricants include, for example, a syloid
silica gel, a coagulated aerosol of synthetic silica, or mixtures
thereof. A lubricant can optionally be added, in an amount of less
than about 1 weight percent of the pharmaceutical composition.
[0224] When aqueous suspensions and/or elixirs are desired for oral
administration, the active ingredient therein may be combined with
various sweetening or flavoring agents, coloring matter or dyes
and, if so desired, emulsifying and/or suspending agents, together
with such diluents as water, ethanol, propylene glycol, glycerin
and various combinations thereof.
[0225] In various embodiments, the present disclosure provides for
a dosage form includes capsules or tablets comprising an effective
amount of nicotine or a salt thereof for treatment of fall-related
symptoms in a subject with neurodegenerative disease such as
Parkinson's disease and Parkinson-related diseases. The capsules
and tablets can be uncoated or coated by known techniques to delay
disintegration and absorption in the gastrointestinal tract and
thereby provide a sustained action over a longer period. For
example, a time delay material such as glyceryl monostearate or
glyceryl distearate can be employed. Formulations for oral use can
also be presented as hard gelatin capsules wherein the active
ingredient is mixed with an inert solid diluent, for example,
calcium carbonate, calcium phosphate or kaolin, or as soft gelatin
capsules wherein the active ingredient is mixed with water or an
oil medium, for example, peanut oil, liquid paraffin or olive
oil.
[0226] In various embodiments, the dosage form of the present
disclosure is a capsule. In various embodiments, the dosage form is
formulated for pulsatile release. In some embodiments, the capsule
comprises a powder comprising nicotine for providing said first
release peak upon administration to a patient, and said capsule
further comprises beads comprising nicotine for providing said
second, third, and fourth release peaks upon administration to a
patient. Beads may be coated with immediate release coatings or
delayed release coatings. Beads are selected from the group
consisting of enteric-coated beads, erodible-matrix beads,
wax-coated beads, ethylcellulose-coated beads, silicone elastomer
coated beads, and combinations thereof. In various embodiments,
said capsule comprises a water-swellable matrix to provide a
gastroretentive formulation with repeated pulsatile release in the
stomach. A water-swellable matrix may comprise polyethylene oxide,
hydroxypropylmethylcellulose, and combinations thereof. The
pulsatile release formulation may provide for a 1 ng/mL to 20 ng/ml
plasma concentration of nicotine about 2 h after administration of
a dopaminergic agent.
[0227] In some embodiments, the dosage form is a tablet. In various
embodiments, the dosage form is formulated for pulsatile release.
Tablets comprising at least one coating and a core, wherein an
outermost coating comprises nicotine for the first release peak,
and said core comprises nicotine for the second, third, and fourth
release peaks, are encompassed. In various embodiments, the coating
is selected from an enteric coating, an erodible-matrix coating, a
wax coating, an ethylcellulose coating, a silicone elastomer
coating, and combinations thereof.
[0228] In some embodiments, the disclosure includes a multilayer
tablet comprising an immediate release layer and pulsatile release
layer(s). In some embodiments, the immediate release layer
comprises nicotine or a metabolite. In some embodiments, each
pulsatile release layer comprises nicotine or a metabolite. In some
embodiments, the immediate release layer and each pulsatile release
layer comprise nicotine or a metabolite.
[0229] The tablet core of the dosage form of the present invention
can comprise a matrix of a drug and a water soluble polymer,
suitable for pulsatile release upon entry and following exit of the
tablet from the acidic environment of the stomach and dissolution
of the coating upon entry into the higher pH environment of the
intestine.
[0230] The tablet core can be prepared by conventional dry
granulation methods without using a solvent. Typically, the enteric
coating is applied using a conventional process known in the
art.
[0231] In some embodiments, the dosage form comprises an enteric
coating comprising an enteric polymer. Suitable enteric polymers
include, but are not limited to, methacrylic acid/methacrylic acid
ester copolymer, a methacrylic acid/acrylic acid ester copolymer,
cellulose acetate phthalate, hydroxypropyl methylcellulose
pthalate, hydroxypropyl methyl cellulose acetate succinate,
cellulose acetate trimellitate, and polyvinyl acetate
phthalate.
[0232] Enteric polymers suitable for use in the present disclosure
include, but are not limited to polyacrylate copolymers such as
methacrylic acid/methacrylic acid ester copolymers or methacrylic
acid/acrylic acid ester copolymers, such as USP/NF, Types A, B, or
C, which are available from Rohm GmbH under the brand name
Eudragit.TM.; cellulose derivatives, such as cellulose acetate
phthalate, hydroxypropyl mefhylcellulose pthalate, hydroxypropyl
methyl cellulose acetate succinate, and cellulose acetate
trimellitate; and polyvinyl acetate phthalate, such as is available
from Colorcon, under the brand name SURETERIC.RTM., and the like.
In some embodiments, the enteric polymer is a polyvinyl acetate
phtalate.
[0233] Suitable water soluble pore-forming agents for use in the
enteric coating in the dosage forms of the present disclosure
include, but are not limited to, povidone K 30, polyvinyl alcohol,
cellulose derivatives such as hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, methyl cellulose or sodium
carboxymefhylcellulose; sucrose; xylitol, sorbitol, mannitol,
maltose, xylose, glucose, potassium chloride, sodium chloride,
polysorbate 80, polyethylene glycol, propylene glycol, sodium
citrate, or combinations of any of the above. The pore-forming
agent preferably comprises hydroxypropyl methyl cellulose.
[0234] The composition of the enteric coating is preferably
designed to ensure adherence of the coating to the tablet core.
Methods for selection of coating compositions that adhere to
compressed tablets are known. See, for example, Pharmaceutical
Dosage Forms: Tablets, 2nd ed., vol. 1, Lieberman et al., ed.
(Marcel Dekker, Inc.; New York, N.Y.; 1989), pp. 266-271,
incorporated herein by reference. Additionally, the cores can be
subcoated prior to coating with an enteric coating. The subcoat can
function; to provide that pores in the core are filled in prior to
coating with an enteric coat to insure against coating failure. The
sub-coat can consist of any film forming formulation examples
include Opadry (Colorcon), Opadry II (Colorcon), AMT (Colorcon) and
HPMC.
[0235] The enteric coating can be about 3% to about 10% by weight
of the dosage form of the present invention. In some cases, the
enteric coating can be about 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%,
13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% by weight of the dosage
form of the present disclosure.
[0236] In some embodiments, the tablet core of a dosage form of the
disclosure comprises at least one hydrophilic polymer. Suitable
hydrophilic polymers include, but are not limited to, hydroxypropyl
methylcellulose (hereinafter, "HPMC"), hydroxypropylcellulose, or
other water soluble or swellable polymers such as sodium
carboxymethyl cellulose, xanthan gum, acacia, tragacanth gum, guar
gum, karaya gum, alginates, gelatin, and albumin The hydrophilic
polymers can be present in amounts ranging from about 5% to about
95% by weight of the system. In some embodiments, the hydrophilic
polymers are selected from the group consisting of cellulose
ethers, such as hydroxypropylmethylcellulose,
hydroxypropylcellulose, methylcellulose, and mixtures thereof.
[0237] Surfactant which can be used to form pharmaceutical
composition and dosage forms of the disclosure include, but are not
limited to, hydrophilic surfactants, lipophilic surfactants, and
mixtures thereof. That is, a mixture of hydrophilic surfactants may
be employed, a mixture of lipophilic surfactants may be employed,
or a mixture of at least one hydrophilic surfactant and at least
one lipophilic surfactant may be employed.
[0238] A suitable hydrophilic surfactant may generally have an HLB
value of at least 10, while suitable lipophilic surfactants may
generally have an HLB value of or less than about 10. An empirical
parameter used to characterize the relative hydrophilicity and
hydrophobicity of non-ionic amphiphilic compounds is the
hydrophilic-lipophilic balance ("HLB" value). Surfactants with
lower HLB values are more lipophilic or hydrophobic, and have
greater solubility in oils, while surfactants with higher HLB
values are more hydrophilic, and have greater solubility in aqueous
solutions. Hydrophilic surfactants are generally considered to be
those compounds having an HLB value greater than about 10, as well
as anionic, cationic, or zwitterionic compounds for which the HLB
scale is not generally applicable. Similarly, lipophilic (i.e.,
hydrophobic) surfactants are compounds having an HLB value equal to
or less than about 10. However, HLB value of a surfactant is merely
a rough guide generally used to enable formulation of industrial,
pharmaceutical and cosmetic emulsions.
[0239] Hydrophilic surfactants may be either ionic or non-ionic.
Suitable ionic surfactants include, but are not limited to,
alkylammonium salts; fusidic acid salts; fatty acid derivatives of
amino acids, oligopeptides, and polypeptides; glyceride derivatives
of amino acids, oligopeptides, and polypeptides; lecithins and
hydrogenated lecithins; lysolecithins and hydrogenated
lysolecithins; phospholipids and derivatives thereof,
lysophospholipids and derivatives thereof, carnitine fatty acid
ester salts; salts of alkylsulfates; fatty acid salts; sodium
docusate; acylactylates; mono- and di-acetylated tartaric acid
esters of mono- and di-glycerides; succinylated mono- and
di-glycerides; citric acid esters of mono- and di-glycerides; and
mixtures thereof.
[0240] Within the aforementioned group, ionic surfactants include,
by way of example: lecithins, lysolecithin, phospholipids,
lysophospholipids and derivatives thereof, carnitine fatty acid
ester salts; salts of alkylsulfates; fatty acid salts; sodium
docusate; acylactylates; mono- and di-acetylated tartaric acid
esters of mono- and di-glycerides; succinylated mono- and
di-glycerides; citric acid esters of mono- and di-glycerides; and
mixtures thereof.
[0241] Ionic surfactants may be the ionized forms of lecithin,
lysolecithin, phosphatidylcholine, phosphatidylethanolamine,
phosphatidylglycerol, phosphatidic acid, phosphatidylserine,
lysophosphatidylcholine, lysophosphatidylethanolamine,
lysophosphatidylglycerol, lysophosphatidic acid,
lysophosphatidylserine, PEG-phosphatidylethanolamine,
PVP-phosphatidylethanolamine, lactylic esters of fatty acids,
stearoyl-2-lactylate, stearoyl lactylate, succinylated
monoglycerides, mono/diacetylated tartaric acid esters of
mono/diglycerides, citric acid esters of mono/diglycerides,
cholylsarcosine, caproate, caprylate, caprate, laurate, myristate,
palmitate, oleate, ricinoleate, linoleate, linolenate, stearate,
lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines,
palmitoyl carnitines, myristoyl carnitines, and salts and mixtures
thereof.
[0242] Hydrophilic non-ionic surfactants may include, but not
limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides;
lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as
polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such
as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol
fatty acid esters such as polyethylene glycol fatty acids
monoesters and polyethylene glycol fatty acids diesters;
polyethylene glycol glycerol fatty acid esters; polyglycerol fatty
acid esters; polyoxyalkylene sorbitan fatty acid esters such as
polyethylene glycol sorbitan fatty acid esters; hydrophilic
transesterification products of a polyol with at least one member
of the group consisting of glycerides, vegetable oils, hydrogenated
vegetable oils, fatty acids, and sterols; polyoxyethylene sterols,
derivatives, and analogues thereof, polyoxyethylated vitamins and
derivatives thereof, polyoxyethylene-polyoxypropylene block
copolymers; and mixtures thereof, polyethylene glycol sorbitan
fatty acid esters and hydrophilic transesterification products of a
polyol with at least one member of the group consisting of
triglycerides, vegetable oils, and hydrogenated vegetable oils. The
polyol may be glycerol, ethylene glycol, polyethylene glycol,
sorbitol, propylene glycol, pentaerythritol, or a saccharide.
[0243] Other hydrophilic-non-ionic surfactants include, without
limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32
laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20
oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400
oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate,
PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate,
PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate,
PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl
oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40
palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil,
PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor
oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6
caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,
polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol,
PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate,
PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9
lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl
ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24
cholesterol, polyglyceryl-10oleate, Tween 40, Tween 60, sucrose
monostearate, sucrose monolaurate, sucrose monopalmitate, PEG
10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and
poloxamers.
[0244] Suitable lipophilic surfactants include, by way of example
only: fatty alcohols; glycerol fatty acid esters; acetylated
glycerol fatty acid esters; lower alcohol fatty acids esters;
propylene glycol fatty acid esters; sorbitan fatty acid esters;
polyethylene glycol sorbitan fatty acid esters; sterols and sterol
derivatives; polyoxyethylated sterols and sterol derivatives;
polyethylene glycol alkyl ethers; sugar esters; sugar ethers;
lactic acid derivatives of mono- and di-glycerides; hydrophobic
transesterification products of a polyol with at least one member
of the group consisting of glycerides, vegetable oils, hydrogenated
vegetable oils, fatty acids and sterols; oil-soluble
vitamins/vitamin derivatives; and mixtures thereof. Within this
group, preferred lipophilic surfactants include glycerol fatty acid
esters, propylene glycol fatty acid esters, and mixtures thereof,
or are hydrophobic transesterification products of a polyol with at
least one member of the group consisting of vegetable oils,
hydrogenated vegetable oils, and triglycerides.
[0245] In one embodiment, the composition may include a solubilizer
to ensure good solubilization and/or dissolution of the compound of
the present disclosure and to minimize precipitation of the
compound of the present disclosure. This can be especially
important for composition for non-oral use, e.g., composition for
injection. A solubilizer may also be added to increase the
solubility of the hydrophilic drug and/or other components, such as
surfactants, or to maintain the composition as a stable or
homogeneous solution or dispersion.
[0246] Examples of suitable solubilizers include, but are not
limited to, the following: alcohols and polyols, such as ethanol,
isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene
glycol, butanediols and isomers thereof, glycerol, pentaerythritol,
sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene
glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl
methylcellulose and other cellulose derivatives, cyclodextrins and
cyclodextrin derivatives; ethers of polyethylene glycols having an
average molecular weight of about 200 to about 6000, such as
tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG;
amides and other nitrogen-containing compounds such as
2-pyrrolidone, 2-piperidone, .epsilon.-caprolactam,
N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,
N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone;
esters such as ethyl propionate, tributylcitrate, acetyl
triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl
oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene
glycol monoacetate, propylene glycol diacetate,
.epsilon.-caprolactone and isomers thereof, .delta.-valerolactone
and isomers thereof, .beta.-butyrolactone and isomers thereof; and
other solubilizers known in the art, such as dimethyl acetamide,
dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin,
diethylene glycol monoethyl ether, and water.
[0247] Mixtures of solubilizers may also be used. Examples include,
but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl
caprylate, dimethylacetamide, N-methylpyrrolidone,
N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl
methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene
glycol 200-100, glycofurol, transcutol, propylene glycol, and
dimethyl isosorbide. Particularly preferred solubilizers include
sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol
and propylene glycol.
[0248] The amount of solubilizer that can be included is not
particularly limited. The amount of a given solubilizer may be
limited to a bioacceptable amount, which may be readily determined
by one of skill in the art. In some circumstances, it may be
advantageous to include amounts of solubilizers far in excess of
bioacceptable amounts, for example to maximize the concentration of
the drug, with excess solubilizer removed prior to providing the
composition to a patient using conventional techniques, such as
distillation or evaporation. Thus, if present, the solubilizer can
be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by
weight, based on the combined weight of the drug, and other
excipients. If desired, very small amounts of solubilizer may also
be used, such as 5%, 2%, 1% or even less. Typically, the
solubilizer may be present in an amount of about 1% to about 100%,
more typically about 5% to about 25% by weight.
[0249] The composition can further include one or more
pharmaceutically acceptable additives and excipients. Such
additives and excipients include, without limitation, detackifiers,
anti-foaming agents, buffering agents, polymers, antioxidants,
preservatives, chelating agents, viscomodulators, tonicifiers,
flavorants, colorants, odorants, opacifiers, suspending agents,
binders, fillers, plasticizers, lubricants, and mixtures
thereof.
[0250] In addition, an acid or a base may be incorporated into the
composition to facilitate processing, to enhance stability, or for
other reasons. Examples of pharmaceutically acceptable bases
include amino acids, amino acid esters, ammonium hydroxide,
potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate,
aluminum hydroxide, calcium carbonate, magnesium hydroxide,
magnesium aluminum silicate, synthetic aluminum silicate, synthetic
hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine,
ethanolamine, ethylenediamine, triethanolamine, triethylamine,
triisopropanolamine, trimethylamine,
tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable
are bases that are salts of a pharmaceutically acceptable acid,
such as acetic acid, acrylic acid, adipic acid, alginic acid,
alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid,
boric acid, butyric acid, carbonic acid, citric acid, fatty acids,
formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid,
isoascorbic acid, lactic acid, maleic acid, oxalic acid,
para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic
acid, salicylic acid, stearic acid, succinic acid, tannic acid,
tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid,
and the like. Salts of polyprotic acids, such as sodium phosphate,
disodium hydrogen phosphate, and sodium dihydrogen phosphate can
also be used. When the base is a salt, the cation can be any
convenient and pharmaceutically acceptable cation, such as
ammonium, alkali metals, alkaline earth metals, and the like.
Example may include, but not limited to, sodium, potassium,
lithium, magnesium, calcium and ammonium.
[0251] Suitable acids are pharmaceutically acceptable organic or
inorganic acids. Examples of suitable inorganic acids include
hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid,
nitric acid, boric acid, phosphoric acid, and the like. Examples of
suitable organic acids include acetic acid, acrylic acid, adipic
acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic
acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric
acid, fatty acids, formic acid, fumaric acid, gluconic acid,
hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic
acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic
acid, propionic acid, p-toluenesulfonic acid, salicylic acid,
stearic acid, succinic acid, tannic acid, tartaric acid,
thioglycolic acid, toluenesulfonic acid, uric acid and the
like.
Pharmaceutical Composition for Injection
[0252] In some embodiments, the disclosure provides a
pharmaceutical composition for injection containing a nicotinic
receptor modulator such as nicotine or a salt thereof and a
pharmaceutical excipient suitable for injection. Components and
amounts of agents in the composition are as described herein.
[0253] The forms in which the novel composition of the present
disclosure may be incorporated for administration by injection
include aqueous or oil suspensions, or emulsions, with sesame oil,
corn oil, cottonseed oil, or peanut oil, as well as elixirs,
mannitol, dextrose, or a sterile aqueous solution, and similar
pharmaceutical vehicles.
[0254] Aqueous solutions in saline are also conventionally used for
injection. Ethanol, glycerol, propylene glycol, liquid polyethylene
glycol, and the like (and suitable mixtures thereof), cyclodextrin
derivatives, and vegetable oils may also be employed. The proper
fluidity can be maintained, for example, by the use of a coating,
such as lecithin, for the maintenance of the required particle size
in the case of dispersion and by the use of surfactants. The
prevention of the action of microorganisms can be brought about by
various antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
[0255] Sterile injectable solutions are prepared by incorporating
the compound of the present disclosure in the required amount in
the appropriate solvent with various other ingredients as
enumerated above, as required, followed by filtered sterilization.
Generally, dispersions are prepared by incorporating the various
sterilized active ingredients into a sterile vehicle which contains
the basic dispersion medium and the required other ingredients from
those enumerated above. In the case of sterile powders for the
preparation of sterile injectable solutions, certain desirable
methods of preparation are vacuum-drying and freeze-drying
techniques which yield a powder of the active ingredient plus any
additional desired ingredient from a previously sterile-filtered
solution thereof.
Pharmaceutical Composition for Inhalation
[0256] Composition for inhalation or insufflation include solutions
and suspensions in pharmaceutically acceptable, aqueous or organic
solvents, or mixtures thereof, and powders. The liquid or solid
composition may contain suitable pharmaceutically acceptable
excipients as described supra. Preferably the composition are
administered by the oral or nasal respiratory route for local or
systemic effect. Composition in preferably pharmaceutically
acceptable solvents may be nebulized by use of inert gases.
Nebulized solutions may be inhaled directly from the nebulizing
device or the nebulizing device may be attached to a face mask
tent, or intermittent positive pressure breathing machine.
Solution, suspension, or powder composition may be administered,
preferably orally or nasally, from devices that deliver the
formulation in an appropriate manner.
Other Pharmaceutical Composition
[0257] Pharmaceutical composition may also be prepared from
composition described herein and one or more pharmaceutically
acceptable excipients suitable for sublingual, buccal, rectal,
intraosseous, intraocular, intranasal, epidural, or intraspinal
administration. Preparations for such pharmaceutical composition
are well-known in the art. See, e.g., See, e.g., Anderson, Philip
O.; Knoben, James E.; Troutman, William G, eds., Handbook of
Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and
Taylor, eds., Principles of Drug Action, Third Edition, Churchill
Livingston, N.Y., 1990; Katzung, ed., Basic and Clinical
Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and
Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth
Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences,
20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The
Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical
Press, London, 1999); all of which are incorporated by reference
herein in their entirety.
Food
[0258] In some aspects, the disclosed pharmaceutical composition is
a food composition comprises a food carrier. In some embodiments,
the food composition comprises nicotine or a salt thereof between
about 0.001 to 1000 mg, 0.01 to 100 mg, 0.1 to 200 mg, 3 to 200 mg,
5 to 500 mg, 10 to 100 mg, 10 to 1000 mg, 50 to 200 mg, or 100 to
1000 mg of nicotine or a salt thereof. In some embodiments, the
food composition comprises about or more than about 0.001 mg, 0.0.1
mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg,
9 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 100 mg, 200 mg, 500
mg, 1000 mg, or more of nicotine or a salt thereof. In some
embodiments, the food composition comprises between about 0.01 to
10 mg of nicotine or a salt thereof. In some embodiments, the food
composition comprises at least about 1 mg of nicotine or a salt
thereof. In some embodiments, the food composition comprises at
least about 2 mg of nicotine or a salt thereof. In some
embodiments, the food composition comprises at least about 3 mg of
nicotine or a salt thereof. In some embodiments, the food
composition comprises at least about 4 mg of nicotine or a salt
thereof. In some embodiments, the food composition comprises at
least about 5 mg of nicotine or a salt thereof. In some
embodiments, the food composition comprises at least about 6 mg of
nicotine or a salt thereof.
[0259] Packaging of the disclosed food composition can be achieved
with any known skill in the art. Without being bound by any theory,
the disclosed food composition may be packaged as a beverage, a
solid food, and/or a semi-solid food. In some cases, the disclosed
food composition is packaged as a food product such as one or more
forms in the group consisting of a snack bar, cereal product,
bakery product, and dairy product.
Pharmaceutical Components
[0260] Dosage forms of the present disclosure may also contain
diluents such as buffers, antioxidants such as ascorbic acid, low
molecular weight (less than about 10 residues) polypeptides,
proteins, amino acids, carbohydrates including glucose, sucrose or
dextrins, chelating agents such as EDTA, glutathione and other
stabilizers and excipients. Neutral buffered saline or saline mixed
with nonspecific serum albumin are exemplary appropriate diluents.
Diluents can be incorporated into the tablet core of a dosage form.
Dosage forms of the invention, preferably a tablet core matrix,
optionally comprise one or more pharmaceutically acceptable
diluents as excipients. Non-limiting examples of suitable diluents
include, either individually or in combination, lactose, including
anhydrous lactose and lactose monohydrate; starches, including
directly compressible starch and hydrolyzed starches (e.g.,
Celutab.TM. and Emdex.TM.); mannitol; sorbitol; xylitol; dextrose
(e.g., Cerelose.TM. 2000) and dextrose monohydrate; dibasic calcium
phosphate dihydrate; sucrose-based diluents; confectioner's sugar;
monobasic calcium sulfate monohydrate; calcium sulfate dihydrate;
granular calcium lactate trihydrate; dextrates; inositol;
hydrolyzed cereal solids; amylose; celluloses including
microcrystalline cellulose, food grade sources of amorphous
cellulose (e.g., Rexcel.TM.) and powdered cellulose; calcium
carbonate; glycine; bentonite; polyvinylpyrrolidone; and the like.
Such diluents, if present, constitute in total about 5% to about
99%.
[0261] In another embodiment of the disclosure, a gastric retained
dosage form of nicotine or a salt thereof is provided. Exemplary
polymers include polyethylene oxides, alkyl substituted cellulose
materials and combinations thereof, for example, high molecular
weight polyethylene oxides and high molecular weight or viscosity
hydroxypropylmethylcellulose materials. Further details regarding
an example of this type of dosage form can be found in Shell, et
al., U.S. Pat. No. 5,972,389 and Shell, et al., WO 9855107, and
U.S. Pat. No. 8,192,756, the contents of each of which are
incorporated by reference in their entirety.
[0262] In yet another embodiment, a bi, tri, or quad-layer tablet
releases nicotine or a salt thereof to the upper gastrointestinal
tract from an active containing layer, while the other layer is a
swelling or floating layer. Details of this dosage may be found in
Franz, et al., U.S. Pat. No. 5,232,704. This dosage form may be
surrounded by a band of insoluble material as described by Wong, et
al., U.S. Pat. No. 6,120,803.
[0263] In some embodiments, nicotine is orally administered using
an orally disintegrating tablet. Examples of orally disintegrating
tablets are known, such as disclosed in U.S. Pat. Nos. 7,282,217;
7,229,641; 6,368,625; 6,365,182; 6,221,392; and 6,024,981.
[0264] Another embodiment of the disclosure uses a gastric retained
swellable tablet having a matrix comprised of polyethylene oxide
and hydroxypropylmethylcellulose. Further details may be found in
Gusler, et al. "Optimal Polymer Mixtures for Gastric Retentive
Tablets," granted as U.S. Pat. No. 6,723,340, the disclosure of
which is incorporated herein by reference.
[0265] Pharmaceutically acceptable carriers for therapeutic use are
well known in the pharmaceutical art, and are described, for
example, in Remington's Pharmaceutical Sciences, Mack Publishing
Co. (A.R. Gennaro edit., 1985). Preservatives, stabilizers, dyes
and other ancillary agents may be provided in the pharmaceutical
composition. For example, sodium benzoate, sorbic acid and esters
of p-hydroxybenzoic acid may be added as preservatives. In
addition, antioxidants and suspending agents may be used.
[0266] In addition, an acid or a base may be incorporated into the
composition to facilitate processing, to enhance stability, or for
other reasons. Examples of pharmaceutically acceptable bases
include amino acids, amino acid esters, ammonium hydroxide,
potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate,
aluminum hydroxide, calcium carbonate, magnesium hydroxide, and
magnesium aluminum silicate.
Kits
[0267] Provided herein are kits, wherein the kits may comprise
pharmaceutical compositions comprising a nicotinic acetylcholine
receptor modulator. In some embodiments, the nicotinic receptor
modulator is a nicotinic receptor agonist. In some embodiments, the
nicotinic receptor modulator is nicotine or a salt thereof. In some
embodiments, the kits comprise nicotine or a salt thereof. The kits
may be used for treating fall-related symptoms in a subject. The
kits may be used for cognitive-related symptoms in a subject. The
kits may be used for reducing a frequency of falls. The kits may be
used for preventing falls. The kits may be used for reducing FOG.
The kits may be used for improving postural stability. In some
embodiments, the subject is elderly or has a central nervous system
disease or disorder. The central nervous system disease or disorder
may be a neurodegenerative disease. The neurodegenerative disease
may be Parkinson's disease. In some embodiments, the pharmaceutical
composition is formulated in a dosage form for administration.
[0268] The kits may provide a total dose of nicotine or a salt
thereof per day. The total dose of nicotine or a salt thereof may
be no more than about 24 mg per day. In some embodiments, the total
dose of nicotine or the salt thereof may be more than 24 mg per
day. The total dose of nicotine or a salt thereof may be no more
than about 4 mg per day, 6 mg per day, 8 mg per day, 10 mg per day,
12 mg per day, 14 mg per day, 16 mg per day, 18 mg per day, 20 mg
per day, 22 mg per day, 24 mg per day, 26 mg per day, 28 mg per
day, 30 mg per day, 32 mg per day, 34 mg per day, 36 mg per day, 38
mg per day, 40 mg per day, 42 mg per day, 44 mg per day, 46 mg per
day, 48 mg per day, or more than 48 mg per day. The total dose of
nicotine or a salt thereof may be in a range of about 1 mg per day
to 24 mg per day, 2 mg per day to 22 mg per day, 3 mg per day to 20
mg per day, 4 mg per day to 18 mg per day, 5 mg per day to 16 mg
per day, 6 mg per day to 14 mg per day, or 8 mg per day to 12 mg
per day. The total dose of nicotine or a salt thereof may be in a
range of about 8 mg per day to 24 mg per day.
[0269] The kits may provide a dose of nicotine or a salt thereof
over a period of time. The kits may provide a plurality of doses.
The kits may provide 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different
doses of the nicotine or salt thereof. The dose of the nicotine or
salt thereof may be about 1 mg to about 6 mg. The dose may be at
least 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg,
11 mg, 12 mg, or more than 12 mg. The dose may be about 1 mg, 2 mg,
3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, or
more than 12 mg. The dose may be at least or about 1 mg, 2 mg, 3
mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg,
14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23
mg, 24 mg, or more than 24 mg. The dose may be in a range of about
0.1 mg to about 6 mg. The dose may be in a range of about 0.1 mg to
about 1 mg, about 0.1 mg to about 2 mg, about 0.1 mg to about 2.5
mg, about 0.1 mg to about 3 mg, about 0.1 mg to about 3.5 mg, about
0.1 mg to about 4 mg, about 0.1 mg to about 4.5 mg, about 0.1 mg to
about 5 mg, or about 0.1 mg to about 6 mg. The period of time may
be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks,
3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10
weeks, 11 weeks, 12 weeks, or more than 12 weeks. The kits may
provide a dose of nicotine or a salt thereof over the period of
time for administration at least once a day. Administration may be
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 more than 12 times a day.
Administration may be every 1 hour, 2 hours, 3 hours, 4 hours, 5
hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12
hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours,
19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours. For
example, for 1 mg dose of nicotine or salt thereof for a period of
time of two weeks and for administration 4 times a day, a total
dosage of the nicotine or salt thereof is 56 mg.
[0270] The kits may provide a dose of nicotine or a salt thereof
over a period of time, wherein the dose can be escalated upward at
treatment intervals. The kits may provide a plurality of doses. The
kits may provide 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different doses
of the nicotine or salt thereof. The dose of the nicotine or salt
thereof may be about 1 mg to about 6 mg. The dose may be at least 1
mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg,
12 mg, or more than 12 mg. The dose may be about 1 mg, 2 mg, 3 mg,
4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, or more
than 12 mg. The dose may be at least or about 1 mg, 2 mg, 3 mg, 4
mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14
mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg,
24 mg, or more than 24 mg. The period of time may be 1 day, 2 days,
3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks,
5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12
weeks, or more than 12 weeks. The kits may provide a dose of
nicotine or a salt thereof over the period of time for
administration at least once a day. Administration may be 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12 more than 12 times a day.
Administration may be every 1 hour, 2 hours, 3 hours, 4 hours, 5
hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12
hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours,
19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours. The
dose may be escalated upward at two weeks treatment intervals. The
dose may be escalated upward at 1 week to 4 week treatment
intervals. The dose may be escalated upward at 1 day, 2 day, 3 day,
4 day, 5 day, 6 day, 1 week, 2 week, 3 week, 4 week, 5 week, 6
week, 7 week, 8 week, or more than 8 week treatment intervals.
[0271] The kits may provide a starting dose of nicotine or a salt
thereof over a period of time, wherein the starting dose can be
escalated upward to a first escalated dose. The first escalated
dose may be 1.5 times, 1.75 times, or 2 times as high as the
starting dose. The first escalated may be 1.5 times, 2 times, 2.5
times, 3.0 times, 3.5 times, 4.0 times, 4.5 times, 5.0 times, 5.5
times, 6.0 times, 6.5 times, 7.0 times, 7.5 times, 8.0 times, 9.0
times, 9.5 times, 10 times, 11 times, or 12 times as high as the
starting dose. In some embodiments, the starting dose is escalated
to a second escalated dose. The second escalated dose may be 2.5
times, 3.0 times, 3.5 times, or 4 times as high as the starting
dose. The second escalated dose may be 2.5 times, 3.0 times, 3.5
times, 4.0 times, 4.5 times, 5.0 times, 5.5 times, 6.0 times, 6.5
times, 7.0 times, 7.5 times, 8.0 times, 9.0 times, 9.5 times, 10
times, 11 times, or 12 times as high as the starting dose. In some
embodiments, the starting dose is escalated to a third escalated
dose. The third escalated dose may be 4.5 times, 5.0 times, 5.5
times, 6.0 times, or 6.5 times as high the starting dose. The
fourth dose may be 4.5 times, 5.0 times, 5.5 times, 6.0 times, 6.5
times, 7.0 times, 7.5 times, 8.0 times, 9.0 times, 9.5 times, 10
times, 11 times, or 12 times as high the starting dose. The kits
may provide for a plurality of escalated doses from a starting
dose. The kits may provide for a plurality of different or
non-identical escalated doses from a starting dose. A number of
different or non-identical escalated doses may be 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, or 12 escalated doses from a starting dose. The
escalated dose may be 1.5 times, 2 times, 2.5 times, 3.0 times, 3.5
times, 4.0 times, 4.5 times, 5.0 times, 5.5 times, 6.0 times, 6.5
times, 7.0 times, 7.5 times, 8.0 times, 9.0 times, 9.5 times, 10
times, 11 times, or 12 times as high the starting dose. For example
if the starting dose is 1 mg, an escalated starting dose that is 6
times as high is 6.0 mg.
[0272] Provided herein are kits comprising a total dosage of
nicotine or salt thereof. In some embodiments, the total dosage of
the nicotine or salt thereof is for a period of time. The total
dosage may be about 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, 2 mg, 30 mg,
35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120
mg, 140 mg, 160 mg, 180 mg, 200 mg, 225 mg, 250 mg, 275 mg 300 mg,
350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750
mg, 800 mg, or more than 800 mg of the nicotine or salt thereof.
The period of time may be 1 day, 2 days, 3 days, 4 days, 5 days, 6
days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks,
8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or more than 12
weeks. The kits may provide for administration of the nicotine or
salt thereof at least once a day. Administration may be 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12 more than 12 times a day. Administration
may be every 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7
hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14
hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours,
21 hours, 22 hours, 23 hours, or 24 hours. For example, for 6 mg
dose of nicotine or salt thereof for 4 weeks and administration 4
times a day, the kit provides a total dosage of the nicotine or
salt thereof of 672 mg.
[0273] The kits may provide a dose of nicotine or a salt thereof
that can be administered at least once a day. The dose of nicotine
or a salt thereof may be administered at least 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, or more than 12 times a day. The dose of nicotine
or a salt thereof may be administered about 1, 2, 3, 4, 5, or 6
times a day. The dose of nicotine or a salt thereof may be
administered once a day. The dose of nicotine or a salt thereof may
be administered twice a day. A time between administration may be
at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7
hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, or more than
12 hours. A time between administration may be in a range of 0
hours to 24 hours, 1 hour to 23 hours, 2 hours to 22 hours, 3 hours
to 21 hours, 4 hours to 20 hours, 5 hours to 19 hours, 6 hours to
18 hours, 7 hours to 17 hours, 8 hours to 16 hours, 9 hours to 15
hours, and 10 hours to 12 hours. A time between administration may
be in a range of about 1 hour to about 6 hours or about 2 hours to
about 6 hours. Administration may be every 1 hour, 2 hours, 3
hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10
hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours,
17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23
hours, or 24 hours.
[0274] The kits may provide a dosage form that delivers an
immediate-release dose of the nicotine or the salt thereof followed
by a second-immediate release dose about 2 hours to 8 hours after
administration. The dosage form may deliver an immediate-release
dose of the nicotine or the salt thereof followed by a
second-immediate release dose about 1 hour to 8 hours, 1 hour to 7
hours, 1 hour to 6 hours, 1 hour to 5 hours, 1 hour to 4 hours, 1
hour to 3 hours, 2 hours to 8 hours, 2 hours to 7 hours, 2 hours to
6 hours, 2 hours to 5 hours, or 2 hours to 4 hours after
administration. In some embodiments, the second-immediate release
dose is followed by a third-immediate release dose about 8 hours to
about 16 hours after administration. In some embodiments, the
third-immediate release dose is followed by a fourth-immediate
release dose about 16 hours to about 24 hours after administration.
The dose of nicotine or the salt thereof may be about 1 mg to about
6 mg over a period of time. For example, the dose of nicotine or
the salt thereof may be about 1 mg to about 6 mg over 6 hours. The
dose may comprise at least or about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6
mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, or more than 12 mg of
nicotine or a salt thereof. The dose may comprise at least or about
1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg,
12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21
mg, 22 mg, 23 mg, 24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg, 36 mg,
38 mg, 40 mg, 42 mg, 44 mg, 46 mg, 48 mg, or more than 48 mg of
nicotine or a salt thereof. The period of time may be 1 hour, 2
hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9
hours, 10 hours, 11 hours, 12 hours, or more than 12 hours. The
dose of nicotine or a salt thereof may be administered at least 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more than 12 times a day.
The dose of nicotine or a salt thereof may be administered about 1,
2, 3, 4, 5, or 6 times a day. The dose of nicotine or a salt
thereof may be administered once a day. The dose of nicotine or a
salt thereof may be administered twice a day. A time between
administration may be at least or within a range spanning 1 hour, 2
hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9
hours, 10 hours, 11 hours, 12 hours, more than 12 hours, or more
than 12 hours. A time between administration may be in a range of 0
hours to 24 hours, 1 hour to 23 hours, 2 hours to 22 hours, 3 hours
to 21 hours, 4 hours to 20 hours, 5 hours to 19 hours, 6 hours to
18 hours, 7 hours to 17 hours, 8 hours to 16 hours, 9 hours to 15
hours, and 10 hours to 12 hours.
[0275] In some embodiments, the kits provide a dosage form of
nicotine or salt thereof that delivers one or more
immediate-release doses of the nicotine or the salt thereof over a
period of time. A number of immediate-release doses of the nicotine
or the salt thereof may be 1, 2, 3, 5, 6, 7, 8, or more than 8
immediate-release doses. A number of immediate-release doses of the
nicotine or salt thereof may be in a range of 1 to 8, 1 to 7, 1 to
6, 1 to 5, 1 to 4, 1 to 3, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4
immediate-release doses. The dosage form may provide an
immediate-release dose about 1 hour to 8 hours, 1 hour to 7 hours,
1 hour to 6 hours, 1 hour to 5 hours, 1 hour to 4 hours, 1 hour to
3 hours, 2 hours to 8 hours, 2 hours to 7 hours, 2 hours to 6
hours, 2 hours to 5 hours, or 2 hours to 4 hours after
administration. The dosage form may provide an immediate-release
dose about 8 hour to 16 hours, 8 hours to 15 hours, 8 hours to 14
hours, or 8 hours to 12 hours after administration. The dosage form
may provide an immediate-release dose about 16 hour to 24 hours, 16
hours to 22 hours, 16 hours to 20 hours, or 16 hours to 18 hours
after administration.
[0276] The kits may provide a dosage form that delivers a
delayed-release pulse of the nicotine or the salt thereof. The
delayed-release pulse of the nicotine or the salt thereof may be
delivered over a period of time. A dose of nicotine or the salt
thereof may be no more than 24 mg per day. In some embodiments, the
dose of nicotine or the salt thereof may be more than 24 mg per
day. The dose may comprise at least or about 1 mg, 2 mg, 3 mg, 4
mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14
mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg,
24 mg, or more than 24 mg of nicotine or a salt thereof. The dose
may comprise at least or about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg,
7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg,
17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 26 mg, 28
mg, 30 mg, 32 mg, 34 mg, 36 mg, 38 mg, 40 mg, 42 mg, 44 mg, 46 mg,
48 mg, or more than 48 mg of nicotine or a salt thereof. The period
of time may be or within a range spanning 1 hour, 2 hours, 3 hours,
4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11
hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours,
18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24
hours, or more than 24 hours.
[0277] Provided herein are kits that may be used for chronic
treatment. The treatment period may be more than 12 weeks. The
treatment period may be 1 week, 2 weeks, 3 weeks, 1 month, 2
months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months,
9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years,
5 years, 6 years, 7 years, 8 years, or more than 8 years.
[0278] The kits may a dose of nicotine or a salt thereof provide as
a unit dose. The kits may comprise one or more unit doses. The one
or more unit doses may comprise about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg,
6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg,
16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, or
more than 24 mg of nicotine or a salt thereof. The one or more unit
doses may comprise at least or at most 1 mg, 2 mg, 3 mg, 4 mg, 5
mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15
mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg,
or more than 24 mg of nicotine or a salt thereof. The kits may
comprise 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 26, 28, 30, 35,
40, 45, 50, or more than 50 unit doses. The kits may comprise one
or more unit doses of different doses of the nicotine or salt
thereof. A number of different or non-identical doses may include,
but is not limited, 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12 or more than
12 different or non-identical doses of the nicotine or salt
thereof. The one or more unit doses may be formulated for oral,
intravenous, intraarterial, parenteral, buccal, topical,
transdermal, rectal, intramuscular, subcutaneous, intraosseous,
transmucosal, or intraperitoneal administration. The one or more
unit doses may be formulated for oral, topical, buccal,
transdermal, or inhalation administration. The one or more unit
doses may be formulated for oral administration. The one or more
unit doses may be formulated as a liquid, gel, semi-liquid,
semi-solid, or solid form. The one or more unit doses may be
formulated as a capsule, cachet, tablet, liquid, or aerosol spray.
The one or more unit doses may be formulated as a tablet. The one
or more unit doses may be formulated as a capsule. The one or more
unit doses may be formulated as a food. The one or more unit doses
may be formulated as a beverage. The one or more unit doses may be
formulated as a dietary supplement.
[0279] The kits may further comprise instructions for use of the
kit according to the various methods and approaches described
herein. The instructions may be related to use of a composition as
described herein. The instructions may be related to use of
nicotine or a salt thereof. For example, the instructions relate to
a total dose per day, total dosage over a period of time, amount of
time between administration, number of times a day for
administration, dose amount at each time of administration, dose
escalation, treatment intervals, evaluative measurements to be
taken, or combinations thereof. The instructions may relate to
evaluation of the subject by a physician. Evaluation of the subject
may include laboratory tests, analysis of concomitant medications,
physical examinations, mental evaluations, physical evaluations,
electrocardiograms (ECGs), vital signs, assessments of impulse
control, nicotine withdrawal symptoms, changes in disease symptoms,
Mini Mental State Examination, examinations using the Jay Midi
Scale, UDysRS, Hoehn and Yahr scale, Clinical Global impression
scale, Patient global impression scale, Lang-Fahn daily activity
scale, and Minnesota Nicotine Withdrawal Scale-Revised (MNWS-R).
Laboratory tests include, but are not limited to, urine analysis,
serum cotinine analysis, urine cotinine analysis, serum nicotine
analysis, hematology, chemistry, and pregnancy. Such kits may also
include information, such as scientific literature references,
package insert materials, clinical trial results, and/or summaries
of these and the like, which indicate or establish the activities
and/or advantages of the composition, and/or which describe dosing,
administration, side effects, drug interactions, or other
information useful to the health care provider. Such information
may be based on the results of various studies, for example,
studies using experimental animals involving in vivo models and
studies based on human clinical trials. Kits described herein can
be provided, marketed and/or promoted to health providers,
including physicians, nurses, pharmacists, formulary officials, and
the like. Kits may also, in some embodiments, be marketed directly
to the consumer. Kits may also comprise an aid to administration of
the active agent formulation, such as an inhaler, spray dispenser
(e.g., nasal spray), syringe for injection or pressure pack for
capsules, tablets, or suppositories.
[0280] In some embodiments, a subject is evaluated after use of the
kits. The subject may be evaluated for a period of at least 1 to 14
months. The subject may be evaluated every day, 2 day, 3 day, 4
day, 5 day, 6 day, 1 week, 2 week, 3 week, 4 week, 5 week, 6 week,
7 week, week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks,
8 weeks, or more than every 8 weeks. The subject may be evaluated
by a physician. The subject may be evaluated to determine optimum
dose.
[0281] In some embodiments, a subject is evaluated after use of the
kits for one or more parameters. The subject may be evaluated for
adverse events. Adverse events include, but are not limited to,
nausea, dizziness, constipation, vomiting, fatigue, pain, diarrhea,
headache, pain in extremity, tremor, nightmare, or insomnia.
Evaluation of subjects may include laboratory tests, analysis of
concomitant medications, physical examinations, mental evaluations,
physical evaluations, electrocardiograms (ECGs), vital signs,
assessments of impulse control, nicotine withdrawal symptoms,
changes in disease symptoms, Mini Mental State Examination,
examinations using the Jay Midi Scale, UDysRS, Hoehn and Yahr
scale, Clinical Global impression scale, Patient global impression
scale, Lang-Fahn daily activity scale, and Minnesota Nicotine
Withdrawal Scale-Revised (MNWS-R). Laboratory tests include, but
are not limited to, urine analysis, serum cotinine analysis, urine
cotinine analysis, serum nicotine analysis, hematology, chemistry,
and pregnancy.
EXAMPLES
[0282] The following examples are given for the purpose of
illustrating various embodiments of the invention and are not meant
to limit the present invention in any fashion. The present
examples, along with the methods described herein are presently
representative of preferred embodiments, are exemplary, and are not
intended as limitations on the scope of the invention. Changes
therein and other uses which are encompassed within the spirit of
the invention as defined by the scope of the claims will occur to
those skilled in the art.
Example 1: NP002 in Combination with Dopaminergic Drugs for
Treatment of Fall-Related Symptoms and Improvement of Posture
Stability
[0283] A total of 20 patients with Parkinson disease, for five
years or more, who have impaired postural stability (balance) and
have fallen are enrolled in an interventional study. The patients
are randomly assigned to NP002 or an identical placebo in addition
to their regular PD dopaminergic medication. Major entry criteria
are as follows: 1) clinical diagnosis of typical Parkinson's
disease, 2) male or female between ages of 30 to 83, 3) Hoehn and
Yahr Stage II-IV while in an "on" state, 4) has had fallen more
than once in past year, 5) has Montreal Cognitive Assessment (MOCA)
score .gtoreq.21, 6) be stable dose of levodopa/caribodpa. They may
be on additional dopaminergic drugs including dopamine agonists
and/or monoamine type B oxidase inhibitors or amantadine. See FIG.
1.
[0284] Patients with the following disorders or symptoms are
excluded from enrollment: Excluded are patients with atypical
Parkinson, disorders that while infrequent, result in a high number
of falls especially early in the disease. These disorders include
Progressive Supranuclear Palsy (PSP), Multiple System Atrophy
(MSA), Primary Freezing of Gait (PFG), and Corticobasiler
Degeneration. Excluded are patients with dementia MOCA .gtoreq.21.
Excluded are patients who are legally blind. Excluded are patients
with major orthopedic problems of their hips or knees, patients who
needed hip or knee replacements. Excluded are patients with
orthostatic hypotension. Excluded are patients with a history of
schizophrenia, schizo-affective disorder, bipolar disorder.
Excluded are patients with hallucinations, psychoses or delusions.
Excluded are patients that had deep brain stimulation (DBS)
Intervention. Excluded are patients with a history of recent stroke
or myocardial infarction.
[0285] The study consists of 3 phases: a treatment period of 6
months, a treatment re-titration period of 2 months, a crossover
treatment period of 6 months. See FIG. 2. Subjects are randomly
assigned to receive either NP002 comprising nicotine or salt
thereof, or placebo. All patients are on stable levodopa/carbidopa
treatment. Patients may have additional dopaminergic drugs
including dopamine agonists and/or monoamine type B oxidase
inhibitors or amantadine. Patients are evaluated in an "off"
period, 16 hours off levodopa/carbidopa and then in an "on" period,
one hour after usual morning dose of levodopa/carbidopa. NP002 or
placebo in a 1:1 ratio is administered as an oral capsule 4 times a
day in a blinded fashion for 6 months, and then a crossover for
another 6 months. In between the treatment regimes, subjects are
given a treatment re-titration period for 2 months. Dosing begins
at 1 mg every 6 hours, total daily dose is 4 mg and escalated
upward at 2 week intervals as follows:
[0286] Two mg every 6 hours total daily dose 8 mg for 2 weeks.
[0287] Four mg every 6 hours total daily dose 16 mg for 2
weeks.
[0288] Six mg every 6 hours total daily dose 24 mg for 2 weeks.
[0289] Patients are maintained on this dose for the duration of the
next few weeks of the study until the cross-over. Because patients
who are on placebo have not been exposed to nicotine, the original
escalation schedule is repeated.
[0290] Safety is assessed by incidences of adverse experiences
(AE), clinical laboratory tests, serum cotinine, ECG and vital
signs. Impulsive symptoms are assessed using the Jay Modified
Minnesota Impulsive Disorders Interview (JayMidi). Withdrawal
symptoms are evaluated using the Minnesota Nicotine Withdrawal
Scale (MNWS-R).
[0291] Efficacy is assessed using the Unified Parkinson's Disease
Rating Scale (UPDRS), Barrow Neurological Institute (BNI) Falls
Evaluation, Hoehn & Yahr Staging System, Romberg test, turning
test, standing on one leg, tandem gait, step length and velocity,
Walking and Balance from questions 2.12 from Movement Disorder
Society Unified Parkinson's Disease Rating Scale (MDS UPDRS),
Freezing of Gait from questions 2.14 from Movement Disorder Society
Unified Parkinson's Disease Rating Scale (MDS UPDRS), Dyskinesias
from questions 32-35 from original Unified Parkinson's Disease
Rating Scale (UPDRS), Response Fluctuation from questions 36-39
from original Unified Parkinson's Disease Rating Scale (UPDRS),
Sleep Disturbance from question 40 from original Unified
Parkinson's Disease Rating Scale (UPDRS), Movement Disorder Society
Unified Parkinson's Disease Rating Scale (MDS UPDRS) 142 points,
Axial, Midline part of Movement Disorder Society Unified
Parkinson's Disease Rating Scale (MDS UPDRS), Gait Subtest from
Movement Disorder Society Unified Parkinson's Disease Rating Scale
(MDS UPDRS, Postural Stability Subtest from Movement Disorder
Society Unified Parkinson's Disease Rating Scale (MDS UPDRS), and
Freezing of Gait Subtest (FOG) from Movement Disorder Society
Unified Parkinson's Disease Rating Scale (MDS UPDRS).
[0292] Improvements of axial UPDRS subtests in either "on" or "off"
or both "on or off" periods, including improvement in Gait subtest,
Pull test, and FOG subtests, improvement in turning, in standing on
one leg, in tandem gait, in step length and velocity, improvement
in quantitative tests.
[0293] All or most of these patients may have response
fluctuations: "wearing off" and/or "on off" Some of these patients
may have freezing of gait (FOG).
Example 2: NP002 in Combination with Dopaminergic Drugs for
Reducing Dyskinesia and Improving Response Fluctuations
[0294] Example 1 is repeated. This is a Phase II single center,
randomized, double-blind, placebo controlled, efficacy, safety and
tolerability study. A total of 20 male and female patients with
typical Parkinson's disease with recurrent falls are included. The
study consists of an initial evaluation, evaluation every 2 months
for 6 months, a cross-over, and then an evaluation every 2 months
for 6 months.
Example 3: Effect of NC001, a Central Cholinergic Agonist on Gait,
Postural Stability and Falls in Parkinson Disease
[0295] The primary objective of the study is to determine whether
treatment with NC001 versus placebo in addition to dopaminergic
drugs improve postural stability and reduce falls and/or severity
of falls in PD patients. This is achieved by demonstrating
improvement of selected MDS-UPDRS subtests in either "on" or "off"
or both periods. The subtests include the "Gait" and "Pull test."
The objective is achieved by demonstrating improvement on subtests
such as "Standing on One Leg" and Step Length.
[0296] Since there are limitations to the above semi-quantitative
tests, they are complemented by tests of motor control time (MCT)
and postural perturbations utilizing a Neurocom system.
[0297] The PD patient population chosen has advanced PD, is on
levodopa, and is having "wearing off" Some of these patients may
have dyskinesias. They are evaluated in an "off" period, 16 hours
without levodopa, at a time when they are without dyskinesias. The
effects of NC001 on gait and postural stability in the absence of
dyskinesias is measured. Patients are then evaluated in an "on"
period an hour after they receive their usual daily dose of
levodopa.
[0298] A problem with such evaluations is that they capture the
patient's gait and postural stability, including phenomena such as
freezing of gait (FOG), a risk factor for falls, over a short
period of time. The evaluation of patients in their "on" and "off"
period is complemented by continuous monitoring, utilizing wearable
Inertial Measuring Units incorporating accelerometers and
gravitometers that monitor gait, FOG, postural stability, and
falls. Patients are monitored for up to three days with the IMUs.
The monitoring is supplemented by dairies kept by the patient.
[0299] The study population includes 20 patients with PD who have
had PD for at least five years, who have impaired postural
stability, who have fallen at least twice in a year, who are on
levodopa, who are having "wearing off" (and who usually fall when
they are "off"). Half of the patients are randomized to NC001 and
half to placebo. The group is treated for six months and then they
are switched.
[0300] A secondary objective of the study is to evaluate the
efficacy of adding NC001 versus placebo in reducing dyskinesias and
in improving response fluctuations: "wearing off."
[0301] Because of the effects of impaired cognition (dementia) on
gait, postural stability, and falls we exclude patients with
dementia.
[0302] Parkinson disease is characterized by a loss of
nigrostriatal dopamine neurons. Nicotine receptors are located in
the striatum as well as the pedunculopontine nucleus and various
thalamic nuclei. NC001 or placebo in a 1:1 ratio is administered as
an oral capsule four times a day in a blinded fashion for six
months, then after a crossover, for another six months. In the
double blind treatment phase dosing is begun at one mg every six
hours to a total daily dose of 4 mg. Then the dose is escalated to
a total dose of 24 mg per day.
Example 4: Formulations and Production of GMP Material for a Human
Clinical Trial
[0303] The primary formulation target is to develop a 2 pulse
formulation that will deliver an immediate-release bolus at time
zero, and deliver a second immediate-release bolus of nicotine
approximately six hours after ingestion. This 2 pulse dosage form
is intended to be administered 2 times in a day spaced 12 hours
apart (q12 hr) in order to mimic the PK profile previously
evaluated in the Phase 2 studies. There have been a number of
formulation approaches that have achieved a bolus release of drug
after an extended lag time after oral ingestion, and these
approaches are characterized in the literature (Sharma, G. S. et
al., 2010). This approach has been used successfully in many drug
development programs, and there are approved drug products on the
market in the US and the rest of the world that are designed as
multiparticulate dosage forms, including Zohydro ER, Adderall XR,
Ritalin LA, Moxatag, Carbatrol, Equetro and others. In each case,
the specific formulation was tailored to the molecule and to the
target pharmacokinetic profile for the drug product. This
formulation development program focuses on a multiparticulate
immediate-release dosage form that is coated with a semi-permeable
membrane. This membrane, once hydrated, allows water flow into the
dosage form, but does not allow drug to leak out through the
membrane. In addition to the active drug substance, the core of the
dosage form may contain organic salts, swellable materials, or
superdisintegrants that provide the driving force for the water
uptake and help dictate the timing of the programmed drug
release.
[0304] A 15% solution of nicotine is prepared including
hypromellose (HPMC) as a binder and succinic acid as the organic
acid modifier. This solution is coated onto nonpareil seeds using a
fluid bed dryer fitted with a precision coater apparatus until a
20% solids weight gain is achieved on the pellets. The final drug
layer formulation contains nicotine, HPMC, and succinic acid in a
5:3.5:1.5 ratios. If necessary, alternative binders may be used in
order to improve the quality of the adherence of the drug layer to
the nonpareil seed. This core drug-loaded pellet may be coated with
an immediate release polymer such as Opadry for aesthetics and used
as the immediate release component of the composite dosage form.
For the delayed release pellets, a separate population of the core
drug loaded pellets is further coated with a separate functional
polymer film coat. An aqueous solution of Eudragit RS is prepared
with triethyl citrate as the plasticizer and talc functioning as
the antitack agent in a 6:1:3 ratios. This solution is coated onto
the drug loaded pellets using a fluid bed dryer fitted with a
precision coater to total solids weight gain of approximately 70%.
The optimum weight gain is determined experimentally by using in
vitro dissolution as the feedback mechanism. Alternative polymer
materials such as Eudragit RL may also be included in the polymer
film coating formulation to modify the lag time or release rate of
the nicotine from the delayed release pellets.
[0305] Length of the lag time and strength of the drug release may
be tailored based on coating formulation and coat weight gain.
Initial formulation development experiments are conducted on small,
laboratory scale equipment and batch sizes (10-50 g/batch). These
batches are manufactured at the laboratory or benchtop scale, and
manufacturing instructions and conditions are documented in a
notebook. This material is suitable for in vitro testing but not
for clinical use.
[0306] Formulation prototypes are evaluated using a standard drug
product testing approach, including evaluation of drug product
content assay, impurities evaluation, uniformity of dosage units,
and in vitro drug nicotine release rate evaluation. An important
tool for evaluation of solid, oral dosage forms, including
modified-release dosage forms, is in vitro dissolution testing.
Dissolution testing is the industry standard for evaluation of the
release rate for all solid, oral dosage forms, both
immediate-release and modified-release. It is used during
development to assess the performance of the prototype
formulations, during routine commercial batch release to ensure
consistency for product that is marketed to patients, and can be
used to predict the in vivo performance with an in vivo/in vitro
correlation (IVIVC). Once an IVIVC has been established, the
pharmacokinetic profile of the dosage form can be predicted by
evaluation of the in vitro release rate. The dissolution test
conditions can be tailored in order to mimic conditions in the
gastrointestinal tract, and provide insight and sometime predict
the in vivo drug release rate. Specifically, the immediate release
formulations are evaluated in dilute HCl, with a pH of 1.1, to
mimic the fasted stomach conditions, and a pH 4.5 buffer to mimic
the fed stomach conditions. Delayed release formulations can be
challenged in dilute HCl media, with a change to pH 6.8 media to
mimic the movement from the stomach to the small intestine.
[0307] The in vitro evaluation of the immediate release pulse and
the delayed release components of the dosage form are evaluated in
a dissolution bath with paddles rotating at 50 RPM at 37.degree. C.
The media that is employed is a dilute HCl solution at pH 1.1 to
simulate the condition in the gastric cavity, and a 50 mM phosphate
buffer solution, pH 6.8, that is used to mimic the intestinal
conditions. A successful immediate release formulation releases at
least 80% of the labelled amount of nicotine within 30 or 45
minutes. The delayed release formulation is evaluated by the amount
of drug released at 6 hours (the leak) and how quickly the entire
dose of the drug is released once the drug release is initiated.
The nicotine concentration is measured in samples of the media
removed from the dissolution vessel over time and injecting the
sample onto a High Performance Liquid Chromatography (HPLC) system
with UV detection. The amount of nicotine released is measured as a
percentage of the target drug load in the dosage form (i.e.--4 mg
of drug released from an 8 mg total dose would provide a 50%
dissolved result). A successful delayed release formulation
releases at least 80% of the labelled amount of nicotine over
approximately 30-45 minutes beginning 6 hours after the first
release. The target is to minimize the amount of leak in the
delayed-release formulation, and maximize the rate of drug release
once the release is initiated. This results in a strong pulse of
drug release and is intended to perform similarly to the
immediate-release dosage form that is administered 6 hours after
the first dose.
[0308] Four different formulations are developed under GMP
guidelines ready for the human study. Once the lead formulations
have been selected, they are scaled-up to larger equipment and
batch sizes. The manufacturing parameters are further developed for
that scale of equipment, and these experiments are documented in a
laboratory notebook. Clinical Trial Material (CTM) drug product is
tested in order to assure their correct quality, identity,
strength, purity, and potency. CTM is then produced in a section of
the facility that is qualified and operated in accordance with Good
Manufacturing Practices (GMPs). A GMP is a system for ensuring that
products are consistently produced and controlled according to
quality standards. It is designed to minimize the risks involved in
any pharmaceutical production that cannot be eliminated through
testing the final product. GMP covers all aspects of production
from the starting materials, premises and equipment to the training
and personal hygiene of staff. Detailed, written procedures are
essential for each process that could affect the quality of the
finished product. There must be systems to provide documented proof
that correct procedures are consistently followed at each step in
the manufacturing process--every time a product is made. These
batches are manufactured using materials that have been released by
a quality unit, and the manufacturing instructions are specified in
a pre-approved batch record. These batches are tested using methods
that have been appropriately qualified, and they are released by a
quality unit prior to dosing in a human clinical trial.
Example 5: Human Normal Volunteer Study of 12-Hr Release
Formulations
[0309] Up to four 12-hr release formulations are tested in man. A
12 mg Pulsatile Release (PR) is intended to provide 2 spikes over
12 hours. The Study is a Bioequivalence Phase 1 study in 12 normal
healthy normal males and females, who are non-smokers, or previous
smokers who are currently non-smokers .times.3 months or social
smokers who are willing and able to abstain from tobacco use for
the duration of the study. Healthy normal volunteers are used to
conduct the study, as the goal is to obtain the highest quality
data with minimal interference from confounding factors. Healthy
volunteer PK studies have been shown to be superior to PK studies
in populations where extended overnight stays are challenging and
compliance is low. For example, subjects who are ill may have a
difficult time refraining from eating, and food may interfere with
the interpretation of data.
[0310] Comparative PK/bioavailability of immediate-release and four
different 12-hr release formulations of nicotine:
[0311] Strength/Form:
[0312] (A) Immediate Release (IR) 6 mg q6 h.times.4 doses
[0313] (B) Pulsatile Release (PR) 12 mg Form 1 q12 h.times.2
doses
[0314] (C) Pulsatile Release (PR) 12 mg Form 2 q12 h.times.2
doses
[0315] (D) Pulsatile Release (PR) 12 mg Form 3 q12 h.times.2
doses
[0316] (E) Pulsatile Release (PR) 12 mg Form 4 q12 h.times.2
doses
[0317] Each subject has a washout time of a minimum of 3 days prior
to entering into the next period. The time of confinement include
Day--1 through to AM of Day 2 (2 bed nights in each period).
[0318] Safety assessments focus on ensuring that all subjects
entering the study are normal and healthy using a screening and
pre-first-dose--vital Signs and Physical Exam, ECG and Standard
Clinical Lab tests. During the study, close attention is paid to
hemoglobin due to the large blood volume from PK sampling to ensure
that subject's levels are within normal range at the beginning of
each period and at the end of the 5th period. PK Sampling: The PK
Sampling Schedule is identical for each period and is as follows:
Pre-dose (0 hr), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 6.5, 7, 7.5, 8, 8.5,
9, 10, 12, 12.5, 13, 13.5, 14, 14.5, 15, 16, 18, 18.5, 19, 19.5,
20, 20.5, 21, 22, 24.
[0319] Analyte(s): Nicotine and cotinine. Nicotine in plasma or
serum, once quantified bioanalytically, are analyzed using
descriptive statistics to summarize the concentration in samples by
treatment and time point. Each individual subject, by treatment,
concentration versus time profiles are analyzed using
non-compartmental pharmacokinetic (PK) methods to derive the PK
parameters of interest. Of main interest, is the peak (Cmax)
exposure, overall systemic exposure (AUC) over a 24-hour period for
the various treatment regimens. In addition, the time to peak
(Tmax), minimum concentration over the 24-hr interval, and
half-life, are computed where possible. The main exposure
parameters are compared statistically by an analysis of variance
(ANOVA) according to the two, one-sided equivalence approach.
Results are presented as the geometric mean ratio between the
proposed modified-release nicotine regimens and the
immediate-release formulation, with corresponding 90% confidence
interval for the difference in means.
Example 6: NP002 in Combination with Dopaminergic Drugs for
Treatment of Cognitive-Related Symptoms and Cognitive
Impairment
[0320] A total of 20 patients with Parkinson disease, for five
years or more, who have impaired cognitive symptoms are enrolled in
an interventional study. The patients are randomly assigned to
NP002 or an identical placebo in addition to their regular PD
dopaminergic medication. Major entry criteria are as follows: 1)
clinical diagnosis of typical Parkinson's disease, 2) male or
female between ages of 30 to 83, 3) Hoehn and Yahr Stage II-IV
while in an "on" state, and 4) be on a stable dose of
levodopa/carbidopa. They may be on additional dopaminergic drugs
including dopamine agonists and/or monoamine type B oxidase
inhibitors or amantadine.
[0321] The study consists of 3 phases: a treatment period of 6
months, a treatment re-titration period of 2 months, a crossover
treatment period of 6 months. Subjects are randomly assigned to
receive either NP002 comprising nicotine or a salt thereof, or
placebo. All patients are on stable levodopa/carbidopa
treatment.
[0322] Patients may have additional dopaminergic drugs including
dopamine agonists and/or monoamine type B oxidase inhibitors or
amantadine. Patients are evaluated in an "off" period, 16 hours off
levodopa/carbidopa and then in an "on" period, one hour after usual
morning dose of levodopa/carbidopa. NP002 or placebo in a 1:1 ratio
is administered as an oral capsule 4 times a day in a blinded
fashion for 6 months, and then a crossover for another 6 months. In
between the treatment regimes, subjects are given a treatment
re-titration period for 2 months. Dosing begins at 1 mg every 6
hours, total daily dose is 4 mg and escalated upward at 2 week
intervals as follows:
[0323] Two mg every 6 hours total daily dose 8 mg for 2 weeks.
[0324] Four mg every 6 hours total daily dose 16 mg for 2
weeks.
[0325] Six mg every 6 hours total daily dose 24 mg for 2 weeks.
[0326] Patients are maintained on this dose for the duration of the
next few weeks of the study until the cross-over. Because patients
who are on placebo have not been exposed to nicotine, the original
escalation schedule is repeated.
[0327] Safety is assessed by incidences of adverse experiences
(AE), clinical laboratory tests, serum cotinine, ECG and vital
signs. Impulsive symptoms are assessed using the Jay Modified
Minnesota Impulsive Disorders Interview (JayMidi). Withdrawal
symptoms are evaluated using the Minnesota Nicotine Withdrawal
Scale (MNWS-R).
[0328] Efficacy is assessed using the Montreal Cognitive Assessment
scale.
Example 7: NP002 in Combination with Dopaminergic Drugs for
Reducing Cognitive Impairments
[0329] Example 1 is repeated. This is a Phase II single center,
randomized, double-blind, placebo controlled, efficacy, safety and
tolerability study. A total of 20 male and female patients with
typical Parkinson's disease with cognitive impairments are
included. The study consists of an initial evaluation, evaluation
every 2 months for 6 months, a cross-over, and then an evaluation
every 2 months for 6 months.
Example 8: Nicotine Reduces LIDs by Acting at Nicotinic
Acetylcholine Receptors (nAChRs)
[0330] Nicotine generally exerts its effect by acting at nAChRs.
Multiple receptors exist throughout the body with .alpha.1.beta.1*,
.alpha.3.beta.4* and .alpha.7 nAChRs being the major subtypes in
the peripheral nervous system and .alpha.4.beta.2*,
.alpha.6.beta.2* and .alpha.7 nAChRs the primary ones in the brain.
The *asterisk denotes the presence of other nAChR subunits in the
receptor. To determine the receptors relevant for nicotine's
antidyskinetic effect, nAChR subtype selective drugs were tested in
rats with a unilateral 6-hydroxydopamine lesion, which is a model
for LID. Varenicline, which acts at all nAChRs, as well as several
.beta.2* selective drugs (A-85380, sazetidine, TC-2696, TI-10165,
TC-8831 and TC-10600) reduced LIDs to varying extents in this
parkinsonian animal model of LIDs. These data indicate that
nicotine reduces LIDs by acting at nAChRs. Studies with genetically
modified mice further support the idea that nicotine mediates its
antidyskinetic effect via nAChRs. L-dopa-treated parkinsonian
.alpha.6.beta.2* nAChR null mutant mice showed a 50% reduction in
baseline LIDs. Nicotine did not exert an antidyskinetic effect in
.alpha.4.beta.2* nAChR knockout mice. By contrast, there was an
increase in LIDs in L-dopa-treated parkinsonian .alpha.7 nAChR
knockout mice. Thus the pharmacological and genetic studies
indicate that the antidyskinetic effect of nicotine is
receptor-mediated and that both .beta.2* and .alpha.7 nAChRs play
an important role.
Example 9: nAChR Drugs Reduce LIDs in Parkinsonian Nonhuman
Primates
[0331] nAChR drugs reduce LIDs in parkinsonian nonhuman primates.
Pharmacological studies were performed to investigate the
therapeutic potential of nAChR in
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys, an
animal model that closely resembles PD. Initial work showed that
varenicline, a general nAChR agonist, and the .beta.2* agonist
TC-8831 decreased LIDs .about.50% in monkeys with no tolerance,
although a limitation of these drugs was the development of emesis
(Table 1). Several other .beta.2* selective agonists were therefore
tested (Table 4). These were ABT-089, a partial .beta.2* nAChR
agonist (Ki=17 nM) and the full .beta.2* agonist ABT-894 (Ki=0.3
nM). ABT-089 maximally decreased LIDs by 40% and ABT-894 reduced
LIDs up to 60% (Zhang et al., 2014b). These effects persisted for
months, with no detectable side effects and no emesis. None of the
agonists worsened Parkinsonism. AZD1446, a .beta.2* nAChR agonist
of relatively low affinity (Ki=30 nM) was also tested. It maximally
reduced LIDs by 30%. Full high affinity .beta.2* nAChR agonists may
be more effective. Two .alpha.7 nAChR agonist ABT-107 (Ki=0. 5 nM)
and AQW051 (Ki=27 nM) also reduced LIDs in parkinsonian monkeys
with varying efficacy which may relate to their affinity and
agonist properties. Of note, the maximum decline in LIDs was
.about.60% with any one nAChR drug or with combined treatment with
an .beta.2* and .alpha.7 agonist (Table 4).
[0332] A summary of the monkey data (Table 4) show that the
greatest reduction in LIDs is associated with higher affinity
(.gtoreq.10 nM) full nAChR agonists such as nicotine, ABT-894 and
ABT-107. Partial agonists or drugs with lower affinities (such as
varenicline, TC-8831, ABT-089, AZD1446, AQW051) appear less
efficacious. Another important consideration is side effects; drugs
such as varenicline and TC-8831 can be associated with nausea, and
thus in some cases, would be less desirable.
TABLE-US-00004 TABLE 4 nAChR agonists reduce LIDs in monkeys nA-
Decline Dose to Side ChR Type in reduce effects sub- of LIDs in
LIDs in Drug type agonist Ki monkeys (mg/kg) monkeys Nicotine All
Full 1-3 nM 60% 1.0 None ABT-894 .beta.2 Full 0.3 nM 60% 0.01 None
ABT-107 .alpha.7 Full 0.5 nM 60% 0.10 None ABT-894 + .beta.2 + Full
-- 60% 0.01 + 0.1 None ABT-107 .alpha.7 Varenicline All Partial 0.1
nM 50% 0.03 Some nausea TC-8831 .beta.2 Full 1-3 nM 30-50% 0.10
Nausea ABT-089 .beta.2 Partial 17 nM 30-50% 0.10 None AZD1446
.beta.2 Full 30 nM 30% 1.0 None AQW051 .alpha.7 Partial 27 nM 0%
8.0 None 60% 15.0
Example 10: nAChR Agonists in Combination with Dopaminergic Drugs
for Treatment of Fall-Related Symptoms and Improvement of Posture
Stability
[0333] A total of 20 patients with Parkinson disease, for five
years or more, who have impaired postural stability (balance) and
have fallen are enrolled in an interventional study. The patients
are randomly assigned to a .beta.2 or .alpha.7 selective nAChR
agonist (such as ABT-894 or ABT-107) or an identical placebo in
addition to their regular PD dopaminergic medication. Major entry
criteria are as follows: 1) clinical diagnosis of typical
Parkinson's disease, 2) male or female between ages of 30 to 83, 3)
Hoehn and Yahr Stage II-IV while in an "on" state, 4) has had
fallen more than once in past year, 5) has Montreal Cognitive
Assessment (MOCA) score .gtoreq.21, 6) be stable dose of
levodopa/caribodpa. They may be on additional dopaminergic drugs
including dopamine agonists and/or monoamine type B oxidase
inhibitors or amantadine.
[0334] Patients with the following disorders or symptoms are
excluded from enrolment: Excluded are patients with atypical
Parkinson, disorders that while infrequent, result in a high number
of falls especially early in the disease. These disorders include
Progressive Supranuclear Palsy (PSP), Multiple System Atrophy
(MSA), Primary Freezing of Gait (PFG), and Corticobasiler
Degeneration. Excluded are patients with dementia MOCA .gtoreq.21.
Excluded are patients who are legally blind. Excluded are patients
with major orthopedic problems of their hips or knees, patients who
needed hip or knee replacements. Excluded are patients with
orthostatic hypotension. Excluded are patients with a history of
schizophrenia, schizo-affective disorder, bipolar disorder.
Excluded are patients with hallucinations, psychoses or delusions.
Excluded are patients that had deep brain stimulation (DBS)
Intervention. Excluded are patients with a history of recent stroke
or myocardial infarction.
[0335] The study consists of 3 phases: a treatment period of 6
months, a treatment re-titration period of 2 months, a crossover
treatment period of 6 months. Subjects are randomly assigned to
receive either nAChR agonist (such as ABT-894 or ABT-107), or
placebo. All patients are on stable levodopa/carbidopa treatment.
Patients may have additional dopaminergic drugs including dopamine
agonists and/or monoamine type B oxidase inhibitors or amantadine.
Patients are evaluated in an "off" period, 16 hours off
levodopa/carbidopa and then in an "on" period, one hour after usual
morning dose of levodopa/carbidopa. Either the .beta.2 or the
.alpha.7 selective nAChR agonist (such as ABT-894 or ABT-107) or
placebo in a 1:1 ratio is administered as an oral capsule 4 times a
day in a blinded fashion for 6 months, and then a crossover for
another 6 months. In between the treatment regimes, subjects are
given a treatment re-titration period for 2 months. Dosing begins
at 1 mg every 6 hours, total daily dose is 4 mg and escalated
upward at 2 week intervals as follows:
[0336] Two mg every 6 hours total daily dose 8 mg for 2 weeks.
[0337] Four mg every 6 hours total daily dose 16 mg for 2
weeks.
[0338] Six mg every 6 hours total daily dose 24 mg for 2 weeks.
[0339] Patients are maintained on this dose for the duration of the
next few weeks of the study until the cross-over. Because patients
who are on placebo have not been exposed to a nAChR agonist such as
ABT-894 or ABT-107, the original escalation schedule is
repeated.
[0340] Safety is assessed by incidences of adverse experiences
(AE), clinical laboratory tests, serum cotinine, ECG and vital
signs. Impulsive symptoms are assessed using the Jay Modified
Minnesota Impulsive Disorders Interview (JayMidi).
[0341] Efficacy is assessed using the Unified Parkinson's Disease
Rating Scale (UPDRS), Barrow Neurological Institute (BNI) Falls
Evaluation, Hoehn & Yahr Staging System, Romberg test, turning
test, standing on one leg, tandem gait, step length and velocity,
Walking and Balance from questions 2.12 from Movement Disorder
Society Unified Parkinson's Disease Rating Scale (MDS UPDRS),
Freezing of Gait from questions 2.14 from Movement Disorder Society
Unified Parkinson's Disease Rating Scale (MDS UPDRS), Dyskinesias
from questions 32-35 from original Unified Parkinson's Disease
Rating Scale (UPDRS), Response Fluctuation from questions 36-39
from original Unified Parkinson's Disease Rating Scale (UPDRS),
Sleep Disturbance from question 40 from original Unified
Parkinson's Disease Rating Scale (UPDRS), Movement Disorder Society
Unified Parkinson's Disease Rating Scale (MDS UPDRS) 142 points,
Axial, Midline part of Movement Disorder Society Unified
Parkinson's Disease Rating Scale (MDS UPDRS), Gait Subtest from
Movement Disorder Society Unified Parkinson's Disease Rating Scale
(MDS UPDRS, Postural Stability Subtest from Movement Disorder
Society Unified Parkinson's Disease Rating Scale (MDS UPDRS), and
Freezing of Gait Subtest (FOG) from Movement Disorder Society
Unified Parkinson's Disease Rating Scale (MDS UPDRS).
[0342] Improvements of axial UPDRS subtests in either "on" or "off"
or both "on or off" periods, including improvement in Gait subtest,
Pull test, and FOG subtests, improvement in turning, in standing on
one leg, in tandem gait, in step length and velocity, improvement
in quantitative tests. All or most of these patients may have
response fluctuations: "wearing off" and/or "on off." Some of these
patients may have freezing of gait (FOG).
Example 11. Development of NC001 Formulations
[0343] NC001 ((formerly NP002), Nicotine Bitartrate) is designed to
treat LIDs. A formulation of nicotine (NC001) may allow the
delivery of nicotine as 4 doses spaced 6 hours apart but delivered
as no more than two pills taken every 12 hours. The formulation
provides short-duration pulses of drug to the system, specifically
so that the nicotine may be nearly absent from the blood system
before the next pulse. In testing, this has been shown to avoid the
building of tolerance to nicotine. This formulation uses
pharmaceutical polymers technology in combination with organic
ionic salts where the permeability is controlled through ionic
interactions in the coating.
Key Technology Objectives
[0344] Medication compliance is a particularly challenging problem
for people with PD. Medications that require a dosage regimen every
4-6 hours cause sleep disturbance, missed doses and in the case of
PD leads to increasing motor complications. This is well
established in PD as can be seen by the multiple different new
dopamine formulations that are being developed to minimize the
problem with medication compliance.
[0345] The controlled release of a drug replace at the preferred
absorption site optimizes delivery of the active ingredient within
the therapeutic window (Stocchi F, et al. 1996), maximizing its
therapeutic benefits. The drug product with 2 discrete drug release
pulses is intended for use in clinical trials for treatment of
LIDs. This formulation approach allows for reduced dosing frequency
in order to provide the pharmacokinetic (PK) profile evaluated in
the previous Phase 2 study. The formulation is a combination of
nicotine drug substance and excipients, in combination with the
specific manufacturing processes, in order to achieve the unique
drug release profile for nicotine, resulting in the targeted PK
profile.
[0346] The first pulse from the 2 pulse formulation is a
traditional immediate release, intended to achieve rapid
therapeutic effectiveness. This is be achieved by drug layering the
nicotine drug substance onto a pellet substrate of microcrystalline
cellulose (MCC) in a fluid bed dryer fitted with a Wurster column
insert for efficient application of the materials. A brand of the
MCC spheres that is commercially-available is Celphere. The drug
substance is sprayed onto the MCC pellets along with a soluble
polymer that helps bind the nicotine to the pellet. This is then
overcoated with an additional immediate-release polymer that can be
purchased in different colors for aesthetics. A brand of
commercially available aesthetic coating is Opadry.
[0347] The second pulse is drug-layered with the nicotine and
soluble polymer in the same manner as the immediate-release
component. The delayed-release pulse also includes an organic acid
salt in the drug layer such as succinic acid. The functional film
coat is then applied to the drug loaded pellets. The functional
film coat is comprised of a copolymer of ethyl acrylate and methyl
methacrylate containing methacrylic acid ester with quaternary
ammonium groups, and triethyl citrate as a plasticizer. The ratios
of the polymers and organic acid modifier determine the time of the
release of the drug from the delayed-release component. A brand of
commercially-available polymer is Eudragit RL and Eudragit RS. The
functional film coat for the delayed release component is also
applied in a fluid bed dryer fitted with a Wurster column. The
organic acid modifier interacts with the copolymer in order to
create pores for the water to leach into the formulation, and
eventually, for the drug to be released.
[0348] Both populations of pellets can be filled into a capsule for
administration, or blended with additional inactive ingredients and
formed into a tablet. Both approaches have been used in commercial
drug products.
[0349] This pulsatile formulation enables target drug delivery and
improve disease management through better compliance and enhanced
patient convenience. It provides a safe drug that does not make PD
worse and allows physicians to treat PD with the most effective
L-dopa therapy regimen.
[0350] 140 patients in treatment and 140 in placebo groups (280
patients total) was calculated as the numbers of patients required,
which is sufficient (90% power) to detect a difference between
NC001 and placebo in the UDysRS total score, assuming a two-sided
two-sample t-test at the 5% level of significance. Sample size
calculations were done based on the continuous outcomes. The mean
change from baseline and standard deviation for each treatment
group were calculated. The sample size calculations were done for
80% and 90% power. The first set of sample sizes is based on a
one-sided alpha=0.05, and the second is a two-sided alpha=0.05.
Sample sizes were calculated assuming a two-sample t-test.
[0351] Nicotine Reduces LIDs in BOTH Rodent AND Primate Models
[0352] The rationale for investigating the anti-dyskinetic
potential of nicotine stemmed from initial basic research findings
from our group. In rats and mice, we found that nicotine reduced
LIDs when administered by any one of several methods including oral
application, injection and slow-release minipumps, with no decline
in its efficacy over time (Quik et al., 2007; Bordia et al., 2010;
Huang et al., 2011a). A critical discovery came when we also
established that nicotine reduced LIDs in parkinsonian monkeys, the
animal model that most closely mimics the motor deficits observed
in PD (Bezard and Przedborski, 2011). Nicotine (which binds and
activates all nicotinic receptors) resulted in a 60% decline in
LIDs in monkeys without worsening of parkinsonism (Quik et al.,
2007; Bordia et al., 2008) (FIG. 4 and FIG. 5). FIG. 4 shows that
NP002 reduces levodopa-induced dyskinesia (LIDs) in a monkey model.
FIG. 5 shows that NP002 does not increase the Parkinsonian symptoms
in the OFF L-dopa or ON L-dopa. This reduction persisted for
months, with no tolerance or loss of efficacy and no detectable
side effects.
[0353] The neurobiological mechanisms underlying LIDs are not well
understood. Extensive studies have implicated multiple
neurotransmitter systems (Huot et al., 2013; Al Dakheel et al.,
2014), including nicotine cholinergic receptors (nAChRs). There is
extensive overlap in the organization and function of the nicotinic
cholinergic and dopaminergic systems in the basal ganglia (Quik and
Wonnacott, 2011). Nicotine is known to influence dopamine release
and alter dopamine-related motor behaviors in animals. Our finding
that nicotine could be used in an animal model of dyskinesia was
only the first step to considering a path for a clinical use of
nicotine. Nicotine is difficult to administer safely, and studies
had suggested that rather high and sustained doses of nicotine were
required for neuroprotection (Belluardo N et al., 2000; Picciotto M
R and Zoli M, 2008; Quik M et al., 2007b). In fact, there had been
anecdotal evidence that using the nicotine patch, which produces
continuous exposure to nicotine, might be useful in slowing
parkinsonian symptoms(currently there is a large NIH funded study
evaluating high dose nicotine patch for neuroprotection in early
stage PD patients.) However, we have noted that sustained
activation of nicotine receptors does not seem to provide
dyskinesia reduction (unpublished clinical observations in patients
with PD and LIDs who have used nicotine patches over the counter or
have been in neuroprotection trials using the patch).
[0354] A major challenge with nAChRs is that they become rapidly
desensitized with continuous exposure to nicotine. Once
desensitized, they lose their responsiveness to agonist drugs, and
in addition, not all receptors desensitize at the same rate. So,
for example, the cardiac receptors may desensitize more slowly than
those in the brain. This leads to multiple problems with safety,
addiction and withdrawal symptoms from continuous treatment with
nicotine. In our clinical trial we utilized a dosing regimen that
provided short-duration pulses of NP002 (nicotine) to the system,
specifically so that the nicotine would be cleared from the blood
system before the next pulse. Fortunately, nicotine is rapidly
absorbed and has a very short half-life (Compton R F et al., 1997;
Schneider N G et al., 2001; Hukkanen J et al., 2005). We sought to
capitalize on this property by developing an oral formulation that
could be swallowed, rapidly absorbed and cleared within about 2
hours. We then waited 6 hours before administering another dose of
the medication. That way, the brain has at least 4 hours free of
nicotine exposure, which should be sufficient to avoid nAChR
desensitization.
[0355] Results: Phase 2 Clinical Trial of Intermittent Doses of
Short-Acting Nicotine in Subjects with PD and Lids
[0356] This study (ClinicalTrials.gov identifiers NCT00957918) was
conducted under an IND (#105268) with the FDA as a multi-center
placebo-controlled, safety, tolerability, and exploratory efficacy
study designed to be used as one of two studies to support
regulatory approval for nicotine for the treatment of LIDs. The
safety and tolerability of nicotine in subjects with idiopathic PD
was assessed by adverse events (AEs), safety laboratory tests,
physical examinations, electrocardiograms (ECGs), vital signs,
assessments of impulse control, nicotine withdrawal symptoms, and
changes in primary parkinsonian symptoms using an escalating dose
of nicotine delivered every six hours for 10 weeks. At the time the
study was performed (2009), there was no FDA accepted instrument
for measuring treatment efficacy for LIDs. Therefore, several
secondary objectives were utilized to assess efficacy including the
Unified Dyskinesia Rating Scale (UDysRS). Since the completion of
this study the UDysRS has been validated in several studies and is
considered by the FDA to be a validated instrument for determining
if a drug is efficacious.
[0357] A total of 65 male and female subjects with idiopathic PD
with LIDs were randomized in the study. The study consisted of 4
phases (FIG. 6A): screening phase (up to 3 weeks), double-blind
treatment phase (10 weeks), taper phase (2 weeks), and follow-up
phase (2 weeks). The approximate duration of the study for each
subject was 17 weeks. Following the screening phase, study subjects
were randomly assigned to receive either treatment with NP002 or
placebo in a 1:1 ratio, administered as an oral capsule 4 times a
day in a blinded fashion for 10 weeks. During the double-blind
treatment phase, dosing was begun at Visit 0 at 1 mg every 6 hours
(total daily dose [TDD]=4 mg/day) and escalated upwards at 2-week
intervals as follows: 2 mg every 6 hours (TDD=8 mg/day) at Visit 1
(Week 2); 4 mg every 6 hours (TDD=16 mg/day) at Visit 2 (Week 4); 6
mg every 6 hours (TDD=24 mg/day) at Visit 3 (Week 6). Subjects were
maintained on 24 mg/day for 4 weeks. The subsequent taper phase (2
weeks total), beginning at Visit 4 (Week 10), consisted of 9 days
of drug taper and 5 days off drug prior to Visit 5 (final safety
visit). All subjects had a follow-up phone call 1 week and 2 weeks
after the final safety visit. Ondansetron was provided by the
sponsor and dispensed with each dose escalation step with
instructions to use it for nausea and vomiting only during the
first 4 days following dose initiation or escalation. Subjects who
tolerated a TDD of 16 mg/day but who did not tolerate 24 mg/day due
to nausea or vomiting, at the investigator's election, were allowed
to drop down to the 16 mg/day dose level. No other dose
down-titration was allowed. See Table 5.
TABLE-US-00005 TABLE 5 Visit Visit 1 Visit 2 Visit 3 Op- Visit 4 0
(Week 2) (Week 4) (Week 6) tional (Week 10) Target mg 1 mg 2 mg 4
mg 6 mg Down Taper per dose titration bottles (or 4 mg placebo)
Total 4 mg 8 mg 16 mg 24 mg 16 mg 9-day Daily taper Dose
[0358] Importantly, a total of 65 subjects (35 in the NP002 group
and 30 in the placebo group) were randomized, and 48 subjects (25
in the NP002 group and 23 in the placebo group) completed the
study. After randomization, 17 subjects withdrew from the study (10
subjects in the NP002 group and 7 subjects in the placebo group).
No subject withdrew before taking any study medication. The most
common reasons for withdrawal were AEs (n=11; 6 subjects in the
NP002 group and 5 in the placebo group) and protocol violations
(n=4; 2 subjects in the NP002 group and 2 in the placebo group). In
addition, there were no issues with impulsivity or withdrawal
symptoms. Importantly, neither the UPDRS Part III nor the Hoehn and
Yahr scales showed any worsening during the study (and showed
slight improvement), demonstrating that there was no worsening of
Parkinson symptoms. Therefore, it was clear that we had established
a safe and well tolerated way to administer nicotine to nicotine
naive patients with PD who were being treated with dopamine agents
(see Table 6).
TABLE-US-00006 TABLE 6 Subject Disposition and Primary Reasons for
Study Discontinuation (All Subjects) NP002 Placebo All Randomized
subjects, N 35 30 65 Subjects who recevied study treatment, n (%)
35 (100.0) 30 (100.0) 65 (100.0) Subjects who required dose
reduction or discontinuation 7 (20.0) 5 (16.7) 12 (18.5) of study
treatment,.sup.a n (%) Subjects who completed study per
protocol,.sup.b n (%) 25 (71.4) 23 (76.7) 48 (73.8) Subjects who
discontinued the study, n (%) 10 (28.6) 7 (23.3) 17 (26.2) Primary
reason for study discontinuation, n (%) Adverse event 6 (17.1) 5
(16.7) 11 (16.9) Protocol violation 2 (5.7) 2 (6.7) 4 (6.2)
Other.sup.c 2 (5.7) 0 (0.0) 2 (3.1) Note: Percentages were based on
the number of subjects randomized in the study in each column.
.sup.aTreated subjects who had any adverse events with action taken
= reduced/discontinued study drug. .sup.bSubjects who completed the
study according to the end-of-study CRF form. .sup.c"Other" reason
was "subject going on vacation" (both subjects)
[0359] NP002 is Efficacious for the Treatment of LIDs and Falls
[0360] NP002 was superior to placebo on ALL patient- and
physician-rated assessments of efficacy, and in some cases achieved
statistical significance.
[0361] Statistically significant differences favoring nicotine
compared to placebo were seen in dyskinesia disability (UDysRS part
3) and Walking (indicating improvement in gait and balance), the
percentage of responders on the Lang-Fahn Activities of Daily
Living (LF-ADL) scale and on the Patient Global Impression-Change
(PGI-C) scale. There was a statistically significant difference
between treatment groups in the number of LF-ADL responders
(subjects with .gtoreq.25% reduction from baseline) at Visit 4
(Week 10) (p=0.0453). In addition, there was a statistically
significant difference between treatment groups in the number of
PGI-C responders (subjects with a score of 1, 2, or 3) at Visit 4
(Week 10) (p=0.0048). There were 21 (77.8%) PGI-C responders in the
NP002 group compared to 9 (37.5%) responders in the placebo group.
Corroborating this response, there was a statistically significant
difference between treatment groups in the numbers of subjects in
the different categories (1 through 7) of the PGI-C scale at Visit
4 (p=0.0230). Importantly, all scales designed to assess dyskinesia
either were numerically and/or statistically significantly superior
to placebo. In addition, using the UPDRS, NP002 was demonstrated to
not cause any worsening of the PD symptoms (trend favored nicotine
compared to placebo and there was no indication of worsening PD and
possible slight improvement). Therefore, results show that nicotine
is efficacious for the treatment of LIDs.
[0362] In summary, this method of delivery of nicotine in our
testing has been shown to avoid the building of tolerance and
dependence on nicotine when patients were withdrawn from therapy.
It is safe and it is efficacious. This critical in formulating the
ultimate successful nicotine product for the treatment of LIDs.
[0363] Innovation
[0364] The use of every 6 hour dosing formulation is not viable in
routine clinical use for this patient population. It would be an
extraordinary challenge for a large clinical study, as compliance
could be low, which would complicate interpretation of the data.
Patient and physician interviews demonstrated that the patients are
already dealing with significant medication challenges with regard
to L-dopa. In spite of the fact that patients often require L-dopa
every 4-8 hours, many patients are non-compliant, and this leads to
major challenges in care. Review of additional data indicated that
large clinical trials (100 patients or greater) have major
compliance constraints when medications must be given every six
hours.
[0365] Approach
[0366] Importantly nicotine's biopharmaceutical properties lend
themselves to improved dosage formulations. Nicotine is available
as a free base and in various salt forms (Siegfried Ltd, 2009). The
nicotine bitartrate dihydrate salt is freely soluble in aqueous
media across the physiological pH range and is commercially
available as pharmaceutical grade material. Nicotine is absorbed
across human tissues, including the skin. It is well-absorbed in
the gastrointestinal tract, with an oral bioavailability of
approximately 30% (20% to 40% reported in literature) (Hukkanen, J.
et al. 2005). Nicotine undergoes first-pass metabolism and is
extensively metabolized into cotinine, resulting in the low and
variable reported absolute bioavailability estimates. These high
solubility and permeability characteristics lend themselves to
development of modified-release (including pulsatile release)
dosage forms including multiple bolus release profiles.
[0367] Phase 1 Aim 1
[0368] Aim 1 is a solid, oral dosage form capable of delivering a
bolus of nicotine to a human approximately every 6 hours. It is a 2
pulse formulation that delivers an immediate-release bolus at time
zero, and a second immediate-release bolus of nicotine
approximately six hours after ingestion. This 2 pulse dosage form
is administered 2 times in a day spaced 12 hours apart (q12 hr) in
order to mimic the PK profile previously evaluated in the Phase 2
studies. This formulation focuses on a multiparticulate
immediate-release dosage form that is coated with a semi-permeable
membrane. This membrane, once hydrated, allows water flow into the
dosage form, but does not allow drug to leak out through the
membrane. In addition to the active drug substance, the core of the
dosage form may contain organic salts, swellable materials, or
superdisintegrants that provides the driving force for the water
uptake and help dictate the timing of the programmed drug release.
An example of a single pellet from the multiparticulate formulation
approach, which is well-suited for a low dose drug, is shown in
FIG. 7. A 15% solution of nicotine is prepared including
hypromellose (HPMC) as a binder and succinic acid as the organic
acid modifier. This solution is coated onto nonpareil seeds using a
fluid bed dryer fitted with a precision coater apparatus until a
20% solids weight gain is achieved on the pellets. The final drug
layer formulation contains nicotine, HPMC, and succinic acid in a
5:3.5:1.5 ratios. If necessary, alternative binders may be used in
order to improve the quality of the adherence of the drug layer to
the nonpareil seed. This core drug-loaded pellet may be coated with
an immediate release polymer such as Opadry for aesthetics and used
as the immediate release component of the composite dosage form.
For the delayed release pellets, a separate population of the core
drug loaded pellets is further coated with a separate functional
polymer film coat. An aqueous solution of Eudragit RS is prepared
with triethyl citrate as the plasticizer and talc functioning as
the antitack agent in a 6:1:3 ratios. This solution is coated onto
the drug loaded pellets using a fluid bed dryer fitted with a
precision coater to total solids weight gain of approximately 70%.
The optimum weight gain is determined experimentally by using in
vitro dissolution as the feedback mechanism. Alternative polymer
materials such as Eudragit RL may also be included in the polymer
film coating formulation to modify the lag time or release rate of
the nicotine from the delayed release pellets.
[0369] Length of the lag time and strength of the drug release can
be tailored based on coating formulation and coat weight gain
(Devane et al., patent).
[0370] Manufacturing Facility
[0371] Initial formulation development experiments are conducted on
small, laboratory scale equipment and batch sizes (10-50 g/batch).
These batches are manufactured at the laboratory or benchtop scale,
and manufacturing instructions and conditions are documented in a
notebook. This material is suitable for in vitro testing but not
for clinical use.
[0372] Formulation Evaluation
[0373] Formulation prototypes are evaluated using a standard drug
product testing approach, including evaluation of drug product
content assay, impurities evaluation, uniformity of dosage units,
and in vitro drug nicotine release rate evaluation. An important
tool for evaluation of solid, oral dosage forms, including
modified-release dosage forms, is in vitro dissolution testing.
Dissolution testing is the industry standard for evaluation of the
release rate for all solid, oral dosage forms, both
immediate-release and modified-release. It is used during
development to assess the performance of the prototype
formulations, during routine commercial batch release to ensure
consistency for product that is marketed to patients, and can be
used to predict the in vivo performance with an in vivo/in vitro
correlation (IVIVC). Once an IVIVC has been established, the
pharmacokinetic profile of the dosage form can be predicted by
evaluation of the in vitro release rate. The dissolution test
conditions can be tailored in order to mimic conditions in the
gastrointestinal tract, and provide insight and sometime predict
the in vivo drug release rate. Specifically, the immediate release
formulations are evaluated in dilute HCl, with a pH of 1.1, to
mimic the fasted stomach conditions, and a pH 4.5 buffer to mimic
the fed stomach conditions. Delayed release formulations can be
challenged in dilute HCl media, with a change to pH 6.8 media to
mimic the movement from the stomach to the small intestine. See
FIG. 8 are examples of theoretical in vitro dissolution profiles
for an immediate-release dosage form, a dosage form with a bolus
release at 6 hours, and a 2 pulse combination of these 2 dosage
forms. FIG. 8 illustrates a drug release profile for an immediate
release (triangles), delayed release (squares), and a 2 pulse drug
release profile (circles). Triangles exhibit an immediate release
of drug, reaching complete dissolution within 1 hour of a start of
a dissolution challenge. A delayed-release component is indicated
by squares and exhibits a similar release to an immediate-release
rate but delayed by approximately 6 hours. A third profile is
indicate by circles and is a composite of 2 different pellet
populations and resulting a 2 pulse drug release profile.
[0374] Formulation Selection and Criteria for Success
[0375] The in vitro evaluation of the immediate release pulse and
the delayed release components of the dosage form are evaluated in
a dissolution bath with paddles rotating at 50 RPM at 37.degree. C.
The media that are employed are a dilute HCl solution at pH 1.1 to
simulate the condition in the gastric cavity, and a 50 mM phosphate
buffer solution, pH 6.8, that are used to mimic the intestinal
conditions. A successful immediate release formulation releases at
least 80% of the labelled amount of nicotine within 30 or 45
minutes. The delayed release formulation is evaluated by the amount
of drug released at 6 hours (the leak) and how quickly the entire
dose of the drug is released once the drug release is initiated.
The nicotine concentration is measured in samples of the media
removed from the dissolution vessel over time and injecting the
sample onto a High Performance Liquid Chromatography (HPLC) system
with UV detection. The amount of nicotine released is measured as a
percentage of the target drug load in the dosage form (i.e.--4 mg
of drug released from an 8 mg total dose would provide a 50%
dissolved result). A successful delayed release formulation
releases at least 80% of the labelled amount of nicotine over
approximately 30-45 minutes beginning 6 hours after the first
release. The target is to minimize the amount of leak in the
delayed-release formulation, and maximize the rate of drug release
once the release is initiated. This results in a strong pulse of
drug release and is intended to perform similarly to the
immediate-release dosage form that is administered 6 hours after
the first dose.
[0376] Phase 1 Aim 2: Manufacturing of GMP Clinical Trial
Material
[0377] Four different formulations are developed under GMP
guidelines ready for the human study. Clinical Trial Material (CTM)
drug product is tested in order to assure their correct quality,
identity, strength, purity, and potency. CTM is then produced in a
section of the facility that is qualified and operated in
accordance with Good Manufacturing Practices (GMPs). These batches
are manufactured using materials that have been released by a
quality unit, and the manufacturing instructions are specified in a
pre-approved batch record. These batches are tested using methods
that have been appropriately qualified, and they are released by a
quality unit prior to dosing in a human clinical trial/
[0378] A barrier to delivering a third and potentially a fourth
pulse from a single dosage form is the delay in drug release
required, coupled with the location of the dosage form at 12 and 18
hours post-dose. As a multiparticulate dosage form is ingested and
travels down the GI tract, the pellets or granules spread out in
the intestine, starting with a variable gastric emptying event. As
small groups of pellets leave the stomach, and spread out along the
small and large intestine, they are be subjected to variable
conditions, including pH and volume of media available for drug
product dissolution. These variable conditions may lead to
different populations of the multiparticulates releasing drug at
different time, and may result in a weaker bolus. Development of a
single, monolithic dosage form approach may address the
multiparticulate pellet spread challenge.
[0379] Human Normal Volunteer Study
[0380] Up to four 12-hr release formulations are tested in man. A
12 mg Pulsatile Release (PR) is intended to provide 2 spikes over
12 hours. The Study is be a Bioequivalence Phase 1 study in 12
normal healthy normal males and females, who are non-smokers, or
previous smokers who are currently non-smokers.times.3 months or
social smokers who are willing and able to abstain from tobacco use
for the duration of the study. We are using healthy normal
volunteers to conduct the study, as the goal is to obtain the
highest quality data with minimal interference from confounding
factors. Healthy volunteer PK studies have been shown to be
superior to PK studies in populations where extended overnight
stays are challenging and compliance is low. For example, subjects
who are ill may have a difficult time refraining from eating, and
food may interfere with the interpretation of data.
[0381] Study Design
[0382] Comparative PK/bioavailability of immediate-release and four
different 12-hr release formulations of nicotine:
Strength/Form
[0383] (A) Immediate Release (IR) 6 mg q6 h.times.4 doses [0384]
(B) Pulsatile Release (PR) 12 mg Form 1 q12 h.times.2 doses [0385]
(C) Pulsatile Release (PR) 12 mg Form 2 q12 h.times.2 doses [0386]
(D) Pulsatile Release (PR) 12 mg Form 3 q12 h.times.2 doses [0387]
(E) Pulsatile Release (PR) 12 mg Form 4 q12 h.times.2 doses
[0388] Each subject has a washout time of a minimum of 3 days prior
to entering into the next period. The time of confinement include
Day--1 through to AM of Day 2 (2 bed nights in each period).
[0389] Safety
[0390] Safety assessments focuses on ensuring that all subjects
entering the study are normal and healthy using a screening and
pre-first-dose--vital Signs and Physical Exam, ECG and Standard
Clinical Lab tests. During the study, close attention is paid to
hemoglobin due to the large blood volume from PK sampling to ensure
that subjects levels are within normal range at the beginning of
each period and at the end of the 5.sup.th period. PK Sampling: The
PK Sampling Schedule is identical for each period and is as
follows: Pre-dose (0 hr), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 6.5, 7,
7.5, 8, 8.5, 9, 10, 12, 12.5, 13, 13.5, 14, 14.5, 15, 16, 18, 18.5,
19, 19.5, 20, 20.5, 21, 22, 24. See FIG. 9.
[0391] Analytical Assay and Statistical Analysis
[0392] Analyte(s): Nicotine and cotinine. Nicotine in plasma or
serum, once quantified bioanalytically, is analyzed using
descriptive statistics to summarize the concentration in samples by
treatment and time point. Each individual subject, by treatment,
concentration versus time profiles is analyzed using
non-compartmental pharmacokinetic (PK) methods to derive the PK
parameters of interest. Of main interest, is the peak (Cmax)
exposure, overall systemic exposure (AUC) over a 24-hour period for
the various treatment regimens. In addition, the time to peak
(Tmax), minimum concentration over the 24-hr interval, and
half-life, is computed where possible. The main exposure parameters
are compared statistically by an analysis of variance (ANOVA)
according to the two, one-sided equivalence approach. Results are
presented as the geometric mean ratio between the proposed
modified-release nicotine regimens and the immediate-release
formulation, with corresponding 90% confidence interval for the
difference in means. Importantly, our team has extensive expertise
in the use of nicotine in pre-clinical and clinical settings. The
combined bioanalytical capabilities include method development,
method transfer and an extensive compendium of assays including the
most sensitive nicotine assay (LLOQ 0.2 ng/mL) on a global platform
in the industry. Table 7 is a listing of the current nicotine
assays available.
TABLE-US-00007 TABLE 7 Available Validated Bionalytical Assays
Species/ Anti- Compound Name Technique Matrix Range coagulant
Nicotine; Cotinine LC-MS/MS Human 0.5-50 ng/mL; 1-200 ng/mL N/A
Serum Nicotine; Cotinine LC-MS/MS Human 0.2-10 ng/mL; 1-100 ng/mL
EDTA Plasma Nicotine; Cotinine LC-MS/MS Human 1-50 ng/mL; 1-100
ng/mL EDTA Plasma Nicotine; Cotinine LC-MS/MS Human 0.2-10 ng/mL;
1-100 ng/mL EDTA, trans-3'-Hydroxycotinine Plasma Heparin Nicotine;
Cotinine LC-MS/MS Human 10-1000 ng/mL; 10-1000 N/A
trans-3'-Hydroxycotinine; Nicotine Urine ng/mL Glucoronide;
Cotinine Glucuronide; 10-1000 ng/mL; 10-1000
trans-3'-Hydroxycotinine ng/mL Glucoronide 20-2000 ng/mL; 50-5000
ng/mL Nicotine; Cotinine LC-MS/MS Human 50-5000 ng/mL; 50-5000 N/A
trans-3'-Hydroxycotinine; Nicotine Urine ng/mL Glucoronide;
Cotinine Glucuronide; 50-5000 ng/mL; 50-5000
trans-3'-Hydroxycotinine ng/mL Glucoronide 200-20000 ng/mL;
200-20000 ng/mL
[0393] Criteria for Success
[0394] The benchmark of success for Phase 2 is the identification
of a formulation of nicotine that can be given to patients once or
twice daily and deliver a nearly identical PK profile as the dosage
regimen of NP002 used in the Phase 2 study.
Example 12. Development of Nicotine Formulations
[0395] Medication compliance.sup.68-70 is a particularly
challenging problem for people with PD. Medications that require a
dosage regimen every 4-6 hours cause sleep disturbance and missed
doses, which, in the case of PD, leads to increasing motor
complications. This is well established in PD.sup.68-70 where 46%
of patients.sup.83 were reported to be non-compliant with their
medication. Therefore it is critical to develop a new formulation
that provides the targeted PK profile with twice a day capsule,
each delivering 2 pulses for a total daily dose of 24 mg.
[0396] The controlled release of a drug at the preferred absorption
site optimizes delivery of the active ingredient within the
therapeutic window.sup.76,9, maximizing its therapeutic benefits.
The side effects of nicotine are related to plasma C.sub.max and,
therefore, spreading the total dose over 4 daily pulses blunts the
C.sub.max and reduces the potential for side effects. Although
patients are rarely troubled by LID during sleep, it is unlikely
that the mechanism for LID is turned off during sleep. Therefore, a
twice daily capsule that provides Q6H pulses of nicotine is a
reasonable approach. This formulation allows for reduced dosing
frequency in order to provide the same PK profile evaluated in the
previous Phase 2 study. The first pulse from the drug capsule
(consisting of 2 pulses) provides a traditional immediate release,
intended to achieve rapid therapeutic effectiveness. This is
achieved by layering the nicotine drug substance onto a pellet
substrate of microcrystalline cellulose (MCC) in a fluid bed dryer
fitted with a Wurster column insert for efficient application of
the materials. A brand of the MCC spheres that is
commercially-available is Celphere. The drug substance is sprayed
onto the MCC pellets along with a soluble polymer that helps bind
the nicotine to the pellet. This is then overcoated with an
additional immediate-release polymer that can be purchased in
different colors for aesthetics. A brand of commercially available
aesthetic coating is Opadry.
[0397] The second pulse of the drug capsule (time released) is
drug-layered with the nicotine and soluble polymer in the same
manner as the immediate-release component. The delayed-release
pulse also includes an organic acid salt in the drug layer such as
succinic acid. The functional film coat, which is then applied to
the drug loaded pellets, is comprised of a copolymer of ethyl
acrylate and methyl methacrylate containing methacrylic acid ester
with quaternary ammonium groups, and triethyl citrate as a
plasticizer. The ratios of the polymers and organic acid modifier
determine the time of drug release from the delayed-release
component. Two commercially-available polymers appropriate for this
use are Eudragit RL and Eudragit RS. The functional film coat for
the delayed release component is also applied in a fluid bed dryer
fitted with a Wurster column. The organic acid modifier interacts
with the copolymer in order to create pores for the water to leach
into the formulation, and eventually, for the drug to be released.
Both populations of pellets can be filled into a capsule for
administration, or blended with additional inactive ingredients and
formed into a tablet.
[0398] This 2-pulse, time released dosage form enables targeted
drug delivery and improve disease management through better
compliance and enhanced patient convenience. It provides a safe
drug that does not desensitize the critical receptors and allows
physicians to treat PD with the most effective L-dopa therapy
regimen.
[0399] Product Development Process Required to Support the NDA
[0400] One of the great strengths of this project is that nicotine
at the dose that we plan to commercialize has already been proven
to be safe. As such, the opportunity for filing an NDA without
additional preclinical safety pharmacology and toxicology or long
term clinical safety data is feasible through the use of the
505(b)(2) pathway. This pathway may allow the utilization of data
in the public domain to support the NDA. A 505(b)(2) is a new drug
application that contains full safety and effectiveness reports,
but allows some of the information required for approval to come
from studies not conducted by or for the applicant. This method
enables a shorter development path for new drugs leading to
potential filing for an NDA in a fraction of the time and cost
required by traditional paths. We have met with the FDA and we
understand that we need a single confirmatory Phase 3 human study
to support the NDA. The FDA also noted that the existing public
domain data on the preclinical safety of nicotine is sufficient to
support our NDA with the exception of the need for a 3 month repeat
dose toxicity study for drug-drug interactions in animals. In
addition to these requirements, a fully updated CMC section may
also be provided to the existing IND. Based on Phase 2 data with
nicotine, our original nicotine formulation, the effect size and
the standard deviation are similar to those observed in phase 2.
Therefore, we calculated that we need 140 patients in treatment and
140 in placebo groups (280 patients total), which is be sufficient
(90% power) to detect a difference between NC001 and placebo in the
UDysRS total score, assuming a two-sided two-sample t-test at the
5% level of significance. Sample size calculations were done based
on the continuous outcomes. The mean change from baseline and
standard deviation for each treatment group were calculated. The
sample size calculations were done for 80% and 90% power. The first
set of sample sizes is based on a one-sided alpha=0.05, and the
second is a two-sided alpha=0.05. Sample sizes were calculated
assuming a two-sample t-test. See Table 8.
TABLE-US-00008 TABLE 8 Scale (Week 10 NC001: NC001: result;
one-sided two-sided change alpha = 0.05 alpha = 0.05 from Nicotine
Placebo 80% 90% 80% 90% baseline) mean sd mean sd power power power
power UDysRS 5.5 6.33 2.5 4.33 102 140 130 172 part III UDysRS 4.4
5.46 0.8 5.00 54 74 70 92 walking
[0401] Impact of Non-Commercial Considerations to the Overall
Significance of the project
[0402] PD is characterized by a loss of nigrostriatal dopaminergic
neurons. Nicotinic receptors are located in the striatum and
peduculopontine nuclei. They are ligand gated ion channels that
regulate the release of dopamine. These receptors are stimulated by
nicotine and acetylcholine. The nicotinic receptor subtype is
localized primarily on dopaminergic terminals which regulates
dopamine release. Nicotine generally exerts its effect by acting at
nAChRs for which multiple receptors exist throughout the
body.sup.11. As an approach to understand the receptors relevant
for nicotine's anti dyskinetic effect, many nAChR subtype agonists
have been tested in the clinic, but none of them have been found
effective in treating LID (see below) nor have they had any effect
on gait, balance and falls.
[0403] From a scientific point of view, successful treatment of LID
with a 2-pulse (total of 4 pulses daily), time released dosage form
nicotine formulation gives us new insights into the mechanisms
underlying gait, postural instability, falls, and LID. It may
provide us with a more accurate assessment of LID, and more
importantly, we may have a safe and effective drug that, in
addition to reducing LID, reduces falls and addresses a >$27
billion/year medical cost of complications in PD patient care.
[0404] Nicotine has been available as a drug product
over-the-counter for many years. In addition, because of extensive
anecdotal evidence, many neurologists have been convinced of
nicotine's usefulness in the treatment of PD
[0405] Market Analysis
[0406] Among the top priorities presented to the National Institute
of Neurological Disorders and Stroke (NINDS) Council.sup.78 as
final recommendations of critical needs for PD research is to
develop effective treatments for L-dopa-resistant features of PD.
These include motor symptoms such as dyskinesia, gait and postural
instability leading to falls. In the U.S., there are approximately
1.5 million Parkinson's patients. Injuries associated with falls
plague PD patients both in terms of human suffering and economic
losses. Annual fall incidence rates in PD range from 50-70% and
recurrent falls are a major cause of disability. The resulting loss
of independence and costs of treatment add substantially to the
healthcare expenditures in PD which is estimated to be $27 billion
annually.sup.79. This cost will rise substantially in the coming
decades as the population ages. An intervention that is cost
effective in reducing falls will have major benefits for the entire
community. In our phase 3 registration study, we will determine
whether treatment with NC001 (when added to levodopa) in addition
to reducing dyskinesia will improve gait, postural stability, and
reduce falls. Occurrence of LID appears to be related to dose and
duration of treatment with levodopa and severity and duration of
disease. In addition, patients who develop PD at a younger age have
an earlier onset and higher rate of LID.sup.66. Based on the number
of PD patients and the percentage of patients who suffer from gait,
postural instability, dyskinesia problems and falls as stated in
the references above, we conclude that there are approximately
750,000 PD patients with these problems and other L-dopa related
motor symptoms in the United States. Internationally, the potential
market is at least double the US market.
[0407] Physician Behavior:
[0408] Nicotine is currently available in many forms as aids for
smoking cessation. These products are generally formulated to
sustain the effect of nicotine over some period of time to provide
lasting protection from cravings (see Research Strategy). These
products (patch and gum) are generally formulated to deliver
sustained and continuous blood levels of nicotine to provide
lasting protection from cravings (FIG. 3). Nicotine, used this way,
will result in desensitization of receptors and cause tolerance and
dependence, and therefore will fail to provide sustained benefit
for PD associated gait disorders. Nicotine tolerance may prevent
the drug from being efficacious in the treatment of LID, NC001 is
designed to provide short-duration pulses of drug to the system,
specifically so that the nicotine will be nearly absent from the
brain at least for 4 hours before the next pulse, thus preventing
the receptor from becoming desensitized. NC001 achieves this
profile, in particular, by timed release dosing, delivering 4
pulses 6 hours apart. In our testing, this has been shown to avoid
the building of tolerance to nicotine, and there has been no
indication of dependence when patients were withdrawn from therapy.
These attributes are critical in formulating a successful nicotine
product for the treatment of gait, postural instability, dyskinesia
and fall reduction in PD and is used for years.
[0409] Development of Nicotine Formulations to Prevents Falls in
Parkinson Disease (PD)
[0410] The major goal of the study is to validate a time release
formulation of nicotine (NC001) that further decreases the
likelihood of inducing desensitization and would increase patient
compliance by changing the dosing from 4 to 2.times./day dosing.
This time release formulation encourages adherence in treatment
especially important given that at the present time as many as
40-60% PD patients do not adhere to their L-dopa 3-4.times./day
dosing regimens.
[0411] Pulsatile administration of nicotine was critical for
treatment of LID. Drug administration compliance is a critical
issue for PD patients. As many as 40-60% of PD patients do not take
their medications as prescribed. Therefore it is essential to
simplify drug administration and develop a method of drug delivery
that results in a far higher rate of compliance. Prior to the Phase
2 clinical trial of nicotine there was a lack of appreciation not
only for the need to improve the safety profile of nicotine AND to
ensure sustained efficacy without inducing desensitization, but
also to develop a twice a day, modified dosage formulation to
insure compliance.
[0412] The 2-pulse, timed released oral formulation of nicotine
that delivers a total of 24 mg/day in two doses provides the needed
exposure and blood profile; ensure maximal effectiveness, safety,
and compliance while avoiding desensitization of receptors and
building tolerance.
[0413] Studies described in humans below confirm that nicotine has
significant anti-LID activity, but more importantly, nicotine
significantly reduces symptoms associated with gait disturbances
associated with falls in PD patients.
[0414] Preliminary Studies
[0415] Rationale for studying nicotine as a potential therapeutic
agent for LIDs and PD associated gait disturbances: The rationale
for using nicotine to reduce falls and dyskinesias stems from
studies in rodents and monkeys rendered parkinsonian by
1-Methyl-4-Phenyl-1,2,3,6 Tetrahydropyridine (MPTP). In this model
nicotine administered orally reduced LIDs through post-synaptic
stimulation of nicotinic acetyl cholinesterase receptors (n-AChRs).
This observation led to a study in PD patients with LIDs. A
challenge with n-AChRs is they become rapidly desensitized with
continuous exposure to nicotine and once desensitized, they lose
their responsiveness. This can lead to withdrawal symptoms
especially from continuous exposure utilizing nicotine patches.
Nicotine is rapidly absorbed, has a short half-life and can be
rapidly cleared (too rapidly with inhaled nicotine, making this
route unsuitable). Thus in clinical trials a dosing regimen was
used that provided short-duration pulses of orally administered
nicotine after the agent is cleared from the blood from the
previous pulse. Nicotine administered orally with a twice daily
drug (4 short pulses) has a peak effect. Most of the drug is
released within an hour (in each pulse), and the residual drug does
desensitize the receptors. This results in the brain being free of
nicotine for at least 4 hours, preventing the receptors from
becoming desensitized, as occurs with the nicotine patch, which
provides continuous exposure to nicotine.
[0416] Nicotine Reduces LIDs in BOTH Rodent AND Primate Models
[0417] The initial basis for investigating the anti-dyskinetic
potential of nicotine stemmed from initial basic research findings
from studies in animal mode. In rats and mice, we found that
nicotine reduced LIDs when administered by any one of several
methods, including oral application, injection and slow-release
mini pumps, with no decline in its efficacy over time.sup.12-14. A
critical discovery came when we also established that nicotine
reduced LIDs in parkinsonian monkeys, the animal model that most
closely mimics the motor deficits observed in PD.sup.29. Nicotine
(which binds and activates all nicotinic receptors) resulted in a
60% decline in LIDs in monkeys without worsening of
parkinsonism.sup.12,15(see FIG. 4 and FIG. 5). This reduction
persisted for months, with no tolerance or loss of efficacy and no
detectable side effects.
[0418] How can Nicotine be Administered Safely and Efficaciously to
Humans for the Treatment of PD Associated LIDs Associated Gait and
Balance Symptoms?
[0419] The neurobiological mechanisms underlying LIDs are not well
understood. Extensive studies have implicated multiple
neurotransmitter systems?.sup.7,16, including nicotine cholinergic
receptors (nAChRs). There is extensive overlap in the organization
and function of the nicotinic cholinergic and dopaminergic systems
in the basal ganglia.sup.18. Nicotine is known to influence
dopamine release and alter dopamine-related motor behaviors in
animals. Our finding that nicotine is effective in animal models of
dyskinesia was only the first step to considering a path for a
clinical use of nicotine. Nicotine is difficult to administer
safely, and studies had suggested that rather high and sustained
doses of nicotine were required for neuroprotection. In parallel
with the efforts to identify how to use nicotine in the clinic, the
field had advanced substantially in its understanding of the
biology of nicotinic receptors. A major challenge with nAChRs is
that they become rapidly desensitized with continuous exposure to
nicotine. NC001 is novel oral formulation of nicotine that was
designed to be administered twice daily, delivery 4 short pulses of
nicotine and not desensitize the receptors. Other formulations of
nicotine (such as patch) are formulated to deliver sustained and
continuous blood levels of nicotine, which causes desensitization
of receptors. Once desensitized, these receptors lose their
responsiveness to agonist drugs, and in addition, not all receptors
desensitize at the same rate, for example, the cardiac receptors
may desensitize more slowly than those in the brain. This leads to
multiple problems with safety, addiction and withdrawal symptoms
from continuous treatment with nicotine. We reasoned that it was
critical to deliver the molecule in a way that avoids
desensitization (see FIG. 3).
[0420] Nicotine is available in many forms as an aid for smoking
cessation. These products are generally formulated to deliver
sustained and continuous blood levels of nicotine to provide
lasting protection from cravings. Nicotine has the potential to
cause tolerance and dependence, but because it is prescribed as a
short-term treatment, this is less of an issue. Therefore, it was
critical to establish that nicotine could be delivered safely to PD
patients being treated with multiple different types of
dopaminergic therapies AND that a dose could be found that would be
delivered in such a way that would be efficacious treating LIDs
without causing tolerance and dependence.
[0421] Clinical Testing of Nicotine in PD Patients
[0422] Rationale: Given the data shown in FIG. 3 for our Phase 2
clinical trial we required a method of drug delivery that provided
4 short-duration pulses of nicotine to the system, specifically so
that the nicotine would be cleared from the blood system before the
next pulse. Fortunately, orally delivered nicotine is rapidly
absorbed and has a very short half-life.sup.23-25. We sought to
capitalize on this property by developing an oral formulation that
could be swallowed, rapidly absorbed and substantially cleared
within about 2 hours. The timing between doses was 6 hours, an
ample time to clear each dose so as not to desensitize AChR
receptor function. We also hypothesized that this method of dosing
might lead to an improved safety profile. Finally, we recognized
that a formulation given every six hours, while not likely to be an
optimal commercial formulation, would be sufficient to test our
hypothesis that short pulses of nicotine would be clinically
efficacious in PD patients and would allow us to titrate the dose
upwards over several weeks and establish how to deliver the drug
safely and efficaciously (please see attachment IND Module 2.3PQOs
CMC details of formulation, clinical trial material and stability
testing). As described below, our trial proved this hypothesis to
be correct.
[0423] Phase 2 Nicotine Study in Patients with PD and LIDs
[0424] Clinical Trial Description and Safety Results
[0425] This study was conducted under IND #105268 as a multi-center
placebo-controlled, safety, tolerability, escalating dose, and
exploratory efficacy study designed to be used as one of two
studies to support regulatory approval for nicotine (NP002) for the
treatment of LIDs. The safety and tolerability of nicotine in
subjects with idiopathic PD was assessed by adverse events (AEs),
safety, laboratory tests, physical examinations, electrocardiograms
(ECGs), vital signs, assessments of impulse control, nicotine
withdrawal symptoms, and changes in primary parkinsonian symptoms
using an escalating dose of nicotine delivered every six hours for
10 weeks. Efficacy was measured with the Unified Dyskinesia Rating
Scale (UDysRS), a semi-quantitative assessment, FDA-validated
instrument to assess gait, balance and dyskinesia in PD. A total of
65 patients, nicotine-naive on levodopa with LIDs from several
clinical sites were randomized. Following screening, patients were
randomly assigned to nicotine administered orally or placebo in a
1:1 ratio 4 times a day in a blinded fashion. Dosing was begun at 1
mg every 6 hours to a final dose of 24 mg per day. Patients who
tolerated a total daily dose of at least 16 mg per day continued in
the study. Six patients in the nicotine group and 5 in the placebo
group withdrew because of adverse effects, which were minor and
reversible.
[0426] Subjects were maintained on 24 mg/day for 4 weeks. The
subsequent taper phase (2 weeks total), beginning at visit 4 (Week
10), consisted of 9 days of drug taper and 5 days off drug prior to
Visit 5 (final safety visit). All subjects had a follow-up phone
call 1 week and 2 weeks after the safety visit. Subjects who
tolerated 16 mg/day but who did not tolerate 24 mg/day due to
nausea or vomiting, at the investigator's election, were allowed to
drop down to the 16 mg/day dose level. No other down-titration was
allowed. Importantly, a total of 65 subjects (35 in the Nicotine
group and 30 in the placebo group) were randomized, and 48 subjects
(25 in the Nicotine group and 23 in the placebo group) completed
the study. After randomization, 17 subjects withdrew from the study
(10 subjects in the nicotine group and 7 subjects in the placebo
group). No subject withdrew before taking any study medication. The
most common reasons for withdrawal were AEs (n=11; 6 subjects in
the Nicotine group and 5 in the placebo group) and protocol
violations (n=4; 2 subjects in the Nicotine group and 2 in the
placebo group). In addition, there were no issues with impulsivity
or withdrawal symptoms. Importantly, neither the UPDRS Part III nor
the Hoehn and Yahr scales showed any worsening during the study
(and showed slight improvement), demonstrating that there was no
worsening of Parkinsonian symptoms. Therefore, it was clear that we
had established a safe and well tolerated way to administer
nicotine to nicotine naive patients with PD who were being treated
with dopamine agents (see attached CSR).
[0427] Phase 2 Clinical Trial Efficacy Evaluations: Nicotine is
Efficacious for the Treatment of Gait, Postural Stability, and LIDs
Given Every 6 Hours
[0428] Nicotine was superior to placebo on ALL patient- and
physician-rated assessments of efficacy, and achieved statistical
significance in reduction of gait, balance and dyskinesia.
Statistically significant differences favoring nicotine compared to
placebo were seen in dyskinesia disability (UDysRS part 3) and
Walking (indicating improvement in gait and balance), the
percentage of responders on the Lang-Fahn Activities of Daily
Living (LF-ADL) scale and on the Patient Global Impression-Change
(PGI-C) scale. There was a statistically significant difference
between treatment groups in the number of LF-ADL responders
(subjects with .gtoreq.25% reduction from baseline) at Visit 4
(Week 10) (p=0.0453). In addition, there was a statistically
significant difference between treatment groups in the number of
PGI-C responders (subjects with a score of 1, 2, or 3) at Visit 4
(Week 10) (p=0.0048). There were 21 (77.8%) PGI-C responders in the
nicotine group compared to 9 (37.5%) responders in the placebo
group. Corroborating this response, there was a statistically
significant difference between treatment groups in the numbers of
subjects in the different categories(1 through 7) of the PGI-C
scale at Visit 4 (p=0.0230) Importantly, all scales designed to
assess posture, gait and dyskinesia either were numerically and/or
statistically significantly superior to placebo. In addition, using
the UPDRS, we demonstrated that nicotine did not cause any
worsening of the PD symptoms. In fact, there was a trend favoring
nicotine compared to placebo. Therefore, we have established that
nicotine delivered in pulsatile doses of 6 mg (every 6 hours) is
efficacious and safe for the treatment of LIDs, and does not induce
desensitization.
[0429] Summary of Clinical Testing:
[0430] In summary, this method of nicotine delivery avoids the
building of tolerance (desensitization) and dependence on nicotine
when patients were withdrawn from therapy. It is safe and it is
efficacious for treatment of gait disturbances associated with PD
and LIDs.
[0431] Nicotine was superior to placebo in all patient and
physician rated assessments of efficacy. Nicotine was statistically
superior to placebo in the Gait-subtest of the UDysRS, indicating
improvement in gait and postural stability. Whether this is because
of a primary improvement in gait and postural stability through
cholinergic mechanisms in the striatum and brainstem
(pedunculopontine nuclei) or whether it is secondary to a reduction
in LIDs is, at present, unclear. This led us to conclude that
nicotine delivered in pulsatile doses of 6 mg (every 6 hours) is a
safe and well tolerated drug to use in PD patients who have LIDs
and gait disturbances with greater likelihood of experiencing
falls.
[0432] Approach:
[0433] The overall goal of this proposal is to develop a time
release formulation of an oral formulation of nicotine previously
shown to be efficacious in a phase 2 clinical trial for use in PD
patient clinical trials for modulation of gait and balance
abnormalities that lead to falls.
[0434] Rationale:
[0435] Nicotine's biopharmaceutical properties lend themselves to
improved dosage formulations. Nicotine is available as a free base
and in various salt forms.sup.26. The nicotine bitartrate dihydrate
salt is freely soluble in aqueous media across the physiological pH
range and is commercially available as pharmaceutical grade
material. Nicotine is absorbed across human tissues, including the
skin. It is well-absorbed in the gastrointestinal tract, with an
oral bioavailability of approximately 30% (20% to 40%) reported.
These high solubility and permeability characteristics lend
themselves to development of a 2-pulse, modified dosage form. The
dosage form is a 12 mg form of nicotine that delivers a
double-pulse of 6 mg nicotine 6 hours apart. This modified dosage
form of nicotine taken orally twice daily is thus critical for
developing a successful nicotine product for the treatment of gait,
postural stability, dyskinesias and falls in PD. Such a drug should
greatly increase patient compliance and improve the quality-of-life
of PD patients. This is a fast track Phase 1-2 proposal.
[0436] Phase 1:
[0437] Develop and select several multiparticulate
immediate-release nicotine dosage forms that are coated with a
semi-permeable membrane that delivers an in vitro dissolution
profile that delivers 2 pulses of nicotine spaced 6 hours apart. In
the Phase 2 study (NCT 000957918), immediate release nicotine was
administered every 6 hours which resulted in an improvement of
UDysRS total, a measure of LIDs. Oral administration of capsules
containing nicotine bitartrate results in rapid absorption with a
T.sub.max of .about.90 minutes. By .about.6 hours (360 min), the
plasma concentration of nicotine returns close to baseline. The
Phase 1 nicotine formulation is taken twice daily, every 12 hours.
The goal is that this modified dosage form would immediately
release a bolus of nicotine and then release a second bolus of
nicotine approximately 6 hours later. FIG. 11B depicts the target
nicotine PK profile after administration of a single capsule of the
2-pulse, modified dosage form. The prototype formulations generated
in this Aim is tested using in vitro dissolution and the ideal drug
release profile presented in FIG. 10. FIG. 10 illustrates a drug
release profile for an immediate release (triangles) and delayed
release (squares). The drug release profile indicated by the
triangles exhibits an immediate release of the drug reaching
complete dissolution within 1 hour of the start of the dissolution
challenge. The delayed-release component, indicated by the squares,
exhibits a similar release rate to the immediate-release, but the
initial drug release is delayed by approximately 6 hours.
[0438] Phase 2, Aim 2
[0439] tests the performance of up to three prototype 2-pulse
modified dosage forms created in Phase 1, and GMP manufactured in
Phase 2, Aim 1. Healthy volunteers are administered these
formulations, and the ideal PK profile would be similar to that
presented in FIG. 11A and FIG. 11B. FIG. 11A illustrates a graph of
single dose nicotine PK profiles. FIG. 11B illustrates a
hypothetical nicotine PK profiles from a 2-pulse modified dosage
form.
[0440] As described above, the formulations generated in phase 1
are tested using in vitro dissolution testing. An example of the
desired in vitro dissolution profile of the individual components
and the composite is shown in FIG. 12.
[0441] The non pareil core is the substrate for application of the
drug layer to the dosage form. See FIG. 7. The uniform size and
shape of the core is ideal for drug layer mechanical strength, and
drug product uniformity. The drug layer contains the active drug
substance and a polymer to adhere the nicotine to the core pellet.
The polymer film layer is the functional film coat that controls
the dissolution of the nicotine from the drug product. The
functional film coat slowly allows water to permeate into the core
pellet, and the rate of this water intrusion is dictated by the
film coat components and the thickness of the film coat. An example
of a core pellet which is well suited is shown in FIG. 7.
[0442] The target PK profile from the dissolution profiles shown in
FIG. 10 is shown in FIG. 12.
[0443] Core Pellet Formulation:
[0444] A 15% solution of nicotine bitartrate dihydrate is prepared
including hypromellose (HPMC) as a binder and succinic acid as the
organic acid modifier (see section 2.3 of the IND CMC attached for
more detail on drug substance). This solution is coated onto
nonpareil seeds using a fluid bed dryer fitted with a precision
coater apparatus until a 20% solids weight gain is achieved on the
pellets. The drug layer on the core pellet formulation contains
nicotine, HPMC, and succinic acid in a 5:3.5:1.5 ratio. If
necessary, alternative levels of HPMC or binders may be used in
order to improve the quality of the adherence of the drug layer to
the nonpareil seed. The final drug layered pellet formulation is
selected based on 1) visual observation of the pellets, 2)
characterization of the drug content on the pellets relative to the
target assay value and 3) the drug release characteristics of each
formulation. The coating should be smooth and uniform under
microscopic evaluation, resulting in good uniformity for the drug
content in the dosage form. In addition, a smooth substrate for
additional functional film coating is desired for efficient coating
and acceptable adherence. The assay value should be within +/-5% of
the target drug content. Both the visual and assay tests are
indicators for quality of the manufacturing process. The drug
release should be rapid from the core pellets, with a target of
>85% dissolved by 15 minutes.
[0445] Immediate-Release Particle Formulation:
[0446] The core drug-loaded pellets is coated with an immediate
release polymer such as Opadry for aesthetics and used as the
immediate release component of the composite dosage form. The
Opadry powder can be reconstituted as a suspension at about 10% for
application onto the Core Pellet to manufacture the Immediate
Release composition for the composite drug product. The suspension
would be coated onto the Core Pellet formulation using a fluid bed
dryer fitted with a precision coater as described above. This
coating can be clear, white, or another color chosen for aesthetic
purposes.
[0447] Modified Release Particle Formulation:
[0448] For the delayed release pellets, a separate population of
the Core Pellets are further coated with a separate functional
polymer film coat. An aqueous dispersion of Eudragit RS is prepared
with triethyl citrate as the plasticizer and talc functioning as
the antitack agent in a 6:1:3 ratio. This dispersion is coated onto
the drug loaded pellets using a fluid bed dryer fitted with a
precision coater to total solids weight gain of approximately 70%.
The optimum weight gain is determined experimentally by using in
vitro dissolution as the feedback mechanism. Formulations are
selected for further evaluation based on their drug release
profile. The formulations may be differentiated by: 1)Amount and/or
type of organic salt included in the formulation to activate the
release of the drug, 2)Weight gain of the polymer formulation on
the Core Pellets, 3) Inclusion of swellable materials under the
modified release polymer film coat and 4) Alternative polymer
materials such as Eudragit RL.
[0449] The amount of organic salt can impact the rate at which the
polymer hydrates to allow water intrusion into the formulation. The
polymer weight gain also serves to modify the rate of water
intrusion, as well as the strength of the film coat. A thicker
coating results in slower water uptake and a delayed drug release
due to the strength of the film coating. Swellable materials can be
added to increase the pressure on the film coat to speed the drug
release. Other polymers may be used to modify the permeability
characteristics of the film coat. Adding Eudragit RL increases the
permeability of the film coat relative to Eudragit RS, increasing
the water uptake rate and reducing the lag time of the drug
release. These formulation materials and conditions may be utilized
to modify the lag time or release rate of the nicotine from the
modified release pellets.
[0450] Composite, Multi-Particulate Drug Product:
[0451] The immediate release and modified release components
particles are filled into small size (#3) capsule shells. Length of
the lag time and strength of the drug release can be tailored based
on coating formulation and coat weight gain.sup.28.
Formulation Evaluation:
[0452] Initial formulation development experiments are conducted on
small, laboratory scale equipment with small batch sizes (10-50
g/batch). These batches are manufactured at laboratory or benchtop
scale, and manufacturing instructions and conditions are documented
in a notebook. This material is suitable for in vitro testing but
not for clinical use. Formulation prototypes are evaluated using
several approaches, including evaluation of content, impurities,
uniformity of dosage units, and in vitro drug (nicotine) release
rate. Other quality attributes such as water content and
microbiological content are evaluated. Stability testing can be
supported by excipient compatibility studies, but is demonstrated
on the actual drug product at room temperature (25.degree. C./60%
RH) and accelerated (40.degree. C./75% RH) conditions. The
stability program evaluates the physical stability of nicotine
(assay and related substances) and the performance of the dosage
form (appearance and dissolution).
[0453] Dissolution Testing:
[0454] Dissolution testing is the industry standard for evaluation
of release rate used during development to assess the performance
of both the immediate release particles, the modified release
particles as well as the prototype capsule formulations. The
dissolution sample concentration is measured using HPLC with UV
detection similar to what was used for release and stability
testing of the clinical materials previously evaluated in the Phase
2 study (see attached IND section 2.3PQOS Assay, Content Uniformity
and Related Substances of Nicotine in Nicotine Capsules by HPLC
AC-AM-00337 for original methods, although more refined methods are
now available). If the initial prototypes do not meet the target
profile, the formulation development process becomes iterative,
using the feedback from the first round of development to guide the
formulation modifications. Prototype formulations are evaluated for
drug release in dilute HCl media, pH 1.1 to mimic the fasted
stomach conditions, as well as pH 6.8 buffer to mimic the
intestinal conditions. In addition, the lead prototypes are also
evaluated in simulated intestinal fluids (FaSSIF and FeSSIF), as
well as pH 4.5 acetate buffer to mimic the fed stomach. The
formulation approach is designed to perform independently of media
pH, resulting in minimal food effect on the PK resulting from
administration of the dosage form.
[0455] Formulation Selection Criteria for Success
[0456] Modified Release Particle Evaluation:
[0457] A delayed release formulation releases at least 90% of the
labelled amount of nicotine over approximately 30-45 minutes
beginning 6 hours after the first release. 10% residual drug does
not desensitize the receptors. Since nicotine is cleared rapidly,
this method of administration of nicotine results in the brain
being free of nicotine for at least 4 hours, preventing the
receptors from becoming desensitized. The target goal is to
minimize the amount of leak in the delayed-release formulation, and
maximize the rate of drug release once the release is initiated.
This results in a strong pulse of drug release and is intended to
perform similarly to the immediate-release dosage form that is
administered 6 hours after the first dose. The modified release
formulation is evaluated by the amount of drug released at 6 hours
(the leak) and how quickly the entire dose of the drug is released
once the drug release is initiated. The nicotine concentration is
measured in samples of the media removed from the dissolution
vessel over time and injecting the sample onto a High Performance
Liquid Chromatography (HPLC) system with UV detection. The amount
of nicotine released is measured as a percentage of the target drug
load in the dosage form (i.e., 4 mg of drug released from an 8 mg
total dose would provide a 50% dissolved result). The in vitro
dissolution performance of the nicotine delayed release formulation
is evaluated according to the decision tree shown in FIG. 13. Each
formulation prototype is evaluated against these criteria and
identified for PK study dosing or modified to meet the dissolution
lag time and release rate criteria.
[0458] The formulations that meet the evaluation criteria from the
in vitro dissolution test are carried forward into in vivo
pharmacokinetic testing in humans. The in vitro dissolution test
may not exactly correlate with the in vivo performance in humans;
therefore 3 prototype formulations are evaluated in the initial PK
study. These formulations differ in targeted lag time and the
qualitative composition of the functional film coat. The levels of
swellable polymer pore formers and organic acid are modified to
evaluate which combination provides the most rapid in vivo
dissolution. Understanding the interaction of these components is
key to designing and selecting the final drug product prototype for
advancement into clinical trials.
[0459] GastroPlus Modeling:
[0460] Another tool that can be used for evaluation and
understanding of formulation performance is GastroPlus. GastroPlus
is a commercially-available modeling and simulation software
program based on Advanced Compartmental Absorption and Transit
(ACAT) model. This is a physiologically based PK model that can
provide understanding of in vivo performance of formulations,
including in vivo dissolution and absorption. Impact of active
transport across the intestinal wall, changes in motility, and drug
metabolism can also be included in the model. Models can also be
developed based on the fed or fasted stomach for a thorough
knowledge of the impact of food on the formulation performance. The
inputs to the model are: drug substance, physical and chemical
characteristics and formulation dissolution rate. PK data from IV
dosing, oral solution, or immediate release formulations are also
useful to develop the model. The FDA actively encourages use of
GastroPlus in evaluation of clinical pharmacology and
biopharmaceutical performance of applicants' NDAs.
[0461] Phase 2 Aim 1: Manufacturing of GMP Clinical Trial
Material:
[0462] Four formulations (nicotine and the three prototype
formulations identified in the phase 1) are manufactured under GMP
guidelines for the human study. This work is conducted at Xcelience
in Tampa, Fla. Xcelience has over 20 years of experience in
formulation and analytical method development, as well as
manufacture and distribution of GMP materials for Phase 1 and Phase
2 studies. Importantly, they have direct experience with nicotine
formulation development activities. The investigators have worked
directly with Xcelience to commercialize similar dosage form
products. The manufacturing parameters are further developed for
the manufacturing scale equipment, and these experiments is
documented in a laboratory notebook
[0463] In vitro dissolution testing is not always predictive of in
vivo performance. As a multiparticulate dosage form is ingested and
travels down the GI tract, the pellets or granules may spread out
in the intestine, starting with a variable gastric emptying event.
As small groups of pellets leave the stomach, and spread out along
the small and large intestine, they may be subjected to variable
conditions, including pH and volume of media available for drug
product dissolution. These variable conditions may lead to
different populations of the multiparticulates releasing drug at
different times, and that could result in a weaker bolus. This
potential effect could provide a barrier to a strong bolus release
at the targeted interval (12 or 18 hours post-dose). However, once
we have the human PK data, we can develop a better In vivo/In vitro
Correlation (IVIVC) for a second round of formulation development.
We have budgeted for this possibility.
[0464] Human Normal Volunteer Study:
[0465] The pulsatile formulation of nicotine requires an immediate
release (IR) component as well as a 6 hour delayed release (DR)
component. The relative absorption of both components (IR and DR)
needs to be similar. This depends on the nature and transit in the
GI tract. Although preliminary data could be obtained in rat or
monkey, gastric emptying and intestinal transit/absorption are
sufficiently different in rat and monkey compared to human.
Therefore, a simple cross-over PK study in human would provide
rapid and definitive information about the performance of the
formulation. A 12 mg, 2-pulses (6 mg each), modified dosage
formulation delivered twice/day is intended to provide 2 spikes
over 12 hours. The side effects of nicotine are related to plasma
C.sub.max. Spreading the total dose over 4 daily administrations
blunts the C.sub.max and potentially reduces the potential for side
effects. Although patients are rarely troubled by LIDs during
sleep, it is unlikely that the mechanism for LIDs is turned off
during sleep. Therefore, a twice daily capsule that provides Q6H
pulses of nicotine is a reasonable approach that covers the waking
day, when dyskinesias are most prominent and disabling and "allow"
the receptors to become "resensitized" overnight. The study is a
Bioequivalence Phase 1 study in 12 normal healthy males and
females, who are non-smokers, or previous smokers who are currently
non-smokers .times.3 months, or social smokers who are willing and
able to abstain from tobacco use for the duration of the study. We
are using healthy normal volunteers to conduct the study, as the
goal is to obtain the highest quality data with minimal
interference from confounding factors. Healthy volunteer PK studies
have been shown to be superior to PK studies in populations where
extended overnight stays are challenging and compliance is low. For
example 2 subjects who are ill may have a difficult time refraining
from eating, and food may interfere with the interpretation of
data. Since the gastric empty effect varies from patient to
patient, each patient acts as their own control.
[0466] Study Design:
[0467] Comparative PK/bioavailability of immediate-release and
2-pulse, modified dosage forms:
[0468] Strength/Form:
A) Immediate Release (IR) 6 mg q6 h.times.4 doses B) 2-pulse,
modified dosage form (PR) 12 mg prototype Form 1 q12 h.times.2
doses C) 2-pulse, modified dosage form (PR) 12 mg prototype Form 2
q12 h.times.2 doses D) 2-pulse, modified dosage form (PR) 12 mg
prototype Form 3 q12 h.times.2 doses Each subject has a washout
time of a minimum of 3 days prior to entering into the next period.
The time of confinement include Day 1 through to AM of Day 2 (2 bed
nights in each period).
[0469] Safety:
[0470] Safety focuses on insuring that all subjects entering the
study are normal and healthy, using a screening and pre-first-dose
Vital Signs and Physical Exam, ECG and Standard Clinical Lab tests.
During the study, close attention is paid to hemoglobin due to the
large blood volume from PK sampling to ensure that subjects' levels
are within normal range at the beginning of each period and at the
end of the 5.sup.th period.
[0471] PK Sampling:
[0472] The PK schedule is identical for each period and is as
follows: Pre-dose (0 hr), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 6.5, 7,
7.5, 8, 8.5, 9, 10, 12, 12.5, 13, 13.5, 14, 14.5, 15, 16, 18, 18.5,
19, 19.5, 20, 20.5, 21, 22, 24.
[0473] Random Assignment
[0474] Analytical Assay & Statistical Analysis:
[0475] Analyte(s): The combined bioanalytical capabilities include
method development, method transfer and an extensive compendium of
assays, including the most sensitive nicotine assay (LLOQ 0.2
ng/mL) on a global platform in the industry.
[0476] Once quantified, nicotine concentrations in plasma or serum
are summarized, by treatment, at each time point using descriptive
statistics. Each individual subject's concentration versus time
profiles are analyzed by treatment using non-compartmental PK
methods to derive the PK parameters of interest. Of primary
interest are the peak (C.sub.max) exposure and the overall systemic
exposure (AUC) determined over the overall 24-hour dosing period
and within each of the four 6-hour intervals (0-6 hr, 6-12 hr,
12-18 hr, and 18-24 hr). The shape of the curves are compared in
addition to several other parameters. Additional parameters to be
measured include: the time to peak (T.sub.max) (24-hour overall and
within each 6-hour interval), minimum concentration over the 24-hr
interval (Cmin), and half-life (T1/2). Exposure parameters are
compared statistically by an analysis of variance (ANOVA) according
to the two one-sided equivalence approaches. Results are presented
as the geometric mean ratio of the parameter values for the
comparison between each of the proposed modified-release nicotine
regimens and the immediate release formulation, with a
corresponding 90% confidence interval for the difference in means.
Importantly, the team has extensive expertise in the use of
nicotine in pre-clinical and clinical settings and expertise in the
analysis of PK data.
[0477] Criteria for Success:
[0478] The benchmark of success for Phase 2 is the identification
of a formulation of nicotine that can be given to patients twice
daily and deliver a nearly identical PK profile to the immediate
release dosage regimen of nicotine used in the Phase 2 study. The
curves are compared visually in addition to review of the
statistical outputs. "Targeted" PK profiles in Bioequivalence
Studies can be identified using LC-MS with human serum, plasma, and
urine. The PK is reviewed within the overall 24-hour dosing
interval, including C.sub.max.times., T.sub.max.times., AUC0-24,
Cmin and T1/2, and within each 6-hour "pulse" dose, including
C.sub.max 0-6, T.sub.max 0-6 and AUC0-6, C.sub.max 6-12,
T.sub.max6-12 and AUC6-12, C.sub.max12-18, T.sub.max12-18 and
AUC12-18, C.sub.max 18-24, T.sub.max 18-24 and AUC18-24. Immediate
and late exposure to nicotine from the 2 doses of each of the 4
test pulse formulations are evaluated relative to the 4 doses of
the IR reference formulation in each of the 6-hour intervals and
overall for the corresponding exposure parameters. Other
calculations that can be used to determine if there is a close
match exposure from 4 unique IR intervals given every 6 hours. For
example, based on the data, it may be more appropriate to evaluate
similarity within each interval, either using the default
bioequivalence (BE) criterion (for "identical" profiles) or another
pre-specified criterion ("similarity" profiles) such as 90%
Confidence Intervals (CIs) around the ratios of geometric
least-squares means (GMR) for the comparison of each time-matched
C.sub.max and AUC between test Form 1, 2, 3 or 4 versus the IR
formulation contained within the standard BE boundary of (0.80,
1.25). However, a wider CI may be considered justifiable from
safety and efficacy prospective: i.e. (0.7, 1.43) if we were to
define success as having peak and overall exposures in each of the
4 intervals within 30% of the IR exposure (matched interval). In
addition, because we are evaluating 2 pulses of drug release from
each test formulation, an immediate release pulse and a 6 hour
delayed release pulse, the early vs. late release characteristics
are compared within each test formulation using nonparametric
comparison of relative T.sub.max values (e.g. both AM and PM doses
combined, as T.sub.max from late release (T.sub.max 6-12 and
T.sub.max 18-24) vs early release (T.sub.max 0-6 and T.sub.max
12-18) for a given formulation).
Example 13. Effect of NC001 a Central Cholinergic Agonist on Gait,
Postural Stability, Dyskinesias and Fall Reduction in Parkinson
Disease (PD)
[0479] Study Objective
[0480] The main objective of this study is to determine whether
treatment with NC001 ((formerly NP002), Nicotine Bitartrate) versus
placebo in addition to dopaminergic drugs will, in addition to
reducing dyskinesias, improve postural stability and reduce falls.
This will be achieved by demonstrating improvement in the motor
portion of the Movement Disorder Society-Unified Parkinson Disease
Rating Scale (MDS-UPDRS) and selected subtests of the MDS-UPDRS in
either "on" or "off" or both "on or off" periods. The subtests will
include the "Gait," the "Pull test," and the "Freezing of Gait"
(FOG) sub-tests. These will be supplemented by selected subtests of
the Barrow Neurological Institute (BNI) Balance Scale including
"Standing on One Leg," "Turning," "Tandem Gait," "Step Length," and
"Velocity.".sup.24 Since there are limitation to these
semi-quantitative sub-tests in assessing gait and postural
stability, these tests will be complemented by quantitative tests
at home and in the clinic. All tests in the clinic will be
performed with the patients wearing IMUs. This will allow us to
correlate information from the semi-quantitative subtests of the
MDS-UPDRS and BNI Balance Scale in both "on" and "off" periods with
information from the quantitative IMUs.
[0481] The above information will be completed by information on
static and dynamic balance in "on" and "off" states utilizing the
Neurocom Equitest and by information from actual falls in both "on"
and "off" states utilizing the Slip-Simulator. Patients undergoing
Neurocom Equitest and Slip Simulator testing will wear IMUs. This
will enable us to correlated information from static and dynamic
balance testing and actual fall testing with information from the
IMUs with a goal of developing a wearable sensor that can predict
falls.
[0482] Testing in the clinic will be complemented by testing at
home that will include 3 days of monitoring utilizing the same
wireless IMUs utilized in the clinic. The IMU technology
incorporating accelerometers and gyroscopes will assess gait,
static and dynamic stability, dyskinesias and energy expenditure.
This will be corroborated by a 3-day standardized diary documenting
dyskinesias and falls. IMUs may provide an accurate assessment of
the severity and percent time occurrence of dyskinesias than
current methods. 6 months of NC001 supplementation may improve gait
and postural stability, reduce falls, and reduce LID.
[0483] Study Design
[0484] A Phase II single center, double-blind, randomized,
placebo-controlled, cross-over, efficacy, safety, and tolerability
study is proposed. The study includes a target enrollment of 40
male and female patients with typical PD with recurrent falls
(>2 per year). Approximately 30% of these patients, 12 patients,
will have LID. Patients will be administered NC001 or placebo in a
1:1 ratio as an oral capsule 4 times a day in a blinded fashion for
6 months, and then after a crossover for another 6 months. Prior to
supplementation an initial base-line evaluation will be conducted.
Afterwards, study will consist of evaluation every 2 months for 6
months, a cross-over, and then an evaluation every 2 months for 6
months. Efficacy will be measured with a set of stability, posture,
gait, and activity measures that have been linked to fall risk
including the Neurocom System, wearable sensors with accelerometers
and gyroscopes and the Slip-Simulator.
[0485] This study will provide insights into the mechanisms
underlying gait, postural instability, falls, and LID. It will
provide us with a more accurate assessment of LID. An assessment
useful for studying other means of reducing dyskinesias such as
deep brain stimulation. Approximately 30% of patients will have
LID, 70% will not. As LID occur when patients are in an "on" state,
and not in an "off" state, an improvement in gait (measured by
IMUs), an improvement in static and dynamic postural stability
(measured by the Neurocom Equitest), and a reduction in falls
(measured by the Slip Simulator) in the 70% of patients without LID
and the 30% of patients with LID in their "off" state, when all
patients are without LID, will establish whether the improvement in
postural stability and reduction in falls is a primary effect of
NC001 or a secondary effect (through reduction in LIDs). Such a
distinction would imply separate and distinct cholinergic
mechanisms for fall reduction versus LID reduction. This in itself
would be an important observation.
[0486] Study Population
[0487] Number of Subjects
[0488] This study will be an interventional one in which 40 people
with PD (please see sample size determination) for .gtoreq.5 years
or more, who have impaired postural stability and have fallen
.gtoreq.2 a year, will be randomly assigned to NC001 or an
identical placebo in addition to their regular PD dopaminergic
medication. All patients will be on levodopa/carbidopa. They may be
on additional dopaminergic drugs including dopamine agonists and/or
monoamine type B oxidase inhibitors. All or most of these patients
may have response fluctuations: "wearing off" Some patients will
have freezing of gait (FOG). Approximately 30% of patients will
have LID.
[0489] Inclusion/Exclusion Criteria
[0490] Participants will be screened from a patient population from
the Muhammad Ali Parkinson Center part of the Barrow Neurological
Institute, St. Joseph's Hospital and Medical Center.
[0491] Inclusion Criteria: [0492] Patient has voluntarily signed
and dated an informed consent form (ICF), approved by an
Independent Ethics Committee (IEC)/Institutional Review Board
(IRB), and provided Health Insurance Portability and Accountability
Act (HIPAA) (or other applicable privacy regulation) authorization
prior to any participation in the study. [0493] Patient is male or
female and is .gtoreq.30 and .ltoreq.83 years of age. [0494] Hoehn
and Yahr Stage II, III in an "on" state. [0495] Fell >2 in past
year. [0496] Montreal Cognitive Assessment (MOCA) score .gtoreq.24.
[0497] Stable dose of levodopa, dopamine agonist and/or monoamine
oxidase B inhibitor, amantadine i.e. unchanged for 3 months. [0498]
Patient is ambulatory and able to walk .gtoreq.10 meters
with/without the use of an assistive device.
[0499] Exclusion Criteria: [0500] Patients with atypical Parkinson
disorders that while infrequent, result in a high number of falls
especially early in the disease. These include: Progressive
Supranuclear Palsy (PSP), Multiple System Atrophy (MSA), Primary
Freezing of Gait (PFG), and Corticobasal Degeneration. [0501]
Patients with dementia MOCA.ltoreq.23. Although dementia is part of
PD and can be a risk for falling, more than half of our patients
with PD and dementia are without a caregiver for at least 4 hours
and we're uncertain if they report all their falls. [0502] Patients
with a drop in blood pressure .gtoreq.systolic (20 pts) and
diastolic (10 pts) [0503] Patients with major orthopedic problems
of their hips or knees, and patients who needed hip or knee
replacements. [0504] Patient with schizophrenia, a schizo-affective
disorder or a bipolar disorder. [0505] Patients with
hallucinations, psychoses or delusions. [0506] Patients with a
history of recent stroke or myocardial infarction [0507] Patients
with a known sensitivity to nicotine or nicotine-containing
products. [0508] Patients taking any of the following medications
or substances within a minimum of 30 days prior to first dose: any
form of nicotine, Cytochrome P450 2A6 (CYP2A6) inducers or
inhibitors during the course of the study or within 30 days of the
planned initial dose of study drug, neuroleptics, anticholinergics
(with the exception of inhaled anticholinergics, e g, ipratropium,
tiatropium), or stimulants [0509] Apomorphine due to its
contraindication with ondansetron (used to treated nausea that may,
initially, accompany administration of nicotine. [0510]
Warfarin
[0511] Study Procedures
[0512] Patients will undergo testing to quantitatively assess gait,
postural stability and falls including the Neurocom to assess
static and dynamic balance, the Slip Simulator, to assess reactions
to an actual fall, and wearable sensors to assess gait, postural
stability and dyskinesias in the clinic and at home.
[0513] Patients will be seen at baseline, 2 months, 4 months and 6
months. At each visit they will undergo "on" and "off" testing, as
well as blood pressure monitoring. After six months, with each
patient serving as their own control, patients on NC001 will be
changed to placebo, and patients who were on placebo will be
changed to NC001. After the cross-over, and a "washout" and
re-titration is completed, all patients will be will undergo
evaluation in both "on" and "off" states. The patients will then be
seen at 2 months, 4 months.sup.25 and 6 months, and initial visits
as before.
[0514] Administration and Titration of NC001
[0515] Parkinson disease is characterized by a loss of
nigrostriatal dopaminergic neurons. Nicotinic receptors are located
in the striatum and peduculopontine nuclei. They are ligand gated
ion channels that regulate the release of dopamine. These receptors
are stimulated by nicotine and acetylcholine. The nicotinic
receptor subtype is localized primarily on dopaminergic terminals
which regulates dopamine release.
[0516] NC001 or placebo in a 1:1 ratio will administered as an oral
capsule 4 times a day in a blinded fashion for 6 months, and then
after a crossover for another 6 months. During the double-blind
treatment phase dosing will be begun at 1 mg every 6 hours, total
daily dose 4 mg and escalated upward at 2 week intervals as
follows:
[0517] 2 mg every 6 hours total daily dose 8 mg for 2 weeks
[0518] Four mg every 6 hours total daily dose 16 mg for 2 weeks
[0519] Six mg every 6 hours total daily dose 24 mg thereafter.
[0520] Nausea, if present, will be treated with ondansetron.
[0521] Patients will be maintained on this dose for the duration of
the study (6 months) until the cross-over. Because patients who are
on placebo will not have been exposed to nicotine, the original
escalation schedule will be repeated. A two week washout period at
crossover, will consist of a 9 day taper and 5 days drug free. The
taper is the reverse of the escalation at a rate of every 3 days as
follows:
[0522] 16 mg for 3 days
[0523] 8 mg for 3 days
[0524] 4 mg for 3 days
[0525] Schedule of Tests
[0526] All patients at each visit will be questioned on fall
frequency and severity .sup.21, 23, they will be instructed to call
if they fall. All patients whether they call or not will be called
once a week and questioned about falls. In clinic measures will
consist of the motor portion of the UPDRS in both an "on" and "off"
state including the subtests of "Gait", "Freezing of Gait" (FOG),
and the "Pull test." Measures will consist of subtests from the BNI
Balance Examination including the "One Legged Stance Test",
"Turning 360 Degrees", "Tandem Gait", "Step Length and Velocity"
after walking 10 meters. Step length and velocity will be corrected
for patient height and calculated from wearable sensors. Testing
will consist of utilizing the Neurocom Equitest with patients in an
"off" and "on" state. The Neurocom Equitest is used to assess motor
control time (MCT) a measure of reactivity to a perturbation.
Testing will consist of walking and slipping on the Slip Simulator
in both "on" and "off" states. During all testing in the clinic
patients will wear an IMU. This will allow us to correlate
information from our semi-quantitative clinical tests, our
information from the Neurocom Equitest, and our information from
the Slip Simulator with information from the IMUs. This may lead to
the development of a single, simple wearable device that will
monitor gait, postural stability, and dyskinesias and falls.
[0527] At home measures will consist of monitoring patients
utilizing wearable sensors incorporating accelerometers and
gyroscopes. These sensors provide information on gait, postural
stability, falls and dyskinesias. The information from the sensors
will be correlated with standardized 3 day diaries.
[0528] Withdrawal
[0529] Participants are free to withdraw from the study at any time
and for any reason. Should the researchers determine that the
participant should be removed from the study, the participants will
be thanked and excused and will be provided with pro-rated
compensation.
[0530] Analytical Methods
[0531] Pathological changes in walking, postural stability and,
postural transition patterns and durations can be used as an
indicator of health/fall-risk status.sup.34,35. The use of wearable
sensors, Inertial Measurement Units (IMU) reduces the human source
of error in gait/postural timing events and is well suited for the
current research. We have tested concurrent validity of IMU based
system measuring time events and transition phases in walking and
sit-to-stand postural movements against those taken from
3-dimensional motion capture system.sup.35. Wavelet de-noising of
IMU signals highlighted postural events and transition durations
that further provided clinical information on postural control and
motor coordination.sup.36. Moreover, IMU can be efficiently used in
monitoring of an individual's daily movements.sup.36 and provide
information regarding movement frequencies and intensities, and can
lead to better diagnosis of gait and postural instabilities and
assessments of falls risk in the environment and situations in
their own living environments.
[0532] Independent Variables: Patients will be evaluated in an
"off" period (16 hours off of levodopa/carbidopa), and then in an
"on" period (one hour after usual morning dose of
levodopa/carbidopa).
[0533] In-Clinic Assessments: Dependent Variables:
[0534] Fall Evaluations: Number and severity of falls including
patient Diary.
[0535] MDS UPDRS: MDS-UPDRS motor portion, Gait, FOG, and Pull test
subtests (questions 3.9-3.14).
[0536] BNI Balance Subtests: Turning 360 degrees, 5, One Legged
stance, and tandem gait. Patients will also be evaluated on their
ability to walk 10 meters. Step-length and velocity will be
determined by wearable sensors.
[0537] FOG Questionnaire: FOG question 2.13 from MDS-UPDRS, and
MDS-UPDRS motor subtest of FOG (3.11).
[0538] TUG test: timed up & go test.
[0539] Question-1 from Orthostatic Hypotension Symptom
Assessment
[0540] Apathy in Parkinson's Disease Questionnaire
[0541] UDysRS: Unified Dyskinesia Rating Scale
[0542] Postural Stability: Postural stability is paramount in
contributing to safely performing activities of daily living.
Indeed, deterioration in this control system is correlated with an
increased risk of falls. In this study, outcome measures that
define stability, and possibly fall risk, will include several
linear measures such as sway area, center of pressure (COP)
velocity, Antero-Posterior, Medio-Lateral sway range and several
nonlinear measures such as approximate entropy and sample entropy.
The postural stability measures will be performed in quiet
standing, with standardized foot placement and the patients looking
in the forward direction with arms at their sides. Two visual
conditions will be performed: eyes-open (EO) and eyes-closed (EC).
Each measurement will last for 30-60 seconds and will be repeated
three times for each condition. A 3 minute rest will be provided
between measurements.
[0543] Motor Control Time (MCT):
[0544] Utilizing the Neurocom system, we will assess motor control
or reaction time to various postural perturbations. Postural
stability can be defined as positional control of the whole body in
space for purpose of balance and orientation.sup.26. Postural
orientation is an ability to maintain appropriate relationship
between body and body segments and is dependent upon goals of
movement task and the environmental context.
[0545] Human postural stability is governed by vestibular, visual,
proprioceptive inputs, and integrated central processing. The
background level of muscle tone activity changes in certain
antigravity postural muscles to counteract the force of gravity.
This increased activity in antigravity muscles is known as postural
tone. Visual inputs and vestibular systems influence postural tone
in various muscles while transition movement occurs (e.g., sit to
stand).
[0546] Postural adjustments associated with movement, anticipatory
postural adjustments (APAs), are preplanned by the central nervous
system (CNS) and counteract the perturbation to postural stability
during the movement.sup.32. In other words, prior to voluntary limb
movement, APAs maintain postural stability by compensating for
destabilizing forces associated with moving a limb and thus prepare
sensory and motor systems for postural demands based on previous
learning. The CNS combines independent but related muscles into
units called muscle synergies, which act together thus reducing the
demand on the CNS. Although it is unknown how at higher levels the
CNS manages APAs to optimize stability in movements, at lower level
changes in postural strategies articulated by the postural demand
of a task (stand-to-sit, sit-to-lay and other daily activities) can
be quantified and investigated with the Neurocom Equitest. This
measure is indicative of the final response of the neuromuscular
system. Many researchers have related postural stability with
understanding balance, motor control and gait problems in the
elderly..sup.26. Postural instability delay can lead to difficulty
in maintaining balance upon a postural disturbance and may increase
the risk of falls.
[0547] Gait and Posture Transition Assessments:
[0548] Patients will walk for a minute and, perform postural
transition movements including dual tasking. Two factors of gait
and postural stability that are relevant to balance control and
dynamic stability during ambulation are: double-support time and
walking speed indicative of gait adaptation to improve stability,
and longer postural transition time indicative of pathology leading
to increased falls. .sup.37,38. Additionally, an increase in the
variability of one or both of these parameters may predispose
people to fall, especially when balance mechanisms are stressed
.sup.39. Double support time and transitional aspects of postures
over several walking cycles will be used to assess gait and
mobility decrements.sup.38. We will measure both walking speed and
postural transitions as proxy for functional mobility status.
Walking speed was chosen because it has been shown to be an
independent predictor of falls leading to
hospitalization.sup.40,41. Postural transition parameter is
important since movements from sit-to-stand and rising from a lying
position are among the most common activities associated with daily
life and the most mechanically demanding functional tasks in daily
activities.sup.42,43. People with PD often fall during these
transitions. Monitoring of postural transitions using the IMU will
be used to assess fall risk. These transitions "slowness in getting
out of a", "inability to rise from a chair of knee height without
using the arms.".
[0549] In order to get away from traditional linear tools that may
mask the true structure of motor variability, a non-linear
dynamical analysis will also be applied to quantify stability
differences and fall risks associated with the treatment
conditions.
[0550] Dynamic stability was chosen to directly represent
individuals' resistant to local perturbations and it has been shown
to be an independent predictor of fall-prone adults .sup.45. Thus
using the IMU system, biomechanical variables that can assess
individuals' fall risk characteristics with high accuracy and that
are comparable to the motion capture laboratories are measured.
After the classification procedure, gait and mobility parameters
such as the double support time and postural transition durations
are calculated using the methods below.
[0551] Trunk Gyro-X (trunk angular velocity with flexion/extension)
signals during standing, walking and various other postures during
7 minute activity is measured. A 3-seconds walking data from
sternum TEMPO is denoised and, Heel Strike and Toe Off events are
identified. Double support time is computed as the duration between
heel strike by the contacting foot and toe-off by the contralateral
foot. The trunk vertical accelerations will represent the whole
body COM transitional acceleration occurring shortly after the heel
strike event.sup.45. Postural transition times will include initial
flexion phase-t1, mid-transition phase-t2, and late extension
phase-t3 (postural durations=sum of all phases). Walking speed will
be calculated from 10 meter walkway using the IMU during the
walking protocol.
[0552] At-Home Assessments (Three Consecutive Days): Dependent
Variables
[0553] In this study, mobility characteristics associated with
activity of daily living such as sitting down, lying down, rising
up, and walking will be assessed. Additionally, characteristics of
postural transitions such as sit-to-stand will be assessed at their
own living environments utilizing an IMU. Furthermore, intensity of
activities, energy expenditure, sleep quality/movements and fall
frequencies will be recorded using an IMU system.
[0554] Physical Activity:
[0555] Being physically active is increasingly being acknowledged
as a way to limit or prevent fall risks and disability. Objective
and accurate information about the physical activities is a
fundamental importance for our research. Prior to the event
detection, IMU signal must be clearly represented and filtered to
remove noises and artifacts from the signal. IMU signals are
non-stationary and need denoising, and an efficient technique for
non-stationary signal processing is the wavelet transform. The
wavelet transform can be used as a decomposition of a signal in the
time-frequency scale plane. Raw and denoised signals are measured.
A robust algorithm to detect postural events occurring in daily
life of an individual without any user-specified parameters will be
deployed.
[0556] Walking Detection:
[0557] Moving window median will be used on denoised gyro-y and
gyro-z and walking threshold will be established. Median windows
helped in removing short postural transitions such as stand-to-sit,
sit-to-stand, sit-to-lay, lay-to-sit etc. from the dynamic events
such as walking.
[0558] Lay Down Detection:
[0559] Lay down event will be classified when detected dynamic
events register acc-z greater than 0.5 g and acc-y less than 0.5 g.
This threshold will be used as a major gravity component shifts
from sensitive y-direction to sensitive z-direction of IMU when
lying in supine posture.
[0560] Sit/Stand Event Detection:
[0561] Sit-to-stand events and stand-to-sit events will be
classified as those dynamic events which were neither classified as
walking nor as lying down. This will be done by replacing the data
interval where walking and laying down events occur by calibration
data points and using the static threshold in truncated acc-z and
truncated gyro-x.
[0562] Outcome Measures of Physical Activity:
[0563] Various physical activities will be recorded for three
consecutive days. Sedentary as well active components of movement
throughout the day will be recorded (FIG. 14 and FIG. 15). FIG. 14
shows activity of seven days including different types of physical
activities.
[0564] Energy Expenditure:
[0565] An Inertial Measurement Unit (IMU) will quantify energy
expenditure (EE). The IMU consists of a tri-axial accelerometer.
Data will be stored in the devices to allow data collection over a
three day period and to capture data in a non-clinical
environment--subjects can perform normal daily activities in their
own environment. Subjects will be instructed how to operate and
attach the device for measurement of daily physical activities. The
device will be worn on the back (L5/S1), attached to a waistline
belt, providing minute-by-minute acceleration in three orthogonal
axes by which EE of physical activity (EEact) will be estimated.
The output of the accelerations, and the subject's physical
characteristics will be utilized to estimate this EEact
(EEact=EE-Resting Energy Expenditure). Individual parameters are
generalized for each subject--body mass, height, gender, and
age--so that with the use of linear and nonlinear models and
acceleration output, one can predict EE and subsequently, EEact
(Chen et al., 1997). Subject's resting energy expenditure (REE) in
kilocalories per minute (4.19 kJ/min) is determined by individual
physical characteristics and predictive equations (1) and (2).
Men : [ 473 .times. weight ( lb ) ] + [ 971 .times. height ( in . )
] - [ 513 .times. age ( yr ) ] + 4687 100 , 000 ( 1 ) Women : [ 331
.times. weight ( lb ) ] + [ 352 .times. height ( in . ) ] - [ 353
.times. age ( yr ) ] + 49 , 584 100 , 000 ( 2 ) ##EQU00001##
[0566] Linear Model: EEact (in kJ/min) is calculated based on the
combined acceleration of all three directions (axes) {square root
over (x.sup.2+y.sup.2+z.sup.2)}. The V component consists of
acceleration in the z-axis, isolated from the x- and y-axes. The
rationale behind separating the axes is due to the fact that the
z-axis is affected by gravity while the other dimensions are
unburdened by this factor. The H component is defined as the square
root of the sum of squared signals of the x- and y-axes {square
root over (x.sup.2+y.sup.2)}. Both .alpha..sub.L and b.sub.L
represent regression parameters in the linear equation and k
comprises time (i.e. EEact at the kth minute).
EEact(k)=a.sub.L.times.H(k)+b.sub.L.times.V(k) (3)
[0567] Nonlinear Model:
[0568] In the nonlinear model, V and H signal were applied by the
two power parameters (p1 and p2) to determine the nonlinear
relationship between EEact and body acceleration. By comparing it
with measured EEact, errors can be determined and used as the
optimization factor. Please refer to the Chen et al. (1997) study
for further information.
EEact(k)=a.sub.N.times.H(k)pl+b.sub.N.times.V(k)p2 (4)
[0569] Finally, the energy expenditures will be categorized
according to the METs levels (light, moderate, vigorous, and very
vigorous) and, itemized activity levels across the day (FIG. 16).
FIG. 16 shows activity levels associated with seven days including
various activities such as light, moderate, vigorous and very
vigorous activities.
[0570] Sleep Movements:
[0571] Insufficient or poor quality sleep may result in drowsiness
and loss of concentration that may increase fall risks. The sleep
movement measures and classifies movement information related to
night's rest. The movement intensity is used to identify
transitions during night's rest. Of each transition the magnitude
and average velocity are calculated, using the change of
inclination of the trunk. Average movement intensity during
movement time is calculated and is illustrated (FIG. 17). Night's
rest detection, going out of the bed, and different postures during
sleep will be quantified. FIG. 17 shows various activities
associated with sleep.
[0572] Freezing of Gait (FOG):
[0573] For objective identification of FOG we are going to use the
FOG index which was proposed by Moore et al.,.sup.46 utilizing
shank IMU. To define freezing of gait index, we will look for a
large increase in the signal energy of leg movement in 3-8 Hz
frequency band during FOG.sup.47. We will use the power spectrum
analysis over 6 s intervals of the vertical linear acceleration of
the left shank. A FOG index at time t will be defined as the square
of the area under the power spectra of a 6 s window of data
(centered at time t) in the `freeze` band, divided by the square of
the area under the spectra in the locomotor band (0.5-3 Hz). For
defining the threshold we will use the individual calibration
[0574] Statistical Statement
[0575] Estimation of required sample size using the MDS UPDRS
scores proceeds from estimates of variability in significant
effects associated with differentiating non-fallers and frequent
fallers.sup.51. Power calculations are performed here by focusing
on sample sizes large enough to determine parameter differences
between two groups with high probability. Utilizing the standard
two-sided T-test: Power=P{|t*|>t(1-a/2; n-2|d)} where d is the
noncentrality parameter, or a measure of the distance between the
means of A and B (13.4): d=|A-B|/s (2/n) where s is the standard
deviation of the distribution of MDS UPDRS scores (largest SD=12.6)
and n is the number of subjects in each group. Specifying that
a=0.05, 15 patients (in a crossover design), should be sufficient
to detect the specified differences in gait and posture scores with
risks of Type I error of 0.05 and Type II error of <0.20
(Power>0.80). Given the exclusionary criteria we will collect 20
participants' data.
[0576] Group Assignment:
[0577] A research assistant, who will not be involved in any
assessments, will assign residents to the treatment or placebo
groups. To further limit selection bias and affirm the groups are
as identical as possible, we will employ an adaptive trial whereby
stratification and randomization are defined after establishing the
spread of baseline levels. Subjects will be assigned to one of two
groups.
[0578] Compliance Assurance:
[0579] Several steps will ensure that the treatment procedure is
followed. First, the supplementations will be distributed to
subjects at each clinic visit and collected at subsequent clinic
visit. Second, a form will be signed by the research assistant
after each distribution and collection of the supplement. Third,
the form will be inspected by the PI to monitor compliance. If not
compliant, the participant will be given a choice to complete their
trial and/or end the experimental protocols.
[0580] Data Processing and Statistical Considerations:
[0581] Primary outcome measure is pull-test and ability to stand on
one-leg, and stability measures (defined by postural sway, motor
control time, and dynamic stability). Secondary outcome measures
are related to dependent variables of interest in determining fall
risks.
[0582] The PI will monitor the results after every clinic visit
using the participants' data to ensure technical success of
testing. To avoid the problem of increased Type I error due to
interim data analysis, a correction to the required p-values will
be applied. For all statistical comparisons, transformations will
be used for data that are not normally distributed, and
non-parametric tests will be employed if extreme violations of
normality are discovered. Transformations will be applied if the
homogeneity of variances assumption is violated (Leven's test).
Corrections for multiple follow-up comparisons will be done using
Bonferroni correction.
[0583] Testing Specific Aim and Optimal Dosing:
[0584] A linear mixed effects models will be performed on all
longitudinal measurements. Additionally, repeated measures ANOVA
will also be performed (in case of no dropouts, and as an
additional sensitivity analysis). The measurements associated with
endpoint assessments will be used in the final model. Primary
endpoints will base on the level of p<0.05 in any batteries of
tests.
[0585] Benchmarks for Success:
[0586] The first three weeks of the trial will be devoted to
assessing the baseline conditions and establishing rater
reliability. Assessor training should be relatively
straight-forward because all outcome measures have been empirically
verified and have well-developed methods/instructions and scoring
systems, increasing the chance of high inter-rater reliability
(Chohen's Kappa). The next six months will be spent assessing
subject outcomes with interim analyses performed early in the trial
to test treatment efficacy. To reach our target enrollment of 20
participants, we will examine our recruitment goals every week, and
if our recruitment effort falls 10% below the required rate to
reach our target enrollment, the research team will discuss about
including additional facilities.
[0587] Adverse Event
[0588] During the treatment, caregivers will report on a
questionnaire whether any problems or adverse events were
encountered. At clinic visits, the research nurse will inquire
about problems or adverse events. Additionally, blood pressure and
heart rate will be monitored and documented prior to the testing.
If an adverse event does occur, an adverse event form will be
filled in which includes the description of the type of adverse
event, the grade of the adverse event (e.g., mild/severe) and if
the adverse event is related to the treatment. Each adverse event
will be discussed with the PI, who will, with the consultation,
determine whether the patient's supplementation should be halted or
discontinued. If a serious adverse event occurs, a special serious
adverse event form will be filed describing the event, the
intensity, if a hospitalization was needed, the outcome of the
event (e.g., recovered/ongoing), and the actions taken. If the
serious adverse event is rated to be related to the
supplementation, the PI and the IRB will determine whether the
entire trial should be halted until further determination can be
made about its safety.
Example 14. NP002 Reduces Falls and Freezing of Gait (FOG) in
Patients with Parkinson Disease (PD)
[0589] Methods
[0590] A total of 65 patients with idiopathic PD and levodopa
induced dyskinesias (LIDs) were randomized. The demographics of the
patients are summarized in Table 9. Patients were required to have
a diagnosis of idiopathic PD and be within a Hoehn & Yahr Stage
II-IV while in a peak "ON" state(levodopa in a therapeutic range).
They had to have moderate to severely disabling LIDs for at least
25% of the waking day, as determined by Questions 32 and 33 in Part
II of the UPDRS and a Mini-Mental State Examination (MMSE) score of
.gtoreq.26. Patients with atypical Parkinson disorders, prior deep
brain stimulation (DBS), unstable angina, a history of ventricular
arrhythmias, or active peptic ulcer or a history of schizophrenia,
schizoaffective disorder, or bipolar disease were excluded.
Patients who actively smoked were also excluded.
TABLE-US-00009 TABLE 9 Demographics NP002 Placebo P Patients
Patients Value Patients 35 27 Age (Years) 68.1 .+-. 8.3 65.5 .+-.
7.2 0.182 NS PD Duration (Years) 11.2 .+-. 4.7 11.1 .+-. 5.6 0.927
NS Levodopa Duration (Years) 9.6 .+-. 4.7 10.2 .+-. 5.4 0.662 NS
LIDs Duration (Years) 5.3 .+-. 3.3 5.2 .+-./- 3.2 0.968 NS Levodopa
Dose (Mg) 612 .+-. 201 582 .+-. 180 0.698 NS Hoehn & Yahr Stage
2.52 .+-. 0.57 2.38 .+-. 0.48 0.9730 NS P- Values for NP002 vs
Placebo calculated using 2- sample t-tests
[0591] The duration of the study was 17 weeks: 10 weeks of active
treatment with NP002 or placebo, a transition period, and a
post-treatment period. PD patients were randomly assigned to either
NP002 or placebo in a 1:1 ratio using a computer-generated program.
The drug, or a placebo identical in appearance and packaging, was
administered orally 4 times a day in a blinded fashion. Patients
were examined while in an "ON" state, when levodopa was in a
therapeutic range. During the treatment phase, dosing was begun at
1 mg every 6 hours (total daily dose=4 mg/day) and escalated
upwards at 2-week intervals as follows: 2 mg every 6 hours at Visit
1; 4 mg every 6 hours at Visit 2; 6 mg every 6 hours at Visit 3.
Patients were maintained on 24 mg/day for 4 weeks. All patients,
study site personnel, raters and the sponsor were blinded to
treatment assignment.
[0592] The original UPDRS scale was used. Part II (Activities of
Daily Living, ADL) and Part III (Motor Examination) were compared
before and after treatments withNP002. In the UPDRS Part II,
Question 13 is on Falling unrelated to Freezing. This is a 5-point
item with responses ranging from "0" (no falls) to "4" falls more
than once/day." Of the 35 NP002 patients, 20 (57%) fell in the past
year and 12 (34%) fell at least twice per month. Of the 27 placebo
patients, 14 (52%) fell in the past year and 9 (30%) fell at least
twice per month. In Part II, Question 14 is on Freezing when
Walking. This is a 5-point item and has two variables freezing and
falls. Of the 35 NP002 patients, 13 (37%) had FOG daily. Of the 27
placebo patients, 10 (37%) had FOG daily. The entire Part II was
compared between NP002 and placebo (Table 10). Questions 13 and 14
were compared separately (Table 11). Retropulsion, a measure of
postural control, assessed by the pull test (Item 30 of the UPDRS
Part III), was also compared (Table 11) between NP002 and placebo
patients.
TABLE-US-00010 TABLE 10 UPDRS Part II (ADL), UPDRS Part III (Motor
Examination) NP002 NP002 Placebo Placebo Patients Patients Patients
Patients at at at at 10 Baseline 10 Weeks Change Baseline Weeks
Change Number 35 30 -8 30 27 0 UPDRS 13.1 .+-. 10.1 .+-. 2.8 .+-.
11.4 .+-. 8.8 .+-. 2.7 .+-. II 6.0 05.3 5.2 5.3 5.0 4.5 UPDRS 20.0
.+-. 17.3 .+-. 2.0 .+-. 16.9 .+-. 16.8 .+-. -0.4 .+-. III 8.8 10.6
7.5 8.3 8.6 6.5 NP002 versus Placebo UPDRS Part II UPDRS Part III
Difference in 10.1 .+-. 0.96 -18.3 .+-. 1.8 LS Means 95% Confidence
(-3.2, 2.0) (-5.8, 2.0) Interval p-value 0.631 0.337 LS = least
squares mean difference. No difference symptoms (Part II ADL) or
signs (Part III Motor Exam) NP002 vs placebo: baseline to 10 weeks
of treatment.
TABLE-US-00011 TABLE 11 UPDRS Part II Question 13 "Falls Unrelated
to FOG" and Question 14 "FOG" Comparison of falls, FOG from
Baseline to Week 10 Falls -3 -2 -1 No Change +1 +2 +3 NP002 1 5 7
16 1 0 0 Placebo 0 0 3 23 1 0 0 FOG -3 -2 -1 No Change +1 +2 +3
NP002 0 2 10 17 1 0 0 Placebo 0 1 3 20 2 1 0 Pull Test -3 -2 -1 No
Change +1 +2 +3 NP002 0 5 5 19 1 0 0 Placebo 0 0 2 24 1 0 0
[0593] LIDs were assessed by the UDysRS, the main measure of LIDs
(Table 12). Compliance was checked with serum cotinine levels
(cotinine is a metabolite of nicotine). Nicotine withdrawal
symptoms were checked with the Nicotine Withdrawal Symptom
Assessment. Adverse events (AEs) potentially related to treatment
were listed in order of frequency in NP002 and placebo patients
(Table 13). The study was conducted in accordance with the
Declaration of Helsinki and Good Clinical Practice Guidelines. All
sites received approval from an institutional review board and
written informed consent was obtained from each patient prior to
participation.
TABLE-US-00012 TABLE 12 Unified Dyskinesia Rating Scale (UDysRS)
NP002 NP002 Placebo Placebo Difference Patients Patients Patients
Patients LS Confidence Baseline Week 10 Baseline Week 10 Means
Interval p-value Number 35 27 27 24 Evaluation of 13.5 +/- 5.4 8.5
+/- 5.4 12.7 +/- 4.9 10.3 +/- 6.1 -2.8 +/- 2.6 -5.7, 0.1 0.062
Dyskinesias on 7 Body Parts Evaluation of 10.5 +/- 4.8 7.0 +/- 5.0
9.4 +/- 5.2 8.2 +/- 5.7 -1.9 +/- 1.4 -4.7, 0.9 0.189 Dyskinesias on
Communication Evaluation of 9.1 +/- 5.6 5.3 +/- 5.0 7.8 +/- 5.4 7.0
+/- 5.1 -2.4 +/- 1.7 -5.8, 1.0 0.171 Dyskinesias on Drinking
Evaluation of 11.3 +/- 6.2 6.9 +/- 5.5 11.1 +/- 5.1 8.7 +/- 5.4
-2.1 +/- 1.4 -5.0, 0.7 0.139 Dyskinesias on Dressing Evaluation of
9.5 +/- 6.0 5.1 +/- 5.3 7.6 +/- 5.0 7.4 +/- 5.7 -3.7 +/- 1.9 -6.5,
-0.9 0.011* Dyskinesias on Ambulation Total Score 51.7 +/- 16.9
36.4 +/- 16.1 48.1 +/- 15.0 38.8 +/- 19.0 -6.7 +/- 4.1 -14.7, -1.3
0.092 UDysRS
TABLE-US-00013 TABLE 13 Adverse Events (AE) NP002 vs Placebo NP002
Placebo Adverse Event (N = 35) (N = 30) Number (%) of subject with
any AE 26 (74.3) 14 (46.7) Nausea 13 (37.1) 2 (6.7) Dizziness 7
(20.0) 1 (3.3) Constipation 5 (14.3) 1 (3.3) Vomiting 4 (11.4) 0
(0.0) Fatigue 3 (8.6) 0 (0.0) Pain 3 (8.6) 0 (0.0) Diarrhea 2 (5.7)
1 (3.3) Headache 2 (5.7) 1 (3.3) Pain in extremity 2 (5.7) 0 (0.0)
Tremor 2 (5.7) 0 (0.0) Nightmare 2 (5.7) 0 (0.0) Insomnia 0 (0.0) 3
(10.0)
[0594] Statistical Methods
[0595] All hypotheses were tested using 2-sided tests with alpha
set at the 0.050 level of significance. In general, efficacy data
were summarized by treatment group, and safety data were summarized
by treatment group and overall. In all analyses, assumptions such
as normality and homogeneity of variance were examined prior to
conducting the proposed parametric statistical procedures.
Categorical variables were analyzed by Fisher's exact 2-tailed test
and continuous variables were tested under 2-sample t-tests. The
equality of variances was examined using an F-test before applying
the 2-sample t-test. The t-test statistics were adjusted if the
variance between 2 groups were significantly unequal.
[0596] Modified Intent-to-Treat (MITT) population consisted of all
patients who were in the randomized population, took at least 1
dose of the study medication, had a baseline and at least 1
scheduled post-baseline assessment. The efficacy analyses were
conducted using the MITT population.
[0597] Sample size calculations were based on the following
assumptions: Type I error of .alpha.=0.05, power=70%, 1-sided test,
placebo response rate=36.8%, a 30% improvement in response compared
to placebo. Initial protocol power calculations were based on a
standard formula for power in 2.times.2 tables using Stata v10.1.
The calculations were confirmed by using a 2-group chi-squared test
of equal proportions using N-Query Advisor 6.01. The calculations
showed that using a 1-sided test, 25 evaluable subjects per arm
would provide a 70% chance of detecting a difference between
placebo and NP002.
[0598] For falls (UPDRS Part II, Question 13), a 5-point scale was
used: 0: No falls to 4: falls more than once per day. For FOG and
falls related to FOG (Question 14), a 5-point scale was used: 0: No
FOG to 3 or 4: frequent falls from FOG. A comparison of
distributions between NP002 and Placebo patients was made using a
distribution that ranged from -3 (a 3-point improvement on the
5-point scale) to +3 (a 3-point worsening on the 5-point scale).
Analysis utilized Fisher's exact 2-tailed test. Improvement or
worsening over baseline was calculated from the last treatment
visit (Table 11).
[0599] The efficacy variables for LIDs were the mean change from
baseline to week 10 in the UDysRS total score; UDysRS sub-scores
(Table 12). An analysis of covariance (ANCOVA) combined features of
regression and analysis of variance (ANOVA). In addition to the
descriptive summary of each variable from baseline to endpoint,
Least Square (LS) means standard errors and 95% Confidence
intervals (CI) of each group, and the difference of LS means
between the 2 treatment groups and its 95% CI are presented. A
similar analysis was applied to comparisons between UPDRS Part II,
UPDRS Part III.
[0600] Results
[0601] Sixty-five patients were randomized: 35 to NP002 and 30 to
placebo. For falls, FOG, and retropulsion, 30 NP002 and 27 placebo
patients had sufficient data to be analyzed. There were no
significant differences in the UPDRS Part II (ADL) and Part III
(Motor Examination) after treatment between NP002 and placebo
(Table 11).
[0602] Fourteen of 30 (47%) of NP002 patients had a reduction in
falls and 12 had no falls during the study. In contrast, only 3 of
27 (11%) of placebo patients had a reduction in falls. These
differences are significant (p=0.00857) (Table 11). Nearly 87% of
NP002 patients had either a reduction or absence of falls during
the active phase of this study. In contrast, only 11% of placebo
patients had reductions or absence of falls. Twelve of 30 (40%) of
NP002 patients had a reduction in FOG, and 10 had no FOG during the
study. Five of 27 (14.8%) of placebo patients had a reduction in
FOG. These differences are significant (p=0.04301) (Table 11).
Nearly 73% of NP002 patients had either a reduction or absence of
FOG during the active phase of this study. In contrast, only 5% of
placebo patients had reductions. Ten of 30 (33.3%) of NP002
patients had a reduction in retropulsion compared to 2 of 27 (7.4%)
placebo patients. These differences are significant (p=0.0228)
(Table 11). See also FIGS. 18-20.
[0603] On the UDysRS ambulation subtest, NP002 patients had a 46%
reduction (improvement) in the effect of LIDs on ambulation while
placebo patients had an 8.6% reduction in the effect of LIDs on
ambulation. These differences were significant in favor of NP002
(p=0.011). On the Total UDysRS, the main measure of LIDs change,
there was a 39% reduction in LIDs on NP002 and a 17.2% reduction on
placebo. These differences trended towards but do not reach
significance (p=0.092) in favor of NP002 (Table 12).
[0604] There were no nicotine withdrawal symptoms on NP002 or
placebo. Serum cotinine levels paralleled dosing of nicotine in
NP002 patients and were absent in placebo patients. Adverse events
in order of frequency are reported in Table 13. The most frequent
adverse event among NP002 patients was nausea. This generally
resolved spontaneously or with ondansetron. The most frequent
adverse event among placebo patients was insomnia. More adverse
events (45) were reported among NP002 than placebo patients (14).
Eleven patients withdrew because of adverse events: 6 who were on
NP002 and 5 who were on placebo.
Example 15. Personalized Treatment Regimen
[0605] A personalized treatment regimen is determined for a
subject. A patient is administered an escalating dose of NP002 up
to the optimum dose tolerated. No more than 24 mg per day is
administered to a subject.
[0606] An exemplary dose escalation schedule is as follows: 1 mg at
Visit 0 and escalated upwards at 1 week to 4 week intervals as
follows: 2 mg at Visit 1, 4 mg at Visit 2, and 6 mg at Visit 3 such
that no more than 24 mg per day is administered. See e.g., FIG. 6B.
The dose of NP002 is administered to the subject one time to six
times a day in a pulsatile manner. A first pulse is administered to
a subject followed by a second pulse at least 2 hours between the
first pulse and the second pulse. A time between each pulse can
also be in a range of 3 hours to 10 hours.
[0607] At each visit, a physician examines the subject for one or
more parameters. Assessments include laboratory tests, analysis of
concomitant medications, physical examinations, mental evaluations,
physical evaluations, electrocardiograms (ECGs), vital signs,
assessments of impulse control, nicotine withdrawal symptoms,
changes in disease symptoms, Mini Mental State Examination,
examinations using Jay Midi Scale, UDysRS, Hoehn and Yahr scale,
Clinical Global impression scale, Patient global impression scale,
Lang-Fahn daily activity scale, and Minnesota Nicotine Withdrawal
Scale-Revised (MNWS-R). Laboratory tests that are performed include
serum cotinine analysis, urine cotinine analysis, serum nicotine
analysis, hematology, chemistry, and pregnancy.
[0608] Based on the examination, a dose of NP002 is adjusted. The
dose of NP002 is adjusted until an optimum dose that is tolerated
is determined. Once the optimum dose is determined, NP002 is used
chronically.
[0609] While preferred embodiments of the present invention have
been shown and described herein, it will be obvious to those
skilled in the art that 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. It is intended that the following claims
define the scope of the invention and that methods and structures
within the scope of these claims and their equivalents be covered
thereby.
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