Compositions and methods for treating falls 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's-related disorders. In some embodiments, the present disclosure utilizes nicotine or a salt thereof in combination with dopamine agonist treatment to reduce fall-related symptoms, such as reducing the frequency of falls, reducing fall-related injuries, reducing the severity of fall-related injuries, improving freezing of gait, improving postural stability, improving motor strength, and improving balance and gait. In some embodiments, the methods predict the frequency of falls and the propensity for recurrent falls in patients with Parkinson's disease, particularly in patients with general Parkinson's disease. [Selected figure] Figure 3

Description

[Technical Field]

[0001] The present application relates to compositions and methods for treating falls and fall frequency associated with neurodegenerative diseases. [Background technology]

[0002] Parkinson's disease (also known as Parkinson's disease, Parkinson's, idiopathic parkinsonism, primary parkinsonism, PD, or paralysis agitans) is a degenerative disorder of the central nervous system. Parkinson's disease results from the death of dopamine-containing cells in midbrain regions, such as the substantia nigra, for unknown reasons. Early in the disease process, the most obvious symptoms are related to movement and balance, including shaking, rigidity, falls, freezing of gait, bradykinesia, and difficulty walking or gait. Collectively, the primary motor symptoms are referred to as parkinsonism, or "parkinsonism." Symptoms of the disease are characterized by the accumulation of a protein called α-synuclein in inclusions called Lewy bodies in neurons and by insufficient formation and activity of dopamine produced by certain neurons in parts of the midbrain.

[0003] Incorporation by Reference 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. Summary of the Invention

[0004] Described herein is a method for reducing the frequency of falls in a subject at risk of falling, comprising administering nicotine or a salt thereof to the subject in an amount of 24 mg or less per day, thereby reducing the frequency of falls. The subject at risk of falls may be elderly or have a central nervous system disease or disorder. The central nervous system disease or disorder may be Parkinson's disease. The nicotine or a 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 to 8 hours after administration. The dosage of nicotine or a salt thereof may be administered to the subject 1 to 6 times per day. The dosage may be 1 mg or less, 2 mg or less, 4 mg or less, 6 mg or less, or 8 mg or less. Administration of nicotine or a salt thereof may result in a plasma nicotine level of less than about 7.5 ng / mL about 180 minutes after administration of the dosage form. Administration of nicotine or a salt thereof can result in a peak plasma nicotine level greater than 10 ng / mL about 25 to about 50 minutes after administration of the dosage form. Administration of nicotine or a salt thereof can result in a peak plasma nicotine level greater than 10 ng / mL about 25 to about 50 minutes after administration of the dosage form, followed by a plasma nicotine level less than about 7.5 ng / mL about 180 minutes after administration of the dosage form. Administration of nicotine or a salt thereof can result in a peak plasma nicotine level greater than 7.5 ng / mL about 25 to about 50 minutes after administration of the dosage form, followed by a plasma nicotine level less than about 5 ng / mL about 180 minutes after administration of the dosage form. Administration of nicotine or a salt thereof can result in a peak plasma nicotine level greater than 5 ng / mL about 25 to about 50 minutes after administration of the dosage form. Administration of nicotine or a salt thereof can result in a peak plasma nicotine level greater than 10 ng / mL about 45 to about 90 minutes after administration of the dosage form. Administration of nicotine or its salts can result in plasma levels of 1.0 ng / mL or less approximately 300 minutes after administration of the dosage form. Nicotine or its salts may be formulated for oral, topical, buccal, transdermal, or inhalation administration. The frequency of falls can be reduced by at least 20%. Falls may be unrelated to freezing of gait (FOG).The falls may be associated with FOG or levodopa-induced dyskinesia (LID). FOG may be reduced. The subject's dyskinesia, walking, gait, balance, or postural control may be improved. Cognitive-related symptoms may be improved. Cognitive-related symptoms may be associated with dementia. The subject may be assessed using UPDRS Part II (Activities of Daily Living (ADL)) Question 13, Falling Unrelated to Freezing, UPDRS Part II (ADL) Question 14, Freezing When Walking, the Unified Dyskinesia Rating Scale (UDysRS) Walking subgroup, or a combination thereof. The subject may further be assessed using UPDRS Part III Item 30. UPDRS Part II (Activities of Daily Living (ADL)) question 13, Falling Unrelated to Freezing, and UPDRS Part II (ADL) question 14, Freezing When Walking, will remain unchanged in subjects, and the Unified Dyskinesia Rating Scale (UDysRS) Walking subgroup may improve in subjects.

[0005] Described herein are methods for reducing freezing of gait (FOG) in a subject, the methods comprising administering nicotine or a salt thereof to the subject in an amount of 24 mg or less per day, thereby reducing FOG. 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. The nicotine or a 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 to 8 hours after administration. The dosage of nicotine or a salt thereof may be administered to the subject 1 to 6 times per day. The dosage may be 1 mg or less, 2 mg or less, 4 mg or less, 6 mg or less, or 8 mg or less. Administration of nicotine or a salt thereof may result in a plasma nicotine level of less than about 7.5 ng / mL about 180 minutes after administration of the dosage form. Administration of nicotine or a salt thereof can result in a peak plasma nicotine level greater than 10 ng / mL about 25 to about 50 minutes after administration of the dosage form. Administration of nicotine or a salt thereof can result in a peak plasma nicotine level greater than 10 ng / mL about 25 to about 50 minutes after administration of the dosage form, followed by a plasma nicotine level less than about 7.5 ng / mL about 180 minutes after administration of the dosage form. Administration of nicotine or a salt thereof can result in a peak plasma nicotine level greater than 7.5 ng / mL about 25 to about 50 minutes after administration of the dosage form, followed by a plasma nicotine level less than about 5 ng / mL about 180 minutes after administration of the dosage form. Administration of nicotine or a salt thereof can result in a peak plasma nicotine level greater than 5 ng / mL about 25 to about 50 minutes after administration of the dosage form. Administration of nicotine or a salt thereof can result in a peak plasma nicotine level greater than 10 ng / mL about 45 to about 90 minutes after administration of the dosage form. Administration of nicotine or its salts can result in plasma levels of 1.0 ng / mL or less approximately 300 minutes after administration of the dosage form. Nicotine or its salts may be formulated for oral, topical, buccal, transdermal, or inhalation administration. FOG can be reduced by at least 20%. The frequency of falls may be reduced. Falls may be prevented. Fall-related complications may be reduced.

[0006] Described herein are methods for improving postural stability in a subject, the methods comprising administering to the subject nicotine or a salt thereof in an amount of 24 mg or less per day, thereby improving postural stability, which may be associated with falls, freezing of gait (FOG), or dyskinesia.

[0007] Described herein is a method for reducing the frequency of falls in a subject at risk of falling, the method comprising administering to the subject a nicotinic acetylcholine receptor (nAChR) agonist in an amount of 24 mg or less per day, thereby reducing the frequency of falls.

[0008] Described herein is a method for preventing falls in a subject, the method comprising administering nicotine or a salt thereof to the subject in an amount of 24 mg or less per day, thereby preventing falls. 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. The nicotine or 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 to 8 hours after administration.

[0009] Described herein are methods for treating a cognitive disease or disorder in a subject, the methods comprising administering to the subject nicotine or a salt thereof in an amount of 24 mg or less per day, which may not result in tolerance or dependence on nicotine or a salt thereof.

[0010] Described herein are multiparticulate formulations comprising nicotine or a salt thereof, which deliver an immediate release dose of nicotine and a second immediate release dose of nicotine about 2 to about 8 hours after administration, with a total dose administered to a subject of 24 mg or less per day. The formulations may be administered to a subject 1 to 6 times per day. The formulations may deliver 1 mg or less every 6 hours, 2 mg or less every 6 hours, 4 mg or less every 6 hours, or 6 mg or less every 6 hours. Administration of the formulations can result in plasma nicotine levels of less than about 7.5 ng / mL about 180 minutes after administration of the formulation. Administration of the formulations can result in peak plasma nicotine levels of greater than 10 ng / mL about 25 to about 50 minutes after administration of the formulation. Administration of the formulation can result in a peak plasma nicotine level greater than 10 ng / mL about 25 to about 50 minutes after administration of the dosage form, followed by a plasma nicotine level less than about 7.5 ng / mL about 180 minutes after administration of the formulation. Administration of the formulation can result in a peak plasma nicotine level greater than 7.5 ng / mL about 25 to about 50 minutes after administration of the dosage form, followed by a plasma nicotine level less than about 5 ng / mL about 180 minutes after administration of the formulation. Administration of the formulation can result in a peak plasma nicotine level greater than 5 ng / mL about 25 to about 50 minutes after administration of the formulation. Administration of the formulation can result in a peak plasma nicotine level greater than 10 ng / mL about 45 to about 90 minutes after administration of the formulation. Administration of the formulation can result in a plasma level of 1.0 ng / mL or less about 300 minutes after administration of the formulation.

[0011] Described herein are kits that include: (a) one or more starting unit doses of nicotine or a salt thereof for administration 1 to 6 times per day for about 1 to about 4 weeks, wherein 1 mg or less of the nicotine or a salt thereof is administered per administration; (b) one or more increasing unit doses of nicotine or a salt thereof for administration 1 to 6 times per day for about 1 to about 4 weeks, wherein no more than two of the starting unit doses of nicotine or a salt thereof are administered per administration; (c) optionally, one or more increasing unit doses of nicotine or a salt thereof for administration 1 to 6 times per day for about 1 to about 4 weeks. (d) optionally, one or more third escalating unit doses of nicotine or a salt thereof for administration 1 to 4 times per day for about 1 to about 4 weeks, wherein one or more starting unit doses of nicotine or a salt thereof are administered 6 or less times per administration; and (e) instructions for escalating the dosage of nicotine or a salt thereof, wherein the total dosage for administration is 24 mg or less per day. The kit can include one or more starting unit doses of nicotine or a salt thereof for administration 4 times per day for 4 weeks. The kit can include a dose of 112 mg of nicotine or a salt thereof. The nicotine or a salt thereof may be formulated for oral administration. The nicotine or a salt thereof may be in solution form. The nicotine or a salt thereof may be in solid form. The nicotine or salt thereof may be in the form of a liquid, a gel, a semi-liquid, a semi-solid, or a solid.

[0012] Described herein are kits that include: (a) a first dose of nicotine or a salt thereof in one or more unit doses over a first period of about 1 to about 4 weeks, wherein the first dose is about 1 mg; (b) a second dose of nicotine or a salt thereof in one or more unit doses over a second period of about 1 to about 4 weeks, wherein the second dose is about 2 mg; and (c) optionally, a third dose of nicotine or a salt thereof in one or more unit doses over a third period of about 1 to about 4 weeks. (d) optionally, a fourth dose of nicotine or a salt thereof in one or more unit doses over a fourth period of about 1 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 the total dose for administration is 24 mg or less per day. The first dose may be administered 1 to 6 times per day. The second dose may be administered 1 to 6 times per day. The third dose may be administered 1 to 6 times per day. The fourth dose may be administered 1 to 4 times per day. The time between the first and second periods may be about 1 to about 4 weeks. The time between the second and third periods may be about 1 to about 4 weeks. The time between the third period and the fourth period may be about 1 to about 4 weeks. The time between the first period and the fourth period may be about 10 weeks or less.

[0013] Described herein are methods of administering nicotine or a salt thereof to a subject, the methods comprising: (a) administering a starting dose of nicotine or a salt thereof 1 to 6 times per day for about 1 to about 4 weeks, wherein the starting dose is about 1 mg; (b) administering a first escalating dose of nicotine or a salt thereof 1 to 6 times per day for about 1 to about 4 weeks, wherein the first escalating dose of nicotine or a salt thereof is about 2 mg; and (c) optionally administering a second escalating dose of nicotine or a salt thereof 1 to 6 times per day for about 1 to about 4 weeks, wherein the first escalating dose of nicotine or a salt thereof is about 2 mg. (d) optionally, administering a second escalating dose of nicotine or a salt thereof 1 to 6 times per day for about 1 to about 4 weeks, wherein the second escalating dose of nicotine or a salt thereof is about 4 mg; (d) optionally, administering a third escalating dose of nicotine or a salt thereof 1 to 4 times per day for about 1 to about 4 weeks, wherein the third escalating dose of nicotine or a salt thereof is about 6 mg; and (e) measuring one or more parameters, wherein the total dose for administration is 24 mg or less per day. The one or more parameters may be adverse events. The subject may have one or more parameters measured using laboratory tests, psychological assessment tests, or physical assessment tests. The method may not result in tolerance or dependence on nicotine or a salt thereof. [Brief explanation 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 embodiments in which the principles of the invention are utilized, and the accompanying drawings in which: [Figure 1] Illustrated is a method for screening and assessing fall-related symptoms in subjects with Parkinson's disease. [Figure 2] 1 illustrates a timeline for evaluating the effectiveness of nicotine or a salt thereof in treating fall-related symptoms in subjects with Parkinson's disease. [Figure 3]Pharmacokinetic profiles of different modes of nicotine administration are illustrated, including via transdermal patch (15 mg / 16 hours), buccal gum (4 mg, assumed hourly administration), or oral tablet (3 mg, 4 mg, or 6 mg). [Figure 4] 1 illustrates a graph of dyskinesia rating / time point on the Y-axis and time (minutes) on the X-axis in control-treated and nicotine-treated monkeys. [Figure 5] 1 illustrates a graph of Parkinson's rating for OFF L-dopa (left bars on the X-axis) and ON L-dopa (right bars on the X-axis) in control-treated and nicotine-treated monkeys. [Figure 6A] Illustrates an outline of the Phase 2 safety and tolerability study design. [Figure 6B] An example of a phase 2 trial schedule is shown below. [Figure 7] 1 illustrates a pH-independent multiparticulate dosage form. The coating substrate is shown in white on the drug-containing layer. The rate-controlling polymer is layered on top of the drug-containing layer. [Figure 8] Drug release profiles are illustrated for immediate release (triangles), delayed release (squares), and two pulsatile drug release profiles (circles). [Figure 9] An example of a PK sampling schedule is shown below. [Figure 10] Immediate release (triangles) and delayed release (squares) drug release profiles are illustrated. [Figure 11A] 1 illustrates a graph of a single dose nicotine PK profile. [Figure 11B] 1 illustrates hypothetical nicotine PK profiles of two pulse-modified dosage forms. [Figure 12] 1 is a graph of the target two-pulse PK profile of nicotine modified release capsules 12 mg (6 mg IR and 6 mg DR). [Figure 13] 1 illustrates a decision tree for the evaluation of delayed in vitro release performance of nicotine. [Figure 14]Illustrate a 7-day activity period that includes different types of physical activity. [Figure 15] Illustrates sedentary and active movements over a 7-day period. [Figure 16] Illustrate 7-day activity levels including a variety of activities such as light, moderate, vigorous, and very vigorous activity. [Figure 17] 1 illustrates various sleep-related activities. [Figure 18] 1 illustrates a graph of the reduction in falls unrelated to freezing of gait (FOG), as assessed by Part II of the Unified Parkinson's Disease Rating Scale (UPDRS), in patients receiving NP002 (left bar) or placebo (right bar) at the end of the treatment period (10 weeks, x-axis). The y-axis shows the percentage (%) of patients experiencing a reduction in falls. [Figure 19] 1 illustrates a graph of the reduction in freezing of gait (FOG), as assessed by Part II of the Unified Parkinson's Disease Rating Scale (UPDRS), in patients receiving NP002 (left bar) or placebo (right bar) at the end of the treatment period (10 weeks, x-axis). The y-axis shows the percentage (%) of patients experiencing a reduction in FOG. [Figure 20] 1 illustrates a graph of the decline in gait as assessed by Part II of the Unified Parkinson's Disease Rating Scale (UPDRS) subtest in patients receiving either the treatment period (NP002 left bar at the end of 10 weeks, x-axis) or placebo (right bar). The y-axis indicates improvement in gait. DETAILED DESCRIPTION OF THE INVENTION

[0015] As used herein, the term "postural instability" (PI) refers to a lack of balance.

[0016] As used herein, the term "balance" refers to the multi-system function that strives to keep the body upright while sitting or standing and while changing positions.

[0017] As used herein, the term "zero order release" refers to a constant or near constant rate of release of a drug from a dosage form over a period of release, i.e., a release rate that is independent of the concentration of the 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 effect while minimizing side effects.

[0018] The term "oral administration," as used herein, refers to a mode of delivery of a drug dosage form to a subject, where the dosage form is placed in the subject's mouth and swallowed.

[0019] As used herein, the term "orally deliverable" means suitable for oral administration.

[0020] The term "enteric coating," as used herein, refers to a tablet shell that is resistant to gastric juices after oral administration to a subject and dissolves after the enteric-coated dosage form is emptied from the stomach.

[0021] The term "therapeutic effect" as used herein encompasses therapeutic benefit and / or prophylactic benefit. Therapeutic benefit refers to the eradication or amelioration of the underlying disorder being treated. Similarly, therapeutic benefit is achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that the patient is observed to improve, even though the patient may still be affected by the underlying disease. With regard to prophylactic benefit, the composition may be administered to a patient at risk of developing a particular disease or to a patient who reports one or more physiological symptoms of the disease, even if no diagnosis of the disease has been made. Prophylactic benefit includes delaying or eliminating the appearance of the disease or disorder, delaying or eliminating the onset of symptoms of the disease or disorder, slowing, halting, or reversing the progression of the disease or disorder, or any combination thereof.

[0022] The term "excipient," as used herein, means any substance, but which is not itself a therapeutic agent, used as a carrier or vehicle for delivering 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 allow or facilitate the formation of a dosage unit of the composition into a separate product such as a capsule or tablet suitable for oral administration. Excipients include, by way of non-limiting example, diluents, disintegrants, binders, adhesives, wetting agents, lubricants, glidants, substances added to mask or neutralize unpleasant tastes or odors, flavorings, dyes, fragrances, and substances added to modify the appearance of the composition.

[0023] The term "pH-independent release" refers to a release rate 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, for example, from an acidic pH to a higher pH. The term "pH-dependent release" refers to a release rate of a drug from a dosage form that changes when the pH of the environment in which the dosage form is found is changed, for example, from an acidic pH to a higher pH.

[0024] The terms "NC001" and "NP002," as used herein, refer to nicotine bitartrate and can be used interchangeably.

[0025] The term "about," as used herein, unless otherwise specified or clear from context, refers to a number or range of numbers that is understood to mean the specified number and + / - 10% of that number, or up to 10% of the recited lower limit and up to 10% of the recited upper limit for recited values ​​in a range.

[0026] In various aspects, the present disclosure relates to compounds, compositions, and methods for treating fall-related symptoms in individuals with neurodegenerative disorders, such as Parkinson's disease (PD) and PD-related disorders, Alzheimer's disease (AD), dementia, amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease, Huntington's disease (HD), multiple sclerosis, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), motor neuron disease (MND), and prion diseases. In some embodiments, the present disclosure is achieved by administering a therapeutically effective amount of nicotine or a salt thereof, or a nicotine receptor modulator to an individual suffering from the disease. In some embodiments, the present disclosure also relates to compositions comprising nicotine or a salt thereof, or a nicotine receptor modulator, and a pharmaceutical carrier, formulated for administration to an individual suffering from the disease. As disclosed herein, administering a therapeutically effective amount of nicotine or a salt thereof, or a nicotine receptor modulator to an individual with a neurodegenerative disease reduces fall-related symptoms, such as reducing the frequency of falls, reducing the frequency of fall-related injuries, reducing the severity of fall-related injuries, improving postural stability, improving static balance, and improving gait. In some embodiments, the subject has Parkinson's disease (PD) or a PD-related disorder. In some embodiments, the subject has generalized Parkinson's disease. In some embodiments, the subject is receiving dopamine agonist treatment.

[0027] Falls and Parkinson's Disease Falls are common among people with neurodegenerative diseases. 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, July 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 result from a lack of movement, slowness, and a lack of postural stability (balance). Falls in the early stages of PD (within 1–5 years of diagnosis), particularly single falls, usually result from a lack of movement and slowness and are often responsive to dopaminergic medications (e.g., levodopa, dopamine agonists, and monoamine oxidase type B inhibitors). Falls, recurrent falls, and falls with injuries usually occur late (more than 5 years after diagnosis).

[0028] Falls are a major risk for people with Parkinson's disease (PD). Most falls result from a lack of movement and slowness, as well as a lack of postural stability or balance. Recent studies have shown that people with PD often experience single or recurrent falls (Lieberman et al., “Comparison of Parkinson's disease patients who fell once with patients who fell more than once (Recurrent fallers)”, J. Alzheimers Dis Parkinsonism, 4(2) , March 15, 2014; doi: 10.4172 / 2161-0460.1000140). Single falls, such as falls occurring once a year in older adults, may be related to the underlying disease or accidental. Recurrent falls, such as falls occurring more than once a year, are more likely to be related to the underlying disease. Recurrent falls also cause injuries or increase the severity of fall-related injuries.

[0029] Recurrent fallers, known to cause recurrent falls, differ significantly in the duration and severity of PD from single fallers and non-fallers, known to cause a single fall or not fall. Recurrent fallers also differ significantly from single fallers and non-fallers in freezing of gait (FOG), postural instability (e.g., "pull test"), and static balance (e.g., inability to stand on one leg for more than 3 seconds).

[0030] People with PD fall more frequently than people without PD. Single falls are common in people with PD within 1 to 5 years of diagnosis. Single falls can usually be treated with dopamine agonists, such as 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.

[0031] Falls in early PD are likely due to motor deficits and slowness. Slowness of movement can be corrected with dopamine agonists, and thus falls in early PD are reduced with these medications. In late PD (more than 5 years after diagnosis), recurrent falls occur despite the use of these medications. Falls in late PD are likely due to a loss of postural stability, which may not respond to or may be exacerbated by dopamine agonists (Chen R, Paradoxical worsening of gait with levodopa in Parkinson's disease Neurology 2012 78: 446-447; Hely MA, Morris GL, Wayne GJ, 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 who fall in the late stages of PD may have recurrent falls, which may sometimes be exacerbated by treatment with dopamine agonists.

[0032] Recurrent fallers have longer-lasting PD and greater disability, and have higher Parkinson's Disease Rating Scale (UPDRS) scores than single fallers. As a non-limiting example, recurrent fallers are likely to be unable to stand on one foot for less than three seconds. In some cases, the ability to stand for less than three seconds can be used to predict recurrent falls in patients with or without freezing of gait. Recurrent fallers are likely to be able to stand on one foot for less than three seconds, which may serve as a better predictor of recurrent falls, although not as well as the ability to stand on one foot for less than three seconds. Together, the ability to stand on one foot for less than three seconds and freezing of gait are more likely to predict recurrent falls and the UPDRS postural stability ("pull test") than the gait subtests.

[0033] The Barlow Neurological Institute Balance Scale, along with the Single Leg Stand for <3 seconds and Freezing Gait Test, may be useful additions to the UPDRS scale, particularly in predicting recurrent falls.

[0034] The severity of a fall can be classified as a fall requiring medical attention or a fall that does not require medical attention. A severe fall typically requires medical attention and can be defined by the following criteria: 1) falling on the floor without loss of consciousness, with all four limbs or the head striking the ground; 2) needing assistance at the time of the fall; 3) spraining a joint or sustaining a fracture. Typically, a person with PD may visit an emergency room or urgent care center.

[0035] Single falls, although severe, may be only partially or not associated with PD. However, some patients with PD experience recurrent falls (Lieberman et al, “Comparison of Parkinson's disease patients who fell once with patients who fell more than once (Recurrent fallers)”, J. Alzheimers Dis Parkinsonism, 4(2), March 15, 2014; doi: 10.4172 / 2161-0460.1000140; Lieberman A, “Falls in Parkinson's disease: the relevance of short steps”, J Nov Physiother 4(3), April 18, 2014; doi:10.4172 / 2165-7025.1000209). These studies highlight the role of postural instability deficits. The underlying mechanisms of postural instability deficits are unknown. However, attention has been drawn to the central nervous system (CNS) cholinergic system (Chung KA, Lobb BM, Nutt JG, Horak FB, “Effects of a central cholinesterase inhibitor on reducing falls in Parkinson's disease”, Neurology 2010 75: 1263-1269; September 1, 2010).

[0036] Movement, e.g., short-distance steps, are significantly reduced in recurrent fallers versus single fallers, and less so in single fallers versus non-fallers. Deficits in balance, not movement, are the primary cause of falls in PD. Without being bound by any theory, cholinergic mechanisms involving cholinergic centers in the basal forebrain and pre-peduncular nucleus (PPN) may play an important role in maintaining postural stability and preventing or ameliorating falls.

[0037] NP002, a central cholinergic agonist, has recently been evaluated as a potential treatment for levodopa-induced dyskinesia (LID) in PD, as disclosed in U.S. Patent Application No. 12 / 901,354, filed October 8, 2010. NP002 is a small molecule, orally available nicotinic receptor agonist that has been shown in preclinical studies to reduce LID without generally affecting Parkinson's disease symptoms. NP002 may also be useful for PD patients who experience falls due to a lack of postural stability.

[0038] Postural instability and balance Postural instability (PI), or balance deficits, are common in patients with idiopathic Parkinson's disease (IPD), especially as disease severity progresses (Bronte-Stewart et al., "Postural instability in idiopathic Parkinson's disease: the role of medication and unilateral pallidotomy," Brain 125: 2100-2114, September 2002). Impaired balance mechanisms can contribute to fall-related injuries, restricted gait patterns, and reduced mobility. These physical impairments result in loss of functional independence and social isolation.

[0039] Balance is required to perform voluntary activities while maintaining the body in proper orientation 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 integration, in which the senses of direction (somatosensory, visual, and vestibular) engage and are integrated within the CNS; (ii) motor coordination processes, which require the execution of coordinated and well-timed neuromuscular responses; and (iii) muscular background tone, through which changes in balance are achieved.

[0040] Directional integration is understood as an adaptive hierarchical system. There are two main frames of reference for the sensory representation of body position relative to space. At lower levels, the weighted combination of directional inputs directly mediates the activity of postural muscles, primarily regulating the horizontal center of gravity (COG) position (bottom-up integration). At higher levels, vestibular inputs provide a directional reference, against which conflicts in the support surface and visual direction are identified, and the combination of inputs is adapted to the task conditions (top-down integration). For postural stability, information from lower levels must be consistent with higher-level inertial-gravitational references, and any conflicting orientation inputs must be rapidly suppressed in favor of those consistent with the internal reference. Thus, in adults, sensory integration processes are context-specific, with rapid weighting and reweighting of sensory inputs to and from lower levels by higher-level adaptive processes.

[0041] Clinical measures of postural control in PD are usually derived from items on standard clinical rating scales, such as the Unified Parkinson's Disease Rating Scale (UPDRS) (Fahn S, Elton RL, 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 (NJ): Macmillan Healthcare Information; 1987. P. 153-163). The commonly accepted postural instability and gait disturbance (PIGD) subscore includes historical questions related to falls, walking, and paralysis, as well as an objective assessment of the patient's ability to change position, walk, and maintain balance during a propulsive retropulsive thrust (Lozano et al., "Effect of GPi pallidotomy on motor function in Parkinson's disease", Lancet 346: 1383-1387; 1995).

[0042] The assessment of postural stability or balance is limited by the MDS-UPDRS motor scale, with only 24 of 132 points allocated to the axial or midline test. As a complementary approach, tests that better reflect postural stability or balance problems may be further assessed using the Romberg test, rotation test, single-leg stance test, and tandem gait test.

[0043] Postural instability (PI), or balance deficits, are common in patients with idiopathic Parkinson's disease (IPD), especially as disease severity progresses (Bronte-Stewart et al., "Postural instability in idiopathic Parkinson's disease: the role of medication and unilateral pallidotomy," Brain 125: 2100-2114, September 2002). Impaired balance mechanisms can contribute to fall-related injuries, restricted gait patterns, and reduced mobility. These physical impairments result in loss of functional independence and social isolation.

[0044] Cognitive impairment The relationship between attention and control of posture and gait has been widely described in patients with Parkinson's disease (PD). Evidence exists that cholinergic mechanisms, associated with cholinergic centers in the basal forebrain and prebrachial nucleus (PPN), play an important role in maintaining postural stability. They also play an important role in preventing or ameliorating falls. Subtle gait disturbances can be observed in aging and in (preclinical) subtypes of dementia not known for significant motor impairment, supporting a close relationship between gait and cognition. Examples of these dementias include mild cognitive impairment, Alzheimer's disease, vascular cognitive impairment, subcortical ischemic vascular dementia, frontotemporal mild cognitive impairment, and frontotemporal dementia.

[0045] Neuroimaging findings are associated with cognition, gait, and fall risk, and white matter changes may be associated with postural instability, gait disturbances, and falls in older adults. If cognitive deficits are in the causal pathway and exacerbate fall risk or prevent appropriate compensatory mechanisms, improving cognitive function can, at least in some embodiments, improve gait and reduce fall risk, particularly under more challenging conditions that rely on executive function.

[0046] Numerous research studies have demonstrated that all aspects of balance control decline with increasing severity of cognitive impairment, and findings indicate that executive function plays a key role in balance control. It has been demonstrated that gait dysfunction predicts cognition, and cognitive impairment is a risk factor for falls in PD. Various cognitive functions in the brain are a function of intact neuronal nicotinic acetylcholine receptors (neuronal nAChRs) localized in individual neurological pathways. Alzheimer's-type dementia provides an example of the correlation between profound cognitive impairment and lack of neuronal nAChR function. Nicotine regulates ACh release from areas involved in cognition, which is likely lacking in schizophrenia. There is ample evidence that these receptors are involved in normal cognitive functions in the brain.

[0047] Nicotine exhibits the ability to enhance cognition and provide neuroprotection. nACHR agonists can act as therapeutic agents to treat cognitive dysfunction in Alzheimer's disease, schizophrenia, and most notably, Parkinson's disease. As PD progresses, treatment of non-motor symptoms, such as cognitive dysfunction, takes priority over treatment of motor symptoms. Much of the morbidity and mortality associated with PD is related to non-motor aspects, including cognition, gait, and balance. Falls and postural instability are major problems in Parkinson's disease (PD) and, unlike gait, are largely unresponsive to dopaminergic replacement. Falls, fall-related injuries, and fear of falling pose major challenges in PD. Improving postural stability and reducing falls would improve the lives of PD patients.

[0048] nicotine In one aspect, the present disclosure provides methods and compositions utilizing nicotine or a salt thereof to treat fall-related symptoms, as well as cognitive symptoms, in subjects with neurodegenerative diseases, such as Parkinson's disease and Parkinson's-related disorders, the details of which are described herein.

[0049] Nicotine can be naturally isolated and purified, or synthesized in any manner. The term "nicotine" is also intended to encompass 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-toluenesulfonate, camphorate, and pamoate. Nicotine is a colorless to pale yellow, strongly alkaline, oily, volatile, and hygroscopic liquid with a molecular weight of 162.23. The systematic name of nicotine is (S)-3-[1-methylpyrrolidin-2-yl]pyridine, and its structure is as follows:

[0050] [ka]

[0051] Nicotine addiction Conductors, metabolites, and derivatives of metabolites are known in the art, including, but not limited to, cotinine, norcotinine, nornicotine, nicotine N-oxide, cotinine N-oxide, 3-hydroxycotinine, and 5-hydroxycotinine, or their pharmaceutically acceptable salts.Many useful nicotine derivatives are disclosed in the Physician's Desk Reference (latest edition) as well as Harrison's Principles of Internal Medicine.Methods for producing nicotine derivatives and analogs are well known in the art.See, for example, U.S. Patent Nos. 4,590,278; 4,321,387; 4,452,984; 4,442,292; and 4,332,945.

[0052] The compounds of the present invention may have asymmetric carbon atoms. All isomers, including racemic mixtures and diastereomeric mixtures such as pure enantiomers, are considered as part of the present invention.

[0053] Without being bound by any one theory, one mechanism of action may be that after prolonged exposure to a nicotine receptor agonist, the nicotine receptor becomes desensitized, and the nicotine receptor agonist begins to function as a nicotine receptor antagonist. In some embodiments, the nicotine receptor agonist functions as an antagonist to reduce or eliminate the side effects induced by dopaminergic drugs.

[0054] In some embodiments, the present disclosure provides compositions for administering nicotine to animals to reduce symptoms of neurodegenerative disorders, for example, for oral delivery of nicotine containing 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 present disclosure provides compositions for administering nicotine to animals to reduce side effects of dopaminergic drugs, for example, for oral delivery of nicotine containing 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 present disclosure provides compositions for oral delivery of nicotine containing about 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99, 99.5, 99.9, 99.99, or 100% or less nicotine. In some embodiments, the present disclosure provides compositions containing about 1-100% nicotine, about 10-100% nicotine, about 20-100% nicotine, about 50-100% nicotine, about 80%-100% nicotine, about 90-100% nicotine, about 95-100% nicotine, or about 99-100% nicotine. In some embodiments, the present disclosure provides compositions containing about 1-90% nicotine, about 10-90% nicotine, about 20-90% nicotine, about 50-90% nicotine, or about 80-90% nicotine. In some embodiments, the present disclosure provides compositions containing about 1-75% nicotine, about 10-75% nicotine, about 20-75% nicotine, or about 50-75% nicotine. In some embodiments, the present disclosure provides compositions containing about 1-50% nicotine, about 10-50% nicotine, about 20-50% nicotine, about 30-50% nicotine, or about 40-50% nicotine. In some embodiments, the present disclosure provides compositions containing about 1-40% nicotine, about 10-40% nicotine, about 20-40% nicotine, or about 30-40% nicotine.In some embodiments, the present disclosure provides compositions containing about 1-30% nicotine, about 10-30% nicotine, or about 20-30% nicotine. In some embodiments, the present disclosure provides compositions containing about 1-20% or about 10-20% nicotine. In some embodiments, the present disclosure provides compositions containing about 1-10% nicotine. In some embodiments, the present disclosure provides compositions containing about 1, 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 96, 97, 98, or 99% nicotine.

[0055] In some embodiments, the concentration of nicotine is 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.

[0056] In some embodiments, the concentration of nicotine is 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%, 9.5 0%, 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%,1.25%,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%,0.0 07%, 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 greater than 0.0001% w / w, w / v, or v / v.

[0057] In some embodiments, the concentration of nicotine is between about 0.0001% and about 50%, between about 0.001% and about 40%, between about 0.01% and about 30%, between about 0.02% and about 29%, between about 0.03% and about 28%, between about 0.04% and about 27%, between about 0.05% and about 26%, between about 0.06% and about 25%, between about 0.07% and about 24%, between about 0.08% and about 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.

[0058] In some embodiments, the concentration of nicotine is in the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w / w, w / v, or v / v.

[0059] In some embodiments, the amount of nicotine is 10g, 9.5g, 9.0g, 8.5g, 8.0g, 7.5g, 7.0g, 6.5g, 6.0g, 5.5g, 5.0g, 4.5g, 4.0g, 3.5g, 3.0g, 2.5g, 2.0g, 1.5g, 1.0g, 0.95g, 0.9g, 0.85g, 0.8g, 0.75g, 0.7g, 0.65g, 0.6g, 0.55g, 0.5g, 0.45g, 0.4g, 0.35g, 0.3g, 0.25g, 0.2g, 0. The content is less than or equal to 15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g.

[0060] In some embodiments, the amount of nicotine is 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.004 ... .0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g , 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.0 35g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.08 5g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5g, 3g, 3.5g, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or 10g or more.

[0061] Nicotinic Receptor Modulators In some embodiments, the present disclosure provides compositions and methods utilizing nicotine receptor modulators, e.g., to reduce or eliminate side effects associated with dopaminergic treatment. Nicotinic receptor modulators can be agonists or antagonists. Details of the disclosure are provided herein.

[0062] In one embodiment, the term "agonist," as used herein, refers to a molecule capable of initiating or enhancing the biological function of a target polypeptide. Thus, the term "agonist" is defined in the context of the biological role of the target polypeptide. Preferred agonists herein specifically interact (e.g., bind) with the target, although specifically included within this definition are molecules that enhance the biological activity of the target polypeptide through interactions with other members of the signal transduction pathway in which the target polypeptide is a member. Agonists, as defined herein, include, but are not limited to, antibodies, antibody derivatives, antibody fragments and immunoglobulin variants, peptides, peptidomimetics, simple or complex organic or inorganic molecules, antisense molecules, oligonucleotide decoys, proteins, oligonucleotides, vitamin derivatives, carbohydrates, and toxins.

[0063] The term "antagonist," as used herein, refers to a molecule capable of inhibiting the biological function of a target polypeptide. Thus, the term "antagonist" is defined in the context of the biological role of the target polypeptide. Preferred antagonists herein specifically interact (e.g., bind) with the target, but also specifically included within this definition are molecules that inhibit the biological activity of the target polypeptide through interactions with other members of the signal transduction pathway in which the target polypeptide is a member. Antagonists, as defined herein, include, but are not limited to, antibodies, antibody derivatives, antibody fragments and immunoglobulin variants, peptides, peptidomimetics, simple or complex organic or inorganic molecules, antisense molecules, oligonucleotide decoys, proteins, oligonucleotides, vitamin derivatives, carbohydrates, and toxins.

[0064] In some embodiments, the nicotine receptor modulator modulates nicotine receptors in the brain. In some embodiments, the nicotine receptor modulator modulates nicotine receptors in the striatum or substantia nigra. In some embodiments, the nicotine receptor modulator modulates a nicotine receptor comprising at least one α subunit, or a nicotine receptor comprising at least one α subunit and at least one β subunit. In some embodiments, the α subunit is selected from the group consisting of α2, α3, α4, α5, α6, α7, α8, α9, and α10, and the β subunit is selected from the group consisting of β2, β3, and β4. In some embodiments, the nicotine receptor modulator modulates a nicotine receptor comprising a subunit selected from the group consisting of α4β2, α6β2, α4α6β2, α4β5β2, α4α6β2β3, α6β2β3, and α4α2β2. In some embodiments, the nicotine receptor modulator modulates a nicotine receptor comprising at least one subunit selected from the group consisting of α4, α6, and α7.

[0065] A nicotine receptor agonist of the present disclosure can be any ligand that binds to and activates a nicotine receptor, resulting in a biological response. The potential of a substance to act as a nicotine receptor agonist can be determined using in vitro binding assays and / or standard in vivo functional tests.

[0066] Other nicotinic receptor agonists include cholinesterase inhibitors (e.g., increasing local concentrations of acetylcholine), derivatives of epibatidine that bind specifically to the neuronal type of nicotinic receptor (having reduced binding to muscarinic receptors) and have reduced adverse side effects (e.g., Epidoxidine, ABT-154, ABT418, ABT-594; Abbott Laboratories (Damaj et al. (1998) J. Pharmacol Exp. Then 284:1058 65, describing various analogs of epibatidine that are equally potent but more specific for the neuronal type of nicotinic receptor). Additionally, nicotinic receptor agonists of interest include, but are not limited to, N-methylcarbamyl and N-methylthio-O-carbamyl esters of choline (e.g., trimethylaminoethanol) (Abood et al. (1988) Pharmacol. Biochem. Behay. 30:403). 8) and acetylcholine (an endogenous ligand for nicotinic receptors).

[0067] Numerous nicotinic acetylcholine receptors (nAChRs) exist throughout the body. nAChRα1β1, α3β4, and α7 nAChRs are the predominant subtypes in the peripheral nervous system, while α4β2, α6β2, and α7 nAChRs are primary subtypes in the brain. Varenicline, which acts on all nAChRs, as well as various β2-selective drugs (A-85380, sazetidine, TC-2696, TI-10165, TC-8831, and TC-10600), can reduce LID. Similarly, other β2-selective agonists such as ABT-089, a partial β2 nAChR agonist (Ki = 17 nM), and the full β2 agonist ABT-894 (Ki = 0.3 nM) can reduce LID. Although AZD1446, a relatively low-affinity (Ki = 30 nM) β2 nAChR agonist, can also reduce LID, a full, high-affinity β2 nAChR agonist may be more effective. Additionally, the α7 nAChR agonists ABT-107 (Ki = 0.5 nM) and AQW051 (Ki = 27 nM) can also reduce LID, with the greatest reduction in LID associated with higher affinity (≥ 10 nM) full nAChR agonists such as ABT-894 and ABT-107. Partial agonists or drugs with lower affinity (such as varenicline, TC-8831, ABT-089, AZD1446, and AQW051) may also be effective. An important consideration is side effects; drugs such as varenicline and TC-8831 are associated with nausea and may therefore be undesirable. The antidyskinetic effects of nicotine may be receptor-mediated through both β2 and α7 nAChRs, and LID may be reduced by applying agonists to preferably β2 and α7 nAChRs, which are optionally paired with other nAChR subunits.β2 and α7 nAChR agonists include 3-bromocytidine, acetylcholine, cytisine, epibatidine, A-84,543, A-366,833, ABT-418, altinicline, dianiline, ispronicline, pozaniline, rivanicline, tevanicline, TC-1827, sazetidine A, N-(3-pyridinyl)-bridged bicyclic diamines, (+)-N-(1-azabicyclo[2.2.2]octadecanoate), and benzophenone-1-one. The agonist may be selected from known agonists such as (3-(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. β2 and α7 nAChR agonists are also new agonists developed to target these receptors.

[0068] Dopamine agonists In some embodiments, the present disclosure provides compositions and methods for reducing or eliminating the side effects of dopaminergic drugs. In some embodiments, the compositions and methods maintain or enhance the desired effects of the dopaminergic drug, such as antiparkinsonian effects. The methods and compositions of the present disclosure are applicable to any dopaminergic drug for which it is desirable to reduce one or more side effects. In some embodiments, the compositions and methods of the present disclosure utilize dopamine precursors. In some embodiments, the compositions and methods of the present disclosure utilize dopamine agonists. The dopaminergic drug includes a dopamine precursor or a dopamine receptor agonist. Examples of dopaminergic drugs include levodopa, bromocriptine, pergolide, pramipexole, cabergoline, ropinolole, apomorphine, carbidopa, dopamine agonists, monoamine oxidase type B inhibitors, amantadine, or combinations thereof.

[0069] In some embodiments, the disclosed compositions and methods utilize one or more agents used in the art in combination with dopaminergic drug treatment to achieve a therapeutic effect. For example, in one exemplary embodiment, the disclosed compositions and methods 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 disclosed compositions and methods utilize levodopa in combination with a dopaminergic agonist. In yet another exemplary embodiment, the disclosed compositions and methods utilize levodopa in combination with a monoamine oxidase type B (MAO-B) inhibitor, such as selegulin. In yet another exemplary embodiment, the disclosed compositions and methods utilize levodopa in combination with amantadine. In yet another exemplary embodiment, the disclosed compositions and methods utilize levodopa in combination with a COMT inhibitor, such as entacapone.

[0070] Levodopa Levodopa, an aromatic amino acid, is a white crystalline compound that is slightly soluble in water and has a molecular weight of 197.2. It is designated as L-3,4-dihydroxyphenylalanine or (S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid. Its structural formula is:

[0071] [ka]

[0072] Levodopa is used to treat Parkinson's disease. Parkinson's disease is a progressive neurodegenerative disorder of the extrapyramidal nervous system that affects the mobility and control of the skeletal musculature. Its hallmarks include resting tremor, rigidity, and bradykinesia. Current evidence indicates that the symptoms of Parkinson's disease are related to the depletion of dopamine in the striatum. Administration of dopamine is apparently ineffective in treating Parkinson's disease because dopamine does not cross the blood-brain barrier. However, levodopa, a metabolic precursor of dopamine, crosses the blood-brain barrier and is likely converted to dopamine in the brain. This is thought to be the mechanism by which levodopa relieves the symptoms of Parkinson's disease.

[0073] However, even though initially highly effective, long-term treatment with levodopa can result in numerous complications. Levodopa treatment can cause nausea, vomiting, involuntary movements (e.g., dyskinesia), psychosis, depression, loss of consciousness, and hallucinations. While the exact pathophysiological mechanisms of levodopa side effects remain a mystery, they are thought to be due to increased brain dopamine levels after levodopa administration. Previous studies have shown that levodopa-induced dyskinesia (LID) results from enhanced intermittent stimulation of D1, D2, and / or other dopamine receptor subtypes. This results in an imbalance in activity between the two major striatal output pathways, with D1 activation and D2 inhibition on the direct and indirect dopaminergic pathways, respectively, although there is some overlap between striatal efferents. Recent data suggest that D1 receptors, via enhanced G protein coupling, may play a more prominent role in the functional hypersensitivity associated with levodopa-induced dyskinesia, whereas D2 receptor activation may be closely linked to the antiparkinsonian effects of dopamine agonists.

[0074] Carbidopa Carbidopa is a white crystalline compound that is slightly soluble in water and has a molecular weight of 244.3. It is chemically designated as (-)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene)propanoic acid monohydrate. Its structural formula is:

[0075] [ka]

[0076] Carbidopa is a drug given to people with Parkinson's disease and is used in conjunction with levodopa. Administration of carbidopa and levodopa can increase levodopa's plasma half-life from 50 minutes to one and a half hours. Carbidopa does not normally 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 inhibits the peripheral metabolism of levodopa, preventing the peripheral conversion of levodopa to dopamine and allowing a higher proportion of peripheral levodopa to cross the blood-brain barrier for central nervous system effects, thereby reducing peripheral dopamine-induced side effects and increasing brain levodopa and dopamine concentrations.

[0077] Carbidopa is commonly used to inhibit the activity of dopamine decarboxylase, an enzyme known to degrade levodopa in the periphery and convert it to dopamine. This can result in the formation of new dopamine that cannot cross the blood-brain barrier, significantly reducing the effectiveness of levodopa treatment. Carbidopa can reduce the amount of levodopa required to produce a given reaction by approximately 75%. When administered with levodopa, it increases both the plasma level and plasma half-life of levodopa, reducing plasma and urinary dopamine and homovanillic acid. Carbidopa can also shorten levodopa's half-life by approximately 1.5 hours.

[0078] In some cases, carbidopa and levodopa are administered in a combined composition. Examples of commercially available carbidopa / levodopa combinations include Kinson, Sinemet, Parcopa, and Atamet, while Stalevo also contains entacapone, which enhances the bioavailability of carbidopa and levodopa.

[0079] Dopamine agonists Dopamine agonists are compounds that activate dopamine receptors in the absence of their physiological ligand, the neurotransmitter dopamine. Dopamine agonists can treat conditions characterized by hypodopamine function (low dopamine levels). They are typically used for Parkinson's disease, attention-deficit hyperactivity disorder (ADHD) (treated with stimulant medications), and certain pituitary tumors (prolactinomas), and may be useful for restless legs syndrome (RLS). Both Requip (ropinirole) and Mirapex (pramipexole) are FDA-approved for the treatment of RLS. Clinical trials are also underway to test the efficacy of the dopamine agonist Requip (ropinirole) in resolving symptoms of SSRI-induced sexual dysfunction and post-SSRI sexual dysfunction (PSSD).

[0080] Some drugs can act as dopamine agonists. There are generally two classes of commercially available dopamine agonists: partial agonists and full / unknown effect agonists. Examples of partial agonists include, but are not limited to, aripiprazole, quinpirole, and salvinorin. Examples of full / unknown effect agonists include, but are not limited to, apomorphine, bromocriptine, cabergoline, ciladopa, dihydrexidine, dinapsolin, doxantrin, epicriptine, lisuride, pergolide, piribedil, pramipexole, propylnorapomorphine, quinagolide, ropinirole, rotigotine, loxindol, sumanilole, and fenoldopam.

[0081] Amantadine Amantadine, commercially known as Simitrel (Endo Pharmaceuticals), is a drug approved by the U.S. Food and Drug Administration for use as both an antiviral and an antiparkinsonian. It is the organic compound 1-adamantylamine or 1-aminoadamantane, which means it consists of an adamantane backbone spine with an amino (aminio) group substituted at one of the four methine positions. Its structural formula is:

[0082] [ka]

[0083] Rimantadine is a closely related derivative of adamantane with similar biological properties.

[0084] Amantadine is a weak antagonist of NMDA-type glutamate receptors. It increases dopamine release, blocks dopamine reuptake, and is a potential treatment for Parkinson's disease. However, as an anti-Parkinsonian, it can be used as a monotherapy or in combination with levodopa to treat levodopa-associated motor fluctuations, such as shortened duration of clinical effect and levodopa-associated dyskinesia.

[0085] Monoamine oxidase B inhibitors Monoamine oxidase inhibitors (MAOIs) are chemicals that inhibit the activity of the monoamine oxidase enzyme family. MAOIs can prevent the breakdown of monoamine neurotransmitters and increase their availability. MAOIs have a long history of use as prescription medications for the treatment of depression, particularly atypical depression, Parkinson's disease, and a variety of other disorders.

[0086] MAOIs, such as celegrine, are commonly used to treat Parkinson's disease. MAOIs can also be used in the treatment of Parkinson's disease by specifically targeting MAO-B to affect dopaminergic neurons, as well as providing an alternative means for migraine prevention.

[0087] Inhibition of both MAO-A and MAO-B is also used to treat clinical depression and anxiety. MAOIs are thought to be particularly indicated for outpatients with "neurotic depression" complicated by panic attacks or hysterical dysphoria, which involves repeated mood suppression in response to negative feelings.

[0088] MAOIs have been shown to be effective in treating agoraphobia, social phobia, atypical or mixed anxiety disorder, depression, bulimia, and post-traumatic stress disorder, as well as panic disorder with borderline personality disorder. MAOIs are considered particularly effective in managing bipolar depression according to recent retrospective analyses. In some cases, MAOIs may be effective in treating obsessive-compulsive disorder (OCD), trichotillomania, dysmorphophobia, and avoidant personality disorder.

[0089] Without being bound by any theory, MAOIs act by inhibiting the activity of monoamine oxidase, thus increasing the availability of monoamine neurotransmitters by preventing their degradation. 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 forms.

[0090] side effects The major adverse reactions of dopamine agonists include headache, diarrhea, hypertension, nausea, vomiting, involuntary movements (eg, dyskinesia), psychosis, depression, loss of consciousness, hallucinations, and abnormal renal function.

[0091] The present disclosure provides compositions and methods utilizing nicotine or a salt thereof, or a nicotine receptor modulator, that reduce or eliminate side effects associated with dopaminergic drug treatment. In some embodiments, the present disclosure provides compositions and methods utilizing nicotine receptor modulators that reduce or eliminate dyskinesias associated with dopaminergic drug treatment. Without being bound by any theory, it is possible that nicotine receptor modulators exert their effects by acting on nicotinic acetylcholine receptors (nAChRs) expressed in the striatum. There is a dense cholinergic innervation in the striatum, largely coinciding with dopaminergic neurons. Under physiological conditions, these cholinergic interneurons normally release acetylcholine, which stimulates nicotine receptors on dopaminergic nerve terminals to release dopamine. Similarly, exogenous application of drugs such as nicotine results in the release of dopamine from striatal terminals.

[0092] Treatment method In one aspect, the present disclosure provides a method for treating fall-related symptoms in a subject with a neurodegenerative disease, the method comprising administering nicotine or a salt thereof to the subject. In some embodiments, nicotine and its salt are administered in a dosage form. Administration of nicotine or its salt can reduce the frequency of falls, the frequency of fall-related injuries, and / or the severity of neurodegenerative disease, fall-related injuries in a subject with, for example, Parkinson's disease or a Parkinson's-related disorder. In some embodiments, the subject has general Parkinson's disease. In some embodiments, the subject has Parkinson's disease but does not have LID. In some embodiments, the subject has been diagnosed with Parkinson's disease for at least five years. In some embodiments, the subject is receiving dopamine agonist treatment. In some embodiments, the subject has fallen in the past year or has recurrent falls. In some embodiments, the method does not result in tolerance or dependence on nicotine or its salt.

[0093] Described herein are methods of administering nicotine dosage forms, the administration of which can result in a pharmacokinetic profile having a plasma nicotine level of less than about 7.5 ng / ml at about 120 minutes after administration of the dosage form. The administration of the dosage form can result in a pharmacokinetic profile having a plasma nicotine level of less than about 7.5 ng / ml at about 180 minutes after administration of the dosage form. The pharmacokinetic profile can have a plasma nicotine level of less than about 5 ng / ml at about 180 minutes after administration. The pharmacokinetic profile can have a plasma nicotine level of less than about 5 ng / ml at about 120 minutes after administration. The pharmacokinetic profile can have a plasma nicotine level of greater than about 5 ng / ml at about 45-90 minutes after administration. The pharmacokinetic profile can have a plasma nicotine level of greater than about 15 ng / ml at about 60 minutes after administration.

[0094] Described herein are methods for treating fall-related symptoms in a subject with a neurodegenerative disease, the methods comprising administering to the subject a dosage form comprising nicotine or a salt thereof. The fall-related symptoms may include fall frequency. The fall frequency of a subject treated with a dosage form comprising nicotine may be reduced. The fall-related symptoms may be associated with freezing of gait (FOG). The fall-related symptoms may be associated with levodopa-induced dyskinesia (LID). The fall-related symptoms may not be associated with levodopa-induced dyskinesia (LID). A subject treated with a dosage form comprising nicotine or a salt thereof may experience reduced fall frequency, reduced freezing of gait (FOG), reduced levodopa-induced dyskinesia (LID), improved postural stability, or a combination thereof. Falls can be prevented in a subject treated with a dosage form comprising nicotine or a salt thereof. Fall-related complications may be reduced. Subjects treated with a dosage form containing nicotine may experience a reduction in fall frequency, a reduction in freezing of gait (FOG), and a reduction in levodopa-induced dyskinesia (LID). The reduction in fall frequency may be at least a 10% reduction. The reduction in fall frequency may be at least or about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more than a 90% reduction. The reduction in freezing of gait (FOG) may be at least or about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more than a 90% reduction. The reduction in freezing of gait (FOG) may be at least a 10% reduction. The reduction in freezing of gait (FOG) can be at least or about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more than a 90% reduction. The reduction in levodopa-induced dyskinesia (LID) can be at least a 10% reduction. The reduction in levodopa-induced dyskinesia (LID) can be at least or about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more than a 90% reduction. The improvement in postural stability can be at least a 10% improvement.The improvement in postural stability can be at least or about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or greater than a 90% improvement. The subject may experience at least a 0.5-fold reduction in fall frequency. The subject may experience 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 greater than 8.0-fold reduction in fall frequency. The subject may experience at least a 0.5-fold reduction in freezing of gait (FOG). The subject may experience 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-fold or more than 8.0-fold reduction in freezing of gait (FOG). The subject may experience at least a 0.5-fold reduction in levodopa-induced dyskinesia (LID). The subject may experience at least a 0.5-fold reduction in levodopa-induced dyskinesia (LID). The subject may experience at least a 0.5-fold reduction in levodopa-induced dyskinesia (LID). The subject may experience at least a 0.5-fold improvement in postural stability. A subject may experience an improvement in postural stability of at least or about 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 times, or more than 8.0 times.

[0095] The reduction in fall frequency, the reduction in freezing of gait (FOG), the reduction in levodopa-induced dyskinesia (LID), the improvement in postural stability, or a combination thereof, can be compared to a control. Falls can be prevented in subjects treated with a dosage form containing nicotine or a salt thereof compared to a control. Fall-related complications can be reduced in subjects treated with a dosage form containing nicotine or a salt thereof compared to a control. The control can be a subject at baseline or a subject administered a placebo. In some examples, the control has idiopathic Parkinson's disease. The control can have LID. The control can be in a peak "on" state of levodopa.

[0096] Nicotine or a salt thereof may not alter dopaminergic activity. Nicotine or a salt thereof may increase cholinergic activity. Fall-related symptoms may include the frequency of fall-related injuries. A subject treated with a dosage form comprising nicotine may have a reduced frequency of fall-related injuries. Fall-related symptoms may include the severity of injurious falls. A subject treated with a dosage form comprising nicotine may have a reduced severity of injurious falls. The subject may have recurrent falls. The subject has fallen at least once in the past. Symptom improvement may include utilizing one or more assessment tests selected from the group consisting of the Unified Parkinson's Disease Rating Scale (UPDRS), Barlow Neurological Institute (BNI) Falls Assessment, Hoehn & Yahr Severity Classification System, Romberg test, rotation test, standing on one leg, stepping gait, stride length and speed. Assessments utilizing the Unified Parkinson's Disease Rating Scale (UPDRS) may be selected from the group consisting of: Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) question 2.12 Walking and Balance, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) question 2.14 Freezing of Gait, original Unified Parkinson's Disease Rating Scale (UPDRS) questions 32-35 Dyskinesias, original Unified Parkinson's Disease Rating Scale (UPDRS) questions 36-39 Response Fluctuation, original Unified Parkinson's Disease Rating Scale (UPDRS) question 40 Sleep Disturbance, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) score 142, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) axis, midline, and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) Gait Subtest, the Postural Stability Subtest of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS), and the Freezing of Gait Subtest (FOG) of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS).Assessment may include UPDRS Part II (Activities of Daily Living (ADL)) Question 13, Falling Unrelated to Freezing, UPDRS Part II (ADL) Question 14, Freezing When Walking, the Walking subgroup of the Unified Dyskinesia Rating Scale (UDysRS), or a combination thereof. Assessment may include UPDRS Part II (Activities of Daily Living (ADL)) Question 13, Falling Unrelated to Freezing, UPDRS Part II (ADL) Question 14, Freezing When Walking, and the Walking subgroup of the Unified Dyskinesia Rating Scale (UDysRS). Symptom improvement may include assessment utilizing the Reason for Fall of the Barlow Neurological Institute (BNI) Falls Assessment. Symptom improvement may include assessment utilizing the Severity of Fall of the Barlow Neurological Institute (BNI) Falls Assessment. Subject evaluation may include laboratory tests, analysis of concomitant medications, physical examination, psychiatric evaluation, physical evaluation, electrocardiogram (ECG), vital signs, assessment of impulse control, nicotine withdrawal symptoms, symptom change, Mini-Mental State Examination, Jay Midi scale, UDysRS, Hoehn and Yahr scale, Clinical Global Impression Scale, Patient Global Impression Scale, Lang-Fahn Activities of Daily Living Scale, and Minnesota Nicotine Withdrawal Scale-Revised (MNWS-R). Laboratory tests include, but are not limited to, urinalysis, serum cotinine analysis, urine cotinine analysis, serum nicotine analysis, hematology, chemistry, and pregnancy testing.

[0097] In various embodiments, the present disclosure provides a method for treating a fall-related symptom in a subject with a neurodegenerative disease, the method comprising administering to the subject a composition comprising a nicotine receptor modulator. In some embodiments, the composition is administered in a dosage form. In some embodiments, the nicotine receptor modulator is a nicotine receptor agonist or antagonist. Administration of the composition can reduce the frequency of falls, the frequency of fall-related injuries, and / or the severity of neurodegenerative disease, fall-related injuries in a subject with, for example, Parkinson's disease or a Parkinson's disease-related disorder. In some embodiments, the subject has generalized Parkinson's disease. In some embodiments, the subject does not have LID.

[0098] In some embodiments, the present disclosure utilizes a nicotine receptor agonist, such as nicotine or a salt thereof, for the treatment of fall-related symptoms in a subject with a neurodegenerative disease. The method includes administering nicotine or a salt thereof to the subject. The method may not result in tolerance or dependence on nicotine or a salt thereof. In some embodiments, the subject has Parkinson's disease or a Parkinson's disease-related disorder. In some embodiments, the subject has previously fallen or is a recurrent faller. In some embodiments, the subject has previously fallen at least once, twice, three times, four times, five times, six times, or more times.

[0099] Described herein are methods for treating postural instability, static balance, movement disorders, and gait in a subject with a neurodegenerative disease, the methods comprising administering to the subject a dosage form comprising nicotine or a salt thereof. Subjects treated with the dosage form comprising nicotine may have improved postural stability. Subjects treated with the dosage form comprising nicotine may have improved static balance. Subjects treated with the dosage form comprising nicotine may have improved motor performance. Subjects treated with the dosage form comprising nicotine may have improved gait. Improvement of symptoms may involve using one or more assessment tests selected from the group consisting of the Unified Parkinson's Disease Rating Scale (UPDRS), BNI Falls Assessment, Hoehn & Yahr Severity Classification System, Romberg test, rotation test, standing on one leg, stepping gait, stride length, and speed. Assessments utilizing the Unified Parkinson's Disease Rating Scale (UPDRS) may be selected from the group consisting of: Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) question 2.12 Walking and Balance, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) question 2.14 Freezing of Gait, original Unified Parkinson's Disease Rating Scale (UPDRS) questions 32-35 Dyskinesias, original Unified Parkinson's Disease Rating Scale (UPDRS) questions 36-39 Response Fluctuation, original Unified Parkinson's Disease Rating Scale (UPDRS) question 40 Sleep Disturbance, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) score 142, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) axis, midline, and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) Gait Subtest, the Postural Stability Subtest of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS), and the Freezing of Gait Subtest (FOG) of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS).The assessment may include UPDRS Part II (Activities of Daily Living (ADL)) Question 13, Falling Unrelated to Freezing, UPDRS Part II (ADL) Question 14, Freezing When Walking, the Walking subgroup of the Unified Dyskinesia Rating Scale (UDysRS), or a combination thereof. The assessment may include UPDRS Part II (Activities of Daily Living (ADL)) Question 13, Falling Unrelated to Freezing, UPDRS Part II (ADL) Question 14, Freezing When Walking, and the Walking subgroup of the 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 be receiving dopaminergic treatment. The dopaminergic treatment may be levodopa, carbidopa, a dopamine agonist, amantadine, a monoamine oxidase B inhibitor, or a combination thereof. The subject may be evaluated during an "off" period, during which the subject has not received dopaminergic treatment for about 16 hours. The "off" period may be about 2, 4, 6, 8, 10, 12, 14, 16, 18, or 24 hours. During the "on" period, the subject may have received their usual morning dose of dopaminergic treatment for about one hour. The dopaminergic treatment may be levodopa, carbidopa, a dopamine agonist, amantadine, a monoamine oxidase B inhibitor, or a combination thereof. The "on" period may be about 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, or 24 hours.The "off" period may be at least about or greater than 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 "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 hours, or longer 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 may have a Montreal Cognitive Assessment (MOCA) score of at least 26. The subject may have a Montreal Cognitive Assessment (MOCA) score of at least about 20, 25, 30, 35, 40, or greater than 40. The subject may be excluded from the group consisting of atypical Parkinson's, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), primary freezing of gait (PFG), corticobasal degeneration, dementia with a Montreal Cognitive Assessment (MOCA) score of less than 21, legal blindness, orthopedic problems in the hip or knee, total hip or knee replacement, orthostatic hypotension, schizophrenia, schizoaffective disorder, bipolar disorder, hallucinations, psychosis, delusions, deep brain stimulation (DBS) intervention, history of recent stroke, and history of myocardial infarction. The dosage form may comprise a nicotine receptor agonist. The dosage form may contain at least 1-6 mg of nicotine or a salt thereof for a period of 6 months, and the dosage form may be titrated upwards at treatment intervals.The dosage form may contain 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 contain about 2, 4, 6, 12, 18, or 24 mg of nicotine or a salt thereof. The duration 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 contain nicotine or a salt thereof and may be titrated upward at 2-week treatment intervals. The dosage form may contain nicotine or a salt thereof and may be titrated upward at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more than 12-week treatment intervals. The dosage form may be administered for longer 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 longer than 8 years. The dosage form may be used for chronic treatment. The dosage form may contain nicotine or a salt thereof and may include at least 1 mg every 6 hours; at least 2 mg every 6 hours; at least 4 mg every 6 hours; or at least 6 mg every 6 hours; the dosage may be titrated upward at 2-week treatment intervals; and the dosage may be maintained at 6 mg every 6 hours until the end of the 6-month treatment period. The nicotine or a salt thereof may be administered in an amount of less than 24 mg in a 24-hour period. In some cases, nicotine or a salt thereof may 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 mg, or more than 60 mg. Nicotine or a salt thereof may be administered in an amount of about 2, 4, 6, 8, 10, 12, 18, or 24 mg. In some cases, the nicotine or salt thereof may be administered for 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 hours or for a period longer than 60 hours.Nicotine or a salt thereof may be administered at least four times in a 24-hour period. Nicotine or a salt thereof 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. Nicotine or a salt thereof may be administered about every 6 hours in a 24-hour period. Nicotine or a salt thereof may 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 24-hour period. The treatment period may be longer 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 longer than 8 years. The treatment may be a chronic treatment. The therapeutic efficacy of the administration may be assessed regularly for at least 2-14 months. The therapeutic efficacy of the administration may be assessed regularly for 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 months, or longer than 60 months. The therapeutic efficacy of the administration may be assessed regularly for at least 6 months. Assessments may occur every 2 months. Assessments may be performed every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more than 12 months. Assessments may include laboratory tests, concomitant medication analysis, physical examination, psychiatric evaluation, physical evaluation, electrocardiogram (ECG), vital signs, assessment of impulse control, nicotine withdrawal symptoms, symptom change, Mini-Mental State Examination, Jay Midi Scale, UDysRS, Hoehn & Yahr Scale, Clinical Global Impression Scale, Patient Global Impression Scale, Lang-Fahn Activities of Daily Living Scale, and Revised Minnesota Nicotine Withdrawal Scale (MNWS-R). Laboratory tests include, but are not limited to, urinalysis, serum cotinine analysis, urine cotinine analysis, serum nicotine analysis, hematology, chemistry, and pregnancy testing.The dosage form can be formulated for oral, intravenous, intraarterial, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, buccal, or intraperitoneal administration. The dosage form can be formulated for oral administration. The dosage form can be formulated as a unit dosage form. The pharmaceutical composition can be formulated as a liquid, gel, semi-liquid, semi-solid, or solid unit dosage form. The dosage form can be formulated in a tablet. The dosage form can be formulated in a capsule. The unit dosage form can be formulated as a food product. The unit dosage form can be formulated as a beverage. The unit dosage form can be formulated as a dietary supplement. Administration of the dosage form results in a drug having a plasma nicotine level of less than about 7.5 ng / ml at about 120 minutes after administration of the dosage form. The dosage form may result in a pharmacokinetic profile having a plasma nicotine level of less than about 7.5 ng / ml at about 180 minutes after administration of the dosage form. The pharmacokinetic profile may have a plasma nicotine level of less than about 5 ng / ml at about 180 minutes after administration. The pharmacokinetic profile may have a plasma nicotine level of less than about 5 ng / ml at about 120 minutes after administration. The pharmacokinetic profile may have a plasma nicotine level of greater than about 5 ng / ml at about 45-90 minutes after administration. The pharmacokinetic profile may have a plasma nicotine level of greater than about 15 ng / ml at about 60 minutes after administration. Administration of the dosage form of nicotine or a salt thereof may not result in tolerance to or dependence on nicotine or a salt thereof.

[0100] In some embodiments, the present disclosure utilizes a nicotine receptor agonist, such as nicotine or a salt thereof, for the treatment of fall-related symptoms in a subject with a neurodegenerative disease. The method may include administering nicotine or a salt thereof to the subject. In some embodiments, the subject has Parkinson's disease or a Parkinson's disease-related disorder. In some embodiments, the subject has Parkinson's disease but does not have LID. In some embodiments, the subject has an increase in the frequency of past falls compared to the previous year. In some embodiments, the frequency of falls has increased by at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 50-fold, 100-fold, 1000-fold, or more in the past. In some embodiments, the frequency of falls has increased by about 1-1000-fold in the past.

[0101] In some embodiments, the present disclosure utilizes a nicotine receptor agonist, such as nicotine or a salt thereof, for treating fall-related symptoms in a subject with a neurodegenerative disease. The method may include administering nicotine or a salt thereof to the subject. In some embodiments, the subject has Parkinson's disease or a Parkinson's disease-related disorder. In some embodiments, the subject has Parkinson's disease but does not have LID. In some embodiments, the present disclosure provides a method for reducing the frequency of falls in a subject with a neurodegenerative disease. In some embodiments, the frequency of falls is reduced by at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 50-fold, 100-fold, 1000-fold, or more. In some embodiments, the frequency of falls is increased by about 1-1000-fold.

[0102] In some embodiments, the present disclosure utilizes a nicotine receptor agonist, such as nicotine or a salt thereof, for the treatment of fall-related symptoms in a subject with a neurodegenerative disease. The method may include administering nicotine or a salt thereof to the subject. In some embodiments, the subject has an increased frequency of fall-related injuries in the past year compared to the previous year. The frequency of fall-related injuries is at least 1-1000 times greater. In some embodiments, the frequency of fall-related injuries has increased by about 1-1000 times greater in the past year.

[0103] In some embodiments, the present disclosure utilizes a nicotine receptor agonist, such as nicotine or a salt thereof, for the treatment of fall-related symptoms in a subject with a neurodegenerative disease. The method may include administering nicotine or a salt thereof to the subject. In some embodiments, the present disclosure provides a method for reducing the frequency of fall-related injuries. In some embodiments, the frequency of fall-related injuries is reduced by at least 1-1000 fold. In some embodiments, the frequency of fall-related injuries has increased by about 1-1000 fold over the past year.

[0104] In some embodiments, the present disclosure utilizes a nicotine receptor agonist, such as nicotine or a salt thereof, for the treatment of fall-related symptoms in a subject with a neurodegenerative disease. The method may include administering nicotine or a salt thereof to the subject. In some embodiments, the subject has experienced an increase in the severity of a fall-related injury in the past year compared to the previous year. In some embodiments, the severity of the fall-related injury is increased by at least 1-1000 fold. In some embodiments, the severity of the fall-related injury is increased by about 1-1000 fold in the past year.

[0105] In some embodiments, the present disclosure utilizes a nicotine receptor agonist, such as nicotine or a salt thereof, for treating fall-related symptoms in a subject with a neurodegenerative disease. The method may include administering nicotine or a salt thereof to the subject. In some embodiments, the present disclosure provides a method for reducing the severity of fall-related injuries. In some embodiments, the severity of the fall is reduced by at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 50-fold, 100-fold, 1000-fold, or more compared to a previous fall. In some embodiments, the severity of the fall-related injuries is increased by about 1-1000-fold compared to a previous fall.

[0106] In some embodiments, the present disclosure provides a method for predicting recurrent falls in a subject with a neurodegenerative disease, the method comprising administering nicotine or a salt thereof to the subject. In some embodiments, nicotine and its salt are administered in a dosage form. Administration of nicotine or its salt can reduce the frequency of falls, the frequency of fall-related injuries, and / or the severity of neurodegenerative disease, fall-related injuries in a subject with, for example, Parkinson's disease or a Parkinson's-related disorder. In some embodiments, the subject has generalized Parkinson's disease. In some embodiments, the subject has been diagnosed with Parkinson's disease for at least five years. In some embodiments, the subject is receiving dopaminergic drug treatment. In some embodiments, the subject has experienced at least one fall and / or has a history of recurrent falls.

[0107] In some embodiments, the present disclosure provides a method for treating fall-related symptoms in a subject with Parkinson's disease or a Parkinson's disease-related disorder, the method comprising administering nicotine or a salt thereof to the subject. Administration of nicotine or a salt thereof can prevent falls. Administration of nicotine or a salt thereof can reduce fall-related complications. Administration of nicotine or a salt thereof can reduce the frequency of falls, the frequency of fall-related injuries, and / or the severity of fall-related injuries in the subject. In some embodiments, the subject is receiving dopamine agonist treatment. Non-limiting examples of dopamine agonists include levodopa, bromocriptine, pergolide, pramipexole, cabergoline, ropinolole, apomorphine, carbidopa, dopamine agonists, monoamine oxidase type B inhibitors, amantadine, or combinations thereof. In some embodiments, the subject is receiving levodopa, carbidopa, a dopamine agonist, amantadine, a monoamine oxidase B inhibitor, or a combination thereof.

[0108] In various embodiments, disclosed herein are methods and compositions for reducing fall-related symptoms in a subject with Parkinson's disease or a Parkinson's-related disorder, wherein the subject is receiving dopamine agonist treatment, e.g., levodopa / carbidopa, and the methods and compositions comprise administering nicotine or a salt thereof to the subject. In some embodiments, the subject has experienced at least one fall or has a history of recurrent falls. Administration of nicotine or a salt thereof in combination with a dopamine agonist can reduce fall-related symptoms, such as the frequency of falls, the frequency of fall-related injuries, and the severity of fall-related injuries. In various embodiments, use of the disclosed methods and compositions reduces side effects associated with dopamine agonist treatment, e.g., reducing dyskinesias and improving response fluctuations: "wearing off and of off."

[0109] In one aspect, the present disclosure provides a method for improving postural stability and gait in a subject with a neurodegenerative disease, the method comprising administering nicotine or a salt thereof to the subject. In some embodiments, nicotine and its salt are administered in a dosage form. In some embodiments, administration of nicotine or its salt improves postural stability, static balance, motor skills, and / or gait in a subject with a neurodegenerative disease, such as Parkinson's disease or a Parkinson's-related disorder. In some embodiments, the subject has generalized Parkinson's disease. In some embodiments, the subject has been diagnosed with Parkinson's disease for at least five years. In some embodiments, the subject is receiving dopaminergic drug treatment. In some embodiments, the subject has fallen in the past year or has recurrent falls.

[0110] In some embodiments, the present disclosure provides a method for improving postural stability and gait in a subject with a neurodegenerative disease, the method comprising administering a nicotine receptor modulator to the subject. In some embodiments, the nicotine receptor modulator is administered in a dosage form. In various embodiments, the nicotine receptor modulator is a nicotine receptor agonist. In various embodiments, the nicotine receptor modulator is a nicotine receptor antagonist. In some embodiments, administration of the nicotine receptor modulator improves postural stability, static balance, motor skills, and / or gait in a subject with a neurodegenerative disease, such as Parkinson's disease or a Parkinson's-related disorder. In some embodiments, the subject has generalized Parkinson's disease. In some embodiments, the subject has been diagnosed with Parkinson's disease for at least five years. In some embodiments, the subject has experienced at least one fall or has a history of recurrent falls.

[0111] In some embodiments, the present disclosure provides a method for improving postural stability in a subject with a neurodegenerative disease, the method comprising administering nicotine or a salt thereof to the subject. In some embodiments, the nicotine receptor agonist is administered in a dosage form. In some embodiments, administration of nicotine or a salt thereof improves postural stability by at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 50-fold, 100-fold, 1000-fold, or more. In some embodiments, the postural stability of the treated subject is improved by about 1-1000-fold.

[0112] In some embodiments, the present disclosure provides a method for improving static balance in a subject with a neurodegenerative disease, the method comprising administering nicotine or a salt thereof to the subject. In some embodiments, the nicotine receptor agonist is administered in a dosage form. In some embodiments, administration of nicotine or a salt thereof improves static balance by at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 50-fold, 100-fold, 1000-fold, or more. In some embodiments, the static balance of the treated subject is improved by about 1-1000-fold.

[0113] In some embodiments, the present disclosure provides a method for improving motor performance in a subject with a neurodegenerative disease, the method comprising administering nicotine or a salt thereof to the subject. In some embodiments, the nicotine receptor agonist is administered in a dosage form. In some embodiments, administration of nicotine or a salt thereof improves motor performance by at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 50-fold, 100-fold, 1000-fold, or more. In some embodiments, the motor performance of the treated subject is improved by about 1-1000 times.

[0114] In some embodiments, the present disclosure provides a method for improving gait, such as freezing or pacing, in a subject with a neurodegenerative disease, the method comprising administering nicotine or a salt thereof to the subject. In some embodiments, the nicotine receptor agonist is administered in a dosage form. In some embodiments, administration of nicotine or a salt thereof improves gait, such as freezing or pacing, by at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 50-fold, 100-fold, 1000-fold, or more. In some embodiments, the gait, such as freezing or pacing, of the treated subject is improved by about 1-1000 times.

[0115] In some embodiments, a subject may experience a lack of movement, slow movement, lack of stability, freezing of gait (FOG), postural instability, problems with static balance, loss of balance, an unsteady gait, and / or short strides. Administration of nicotine or a salt thereof, or a nicotine receptor modulator to a subject can improve movement, gait, postural stability, balance, and / or walking. In some embodiments, the subject's movement, gait, postural stability, balance, and / or walking are improved by at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 50-fold, 100-fold, or more. In some embodiments, the subject's movement, gait, postural stability, balance, and / or walking are improved by about 1-1000-fold compared to previous years.

[0116] In some embodiments, improvement in fall-related symptoms is assessed using standard tests, such as the Unified Parkinson's Disease Rating Scale (UPDRS), the Barlow Neurological Institute (BNI) Fall Assessment, the Hoehn & Yahr severity classification system, the Tinetti score, the Romberg test, the rotation test, standing on one leg, stepping, and step length and velocity.

[0117] In some embodiments, the method includes evaluating a subject with a neurodegenerative disease on dopaminergic treatment, the method including (a) an "off" period during which the subject discontinues dopaminergic treatment for about 16 hours, and (b) an "on" period during which the subject receives their usual morning dose of dopaminergic treatment for about 1 hour. In some embodiments, the subject is receiving dopaminergic treatment, such as levodopa, carbidopa, a dopamine agonist, a monoamine oxidase type B inhibitor, and / or amantadine. In some embodiments, the subject has Parkinson's disease or a Parkinson's-related disorder.

[0118] In some embodiments, subjects are evaluated using laboratory tests, concomitant medication analysis, physical examination, psychiatric evaluation, physical evaluation, electrocardiogram (ECG), vital signs, assessment of impulse control, nicotine withdrawal symptoms, symptom change, Mini-Mental Status Examination, Jay Midi scale, UDysRS, Hoehn & Yahr scale, Clinical Global Impression Scale, Patient Global Impression Scale, Lang-Fahn Activities of Daily Living Scale, and Minnesota Nicotine Withdrawal Scale-Revised (MNWS-R). Laboratory tests include, but are not limited to, urinalysis, serum cotinine analysis, urine cotinine analysis, serum nicotine analysis, hematology, chemistry, and pregnancy tests.

[0119] Described herein are methods for treating cognitive function-related symptoms in a subject with a neurodegenerative disease, which may include administering to the subject a dosage form containing nicotine or a salt thereof. The cognitive function-related symptoms may be impairments in visuospatial memory, executive function, short-term memory, working memory, long-term memory, attention, language, absentmindedness, or spatial orientation. The symptomatic improvement may involve the use of one or more assessment tests, such as the Montreal Cognitive Assessment. 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 be receiving dopamine agonist treatment. The dopaminergic agent may be levodopa, carbidopa, a dopamine agonist, amantadine, a monoamine oxidase B inhibitor, or a combination thereof. The subject may be evaluated during an "off" period, during which the subject may not have received dopaminergic treatment for about 16 hours. When evaluated during an "on" period, the subject may have received their usual morning dose of dopaminergic treatment for about 1 hour. The dopaminergic treatment may be levodopa, carbidopa, a dopamine agonist, amantadine, a monoamine oxidase B inhibitor, or a combination thereof. The "off" period may be at least about or greater than 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 "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 hours, or longer 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 may have a Montreal Cognitive Assessment (MOCA) score of at least 26. The dosage form may contain a nicotine receptor agonist. The dosage form may contain at least 1-6 mg of nicotine or a salt thereof over a 6-month period, and the dosage form may be titrated upward during the treatment interval. The dosage form may contain 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 contain nicotine or a salt thereof and may be titrated upward during a 2-week treatment interval. The dosage form may contain nicotine or a salt thereof and may be titrated upward during a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more than 12-week treatment interval. The dosage form comprises nicotine or a salt thereof and may comprise at least 1 mg every 6 hours; at least 2 mg every 6 hours; at least 4 mg every 6 hours; or at least 6 mg every 6 hours; the dosage may be titrated upward at two-week treatment intervals; and the dosage may be maintained at 6 mg every 6 hours until the end of the six-month treatment period. The dosage form may comprise 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 mg, or more than 60 mg of nicotine or a salt thereof.The dosage form may comprise nicotine or a salt thereof administered for 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 hours or for a period greater than 60 hours. The dosage form may be upwardly titrated at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks or greater than 12 weeks of treatment interval. The dosage form may be administered for greater 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 for more than 8 years. The dosage form may be used for chronic treatment. The dosage may be maintained at at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 mg, or more than 12 mg. The dosage 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 hours, or for a period of more than 24 hours. The treatment period may be at least 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 hours, or more than 24 hours. The treatment period may be longer than 12 weeks. The treatment period may be longer than 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 8 years. The treatment may be a chronic treatment. The nicotine or salt thereof may be administered in an amount of less than 24 mg in a 24-hour period. The nicotine or salt thereof may be administered at least four times in a 24-hour period. The nicotine or salt thereof may be administered about every 6 hours in a 24-hour period. The nicotine or salt thereof 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 nicotine or salt thereof may be administered about every 6 hours in a 24 hour period.Nicotine or a salt thereof may 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 24-hour period. The therapeutic effectiveness of the administration may be assessed regularly for at least 2-14 months. The therapeutic effectiveness of the administration may be assessed regularly for at least 6 months. The therapeutic effectiveness of the administration may be assessed regularly for 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 months, or for a period longer than 60 months. Assessments may occur every two months. Assessments may be performed every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more than 12 months. Assessments may include laboratory tests, concomitant medication analysis, physical examination, psychiatric evaluation, physical evaluation, electrocardiogram (ECG), vital signs, assessment of impulse control, nicotine withdrawal symptoms, symptom change, Mini-Mental State Examination, Jay Midi Scale, UDysRS, Hoehn & Yahr Scale, Clinical Global Impression Scale, Patient Global Impression Scale, Lang-Fahn Activities of Daily Living Scale, and Revised Minnesota Nicotine Withdrawal Scale (MNWS-R). Laboratory tests include, but are not limited to, urinalysis, serum cotinine analysis, urine cotinine analysis, serum nicotine analysis, hematology, chemistry, and pregnancy testing. The dosage form can be formulated for oral, intravenous, intraarterial, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, buccal, or intraperitoneal administration. The dosage form can be formulated for oral administration. The dosage form can be formulated as a unit dosage form. The dosage form can be formulated as a liquid, gel, semi-liquid, semi-solid, or solid unit dosage 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.Administration of the dosage form can result in a pharmacokinetic profile having a plasma nicotine level of less than about 7.5 ng / ml at about 120 minutes after administration of the dosage form. The dosage form can be formulated as a dietary supplement. Administration of the dosage form can result in a pharmacokinetic profile having a plasma nicotine level of less than about 7.5 ng / ml at about 180 minutes after administration of the dosage form. The pharmacokinetic profile can have a plasma nicotine level of less than about 5 ng / ml at about 180 minutes after administration. The pharmacokinetic profile can have a nicotine level of less than about 5 ng / ml at about 120 minutes after administration. The pharmacokinetic profile can have a plasma nicotine level of greater than about 5 ng / ml at about 45-90 minutes after administration. The pharmacokinetic profile can have a plasma nicotine level of greater than about 15 ng / ml at about 60 minutes after administration. The dosage form can be a multiparticulate formulation. The dosage form can provide a plasma concentration of nicotine of 1 ng / ml to 20 ng / ml about 2 hours after administration of a dopamine agonist. The dosage form can provide a plasma concentration of nicotine of 1 ng / mL to 20 ng / mL at about 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours after administration of the dopamine agonist. The dosage form can provide a plasma concentration of nicotine of 1 ng / mL to 20 ng / mL at about 1 to 8 hours, 1 to 7 hours, 1 to 6 hours, 1 to 5 hours, 1 to 4 hours, 1 to 3 hours, 2 to 8 hours, 2 to 7 hours, 2 to 6 hours, 2 to 5 hours, or 2 to 4 hours after administration of the dopamine agonist. The dosage form can provide a plasma concentration of nicotine of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35 ng / mL, or greater than 35 ng / mL, about 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 greater than 12 hours after administration of the dopamine agonist. 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 ischemic vascular dementia, frontotemporal mild cognitive impairment, and frontotemporal dementia.

[0120] Described herein are methods for treating fall-related symptoms in a subject with a neurodegenerative disease, which may include administering to the subject a dosage form containing a nicotinic acetylcholine receptor (nAChR) agonist. The nAChR agonist may be specific for the α7, β2, or α7 and β2 subunits of the nAChR. The nAChR agonist may be a full agonist. nAChR agonists include 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-bromocytidine, acetylcholine, cytisine, epibatidine, A-84,543, A-366,833, ABT-418, altinicline, dianiline, ispronicline, pozaniline, rivanicline, tevanicline, and TC-1827. , sazetidine A, N-(3-pyridinyl)-bridged bicyclic diamine, (+)-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 include frequency of falls. The frequency of falls may be reduced in a subject treated with a dosage form comprising an nAChR agonist. The fall-related symptoms may include frequency of fall-related injuries. A subject treated with a dosage form comprising an nAChR agonist may have a reduced frequency of fall-related injuries. The fall-related symptoms may include severity of falls resulting in injury. A subject treated with a dosage form comprising an nAChR agonist may have a reduced severity of falls resulting in injury. The subject may have recurrent falls.The subject has experienced at least one fall in the past. Symptom improvement may include utilizing one or more assessment tests selected from the group consisting of: Unified Parkinson's Disease Rating Scale (UPDRS), Barlow Neurological Institute (BNI) Falls Assessment, Hoehn & Yahr Severity Classification System, Romberg test, rotation test, standing on one leg, stepping, stride length and velocity. Assessments utilizing the Unified Parkinson's Disease Rating Scale (UPDRS) may be selected from the group consisting of: Walking and Balance, question 2.12 on the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS); Freezing of Gait, question 2.14 on the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS); Dyskinesias, questions 32-35 on the original Unified Parkinson's Disease Rating Scale (UPDRS); Response Fluctuation, questions 36-39 on the original Unified Parkinson's Disease Rating Scale (UPDRS); and Sleep Disturbance, question 40 on the original Unified Parkinson's Disease Rating Scale (UPDRS). The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) 142 score, the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) axis, midline segment, the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) Gait Subtest, the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) Postural Stability Subtest, and the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) Freezing of Gait Subtest (FOG). Assessments may include UPDRS Part II (Activities of Daily Living (ADL)) Question 13: Falling Unrelated to Freezing, UPDRS Part II (ADL) Question 14: Freezing When Walking, the Unified Dyskinesia Rating Scale (UDysRS) Gait subgroup, or a combination thereof. Assessment may include UPDRS Part II (Activities of Daily Living (ADL)) question 13, Falling Unrelated to Freezing, UPDRS Part II (ADL) question 14, Freezing When Walking, and the walking subgroup of the Unified Dyskinesia Rating Scale (UDysRS). Symptom improvement may include assessment utilizing the Reason for Fall of the Barlow Neurological Institute (BNI) Falls Assessment. Symptom improvement may include assessment utilizing the Severity of Fall of the Barlow Neurological Institute (BNI) Falls Assessment.

[0121] Described herein are methods for treating postural instability, static balance, movement disorders, and gait in a subject with a neurodegenerative disease, the methods comprising administering to the subject a dosage form containing a nicotinic acetylcholine receptor (nAChR) agonist. The nAChR agonist may be specific for the α7, β2, or α7 and β2 subunits of the nAChR. The nAChR agonist may be a full agonist. nAChR agonists include 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-bromocytidine, acetylcholine, cytisine, epibatidine, A-84,543, A-366,833, ABT-418, altinicline, dianiline, ispronicline, pozaniline, rivanicline, tevanicline, and TC-1827. , sazetidine A, N-(3-pyridinyl)-bridged bicyclic diamine, (+)-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 a dosage form comprising nicotine may have improved postural stability. A subject treated with a dosage form comprising nicotine may have improved static balance. A subject treated with a dosage form comprising nicotine may have improved motor skills. A subject treated with a dosage form comprising nicotine may have improved gait.Symptom improvement may include utilizing one or more assessment tests selected from the group consisting of: Unified Parkinson's Disease Rating Scale (UPDRS), BNI Falls Assessment, Hoehn & Yahr Severity Classification System, Romberg test, rotation test, standing on one leg, stepping, stride length and speed. Assessments utilizing the Unified Parkinson's Disease Rating Scale (UPDRS) may be selected from the group consisting of: Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) question 2.12 Walking and Balance, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) question 2.14 Freezing of Gait, original Unified Parkinson's Disease Rating Scale (UPDRS) questions 32-35 Dyskinesias, original Unified Parkinson's Disease Rating Scale (UPDRS) questions 36-39 Response Fluctuation, original Unified Parkinson's Disease Rating Scale (UPDRS) question 40 Sleep Disturbance, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) score 142, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) axis, midline, and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) Gait Subtest, the Postural Stability Subtest of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS), and the Freezing of Gait Subtest (FOG) of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS). Assessments may include UPDRS Part II (Activities of Daily Living (ADL)) Question 13, Falling Unrelated to Freezing, UPDRS Part II (ADL) Question 14, Freezing When Walking, the Unified Dyskinesia Rating Scale (UDysRS) Gait Subgroup, or a combination thereof.Assessments may include UPDRS Part II (Activities of Daily Living (ADL)) Question 13, Falling Unrelated to Freezing, UPDRS Part II (ADL) Question 14, Freezing When Walking, and the Unified Dyskinesia Rating Scale (UDysRS) Walking subgroup. 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 be receiving dopamine agonist treatment. The dopamine agonist may be levodopa, carbidopa, a dopamine agonist, amantadine, a monoamine oxidase B inhibitor, or a combination thereof. A subject can be evaluated during an "off" period, during which the subject has not received dopaminergic treatment for about 16 hours. When evaluated during an "on" period, the subject can be evaluated about 1 hour after receiving their usual morning dose of dopaminergic treatment, wherein the dopaminergic treatment can be levodopa, carbidopa, a dopamine agonist, amantadine, a monoamine oxidase B inhibitor, or a combination thereof. The "off" period can be at least 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 longer 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 hours, or longer 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 may have a Montreal Cognitive Assessment (MOCA) score of at least 26. Subjects may have a Montreal Cognitive Assessment (MOCA) score of at least about 20, 25, 30, 35, 40, or greater than 40. Subjects may be excluded from the group consisting of atypical Parkinson's disease, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), primary freezing of gait (PFG), corticobasal degeneration, dementia with a Montreal Cognitive Assessment (MOCA) score of less than 21, legal blindness, orthopedic problems in the hip or knee, total hip or knee replacement, orthostatic hypotension, schizophrenia, schizoaffective disorder, bipolar disorder, hallucinations, psychosis, delusions, deep brain stimulation (DBS) intervention, history of recent stroke, and history of myocardial infarction. The dosage form may contain at least 1-6 mg of nAChR agonist over a 6-month period, and the dosage form may be titrated upward during treatment intervals. The dosage form may contain 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 duration 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 containing the nAChR agonist may be upwardly titrated at 2-week treatment intervals. The dosage form containing the nAChR agonist may be upwardly titrated at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more than 12-week treatment intervals.The dosage form containing the nAChR agonist may be administered for more than 12 weeks. The dosage form containing the nAChR agonist may be administered for more than 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 8 years. The dosage form containing the nAChR agonist may be used for chronic treatment. The treatment period may be more than 12 weeks. The treatment period may be more than 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 8 years. The treatment period may be chronic treatment. The nAChR agonist may be administered in an amount less than 24 mg over a 24 hour period. The nAChR agonist may 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 mg, or more than 60 mg. The nAChR agonist may be administered for 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 may be administered at least four times in a 24-hour period. 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 may be administered about every 6 hours in a 24-hour period. The nAChR agonist may 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 24-hour period. The therapeutic effectiveness of the administration may be assessed regularly for at least 2 to 14 months. The therapeutic effectiveness of the administration may be assessed regularly for at least 6 months.The therapeutic effectiveness of the administration can be assessed regularly for 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 months, or for more than 60 months. Assessments can occur every two months. Assessments can occur every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more than 12 months. Assessments may include laboratory tests, analysis of concomitant medications, physical examination, psychiatric evaluation, physical evaluation, electrocardiogram (ECG), vital signs, assessment of impulse control, nicotine withdrawal symptoms, symptom change, Mini-Mental Status Examination, Jay Midi scale, UDysRS, Hoehn & Yahr scale, Clinical Global Impression Scale, Patient Global Impression Scale, Lang-Fahn Activities of Daily Living Scale, and Revised Minnesota Nicotine Withdrawal Scale (MNWS-R). Laboratory tests include, but are not limited to, urinalysis, serum cotinine analysis, urine cotinine analysis, serum nicotine analysis, hematology, chemistry, and pregnancy tests. The can be formulated for oral, intravenous, intraarterial, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, buccal, or intraperitoneal administration. The dosage form can be formulated for oral administration. The dosage form can be formulated as a unit dosage form. The composition can be formulated as a liquid, gel, semi-liquid, semi-solid, or solid unit dosage 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.

[0122] Described herein is a method for reducing the 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. Also described herein is a method for reducing freezing of gait (FOG), the method comprising administering to a subject a dosage form comprising nicotine or a salt thereof. The number of falls and FOG may be associated with levodopa-induced dyskinesia (LID). The number of falls and FOG may not be associated with levodopa-induced dyskinesia (LID). The method can improve postural stability. Falls can be prevented in subjects treated with a dosage form comprising nicotine or a salt thereof. The frequency of falls can be reduced by at least 10%. The frequency of falls can 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 can be reduced by at least 20%. FOG can be reduced by at least 10%. FOG can 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 can be reduced by at least 20%. LID can be reduced by at least 10%. The LID can 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 LID can be reduced by at least 20%. The improvement in postural stability can be at least a 10% improvement. The improvement in postural stability can be at least or about a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or more than a 90% improvement. The subject may experience at least a 0.5-fold reduction in the frequency of falls.The subject may experience at least a 0.5-, 1.0-, 1.5-, 2.0-, 2.5-, 3.0-, 4.0-, 4.5-, or 5-fold reduction in frequency of falls. The subject may experience at least a 0.5-, 1.0-, 1.5-, 2.0-, 2.5-, 3.0-, 4.0-, 4.5-, or 5-fold reduction in FOG. The subject may experience at least a 0.5-, 1.0-, 1.5-, 2.0-, 2.5-, 3.0-, 4.0-, 4.5-, or 5-fold reduction in levodopa-induced dyskinesia (LID). The subject may experience at least a 0.5-fold improvement in postural stability. The subject may experience at least or about 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 times, or more than 8.0 times, improvement in postural stability. Falls and FOG may occur independently. Falls may be associated with FOG.

[0123] Described herein is a method for reducing the 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 have a central nervous system disease or disorder. The subject at risk of falling may have Parkinson's disease.

[0124] Described herein are methods for preventing falls, comprising administering to a subject a dosage form containing nicotine or a salt thereof. In some embodiments, the subject is administered an nAChr agonist or antagonist. For example, the method for preventing falls reduces the incidence of falls. The incidence of falls can 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 can be reduced by at least 20%.

[0125] Described herein are methods for reducing fall-related complications, comprising administering to a subject a dosage form containing nicotine or a salt thereof. In some embodiments, the subject is administered an nAChr agonist or antagonist. Fall-related complications include, but are not limited to, postural instability, abnormal postural balance, slowed reaction time, lack of ambulatory-dependent activities, lack of daily activities, and injury. Fall-related complications can be reduced by at least 10%. Fall-related complications can 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 can be reduced by at least 20%.

[0126] Described herein is a method for improving cognitive function-related symptoms, comprising administering to a subject a dosage form containing nicotine or a salt thereof. In some embodiments, the subject is administered an nAChr agonist or antagonist. The cognitive function-related symptoms may be associated with a neurodegenerative disease or disorder. The cognitive function-related symptoms may be associated with mild cognitive impairment, Alzheimer's disease, vascular cognitive impairment, subcortical ischemic vascular dementia, frontotemporal mild cognitive impairment, and frontotemporal dementia. The cognitive function-related symptoms may be improved by at least 10%. The cognitive function-related symptoms may be improved 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 cognitive function-related symptoms may be reduced by at least 20%.

[0127] The reduction in fall frequency, reduction in freezing of gait (FOG), reduction in levodopa-induced dyskinesia (LID), prevention of falls, reduction in fall-related complications, improvement in postural stability, improvement in cognitive-related symptoms, or a combination thereof can be compared to a control. The control can be a subject at baseline or a subject administered a placebo. In some examples, the control has idiopathic Parkinson's disease. The control may have LID. The control may be in the peak "on" state of levodopa. Nicotine or its salts may not alter dopaminergic activity. Nicotine or its salts may not increase cholinergic activity. Subject assessments may include the UPDRS Part II (Activities of Daily Living (ADL)) Question 13, "Falling Unrelated to Freezing," UPDRS Part II (ADL) Question 14, "Freezing When Walking," the Unified Dyskinesia Rating Scale (UDysRS) walking subgroup, or a combination thereof. The dosage form can be formulated for oral administration. Evaluations can include laboratory tests, analysis of concomitant medications, physical examination, psychiatric evaluation, physical evaluation, electrocardiogram (ECG), vital signs, assessment of impulse control, nicotine withdrawal symptoms, symptom change, Mini-Mental Status Examination, Jay Midi Scale, UDysRS, Hoehn & Yahr Scale, Clinical Global Impression Scale, Patient Global Impression Scale, Lang-Fahn Activities of Daily Living Scale, and Revised Minnesota Nicotine Withdrawal Scale (MNWS-R). Laboratory tests include, but are not limited to, urinalysis, serum cotinine analysis, urine cotinine analysis, serum nicotine analysis, hematology, chemistry, and pregnancy tests.

[0128] The methods as described herein include administering a dose of nicotine or a salt thereof to a subject over a period of time. In some embodiments, the subject is administered an nAChr agonist or antagonist. The methods may be associated with a reduction in the frequency of falls. The methods may be associated with a reduction in freezing of gait (FOG). In some embodiments, the methods may be associated with a reduction in levodopa-induced dyskinesia (LID). The methods may be associated with the prevention of falls. The methods may be associated with a reduction in fall-related complications. The methods may be associated with improving postural stability. The methods may be associated with an improvement in cognitive function-related symptoms. The methods as described herein may not result in tolerance or dependence on nicotine or a salt thereof. The subject may be elderly or have a central nervous system disease or disorder. The subject may have Parkinson's disease. The subject may have Parkinson's disease or LIDs.

[0129] The method as described herein comprises administering nicotine or its salt, wherein the amount of nicotine or its salt is administered in an amount of 24 mg or less per day.In some embodiments, the amount or total dosage of nicotine or its salt can be more than 24 mg per day.The amount or total dosage of nicotine or its salt can be 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 less, or more than 48 mg per day. The amount or total dosage of nicotine or a salt thereof may range from about 1 to 24 mg per day, 2 to 22 mg per day, 3 to 20 mg per day, 4 to 18 mg per day, 5 to 16 mg per day, 6 to 14 mg per day, or 8 to 12 mg per day. The amount or total dosage of nicotine or a salt thereof may range from about 8 to 24 mg per day.

[0130] In some embodiments, the method for administering nicotine or a salt thereof includes administering nicotine or a salt thereof at a dose equivalent to an oral dose, for example, nicotine or a salt thereof at a dose equivalent to an oral dose of 24 mg per day. In some embodiments, nicotine or a salt thereof is administered as a dose equivalent to an oral dose of 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. In some embodiments, nicotine or a salt thereof is administered as a dose equivalent to an oral dose of 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.In some embodiments, nicotine or a salt thereof is administered at a dosage equivalent to an oral dose of 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. In some embodiments, the dosage of nicotine or a salt thereof is equivalent to the dosage 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, oral mucosal, inhalation, or intraperitoneal administration. In some embodiments, nicotine or a salt thereof is formulated for intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, oral mucosal, inhalation, or intraperitoneal administration, at most 1 mg per day, 2 mg per day, 4 mg per day, or 5 mg per day. It may be administered as an oral dose equivalent to 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 greater than 48 mg per day.

[0131] In some embodiments, multiple doses are administered to a subject. In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different doses of nicotine or a salt thereof are administered. The dose of nicotine or a salt thereof may be about 1 to about 6 mg. The dose may be at least 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 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 range from about 0.1 to about 6 mg. Dosages may range from about 0.1 to about 1 mg, about 0.1 to about 2 mg, about 0.1 to about 2.5 mg, about 0.1 to about 3 mg, about 0.1 to about 3.5 mg, about 0.1 to about 4 mg, about 0.1 to about 4.5 mg, about 0.1 to about 5 mg, or about 0.1 to about 6 mg. The duration 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 duration 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 longer than 8 years. Doses of nicotine or its salts may be used for chronic treatment.

[0132] The method as described herein may include providing a dosage of nicotine or a salt thereof over a 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, or 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.

[0133] In some embodiments, the method of administering nicotine or a salt thereof includes escalating the dose of nicotine or a salt thereof upward over a treatment interval. The method can provide multiple doses. The method can provide 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different doses of nicotine or a salt thereof. The dose of nicotine or a salt thereof can be about 1 to about 6 mg. The dose can be at least 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. Dosages may be at least 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. Dosages may be titrated upward at 2-week treatment intervals. Dosages may be titrated upward at 1-4 week treatment intervals. Dosages may be titrated upward at 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, or more than 8 weeks treatment intervals. Dosages may be titrated upward until an optimal dose is determined, after which chronic treatment may be used.

[0134] The methods described herein may include providing a starting dose of nicotine or a salt thereof over a period of time, where the starting dose may be titrated upward to a first escalating dose. The first escalating dose may be 1.5, 1.75, or 2 times greater than the starting dose. The first escalating dose may be 1.5, 2, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 9.0, 9.5, 10, 11, or 12 times greater than the starting dose. In some embodiments, the starting dose is titrated to a second escalating dose. The second escalating dose may be 2.5, 3.0, 3.5, or 4 times greater than the starting dose. The second escalating dose may be 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 9.0, 9.5, 10, 11, or 12 times greater than the starting dose. In some embodiments, the starting dose is escalated to a third escalating dose. The third escalating dose may be 4.5, 5.0, 5.5, 6.0, or 6.5 times greater than the starting dose. The fourth dose may be 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 9.0, 9.5, 10, 11, or 12 times greater than the starting dose. The kit can provide multiple escalating doses from the starting dose. The method can provide multiple different or non-identical escalating doses from the starting dose. The number of different or unequal escalating doses can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 escalating doses from the starting dose. The escalating doses can also be 1.5, 2, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 9.0, 9.5, 10, 11, or 12 times greater than the starting dose.

[0135] The method as described herein may include 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 can 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 can be administered about 1, 2, 3, 4, 5, or 6 times a day. The dose of nicotine or a salt thereof can be administered once a day. The dose of nicotine or a salt thereof can be administered twice a day. The time between administrations 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. The time between doses can range from 0 to 24 hours, 1 to 23 hours, 2 to 22 hours, 3 to 21 hours, 4 to 20 hours, 5 to 19 hours, 6 to 18 hours, 7 to 17 hours, 8 to 16 hours, 9 to 15 hours, and 10 to 12 hours. The time between doses can range from about 1 to 6 hours, or about 2 to 6 hours. Doses can be administered 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.

[0136] In some embodiments, the methods described herein provide a nicotine or salt thereof dosage form that delivers an immediate release dose of nicotine or a salt thereof, followed by a second immediate release dose about 2 to 8 hours after administration. The dosage form can deliver an immediate release dose of nicotine or a salt thereof, followed by a second immediate release dose about 1 to 8 hours, 1 to 7 hours, 1 to 6 hours, 1 to 5 hours, 1 to 4 hours, 1 to 3 hours, 2 to 8 hours, 2 to 7 hours, 2 to 6 hours, 2 to 5 hours, or 2 to 4 hours after administration. In some embodiments, the second immediate release dose is followed by a third immediate release dose about 8 to 16 hours after administration. In some embodiments, the third immediate release dose is followed by a fourth immediate release dose about 16 to 24 hours after administration. The dosage of nicotine or a salt thereof can be about 1 mg to about 6 mg over a period of time. For example, the dosage of nicotine or a salt thereof can be about 1 mg to about 6 mg over a 6-hour period. A dosage may contain 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.A dosage may contain 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 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 dosage 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 per day. The dosage of nicotine or a salt thereof may be administered about 1, 2, 3, 4, 5, or 6 times per day. The dosage of nicotine or a salt thereof may be administered once per day. The dosage of nicotine or a salt thereof may be administered twice per day.The time between doses can 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, or can range from 0 to 24 hours, 1 to 23 hours, 2 to 22 hours, 3 to 21 hours, 4 to 20 hours, 5 to 19 hours, 6 to 18 hours, 7 to 17 hours, 8 to 16 hours, 9 to 15 hours, and 10 to 12 hours.

[0137] In some embodiments, the methods described herein provide a nicotine or salt thereof dosage form that delivers one or more immediate release doses of nicotine or salt thereof over a period of time. The number of immediate release doses of nicotine or salt thereof can be 1, 2, 3, 5, 6, 7, 8, or more than 8 immediate release doses. The number of immediate release doses of nicotine or salt thereof can be in the range of 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 2-8, 2-7, 2-6, 2-5, or 2-4 immediate release doses. The dosage form can provide an immediate release dose at about 1-8 hours, 1-7 hours, 1-6 hours, 1-5 hours, 1-4 hours, 1-3 hours, 2-8 hours, 2-7 hours, 2-6 hours, 2-5 hours, or 2-4 hours after administration. The dosage form can provide an immediate release dose about 8 to 16 hours, 8 to 15 hours, 8 to 14 hours, or 8 to 12 hours after administration. The dosage form can provide an immediate release dose about 16 to 24 hours, 16 to 22 hours, 16 to 20 hours, or 16 to 18 hours after administration.

[0138] In some embodiments, the method can provide a dosage form that delivers delayed-release pulses of nicotine or a salt thereof. The delayed-release pulses of nicotine or a salt thereof can be delivered over a period of time. The dosage of nicotine or a salt thereof can be 24 mg or less per day. In some embodiments, the dosage of nicotine or a salt thereof can be more than 24 mg per day. The dosage can include 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. Doses may contain 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 can 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, 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, or within a range of such hours.

[0139] Unified Parkinson's Disease Rating Scale (UPDRS) The Unified Parkinson's Disease Rating Scale (UPDRS) is typically used to follow the course of Parkinson's disease over time. Generally, the UPDRS consists of five sections: Part I: assessment of mental status, behavior, and mood; Part II: self-assessment of activities of daily living (ADL), including speech, swallowing, handwriting, dressing, hygiene, falls, saliva production, turning over, walking, and cutting food; Part III: clinically scored and monitored motor assessment; Part IV: Hoehn and Yahr classification of Parkinson's disease severity; and Part V: Schwab and England ADL scale.

[0140] These UPDRS sections are assessed through interviews and clinical observations. In some cases, sections may require multiple grades to be assigned to each limb. Typically, clinicians, medical professionals, or researchers will use the UPDRS and motor sections specifically to track a person's Parkinson's disease progression. For example, research may utilize it to measure the benefit from a treatment. As another example, medical professionals may use it in clinical practice to track the progression of a patient's symptoms. Tracking UPDRS scores over time can provide insight into a patient's disease progression. Typically, "mental state, behavior, and mood" is scored to track later increases in the disease.

[0141] The Unified Parkinson's Disease Rating Scale (UPDRS) is the most widely used test for assessing patients with Parkinson's disease. The original UPDRS includes a question about activities of daily living related to falls. This question is not present in the revised Movement Disorder Society UPDRS (MDS-UPDRS). Both the original UPDRS and the MDS-UPDRS include only one subtest for balance (postural instability), known as the "pull test." This subtest contributes only 4 points out of a total of 132, representing approximately 3% of the motor test and a small portion for assessing falls in patients with Parkinson's disease.

[0142] Movement Disorder Society UPDRS (MDS-UPDRS) revised version The Movement Disorder Society (MDS) has published a revised version of the UPDRS, known as the MDS-UPDRS. This revision highlights limitations of the original UPDRS. Two major limitations include the lack of consistent anchors between subscales and a lack of emphasis on nonmotor features of PD. The revised UPDRS retains the four-item structure with various subscale reorganizations. The scales are titled as follows: (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 (6 items). Each subscale now has a rating of 0–4, with 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe.

[0143] Tinetti test (TT) The Tinetti Test (TT), also known as the Performance Oriented Mobility Assessment (POMA), is a common clinical test used to assess a person's static and dynamic balance. The test consists of two short sections: one that assesses static balance in sitting and standing, and one that assesses gait. In some cases, the two sections are used as separate tests.

[0144] Barlow Neurological Institute (BNI) Unlike the Tinetti score, which is typically used to assess balance, the Barlow Neurological Institute (BNI) Balance Scale focuses on Parkinson's disease and addresses the problems 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, November 30, 2012). Non-limiting examples of problems that result in falls in Parkinson's disease include turning, standing upright on one leg while reaching or climbing stairs, and walking in a restricted space. In addition, the BNI Balance Scale does not replicate some aspects of the MDS-UPDRS. Therefore, the BNI Balance Scale can be used as a supplement to the MDS-UPDRS.

[0145] The BNI Balance Scale includes five subsets in three major categories for assessing balance and predicting falls. The BNI Balance Scale incorporates subtests appropriate for Parkinson's disease-related falls, including the turning and single-leg standing subtests of the Tinett (item 8 in the balance section) and Berg (items 11 and 14) scales. Patients are assessed for turning, single-leg standing, and toeing. Patient performance is assessed using a maximum score of 20 points. Details of the assessment are described herein.

[0146] Patients undergoing rotation testing are asked to rotate 360 ​​degrees and are scored against an 8-point scoring system (Table 1). First, the patient is asked to rotate to the right and is scored as a 4. Next, the patient is asked to rotate to the left and is scored as a 4. Generally, the scoring is similar to the Berg, except that 4 is normal or baseline in the Berg and 0 is normal or baseline in the BNI.

[0147] [Table 1]

[0148] Patients performing the single-leg standing test are asked to independently lift one leg and maintain it for a period of time. First, the patient is asked to stand on the right leg only and is scored as a 4. Next, the patient is asked to stand on the left leg only and is scored as a 4. The ability to maintain leg lift is assessed against an 8-point scoring system (Table 2). Generally, the scoring is similar to the Berg, except that 4 is normal or baseline for the Berg and 0 is normal or baseline for the BNI.

[0149] [Table 2]

[0150] Typically, the toe-toe test requires the patient to place one foot in front of the other and take 10 steps, trying to touch the heel of one foot to the toe of the other. Patients are assessed against a 4-point scoring system (Table 3). A score of 0 is normal or baseline.

[0151] [Table 3]

[0152] In some embodiments, improvement in fall-related symptoms is assessed by utilizing the Reason for Fall from the Barlow Neurological Institute (BNI) Fall Assessment. In some embodiments, improvement in fall-related symptoms is assessed by utilizing the Severity of Fall from the Barlow Neurological Institute (BNI) Fall Assessment.

[0153] In some embodiments, the likelihood of falling in subjects with neurological disorders is predicted using the Barlow Neurological Institute (BNI) Balance Scale. As a non-limiting example, a patient who has fallen at least three times in the three months prior to testing is considered a faller and typically scores at least a 3 on the BNI single-leg standing test, at least a 3 on the BNI rotation test, and at least a 2 on the BNI tangent walking test. As another non-limiting example, a patient who reports balance difficulties when questioned by the BNI may also have an MDS-UPDRS postural stability (PS) of at least 2, and may fall at least three times per month.

[0154] In some embodiments, the present disclosure provides a method for assessing fall-related symptoms in subjects with neurodegenerative disorders, such as Parkinson's disease or a Parkinson's-related disorder, using a modified version of the BNI Balance Scale, which is comprised of the original UPDRS, the MDS-UPDRS, the Romberg test, the rotation test, the one-legged standing test, and the toe-toe gait test. Exemplary tests include Dyskinesias (questions 32-35) from the original UPDRS, Response Fluctuation (questions 36-39) from the original UPDRS, Sleep Disturbance (question 40) from the original UPDRS, the Hoehn & Yahr severity classification system (0V), the MDS-UPDRS 132 score, the MDS-UPDRS 24 score for Axis-Midline segment, the MDS-UPDRS Gait Subtest, Postural Stability (also known as the "Pull Test") from the MDS-UPDRS, and the Freezing of Gait (FOG) subtest from the MDS-UPDRS.

[0155] In some embodiments, the present disclosure provides a method for assessing fall-related symptoms in a subject with a neurodegenerative disease, such as Parkinson's disease or a Parkinson's-related disorder. In some embodiments, the subject is assessed based on their ability to walk a distance equivalent to 25 feet, or 7.62 meters. The number of steps taken by the subject to walk a distance equivalent to 25 feet, or 7.62 meters, is counted and the time is measured.

[0156] In some embodiments, the present disclosure provides a method for assessing fall-related symptoms in a subject with a neurodegenerative disease, such as Parkinson's disease or a Parkinson's-related disorder. In some embodiments, the subject is assessed for freezing of gait in the "on" and "off" states using the MDS-UPDRS and FOG question 2.13 of the MDS-UPDRS subtest of the FOG (Espay AJ, Fasano A, van Nuenen BFL, "On state freezing of gait in Parkinson's disease: a paradoxical levodopa-induced complication", Neuerology 78:454-457, January 18, 2012).

[0157] In some embodiments, the present disclosure provides methods and compositions for treating fall-related symptoms in a subject with Parkinson's disease or a Parkinson's-related disorder, the methods comprising administering the composition to the subject and assessing the subject's response to treatment. In some embodiments, the composition is administered to the subject over a six-month period (Fahn S, Elton RL, Members of the UPDRS Development Committee Unified Parkinson's Disease Rating Scale, Fahn S, Marsden CD, Calne D, Goldstein M, "Recent Developments in Parkinson's Disease," Macmillan Healthcare Information Florham Park NJ, pp. 3-163, 1988). The efficacy of the treatment is assessed by the subject's performance in an "on-off" test. In some embodiments, assessments are performed every two months for up to six months. After the six-month period, the subject is administered a placebo and assessed two months after crossover by an "on-off" test. In some cases, subjects receive a treatment re-titration two months after crossover. After the crossover and re-titration period, subjects' performance on the "on-off" test is assessed every two months for up to six months.

[0158] In some embodiments, the present disclosure provides methods and compositions for treating fall-related symptoms in a subject with Parkinson's disease or a Parkinson's-related disorder, the methods comprising administering to the subject a composition comprising nicotine or a salt thereof and assessing the subject's response to the treatment. In some embodiments, a placebo is administered to the subject over a six-month period. The effectiveness of the treatment is assessed by the subject's performance on an "on-off" test. In some embodiments, assessments are performed every two months for up to six months. After six months, the subject is administered a composition comprising nicotine or a salt thereof to serve as their own identical control. Without being bound by any theory, subjects receiving the placebo may not tolerate the full amount of the composition, and the subject may undergo another titration period of treatment. Two months after crossover and re-titration are complete, the effectiveness of the treatment is assessed by the subject's performance on an "on-off" test every two months for up to six months.

[0159] In some embodiments, the present disclosure provides methods and compositions for treating fall-related symptoms in a subject with Parkinson's disease or a Parkinson's disease-related disorder, the methods comprising administering to the subject a composition comprising nicotine or a salt thereof and assessing the subject's response to the treatment. In some embodiments, the composition is administered to the subject for a period of six months. The efficacy of the treatment is assessed by the subject's performance on an "on-off" test every two months for up to six months. After six months, the subject is administered a placebo to serve as their own matched control. Two months after crossover and re-titration are complete, the efficacy of the treatment is assessed by the subject's performance on an "on-off" test every two months for up to six months.

[0160] In some embodiments, the effectiveness of treating fall-related symptoms in a subject with Parkinson's disease or a Parkinson's disease-related condition is regularly monitored by assessing the subject's response to treatment. Assessments can be performed by a medical professional who provides protective, curative, promotive, or rehabilitative health care services, etc., to individuals, families, or communities in a systematic manner. The medical professional can be a health care worker. Examples of health care workers include doctors, dentists, pharmacists, physician assistants, nurses (including advanced practice nurses), surgeons, surgical assistants, surgical technicians, midwives (obstetricians), nutritionists, therapists, psychologists, chiropractors, clinical officers, social workers, phlebotomists, physical therapists, respiratory therapists, occupational therapists, audiologists, speech-language pathologists, optometrists, paramedics, emergency medical technicians, drug laboratory scientists, medical prosthetists, radiologists, and a wide variety of other personnel trained to provide health care services of all types. Health professionals often work in hospitals, health centers, and other service delivery locations, as well as university training institutes and governments. Some provide care and treatment services to patients in their homes. In some cases, community health workers may work outside of public health care institutions. Health professionals are commonly grouped into a number of professions: medicine (including general practitioners and specialists); nursing (including various specialty titles); midwifery (obstetrics); dentistry; and other health professions, including occupational therapy, pharmacy, physiotherapy, paramedicine, respiratory therapy, radiologists, and many other health professionals.

[0161] In some embodiments, the effectiveness of treating fall-related symptoms using the present methods and compositions is assessed by monitoring the subject's response to treatment, such as the subject's performance on an "on-off" test. In some embodiments, the subject is assessed every two months for at least six to fourteen months. In some embodiments, the subject is assessed at least four times over a six-month period. For example, the subject is assessed at the time of treatment, two months after receiving the initial treatment; four months after receiving the initial treatment; and six months after receiving the initial treatment, known as the initial visit. In various embodiments, the subject undergoes a treatment crossover and retitration period of approximately two months. The subject's performance on the "on-off" test is assessed. After the expiration of the retitration period, the subject is assessed every two months for at least six months. In some embodiments, the subject is assessed at least four times over a six-month period after the treatment crossover and retitration period. For example, subjects are evaluated at the completion of treatment crossover and retitration; 2 months after completion of treatment crossover and retitration; 4 months after completion of treatment crossover and retitration; and 6 months after completion of treatment crossover and retitration.

[0162] The present disclosure also provides methods for assessing fall-related symptoms or predicting recurrent falls in a subject with a neurodegenerative disease, such as Parkinson's disease or a Parkinson's-related disorder. In various embodiments, the subject has been diagnosed with generalized Parkinson's disease. The subject may be male or female, aged 30 to 83 years. The subject is in the "ON" state according to Hoehn and Yahr severity classification II, III, or IV and has a Montreal Cognitive Assessment (MOCA) score of ≥26. In some embodiments, the subject has previously experienced at least one fall. The subject is also receiving a stable dose of levodopa, a dopamine agonist, amantadine, and / or a monoamine oxidase B inhibitor.

[0163] In some embodiments, subjects with neurodegenerative diseases and fall-related conditions can be treated with the present methods and compositions. Subjects may not have atypical Parkinson's disease or other rare disorders that result in numerous falls, especially early in the disease course. These disorders include progressive supranuclear palsy (PSP), multiple system atrophy (MSA), primary freezing of gait (PFG), and corticobasal degeneration. Subjects may not have Parkinson's disease or dementia. Also excluded are legally blind subjects, subjects with major orthopedic hip or knee problems, or patients requiring hip or knee replacement. Orthostatic hypotension, reflecting autonomic nervous system (ANS) involvement, may be part of Parkinson's disease but may also result from the use of antihypertensives, diuretics, selected antidepressants, and dehydration. Because it is often difficult to determine whether falls due to orthostatic hypotension are due to ANS dysfunction or to medications or dehydration, subjects with orthostatic hypotension are excluded. Also excluded are subjects with a history of schizophrenia, schizoaffective disorder, bipolar disorder, hallucinations, psychosis, or delusions, subjects with deep brain stimulation (DBS) interventions, and / or a history of recent stroke or myocardial infarction.

[0164] In one aspect, the present disclosure provides a method for treating cognitive function-related symptoms in a subject with a neurodegenerative disease, the method comprising administering nicotine or a salt thereof to the subject. In some embodiments, nicotine and its salt are administered in a dosage form. Administration of nicotine or its salt 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 ischemic vascular dementia, frontotemporal mild cognitive impairment, and frontotemporal dementia. In some embodiments, the subject has generalized Parkinson's disease. In some embodiments, the subject has been diagnosed with Parkinson's disease for at least five years. In some embodiments, the subject is receiving dopaminergic drug treatment. In some embodiments, the subject has a history of falls or recurrent falls.

[0165] In various embodiments, the present disclosure provides a method for treating cognitive function-related symptoms in a subject with a neurodegenerative disease, the method comprising administering to the subject a composition comprising a nicotine receptor modulator. In some embodiments, the composition is administered in a dosage form. In some embodiments, the nicotine receptor modulator is a nicotine receptor agonist or antagonist. Administration of the composition 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 ischemic vascular dementia, frontotemporal mild cognitive impairment, and frontotemporal dementia. In some embodiments, the subject has common Parkinson's disease.

[0166] In some embodiments, the present disclosure provides a method for treating cognitive symptoms in a subject suffering from Parkinson's disease, schizophrenia, mild cognitive impairment, Alzheimer's disease, vascular cognitive impairment, subcortical ischemic vascular dementia, frontotemporal mild cognitive impairment, or frontotemporal dementia, the method comprising administering nicotine or a salt thereof to the subject. Administration of nicotine or a salt thereof can reduce cognitive impairment. In some embodiments, the subject is receiving dopaminergic treatment. Non-limiting examples of dopaminergic treatment include levodopa, bromocriptine, pergolide, pramipexole, cabergoline, ropinolole, apomorphine, carbidopa, a dopamine agonist, a monoamine oxidase type B inhibitor, amantadine, or a combination thereof. In some embodiments, the subject is receiving levodopa, carbidopa, a dopamine agonist, amantadine, a monoamine oxidase B inhibitor, or a combination thereof.

[0167] In various embodiments, disclosed herein are methods and compositions for reducing cognitive symptoms in a subject with Parkinson's disease, schizophrenia, mild cognitive impairment, Alzheimer's disease, vascular cognitive impairment, subcortical ischemic vascular dementia, frontotemporal mild cognitive impairment, or frontotemporal dementia, wherein the subject is receiving dopamine agonist treatment, e.g., levodopa / carbidopa, and the method comprises administering nicotine or a salt thereof to the subject. Administering nicotine or a salt thereof in combination with a dopamine agonist can reduce the cognitive symptoms. In various embodiments, use of the disclosed methods and compositions reduces side effects associated with dopamine agonist treatment, e.g., reducing dyskinesias and improving response fluctuations: "wearing off and of off."

[0168] Pharmaceutical Composition In some embodiments, the present disclosure provides a pharmaceutical composition comprising nicotine or a salt thereof for treating fall-related symptoms and cognitive function-related symptoms in a subject with a neurodegenerative disease. In some embodiments, the composition can be any nicotine-containing composition described herein. In some embodiments, the pharmaceutical composition is formulated in a dosage form for administration. In related embodiments, the composition comprises a nicotine receptor modulator, such as nicotine or a salt thereof, described herein. In some embodiments, the nicotine receptor modulator is a nicotine receptor agonist. In related embodiments, the dosage form is a pharmaceutical composition comprising a pharmaceutically acceptable carrier, examples of which are described herein.

[0169] Pharmaceutical compositions of the present invention suitable for oral administration can be provided in discrete dosage forms such as capsules, cachets, tablets, liquids, powders, or as aerosol sprays, each containing a predetermined amount of the active ingredient in granules, solutions, suspensions in aqueous or non-aqueous solutions, oil-in-water emulsions, or water-in-oil emulsions. Such dosage forms can be prepared by any of the methods of pharmacy, all of which include the step of combining the active ingredient with the carrier, which constitutes one or more necessary ingredients.

[0170] In some embodiments, the composition contains nicotine or a salt thereof in an amount of about 0.001-1000 mg, 0.01-100 mg, 0.1-200 mg, 3-200 mg, 5-500 mg, 10-100 mg, 10-1000 mg, 50-200 mg, or 100-1000 mg. In some embodiments, the pharmaceutical composition contains 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.

[0171] In some embodiments, the composition contains nicotine or a salt thereof in an amount of about 0.1 mg to 5 mg, about 1 mg to 3 mg, about 2 mg to 20 mg, about 10 mg to 25 mg, about 15 mg to 50 mg, about 20 mg to 200 mg, about 100 mg to 500 mg, or about 150 mg to 1000 mg. In some embodiments, the amount of nicotine or a salt thereof is 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, or 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, or 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.

[0172] formulation In some embodiments, a composition is formulated for administration to a subject, the composition comprising nicotine or a salt thereof in an amount effective to reduce fall-related symptoms. Treatment may include reducing the frequency of falls, reducing fall-related injuries, reducing the severity of fall-related injuries, and reducing fall-related symptoms, such as improving balance, postural stability, and gait. Treatment may also include reducing cognitive function-related symptoms. Treatment may also include reducing FOG. Treatment may also include reducing LID. The composition can be formulated in a dosage form. In some embodiments, the composition is formulated in a dosage form comprising a nicotine receptor modulator, such as a nicotine receptor agonist. In various embodiments, the composition is formulated for administration in combination with a dopamine agonist, such as levodopa, carbidopa, a dopamine agonist, amantadine, and a monoamine oxidase B inhibitor, or a combination thereof.

[0173] In various embodiments, the composition comprises about 0.001-1000 mg, 0.01-100 mg, 0.1-200 mg, 3-200 mg, 5-500 mg, 10-100 mg, 10-1000 mg, 50-200 mg, or 100-1000 mg of nicotine or a salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.001 mg, 0.01 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 nicotine or a salt thereof in an amount of about 1-10 mg.

[0174] In some embodiments, compositions are formulated to provide a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof, as an active ingredient. If desired, pharmaceutical compositions contain a pharmaceutically acceptable salt and / or coordination compound thereof, and one or more pharmaceutically acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants.

[0175] The compositions disclosed herein can be formulated for oral, intravenous, and / or topical administration. In some embodiments, the disclosed pharmaceutical compositions are formulated for topical administration.

[0176] In some embodiments, the composition further comprises a carrier suitable for intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, buccal, inhalation, or intraperitoneal administration.

[0177] In some embodiments, the composition is formulated as a unit dosage form in liquid, gel, semi-liquid, semi-solid, and / or solid form.

[0178] In some embodiments, the composition is formulated as a topical cream.

[0179] In some embodiments, the composition is formulated in a food product, in some embodiments, the composition is formulated in a beverage, in some embodiments, the composition is formulated in a dietary supplement.

[0180] Described herein are multi-particulate formulations capable of delivering an immediate release dose of nicotine and a second immediate release dose of nicotine about 2 to 4 hours after administration. The formulations can deliver the immediate release dose of nicotine at time 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. The formulations can deliver the second immediate release dose of nicotine about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more hours after administration. The formulations can deliver the immediate release dose of nicotine 1 to 8 hours, 1 to 7 hours, 1 to 6 hours, 1 to 5 hours, 1 to 4 hours, 1 to 3 hours, 2 to 8 hours, 2 to 7 hours, 2 to 6 hours, 2 to 5 hours, or 2 to 4 hours after administration. The formulation can deliver a second immediate-release dose of nicotine 1 to 8 hours, 1 to 7 hours, 1 to 6 hours, 1 to 5 hours, 1 to 4 hours, 1 to 3 hours, 2 to 8 hours, 2 to 7 hours, 2 to 6 hours, 2 to 5 hours, or 2 to 4 hours after administration. The multiparticulate formulation may include a first population of particles coated with a drug layer containing nicotine; and a second population coated with a drug layer containing nicotine and 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 include a polymer, a plasticizer, and an anti-adhesive agent. The polymer, plasticizer, and anti-adhesive agent may be present in a 6:1:3 ratio. The polymer may be Eudragit RS and / or Eudragit RL. The plasticizer may be triethyl citrate. The anti-adhesive agent may be talc. Administration of the multi-particulate formulation can result in a pharmacokinetic profile having a plasma nicotine level of less than about 7.5 ng / ml at about 120 minutes after administration of the dosage form. Administration of the multi-particulate formulation can result in a pharmacokinetic profile having a plasma nicotine level of less than about 7.5 ng / ml at about 180 minutes after administration of the dosage form. The pharmacokinetic profile can have a plasma nicotine level of less than about 5 ng / ml at about 180 minutes after administration. The pharmacokinetic profile can have a plasma nicotine level of less than about 5 ng / ml at about 120 minutes after administration.The pharmacokinetic profile may have a plasma nicotine level of greater than about 5 ng / ml at about 45-90 minutes after administration.The pharmacokinetic profile may have a plasma nicotine level of greater than about 15 ng / ml at about 60 minutes after administration.

[0181] Described herein are formulations and methods relating to the use of formulations comprising nicotine or a salt thereof, wherein administration can result in a pharmacokinetic profile having a plasma nicotine level of less than about 7.5 ng / ml at about 120 minutes after administration of the dosage form. Administration of the dosage form can result in a pharmacokinetic profile having a plasma nicotine level of less than about 7.5 ng / ml at about 180 minutes after administration of the dosage form. The pharmacokinetic profile can have a plasma nicotine level of less than about 5 ng / ml at about 180 minutes after administration. The pharmacokinetic profile can have a plasma nicotine level of less than about 5 ng / ml at about 120 minutes after administration. The pharmacokinetic profile can have a plasma nicotine level of greater than about 5 ng / ml at about 45-90 minutes after administration. The pharmacokinetic profile can have a plasma nicotine level of greater than about 15 ng / ml at about 60 minutes after administration.

[0182] Provided herein are formulations and methods relating to the use of formulations comprising nicotine or a salt thereof. The formulations and methods as described herein can reduce the frequency of falls in subjects at risk of falling. The formulations and methods as described herein can prevent falls. The formulations and methods as described herein can reduce FOG. In some embodiments, the formulations and methods as described herein can reduce fall-related symptoms. In some embodiments, the formulations and methods as described herein reduce the frequency of fall-related complications. In some embodiments, the formulations and methods as described herein reduce the frequency of falls, reduce the frequency of fall-related injuries, reduce the severity of fall-related injuries, improve postural stability, improve static balance, or improve gait. In some embodiments, the formulations and methods as disclosed herein do not result in tolerance or dependence on nicotine or a salt thereof. In some embodiments, the subject has Parkinson's disease (PD) or a PD-related disorder.

[0183] Described herein are formulations and methods relating to the use of formulations comprising nicotine or a salt thereof, wherein administration of nicotine or a salt thereof results in a plasma nicotine level of 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, 25 ng / mL, 26 ng / mL, 27 ng / mL, 28 ng / mL, 29 ng / mL, 30 ng / mL, 31 ng / mL, 32 ng / mL, 33 ng / mL, 34 ng / mL, 35 ng / mL, 36 ng / mL, 37 ng / mL, 38 ng / mL, 39 ng / mL, 40 ng / mL, 41 ng / mL, 42 ng / mL, 43 ng / mL, 44 ng / mL Administration of nicotine or a salt thereof can result in a plasma nicotine level of less 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, or 9.0 ng / mL at a time point after administration. , 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or above 25ng / mL.Administration of nicotine or a salt thereof results in plasma nicotine levels of approximately 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 49 mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 1 It can be 6ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL. Administration of nicotine or a salt thereof can result in plasma nicotine levels in the 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 some time after administration. The subsequent time points after administration were approximately 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 410, 420, 430, 440, 450, 460, 470, 480, 490, 510, 520, 530, 540, 550, 560, 570, 580, 590, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 1000, 1100, 1200, It may be 0 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 a time greater than 600 minutes, or within a range spanning those times.

[0184] In some embodiments, administration of nicotine or a salt thereof results in a peak plasma nicotine level of 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, or , 8.0ng / mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL. Administration of nicotine or a salt thereof results in plasma nicotine levels of approximately 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 49 , 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or above 25ng / mL.Administration of nicotine or a salt thereof results in plasma nicotine levels of approximately 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 49 mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 1 It can be 6ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL. Administration of nicotine or a salt thereof can result in plasma nicotine levels in the 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 some time after administration. The subsequent time points after administration were approximately 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 410, 420, 430, 440, 450, 460, 470, 480, 490, 510, 520, 530, 540, 550, 560, 570, 580, 590, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 1000, 1100, 1200, It may be 0 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 a time greater than 600 minutes, or within a range spanning those times.Following the peak plasma nicotine level, plasma nicotine levels may be at or 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, or 6.0 ng / mL at about 30, 40, 60, 75, 90, 120, 140, 150, 160, 180, 200, 240, 270, 300, 350, 400, 500, 600, or greater than 600 minutes after administration. L, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL or less.

[0185] Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL. Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or above 25ng / mL.Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 The concentration can be 0.0, 1.0, 1.0, 1.5, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 ng / mL. The time point can be less than 25 minutes after administration. The time point can be more than 25 minutes after administration. The time point can be 0-25 minutes, 5-20 minutes, or 10-15 minutes after administration. Following peak plasma nicotine levels approximately 25 minutes after administration, plasma nicotine levels may increase to approximately 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, 6.5 ng / mL, 7.5 ng / mL, 8.5 ng / mL, 9.5 ng / mL, 10.5 ng / mL, 11.5 ng / mL, 12.5 ng / mL, 13.5 ng / mL, 14.5 ng / mL, 15.5 ng / mL, 16.5 ng / mL, 17.5 ng / mL, 18.5 ng / mL, 19.5 ng / mL, 20.5 ng / mL, 21.5 ng / mL, 22.5 ng / mL, 23.5 ng / mL, 24.5 ng / mL, 25.5 ng / mL, 26.5 ng / mL, 27.5 ng / mL, 28.5 ng / mL, 29.5 ng / mL, 30.5 ng / mL, 31.5 ng / mL, 32.5 ng / mL, 33.5 ng / mL, 34.5 ng / mL, 35.5 ng / mL, 36.5 ng / mL, 37.5 ng / mL, 38.5 ng / mL, 39.5 ng / mL, 40.5 ng / mL, 41.5 ng / mL, 42.5 ng / mL, 43.5 ng / mL, 44.5 ng / mL 0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13n g / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL or less.

[0186] Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL. Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or above 25ng / mL.Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 The concentration can be 0.0, 1.0, 1.0, 1.0.5, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 ng / mL. The time point can be less than 60 minutes after administration. The time point can be more than 60 minutes after administration. The time point can be in the range of 0-60 minutes, 5-55 minutes, 10-50 minutes, 15-45 minutes, 20-40 minutes, or 25-30 minutes after administration. Following a peak plasma nicotine level at about 60 minutes after administration, 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, 7.0 ng / mL, 8.0 ng / mL, 9.0 ng / mL, 10.0 ng / mL, 11.0 ng / mL, 12.0 ng / mL, 13.0 ng / mL, 14.0 ng / mL, 15.0 ng / mL, 16.0 ng / mL, 18.0 ng / mL, 20.0 ng / mL, 24.0 ng / mL, 27.0 ng / mL, 30.0 ng / mL, 35.0 ng / mL, 40.0 ng / mL, 45.0 ng / mL, 50.0 ng / mL, 65.0 ng / mL, 75.0 ng / mL, 90.0 ng / mL, 120.0 ng / mL, 140.0 ng / mL, 150.0 ng / mL, 160.0 ng / mL, 180.0 ng / mL, 200.0 ng / mL, 240.0 ng / mL, 270.0 ng / mL, 300.0 ng / mL, 350.0 ng / mL, 400.0 ng / mL, 500.0 ng / mL, 600.0 ng / mL, 750.0 ng / mL, 800 mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL or less.

[0187] Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL. Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or above 25ng / mL.Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 The concentration can be 0.0, 1.0, 1.0, 1.0.5, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5 ng / mL. The time point can be less than 90 minutes after administration. The time point can be more than 90 minutes after administration. The time point can be in the range of 0-90 minutes, 5-85 minutes, 10-80 minutes, 15-75 minutes, 20-70 minutes, 25-65 minutes, 30-60 minutes, 35-55 minutes, or 40-50 minutes. Following peak plasma nicotine levels at about 90 minutes after administration, plasma nicotine levels may reach or exceed 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, or 6.0 ng / mL at about 95 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 after administration. / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL or less.

[0188] Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 / mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL. Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or above 25ng / mL.Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 The concentration can be 120 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 point can be less than 120 minutes after administration. The time point can be more than 120 minutes after administration. The time points may range from 0 to 120 minutes, 5 to 115 minutes, 10 to 110 minutes, 15 to 105 minutes, 20 to 100 minutes, 25 to 95 minutes, 30 to 90 minutes, 35 to 85 minutes, 40 to 75 minutes, 45 to 70 minutes, or 50 to 65 minutes. Following peak plasma nicotine levels at about 120 minutes after administration, plasma nicotine levels may increase to 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, 7.0 ng / mL, 8.0 ng / mL, 9.0 ng / mL, 10.0 ng / mL, 11.0 ng / mL, 12.0 ng / mL, 13.0 ng / mL, 14.0 ng / mL, 15.0 ng / mL, 16.0 ng / mL, 18.0 ng / mL, 20.0 ng / mL, 24.0 ng / mL, 27.0 ng / mL, 30.0 ng / mL, 35.0 ng / mL, 40.0 ng / mL, 50.0 ng / mL, 60.0 ng / mL, 75.0 ng / mL, 80.0 ng / mL, 85.0 ng / mL, 90.0 ng / mL, 95.0 ng / mL, 100.0 ng / mL, 115.0 ng / mL, 120.0 ng / mL, 130.0 ng / mL, 140.0 ng / mL, 150.0 ng / mL, 160.0 ng / mL, 180.0 ng / mL, 200.0 ng / mL, 240.0 ng / mL, 270.0 ng / mL, 300.0 ng / mL, 350. ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, May be less than 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL.

[0189] Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 / mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL. Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or above 25ng / mL.Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 The time point can be 180 minutes or less after administration. The time point can be 180 minutes or more after administration. The time points may range from 0 to 180 minutes, 5 to 175 minutes, 10 to 170 minutes, 15 to 165 minutes, 20 to 160 minutes, 25 to 155 minutes, 30 to 150 minutes, 35 to 145 minutes, 40 to 140 minutes, 45 to 135 minutes, 50 to 130 minutes, 55 to 125 minutes, 60 to 120 minutes, 65 to 115 minutes, 70 to 110 minutes, 75 to 105 minutes, or 80 to 100 minutes. Following a peak plasma nicotine level at about 180 minutes after administration, 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, or greater at about 185 minutes, 200 minutes, 240 minutes, 270 minutes, 300 minutes, 350 minutes, 400 minutes, 500 minutes, 600 minutes, or greater than 600 minutes after administration. g / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL or less.

[0190] Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 / mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL. Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or above 25ng / mL.Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 The time point can be 100 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 point can be less than 240 minutes after administration. The time point can be more than 240 minutes after administration. The time points may range from 0 to 240 minutes, 5 to 220 minutes, 10 to 200 minutes, 15 to 180 minutes, 20 to 170 minutes, 25 to 160 minutes, 30 to 150 minutes, 35 to 145 minutes, 40 to 140 minutes, 45 to 135 minutes, 50 to 130 minutes, 55 to 125 minutes, 60 to 120 minutes, 65 to 115 minutes, 70 to 110 minutes, 75 to 105 minutes, or 80 to 100 minutes. Following peak plasma nicotine levels at about 240 minutes after administration, plasma nicotine levels may range from 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, 8.0 ng / mL, 9.0 ng / mL, 10.0 ng / mL, 11.0 ng / mL, 12.0 ng / mL, 13.0 ng / mL, 14.0 ng / mL, 15.0 ng / mL, 16.0 ng / mL, 17.0 ng / mL, 18.0 ng / mL, 19.0 ng / mL, 20.0 ng / mL, 21.0 ng / mL, 22.0 ng / mL, 23.0 ng / mL, 24.0 ng / mL, 25.0 ng / mL, 26.0 ng / mL, 27.0 ng / mL, 28.0 ng / mL, 29.0 ng / mL, 30.0 ng / mL, 31.0 ng / mL, 32.0 ng / mL, 33.0 ng / mL, 34.0 ng / mL, 35.0 ng / mL, 36.0 ng / mL, 37.0 ng / mL, 38.0 ng / mL, 39.0 ng / mL, 40.0 ng / mL, 41.0 ng / mL, 42.0 ng / mL, 43.0 ng / 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL , 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL or less.

[0191] Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 / mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL. Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or above 25ng / mL.Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 The concentration can be 100 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 point can be less than 300 minutes after administration. The time point can be more than 300 minutes after administration. The time points may range from 0 to 300 minutes, 5 to 280 minutes, 10 to 260 minutes, 15 to 240 minutes, 20 to 220 minutes, 25 to 200 minutes, 30 to 180 minutes, 35 to 160 minutes, 40 to 140 minutes, 45 to 135 minutes, 50 to 130 minutes, 55 to 125 minutes, 60 to 120 minutes, 65 to 115 minutes, 70 to 110 minutes, 75 to 105 minutes, or 80 to 100 minutes. Following peak plasma nicotine levels at approximately 300 minutes after administration, plasma nicotine levels decreased to approximately 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, and 7.0ng / mL at approximately 310, 320, 350, 400, 500, 600, or greater than 600 minutes after administration. 0ng / mL, 7.5ng / mL, 8.0ng / mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, May be less than 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL.

[0192] Administration of nicotine or a salt thereof results in peak plasma nicotine levels of about 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 9.0ng / mL, 10.0ng / mL, 11.0ng / mL, 12.0ng / mL, 13.0ng / mL, 14.0ng / mL, 15.0ng / mL, 16.0ng / mL, 17.0ng / mL, 18.0ng / mL, 19.0ng / mL, 20.0ng / mL, 21.0ng / mL, 22.0ng / mL, 23.0ng / mL, 24.0ng / mL, 25.0ng / mL, 26.0ng / mL, 27.0ng / mL, 28.0ng / mL, 29.0ng / mL, 30.0ng / mL, 31.0ng / mL, 32.0ng / mL, 33.0ng / mL, 34.0ng / mL, 35.0ng / mL, 36.0ng / mL, 37.0ng / mL, 38.0ng / mL, 39.0ng / mL, 40.0ng / mL, 41.0ng / mL, 42.0ng / mL, 43.0ng / mL, 44.0ng / mL, 45.0ng / mL, 46.0ng / mL, 47.0ng / mL, 48.0ng / mL, 4 / mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL. As a result of administration, peak plasma nicotine levels were measured approximately 360 minutes after administration at approximately 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, and 8.5ng / mL. The time point can be greater than 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 point can be less than 360 minutes after administration.As a result of administration, peak plasma nicotine levels were measured approximately 360 minutes after administration at approximately 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, and 8.5ng / mL. The time point can be 0.5 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 point can be less than 360 minutes after administration. The time point can be more than 360 minutes after administration. The time points may range from 0 to 360 minutes, 5 to 320 minutes, 10 to 280 minutes, 15 to 240 minutes, 20 to 200 minutes, 25 to 180 minutes, 30 to 160 minutes, 35 to 150 minutes, 40 to 140 minutes, 45 to 135 minutes, 50 to 130 minutes, 55 to 125 minutes, 60 to 120 minutes, 65 to 115 minutes, 70 to 110 minutes, 75 to 105 minutes, or 80 to 100 minutes. Following peak plasma nicotine levels at approximately 360 minutes after administration, plasma nicotine levels decreased to approximately 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, and 7.0ng / mL at approximately 370, 380, 390, 400, 500, 600, or greater than 600 minutes after administration. 0ng / mL, 7.5ng / mL, 8.0ng / mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, May be less than 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL.

[0193] Provided herein is administration of nicotine or a salt thereof, wherein the plasma nicotine level is a percentage lower than the peak plasma nicotine level at a particular time. The plasma nicotine level 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 the peak plasma nicotine level. The plasma nicotine 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 the peak plasma nicotine level. The plasma nicotine level may be 5%-100%, 10%-95%, 15%-90%, 20%-85%, 25%-80%, 30%-75%, 35%-70%, or 40%-65% lower than the peak plasma nicotine level. The specific time may be 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, It may be 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, or within a range of such times.For example, plasma nicotine levels may be measured at approximately 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, 330 minutes, 340 minutes, 350 minutes, 360 minutes, 370 minutes, 380 minutes, 390 minutes, 400 minutes, 410 minutes, 420 minutes, 430 minutes, 440 minutes, 450 minutes, 460 minutes, 470 minutes, 480 minutes, 490 minutes, 500 minutes, 510 minutes, 520 minutes, 530 minutes, 540 minutes, 550 minutes, 560 minutes, 570 minutes, 580 minutes, 590 minutes, 600 minutes, 610 minutes, 620 minutes, 630 minutes, 640 minutes, 650 minutes, 660 minutes, 670 minutes, 680 minutes, 690 minutes, 700 minutes, 710 minutes, 720 minutes, 730 minutes, 740 minutes, 750 minutes, 760 minutes, 770 minutes, 780 minutes, 790 minutes, 800 minutes, 810 minutes, 820 minutes, It 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 at 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 for times greater than 600 minutes.

[0194] In some embodiments, the plasma nicotine level at a particular time after the peak plasma level is reached is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% lower than the peak plasma nicotine level. In some embodiments, the plasma nicotine level at a particular time after the peak plasma level is reached 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 the peak plasma nicotine level. The plasma nicotine level at a particular time after the peak plasma level is reached may be 5%-100%, 10%-95%, 15%-90%, 20%-85%, 25%-80%, 30%-75%, 35%-70%, or 40%-65% lower than the peak plasma nicotine level, in certain embodiments, the plasma nicotine level 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 the peak plasma nicotine level. The nicotine level at a particular time after administration is about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% lower than the peak plasma nicotine level. The plasma nicotine level at a particular time after administration may be 5%-100%, 10%-95%, 15%-90%, 20%-85%, 25%-80%, 30%-75%, 35%-70%, or 40%-65% lower than the peak plasma nicotine level.Specific times are approximately 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, and 200 minutes after administration. , 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, or may be within a range of such times. For example, plasma nicotine levels may be measured at approximately 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, 330 minutes, 340 minutes, 350 minutes, 360 minutes, 370 minutes, 380 minutes, 390 minutes, 400 minutes, 410 minutes, 420 minutes, 430 minutes, 440 minutes, 450 minutes, 460 minutes, 470 minutes, 480 minutes, 490 minutes, 500 minutes, 510 minutes, 520 minutes, 530 minutes, 540 minutes, 550 minutes, 560 minutes, 570 minutes, 580 minutes, 590 minutes, 600 minutes, 610 minutes, 620 minutes, 630 minutes, 640 minutes, 650 minutes, 660 minutes, 670 minutes, 680 minutes, 690 minutes, 700 minutes, 710 minutes, 720 minutes, 730 minutes, 740 minutes, 750 minutes, 760 minutes, 770 minutes, 780 minutes, 790 minutes, 800 minutes, 810 minutes, 820 minutes, 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 times greater than 600 minutes 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.

[0195] In some embodiments, administration of nicotine or a salt thereof results in a peak plasma nicotine level, and following the peak plasma nicotine level, the plasma nicotine level is at or near 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. less than or greater than 0ng / mL, 7.5ng / mL, 8.0ng / mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL. Administration of nicotine or a salt thereof results in a peak plasma nicotine level, which is followed by plasma nicotine levels of 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, 8.0 ng / mL, 9.0 ng / mL, 10.0 ng / mL, 11.0 ng / mL, 12.0 ng / mL, 13.0 ng / mL, 14.0 ng / mL, 15.0 ng / mL, 16.0 ng / mL, 17.0 ng / mL, 18.0 ng / mL, 19.0 ng / mL, 20.0 ng / mL, 21.0 ng / mL, 22.0 ng / mL, 23.0 ng / mL, 24.0 ng / mL, 25.0 ng / mL, 26.0 ng / mL, 27.0 ng / mL, 28.0 ng / mL, 29.0 ng / mL, 30.0 ng / mL, 31.0 ng / mL, 32.0 ng / mL, 33.0 ng / mL, 34.0 ng / mL, 35.0 ng / mL, 36.0 ng / mL, 37.0 ng / mL, 38.0 ng / mL, 39.0 ng / mL, 40.0 ng / mL, 41.0 ng / mL, 42.0 ng / mL, 43 mL, 7.5ng / mL, 8.0ng / mL, 8.5ng / mL, 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL , 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL.Peak plasma levels were 0.25ng / mL, 0.5ng / mL, 1.0ng / mL, 1.5ng / mL, 2.0ng / mL, 2.5ng / mL, 3.0ng / mL, 3.5ng / mL, 4.0ng / mL, 4.5ng / mL, 5.0ng / mL, 6.0ng / mL, 6.5ng / mL, 7.0ng / mL, 7.5ng / mL, 8.0ng / mL, 8.5ng / mL, and 9.0ng / mL at some point during administration. The subsequent time points after administration may be less than or equal to about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130 minutes after administration. The time may be 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 a time greater than 600 minutes, or within a range of such times.

[0196] In some embodiments, the peak plasma nicotine level varies over time. For example, administration of nicotine or a salt thereof can result in a peak plasma nicotine level greater than 10 ng / mL about 25 to about 50 minutes after administration, followed by a plasma nicotine level less than about 7.5 ng / mL about 180 minutes after administration. Administration of nicotine or a salt thereof can result in a peak plasma nicotine level greater than 7.5 ng / mL about 25 to about 50 minutes after administration, followed by a plasma nicotine level less than about 5 ng / mL about 180 minutes after administration. The peak plasma nicotine level can vary with any peak plasma nicotine level as described herein at any time after administration as described herein.

[0197] In some embodiments, the time from peak plasma nicotine level to baseline is varied, for example, from 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, 210 minutes, 220 minutes, 230 minutes, 240 minutes, 250 minutes, 260 minutes, 270 minutes, 280 minutes, 290 minutes, 300 minutes, 310 minutes, 320 minutes, 330 minutes, 340 minutes, 350 minutes, 360 minutes, 370 minutes, 380 minutes, 390 minutes, 400 minutes, 410 minutes, 420 minutes, 430 minutes, 440 minutes, 450 minutes, 460 minutes, 470 minutes, 480 minutes, 490 minutes, 500 minutes, 510 minutes, 520 minutes, 530 minutes, 540 minutes, 550 minutes, 560 minutes, 570 minutes, 580 minutes, 590 minutes, 600 minutes, 610 minutes, 620 minutes, 630 minutes, 640 minutes, 650 minutes, 660 minutes, 670 minutes, 680 minutes, 690 minutes, 700 minutes, 710 minutes, 720 minutes, 730 minutes, 740 minutes, 75 The baseline nicotine may be less than about 3 ng / mL. Baseline nicotine may be about 0.25ng / mL, 0.50ng / mL, 0.75ng / mL, 1.0ng / mL, 1.25ng / mL, 1.5ng / mL, 1.75ng / mL, 2.0ng / mL, 2.25ng / mL, 2.5ng / mL, 2.75ng / mL, 3.0ng / mL, 3.25ng / mL, 3.5ng / mL, 3.75ng / mL, or 4.0ng / mL. Baseline nicotine may be in the range of 0.1ng / mL to 3.0ng / mL, 0.25ng / mL to 2.75ng / mL, 0.5ng / mL to 2.5ng / mL, 0.75ng / mL to 2.25ng / mL, or 1.0ng / mL to 2ng / mL.

[0198] The time from the first peak plasma nicotine level to the second peak plasma nicotine level can vary. The first peak plasma nicotine level or the second peak plasma nicotine level can 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, 11.0 ng / mL, 11.5 ng / mL, 12.0 ng / mL, 12.5 ng / mL, 13.0 ng / mL, 13.5 ng / mL, 14.0 ng / mL, 14.5 ng / mL, 15.0 ng / mL, 16.0 ng / mL, 16.5 ng / mL, 17.0 ng / mL, 17.5 ng / mL, 18.0 ng / mL, 18.5 ng / mL, 19.0 ng / mL, 20.0 ng / mL, 21.0 ng / mL, 22.0 ng / mL, 23.0 ng / mL, 24.0 ng / mL, 25.0 ng / mL, 26.0 ng / mL, 27.0 ng / mL, 28.0 ng / mL, 29.0 ng / mL, 30.0 ng / mL, 3 It may be less than or greater than 9.0ng / mL, 9.5ng / mL, 10.0ng / mL, 10.5ng / mL, 11ng / mL, 12ng / mL, 13ng / mL, 14ng / mL, 15ng / mL, 16ng / mL, 17ng / mL, 18ng / mL, 19ng / mL, 20ng / mL, 21ng / mL, 22ng / mL, 23ng / mL, 24ng / mL, or 25ng / mL. The time from the first peak plasma nicotine level to the second peak plasma nicotine level is approximately 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, 210 minutes, 220 minutes, 230 minutes, 240 minutes, 250 minutes, 260 minutes, 270 minutes, 280 minutes, 290 minutes, 300 minutes, 310 minutes, 320 minutes, 330 minutes, 340 minutes, 350 minutes, 360 minutes, 370 minutes, 380 minutes, 390 minutes, 410 minutes, 420 minutes, 430 minutes, 440 minutes, 450 minutes, 460 minutes, 470 minutes, 480 minutes, 490 minutes, 500 minutes, 510 minutes, 520 minutes, 530 minutes, 540 minutes, 550 minutes, 560 minutes, 570 minutes, 580 minutes, 590 minutes, 600 minutes, 610 minutes, 620 minutes, 630 minutes, 640 minutes, 650 minutes, 660 minutes, 670 minutes, 680 minutes, 690 minutes, 700 minutes, 710 minutes, 720 minutes, 730 minutes, 740 minutes, 750 minutes, 760 minutes, 77 The time from the first peak plasma nicotine level to the second peak plasma nicotine level may be, or may be a range spanning, 0 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 from the first peak plasma nicotine level to the second peak plasma nicotine level may be at least 180 minutes. The time from the first peak plasma nicotine level to the second peak plasma nicotine level may be at most 600 minutes.

[0199] 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 approximately 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, 25 ng / mL, 26 ng / mL, 27 ng / mL, 28 ng / mL, 29 ng / mL, 30 ng / mL, 31 ng / mL, 32 ng / mL, 33 ng / mL, 34 ng / mL, 35 ng / mL, 36 ng / mL, 37 ng / mL, 38 ng / mL, 39 ng / mL, 40 ng / mL, 41 ng / mL, 42 ng / mL, 43 ng / mL, 44 ng / mL, 45 ng / mL, 46 ng / mL, 47 ng / mL, 48 ng / mL, 49 ng / mL, 50 ng / mL, 51 ng / mL, 52 ng / mL, 53 ng / mL, 54 ng / mL, 55 ng / mL, 56 ng / mL, 57 ng / mL, 58 ng / mL, 59 ng / mL, 60 ng / mL, 61 ng / mL, 62 ng / mL, 63 ng / mL, 64 ng / mL, 65 26ng / mL, 28ng / mL, 30.0ng / mL, 32ng / mL, 34ng / mL, 36ng / mL, 38ng / mL, 40ng / mL, 42ng / mL, 44ng / mL, 46ng / mL, 48ng / mL, 50ng / mL, 52ng / mL, 54ng / mL, 56ng / mL, 58ng / mL, 60ng / mL, 10ng / mL, 20ng / mL, 30ng / mL, 40ng / mL, 50ng / mL, 60ng / mL, 70ng / mL, 80ng / mL, 90ng / mL, 100ng / mL, 160ng / mL, 180ng / mL, 200ng / mL, 220ng / mL, 240ng / mL, 260ng / mL, 280 ng / mL, 300ng / mL, 32ng / mL, 340ng / mL, 360ng / mL, 380ng / mL, 400ng / mL, 420ng / mL, 440ng / mL, 460ng / mL, 480ng / mL, The plasma nicotine concentration can be 500ng / mL, 520ng / mL, 540ng / mL, 560ng / mL, 580ng / mL, 600ng / mL, 640ng / mL, 700ng / mL, 750ng / mL, 800ng / mL, 850ng / mL, 900ng / mL, 1000ng / mL, 1100ng / mL, 1200ng / mL, 1400ng / mL, 1600ng / mL, or less or more than 1600ng / mL. Administration of nicotine or a salt thereof can result in peak plasma nicotine levels in the range of about 10ng / mL to about 50ng / mL. Administration of nicotine or a salt thereof can result in peak plasma nicotine levels in the range of about 10ng / mL to about 1100ng / mL.Administration of nicotine or a salt thereof can result in peak plasma nicotine levels ranging from about 30 ng / mL to about 1200 ng / mL, or from about 30 ng / mL to about 500 ng / mL, at the following time points after administration: about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 410, 420, 430, 440, 450, 460, 470, 480, 490, 510, 520, 530, 540, 550, 560, 570, 580, 590, 610, 620, 630, 640, 650, 660, 670, 680, 690, 710, 720, 730, 740, 750, 760, 770, 780, 790, 810, 820, 830, 840, 850, 860, 870, 880 The time may be 00 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 a time greater than 600 minutes, or within a range spanning those times.

[0200] In some embodiments, the time from peak plasma cotinine level to baseline is varied, for example, from 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, 210 minutes, 220 minutes, 230 minutes, 240 minutes, 250 minutes, 260 minutes, 270 minutes, 280 minutes, 290 minutes, 300 minutes, 310 minutes, 320 minutes, 330 minutes, 340 minutes, 350 minutes, 360 minutes, 370 minutes, 380 minutes, 390 minutes, 400 minutes, 410 minutes, 420 minutes, 430 minutes, 440 minutes, 450 minutes, 460 minutes, 470 minutes, 480 minutes, 490 minutes, 500 minutes, 510 minutes, 520 minutes, 530 minutes, 540 minutes, 550 minutes, 560 minutes, 570 minutes, 580 minutes, 590 minutes, 600 minutes, 610 minutes, 620 minutes, 630 minutes, 640 minutes, 650 minutes, 660 minutes, 670 minutes, 680 minutes, 690 minutes, 700 minutes, 710 minutes, 720 minutes, 730 minutes, 740 minutes, 750 The baseline nicotine may be less than about 1 ng / mL. The 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. The baseline nicotine may be in the range of 0.1 ng / mL to 1.0 ng / mL.

[0201] Pharmaceutical Composition for Oral Administration In some embodiments, the present disclosure provides a pharmaceutical composition for oral administration, comprising a nicotine 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.

[0202] Pharmaceutical compositions of the present disclosure suitable for oral administration can be provided in discrete dosage forms, such as capsules, cachets, tablets, liquids, powders, or aerosol sprays, solutions, suspensions in aqueous or non-aqueous solutions, oil-in-water emulsions, or water-in-oil emulsions, each containing a predetermined amount of the active ingredient in granules. Such dosage forms can be prepared by any of the methods of pharmacy, which typically involve mixing the active ingredient with a carrier. Generally, the compositions are prepared by uniformly and intimately admixing the active ingredient with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired presentation. For example, tablets 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 a powder or granules, optionally mixed with excipients, such as, but not limited to, binders, lubricants, inert diluents, and / or surfactants and dispersants. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0203] The present disclosure also includes anhydrous pharmaceutical compositions and dosage forms containing active ingredients, since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in pharmaceutical techniques as a means of simulating long-term storage to determine characteristics such as the shelf life or stability of a formulation over time. The anhydrous pharmaceutical compositions and dosage forms of the present disclosure can be prepared using anhydrous or low-moisture-containing ingredients and low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms of the present disclosure containing lactose can be manufactured anhydrous if substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous nature. Thus, anhydrous compositions can be packaged using materials known to prevent exposure to water, allowing them to be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils or plastics, unit-dose containers, blister packs, and strip packs.

[0204] The active ingredient can be combined in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a variety of forms depending on the form of preparation desired for administration. In preparing compositions for oral dosage forms, any of the usual pharmaceutical media can be used as a carrier, such as water, glycols, oils, alcohols, flavorings, preservatives, coloring agents, etc., for oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or, in some embodiments that do not use lactose, carriers such as starch, sugars, microcrystalline cellulose, diluents, granules, lubricants, binders, and disintegrants can be used for oral solid preparations. For example, suitable carriers include powders, capsules, and tablets, including solid oral preparations. If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

[0205] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, starches such as corn starch and potato starch, gelatin, natural and synthetic gums, such as acacia, alginates such as sodium alginate and alginic acid, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0206] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0207] Disintegrants can be used in the compositions of the present disclosure to provide tablets that disintegrate when exposed to an aqueous environment. Too much disintegrant can produce tablets that may disintegrate in the bottle. Too little disintegrant can cause disintegration, thereby altering the rate and extent of release of the active ingredient from the dosage form. Therefore, a sufficient amount of disintegrant can be used to form a dosage form of the compounds disclosed herein, without adversely altering the release of the active ingredient by using too little or too much. The amount of disintegrant used can vary based on the type of formulation and dosage form and can be readily discerned by one 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, can be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the present disclosure include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, starches such as potato or tapioca starch, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

[0208] Lubricants that can be used to form the pharmaceutical compositions and dosage forms of the present disclosure include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycols such as polyethylene glycol, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, syloidal silica gel, agglomerated 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.

[0209] When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredients therein can be mixed with emulsifying and / or suspending agents, along with various sweeteners or flavorings, dyes or dyes, and, if desired, diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0210] In various embodiments, the present disclosure provides dosage forms including capsules or tablets containing nicotine or a salt thereof in an amount effective to treat fall-related symptoms in subjects with a neurodegenerative disease, such as Parkinson's disease or a Parkinson's-related disorder. Capsules and tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0211] In various embodiments, the dosage form of the present disclosure is a capsule. In various embodiments, the dosage form is formulated for oral release. In some embodiments, the capsule contains a powder containing nicotine to provide a patient with a first peak release upon administration, and the capsule further contains beads containing nicotine to provide a patient with second, third, and fourth peak release upon administration. The beads can be coated with an immediate-release or delayed-release coating. The 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, the capsule contains a water-swellable matrix to provide a gastroretentive formulation with repeated pulsed release in the stomach. The water-swellable matrix can include polyethylene oxide, hydroxypropyl methylcellulose, and combinations thereof. Pulsatile-release formulations can provide plasma concentrations of nicotine of 1 ng / mL to 20 ng / mL approximately 2 hours after administration of the dopamine agonist.

[0212] In some embodiments, the dosage form is a tablet. In various embodiments, the dosage form is formulated for oral release. Included are tablets comprising at least one coating and a core, wherein the outermost coating comprises nicotine of the first peak, and the core comprises nicotine of the second, third, and fourth peaks. 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.

[0213] In some embodiments, the present disclosure includes a multi-layer tablet comprising an immediate-release layer and a pulsed-release layer. In some embodiments, the immediate-release layer comprises nicotine or a metabolite. In some embodiments, each pulsed-release layer comprises nicotine or a metabolite. In some embodiments, the immediate-release layer and each pulsed-release layer comprise nicotine or a metabolite.

[0214] The tablet core of the dosage form of the present invention may comprise a matrix of drug and water-soluble polymer suitable for pulsatile release upon entry and following the elimination of the tablet from the acidic environment of the stomach and the dissolution of the coating upon entry into the high pH environment of the intestine.

[0215] The tablet cores can be prepared by conventional dry granulation methods without the use of solvents. Typically, enteric coatings are applied using conventional processes known in the art.

[0216] In some embodiments, the dosage form includes an enteric coating comprising an enteric polymer. Suitable enteric polymers include, but are not limited to, methacrylic acid / methacrylic acid ester copolymer, methacrylic acid / acrylic acid ester copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, and polyvinyl acetate phthalate.

[0217] Suitable enteric polymers 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, available from Rohm GmbH under the trademark Eudragit™; cellulose derivatives such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and cellulose acetate trimellitate; and polyvinyl acetate phthalates, such as those available from Colorcon under the trademark SURETERIC®. In some embodiments, the enteric polymer is polyvinyl acetate phthalate.

[0218] 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, cellulose derivatives such as povidone K30, polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, or sodium carboxymethylcellulose; sucrose; xylitol, sorbitol, mannitol, maltose, xylose, glucose, potassium chloride, sodium chloride, polysorbate 80, polyethylene glycol, propylene glycol, sodium citrate, or any combination of the above. Preferably, the pore-forming agent comprises hydroxypropyl methylcellulose.

[0219] The enteric coating composition is preferably designed to ensure adhesion of the coating to the tablet core. Methods for selecting coating compositions to 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, NY; 1989), pp. 266-271, incorporated herein by reference. Additionally, the core can be subcoated before coating with the enteric coating. The subcoat serves to prevent coating defects by filling the pores of the core before coating with the enteric coat. The subcoat can be composed of any of the following film-forming formulations, including Opadry (Colorcon), Opadry II (Colorcon), AMT (Colorcon), and HPMC.

[0220] The enteric coating may be about 10 to about 3% by weight of the dosage form of the present invention. In some cases, the enteric coating may 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.

[0221] In some embodiments, the tablet core of the dosage form of the present disclosure comprises at least one hydrophilic polymer. Suitable hydrophilic polymers include, but are not limited to, hydroxypropyl methylcellulose (hereinafter "HPMC"), hydroxypropyl cellulose, or other water-soluble or swellable polymers such as sodium carboxymethylcellulose, xanthan gum, acacia, tragacanth gum, guar gum, karaya gum, alginate, gelatin, and albumin. The hydrophilic polymer may be present in an amount ranging from about 5 to 95% by weight of the system. In some embodiments, the hydrophilic polymer is selected from the group consisting of cellulose ethers, such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, and mixtures thereof.

[0222] Surfactants that can be used to form pharmaceutical compositions and dosage forms of the present disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof, i.e., a mixture of hydrophilic surfactants can be utilized, a mixture of lipophilic surfactants can be utilized, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be utilized.

[0223] Suitable hydrophilic surfactants typically have an HLB value of at least 10, while suitable lipophilic surfactants typically have an HLB value of about 10 or less. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with low HLB values ​​are more lipophilic or hydrophobic and have greater solubility in oils, while surfactants with high HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions. Hydrophilic surfactants are typically considered to be compounds with 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 with an HLB value of about 10 or less. However, the HLB value of a surfactant is merely a rough guide, typically used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0224] Hydrophilic surfactant can be ionic or nonionic.Suitable ionic surfactant includes but is not limited to alkylammonium salt; fusidate salt; fatty acid derivatives of amino acid, oligopeptide and polypeptide; glyceride derivatives of amino acid, oligopeptide and polypeptide; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and their derivatives; lysophospholipids and their derivatives; carnitine fatty acid ester salt; alkyl sulfate salt; fatty acid salt; sodium docusate; acyl acrylate; monoacetylated and diacetylated tartaric acid esters of monoglycerides and diglycerides; succinylated monoglycerides and diglycerides; citrate esters of monoglycerides and diglycerides; and mixtures thereof.

[0225] Among the above groups, ionic surfactants include, for example, lecithin, lysolecithin, phospholipids, lysophospholipids, and derivatives thereof; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acyl acrylates; monoacetylated and diacetylated tartaric acid esters of mono- and diglycerides; succinylated mono- and diglycerides; citrate esters of mono- and diglycerides; and mixtures thereof.

[0226] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactic acid esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate The ionic forms may be esters of glyceryl stearate, succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citrate esters of mono / diglycerides, cholyl sarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teraceyl sulfate, docusate, lauroylcarnitine, palmitoylcarnitine, myristoylcarnitine, and salts and mixtures thereof.

[0227] Hydrophilic nonionic surfactants include, but are not limited to, alkyl glucosides; alkyl maltosides; alkyl thioglucosides; lauryl macrogol glycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkylphenols; polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid 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 polyols having at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives and analogs thereof; polyoxyethylenated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; hydrophilic transesterification products of polyethylene glycol sorbitan fatty acid esters and polyols having 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.

[0228] Other hydrophilic nonionic surfactants include, but are not limited to, 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, PE G-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Capric / Caprylic Glycerides, PEG-8 Capric / Caprylic Glycerides, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterols, PEG-30 Soybean Sterols, PEG-20 Trioleate, PEG-40 Sorbitan Oleate, PEG-80 Sorbitan Laurate, Polysorbate 20, Polysorbate 80, POE-9 Lauryl Ether, PO Examples of suitable glycerin-based copolymers include E-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG10-100 nonylphenol series, PEG15-100 octylphenol series, and poloxamer.

[0229] Suitable lipophilic surfactants include, by way of example only, fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid 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 monoglycerides and diglycerides, hydrophilic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols, fat-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 hydrophobic transesterification products of polyols with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0230] In one embodiment, the composition may contain a solubilizer to ensure good solubilization and / or dissolution of the compound of the present disclosure and minimize precipitation of the compound of the present disclosure. This may be particularly important for parenteral compositions, such as compositions for injection. Solubilizers may also be added to increase the solubility of hydrophilic drugs and / or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0231] Examples of suitable stabilizers include, but are not limited to, alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrin and cyclodextrin derivatives; ethers of polyethylene glycol 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. , ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyltriethyl citrate, acetyltributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizing agents known in the art, such as dimethylacetamide, dimethylisosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0232] Mixtures of solubilizers may also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, 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.

[0233] The amount of solubilizer that can be included is not particularly limited. The amount of a certain solubilizer may be limited to a biologically acceptable amount, which can be easily determined by one of ordinary skill in the art. In some situations, for example, to maximize drug concentration, it may be advantageous to include an amount of solubilizer that excessively exceeds the biologically acceptable amount, with the excess solubilizer being removed using conventional techniques such as distillation or evaporation before providing the composition to a patient. Thus, when present, the solubilizer may be present 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, such as 5%, 2%, 1%, or less, can also be used. Typically, the solubilizer can be present in an amount of about 1% to about 100% by weight, more typically about 5% to about 25% by weight.

[0234] The composition may further comprise one or more pharmaceutically acceptable additives and excipients, including, but not limited to, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavors, colors, oils, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0235] Additionally, acids or bases can be incorporated into the compositions to facilitate processing, for reasons such as enhancing stability, etc. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, 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 pharmaceutically acceptable acids, 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, and uric acid. 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, an alkali metal, or an alkaline earth metal. Examples include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0236] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, etc. Examples of suitable organic acids include 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, 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, etc.

[0237] Injectable pharmaceutical composition In some embodiments, the present disclosure provides an injectable pharmaceutical composition comprising a nicotine receptor modulator, such as nicotine or a salt thereof, and a pharmaceutical excipient suitable for injection, wherein the components and amounts of the agents in the composition are as described herein.

[0238] Forms in which the novel compositions of the present disclosure can be incorporated into injections for administration include aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0239] Aqueous solutions in physiological saline have also been 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. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin to maintain the required particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.).

[0240] Sterile injectable solution is prepared by incorporating the compound of the present disclosure in the required amount in a suitable solvent containing various other components as listed above, and then sterilizing as needed.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains the basic dispersion medium and other necessary components as listed above.For the sterile powder used to prepare sterile injectable solution, the preferred method of preparation is vacuum drying and freeze-drying technology, which produces a powder of active ingredient in addition to any additional desired components of the solution that has been previously sterile filtered.

[0241] Pharmaceutical Composition for Inhalation Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered via the oral or nasal respiratory route for local or systemic effect. Compositions, preferably in pharmaceutically acceptable solvents, may be nebulized using an inert gas. Nebulized solutions can be inhaled directly from a nebulizing device, or the nebulizing device can be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0242] Other pharmaceutical compositions Pharmaceutical compositions can also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. The preparation of such pharmaceutical compositions is well known in the art. For example, 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, New York, 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 herein by reference in their entireties.

[0243] food In some embodiments, the disclosed pharmaceutical compositions are food compositions comprising a food carrier. In some embodiments, the food compositions comprise about 0.001-1000 mg, 0.01-100 mg, 0.1-200 mg, 3-200 mg, 5-500 mg, 10-100 mg, 10-1000 mg, 50-200 mg, or 100-1000 mg of nicotine or a salt thereof. In some embodiments, the food compositions comprise about 0.001 mg, 0.01 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, 100 mg, 200 mg, 500 mg, 1000 mg, or more of nicotine or a salt thereof. In some embodiments, the food compositions comprise about 0.01-10 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.

[0244] Packaging of the disclosed food compositions can be accomplished by those skilled in the art. Without being bound by any theory, the disclosed food compositions may be packaged as beverages, solid meals, and / or semi-solid meals. In some cases, the disclosed food compositions are packaged as food products, such as in the form of one or more of the following: snack bars, cereal products, bakery products, and dairy products.

[0245] Pharmaceutical ingredients The dosage forms of the present disclosure may also contain diluents such as buffers, ascorbic acid, low molecular weight (less than about 10 residues) polypeptides, proteins, amino acids, carbohydrates including glucose, sucrose, or antioxidants such as dextrin, chelating agents such as EDTA, glutathione, and other stabilizers and excipients. Neutral buffered saline or saline mixed with nonspecific serum albumin are typical suitable diluents. Diluents can be incorporated into the tablet core of the dosage form. The dosage forms of the present invention, preferably the tablet core matrix, optionally contain one or more pharmaceutically acceptable diluents as excipients. Non-limiting examples of suitable diluents include, individually or in combination, lactose, including anhydrous lactose and lactose monohydrate; starch, including directly compressible starch and hydrolyzed starch (e.g., Celutab™ and Emdex™); mannitol; sorbitol; xylitol; dextrose (e.g., Cerelose™ 2000) and dextrose monohydrate; dicalcium phosphate dihydrate; sucrose-based diluents; powdered sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; granular calcium lactate trihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose; cellulose, including microcrystalline cellulose, food-grade sources of amorphous cellulose (e.g., Rexcel™), and powdered cellulose; calcium carbonate; glycine; bentonite; polyvinylpyrrolidone; and the like. Such diluents, when present, comprise from about 5 to about 99% of the total.

[0246] In another embodiment of the present disclosure, a gastric-restricted dosage form of nicotine or its salts is provided. Typical polymers include polyethylene oxide, alkyl-substituted cellulose materials, and combinations thereof, such as high-molecular-weight polyethylene oxide and high-molecular-weight or high-viscosity hydroxypropylmethylcellulose materials. Details regarding an example of this type of dosage form can be found in U.S. Patent No. 5,972,389, WO 9855107 to Shell et al., and U.S. Patent No. 8,192,756, the contents of each of which are incorporated by reference in their entirety.

[0247] In yet another embodiment, a bilayer, trilayer, or quadrilayer tablet releases nicotine or a salt thereof from an active-containing layer to the upper gastrointestinal tract, while the other layers are swelling or floating layers. Details of this dosage can be found in U.S. Patent No. 5,232,704 to Franz et al. This dosage form may be encapsulated by binding insoluble materials, such as those described in U.S. Patent No. 6,120,803 to Wong et al.

[0248] In some embodiments, nicotine is orally administered using an orally disintegrating tablet, such as those disclosed in U.S. Patent Nos. 7,282,217; 7,229,641; 6,368,625; 6,365,182; 6,221,392; and 6,024,981.

[0249] Another embodiment of the present disclosure uses gastric retentive expandable tablets having a matrix composed of polyethylene oxide and hydroxypropyl methylcellulose. Further details can be found in Gusler, et al., "Optimal Polymer Mixtures for Gastric Retentive Tablets," patented U.S. Patent No. 6,723,340, the disclosure of which is incorporated herein by reference.

[0250] Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical industry and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro, ed., 1985). Preservatives, stabilizers, dyes, and other accessory 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.

[0251] Additionally, acids or bases can be incorporated into the compositions to facilitate processing, for reasons such as enhancing stability, etc. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, and magnesium aluminum silicate.

[0252] kit Kits are provided herein, which may include a pharmaceutical composition 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 kit comprises nicotine or a salt thereof. The kit can be used to treat a fall-related symptom in a subject. The kit can be used to treat a cognitive function-related symptom in a subject. The kit can be used to reduce the frequency of falls. The kit can be used to prevent falls. The kit can be used to reduce FOG. The kit can be used to improve 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 can be a neurodegenerative disease. The neurodegenerative disease can be Parkinson's disease. In some embodiments, the pharmaceutical composition is formulated in a dosage form for administration.

[0253] The kit can provide a total daily dose of nicotine or its salt. The total dose of nicotine or its salt may be about 24 mg or less per day. In some embodiments, the total dose of nicotine or its salt may be more than 24 mg per day. The total dose of nicotine or its salt may be 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 less, or more than 48 mg per day. The total dosage of nicotine or its salts may range from about 1 to 24 mg per day, 2 to 22 mg per day, 3 to 20 mg per day, 4 to 18 mg per day, 5 to 16 mg per day, 6 to 14 mg per day, or 8 to 12 mg per day. The total dosage of nicotine or its salts may range from about 8 to 24 mg per day.

[0254] The kit can provide a dosage of nicotine or a salt thereof over a period of time. The kit can provide multiple dosages. The kit can provide 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different dosages of nicotine or a salt thereof. The dosage of nicotine or a salt thereof can be about 1 to about 6 mg. The dosage can 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 dosage can 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 dosage may be at least 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 dosage may be in the range of about 0.1 to about 6 mg. The dosage may be in the range of about 0.1 to about 1 mg, about 0.1 to about 2 mg, about 0.1 to about 2.5 mg, about 0.1 to about 3 mg, about 0.1 to about 3.5 mg, about 0.1 to about 4 mg, about 0.1 to about 4.5 mg, about 0.1 to about 5 mg, or about 0.1 to about 6 mg. The period 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 kit may provide a dosage of nicotine or a salt thereof over a period of time for administration at least once daily. Administration may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more than 12 times per day. Administration may occur 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, a 1 mg dose of nicotine or a salt thereof administered four times daily over a two week period provides a total dose of nicotine or a salt thereof of 56 mg.

[0255] The kit can provide a dosage of nicotine or a salt thereof over a period of time, and the dosage can be titrated upward at treatment intervals. The kit can provide multiple dosages. The kit can provide 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different dosages of nicotine or a salt thereof. The dosage of nicotine or a salt thereof can be about 1 to about 6 mg. The dosage can 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 dosage can 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 dosage may be at least 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 duration 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 kit may provide a dosage of nicotine or a salt thereof over a period of time for administration at least once daily. Administration may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more than 12 times per day. Administration can 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. Dosage can be escalated upward at 2-week treatment intervals. Dosage can be escalated upward at 1-4 week treatment intervals. Dosage can be escalated by 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, or more than 8 weeks.

[0256] The kit can provide a starting dose of nicotine or a salt thereof over a period of time, and the starting dose can be titrated upward to a first escalating dose. The first escalating dose can be 1.5, 1.75, or 2 times greater than the starting dose. The first escalating dose can be 1.5, 2, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 9.0, 9.5, 10, 11, or 12 times greater than the starting dose. In some embodiments, the starting dose is titrated to a second escalating dose. The second escalating dose can be 2.5, 3.0, 3.5, or 4 times greater than the starting dose. The second escalating dose may be 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 9.0, 9.5, 10, 11, or 12 times greater than the starting dose. In some embodiments, the starting dose is escalated to a third escalating dose. The third escalating dose may be 4.5, 5.0, 5.5, 6.0, or 6.5 times greater than the starting dose. The fourth dose may be 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 9.0, 9.5, 10, 11, or 12 times greater than the starting dose. The kit may provide multiple escalating doses from the starting dose. The kit may provide multiple different or non-identical escalating doses from the starting dose. The number of different or unequal escalating doses can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 escalating doses from the starting dose. The escalating doses can also be 1.5, 2, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 9.0, 9.5, 10, 11, or 12 times greater than the starting dose. For example, if the starting dose is 1 mg, a 6-fold greater escalating dose is 6.0 mg.

[0257] Provided herein is a kit comprising a total dose of nicotine or a salt thereof. In some embodiments, the total dose of nicotine or a salt thereof is administered over a period of time. The total dose 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 nicotine or a salt thereof. The period 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 kit may administer nicotine or a salt thereof at least once daily. Administration may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more than 12 times per 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, at a 6 mg dose of nicotine or a salt thereof administered four times daily for a four week period, the kit provides a total dose of 672 mg of nicotine or a salt thereof.

[0258] The kit can provide a dosage of nicotine or a salt thereof that can be administered at least once daily. The dosage of nicotine or a salt thereof can be administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more than 12 times daily. The dosage of nicotine or a salt thereof can be administered about 1, 2, 3, 4, 5, or 6 times daily. The dosage of nicotine or a salt thereof can be administered once daily. The dosage of nicotine or a salt thereof can be administered twice daily. The time between administrations can 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. The time between doses can range from 0 to 24 hours, 1 to 23 hours, 2 to 22 hours, 3 to 21 hours, 4 to 20 hours, 5 to 19 hours, 6 to 18 hours, 7 to 17 hours, 8 to 16 hours, 9 to 15 hours, and 10 to 12 hours. The time between doses can range from about 1 to 6 hours, or about 2 to 6 hours. Doses can be administered 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.

[0259] The kit can provide a dosage form that delivers an immediate release dose of nicotine or a salt thereof, followed by a second immediate release dose about 2-8 hours after administration. The dosage form can deliver an immediate release dose of nicotine or a salt thereof, followed by a second immediate release dose about 1-8 hours, 1-7 hours, 1-6 hours, 1-5 hours, 1-4 hours, 1-3 hours, 2-8 hours, 2-7 hours, 2-6 hours, 2-5 hours, or 2-4 hours after administration. In some embodiments, the second immediate release dose is followed by a third immediate release dose about 8-16 hours after administration. In some embodiments, the third immediate release dose is followed by a fourth immediate release dose about 16-24 hours after administration. The dosage of nicotine or a salt thereof can be about 1 mg to about 6 mg over a period of time. For example, the dosage of nicotine or a salt thereof can be about 1 mg to about 6 mg over a 6-hour period. A dosage may include at least 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.A dosage may include at least 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 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 dosage 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 per day. The dosage of nicotine or a salt thereof may be administered about 1, 2, 3, 4, 5, or 6 times per day. The dosage of nicotine or a salt thereof may be administered once per day. The dosage of nicotine or a salt thereof may be administered twice per day.The time between doses can 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 greater than 12 hours, and can range from 0 to 24 hours, 1 to 23 hours, 2 to 22 hours, 3 to 21 hours, 4 to 20 hours, 5 to 19 hours, 6 to 18 hours, 7 to 17 hours, 8 to 16 hours, 9 to 15 hours, and 10 to 12 hours.

[0260] In some embodiments, the kit provides a nicotine or salt thereof dosage form that delivers one or more immediate-release doses of nicotine or salt thereof over a period of time. The number of immediate-release doses of nicotine or salt thereof can be 1, 2, 3, 5, 6, 7, 8, or more than 8 immediate-release doses. The number of immediate-release doses of nicotine or salt thereof can be in the range of 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 2-8, 2-7, 2-6, 2-5, or 2-4 immediate-release doses. The dosage form can provide an immediate-release dose at about 1-8 hours, 1-7 hours, 1-6 hours, 1-5 hours, 1-4 hours, 1-3 hours, 2-8 hours, 2-7 hours, 2-6 hours, 2-5 hours, or 2-4 hours after administration. The dosage form can provide an immediate-release dose at about 8-16 hours, 8-15 hours, 8-14 hours, or 8-12 hours after administration. The dosage form can provide an immediate release dose about 16 to 24 hours, 16 to 22 hours, 16 to 20 hours, or 16 to 18 hours after administration.

[0261] The kit can provide a dosage form that delivers delayed-release pulses of nicotine or a salt thereof. The delayed-release pulses of nicotine or a salt thereof can be delivered over a period of time. The dosage of nicotine or a salt thereof can be 24 mg or less per day. In some embodiments, the dosage of nicotine or a salt thereof can be more than 24 mg per day. The dosage can include 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. Doses may contain 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 can 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, 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, or within a range of such hours.

[0262] Provided herein is a kit that can be used for long-term treatment. The treatment period can be longer than 12 weeks. The treatment period can 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 longer than 8 years.

[0263] The kit can include a dosage of nicotine or a salt thereof provided as a unit dose. The kit can include one or more unit doses. One or more unit doses can include 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. One or more unit doses can include 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 kit may include 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 kit may include one or more unit doses of nicotine or a salt thereof in different dosages. The multiple different or non-identical dosages may include, but are not limited to, 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12, or more than 12 different or non-identical doses of nicotine or a salt thereof. One or more unit doses may be formulated for oral, intravenous, intraarterial, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, oromucosal, or intraperitoneal administration. One or more unit doses may be formulated for oral, topical, buccal, transdermal, or inhalation administration. One or more unit doses may be formulated for oral administration. One or more unit doses can be formulated as a liquid, gel, semi-liquid, semi-solid, or solid form. One or more unit doses can be formulated as a capsule, cachet, tablet, liquid, or aerosol spray. One or more unit doses can be formulated as a tablet. One or more unit doses can be formulated as a capsule. One or more unit doses can be formulated as a food. One or more unit doses can be formulated as a beverage.One or more unit dosages may be formulated as a dietary supplement.

[0264] The kit may further include instructions for using the kit according to the various methods and techniques described herein. The instructions may relate to the use of a composition as described herein. The instructions may relate to the use of nicotine or a salt thereof. For example, the instructions may relate to a total dose per day, a total dose over a period of time, time between doses, number of doses per day, doses by time of administration, dose escalation, treatment intervals, the instructions relating to a total dose per day, total doses, over a period of time, time between doses, assessment measurements to be taken, or a combination thereof. The instructions may relate to a physician's evaluation of a subject. Subject evaluation may include laboratory tests, analysis of concomitant medications, physical examination, psychiatric evaluation, physical evaluation, electrocardiogram (ECG), vital signs, assessment of impulse control, nicotine withdrawal symptoms, symptom change, Mini-Mental Status Examination, Jay Midi Scale, UDysRS, Hoehn & Yahr Scale, Clinical Global Impression Scale, Patient Global Impression Scale, Lang-Fahn Activities of Daily Living Scale, and Revised Minnesota Nicotine Withdrawal Scale (MNWS-R). Laboratory tests include, but are not limited to, urinalysis, serum cotinine analysis, urinary cotinine analysis, serum nicotine analysis, hematology tests, chemistry tests, and pregnancy tests. Such kits may also include information such as scientific literature, package inserts, clinical trial results, and / or summaries thereof, which demonstrate or establish the activity and / or benefits of the composition and / or describe dosing, administration, side effects, pharmacological interactions, or other information useful to healthcare professionals. Such information may be based on the results of various studies, for example, studies using laboratory animals requiring in vivo models, and studies based on human clinical trials. The kits described herein may be provided, sold, and / or promoted to healthcare providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in some embodiments, be sold directly to consumers. Kits may also include aids for administration of the active agent formulation, such as an inhaler, spray, dispenser (e.g., nasal spray), syringe for injection, or compression packs for capsules, tablets, or suppositories.

[0265] In some embodiments, the subject is evaluated after use of the kit. The subject may be evaluated for a period of at least 1 to 14 months. The subject may be evaluated daily, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, or more. The subject may be evaluated by a physician. The subject may be evaluated to determine an appropriate dosage.

[0266] In some embodiments, the subject is evaluated for one or more parameters after use of the kit. 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 the extremities, tremors, nightmares, or insomnia. Subject evaluations may include laboratory tests, analysis of concomitant medications, physical examination, psychiatric evaluation, physical evaluation, electrocardiogram (ECG), vital signs, assessment of impulse control, nicotine withdrawal symptoms, changes in symptoms, Mini-Mental State Examination, Jay Midi Scale, UDysRS, Hoehn & Yahr Scale, Clinical Global Impression Scale, Patient Global Impression Scale, Lang-Fahn Daily Activities Scale, and Revised Minnesota Nicotine Withdrawal Scale (MNWS-R). Laboratory tests include, but are not limited to, urinalysis, serum cotinine analysis, urine cotinine analysis, serum nicotine analysis, hematology tests, chemistry tests, and pregnancy tests. [Example]

[0267] The following ex...

Claims

1. A pharmaceutical composition for reducing the frequency of falls in a subject, comprising: The pharmaceutical composition comprises nicotine or a salt thereof as an active ingredient, The pharmaceutical composition is administered to the subject in an amount of 8 mg to 24 mg of an active ingredient per day; and The pharmaceutical composition, wherein the subject is a Parkinson's disease patient and is receiving levodopa.

2. The pharmaceutical composition of claim 1, wherein the subject has recurrent falls.

3. The pharmaceutical composition of claim 1 , wherein the subject has experienced at least one fall in the past.

4. 2. The pharmaceutical composition of claim 1, wherein the frequency of falls is assessed using an assessment test selected from the group consisting of the Unified Parkinson's Disease Rating Scale (UPDRS), the Barlow Neurological Institute (BNI) Balance Scale, the Hoehn & Yahr severity classification system, the Romberg test, the rotation test, standing on one leg, stepping, stride length and velocity.

5. 2. The method of claim 1, wherein the frequency of falls is assessed using the upright test of the BNI balance scale.

6. 3. The pharmaceutical composition of claim 2, wherein the subject with recurrent falls takes less than 3 seconds to stand on the upright test of the BNI Balance Scale.

7. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered orally, intravenously, intraarterially, parenterally, bucally, topically, transdermally, rectally, intramuscularly, subcutaneously, intraosseously, buccally, by inhalation, or intraperitoneally.

8. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is administered orally.

9. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated as a unit dosage.

10. 10. The pharmaceutical composition of claim 9, wherein the unit dosage is in liquid, gel, semi-liquid, semi-solid, or solid form.

11. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated in a tablet or capsule.

12. 10. The pharmaceutical composition of claim 9, wherein the unit dosage is formulated as a food, beverage, or dietary supplement.

13. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a dosage form that, when administered, results in a pharmacokinetic profile having a plasma nicotine level of less than 7.5 ng / mL at 120 minutes after administration of the pharmaceutical composition.

14. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a dosage form that, when administered, results in a pharmacokinetic profile having a plasma nicotine level of less than 7.5 ng / mL at 180 minutes after administration of the pharmaceutical composition.

15. 15. The pharmaceutical composition of claim 14, wherein the pharmacokinetic profile has a plasma nicotine level of less than 5 ng / mL 180 minutes after administration.

16. 14. The pharmaceutical composition of claim 13, wherein the pharmacokinetic profile has a plasma nicotine level of less than 5 ng / mL 120 minutes after administration.

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