WO2019071270A1

WO2019071270A1 - Pharmaceutical compositions

Info

Publication number: WO2019071270A1
Application number: PCT/US2018/055013
Authority: WO
Inventors: Gopi Venkatesh; Nicole A. Beinborn; Michael A. Gosselin; Jin-Wang Lai; Michelle Schilling
Original assignee: Adare Pharmaceuticals, Inc.
Priority date: 2017-10-06
Filing date: 2018-10-09
Publication date: 2019-04-11

Abstract

The disclosure is directed to pharmaceutical compositions of Zaleplon or a pharmaceutically acceptable salt thereof comprising at least two (e.g. two or three) components: an immediate release Zaleplon-containing component and one or more timed, drug release (TDR) Zaleplon-containing components. The pharmaceutical compositions induce sleep within about 30 minutes and maintain sleep over about 7-8 hours, while avoiding significant next-day side-effects. If the subject wakes in the middle of the night, the composition promotes the ability to fall back to sleep and continue to sleep throughout the night.

Description

PHARMACEUTICAL COMPOSITIONS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 62/568,990, filed on October 6, 2017, and U.S. Provisional Application No. 62/592,161, filed on November 29, 2017, the entire contents of each of which are hereby incorporated by reference in its entirety.

FIELD OF THE DISCLOSURE

[0002] The present disclosure relates to a pharmaceutical composition of Zaleplon or a pharmaceutically acceptable salt thereof for oral administration.

BACKGROUND

[0003] Sleep is a complex physiological process that has been linked to the function of every organ system, and dysregulation of sleep has important consequences for health and well-being. Sleep is controlled by two biological processes, the homeostatic and circadian. The homeostatic drive manifests itself as an increased drive for sleep. This drive for sleep accumulates across the period of wakefulness (typically daytime) and dissipates across the sleep period. The circadian rhythm of sleep-wake shows a biphasic curve with the greatest drive for sleep occurring between midnight and 5AM in the morning, and between 2PM and 4PM in the afternoon. It is the interaction of these two processes which give rise to the 24-hour sleep cycle. For individuals with a usual sleep period of 11PM to 7AM, sleep onset in the evening occurs primarily as a function of homeostatic drive. After about four hours of sleep (about 3AM) homeostatic drive dissipates significantly and wakefulness begins to intrude into the sleep period. This propensity to increased wakefulness is further increased by the rise in the circadian alerting pulse at about 5AM. Certain medical disorders, such as insomnia, are associated with abnormalities in these rhythms.

[0004] Insomnia is a common sleep disorder with potentially serious economic, health and quality of life ramifications if left untreated. It is characterized by symptoms of difficulty falling asleep, difficulty staying asleep, waking too early or poor quality or non-restorative sleep. Specific medical conditions associated with insomnia include coronary artery disease, hypertension and musculoskeletal problems. Consequences of insomnia can include increased risk of depression, poor memory, reduced concentration, and poor work performance. Insomnia has been associated with poor general health, greater healthcare utilization, lower quality of life, lower socioeconomic status, and poorer social relationships, mood, and cognitive function.

[0005] Zaleplon, in the branded product SONATA^® (immediate release tablets), is a commercially available non-benzodiazepine agent administered for the treatment of insomnia. Although Zaleplon has poor aqueous solubility, it is rapidly and completely absorbed following oral administration. Zaleplon undergoes extensive first pass hepatic metabolism after absorption, with only 30% of Zaleplon being systemically available, and has a time to peak concentration (Tmax) of approximately 1 hour and a terminal-phase elimination half-life (ti/₂) of approximately 1 hour. Cmax and area under the plasma concentration-time curve (AUC) both exhibit linear dose proportionality at doses up to 60 mg. After multiple dosing at 15 and 30 mg Zaleplon for 10 days, AUC and ti/₂ are similar on day 1 and day 10, indicating no accumulation of the drug.

[0006] Because of the short elimination half-life of Zaleplon, blood plasma levels may fall below levels necessary to promote sleep a few hours after administration when the homeostatic drive dissipates significantly and wakefulness begins to intrude into the sleep period. Thus, patients with a sleep disorder characterized by difficulty staying asleep, waking too early, or poor quality or non-restorative sleep do not fully benefit from Zaleplon. Further, repeat administration of Zaleplon during a sleep period results in higher blood plasma levels which cause next-day side effects, such as somnolence, dizziness, and impaired motor function, memory and reaction time.

[0007] Thus, there is a need for pharmaceutical compositions of Zaleplon which can achieve rapid sleep induction in patients, typically in about 30 minutes following administration, mitigate middle of the night (MOTN) awakening and/or induce sleep if awakening occurs after sleep induction (and thereby maintaining sleep over about 7 hours), while limiting next-day side-effects, such as somnolence, dizziness, and impaired motor function, memory and reaction time.

[0008] The present disclosure achieves these objectives using a multicomponent pharmaceutical composition of Zaleplon or a pharmaceutically acceptable salt thereof. SUMMARY

[0009] The disclosure is directed to an oral pharmaceutical composition of Zaleplon or a pharmaceutically acceptable salt thereof, wherein the composition comprises a combination of different drug-containing components for multiphasic (e.g. biphasic or triphasic) pulsatile delivery of the drug. The components induce sleep within about 30 minutes following oral administration and maintain sleep over about 7 hours, whilst ensuring that the plasma concentration level of Zaleplon substantially tapers off after about 7-8 hours to a level that significantly mitigates next day hangover effects. In some embodiments, the pharmaceutical composition comprises at least two populations (e.g. two or three) of drug-containing particles with an immediate release component to induce sleep and at least one extended-release component (TDR) to enhance sleep maintenance.

[0010] In some embodiments, the disclosure provides for an oral pharmaceutical composition of Zaleplon or a pharmaceutically acceptable salt thereof, comprising IR drug-containing particles in combination with a single population of TDR drug-containing particles, wherein the release of Zaleplon from the TDR particles is delayed by about 2-3 hours or longer, following oral administration.

[0011] In other embodiments, the disclosure provides for an oral pharmaceutical composition of Zaleplon or a pharmaceutically acceptable salt thereof, comprising IR drug-containing particles in combination with two populations of TDR drug-containing particle - a first TDR population providing a delayed release of drug by about 2 hours following oral administration, and a second TDR population providing a delayed release of drug by about 3 to about 5 hours following oral administration.

[0012] Thus, in various embodiments, the disclosure provides for an oral pharmaceutical composition comprising at least two different populations of particles, where the first population of particles are IR particles comprising Zaleplon or a pharmaceutically acceptable salt thereof, and the second population of particles are TDR particles comprising the sedative-hypnotic compound Zaleplon or a pharmaceutically acceptable salt thereof, wherein following administration of the said composition to a patient, the composition achieves in the patient: a. a time to a first maximum plasma concentration (Tmaxi) of Zaleplon of about one hour following administration;

b. a time to a second maximum plasma concentration (Tmax₂) of Zaleplon of about three to about five hours following administration, wherein the plasma concentration of Zaleplon at Tmax₂ is from about 50% to about 95% of the plasma concentration at Tmaxi; and

c. a plasma concentration of Zaleplon at eight hours following administration of no more than about 25% of the plasma concentration at Tmaxi.

[0013] In some embodiments, the pharmaceutical composition disclosed herein further comprises a second population of TDR particles comprising Zaleplon, or a pharmaceutically acceptable salt thereof. In some such embodiments, the second population of TDR particles provides a time to a third maximum plasma concentration (Tmax₃) of Zaleplon of about 6-7 hours following administration. The plasma concentration of Zaleplon at T_max3 is for example from about 50% to about 70%) of the plasma concentration at Tmaxi.

[0014] The pharmaceutical compositions disclosed herein are formulated to induce sleep onset within about 30 minutes (via IR particles), maintain sufficient drug in the patient to avoid MOTN awakening, or if awakened induce the patient to go back to sleep, and maintain sleep for about 7 hours (via TDR particles), whilst limiting the overall amount of drug administered and the amount present in the patient in the morning in a release profile tailored to significantly mitigate next day hangover effects.

[0015] In some embodiments, the present disclosure provides pharmaceutical compositions comprising Zaleplon or an acceptable salt thereof, wherein the pharmaceutical compositions comprise:

a. an immediate release component comprising about 25% to about 90% of the total amount of Zaleplon in the pharmaceutical composition; and

b. at least one timed drug release (TDR) component comprising about 10% to about 75% of the total amount of Zaleplon in the pharmaceutical composition,

wherein the pharmaceutical composition provides therapeutically effective plasma concentrations of Zaleplon for up to about 8 hours and reduces next-day side effects in a subject. In some embodiments, the TDR component has a lag time within the range of from about 2 to about 4 hours as measured using a standard USP Apparatus 1 (Baskets at 100 rpm) or 2 (Paddles at 50/75 rpm) and a two-stage dissolution media (700 mL of 0.1N HCl at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer). In some embodiments, a) the immediate release component comprises about 40-60% (e.g., about 50%) of the total amount of Zaleplon in the pharmaceutical composition; and b) the timed drug release (TDR) component comprises about 40-60% (e.g., about 50%) of the total amount of Zaleplon in the pharmaceutical composition. In some embodiments, a) the immediate release component comprises about 65% to about 85% (about 75%) of the total amount of Zaleplon in the pharmaceutical composition; and b) the timed drug release (TDR) component comprises about 15% to about 35% (about 25%) of the total amount of Zaleplon in the pharmaceutical composition. In some embodiments, about 30% to about 60% of Zaleplon is released within about 3 hours and not less than about 85% of Zaleplon is released after about 5 hours as measured using a standard USP Apparatus 1 (Baskets at 100 rpm) or 2 (Paddles at 50/75 rpm) and a two-stage dissolution media (700 mL of 0.1N HCl at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer). In some embodiments, about 65% to about 85% of Zaleplon is released within about 30 minutes and not less than about 85% of Zaleplon is released after about 5 hours as measured using a standard USP Apparatus 1 (Baskets at 100 rpm) or 2 (Paddles at 50/75 rpm) and a two-stage dissolution media (700 mL of 0.1N HCl at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer).

[0016] In some embodiments, the total dose of Zaleplon is in the range of from about 5 mg to about 50 mg. For example, in some embodiments, the total dose of Zaleplon is in the range of from about 10 mg to about 20 mg.

[0017] In some embodiments, the present disclosure provides a pharmaceutical composition formulated to achieve an average maximum plasma concentration (Cmax) no more than about 50 ng/mL following oral administration of about 10 to about 20 mg Zaleplon. In some embodiments, the present disclosure provides a pharmaceutical composition formulated to maintain an average minimum plasma concentration (Cmin) of at least about 1 ng/mL for up to about 8 following oral administration of about 10 to about 20 mg Zaleplon. In some embodiments, the present disclosure provides a pharmaceutical composition formulated to maintain blood plasma concentration of Zaleplon within the range of 1 ng/mL to about 50 ng/mL for up to about 8 hours following oral administration of about 10 to about 20 mg Zaleplon. In some embodiments, the present disclosure provides a pharmaceutical composition formulated to provide a first average maximum plasma concentration (Cmaxi) of Zaleplon within about 80% to about 125% of the range of from about 6.0 ng/mL to about 50.0 ng/mL after oral administration of from about 10 to about 20 mg Zaleplon.

[0018] In some embodiments, the Cmaxi is within 80%> to about 125%) of the range of from about 12 ng/mL to about 45 ng/mL after oral administration of about 20 mg of Zaleplon. In some embodiments, the Cmaxi is within about 80%> to about 125%) of the range of from about 6 ng/mL to about 21 ng/mL after oral administration is of 10 mg Zaleplon. In some embodiments, the pharmaceutical compositions of the present disclosure are formulated to provide a second average maximum plasma concentration (Cmax₂) of Zaleplon which is about 25% to about 95% of Cmaxi. In some embodiments, the pharmaceutical compositions of the present disclosure are formulated to provide a second average Cmax₂ within about 80%> to about 125% of the range of from about 1 ng/mL to about 20 ng/mL after oral administration of from about 10 to about 20 mg Zaleplon. In some embodiments, the Cmax₂ of Zaleplon is within about 80%> to about 125% of the range of about 2 ng/mL to about 10 ng/mL after oral administration of about 20 mg of Zaleplon. In some embodiments, the Cmax₂ of Zaleplon is within about 80% to about 125% of about 1 ng/mL to about 5 ng/mL after oral administration of about 10 mg of Zaleplon.

[0019] In some embodiments, the present disclosure provides a pharmaceutical formulation which is formulated to provide an average plasma concentration of Zaleplon at a time point from about 7 hours to about 9 hours after oral administration that is about 10% to about 60% of the Cmaxi. In some embodiments, the present disclosure provides a pharmaceutical formulation which is formulated to provide the average plasma concentration of Zaleplon at the time point from about 7 hours to about 9 hours after oral administration that is about 20 % to about 30% of the Cmaxi. In some embodiments, the present disclosure provides a pharmaceutical formulation which is formulated to provide an average plasma concentration of Zaleplon at a time point from about 5 hours to about 6 hours after oral administration which is about 30% to about 60% of the Cmaxi. In some embodiments, the present disclosure provides a pharmaceutical formulation which is formulated to provide a plasma concentration of Zaleplon at a time point from about 7 hours to about 9 hours after oral administration that is within the range of about 1 ng/mL to about 6 ng/mL.

[0020] In some embodiments, the present disclosure provides a pharmaceutical formulation which is formulated to provide an area under the plasma concentration-time curve from dosing to the last observed concentration (AUCo-t) of Zaleplon within about 80% to about 125% of the range of from about 20 h*ng/mL to about 125 h*ng/mL after oral administration of from about 10 to about 20 mg Zaleplon. In some embodiments, the present disclosure provides a pharmaceutical formulation which is formulated to provide an AUCo-t of Zaleplon within about 80% to about 125% of the range of from about 45 h*ng/mL to about 110 h*ng/mL after oral administration of about 20 mg Zaleplon. In some embodiments, the present disclosure provides a pharmaceutical formulation which is formulated to provide AUCo-t of Zaleplon within about 80% to about 125% of the range of from about 25 h*ng/mL to about 55 h*ng/mL following oral administration of about 10 mg Zaleplon. In some embodiments, the present disclosure provides a pharmaceutical formulation which is formulated to provide an area under the plasma concentration-time curve from dosing to 4h (AUC0-4) of Zaleplon within about 80% to about 125% of the range of from about 5 h*ng/mL to about 60 h*ng/mL following oral administration of from about 10 mg to about 20 mg Zaleplon. In some embodiments, the present disclosure provides a pharmaceutical formulation which is formulated to provide an AUC0-4 of Zaleplon within the range of about 80% to about 125% of about 18 h*ng/mL to about 54 h*ng/mL after oral administration of about 20 mg Zaleplon. In some embodiments, the present disclosure provides a pharmaceutical formulation which is formulated to provide an AUC0-4 of Zaleplon within about 80% to about 125% of the range of from about 9 h*ng/mL to about 27 h*ng/mL after oral administration of about 10 mg Zaleplon. In some embodiments, the present disclosure provides a pharmaceutical formulation which is formulated to provide an area under the plasma concentration-time curve from 4h to 8h post-dosing (AUC4-8) of Zaleplon within about 80% to about 125% of the range of from about 5 h*ng/mL to about 45 h*ng/mL after oral administration of from about 10 mg to about 20 mg Zaleplon. In some embodiments, the present disclosure provides a pharmaceutical formulation which is formulated to provide an AUC4-8 of Zaleplon within the range of about 80% to about 125% of about 13 h*ng/mL to about 41 h*ng/mL after oral administration of about 20 mg Zaleplon. In some embodiments, the present disclosure provides a pharmaceutical formulation which is formulated to provide an AUC4-8 of Zaleplon within about 80% to about 125% of the range of from about 7 h*ng/mL to about 21 h*ng/mL after oral administration of about 10 mg Zaleplon.

[0021] In some embodiments, the present disclosure provides a pharmaceutical formulation wherein the average time to Cmaxi (Tmaxi) is within the range of about 80% to about 125% of about 1 hours to about 2 hours after oral administration. In some embodiments, the average time to Cmax2 (Tmax2) of Zaleplon is within the range of about 80% to about 125% of about 3 hours to about 6 hours.

[0022] In some embodiments, the present disclosure provides a pharmaceutical formulation wherein the TDR component release at least about 90% of the Zaleplon in the TDR component over a period of from about 1 hour to about 3 hours following the lag time. In some embodiments, the IR component comprises about 65-85%> of the total amount of Zaleplon and the TDR component comprises about 15-35%) of the total amount of Zaleplon. In some embodiments, the IR component comprises about 15 mg Zaleplon, and the TDR component comprises about 5 mg Zaleplon. In some embodiments, the IR component comprises about 7.5 mg Zaleplon, and the TDR component comprises about 2.5 mg Zaleplon. In some embodiments, the IR component comprises about 40-60%> of the total amount of Zaleplon and the TDR component comprises about 40-60%) of the total amount of Zaleplon. In some embodiments, the IR component comprises about 10 mg Zaleplon, and the TDR component comprises 10 mg Zaleplon.

[0023] In some embodiments, the present disclosure provides a pharmaceutical formulation wherein the immediate release component and the TDR component are each in the form of particles. In some embodiments, the present disclosure provides a pharmaceutical formulation wherein the immediate release particles comprise:

i. beads comprising Zaleplon present as a layer onto an inert core; or

ii. mini -tablets comprising Zaleplon and one or more pharmaceutically acceptable excipients; or

iii. a powder blend comprising Zaleplon present as an admixture with one or more pharmaceutically acceptable excipients.

In some embodiments, the TDR particles are delayed release particles or acid resistant delayed release particles (DR). In some embodiments, the delayed release particles comprise a coating comprising an enteric polymer selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, methacrylic acid/methylmethacrylate copolymers, and mixtures thereof. In some embodiments, the acid resistant delayed release particles comprise a coating comprising one or more enteric polymers selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, methacrylic acid/methylmethacrylate copolymers and mixtures thereof. In some embodiments, the TDR particles are TPR particles. In some embodiments, the TPR particles have a coating comprising one or more enteric polymers in combination with one or more water-insoluble polymers. In some embodiments, the one or more enteric polymers are selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, methacrylic acid/methylmethacrylate copolymers, and mixtures thereof. In some embodiments, the one or more water-insoluble polymer is selected from the group consisting of cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, ethylcellulose, pH-insensitive ethyl aery late-methyl methacrylate copolymers; and mixtures thereof.

[0024] In some embodiments, the present disclosure provides a pharmaceutical composition, wherein about 30% to about 70% of the total amount of Zaleplon is released within about 3 hours and not less than about 85% of the total amount of Zaleplon is released within about 5 hours when the oral pharmaceutical composition is tested using a standard USP Apparatus 1 (Baskets at 100 rpm) or 2 (Paddles at 50/75 rpm) and a two-stage dissolution media (700 mL of 0.1N HCl at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer). In some embodiments, about 65% to about 75% of the total amount of Zaleplon is released within about 30 minutes, and not less than 85% of the total amount of Zaleplon is released within about 5 hours when tested using a standard USP Apparatus 1 (Baskets at 100 rpm) or 2 (Paddles at 50/75 rpm) and a two- stage dissolution media (700 mL of 0.1N HCl at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer).

[0025] In some embodiments, pharmaceutical composition is in the form of a capsule.

[0026] In some embodiments, the present disclosure provides a method of treating insomnia, comprising administering the pharmaceutical composition of the present disclosure to a patient in need thereof. In some embodiments, the pharmaceutical composition induces sleep in the patient within about 30 minutes after the administration. In some embodiments, the pharmaceutical composition provides sleep maintenance for up to about 8 hours. In some embodiments, the pharmaceutical composition mitigates one or more next day side effects selected from hangover, somnolence, dizziness, impaired motor function, memory and reaction time.

[0027] In some embodiments, the subject's reduction in next-day side effects is characterized by one or more of the following pharmacodynamic assessments: In some embodiments, the subject's reduction in next-day side effects is characterized by one or more of the following tests: Bond- Lader Self-Rated Alertness Factor; Bond-Lader Self-Rated Contentment Factor; Bond-Lader Self- Rated Calmness Factor; Karolinska Sleepiness Scale; Simple Reaction Time; WAIS-IV Digit Symbol Substitution Test; Choice Reaction Time; Tracking; Numeric Working Memory; Profile of Mood States; Body Sway; Digit Vigilence Speed; or Power of Attention. In some embodiments, the subject's reduction in next-day side effects is at least characterized by the Bond-Lader Self- Rated Alertness Factor, wherein the subject is alert 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition. In some embodiments, the subject's reduction in next-day side effects is at least characterized by the Bond-Lader Self-Rated Contentness Factor, wherein the subject is content 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition. In some embodiments, the subject's reduction in next-day side effects is at least characterized by the Bond-Lader Self-Rated Alertness Factor, wherein the subject is alert 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition. In some embodiments, the subject's reduction in next-day side effects is at least characterized by the Bond-Lader Self-Rated Contentness Factor, wherein the subject is content 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition. In some embodiments, the subject's reduction in next-day side effects is at least characterized by the Bond-Lader Self-Rated Calmness Factor, wherein the subject is calm 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition. In some embodiments, the subject's reduction in next-day side effects is at least characterized by the Karolinska Sleepiness Scale, wherein the subject has a KSS value of 1-8 at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition. In some embodiments, the subject's reduction in next-day side effects is at least characterized by Simple Reaction Time, wherein the subject has Mean Simple Reaction Time is from about 100 - about 1000 ms at 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition. In some embodiments, the subject's reduction in next-day side effects is at least characterized by the WAIS-IV Digit Symbol Substitution Test, wherein the subject scores at least 50 at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition. In some embodiments, the subject's reduction in next-day side effects is at least characterized by Choice Reaction Time, wherein the subject's Mean Choice Reaction Time is from about 100 - about 1000 ms at 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition. In some embodiments, the subject's reduction in next-day side effects is at least characterized by Tracking, wherein a subject's tracking average distance may be about 0.5 mm to about 50 mm at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition. In some embodiments, the subject's reduction in next-day side effects is at least characterized by Numeric Working Memory, wherein the Mean Numeric Working Memory Speed of Correct Responses is from about 100 - about 1000 ms at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition. In some embodiments, the subject's reduction in next-day side effects is at least characterized by Profile of Mood States (POMS). In some embodiments, the subject is not depressed as measured by POMS at 6, 7, 8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition. In some embodiments, the subject is not angry as measured by POMS at 6, 7, 8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition. In some embodiments, the subject is not fatigued as measured by POMS at 6, 7, 8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition. In some embodiments, the subject is not confused as measured by POMS at 6, 7, 8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition. In some embodiments, the subject has vigour as measured by POMS at 6, 7, 8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition. In some embodiments, the subject's reduction in next-day side effects is at least characterized by Digit Vigilence Speed, wherein the target detection speed is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition. In some embodiments, the subject's reduction in next-day side effects is at least characterized by a two point decrease in Karolinska Sleepiness Scale score relative to prior to treatment. In some embodiments, the subject's reduction in next-day side effects is at least characterized by a maximum increase in standard deviation of lateral position (SDLP) of about 4.4 cm.

[0028] In some embodiments, the present disclosure provides for the use of Zaleplon for treating insomnia, comprising administering a pharmaceutical composition according to the present disclosure. In some embodiments, the pharmaceutical composition induces sleep in the patient within about 30 minutes after the administration. In some embodiments, the pharmaceutical composition provides sleep maintenance for up to about 8 hours. In some embodiments, the pharmaceutical composition mitigates one or more next day side effects selected from hangover, somnolence, dizziness, impaired motor function, memory and reaction time. In some embodiments, the mitigation of next day side effects is characterized according to pharmacodynamics endpoints as described in the present disclosure. BRIEF DESCRIPTIONS OF THE FIGURES

[0029] In the following, the in vitro dissolution data from Figures 1 to 7 and the PK profile data from Figures 1 to 13 are simulated/projected data points. In vitro dissolution may be tested using conventional means, such as a standard USP Apparatus 1 (Baskets at 100 rpm) or 2 (Paddles at 50/75 rpm) and a two-stage dissolution media (700 mL of 0.1N HC1 at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer) and HPLC methodology for quantification.

[0030] FIG. 1 shows the PK profile (i.e. plasma concentration) upon oral administration to a patient of a single 10 mg Zaleplon IR dose using GASTROPLUS™ software and compared to actual plasma concentration data generated by Greenblatt et al. (1998) and Rosen et al. (1999).

[0031] FIG. 2 A shows the in vitro release profiles of compositions of the invention containing IR particles (e.g. beads, mini-tablets or powder mix) together with a single population of TDR particles (e.g. beads or mini-tablets) in two different presentations to provide (i) a lag time of about 2 hours, followed by complete Zaleplon release in about an hour and (ii) a lag time of about 3 hours, followed by complete Zaleplon release in about an hour.

[0032] FIG. 2 B shows the corresponding plasma concentration-time profiles.

[0033] FIG. 3 A shows the in vitro release profiles of compositions of the invention containing IR particles (e.g. beads, mini-tablets or powder mix) together with a single population of TDR particles (e.g. beads or mini-tablets) in four different presentations to provide (i) a lag time of about 2 hours, followed by complete Zaleplon release in about an hour, (ii) a lag time of about 2 hours, followed by complete Zaleplon release in about 3 hours, (iii) a lag time of about 3 hours, followed by complete Zaleplon release in about an hour, and (iv) a lag time of about 3 hours, followed by complete Zaleplon release in pseudo-zero order in about 3 hours.

[0034] FIG. 3 B shows the corresponding plasma concentration-time profiles.

[0035] The dotted line in FIG. 3 A and B projects a possible scenario where, due to inter-subject variability or otherwise, the target lag-time of 2 hours extends to up to 3 hours and/or the release rate in the 2 to 3 hours following the lag-time may more closely resemble a pseudo-zero order release rather than a pulsed release. As shown in FIG. 3 B, such a scenario can lead to mean plasma concentration-time profile around the trough (Tmin of about 3 hours) that is below 6 ng/mL, which is considered to be "no effect" plasma concentration level (i.e., neither therapeutically effective nor capable of inducing next-day side effects).

[0036] FIG. 4 A shows the in vitro release profiles of compositions of the invention containing IR particles (e.g. beads, mini-tablets or powder mix) together with two populations of TDR particles (e.g. beads or mini-tablets) having (i) a lag time of about 2 hours, followed by complete Zaleplon release in about an hour (TDRl) and (ii) a lag time of about 4 hours, followed by complete Zaleplon release in about 2 hours (TDR2), at a weight ratio of 10:4:6 (IR:TDR1 :TDR2).

[0037] FIG. 4 B shows the corresponding plasma concentration-time profiles.

[0038] FIG. 5 A shows the in vitro release profiles of compositions of the invention containing IR particles (e.g. beads, mini-tablets or powder mix) together with two populations of TDR particles (e.g. beads or mini-tablets) having (i) a lag time of 2 or 2.5 or 3 hours, followed by complete Zaleplon release in about 2 hours (TDRl) and (ii) a lag time of about 4 hours, followed by complete Zaleplon release in about 2 hours (TDR2), at a weight ratio of 10:4:6 (IR : TDR 1 : TDR2) .

[0039] FIG. 5 B shows the corresponding plasma concentration-time profiles and, in particular, the effect of different lag times (2, 2.5 or 3 hours) on the second trough, Tmin₂. The plasma concentration level of Zaleplon at Tmin₂ should still be sufficient to mitigate MOTN awakening from sleep.

[0040] FIG. 6 A shows the in vitro release profiles of compositions of the invention containing IR particles (e.g. beads, mini-tablets or powder mix) together with two populations of TDR particles (e.g. beads or mini-tablets) having (i) a lag time of about 2 hours, followed by complete Zaleplon release in about 2 hours (TDRl) and (ii) a lag time of about 4 hours, followed by complete Zaleplon release in about 2 hours (TDR2), at a weight ratio of 10:4:6 (IR:TDR1 :TDR2), where TDRl provides a rapid pulse Zaleplon delivery (solid line) or a pseudo-zero order drug release over a period of from 2 to 4 hours (dashed line) after dosing.

[0041] FIG. 6 B shows the corresponding plasma concentration-time profiles.

[0042] The dotted line in FIG. 6 (A and B) projects an embodiment where, due to inter-subject variability, the target lag-time of 2 hours extends to up to 3 hours and/or the release rate in the 60 to 90 minutes following the lag-time may more closely resemble a pseudo-zero order release rather than a pulsed release. As shown in FIG. 6 B, such a scenario can lead to mean plasma concentration-time profile between 2 and 3 hours that is not a pulse.

[0043] FIG.7 A shows the in vitro release profiles of compositions of the invention containing modified IR particles (e.g. mini-tablets) together with a single population of TDR particles (e.g. mini-tablets) having a lag time of about 3 hours, followed by complete Zaleplon release in about 2 hours (TDR) at a weight ratio of 14:6 (IR:TDR), wherein at least 70% of the dose is released in about 30 minutes from the modified IR component.

[0044] FIG. 7 B shows the corresponding plasma concentration-time profiles.

[0045] FIG. 8 shows the in vitro release profiles of different TDR beads having about a 2 hour lag time before release of Zaleplon, when tested using the USP Apparatus 1 (Baskets at 100 rpm) and a two-stage dissolution media (700 mL of 0.1N HC1 at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer) and HPLC methodology for quantification.

[0046] FIG. 9 shows the in vitro release profiles of different TDR mini-tablets having about a 2 or 3 hour lag time before release of Zaleplon, when tested using the USP Apparatus 1 (Baskets at 100 rpm) and a two-stage dissolution media (700 mL of 0. IN HC1 at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer) and HPLC methodology for quantification.

[0047] FIG. 10 A shows the in vitro release profiles of capsules of the invention (Prototype 1 as described in Example 3.K.) containing an IR powder mix together with a single population of acid- resistant DR beads, and having a lag time of about 2 hours, followed by complete Zaleplon release in about 2 hours - at initial time point or stored at accelerated stability conditions (40°C/75% RH) for 1, 2, and 3 months, when tested using the USP Apparatus 1 (Baskets at 100 rpm) and a two- stage dissolution media (700 mL of 0.1N HC1 at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer) and HPLC methodology for quantification.

[0048] FIG. 10 B shows the in vitro release profiles of capsules of the invention (Prototype A as described in Example 3.K.) containing an IR powder mix together with a single population of TPR beads, and having a lag time of about 2 hours, followed by complete Zaleplon release in about 3 hours - at initial time point or stored at accelerated stability conditions (40°C/75% RH) for 1, 2, and 3 months, when tested using the USP Apparatus 1 (Baskets at 100 rpm) and a two-stage dissolution media (700 mL of 0.1N HC1 at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer) and HPLC methodology for quantification. The physical and chemical stability of the capsules of the invention demonstrated in Figure 10 indicate such capsules will have an acceptable shelf-life per ICH guidelines.

[0049] FIG. 11 A shows the in vitro release profile of capsules of the invention (Prototype 1 as described in Example 3.K.) containing an IR powder mix together with a single population of acid- resistant DR beads having a lag time of about 2 hours, followed by complete Zaleplon release in about 2 hours, when tested using the USP Apparatus 1 (Baskets at 100 rpm) and a two-stage dissolution media (700 mL of 0.1N HC1 at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer) and HPLC methodology for quantification.

[0050] FIG. 11 B shows the corresponding plasma concentration-time profiles.

[0051] FIG. 12 A shows the in vitro release profile of capsules of the invention (Prototype 2 as described in Example 3.K.) containing an IR powder mix together with a single population of TPR mini-tablets having a lag time of about 3 hours, followed by complete Zaleplon release in about 2 hours, when tested using the USP Apparatus 1 (Baskets at 100 rpm) and a two-stage dissolution media (700 mL of 0.1N HC1 at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer) and HPLC methodology for quantification.

[0052] FIG. 12 B shows the corresponding plasma concentration-time profiles.

[0053] FIG.13 A shows the in vitro release profile of capsules of the invention (Prototype 3 as described in Example 3.K.) containing an IR powder mix together with a population of DR mini- tablets and a population of TPR mini-tablets having (i) a lag time of about 2 hours, followed by complete Zaleplon release in about 1 hour (DR) and (ii) a lag time of about 3.5 hours, followed by complete Zaleplon release in about 2 hours (TPR), at a weight ratio of 10:4:6 (IR:DR:TPR), when tested using the USP Apparatus 1 (Baskets at 100 rpm) and a two-stage dissolution media (700 mL of 0. IN HC1 at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer) and HPLC methodology for quantification.

[0054] FIG. 13 B shows the corresponding plasma concentration-time profiles.

[0055] FIG. 14 A shows the plasma concentration-time profiles of three Zaleplon formulations disclosed herein compared to Sonata®. [0056] FIG. 14 B shows the semi-log scale plasma concentration-time profiles of three Zaleplon formulations disclosed herein compared to Sonata®.

DETAILED DESCRIPTION

[0057] The following description includes information that may be useful in understanding the present disclosure. It is not an admission that any of the information provided herein is prior art or that any publication specifically or implicitly referenced is prior art.

[0058] All documents cited herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

[0059] As used in this specification and appended claims, the singular forms "a", "an", and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a water-soluble polymer" includes a mixture of one or more water-soluble polymers, and the like.

[0060] The term "disorder" refers to any condition or illness, requiring medication and/or medical attention.

[0061] The term "insomnia" refers to a sleep disorder characterized by symptoms including, without limitation, difficulty in falling asleep, difficulty in staying asleep, intermittent wakefulness, and/or waking up too early. The term also encompasses daytime symptoms such as sleepiness, anxiety, impaired concentration, impaired memory, and irritability. Types of insomnia suitable for treatment with the compositions of the present invention include, without limitation, transient, acute (short-term), and chronic insomnia. The term "transient insomnia" refers to insomnia lasting for a few nights. The term "acute insomnia" refers to insomnia lasting for about one to about four weeks. The term "chronic insomnia" refers to insomnia lasting for at least one month. The term, "rebound insomnia" is defined as a dose-dependent temporary worsening in sleep parameters (latency, total sleep time, and number of awakenings) compared to baseline following discontinuation of treatment.

[0062] The terms "drug", "active", or "active ingredient" as used herein refers to the sedative hypnotic drug Zaleplon, including any polymorphic form, the corresponding deuterated analog, and pharmaceutically acceptable salts thereof. Further, any reference to Zaleplon herein also refers to the polymorphs, deuterated analogs, and pharmaceutically acceptable salts thereof.

[0063] The term "particles", as used herein, includes beads, granules, pellets, micro-particles, micro-parti culates, mini -tablets, or a powder mix or blend (e.g. suitable for preparing mini-tablets). The term "drug micro-particulates" or "drug micro-particles" refer to drug particles with particle size in the micrometer range. The term "multi-particulates" refer to multiple particles.

[0064] The terms "biphasic" and "triphasic", as used herein, mean having two and three release and/or plasma-concentration phases, respectively. In some embodiments, the phases can be characterized by pulsatile release profiles of the drug.

[0065] The term "subject" is inclusive of the definition of the term "patient" as used herein, does not exclude individuals who are entirely normal in all respects or with respect to a particular condition. The term "patient", "subject with insomnia", or "insomnia patient", or variants thereof, as used herein, means a subject who has presented a clinical manifestation of a particular disorder with symptom or symptoms suggesting the need for treatment, who is treated preventatively or prophylactically for a condition, or who has been diagnosed with a condition to be treated. In some embodiments, the subject is a child (ages 7-12), adolescent (ages 13-17), adult (ages 18-64) or geriatric (ages 65 and over).

[0066] The term "therapeutically effective plasma concentration", as used herein, means a plasma concentration of Zaleplon sufficient to induce and/or maintain sleep over a desired period of time.

[0067] The term "therapeutically effective amount", as used herein, means the amount of Zaleplon sufficient to induce and/or maintain sleep over a desired period of time.

[0068] The term "disposed over", as used herein, refers to a coating over a substrate, that denotes a relative location of the coating, e.g. a coating disposed over a substrate requires that the coating is outside of the substrate but need not be in direct contact with the substrate, i.e. another coating or material could be interposed there between. For example, a first coating "disposed over" a substrate can be in direct contact with the substrate, or one or more intervening materials or coatings can be interposed between the first coating and the substrate.

[0069] The term "absorption-enhancing agent" or "absorption-enhancing polymer", as used herein, refers to pharmaceutically acceptable agents or polymer that improve bioavailability of a drug. Non-limiting examples include polyvinyl acetate-co-vinyl pyrrolidone at about 60:40 (KOLLIDON^® VA 64); ethylene glycol/vinyl caprolactam/vinyl acetate copolymer at about 13 :57:30 (SOLUPLUS^®); cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate (EUDRAGIT^® EPO); polyethylene oxide; polyethylene glycol; hydroxypropyl cellulose; hypromellose (also referred to herein as hydroxypropyl methylcellulose); hypromellose phthalate (HP-50); polyvinyl pyrrolidone (PVP, povidone); d- alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS); lipids; triglycerides; and bile acids such as sodium cholate and mixtures thereof. In some embodiments, the weight ratio of drug to absorption-enhancing agent may be from about 1 : 10 to about 1 : 1, including about 1 :9, about 1 :8, about 1 :7, about 1 :6, about 1 :5, about 1 :4, about 1 :3, and about 1 :2, inclusive of all values and subranges therebetween. The drug and absorption-enhancing agent (which may also act as a solubility-enhancer or crystallization-inhibitor) may be dissolved in a common solvent mixture, such as a mixture of acetone, ethanol, and water, and layered onto inert cores or spray dried.

[0070] The term "immediate release" or "IR" refers to a component (e.g., a particle, or bead, or a powder, or a pharmaceutical composition, such as a dosage form or a component of a dosage form, such as a capsule or an orally disintegrating tablet, a hot melt extruded or spray-congealed dosage form), wherein at least about 50%, or at least about 75%, or at least about 90% (e.g. about 95% or greater) of Zaleplon is released within about 30 minutes following administration. It is to be understood that the term "immediate release" or "IR" also encompasses the term "Modified immediate release" (MIR). Specifically, MIR refers to a drug release from a component (e.g., a particle or pharmaceutical composition, such as a dosage form or a component of a dosage form, or a capsule, or extended release beads within a capsule, or coated or polymer matrix mini-tablets within a capsule), which provides for the release of a portion of the total amount of Zaleplon in the MIR component (for example at least about 50% of Zaleplon in the MIR component) in an IR- like bolus dose within about thirty minutes after administration, followed by the complete release of the remainder of the Zaleplon in the MIR component within about two hours.

[0071] In some embodiments, the MIR component can be prepared by coating IR particles with a low viscosity water-insoluble polymer alone or in combination with a water-soluble low viscosity cellulosic polymer, e.g., having a Brookfield 2% aqueous solution viscosity of 15 to 400 cps, such as hydroxypropyl methylcellulose ("HPMC"), available under the trade name METHOCEL K100 LV, METHOCEL El 5 LV or a mixture thereof. In other embodiments, the MIR component may be prepared by coating IR particles with a coating comprising an enteric polymer (e.g., as described herein), a water-soluble polymer (e.g., as described herein), or a mixture thereof, and a plasticizer at a polymer to plasticizer weight ratio of from about 7:3 to about 95:5. In still other embodiments, the MIR component may also be produced by spray-coating onto inert cores a coating formulation comprising Zaleplon, a polymer binder (e.g., as described herein) and one or more hydrophilic polymers selected from the group consisting of water-insoluble ethylcellulose, hydroxyl propyl cellulose, hypromellose or a mixture thereof. Alternatively, in various embodiments, the MIR component may also comprise active particles embedded in a matrix comprising (i) a mixture of pharmaceutically acceptable water-insoluble and water-soluble polymers or (ii) a mixture of pharmaceutically acceptable water-soluble/enteric polymer matrix. These matrix particles may be further coated to deliver the target release profile. Suitable coating weights to form MIR particles are in the range of from about 1% to about 10%, including about 2%, about 3%, about 5%, about 7%, about 9%, and inclusive of all ranges and sub-ranges there between.

[0072] The term "timed drug release" (TDR) refers generally herein to a controlled release component, e.g., controlled release particles or a pharmaceutical composition containing controlled release particles (e.g. a controlled release capsule, an orally disintegrating tablet, or a hot melt extruded or spray-congealed dosage form), where upon oral administration the release of Zaleplon, or a pharmaceutically acceptable salt thereof, from the TDR component is delayed for at least about two hours following administration before becoming available for absorption into the patient's bloodstream.

[0073] The TDR component can employ any appropriate technology which delays the release of the drug after administration. Non-limiting examples of suitable technologies include diffusion systems (e.g., reservoir devices and matrix devices) in which drug release is controlled by the rate of drug diffusion through a polymer, dissolution systems in which drug release is controlled by the rate at which the system (e.g., polymer coating, matrix, etc.) dissolves in biological fluids, osmotic pumps, ion-exchange resins, and the like. For example, multiple matrices having different release characteristics can be combined to achieve the pharmacokinetic characteristics described herein. In particular embodiments, the TDR component is a delayed release (DR) component or a timed pulsatile release (TPR) component. [0074] In various embodiments, the TDR component (or components) is in the form of a particle, or beads, or tablets, or population thereof. In one embodiment, the TDR particles comprise a coating comprising one or more pharmaceutically acceptable enteric polymers (e.g., as described herein) which are insoluble under acidic conditions but start to dissolve at about pH 6.5 or higher (also referred to herein as a delayed-release coating). Non-limiting examples of such pharmaceutically acceptable enteric polymers include certain hydroxypropyl methylcellulose acetate succinate (eg. HPMC-AS HG) and/or methacrylic acid copolymers sold under the name EUDRAGIT^® L and EUDRAGIT^® S (e.g., EUDRAGIT^® S100, S12,5, and FS 30D). Such TDR particles are referred to herein as "acid-resistant delayed release particles" or "acid-resistant DR particles".

[0075] In another embodiment, TDR component comprise a coating of one or more enteric polymers (e.g., as described herein) which start to dissolve at about pH 5.0 or higher. Non-limiting examples of such pharmaceutically acceptable enteric polymers include methacrylic acid copolymers sold under the name EUDRAGIT^® L 100-55 and L 30 D-55. Such TDR particles are referred to herein as "delayed release component", "delayed release particles", or "DR particles".

[0076] In various embodiments, the TDR particles comprise a coating comprising one or more pharmaceutically acceptable enteric polymer in combination with one or more pharmaceutically acceptable water-insoluble polymers (i.e., a timed-pulsatile release coating). Such TDR particles are referred to herein as "timed-pulsatile release component", "timed-pulsatile release particles", or "TPR beads", or "TPR particles". The duration of release of the majority of Zaleplon from such TPR particles is dictated by the specific composition of the coating and the coating thickness, as opposed to DR or acid-resistant DR particles, whose release is dictated primarily by the pH environment.

[0077] In various embodiments, TDR particles comprise a coating which gives the TDR particles the following release characteristics: no more than about 10% of is released in the first about 2 to about 4 hours following administration, and the remaining Zaleplon is then released over a defined period (which may be, e.g., from about 2 to about 6 hours after administration) when the particles transition from the very acidic environment of the stomach to the less acidic (about pH 5.0 or higher) intestinal tract. [0078] The TPR particles may be IR particles (e.g. IR beads or mini-tablets) coated with an enteric polymer in combination with a water-insoluble polymer.

[0079] The term "pharmaceutically acceptable salts" include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. In particular embodiments, the term "pharmaceutically acceptable salt" includes salts disclosed in US 20080045547 Al, such as hydrohalide (e.g. hydrochloride and hydrobromide), sulfate or phosphate salts. US 20080045547 Al is hereby incorporated by reference for all purposes. All references to "Zaleplon" herein also include all pharmaceutically acceptable salts as each and every pharmaceutically acceptable salt in this paragraph were recited, and even if the term "Zaleplon" is not followed by the phrase "and pharmaceutically acceptable salts thereof.

[0080] The term "TPR coating" (also called lag-time coating) refers broadly to a coating disposed over an IR component, which delays the release of the active (e.g., Zaleplon) from the TPR component. The TPR coating may include a pharmaceutically acceptable water insoluble polymer combined with a pharmaceutically acceptable enteric polymer. The thickness of the lag-time coating and ratio of components may influence the lag-time prior to release of Zaleplon. In some embodiments, a barrier coating may be applied between the IR particle core and the lag-time coating layer.

[0081] In various embodiments, the coating weight of a TPR coating ranges from about 5% to about 50%, or about 10% to about 40%, e.g., about 5% about 10%, about 15%, about 20%, about 25%), about 30%), about 35%, about 40%, about 45%, and about 50%, inclusive of all ranges and sub-ranges therebetween. When the coating comprises a combination of pharmaceutically acceptable water-insoluble and pharmaceutically acceptable enteric polymers, the ratio of the water-insoluble polymer to the enteric polymer ranges from about 9: 1 to about 1 :3, including about 4: 1 to about 1 :2, about 4: 1 to about 2:3, about 4: 1 to about 1 : 1, about 7:3 to about 1 : 1, and inclusive of all ranges and subranges there between. [0082] Pharmaceutically acceptable water-insoluble polymers, pharmaceutically acceptable water-soluble polymers, pharmaceutically acceptable enteric polymers, and mixtures thereof, as further described herein with reference to their ability to modify the release of drug when included in a TDR component described herein, may generally be classified as "functional polymers". Functional polymers may, for example, be part of a coating applied over an IR particle, a drug- layered core particle, or a solubility-enhanced drug-containing core particle. For example, when part of an acid-resistant DR particle, the functional polymer may be an enteric polymer such as HPMC-AS HG or EUDRAGIT SI 00 that dissolves at pH 6.5 or higher. The functional polymer may be applied, for example, as part of a coating to an IR bead or mini-tablet. When a combination of two or more functional polymers are used in the components described herein, the polymers can be applied as distinct layers, or as a single layer as a mixture of the two or more functional polymers.

[0083] The TDR component may, in one embodiment, include one or more functional polymers optionally mixed with a plasticizer and/or an anti-tacking agent.

[0084] Non-limiting examples of plasticizers include glycerin, triacetin, citrate esters, triethyl citrate, acetyltri ethyl citrate, tributyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, substituted triglycerides and glycerides, monoacetylated and diacetylated glycerides (e.g., Myvacet® 9-45), glyceryl monostearate, glycerol tributyrate, polysorbate 80, polyethylene glycol, propylene glycol, oils (e.g. castor oil, hydrogenated castor oil, sesame oil, olive oil, etc.), fatty acids, and mixtures thereof.

[0085] In another embodiment, a functional polymer (e.g. a pharmaceutically acceptable water- insoluble polymer and/or pharmaceutically acceptable enteric polymer) may be mixed with a plasticizer and used as a coating. The amount of plasticizer required in the coating depends upon the nature of the plasticizer, the properties of the polymer, and the ultimate desired properties of the coating. The plasticizer may constitute from about 2% to about 40% (e.g. about 5% to about 30%) by weight of the polymer(s) in the coating, including, for example, about 2% about 3%, about 5%, about 7%, about 10%, about 12%, about 15%, about 17%, about 20%, about 22%, about 25%), about 27%), and about 28%>, about 30%>, about 35%>, and about 40%>, and inclusive of all ranges and sub-ranges there between. [0086] Non-limiting examples of suitable anti-tacking agents include colloidal silicon dioxide, magnesium stearate, talc, glyceryl monostearate, and mixtures thereof. In one embodiment, the ratio of the functional polymer plus plasticizer to anti-tacking agent ranges from about 9: 1 to about 3 :2 by weight. In another embodiment, the ratio of the functional polymer plus plasticizer to anti-tacking agent ranges from about 4: 1 to about 7:3 by weight.

[0087] Non-limiting examples of pharmaceutically acceptable water-insoluble polymers include ethylcellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, copolymers of ethyl acrylate and methyl methacrylate, such as EUDRAGIT^® RL, EUDRAGIT^® RS, EUDRAGIT^® NE, and mixtures thereof. In a particular embodiment, the water-insoluble polymer comprises ethylcellulose with a mean viscosity of 10 cps in a 5% solution in 80/20 toluene/alcohol measured at 25°C on an Ubbelohde viscometer.

[0088] Non-limiting examples of pharmaceutically acceptable water-soluble polymers include hydroxypropyl methylcellulose (HPMC or hypromellose), hydroxypropylcellulose, polyvinylpyrrolidone, and polyethylene glycol (e.g., low molecular weight polyethylene glycol, such as those having a molecular weight less than about 10,000 g/mol, less than about 9,000 g/mol, less than about 8,000 g/mol, less than about 7,000 g/mol, less than about 6,000 g/mol, less than about 5,000 g/mol, less than about 4,000 g/mol, or less than about 3,000 g/mol).

[0089] Non-limiting examples of pharmaceutically acceptable enteric polymers include cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (HPMC-AS LG, MG or HG dissolving above a pH of 5.0, 5.5 or 6.5, respectively), polyvinyl acetate phthalate, pH-sensitive methacrylic acid/methylmethacrylate copolymers, also referred to interchangeably herein as methacrylic acid copolymers (e.g., EUDRAGIT^® L, L-55, S and FS polymers), shellac, and mixtures thereof. These enteric polymers may be used as a solution in a solvent mixture or an aqueous dispersion. Commercially available materials that may be used include methacrylic acid/methylmethacrylate copolymers sold under the trademark EUDRAGIT (LI 00, S I 00, L30D) from Evonik, Cellacefate (cellulose acetate phthalate) from Eastman Chemical Co, AQUATERIC (cellulose acetate phthalate aqueous dispersion) from FMC Corp., and AQOAT (hydroxypropyl methylcellulose acetate succinate aqueous dispersion) from Shin Etsu K.K. [0090] The term "seal coat" refers to a protective membrane disposed over a drug-containing core particle. The seal coat protects the particle from abrasion and attrition during handling. In one embodiment, the seal coat comprises a hydrophilic polymer. The seal coat may be applied at a coating weight of about 1% to about 10%, for example about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, and inclusive of all ranges and sub-ranges there between.

[0091] Non-limiting examples of suitable hydrophilic polymers as a sealant coating include hydrophilic hydroxypropylcellulose (e.g., KLUCEL^® LF), hydroxypropyl methylcellulose or hypromellose (e.g., OPADRY^® CLEAR or PH ARM AC OAT™ 603), low-viscosity ethylcellulose, and mixtures thereof.

[0092] The terms "plasma concentration", "Cmax," "AUC," "Tmax," and "elimination half-life" have their generally accepted meanings as defined in the FDA Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations (issued March 2003). Such terms refer to the average values measured for a population of patients. ). All references to "plasma concentration", "Cmax ", "AUC", "Tmax" and "elimination half-life" refer to the average values as measured among a population of patients.

[0093] The term "time point" as used here refers either to any period of time within a range or the entire range. For example, a time point from about 7 to about 9 hours, encompasses all times from about 7 to about 9 hours (e.g., 7.3 hours, 8.1 hours, 9.7 hours, etc), subranges within the range of about 7 to about 9 hours (e.g., 7-7.5 hours, or 7-8 hours, or 7.5-8.5 hours etc), or the range of from about 7 hours to about 9 hours.

[0094] The term "lag time" refers to a time period administration or after subjecting a pharmaceutical composition or component thereof to dissolution conditions wherein about 10% or less of the active is released.

[0095] The term "about" is used herein to refer to a numerical quantity, and includes "exactly" the numerical quantity as well as numerical quantities close to the exact quantity. For example, "about 60 seconds" includes 60 seconds, exactly, as well as values close to 60 seconds (e.g., 50 seconds, 55 seconds, 59 seconds, 61 seconds, 65 seconds, 70 seconds, etc.). When a series of numerical quantities are recited, the term "about" includes each value between two consecutive numbers. [0096] The amount of coatings or layers described herein (the "coating weight" or "coating thickness") is expressed as the percentage weight gain provided by the coating, relative to the initial weight of the particles or beads prior to coating. Thus, a 10% coating weight refers to a coating which increases the weight of a particle or bead by 10%.

[0097] Unless indicated otherwise, all percentages and ratios are calculated by weight based on the total component, such as coated particle, or composition, such as capsule or tablet.

Pharmaceutical Compositions and Dosage Forms

[0098] As discussed above, Zaleplon is effective in treating insomnia characterized by difficulty falling asleep. However, because of the short elimination half-life of Zaleplon, conventional immediate release formulations do not provide blood plasma levels necessary to maintain a sedative effect throughout the nighttime, particularly about 2-3 hours after induction when the homeostatic drive dissipates significantly and wakefulness begins to intrude into the sleep period. Thus, immediate release Zaleplon formulations do not adequately treat patients with sleep disorder characterized by difficulty staying asleep, waking too early or poor quality or non-restorative sleep, because plasma levels drop below concentrations associated with sleep maintenance about 2-3 hours after administration. Multiple administrations of immediate release formulations of Zaleplon during a sleep period can cause next-day side effects, such as somnolence, dizziness, and impaired motor function, memory and reaction time, and thus is not a reasonable treatment strategy.

[0099] Existing extended release formulations of Zaleplon also cause next-day side effects, such as somnolence, dizziness, and impaired motor function, memory and reaction time, because of high plasma concentrations 7-8 hours after administration.

[00100] The present invention overcomes the limitations of earlier compositions by providing an improved delivery system (e.g., pulsatile release system) wherein the system comprises at least two pulses (e.g. an IR delivery together with one or two TDR deliveries), each pulse with a predetermined onset of release of active ingredient. The compositions of the invention give a plasma concentration profile upon oral administration that is beneficial not only for rapid sleep onset but also for sleep maintenance, without experiencing undesirable severe side effects, such as somnolence, dizziness, headache, as well as next-day impaired motor function, memory and reaction time, e.g., as measured using the pharmacodynamic assessments described herein. [00101] In various embodiments, the disclosure provides pharmaceutical compositions for the treatment of a patient with a sleep disorder related to one or more of the three phases of sleep: (i) sleep initiation period: (ii) 2-3 hour period after sleep initiation; and (iii) MOTN period. Thus, in various embodiments, the disclosure provides for a composition to treat a sleep disorder which achieves one or more of the following: (i) induction of the sleep initiation period; (ii) prevention or reduction of waking, or allows a patient go back to sleep, during the 2-3 hour period after sleep initiation; and (iii) treatment of a MOTN awakening period. Such sleep disorders, and the need for treatment, may be based on a patient's sleep cycle or as diagnosed by a doctor or electronic health monitor. The compositions of the disclosure also provide for sleep maintenance in a patient for up to about 8 hours post sleep initiation. The compositions further provide for plasma concentration levels of drug to recede to less than about 6 ng/mL after about 7-8 hours following administration to a patient, thereby allowing the patient to avoid experiencing significant severe side-effects, such as somnolence, dizziness, as well as next-day impaired motor function, memory and reaction time.

[00102] In some embodiments, the pharmaceutical compositions of the present disclosure comprise: (a) an IR component comprising Zaleplon; and (b) at least one TDR component comprising Zaleplon, wherein the pharmaceutical composition provides therapeutically effective plasma concentrations of Zaleplon for up to about 8 hours and reduces next-day side effects in a subject.

[00103] In embodiments, the pharmaceutical compositions of the disclosure are administered once-daily to patients in a total daily dose of from about 4 mg to about 48 mg (e.g. about 8 mg to about 36 mg, and particularly about 16 mg to about 30 mg, including about 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, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, and 47 mg, inclusive of all values and subranges there between).

[00104] The dose may be divided among the components in any suitable manner to achieve sleep onset and/or maintenance. For example, in some embodiments, the IR component may have from about 10% to about 90% of the total dose Zaleplon in the pharmaceutical composition, e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, and about 90%, inclusive of all values and subranges therebetween. In particular embodiments, immediate release component includes about 25% to about 90% of the total amount of Zaleplon in the pharmaceutical composition. In some embodiments, the TDR component(s) may have from about 10%) to about 90% of the total dose Zaleplon in the pharmaceutical composition, e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, and about 90%), inclusive of all values and subranges therebetween. In particular embodiments, TDR components(s) includes about 10% to about 75% of the total amount of Zaleplon in the pharmaceutical composition.

[00105] In some embodiments, the ratio of Zaleplon the IR component relative to the one or more TDR components is in the range of from about 10:90 to about 90: 10, e.g., about 15:85, about 20:80, about 25:75, about 30:70, about 35:65, about 40:60, about 45:55, about 50:50, about 55:45, about 60:40, about 65:35, about 70:30, about 75:25, about 80:20, about 85:25, and about 90: 10, inclusive of all values and subranges therebetween.

[00106] In a particular embodiment, the compositions of the invention comprise at least 4 mg Zaleplon or a pharmaceutically acceptable salt thereof in each component (e.g., each population of particles) for a total dose of 12 mg or higher, or total dose of 16 mg or higher. In another particular embodiment, the compositions of the invention comprise about 10 mg Zaleplon or a pharmaceutically acceptable salt thereof each component, for a total dose of 20 mg. For example, in some embodiments, the IR component (e.g., particle) comprises about 10 mg of Zaleplon, and about 10 mg are present in the TDR component (e.g., DR component). In other embodiments, the IR component (e.g., particle) comprises about 10 mg of Zaleplon, and about at least 4 mg of Zaleplon is present in each TDR component (e.g. about 4 mg in the first TDR component and about 6 mg in the second TDR component). In other embodiments, the IR component (e.g., particle) comprises about 7.5 mg of Zaleplon, and about at least 2.5 mg of Zaleplon is present in each TDR component. In another particular embodiment, the compositions of the invention can comprise a higher dose of Zaleplon or a pharmaceutically acceptable salt thereof for the IR component with remaining components adjusted for a total dose of 20 mg. For example, in some embodiments, the IR component (e.g., particle) comprises about 15 mg of Zaleplon, and about 5 mg are present in the TDR component (e.g., DR component). [00107] In some embodiments, the disclosure provides for an oral pharmaceutical composition comprising an IR component comprising Zaleplon, or a pharmaceutically acceptable salt thereof, and at least one TDR component comprising Zaleplon or a pharmaceutically acceptable salt thereof, wherein following administration of said composition to a patient, the composition achieves in the patient:

a. a time to a first maximum plasma concentration (Tmaxi) of Zaleplon about one hour or less following administration;

b. a time to a second maximum plasma concentration (Tmax₂) of Zaleplon about three to about five hours (e.g. about three to about four hours) following administration, wherein the plasma concentration of Zaleplon at Tmax₂ is from about 25% to about 95% of the plasma concentration at Tmaxi; and

c. a plasma concentration of Zaleplon at time point within about seven to about nine hour following administration of no more than about 25% of the plasma concentration at Tmaxi.

[00108] In some embodiments, the pharmaceutical compositions described herein include one TDR component. In other embodiments, the pharmaceutical compositions described herein include two TDR components - a first TDR component and a second TDR component.

[00109] In embodiments, the IR component and the TDR component(s) may be in the form of particles.

[00110] In some embodiments, the pharmaceutical compositions described herein comprise an IR component (e.g., particles) and one or two TDR components (e.g., one or two populations on TDR particles, for example (a) one DR component, which may be an acid-resistant DR component, or TPR component, or (b) two TDR components which include one or more TPR components, DR components, or combinations thereof).

[00111] In yet another embodiment, the composition comprises an MIR component (e.g., particles), and one or two TDR components (e.g., particles).

[00112] In another embodiment, the IR particles are selected from beads, granules, mini- tablets, pellets (such as high shear granulated-extruded-spheronized pellets, hot melt extruded pellets, or melt-congealed particles), a powder-blend, micro-particles, or multi-particulates and at least one pharmaceutically acceptable excipient. [00113] Accordingly, in some embodiments, the pharmaceutical compositions disclosed herein comprise IR bead particles comprising an inert core (e.g. made of sugar or microcrystalline cellulose) coated with Zaleplon or a pharmaceutically acceptable salt thereof and a polymeric binder (e.g. povidone or hypromellose at a Zaleplon to binder weight ratio of about 7:3 to about 9: 1), and optionally further comprising an external protective seal coating, e.g. a seal coating comprising polyvinyl alcohol (e.g. OPADRY CLEAR™ from Colorcon), for a weight gain of about 2%. In another embodiment, the pharmaceutical composition comprises IR mini-tablet particles comprising Zaleplon or a pharmaceutically acceptable salt thereof, lactose monohydrate (e.g. 316 FAST FLO^®), silicified microcrystalline cellulose (e.g. PROSOLV^® SMCC 90), pre- gelatinized starch (e.g. STARCH 1500^®), sodium lauryl sulfate and lubricated with sodium stearyl fumarate, and optionally further comprising an external protective seal coating comprising polyvinyl alcohol (e.g. OPADRY CLEAR™ from Colorcon), for a weight gain of about 2% to about 4%. In yet another embodiment, the pharmaceutical composition comprises IR beads comprising an inert core (e.g. sugar spheres) coated with Zaleplon or a pharmaceutically acceptable salt thereof and an absorption-enhancing polymer. The coating may be achieved by spray coating the core with a mixture of Zaleplon or a pharmaceutically acceptable salt thereof and an absorption-enhancing polymer in solution.

[00114] Thus, in various embodiments, the IR particles may be selected from:

a) beads comprising Zaleplon or a pharmaceutically acceptable salt thereof and a polymeric binder layered onto an inert core. The binder may, for example, be selected from the group consisting of povidone, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (hypromellose), polyethylene glycol, or mixtures thereof. The drug to binder weight ratio may be, for example, from about 9: 1 to about 7: 1;

b) beads, comprising Zaleplon or a pharmaceutically acceptable salt thereof and a solubility/absorption-enhancing polymer layered onto an inert core. The solubility / absorption-enhancing polymer may, for example, be selected from the group consisting of an ethyl aciylate-methacrylic acid copolymer; ethyl acrylate-methyl methacrylate copolymer; cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, EUDRAGIT^® EPO; hydroxypropyl methylcellulose; hydroxypropyl cellulose; hypromellose phthalate; hypromellose acetate succinate; polyvinyl acetate phthalate; polyvinyl pyrrolidone (PVP, povidone); α-, β-, or γ-cyclodextrin, 2-hydroxypropyl β -cyclodextrin, and sulfobutyl ether β -cyclodextrin, polyvinyl acetate-co-vinyl pyrrolidone at about 60:40; ethylene glycol/vinyl caprolactam/vinyl acetate copolymer at about 13 :57:30; d-alpha-tocopheryl polyethylene glycol 1000 succinate; lipids; lecithins; triglycerides, bile acids. The drug to excipient weight ratio may be, for example, from about 2: 1 to about 1 : 10;

c) particles, comprising Zaleplon or a pharmaceutically acceptable salt thereof and one or more solubility- or absorption-enhancing polymers. The solubility /absorption- enhancing polymer may, for example, be selected form the group consisting of polyvinyl acetate-co-vinyl pyrrolidone at about 60:40; ethylene glycol/vinyl caprolactam/vinyl acetate copolymer at about 13 :57:30; hypromellose acetate succinate; cationic copolymer based on dimethyl aminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, EUDRAGIT^® EPO or mixtures thereof;

d) mini-tablets, comprising Zaleplon or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The excipients may, for example, be selected from lactose monohydrate, silicified microcrystalline cellulose, microcrystallme cellulose, pregelatinized starch, spray-dried mannitol, povidone, hypromellose, crospovidone, sodium lauryl sulfate, and a lubricant (e.g. magnesium stearate or sodium stearyl fumarate);

e) granules (i.e. a powder blend), comprising Zaleplon or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The excipients may, for example, be selected from lactose monohydrate, mannitol, calcium sulfate, microcrystalline cellulose, pregelatinized starch, povidone, hypromellose (HPMC E5), crospovidone, sodium lauryl sulfate, and a lubricant (e.g. magnesium stearate or sodium stearyl fumarate);

f) extruded-spheronized pellets comprising Zaleplon or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, and optionally further comprising a seal coating. The excipients may, for example, be selected from lactose monohydrate, mannitol, calcium sulfate, microcrystalline cellulose, pregelatinized starch, povidone, hypromellose (HPMC E5), crospovidone, sodium lauryl sulfate, and a lubricant (e.g. magnesium stearate or sodium stearyl fumarate); g) hot-melt extruded particles comprising Zaleplon or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, and optionally further comprising a protective seal coating. The excipients may, for example, be selected from ethylene glycol/vinyl caprolactam/vinyl acetate copolymer (SOLUPLUS^®), Kollidon^® VA 64, LUTROL^®, CHREMOPHOR^® RH 40, Polyethylene oxide, and mixtures thereof; and

h) melt-congealed particles comprising Zaleplon or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The excipients may, for example, be selected from the group consisting of polyethylene oxide, polyethylene glycol, LUTROL^®, CHREMOPHOR^® RH 40, ethyl acrylate-methacrylic acid copolymer, such as EUDRAGIT^® L, EUDRAGIT^® S, EUDRAGIT^® FS; ethyl acrylate- methyl methacrylate copolymer; and mixtures thereof.

[00115] Yet another embodiment of the invention comprises applying a seal coating to IR particles (e.g. drug-layered beads or mini-tablets) prepared as described above. Such seal coated IR particles may then be used in the preparation of DR or TPR particles.

[00116] MIR particles may be, for example, IR particles as herein described having a coating comprising a hydrophilic polymer and a plasticizer, where the polymer to plasticizer weight ratio may, for example, be from about 60:40 to about 90: 10 (e.g., about 60:40, about 65:35, about 70:30, about 75:25, about 80:20, about 85: 15, and about 90: 10, inclusive of all values and subranges therebetween). The coating may optionally further comprise talc at from about 10% to about 30%) (e.g., about 10%>, about 20%, and about 30%>, inclusive of all values and subranges therebetween) by weight of the total coating weight, for a weight gain of about 1%> to about 10%> by weight (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%), about 9%), and about 10%, inclusive of all values and subranges therebetween).

[00117] In various embodiments, the TDP component described herein is formed by appropriately coating any of the IR components described above with one or more functional polymers to achieve a desired lag time and release profile. For example, in a particular embodiment, DR or acid-resistant DR particles consist of IR beads or mini -tablets coated with an enteric polymer (as described herein), a plasticizer, and optionally an anti-tacking agent (e.g. talc). In another particular embodiment, TPR particles consist of IR beads or mini-tablets coated with an enteric polymer (as described herein), a plasticizer, one or more water-insoluble (as described herein) polymers and optionally an anti-tacking agent (e.g. talc).

[00118] Suitable plasticizer which may be used in the preparation of TDR particles include plasticizers selected from the group consisting of glycerin, triacetin, citrate esters, triethyl citrate, acetyltriethyl citrate, tributyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, substituted triglycerides and glycerides, monoacetylated and diacetylated glycerides (e.g., Myvacet® 9-45), glyceryl monostearate, glycerol tributyrate, polysorbate 80, polyethylene glycol, propylene glycol, oils, fatty acids, and mixtures thereof.

[00119] In some embodiments, the TDR particles are TPR particles comprising a TPR coating disposed over Zaleplon. In some embodiments, the TPR coating comprises pharmaceutically acceptable a water-insoluble polymer in combination with (e.g., present as an admixture) with pharmaceutically acceptable enteric polymer. Suitable enteric polymers includes cellulose acetate phthalate (e.g. CELLACEFATE), hydroxypropyl methyl cellulose phthalate (e.g. HP-55), hydroxypropyl methylcellulose acetate succinate (e.g. AQUOT or AQUASOLVE HPMC-AS such as HPMC-AS LG, HPMC-AS MG or HPMC-AS HG), methacrylic acid/methylmethacrylate copolymers (such as EUDRAGIT^® L, EUDRAGIT^® S and EUDRAGIT^® FS). Suitable water-insoluble polymers cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, ethylcellulose, pH-insensitive ethyl acrylate-methyl methacrylate copolymers, such as EUDRAGIT^® RL and EUDRAGIT^® RS; and mixtures thereof. In a particular embodiment, the lag time coating comprises a water-insoluble polymer in combination with an enteric polymer at a weight ratio of from about 4: 1 to about 1 : 1 (including about 3 : 1 and about 2: 1) for a weight gain of from about 5% to about 50% (including about 5%, about 10%, about 15%, about 20%, about 25%), about 30%), about 35%, about 40%, about 45%, and about 50%). The lag time coating may be disposed over enteric polymer coated IR particles or directly over uncoated IR particles. In this embodiment, the water-insoluble polymer may be, for example, ethylcellulose, and the enteric polymer in the lag time coating may be, for example, hydroxypropyl methylcellulose phthalate (i.e., hypromellose phthalate).

[00120] Yet another embodiment, the pharmaceutical compositions described herein comprise two particle populations, namely IR particles and DR particles. In some embodiments, the DR particles are formed by appropriately coating IR particles (e.g. beads or mini-tablets) with one or more functional polymers, including pharmaceutically acceptable enteric polymers. Suitable enteric polymers includes cellulose acetate phthalate (e.g. CELLACEFATE), hydroxypropyl methylcellulose phthalate (e.g. HP-55), hydroxypropyl methylcellulose acetate succinate (e.g. AQUOT or AQUASOLVE HPMC-AS such as HPMC-AS LG, HPMC-AS MG or HPMC-AS HG), methacrylic acid/methylmethacrylate copolymers (such as EUDRAGIT^® L, EUDRAGIT^® S and EUDRAGIT^® FS). In some embodiments, the DR coating consists one or more pharmaceutically acceptable enteric polymers (as described herein) together with a plasticizer at an enteric polymer: plasticizer weight ratio of about 70:30 to about 95:5 (including, about 70:30, about 75:25, about 80:20, about 85: 15, about 90: 10, and about 95:5, inclusive of all values and subranges therebetween), and optionally comprising an anti-tacking agent such as talc at 10 to 30% by weight (including about 10%, about 15%, about 20%, about 25%, and about 30%, inclusive of all values and subranges therebetween) of the total coating weight for a weight gain 2% to 40% (including about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%), about 35%), and about 40%, inclusive of all values and subranges therebetween). These DR or acid-resistant DR particles may be coated with a lag-time coating to form TPR particles. The lag-time coating may comprise a water-insoluble polymer in combination with an enteric polymer. In a particular embodiment, the combination of water-insoluble polymer and enteric polymer are at a weight ratio of from about 4: 1 to about 1 : 1 (including about 3 : 1 and about 2: 1) for a weight gain of from about 5% to 50% (including about 10%, about 15%, about 20%, about 25%, about 30%), about 35%), about 40%, and about 45%, inclusive of all values and subranges therebetween).

[00121] In another embodiment, acid-resistant DR particles may be prepared by coating IR particles (e.g. IR beads) with a coating comprising a suitable acid-resistant enteric polymer, such as hydroxypropyl methylcellulose acetate succinate (e.g. AQUASOLVE™; HPMC-AS HG from Ashland Inc., USA), or methacrylic acid/methylmethacrylate copolymer (e.g. EUDRAGIT® S or EUDRAGIT® FS from Evonik Industry, Germany) alone or in combination with HPMC-AS LG, HPMC-AS MG or EUDRAGIT L together with a plasticizer, such as dibutyl sebacate or triethyl citrate at a total polymer to plasticizer weight ratio of from about 80:20 to about 95:5 (including about 80:20, about 85: 15, about 90: 10, and about 95:5, inclusive of all values and subranges therebetween) for a weight gain of 10% to 30% (including about 10%, about 15%, about 20%, about 25%), and about 30% inclusive of all values and subranges therebetween). [00122] In yet another embodiment, the TPR particles comprise IR beads having a lag-time coating comprising any combination of the enteric polymers and the water-insoluble polymers described herein, including methacrylic acid/methylmethacrylate copolymers (such as EUDRAGIT^® L, EUDRAGIT^® S or EUDRAGIT^® FS) and pH-insensitive ethyl acrylate-methyl methacrylate copolymers (such as EUDRAGIT^® RL or EUDRAGIT^® RS).

[00123] In still yet another embodiment, the TPR particles comprise IR particles (e.g., mini- tablets) having a lag-time coating comprising any combination of the enteric polymers and the water-insoluble polymers described herein, such as hydroxypropyl methylcellulose phthalate, a plasticizer such as diethyl phthalate and a water-insoluble polymer such as ethylcellulose. Such mini-tablets may optionally have a sub-coat comprising an enteric polymer such as hydroxypropyl methylcellulose phthalate and a plasticizer such as diethyl phthalate and/or over-coat comprising an enteric polymer such as hydroxypropyl methylcellulose phthalate or a water-insoluble polymer such as ethyl cellulose, and a plasticizer such as diethyl phthalate.

[00124] The TPR particles may further comprise an anti-tacking agent such as talc. In embodiments, the anti-tacking agent may be present in an amount of from about 10% to about 30%) (including about 10, about 15%, about 20%, about 25%, and about 30%>) by weight of the total coating weight.

[00125] The TPR particles may also comprise multiple (e.g. two) coats of the lag-time coating comprising the same or different enteric/water-insoluble polymer combinations to extend the lag time before release of the active ingredient from the composition.

Biphasic Capsule Formulations of the Present Invention :

[00126] In various embodiments, the disclosure provides for a biphasic pulsatile drug delivery pharmaceutical composition which includes an IR component (in the form of particles or powder blend) and a TPR component (e.g. particles). In some embodiments, the TPR particles are IR particles (e.g. beads or mini-tablets) coated with a lag-time coating comprising a combination of water-insoluble and enteric polymers at a weight ratio of from about 4: 1 to about 2:3, a plasticizer at a polymer to plasticizer weight ratio of from about 80:20 to about 95:5 (including about 85: 15 and about 90: 10), and optionally further comprising an anti-tacking agent such as talc at from about 10%> to about 30%> (including about 15%, about 20%, and about 25%) by weight of the total coating weight for a weight gain of from about 5% to about 50% (including about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, and about 45%).

[00127] In an embodiment, the biphasic pulsatile drug delivery pharmaceutical composition is in the form of capsules, comprising: (i) an IR powder blend; and (ii) a population of acid-resistant DR particles comprising IR particles (e.g. beads or mini-tablets) coated with an acid-resistant enteric polymer (e.g. HPMC-AS HG) and a plasticizer (e.g. dibutyl sebacate) and optionally talc at a weight ratio of about 65-95:5-15:0-30 for a weight gain of about 10 to about 30% (including about 15%, about 20%, and about 25%).

[00128] In another embodiment, the biphasic pulsatile drug delivery pharmaceutical composition is in the form of capsules, comprising: (i) IR particles (in the form of powder blend, beads or mini-tablets); and (ii) a population of TPR particles (in the form of beads or mini-tablets) comprising IR particles (e.g. beads or mini-tablets) coated with ethylcellulose (e.g. ETHOCEL Standard Premium with a viscosity of 10 cps commercially available from Colorcon), hypromellose phthalate (e.g. HP 55 commercially available from Shin Etsu K.K.) and diethyl phthalate at a weight ratio of about 50-65:25-40:5-15 for a weight gain of about 10% to about 40% (including about 15%, about 20%, about 25%, about 30%, and about 35%).

[00129] In yet another embodiment, the biphasic pulsatile drug delivery pharmaceutical composition is in the form of capsules, comprising: (i) IR particles (in the form of powder blend, beads or mini-tablets); and (ii) a population of TPR particles (in the form of beads or mini-tablets) prepared by coating IR particles (e.g. beads or mini-tablets) with a water-insoluble ethyl acrylate- methyl methacrylate copolymer (such as EUDRAGIT^® RL or EUDRAGIT^® RS or a mixture thereof), methacrylic acid/methylmethacrylate copolymer (such as EUDRAGIT^® L, EUDRAGIT^® S or EUDRAGIT^® FS), and a plasticizer (such as tri ethyl citrate) and optionally talc at a weight ratio of about 35-65:35-65:5-15:0-25 for a weight gain of about 10 to about 30% (including about 15%, about 20%, and about 25%).

[00130] In still yet another embodiment, the biphasic pulsatile drug delivery pharmaceutical composition is in the form of capsules, comprising: (i) IR particles (in the form of powder blend, beads or mini-tablets); and (ii) a population of TPR particles (e.g. beads or mini-tablets) prepared by coating IR particles (e.g. beads or mini-tablets) firstly with a DR coating comprising hypromellose phthalate (e.g. HP 55), diethyl phthalate and optionally talc at a weight ratio of about 65-95:5-15:0-30 for a weight gain of about 10% to about 30% (including about 15%, about 20%, and about 25%), followed by a TPR overcoating using ethyl cellulose, hypromellose phthalate, diethyl phthalate and optionally talc, at a weight ratio of about 35-65:35-65:5-15:0-30 for a weight gain of about 2% to about 15% (including about 5%, and about 10%).

Triphasic Capsule Formulations of the Present Invention :

[00131] In various embodiments, the disclosure provides for a triphasic pulsatile delivery pharmaceutical compositions. Such compositions may include a population of IR particles and two populations of TDR particles (referred to herein as a first population of TDR particles and a second population of TDR particles). In some embodiments, the first population of TDR particles are IR particles (e.g. mini-tablets) having a delayed-release coating comprising one or more pharmaceutically acceptable enteric polymers (for preparing DR or acid-resistant DR particles) or with a TPR coating comprising a pharmaceutically acceptable enteric polymer in combination with a pharmaceutically acceptable water-insoluble polymer (for preparing TPR particles), together with a plasticizer and optionally an anti-tacking agent such as talc. In some embodiments, the second population of TPR particles are IR particles (e.g. mini-tablets) coated with a first delayed- release coating comprising a combination of one or more pharmaceutically acceptable enteric polymers and a plasticizer and (optionally) an anti-tacking agent such as talc to initially form DR or acid-resistant DR particles, and then a second outer lag time coating comprising a combination of pharmaceutically acceptable water-insoluble and pharmaceutically acceptable enteric polymers and a plasticizer and (optionally) an anti-tacking agent such as talc. In various embodiments, the polymer to plasticizer weight ratio in the first coating is from about 70:30 to about 95:5 (including about 70:30, about 75:25, about 80:20, about 85: 15 about 90: 10, and about 95:5) and the talc is present in about 10% to about 30% (including about 10%, about 15%, about 20%, about 25%, and about 30%)) by weight of the total coating weight for a weight gain of from about 2% to about 40% (including about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%), and about 40%). In various embodiments, the water-insoluble polymer to enteric polymer weight ratio in the second outer lag time coating is from about 4: 1 to about 2:3, the polymer (i.e. water-insoluble polymer plus enteric polymer) to plasticizer weight ratio is from about 80:20 to about 95:5 (including about 85: 15 and about 90: 10), and the talc is present at from about 10% to about 30%) (including about 15%, about 20%, and about 25%) by weight of the total coating weight for a weight gain of from about 2% to about 50% (including about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, and about 45%).

[00132] In some embodiments, the disclosure provides a triphasic pulsatile delivery pharmaceutical composition comprising: (i) one population of IR particles; (ii) a first population DR particles comprising IR particles coated with one or more suitable enteric polymers (e.g. hypromellose phthalate), a plasticizer (e.g. diethyl phthalate), and optionally an anti-tacking agent, or acid-resistant DR particles comprising IR particles coated with an acid-resistant enteric polymer (e.g. HPMC-AS HG) and a plasticizer (e.g. triethyl citrate); and (iii) a second acid-resistant DR particles or TPR particles. In some such embodiments, the DR particles comprise IR particles having a coating of, e.g., acid-resistant hydroxypropyl methylcellulose acetate succinate (e.g. AQUASOLVE™; HPMC-AS MG) combined with a plasticizer such as dibutyl sebacate. In some such embodiments, the TPR particles comprise IR particles having a first coating of one or more suitable enteric polymers (e.g. hypromellose phthalate), a plasticizer such as diethyl phthalate and talc and an outer TPR coating comprising a water-insoluble polymer (e.g. ethylcellulose), one or more suitable enteric polymers (e.g. hypromellose phthalate), a plasticizer such as diethyl phthalate, and talc at a weight ratio of about 3 :3 : 1 :3.

[00133] In another embodiment, the present pharmaceutical compositions are in the form of triphasic capsules comprising IR mini-tablets, a first population of TPR mini-tablets with a short lag-time coating and a second population of TPR mini-tablets with a long lag-time coating. In some embodiments, the first population of TPR mini -tablets comprises IR mini -tablets with a first coating of an enteric polymer described herein (e.g., hypromellose phthalate for a weight gain of 10 to 30%) and a second lag-time coating comprising a water-insoluble polymer described herein (e.g. ethylcellulose), an enteric polymer described herein (e.g., hypromellose phthalate) and a plasticizer (e.g. diethyl phthalate) at a weight ratio of 50:40: 10 for a weight gain of 2 to 15%. In some embodiments, the second population of TPR mini-tablets comprises IR mini-tablets with a first coating with an enteric polymer described herein for a weight gain of 10 to 30% and a second lag-time coating comprising a water-insoluble polymer described herein (e.g. ethylcellulose), an enteric polymer described herein (such as hypromellose phthalate) and a plasticizer (e.g. triethyl citrate) at a weight ratio of about 65:25: 10 for a weight gain of about 5% to about 15%. [00134] In still other embodiments, the pharmaceutical composition is in the form of triphasic capsules, comprising: (i) a population of IR particles (e.g. powder mix, beads or mini- tablets); (ii) a first population of (a) DR particles (e.g. beads or mini-tablets) having a coating comprising an enteric polymer as described herein (e.g., hypromellose phthalate), (b) acid-resistant DR particles (e.g. beads or mini-tablets) having a coating comprising an acid-resistant enteric polymer as described herein (e.g., HPMC-AS HG or MG), or (c) TPR particles having a short lag- time coating (e.g. coated with EUDRAGIT RSlOO/LlOO/tri ethyl citrate or ethylcellulose/hypromellose phthalate/diethyl phthalate with or without talc in order to have a lag- time of about 2 hours); and (iii) a second population of (a) acid-resistant DR particles (e.g. beads or mini-tablets) having a coating comprising an acid-resistant enteric polymer as described herein (e.g., HPMC-AS HG, a plasticizer DBS and optionally talc at a weight ratio of about 65-95:5-15:0- 30 for a weight gain of about 10% to about 30%>) or (b) TPR particles (e.g. beads or mini-tablets) having a long lag-time coating comprising, e.g., EUDRAGIT RSlOO/LlOO/tri ethyl citrate or ethylcellulose /hypromellose phthalate/diethyl phthalate and optionally talc at a weight ratio of about 65-95:5-15:0-30 for a weight gain of about 10%> to about 30%> with or without an under-coat of hypromellose phthalate/diethyl phthalate and optionally talc at a weight ratio of about 65-50:25- 40:5-15:0-30 for a weight gain of about 5% to about 15%> to provide a long lag-time of up to about 4 hours.

[00135] An yet another embodiment, the pharmaceutical composition in the form of capsules, comprising (i) IR particles (in the form of powder blend, beads or mini-tablets), (ii) a population of DR particles (e.g. beads or mini-tablets) prepared by coating IR particles (e.g. beads or mini-tablets) with a DR coating consisting of hypromellose phthalate, diethyl phthalate and optionally talc at a weight ratio of about 65-95:5-15:0-30 for a weight gain of about 5% to about 15% (including about 5%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%), and about 14%), and (iii) a population of (a) acid-resistant DR particles comprising IR particles (e.g. beads or mini-tablets) coated with an acid-resistant enteric polymer (e.g. HPMC-AS HG) and a plasticizer (e.g. dibutyl sebacate) and optionally talc at a weight ratio of about 65-95:5- 15:0-30 for a weight gain of about 10 to about 20% (including about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, and about 19%), or (b) TPR particles prepared by first coating IR particles (e.g. beads or mini-tablets) with a DR coating of hypromellose phthalate for a weight gain of 10 to 30%, followed by a TPR overcoating of ethylcellulose, hypromellose phthalate, diethyl phthalate and optionally talc for a weight gain of 5% to 15% (including about 5%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, and about 14%).

[00136] A further embodiment of the invention is the pharmaceutical composition in the form of capsules, wherein the multi-particulate populations comprise (i) IR particles in the form of powder blend, beads or mini -tablets), (ii) a population of TPR particles (in the form of beads or mini-tablets) prepared by coating IR particles (e.g. beads or mini-tablets) firstly with a DR coating consisting of hypromellose phthalate, followed by a TPR overcoating (iii) another population of TPR particles (e.g. beads or mini -tablets) prepared by coating IR particles (e.g. beads or mini-tablets) firstly with a DR coating of hypromellose phthalate, followed by a TPR overcoating of ethylcellulose and hypromellose phthalate for a weight gain of 5% to 15% (including about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, and about 14%).

[00137] Alternatively, biphasic capsules may contain a single population of suitably coated particles (e.g., beads or mini-tablets). Similarly, triphasic capsules may alternatively contain a single population or two populations of suitably coated particles (e.g., beads or mini-tablets).

[00138] Thus, in some embodiments, any of the TDR particles described herein may be coated with an IR component (e.g., an IR layer comprising Zaleplon). For example, in embodiments, triphasic capsules may contain two TDR particle populations, comprising of (a) a DR or TPR particle (e.g. beads and mini-tablets) population with a lag-time of about 2-3 hours and (b) an acid-resistant DR or TPR particle (e.g. beads and mini-tablets) population with a lag-time of about 3-4 hours, that is coated with an instant release layer of Zaleplon plus a binder, and having a protective seal-coat as an overcoat.

[00139] In other embodiments, the IR component, first TDR component, and second TDR component can be formulated as a single particle. For example, triphasic capsules may also contain a single population of particles, comprising acid-resistant DR or TPR particles with a lag-time of about 3-4 hours, that is coated with a layer of Zaleplon plus a binder, followed by coating with a protective seal-coat and then coated with an acid-resistant DR or TPR coating to achieve a lag- time of about 2-3 hours, and followed by further coating of an IR component (e.g. Zaleplon plus a binder followed by a protective seal-coat as an overcoat). [00140] Yet another embodiment of the invention is a pharmaceutical composition of the invention in the form of an orally disintegrating tablet (ODT), comprising IR micro-particles together with DR or TPR micro-particles and rapidly dispersing micro-granules. The DR or TPR micro-particles can be prepared as described above, e.g., by coating IR micro-particles with an enteric polymer (e.g., HPMC-AS MG, HPMC-AS HG or EUDRAGIT L+S combination) or with a TPR coating of EUDRAGIT RL/RS polymers combined in combination with an EUDRAGIT L polymer. The ODT composition may also contain pharmaceutically acceptable excipients, such as a flavorant, a sweetener, a disintegrant, microcrystalline cellulose, and/or a lubricant.

[00141] The rapidly dispersing micro-granules comprise a disintegrant, such as crospovidone or low substituted hydroxypropyl cellulose, a sugar alcohol, such as mannitol with an average particle size of less than 30 microns or less than 60 microns, a saccharide, or a combination thereof, together with pre-gelatinized starch at a weight ratio of 10-1 :90-99:0-3. Such rapidly dispersing micro-granules may be prepared in accordance with the disclosures in U.S. Patent Number 8,071, 128 and U.S. Patent Publication Number 20120282335.

[00142] Appropriate amounts of IR micro-particles, DR or TPR micro-particles and rapidly dispersing micro-granules may be blended together along with ODT excipients (e.g., a flavorant, a sweetener, a disintegrant, microcrystalline cellulose, and/or a lubricant) to achieve blend homogeneity and compressed into ODTs using a rotary tablet press. The ODT is designed to disintegrate on contact with saliva in the oral cavity of a patient in approximately 60 seconds, thereby creating a smooth viscous suspension containing coated micro-particles for ease of swallowing. The ODT disintegration time may be tested using the USP <701> method, and the ODT may be, for example, designed to disintegrate within 30 seconds when tested using this method.

Pharmacokinetic Characteristics

[00143] The pharmaceutical compositions described herein provide therapeutically effective blood plasma concentrations of Zaleplon, or pharmaceutically acceptable salts thereof, for up to about 7 hours after oral administration (i.e., during sleep time), and then blood plasma concentrations recede to levels which reduce or avoid next-day side-effects such as somnolence, dizziness, as well as next-day impaired motor function, memory and reaction time. In some embodiments, the plasma concentration of Zaleplon at a time point between about seven to about nine hours (e.g., about eight) hours following administration of a composition to a patient is within the range of from about 2 ng/mL to about 6 ng/mL.

[00144] In some embodiments, the present pharmaceutical compositions are formulated to achieve an average maximum plasma concentration (Cmax) no more than about 50 ng/mL following oral administration of about 10 to about 20 mg Zaleplon, e.g., about 50 ng/mL, about 45 ng/mL, about 40 ng/mL, about 35 ng/mL, about 30 ng/mL, about 25 ng/mL ng/mL, inclusive of all values and subranges therebetween.

[00145] In some embodiments, the present pharmaceutical compositions are formulate to maintain an average minimum plasma concentration (Cmin) of at least about 1 ng/mL for up to about 8 following oral administration of about 10 to about 20 mg Zaleplon, e.g., about 1 ng/mL, about 2 ng/mL, about 3 ng/mL, about 4 ng/mL, about 5 ng/mL, about 6 ng/mL, about 7 ng/mL, about 8 ng/mL, about 9 ng/mL, about 10 ng/mL, inclusive of all values and subranges therebetween.

[00146] In some embodiments, the present pharmaceutical compositions are formulated to maintain blood plasma concentration of Zaleplon within the range of 1 ng/mL to about 75 ng/mL for up to about 8 hours following oral administration of about 10 to about 20 mg Zaleplon, e.g., about 1 ng/mL, about 1.5 ng/mL, about 2 ng/mL, about 2.5 ng/mL, about 3 ng/mL, about 3.5 ng/mL, about 4 ng/mL, about 4.5 ng/mL, about 5 ng/mL, about 5.5 ng/mL, about 6 ng/mL, about 6.5 ng/mL, about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.6 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, about 10.5 ng/mL, about 11 ng/mL, about 11.5 ng/mL, about 12 ng/mL, about 12.5 ng/mL, about 13 ng/mL, about 13.5 ng/mL, about 14 ng/mL, about 14.5 ng/mL, about 15 ng/mL, about 15.5 ng/mL, about 16 ng/mL, about 16.5 ng/mL, about 17 ng/mL, about 17.5 ng/mL, about 18 ng/mL, about 18.5 ng/mL, about 19 ng/mL, about 19.5 ng/mL, about 20 ng/mL, 20.5 ng/mL, about 21 ng/mL, about 21.5 ng/mL, about 22 ng/mL, about 22.5 ng/mL, about 23 ng/mL, about 23.5 ng/mL, about 24 ng/mL, about 24.5 ng/mL, about 25 ng/mL, about 25.5 ng/mL, about 26 ng/mL, about 26.5 ng/mL, about 27 ng/mL, about 27.5 ng/mL, about 28 ng/mL, about 28.5 ng/mL, about 29 ng/mL, about 29.5 ng/mL, about 30 ng/mL, about 30.5 ng/mL, about 31 ng/mL, about 31.5 ng/mL, about 32 ng/mL, about 32.5 ng/mL, about 33 ng/mL, about 33.5 ng/mL, about 34 ng/mL, about 34.5 ng/mL, about 35 ng/mL, about 35.5 ng/mL, about 36 ng/mL, about 36.5 ng/mL, about 37 ng/mL, about 37.5 ng/mL, about 38 ng/mL, about 38.5 ng/mL, about 39 ng/mL, about 39.5 ng/mL, about 40 ng/mL, about 40.5 ng/mL, about 41 ng/mL, about 41.5 ng/mL, about 42 ng/mL, about 42.5 ng/mL, about 43 ng/mL, about 43.5 ng/mL, about 44 ng/mL, about 44.5 ng/mL, about 45 ng/mL, about 45.5 ng/mL, about 46 ng/mL, about 46.5 ng/mL, about 47 ng/mL, about 47.5 ng/mL, about 48 ng/mL, about 48.5 ng/mL, about 49 ng/mL, about 49.5 ng/mL, and about 50 ng/mL, about 50.5 ng/mL, about 51 ng/mL, about 51.5 ng/mL, about 52 ng/mL, about 52.5 ng/mL, about 53 ng/mL, about 53.5 ng/mL, about 54 ng/mL, about 54.5 ng/mL, about 55 ng/mL, about 55.5 ng/mL, about 56 ng/mL, about 56.5 ng/mL, about 57 ng/mL, about 57.5 ng/mL, about 58 ng/mL, about 58.5 ng/mL, about 59 ng/mL, about 59.5 ng/mL, about 60 ng/mL, about 60.5 ng/mL, about 61 ng/mL, about 61.5 ng/mL, about 62 ng/mL, about 62.5 ng/mL, about 63 ng/mL, about 63.5 ng/mL, about 64 ng/mL, about 64.5 ng/mL, about 65 ng/mL, about 65.5 ng/mL, about 66 ng/mL, about 66.5 ng/mL, about 67 ng/mL, about 67.5 ng/mL, about 68 ng/mL, about 68.5 ng/mL, about 69 ng/mL, about 69.5 ng/mL, and about 70 ng/mLinclusive of all values and subranges therebetween.

[00147] As discussed above, pharmaceutical compositions described herein release Zaleplon in a series of pulses (i.e., in a biphasic or triphasic release profile) which provide a blood plasma profile appropriate to initiate sleep onset within 30 minutes after administration and sleep maintenance for 7-8 hours after administration. That is, the first pulse of Zaleplon provides blood plasma concentrations (e.g. Cmaxi) that provide sleep onset, and the second pulse (and, in some embodiments, a third pulse) provides blood plasma concentrations (e.g., Cmax₂) that maintain sleep throughout the nights.

[00148] In some embodiments, the present pharmaceutical compositions are formulated to provide a first average maximum plasma concentration (Cmaxi) of Zaleplon (e.g,. a Cmax associated with the immediate release component) within about 80% to about 125% of the range of from about 6.0 ng/mL to about 50.0 ng/mL after oral administration of from about 10 to about 20 mg Zaleplon, e.g., about 6 ng/mL, about 6.5 ng/mL, about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, about 10.5 ng/mL, about 11 ng/mL, about 11.5 ng/mL, about 12 ng/mL, about 12.5 ng/mL, about 13 ng/mL, about 13.5 ng/mL, about 14 ng/mL, about 14.5 ng/mL, about 15 ng/mL, about 15.5 ng/mL, about 16 ng/mL, about 16.5 ng/mL, about 17 ng/mL, about 17.5 ng/mL, about 18 ng/mL, about 18.5 ng/mL, about 19 ng/mL, about 19.5 ng/mL, about 20 ng/mL, 20.5 ng/mL, about 21 ng/mL, about 21.5 ng/mL, about 22 ng/mL, about 22.5 ng/mL, about 23 ng/mL, about 23.5 ng/mL, about 24 ng/mL, about 24.5 ng/mL, about 25 ng/mL, about 25.5 ng/mL, about 26 ng/mL, about 26.5 ng/mL, about 27 ng/mL, about 27.5 ng/mL, about 28 ng/mL, about 28.5 ng/mL, about 29 ng/mL, about 29.5 ng/mL, about 30 ng/mL, about 30.5 ng/mL, about 31 ng/mL, about 31.5 ng/mL, about 32 ng/mL, about 32.5 ng/mL, about 33 ng/mL, about 33.5 ng/mL, about 34 ng/mL, about 34.5 ng/mL, about 35 ng/mL, about 35.5 ng/mL, about 36 ng/mL, about 36.5 ng/mL, about 37 ng/mL, about 37.5 ng/mL, about 38 ng/mL, about 38.5 ng/mL, about 39 ng/mL, about 39.5 ng/mL, about 40 ng/mL, about 40.5 ng/mL, about 41 ng/mL, about 41.5 ng/mL, about 42 ng/mL, about 42.5 ng/mL, about 43 ng/mL, about 43.5 ng/mL, about 44 ng/mL, about 44.5 ng/mL, about 45 ng/mL, about 45.5 ng/mL, about 46 ng/mL, about 46.5 ng/mL, about 47 ng/mL, about 47.5 ng/mL, about 48 ng/mL, about 48.5 ng/mL, about 49 ng/mL, about 49.5 ng/mL, about 50 ng/mL, about 50.5 ng/mL, about 51 ng/mL, about 51.5 ng/mL, about 52 ng/mL, about 52.5 ng/mL, about 53 ng/mL, about 53.5 ng/mL, about 54 ng/mL, about 54.5 ng/mL, about 55 ng/mL, about 55.5 ng/mL, about 56 ng/mL, about 56.5 ng/mL, about 57 ng/mL, about 57.5 ng/mL, about 58 ng/mL, about 58.5 ng/mL, about 59 ng/mL, about 59.5 ng/mL, and about 50 ng/mL, inclusive of all values and subranges therebetween.

[00149] In some embodiments, the Cmaxi is within 80% to about 125% of the range of from about 12 ng/mL to about 45 ng/mL after oral administration of about 20 mg of Zaleplon (e.g., in embodiments in which the IR component contains 15 mg of Zaleplon), such as about 8 ng/mL, about 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, about 10.5 ng/mL, about 11 ng/mL, about 11.5 ng/mL, about 12 ng/mL, about 12.5 ng/mL, about 13 ng/mL, about 13.5 ng/mL, about 14 ng/mL, about 14.5 ng/mL, about 15 ng/mL, about 15.5 ng/mL, about 16 ng/mL, about 16.5 ng/mL, about 17 ng/mL, about 17.5 ng/mL, about 18 ng/mL, about 18.5 ng/mL, about 19 ng/mL, about 19.5 ng/mL, about 20 ng/mL, 20.5 ng/mL, about 21 ng/mL, about 21.5 ng/mL, about 22 ng/mL, about 22.5 ng/mL, about 23 ng/mL, about 23.5 ng/mL, about 24 ng/mL, about 24.5 ng/mL, about 25 ng/mL, about 25.5 ng/mL, about 26 ng/mL, about 26.5 ng/mL, about 27 ng/mL, about 27.5 ng/mL, about 28 ng/mL, about 28.5 ng/mL, about 29 ng/mL, about 29.5 ng/mL, about 30 ng/mL, about 30.5 ng/mL, about 31 ng/mL, about 31.5 ng/mL, about 32 ng/mL, about 32.5 ng/mL, about 33 ng/mL, about 33.5 ng/mL, about 34 ng/mL, about 34.5 ng/mL, about 35 ng/mL, about 35.5 ng/mL, about 36 ng/mL, about 36.5 ng/mL, about 37 ng/mL, about 37.5 ng/mL, about 38 ng/mL, about 38.5 ng/mL, about 39 ng/mL, about 39.5 ng/mL, about 40 ng/mL, about 40.5 ng/mL, about 41 ng/mL, about 41.5 ng/mL, about 42 ng/mL, about 42.5 ng/mL, about 43 ng/mL, about 43.5 ng/mL, about 44 ng/mL, about 44.5 ng/mL, about 45 ng/mL, about 45.5 ng/mL, about 46 ng/mL, about 46.5 ng/mL, about 47 ng/mL, about 47.5 ng/mL, about 48 ng/mL, about 48.5 ng/mL, about 49 ng/mL, about 49.5 ng/mL, about 50 ng/mL, about 50.5 ng/mL, about 51 ng/mL, about 51.5 ng/mL, about 52 ng/mL, about 52.5 ng/mL, about 53 ng/mL, about 53.5 ng/mL, about 54 ng/mL, about 54.5 ng/mL, about 55 ng/mL, about 55.5 ng/mL, about 56 ng/mL, about 56.5 ng/mL, about 57 ng/mL, about 57.5 ng/mL, and about 58 ng/mL, inclusive of all values and subranges therebetween.

[00150] In some embodiments, the pharmaceutical compositions described herein provide a Cmaxi of Zaleplon within the range of about 80% to about 125% of about 9.321 ng/mL to about 27.008 ng/mL following oral administration of about 20 mg of Zaleplon (e.g., containing about 10 mg of Zaleplon in an immediate release component), including about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, about 10.5 ng/mL, about 11 ng/mL, about 11.5 ng/mL, about 12 ng/mL, about 12.5 ng/mL, about 13 ng/mL, about 13.5 ng/mL, about 14 ng/mL, about 14.5 ng/mL, about 15 ng/mL, about 15.5 ng/mL, about 16 ng/mL, about 16.5 ng/mL, about 17 ng/mL, about 17.5 ng/mL, about 18 ng/mL, about 18.5 ng/mL, about 19 ng/mL, about 19.5 ng/mL, about 20 ng/mL, 20.5 ng/mL, about 21 ng/mL, about 21.5 ng/mL, about 22 ng/mL, about 22.5 ng/mL, about 23 ng/mL, about 23.5 ng/mL, about 24 ng/mL, about 24.5 ng/mL, about 25 ng/mL, about 25.5 ng/mL, about 26 ng/mL, about 26.5 ng/mL, about 27 ng/mL, about 27.5 ng/mL, about 28 ng/mL, about 28.5 ng/mL, about 29 ng/mL, about 29.5 ng/mL, about 30 ng/mL, about 30.5 ng/mL, about 31 ng/mL, about 31.5 ng/mL, about 32 ng/mL, about 32.5 ng/mL, about 33 ng/mL, about 33.5 ng/mL, and about 34 ng/mL, inclusive of all values and subranges therebetween.

[00151] In some embodiments, the pharmaceutical compositions described herein provide a Cmaxi of Zaleplon within the range of about 80% to about 125% of about 6 ng/mL to about 21 ng/mL following oral administration of about 10 of Zaleplon (e.g., in embodiments, in which the IR component contains about 7.5 mg of Zaleplon), e.g., about 4 ng/mL, about 4.5 ng/mL, about 5 ng/mL, about 5.5 ng/mL, about 6 ng/mL, about 6.5 ng/mL, about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, about 10.5 ng/mL, about 11 ng/mL, about 11.5 ng/mL, about 12 ng/mL, about 12.5 ng/mL, about 13 ng/mL, about 13.5 ng/mL, about 14 ng/mL, about 14.5 ng/mL, about 15 ng/mL, about 15.5 ng/mL, about 16 ng/mL, about 16.5 ng/mL, about 17 ng/mL, about 17.5 ng/mL, about 18 ng/mL, about 18.5 ng/mL, about 19 ng/mL, about 19.5 ng/mL, about 20 ng/mL, 20.5 ng/mL, about 21 ng/mL, about 21.5 ng/mL, about 22 ng/mL, about 22.5 ng/mL, about 23 ng/mL, about 23.5 ng/mL, about 24 ng/mL, about 24.5 ng/mL, about 25 ng/mL, about 25.5 ng/mL, about 26 ng/mL, about 26.5 ng/mL, about 27 ng/mL, about 27.5 ng/mL, about 28 ng/mL, about 28.5 ng/mL, about 29 ng/mL, about 29.5 ng/mL, about 30 ng/mL, about 30.5 ng/mL, about 31 ng/mL, and about 31.5 ng/mL, inclusive of all values and subranges therebetween.

[00152] In some embodiments, the pharmaceutical compositions described herein provide a Cmaxi of Zaleplon within the range of about 80% to about 125% of about 18.212 (48.3%) ng/mL following oral administration of about 20 mg of Zaleplon, e.g., about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, about 10.5 ng/mL, about 11 ng/mL, about 11.5 ng/mL, about 12 ng/mL, about 12.5 ng/mL, about 13 ng/mL, about 13.5 ng/mL, about 14 ng/mL, about 14.5 ng/mL, about 15 ng/mL, about 15.5 ng/mL, about 16 ng/mL, about 16.5 ng/mL, about 17 ng/mL, about 17.5 ng/mL, about 18 ng/mL, about 18.5 ng/mL, about 19 ng/mL, about 19.5 ng/mL, about 20 ng/mL, 20.5 ng/mL, about 21 ng/mL, about 21.5 ng/mL, about 22 ng/mL, about 22.5 ng/mL, about 23 ng/mL, about 23.5 ng/mL, about 24 ng/mL, about 24.5 ng/mL, about 25 ng/mL, about 25.5 ng/mL, about 26 ng/mL, about 26.5 ng/mL, about 27 ng/mL, about 27.5 ng/mL, about 28 ng/mL, about 28.5 ng/mL, about 29 ng/mL, about 29.5 ng/mL, about 30 ng/mL, about 30.5 ng/mL, about 31 ng/mL, about 31.5 ng/mL, about 32 ng/mL, about 32.5 ng/mL, about 33 ng/mL, about 33.5 ng/mL, and about 34 ng/mL, inclusive of all values and subranges therebetween.

[00153] In some embodiments, the pharmaceutical compositions described herein provide a Cmaxi of Zaleplon within the range of about 80% to about 125% of about 15.469 (39.8%) ng/mL following oral administration of about 20 mg of Zaleplon, e.g., about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, about 10.5 ng/mL, about 11 ng/mL, about 11.5 ng/mL, about 12 ng/mL, about 12.5 ng/mL, about 13 ng/mL, about 13.5 ng/mL, about 14 ng/mL, about 14.5 ng/mL, about 15 ng/mL, about 15.5 ng/mL, about 16 ng/mL, about 16.5 ng/mL, about 17 ng/mL, about 17.5 ng/mL, about 18 ng/mL, about 18.5 ng/mL, about 19 ng/mL, about 19.5 ng/mL, about 20 ng/mL, about 20.5 ng/mL, about 21 ng/mL, about 21.5 ng/mL, about 22 ng/mL, about 22.5 ng/mL, about 23 ng/mL, about 23.5 ng/mL, about 24 ng/mL, about 24.5 ng/mL, about 25 ng/mL, about 25.5 ng/mL, about 26 ng/mL, about 26.5 ng/mL, about 27 ng/mL, about 27.5 ng/mL, and about 28 ng/mL, inclusive of all values and subranges therebetween.

[00154] In some embodiments, the pharmaceutical compositions described herein provide a Cmaxi of Zaleplon within the range of about 80% to about 125% of about 18.443 (45.9%) ng/mL following oral administration of about 20 mg of Zaleplon, e.g., about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, about 10.5 ng/mL, about 11 ng/mL, about 11.5 ng/mL, about 12 ng/mL, about 12.5 ng/mL, about 13 ng/mL, about 13.5 ng/mL, about 14 ng/mL, about 14.5 ng/mL, about 15 ng/mL, about 15.5 ng/mL, about 16 ng/mL, about 16.5 ng/mL, about 17 ng/mL, about 17.5 ng/mL, about 18 ng/mL, about 18.5 ng/mL, about 19 ng/mL, about 19.5 ng/mL, about 20 ng/mL, about 20.5 ng/mL, about 21 ng/mL, about 21.5 ng/mL, about 22 ng/mL, about 22.5 ng/mL, about 23 ng/mL, about 23.5 ng/mL, about 24 ng/mL, about 24.5 ng/mL, about 25 ng/mL, about 25.5 ng/mL, about 26 ng/mL, about 26.5 ng/mL, about 27 ng/mL, about 27.5 ng/mL, about 28 ng/mL, about 28.5 ng/mL, about 29 ng/mL, about 29.5 ng/mL, about 30 ng/mL, about 30.5 ng/mL, about 31 ng/mL, about 31.5 ng/mL, about 32 ng/mL, about 32.5 ng/mL, about 33 ng/mL, about 33.5 ng/mL, and about 34 ng/mL, inclusive of all values and subranges therebetween.

[00155] In some embodiments, the pharmaceutical compositions described herein provide a second average maximum plasma concentration (Cmax₂) of Zaleplon which is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, or about 85%, or about 90% lower than the Cmaxi. In other embodiments, the Cmax₂ of Zaleplon is about 25% to about 95% of Cmaxi, e.g., about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, and about 90%,

[00156] In some embodiments, the pharmaceutical compositions of the present disclosure provide a Cmax₂ of Zaleplon that is within about 80% to about 125% of the range of about 2 ng/mL to about 10 ng/mL after oral administration of about 20 mg of Zaleplon (e.g., in embodiments, in which the TDR component includes about 5 mg of Zaleplon), including about 1 ng/mL, about 1.5 ng/mL, about 2 ng/mL, about 2.5 ng/mL, about 3 ng/mL, about 3.5 ng/mL, about 4.0 ng/mL, about 4.5 ng/mL, about 5 ng/mL, about 5.5 ng/mL, about 6.0 ng/mL, about 6.5 ng/mL, about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, about 10.5 ng/mL, about 11 ng/mL, about 1 1.5 ng/mL, about 12 ng/mL, about 12.5 ng/mL, about 13 ng/mL, about 13.5 ng/mL, and about 14 ng/mL, inclusive of all values and subranges therebetween.

[00157] In some embodiments, the pharmaceutical compositions provide a Cmax₂ of

Zaleplon that is within about 80% to about 125% of about 1 ng/mL to about 5 ng/mL after oral administration of about 10 mg of Zaleplon (e.g., in embodiments in which the TDR component comprises 2.5 mg Zaleplon), including about 0.5 ng/mL, about 1 ng/mL, about 1.5 ng/mL, about 2 ng/mL, about 2.5 ng/mL, about 3 ng/mL, about 3.5 ng/mL, about 4.0 ng/mL, about 4.5 ng/mL, about 5 ng/mL, about 5.5 ng/mL, about 6.0 ng/mL, about 6.5 ng/mL, about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL.

[00158] In some embodiments, the pharmaceutical compositions described herein provide

Cmax₂ of Zaleplon within the range of about 80%> to about 125% of about 5.776 ng/mL to about 18.753 ng/mL following oral administration of about 20 mg of Zaleplon, e.g., about 4.0 ng/mL, about 4.5 ng/mL, about 5 ng/mL, about 5.5 ng/mL, about 6.0 ng/mL, about 6.5 ng/mL, about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, about 10.5 ng/mL, about 11 ng/mL, about 11.5 ng/mL, about 12 ng/mL, about 12.5 ng/mL, about 13 ng/mL, about 13.5 ng/mL, about 14 ng/mL, about 14.5 ng/mL, about 15 ng/mL, about 15.5 ng/mL, about 16 ng/mL, about 16.5 ng/mL, about 17 ng/mL, about 17.5 ng/mL, about 18 ng/mL, about 18.5 ng/mL, about 19 ng/mL, about 19.5 ng/mL, about 20 ng/mL, about 20.5 ng/mL, and about 21 ng/mL, inclusive of all values and subranges therebetween.

[00159] In some embodiments, the pharmaceutical compositions described herein provide an second average maximum plasma concentration (e.g., Cmax₂) of Zaleplon (e.g., a Cmax associated with a first TDR component) within about 80% to about 125% of the range of about 2.0 ng/mL to about 15.0 ng/mL following oral administration of about 20 mg of Zaleplon, e.g., about 1.5 ng/mL, about 2.0 ng/mL, about 2.5 ng/mL, about 3.0 ng/mL, about 3.5 ng/mL, about 4.0 ng/mL, about 4.5 ng/mL, about 5 ng/mL, about 5.5 ng/mL, about 6.0 ng/mL, about 6.5 ng/mL, about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, about 10.5 ng/mL, about 11 ng/mL, about 11.5 ng/mL, about 12 ng/mL, about 12.5 ng/mL, about 13 ng/mL, about 13.5 ng/mL, about 14 ng/mL, about 14.5 ng/mL, about 15 ng/mL, about 15.5 ng/mL, about 16 ng/mL, about 16.5 ng/mL, about 17 ng/mL, about 17.5 ng/mL, about 18 ng/mL, about 18.5 ng/mL, and about 19 ng/mL, inclusive of all values and subranges therebetween.

[00160] In some embodiments, the pharmaceutical compositions described herein provide an second average maximum plasma concentration (e.g., Cmax₂) of Zaleplon (e.g., a Cmax associated with a first TDR component) within the range of about 80% to about 125% of about 1.5 ng/mL to about 13.0 ng/mL following oral administration of about 12.5 mg of Zaleplon, e.g., about 1, about 1.5 ng/mL, about 2.0 ng/mL, about 2.5 ng/mL, about 3.0 ng/mL, about 3.5 ng/mL, about 4.0 ng/mL, about 4.5 ng/mL, about 5 ng/mL, about 5.5 ng/mL, about 6.0 ng/mL, about 6.5 ng/mL, about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, about 10.5 ng/mL, about 11 ng/mL, about 11.5 ng/mL, about 12 ng/mL, about 12.5 ng/mL, about 13 ng/mL, about 13.5 ng/mL, about 14 ng/mL, about 14.5 ng/mL, and about 15 ng/mL, inclusive of all values and subranges therebetween.

[00161] In some embodiments, the pharmaceutical compositions described herein provide a Cmax₂ of Zaleplon within the range of about 80% to about 125% of about 11.858 (23.6%) ng/mL following oral administration of about 20 mg of Zaleplon, e.g., about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, about 10.5 ng/mL, about 11 ng/mL, about 11.5 ng/mL, about 12 ng/mL, about 12.5 ng/mL, about 13 ng/mL, about 13.5 ng/mL, about 14 ng/mL, about 14.5 ng/mL, about 15 ng/mL, about 15.5 ng/mL, about

16 ng/mL, about 16.5 ng/mL, about 17 ng/mL, about 17.5 ng/mL, about 18 ng/mL, about 18.5 ng/mL, about 19 ng/mL, about 19.5 ng/mL, about 20 ng/mL, about 20.5 ng/mL, and about 21 ng/mL, inclusive of all values and subranges therebetween.

[00162] In some embodiments, the pharmaceutical compositions described herein provide a Cmax₂ of Zaleplon within the range of about 80% to about 125% of about 12.969 (44.6%) ng/mL following oral administration of about 20 mg of Zaleplon, e.g., about 6.0 ng/mL, about 6.5 ng/mL, about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, about 10.5 ng/mL, about 11 ng/mL, about 11.5 ng/mL, about 12 ng/mL, about 12.5 ng/mL, about 13 ng/mL, about 13.5 ng/mL, about 14 ng/mL, about 14.5 ng/mL, about 15 ng/mL, about 15.5 ng/mL, about 16 ng/mL, about 16.5 ng/mL, about 17 ng/mL, about 17.5 ng/mL, and about 18 ng/mL, inclusive of all values and subranges therebetween. [00163] In some embodiments, the pharmaceutical compositions described herein provide a Cmax2 of Zaleplon within the range of about 80% to about 125% of about 9.331 (38.1%) ng/mL following oral administration of about 20 mg of Zaleplon, e.g., about 4.0 ng/mL, about 4.5 ng/mL, about 5 ng/mL, about 5.5 ng/mL, about 6.0 ng/mL, about 6.5 ng/mL, about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, about 10.5 ng/mL, about 11 ng/mL, about 11.5 ng/mL, about 12 ng/mL, about 12.5 ng/mL, about 13 ng/mL, about 13.5 ng/mL, about 14 ng/mL, about 14.5 ng/mL, about 15 ng/mL, about 15.5 ng/mL, about 16 ng/mL, about 16.5 ng/mL, and about 17 ng/mL, inclusive of all values and subranges therebetween.

[00164] In embodiments in which the pharmaceutical composition comprises two TDR components (referred as a first TDR component and a second TDR component), the first TDR component provides any of the Cmax₂ values set forth above, and the second TDR component provides an average maximum plasma concentration of Zaleplon (Cmax₃) within the range of about 80%) to about 125% of about 7.115 (36.4%) ng/mL following oral administration of about 20 mg of Zaleplon, e.g., about 3.0 ng/mL, about 3.5 ng/mL, about 4.0 ng/mL, about 4.5 ng/mL, about 5 ng/mL, about 5.5 ng/mL, about 6.0 ng/mL, about 6.5 ng/mL, about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, about 10.5 ng/mL, about 11 ng/mL, about 11.5 ng/mL, about 12 ng/mL, about 12.5 ng/mL, and about 13 ng/mL, inclusive of all values and subranges therebetween.

[00165] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated to provide an area under the plasma concentration-time curve from dosing to the last observed concentration (AUCo-t) of Zaleplon within about 80% to about 125% of the range of from about 20 h*ng/mL to about 125 h*ng/mL after oral administration of from about 10 to about 20 mg Zaleplon, e.g., about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 20, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 100, about 101, about 102, about 103, about 104, about 105, about 106, about 107, about 108, about 109, about 1 10, about 1 1 1, about 1 12, about 1 13, about 1 14, about 1 15, about 1 16, about 1 17, about 1 18, about 1 19, about 120, about 121, about 122, about 123, about 124, about 125, about 126, about 127, about 128, about 129, about 130, about 131, about 132, about 133, about 134, about 135, about 136, about 137, about 138, about 139, about 140 h*ng/mL, about 141, about 142, about 143, about 144, about 145, about 146, about 147, about 148, about 149, about 150, about 151, about 152, about 153, about 154, about 155, about 156, about 157, about 158, about 159, and about 160 *ng/mL inclusive of all values and subranges therebetween.

[00166] In some embodiments, the pharmaceutical compositions described herein provide an AUCo-t within the range of about 80% to about 125% of about 45 h*ng/mL to about 1 10 h*ng/mL following oral administration of about 20 mg Zaleplon, e.g., about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 100, about 101, about 102, about 103, about 104, about 105, about 106, about 107, about 108, about 109, about 1 10, about 1 1 1, about 1 12, about 1 13, about 1 14, about 1 15, about 1 16, about 1 17, about 1 18, about 1 19, about 120, about 121, about 122, about 123, about 124, about 125, about 126, about 127, about 128, about 129, and about 130 h*ng/mL, inclusive of all values and subranges therebetween.

[00167] In some embodiments, the pharmaceutical compositions described herein provide

AUCo-t of Zaleplon within the range of about 80% to about 125% of about 25 h*ng/mL to about 55 h*ng/mL following oral administration of about 10 mg Zaleplon, e.g., about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, and about 75, inclusive of all values and subranges therebetween.

[00168] In some embodiments, the pharmaceutical compositions described herein provide an AUCo-t within the range of about 80% to about 125% of about 30 h*ng/mL to about 80 h*ng/mL following oral administration of about 15 mg Zaleplon, e.g., about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, and about 100, inclusive of all values and subranges therebetween.

[00169] In some embodiments, the pharmaceutical compositions described herein provide an AUCo-t within the range of about 80% to about 125% of about 25 h*ng/mL to about 70 h*ng/mL following oral administration of about 12.5 mg Zaleplon, e.g., about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about

43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about

53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, inclusive of all values and subranges therebetween.

[00170] In some embodiments, the pharmaceutical compositions described herein provide an AUCo-t within the range of about 80% to about 125% of about 79.731 (27.6) h*ng/mL following oral administration of about 20 mg Zaleplon, e.g., about 40, about 41, about 42, about 43, about

44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about

54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 100, about 101, about 102, about 103, about 104, about 105, about 106, about 107, about 108, about 109, about 1 10, about 1 1 1, about 1 12, about 1 13, about 1 14, about 1 15, about 1 16, about 1 17, about 1 18, about 1 19, about 120, about 121, about 122, about 123, about 124, about 125, about 126, about 127, about 128, about 129, and about 130 h*ng/mL, inclusive of all values and subranges therebetween.

[00171] In some embodiments, the pharmaceutical compositions described herein provide an AUCo-t within the range of about 80% to about 125% of about 71.249 (34.8) h*ng/mL following oral administration of about 20 mg Zaleplon, e.g., about 34, about 35, about 36, about 37, about

38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about

48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about

58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about

68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about

78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about

88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 100, about 101, about 102, about 103, about 104, about 105, about 106, about 107, about 108, about 109, about 1 10, about 1 1 1, about 1 12, about 1 13, about 1 14, about 1 15, about 1 16, about 1 17, about 1 18, about 1 19, about 120, about 121, about 122, about 123, about 124, about 125, about 126, about 127, about 128, about 129, and about 130 h*ng/mL, inclusive of all values and subranges therebetween.

[00172] In some embodiments, the pharmaceutical compositions described herein provide an AUCo-t within the range of about 80% to about 125% of about 72.093 (32.6) h*ng/mL following oral administration of about 20 mg Zaleplon, e.g., about 35, about 36, about 37, about 38, about

39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about

49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about

59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about

69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about

79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about

89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 100, about 101, about 102, about 103, about 104, about 105, about 106, about 107, about 108, about 109, about 1 10, about 1 1 1, about 1 12, about 1 13, about 1 14, about 1 15, about 1 16, about 1 17, about 1 18, about 1 19, about 120, about 121, about 122, about 123, about 124, about 125, about 126, about 127, about 128, about 129, about 130, about 131, about 132, about 133, about 134, and about 135 h*ng/mL, inclusive of all values and subranges therebetween.

[00173] In some embodiments, the pharmaceutical compositions described herein provide an area under the plasma concentration-time curve from dosing extrapolated to infinity of Zaleplon (AUCo-inf) within the range of about 80% to about 125% of about 47.562 h*ng/mL to about 106.426 h*ng/mL following oral administration of about 20 mg Zaleplon, e.g., about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about

85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 100, about 101, about 102, about 103, about 104, about 105, about 106, about 107, about 108, about 109, about 1 10, about 1 1 1, about 1 12, about 1 13, about 1 14, about 1 15, about 1 16, about 1 17, about 1 18, about 1 19, about 120, about 121, about 122, about 123, about 124, about 125, about 126, about 127, about 128, about 129, about 130, about 131, about 132, about 133, about 134, and about 135 h*ng/mL, inclusive of all values and subranges therebetween.

[00174] In some embodiments, the pharmaceutical compositions described herein provide an AUCo-inf within about 80% to about 125% of the range of about 30 h*ng/mL to about 80 h*ng/mL following oral administration of about 15 mg Zaleplon, e.g., about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about

86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, and about 100, inclusive of all values and subranges therebetween.

[00175] In some embodiments, the pharmaceutical compositions described herein provide an AUCo-inf within about 80% to about 125% of the range of about 25 h*ng/mL to about 70 h*ng/mL following oral administration of about 12.5 mg Zaleplon, e.g., about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, inclusive of all values and subranges therebetween.

[00176] In some embodiments, the pharmaceutical compositions described herein provide an AUCo-inf within about 80% to about 125% of the range of about 20 h*ng/mL to about 60 h*ng/mL following oral administration of about 10 mg Zaleplon, e.g., about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, and about 75, inclusive of all values and subranges therebetween.

[00177] In some embodiments, the pharmaceutical compositions described herein provide an AUCo-inf within the range of about 80% to about 125% of about 83.145 (28.0) h*ng/mL following oral administration of about 20 mg Zaleplon, e.g., about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about

97, about 98, about 99, about 100, about 101, about 102, about 103, about 104, about 105, about

106, about 107, about 108, about 109, about 1 10, about 1 1 1, about 1 12, about 1 13, about 1 14, about 1 15, about 1 16, about 1 17, about 1 18, about 1 19, about 120, about 121, about 122, about

123, about 124, about 125, about 126, about 127, about 128, about 129, about 130, about 131, about 132, about 133, about 134, and about 135 h*ng/mL, inclusive of all values and subranges therebetween.

[00178] In some embodiments, the pharmaceutical compositions described herein provide an AUCo-inf within the range of about 80% to about 125% of about 74.666 (36.3) h*ng/mL following oral administration of about 20 mg Zaleplon, e.g., about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about

88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about

98, about 99, about 100, about 101, about 102, about 103, about 104, about 105, about 106, about

107, about 108, about 109, about 1 10, about 1 1 1, about 1 12, about 1 13, about 1 14, about 1 15, about 1 16, about 1 17, about 1 18, about 1 19, about 120, about 121, about 122, about 123, about

124, about 125, about 126, about 127, about 128, about 129, and about 130 h*ng/mL, inclusive of all values and subranges therebetween.

[00179] In some embodiments, the pharmaceutical compositions described herein provide an AUCo-inf within the range of about 80% to about 125% of about 75.786 (32.4) h*ng/mL following oral administration of about 20 mg Zaleplon, e.g., about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 100, about 101, about 102, about 103, about 104, about 105, about 106, about 107, about 108, about 109, about 110, about 111, about 112, about 113, about 114, about 115, about 116, about 117, about 118, about 119, about 120, about 121, about 122, about 123, about 124, about 125, about 126, about 127, about 128, about 129, and about 130 h*ng/mL, inclusive of all values and subranges therebetween.

[00180] In some embodiments, pharmaceutical compositions of the present disclosure are formulated to provide an area under the plasma concentration-time curve from dosing to 4h (AUCo- ₄) of Zaleplon within about 80% to about 125% of the range of from about 5 h*ng/mL to about 60 h*ng/mL following oral administration of from about 10 mg to about 20 mg Zaleplon, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 20, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, and about 75 h*ng/mL, inclusive of all values and subranges therebetween.

[00181] The pharmaceutical composition of any of claims 1-20, wherein the pharmaceutical composition provides AUC0-4 of Zaleplon within the range of about 80% to about 125% of about 18 h*ng/mL to about 54 h*ng/mL after oral administration of about 20 mg Zaleplon, e.g., , e.g., about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, and about 70 h*ng/mL, inclusive of all values and subranges therebetween.

[00182] In some embodiments, the pharmaceutical compositions described herein provide an AUCo-4 within about 80% to about 125% of the range of about 18.156 h*ng/mL to about 53.579 h*ng/mL following oral administration of about 20 mg Zaleplon, e.g., about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, and about 70 h*ng/mL, inclusive of all values and subranges therebetween.

[00183] In some embodiments, the pharmaceutical compositions described herein are formulated to provide an AUCo-4 within about 80% to about 125% of the range of about 15.0 h*ng/mL to about 45.0 h*ng/mL following oral administration of about 15 mg Zaleplon, e.g., about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, and about 57, inclusive of all values and subranges therebetween.

[00184] In some embodiments, the pharmaceutical compositions described herein are formulated to provide an AUCo-4 within the range of about 80% to about 125% of about 12.5 h*ng/mL to about 40.0 h*ng/mL mL following oral administration of about 12.5 mg Zaleplon, e.g., about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, and about 46, inclusive of all values and subranges therebetween.

[00185] In some embodiments, the pharmaceutical compositions described herein provide an AUCo-4 within about 80% to about 125% of the range of about 9.0 h*ng/mL to about 27.0 h*ng/mL mL following oral administration of about 10 mg Zaleplon, e.g., about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, and about 44 h*ng/mL, inclusive of all values and subranges therebetween. [00186] In some embodiments, the pharmaceutical compositions described herein provide an AUCo-4 within about 80% to about 125% of the range of about 39.743 (32.9) h*ng/mL following oral administration of about 20 mg Zaleplon, e.g., about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, and about 70 h*ng/mL, inclusive of all values and subranges therebetween.

[00187] In some embodiments, the pharmaceutical compositions described herein provide an AUCo-4 within about 80% to about 125% of the range of about 31.303 (42.0) h*ng/mL following oral administration of about 20 mg Zaleplon, e.g., about 10, about 1 1, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, and about 60 h*ng/mL, inclusive of all values and subranges therebetween.

[00188] In some embodiments, the pharmaceutical compositions described herein provide an AUCo-4 within about the range of about 80% to about 125% of about 38.657 (38.6) h*ng/mL following oral administration of about 20 mg Zaleplon, e.g., about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64,about 65, about 66, about 67, about 68, about 69, and about 70 h*ng/mL, inclusive of all values and subranges therebetween.

[00189] In some embodiments, the pharmaceutical compositions are formulated to provide an area under the plasma concentration-time curve from 4h to 8h post-dosing (AUC4-8) of Zaleplon within about 80% to about 125% of the range of from about 5 h*ng/mL to about 45 h*ng/mL after oral administration of from about 10 mg to about 20 mg Zaleplon, e.g., about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 20, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, and about 60 h*ng/mL, inclusive of all values and subranges therebetween.

[00190] In some embodiments, the pharmaceutical compositions are formulated to provide an AUC4-8 of Zaleplon within about 80% to about 125% of the range of about 13 h*ng/mL to about 41 h*ng/mL after oral administration of about 20 mg Zaleplon, e.g., about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 20, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, inclusive of all values and subranges therebetween.

[00191] In some embodiments, the pharmaceutical compositions are formulated to provide an AUC4-8 of Zaleplon within about 80% to about 125% of the range of from about 7 h*ng/mL to about 21 h*ng/mL after oral administration of about 10 mg Zaleplon, e.g., about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 20, about 30, about 31, about 32, about 33, about 34, about 35,

[00192] In some embodiments, the pharmaceutical compositions described herein provide an AUC4-8 within the range of about 80% to about 125% of about 13.466 h*ng/mL to about 40.613 h*ng/mL following oral administration of about 20 mg Zaleplon, e.g., e.g., about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, and about 55 h*ng/mL, inclusive of all values and subranges therebetween. [00193] In some embodiments, the pharmaceutical compositions described herein provides an area under the plasma concentration-time curve of Zaleplon from 4h to 8h post-dosing (AUC_4- ₈) within the range of about 80% to about 125% of about 10.0 h*ng/mL to about 30.0 h*ng/mL following oral administration of about 15 mg Zaleplon, e.g., about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, and about 38, inclusive of all values and subranges therebetween.

[00194] In some embodiments, the pharmaceutical compositions described herein provides an AUC₄-₈ within about 80% to about 125% of the range of about 8.0 h*ng/mL to about 25.0 h*ng/mL following oral administration of about 12.5 mg Zaleplon, e.g., about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, and about 32, inclusive of all values and subranges therebetween.

[00195] In some embodiments, the pharmaceutical compositions described herein provide an AUC_4-8 within the range of about 80% to about 125% of about 31.145 (30.4) h*ng/mL following oral administration of about 20 mg Zaleplon, e.g., about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, and about 55 h*ng/mL, inclusive of all values and subranges therebetween.

[00196] In some embodiments, the pharmaceutical compositions described herein provides an AUC_4-8 within the range of about 80% to about 125% of about 13.466 h*ng/mL to about 40.613 h*ng/mL following oral administration of about 20 mg Zaleplon, e.g., about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, and about 55 h*ng/mL, inclusive of all values and subranges therebetween.

[00197] In some embodiments, the pharmaceutical compositions described herein provide an AUC4-8 within the range of about 80% to about 125% of about 28.131 (40.2) h*ng/mL following oral administration of about 20 mg Zaleplon, e.g., about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, and about 55 h*ng/mL, inclusive of all values and subranges therebetween.

[00198] In some embodiments, the pharmaceutical compositions described herein provide an AUC4-8 within the range of about 80% to about 125% of about 23.460 (42.6) h*ng/mL following oral administration of about 20 mg Zaleplon, e.g., about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, and about 45 h*ng/mL, inclusive of all values and subranges therebetween.

[00199] In some embodiments, the time to reach the first maximum plasma concentration

(Tmaxi) of Zaleplon within the range of about 80% to about 125% of about 1 h to about 2 h, e.g., about 0.7 h, about 0.8 h, about 0.9 h, about 1.0 h, about 1.1 h, about 1.2 h, about 1.3 h, about 1.4 h, about 1.5 h, about 1.6 h, about 1.7 h, about 1.8 h, about 1.9 h, about 2.0 h, about 2.1 h, and about 2.2 h, inclusive of all values and subranges therebetween. In particular embodiments, the Tmaxi of Zaleplon within the range of about 80% to about 125% of about 1.5 (±0.33).

[00200] In some embodiments, the time to reach the second maximum plasma concentration

(Tmax₂) of Zaleplon within the range of about 80% to about 125% of about 3 h to about 6 h, e.g., about 2.5 h, about 2.6 h, about 2.7 h, about 2.8 h, about 2.9 h, about 3.0 h, about 3.1 h, about 3.2 h, about 3.3 h, about 3.4 h, about 3.5 h, about 3.6 h, about 3.7 h, about 3.8 h, about 3.9 h, about 4.0 h, about 4.1 h, about 4.2 h, about 4.3 h, about 4.4 h, about 4.5 h, about 4.6 h, about 4.7 h, about 4.8 h, about 4.9 h, about 5.0 h, about 5.1 h, about 5.2 h, about 5.2 h, about 5.3 h, about 5.4 h, about 5.5 h, about 5.6 h, about 5.7 h, about 5.8 h, about 5.9 h, about 6.0 h, about 6.1 h, about 6.2 h, about 6.3 h, about 6.4 h, about 6.5 h, about 6.6 h, about 6.7 h, about 6.8 h, about 6.9 h, about 7.0 h, about 7.1 h, about 7.2 h, about 7.3 h, about 7.4 h, and about 7.5 h, inclusive of all values and subranges therebetween. In particular embodiments, the Tmax₂ of Zaleplon within the range of about 80% to about 125% of about 5.0 (±3.5).

[00201] In embodiments in which the pharmaceutical composition comprises two TDR components (referred as a first TDR component and a second TDR component), the first TDR component provides any of the Tmax₂ values set forth above, and the second TDR component provides an average time to maximum plasma concentration of Zaleplon (Tmax₃) within the range of about 80%) to about 125% of about 5 h to about 8 h, e.g., about 3.8 h, about 3.9 h, about 4.0 h, about 4.1 h, about 4.2 h, about 4.3 h, about 4.4 h, about 4.5 h, about 4.6 h, about 4.7 h, about 4.8 h, about 4.9 h, about 5.0 h, about 5.1 h, about 5.2 h, about 5.2 h, about 5.3 h, about 5.4 h, about 5.5 h, about 5.6 h, about 5.7 h, about 5.8 h, about 5.9 h, about 6.0 h, about 6.1 h, about 6.2 h, about 6.3 h, about 6.4 h, about 6.5 h, about 6.6 h, about 6.7 h, about 6.8 h, about 6.9 h, about 7.0 h, about 7.1 h, about 7.2 h, about 7.3 h, about 7.4 h, about 7.5 h, about 7.6 h, about 7.7 h, about 7.8 h, about 7.9 h, about 8.0 h, about 8.1 h, about 8.2 h, about 8.3 h, about 8.4 h, about 8.5 h, about 8.6 h, about 8.7 h, about 8.8 h, about 8.9 h, about 9.0 h, about 9.1 h, about 9.2 h, about 9.3 h, about 9.4 h, and about 9.5 h, about 9.6 h, about 9.7 h, about 9.8 h, about 9.9 h, about 10.0 h, about 10.1 h, about 10.2 h, about 10.3 h, about 10.4 h, and about 10.5 h, inclusive of all values and subranges therebetween. In particular embodiments, the Tmax₃ of Zaleplon within the range of about 80%> to about 125% of about 6.5 (±4.5).

[00202] In some embodiments, the plasma concentration of Zaleplon at a time point between about seven to about nine hours (e.g., at about eight) hours following administration of a composition of the invention to a patient is within the range of from about 6 ng/mL to about 2 ng/mL, e.g., about 5.9, about 5.8, about 5.7, about 5.6, about 5.5, about 5.4, about 5.3, about 5.2, about 5.1, about 5.0, about 4.9, about 4.8, about 4.7, about 4.6, about 4.5, about 4.4, about 4.3, about 4.2, about 4.1, about 4.0, about 3.9, about 3.8, about 3.7, about 3.6, about 3.5, about 3.4, about 3.3, about 3.2, about 3.1, about 3.0, about 2.9, about 2.8, about 2.7, about 2.6, about 2.5, about 2.4, about 2.3, about 2.2, about 2.1 , about 2.0, about 1.9, about 1.8, about 1.7, about 1.6, about 1.5, about 1.4, about 1.3, about 1.2, about 1.1, or 1.0 ng/m or less, inclusive of all values and ranges therebetween. [00203] In a particular embodiment, following Tmaxi and prior to Tmax₂, the plasma concentration of Zaleplon reduces to a minimum concentration which is between about 5% and about 50% of the plasma concentration at Tmaxi, e.g., about 10%, about 15%, about 20%, about 25%), about 30%), about 35%, about 40%, and about 45%, inclusive of all values and subranges therebetween.

[00204] In another particular embodiment, the average plasma concentration of Zaleplon at a time point from about 5-6 hours is at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50% lower than Cmaxi. In other embodiments, the average plasma concentration of Zaleplon at time point from about 5 hours to about 6 hours following oral administration which is about 30%) to about 60% of the Cmaxi, e.g., about 35%, about 40%, about 45%, about 50%, and about 55%), inclusive of all value and subranges therebetween.

[00205] In some embodiments, the pharmaceutical composition provides an average plasma concentration of Zaleplon at a time point from about 7 hours to about 9 hours following oral administration which is about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, and about 45%, about 50%, about 55%, about 60%, about 65%, about 75%, about 80%), about 85%), or about 90%. of Cmaxi. In other embodiments, the pharmaceutical composition provides an average plasma concentration of Zaleplon at a time point from about 5 hours to about 9 hours following oral administration which is about 10% to about 60% of the Cmaxi, e.g., about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, and about 45%, about 50%, about 55%), inclusive of all values and subranges therebetween.

[00206] In some embodiments, the disclosure provides for a biphasic pulsatile drug delivery system comprising an IR component and one TDR component (e.g. acid-resistant DR or TPR particles), that provides a combined plasma concentration profile to achieve sleep induction within about 30 minutes and sleep maintenance over about 7 hours, and substantially tapers off after about 7-8 hours to less than about 6 ng/mL (e.g., about 5.5 ng/mL, about 5 ng/mL, about 4.5 ng/mL, about 4 ng/mL, about 3.5 ng/mL, about 3 ng/mL, about 2.5 ng/mL, about 2 ng/mL, about 1.5 ng/mL, about 1 ng/mL), in order to allow the patient to avoid experiencing significant severe side- effects, such as somnolence, dizziness, as well as next-day impaired motor function, memory and reaction time. [00207] In other embodiments, the disclosure provides a triphasic pulsatile drug delivery system comprising an IR component and two TDR components (e.g. two TPR particle populations, or one TPR particle population together with one DR or acid-resistant DR particle population), that provides a combined plasma concentration profile to achieve sleep induction within about 30 minutes and sleep maintenance over about 7 hours, and substantially tapers off after about 7-8 hours to less than about 6 ng/mL (e.g., about 5.5 ng/mL, about 5 ng/mL, about 4.5 ng/mL, about 4 ng/mL, about 3.5 ng/mL, about 3 ng/mL, about 2.5 ng/mL, about 2 ng/mL, about 1.5 ng/mL, about 1 ng/mL), in order to allow the patient to avoid experiencing significant severe side-effects, such as somnolence, dizziness, as well as next-day impaired motor function, memory and reaction time.

Lag Time

[00208] As discussed above, in various embodiments, the TDR component is coated with a lag-time coating or delayed-release coating which prevents release of the drug from the pharmaceutical composition for a certain period of time following administration. The lag time of the one or more TDR components may be any appropriate amount of time following release of Zaleplon from the IR component which allows for sufficient a blood plasma concentration of Zaleplon to be maintained to promote sleep maintenance while limiting next-day side effects.

[00209] In some embodiments, the TDR component has a lag time of from about 2 hours to about 6 hours after administration before drug release from the TDR component occurs, e.g, about 2, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5 hours, and about 6, inclusive of all values and subranges therebetween. In a particular embodiment, the TDR component has a lag time of from about 2 to about 4 hours after administration before drug release from the TDR component, e.g., about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, and about 3.9, inclusive of all values and subrange therebetween.

[00210] In some embodiments, the TDR component is a TPR particle which has a lag-time of about 3 to about 4 hours following oral administration before drug release from the TPR particle occurs, e.g., about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, and about 3.9 hours, inclusive of all values and subrange therebetween. In other embodiments, the TDR component is a TPR particle which has a lag-time of about 2 to about 3 hours following oral administration before drug release from the TPR particle occurs, e.g., about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, and about 2.9 hours, inclusive of all values and subrange therebetween.

[00211] In still other embodiments, the TDR component is a DR particle which has a lag- time of about 3 to about 4 hours following oral administration before drug release from the TPR particle occurs, e.g., about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, and about 3.9 hours, inclusive of all values and subrange therebetween. In yet still other embodiments, the TDR component is a DR particle which has a lag-time of about 2 to about 3 hours following oral administration before drug release from the TPR particle occurs, e.g., about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, and about 2.9 hours, inclusive of all values and subrange therebetween.

[00212] In embodiments in which the composition comprise at least two TDR components

(which may be referred to as a first TDR component and a second TDR component), the first TDR component may have any lag time set forth above, and the second TDR component may have a lag-time of about 3 to about 6 hours following administration before release of Zaleplon, e.g., about 3.5, about 4.0, about 4.5, about 5.5 hours, and about 6 hours, inclusive of all values and subranges therebetween. In particular embodiments, the second TPR component has a lag time of about 4 to about 6 hours, e,g„ about 4.5 to about 5.5 hours (including about 4.0, about 4.5, about 5.5 hours, and about 6 hours) following administration before release of Zaleplon.

[00213] In embodiments, the first TDR component and the second TDR component are in the form of particles. In a particular embodiment, the first TPR particle population exhibits a short lag time (e.g. about 2-3 hours) and the second TPR particle population exhibits a lag time of about 4 hours following oral administration.

Release Profiles

[00214] As used herein, "complete release" refers to release of at least about 90% (e.g., about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%), about 99%>) of Zaleplon. In some embodiments, drug release is described with respect to the pharmaceutical composition. For example, in some embodiments, In other embodiments, drug release is described with respect to a particular component of the composition, for example, release from a TDR component. [00215] In embodiments, the pharmaceutical compositions described herein provide for multiphasic drug release for up to about 4-7 hours following administration (e.g., up to about 4.5, about 5.0, about 5.5, about 6.0, and about 6.5 hours), in order to maintain therapeutically effective plasma concentrations of Zaleplon for up 8 hours. For example, in certain embodiments, the disclosure provides for a biphasic pulsatile drug delivery system comprising an IR component and a TDR component, in which the IR component completely releases Zaleplon within about 2 hours following administration (e.g., within about 30 minutes), and the TDR component completely releases Zaleplon over a period of from about 2-6 hours following administration. In other embodiments, the disclosure provides a triphasic pulsatile drug delivery system, in which an IR component completely releases Zaleplon within about 2 hours following administration, a first TDR component completely releases Zaleplon over a period of from about 2-6 hours following administration, and a second TDR component completely releases Zaleplon over a period of from about 4-7 hours following administration.

[00216] In particular embodiments, a first drug release (e.g., from the IR component, such as IR particles) occurs over about 0.5 to 2 hours, about 0.6, about 0.7, about 0.8, about, about 09, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 hours, inclusive of all values and subranges therebetween. In preferred embodiments, the IR component substantially releases Zaleplon with 1 hour (e.g., within 30 minutes) following oral administration. In other preferred embodiments the MIR component substantially releases Zaleplon within 2 hours following oral administration.

[00217] In some embodiments, the second drug release (e.g., from the TDR component in the biphasic or triphasic pulsatile drug delivery systems described herein) occurs from about 2 to about 7 hours following oral administration, e.g., about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, and about 6.5 hours, inclusive of all values and subranges therebetween. In particular embodiments in which the pharmaceutical composition is a biphasic pulsatile drug delivery system comprising an IR component and one TDR component, drug release from the TDR component occurs from about 2 to about 6 hours following oral administration, e.g., about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, inclusive of all values and subranges therebetween. For example, drug release from the TDR component can occur for about 0.5 to about 4 hours following the lag time of the TDR component, e.g., about 1, about 1.5, about 2.0, about 2.5, about 3.0, and about 3.5 hours, inclusive of all values and subranges therebetween.

[00218] In embodiments in which the pharmaceutical composition is a triphasic pulsatile drug delivery system comprising an IR component and two TDR components, the first TDR component provides any drug release profile set forth above (e.g., from about 2-4 hours following oral administration), and drug release from the second TDR component occurs from about 4 to about 7 hours following administration, e.g., about 4.5, about 5.0, about 5.5, about 6.0, and about 6.5 hours, inclusive of all values and subranges therebetween. In particular embodiments, drug release from the second TDR component occurs from about 4 to about 6 hours following administration, e.g., about 4.5, about 5.0, and about 5.5 hours, inclusive of all values and subranges therebetween. For example, drug release from the second TDR component can occur for about 0.5 to about 2 hours following the lag time of the second TDR component.

[00219] In a particular embodiment, the delayed release of Zaleplon, following release of IR particles, is achieved in two pulses, in which the first TDR component (e.g., particles) release Zaleplon following a lag-time of about two hours after administration and the second TDR component (e.g., particles) release Zaleplon following a lag-time of about four hours from administration.

[00220] In the embodiment immediately above, the TDR component may be, for example,

DR or acid-resistant DR particles (e.g. mini-tablets) which provide for a rapid release of Zaleplon, for example with the complete release of Zaleplon from the DR or acid-resistant DR particles within about 30 to about 60 minutes following a lag-time of about two hours from administration. The second TDR component may be, for example, TPR particles (e.g. mini-tablets) which provide for the complete release of Zaleplon from the TPR particles within about one to about two hours following a lag-time of about 3 to about 4 hours.

[00221] In other embodiments, the delayed release of Zaleplon, following release of IR particles, may be achieved in a single TDR pulse (for example from a single population of acid- resistant DR particles or from TPR particles), in which the pulse releases Zaleplon following a lag- time of about two to about three hours after administration. In some such embodiments, the single population of TDR particles may be, for example, acid-resistant DR particles (e.g. DR beads) which provide for the complete release of Zaleplon from the DR particles. In another such embodiment, the single population of TDR particles may also be, for example, TPR particles (e.g. TPR mini-tablets) which provide for the complete release of Zaleplon from the TPR particles within about one to about three hours following a lag-time of about 3 to about 4 hours.

[00222] In a further embodiment, the pharmaceutical composition is a triphasic pulsatile delivery system where Zaleplon is first released within about 30 minutes from administration via IR particles, a second release of Zaleplon occurs following a lag-time of about 2 hours from administration via a first population of acid-resistant DR particles, and a third release of Zaleplon following a lag-time of about 4 hours from administration via a second population of TPR particles.

[00223] In a particular embodiment, a first drug release from the IR particles (e.g., m-IR particles) occurs over about 0.5 to 2 hours and the second drug release from the acid-resistant DR particles occurs at a lag-time of about 3 to about 4 hours following oral administration.

[00224] Release profiles from representative Zaleplon DR, acid-resistant DR and TPR beads and mini-tablets are shown in Figures 8 and 9 respectively. The presence of an enteric polymer ensures that no Zaleplon is released within the first 2 hours of dissolution testing. DR mini-tablets and TPR mini-tablets, with or without a sub-coat of enteric polymers, exhibited well defined lag-times and rapid-release of Zaleplon following the lag-time as shown in Figure 9. The lag time of TPR mini-tablets increases with increasing enteric polymer sub-coating level (i.e., applied before TPR coating). The substitution of triethyl citrate with diethyl phthalate and inclusion of talc in the coating formulation resulted in longer lag-times and/or more complete release of Zaleplon from multi-coated particles.

Dissolution Methodology

[00225] Lag time and release rate of the pharmaceutical compositions described herein or the components thereof can be determined using dissolution testing methods known in the art.

[00226] Specifically, dissolution testing for drug release profiles is performed using USP

Apparatus 1 (baskets at 100 rpm) or Apparatus 2 (paddles at 50 or 75 rpm)-and two-stage dissolution methodology (first 2 hours in 700 mL of 0.1N HC1 at 37°C followed by dissolution testing at pH 6.8 obtained by the addition of 200 mL of a pH modifier). Drug release with time is determined by UPLC on samples pulled at selected intervals. The quantitative in vitro release tests for IR/ acid-resistant DR/TPR micro-particles (beads or mini-tablets) or ZTR pulse delivery systems have been performed using USP 2-stage dissolution - HPLC methodology, as discussed in various embodiments exemplified in this invention.

[00227] In some embodiments, pharmaceutical compositions comprise two different populations of particles, where the first population of particles comprises of IR particles comprising about 50 % of the total amount of Zaleplon or a pharmaceutically acceptable salt thereof in the pharmaceutical composition, and the second population of particles comprises of DR particles comprising about 50 % of the total amount of Zaleplon or a pharmaceutically acceptable salt thereof in the pharmaceutical composition, where the composition provides for a dissolution profile, when tested using, for example, a standard USP Apparatus 1 (Baskets at 100 rpm) or 2 (Paddles at 50/75 rpm) and a two-stage dissolution media (700 mL of 0.1N HC1 at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer), where about 30% to 60% of Zaleplon is released within about 3 hours and not less than about 85% of Zaleplon is released after about 5 hours.

[00228] In some embodiments, pharmaceutical compositions comprise two different populations of particles, where the first population of particles comprises of IR particles comprising about 75 % of the total amount of Zaleplon or a pharmaceutically acceptable salt thereof in the pharmaceutical composition, and the second population of particles comprises DR particles comprising about 25 % of the total amount of Zaleplon or a pharmaceutically acceptable salt thereof in the pharmaceutical composition, where the composition provides for a dissolution profile, when tested using, for example, a standard USP Apparatus 1 (Baskets at 100 rpm) or 2 (Paddles at 50/75 rpm) and a two-stage dissolution media (700 mL of 0.1N HC1 at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer), where about 65% to 85% of Zaleplon is released within about 30 minutes and not less than 85% of Zaleplon is released after about 5 hours.

[00229] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated to provide a dissolution profile wherein about 65% to about 75% of the total amount of Zaleplon is released within about 30 minutes, and not less than 85% of the total amount of Zaleplon is released within about 5 hours when tested using a standard USP Apparatus 1 (Baskets at 100 rpm) or 2 (Paddles at 50/75 rpm) and a two-stage dissolution media (700 mL of 0.1N HC1 at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer). [00230] In some embodiments, the disclosure provides for an pharmaceutical compositions comprising three different populations of particles: (i) a population of IR particles comprising Zaleplon or a pharmaceutically acceptable salt thereof; (ii) a first population of TPR particles comprising Zaleplon or a pharmaceutically acceptable salt thereof; and (iii) the second population of TPR particles, DR particles, or acid-resistant DR particles comprising Zaleplon or a pharmaceutically acceptable salt thereof; wherein the pharmaceutical composition provides for a dissolution profile where about 30% to 50% of Zaleplon is released within about 30 minutes, about 30%) to 80%) of Zaleplon is released after about 4 hours and not less than 85%> of Zaleplon is released after about 6 hours, when the pharmaceutical oral composition is tested using, for example, a standard USP Apparatus 1 (Baskets at 100 rpm) or 2 (Paddles at 50/75 rpm) and a two- stage dissolution media (700 mL of 0.1N HC1 at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer).

Methods of Treatment

[00231] In various embodiments, the disclosure provides for methods of treating patients with insomnia comprising orally administering a pharmaceutical composition of the invention to the patient at bedtime, in order to achieve both rapid sleep onset and sleep maintenance.

[00232] In a particular embodiment, the pharmaceutical compositions of the disclosure, when administered to a patient, induces sleep in the patient within about 30 minutes of the administration. In further embodiments, the pharmaceutical compositions described herein, , when administered to a patient, provide sleep maintenance for up to about 8 hours (e.g. about 6 to about 8 hours).

[00233] In some embodiments, the pharmaceutical compositions, when administered to a patient, mitigates one or more next day side effects selected from hangover, somnolence, dizziness, impaired motor function, memory and reaction time (e.g., measuring used the pharmacodynamic assessments described herein).

[00234] In yet a further embodiment, the pharmaceutical compositions disclosed herein, when administered to a patient, provide for a biphasic pulsatile delivery of the drug to induce sleep within about 30 minutes of the administration, and provide sleep maintenance for up to about 8 hours, wherein the plasma concentration level substantially tapers off after about 7-8 hours to less than 6 ng/mL. [00235] In some embodiments, the compositions disclosed herein comprise IR particles and one population of TDR particles (e.g., DR particle, acid-resistant DR particle, or TPR particle), wherein the composition provides for a biphasic pulsatile delivery of the drug to induce sleep within about 30 minutes of the administration, and provide sleep maintenance for up to about 8 hours, wherein the plasma concentration level substantially tapers off after about 7-8 hours to less than 6 ng/mL.

[00236] In some embodiments, the compositions disclosed herein comprise a population of

IR particles and two TPR particle populations (e.g., one population of acid-resistant DR particles and one population of TPR), wherein the combination provides for a triphasic pulsatile delivery of the drug to induce sleep within about 30 minutes of the administration, and provide sleep maintenance for up to about 8 hours, wherein the plasma concentration level substantially tapers off after about 7-8 hours to less than 6 ng/mL.

[00237] In other embodiments, the compositions disclosed herein comprise multiparticulate populations comprising a population of IR particles, one population of acid-resistant DR particles and one population of TPR, wherein the combination provides for a triphasic pulsatile delivery of the drug to induce sleep within about 30 minutes of the administration, and provide sleep maintenance over for up to about 7 hours, wherein the plasma concentration level substantially tapers off after about 7-8 hours to less than 6 ng/mL. In a particular embodiment the acid-resistant DR particle population exhibits a short lag time (e.g. about 2.5 hours) and the TPR particle population exhibits a lag time of about 4 hours upon oral administration.

[00238] Thus, the compositions and dosage forms disclosed herein, when administered to insomnia patients at bedtime, provide therapeutically effective drug plasma concentrations to allow for sleep induction within about 30 minutes as well as for up to about 8 hours of uninterrupted sleep while minimizing the occurrence of side-effects.

[00239] In another particular embodiment, the pharmaceutical compositions of the disclosure, when administered to a patient, limit one or more next day side effects selected from hangover, somnolence, dizziness, and impaired motor function, memory and reaction time.

Methods of Manufacture [00240] The present disclosure provides for methods for preparing the pharmaceutical compositions disclosed herein. In various embodiments, the methods comprise the steps of:

A. Preparing IR particles comprising: i. dissolving Zaleplon and a polymeric binder, such as povidone, or a solubility- enhancing polymer (e.g. KOLLIDON VA 64) and optionally a surfactant (e.g. sodium lauryl sulfate), in a common solvent mixture, spraying the solution onto desired mesh size spheres (e.g. sugar or cellulose spheres) in a fluid bed coater for a desired drug load (e.g. about 10%-30% by weight) and applying a protective seal coat comprising a hydrophilic polymer (e.g. at about 2-4% by weight); or ii. blending a powder mixture comprising Zaleplon and one or more pharmaceutically acceptable excipients (for example excipients selected from the group consisting of mannitol, lactose, povidone, pregelatinized starch, sodium lauryl sulfate, silicified microcrystalline cellulose and sodium stearyl fumarate), compressing the blended mixture into mini-tablets, and optionally applying a protective seal coat coating (e.g. comprising a hydrophilic polymer, such as hydroxypropylcellulose, hypromellose, low viscosity ethylcellulose and mixtures thereof); or iii. dissolving and homogeneously dispersing Zaleplon in a molten absorption- enhancing polymer, hot-melt extruding and pelletizing the mixture to produce absorption-enhanced immediate release pellets that may be milled and coated with a seal coating to produce protective seal coated melt pellets; or iv. dissolving Zaleplon and at least one absorption-enhancing agent (e.g. selected from the group containing KOLLIDON^® VA 64, SOLUPLUS^®, cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, methyl methacrylate, EUDRAGIT^® EPO or a combination thereof) in a common solvent; spray-coating the solution onto inert cores for a desired weight gain and optionally applying a protective seal coating to form MIR particles; or v. preparing a solution of Zaleplon with a polymeric binder and a low viscosity release rate controlling polymer (e.g. selected from the group consisting of ethylcellulose, hydroxypropylcellulose, hypromellose, or a mixture thereof), and spray coating the solution onto inert cores to form modified MIR particles;

B. Preparing DR particles comprising:

i. coating IR particles from any of Steps Ai. to Aiii. above with one or more enteric polymers and a plasticizer at a weight ratio of from about 70/30 to 95/5, and optionally further comprising an anti-tacking agent such as talc at from about 10% to about 30% by weight of the total coating, for a weight gain of from about 2% to about 40% by weight;

C. Preparing acid-resistant DR particles comprising:

i. coating IR particles from any of Step Ai. or Aii. above with an acid-resistant enteric polymer, such as hypromellose acetate succinate HG grade (HPMC-AS HG), EUDRAGIT SI 00, or EUDRAGIT FSlOO alone or as a major component when combined with another enteric polymer that dissolves at a lower pH (e.g. <pH 6.5) and a plasticizer at a weight ratio of from about 70/30 to 95/5, and optionally further comprising an anti-tacking agent such as talc at from about 10%) to about 30%) by weight of the total coating, for a weight gain of from about 2% to about 40% by weight;

D. Preparing TPR particles comprising: i. coating IR particles from any of Steps Ai. to Aiii. above with an enteric polymer, such as hypromellose phthalate, in combination with a water- insoluble polymer, such as ethylcellulose, at a weight ratio of about 9: 1 to about 3 :7 and a plasticizer at a weight ratio of total polymer to plasticizer from about 70/30 to about 95/5, and optionally further comprising an anti-tacking agent such as talc at from about 10%> to about 30%> by weight of the total coating, for a weight gain of from about 2% to about 40% by weight; or ii. coating IR particles from either of Steps Ai. or Aii. above with a lag-time polymer combination comprising a water-insoluble EUDRAGIT RL or RS polymer, an EUDRAGIT enteric polymer, L or S polymer, and a plasticizer at a weight ratio of from about 70/25/5 to about 40/40/20, and optionally further comprising an anti-tacking agent such as talc at from about 10% to about 30% by weight of the total coating weight, for a weight gain of from about 2% to 20% by weight; iii. coating IR particles from either of Steps Ai. or Aii. above with one or more enteric polymers and a plasticizer at a weight ratio of from about 70/30 to 95/5, and optionally further comprising an anti-tacking agent such as a talc at from about 10%) to about 30%> by weight of the total coating weight, for a weight gain of from about 10%> to about 40% by weight to form DR particles; and are further coating these particles with a lag-time coating comprising a water-insoluble polymer, an enteric polymer, and a plasticizer at a weight ratio of from about 70/25/5 to about 40/40/20, and optionally further comprising an anti-tacking agent such as talc at from about 10%> to about 30%> by weight of the total coating weight, for a weight gain of from about 2% to 20%. paring capsules according to the invention comprising:

i. combining in appropriate quantities in hard gelatin capsules IR particles (e.g. beads, powder mix or mini-tablets) and acid-resistant DR particles of Step C.i. (e.g. IR beads or IR mini-tablets coated with an acid-resistant hypromellose acetate succinate HG grade such as HPMC-AS HG or a combination of EUDRAGIT SI 00 and LI 00 55) to achieve a biphasic capsule formulation with a lag-time of about 3 hours upon oral administration.

ii. comprising combining in appropriate quantities in hard gelatin capsules IR particles (e.g. beads, powder mix or mini-tablets) and TPR particles of Step D.i., D.ii., or D.iii. (e.g. IR beads or IR mini-tablets coated with a lag-time coating with or without a DR under-coat) to achieve a biphasic capsule formulation with a lag-time of about 3 to about 4 hours upon oral administration.

iii. comprising IR particles (e.g. beads, powder mix or mini-tablets), DR particles of Step B.i., acid-resistant DR particles of Step C.i., or TPR particles of Step D.i., D.ii., or D.iii. having a lag-time of about 2 hours, together with TPR particles of Step D.i., D.ii., or D.iii. (e.g. IR beads or IR mini-tablets coated with a lag-time coating with or without a DR under-coat) to achieve a triphasic capsule formulation with a lag-time of about 3 to about 4 hours upon oral administration.

Pharmacodynamic Assessments

[00241] Bond-Lader VAS of Mood and Alertness - This measure was originally described in Bond & Lader, Br. J. Med. Psychol. 47, 211-18 (1974), which is hereby incorporated by reference in its entirety. The test has been utilized in numerous pharmacological, psychopharmacological and medical trials. The scales comprise a total of sixteen lines (approximately 100 mm on screen) anchored at either end by antonyms (e.g. alert-drowsy, calm- excited). Subjects indicate their current subjective position between the antonyms on the line. Individual item scores were calculated as % distance along the line. Outcomes comprised three factor analysis derived scores: 'Alertness', 'Calmness' and 'Contentment' . This is a 16-item inventory on which subjects are asked to rate their current state on 100 mm visual analogue scales. The scale measures the following feelings: Alert/Drowsy, Calm/Excited, Strong/Feeble, Muzzy/Clear-headed, Well-coordinated/Clumsy, Lethargic/Energetic, Contented/Discontented, Troubled/Tranquil, Mentally slow/Quick-witted, Tense/Relaxed, Attentive/Dreamy, Incompetent/Proficient, Happy/Sad, Antagonistic/ Amicable, Interested/Bored, and Withdrawn/Gregarious. The task lasts for approximately 2 minutes. In some embodiments, the subject is alert, energetic, quick-witted, and/or attentive (and/or has any other of the above feelings) after taking a pharmaceutical composition of the present disclosure. For example, the subject is alert 6, 7, 8, 9, 10, 11, or 12 (inclusive of all values and ranges therebetween)

[00242] The Bond-Lader Self-Rated Alertness Factor is one of the most widely used self- rating scales in psychopharmacology and has historically shown high sensitivity to the effects of hypnotic medications. In some embodiments, the subject is alert after taking a pharmaceutical composition of the present disclosure. For example, the subject is alert 6, 7, 8, 9, 10, 11, or 12 (inclusive of all values and ranges therebetween) hours after taking the pharmaceutical composition of the present disclosure.

[00243] The Bond-Lader Self-Rated Contentment Factor reflects the subject's self-rating of contentment and is expected to increase with the use of hypnotic medications. In some embodiments, the subject is content after taking a pharmaceutical composition of the present disclosure. For example, the subject is content 6, 7, 8, 9, 10, 11, or 12 hours (inclusive of all values and ranges therebetween) after taking the pharmaceutical composition of the present disclosure.

[00244] The Bond-Lader Self-Rated Calmness Factor measure reflects the subject's self- report of calmness and is generally expected to increase with the use of hypnotic medications. In some embodiments, the subject is calm after taking a pharmaceutical composition of the present disclosure. For example, the subject is calm 6, 7, 8, 9, 10, 11, or 12 hours (inclusive of all values and ranges therebetween) after taking the pharmaceutical composition of the present disclosure.

[00245] Karolinska Sleepiness Scale - The Karolinska Sleepiness Scale ("KSS") measures the subjective level of sleepiness at a particular time during the day. On this scale subjects indicate which level best reflects the psycho-physical sate experienced in the last 10 min. The KSS is a measure of situational sleepiness. It is sensitive to fluctuations.. This is a 9-point scale (1 = extremely alert, 3 = alert, 5 = neither alert nor sleepy, 7 = sleepy - but no difficulty remaining awake, and 9 = extremely sleepy - fighting sleep). There is a modified KSS that contains one other item: 10 = extremely sleepy, falls asleep all the time. Scores on the KSS increase with longer periods of wakefulness and it strongly correlate with the time of the day. In some embodiments, the subject has a KSS value of 1 at 6, 7, 8, 9, 10, 11, or 12 hours (inclusive of all values and ranges therebetween) after taking the pharmaceutical composition of the present disclosure. In some embodiments, the subject has a KSS value of 2 at 6, 7, 8, 9, 10, 11, or 12 hours (inclusive of all values and ranges therebetween) after taking the pharmaceutical composition of the present disclosure. In some embodiments, the subject has a KSS value of 3 at 6, 7, 8, 9, 10, 11, or 12 hours (inclusive of all values and ranges therebetween) after taking the pharmaceutical composition of the present disclosure. In some embodiments, the subject has a KSS value of 4 at 6, 7, 8, 9, 10, 11, or 12 hours (inclusive of all values and ranges therebetween) after taking the pharmaceutical composition of the present disclosure. In some embodiments, the subject has a KSS value of 5 at 6, 7, 8, 9, 10, 11, or 12 hours (inclusive of all values and ranges therebetween) after taking the pharmaceutical composition of the present disclosure. In some embodiments, the subject has a KSS value of 6 at 6, 7, 8, 9, 10, 11, or 12 hours (inclusive of all values and ranges therebetween) after taking the pharmaceutical composition of the present disclosure. In some embodiments, the subject has a KSS value of 7 at 6, 7, 8, 9, 10, 11, or 12 (inclusive of all values and ranges therebetween) hours after taking the pharmaceutical composition of the present disclosure. In some embodiments, the subject has a KSS value of 8 at 6, 7, 8, 9, 10, 11, or 12 hours (inclusive of all values and ranges therebetween) after taking the pharmaceutical composition of the present disclosure. In some embodiments, the subject exhibits a 1, 2, 3, 4, 5, 6, 7, 8, or 9 point (inclusive of all subranges therebetween) decrease in Karolinska Sleepiness Scale score relative to prior to treatment. In some embodiments, the subject exhibits a two point (or more) decrease in Karolinska Sleepiness Scale score relative to prior to treatment. As used herein, "prior to treatment" refers to a measurement occurring on a previous day in which the subject was not administered the pharmaceutical compositions described herein on or about the same time that the pharmacodynamic assessment (e.g., Karolinska Sleepiness) was performed.

[00246] Simple Reaction Time - The subject is instructed to press the 'YES' response button as quickly as possible every time the word 'YES' is presented on the screen. Fifty stimuli are presented with a varying inter-stimulus interval. The task lasts for approximately 2 minutes. The results of the Simple Reaction Time test can be measured in ms. In some embodiments, the subject's Mean Simple Reaction Time is from about 100 - about 1000 ms at 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition, including all ranges and subranges therein. For example, a subject's Mean Simple Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Simple Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 6 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Simple Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 7 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Simple Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 8 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Simple Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 9 hour after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Simple Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 10 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Simple Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 1 1 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Simple Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 12 hours after taking the pharmaceutical composition, including all ranges and subranges therein.

[00247] WAIS-IV Digit Symbol Substitution Test (DSST or WAIS-IV DSST) - The Digit

Symbol Substitution Test (DSST) is a performance subtest of the Wechsler Adult Intelligence Scale-R (WAIS-R) (see Wechsler D., The measurement of adult intelligence (3 ^rd ed.) Baltimore: Williams & Wilkins, 1944 and Wechsler D. WAIS-R manual, New York: Psychological corporation, 1981, both of which are incorporated herein by reference in their entireties). "It consists of four rows containing 100 small blank squares, each paired with a randomly assigned number from one to nine. Above these rows is a printed key that pairs each number with a different nonsense symbol. The task is to fill in the blank spaces with the symbol that is paired to the number above the blank space as quickly as possible for 90 seconds. Digit symbol is a test of psychomotor performance that is relatively unaffected by intellectual prowess, memory or learning. The score (point total) is the total number of squares filled in correctly. As will be readily appreciated by a skilled artisan, a higher score is correlated with a higher alertness. Thus in some embodiments, a subject will score at least 50 at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition, inclusive of all values and ranges therebetween. For example, the subject may score a 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition, inclusive of all ranges and subranges therebetween. In some embodiments, the subject may score a 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 at 6 hours after taking the pharmaceutical composition, inclusive of all ranges and subranges therebetween. In some embodiments, the subject may score a 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 at 7 hours after taking the pharmaceutical composition, inclusive of all ranges and subranges therebetween. In some embodiments, the subject may score a 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 at 8 hours after taking the pharmaceutical composition, inclusive of all ranges and subranges therebetween. In some embodiments, the subject may score a 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 at 9 hours after taking the pharmaceutical composition, inclusive of all ranges and subranges therebetween. In some embodiments, the subject may score a 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 at 10 hours after taking the pharmaceutical composition, inclusive of all ranges and subranges therebetween. In some embodiments, the subject may score a 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 at 11 hours after taking the pharmaceutical composition, inclusive of all ranges and subranges therebetween. In some embodiments, the subject may score a 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 at 12 hours after taking the pharmaceutical composition, inclusive of all ranges and subranges therebetween.

[00248] Choice Reaction Time - Either the word 'NO' or the word 'YES' is presented on the screen and the subject is instructed to press the corresponding button as quickly as possible. There are 50 trials for which each stimulus word is chosen randomly with equal probability and there is a varying inter-stimulus interval. The task lasts for approximately 2 minutes. The Choice Reaction Time can be measured by speed (ms) or accuracy (%). As will be appreciated by a skilled artisan, a higher speed and accuracy are indicative of alertness and a lower speed and accuracy are indicative of a sedative effect. In some embodiments, the subject's Mean Choice Reaction Time is from about 100 - about 1000 ms at 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition, including all ranges and subranges therein. For example, a subject's Mean Choice Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Choice Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 1 hour after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Choice Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 2 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Choice Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 3 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Choice Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 4 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Choice Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 5 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Choice Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 6 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Choice Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 7 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Choice Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 8 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Choice Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 9 hour after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Choice Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 10 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Choice Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 1 1 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Choice Reaction Time is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 12 hours after taking the pharmaceutical composition, including all ranges and subranges therein.

[00249] Tracking - The subject uses a joystick to track a randomly moving target on the screen for 1 minute. The distance off-target per second is recorded. The task lasts for approximately 2 minutes. Tracking average distance from target may be expressed in mm. For example, a subject's tracking average distance may be about 0.5, 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 40, 41, 42, 43, 44, 45, 56, 57, 58, 59, or about 50 mm at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's tracking average distance is about 0.5, 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 56, 57, 58, 59, or about 50 mm at 1 hour after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's tracking average distance is about 0.5, 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 56, 57, 58, 59, or about 50 mm at 2 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's tracking average distance is about 0.5, 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 56, 57, 58, 59, or about 50 mm at 3 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's tracking average distance is about 0.5, 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 56, 57, 58, 59, or about 50 mm at 4 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's tracking average distance is about 0.5, 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 56, 57, 58, 59, or about 50 mm at 5 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's tracking average distance is about 0.5, 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 56, 57, 58, 59, or about 50 mm at 6 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's tracking average distance is about 0.5, 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 56, 57, 58, 59, or about 50 mm at 7 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's tracking average distance is about 0.5, 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 56, 57, 58, 59, or about 50 mm at 8 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's tracking average distance is about 0.5, 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 56, 57, 58, 59, or about 50 mm at 9 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's tracking average distance is about 0.5, 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 56, 57, 58, 59, or about 50 mm at 10 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's tracking average distance is about 0.5, 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 56, 57, 58, 59, or about 50 mm at 11 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's tracking average distance is about 0.5, 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 56, 57, 58, 59, or about 50 mm at 12 hours after taking the pharmaceutical composition, including all ranges and subranges therein.

[00250] Numeric Working Memory - A series of 5 digits is presented for the subject to hold in memory. This is followed by a series of 30 probe digits for each of which the subject has to decide whether or not it was in the original series and press the 'YES' or 'NO' response button as appropriate, as quickly as possible. This procedure is repeated twice, using 2 different series and probes. The task lasts for approximately 2 minutes. As will be appreciated by a skilled artisan, hypnotic medications are expected to slow the speed with which test digits can be correctly identified. In some embodiments, the subj ect' s Mean Numeric Working Memory Speed of Correct Responses is from about 100 - about 1000 ms at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition, including all ranges and subranges therein. For example, a subject's Mean Numeric Working Memory Speed of Correct Responses is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Numeric Working Memory Speed of Correct Responses is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 6 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Numeric Working Memory Speed of Correct Responses is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 7 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Numeric Working Memory Speed of Correct Responses is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 8 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Numeric Working Memory Speed of Correct Responses is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 9 hour after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subj ect' s Mean Numeric Working Memory Speed of Correct Responses is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 10 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Numeric Working Memory Speed of Correct Responses is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 11 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, a subject's Mean Numeric Working Memory Speed of Correct Responses is from about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 12 hours after taking the pharmaceutical composition, including all ranges and subranges therein. [00251] Profile of Mood States - POMS is a set of 65 items that permit a quick assessment of transient, fluctuating feelings, and enduring affect states. The test takes approximately 5-10 minutes to complete. The test can be used to score a subject's tension, depression, anger, vigour, fatigue, and confusion. The Profile of Mood States Total Mood Disturbance factor (POMS/TMD) is another POMS-related metric which is composite score derived from POMS factor scores according to the following formula: Total Mood Disturbance = Tension + Depression + Anger + Fatigue + Confusion - Vigour. In some embodiments, a subject is not depressed as measured by POMS at 6, 7, 8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition of the present disclosure. In some embodiments, a subject is not angry as measured by POMS at 6, 7, 8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition of the present disclosure. In some embodiments, a subject is not fatigued as measured by POMS at 6, 7, 8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition of the present disclosure. In some embodiments, a subject is not confused as measured by POMS at 6, 7, 8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition of the present disclosure. In some embodiments, a subject has vigour as measured by POMS at 6, 7, 8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition of the present disclosure.

[00252] Body Sway - The ability to stand upright without moving is assessed using the CDR meter that is modelled on the Wright Ataxiameter (Wright BM. A simple mechanical ataxiameter. J Physiol. 1971; 81 : 27-28, which is hereby incorporated by reference in its entirety). A cord from the meter is attached to the subject who is required to stand as still as possible with feet apart and eyes closed for 1 minute. Body Sway is measured and reported as Numeric score on 1/3° Angle of Arc. The values and measurement for determining body sway are readily apparent to a skilled artisan. In some embodiments, a subject's body sway is negligible suggesting low impairment. In some embodiments, a subject's body sway is indicative of low impairment at 6, 7, 8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition of the present disclosure.

[00253] Digit Vigilience Speed - In the digit vigilance assessment, a target digit is randomly selected and constantly displayed to the right of the screen. A series of digits is then presented in the center of the screen at the rate of 150 per minute and the subject is required to press the 'YES' button as quickly as possible every time the digit in the series matches the target digit. There are 45 targets in the series. The task lasts for approximately 3 minutes. The score Digit Vigilance can be scored as the percentage of target detected, the speed (ms) and the percentage of false alarms. As will be readily appreciated by a skilled artisan, a higher speed and percentage of targets detected is correlated with a higher alertness. Thus in some embodiments, the target detection speed is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, the subject's target detection speed is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 6 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, the subject's target detection speed is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 7 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, the subject's target detection speed is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 8 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, the subject's target detection speed is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 9 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, the subject's target detection speed is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 10 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, the subject's target detection speed is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 11 hours after taking the pharmaceutical composition, including all ranges and subranges therein. In some embodiments, the subject's target detection speed is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 12 hours after taking the pharmaceutical composition, including all ranges and subranges therein.

[00254] Power of Attention is a highly sensitive measure of focused attention. Power of

Attention is likely to decline after administration of hypnotic medications. The Power of Attention score, expressed in milliseconds, is derived by adding Simple Reaction Time + Choice Reaction Time + Digit Vigilance Speed. In some embodiments, a subject's power of attention score is indicative of alertness at 6, 7, 8, 9, 10, 11, or 12 hours. [00255] In particular embodiments, to achieve the above pharmacodynamic and dissolution profiles, the pharmaceutical compositions are formulated with a total dose of Zaleplon of about 10-20 mg, wherein the IR component (e.g., particle) comprises about 10-15 mg of Zaleplon (e.g., about 10 mg or about 15mg), and the TDR component (e.g., particle) comprises about 2.5-5 mg of Zaleplon. In particular embodiments, the TDR component (e.g., particle) is a DR component (e.g., particle) comprising a delayed-release coating of one or more pharmaceutically acceptable enteric polymers (e.g., hypromellose phthalate or hypromellose acetate succinate HG) and having a coating weight in the range of from about 10% to about 30%. In further embodiments, the DR component is an acid-resistant DR particle comprising a coating of one or more pharmaceutically acceptable acid-resistant enteric polymers (e.g., HPMC-AS HG) having a coating weight of from about 10%) to about 20%. In other particular embodiments, the TDR component (e.g., particle) is a TPR component (e.g., particle), comprising a TPR coating of one of one or more pharmaceutically acceptable enteric polymers (e.g., hypromellose phthalate or hypromellose acetate succinate HG) present as an admixture with one or more pharmaceutically acceptable water-insoluble polymers (e.g., ethylcellulose) and having a coating weight in the range of from about 10%) to about 30%>. In some embodiments, the weight ratio of the water-insoluble polymer in combination with an enteric polymer at a weight ratio of from about 4: 1 to about 1 : 1 (e.g. about 3 : 1 and about 2: 1).

[00256] The following, non-limiting, examples illustrate the various embodiments of the invention, including the preparation of IR, acid-resistant DR, and TPR particles and the pharmaceutical compositions including such IR, acid-resistant DR, and TPR particles.

EXAMPLES

Example 1 :

[00257] PK Plasma Profile Modeling: GastroPlus™ (Simulations Plus, Inc., Lancaster, California), a physiologically based pharmacokinetic (PBPK) modeling & simulation software package, was used to simulate oral absorption, pharmacokinetics, and pharmacodynamics in humans. Pharmacokinetic parameters were optimized using the actual human plasma concentration-time data upon single intravenous injection and oral single dose of 10 or 20 mg administration or at steady state in normal subjects (Greenblatt' s study and Rosen). The optimized simulated PK profile of a 10-mg IR dose along with the actual data points are shown in FIG. 1.

[00258] Numerous conceptual, in vitro release profiles were conceived and PK modeling and simulations were performed using the optimized PK parameters listed in Table 1 to create biphasic and triphasic Zaleplon plasma concentration-time profiles in subjects with insomnia, and thereby determine which profiles would be suitable to achieve both rapid sleep induction within about 30 minutes and sleep maintenance over about 7 hours upon oral administration of intended once-daily dosage forms.

Table 1 : Pharmacokinetic parameters for Zaleplon from IR formulations

Example 2:

[00259] Fluid bed Processing Zaleplon-containing Particles

[00260] GLATT™ GPCG Fluid-Bed Systems (Glatt GmbH Process Technology, Binzen, Germany; www.glatt.com) offers a series of GPCG fluid-bed coaters equipped with the twin- chamber filter system and a bottom spray Glatt HS Wurster insert, for uninterrupted processing.

[00261] A. Zaleplon IR Beads at a drug load of 16% by weight

[00262] Preparation of drug-layering solution at a solids content of 5% by weight: Acetone (2462.4 g) and purified water (615.6 g) were well mixed in a stainless steel container using a low shear agitator. Zaleplon (144.0 g) was added and mixing was continued for not less than 10 minutes until Zaleplon was completely dissolved. HPMC E5 (18.0 g) was added to the solution and mixing was continued for not less than 15 minutes until all solids were completely dissolved.

[00263] Preparation of seal coating solution at a solids content of 6% by weight: Opadry Clear YS- 17006 (18.0 g) was added to 282 g of water in a stainless steel container and mixed with a low shear agitator until completely dissolved. [00264] Glatt GPCG Set-up: Glatt GPCG-3 was set up with a 6" Wurster insert; 20 mm partition; Nozzle tip: 1 mm (diameter); Nozzle height: Flush with air cap; 14 mm tubing; 100 mesh screen; Distribution plate: C; Nozzle tip size: 1.0 mm; Atomization air pressure: 0.8 bar; a dedicated filter bag with Shake interval/duration: 30 seconds/5 seconds.

[00265] Step A. l : Preparation of IR Beads: The pre-heated GPCG 3 was charged with 25- 30 mesh sugar spheres (720 g) and the air flow adjusted to achieve adequate fluidization. The IR coating solution prepared above was sprayed onto the sugar spheres at an initial spray rate of 64 mL/minutes, while adjusting the inlet temperature (e.g. 40-44°C) and airflow (e.g. 30-31 cfms) to achieve the target bed temperature of 30-31°C. After 10-20 minutes, the spray rate was gradually increased to 16 mL/minute while adjusting the flow parameters to maintain the target bed temperature of 30°C. After the entire drug-layering solution was sprayed, the seal coating solution was sprayed at 6 mL/minute with an atomization air pressure of 1.5 bar and target bed temperature of 45°C. The seal coated beads were dried for 2 minutes, discharged and sieved through 20-mesh and 30-mesh screens to any discard agglomerates and/or fines, to provide Zaleplon IR Beads at a drug load of 16%.

[00266] Step A.2: IR beads were also prepared by spraying a drug layering solution onto the sugar spheres at a solids content of 5% by weight for a drug load of 10% by weight including a 2% of seal-coat.

[00267] Step A.3 : Another batch of IR beads was prepared by spraying a drug layering solution containing 1% sodium lauryl sulfate onto the sugar spheres for a drug load of 10% by weight including a 2% of seal-coat.

[00268] A-BIS. Zaleplon IR Beads at a drug load of 16% by weight

[00269] Preparation of drug-layering solution at a solids content of 5% by weight: Acetone (4.514 Kg) and purified water (1.129kg) were well mixed in a stainless steel container using a low shear agitator. Zaleplon (0.264 Kg) was added and mixing was continued for not less than 10 minutes until Zaleplon was completely dissolved. HPMC E5 (0.033 Kg) was added to the solution and mixing was continued for not less than 15 minutes until all solids were completely dissolved.

[00270] Preparation of seal coating solution at a solids content of 6% by weight: Opadry Clear YS-17006 (0.033 Kg) was added to 0.517 Kg of water in a stainless steel container and mixed with a low shear agitator until completely dissolved. [00271] Glatt GPCG Set-up: Glatt GPCG-3 was set up with a 6" Wurster insert; 20 mm partition; Nozzle tip: 1 mm (diameter); Nozzle height: Flush with air cap; 14 mm tubing; 100 mesh screen; Distribution plate: C; Nozzle tip size: 1.0 mm; Atomization air pressure: 0.8 bar; a dedicated filter bag with Shake interval/duration: 30 seconds/5 seconds.

[00272] Step A. l-BIS: Preparation of IR Beads: The pre-heated GPCG 3 was charged with 25-30 mesh sugar spheres (1.320 Kg) and the air flow adjusted to achieve adequate fluidization. The IR coating solution prepared above was sprayed onto the sugar spheres at an initial spray rate of 6 mL/minutes, while adjusting the inlet temperature (e.g. 40-44°C) and airflow (e.g. 30-40 cfms) to achieve the target bed temperature of 32°C. After 10 minutes, the spray rate was gradually increased to 16 mL/minute while adjusting the flow parameters to maintain the target bed temperature of 32°C. After the entire drug-layering solution was sprayed, the seal coating solution was sprayed at 7 mL/minute with an atomization air pressure of 1.5 bar and target bed temperature of 45°C. The seal coated beads were dried for 2 minutes, discharged and sieved through 20-mesh and 30-mesh screens to any discard agglomerates and/or fines, to provide Zaleplon IR Beads at a drug load of 16%.

[00273] B. Zaleplon IR Beads containing KOLLIDON VA 64

[00274] Preparation of drug-layering solution at a solids content of 10% by weight:

Zaleplon (80.0 g) was added to acetone (1367.1 g) and purified water (27.9 g) in a stainless steel container and mixed using a low shear agitator for not less than 10 minutes until Zaleplon was completely dissolved. KOLLIDON VA 64 (25.0 g) was added to the solution which was mixed for not less than 15 minutes until all solids were completely dissolved.

[00275] Preparation of IR Beads: 25-30 mesh sugar spheres (770 g) were coated with the IR coating solution while optimally fluidizing the sugar spheres under processing conditions similar to those in A. l above. Following completion of drug layering, the beads were coated with a seal coat solution as prepared in A. above at a solids content of 6% by weight for a weight gain of 2% to provide Zaleplon IR Beads at a drug load of 10% by weight.

[00276] Step B. l : Another batch of IR beads was prepared by spraying sugar spheres according to the aforementioned Method with a Zaleplon IR coating solution (a solids content of 13%) containing Zaleplon (160 g) and KOLLIDON VA 64 (20 g), and seal coat solution prepared as in step A. above for a drug load of 16% by weight, including a 2% seal-coat.

[00277] C. Zaleplon PR Beads at a Coating Weight of 22.5%

[00278] Hypromellose phthalate (HP-55 at 222.1 g) was added to a mixture of acetone (2109.9 g) and purified water (111.0 g) in a stainless steel container and mixed using a low shear agitator for not less than 10 minutes (until visually dissolved). Triethyl citrate (24.7 g) was mixed for not less than 30 minutes. The preheated Glatt GPCG-3 was charged with 850 g IR beads from step A.1 and spray coated by spraying at an initial spray rate of 8 mL/minute; Inlet air temperature: 37°C; Airflow: 30 cfm or so to achieve adequate fluidization and dew point: 5-6°C. After 10-20 minutes, the spray rate was gradually increased to 18 mL/minute while adjusting flow parameters to maintain the target bed temperature of about 30°C. A sample at a coating weight of 15% was also taken for dissolution testing.

[00279] D. Zaleplon Acid-resistant PR Beads Coated with HPMC-AS HG at 15%

[00280] Hypromellose acetate succinate HG (222.1 g) was added to a mixture of acetone (2109.9 g) and purified water (111.0 g) in a stainless steel container and mixed using a low shear agitator for not less than 10 minutes (until visually dissolved). Dibutyl sebacate (24.7 g) was mixed for not less than 30 minutes. The preheated Glatt GPCG-3 was charged with 850g IR beads from step A.1 and spray coated by spraying at an initial spray rate of 8 mL/minute; Inlet air temperature: 37°C; Airflow: 30 cfm or so to achieve adequate fluidization and dew point: 8°C. After 10-20 minutes, the spray rate was gradually increased to 14 mL/minute while adjusting flow parameters to maintain the target bed temperature of 30-31°C. Samples were pulled at 10% and 12.5% coating for dissolution testing. The coated beads were dried in the Glatt for about 5 minutes before discharging and sieved through 18- and 25-mesh screens.

[00281] D-BIS Zaleplon Acid-resistant PR Beads Coated with HPMC-AS HG at 15%

[00282] Hypromellose acetate succinate HG (0.203 Kg) was added to a mixture of acetone (1.924 Kg) and purified water (0. lOlKg) in a stainless steel container and mixed using a low shear agitator for not less than 10 minutes (until visually dissolved). Dibutyl sebacate (0.022 Kg) was mixed for not less than 30 minutes. The preheated Glatt GPCG-3 was charged with 1.275 Kg IR beads from step A.1 and spray coated by spraying at an initial spray rate of 8 mL/minute; Inlet air temperature: 38°C; Airflow: 36 cfm or so to achieve adequate fluidization and dew point: 8°C. After 10-20 minutes, the spray rate was gradually increased to 14 mL/minute while adjusting flow parameters to maintain the target bed temperature of 30-31°C. The coated beads were dried in the Glatt for about 5 minutes before discharging and sieved through 18- and 25-mesh screens.

[00283] E. Zaleplon TPR beads (EC-10/HP 55/TEC at 40/50/10) - TPR Coating on IR beads at 16% drug load

[00284] (a) Preparation of TPR coating formulation: Ethyl cellulose (102.7 g), having a viscosity of 10 cps, was added to a 90: 10 mixture of acetone (2079 g) and water (231 g) in a stainless steel container and mixed using a low shear agitator for not less than 15 minutes until the ethyl cellulose was completely dissolved. Hypromellose phthalate, HP-55 (128.3 g) was added while mixing for not less than 10 minutes (until visually dissolved), and then triethyl citrate (25.7 g) was added and the mixture stirred for not less than 30 minutes.

[00285] (b) Preparation of Zaleplon TPR beads: IR beads from Step A.2 of Example 2 were coated with the TPR coating formulation from Step (a) above in GPCG 3 under the following processing conditions: Inlet air temp: 40°C; Air flow: 30 cfm; Initial spray rate: 8 mL/minute; Dew point: 5-6°C; Target bed temp: 31-33°C. After 10-20 minutes, the spray rate was gradually increased to 18 mL/minute while adjusting the process parameters to maintain the product bed temperature. Samples were pulled after a weight gain of 10%, 15% and 20% for assay and dissolution testing. Following completion of TPR coating, TPR beads were dried in the same unit for 5 minutes and sieved through 18 and 20 mesh sieves to discard agglomerates and/or fines.

[00286] F. Zaleplon TPR beads (EC-10/HPMC-AS LG/TEC at 40/50/10) - TPR Coating on

IR beads at up to 25%) weight gain

[00287] IR beads from Step A.2 of Example 2 were coated with a TPR coating formulation comprising ethylcellulose, UPMC-AS LG and triethyl citrate at a ratio of 40:50: 10 dissolved in an acetone-water 90/10 mixture using a similar process to that described in Example 2E(b) above, for a weight gain of 25% while pulling samples at 15% and 20% by weight coating for assay and dissolution testing.

[00288] G. Zaleplon TPR beads (EUDRAGIT™ RSPO/ EUDRAGIT™ L100-55/TEC/Talc at 32/32/13/23) - TPR Coating on IR beads at up to 25% weight gain [00289] Method: EUDRAGIT™ RSPO (92.6 g) was added to a mixture of acetone (2340.5 g) and purified water (260.1 g) in a stainless steel container and mixed using a low shear agitator for not less than 30 minutes until the EUDRAGIT™ RSPO dissolved. EUDRAGIT™ L100-55 (92.6 g) was then slowly added to the solution followed by triethyl citrate (37.0 g) and the solution mixed for not less than 30 minutes. Talc (66.7 g) was then added to give a homogeneous suspension which was sprayed onto IR beads (866.8 g) from Step B. of Example 2 above, with continued agitation in the Glatt GPCG 3 at an initial spray rate of 8 mL/minute for a coating weight gain of 25%. Samples of the TPR beads are taken after 16%, 22%, and 25% coating. Following completion of spraying, the beads were dried in the same unit for 5 minutes and sieved through 16 and 20 mesh sieves to discard agglomerates and/or fines.

[00290] H. Zaleplon TPR beads (EC-10/HP-55/TEC at 45/45/10) coated over 28% HP- 55/TEC DR sub-coat

[00291] (a) Preparation of DR coating solution: Triethyl citrate (29.3 g) was dissolved, under constant stirring, in a solution of hypromellose phthalate (grade HP-55; 263.3 g) in 90: 10 acetone (2369.6 g)/water (263.3 g) at solids content of 10% by weight.

[00292] (b) Preparation of TPR coating solution: Ethyl cellulose (23.5 g), having a viscosity of 10 Cps, was added to a 90: 10 mixture of acetone (423.1 g) and water (47 g) in a stainless steel container and mixed using a low shear agitator for not less than 10 minutes (until visually dissolved). HP-55 (23.5 g) was added while mixing for not less than 15 minutes, and then triethyl citrate (5.2 g) was added and the mixture stirred for not less than 30 minutes.

[00293] (c) Preparation of TPR beads: IR beads (700 g) from Step A.3 of Example 2 were properly fluidized in Glatt GPCG-3 under the following processing conditions: Inlet air temp: 40°C; Air flow: 30 cfm; Spray rate: 8 mL/minute; Dew point: 3.5-5.5°C; Target product bed temp: 30-33°C. After approximately 10 minutes of coating with the DR coating solution of Example 2H(a) above, the spray rate was gradually increased to 18 mL/minute while appropriately adjusting flow parameters to maintain target product temperature of 32-33°C. After completion of the DR coating, the beads were then further coated with the TPR coating solution of Example 2H(b) above, dried in the same unit for 5 minutes and sieved through 18 and 20 mesh sieves to discard agglomerates and/or fines to give a total TPR coating weight gain of 8% and 10%. [00294] I. Zaleplon TPR beads (EC-10/HP-55/DEP/talc) coated over 25% HP-55/DEP/talc DR sub-coat

[00295] (a) Preparation of DR coating solution: Hypromellose phthalate (grade HP-55;

157.8 g) was dissolved in 90: 10 acetone (1879.2 g)/water (208.8 g) under constant stirring with a low shear agitator for not less than 10 minutes (until visually dissolved), Diethyl phthalate (27.8 g) and talc (46.4 g) were added and mixing was continued for not less than 30 minutes,

[00296] (b) Preparation of TPR coating solution: Ethyl cellulose (54.7 g) was added to a 90: 10 mixture of acetone (1223.7 g) and water (136 g) in a stainless steel container and mixed using a low shear agitator for not less than 10 minutes (until visually dissolved). HP-55 (48.7 g) was added while mixing for not less than 15 minutes, and then triethyl citrate (18.1 g) and talc (30.2) were added and the mixture stirred for not less than 30 minutes.

[00297] (c) Preparation of TPR beads: While continuing mixing, IR beads (696 g) from Step

A.3 of Example 2 were coated with the DR coating solution of Example 21(a) above in Glatt GPCG 3 under the processing conditions of Inlet temp: 40°C; Air flow: 40 cfm; Initial spray rate: 8 mL/minute; Dew point: 8°C; Target bed temp: 32-33°C. After approximately 10 minutes of coating, the spray rate was gradually increased to 18 mL/minute while appropriately adjusting flow parameters to maintain target product temperature. After completion of spraying with the DR coating solution, the TPR coating solution of Example 21(b) above was sprayed onto the beads. Samples were pulled after 5%, 8%, 11% and 14% TPR weight gain for assay and dissolution testing. After the TPR coat, the TPR beads were dried in the unit for 5 minutes to drive off residual solvents and sieved through 16-mesh and 20-mesh mesh screen sieves to discard agglomerates and/or fines.

Example 3

[00298] A. Zaleplon IR Powder Blend

[00299] (a) IR Powder Blend (8 mg; magnesium stearate): A 15 liter blender was charged with Starch 1500, sodium lauryl sulfate and Zaleplon and the mixture blended at 10 RPM for 5 minutes. PROSOLV SMCC 90 followed by lactose monohydrate were added and mixing continued for 5 minutes after each addition. The resulting blend was removed from the blender and milled using a COMIL equipped with a 032R screen and rotating at 2300 RPM. The blender was then charged with the milled blend and mixed with the lubricant magnesium stearate. The blend was the passed through a 35 mesh screen for 2 minutes to give the product blend. The ingredient amounts used are described in Table 2 hereinafter (Formula 1.0).

[00300] (a)-BIS IR Powder Blend (8 mg; magnesium stearate): A 15 liter blender was charged with Starch 1500, sodium lauryl sulfate and Zaleplon and the mixture blended at 10 RPM for 10 minutes. PROSOLV SMCC 90 followed by lactose monohydrate were added and mixing continued for 10 minutes after each addition. The resulting blend was removed from the blender and milled using a COMIL equipped with a 032R screen and rotating at 2300 RPM. The blender was then charged with the milled blend and mixed with the lubricant magnesium stearate. The blend was the passed through a 35 mesh screen for 2 minutes to give the product blend. The ingredient amounts are those described in Table 2 for Formula 1.0).

[00301] (b) IR Powder Blend (8 mg; sodium stearyl fumarate): Prepared in a similar manner to that described in Example 3(a) using sodium stearyl fumarate as the lubricant. The ingredient amounts used are described in Table 2 hereinafter (Formula 1.1).

[00302] (c) IR Powder Blend (5.5 mg; sodium stearyl fumarate): Prepared in a similar manner to that described in Example 3(a) using sodium stearyl fumarate as the lubricant. The ingredient amounts used are described in Table 2 hereinafter (Formula 2.0).

[00303] (c)-BIS IR Powder Blend (5.5 mg; sodium stearyl fumarate): Prepared in a similar manner to that described in Example 3(a)-BIS using sodium stearyl fumarate as the lubricant. The ingredient amounts used are described in Table 2 hereinafter (Formula 2.0-BIS).

[00304] B. Zaleplon IR Mini-tablets

[00305] (a) IR mini-tablets (8.0 mg; magnesium stearate): The IR powder blend from Step A(a) of Example 3 was compressed into mini -tablets using a MA ESTY Beta Press, that was set up with 8 2-mm round mini-tablets tooling and the following parameters: fill depth 3 mm; pre- compression setting 6 mm; Main compression setting 2.65 mm; Target weight 8 mg; Hardness 10- 13 N. The resulting IR mini-tablets are described in Table 2 hereinafter (Formula 1.0). [00306] (b) IR mini-tablets (8.0 mg; sodium stearyl fumarate): The IR powder blend from

Step A(b) of Example 3 was compressed into mini-tablets using a MA ESTY Beta Press, that was set up with 16 2-mm round mini-tablets tooling and the following parameters: fill depth 2.5 mm; pre-compression setting 8 mm; Main compression setting 2.5 mm; Target weight 8 mg; Hardness 10-20 N. The resulting IR mini-tablets are described in Table 2 hereinafter (Formula 1.1).

[00307] (c) IR mini -tablets (5.5 mg; sodium stearyl fumarate): The IR powder blend from

Step A(c) of Example 3 was compressed into mini -tablets using a MANESTY Beta Press, that was set up with 16 2-mm round mini-tablets tooling and the following parameters: fill depth 2.5 mm; pre-compression setting 8 mm; Main compression setting 2.5 mm; Target weight 5.5 mg; Hardness 8-10 N. The resulting IR mini -tablets are described in Table 2 hereinafter (Formula 2.0).

Table 2: Compositions of Zaleplon IR Mini-tablets/Powder Blend

Magnesium Stearate 0.5% - - -

Sodium Stearyl Fumarate - 0.75% 0.75% 0.75%

[00308] C. Zaleplon PR Mini-tablets (20% HP-55/TEC Coat)

[00309] The DR coating formulation comprising HP-55 (170 g) and triethyl citrate (30 g) dissolved in 90/10 acetone/water (1620 g/180 g) for a solids content of 10%, was prepared as described in Step C of Example 2 above. Glatt GPCG 3 equipped with a 6" bottom spray/8" column height Wurster insert, 20 mm partition gap, and air distribution plate: D (100 mesh screen), 1.0 mm nozzle port, atomization air pressure of 1.0 bar, and 16 mm single-head tubing, was charged with IR mini-tablets (750 g) from Example 3B(a) above and spray-coated with the DR coating formulation at a spray rate of 8 mL/min per the disclosure of Step C of Example 2 (i.e. at inlet air temp.: 40°C; Air flow: 30 cfm; target bed temp. : 33°C; Dew point: 7-8°C) for a weight gain of 20%). Samples were pulled at 10%> and 15%> DR coating for assay and dissolution testing.

[00310] D. Zaleplon DR Mini-tablets (HP-55/DEP/talc at 59.5/10.5/30)

[00311] The DR coating formulation was prepared by adding HP-55 (52.6 g) to 80:20 ethanol:water (939.5 g; 234.9 g) in a stainless steel container equipped with a low shear agitator mixing for not less than 45 minutes (until visibly dissolved). Diethyl phthalate (DEP; 9.3 g) and talc (26.5 g) were added and mixing continued for not less than 30 minutes, and mixing was continued during spray. Glatt GPCG 3 equipped with a 6" bottom spray/8" column height Wurster insert, 20 mm partition gap, and air distribution plate: D (100 mesh screen), 1.0 mm nozzle port, atomization air pressure of 1.0 bar, and 16 mm single-head tubing, was charged with IR mini- tablets (750 g) from Example 3B(c) above and spray coated at a spray rate of 6 mL/min at Inlet air temp.: 38°C; Air flow: 75 cfm; target bed temp. : 34-35°C; Dew point: 7-8°C) for a weight gain of 10%). The mini -tablets were then dried for 5 minutes before discharging and sieving through 7- and 10-mesh sieves.

[00312] E. 5% TPR Mini-tablets (EC/HP/TEC/talc at 36/32/12/20) - TPR coating on DR coated IR Mini-tablets (HP/TEC/talc at 68/12/20 and 20%)

[00313] The TPR coating formulation was prepared by first dissolving ethylcellulose (43.0 g) in 90/10 acetone/water (961.2 g/106.8 g) for a solids content of 10%> in a stainless steel container equipped with a low shear agitator while mixing for not less than 10 minutes (until visibly dissolved). HP-55 (37.7 g) was added while continuing mixing for not less than 10 minutes. DEP (14.3 g) and talc (23.7 g) were added while continuing mixing for not less than 30 minutes.

[00314] Glatt GPCG 3 equipped with a 6" bottom spray/8" column height Wurster insert,

20 mm partition gap, and air distribution plate: D (100 mesh screen), 1.0 mm nozzle port, atomization air pressure of 1.0 bar, and 16 mm single-head tubing, was charged with IR mini- tablets (693.5 g) from Example 3B(b) above and spray coated at a spray rate of 8 mL/min per the disclosure of Step C. of Example 2 (i.e. at Inlet air temp.: 37°C; Air flow: 70-75 cfm; target bed temp.: 32-33°C; Dew point: 8°C) for a weight gain of 8%. Samples were pulled at 2%, 5% and 8% TPR coating for assay and dissolution testing. The coated mini-tablets were dried for about 2 minutes, discharged, and sieved through 7 and 10 mesh sieves.

[00315] F. 8% TPR Mini-tablets (EC/HP/DEP/talc at 36/32/12/20) - TPR coating on PR coated IR Mini-tablets (HP/DEP/talc at 68/12/20 and 20%)

[00316] The DR coating formulation comprising HP-55 (130.6 g) and diethyl phthalate

(23.0 g) dissolved in 90/10 acetone/water (1555.7 g/172.9 g) for a solids content of 10%, was prepared as described in Step C. of Example 2 above. Talc (38.4g) was added to disperse in the DR coating solution while continuing to mix for not less than 30 minutes. The TPR coating solution was prepared by first dissolving HP-55 (25.8 g) in 90/10 acetone/water (656.4 g/72.9 g), adding ethylcellulose (29.3 g) and diethyl phthalate (9.7g) and continuing mixing for not less than minutes after the addition of talc (16.2 g).

[00317] Glatt GPCG 3 equipped with a 6" bottom spray/8" column height Wurster insert,

20 mm partition gap, and air distribution plate: D (100 mesh screen), 1.0 mm nozzle port, atomization air pressure of 1.0 bar, and 14 mm single-head tubing, was charged with IR mini- tablets (750 g) from Example 3B(b) above and spray coated at a spray rate of 8 mL/min per the disclosure of Step C. of Example 2 (i.e., at inlet air temp.: 37°C; Air flow: 70 cfm; target bed temp.: 33°C; Dew point: 8°C) for a weight gain of 20%. Samples were pulled at 10% and 20% DR coating for assay and dissolution testing. Following completion of DR coating, the DR coated mini -tablets were coated by spraying with the TPR solution at a rate of 16 mL per min for a weight gain of 8%) while pulling samples at a coating of 2%, 5% and 8% for assay and dissolution testing. [00318] G. 10% TPR Mini-tablets (EC/HP/DEP/talc at 31.7/27.8/10.5/30) - TPR coating on

DR coated IR Mini-tablets (HP/DEP/talc at 59.5/10.5/30 and 20%)

[00319] To prepare the DR coating formulation, HP-55 (107. lg) was added to 90/10 acetone/water (1458 g/162 g) in a stainless steel container equipped with a low shear agitator while mixing for not less than 30 minutes (until visually dissolved). DEP (18.9 g) and talc (54 g) were added while continuing mixing for not less than 30 minutes. To prepare the TPR coating formulation, ethylcellulose (31.7 g) was added to 90/10 acetone/water (810 g; 90 g) while mixing for not less than 15 minutes (until visually dissolved), and HP-55 (27.8 g) was added while mixing for not less than 15 minutes (until visually dissolved). DEP (10.5 g) and talc (30 g) were added while continuing mixing for not less than 30 minutes.

[00320] Glatt GPCG 3 equipped with a 6" bottom spray/8" column height Wurster insert,

20 mm partition gap, and air distribution plate: D (100 mesh screen), 1.0 mm nozzle port, atomization air pressure of 1.0 bar, and 14 mm single-head tubing, was charged with IR mini- tablets (720 g) from Example 3B(b) above and spray coated with the DR coating formulation at a spray rate of 6 mL/min per the disclosure of Step C. of Example 2 (i.e., at inlet air temp. : 37°C; Air flow: 70 cfm; target bed temp.: 33°C; Dew point: 5°C) for a weight gain of 20%. After 10-20 minutes of coating, the spray rate was gradually increased to 16 mL/minute while adjusting flow parameters to maintain the product bed temperature. Samples were pulled at 10% and 15% DR coating for assay and dissolution testing. Following completion of DR coating, the DR coated mini-tablets were coated by spraying the TPR coating formulation prepared just above at a rate of 16 mL per min for a weight gain of 10%, while pulling samples at a coating of 5%, 8% and 10% for assay and dissolution testing.

[00321] H. 14% TPR Mini-tablets (EC/HP/DEP/talc at 31.7/27.8/10.5/30) - TPR coating on

DR coated IR Mini-tablets (HP/DEP/talc at 59.5/10.5/30 and 25%)

[00322] To prepare the DR coating formulation, HP-55 (142.8 g) was added to 90/10 acetone/water (1944 g; 216 g) in a stainless steel container equipped with a low shear agitator while mixing for not less than 45 minutes (until visually dissolved). DEP (25.2 g) and talc (72 g) were added while continuing mixing for not less than 30 minutes. To prepare the TPR coating formulation, ethylcellulose (49.5 g) was added to 90/10 acetone/water (1265.9 g; 140.7 g) while mixing for not less than 15 minutes (until visually dissolved), and HP-55 (43.4 g) was added while mixing for not less than 15 minutes (until visually dissolved). DEP (16.4 g) and talc (46.9 g) were added while continuing mixing for not less than 30 minutes. Mixing was continued throughout spray.

[00323] Glatt GPCG 3 equipped with a 6" bottom spray/8" column height Wurster insert,

20 mm partition gap, and air distribution plate: D (100 mesh screen), 1.0 mm nozzle port, atomization air pressure of 1.0 bar, and 16 mm single-head tubing, was charged with IR mini- tablets (720.0 g) from Example 3B(c) above and spray-coated with the DR coating formulation prepared just above at a spray rate of 8 mL/min per the disclosure of Step C. of Example 2 (i.e. at Inlet air temp.: 37°C; Air flow: 70 cfm; target bed temp.: 32-33°C; Dew point: 8°C) for a weight gain of 25%. After 10-20 minutes of coating, the spray rate was gradually increased to 18 mL/minute while adjusting flow parameters to maintain the product bed temperature. Samples were pulled at 10% and 15% DR coating for assay and dissolution testing. Following completion of DR coating, the DR coated mini -tablets were coated by spraying the TPR coating formulation prepared just above at a rate of 18 mL per min for a weight gain of 8%, 10%, 12% and 14% for assay and dissolution testing. The coated mini-tablets were dried in the unit for 5 minutes and discharged through sieving through 7 and 10 mesh sieves.

[00324] I. 8% TPR Mini-tablets (EC/HP/DEP/talc at 31.7/27.8/10.5/30) - TPR coating on

DR coated IR Mini-tablets (HP/DEP/talc at 59.5/10.5/30 and 25%)

[00325] To prepare the DR coating formulation, HP-55 (142.8 g) was added to 80/20 ethanol/water (1728 g; 432 g) in a stainless steel container equipped with a low shear agitator while mixing for not less than 45 minutes (until visually dissolved). DEP (25.2 g) and talc (72 g) were added while continuing mixing for not less than 30 minutes. To prepare the TPR coating formulation, HP-55 (23.2 g) was added to 90/10 acetone/water (601.2 g; 150.3 g) while mixing for not less than 45 minutes (until visually dissolved), and ethylcellulose (26.5 g) was added while mixing for not less than 15 minutes (until visually dissolved). DEP (8.8 g) and talc (25 g) were added while continuing mixing for not less than 30 minutes. The coating formulation is continually mixed during coating to avoid precipitation or settling of talc.

[00326] IR mini -tablets (720 g) from Example 3B(c) above were coated with the DR coating formulation prepared just above for an inner coating of 25% by weight in the Glatt GPCG 3 under the following spraying conditions: Inlet air temperature: 37°C; Air flow: 70 cfm; Initial spray rate: 6- 10 mL/minute; Target bed temp. 32-34°C; Dew point: 7-8°C. Upon completion of DR coating, the mini-tablets were further coated with the TPR coating formulation prepared just above at a spray rate of 16 mL/minute for a weight gain of 8%. The coated mini-tablets were dried in the Glatt for 5 minutes, discharged, and sieved through 7- and 10-mesh sieves to discard agglomerates and fines.

[00327] J. 12% TPR Mini-tablets (EC/HP/DEP/talc at 31.7/27.8/10.5/30) - TPR coating on

DR coated IR Mini-tablets (HP/DEP/talc at 59.5/10.5/30 and 25%)

[00328] Hypromellose phthalate (HP-55; 166.8 g) was added to 80/20 ethanol/water (2980 g; 745.1 g) in a stainless steel container equipped with a low shear agitator while mixing for not less than 30 minutes (until visually dissolved). DEP (29.5 g) and talc (84.1 g) were added while continuing mixing for not less than 30 minutes to prepare a DR coating formulation. To prepare the TPR coating formulation, ethylcellulose (48.4 g) was added to 90/10 acetone/water (1583.6 g; 175.9 g) while mixing for not less than 15 minutes (until visually dissolved), and HP-55 (42.6 g) was added while mixing for not less than 15 minutes (until visually dissolved). DEP (16.1 g) and talc (45.9 g) were added while continuing mixing for not less than 30 minutes. Mixing was continued throughout spray.

[00329] IR mini-tablets (841.2 g) from Example 3B(c) above were coated with the DR coating formulation prepared just above for an inner coating of 25% by weight in the Glatt GPCG 3 under the spraying conditions used in step I above. Upon completion of DR coating, the mini- tablets were further coated with the TPR coating formulation prepared just above at a spray rate of 12 mL/minute for a weight gain of 12%.

[00330] K. Capsules of the Invention - Prototypes 1 to 4

[00331] Prototype 1 : IR powder blend from Example 3A(c) (110.0 mg IR powder blend equivalent to 10 mg Zaleplon) and acid-resistant DR Beads from Step D of Example 2 (73.5 mg equivalent to 10 mg Zaleplon) were filled into Size# 1 Capsugel hard gelatin capsules weighing 76.0 mg for a total capsule weight of 259.5.

[00332] Prototype 2: IR powder blend from Example 3A(c) (110.0 mg equivalent to 10 mg

Zaleplon) and TPR Mini-tablets of Step I of Example 3 (159.0 mg equivalent to 10 mg Zaleplon) were filled into Size# 1 Capsugel hard gelatin capsules weighing 76.0 mg for a total capsule weight of 345.0.

[00333] Prototype 3 : IR powder blend from Example 3A(c) (110.0 mg blend equivalent to

10 mg Zaleplon), DR mini-tablets of Step D of Example 3 (48.0 mg equivalent to 4 mg Zaleplon), and TPR mini-tablets of Step J of Example 3 (100.1 mg equivalent to 6 mg Zaleplon) were filled into Capsugel Size# 1 hard gelatin capsules weighing 76.0 mg for a total capsule weight of 334.1.

[00334] Prototype 4: IR powder blend from Example 3A(c) (110.0 mg IR powder blend equivalent to 10 mg Zaleplon) and TPR Beads of Step G of Example 2 (148.8 mg equivalent to 10 mg Zaleplon) were filled into Size# 1 Capsugel hard gelatin capsules weighing 76.0 mg for a total capsule weight of 334.8.

Example 4

[00335] A. IR powder blend

[00336] A 15L IBC blender was charged with half of the pre-gelatinized Starch (365.0 g), sodium lauryl sulfate (45.6 g) and Zaleplon (331.8 g) and the remaining half of pre-gelatinized Starch (365.0 g) was added and the mixture blended for 5 minutes at 10 rpm. PROSOLV SMCC 90 (1095.0 g) and lactose monohydrate (1420.2 g) were added to the blender and blended in for 10 minutes. The contents were discharged through a 20 mesh sieve and added back to the blender and sodium lauryl sulfate sieved through a 35 mesh sieve into the blender and blended for an additional 5 minutes to provide the product blend.

[00337] B. IR mini-tablets (0.5 mg; 5.5 mg)

[00338] A Manesty Beta Press was set up with 16 stations of 2 mm tooling and the press was configured to manufacture mini -tablets with a target weight of 5.5 mg using the mini -tablet powder blend (IR Powder Blend) from Example 4 A above and the procedure disclosed in Example 3B above [fill depth: approximately 2mm and compression force > 1.3 kN (Main compression: approximately 2.5 mm) and (pre-compression force set at 1.2 kN or at approximately 8 mm). Force feeder set at 0 and turret RPM: 35]. [00339] C. Capsules containing 10 mg IR powder blend and 10 mg acid-resistant PR beads [00340] (i) IR beads at a drug load of 16% by weight

[00341] For the preparation of the IR coating solution at a solids content of 5% by weight,

Zaleplon (264.0 g) was dissolved in an acetone (4514.4 g) and water (1128.6 g) mixture containing HPMC E5 (33.0 g) in a stainless steel container, and mixed well using a low shear agitator for not less than 15 minutes until all solids were completely dissolved. In order to prepare the seal coating solution at a solids content of 6% by weight, Opadry Clear YS-17006 (33.0 g) was added to 517.0 g of water in a stainless steel container and mixed with a low shear agitator for not less than 60 minutes.

[00342] Preparation IR beads: The pre-heated Glatt GPCG 3 [set up with a 6" Wurster insert; 20 mm partition; Nozzle tip: 1 mm (diameter); Nozzle height: Flush with air cap; 14 mm tubing; 100 mesh screen; Distribution plate: C; Nozzle tip size: 1.0 mm; Atomization air pressure: 0.8 bar; a dedicated filter bag with Shake interval/ duration: 30 sec/5 seconds] was charged with 25-30 mesh sugar spheres (1320 g) and the air flow was adjusted to achieve adequate fluidization. The IR coating solution prepared above was sprayed onto the sugar spheres at an initial spray rate of 6 mL/minutes while adjusting the inlet temperature (47°C) and airflow (32 cfm) to achieve target bed temperature of 32°C. After 10-20 minutes, the spray rate was gradually increased to 16 mL/minute while adjusting the flow parameters to maintain the target bed temperature of 32°C. After the entire IR coating solution was sprayed, the seal coating solution was sprayed with an atomization air pressure of 1.5 bar. The seal coated beads were dried for 2 minutes, discharged and sieved through 20-mesh and 30-mesh screens to remove any discard agglomerates and/or fines, and thereby provide IR Beads at a drug load of 16% by weight.

[00343] (ii) Preparation of acid-resistant PR (HPMC-AS HG/DBS) beads

[00344] For the preparation of the acid-resistant coating formulation, HPMC-AS HG (202.5 g) was dissolved in a 95:5 acetone/water mixture (1923.8 g: 101.2 g) while mixing with a low shear agitator for not less than 10 minutes. Dibutyl sebacate (22.5 g) was added while continuing mixing for not less than 30 minutes, and mixing was continued for a further not less than 30 minutes until dispersed. [00345] Preparation of acid-resistant DR beads: Glatt GPCG 3 equipped with a 6" bottom spray/8" column height Wurster insert, 18 mm partition gap, and air distribution plate: C (100 mesh screen), 1.0 mm nozzle port, atomization air pressure of 1.0 bar, and 14 mm single-head tubing, was charged with IR beads (1275.0 g) from Example 4C.i above and spray coated with the acid-resistant coating formulation just above at a spray rate of 8 mL/min (gradually increased to- 14 mL/min) while adjusting the flow parameters to maintain the target bed temperature of 30- 32°C. After completion of coating, the beads were dried in the coater for not less than (NLT) 5 minutes prior to discharging for sieving using US 18 and 25 mesh screens to discard overs and unders.

[00346] (iv) Acid-resistant DR beads (73.5 mg) of Example 4.ii above and IR Powder Blend

(110.0 mg) from Example 4A were filled into Size# 1 hard gelatin capsules weighing 76.0 mg for the total mean weight of final product of 259.5 mg.

[00347] Ιλ Capsules containing IR powder blend and TPR mini-tablets

[00348] (i) DR (HP-55/DEP/talc) coating formulation: HP-55 (166.8 g) was dissolved in a

80:20 ethanol/water mixture (2980.2 g: 745.1 g) while mixing with a low shear agitator for not less than 45 minutes. Diethyl phthalate (29.5 g) and talc (84.1 g) were added while mixing was continued for not less than 30 minutes to disperse the solids.

[00349] (ii) TPR (EC-10/HP-55/DEP/talc) coating formulation: HP-55 (27.1 g) was first dissolved in a 90: 10 acetone/water mixture (1010.2 g: 112.2 g) followed by dissolving ethylcellulose (31.0 g) while mixing with a low shear agitator. Diethyl phthalate (10.2 g) and talc (29.3 g) were added and allowed to disperse while continuing mixing for not less than 30 minutes.

[00350] (iii) TPR mini-tablets: Glatt GPCG 3 equipped with a 6" bottom spray/8" column height Wurster insert, 20 mm partition gap, and air distribution plate: D (100 mesh screen), 1.0 mm nozzle port, atomization air pressure of 1.0 bar, and 16 mm single-head tubing, was charged with IR mini-tablets (841.2 g; each mini-tablet weighing 5.5 mg with 0.5 mg Zaleplon per mini- tablet) from Example 4B and spray-coated with the DR coating formulation from Example 4D.i above at a spray rate of 6 mL/min (gradually increased to-7 mL/min). After DR coating, the TPR coating formulation from Example 4D.ii above was sprayed onto the mini-tablets, and air flow was adjusted appropriately to maintain target bed temperature of 33-34°C, and mini-tablets were dried in the coater for not less than 5 minutes prior to discharging for sieving to discard overs and unders.

[00351] IR powder blend (110.0 mg) from Example 4A and TPR mini-tablets (159.0 mg) from Example 4D.iii above were filled into Size# 1 hard gelatin capsules (76.0 mg) for total capsule weight of 345.0 mg.

[00352] E. Capsules containing IR powder blend, DR mini-tablets and TPR mini-tablets

[00353] (Ϊ) DR (HP-55/DEP/talc) mini-tablets: HP-55 (52.6 g) was dissolved in a 80:20 ethanol/water mixture (939.5 g: 234.9 g) while mixing with a low shear agitator for not less than 45 minutes. Diethyl phthalate (9.3 g) and talc (26.5 g) were added while continuing mixing for not less than 30 minutes to disperse the solids and provide the DR coating formulation.

[00354] Glatt GPCG 3 equipped with a 6" bottom spray/8" column height Wurster insert;

20 mm partition gap, and air distribution plate: D (100 mesh screen), 1.0 mm nozzle port, atomization air pressure of 1.0 bar; Inlet air temp. : 36°C; Air Flow: 75 cfm; Target bed temp: 34- 35°C and 16 mm single-head tubing, was charged with IR mini -tablets (750 g each mini -tablet weighing 5.5 mg with 0.5 mg Zaleplon per mini -tablet) from Example 4B and spray coated with the DR coating formulation prepared just above at a spray rate of 6 mL/min (gradually increased to 8 mL/min). After 10% enteric coating, air flow was reduced to 60 cfm and the resulting mini- tablets were dried in the coater for not less than 5 minutes prior to discharging.

[00355] (ii) TPR mini-tablets: ( 12% TPR coat on 25% DR coat):

[00356] DR coating formulation: HP-55 (166.8 g) was dissolved in a 80:20 ethanol/water mixture (2980.2 g: 745.1 g) while mixing with a low shear agitator for not less than 45 minutes. Diethyl phthalate was added while mixing with a low shear agitator for not less than 45 minutes. Additional diethyl phthalate (29.5 g) and talc (84.1 g) were added and mixing continued for not less than 30 minutes until the solids dispersed to provide the DR coating formulation.

[00357] TPR (EC-10/HP-55/DEP/talc) coating formulation: HP-55 (42.6 g) was first dissolved in a 90: 10 acetone/water mixture (1583.6 g: 175.9 g) while mixing for not less than 45 mins with a low shear agitator, followed by dissolving ethylcellulose (48.4 g) while continuing mixing. Diethyl phthalate (16.1 g) and talc (45.9 g) were added while mixing continued for not less than 30 minutes to disperse the solids. [00358] TPR Mini-tablets: Glatt GPCG 3 equipped with a 6" bottom spray/8" column height

Wurster insert, 20 mm partition gap, and air distribution plate: D (100 mesh screen), 1.0 mm nozzle port, atomization air pressure of 1.0 bar, and 14 mm single-head tubing, was charged with IR mini- tablets (841.2 g; each mini-tablets weighing 5.5 mg with 0.5 mg Zaleplon per mini-tablet) from Example 4B and spray-coated with the DR coating formulation prepared just above at a spray rate of 6 mL/min (gradually increased to- 10 mL/min). After completion of DR coating, the TPR coating formulation prepared just above was sprayed onto the mini-tablets, and air flow was adjusted appropriately to maintain target bed temperature, and the mini-tablets were dried in the coater for not less than 5 minutes prior to discharging for sieving to discard overs and unders.

[00359] (i) Capsules containing 10 mg IR powder blend; 4 mg DR mini -tablets and 6 mg

TPR mini-tablets

[00360] IR powder blend from Example 4A (110.0 mg), DR mini-tablets from Example

4E.i above (48.89 mg), and TPR mini-tablets from Example 4E.ii above (100.01 mg) were filled into Size# 1 hard gelatin capsules (76.0 mg) for a total capsule weight of 334.9 mg.

Example 5

[00361] A. IR powder blend

[00362] A 15L IBC blender was charged with half of the pre-gelatinized Starch (365.0 g), sodium lauryl sulfate (45.6 g) and Zaleplon (331.8 g) and the remaining half of pre-gelatinized Starch (365.0 g) was added and the mixture blended for 5 minutes at 10 rpm. PROSOLV SMCC 90 (1095.0 g) and lactose monohydrate (1420.2 g) were added to the blender and blended in for 10 minutes. The contents were discharged through a 20 mesh sieve and added back to the blender and sodium lauryl sulfate sieved through a 35 mesh sieve into the blender and blended for an additional 5 minutes to provide the product blend.

[00363] B. IR mini-tablets (0.5 mg: 5.5 mg)

[00364] A Manesty Beta Press was set up with 16 stations of 2 mm tooling and the press was configured to manufacture mini -tablets with a target weight of 5.5 mg using the mini -tablet powder blend (IR Powder Blend) from Example 5 A above and the procedure disclosed in Example 3B above [fill depth: approximately 2mm and compression force > 1.3 kN (Main compression: approximately 2.5 mm) and (pre-compression force set at 1.2 kN or at approximately 8 mm). Force feeder set at 0 and turret RPM: 35].

[00365] C. IR beads at a drug load of 5.6% by weight

[00366] For the preparation of the IR coating solution at a solids content of 5% by weight,

Zaleplon (92.4 g) was dissolved in an acetone (1580.8 g) and water (395.2 g) mixture containing FIPMC E5 (11.6 g) in a stainless steel container, and mixed well using a low shear agitator for not less than 15 minutes until all solids were completely dissolved. In order to prepare the seal coating solution at a solids content of 6% by weight, Opadry Clear YS-17006 (33.0 g) was added to 517.0 g of water in a stainless steel container and mixed with a low shear agitator for not less than 60 minutes.

[00367] Preparation IR beads: The pre-heated Glatt GPCG 3 [set up with a 6" Wurster insert; 20 mm partition; Nozzle tip: 1 mm (diameter); Nozzle height: Flush with air cap; 14 mm tubing; 100 mesh screen; Distribution plate: C; Nozzle tip size: 1.0 mm; Atomization air pressure: 0.8 bar; a dedicated filter bag with Shake interval/ duration: 30 sec/5 seconds] was charged with 25-30 mesh sugar spheres (1513 g) and the air flow was adjusted to achieve adequate fluidization. The IR coating solution prepared above was sprayed onto the sugar spheres at an initial spray rate of 6 mL/minutes while adjusting the inlet temperature (47°C) and airflow (32 cfm) to achieve target bed temperature of 32°C. After 10-20 minutes, the spray rate was gradually increased to 16 mL/minute while adjusting the flow parameters to maintain the target bed temperature of 32°C. After the entire IR coating solution was sprayed, the seal coating solution was sprayed with an atomization air pressure of 1.5 bar. The seal coated beads were dried for 2 minutes, discharged and sieved through 20-mesh and 30-mesh screens to remove any discard agglomerates and/or fines, and thereby provide IR Beads at a drug load of 5.6 % by weight.

[00368] Γ Preparation of acid-resistant PR (HPMC-AS HG/DBS) beads

[00369] For the preparation of the acid-resistant coating formulation, HPMC-AS HG (202.5 g) was dissolved in a 95:5 acetone/water mixture (1923.8 g: 101.2 g) while mixing with a low shear agitator for not less than 10 minutes. Dibutyl sebacate (22.5 g) was added while continuing mixing for not less than 30 minutes, and mixing was continued for a further not less than 30 minutes until dispersed. [00370] Preparation of acid-resistant PR beads: Glatt GPCG 3 equipped with a 6" bottom spray/8" column height Wurster insert, 18 mm partition gap, and air distribution plate: C (100 mesh screen), 1.0 mm nozzle port, atomization air pressure of 1.0 bar, and 14 mm single-head tubing, was charged with IR beads (1275.0 g) from Example 5C above and spray coated with the acid-resistant coating formulation just above at a spray rate of 8 mL/min (gradually increased to- 14 mL/min) while adjusting the flow parameters to maintain the target bed temperature of 30- 32°C. After completion of coating, the beads were dried in the coater for not less than (NLT) 5 minutes prior to discharging for sieving using US 18 and 25 mesh screens to discard overs and unders.

[00371] E. Capsules of the Invention

[00372] (i) Capsules containing 15 mg IR Blend and 5 mg PR Beads:

[00373] IR powder blend from Example 5A (165.0 mg IR powder blend equivalent to 15 mg Zaleplon) and PR Beads of Step P of Example 5 (105.0 mg equivalent to 5 mg Zaleplon) were filled into Size# 1 Capsugel hard gelatin capsules weighing 76.0 mg for a total capsule weight of 346.0.

[00374] (ii) Capsules containing 7.5 mg IR Blend and 2.5 mg PR Beads:

[00375] IR powder blend from Example 5 A (82.5 mg IR powder blend equivalent to 7.5 mg

Zaleplon) and PR Beads of Step P of Example 5 (52.5 mg equivalent to 2.5 mg Zaleplon) were filled into Size# 3 Capsugel hard gelatin capsules weighing 47.0 mg for a total capsule weight of 182.0.

[00376] (iii) Capsules containing 15 mg IR Mini -tablets and 5 mg PR Beads:

[00377] IR mini-tablets from Example 5B (165.0 mg mini-tablets equivalent to 15 mg

Zaleplon) and PR Beads of Step P of Example 5 (105.0 mg equivalent to 5 mg Zaleplon) were filled into Size# 1 Capsugel hard gelatin capsules weighing 76.0 mg for a total capsule weight of 346.0.

[00378] (iv) Capsules containing 7.5 mg IR Mini-tablets and 2.5 mg PR Beads:

[00379] IR mini-tablets from Example 5A (82.5 mg IR mini-tablets equivalent to 7.5 mg

All patents, patent publications, and other publications listed in this spec fication, are incorporated herein by reference for all purposes. While the invention has been described with reference to a particular embodiment, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are intended to fail within the scope of the appended claims.

[00380] Objectives

[00381] A clinical trial was performed to characterize the PK properties of 3 extended formulations of zaleplon (ZER) of the present disclosure. The formulations contained 20 mg zaleplon and a single does was administered to healthy subjects.

[00382] Study Design and Methodology

[00383] This was a 5-way crossover, randomized, double-blind trial comparing the three

ZER formulations of zaleplon to matching placebo to evaluate the subjective component of possible pharmacodynamic (PD) effects, safety, and tolerability. Blood samples were drawn and PK was measured according to standard techniques. .

[00384] On each dosing day (Days 1, 4, 7, 10 and 13), following a standard breakfast served at 6:30 a.m. treatment was administered at 8:00 a.m. (± 15 minutes).

[00385] On dosing days, PK blood samples were drawn in order to determine concentrations of the three different ZER formulations at the following time points (± 5 minutes): Pre-dose (within the 30 minutes prior to dosing) and at 20 and 40 minutes and at 1.0, 1. 5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0, 11.0 and 12.0 hours post-dose.

[00386] On dosing days, PD assessments were performed at the following time points (± 10 minutes): One (1) hour pre-dose and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 12 hours post-dose.

[00387] Treatment A (ZER A): 1 capsule containing zaleplon 10 mg immediate-release (IR) ± zaleplon 10 mg coated beads with a 3-hour delayed release, dosed with 1 matching placebo capsule; oral administration. [00388] Treatment B (ZER B): 1 capsule containing zaleplon 10 mg IR + zaleplon 10 mg mini-tabs with a 3- hour delayed release, dosed with 1 matching placebo capsule; oral administration.

[00389] Treatment C (ZER C): 1 capsule containing zaleplon 10 mg IR + zaleplon 4 mg mini-tabs with a 2-hour delayed release + zaleplon 6 mg mini-tabs with a 4-hour delayed release, dosed with 1 matching placebo capsule; oral administration.

[00390] Placebo and Dosing Regimen Treatment E (Placebo): 2 matching placebo capsules; oral administration.

[00391] Pharmacokinetic, Pharmacodynamics and Safety Variables Pharmacokinetics: Plasma concentration of zaleplon was measured pre-dose and for 12 hours after dosing with each study treatment. Blood samples for PK analysis were collected at the following time points (± 5 min): Pre-dose (within the 30 minutes prior to dosing) and at 20 and 40 minutes and at 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0, 11.0 and 12.0 hours post-dose.

[00392] PK parameters derived from zaleplon concentration data are shown in Table 5.

Table 5 Pharmacokinetic Parameters

extrapolated to infinity, yielding the total AUC, as follows: Total

AUC = Truncated AUC + (Ci_ast)/beta

Percent Extrapolated Percentage of Total AUC derived by extrapolation from the last Area (%) observed concentration, calculated as: [(Ci_ast) beta / (Total AUC)] x

100

[00393] Summary statistics for T_max and T½ are described by number of observations (n), arithmetic mean (mean), arithmetic mean standard deviation (SD), arithmetic coefficient of variation (CV), minimum (min), median, and maximum (max) values. All other parameters are described by number of observations (n), arithmetic mean (mean), arithmetic mean standard deviation (SD), arithmetic coefficient of variation (CV), geometric mean, geometric mean SD, geometric % CV, minimum, median, and maximum values. PK parameters are summarized by treatment and are listed by individual study subject.

[00394] For each of the three primary endpoints, AUCo-t, AUCo-inf, and Cmaxi, a repeated measures analysis of variance (RM ANOVA) was used to analyze ZER treatments A, B and C and Sonata Treatment D with a model including sequence, period, treatment, sex and subject as class variables and sequence, period, treatment, sex and subject nested within sequence. These were performed for the untransformed results and each formulation was compared pairwise using the Student-Newman-Keuls (SNK) multiple comparison adjustment. The model was also implemented using the ranks of the untransformed results and compared using the Friedman test.

[00395] For PK parameters, ZER Treatments A, B and C were individually compared to

Sonata Treatment D by ANOVA with Dunnett's test as a post hoc comparison.

[00396] Additionally, the arithmetic means of the individual ratios (ZER/Sonata) were compared with 1.0 using Student's t-test. Lastly, the geometric means of the individual ratios (ZER/Sonata) and their 90% confidence intervals were calculated using log-transformed data using RM ANOVA and a model including sequence, period, treatment, sex and subject as class variables and sequence, period, treatment, sex and subject nested within sequence. To test forbioequivalence (BE), these results were compared to the BE acceptance interval of 0.8 to 1.25, inclusive.

I l l [00397] The individual plasma-concentration vs. time curves, and geometric means of plasma-concentration vs. time curves were plotted by treatment and by treatment and sex using both a linear and semi-logarithmic scale. The average concentration time profile together with the individual plots were drawn to illustrate variability. Graphs were plotted based on scheduled sample times.

[00398] Pharmacodynamics: The following sequence of pharmacodynamics assessments was administered on each dosing day (Days 1, 4, 7, 10, and 13) pre-dose and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 12 hours post dose:

• Bond-Lader VAS of Mood and Alertness

• Karolinska Sleepiness Scale

• Simple Reaction Time

• WAIS-IV DSST

• Choice Reaction Time

• Tracking

• Numeric Working Memory

• Profile of Mood States (POMS)

• Body Sway

[00399] For the above continuous outcomes of PD measures, results for Treatment A through Treatment E were compared using RM ANOVA with a model including sequence, period, treatment and subject as class variables and with sequence, period, treatment, sex and subject nested within sequence. Additionally, follow-up comparisons were conducted using the Student- Newman-Keuls multiple comparison adjustment.

[00400] Additional Endpoints: For ZER Treatments A, B, and C, a time-to-event logistic regression analysis was performed in order to identify the final time post-dose at which the declining plasma concentration had reached < 6ng/mL (event=l). The model includes the variables sex and treatment as predictors.

[00401] PK and PD correlations were also assessed within and between Treatments A, B, C, D, and E. For each PD parameter at each time point, subjects' responses were normalized relative to the response measured at the corresponding time point during treatment with placebo (Treatment D) and the result obtained prior to dosing for the treatment period.

[00402] Spearman correlations were used to study the relation between mean ZER plasma concentrations to mean PD changes over baseline (placebo-normalized). To evaluate the concentration-effect relation, mean placebo changes in PD responses were plotted against total exposure (AUCo-t). These additional analyses were performed separately for male and female subjects.

[00403] RESULTS

[00404] Thirty (30) subjects were originally enrolled in the study

[00405] Safety Results:

[00406] During the study there were no deaths, AEs of severe intensity, or AEs that led to discontinuation of treatment or study participation. All AEs were treatment-emergent adverse events (TEAEs). There was one serious adverse event (SAE), due to pregnancy.

[00407] All other AEs were of mild intensity.

[00408] Pharmacokinetic Results:

[00409] Plasma Zaleplon Concentrations

[00410] Mean (SD) plasma zaleplon concentration is shown by treatment in Fig. 14A and

14B(semi-log scale) for the Completer Population PK Subset (N=27).

[00411] PK parameters for plasma zaleplon are summarized by treatment in Table 6. Note that these parameters are based on all available PK data from the Completer Population (N=29), including the 2 subjects excluded from the Completer Population PK Subset (N=27) used in the Section 14.2 PK analyses.

Table 6 Plasma Zaleplon PK Parameters by Treatment - Completer Population (N=29)

Area (%)

A

Abbreviations: NA = Not Applicable; NC = Not Calculated

Treatment A = 1 capsule containing zaleplon 10 mg IR + zaleplon 10 mg coated beads with a 3-hour delayed release (ZER A), dosed with 1 matching placebo capsule; oral administration

Treatment B = 1 capsule containing zaleplon 10 mg IR + zaleplon 10 mg mini-tabs with a 3- hour delayed release (ZER B), dosed with 1 matching placebo capsule; oral administration

Treatment C = 1 capsule containing zaleplon 10 mg IR + zaleplon 4 mg mini -tabs with a 2- hour delayed release + zaleplon 6 mg mini-tabs with a 4-hour delayed release (ZER C), dosed with 1 matching placebo capsule; oral administration

[00412] Pharmacokinetic/Pharmacodynamic Correlation Results:

[00413] Statistically Significant Parameter Correlations

[00414] Total exposure (AUCo-t) demonstrated a statistically significant correlation with some PD responses for some treatments. All correlations were consistent with expected drug effects with the exception of treatment with ZER C and Sonata, for which Power of Attention showed a positive correlation (increased Power of Attention relative to placebo and baseline) for the overall population - but not for male or female subjects considered alone. PD parameters demonstrating a significant correlation with exposure (AUCo-t) for at least one treatment and one sex subgroup or all subjects were Mean Reaction Time; Digit Vigilance Speed; Mean Choice Reaction Time; Mean Numeric Working Memory; Tracking Average Distance from Target; Power of Attention; Bond-Lader Calmness; KSS Sleepiness; POMS Tension, Depression, Anger, Fatigue, Confusion, and Total Mood Disturbance.

[00415] ZER Formulation PK/PD Profile Comparisons

[00416] All three ZER formulations demonstrated relatively rapid onset of impairments consistent with the sedative-hypnotic effects of zaleplon, for many clinically relevant PD responses.

[00417] ZER A, the test formulation containing 10 mg zaleplon IR and 10 mg of zaleplon ER coated beads which begin to be released 3 hours post dose, produced a notable correlation between total exposure (AUCo-t) and PD impairments during 1 to 4 hours post dose, demonstrating that for the first half of a typical sleep period, higher plasma levels are

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significantly associated with greater PD impairment, a surrogate for hypnotic efficacy. From 9 to 10 hours post dose, when next-day activities such as driving would typically occur, ZER A showed a zero slope, indicating that during this period there is no correlation between PK and PD impairment.

[00418] Pharmacokinetic Summary:

[00419] While the three ZER treatments showed some differences among concentration- time profiles, with AUCo- inffor Treatment A approximately 10% higher than for Treatments B or C, overall exposures were similar after administration of a single dose. In all cases, a plateau after Cmaxi appears to be maintained for at least 8 hours after dosing. Because the immediate- release drug components were identical for each of the three ZER formulations, the concentration-time differences observed are likely related to the specific extended- release characteristics of each treatment.

[00420] Treatment A demonstrated greater AUCo-inf than those observed with

Treatments B and C, which appears related to higher partial AUCs occurring between 0 and 4 hours (AUCo-4h) as well as between 4 and 8 hours (AUC4-8I1).

[00421] When comparing the mean concentration profiles of the 3 ZER formulations vs. Sonata, the main differences were the much higher Cmaxi of Treatment D and its absence of a plateau. Consistent with the mean concentration profiles, Cmaxi for Treatment D was 1.8-fold higher when compared to Treatments A and C and 2.1 -fold higher than that of Treatment B. All 3 ZER formulations displayed s

[00422] For the 6.5, 7.0, and 8.0 hours post-dose time points associated with the final hours of a typical sleep cycle, geometric mean plasma zaleplon concentrations were at least 2.5-fold higher for each of the 3 ZER formulations than for treatment with Sonata.

[00423] In conclusion, all three ZER formulations had PK profiles similar to one another and considerably different from the reference drug, Sonata 20 mg.

[00424] Relative Bioavailability Summary:

[00425] With respect to plasma exposures, all four zaleplon treatments produced similar results. The 90% CIs for exposure comparisons of Sonata to the ZER formulations fall within the bioequivalence acceptance range of 0.80 to 1.25, inclusive.

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[00426] However, with respect to Cmaxi, as expected the 20 mg zaleplon immediate- release of the reference treatment with Sonata yielded significantly higher values than the 10 mg zaleplon immediate-release drug component contained in each of the three ZER formulations.

[00427] Pharmacokinetic/Pharmacodynamic Correlation Summary:

[00428] The ZER formulations disclosed herein demonstrate a rapid onset of PD impairments after dosing, representing an efficient reduction of sleep latency. These effects substantially persist throughout the first 8 hours, corresponding to maintenance of sleep over the usual sleep duration. However, by 9 and 10 hours post dose, the time corresponding to early morning hours after a typical night-time sleep period, drug- induced PD impairments substantially decline.

Example 7

[00429] Study Objectives and Design

[00430] Zaleplon 20 mg extended release (ER) has been developed for the indication of insomnia. The present study was conducted to characterize the next-day effects of a nightime dose of zaleplon 20 mg ER compared to placebo, and zopiclone 7.5 mg. Zopiclone, a non- benzodiazepine sedative hypnotic indicated for the treatment of insomnia, known to impair next-day driving performance was included as a positive control to validate model sensitivity. In addition to evaluating the acute effects on driving, the study also addressed cognitive and self-report endpoints.

[00431] Next day performance was assessed via a simulated driving test performed after a 9 hour sleep period. The study employed the validated CRC/MiniSim driving simulator using a driving scenario requiring the driver to drive 100 km at 95 kph on a 2-lane highway. Standard deviation of lateral position (SDLP) was considered the primary endpoint, while lane exceedances and total collisions were considered secondary driving endpoints. Other measures evaluated during the study included a self-report measure of sleepiness (i.e., the Karolinska Sleepiness Scale), and a test of information processing speed (i.e., CogScreen^® Symbol Digit Coding test, number of correct responses).

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[00432] The study was a randomized, single-dose, double-blind, placebo-controlled, 3- period crossover study conducted at one research center. For each treatment period subjects were dosed with either zaleplon, zopiclone or matching placebo the evening prior to testing, at bedtime. Subjects remained at the center overnight. Cognitive testing and driving simulation testing was conducted the following morning, approximately 9 hours post dosing.

[00433] This study was designed to test non-inferiority of zaleplon 20 mg ER capsules relative to placebo, with a zopiclone test versus placebo to confirm the sensitivity of the simulator to detect treatment effects.

[00434] Study Results

[00435] Efficacy Findings

[00436] Primary Endpoint:

[00437] Standard deviation of lateral position (SDLP) was used to assess next-day effects.

[00438] Zaleplon 20 mg ER was found to be non-inferior to placebo with respect to SDLP. The upper 95% confidence limit on the difference in SDLP between Zaleplon and placebo (2.7422 cm) is less than the pre-established non-inferiority criteria (i.e., 4.4 cm). In contrast, zopiclone was significantly worse than placebo (3.251 cm, p-value<0.0001), thus establishing model sensitivity. The impact of zaleplon 20 mg ER on SDLP (1.627 cm, 95% CI = 0.5124, 2.7422) was significantly less than that seen for zopiclone (estimated difference between zaleplon and zopiclone= 1.624 cm; p-value=0.0050).

[00439] The magnitude of the increase in SDLP for zopiclone compared to placebo approached the increase in SDLP seen with a blood alcohol level of 0.05%. The results show that significantly more subjects receiving zopiclone exceeded the 4.4 cm SDLP threshold (p<0.0001 vs. placebo), compared to the number subjects treated with zaleplon thatexceeded the 4.4 cm SDLP threshold (p=0.125 vs. placebo) (Tables 9A and 9B). In addition, the mean increase in SDLP following treatment with zaleplon was estimated to be less than that seen following nighttime treatment with diphenhydramine citrate 75 mg using the same simulator and driving scenario (Kay et al, 2016).

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[00440] Comparison of within-subject differences between zopi clone and zaleplon

(Table 9C) supports the finding of significantly worse performance in lane position control for zopi clone compared to zaleplon (Maximum McNemar Test Statistic > 7.048).

[00441] Lane Exceedances and Total Collisions (secondary driving endpoints):

[00442] Zopiclone was significantly impairing compared to placebo on the measure of frequency of Lane Exceedances (0.598, p-value<0.0001)(Table 11). Zaleplon also resulted in an increase in frequency of Lane Exceedance (0.340, p-value=0.0199). The difference between zopiclone and zaleplon with respect to Lane Exceedance approached significance (p=0.0765).

[00443] The vast majority of subjects had no crashes while completing the monotonous driving task .

[00444] Self-Reported Sleepiness:

[00445] Self-reported sleepiness on the Karolinska Sleepiness Scale (KSS) was significantly higher for zopiclone compared to placebo (p-value=0.0165). In contrast, there was no significant increase in self-reported sleepiness for zaleplon compared to placebo (p- value=0.6915). There was also significantly more self-reported sleepiness following treatment with zopiclone compared to zaleplon (p-value=0.0451).

[00446] Summary

[00447] 1. Following treatment with Zaleplon 20 mg ER, the increase in standard deviation of lateral position (SDLP) did not exceed the pre-established non-inferiority criteria of 4.4 cm (i.e., the increase in SDLP seen with a blood alcohol level of 0.05% using the same driving simulator and driving scenario; CRC data on file). Therefore, it is concluded that next- day performance on a sensitive measure of driving performance following treatment with zaleplon 20 mg ER is non-inferior compared to placebo. Notably, the magnitude of this effect was estimated to be less than the residual effect of a nighttime dose of a common over-the- counter antihistamine (i.e., diphenhydramine citrate 75 mg).

[00448] 2. The sensitivity of the driving simulator to impairment was demonstrated on all driving endpoints for the zopiclone (positive control) treatment condition including; standard deviation of lateral position (SDLP), and on a measure of the frequency with which drivers drove outside of their lane (i.e., Lane Exceedance).

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[00449] 3. On a measure of self-reported sleepiness, (the Karolinska Sleepiness Scale), there was no significant difference found between zaleplon and placebo. In contrast, treatment with zopiclone resulted in significantly greater reporting of self-reported sleepiness.

[00450] 4. In summary, validated measures of driving performance, sleepiness, and attention were found to be less impacted by zaleplon than zopiclone. While the magnitude of the effect of zopiclone was found to approach the range of impairment seen at a 0.05% BAC, the impact of zaleplon 20 mg ER (relative to placebo), was less than that previously found following a nighttime dose of an over-the counter antihistamine (i.e., diphenhydramine citrate 75 mg) using the same simulators and driving scenario.

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Claims

1 A pharmaceutical composition comprising Zaleplon or an acceptable salt thereof, wherein the pharmaceutical composition comprises: a. an immediate release (IR) component comprising about 25% to about 90% of the total amount of Zaleplon in the pharmaceutical composition; and

b. at least one timed drug release (TDR) component comprising about 10% to about 75% of the total amount of Zaleplon in the pharmaceutical composition, wherein the pharmaceutical composition provides therapeutically effective plasma concentrations of Zaleplon for up to about 8 hours and reduces next-day side effects in a subject.

2. The pharmaceutical composition of claim 1 ,

wherein the TDR component has a lag time within the range of from about 2 to about 4 hours as measured using a standard USP Apparatus 1 (Baskets at 100 rpm) or 2 (Paddles at 50/75 rpm) and a two-stage dissolution media (700 mL of 0. IN HC1 at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer).

3. The pharmaceutical composition of claim 1, where a) the immediate release component comprises about 40% to about 60% of the total amount of Zaleplon in the pharmaceutical composition; and b) the timed drug release (TDR) component comprises about 40% to about 60% of the total amount of Zaleplon in the pharmaceutical composition.

4. The pharmaceutical composition of claim 1 , wherein a) the immediate release component comprises about 65% to about 85% of the total amount of Zaleplon in the pharmaceutical composition; and b) the timed drug release (TDR) component comprises about 15% to about 35% of the total amount of Zaleplon in the pharmaceutical composition.

5. The pharmaceutical composition of claim 3, wherein about 30% to about 60% of Zaleplon is released within about 3 hours and not less than about 85% of Zaleplon is released after about 5 hours as measured using a standard USP Apparatus 1 (Baskets at 100 rpm) or 2 (Paddles at 50/75 rpm) and a two-stage dissolution media (700 mL of 0.1N HCl at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer).

6. The pharmaceutical composition of claim 4 wherein about 65% to about 85% of Zaleplon is released within about 30 minutes and not less than about 85% of Zaleplon is released after about 5 hours as measured using a standard USP Apparatus 1 (Baskets at 100 rpm) or 2 (Paddles at 50/75 rpm) and a two-stage dissolution media (700 mL of 0. IN HCl at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer).

7. The pharmaceutical composition of anyone of claim 1-6, comprising a total dose of Zaleplon in the range of from about 5 mg to about 50 mg.

8. The pharmaceutical composition of claim 3 comprising a dose of from 10 mg to 20 mg.

9. The pharmaceutical composition of anyone of claims 1-8, which is formulated to achieve an average maximum plasma concentration (Cmax) no more than about 50 ng/mL following oral administration of about 10 to about 20 mg Zaleplon.

10. The pharmaceutical composition of any of claims 1-9, which is formulated to maintain an average minimum plasma concentration (Cmin) of at least about 1 ng/mL for up to about 8 following oral administration of about 10 to about 20 mg Zaleplon.

11. The pharmaceutical composition of any of claims 1-10, which is formulated to maintain blood plasma concentration of Zaleplon within the range of 1 ng/mL to about 50 ng/mL for up to about 8 hours following oral administration of about 10 to about 20 mg Zaleplon.

12. The pharmaceutical composition of any of claims 1 -1 1, which is formulated to provide a first average maximum plasma concentration (Cmaxi) of Zaleplon within about 80% to about 125% of the range of from about 6.0 ng/mL to about 50.0 ng/mL after oral administration of from about 10 to about 20 mg Zaleplon.

13. The pharmaceutical composition of claim 12, wherein the Cmaxi is within 80% to about 125% of the range of from about 12 ng/mL to about 45 ng/mL after oral administration of about 20 mg of Zaleplon.

14. The pharmaceutical composition of claim 12, wherein the Cmaxi is within about 80% to about 125% of the range of from about 6 ng/mL to about 21 ng/mL after oral administration is of 10 mg Zaleplon.

15. The pharmaceutical composition of any of claims 1 -14, which is formulated to provide a second average maximum plasma concentration (Cmax2) of Zaleplon which is about 25% to about 95% of Cmaxi.

16. The pharmaceutical composition of any of claim 1-14, which is formulated to provide a second average Cmax2 within about 80% to about 125% of the range of from about 1 ng/mL to about 20 ng/mL after oral administration of from about 10 to about 20 mg Zaleplon.

17. The pharmaceutical composition of claim 16, wherein the Cmax2 of Zaleplon is within about 80% to about 125% of the range of about 2 ng/mL to about 10 ng/mL after oral administration of about 20 mg of Zaleplon.

18. The pharmaceutical composition of claim 16 wherein the Cmax2 of Zaleplon is within about 80% to about 125% of about 1 ng/mL to about 5 ng/mL after oral administration of about 10 mg of Zaleplon.

19. The pharmaceutical composition of any of claims 1 -18, which is formulated to provide an average plasma concentration of Zaleplon at a time point from about 7 hours to about 9 hours after oral administration that is about 10% to about 60% of the Cmaxi.

20. The pharmaceutical composition of any of claims 1 -19, which is formulated to provide the average plasma concentration of Zaleplon at the time point from about 7 hours to about 9 hours after oral administration that is about 20 % to about 30% of the Cmaxi.

21. The pharmaceutical composition of any of claims 1 -20, which is formulated to provide an average plasma concentration of Zaleplon at a time point from about 5 hours to about 6 hours after oral administration which is about 30% to about 60% of the Cmaxi.

22. The pharmaceutical composition of any of claims 1-21, which is formulated to provide a plasma concentration of Zaleplon at a time point from about 7 hours to about 9 hours after oral administration that is within the range of about 1 ng/mL to about 6 ng/mL.

23. The pharmaceutical composition of any of claims 1-22, which is formulated to provide an area under the plasma concentration-time curve from dosing to the last observed concentration (AUCo-t) of Zaleplon within about 80% to about 125% of the range of from about 20 h*ng/mL to about 125 h*ng/mL after oral administration of from about 10 to about 20 mg Zaleplon.

24. The pharmaceutical composition of any of claims 1-23, which is formulated to provide AUCo-t of Zaleplon within about 80% to about 125% of the range of from about 45 h*ng/mL to about 110 h*ng/mL after oral administration of about 20 mg Zaleplon.

25. The pharmaceutical composition of any of claims 1-24, which is formulated to provide AUCo-t of Zaleplon within about 80% to about 125% of the range of from about 25 h*ng/mL to about 55 h*ng/mL following oral administration of about 10 mg Zaleplon.

26. The pharmaceutical composition of any of claims 1-25, which is formulated to provide an area under the plasma concentration-time curve from dosing to 4h (AUC0-4) of Zaleplon within about 80% to about 125% of the range of from about 5 h*ng/mL to about 60 h*ng/mL following oral administration of from about 10 mg to about 20 mg Zaleplon.

27. The pharmaceutical composition of any of claims 1-26, wherein the pharmaceutical composition provides AUC0-4 of Zaleplon within the range of about 80% to about 125% of about 18 h*ng/mL to about 54 h*ng/mL after oral administration of about 20 mg Zaleplon.

28. The pharmaceutical composition of any of claims 1-26, wherein the pharmaceutical composition provides an AUC0-4 of Zaleplon within about 80% to about 125% of the range of from about 9 h*ng/mL to about 27 h*ng/mL after oral administration of about 10 mg Zaleplon.

29. The pharmaceutical composition of any of claims 1-28, wherein the pharmaceutical composition provides an area under the plasma concentration-time curve from 4h to 8h post- dosing (AUC4-8) of Zaleplon within about 80% to about 125% of the range of from about 5 h*ng/mL to about 45 h*ng/mL after oral administration of from about 10 mg to about 20 mg Zaleplon.

30. The pharmaceutical composition of any of claims 1-28, wherein the AUC4-8 of Zaleplon within the range of about 80% to about 125% of about 13 h*ng/mL to about 41 h*ng/mL after oral administration of about 20 mg Zaleplon.

31. The pharmaceutical composition of claim 30, wherein the AUC4-8 of Zaleplon within about 80% to about 125% of the range of from about 7 h*ng/mL to about 21 h*ng/mL after oral administration of about 10 mg Zaleplon.

32. The pharmaceutical composition of any of claims 1-31 , wherein the average time to Cmaxi (Tmaxi) is within the range of about 80% to about 125% of about 1 hours to about 2 hours after oral administration.

33. The pharmaceutical composition of any of claims 1 -32, wherein the average time to Cmax2 (Tmax2) of Zaleplon is within the range of about 80% to about 125% of about 3 hours to about 6 hours.

34. The pharmaceutical composition of claim 1, wherein the TDR component release at least about 90% of the Zaleplon in the TDR component over a period of from about 1 hour to about 3 hours following the lag time.

35. The pharmaceutical composition of any of claims 1-34, wherein the IR component comprises about 70-80% of the total amount of Zaleplon and the TDR component comprises about 20-35% of the total amount of Zaleplon.

36. The pharmaceutical composition of any of claims 1-34, wherein the IR component comprises about 15 mg Zaleplon, and the TDR component comprises about 5 mg Zaleplon.

37. The pharmaceutical composition of any of claims 1-34, wherein the IR component comprises about 7.5 mg Zaleplon, and the TDR component comprises about 2.5 mg Zaleplon.

38. The pharmaceutical composition of any of claims 1-34, wherein the IR component comprises about 40-60% of the total amount of Zaleplon and the TDR component comprises about 40-60% of the total amount of Zaleplon.

39. The pharmaceutical composition of any of claims 1-38, wherein the IR component comprises about 10 mg Zaleplon, and the TDR component comprises 10 mg Zaleplon.

40. The pharmaceutical composition of any of claims 1-39, wherein the immediate release component and the TDR component are each in the form of particles.

41. The pharmaceutical composition of claim 40, wherein the immediate release particles comprise: iv. beads comprising Zaleplon present as a layer onto an inert core; or v. mini-tablets comprising Zaleplon and one or more pharmaceutically acceptable excipients; or vi. a powder blend comprising Zaleplon present as an admixture with one or more pharmaceutically acceptable excipients.

42. The pharmaceutical composition of claim 40, wherein the TDR particles are delayed release particles or acid resistant delayed release particles (DR).

43. The pharmaceutical composition of claim 42, wherein the delayed release particles comprise a coating comprising an enteric polymer selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, methacrylic acid/methylmethacrylate copolymers, and mixtures thereof.

44. The pharmaceutical composition of claim 42, wherein the acid resistant delayed release particles comprise a coating comprising one or more enteric polymers selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, methacrylic acid/methylmethacrylate copolymers and mixtures thereof.

45. The pharmaceutical composition of claim 42, wherein the TDR particles are TPR particles.

46. The pharmaceutical composition of claim 45, wherein the TPR particles have a coating comprising one or more enteric polymers in combination with one or more water-insoluble polymers.

47. The pharmaceutical composition of claim 46, the one or more enteric polymers are selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, methacrylic acid/methylmethacrylate copolymers, and mixtures thereof.

48. The pharmaceutical composition of claim 46, wherein the one or more water-insoluble polymer is selected from the group consisting of cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, ethylcellulose, pH-insensitive ethyl aery late-methyl methacrylate copolymers; and mixtures thereof.

49. The pharmaceutical composition of any of claims 1 -48, wherein about 30% to about 70% of the total amount of Zaleplon is released within about 3 hours and not less than about 85% of the total amount of Zaleplon is released within about 5 hours when the oral pharmaceutical composition is tested using a standard USP Apparatus 1 (Baskets at 100 rpm) or 2 (Paddles at 50/75 rpm) and a two-stage dissolution media (700 mL of 0.1N HCl at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer).

50. The pharmaceutical composition of any of claims 1 -48, wherein about 65% to about 75% of the total amount of Zaleplon is released within about 30 minutes, and not less than 85% of the total amount of Zaleplon is released within about 5 hours when tested using a standard USP Apparatus 1 (Baskets at 100 rpm) or 2 (Paddles at 50/75 rpm) and a two-stage dissolution media (700 mL of 0.1N HCl at 37±0.5°C for 2 hours followed by further testing 900 mL pH 6.8 buffer).

51. The pharmaceutical composition of any of claims 1-50, wherein pharmaceutical composition is in the form of a capsule.

52. The pharmaceutical composition of any of claims 1-51, wherein the subj ect' s reduction in next-day side effects is characterized by one or more of the following tests: Bond-Lader Self-Rated Alertness Factor; Bond-Lader Self-Rated Contentment Factor; Bond-Lader Self- Rated Calmness Factor; Karolinska Sleepiness Scale; Simple Reaction Time; WAIS-IV Digit Symbol Substitution Test; Choice Reaction Time; Tracking; Numeric Working Memory; Profile of Mood States; Body Sway; Digit Vigilence Speed; or Power of Attention.

53. The pharmaceutical composition of claim 52, wherein the subject's reduction in next- day side effects is at least characterized by the Bond-Lader Self-Rated Alertness Factor, wherein the subject is alert 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

54. The pharmaceutical composition of claim 52, wherein the subject's reduction in next- day side effects is at least characterized by the Bond-Lader Self-Rated Contentness Factor, wherein the subject is content 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

55. The pharmaceutical composition of claim 52, wherein the subject's reduction in next- day side effects is at least characterized by the Bond-Lader Self-Rated Calmness Factor, wherein the subject is calm 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

56. The pharmaceutical composition of claim 52, wherein the subject's reduction in next- day side effects is at least characterized by the Karolinska Sleepiness Scale, wherein the subject has a KSS value of 1-8 at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

57. The pharmaceutical composition of claim 52, wherein the subject's reduction in next- day side effects is at least characterized by Simple Reaction Time, wherein the subject has Mean Simple Reaction Time is from about 100 - about 1000 ms at 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

58. The pharmaceutical composition of claim 52, wherein the subject's reduction in next- day side effects is at least characterized by the WAIS-IV Digit Symbol Substitution Test, wherein the subject scores at least 50 at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

59. The pharmaceutical composition of claim 52, wherein the subject's reduction in next- day side effects is at least characterized by Choice Reaction Time, wherein the subject's Mean Choice Reaction Time is from about 100 - about 1000 ms at 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

60. The pharmaceutical composition of claim 52, wherein the subject's reduction in next- day side effects is at least characterized by Tracking, wherein a subject's tracking average distance may be about 0.5 mm to about 50 mm at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

61. The pharmaceutical composition of claim 52, wherein the subject's reduction in next- day side effects is at least characterized by Numeric Working Memory, wherein the Mean Numeric Working Memory Speed of Correct Responses is from about 100 - about 1000 ms at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

62. The pharmaceutical composition of claim 52, wherein the subject's reduction in next- day side effects is at least characterized by Profile of Mood States (POMS).

63. The pharmaceutical composition of claim 62, wherein the subject is not depressed as measured by POMS at 6, 7, 8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition.

64. The pharmaceutical composition of claim 62, wherein the subject is not angry as measured by POMS at 6, 7, 8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition.

65. The pharmaceutical composition of claim 62, wherein the subject is not fatigued as measured by POMS at 6, 7, 8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition.

66. The pharmaceutical composition of claim 62, wherein the subject is not confused as measured by POMS at 6, 7, 8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition.

67. The pharmaceutical composition of claim 62, wherein the subject has vigour as measured by POMS at 6, 7, 8, 9, 10, 11 , or 12 hours after taking a pharmaceutical composition.

68. The pharmaceutical composition of claim 62, wherein the subject's reduction in next- day side effects is at least characterized by Digit Vigilence Speed, wherein the target detection speed is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

69. A method of treating insomnia, comprising administering the pharmaceutical composition of any of claims 1-68 to a patient in need thereof.

70. The method of claim 69, wherein the pharmaceutical composition induces sleep in the patient within about 30 minutes after the administration.

71. The method of any one of claim 69 or 70, wherein the pharmaceutical composition provides sleep maintenance for up to about 8 hours.

72. The method of any of claims 69-71, wherein the pharmaceutical composition mitigates one or more next day side effects selected from hangover, somnolence, dizziness, impaired motor function, memory and reaction time.

73. The method of claim 72, wherein the subject's reduction in next-day side effects is characterized by one or more of the following tests: Bond-Lader Self-Rated Alertness Factor; Bond-Lader Self-Rated Contentment Factor; Bond-Lader Self-Rated Calmness Factor; Karolinska Sleepiness Scale; Simple Reaction Time; WAIS-IV Digit Symbol Substitution Test; Choice Reaction Time; Tracking; Numeric Working Memory; Profile of Mood States; Body Sway; Digit Vigilence Speed; or Power of Attention.

74. The method of claim 73, wherein the subject's reduction in next-day side effects is at least characterized by the Bond-Lader Self-Rated Alertness Factor, wherein the subject is alert 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

75. The method of claim 73, wherein the subject's reduction in next-day side effects is at least characterized by the Bond-Lader Self-Rated Contentness Factor, wherein the subject is content 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

76. The method of claim 73, wherein the subject's reduction in next-day side effects is at least characterized by the Bond-Lader Self-Rated Calmness Factor, wherein the subject is calm 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

77. The method of claim 73, wherein the subject's reduction in next-day side effects is at least characterized by the Karolinska Sleepiness Scale, wherein the subject has a KSS value of 1-8 at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

78. The method of claim 73, wherein the subject's reduction in next-day side effects is at least characterized by Simple Reaction Time, wherein the subject has Mean Simple Reaction Time from about 100 - about 1000 ms at 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

79. The method of claim 73, wherein the subject's reduction in next-day side effects is at least characterized by the WAIS-IV Digit Symbol Substitution Test, wherein the subject scores at least 50 at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

80. The method of claim 73, wherein the subject's reduction in next-day side effects is at least characterized by Choice Reaction Time, wherein the subject's Mean Choice Reaction Time is from about 100 - about 1000 ms at 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

81. The method of claim 73, wherein the subject's reduction in next-day side effects is at least characterized by Tracking, wherein a subject's tracking average distance may be about 0.5 mm to about 50 mm at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

82. The method of claim 73, wherein the subject's reduction in next-day side effects is at least characterized by Numeric Working Memory, wherein the Mean Numeric Working Memory Speed of Correct Responses is from about 100 - about 1000 ms at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

83. The method of claim 73, wherein the subject's reduction in next-day side effects is at least characterized by Profile of Mood States (POMS).

84. The method of claim 83, wherein the subject is not depressed as measured by POMS at

6, 7, 8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition.

85. The method of claim 83, wherein the subject is not angry as measured by POMS at 6,

7, 8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition.

86. The method of claim 83, wherein the subject is not fatigued as measured by POMS at 6, 7, 8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition.

87. The method of claim 83, wherein the subject is not confused as measured by POMS at 6, 7, 8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition.

88. The method of claim 83, wherein the subject has vigour as measured by POMS at 6, 7,

8, 9, 10, 11, or 12 hours after taking a pharmaceutical composition.

89. The method of claim 83, wherein the subject's reduction in next-day side effects is at least characterized by Digit Vigilence Speed, wherein the target detection speed is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 960 to about 1000 ms at 6, 7, 8, 9, 10, 11, or 12 hours after taking the pharmaceutical composition.

90. Use of Zaleplon for treating insomnia, comprising administering a pharmaceutical composition according to claims 1-68.

91. The use of Zaleplon according to claim 90, wherein the pharmaceutical composition induces sleep in the patient within about 30 minutes after the administration.

92. The use of Zaleplon according to claim 90, wherein the pharmaceutical composition provides sleep maintenance for up to about 8 hours.

93. The use of Zaleplon according to claim 90, wherein the pharmaceutical composition mitigates one or more next day side effects selected from hangover, somnolence, dizziness, impaired motor function, memory and reaction time.

94. The use Zaleplon according to claim 93, wherein the mitigation of next day side effects is characterized according to claims 46-62.

95. The pharmaceutical composition of claim 52, wherein the subject's reduction in next- day side effects is at least characterized by a two point decrease in Karolinska Sleepiness Scale score compared to prior to treatment.

96. The method of claim 73, wherein the subject's reduction in next-day side effects is at least characterized by a two point decrease in Karolinska Sleepiness Scale score compared to prior to treatment.

97. The pharmaceutical composition of any of claims 1-68, wherein the subj ect's reduction in next-day side effects is at least characterized by a maximum increase in standard deviation of lateral position (SDLP) of about 4.4 cm.

98. The method of any of claims 69-89, wherein the subj ect's reduction in next-day side effects is at least characterized by a maximum increase in standard deviation of lateral position (SDLP) of about 4.4 cm.

99. The pharmaceutical composition of any of claims 1-68, wherein the total amount of Zaleplon in the pharmaceutical composition is from about 10 to about 20 mg.

100. The pharmaceutical composition of claim 99, wherein the total amount of Zaleplon in the pharmaceutical composition is about 20 mg.

101. The pharmaceutical composition of claim 100, wherein the IR component comprises about 10 mg of Zaleplon, and the TDR component comprises about 10 mg.

102. The pharmaceutical composition of claim 100, wherein the IR component comprises about 15 mg of Zaleplon, and the TDR component comprises about 5 mg.

103. The pharmaceutical composition of claim 99, wherein the total amount of Zaleplon in the pharmaceutical composition is about 15 mg.

104. The pharmaceutical composition of claim 103, wherein the IR component comprises about 7.5 mg of Zaleplon, and the TDR component comprises about 2.5 mg.

105. The pharmaceutical composition of any of claims 1-68 and 99-104 wherein the TDR component is in the form of TPR particles.

106. The pharmaceutical composition of claim 105, wherein the TPR particles have a coating comprising one or more pharmaceutically acceptable enteric polymers in combination with one or more pharmaceutically acceptable water-insoluble polymers.

107. The pharmaceutical composition of claim 106, wherein the TPR coating ranges from about 5% to about 50% by weight.

108. The pharmaceutical composition of claim 107, wherein the TPR coating ranges from about 10% to about 40% by weight.

109. The pharmaceutical composition of any of claims 106-108, wherein, the TPR coating comprises a pharmaceutically acceptable water-insoluble polymer in combination with a pharmaceutically acceptable enteric polymer at a weight ratio of from about 4: 1 to about 1 : 1.

110. The pharmaceutical composition of any of claims 106-109, wherein, the TPR coating comprises a pharmaceutically acceptable water-insoluble polymer in combination with a pharmaceutically acceptable enteric polymer at a weight ratio of from about 3: 1 to about 2: 1.

111. The pharmaceutical composition of any of claims 1-68 and 99-104 wherein the TDR component is in the form of DR particles.

112. The pharmaceutical composition of claim 111, wherein the DR particles a coating comprising one or more pharmaceutically acceptable enteric polymers.

113. The pharmaceutical composition of claim 112, wherein the DR coating ranges from about 10% to about 20% by weight.

114. The pharmaceutical composition of any of claims 112-113, wherein the delayed release particles are acid resistant delayed release particles comprising a coating of one or more enteric polymers selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, methacrylic acid/methylmethacrylate copolymers and mixtures thereof.