WO2019071272A1

WO2019071272A1 - Pharmaceutical compositions for the treatment of the attention-deficit/hyperactivity disorder (adhd)

Info

Publication number: WO2019071272A1
Application number: PCT/US2018/055018
Authority: WO
Inventors: Gopi M. Venkatesh; Ana C. FERREIRA ARROYO; Chinmay Maheshwari; Peng Guo; Jin-Wang Lai
Original assignee: Adare Pharmaceuticals Inc
Current assignee: Adare Pharma Solutions Inc
Priority date: 2017-10-06
Filing date: 2018-10-09
Publication date: 2019-04-11
Anticipated expiration: 2020-04-06

Abstract

The present invention relates to an extended release pharmaceutical composition for once-daily oral administration for the treatment of ADHD, characterized by a triphasic pulsatile release of methylphenidate or a pharmaceutically acceptable salt thereof. The composition provides a fast onset of action upon oral administration and maintains appropriate plasma concentrations to sustain efficacy whilst mitigating the potential for side-effects such as insomnia and appetite suppression.

Description

PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF THE ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD)

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 62/569,037, filed on October 6, 2017, the entire contents of each of which are hereby incorporated by reference in its entirety.

TECHNICAL FIELD OF THE INVENTION

This invention relates to pharmaceutical compositions for oral dosing comprising methylphenidate or a salt thereof. This invention also relates to methods of manufacture as well as treatment of patients with ADHD. BACKGROUND OF THE INVENTION

ADHD is currently defined as a cognitive developmental disorder where all clinical criteria are behavioral. Over-activity, impulsiveness, and inattentiveness are presently regarded as the main clinical symptoms.

Pharmacotherapy remains the mainstay treatment for ADHD in patients of all ages, although multimodal treatments, environmental, educational, and school-based interventions are generally advocated. Extended-release drug products for oral administration containing methylphenidate hydrochloride are commercially available for pediatric patients (6-12 years of age), adolescent patients (13-17 years of age) and adults (aged 18 years and above). These products include RITALIN LA extended-release capsules, APTENSIO XR extended-release capsules, METADATE CD extended-release capsules, QUILLIVANT XR extended-release suspension, QUILLICHEW extended-release chewable tablets, METHYLIN 5mg/5mL oral suspension and CONCERTA extended-release tablets. Dexmethylphenidate (also known as d-threo methylphenidate) extended-release products include FOCALIN XR extended-release capsules. The currently available methylphenidate extended-release products are administered once-daily (QD) and target a duration of action from 8 to 12 hours.

While usually providing therapeutically effective levels of methylphenidate for the first 8 hours or more after the initial administration, many patients taking existing extended-release products require an additional immediate-release dose to maintain the same therapeutic effects throughout an entire day. Efforts to date that achieve this effect in a single dosage form have fallen short, e.g., because patients experience insomnia and significant appetite suppression. Thus, there remains a need for a single, once-daily dosage form that delivers methylphenidate in a controlled, precise and effective drug delivery system and provides a therapeutic amount of drug throughout a patient's waking hours.

SUMMARY OF THE INVENTION

This invention relates to an oral pharmaceutical composition comprising three pulsatile release populations each containing methylphenidate or a salt thereof (e.g. the hydrochloride) for the treatment of ADHD. The product is designed to exhibit, upon oral administration in the morning, a fast onset of action, and maintain appropriate plasma concentrations throughout the day and into the evening to sustain the efficacy for up to at least about 14-16 hours. During evening hours, blood levels of drug decline sufficiently to limit the potential for insomnia and/or appetite suppression without meaningfully reducing efficacy, and/or without interfering with ensuing activities before going to bed. The invention further relates to a method of preparing the oral pharmaceutical composition herein.

In various embodiments, the present disclosure provides a pharmaceutical composition for the treatment of ADHD comprising:

a. a population of immediate release (IR) particles comprising methylphenidate or a pharmaceutically acceptable salt thereof;

b. a first population of timed, pulsatile release (TPRi) particles comprising methylphenidate or a pharmaceutically acceptable salt thereof; and

c. a second population of timed, pulsatile release (TPR2) particles comprising methylphenidate or a pharmaceutically acceptable salt thereof,

wherein oral administration of the composition to a patient in need thereof provides treatment of ADHD for between about 16 hours to about 24 hours.

In some embodiments, the methylphenidate or a pharmaceutically acceptable salt thereof is selected from the group consisting of i/J-methylphenidate hydrochloride, <i-methylphenidate hydrochloride, or a mixture thereof. In certain embodiments, the methylphenidate or a pharmaceutically acceptable salt thereof is d, /-methylphenidate hydrochloride. In some embodiments, the composition described herein is orally administered once a day. In some embodiments, the pharmaceutical composition is a capsule. In some embodiments, the composition comprises about 5 mg to about 200 mg of methylphenidate or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 5 mg to about 125 mg of methylphenidate or a pharmaceutically acceptable salt thereof.

In some embodiments, the population of IR particles contains about 20% to about 40% by weight of the total dose of methylphenidate or a pharmaceutically acceptable salt thereof. In some embodiments, the IR particles comprise methylphenidate or a pharmaceutically acceptable salt thereof as a layer onto the outer surface of an inert core. In some embodiments, the inert core is selected from sugar spheres or microcrystalline cellulose spheres. In some embodiments, the average particle size of the inert core ranges from about 20 μιη to about 300 μιη. In some embodiments, the IR particles further comprise a polymeric binder. In some embodiments, the IR particles comprise a binder selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (hypromellose), povidone, polyethylene glycol, or a mixture thereof.

In some embodiments, the TPRi particles contain about 30% to about 60% by weight of the total dose of methylphenidate or a pharmaceutically acceptable salt thereof. In some embodiments, the TPR2 particles contain about 20% to about 60% by weight of the total dose of methylphenidate or a pharmaceutically acceptable salt thereof. In some embodiments, the weight ratio of methylphenidate or a pharmaceutically acceptable salt in the IR particles, TPRi particles and TPR2 particles is about 1 : 1 : 1 (IR : TPRi : TPR2). In some embodiments, the weight ratio of methylphenidate or a pharmaceutically acceptable salt in the IR particles, TPRi particles and TPR2 particles is about 1 : 1 : 2 (IR : TPRi : TPR2). In some embodiments, the weight ratio of methylphenidate or a pharmaceutically acceptable salt in the IR particles, TPRi particles and TPR2 particles is about 3 : 5 : 2 (IR : TPRi : TPR2).

In some embodiments, the TPRi and TPR2 particles comprise an IR particle coated with a TPR coating. In some embodiments, at least one population of particles further comprise a seal coating layer. In some embodiments, the seal coating layer comprises one or more hydrophilic polymers. In some embodiments, the IR particles are coated with the seal coat. In some embodiments, the TPR coating comprises one or more pharmaceutically acceptable water insoluble polymers and one or more pharmaceutically acceptable enteric polymers. In some embodiments, the weight ratio of the pharmaceutically acceptable water insoluble polymer to the pharmaceutically acceptable enteric polymer is from about 85: 15 to about 35:65. In some embodiments, the ratio of the pharmaceutically acceptable water insoluble polymer to the pharmaceutically acceptable enteric polymer on the TPRi particle is from about 65:35 to about 50:50. In some embodiments, the ratio of the water insoluble polymer to the enteric polymer in the TPR2 particle is from about 75:25 to about 55:45. In some embodiments, the TPR coating is present at a weight gain of from about 5% to about 20%. In some embodiments, the TPR coating is present at a weight gain of 15% to about 50%. In some embodiments, the TPR coating further comprises a plasticizer selected from the group consisting of triethyl citrate, triacetin, substituted glycerides (e.g., MYVACET® 9-45), glyceryl monostearate, diethyl phthalate, triethyl citrate, dibutyl sebacate, acetyltributyl citrate, polyethylene glycols, and vegetable oils (e.g., hydrogenated castor oil). In some embodiments, in the TPR coating, the water insoluble polymer is ethylcellulose, the enteric polymer is hypromellose phthalate, and the plasticizer is diethyl phthalate or triethyl citrate. In some embodiments, the water insoluble polymer is ammonio methacrylate copolymer (EUDRAGIT RSPO) or a mixture thereof, and the enteric polymer is a mixture of pH-sensitive methacrylic acid/methylmethacrylate copolymers. In some embodiments, the pH-sensitive methacrylic acid/methylmethacrylate copolymer is anionic. In some embodiments, the pharmaceutical composition further comprising a barrier coating disposed over the IR particle, wherein the barrier coating comprises (i) a pharmaceutically acceptable water-insoluble polymer, (ii) a pharmaceutically acceptable enteric polymer, or (iii) a pharmaceutically acceptable water-insoluble polymer and a pharmaceutically acceptable water- soluble polymer. In some embodiments, the water-insoluble polymer is selected from the group consisting of polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, methacrylic acid/methylmethacrylate copolymers (e.g., EUDRAGIT^® RS and RL polymers and their dispersions, EUDRAGIT^® RS30D and EUDRAGIT^® RL30D, EUDRAGIT RSPO; EUDRAGIT^® E30D, AQUACOAT^®, SURELEASE^®, KOLLICOAT^® SR30D), and cellulose acetate latex, and mixtures thereof. In some embodiments, the enteric polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, pH-sensitive methacrylic acid/methylmethacrylate copolymers, such as EUDRAGIT^® L, S and FS polymers and hydroxypropyl methylcellulose acetate succinate, such as AQUASOLVE HPMC-AS (HPMC-AS LG, HPMC-AS MG, HPMC-AS HG), and mixtures thereof.

In some embodiments, the water-soluble polymer is selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (hypromellose), povidone, polyethylene glycol or mixtures thereof.

In some embodiments, the barrier coating further comprises a plasticizer selected from the group consisting of triethyl citrate, triacetin, substituted glycerides (e.g., MYVACET® 9-45), glyceryl monostearate, diethyl phthalate, triethyl citrate, dibutyl sebacate, acetyltributyl citrate, polyethylene glycols, and vegetable oils (e.g., hydrogenated castor oil).

In some embodiments, at least about 90% of the methylphenidate or a pharmaceutically acceptable saltthereof in the IR population is released within about 30 minutes as determined by United States Pharmacopeia (USP) apparatus two-stage dissolution methodology. In some embodiments, at least about 90% of the methylphenidate or a pharmaceutically acceptable salt thereof in the TPRi population is released over a period of about 30 minutes to about 4 hours following the lag time as determined by USP apparatus two-stage dissolution methodology. In some embodiments, at least about 90% of the methylphenidate or a pharmaceutically acceptable salt thereof in the TPR2 population is released over a period of about 1 hour to about 5 hours following the lag-time as determined by USP apparatus two-stage dissolution methodology. In some embodiments, at least about 90% of the methylphenidate or a pharmaceutically acceptable salt thereof in the TPRi population is released over a period of about 30 minutes to about 2 hours following the lag time as determined by USP apparatus two-stage dissolution methodology. In some embodiments, at least about 90% of the methylphenidate or a pharmaceutically acceptable salt thereof in the TPR2 population is released over a period of about 1 hour to about 4 hours following the lag-time as determined by USP apparatus two-stage dissolution methodology.

In some embodiments, the TPRi particles provide a lag time of from about 1 hour to about 7 hours as determined by United States Pharmacopeia (USP) apparatus two-stage dissolution methodology and the TPR2 particles provide a lag time of from about 7 hours to about 14 hours as determined by USP apparatus two-stage dissolution methodology. In some embodiments, the TPRi particles provide a lag time of from about 3 hours to about 5 hours as determined by USP apparatus two- stage dissolution methodology; and the TPR2 particles provide a lag time of from about 7 hours to about 9 hours as determined by USP apparatus two-stage dissolution methodology.

In some embodiments, upon oral administration to a patient in need thereof the composition provides a plasma concentration of methylphenidate that is at least about 3.5 ng/mL or more for at least about 12 hours to about 16 hours following the administration. In some embodiments, upon oral administration to a patient in need thereof the composition provides a mean steady state blood plasma AUC (0-24) hours of methylphenidate from about 25 ng*h/ml to about 350 ng*h/ml. In some embodiments, upon oral administration to a patient in need thereof the composition provides a steady state blood plasma Cmax of methylphenidate that does not exceed 25 ng/ml. In some embodiments, the steady state blood plasma Cmaxl and steady state blood plasma Cmax2 are substantially equivalent. In some embodiments, the steady state blood plasma Cmax3 is at least 50% of Cmaxi. In some embodiments, Cmaxi and Cmax3 are substantially equivalent. In some embodiments, upon oral administration to a patient in need thereof the composition provides a steady state blood plasma Cmin that is not less than about 3.5 ng/ml of methylphenidate for at least about 12 hours to about 16 hours following the administration.

The present disclosure also provides a method of treating ADHD in a subject in need thereof, comprising orally administering a pharmaceutical composition disclosed herein. In some embodiments, the composition is administered in the morning. In some embodiments, after said administering, the patient experiences a substantial reduction in ADHD compared to prior to said administering. In some embodiments, after administering a disclosed pharmaceutical composition to a subject (i.e., patient) in need thereof, the subject experiences a substantial reduction in ADHD compared to prior to said administering. In some embodiments, after said administering, the patient experiences a reduction of ADHD that is characterized by an at least two point decline in DSM-IV Attention-Deficit/Hyperactivity Disorder Rating (DSM-IV ADHD) Scale value. In some embodiments, after said administering, the patient experiences a reduction of ADHD that is characterized by an at least 20% reduction in DSM-IV ADHD Scale value. In some embodiments, after said administering, the patient experiences a reduction of ADHD that is characterized by an at least two point decline in Adult Self-Report Scale (ASRS vl . l) for ADHD Scale value. In some embodiments, after said administering, the patient experiences a reduction of ADHD that is characterized by an at least 20% reduction in DSM-V ADHD Scale value. In some embodiments, after said administering, the patient experiences a reduction of ADHD that is characterized by an at least two point decline in Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale (SKAMP) value. In some embodiments, after said administering, the patient experiences a reduction of ADHD that is characterized by an at least 20% reduction in SKAMP Scale value. In some embodiments, after said administering, the patient experiences a reduction of ADHD that is characterized by an at least two point decline in Daily Parent Rating of Evening and Morning Behavior, Revised (PREMB-R) value. In some embodiments, after said administering, the patient experiences a reduction of ADHD that is characterized by an at least 20% reduction in PREMB-R value. In some embodiments, after said administering, the patient experiences a reduction of ADHD that is characterized by an at least one point decline in Before School Functioning Questionnaire (BSFQ) value.

In some embodiments, after said administering, the patient experiences a substantial reduction of ADHD and does not experience a substantial increase in insomnia compared to prior to said administering. In some embodiments, after said administering, the patient experiences an increase in Insomnia Severity Index scale value of not more than one point compared to prior to said administering. In some embodiments, after said administering, the patient experiences an increase in Global Pittsburgh Sleep Quality Index of not more than one point compared to prior to said administering. In some embodiments, after said administering, the patient experiences an increase in Epworth Sleepiness Scale of not more than one point compared to prior to said administering. In some embodiments, after said administering, the patient does not experience an increase in Dysfunctional Beliefs and Attitudes about Sleep-16 (DBAS-16) of more than 1 point compared to prior to said administering.

In some embodiments, after said administering, the patient experiences a substantial reduction of ADHD and does not experience a substantial reduction in appetite compared to prior to said administering. In some embodiments, after said administering, the patient does not experience a decrease in Council on Nutrition appetite questionnaire (CNAQ) scale value of more than 1 point compared to prior to said administering. In some embodiments, after said administering, the patient does not experience a decrease in simplified nutritional appetite questionnaire (SNAQ) scale value of more than 1 point compared to prior to said administering. In some embodiments, after said administering, the patient does not experience a decrease in body weight of more than about 5% compared to prior to said administering. In some embodiments, after said administering, the patient does not experience a decrease in appetite hunger and sensory perception questionnaire (AHSP) scale value of more than about 20% compared to prior to said administering. In some embodiments, after said administering, the patient does not experience a decrease in appetite hunger and sensory perception questionnaire (AHSP) scale value of more than about two points compared to prior to said administering.

BRIEF DESCRIPTIONS OF THE FIGURES

FIG. 1 shows the simulated plasma d, /-methylphenidate concentration for a 20 mg total daily dose delivered by twice-daily (bid), flat, and ascending dosing regimens (Reproduced from J. Swanson et al., Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children. Clin. Pharmacol. Thera. (1999) 66(3): 295-305).

FIG. 2 shows the simulated plasma dex-methylphenidate hydrochloride concentration upon oral administration to subjects of single 20 mg dose using GASTROPLUS™ software and compared to actual mean plasma concentration - time profile observed in healthy adult subj ects (n=5) after 20 mg Focalin^® (2 x 10 mg) in the fasting state (Reported in Focalin^® product label).

FIG. 3 shows the PK profiles of proposed dex-methylphenidate triple pulsatile delivery systems (total dose: 30 mg <fex-methylphenidate with a weight ratio of IR/TPR1/TPR2 of 30/50/20) - [IR + TPR₄-hr,i-hr + TPR₈-hr,i-hr] beads, [IR + TPR₄-hr,i-hr + TPR_8-hr,3-hr] beads, and [IR + TPR_4-hr, 1-hr + TPRio-hr,3-hr] beads.

FIG. 4 shows the in vitro dex-methylphenidate release profiles of proposed triple pulsatile delivery systems (total dose: 30 mg dex-methylphenidate with each of IR, TPRi and TPR2 equivalent to 10 mg) - MER-2, MER-3, and MER-4 (see Table 2 for descriptions and compositions) vs MER-1 [3 x 10 mg dex-methylphenidate dosed at 'Ο', 4, and 8 hours (A) and the corresponding PK plasma profiles (B).

FIG. 5 shows the in vitro dex-methylphenidate release profiles of proposed triple pulsatile delivery systems (total dose: 30 mg dex-methylphenidate with each of IR, TPRi and TPR2 equivalent to 10 mg) - MER-5, MER-6, MER-7, MER-8, MER-9, and MER-10 (A) (see Table 2 for descriptions and compositions) and the corresponding PK plasma profiles (B).

FIG. 6 shows the in vitro i/-methylphenidate release profiles of proposed triple pulsatile delivery systems (total dose: 30 mg MPH with each of IR, TPRi and TPR₂ equivalent to 10 mg) - MER- 11, MER-12, MER-13, and MER-14 (A) (see Table 2 for descriptions and compositions) and the corresponding PK plasma profiles (B).

FIG. 7 shows the in vitro i/-methylphenidate release profiles of proposed triple pulsatile delivery systems (total dose: 30 mg methylphenidate with each of IR, TPRi and TPR₂ equivalent to 10 mg) - MER-15, MER-16, and MER-17 (A) (see Table 2 for descriptions and compositions) and the corresponding PK plasma profiles (B).

FIG. 8 shows the in vitro i/J-methylphenidate release profiles of proposed triple pulsatile delivery systems (total dose: 15 mg ^/-methylphenidate) - MER-A: IR(0,0.5) 5mg + TPRi(4,2) 5mg + TPR₂(8,2) 5mg; MER-B: IR(0,0.5) 5mg + TPRi(5,4) 5mg + TPR₂ (9,4) 5mg; and MER-C: IR(0,0.5) 4mg + TPRi(5,2) 4mg + TPR₂ (10,3) 7mg), (A) and the corresponding PK plasma profiles along with the mean d, /-methylphenidate plasma concentration - time profile observed in 36 adults, following a single dose of Concerta^® 18 mg once daily (B).

FIG. 9 shows the in vitro dex-methylphenidate release profiles of proposed TPR beads wherein IR beads were coated with a lag-time coating with functional polymers comprising water-insoluble ethylcellulose in combination with enteric hypromellose phthalate at different ratios. FIG. 10 shows the in vitro i/-methylphenidate release profiles of proposed TPR bead populations wherein IR beads are coated with a lag-time coating with functional polymers comprising water- insoluble Ammonio Methacrylate Copolymer (e.g., EUDRAGIT RSPO) in combination with enteric methacrylic acid copolymer (e.g., EUDRAGIT LI 00) for different weight gains.

FIG. 11 shows the in vitro i/-methylphenidate release profiles of proposed TPR bead populations wherein IR beads are coated with a lag-time coating with functional polymers comprising water- insoluble Ammonio Methacrylate Copolymer, Type A (EUDRAGIT RSPO) and enteric Methacrylic Acid Copolymer, Type A (EUDRAGIT LI 00) in combination with Methacrylic Acid Copolymer, Type B (EUDRAGIT SI 00) at a weight ratio of 2: 1 : 1 and for different weight gains. FIG. 12 shows the in vitro <i-methylphenidate release profiles of proposed TPR bead populations wherein IR beads are coated with a lag-time coating with functional polymers comprising water- insoluble Ammonio Methacrylate Copolymer, Type A (EUDRAGIT RSPO) in combination with Methacrylic Acid Copolymer, Type A (EUDRAGIT LI 00) and Methacrylic Acid Copolymer, Type B (EUDRAGIT S100) at a weight ratio of 1 :0.65:0.35 and for different weight gains.

FIG. 13 shows the in vitro methylphenidate release profiles of proposed TPR bead populations wherein IR beads are coated with a lag-time coating with functional polymers comprising water- insoluble Ammonio Methacrylate Copolymer, Type A (EUDRAGIT RSPO) in combination with Methacrylic Acid Copolymer, Type A (EUDRAGIT LI 00) and Methacrylic Acid Copolymer, Type B (EUDRAGIT S100) at a weight ratio of 1 :0.75:0.25 and for different weight gains.

FIG. 14 shows the in vitro methylphenidate release profiles of proposed TPR bead populations wherein IR beads are coated with a lag-time coating with functional polymers comprising water- insoluble Ammonio Methacrylate Copolymer, Type A (EUDRAGIT RSPO) in combination with Methacrylic Acid Copolymer, Type A (EUDRAGIT LI 00) and Methacrylic Acid Copolymer, Type B (EUDRAGIT S 100) at a weight ratio of 0.9:0.8:0.3 and for different weight gains.

FIG. 15 shows the in vitro methylphenidate release profiles of proposed TPR bead populations wherein IR beads are coated with a lag-time coating with functional polymers comprising water- insoluble Ammonio Methacrylate Copolymer, Type A (EUDRAGIT RSPO) in combination with Methacrylic Acid Copolymer, Type A (EUDRAGIT LI 00) and Methacrylic Acid Copolymer, Type B (EUDRAGIT S 100) at a weight ratio of 0.9:0.7:0.4 and for different weight gains.

FIG. 16 shows the in vitro <i-methylphenidate release profiles of proposed TPR bead populations wherein IR beads are coated with a lag-time coating with functional polymers comprising water- insoluble Ammonio Methacrylate Copolymer, Type A (EUDRAGIT RSPO) in combination with Methacrylic Acid Copolymer, Type A (EUDRAGIT LI 00) and Methacrylic Acid Copolymer, Type B (EUDRAGIT S 100) at a weight ratio of 0.9:0.85:0.25 and for different weight gains.

DETAILED DESCRIPTION OF THE INVENTION The following description includes information that may be useful in understanding the present invention. 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.

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.

Definitions

As herein used, the singular forms "a", "an", and "the" include plural references unless the content clearly dictates otherwise. Thus, for example, "a water-soluble polymer" includes a mixture of one or more water-soluble polymers.

The term "about" is used herein to refer to a numerical quantity, and includes "exactly." 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.).

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.

Unless stated otherwise, the amount of coatings or layers described herein (the "coating weight") 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%. As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

"Barrier coating" refers broadly to a "sustained release (SR) coating" or an "enteric or delayed release (DR) coating", disposed directly over an active agent-containing particle (e.g., crystal, bead, granule, pellet, or mini-tablet), or alternately over a protective seal-coat disposed over an active agent-containing particle. An SR coating may be, for example, a pharmaceutically acceptable water-insoluble polymer (e.g. ethyl cellulose) alone or in combination with a pharmaceutically acceptable water-soluble polymer (e.g. methylcellulose, hydroxy ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, and mixtures thereof. An enteric or DR coating may be, for example, an enteric polymer with pH-dependent solubility characteristics. "Controlled-release" coating encompasses coatings that delay, sustain, prevent, extend, modify, and/or otherwise prolong the release of a drug from a particle coated with a controlled-release coating. The term "controlled-release" encompasses "sustained-release", "modified-release", "extended-release" and "timed, pulsatile release".

"Disorder" refers to any condition or illness, requiring medication and/or medical attention. The term "patient" 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.

"Disposed over" 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.

"Effective amount" or "therapeutically effective amount", as used herein, means the amount of the drug to be dosed once or multiple times daily in a patient with the disorder to cause the desired therapeutic effect.

"Enteric polymer" refers to a pH sensitive polymer that is resistant to gastric juice (i.e. relatively insoluble at the low pH levels found in the stomach), and that dissolves at the higher pH levels found in the intestinal tract. "Functional polymer" means a polymer comprising a group selected from a water-insoluble polymer, a water-soluble polymer, an enteric polymer, or a mixture thereof. The functional polymer may, for example, be applied as a coating to an IR particle (e.g. bead, pellet, or mini- tablet). "Immediate release" or "IR" refers to a pharmaceutical composition that releases greater than or equal to about 50% of the active, e.g. greater than about 75% of the active, more particularly greater than about 90% of the active, and especially greater than about 95% of the active, within about 60 minutes or less, following administration of the composition. In particular embodiments, an "immediate release" refers to a component that releases at least about 90% (e.g. about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%)) of the active within about 30 minutes, following oral administration or when in vitro dissolution tested per United States Pharmacopeia using USP Apparatus 1 (baskets at 100 rpm) or Apparatus 2 (paddles at 50 or 75 rpm) in 700 mL of 0.1N HCl at 37°C. "Immediate release particle" refers broadly to an active agent-containing crystal, bead, pellet or mini-tablet that exhibits "immediate release" properties.

"Lag-time coating" or "TPR coating" are used interchangeably to refer to a controlled-release coating, such as, for example, a combination of pharmaceutically acceptable water-insoluble polymers (as described herein) and pharmaceutically acceptable enteric polymers (as described herein). A TPR coating can provide an immediate release pulse of the drug, or a sustained release of the drug over a period of time, each following a pre-determined lag-time.

"Lag-time bead", "TPR bead," or "lag-time particle" are used interchangeably herein to refer to a bead or particle comprising a TPR coating disposed over a drug crystal or drug-containing bead, pellet or mini-tablet. "Lag-time" refers to a time period wherein less than about 10% of the active agent is released from a pharmaceutical composition after ingestion of the pharmaceutical composition (or a dosage form comprising the pharmaceutical composition), or after exposure of the pharmaceutical composition, or dosage form comprising the pharmaceutical composition, to simulated body fluid(s), for example evaluated with a United States Pharmacopeia (USP) apparatus two-stage dissolution methodology (first 2 hours in 500 mL of 0.1 N HCl at 37°C followed by dissolution testing with 500 mL of pH 6.8 buffer obtained by switching dissolution media). For example, depending on the active ingredient and the coating composition, a lag-time of up to about 1 hour, up to about 2 hours, up to about 3 hours, up to about 4 hours, up to about 5 h, up to about 6 hours, up to about 7 hours, up to about 8 hours, up to about 9 hours, up to about 10 hours, up to about 11 hours, up to about 12 hours, up to about 13 hours, and up to about 14 hours, including all ranges and values therebetween, can be achieved under in vitro dissolution conditions or upon oral administration.

"Methylphenidate", "MPH" and the generic terms "drug", "active", "active agent", and "active pharmaceutical ingredient" include all four optical isomers of methylphenidate (namely <i-threo- methylphenidate, /-threo-methylphenidate, <i-erythro-methylphenidate, and /-erythro- methylphenidate) and mixtures thereof, including racemic mixtures, together with their salts (e.g. pharmaceutically acceptable salts), solvates (including hydrates), polymorphs, metabolites, prodrugs and deuterated analogs thereof. Racemic methylphenidate is also referred to herein as "d, /-methylphenidate". <i-Threo-methylphenidate is also referred to herein as 'dex- methylphenidate", "the dex isomer", "<i-methylphenidate" and ' -MPH"

"Particles" includes beads, granules, pellets, micro-particles, micro-particulates, 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. "Pharmaceutically acceptable salt" includes acid addition salts such as hydrohalide (e.g. hydrochloride and hydrobromide), sulfate or phosphate salts.

"Plasma concentration - time profile", "Cmax", "AUC", "Tmax" and "elimination half-life" have their generally accepted meanings as defined in the FDA Guidance for Industry: Bioavailability and Bioequi valence Studies for Orally Administered Drug Products - General Considerations (issued March 2003). All references to "plasma concentration - time profile", "Cmax", "AUC", "Tmax" and "elimination half-life" refer to the average values for such parameters as measured for a population of patients.

"Sealant layer" or "protective seal or under-coating" refers to a protective membrane disposed over a drug-containing core particle or a functional polymer coating. The sealant layer protects the particle from abrasion and attrition during handling, and/or minimizes static during processing. In general, the sealant coating can have a stabilizing effect. "Triphasic" means having three pulsatile phases, wherein one pulsatile component is a rapid drug release pulse (e.g. immediate release pulse) and the other pulsatile components each have a different lag-time before release of the drug over an appropriate period of time.

"Water-insoluble polymer" refers to a polymer that is insoluble or very sparingly soluble in aqueous media, independent of gastrointestinal pH, or over a broad pH range (e.g. less than 1 to 8). A polymer other than an enteric (enterosoluble) or gastrosoluble (reverse enteric) polymer that may swell but does not dissolve in aqueous media is considered "water-insoluble," as used herein. In contrast, a "water-soluble polymer" refers to a polymer that is soluble or miscible in aqueous media, independent of gastrointestinal pH, or over a broad pH range (e.g. less than 1 to 8). A polymer other than an enteric (enterosoluble) or gastrosoluble (reverse enteric) polymer that dissolves in aqueous media is considered "water-soluble," as used herein.

Unless stated otherwise, the amount of coatings or layers described herein (the "coating weight") 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%.

Compositions

The present disclosure provides a pharmaceutical composition comprising: (a) a population of immediate release (IR) particles comprising methylphenidate or a pharmaceutically acceptable salt thereof; (b) a first population of timed, pulsatile release (TPRi) particles comprising methylphenidate or a pharmaceutically acceptable salt thereof; and (c) a second population of timed, pulsatile release (TPR2) particles comprising methylphenidate or a pharmaceutically acceptable salt thereof, wherein oral administration of the composition to a patient in need thereof provides treatment of ADHD for between about 12 hours to about 16 hours. In some embodiments, the composition is orally administered once a day. In some embodiments, the composition is orally administered once a day in morning.

In some embodiments of the pharmaceutical composition, the methylphenidate or a pharmaceutically acceptable salt thereof is selected from the group consisting of d,l- methylphenidate hydrochloride, <i-methylphenidate hydrochloride, or a mixture thereof. In a specific embodiment, the methylphenidate or a pharmaceutically acceptable salt thereof is d,l- methylphenidate hydrochloride. In another specific embodiment, the methylphenidate or a pharmaceutically acceptable salt thereof is dex-methylphenidate hydrochloride.

In some embodiments, the pharmaceutical compositions of the present disclosure comprise about 5 mg to about 200 mg, or about 5 mg to about 125 mg, of methylphenidate or a pharmaceutically acceptable salt thereof, e.g., about 5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27.5 mg, about 30 mg, about 32.5 mg, about 35 mg, about 37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, about 47.5 mg, about 50 mg, about 52.5 mg, about 55 mg, about 57.5 mg, about 60 mg, about 62.5 mg, about 65 mg, about 67.5 mg, about 70 mg, about 72.5 mg, about 75 mg, about 77.5 mg, about 80 mg, about 82.5 mg, about 85 mg, about 87.5 mg, about 90 mg, about 92.5 mg, about 95 mg, about 97.5 mg, about 100 mg, about 102.5 mg, about 105.0 mg, about 107.5 mg, about 110 mg, about 112.5 mg, about 115 mg, about 117.5 mg, about 120 mg, about 122.5 mg, about 125 mg, about 127.5 mg, about 130 mg, about 132.5 mg, about 135 mg, about 137.5 mg, about 140 mg, about 142.5 mg, about 145 mg, about 147.5 mg, about 150 mg, about 152.5 mg, about 155 mg, about 157.5 mg, about 160 mg, about 162.5 mg, about 165 mg, about 167.5 mg, about 170 mg, about 172.5 mg, about 175 mg, about 177.5 mg, about 180 mg, about 182.5 mg, about 185 mg, about 187.5 mg, about 190 mg, about 192.5 mg, about 195 mg, about 197.5 mg, or about 200 mg, including all ranges and values therebetween. In other embodiments, the pharmaceutical compositions comprise about 20 mg to about 100 mg of methylphenidate or a pharmaceutically acceptable salt thereof. In specific embodiments, the pharmaceutical compositions comprise about 20 mg of methylphenidate or a pharmaceutically acceptable salt thereof. In specific embodiments, the pharmaceutical compositions comprise about 40 mg of methylphenidate or a pharmaceutically acceptable salt thereof. In specific embodiments, the pharmaceutical compositions comprise about 60 mg of methylphenidate or a pharmaceutically acceptable salt thereof. In specific embodiments, the pharmaceutical compositions comprise about 80 mg of methylphenidate or a pharmaceutically acceptable salt thereof. In specific embodiments, the pharmaceutical compositions comprise about 100 mg of methylphenidate or a pharmaceutically acceptable salt thereof.

As discussed herein, the total dose of methylphenidate can be distributed between the three particle populations (IR, TPRi and TPR2) of the disclosed pharmaceutical composition. The pharmaceutical composition of the disclosure may contain any ratio of methylphenidate, or the pharmaceutically acceptable salt thereof, in the IR, TPRi, and TPR2 particles. For example, in some embodiments, the ratio of methylphenidate, or the pharmaceutically acceptable salt thereof, in the IR particle to the combined amount in both the TPRi and TPR2 particles may be in the range of about 10:90 to about 90: 10, e.g., about 10:90, about 20:80, about 30:70, about 40:60, about 50:50, about 60:40, about 30:70, about 20:80, and about 90: 10, inclusive of all values and subranges therebetween. In some embodiments, the ratio of methylphenidate, or the pharmaceutically acceptable salt thereof, in the TPRi particle to the TPR2 particle may be in the range of about 10:90 to about 90: 10, e.g., about 10:90, about 20:80, about 30:70, about 40:60, about 50:50, about 60:40, about 30:70, about 20:80, and about 90: 10, inclusive of all values and subranges therebetween. In some embodiments, the ratio of methylphenidate, or the pharmaceutically acceptable salt thereof, in the IR particle : TPRi particle : TPR2 particle may be in the range of about 1 : 1 : 1; about 1 :2:2; about 1 : 1 :2; about 1 :2: 1; or about 3 :5:2.

In some embodiments, the pharmaceutical composition of the present disclosure is a capsule, an orally disintegrating tablet, or a hot melt extruded or spray-congealed composition. As discussed above, the pharmaceutical compositions of the present disclosure comprise multiple populations of particles having the desired (target) drug release profiles. The particles may be in the form of granules, granulated-extruded-spheronized pellets, DIFFUCAPS^® beads or mini- tablets, coated with one or more functional polymers to provide the desired drug release profiles. Functional polymers useful for coating multi-particulates or incorporating in polymer matrix- containing granules or pellets include: pharmaceutically acceptable water-soluble polymers (e.g., as hypromellose, hydroxypropylcellulose, and polyvinylpyrrolidone, and the like); pharmaceutically acceptable water-insoluble polymers (e.g., ethyl cellulose, cellulose acetate, polyvinyl acetate, ammonio methacrylate copolymer, such as EUDRAGIT E30D, EUDRAGIT RLPO, and EUDRAGIT RSPO that are not soluble in water and physiological buffers, and the like); enterosoluble or enteric polymers (e.g., hypromellose phthalate (HP-55), hypromellose acetate succinate type HG, MG or LG (e.g. UPMC-AS HG, MG or LG), pH-sensitive methacrylic acid/methylmethacrylate copolymers (such as EUDRAGIT LI 00 polymer, and EUDRAGIT SI 00 polymer) that are gastric acid resistant, but dissolve in an alkaline buffer at or above a designated pH, and the like); and gastrosoluble polymer (e.g., cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, such as EUDRAGIT EPO, that dissolves in aqueous buffer at a pH of 5.5 or less).

Examples of fillers/diluents typically used in the manufacture of granules by high shear granulation or pellets by granulation-extrusion-spheronization or mini-tablets by compression of high shear granules, include lactose, calcium carbonate, calcium phosphate, calcium sulfate, microcrystalline cellulose, dextran, starches, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

IR Particles

In some embodiments, the population of IR particles comprises about 10% to about 80% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 45%, about 50%, about 55%), about 60%, about 65%, about 70%, about 75%, and about 80%, inclusive of all values and subranges therebetween) of the total dose of methylphenidate or pharmaceutically acceptable salt thereof. In some embodiments, the population of IR particles comprises 20% to about 40% by weight of the total dose of methylphenidate or pharmaceutically acceptable salt thereof, 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%, or about 40%, inclusive of all ranges and values therebetween. In some embodiments, the population of IR particles comprises about 20% to about 30%) by weight of the total dose of methylphenidate or pharmaceutically acceptable salt thereof. In other embodiments, the population of IR particles comprises about 30% to about 40% by weight of the total dose of methylphenidate or pharmaceutically acceptable salt thereof.

In some embodiments, the IR particles comprise methylphenidate (MPH)-containing particles in the form of crystals, beads, pellets or mini-tablets. In some embodiments, the beads are sugar spheres or microcrystalline cellulose spheres layered with MPH and optionally a polymeric binder. In some embodiments, the IR particles comprise methylphenidate or a pharmaceutically acceptable salt thereof as a layer onto the outer surface of an inert core. In some embodiments, the average particle size of the inert core ranges from about 20 μιη to about 300 μιη (e.g., about 20 μηι, about 50 μηι, about 100 μηι, about 150 μηι, about 200 μηι, about 250 μηι, or about 300 μηι, inclusive of all values and subranges therebetween). In some embodiments, the IR particles further comprise a polymeric binder. Examples of polymeric binders include cellulose derivatives such as methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyethylene glycol, and the like. In some embodiments, the IR particles comprise a binder selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (hypromellose), povidone, polyethylene glycol, or a mixture thereof.

TPR particles

To achieve a triphasic delivery of drug, the active can be appropriately coated (e.g., a TPR coating, at different weights and/or different ratios of polymers) as described herein or present in a matrix in order to impart the desired release characteristics. In some embodiments, the TPRi and TPR2 particles comprise an IR particle coated with a TPR coating. The TPR coatings to be disposed over methylphenidate-containing particles may conveniently be prepared according to procedures described in US 6,627,223, U.S. 9,161,918 and U.S. 9,161,919, the contents of which are incorporated herein in their entirety for all purposes.

In some embodiments, TPR particles having the desired lag-time (i.e. a time period of no drug release or less than 10% of the dose released when tested for dissolution) followed by complete drug release over a desired time interval, may be prepared by coating IR particles (e.g. beads or mini-tablets) with a lag-time coating comprising a pharmaceutically acceptable water-insoluble polymer (e.g., ethylcellulose) in combination with a pharmaceutically acceptable enteric polymer (e.g., hypromellose phthalate (HP-55)). A higher relative content of the water-insoluble polymer to enteric polymer in the lag-time coating membrane or a higher coating level will result in a longer lag-time. To further modulate drug release, a barrier coating comprising a water-insoluble polymer or an enteric polymer may be applied over IR particles (e.g. beads, pellets or mini-tablets) prior to the lag-time coating.

In some embodiments, the TPRi particles may comprise about 10% to about 80% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 45%, about 50%, about 55%, about 60%), about 65%, about 70%, about 75%, and about 80%, inclusive of all values and subranges therebetween) of the total dose of methylphenidate or pharmaceutically acceptable salt thereof. In some embodiments, the TPRi particles may comprise about 30% to about 60% by weight of the total dose of methylphenidate or a pharmaceutically acceptable salt thereof, e.g., 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%, or about 60%, inclusive of all ranges and values therebetween. In some embodiments, the population of TPRi particles comprises about 30% to about 40% by weight of the total dose of methylphenidate or pharmaceutically acceptable salt thereof. In other embodiments, the population of TPRi particles comprises about 20% to about 45% by weight of the total dose of methylphenidate or pharmaceutically acceptable salt thereof. In still other embodiments, the population of TPRi particles comprises about 35% to about 45% by weight of the total dose of methylphenidate or pharmaceutically acceptable salt thereof.

In some embodiments, the TPR2 particles may comprise about 10% to about 80% (e.g., about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 45%, about 50%, about 55%, about 60%), about 65%, about 70%, about 75%, and about 80%, inclusive of all values and subranges therebetween) of the total dose of methylphenidate or pharmaceutically acceptable salt thereof. In some embodiments, the of TPR2 particles contains about 20% to about 60% by weight of the total dose of methylphenidate or a pharmaceutically acceptable salt thereof, 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%, or about 60%, inclusive of all ranges and values therebetween. In some embodiments, the second population of TPR2 particles comprises about 25% to about 40% by weight of the total dose of methylphenidate or pharmaceutically acceptable salt thereof. In other embodiments, the population of TPR2 particles comprises about 30% to about 50% by weight of the total dose of methylphenidate or pharmaceutically acceptable salt thereof. In still other embodiments, the population of TPR2 particles comprises about 35% to about 55% by weight of the total dose of methylphenidate or pharmaceutically acceptable salt thereof. In some embodiments of the present disclosure, the drug load in TPRi particles is higher than in TPR.2 particles, i.e., greater than a weight ratio of about 1:1. In some embodiments, the weight ratio of methylphenidate or a pharmaceutically acceptable salt in the TPRi and TPR2 particles is in a range of about 1.1:1 to about 4:1, e.g., about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, about 2.5:1, about 2.6:1, about 2.7:1, about 2.8:1, about 2.9:1, about 3:1, about 3.1:1, about 3.2:1, about 3.3:1, about 3.4:1, about 3.5:1, about 3.6:1, about 3.7:1, about 3.8:1, about 3.9:1, or about 4:1, including all ranges and values therebetween. In other embodiments, the weight ratio of methylphenidate or a pharmaceutically acceptable salt in the TPRiand TPR2 particles is from about 1:0.10 and about 1:0.95, e.g., about 1:0.10, about 1:0.15, about 1:0.20, about 1:0.25, about 1:0.3, about 1:0.35, about 1:0.4, about 1:0.45, about 1:0.5, about 1:0.55, about 1:0.6, about 1:0.65, about 1:0.7, about 1:0.75, about 1:0.8, about 1:0.85, about 1:0.9, or about 1:0.95, including all ranges and values therebetween. In some embodiments, the weight ratio of methylphenidate or a pharmaceutically acceptable salt in the TPRi and TPR2 particles is from about 1 :0.60 and about 1 :0.90, including about 1 :0.70.

In some embodiments, the drug load in TPR2 is higher than in TPRi, i.e., greater than a weight ratio of about 1:1. In some embodiments, the weight ratio of methylphenidate or a pharmaceutically acceptable salt in the TPR2 and TPRi particles is in a range of about 1.1:1 to about 4:1, e.g., about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, about 2.5:1, about 2.6:1, about 2.7:1, about 2.8:1, about 2.9:1, about 3:1, about 3.1:1, about 3.2:1, about 3.3:1, about 3.4:1, about 3.5:1, about 3.6:1, about 3.7:1, about 3.8:1, about 3.9:1, or about 4:1, including all ranges and values therebetween. In other embodiments, the weight ratio of methylphenidate or a pharmaceutically acceptable salt in the TPR2 and TPRi particles is in a range of about 1:0.10 and about 1:0.95, e.g., about 1:0.10, about 1:0.15, about 1:0.20, about 1:0.25, about 1:0.3, about 1:0.35, about 1:0.4, about 1:0.45, about 1:0.5, about 1:0.55, about 1:0.6, about 1:0.65, about 1:0.7, about 1:0.75, about 1:0.8, about 1:0.85, about 1:0.9, or about 1:0.95, including all ranges and values therebetween. In some embodiments, the weight ratio of methylphenidate or a pharmaceutically acceptable salt in the TPR2 and TPRi particles is in a range of about 1:0.60 and about 1 :0.90, including about 1 :0.70. As discussed above, the TPR coating comprises a combination of water-insoluble polymers (as described herein) and enteric polymers (as described herein). In some embodiments, the TPR coating is present as a layer containing a mixture of water-insoluble polymers and enteric polymers. In other embodiments, the TPR coating comprises a first membrane comprising the water-insoluble polymer and a second membrane comprising the enteric polymer. The first membrane can be disposed over the second membrane or the second membrane can be disposed over the first membrane.

In various embodiments, the TPR coating comprises one or more water-insoluble polymers and one or more enteric polymers. In some embodiments, the ratio of the water-insoluble polymer to the enteric polymer is the range of from of about 1 :99 to about 99: 1, e.g., about 1 :99, about 10:90, about 20:80, about 30:70, about 40:60, about 50:50, about 60:40, about 30:70, about 20:80, about 90: 10, and about 99: 1, inclusive of all values and subranges therebetween. When the TPR coating comprises a combination of water-insoluble and enteric polymers, the ratio of the water-insoluble polymer to the enteric polymer ranges from about 9: 1 to about 1 :3, including about 9: 1, about 8: 1, about 7: 1, about 6: 1, about 5: 1, about 4: 1, about 3: 1, about 2: 1, about 1 : 1, about 1 :2, or about 1 :3, inclusive of all ranges and values therebetween. In some embodiments, the ratio of the water- insoluble polymer to the enteric polymer is from about 8:2 to about 2:3, e.g., about 8:2, about 7:2, about 3 : 1, about 5:2, about 2: 1, about 3 :2, about 1 : 1, or about 2:3, including all ranges and values therebetween. In other embodiments, the ratio of the water-insoluble polymer to the enteric polymer in the TPR coating is from about 4: 1 to about 1 :2, from about 4: 1 to about 2:3, from about 4: 1 to about 1 : 1, or from about 7:3 to about 1 : 1, inclusive of all ranges and values therebetween. In some embodiments, the ratio of the water-insoluble polymer to the enteric polymer is from about 7:3 to about 1 : 1. In other embodiments, the ratio is from about 7:3 to about 6:4, inclusive of all ranges and values therebetween. In still other embodiments, the ratio is from about 1 : 1 to about 2:3, inclusive of all ranges and values therebetween. In certain embodiments, the weight ratio of the water-insoluble polymer to the enteric polymer in the TPR coating is from about 85: 15 to about 35:65. In other embodiments, the ratio of the water-insoluble polymer to the enteric polymer on the TPRi particle is from about 65:35 to about 50:50. In some embodiments, the ratio of the water-insoluble polymer to the enteric polymer in the TPR2 particle is from about 75:25 to about 55:45. In some embodiments, the TPR coating is present at a weight gain of from about 5% to about 20%. In other embodiments, the TPR coating is present at a weight gain of 15% to about 50%.

The coating weight of a TPR coating may range from about 5% to about 60% of the total weight of the coated bead or particle, e.g., about 5%, about 7.5%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about 22.5%, about 25%, about 27.5%, about 30%, about 32.5%, about 35%, about 37.5%, about 40%, about 42.5%, about 45%, about 47.5%, about 50%, about 52.5%, about 55%), about 57.5%, or about 60%, including all ranges and values therebetween. In some embodiments, the coating weight of a TPR coating may range from about 10% to about 50% of the total weight of the coated bead or particle (e.g., about 10%, about 15%, about 20%, about 25%, about 30%), about 35%, about 40%, about 45%, or about 50%, and inclusive of all ranges and values therebetween).

In some embodiments, the coating weight of the TPRi coating ranges from about 5% to about 30% of the total weight of the coated bead or particle, 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%, or about 30%, inclusive of all ranges and values therebetween. In some embodiments, the coating weight is from about 5% to about 20%). In other embodiments, the coating weight is from about 10% to about 25%. In still other embodiments, the coating weight is from about 20% to about 30%. In another embodiment, the coating weight of the TPR2 coating ranges from about 15% to about 60%, e.g., about 15%, about 17.5%, about 20%, about 22.5%, about 25%, about 27.5%, about 30%, about 32.5%, about 35%, about 37.5%, about 40%, about 42.5%, about 45%, about 47.5%, about 50%), about 52.5%, about 55%, about 57.5%, or about 60%, inclusive of all ranges and values therebetween. In some embodiments, the coating weight of the TPR2 coating is from about 20% to about 50%). In other embodiments, the coating weight is from about 20% to about 35%. In yet another embodiment, the coating weight is from about 20% to about 25%.

Non-limiting examples of pharmaceutically acceptable water-insoluble polymers include polyvinyl acetate (e.g., KOLLICOAT^® SR30D), cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate latex, ethyl cellulose (e.g., AQUACOAT^® , SURELEASE^®), copolymers of ethyl acrylate and methyl methacrylate optionally copolymerized with a trialkyl ammonioalkyl methacrylate (referred to interchangeably herein as "ammonium methacrylate copolymers" or "ammonio methacrylate copolymers"), such as EUDRAGIT^® RS and RL polymers and their dispersions, EUDRAGIT^® RS30D and EUDRAGIT^® RL30D, EUDRAGIT RSPO, EUDRAGIT^® E30D, and mixtures thereof.

Non-limiting examples of pharmaceutically acceptable enteric polymers include cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, pH-sensitive methacrylic acid/methylmethacrylate copolymers optionally comprising anionic groups (referred to interchangeably herein as methyacrylic acid/methylmethacrylate copolymer or methacrylic acid copolymer, such as EUDRAGIT^® L (e.g. EUDRAGIT^® L12.5, L100, L30D), S (e.g., EUDRAGIT^® S12.5 and S100) and FS polymers and hydroxypropyl methylcellulose acetate succinate, such as AQUASOLVE, HPMC-AS (HPMC-AS LG, HPMC-AS MG, HPMC-AS HG), and mixtures thereof. In some embodiments, the pharmaceutically acceptable water insoluble polymer is an ammonio methacrylate copolymer (e.g., EUDRAGIT RSPO), and the enteric polymer is a mixture of pH- sensitive methacrylic acid/methylmethacrylate copolymer (e.g., EUDRAGIT^® L100, EUDRAGIT^® SI 00 or a mixture). In some embodiments, the pH-sensitive methacrylic acid/methylmethacrylate copolymer is anionic. In some embodiments, the water-insoluble or the enteric polymer of the TPR coating may include a plasticizer. The amount of plasticizer required depends upon the plasticizer, the properties of the water-insoluble polymer, and the ultimate desired properties of the coating. The plasticizer can be present in any appropriate weight percent of the total coating disclosed herein. For example, in some embodiments, the plasticizer may constitute from about 2% to about 50% (e.g. about 5% to about 45%) by weight of the coated particle, including, for example, about 2%, about 4%, about 6%, about 8%, about 10%, about 12%, about 14%, about 16%, about 18%, about 20%, about 22%, about 24%, about 26%, about 28%, about 30%, about 32%, about 34%, about 36%, about 38%, about 40%, about 42%, about 44%, about 46%, about 48%, or 50%, inclusive of all ranges and values therebetween. In some embodiments, the plasticizer may constitute from about 3% to about 30%) by weight of the polymer(s) in the lag-time coating, e.g., 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 29% or about 30%), including all ranges and values therebetween. Other suitable, but non-limiting levels of plasticizer range from about 1% to about 20% by weight of the total coating weight, 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%), or about 20% by weight of the total coating weight, including all ranges and values therebetween. In other embodiments, the plasticizer range is from about 3% to about 20% by weight of the total coating weight. In still other embodiments, the plasticizer range is from about 3%) to about 5% by weight of the total coating weight. In yet other embodiments, the plasticizer range is from about 7% to about 10% by weight of the total coating weight. In certain embodiments, the plasticizer range is from about 12% to about 15% by weight of the total coating weight. In certain other embodiments, the plasticizer range is from about 17% to about 20% by weight of the total coating weight. In still other embodiments, the amount of plasticizer relative to the weight of the polymer(s) in the controlled-release coating is from about 3%, to about 15%, inclusive of all ranges and values therebetween. In yet another embodiment, the amount of plasticizer relative to the weight of the polymer(s) is from about 10% to about 25%, inclusive of all ranges and values therebetween. One of ordinary skill in the art will recognize that the presence of plasticizer, or type(s) and amount(s) of plasticizer(s) can be selected based on the polymer or polymers and nature of the coating system (e.g., aqueous or solvent-based, solution or dispersion- based and the total solids).

Non-limiting examples of suitable plasticizers include glycerin, triacetin, citrate esters, tri ethyl 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 (e.g. castor oil, hydrogenated castor oil, sesame oil, olive oil, etc.), fatty acids, and mixtures thereof. In some embodiments, the plasticizer is selected from the group consisting of triethyl citrate, triacetin, substituted glycerides (e.g., MYVACET® 9-45), glyceryl monostearate, diethyl phthalate, triethyl citrate, dibutyl sebacate, acetyltributyl citrate, polyethylene glycols, and vegetable oils (e.g., hydrogenated castor oil). In some embodiments, triethyl citrate or diethyl phthalate may be used as a plasticizer in an amount of about 10-15% by weight of the total coating weight, e.g., about 10%, about 10.25%, about 10.5%, about 10.75%, about 11%, about 11.25%, about 11.5%, about 11.75%, about 12%, about 12.25%, about 12.5%, about 12.75%, about 13%, about 13.25%, about 13.5%, about 13.75%, about 14%), about 14.25%, about 14.5%, about 14.75%, or about 15%, including all ranges and values therebetween.

In some embodiments, in the TPR coating, the water-insoluble polymer is ethylcellulose, the enteric polymer is hypromellose phthalate, and the plasticizer is diethyl phthalate or triethyl citrate.

As discussed, the present disclosure provides a pharmaceutical composition comprising: (a) a population of immediate release (IR) particles comprising methylphenidate or a pharmaceutically acceptable salt thereof; (b) a first population of timed, pulsatile release (TPRi) particles comprising methylphenidate or a pharmaceutically acceptable salt thereof; and (c) a second population of timed, pulsatile release (TPR2) particles comprising methylphenidate or a pharmaceutically acceptable salt thereof, wherein oral administration of the composition to a patient in need thereof provides treatment of ADHD for between about 12 hours to about 16 hours. In some embodiments, the TPR coating comprises one or more pharmaceutically acceptable water insoluble polymers and one or more pharmaceutically acceptable enteric polymers, examples of which are disclosed herein. The weight ratio of the pharmaceutically acceptable water insoluble polymer to the pharmaceutically acceptable enteric polymer in the TPR coating is from about 85: 15 to about 35:65, including all ranges and values therebetween. In some embodiments, the ratio of water insoluble polymer to the enteric polymer on the TPRi particle is from about 65:35 to about 50:50, including all ranges and values therebetween. In some embodiments, the ratio of the water insoluble polymer to the enteric polymer in the TPR2 particle is from about 75:25 to about 55:45, including all ranges and values therebetween. The TPR coating of the presently disclosed compositions can be present at a weight gain of from about 5% to about 20%. In some embodiments, the TPR coating is present at a weight gain of 15% to about 50%.

The pharmaceutical compositions disclosed herein can be orally administered once a day. In some embodiments, the composition is orally administered once a day in morning. In particular embodiments, an immediate release particle population may be coated with Ammonio Methacrylate Copolymer, Type A (EUDRAGIT RSPO) in combination with Methacrylic Acid Copolymer, Type A (EUDRAGIT LI 00) and with Methacrylic Acid Copolymer, Type B (EUDRAGIT S100) (e.g., as a mixture in a layer) at a weight ratio 0.9:0.7:0.4 to form the TPRi particles while the TPR coating of the TPR2 particles may comprise Ammonio Methacrylate Copolymer, Type A (EUDRAGIT RSPO) in combination with Methacrylic Acid Copolymer, Type B (EUDRAGIT SI 00) and with Methacrylic Acid Copolymer, Type A (EUDRAGIT LI 00) at a ratio of 0.9:0.25:0.85. The drug load in TPRi may be a different from that present in TPR2, including options where the drug load in TPRi is higher. Triethyl citrate may conveniently be used as a plasticizer in an amount of about 10-15% by weight of the total coating weight, of each coating, respectively.

In another embodiment, an immediate release particle population may be coated with Ammonio Methacrylate Copolymer, Type A (EUDRAGIT RSPO) in combination with Methacrylic Acid Copolymer, Type A (EUDRAGIT LI 00) and with Methacrylic Acid Copolymer, Type B (EUDRAGIT S100) at a weight ratio 0.9:0.7:0.4 to form the TPRi particles while the TPR coating of the TPR2 particles may comprise Ammonio Methacrylate Copolymer, Type A (EUDRAGIT RSPO) in combination with Methacrylic Acid Copolymer, Type A (EUDRAGIT LI 00) and with Methacrylic Acid Copolymer, Type B (EUDRAGIT S100) at a ratio of 0.9:0.85:0.25. In either case, triethyl citrate may conveniently be used as a plasticizer in an amount of about 10-15% by weight of the total coating weight, of each coating, respectively.

In another embodiment, an immediate release particle population may be coated with Ammonio Methacrylate Copolymer, Type A (EUDRAGIT RSPO) in combination with Methacrylic Acid Copolymer, Type A (EUDRAGIT LI 00) and with Methacrylic Acid Copolymer, Type B (EUDRAGIT S100) at a weight ratio 0.1 :0.5:0.5 to form the first group of TPR particle population while the TPR coating of the second TPR particle population, may comprise Ammonio Methacrylate Copolymer, Type A (EUDRAGIT RSPO) in combination with Methacrylic Acid Copolymer, Type A (EUDRAGIT LI 00) and with Methacrylic Acid Copolymer, Type B (EUDRAGIT S100) at a ratio of 0.9:0.85:0.25. Triethyl citrate may conveniently be used as a plasticizer in an amount of about 10-15%> by weight of the total coating weight, of each coating, respectively. In particular embodiments of the present disclosure, the TPR coating of the TPRi particle or the TPR2 particle, may comprise ethylcellulose (e.g., Ethocel Premium Standard 10 (EC-10 with a viscosity of 10 cps) as the water-insoluble polymer and hypromellose phthalate (e.g., HP-50 or HP-55, the enteric polymer which starts dissolving in a buffer at pH 5.0, 5.5, or above) as the enteric polymer at a ratio of from about 9: 1 to about 1 : 1, e.g., about 9: 1, about 8.5: 1, about 8: 1, about 7.5 : 1, about 7: 1, about 6.5: 1, about 6: 1, about 5.5: 1, about 5: 1, about 4.5: 1, about 4: 1, about 3.5: 1, about 3 : 1, about 2.5: 1, about 2: 1, about 1.5: 1, or about 1 : 1, including all ranges and values therebetween, for a weight gain of up to 50%.

In particular embodiments of the present disclosure, an immediate release particle population may be coated with ethylcellulose in combination with HP-55 at a weight ratio of 50/50 for a weight gain of 10-20%) to form the TPRi particles, while the TPR coating of the TPR2 particles, may comprise ethylcellulose and HP-55 at a ratio of 60/40 for a weight gain of about 20-30%>. In either case, tri ethyl citrate may conveniently be used as a plasticizer in an amount of about 10-15%) by weight of the total coating weight. In certain other embodiments, the TPR coating of the second TPR particle population, may comprise ethylcellulose and HP-55 at a ratio of 70/30 by weight for a weight gain of about 15-30%, 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%> or about 30%>, including all ranges and values therebetween.

In particular embodiments of the present disclosure, an immediate release particle population (sealed coated) may be coated with Methacrylic Acid Copolymer, Type A (EUDRAGIT LI 00) in combination with Methacrylic Acid Copolymer, Type B (EUDRAGIT SI 00) and with Ammonio Methacrylate Copolymer, Type A (EUDRAGIT RSPO) at a weight ratio of 0.5/0.5/1 to form the first group of TPR particle population, while the TPR coating of the second TPR particle population, may comprise Ammonio Methacrylate Copolymer, Type A (EUDRAGIT RSPO) in combination with Methacrylic Acid Copolymer, Type A (EUDRAGIT LI 00) and with Methacrylic Acid Copolymer, Type B (EUDRAGIT S100) at a ratio of 1/0.5/0.5, wherein the methylphenidate drug load of TPRi is different from the drug load in TPR2.

In some embodiments, the present disclosure describes a pharmaceutical composition comprising: a) a population of IR particles, wherein each IR particle comprises an MPH-containing particle, e.g. crystals, beads (for example sugar spheres or microcrystalline cellulose spheres layered with MPH and optionally a polymeric binder), pellets or mini-tablets and at least one pharmaceutically acceptable excipient, coated with a protective seal coat comprising a hydrophilic polymer or OPADRY CLEAR, OPADRY WHITE, or OPADRY II available from Colorcon; b) a first population of TPR particles (TPRi), wherein IR particles are coated with a lag- time coating comprising a water-insoluble polymer, such as ethylcellulose, in combination with an enteric polymer, such as hypromellose phthalate (HP-55) at a weight ratio of from about 50/50 to about 65/35 for a weight gain of from about 5% to about 20% by weight to achieve a lag-time of approximately 4 hours; and c) a second population of TPR particles (TPR2), wherein IR particles are coated with a lag- time coating comprising a water-insoluble polymer, such as ethylcellulose, in combination with an enteric polymer, such as hypromellose phthalate (HP-55), at a weight ratio of from about 55/45 to about 75/25 for a weight gain of from about 15% to about 50% by weight to deliver d-MPH as a moderate release pulse following the lag-time of about 7-9 hours.

The three particle populations of steps (a) to (c) above may conveniently be contained in hard gelatin or HPMC capsules with suitable proportions of the active ingredient such that the triple pulse delivery system not only provides for rapid onset of ADHD symptom control but also provides for longer duration of efficacy, i.e., for up to about 14 to about 16 hours, with a high drug benefit to risk ratio.

In some embodiments, at least one population of particles (e.g., IR, TPRi or TPR2) further comprises a seal coating layer. In some embodiments, the IR particles are coated with a seal coating layer. In some embodiments, the seal coating layer comprises one or more pharmaceutically acceptable hydrophilic polymers. In various embodiments, the hydrophilic polymers are selected from the group consisting of hydroxypropyl celluloses (HPC), hydroxypropyl methylcelluloses, methylcelluloses, polyethylene oxides, sodium carboxymethyl celluloses, and the like, or combinations thereof.

Barrier coating

Certain embodiments of this invention further optionally comprise a barrier coating disposed over the immediate release particle population prior to applying the TPR coating forming the second TPR particle population to modulate the drug release. The barrier coating may comprise a sustained release (SR) coating comprising a pharmaceutically acceptable water-insoluble polymer (as described herein) alone, or a pharmaceutically water-insoluble polymer (as described herein, e.g., ethylcellulose) in combination with a pharmaceutically water-soluble polymer (as described herein, e.g., povidone or polyethylene glycol) or a delayed release (DR) coating comprising an enteric polymer (as described herein, e.g., hypromellose phthalate).

In various embodiments, pharmaceutical compositions of the present disclosure further comprise a barrier coating disposed over the IR particle, wherein the barrier coating comprises (i) a water- insoluble polymer, (ii) an enteric polymer, or (iii) a water-insoluble polymer and a water-soluble polymer. In some embodiments, the water-insoluble polymer is selected from the group consisting of polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, and methacrylic acid/methylmethacrylate copolymers, such as EUDRAGIT^® RS and RL polymers and their dispersions, EUDRAGIT^® RS30D and EUDRAGIT^® RL30D, EUDRAGIT RSPO; EUDRAGIT^® E30D, AQUACOAT^®, SURELEASE^®, KOLLICOAT^® SR30D, and cellulose acetate latex, and mixtures thereof. In some embodiments, the enteric polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, pH-sensitive methacrylic acid/methylmethacrylate copolymers, such as EUDRAGIT^® L, S and FS polymers and hydroxypropyl methylcellulose acetate succinate, such as AQUASOLVE HPMC-AS (HPMC-AS LG, HPMC-AS MG, HPMC-AS HG), and mixtures thereof. In some embodiments, the barrier coating further comprises a plasticizer selected from the group consisting of triethyl citrate, triacetin, substituted glycerides (e.g., MYVACET® 9-45), glyceryl monostearate, diethyl phthalate, triethyl citrate, dibutyl sebacate, acetyltributyl citrate, polyethylene glycols, and vegetable oils (e.g., hydrogenated castor oil). In some embodiments, the water-soluble polymer is selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (hypromellose), povidone, polyethylene glycol or mixtures thereof.

In some embodiments, the barrier coatings may be present at a weight gain of from about 1-30%, 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 29% or about 30%, including all ranges and values therebetween.

In some embodiments, the barrier (coatings may include a plasticizer, such as triethyl citrate used at a plasticizer content of about 10-15% by weight of the total coating weight, e.g., about 10%, about 10.25%, about 10.5%, about 10.75%, about 11%, about 11.25%, about 11.5%, about 11.75%, about 12%, about 12.25%, about 12.5%, about 12.75%, about 13%, about 13.25%, about 13.5%, about 13.75%, about 14%, about 14.25%, about 14.5%, about 14.75%, or about 15%, including all ranges and values therebetween.

Lag-time and Release Profiles Various embodiments of the invention are directed to pharmaceutical compositions for once-daily dosing consisting of at least three different particle populations - one immediate-release (IR) and at least two timed, pulsatile-release (TPR) particle populations (herein referred to as TPRi and TPR2), each population comprising methylphenidate or a salt thereof (e.g. the hydrochloride salt). The pharmaceutical compositions of the disclosure are formulated to achieve a rapid onset of action and a duration of efficacy for up to at least about 14 to about 16 hours. This therapeutic profile is achieved by releasing methylphenidate (or a pharmaceutically acceptable salt thereof) in three pulses which approximate (e.g., is bioequivalent to) thrice-daily dosing (TID) of an immediate release formulation containing methylphenidate or a pharmaceutically acceptable salt thereof. The timing of drug release and lag-times are designed to maintain therapeutically effective blood plasma concentrations of methylphenidate. In some embodiments, the pharmaceutical composition of the invention provides a triple pulsatile plasma MPH concentration-time profile in the range of approximately 8±4 ng/mL over the range of from about 1 hour up to about 16 hours post-dosing.

In some embodiments, at least about 90% of the methylphenidate or a pharmaceutically acceptable saltthereof in the IR population is released within about 30 minutes as determined by United States Pharmacopeia (USP) apparatus two-stage dissolution methodology.

As discussed above, the present pharmaceutical compositions are formulated to approximate (e.g., provide blood plasma levels that are bioequivalent to) thrice-daily dosing (tid) of an immediate release formulation of methylphenidate or a pharmaceutically acceptable salt thereof. In some embodiments, the TPRi particle is formulated to provide drug release that is equivalent to dosing an immediate release methylphenidate composition about 4-6 hours after administering a first immediate release component. In some embodiments, the TPR2 particle is formulated to provide drug release that is equivalent to dosing an immediate release methylphenidate composition about 4-6 hours after administering a second immediate release component, or 8-12 hours after dosing the first immediate release methylphenidate composition.

In some embodiments , the TPRi particles provide a lag time of from about 1 hour to about 7 hours (e.g., about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2 h, about 2.25 h, about 2.5 h, about, 2.75 h, about 3 h, about 3.25, about 3.5 h, about 3.75 h, about 4 h, about 4.25 h, about 4.5 h, about 4.75 h, about 5 h, about 5.25 h, about 5.5 h, 5.75 h, about 6 h, about 6.25 h, about 6.5 h, about 6.75 h, or about 7 h, inclusive of all ranges and values therebetween) as determined by United States Pharmacopeia (USP) apparatus two-stage dissolution methodology. In some embodiments, the TPR2 particles provide a lag time of from about 7 hours to about 14 hours (e.g., about 7 h, about 7.25 h, about 7.5 h, about 7.75 h, about 8 h, about 8.25 h, about 8.5 h, about, 8.75 h, about 9 h, about 9.25, about 9.5 h, about 9.75 h, about 10 h, about 10.25 h, about 10.5 h, about 10.75 h, about 11 h, about 11.25 h, about 11.5 h, 11.75 h, about 12 h, about 12.25 h, about 12.5 h, about 12.75 h, about 13 h, about 13.25 h, about 13.5 h, about 13.75 h, or about 14 h, inclusive of all ranges and values therebetween) as determined by USP apparatus two-stage dissolution methodology.

In other embodiments, the TPRi particles provide a lag time of from about 2 hours to about 5 hours (e.g., about 2 h, about 2.25 h, about 2.5 h, about, 2.75 h, about 3 h, about 3.25, about 3.5 h, about 3.75 h, about 4 h, about 4.25 h, about 4.5 h, about 4.75 h, or about 5 h, inclusive of all ranges and values therebetween) as determined by USP apparatus two-stage dissolution methodology. In some embodiments, the TPR2 particles provide a lag time of from about 7 hours to about 9 hours (e.g., about 7 h, about 7.25 h, about 7.5 h, about 7.75 h, about 8 h, about 8.25 h, about 8.5 h, about, 8.75 h, or about 9 h, inclusive of all ranges and values therebetween) as determined by USP apparatus two-stage dissolution methodology.

In other embodiments, the TPRi particles provide a lag time of from about 3 hours to about 6 hours, e.g., about 3 h, about 3.25, about 3.5 h, about 3.75 h, about 4 h, about 4.25 h, about 4.5 h, about 4.75 h, about 5 h, about 5.25 h, about 5.5 h, 5.75 h, or about 6 h, inclusive of all ranges and values therebetween. In other embodiments, the TPR2 particles provide a lag time of up to about 8 hours or up to about 10 hours, e.g., about 8 h, about 8.25 h, about 8.5 h, about, 8.75 h, about 9 h, about 9.25 h, about 9.5 h, about 9.75 h, or about 10 h, inclusive of all ranges and values therebetween.

The duration of drug release following the TPRi or TPR2 lag-time may range from about 0.5 h to about 4 hours, including about 0.5 h, about 0.75 h, 1 h, 1.25 h, 1.5 h, 1.75 h, 2 h, 2.25 h, 2.5 h, 2.75 h, 3 h, 3.25 h, 3.5 h, 3.75 h, or 4 h, including all ranges and values therebetween. In some embodiments, the duration of drug release following the lag-time may be up to about 4 hours or up to about 6 hours, including all ranges and values therebetween. Lag-time, as disclosed, is determined by United States Pharmacopeia (USP) apparatus two-stage dissolution methodology. In some embodiments, at least about 90% of the methylphenidate or a pharmaceutically acceptable salt thereof in the TPRi population is released over a period of about 30 minutes (0.5 h) to about 4 hours (e.g., about 0.5 h, about 0.75 h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3 h, about 3.25 h, about 3.5 h, about 3.75 h, or about 4 h, including all ranges and values therebetween) following the lag time as determined by USP apparatus two-stage dissolution methodology. In other embodiments, at least about 90% of the methylphenidate or a pharmaceutically acceptable salt thereof in the TPRi population is released over a period of about 30 minutes to about 2 hours following the lag time as determined by USP apparatus two-stage dissolution methodology.

In some embodiments, at least about 90% of the methylphenidate or a pharmaceutically acceptable salt thereof in the TPR2 population is released over a period of about 1 hour to about 5 hours (e.g., about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4 h, about 4.25 h, about 4.5 h, about 4.75 h, or about 5 h, including all ranges and values therebetween) following the lag-time as determined by USP apparatus two-stage dissolution methodology. In other embodiments, at least about 90% of the methylphenidate or a pharmaceutically acceptable salt thereof in the TPR2 population is released over a period of about 1 hour to about 4 hours following the lag-time as determined by USP apparatus two-stage dissolution methodology.

In one aspect, the pharmaceutical composition of the invention (e.g. presented as a capsule) comprises one IR particle population together with TPRi particles exhibiting a delay in initiation of MPH release (i.e. lag-time) of about 1 hour to about 7 hours as determined by United States Pharmacopeia (USP) apparatus two-stage dissolution methodology, e.g., about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4 h, about 4.25 h, about 4.5 h, about 4.75 h, about 5 h, about 5.25 h, about 5.5 h, about 5.75 h, about 6 h, about 6.25 h, about 6.5 h, about 6.75 h, or about 7 h, including all ranges and values therebetween, and a duration of MPH release of about 0.5 hours to about 5 hours, e.g., about 0.5 h, about 0.75 h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4 h, about 4.25 h, about 4.5 h, about 4.75 h, or about 5 h, including all ranges and values therebetween. In some embodiments, the TPR2 particles exhibit a lag-time of about 6 hours to about 12 hours as determined by United States Pharmacopeia (USP) apparatus two-stage dissolution methodology, e.g., about 6 h, about 6.25 h, about 6.5 h, about 6.75 h, about 7 h, about 7.25 h, about 7.5 h, about 7.75 h, about 8 h, about 8.25 h, about 8.5 h, about 8.75 h, about 9 h, about 9.25 h, about 9.5 h, about 9.75 h, about 10 h, about 10.25 h, about 10.5 h, about 10.75 h, about 11 h, about 11.25 h, about 11.5 h, about 11.75 h, about 12 h, about 12.25 h, about 12.5 h, about 12.75 h, about 13 h, about 13.25 h, about 13.5 h, about 13.75 h, or about 14 h, including all ranges and values therebetween, and a duration of MPH release of about 0.5 hours to about 7 hours, e.g., about 0.5 h, about 0.75 h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4 h, about 4.25 h, about 4.5 h, about 4.75 h, about 5 h, about 5.25 h, about 5.5 h, about 5.75 h, about 6 h, about 6.25 h, about 6.5 h, about 6.75 h, or about 7 h, including all ranges and values therebetween.

In another aspect, the pharmaceutical composition of the invention (e.g. presented as a capsule) comprises one IR particle population together with TPRi particles exhibiting a delay in initiation of MPH release (i.e. lag-time) of about 3 hours to about 6 hours, and a duration of MPH release of about 0.5 hours to about 4 hours, and TPR2 particles exhibiting a lag-time of about 8 hours to about 11 hours, and a duration of MPH release of about 1 hour to about 5 hours.

In certain embodiments, the TPRi beads (e.g. IR particles coated with a TPR coating) have a lag- time of about 2 h to about 6 h, e.g., about 2 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4 h, about 4.25 h, about 4.5 h, about 4.75 h, or about 5 h, about 5.25 h, about 5.5 h, about 5.75 h, or about 6 h, including all ranges and values therebetween, followed by complete release over about 0.5 hours to about 10 hours, e.g., about 0.5 h, about 0.75 h, about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4 h, about 4.25 h, about 4.5 h, about 4.75 h, or about 5 h, about 5.25 h, about 5.5 h, about 5.75 h, about 6 h, about 6.25 h, about 6.5 h, about 6.75 h, about 7 h, about 7.25 h, about 7.5 h, about 7.75 h, about 8 h, about 8.25 h, about 8.5 h, about 8.75 h, about 9 h, about 9.25 h, about 9.5 h, about 9.75 h, or about 10 h, including all ranges and values therebetween. In some embodiments, the TPR2 beads (e.g. IR particles coated with a TPR coating) have a lag-time of about 6 hours to about 11 hours, e.g., about 6 h, about 6.25 h, about 6.5 h, about 6.75 h, about 7 h, about 7.25 h, about 7.5 h, about 7.75 h, about 8 h, about 8.25 h, about 8.5 h, about 8.75 h, about 9 h, about 9.25 h, about 9.5 h, about 9.75 h, about 10 h, about 10.25 h, about 10.5 h, about 10.75 h, or about 11 h, including all ranges and values therebetween followed by complete release over about 1 hour to about 14 hours, e.g., about 1 h, about 1.25 h, about 1.5 h, about 1.75 h, about 2 h, about 2.25 h, about 2.5 h, about 2.75 h, about 3 h, about 3.25 h, about 3.5 h, about 3.75 h, about 4 h, about 4.25 h, about 4.5 h, about 4.75 h, or about 5 h, about 5.25 h, about 5.5 h, about 5.75 h, about 6 h, about 6.25 h, about 6.5 h, about 6.75 h, about 7 h, about 7.25 h, about 7.5 h, about 7.75 h, about 8 h, about 8.25 h, about 8.5 h, about 8.75 h, about 9 h, about 9.25 h, about 9.5 h, about 9.75 h, about 10 h, about 10.25 h, about 10.5 h, about 10.75 h, about 11 h, about 11.25 h, about 11.5 h, about 11.75 h, about 12 h, about 12.25 h, about 12.5 h, about 12.75 h, about 13 h, about 13.25 h, about 13.5 h, about 13.75 h, or about 14 h, including all ranges and values therebetween.

In other embodiments, the TPRi beads have a lag-time of about 2 h to about 4 h, followed by complete release (i.e., at least about 90%) over about 0.5 h to about 10 h. In some embodiments, complete release is over about 0.5 h to about 6 h. In some embodiments, complete release is over about 2 h to about 10 h. In certain embodiments, complete release is over about 2 h to about 8 h. In some embodiments, complete release is over about 1 h to about 4 h.

In other embodiments, the TPRi beads have a lag-time of about 3 h to about 5 h, followed by complete release over about 0.5 h to about 6 h. In some embodiments, complete release is over about 2 h to about 10 h. In certain embodiments, complete release is over about 2 h to about 8 h. In some embodiments, complete release is over about 2 h to about 10 h. In certain embodiments, complete release is over about 2 h to about 8 h. In some embodiments, complete release is over about 1 h to about 4 h.

In other embodiments, the second population of TPR2 beads has a lag-time of about 6 h to about 8 h, followed by complete release over about 1 h to about 14 h. In some embodiments, complete release of the second population of TPR2 beads is over about 10 h to about 14 h. In some embodiments, complete release of the second population of TPR2 beads is over about 1 to about 6 h. In some embodiments, complete release is over about 10 h to about 14 h.

In other embodiments, the second population of TPR2 beads has a lag-time of about 7 h to about 11 h, followed by complete release over about 1 h to about 14 h. In some embodiments, complete release of the second population of TPR2 beads is over about 10 h to about 14 h. In some embodiments, complete release of the second population of TPR2 beads is over about 1 h to about 6 h. In some embodiments, complete release is over about 10 h to about 14 h.

Lag-time and the duration of drug release is determined by United States Pharmacopeia (USP) apparatus two-stage dissolution methodology, wherein the pharmaceutical composition, or the IR, TPR1, and TPR2 particle, is dissolution tested for 2 hours in 500 mL of 0.01N HC1 at 37°C followed by dissolution testing with 500mL of pH 6.8 buffer obtained by switching dissolution media).

Methods of manufacturing the core particles include: a. Extrusion-Spheronization - Drug and one or more pharmaceutically acceptable excipients are granulated by addition of a binder solution. The wet mass is passed through an extruder equipped with a certain size screen. The extrudates are spheronized in a marumerizer. The resulting pellets are dried and sieved for further applications: and b. Hi h-shear Granulation - Drug and one or more pharmaceutically acceptable excipients are dry- mixed and then the mixture is granulated by addition of a binder solution in a high shear- granulator. The resulting granules are dried and sieved/milled for further applications.

Exemplary pH dependent coatings include cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hypromellose acetate succinate, polyvinyl acetate phthalate, carboxymethylethylcellulose, and pH-sensitive methacrylic acid /methylmethacrylate copolymers (e.g., EUDRAGIT^® L, S and FS polymers).

Exemplary water-insoluble polymers used for lag-time coatings can include polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, and methacrylic acid/methylmethacrylate copolymers, such as EUDRAGIT^® RS and RL polymers and their dispersions, EUDRAGIT^® RS30D and EUDRAGIT^® RL30D, EUDRAGIT RSPO; EUDRAGIT^® E30D, AQUACOAT^®, SURELEASE^®, KOLLICOAT^® SR30D, and cellulose acetate latex.

Examples of fillers/diluents typically used in the manufacture of granules by high shear granulation, pellets by granulation-extrusion-spheronization, or mini-tablets by compression of high shear granules, include lactose, calcium carbonate, calcium phosphate, calcium sulfate, microcrystalline cellulose, dextran, starches, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

The invention also provides, in one embodiment, a method of making a pulsatile drug delivery system comprising one IR and two TPR bead populations comprising the steps of:

Step 1. Preparing drug-containing cores by coating inert particles, such as sugar spheres or cellulose spheres, with drug from a polymeric binder solution and applying a protective seal-coat to form immediate release (IR) beads;

Step 2. Coating the IR beads with a water-insoluble polymer alone or in combination with a water- soluble polymer or with an enteric polymer, optionally together with a plasticizer, to form barrier coated beads with a membrane thickness of from about 1.5% to 30% by weight;

Step 3. Coating the IR beads from Step 1. with a mixture of a water-insoluble polymer and an enteric polymer, optionally together with a plasticizer, to achieve a coating and thereby form TPRi beads, wherein the TPR beads exhibit a target lag-time of about 2, or about 2-4 hours, or about 2- 6 hours (Range: from about 2 to about 6 hours);

Step 4. Coating IR beads from Step 1. with a mixture of a water-insoluble polymer and an enteric polymer, optionally together with a plasticizer, to achieve a coating and thereby form TPR2 beads, wherein the TPR2 beads exhibit a target lag-time of about 6 hours, or about 6-8 hours (Range: from about 6 to about 8 hours).

Step 5. Filling required amounts of three bead populations, namely IR beads from Step 1, and TPRi and TPR2 beads from Steps 3 and 4, into a hard gelatin or HPMC capsule, or compressing into an orally disintegrating tablet (ODT), to produce a once-daily triple pulsatile delivery system that provides for rapid onset and ideal duration of efficacy or symptom control for up to about 14 to about 16 hours, without interfering with ensuing activities before going to bed or without being subjected to the potential excessive insomnia and appetite suppression.

The rapidly-dispersible microgranules comprising a sugar alcohol such as mannitol and a disintegrant such as crospovidone may conveniently be prepared by high shear granulation following the procedures disclosed in U.S. Patent No. US 8,545,881 or fluid-bed granulated rapidly-dispersible microgranules comprising a sugar alcohol such as mannitol and a disintegrant such as low-substituted hydroxypropyl cellulose, and a multi-functional additive, such as pregelatinized starch (STARCH 1500™ from Colorcon) and having an average particle size in the range of approximately 50-200μπι, following the procedures disclosed in the co-pending U.S. Patent Application Publication No. 20120282335, the contents of which are hereby incorporated for all purposes by reference.

The triple pulsatile delivery system in the form of HPMC capsules, in one particular embodiment, comprise appropriate amounts of IR beads, TPRi beads, and TPR2 beads. The strength of drug may be 5, or 10, or 15, or 20, or 54, or 80, or 100 mg. The dosage strength is comprised in the ranges 5-100 mg, or 5-80 mg, or 10-54 mg, or 10-80 mg, or 15-20 mg.

The triple pulsatile delivery system in the form of an ODT may, in one particular embodiment, comprise appropriate amounts of IR beads, TPRi beads, and TPR2 beads, blended with rapidly dispersing microgranules (RDMs) at a weight ratio of the total IR and TPR beads to RDMs of from about 1 :4 to about 1 : 1. Additional agents such as microcrystalline cellulose (e.g. at about 10% by weight) and pre-blend comprising a flavor (e.g. at about 0.5-1.2%), a sweetener (e.g. at about 0.5- 1%)), additional disintegrant (e.g. at about 5% by weight) may be added in a blender for sufficient time to achieve acceptable blend homogeneity. The homogeneous blend may be compressed on a rotary tablet press equipped with an external lubrication system or the blend is first blended with a lubricant such as sodium stearyl fumarate (0.5-1.5% by weight) prior to compression into once- daily ODTs with acceptable hardness and friability. The orally disintegrating tablet thus produced disintegrates on contact with saliva in the oral cavity of a patient in approximately 60 seconds creating a smooth viscous suspension containing coated microparticles, that may be swallowed without experiencing drug taste. Such orally disintegrating tablets may also disintegrate within 30 seconds when tested for disintegration time by USP <701> methods.

Pharmacokinetics

In various embodiments, the once-daily pharmaceutical dose of the present disclosure provides three pulsatile releases of methylphenidate to achieve a therapeutically effective blood plasma concentrations of methylphenidate up to about 16 h following administration.

In some embodiments, the present pharmaceutical composition provides a triple pulsatile plasma MPH concentration-time profile in the range of approximately 3-30 ng/mL over the range of from about 1 hour up to about 16 hours post-dosing. The present pharmaceutical compositions maintain a minimum blood plasma concentration that is sufficient to maintain therapeutic efficacy for about 12-16 hours.

In some embodiments, upon oral administration of from about 5-125 mg of methylphenidate or a pharmaceutically acceptable salt thereof the pharmaceutical composition is formulated to provide a plasma concentration of methylphenidate that is at least about 3.5 ng/mL or more for at least about 12 hours to about 16 hours (e.g., about 12 h, about 12.25 h, about 12.5 h, about 12.75 h, about 13 h, about 13.25 h, about 13.5 h, about 13.75 h, about 14 h, about 14.25 h, about 14.5 h, about 14.75 h, about 15 h, about 15.25 h, about 15.5 h, about 15.75 h, or about 16 h, inclusive of all ranges and values therebetween) following the administration. In some embodiments, the plasma concentration of methylphenidate is at least 3.5 ng/mL, about 3.6 ng/mL, about 3.7 ng/mL, about 3.8 ng/mL, about 3.9 ng/mL, about 4 ng/mL, about 4.1 ng/mL, about 4.2 ng/mL, about 4.3 ng/mL, about 4.4 ng/mL, about 4.5 ng/mL, about 4.6 ng/mL, about 4.7 ng/mL, about 4.8 ng/mL, about 4.9 ng/mL, about 5 ng/mL, about 5.1 ng/mL, about 5.2 ng/mL, about 5.3 ng/mL, about 5.4 ng/mL, about 5.5 ng/mL, about 5.6 ng/mL, about 5.7 ng/mL, about 5.8 ng/mL, about 5.9 ng/mL, about 6 ng/mL, about 6.1 ng/mL, about 6.2 ng/mL, about 6.3 ng/mL, about 6.4 ng/mL, about 6.5 ng/mL, about 6.6 ng/mL, about 6.7 ng/mL, about 6.8 ng/mL, about 6.9 ng/mL, about 7 ng/mL, about 7.1 ng/mL, about 7.2 ng/mL, about 7.3 ng/mL, about 7.4 ng/mL, about 7.5 ng/mL, about 7.6 ng/mL, about 7.7 ng/mL, about 7.8 ng/mL, about 7.9 ng/mL, about 8 ng/mL, about 8.1 ng/mL, about 8.2 ng/mL, about 8.3 ng/mL, about 8.4 ng/mL, about 8.5 ng/mL, about 8.6 ng/mL, about 8.7 ng/mL, about 8.8 ng/mL, about 8.9 ng/mL, about 9 ng/mL, about 9.1 ng/mL, about 9.2 ng/mL, about 9.3 ng/mL, about 9.4 ng/mL, about 9.5 ng/mL, about 9.6 ng/mL, about 9.7 ng/mL, about 9.8 ng/mL, about 9.9 ng/mL, about 10 ng/mL, 10.1 ng/mL, about 10.2 ng/mL, about 10.3 ng/mL, about 10.4 ng/mL, about 10.5 ng/mL, about 10.6 ng/mL, about 10.7 ng/mL, about 10.8 ng/mL, about 10.9 ng/mL, about 11 ng/mL, about 11.1 ng/mL, about 11.2 ng/mL, about 1 1.3 ng/mL, about 11.4 ng/mL, about 11.5 ng/mL, about 11.6 ng/mL, about 11.7 ng/mL, about 11.8 ng/mL, about 11.9 ng/mL, about 12 ng/mL, about 12.1 ng/mL, about 12.2 ng/mL, about 12.3 ng/mL, about 12.4 ng/mL, or about 12.5 ng/mL, including all ranges and values therebetween for about 12 h to about 16 h.

In some embodiments, upon oral administration of from about 5-125 mg of methylphenidate or a pharmaceutically acceptable salt thereof the composition is formulated to provide a steady state blood plasma Cmin that is not less than about 3.5 ng/ml of methylphenidate for at least about 12 hours to about 16 hours, e.g., not less than 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 8.5 ng/mL, about 9 ng/mL, about 9.5 ng/mL, about 10 ng/mL, inclusive of all ranges and values therebetween.

In some embodiments, upon oral administration of from about 5-125 mg of methylphenidate or a pharmaceutically acceptable salt thereof the pharmaceutical composition is formulated to provide a steady state blood plasma Cmax of methylphenidate that does not exceed about 30 ng/mL, e.g., about 30 ng/mL, about 29 ng/mL, about 28 ng/mL, about 27 ng/mL, about 26 ng/mL, about 25 ng/mL, about 24 ng/mL, about 23 ng/mL, about 22 ng/mL, about 21 ng/mL, about 20 ng/mL, about 19 ng/mL, about 18 ng/mL, about 17 ng/mL, about 16 ng/mL, about 15 ng/mL, about 14 ng/mL, about 13 ng/mL, about 12 ng/mL, about 11 ng/mL, or about 10 ng/mL, including all ranges and values therebetween. In some embodiments, upon oral administration of from about 5-125 mg of methylphenidate or a pharmaceutically acceptable salt thereof the composition is formulated to provide a steady state blood plasma concentration within about 80%- 125% of the range of from about 3.5 ng/mL to about 25 ng/mL, e.g. 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 8.5 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, or about 25 ng/mL, about 4.5 ng/mL, including all ranges and values therebetween.

In some embodiments, upon oral administration of from about 5-125 mg of methylphenidate or a pharmaceutically acceptable salt thereof the composition is formulated to provide a mean steady state blood plasma AUC (0-24) hours of methylphenidate from about 25 ng*h/ml to about 350 ng*h/ml, e.g., about 25 ng*h/ml, about 50 ng*h/ml, about 75 ng*h/ml, about 100 ng*h/ml, about 125 ng*h/ml, about 150 ng*h/ml, about 175 ng*h/ml, about 200 ng*h/ml, about 225 ng*h/ml, about 250 ng*h/ml, about 275 ng*h/ml, about 300 ng*h/ml, about 325 ng*h/ml, and about 350 ng*h/ml, inclusive of all values and subranges therebetween. In some embodiments, the pharmaceutical compositions of the present disclosure provide a blood plasma profile that is bioequivalent to that of FOQUEST^®. In some embodiments, the pharmaceutical compositions of the present disclosure provide a blood plasma profile that is bioequivalent to that of FOQUEST^®, but blood plasma levels in the evening decrease more rapidly to decrease insomnia and appetite suppression (e.g., as measured using the pharmacodynamic tests disclosed herein). In other embodiments, the pharmaceutical compositions of the present disclosure provide a blood plasma profile that it superior to that provided by FOQUEST^® because evening blood plasma levels decrease more rapidly than those provided by FOQUEST^®, resulting in a significant decrease in insomnia and appetite suppression (e.g., as measured using the pharmacodynamic tests disclosed herein). FOQUEST^® is currently formulated with 25, 35, 45, 55, 70, 85, and 100 mg of methylphenidate or a pharmaceutically acceptable salt thereof. The present pharmaceutical compositions may be formulated with the same dosage of methylphenidate or a pharmaceutically acceptable salt thereof as FOQUEST^®, and provide an average Cmax and average AUC that is about 80%-125% of that of FOQUEST^®. In other embodiments, the present pharmaceutical compositions may be formulated with a different (i.e., equivalent) dosage of methylphenidate or a pharmaceutically acceptable salt thereof than FOQUEST^® and still provide an average Cmax and average AUC that is about 80%-125% of that of FOQUEST^®, e.g., by appropriately modifying the release profile of the TPRi and/or TPR2 particles. As used here, an "equivalent dose" refers to a dose which provides a bioequivalent Cmax and/or AUC parameters as a reference dose from a reference product (e.g., any reference product disclosed herein), and such a dose may be the same or different from the reference dose in the reference product. For example, the present pharmaceutical compositions may be formulated with about 110 mg of methylphenidate or a pharmaceutically acceptable salt thereof and provide an average Cmax and average AUC that is about 80%-125% of that provided by FOQUEST^® composition having 100 mg of methylphenidate or a pharmaceutically acceptable salt thereof. Alternatively, the present pharmaceutical compositions may be formulated with about 110 mg of methylphenidate or a pharmaceutically acceptable salt thereof and provide an average Cmax and average AUC that is about 80%- 125% of that provided by FOQUEST^® composition having 100 mg of methylphenidate or a pharmaceutically acceptable salt thereof. In embodiments, both the 100 mg dose and the 110 mg dose in the present pharmaceutical compositions would be equivalent to a 100 mg dose in FOQUEST^®.

In some embodiments, a pharmaceutical composition of the present disclosure having a dose of methylphenidate that is equivalent to 100 mg of methylphenidate in FOQUEST^® is formulated to achieve a maximum blood plasma concentration (Cmax) of methylphenidate within about 80% to about 125% of the range of 12,8775.81 ± 4,590.88 pg/mL, e.g., about 8000 pg/mL, about 8100 pg/mL, about 8200 pg/mL, about 8300 pg/mL, about 8400 pg/mL, about 8500 pg/mL, about 8600 pg/mL, about 8700 pg/mL, about 8800 pg/mL, about 8900 pg/mL, about 9000 pg/mL, about 9100 pg/mL, about 9200 pg/mL, about 9300 pg/mL, about 9400 pg/mL, about 9500 pg/mL, about 9600 pg/mL, about 9700 pg/mL, about 9800 pg/mL, about 9900 pg/mL, about 10000 pg/mL, about 10100 pg/mL, about 10200 pg/mL, about 10300 pg/mL, about 10400 pg/mL, about 10500 pg/mL, about 10600 pg/mL, about 10700 pg/mL, about 10800 pg/mL, about 10900 pg/mL, about 11000 pg/mL, about 11100 pg/mL, about 11200 pg/mL, about 11300 pg/mL, about 11400 pg/mL, about 11500 pg/mL, about 11600 pg/mL, about 11700 pg/mL, about 11800 pg/mL, about 11900 pg/mL, about 12000 pg/mL, about 12100 pg/mL, about 12200 pg/mL, about 12300 pg/mL, about 12400 pg/mL, about 12500 pg/mL, about 12600 pg/mL, about 12700 pg/mL, about 12800 pg/mL, about 12900 pg/mL, about 13000 pg/mL, about 13100 pg/mL, about 13200 pg/mL, about 13300 pg/mL, about 13400 pg/mL, about 13500 pg/mL, about 13600 pg/mL, about 13700 pg/mL, about 13800 pg/mL, about 13900 pg/mL, about 14000 pg/mL, about 14100 pg/mL, about 14200 pg/mL, about 14300 pg/mL, about 14400 pg/mL, about 14500 pg/mL, about 14600 pg/mL, about 14700 pg/mL, about 14800 pg/mL, about 14900 pg/mL, about 15000 pg/mL, about 15100 pg/mL, about 15200 pg/mL, about 15300 pg/mL, about 15400 pg/mL, about 15500 pg/mL, about 15600 pg/mL, about 15700 pg/mL, about 15800 pg/mL, about 15900 pg/mL, about 16000 pg/mL, about 16100 pg/mL, about 16200 pg/mL, about 16300 pg/mL, about 16400 pg/mL, about 16500 pg/mL, about 16600 pg/mL, about 16700 pg/mL, about 16800 pg/mL, about 16900 pg/mL, about 17000 pg/mL, about 17100 pg/mL, about 17200 pg/mL, about 17300 pg/mL, about 17400 pg/mL, about 17500 pg/mL, about 17600 pg/mL, about 17700 pg/mL, about 17800 pg/mL, about 17900 pg/mL, about 18000 pg/mL, about 18100 pg/mL, about 18200 pg/mL, about 18300 pg/mL, about 18400 pg/mL, about 18500 pg/mL, about 18600 pg/mL, about 18700 pg/mL, about 18800 pg/mL, about 18900 pg/mL, about 19000 pg/mL, about 19100 pg/mL, about 19200 pg/mL, about 19300 pg/mL, about 19400 pg/mL, about 19500 pg/mL, about 19600 pg/mL, about 19700 pg/mL, about 19800 pg/mL, about 19900 pg/mL, about 20000 pg/mL, about 20100 pg/mL, about 20200 pg/mL, about 20300 pg/mL, about 20400 pg/mL, about 20500 pg/mL, about 20600 pg/mL, about 20700 pg/mL, about 20800 pg/mL, about 20900 pg/mL, about 21000 pg/mL, about 21100 pg/mL, about 21200 pg/mL, about 21300 pg/mL, about 21400 pg/mL, about 21500 pg/mL, about 21600 pg/mL, about 21700 pg/mL, about 21800 pg/mL, about 21900 pg/mL, or about 22000 pg/mL, including all ranges and values therebetween.

In some embodiments, a pharmaceutical composition of the present disclosure having a dose of methylphenidate that is equivalent to 100 mg of methylphenidate in FOQUEST^® is formulated to achieve a blood plasma exposure level (AUCo-t) of methylphenidate within about 80% to about 125% of the range of at least 161,271.48 ± 40,500.38 h*pg/mL, e.g., about 96,000 h*pg/mL, about 98,000 h*pg/mL, about 100,000 h*pg/mL, about 100,000 h*pg/mL, about 104,000 h*pg/mL, about 106,000 h*pg/mL, about 108,000 h*pg/mL, about 110,000 h*pg/mL, about 112,000 h*pg/mL, about 114,000 h*pg/mL, about 116,000 h*pg/mL, about 118,000 h*pg/mL, about 120,000 h*pg/mL, about 122,000 h*pg/mL, about 124,000 h*pg/mL, about 126,000 h*pg/mL, about 128,000 h*pg/mL, about 130,000 h*pg/mL, about 132,000 h*pg/mL, about 134,000 h*pg/mL, about 136,000 h*pg/mL, about 138,000 h*pg/mL, about 140,000 h*pg/mL, about 142,000 h*pg/mL, about 144,000 h*pg/mL, about 146,000 h*pg/mL, about 148,000 h*pg/mL, about 150,000 h*pg/mL, about 152,000 h*pg/mL, about 154,000 h*pg/mL, about 156,000 h*pg/mL, about 158,000 h*pg/mL, about 160,000 h*pg/mL, about 162,000 h*pg/mL, about 164,000 h*pg/mL, about 166,000 h*pg/mL, about 168,000 h*pg/mL, about 170,000 h*pg/mL, about 172,000 h*pg/mL, about 174,000 h*pg/mL, about 176,000 h*pg/mL, about 178,000 h*pg/mL, about 180,000 h*pg/mL, about 182,000 h*pg/mL, about 184,000 h*pg/mL, about 186,000 h*pg/mL, about 188,000 h*pg/mL, about 190,000 h*pg/mL, about 192,000 h*pg/mL, about 194,000 h*pg/mL, about 196,000 h*pg/mL, about 198,000 h*pg/mL, about 200,000 h*pg/mL, about 202,000 h*pg/mL, about 204,000 h*pg/mL, about 206,000 h*pg/mL, about 208,000 h*pg/mL, about 210,000 h*pg/mL, about 212,000 h*pg/mL, about 214,000 h*pg/mL, about 216,000 h*pg/mL, about 218,000 h*pg/mL, about 220,000 h*pg/mL, about 222,000 h*pg/mL, about 224,000 h*pg/mL, about 226,000 h*pg/mL, about 228,000 h*pg/mL, about 230,000 h*pg/mL, about 232,000 h*pg/mL, about 234,000 h*pg/mL, about 236,000 h*pg/mL, about 238,000 h*pg/mL, about 240,000 h*pg/mL, about 242,000 h*pg/mL, about 244,000 h*pg/mL, about 246,000 h*pg/mL, about 248,000 h*pg/mL, about 250,000 h*pg/mL, about 252,000 h*pg/mL, about 254,000 h*pg/mL, about 256,000 h*pg/mL, about 258,000 h*pg/mL, about 260,000 h*pg/mL, about 262,000 h*pg/mL, about 264,000 h*pg/mL, about 266,000 h*pg/mL, about 268,000 h*pg/mL, about 270,000 h*pg/mL, about 272,000 h*pg/mL, about 274,000 h*pg/mL, about 276,000 h*pg/mL, about 278,000 h*pg/mL, or about 280,000 h*pg/mL, including all ranges and values therebetween. In some embodiments, a pharmaceutical composition of the present disclosure having a dose of methylphenidate that is equivalent to 100 mg of methylphenidate in FOQUEST^® is formulated to achieve a blood plasma exposure level (AUCo-inf) of methylphenidate within about 80% to about 125% of the range of at least 215,610.43 ± 61,472.88 h*pg/mL, e.g., about 114,000 h*pg/mL, about 116,000 h*pg/mL, about 118,000 h*pg/mL, about 120,000 h*pg/mL, about 122,000 h*pg/mL, about 124,000 h*pg/mL, about 126,000 h*pg/mL, about 128,000 h*pg/mL, about 130,000 h*pg/mL, about 132,000 h*pg/mL, about 134,000 h*pg/mL, about 136,000 h*pg/mL, about 138,000 h*pg/mL, about 140,000 h*pg/mL, about 142,000 h*pg/mL, about 144,000 h*pg/mL, about 146,000 h*pg/mL, about 148,000 h*pg/mL, about 150,000 h*pg/mL, about 152,000 h*pg/mL, about 154,000 h*pg/mL, about 156,000 h*pg/mL, about 158,000 h*pg/mL, about 160,000 h*pg/mL, about 162,000 h*pg/mL, about 164,000 h*pg/mL, about 166,000 h*pg/mL, about 168,000 h*pg/mL, about 170,000 h*pg/mL, about 172,000 h*pg/mL, about 174,000 h*pg/mL, about 176,000 h*pg/mL, about 178,000 h*pg/mL, about 180,000 h*pg/mL, about 182,000 h*pg/mL, about 184,000 h*pg/mL, about 186,000 h*pg/mL, about 188,000 h*pg/mL, about 190,000 h*pg/mL, about 192,000 h*pg/mL, about 194,000 h*pg/mL, about 196,000 h*pg/mL, about 198,000 h*pg/mL, about 200,000 h*pg/mL, about 202,000 h*pg/mL, about 204,000 h*pg/mL, about 206,000 h*pg/mL, about 208,000 h*pg/mL, about 210,000 h*pg/mL, about 212,000 h*pg/mL, about 214,000 h*pg/mL, about 216,000 h*pg/mL, about 218,000 h*pg/mL, about 220,000 h*pg/mL, about 222,000 h*pg/mL, about 224,000 h*pg/mL, about 226,000 h*pg/mL, about 228,000 h*pg/mL, about 230,000 h*pg/mL, about 232,000 h*pg/mL, about 234,000 h*pg/mL, about 236,000 h*pg/mL, about 238,000 h*pg/mL, about 240,000 h*pg/mL, about 242,000 h*pg/mL, about 244,000 h*pg/mL, about 246,000 h*pg/mL, about 248,000 h*pg/mL, about 250,000 h*pg/mL, about 252,000 h*pg/mL, about 254,000 h*pg/mL, about 256,000 h*pg/mL, about 258,000 h*pg/mL, about 260,000 h*pg/mL, about 262,000 h*pg/mL, about 264,000 h*pg/mL, about 266,000 h*pg/mL, about 268,000 h*pg/mL, about 270,000 h*pg/mL, about 272,000 h*pg/mL, about 274,000 h*pg/mL, about 276,000 h*pg/mL, about 278,000 h*pg/mL, about 280,000 h*pg/mL, about 282,000 h*pg/mL, about 284,000 h*pg/mL, about 286,000 h*pg/mL, about 288,000 h*pg/mL, about 290,000 h*pg/mL, about 292,000 h*pg/mL, about 294,000 h*pg/mL, about 296,000 h*pg/mL, about 298,000 h*pg/mL, about 300,000 h*pg/mL, about 302,000 h*pg/mL, about 304,000 h*pg/mL, about 306,000 h*pg/mL, about 308,000 h*pg/mL, about 310,000 h*pg/mL, about 312,000 h*pg/mL, about 314,000 h*pg/mL, about 316,000 h*pg/mL, about 318,000 h*pg/mL, about 320,000 h*pg/mL, about 322,000 h*pg/mL, about 324,000 h*pg/mL, about 326,000 h*pg/mL, about 328,000 h*pg/mL, about 330,000 h*pg/mL, about 332,000 h*pg/mL, about 334,000 h*pg/mL, about 336,000 h*pg/mL, about 338,000 h*pg/mL,or about 340,000 h*pg/mL, including all ranges and values therebetween. In some embodiments, a pharmaceutical composition of the present disclosure having a dose of methylphenidate that is equivalent to 100 mg of methylphenidate in FOQUEST^® is formulated to achieve an elimination half-life (Ti/2-eiim) of methylphenidate within the range of about 3 h to about 11 h, e.g., about 3 h, about 3.5 h, about 4 h, about 4.5 h, about 5 h, about 5.5 h, about 6 h, about 6.5 h, about 7 h, about 7.5 h, about 8 h, about 8.5 h, about 9 h, about 9.5 h, about 10 h, about 10.5 h, or about 11 h, including all ranges and values therebetween. In specific embodiments, the T1/2- eiim is about 1 h. In other specific embodiments, the Τι/2-eiim is about 1.5 h. In other specific embodiments, the Τι/2-eiim is about 2 h. In other specific embodiments, the Τι/2-eiim is about 2.5 h. In other specific embodiments, the Τι/2-eiim is about 3 h. In other specific embodiments, the T1/2- eiim is about 3.5 h. In other specific embodiments, the Τι/2-eiim is about 4 h. In other specific embodiments, the Τι/2-eiim is about 4.5 h. In other specific embodiments, the Τι/2-eiim is about 5 h. In other specific embodiments, the Τι/2-eiim is about 5.5 h. In other specific embodiments, the T1/2- eiim is about 6 h. In other specific embodiments, the Τι/2-eiim is about 6.5 h. In other specific embodiments, the Τι/2-eiim is about 7 h. In other specific embodiments, the Τι/2-eiim is about 7.5 h. In other specific embodiments, the Τι/2-eiim is about 8 h. In other specific embodiments, the T1/2- eiim is about 8.5 h. In other specific embodiments, the Τι/2-eiim is about 9 h. In other specific embodiments, the Τι/2-eiim is about 9.5 h. In other specific embodiments, the Τι/2-eiim is about 10 h. In other specific embodiments, the Τι/2-eiim is about 10.5 h. In other specific embodiments, the T1/2- elim IS about 11 h.

In some embodiments, the pharmaceutical composition of the present disclosure is formulated to achieve a maximum concentration (Tmax) that is less than or equal to about 14.5 h, e.g., about 14.5 h, about 14 h, about 13.5 h, about 13 h, about 12.5 h, about 12 h, about 11.5 h, about 11 h, about 10.5 h, about 10 h, about 9.5 h, about 9 h, about 8.5 h, about 8 h, about 7.5 h, about 7 h, about 6.5 h, about 6 h, about 5.5 h, about 5 h, about 4.5 h, about 4 h, about 3.5 h, about 3 h, about 2.5 h, about 2 h, about 1.5, or about 1 h, including all ranges and values therebetween. In some embodiments, the once-daily dosage the median time for reaching Tmax is from about 9 h to about 13 h, e.g., about 9 h, about 9.5 h, about 10 h, about 10.5 h, about 11 h, about 11.5 h, about 12 h, about 12.5, about 13 h, including all ranges and values therebetween.

In some embodiments, the pharmaceutical compositions of the present disclosure provide a blood plasma profile that is bioequivalent to that of JORNAY PM^®. In some embodiments, the pharmaceutical compositions of the present disclosure provide a blood plasma profile that is bioequivalent to that of JORNAY PM^®, but blood plasma levels in the evening decrease more rapidly to decrease insomnia and appetite suppression (e.g., as measured using the pharmacodynamic tests disclosed herein). In other embodiments, the pharmaceutical compositions of the present disclosure provide a blood plasma profile that it superior to that provided by JORNAY PM^® because evening blood plasma levels decrease more rapidly than those provided by JORNAY PM^®, resulting in a significant decrease in insomnia and appetite suppression (e.g., as measured using the pharmacodynamic tests disclosed herein).

JORNAY PM^® is currently formulated with 20, 40, 60, 80, and 100 mg of methylphenidate or a pharmaceutically acceptable salt thereof. The present pharmaceutical compositions may be formulated with the same dosage of methylphenidate or a pharmaceutically acceptable salt thereof as JORNAY PM^®, and provide an average Cmax and average AUC that is about 80%-125% of that of JORNAY PM^®. In other embodiments, the present pharmaceutical compositions may be formulated with a different (i.e., equivalent) dosage of methylphenidate or a pharmaceutically acceptable salt thereof than JORNAY PM^® and still provide an average Cmax and average AUC that is about 80%-125% of that of JORNAY PM^® e.g., by appropriately modifying the release profile of the TPRi and/or TPR2 particles.

In some embodiments, a pharmaceutical composition of the present disclosure having a dose of methylphenidate that is equivalent to 54 mg of methylphenidate in JORNAY PM^® is formulated to achieve a weight-adjusted mean maximum blood plasma concentration (Cmax) of methylphenidate ([ng/mL]/[mg/kg]) (coefficient of variation%) within about 80% to about 125% of the range of 9.1 (35.2%) ([ng/mL]/[mg/kg]) in adults, 8.8(34.5%) ([ng/mL]/[mg/kg]) in adolescents, and 7.4 (30.1%)([ng/mL]/[mg/kg]) in children, e.g., about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, about 10.5, about 11, about 11.5, about 12, about 12.5, about 13, about 13.5, about 14, about 14.5, about 15, about 15.5 about 16, about 16.5, about 17, about 17.5, about 18, about 18.5, about 19, about 19.5, and about 20 ([ng/mL]/[mg/kg]) including all ranges and values therebetween.

In some embodiments, a pharmaceutical composition of the present disclosure having a dose of methylphenidate that is equivalent to 54 mg of methylphenidate in JORNAY PM^® is formulated to achieve a weight-adjusted mean blood plasma exposure level (AUCo-t) of methylphenidate ([ng · h/mL]/[mg/kg]) (coefficient of variation) within about 80% to about 125% of the range of ofs 126.5 (35.5%) in adults, 129.4 (34.8%) in adolescents, and 129.7 (27.3%) in children, e.g., about 65([ng · h/mL]/[mg/kg]), about 70([ng · h/mL]/[mg/kg]), about 75([ng · h/mL]/[mg/kg]), about 80([ng · h/mL]/[mg/kg]), about 85([ng · h/mL]/[mg/kg]), about 90([ng · h/mL]/[mg/kg]), about 95([ng · h/mL]/[mg/kg]), about lOOflng · h/mL]/[mg/kg]), about 105([ng · h/mL]/[mg/kg]), about 110([ng · h/mL]/[mg/kg]), about 115([ng · h/mL]/[mg/kg]), about 120([ng · h/mL]/[mg/kg]), about 125([ng · h/mL]/[mg/kg]), about 130([ng · h/mL]/[mg/kg]), about 135([ng · h/mL]/[mg/kg]), about 140([ng · h/mL]/[mg/kg]), about 145([ng · h/mL]/[mg/kg]), about 150([ng · h/mL]/[mg/kg]), about 155([ng · h/mL]/[mg/kg]), about 160([ng · h/mL]/[mg/kg]), about 165([ng · h/mL]/[mg/kg]), about 170([ng · h/mL]/[mg/kg]), about 175([ng · h/mL]/[mg/kg]), about 180([ng · h/mL]/[mg/kg]), about 185([ng · h/mL]/[mg/kg]), about 190([ng · h/mL]/[mg/kg]), about 195([ng · h/mL]/[mg/kg]), about 200([ng · h/mL]/[mg/kg]), about 205([ng · h/mL]/[mg/kg]), about 210([ng · h/mL]/[mg/kg]), about 220([ng · h/mL]/[mg/kg]), about 225([ng · h/mL]/[mg/kg]), about 230([ng · h/mL]/[mg/kg]), including all ranges and values therebetween.

In some embodiments, the pharmaceutical compositions of the present disclosure exhibit dose proportional (e.g., linear) pharmacokinetic profiles. That is, in some embodiments, the present pharmaceutical compositions may be formulated to provide pharmacokinetic parameters that are directly proportional to any of the pharmacokinetic parameters disclosed herein, such as the Cmax and AUC disclosed above for 100 mg of methylphenidate in FOQUEST^® or 54 mg of JORNAY PM^®. For example, 50% of a 100 mg dose (i.e., 50 mg dose) would provide a Cmax and/or AUC that is about 50% of the the Cmax and/or AUC, respectively of the 100 mg dose; a does that is about 25%) of 100 mg (i.e., a 25 mg dose) would have a Cmax and/or AUC that is about 25% of the Cmax and/or AUC, respectively of a 100 mg dose. In other embodiments of the present disclosure, increasing or decreasing a once-daily dose of a pharmaceutical composition disclosed herein result in non-linear pharmacokinetics (i.e., a non-linear pharmacokinetic profile). In some embodiments, the pharmaceutical compositions of the present disclosure are formulated to achieve a maximum blood plasma concentration (Cmax) of methylphenidate within about 80% to about 125%) of the range of at least 3.7 ± 1.0 ng/mL following administration to a child of a dose equivalent to 18 mg of CONCERTA^®, e.g., about 2 ng/mL, about 2.1 ng/mL, about 2.2 ng/mL, about 2.3 ng/mL, about 2.4 ng/mL, about 2.5 ng/mL, about 2.6 ng/mL, about 2.7 ng/mL, about 2.8 ng/mL, about 2.9 ng/mL, about 3 ng/mL, about 3.1 ng/mL, about 3.2 ng/mL, about 3.3 ng/mL, about 3.4 ng/mL, about 3.5 ng/mL, about 3.6 ng/mL, about 3.7 ng/mL, about 3.8 ng/mL, about 3.9 ng/mL, about 4 ng/mL, about 4.1 ng/mL, about 4.2 ng/mL, about 4.3 ng/mL, about 4.4 ng/mL, about 4.5 ng/mL, about 4.6 ng/mL, about 4.7 ng/mL, about 4.8 ng/mL, about 4.9 ng/mL, about 5 ng/mL, about 5.1 ng/mL, about 5.2 ng/mL, about 5.3 ng/mL, about 5.4 ng/mL, about 5.5 ng/mL, about 5.6 ng/mL, about 5.7 ng/mL, about 5.8 ng/mL, about 5.9 ng/mL, about 6 ng/mL, about 6.1 ng/mL, or about 6.2 ng/mL, including all ranges and values therebetween.

In some embodiments, the pharmaceutical compositions of the present disclosure are formulated to achieve a maximum blood plasma concentration (Cmax) of methylphenidate within about 80% to about 125% of the range of at least 10.2 ± 5.9 ng/mL following administration of a dose equivalent to 20 mg of RITALIN LA^®, e.g., about 3.3 ng/mL, about 3.4 ng/mL, about 3.5 ng/mL, about 3.6 ng/mL, about 3.7 ng/mL, about 3.8 ng/mL, about 3.9 ng/mL, about 4 ng/mL, about 4.1 ng/mL, about 4.2 ng/mL, about 4.3 ng/mL, about 4.4 ng/mL, about 4.5 ng/mL, about 4.6 ng/mL, about 4.7 ng/mL, about 4.8 ng/mL, about 4.9 ng/mL, about 5 ng/mL, about 5.1 ng/mL, about 5.2 ng/mL, about 5.3 ng/mL, about 5.4 ng/mL, about 5.5 ng/mL, about 5.6 ng/mL, about 5.7 ng/mL, about 5.8 ng/mL, about 5.9 ng/mL, about 6 ng/mL, about 6.1 ng/mL, about 6.2 ng/mL, about 6.3 ng/mL, about 6.4 ng/mL, about 6.5 ng/mL, about 6.6 ng/mL, about 6.7 ng/mL, about 6.8 ng/mL, about 6.9 ng/mL, about 7 ng/mL, about 7.1 ng/mL, about 7.2 ng/mL, about 7.3 ng/mL, about 7.4 ng/mL, about 7.5 ng/mL, about 7.6 ng/mL, about 7.7 ng/mL, about 7.8 ng/mL, about 7.9 ng/mL, about 8 ng/mL, about 8.1 ng/mL, about 8.2 ng/mL, about 8.3 ng/mL, about 8.4 ng/mL, about 8.5 ng/mL, about 8.6 ng/mL, about 8.7 ng/mL, about 8.8 ng/mL, about 8.9 ng/mL, about 9 ng/mL, about 9.1 ng/mL, about 9.2 ng/mL, about 9.3 ng/mL, about 9.4 ng/mL, about 9.5 ng/mL, about 9.6 ng/mL, about 9.7 ng/mL, about 9.8 ng/mL, about 9.9 ng/mL, about 10 ng/mL, 10.1 ng/mL, about 10.2 ng/mL, about 10.3 ng/mL, about 10.4 ng/mL, about 10.5 ng/mL, about 10.6 ng/mL, about 10.7 ng/mL, about 10.8 ng/mL, about 10.9 ng/mL, about 11 ng/mL, about 11.1 ng/mL, about 11.2 ng/mL, about 11.3 ng/mL, about 11.4 ng/mL, about 11.5 ng/mL, about 11.6 ng/mL, about 11.7 ng/mL, about 11.8 ng/mL, about 11.9 ng/mL, about 12 ng/mL, about 12.1 ng/mL, about 12.2 ng/mL, about 12.3 ng/mL, about 12.4 ng/mL, about 12.5 ng/mL, about 12.6 ng/mL, about 12.7 ng/mL, about 12.8 ng/mL, about 12.9 ng/mL, about 13 ng/mL, about 13.1 ng/mL, about 13.2 ng/mL, about 13.3 ng/mL, about 13.4 ng/mL, about 13.5 ng/mL, about 13.6 ng/mL, about 13.7 ng/mL, about 13.8 ng/mL, about 13.9 ng/mL, about 14 ng/mL, about 14.1 ng/mL, about 14.2 ng/mL, about 14.3 ng/mL, about 14.4 ng/mL, about 14.5 ng/mL, about 14.6 ng/mL, about 14.7 ng/mL, about 14.8 ng/mL, about 14.9 ng/mL, about 15 ng/mL, about 15.1 ng/mL, about 15.2 ng/mL, about 15.3 ng/mL, about 15.4 ng/mL, about 15.5 ng/mL, about 15.6 ng/mL, about 15.7 ng/mL, about 15.8 ng/mL, about 15.9 ng/mL, about 16 ng/mL, about 16.1 ng/mL, about 16.2 ng/mL, about 16.3 ng/mL, about 16.4 ng/mL, about 16.5 ng/mL, about 16.6 ng/mL, about 16.7 ng/mL, about 16.8 ng/mL, about 16.9 ng/mL, about 17 ng/mL, about 17.1 ng/mL, about 17.2 ng/mL, about 17.3 ng/mL, about 17.4 ng/mL or about 17.5 ng/mL, including all ranges and values therebetween.

In some embodiments, the pharmaceutical compositions of the present disclosure are formulated to achieve a maximum blood plasma concentration (Cmax) of methylphenidate within about 80% to about 125% of the range of at least 10.9 ± 3.9 ng/mL following administration to a child of a dose equivalent to 20 mg of MET AD ATE CD^®, e.g., about 6.4 ng/mL, about 6.6 ng/mL, about 6.8 ng/mL, about 7 ng/mL, about 7.2 ng/mL, about 7.4 ng/mL, about 7.6 ng/mL, about 7.8 ng/mL, about 8 ng/mL, about 8.2 ng/mL, about 8.4 ng/mL, about 8.6 ng/mL, about 8.8 ng/mL, about 9 ng/mL, about 9.2 ng/mL, about 9.4 ng/mL, about 9.6 ng/mL, about 9.8 ng/mL, about 10 ng/mL, about 10.2 ng/mL, about 10.4 ng/mL, about 10.6 ng/mL, about 10.8 ng/mL, about 11 ng/mL, about 11.2 ng/mL, about 11.4 ng/mL, about 11.6 ng/mL, about 11.8 ng/mL, about 12 ng/mL, about 12.2 ng/mL, about 12.4 ng/mL, about 12.6 ng/mL, about 12.i > ng/mL, about 13 ng/mL, about 13.2 ng/mL, about 13.4 ng/mL, about 13.6 ng/mL, about 13. £ > ng/mL, about 14 ng/mL, about 14.2 ng/mL, about 14.4 ng/mL, about 14.6 ng/mL, about 14.Ϊ > ng/mL, about 15 ng/mL, about 15.2 ng/mL, about 15.4 ng/mL, about 15.6 ng/mL, about 15. £ > ng/mL, about 16 ng/mL, about 16.2 ng/mL, about 16.4 ng/mL, about 16.6 ng/mL, about 16.ί > ng/mL, about 17 ng/mL, about 17.2 ng/mL, about 17.4 ng/mL, about 17.6 ng/mL, about 17.ί > ng/mL, about 18 ng/mL, about 18.2 ng/mL, about 18.4 ng/mL, about 18.6 ng/mL, about 18. £ > ng/mL, about 19 ng/mL, about 19.2 ng/mL, or about 19.4 ng/mL, including all ranges and values therebetween. In some embodiments, the pharmaceutical compositions of the present disclosure are formulated to achieve a maximum blood plasma concentration (Cmax) of methylphenidate within about 80% to about 125%) of the range of at least 15.1 ± 5.8 ng/mL following administration to a child of a dose equivalent to 40 mg METADATE CD^®, e.g., about 7.4 ng/mL, about 7.6 ng/mL, about 7.8 ng/mL, about 8 ng/mL, about 8.2 ng/mL, about 8.4 ng/mL, about 8.6 ng/mL, about 8.8 ng/mL, about 9 ng/mL, about 9.2 ng/mL, about 9.4 ng/mL, about 9.6 ng/mL, about 9.8 ng/mL, about 10 ng/mL, about 10 2 ng/mL, about 10 4 ng/mL, about 10 6 ng/mL, about ΙΟ.ί ! ng/mL, about 11 ng/mL, about 11 2 ng/mL, about 11 4 ng/mL, about 11 6 ng/mL, about l l .i ! ng/mL, about 12 ng/mL, about 12 2 ng/mL, about 12 4 ng/mL, about 12 6 ng/mL, about 12.i ! ng/mL, about 13 ng/mL, about 13 2 ng/mL, about 13 4 ng/mL, about 13 6 ng/mL, about 13. £ ! ng/mL, about 14 ng/mL, about 14 2 ng/mL, about 14 4 ng/mL, about 14 6 ng/mL, about 14.Ϊ ! ng/mL, about 15 ng/mL, about 15 2 ng/mL, about 15 4 ng/mL, about 15 6 ng/mL, about 15. £ ! ng/mL, about 16 ng/mL, about 16 2 ng/mL, about 16 4 ng/mL, about 16 6 ng/mL, about 16.ί ! ng/mL, about 17 ng/mL, about 17 2 ng/mL, about 17 4 ng/mL, about 17 6 ng/mL, about ll.i ! ng/mL, about 18 ng/mL, about 18 2 ng/mL, about 18 4 ng/mL, about 18 6 ng/mL, about 18. £ ! ng/mL, about 19 ng/mL, about 19 2 ng/mL, about 19 4 ng/mL, about 19 6 ng/mL, about 19.ί ! ng/mL, about 20 ng/mL, about 20 2 ng/mL, about 20 4 ng/mL, about 20 6 ng/mL, about 20 ! ng/mL, about 21 ng/mL, about 21 2 ng/mL, about 21 4 ng/mL, about 21 6 ng/mL, about 21. £ ! ng/mL, about 22 ng/mL, about 22 2 ng/mL, about 22 4 ng/mL, about 22 6 ng/mL, about 22 ! ng/mL, about 23 ng/mL, about 23 2 ng/mL, about 23 4 ng/mL, about 23 6 ng/mL, about 23. £ ! ng/mL, about 24 ng/mL, about 24 2 ng/mL, about 24 4 ng/mL, about 24 6 ng/mL, about 24 ! ng/mL, about 25 ng/mL, about 25 2 ng/mL, about 25 4 ng/mL, about 25 6 ng/mL, about 25. £ ! ng/mL, about 26 ng/mL, about 26 2 ng/mL, about 26 4 ng/mL, about 26 6 ng/mL, about 26 ! ng/mL, about 27 ng/mL about 27.2 ng/mL, about 27.4 ng/mL, or about 27.6 ng/mL, including all ranges and values therebetween. In some embodiments, the pharmaceutical compositions of the present disclosure are formulated to achieve a maximum blood plasma concentration (Cmax) of methylphenidate within about 80% to about 125% of the range of at least 32.8 ± 8.1 ng/mL following administration to an adult of a dose equivalent to 60 mg METADATE CD^®, e.g., about 19.4 ng/mL, about 19.6 ng/mL, about 19.8 ng/mL, about 20 ng/mL, about 20.2 ng/mL, about 20.4 ng/mL, about 20.6 ng/mL, about 20.8 ng/mL, about 21 ng/mL, about 21.2 ng/mL, about 21.4 ng/mL, about 21.6 ng/mL, about 21.8 ng/mL, about 22 ng/mL, about 22.2 ng/mL, about 22.4 ng/mL, about 22.6 ng/mL, about 22.8 ng/mL, about 23 ng/mL, about 23.2 ng/mL, about 23.4 ng/mL, about 23.6 ng/mL, about 23.8 ng/mL, about 24 ng/mL, about 24.2 ng/mL, about 24.4 ng/mL, about 24.6 ng/mL, about 24.8 ng/mL, about 25 ng/mL, about 25.2 ng/mL, about 25.4 ng/mL, about 25.6 ng/mL, about 25.8 ng/mL, about 26 ng/mL, about 26.2 ng/mL, about 26.4 ng/mL, about 26.6 ng/mL, about 26.8 ng/mL, about 27 ng/mL, about 27.2 ng/mL, about 27.4 ng/mL, about 27.6 ng/mL, about 27.8 ng/mL, about 28 ng/mL, about 28.2 ng/mL, about 28.4 ng/mL, about 28.6 ng/mL, about 28 ng/mL, about 29 ng/mL, about 29.2 ng/mL, about 29.4 ng/mL, about 29.6 ng/mL, about 29 ng/mL, about 30 ng/mL, about 30.2 ng/mL, about 30.4 ng/mL, about 30.6 ng/mL, about 30 ng/mL, about 31 ng/mL, about 31.2 ng/mL, about 31.4 ng/mL, about 31.6 ng/mL, about 31 ng/mL, about 32 ng/mL, about 32.2 ng/mL, about 32.4 ng/mL, about 32.6 ng/mL, about 32 ng/mL, about 33 ng/mL, about 33.2 ng/mL, about 33.4 ng/mL, about 33.6 ng/mL, about 33 ng/mL, about 34 ng/mL, about 34.2 ng/mL, about 34.4 ng/mL, about 34.6 ng/mL, about 34 ng/mL, about 35 ng/mL, about 35.2 ng/mL, about 35.4 ng/mL, about 35.6 ng/mL, about 35 ng/mL, about 36 ng/mL, about 36.2 ng/mL, about 36.4 ng/mL, about 36.6 ng/mL, about 36 ng/mL, about 37 ng/mL, about 37.2 ng/mL, about 37.4 ng/mL, about 37.6 ng/mL, about 37 ng/mL, about 38 ng/mL, about 38.2 ng/mL, about 38.4 ng/mL, about 38.6 ng/mL, about 38 ng/mL, about 39 ng/mL, about 39.2 ng/mL, about 39.4 ng/mL, about 39.6 ng/mL, about 39 ng/mL, about 40 ng/mL, about 40.2 ng/mL, about 40.4 ng/mL, about 40.6 ng/mL, about 40 ng/mL, about 41 ng/mL, about 41.2 ng/mL, about 41.4 ng/mL, about 41.6 ng/mL, about 41 ng/mL, about 42 ng/mL, about 42.2 ng/mL, about 42.4 ng/mL, about 42.6 ng/mL, about 42 ng/mL, about 43 ng/mL, about 43.2 ng/mL, about 43.4 ng/mL, about 43.6 ng/mL, about 43 ng/mL, about 44 ng/mL, about 44.2 ng/mL, about 44.4 ng/mL, about 44.6 ng/mL, about 44 ng/mL, about 45 ng/mL, about 45.2 ng/mL, about 45.4 ng/mL, about 45.6 ng/mL, about 45 ng/mL, about 46 ng/mL, about 46.2 ng/mL, about 46.4 ng/mL, about 46.6 ng/mL, about 46 ng/mL, about 47 ng/mL, about 47.2 ng/mL, about 47.4 ng/mL, about 47.6 ng/mL, about 47 ng/mL, about 48 ng/mL, about 48.2 ng/mL, about 48.4 ng/mL, about 48.6 ng/mL, about 48 ng/mL, about 49 ng/mL, about 49.2 ng/mL, about 49.4 ng/mL, about 49.6 ng/mL, about 49 ng/mL, about 50 ng/mL, about 50.2 ng/mL, about 50.4 ng/mL, about 50.6 ng/mL, about 50 ng/mL, about 51 ng/mL, about 51.2 ng/mL, about 51.4 ng/mL, about 51.6 ng/mL, about 51 ng/mL, or about 52 ng/mL, including all ranges and values therebetween.

In some embodiments, the pharmaceutical compositions of the present disclosure are formulated to achieve a blood plasma exposure level (AUC0-9) of methylphenidate within about 80% to about 125% of the range of at least 120 ± 39.6 h*ng/mL following oral administration to a child of a dose equivalent to 40 mg MET AD ATE CD^®, e.g., about 60 h*ng/mL, about 62 h*ng/mL, about 64 h*ng/mL, about 66 h*ng/mL, about 68 h*ng/mL, about 70 h*ng/mL, about 72 h*ng/mL, about 74 h*ng/mL, about 76 h*ng/mL, about 78 h*ng/mL, about 80 h*ng/mL, about 82 h*ng/mL, about 84 h*ng/mL, about 86 h*ng/mL, about 88 h*ng/mL, about 90 h*ng/mL, about 92 h*ng/mL, about 94 h*ng/mL, about 96 h*ng/mL, about 98 h*ng/mL, about 100 h*ng/mL, about 102 h*ng/mL, about 104 h*ng/mL, about 106 h*ng/mL, about 108 h*ng/mL, about 110 h*ng/mL, about 112 h*ng/mL, about 114 h*ng/mL, about 116 h*ng/mL, about 118 h*ng/mL, about 120 h*ng/mL, about 122 h*ng/mL, about 124 h*ng/mL, about 126 h*ng/mL, about 128 h*ng/mL, about 130 h*ng/mL, about 132 h*ng/mL, about 134 h*ng/mL, about 136 h*ng/mL, about 138 h*ng/mL, about 140 h*ng/mL, about 142 h*ng/mL, about 144 h*ng/mL, about 146 h*ng/mL, about 148 h*ng/mL, about 150 h*ng/mL, about 152 h*ng/mL, about 154 h*ng/mL, about 156 h*ng/mL, about 158 h*ng/mL, about 160 h*ng/mL, about 162 h*ng/mL, about 164 h*ng/mL, about 166 h*ng/mL, about 168 h*ng/mL, about 170 h*ng/mL, about 172 h*ng/mL, about 174 h*ng/mL, about 176 h*ng/mL, about 178 h*ng/mL, about 180 h*ng/mL, about 182 h*ng/mL, about 184 h*ng/mL, about 186 h*ng/mL, about 188 h*ng/mL, about 190 h*ng/mL, about 192 h*ng/mL, about 194 h*ng/mL, about 196 h*ng/mL, about 198 h*ng/mL, or about 200 h*ng/mL, including all ranges and values therebetween. In some embodiments, the pharmaceutical compositions of the present disclosure are formulated to achieve a maximum blood plasma concentration (Cmax) of methylphenidate within about 80% to about 125% of the range of at least 32.7 ± 9.83 ng/mL following administration to a child of a dose equivalent to 51.8 mg CONTEMPLA XR^®, e.g., about 18 ng/mL, about 18.2 ng/mL, about 18.4 ng/mL, about 18.6 ng/mL, about 18.8 ng/mL, about 19 ng/mL, about 19.2 ng/mL, about 19.4 ng/mL, about 19 .6 ng/mL, about 19. Ϊ I ng/mL, about 20 ng/mL, about 20 .2 ng/mL, about 20.4 ng/mL, about 20 .6 ng/mL, about 20.Σ I ng/mL, about 21 ng/mL, about 21 .2 ng/mL, about 21.4 ng/mL, about 21 .6 ng/mL, about 21.i I ng/mL, about 22 ng/mL, about 22 .2 ng/mL, about 22.4 ng/mL, about 22 .6 ng/mL, about 22.Σ I ng/mL, about 23 ng/mL, about 23 .2 ng/mL, about 23.4 ng/mL, about 23 .6 ng/mL, about 23.∑ I ng/mL, about 24 ng/mL, about 24 .2 ng/mL, about 24.4 ng/mL, about 24 .6 ng/mL, about 24.Σ I ng/mL, about 25 ng/mL, about 25 .2 ng/mL, about 25.4 ng/mL, about 25 .6 ng/mL, about 25.∑ I ng/mL, about 26 ng/mL, about 26 .2 ng/mL, about 26.4 ng/mL, about 26 .6 ng/mL, about 26.Σ I ng/mL, about 27 ng/mL, about 27 .2 ng/mL, about 27.4 ng/mL, about 27 .6 ng/mL, about 27.Σ I ng/mL, about 28 ng/mL, about 28 .2 ng/mL, about 28.4 ng/mL, about 28 .6 ng/mL, about 28.∑ I ng/mL, about 29 ng/mL, about 29 .2 ng/mL, about 29.4 ng/mL, about 29 .6 ng/mL, about 29.Σ I ng/mL, about 30 ng/mL, about 30 .2 ng/mL, about 30.4 ng/mL, about 30 .6 ng/mL, about 30.Σ I ng/mL, about 31 ng/mL, about 31 .2 ng/mL, about 31.4 ng/mL about 31 6 ng/mL, about 31.i 5 ng/mL, about 32 ng/mL, about 32 2 ng/mL, about 32.4 ng/mL about 32 6 ng/mL, about 32.Σ 5 ng/mL, about 33 ng/mL, about 33 2 ng/mL, about 33.4 ng/mL about 33 6 ng/mL, about 33.∑ ng/mL, about 34 ng/mL, about 34 2 ng/mL, about 34.4 ng/mL about 34 6 ng/mL, about 34.Σ 5 ng/mL, about 35 ng/mL, about 35 2 ng/mL, about 35.4 ng/mL about 35 6 ng/mL, about 35.∑ 5 ng/mL, about 36 ng/mL, about 36 2 ng/mL, about 36.4 ng/mL about 36 6 ng/mL, about 36.Σ 5 ng/mL, about 37 ng/mL, about 37 2 ng/mL, about 37.4 ng/mL about 37 6 ng/mL, about 37.Σ 5 ng/mL, about 38 ng/mL, about 38 2 ng/mL, about 38.4 ng/mL about 38 6 ng/mL, about 38.∑ ng/mL, about 39 ng/mL, about 39 2 ng/mL, about 39.4 ng/mL about 39 6 ng/mL, about 39.Σ 5 ng/mL, about 40 ng/mL, about 40 2 ng/mL, about 40.4 ng/mL about 40 6 ng/mL, about 40.Σ 5 ng/mL, about 41 ng/mL, about 41 2 ng/mL, about 41.4 ng/mL about 41 6 ng/mL, about 41.Ϊ 5 ng/mL, about 42 ng/mL, about 42 2 ng/mL, about 42.4 ng/mL about 42 6 ng/mL, about 42.Σ 5 ng/mL, about 43 ng/mL, about 43 2 ng/mL, about 43.4 ng/mL about 43 6 ng/mL, about 43.∑ ng/mL, about 44 ng/mL, about 44 2 ng/mL, about 44.4 ng/mL about 44 6 ng/mL, about 44.Σ 5 ng/mL, about 45 ng/mL, about 45 2 ng/mL, about 45.4 ng/mL about 45 6 ng/mL, about 45.∑ 5 ng/mL, about 46 ng/mL, about 46 2 ng/mL, about 46.4 ng/mL about 46 6 ng/mL, about 46.Σ 5 ng/mL, about 47 ng/mL, about 47 2 ng/mL, about 47.4 ng/mL about 47 6 ng/mL, about 47.Σ 5 ng/mL, about 48 ng/mL, about 48 2 ng/mL, about 48.4 ng/mL about 48 6 ng/mL, about 48.∑ ng/mL, about 49 ng/mL, about 49 2 ng/mL, about 49.4 ng/mL about 49 6 ng/mL, about 49.Σ 5 ng/mL, about 50 ng/mL, about 50 2 ng/mL, about 50.4 ng/mL about 50 6 ng/mL, about 50.Σ 5 ng/mL, about 51 ng/mL, about 51 2 ng/mL, about 51.4 ng/mL, about 51.6 ng/mL, about 51.8 ng/mL, about 52 ng/mL, about 52.2 ng/mL about 52.4 ng/mL about 52.6 ng/mL about 52.8 ng/mL about 53 ng/mL about 53.2 ng/mL about 53.4 ng/mL about 53.6 ng/mL about 53.8 ng/mL about 54 ng/mL about 54.2 ng/mL about 54.4 ng/mL about 54.6 ng/mL about 54.8 ng/mL or about 55 ng/mL, including all ranges and values therebetween.

In some embodiments the pharmaceutical compositions of the present disclosure are formulated to achieve a maximum blood plasma concentration (Cmax) of methylphenidate within about 80% to about 125% of the range of at least 20.2 ± 5.79 ng/mL following administration to an adult or adolescent of a dose equivalent to 51.8 mg CONTEMPLA XR^®, e.g., about 11 ng/mL, about 11.2 ng/mL, about 11.4 ng/mL, about 11.6 ng/mL, about 11.8 ng/mL, about 12 ng/mL, about 12.2 ng/mL, about 12.4 ng/mL, about 12.6 ng/mL, about 12.8 ng/mL, about 13 ng/mL, about 13.2 ng/mL, about 13.4 ng/mL, about 13.6 ng/mL, about 13.8 ng/mL, about 14 ng/mL, about 14.2 ng/mL about 14.4 ng/mL about 14.6 ng/mL, about 14.: ! ng/mL about 15 ng/mL about 15.2 ng/mL about 15.4 ng/mL about 15 .6 ng/mL, about 15.: ! ng/mL about 16 ng/mL about 16.2 ng/mL about 16.4 ng/mL about 16 .6 ng/mL, about 16.: ! ng/mL about 17 ng/mL about 17.2 ng/mL about 17.4 ng/mL about 17 .6 ng/mL, about 17.: ! ng/mL about 18 ng/mL about 18.2 ng/mL about 18.4 ng/mL about 18 .6 ng/mL, about 18.: ! ng/mL about 19 ng/mL about 19.2 ng/mL about 19.4 ng/mL about 19 .6 ng/mL, about 19.: ! ng/mL about 20 ng/mL about 20.2 ng/mL about 20.4 ng/mL about 20 .6 ng/mL, about 20.: ! ng/mL about 21 ng/mL about 21.2 ng/mL about 21.4 ng/mL about 21 .6 ng/mL, about 21.: ! ng/mL about 22 ng/mL about 22.2 ng/mL about 22.4 ng/mL about 22 .6 ng/mL, about 22.: ! ng/mL about 23 ng/mL about 23.2 ng/mL about 23.4 ng/mL about 23 .6 ng/mL, about 23.: ! ng/mL about 24 ng/mL about 24.2 ng/mL about 24.4 ng/mL about 24 .6 ng/mL, about 24.: ! ng/mL about 25 ng/mL about 25.2 ng/mL about 25.4 ng/mL about 25 .6 ng/mL, about 25.: ! ng/mL about 26 ng/mL about 26.2 ng/mL about 26.4 ng/mL about 26 .6 ng/mL, about 26.: ! ng/mL about 27 ng/mL about 27.2 ng/mL about 27.4 ng/mL about 27 .6 ng/mL, about 27.: ! ng/mL about 28 ng/mL about 28.2 ng/mL about 28.4 ng/mL about 28 .6 ng/mL, about 28.: ! ng/mL about 29 ng/mL about 29.2 ng/mL about 29.4 ng/mL about 29 .6 ng/mL, about 29.: ! ng/mL about 30 ng/mL about 30.2 ng/mL about 30.4 ng/mL about 30 .6 ng/mL, about 30.: ! ng/mL about 31 ng/mL about 31.2 ng/mL about 31.4 ng/mL about 31 .6 ng/mL, about 31.: ! ng/mL about 32 ng/mL about 32.2 ng/mL about 32.4 ng/mL about 32 .6 ng/mL, about 32.: ! ng/mL about 33 ng/mL about 33.2 ng/mL about 33.4 ng/mL about 33 .6 ng/mL, about 33.: ! ng/mL about 34 ng/mL about 34.2 ng/mL about 34.4 ng/mL, about 34.6 ng/mL, about 34.8 ng/mL, about 35 ng/mL, including all ranges and values therebetween.

In some embodiments, the pharmaceutical compositions of the present disclosure are formulated to achieve a maximum blood plasma concentration (Cmax) of methylphenidate within about 80% to about 125% of the range of at least 23.5 ± 11.4 ng/mL following administration to an adult of a dose equivalent to 80 mg APTENSIO XR®, e.g., about 9 ng/mL, about 9.2 ng/mL, about 9.4 ng/mL, about 9.6 ng/mL, about 9.8 ng/mL, about 10 ng/mL, about 10.2 ng/mL, about 10.4 ng/mL, about 10.6 ng/mL, about 10.8 ng/mL, about 11 ng/mL, about 11.2 ng/mL, about 11.4 ng/mL, about 11.6 ng/mL, about 11.8 ng/mL, about 12 ng/mL, about 12.2 ng/mL, about 12.4 ng/mL, about 12.6 ng/mL, about 12.8 ng/mL, about 13 ng/mL, about 13.2 ng/mL, about 13.4 ng/mL, about 13.6 ng/mL, about 13.8 ng/mL, about 14 ng/mL, about 14.2 ng/mL, about 14.4 ng/mL, about 14.6 ng/mL, about 14.3 ng/mL, about 15 ng/mL, about 15 2 ng/mL, about 15 4 ng/mL, about 15.6 ng/mL, about 15. 3 ng/mL, about 16 ng/mL, about 16 2 ng/mL, about 16 4 ng/mL, about 16.6 ng/mL, about 16. 3 ng/mL, about 17 ng/mL, about 17 2 ng/mL, about 17 4 ng/mL, about 17.6 ng/mL, about 17. 3 ng/mL, about 18 ng/mL, about 18 2 ng/mL, about 18 4 ng/mL, about 18.6 ng/mL, about 18. 3 ng/mL, about 19 ng/mL, about 19 2 ng/mL, about 19 4 ng/mL, about 19.6 ng/mL, about 19. 3 ng/mL, about 20 ng/mL, about 20 2 ng/mL, about 20 4 ng/mL, about 20.6 ng/mL, about 20. 3 ng/mL, about 21 ng/mL, about 21 2 ng/mL, about 21 4 ng/mL, about 21.6 ng/mL, about 21. 3 ng/mL, about 22 ng/mL, about 22 2 ng/mL, about 22 4 ng/mL, about 22.6 ng/mL, about 22. 3 ng/mL, about 23 ng/mL, about 23 2 ng/mL, about 23 4 ng/mL, about 23.6 ng/mL, about 23. 3 ng/mL, about 24 ng/mL, about 24 2 ng/mL, about 24 4 ng/mL, about 24.6 ng/mL, about 24. 3 ng/mL, about 25 ng/mL, about 25 2 ng/mL, about 25 4 ng/mL, about 25.6 ng/mL, about 25. 3 ng/mL, about 26 ng/mL, about 26 2 ng/mL, about 26 4 ng/mL, about 26.6 ng/mL, about 26. 3 ng/mL, about 27 ng/mL, about 27 2 ng/mL, about 27 4 ng/mL, about 27.6 ng/mL, about 27. 3 ng/mL, about 28 ng/mL, about 28 2 ng/mL, about 28 4 ng/mL, about 28.6 ng/mL, about 28. 3 ng/mL, about 29 ng/mL, about 29 2 ng/mL, about 29 4 ng/mL, about 29.6 ng/mL, about 29. 3 ng/mL, about 30 ng/mL, about 30 2 ng/mL, about 30 4 ng/mL, about 30.6 ng/mL, about 30. 3 ng/mL, about 31 ng/mL, about 31 2 ng/mL, about 31 4 ng/mL, about 31.6 ng/mL, about 31. 3 ng/mL, about 32 ng/mL, about 32 2 ng/mL, about 32 4 ng/mL, about 32.6 ng/mL, about 32. 3 ng/mL, about 33 ng/mL, about 33 2 ng/mL, about 33 4 ng/mL, about 33.6 ng/mL, about 33. 3 ng/mL, about 34 ng/mL, about 34 2 ng/mL, about 34 4 ng/mL, about 34.6 ng/mL, about 34. 3 ng/mL, about 35 ng/mL, about 35 2 ng/mL, about 35 4 ng/mL, about 35.6 ng/mL, about 35. 3 ng/mL, about 36 ng/mL, about 36 2 ng/mL, about 36 4 ng/mL, about 36.6 ng/mL, about 36. 3 ng/mL, about 37 ng/mL, about 37 2 ng/mL, about 37 4 ng/mL, about 37.6 ng/mL, about 37. 3 ng/mL, about 38 ng/mL, about 38 2 ng/mL, about 38 4 ng/mL, about 38.6 ng/mL, about 38. 3 ng/mL, about 39 ng/mL, about 39 2 ng/mL, about 39 4 ng/mL, about 39.6 ng/mL, about 39. 3 ng/mL, about 40 ng/mL, about 40 2 ng/mL, about 40 4 ng/mL, about 40.6 ng/mL, about 40. 3 ng/mL, about 41 ng/mL, about 41 2 ng/mL, about 41 4 ng/mL, about 41.6 ng/mL, about 41. 3 ng/mL, about 42 ng/mL, about 42 2 ng/mL, about 42 4 ng/mL, about 42.6 ng/mL, about 42. 3 ng/mL, about 43 ng/mL, about 43 2 ng/mL, about 43 4 ng/mL, about 43.6 ng/mL, about 43. 3 ng/mL, about 44 ng/mL, about 44 2 ng/mL, about 44 4 ng/mL, about 44.6 ng/mL, about 44.8 ng/mL, or about 45 ng/mL, including all ranges and values therebetween. As discussed above, the present pharmaceutical compositions release methylphenidate, or the pharmaceutically acceptable salt thereof, in three pulses. Thus, each pulse can be considered to provide a Cmax. As used herein, Cmaxi is associated with the IR particles, Cmax2 is associated with the TPRi particles, and Cmax3 is associated with the TPR3 particles. In some embodiments, the steady state blood plasma Cmaxi and the steady state blood plasma Cmax2 are substantially equivalent. As used herein, "substantially equivalent refers" to a Cmax within the range of ± about 25% (e.g., ± about 20%, ± about 15%, ± about 10%, ± about 5%). In some embodiments, the steady state blood plasma Cmaxi at least about 125%, about 124%, about 123%, about 122%, about 121%, about 120%, about 1 19%, about 118%, about 117%, about 116 about 115%, about 114%, about 113%, about 112%, about 111%, about 110%, about 109%, about 108%, about 107%, about 106%, about 105%, about 104%, about 103%, about 102%, about 101 about 100%, about 99%, about 98%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 89%, about 88%, about 87%, about 86%, about 85%, about 84%, at least 83%, about 82%, about 81%, about 80%, about 79%, about 78%, about 77%, about 76%, about 75%, about 74%, about 73%, about 72%, about 71%, about 70%, about 69%, about 68%, about 67%, about 66%, about 65%, about 64%, about 63%, about 62%, about 61%, about 60%, about 59%, about 58%, about 57%, about 56%, about 55%, about 54%, about 53%, about 52%, about 51%), or about 50% of the steady state blood plasma Cmax2, including all ranges and values therebetween. In certain embodiments, the steady state blood plasma Cmaxi is at least 50% of the steady state blood plasma Cmax2.

In some embodiments, the steady state blood plasma Cmax2 and steady state blood plasma Cmax3 are substantially equivalent. In some embodiments, the steady state blood plasma Cmax3 is at least about 125%, about 124%, about 123%, about 122%, about 121%, about 120%, about 119%, about 118%, about 117%, about 116 about 115%, about 114%, about 113%, about 112%, about 111%, about 110%, about 109%, about 108%, about 107%, about 106%, about 105%, about 104%, about 103%, about 102%, about 101 about 100%, about 99%, about 98%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 89%, about 88%, about 87%, about 86%, about 85%, about 84%, at least 83%, about 82%, about 81%, about 80%, about 79%, about 78%, about 77%, about 76%, about 75%, about 74%, about 73%, about 72%, about 71%, about 70%, about 69%, about 68%, about 67%, about 66%, about 65%, about 64%, about 63%, about 62%, about 61%, about 60%, about 59%, about 58%, about 57%, about 56%, about 55%, about 54%), about 53%), about 52%, about 51%, or about 50% of the steady state blood plasma Cmax2, including all ranges and values therebetween.

In some embodiments, the steady state blood plasma Cmax3 is at least 50% of the steady state blood plasma Cmax2, e.g., about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 905, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100

In some embodiments of the pharmaceutical composition, the steady state blood plasma Cmaxi and the steady state blood plasma Cmax3 are substantially equivalent. In some embodiments, the steady state blood plasma Cmax3 is at least about 125%, about 124%, about 123%, about 122%, about 121%, about 120%, about 119%, about 118%, about 117%, about 116 about 115%, about 114%, about 113%, about 112%, about 111%, about 110%, about 109%, about 108%, about 107%, about 106%, about 105%, about 104%, about 103%, about 102%, about 101 about 100%, about 99%, about 98%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 89%, about 88%, about 87%, about 86%, about 85%, about 84%, at least 83%, about 82%, about 81%, about 80%, about 79%, about 78%, about 77%, about 76%, about 75%, about 74%, about 73%, about 72%, about 71%, about 70%, about 69%, about 68%, about 67%, about 66%, about 65%, about 64%, about 63%, about 62%, about 61%, about 60%, about 59%, about 58%, about 57%, about 56%, about 55%, about 54%, about 53%, about 52%, about 51%, or about 50% of the steady state blood plasma Cmaxi, including all ranges and values therebetween. In certain embodiments, the steady state blood plasma Cmax3 is at least 50% of the steady state blood plasma

Cmaxl.

Methods of Treatment

The pharmaceutical compositions described herein are particularly useful in treating children (6- 12 years of age), adolescents (13-17 years of age), and adult patients (18+ years of age) with ADHD requiring alertness throughout the day, but without interfering with ensuing activities before going to bed. The presently disclosed pharmaceutical compositions are formulated such that blood levels of drug slowly decline to limit the potential for insomnia and/or appetite suppression without meaningfully reducing efficacy. In some embodiments, the present disclosure provides a method of treating ADHD in a subject in need thereof, comprising orally administering a pharmaceutical composition as disclosed herein.

In some embodiments, the composition is administered in the morning. Administration in this manner provides an effective treatment of ADHD for up to about 16 h by maintaining suitable blood plasma levels, while impact on sleep and appetite is minimized. After administering, the patient experiences a substantial reduction in ADHD compared to prior to said administering

A number of rating scales are available to assess the impairment in ADHD achieved after administering the pharmaceutical compositions of the present invention to a patient in need thereof. These scales provide a quantitative assessment for the reduction of ADHD by scoring certain behaviors and symptoms associated with the disease. In various embodiments, a patient experiences a reduction in ADHD characterized by a decline in points or a percent reduction in scale value. For example, in some embodiments, after administration, the patient experiences a reduction of ADHD that is characterized by an at least a one point decline, at least a two point decline, at least a three point decline, or at least a four point decline, or at least a five point decline in the scale value. In other embodiments, the patient experiences a reduction of ADHD that is characterized by an at least 5% reduction, an at least 10% reduction, an at least 15% reduction, an at least 20% reduction, an at least 25% reduction, an at least 30% reduction, or an at least 35% reduction in scale value.

One example of a rating system is the DSM-IV scale that quantifies each of the 18 symptoms of ADHD on a 0 to 3 scale, with a maximum score of 54 points. The 18 symptoms are subdivided, such that 9 of the 18 indicators score for inattention, while the remaining assess hyperactivity with a maximum of 27 points each. In some embodiments, the patient experiences a reduction of ADHD that is characterized by at least a one point decline or at least a two point decline in DSM- IV Attention-Deficit/Hyperactivity Disorder Rating (DSM-IV ADHD) Scale value. In certain embodiments, the patient experiences a reduction of ADHD that is characterized by an at least two point decline in DSM-IV Attention-Deficit/Hyperactivity Disorder Rating (DSM-IV ADHD) Scale value. In certain embodiments, the patient experiences a reduction of ADHD that is characterized by an at least 10% reduction or an at least a 20% reduction in DSM-IV ADHD Scale value. In certain embodiments, the patient experiences a reduction of ADHD that is characterized by an at least 20% reduction in DSM-IV ADHD Scale value. Another scale available for assessing impairment in ADHD is the Adult Self-Report Scale (ASRS vl .1). This scale consists of 18 questions based on the DSM-V diagnostic criteria for ADHD. The questions are measured on a 5-point scale for a possible scoring range of 0-72. In various embodiments, after administration of a pharmaceutical composition disclosed herein, the patient experiences a reduction of ADHD that is characterized by at least a one point decline or at least a two point decline in Adult Self-Report Scale (ASRS vl . l) for ADHD Scale value. In certain embodiments, after administration of a pharmaceutical composition disclosed herein, the patient experiences a reduction of ADHD that is characterized by an at least two point decline in Adult Self-Report Scale (ASRS vl . l) for ADHD Scale value. In some embodiments, after said administering, the patient experiences a reduction of ADHD that is characterized by an at least 10% reduction or an at least 20% reduction in DSM-V ADHD Scale value. In certain embodiments, after said administering, the patient experiences a reduction of ADHD that is characterized by an at least 20% reduction in DSM-V ADHD Scale value.

Yet another scale available for assessing impairment in ADHD is the Swanson, Kotkin, Agler, M- Flynn, and Pelham Rating Scale (SKAMP). In one version, the SKAMP combined score is calculated as the total score of all 13 items scored by this assessment. Each item is rated on a 7- point impairment scale (0=normal and 6=maximal impairment) for a total possible score in the range of 0 to 78. Accordingly, a lower score indicates less symptomology. In some embodiments, after administration of a pharmaceutical composition disclosed herein, the patient experiences a reduction of ADHD that is characterized by an at least one point or an at least two point decline in Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale (SKAMP) value. In certain embodiments, after administration of a pharmaceutical composition disclosed herein, the patient experiences a reduction of ADHD that is characterized by an at least two point decline in Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale (SKAMP) value. In some embodiments, after said administering, the patient experiences a reduction of ADHD that is characterized by an at least 10%) reduction or an at least 20% reduction in SKAMP Scale value. In certain embodiments, after said administering, the patient experiences a reduction of ADHD that is characterized by an at least 20% reduction in SKAMP Scale value.

The Daily Parent Rating of Evening and Morning Behavior, Revised (PREMB-R) Scale is also used to assess ADHD impairment. The total score for this 11 -item scale (evening + morning) ranges from 0 to 33, where higher scores indicate greater difficulty in evening and morning behavior. In some embodiments, after administration of a pharmaceutical composition disclosed herein, the patient experiences a reduction of ADHD that is characterized by an at least one point or an at least two point decline in Daily Parent Rating of Evening and Morning Behavior, Revised (PREMB-R) value. In certain embodiments, after administration of a pharmaceutical composition disclosed herein, the patient experiences a reduction of ADHD that is characterized by an at least two point decline in Daily Parent Rating of Evening and Morning Behavior, Revised (PREMB-R) value. In some embodiments, after said administering, the patient experiences a reduction of ADHD that is characterized by an at least 10% reduction or an at least 20% reduction in Daily Parent Rating of Evening and Morning Behavior, Revised (PREMB-R) value. In certain embodiments, after said administering, the patient experiences a reduction of ADHD that is characterized by an at least 20% reduction in Daily Parent Rating of Evening and Morning Behavior, Revised (PREMB-R) value.

The Before School Functioning Questionnaire (BSFQ) value is a 20-item questionnaire developed as a hybrid measure to assess commonly reported areas of early morning dysfunction. The BSFQ measures both behaviors and functions associated with the post-waking, early morning period in children and adolescents with ADHD. In some embodiments, after administration of a pharmaceutical composition disclosed herein, the patient experiences a reduction of ADHD that is characterized by an at least one point or an at least two point decline in Before School Functioning Questionnaire (BSFQ). In certain embodiments, after administration of a pharmaceutical composition disclosed herein, the patient experiences a reduction of ADHD that is characterized by an at least two point decline in Before School Functioning Questionnaire (BSFQ). In some embodiments, after said administering, the patient experiences a reduction of ADHD that is characterized by an at least 10% reduction or an at least 20% reduction in Before School Functioning Questionnaire (BSFQ). In certain embodiments, after said administering, the patient experiences a reduction of ADHD that is characterized by an at least 20% reduction in Before School Functioning Questionnaire (BSFQ).

A common side effect of ADHD treatment is a noted increase in insomnia, a sleep disorder characterized by trouble sleeping, including difficulty falling asleep or staying asleep as long as desired, insomnia is typically followed by daytime sleepiness, low energy, irritability, and a depressed mood. However, in various embodiments of the present disclosure, after administration of a pharmaceutical composition disclosed herein, the patient experiences a substantial reduction of ADHD and does not experience a substantial increase in insomnia compared to prior to said administering. As used herein, "prior to administering" refers to a previous day in which the patient was not administered the present pharmaceutical compositions.

Several scales are available to determine the level of insomnia that arises from ADHD treatment. For example, the Insomnia Severity Index has seven questions, where answers provide a total score ranging from 0 to 28. A total score of 0 to 7 indicates no significant insomnia; 8 to 14 indicates subthreshold insomnia; 15 to 21 indicates clinical insomnia - moderate severity; and 22-28 indicates clinical insomnia - severe. In some embodiments, after administration of a pharmaceutical composition disclosed herein, the patient experiences an increase in Insomnia Severity Index scale value of not more than 5 points, not more than four points, not more than three points, not more than two points, or not more than one point compared to prior to said administering. In certain embodiments, after administration of a pharmaceutical composition disclosed herein, the patient experiences an increase in Insomnia Severity Index scale value of not more than one point compared to prior to said administering.

The Pittsburgh Sleep Quality Index (PSQI) is a 19-item self-report scale that assesses sleep quality and disturbances for the month preceding the assessment (Buysse D.J., The Pittsburgh Sleep Quality Index: a New Instrument for Psychiatric Practice and Research. Psychiatry Res. 1989 May; 28(2), pages 193-213.). The scale generates seven "component" scores that differentiate "poor" from "good" sleep quality: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of scores for these seven components yields the Global PSQI score. A Global PSQI score of "5" or greater indicates poor sleep quality. In some embodiments, after administration of a pharmaceutical composition disclosed herein, the patient experiences an increase in Global Pittsburgh Sleep Quality Index of not more than 5 points, not more than four points, not more than three points, not more than two points, or not more than one point compared to prior to said administering. In certain embodiments, after administration of a pharmaceutical composition disclosed herein, the patient experiences an increase in Global Pittsburgh Sleep Quality Index of not more than one point compared to prior to said administering.

The Epworth Sleepiness Scale (ESS) is also useful for determining the extent of insomnia upon treatment of ADHD with the presently disclosed compositions. In scoring the ESS, each item is rated on a 4-point scale from 0 = would never doze to 3 = high chance of dozing. The item scores are summed to produce a total score (range 0 - 24). A sum of 10 or more from the 8 individual scores reflects above normal daytime sleepiness and need for further evaluation. In some embodiments, after administration of a pharmaceutical composition disclosed herein, the patient experiences an increase in Epworth Sleepiness Scale of not more than 5 points, not more than four points, not more than three points, not more than two points, or not more than one point compared to prior to said administering. In certain embodiments, after administration of a pharmaceutical composition disclosed herein, the patient experiences an increase in Epworth Sleepiness Scale of not more than one point compared to prior to said administering. In certain other embodiments, after administration of a pharmaceutical composition disclosed herein, the patient experiences an increase in Epworth Sleepiness Scale of not more than two points compared to prior to said administering.

The DBAS- 16 is a self-rating inventory consisting of 16 items (measuring a subject's worry about loss of control over abilities to sleep) with 10-point scales, ranging from 0 {strongly disagree) to 10 {strongly agree). The total score is calculated from the average score of all the items on the scale and could range from 0 to 10, with higher scores indicating higher levels of dysfunctional beliefs about sleep. In some embodiments, after administration of a pharmaceutical composition disclosed herein, the patient does not experience an increase in Dysfunctional Beliefs and Attitudes about Sleep- 16 (DBAS- 16) of more than 5 points, more than four points, more than three points, more than two points, or more than one point compared to prior to said administering. In certain embodiments, after administration of a pharmaceutical composition disclosed herein, the patient does not experience an increase in Dysfunctional Beliefs and Attitudes about Sleep- 16 (DBAS- 16) of more than 1 point compared to prior to said administering.

Reduction in appetite can also be a side effect of commonly used ADHD treatments. Several rating scales are used to quantify this condition. However, in various embodiments of the present disclosure, after administration of a pharmaceutical composition disclosed herein, the patient experiences a substantial reduction of ADHD and does not experience a substantial reduction in appetite compared to prior to said administering.

In some embodiments, after administration of a pharmaceutical composition disclosed herein, the patient does not experience a decrease in Council on Nutrition appetite questionnaire (CNAQ) scale value of more than 5 points, more than four points, more than three points more than two points, or more than one point compared to prior to said administering. In certain embodiments, after administration of a pharmaceutical composition disclosed herein, the patient does not experience a decrease in Council on Nutrition appetite questionnaire (CNAQ) scale value of more than 1 point compared to prior to said administering. The Council on Nutrition appetite questionnaire (CNAQ) is a survey consisting of 8 items with 5 point scale (1-5) that can be used to quantify reduction in appetite for a subject undergoing treatment for ADHD. The item scores are summed to produce a total CNAQ score. Total score ranges from 8-40 with a score of less than or equal to 28 indicating significant risk of at least 5% weight loss in six months. In some embodiments, the pharmaceutical compositions disclosed herein provide a scope of greater than 28.

In some embodiments, after administration of a pharmaceutical composition disclosed herein, the patient does not experience a decrease in simplified nutritional appetite questionnaire (SNAQ) scale value of more than 5 points, more than four points, more than three points, more than two points, or more than one point compared to prior to said administering. In certain embodiments, after administration of a pharmaceutical composition disclosed herein, the patient does not experience a decrease in simplified nutritional appetite questionnaire (SNAQ) scale value of more than 1 point compared to prior to said administering. The simplified nutritional appetite questionnaire (SNAQ) is a survey consisting of 4 items with 5 point scale (1-5) that can be used to quantify reduction in appetite for a subject undergoing treatment for ADHD. The item scores are summed to produce a total SNAQ score. Total score ranges from 4-20 with a score of less than or equal to 14 indicating significant risk of at least 5% weight loss in six months. In some embodiments, the pharmaceutical compositions disclosed herein provide a scope of greater than 14.

In some embodiments, after administration of a pharmaceutical composition disclosed herein, the does not experience a decrease in appetite hunger and sensory perception questionnaire (AHSP) scale value of more than about 5%, more than about 10%, more than about 15%, more than about 20%), more than about 25%, or more than about 30%> compared to prior to said administering. In certain embodiments, after administration of a pharmaceutical composition disclosed herein, the patient does not experience a decrease in appetite hunger and sensory perception questionnaire (AHSP) scale value of more than about 20% compared to prior to said administering. In some embodiments, after administration of a pharmaceutical composition disclosed herein, the patient does not experience a decrease in appetite hunger and sensory perception questionnaire (AHSP) scale value of more than about one point, more than about 2 points, more than about 3 points, or more than about 4 points compared to prior to said administering. In certain embodiments, after administration of a pharmaceutical composition disclosed herein, the patient does not experience a decrease in appetite hunger and sensory perception questionnaire (AHSP) scale value of more than about two points compared to prior to said administering. In certain other embodiments, after administration of a pharmaceutical composition disclosed herein, the patient does not experience a decrease in appetite hunger and sensory perception questionnaire (AHSP) scale value of more than about one point compared to prior to said administering. The AHSP is a validated, 29-item, multi-domain appetite assessment tool that is scored with a 5-point (A to E) Likert-type scale with verbally labeled categories. Items on the AHSP are grouped into 3 domains: taste (14 items), smell (6 items), and hunger (9 items). The score for each domain is the sum of scores on the individual items, with lower scores indicating deterioration. The total AHSP score is the sum of scores on the 3 domains. Possible scores range from 29 (worst) to 145 (best).

As appetite suppression is not observed upon treatment of ADHD with the pharmaceutical compositions disclosed herein, a patient receiving treatment is able to maintain body weight. In some embodiments, after administration of a pharmaceutical composition disclosed herein, the patient does not experience a decrease in body weight of more than about 5%, more than about 7.5%), more than about 10%>, no more than about 12.5%, or more than about 15% compared to prior to said administering. In certain embodiments, after administration of a pharmaceutical composition disclosed herein, the patient does not experience a decrease in body weight of more than about 5% compared to prior to said administering.

The following non-limiting examples illustrate the various embodiments of the pharmaceutical compositions and dosage forms of the present invention. Such compositions and dosage forms, when properly administered, provide therapeutically effective drug plasma concentrations while minimizing the occurrence of side-effects associated with Cmax or Cmin, i.e., the triple pulsatile delivery system provides for rapid onset of ADHD symptom control and ideal duration of efficacy for up to about 14 to 20 hours, with said plasma psychostimulant medication level slowly declining to reduce the potential for insomnia and appetite suppression without meaningfully reducing efficacy.

EXAMPLES

Example 1

Pharmacokinetic/biopharmaceutical modeling and simulation was performed using GastroPlus™ (available from Simulation Plus, Inc.), a physiologically based pharmacokinetic (PBPK) modeling & simulation software package. Pharmacokinetic parameters were optimized using the actual human plasma concentration-time data upon oral administration of IR and TPR dosage forms of methylphenidate as a guide in the design of methylphenidate pulsatile delivery systems of this invention comprising one IR and two TPR populations. Table 1 shows the fitted pharmacokinetics parameters for dex-methylphenidate (d-MPH).

Table 1 : Fitted PK parameters for d-MPH

A. Simulations for Dexmethylphenidate HC1

In vitro release profiles were conceived and PK modeling and simulations performed using these optimized PK parameters. FIG. 3 to FIG. 7 show the conceived in vitro release profiles (see Table 2 for descriptions and compositions) and the corresponding triphasic plasma concentration-time profiles.

FIG. 3 shows the simulated plasma d-MPH concentration - time profiles for proposed triple pulsatile delivery systems at a d-MPH weight ratio of 30:50:20. FIG. 4 shows the PK profiles corresponding to the in vitro release profiles of MER-1 (combined 10 mg IR <i-methylphenidate pulse dosed at 0, 4 and 8 hours) and MER-2, MER-3 and MER-4 (combined IR beads, TPRi beads, and TPR2 beads of <i-methylphenidate). In MER-2, MER-3, and MER-4 the lag-time of the first TPR pulse is varied from 4 hours to 6 hours and that of the second TPR pulse is varied from 8 hours to 10 hrs.

FIG. 5 shows the PK profiles corresponding to the in vitro <i-methylphenidate release profiles of MER-5, MER-6, MER-7, MER-8, MER-9, and MER-10 with the first TPR having a lag- time of 3, 4, or 5 hours and the second TPR having an 8 hour lag (see Table 3 for details).

FIG. 6 and FIG. 7 show the conceived alternate in vitro <i-methylphenidate release profiles for MER-11 to MER-17 (A) (see Table 2 for descriptions and compositions) and the corresponding PK plasma profiles (B) (see also Table 3 for details).

Table 2: Compositions of the invention having varied in vitro MPH release profiles with simulated PK profiles

MER-9 (30 mg) (0, 0.5) (4, 2) (8, 2)

MER-10(30mg) (0, 0.5) (4, 2) (10, 4)

MER-11 (30 mg) (0, 0.5) (5,2) (12, 2)

MER-12(30mg) (0, 0.5) (4, 2) (8, 2)

MER-13 (30 mg) (0, 0.5) (4, 2) (10, 4)

MER-14(30mg) (0, 0.5) (5,2) (12, 2)

MER-15 (30 mg) (0, 0.5) (4, 2) (8, 2)

MER-16(30mg) (0, 0.5) (4, 2) (10, 4)

MER-17(30mg) (0, 0.5) (5,2) (12, 2)

Table 3 : Time duration wherein the plasma concentration is at or above 3.5 ng/mL and plasma concentration at 14 hours or 16 hours.

MER-17 17.3 7.78 4.93

FIG. 8 (A) shows the in vitro i/J-MPH release profiles for once-daily triple pulse MER formulations MER-A, MER-B, and MER-C comprising a total dose of 15 mg <i,/-MPH (see below for lag-time, release duration, and dose of IR, TPRi and TPR2 components). FIG. 8 (B) shows the corresponding PK profiles, along with the mean ^/-Methylphenidate plasma concentration - time profile observed in 36 adults, following a single dose of Concerta^® 18 mg once daily.

It is clear from FIG.8 that the i/J-MPH plasma concentration at 12 and 14 hour post dosing of 18 mg Concerta are slightly or significantly lower than the corresponding levels from triple pulse MER formulations MER-A [IR(0,0.5) 5mg + TPRi(4,2) 5mg + TPR₂(8,2) 5mg], MER- B [IR(0,0.5) 5mg + TPRi(5,4) 5mg + TPR₂(9,4) 5mg] and MER-C [IR(0,0.5) 4mg + TPRi(5,2) 4mg + TPR₂(10,3) 7mg].

Table 4 summarizes the PK data for MER-A, MER-B, MER-C, and Concerta^® presented in FIG. 8. In Concerta 18 mg, the plasma concentration is ascending up to about 3.35 ng/mL at about 8 hours following Cmaxl at approximately 1.5 hours post dosing, and rapidly declines thereafter such that the concentration at 12 hours and beyond is less than 1.4 ng/mL, thereby explaining why the ADHD symptoms control does not last beyond 12 hours post dosing. In contrast, MER-A, MER-B and MER-C formulations maintain a significantly higher plasma concentration up to 12 hours post dosing. Indeed, especially the MER-B and MER-C formulations maintain a plasma level of >1.4 ng/mL up to 16 hours post dosing.

Table 4 Summary of PK parameters and plasma concentrations

Concentration @ 12 Hour 2.55 ng/mL 2.40 ng/mL 2.16 ng/mL

Concentration @ 14 Hour 1.69 ng/mL 2.17 ng/mL 2.49 ng/mL

Concentration @ 16 Hour 1.03 ng/mL 1.45 ng/mL 1.73 ng/mL

Cmaxl @ Tmaxl 2.45@1.7 hr 2.45@1.7 hr 1.96@1.76 hr

Cmax2 @ Tmax2 2.54@6.6 hr 1.53@7.2 hr 1.87@7.7 hr

Cmax3 @ Tmax3 3.06@10.3 hr 2.43@13.0 hr 2.63@13.2 hr

Example 2

A. Dexmethylphenidate HC1 IR Beads (15% drug load)

Polyvinylpyrrolidone (75 g Povidone K-30) was slowly added to purified water (3500 g) while stirring rigorously to dissolve and then d-MPH (750 g) was slowly added to the aqueous binder solution to dissolve while stirring for additional 10 minutes. Glatt GPCG 5 equipped with a 10" bottom spray Wurster insert, 14" high partition column with 1" gap, 'B' air distribution plate covered with a 200 mesh product retention screen, and 14 mm tubing (peristaltic pump) was charged with 4075 g of 25-30 mesh sugar spheres. The sugar spheres were layered with the d-MPH solution while maintaining the product temperature at about 37-38°C and inlet air volume 45-50 cfm. The flow rate was increased from 5 mL/min to 15 mL/min at an atomization air pressure of 1.25 bar and nozzle port of 1.0 mm. A protective seal coat of OPADRY CLEAR (hydroxypropylcellulose) was applied over the drug layered beads that were dried in the unit for 10 minutes to drive off residual solvent/moisture and sieved through 20-30 mesh screens. B. Dexmethylphenidate HC1 TPR beads

Ethylcellulose (EC- 10, Ethocel Premium 10 from Colorcon; 67.5 g) was slowly added to a 90/10 mixture of acetone and water while stirring constantly until dissolved. Hypromellose phthalate (HP-55 from Shin Etsu Japan; 60 g) was slowly added to the EC- 10 solution until dissolved, followed by the addition of tri ethyl citrate (TEC; 22.5 g), until the tri ethyl citrate was dissolved/dispersed homogeneously. A Glatt GPCG 3 equipped with a 6" bottom spray Wurster 6" insert, 'Β" bottom air distribution plate covered with a 200 mesh product retention screen, 1.2 mm port nozzle, was charged with 1350 g of IR beads from Example 2. A. above. The IR beads were sprayed with the ethylcellulose/hypromellose phthalate coating formulation (7.5% solids) at a product temperature of 35-36°C, atomization air pressure of 1.5 bar, inlet air flow of 70-110 m³/hr, and a spray rate of 9 -12 g/min for a TPR coating level of 15% by weight. Samples were pulled at a coating of 7.5%, 10%, 12.5% and subjected to analytical testing (i.e., HPLC assay and drug release). Following spraying, the coated beads were dried in the Glatt unit for 10 minutes to drive off residual solvents (including moisture) to provide the product TPR beads with a 4 hour lag-time.

C. Dexmethylphenidate HC1 TPR beads

The IR beads from Example 2. A. above were sprayed with the ethylcellulose/hypromellose phthalate/triethylcitrate at 60/30/10 coating formulation (7.5% solids) for a weight gain of 30% under processing conditions established in Example 2.B. above. Samples were pulled at a coating of 20%, 22.5%, 25% and subjected to analytical testing (i.e., HPLC assay and drug release). Following spraying, the coated beads are dried in the Glatt unit for 3 min to drive off residual solvents (including moisture content) to provide the product TPR beads with an 8 hour lag-time. D. Dexmethylphenidate HC1 TPR beads

The IR beads from Example 2. A. above are sprayed with the ethylcellulose/hypromellose phthalate/triethylcitrate at 65/25/10 coating formulation (7.5% solids) for a weight gain of 35% under processing conditions established in Example 2.B. and 2.C. above. Samples are pulled at a coating of 20%, 25%, 27.5%, 30% and subjected to analytical testing (i.e., HPLC assay and drug release). Following spraying, the coated beads are dried in the Glatt unit for 5 min to drive off residual solvents (including moisture) to provide the product TPR beads with a 10 hour lag-time.

FIG. 9 shows the in vitro dex-methylphenidate release profiles of TPR prototypes wherein IR beads were coated with a lag-time coating of EC-10/HP-55/DEP at a ratio of 50/40/10 at 25% and 43%) by weight or first coated with enteric hypromellose phthalate and DEP at 80/20 for a weight gain of 20% followed by coating with functional polymers comprising water-insoluble ethylcellulose in combination with enteric hypromellose phthalate and diethyl phthalate at a ratio of 45.5/40/14.5 for a weight gain of 40%. E. Dexmethylphenidate HCl Pulsatile Delivery Systems

Appropriate amounts of Dexmethylphenidate HCl IR beads (drug load: 15%), Dexmethylphenidate HCl TPRi beads, and either Dexmethylphenidate HCl TPRi beads or Dexmethylphenidate HCl TPR2 beads, are filled into hard gelatin capsules using an MG Capsule Filling Machine with triple bead filling hoppers to produce pulsatile delivery systems: 20-mg Dexmethylphenidate HCl Capsules (30 IR/50 TPRi/20 TPR2) and 20 mg Dexmethylphenidate HCl Capsules (30 IR/50 TPRi/20 TPR2).

Example 3

A. Dexmethylphenidate HCl IR beads (16-18 mesh sugar spheres) Polyvinylpyrrolidone (10 g Povidone K-30) was slowly added to purified water (660 g) while stirring rigorously to dissolve and then Dexmethylphenidate HCl (80 g) was slowly added to the aqueous binder solution to dissolve while stirring for additional 10 minutes. Glatt GPCG 3 equipped with a 6" bottom spray Wurster insert, 18 mm high partition column with 1" gap, 'B' air distribution plate covered with a 100 mesh product retention screen, and 14 mm tubing (peristaltic pump) was charged with 890 g of 16-18 mesh sugar spheres. The sugar spheres were layered with the dexmethylphenidate HCl solution while maintaining the product temperature at about 43°C and inlet air temperature of 70-63°C and air volume of 32 cfm. The flow rate was increased from 6 mL/min to 10 mL/min at an atomization air pressure of 1.25 bar and nozzle port of 1.0 mm. A protective seal coat of OPADRY CLEAR (hydroxypropylcellulose) was applied over the drug layered beads at a spray rate of 6 mL/min and at an atomization air pressure of 1.5 bar. The IR beads were dried in the unit for 2 minutes to drive off residual moisture and sieved through 14-18 mesh screens.

B. Dexmethylphenidate HCl TPR (Eudragit RSPO/L100/S100 at 1 : 1 :0.25) beads

EUDRAGIT RSPO (233.4 g) was added to a mixture of acetone (6228.7 g) and purified water (327.8 g) in a stainless steel container and mixed using a low shear agitator for not less than ( LT) 10 minutes (until visually dissolved). EUDRAGIT L100 (233.4 g) was mixed for LT 10 minutes, EUDRAGIT S100 (57.6 g) was mixed for NLT 10 minutes, and triethyl citrate (93.1 g) was mixed for NLT 30 minutes. Talc (168.6 g) was added and mixed for NLT 30 minutes and mixing the suspension continued at low speed while spraying. The preheated Glatt GPCG-3 was charged with 700 g IR beads (16-18 mesh) from Example 3. A. above and spray coated by spraying at an initial spray rate of 8 mL/minute; Inlet air temperature: 41°C; Airflow: 32-35 cfm or so to achieve adequate fluidization and recorded dew point: about 5-7°C. After about 10 minutes, the spray rate was gradually increased to 18 mL/minute by adjusting flow parameters to maintain the target bed temperature of 32°C. Samples were pulled after different coating for dissolution testing. The TPR beads were dried in the unit for 5 minutes and discharged.

C. Dexmethylphenidate HC1 IR beads (20-25 mesh sugar spheres) The (20-25 mesh) sugar spheres (700 g) were layered with the solution of dexmethylphenidate HC1 (62.9 g dissolved along with 7.9 g of povidone in 519.2 g purified water) while maintaining the product temperature at about 43°C and air volume of 32 cfm. The flow rate was increased from 6 mL/min to 10 mL/min at an atomization air pressure of 1.25 bar and nozzle port of 1.0 mm. Following completion of seal coat, the spray system was rinsed with purified water for 3 minutes.

D. Dexmethylphenidate HC1 TPR (Eudragit RSPO/L100 at 1 : 1) beads

The seal coated IR beads from Example 3.C. were coated with the functional polymer formulation of EUDRAGIT RSPO (262.4 g), EUDRAGIT L100 (262.4 g), tri ethyl citrate (104.7 g) and talc (189.1 g) in acetone (9086.5 g) and water (1000.6 g) mixture at an inlet air temperature of 38°C, air volume of 32 cfm, spray rate of 8 to 18 mL/min (ramp up) and product temperature of 32-33°C. The TPR beads were dried in the unit for 5 min before discharging to sieve through Number 14 and 20 mesh sieves.

Example 4 A. Dexmethylphenidate HC1 TPR (Eudragit RSPO/L100/S100 at 2: 1 : 1) beads (drug load:

5.76%)

Polyvinylpyrrolidone (8.4 g Povidone K-30) was slowly added to purified water (559.9 g) to dissolve while stirring rigorously for 15 minutes and then dexmethylphenidate HC1_(67.4 g) was slowly added to the aqueous binder solution to dissolve while stirring for additional 10 minutes. Glatt GPCG 3 equipped with a 6" bottom spray Wurster insert, 20 mm high partition column with flush with air cap, 'C air distribution plate covered with a 100 mesh product retention screen, and 14 mm tubing for drug layering or 16 mm tubing for seal coating (peristaltic pump) was charged with 750 g of 20-25 mesh sugar spheres. The sugar spheres were layered with the dexmethylphenidate HC1 solution at an initial spray rate of 6 mL/minute, inlet air temperature of 68°C and inlet air volume 30 cfm while maintaining the product temperature at about 45°C. The flow rate was increased to 10 mL/min at an atomization air pressure of 1.25 bar and nozzle port of 1.0 mm. A protective seal coat of OPADRY CLEAR (hydroxypropylcellulose) was applied over the drug layered beads at a spray rate of 8-18 mL/min and atomization air pressure of 1.5 bar. Upon completion, the IR beads were dried in the unit for 2 minutes to drive off residual moisture and sieved through 16-25 mesh screens to discard overs and unders.

EUDRAGIT RSPO (105.1 g) was slowly added to a mixture of acetone (2802.7 g) and water (147.5 g) in a stainless steel container to dissolve while stirring with a low shear agitator for 10 minutes. Next Eudragit LlOO (52.6 g) and Eudragit SlOO (52.6 g) were added sequentially to dissolve while constantly stirring. Then tri ethyl citrate (41.8 g) was added to dissolve, and finally talc (75.7 g) was added to disperse while stirring for NLT 30 minutes and mixing the suspension continued at low speed while spraying. The preheated Glatt GPCG-3 was charged with 600 g IR beads (25-30 mesh) from step 4. A above and spray coated by spraying at an initial spray rate of 8 mL/minute; Inlet air temperature: 41°C; Airflow: 30 cfm or so to achieve adequate fluidization and dew point: about 8°C. After about 10 minutes, the spray rate was gradually increased to 18 mL/minute by adjusting flow parameters to maintain the target bed temperature of 30-31°C. Samples were pulled after different coating for dissolution testing. The TPR beads were dried in the unit for 2 minutes and discharged.

B. Dexmethylphenidate HC1 TPR (RSPO/L100/S100 at 1/0.65/0.35) beads

The preheated GPCG 3 was charged with the IR beads (850 g) from Example 3. A. above and coated with the functional polymer formulation containing EUDRAGIT RSPO (106 g), EUDRAGIT LlOO (68.8 g), EUDRAGIT SlOO (37.1 g), triethylcitrate (42.3 g) and talc (76.4 g), prepared following the procedure disclosed in Example 3. A. above at 8-18 mL/min (ramp up after about 10 min) at an inlet air temperature of 40°C, air volume of 30 cfm while maintaining the product temperature of 32°C.

FIG. 10 shows the in vitro dexmethylphenidate HCl release profiles for TPR beads coated with EUDRAGIT RSPO/EUDRAGIT LI 00 at 1/1 combined with TEC and talc, wherein different coating levels resulted in varying lag-times and extended release profiles.

FIG. 11 shows the in vitro dexmethylphenidate HCl release profiles for TPR beads coated with EUDRAGIT RSPO/EUDRAGIT LIOO/EUDRAGIT SI 00 at 2/1/1 combined with TEC and talc, wherein different coating levels resulted in varying lag-times and extended release profiles. FIG. 12 shows the in vitro dexmethylphenidate HCl release profiles for TPR beads coated with EUDRAGIT RSPO/EUDRAGIT LIOO/EUDRAGIT SI 00 at 2/1/1 combined with TEC and talc, wherein different coating levels resulted in varying lag-times and extended release profiles.

Example 5 A. ^J-Methylphenidate IR beads (20-25 mesh sugar spheres)

Polyvinylpyrrolidone (33.7 g Povidone K-30) was slowly added to purified water (1831.5 g) while stirring rigorously to dissolve the solid, and then racemic <i,/-Methylphenidate (216.0 g) was slowly added to the solution while stirring for additional 10 minutes until dissolved. Glatt GPCG 3 equipped with a 6" bottom spray Wurster insert, 18 mm high partition column with 1" gap, 'B' air distribution plate covered with a 100 mesh product retention screen, and 14 mm tubing (peristaltic pump) was charged with 1200 g of 20-25 mesh sugar spheres. The sugar spheres were layered with the drug solution while maintaining the temperature at about 44- 46°C and inlet air temperature of 70-65°C and air volume of 38 cfm. The flow rate was increased from 4 mL/min to 10 mL/min at an atomization air pressure of 1.5 bar and nozzle port of 1.0 mm. A protective seal coat of OPADRY CLEAR (hydroxypropylcellulose) (29.6 g dissolved in 462.9 g purified water) was then applied over the drug layered beads at a spray rate of 6 mL/min and at an atomization air pressure of 1.5 bar. The resulting IR beads were dried in the unit for 2 minutes to drive off residual moisture and sieved through 16-25 mesh screens.

B. ^/-Methylphenidate TPR (RSPO/L100/S100 at 1/0.75/0.25) beads

The preheated GPCG 3 was charged with the IR beads (1400 g) from Example 5. A above and coated with the functional polymer formulation from Example 4. A above containing EUDRAGIT RSPO (371.1 g), EUDRAGIT L100 (278.5 g), EUDRAGIT S100 (92.9 g), triethylcitrate (146.6 g) and talc (146.6 g) dissolved in acetone (9793.6 g) and purified water (515.5 g), at 8-18 mL/min (ramp up after about 10 min) at an inlet air temperature of 40°C, air volume of 39-33 cfm while maintaining the product temperature of 30°C. The TPR beads were dried in the unit for 3 minutes to drive off residual moisture and sieved through 14-20 mesh screens to discard overs and unders.

Example 6

A. Methylphenidate HC1 IR beads (20-25 mesh sugar spheres)

The (20-25 mesh) sugar spheres (1200.0 g) were layered with the solution of methylphenidate HC1 (216.0 g dissolved along with 33.7 g of povidone in 1831.5 g purified water) while maintaining the product temperature at about 45°C. The flow rate was increased from 4 mL/min to 18 mL/min at an atomization air pressure of 1.0 bar and nozzle port of 1.0 mm. Following completion of seal coat (as described in Ex 5. A), the spray system was rinsed with purified water for 3 minutes. B. Methylphenidate HC1 TPR (Eudragit RSPO/L100/S100 at 1 :0.75:0.25) beads

The seal coated IR beads from Example 6. A. were coated with the functional polymer formulation of EUDRAGIT RSPO (371.1 g), EUDRAGIT L100 (278.5 g), EUDRAGIT S100 (92.9 g), triethylcitrate (146.6 g) and talc (256.3 g) in acetone (9793.6 g) and water (515.5 g) mixture while maintaining the product temperature at 30°C. The flow rate was increased from 8 mL/min to 18 mL/min at an atomization air pressure of 1.0 bar and nozzle port of 1.0 mm. The TPR beads were dried in the unit for 2 min before discharging to sieve through Number 14 and 20 mesh sieves. FIG. 13 shows the in vitro methylphenidate release profile for TPR beads coated with EUDRAGIT RSPO/EUDRAGIT LIOO/EUDRAGIT SlOO at 1/0.75/0.25 combined with TEC and talc, wherein different coating levels resulted in varying lag-times and extended release profiles.

Example 7 A. Methylphenidate HC1 IR beads (20-25 mesh sugar spheres)

The (20-25 mesh) sugar spheres (3250.0 g) were layered with the solution of methylphenidate HC1 (584.9 g dissolved along with 91.3 g of povidone in 4958.8 g purified water) while maintaining the product temperature at about 45°C. The flow rate was increased from 10 mL/min to 20 mL/min at an atomization air pressure of 1.5 bar and nozzle port of 1.0 mm. Following completion of seal coat, the spray system was rinsed with purified water for 5 minutes.

B. Methylphenidate HC1 TPR (Eudragit RSPO/L100/S100 at 0.9:0.8:0.3) beads

The seal coated IR beads from Example 7. A. were coated with the functional polymer formulation of EUDRAGIT RSPO (175.2 g), EUDRAGIT L100 (155.4 g), EUDRAGIT SlOO (58.2 g), triethylcitrate (76.8 g) and talc (134.4 g) in acetone (5130.0 g) and water (270.0 g) mixture while maintaining the product temperature at 30°C. The flow rate was increased from 8 mL/min to 18 mL/min at an atomization air pressure of 1.0 bar and nozzle port of 1.0 mm. The TPR beads were dried in the unit for 2 min before discharging to sieve through Number 14 and 20 mesh sieves.

FIG. 14 shows the in vitro methylphenidate release profile for TPR beads coated with EUDRAGIT RSPO/EUDRAGIT LIOO/EUDRAGIT SlOO at 0.9/0.8/0.3 combined with TEC and talc, wherein different coating levels resulted in varying lag-times and extended release profiles.

C. Methylphenidate HC1 TPR (Eudragit RSPO/L100/S100 at 0.9:0.7:0.4) beads

The seal coated IR beads from Example 7. A. were coated with the functional polymer formulation of EUDRAGIT RSPO (179.2 g), EUDRAGIT L100 (139.4 g), EUDRAGIT SlOO (79.2 g), triethylcitrate (78.5 g) and talc (137.3 g) in acetone (5246.6 g) and water (276.1 g) mixture while maintaining the product temperature at 30°C. The flow rate was increased from 8 mL/min to 18 mL/min at an atomization air pressure of 1.0 bar and nozzle port of 1.0 mm. The TPR beads were dried in the unit for 2 min before discharging to sieve through Number 14 and 20 mesh sieves.

FIG. 15 shows the in vitro methylphenidate release profile for TPR beads coated with EUDRAGIT RSPO/EUDRAGIT LIOO/EUDRAGIT SlOO at 0.9/0.7/0.4 combined with TEC and talc, wherein different coating levels resulted in varying lag-times and extended release profiles.

D. Methylphenidate HC1 TPR (Eudragit RSPO/L100/S100 at 0.9:0.85:0.25) beads

The seal coated IR beads from Example 7. A. were coated with the functional polymer formulation of EUDRAGIT RSPO (219.0 g), EUDRAGIT L100 (206.3 g), EUDRAGIT SlOO (60.8 g), triethylcitrate (96.0 g) and talc (168.0 g) in acetone (6412.5 g) and water (337.5 g) mixture while maintaining the product temperature at 30°C. The flow rate was increased from 8 mL/min to 18 mL/min at an atomization air pressure of 1.0 bar and nozzle port of 1.0 mm. The TPR beads were dried in the unit for 2 min before discharging to sieve through Number 14 and 20 mesh sieves.

FIG. 16 shows the in vitro methylphenidate release profile for TPR beads coated with EUDRAGIT RSPO/EUDRAGIT LIOO/EUDRAGIT SlOO at 0.9/0.85/0.25 combined with TEC and talc, wherein different coating levels resulted in varying lag-times and extended release profiles.

Example 8

A. Methylphenidate HC1 IR beads (20-25 mesh sugar spheres)

The (20-25 mesh) sugar spheres (3325 g) were layered with the solution of methylphenidate HC1 (599 g dissolved along with 94 g of povidone in 6360 g purified water) while maintaining the product temperature at about 45°C. The flow rate was increased from 8 mL/min to 20 mL/min at an atomization air pressure of 1.5 bar and nozzle port of 1.0 mm. Following completion of seal coat, the spray system was rinsed with purified water for 3 minutes.

B. Methylphenidate HC1 TPR (Eudragit RSPO/L100/S100 at 1 :0.5:0.5) beads (drug load:

12.12%)

The seal coated IR beads from Example 8. A. were coated with the functional polymer formulation of EUDRAGIT RSPO (83 g), EUDRAGIT LI 00 (41 g), EUDRAGIT SlOO (41 g), tri ethyl citrate (33 g) and talc (57 g) in acetone (2181 g) and water (115 g) mixture while maintaining the product temperature at 30°C. The flow rate was increased from 8 mL/min to 18 mL/min at an atomization air pressure of 1.0 bar and nozzle port of 1.0 mm. The TPR beads were dried in the unit for 2 min before discharging to sieve through Number 18 and 20 mesh sieves.

C. Methylphenidate HC1 TPR (Eudragit RSPO/L100/S100 at 1 :0.5:0.5) beads (drug load:

10.51%)

The seal coated IR beads from Example 8. A. were coated with the functional polymer formulation of EUDRAGIT RSPO (136 g), EUDRAGIT LI 00 (68 g), EUDRAGIT SI 00 (68 g), tri ethyl citrate (54 g) and talc (94 g) in acetone (3591 g) and water (189 g) mixture while maintaining the product temperature at 30°C. The flow rate was increased from 8 mL/min to 18 mL/min at an atomization air pressure of 1.0 bar and nozzle port of 1.0 mm. The TPR beads were dried in the unit for 2 min before discharging to sieve through Number 18 and 20 mesh sieves. D. Methylphenidate HC1 TPR (Eudragit RSPO/L100/S100 at 0.9:0.7:0.4) beads (drug load:

12.12%)

The seal coated IR beads from Example 8. A. were coated with the functional polymer formulation of EUDRAGIT RSPO (74 g), EUDRAGIT LI 00 (58 g), EUDRAGIT SI 00 (33 g), tri ethyl citrate (33 g) and talc (57 g) in acetone (2180 g) and water (115 g) mixture while maintaining the product temperature at 30°C. The flow rate was increased from 8 mL/min to 18 mL/min at an atomization air pressure of 1.0 bar and nozzle port of 1.0 mm. The TPR beads were dried in the unit for 2 min before discharging to sieve through Number 18 and 20 mesh sieves.

E. Methylphenidate HC1 TPR (Eudragit RSPO/L100/S100 at 0.9:0.85:0.25) beads (drug load: 8.32%)

The seal coated IR beads from Example 8. A. were coated with the functional polymer formulation of EUDRAGIT RSPO (188 g), EUDRAGIT L100 (178 g), EUDRAGIT S100 (52 g), tri ethyl citrate (83 g) and talc (144 g) in acetone (5515 g) and water (290 g) mixture while maintaining the product temperature at 30°C. The flow rate was increased from 8 mL/min to 18 mL/min at an atomization air pressure of 1.0 bar and nozzle port of 1.0 mm. The TPR beads were dried in the unit for 2 min before discharging to sieve through Number 16 and 18 mesh sieves. Example 9

A. Capsules containing 21.42% IR beads; 25.81% TPR and 25.51% TPR beads

IR Beads from Example 8.A. (21.42%), TPR beads from Example 8.B (25.81%), and TPR beads from Example 8.C above (25.51%) were filled into Size# 2 hard gelatin capsules

(27.26%) for a total capsule weight of 100%. B. Capsules containing 20.08% IR beads; 24.19% TPR and 30.19% TPR beads

IR Beads from Example 8. A. (20.08%), TPR beads from Example 8.D (24.19%), and TPR beads from Example 8.E above (30.19%>) were filled into Size# 2 hard gelatin capsules (25.54%) for a total capsule weight of 100%>.

Example 10 A. Rapi dl y-di sper sibl e Mi cro- granul e s

The rapidly-dispersible micro-granules comprising at least a sugar alcohol such as mannitol and a disintegrant such as crospovidone are prepared following the procedure disclosed in US 8,545,881 or U.S. Patent Application Publication No. 20120282335, the contents each of which are hereby incorporated by reference in its entirety for all purposes. D-mannitol (152 kg) with an average particle size of approximately 20μπι or less (PEARLITOL 25 from Roquette, France) is blended with 8 kg of cross-linked povidone (Crospovidone XL-10 from ISP) in a high shear granulator (GMX 600 from Vector) and granulated with purified water (approximately 32 kg) and wet-milled using Comil from Quadro and tray-dried for a loss on drying of less than about 0.8%>. The dried granules were sieved and oversize material was milled to produce rapidly-dispersible micro-granules with an average particle size in the range of approximately 175-300μπι.

B. Preparation of IR beads in Commercial Scale GLATT GPCG 120 Polyvinylpyrrolidone (Povidone K-30, 1.11 kg) was slowly added to purified water USP (60.1 kg) in a stainless steel tank to dissolve while stirring rigorously at 850±25 rpm. Dexmethylphenidate HC1 (7.08 kg) was added to dissolve in the binder solution while stirring for additional 15 minutes. Glatt GPCG 120 equipped with an 18" bottom spray Wurster column (23.75" long) and 53±2 partition height, Inner "G" and Outer 'C" bottom air distribution plates covered with a 100 mesh product retention screen, 1.5 mm port nozzle, was charged with 75.4 kg of 25-30 mesh sugar spheres and the batch recipe started the drug layering at 100 g/minute and automatically adjusted the flow rates and inlet temperatures at to achieve steady state values of 100-250 g/minute (ramp up) of spray rate, inlet process air temperature of 83°C, inlet air volume of 500 CFM, air atomization pressure of 1.25 bar and dew point at 8°C while maintaining the product temperature of 44-46°C. The process parameters were recorded approximately every 30 minutes on the process parameters in-process data sheet. Following completion of the drug layering, the seal-coat solution was sprayed at 100-150 g/min (ramp-up), in-process air temperature of 75°C, air volume of 500 cfm and product temperature of 44-46°C. Upon completion of seal coat, the spray system was rinsed with 0.5 kg of purified water. Following drying of IR beads thus produced in the unit for 5 min to drive off residual moisture, the IR beads were, discharged, sieved through 18 and 30 mesh screens to discard oversized particles and fines and stored in properly labeled 30 gallon fiber drums.

C. Dexmethylphenidate HC1 TPR (EUDRAGIT RSPO/EUDRAGIT LI 00) beads EUDRAGIT RSPO (6.35 kg) was added to a mixture of acetone (190.2 kg) and purified water (10 kg) in a stainless steel tank and mixed using a low shear agitator at 250±25 rpm for LT 10 minutes (until visually dissolved). EUDRAGIT L100 (6.35 g) was mixed for NLT 10 minutes, and triethyl citrate (2.53 kg) was mixed for NLT 10 minutes. Talc 140 USP (4.57 g) was added and mixed for NLT 30 minutes and continued mixing the suspension at low speed (e.g. 200 rpm) while spraying. The Glatt GPCG 120 equipped with an 18" bottom spray Wurster column (23.75" long) and 53±2 partition height, Inner "G" and Outer 'C" bottom air distribution plates covered with a 100 mesh product retention screen, 1.5 mm port nozzle, was charged with 40.2 kg IR beads (25-30 mesh) from Example 10. B. above and via computer recipe driven spray coated at a spray rate of 200-500 g/minute (ramp-up) and steady-state values of Inlet air temperature: 47°C; Airflow: 700 cfm, dew point: 8°C, and product temperature of 32-33°C. Samples were pulled after different coating for dissolution testing. After rinsing the spray system, the TPR beads were dried in the unit for 5 minutes and then discharged, and sieved through 18 and 30 mesh sieves to discard overs and unders.

Example 11. Dissolution testing of beads prepared according to previous examples. The dissolution testing for drug release profiles is performed using USP Apparatus 1 (baskets at 100 rpm) or Apparatus 2 (paddle at 50 or 75rpm) and two-stage dissolution methodology (first 2 hours in 500 mL of 0.01N HCl at 37°C followed by dissolution testing with 500mL of pH 6.8 buffer obtained by switching dissolution media). Drug release with time is determined by HPLC on samples pulled at selected intervals. The quantitative in vitro release tests for the particles (e.g. IR, TPRi, and TPR2 beads or mini-tablets) can be performed using USP 2-stage dissolution-HPLC methodology.

The IR beads release substantially all of the Methylphenidate or the pharmaceutically acceptable salt thereof within 30 minutes following administration as measured using USP Apparatus 1 (baskets at 100 rpm) or Apparatus 2 (paddles at 50 or 75 rpm) in 500 mL of 0.01N HCl at 37°C for 30 minutes.

The TPRi beads have a lag-time of least two hours (e.g. about 2-4 hours, or about 2-6 hours) after administration before release of Methylphenidate or the pharmaceutically acceptable salt thereof as measured using USP Apparatus 1 (baskets at 100 rpm) or Apparatus 2 (paddles at 50 or 75 rpm), wherein the TPRi particles are first held for 2 hours in 500 mL of 0.01N HCl at 37°C followed by dissolution testing with 500mL of pH 6.8 buffer obtained by switching dissolution media. In some embodiments, Methylphenidate or the pharmaceutically acceptable salt thereof is released from the TPRi particles over a period from about 2-10 (e.g., about 2-8) hours following dissolution testing.

The TPR2 beads have a lag-time of least 6 hours (e.g., about 6-8 hours) after administration before release of Methylphenidate or the pharmaceutically acceptable salt thereof as measured using USP Apparatus 1 (baskets at 100 rpm) or Apparatus 2 (paddles at 50 or 75 rpm), wherein the TPR2 particles are first held for 2 hours in 500 mL of 0.01N HCl at 37°C followed by dissolution testing with 500 mL of pH 6.8 buffer obtained by switching dissolution media. In some embodiments, Methylphenidate or the pharmaceutically acceptable salt thereof is released from the TPR2 particles over a period of about 10-14 hours following dissolution testing.

Claims

is claimed is:

A pharmaceutical composition for the treatment of ADHD comprising:

c. a second population of timed, pulsatile release (TPR2) particles comprising methylphenidate or a pharmaceutically acceptable salt thereof, wherein oral administration of the composition to a patient in need thereof provides treatment of ADHD for between about 12 hours to about 16 hours.

The pharmaceutical composition of claim 1, wherein

the TPRi particles provide a lag time of from about 1 hour to about 7 hours as determined by United States Pharmacopeia (USP) apparatus two-stage dissolution methodology and the TPR2 particles provide a lag time of from about 7 hours to about 14 hours as determined by USP apparatus two-stage dissolution methodology.

The pharmaceutical composition of any one of claims 1-2, wherein:

the TPRi particles provide a lag time of from about 3 hours to about 5 hours as determined by USP apparatus two-stage dissolution methodology; and

the TPR2 particles provide a lag time of from about 7 hours to about 9 hours as determined by USP apparatus two-stage dissolution methodology.

The pharmaceutical composition of any one of claims 1-3, wherein the methylphenidate or a pharmaceutically acceptable salt thereof is selected from the group consisting of d,l- methylphenidate hydrochloride, <i-methylphenidate hydrochloride, or a mixture thereof.

The pharmaceutical composition of any one of claims 1-4, wherein the methylphenidate or a pharmaceutically acceptable salt thereof is d, /-methylphenidate hydrochloride.

6. The pharmaceutical composition of any one of claims 1-5, wherein the population of IR particles contains about 20% to about 40% by weight of the total dose of methylphenidate or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition of any one of claims 1-6, wherein the TPRi particles contain about 30% to about 60% by weight of the total dose of methylphenidate or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition of any one of claims 1-7, wherein the TPR2 particles contain about 20% to about 60% by weight of the total dose of methylphenidate or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition of any one of claims 1-8, wherein the weight ratio of methylphenidate or a pharmaceutically acceptable salt in the IR particles, TPRi particles and TPR₂ particles is about 1 : 1 : 1 (IR : TPRi : TPR2).

10. The pharmaceutical composition of any one of claims 1-8, wherein the weight ratio of methylphenidate or a pharmaceutically acceptable salt in the IR particles, TPRi particles and TPR₂ particles is about 1 : 1 : 2 (IR : TPRi : TPR2).

11. The pharmaceutical composition of any one of claims 1-8, wherein the weight ratio of methylphenidate or a pharmaceutically acceptable salt in the IR particles, TPRi particles and TPR₂ particles is about 3 : 5 : 2 (IR : TPRi : TPR2).

12. The pharmaceutical composition of any one of claims 1-11, wherein at least about 90% of the methylphenidate or a pharmaceutically acceptable salt thereof in the IR population is released within about 30 minutes as determined by United States Pharmacopeia (USP) apparatus two-stage dissolution methodology.

13. The pharmaceutical composition of any one of claims 1-12, wherein at least about 90% of the methylphenidate or a pharmaceutically acceptable salt thereof in the TPRi population is released over a period of about 30 minutes to about 4 hours following the lag time as determined by USP apparatus two-stage dissolution methodology.

14. The pharmaceutical composition of any one of claims 1-13, wherein at least about 90% of the methylphenidate or a pharmaceutically acceptable salt thereof in the TPR2 population is released over a period of about 1 hour to about 5 hours following the lag-time as determined by USP apparatus two-stage dissolution methodology.

15. The pharmaceutical composition of any one of claims 1-14, wherein at least about 90% of the methylphenidate or a pharmaceutically acceptable salt thereof in the TPRi population is released over a period of about 30 minutes to about 2 hours following the lag time as determined by USP apparatus two-stage dissolution methodology.

16. The pharmaceutical composition of any one of claims 1-15, wherein at least about 90% of the methylphenidate or a pharmaceutically acceptable salt thereof in the TPR2 population is released over a period of about 1 hour to about 4 hours following the lag-time as determined by USP apparatus two-stage dissolution methodology.

17. The pharmaceutical composition of any one of claims 1-16, wherein upon oral administration to a patient in need thereof the composition provides a plasma concentration of methylphenidate that is at least about 3.5 ng/mL or more for at least about 12 hours to about 16 hours following the administration.

18. The pharmaceutical composition of any one of claims 1-17, wherein upon oral administration to a patient in need thereof the composition provides a mean steady state blood plasma AUC (0-24) hours of methylphenidate from about 25 ng*h/ml to about 350 ng*h/ml.

19. The pharmaceutical composition of any one of claims 1-18, wherein upon oral administration to a patient in need thereof the composition provides a steady state blood plasma Cmax of methylphenidate that does not exceed 25 ng/ml.

20. The pharmaceutical composition of any one of claims 1-19, wherein upon oral administration to a patient in need thereof the composition provides a steady state blood plasma Cmin that is not less than about 3.5 ng/ml of methylphenidate for at least about 12 hours to about 16 hours following the administration.

21. The pharmaceutical composition of any one of claims 1-20, wherein the steady state blood plasma Cmaxl and steady state blood plasma Cmax2 are substantially equivalent.

22. The pharmaceutical composition of any one of claims 1-21, wherein the steady state blood plasma Cmax3 is at least 50% of Cmaxi.

23. The pharmaceutical composition of claim 22, wherein Cmaxi and Cmax3 are substantially equivalent.

24. The pharmaceutical composition of any one of claims 1-23, wherein the IR particles comprise methylphenidate or a pharmaceutically acceptable salt thereof as a layer onto the outer surface of an inert core.

25. The pharmaceutical composition of claim 24, wherein the IR particles further comprise a polymeric binder.

26. The pharmaceutical composition of any one of claims 24 or 25, wherein the inert core is selected from sugar spheres or microcrystalline cellulose spheres.

27. The pharmaceutical composition of any one of claims 24-26, wherein the average particle size of the inert core ranges from about 20 μιη to about 300 μιη.

28. The pharmaceutical composition of any one of claims 1-27, wherein the IR particles comprise a binder selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (hypromellose), povidone, polyethylene glycol, or a mixture thereof.

29. The pharmaceutical composition of any one of claims 1-28, wherein at least one population of particles further comprise a seal coating layer.

30. The pharmaceutical composition of claim 29, wherein the seal coating layer comprises one or more hydrophilic polymers.

31. The pharmaceutical composition of any one of claims 1-30, wherein the TPRi and TPR2 particles comprise an IR particle coated with a TPR coating.

32. The pharmaceutical composition of claim 31, wherein the TPR coating comprises one or more pharmaceutically acceptable water insoluble polymers and one or more pharmaceutically acceptable enteric polymers.

33. The pharmaceutical composition of claim 32, wherein the weight ratio of the pharmaceutically acceptable water insoluble polymer to the pharmaceutically acceptable enteric polymer is from about 85: 15 to about 35:65.

34. The pharmaceutical composition of claim 33, wherein the ratio of the pharmaceutically acceptable water insoluble polymer to the pharmaceutically acceptable enteric polymer on the TPRi particle is from about 65:35 to about 50:50.

35. The pharmaceutical composition of claim 33 or 34, wherein the TPR coating is present at a weight gain of from about 5% to about 20%.

36. The pharmaceutical composition of 33, wherein the ratio of the water insoluble polymer to the enteric polymer in the TPR2 particle is from about 75:25 to about 55:45.

37. The pharmaceutical composition of any of claims 33 or 36, wherein the TPR coating is present at a weight gain of 15% to about 50%.

38. The pharmaceutical composition of any one of claims 31-37, further comprising a barrier coating disposed over the IR particle, wherein the barrier coating comprises (i) a pharmaceutically acceptable water-insoluble polymer, (ii) a pharmaceutically acceptable enteric polymer, or (iii) a pharmaceutically acceptable water-insoluble polymer and a pharmaceutically acceptable water-soluble polymer.

39. The pharmaceutical composition of any one of claims 32-38, wherein the water-insoluble polymer is selected from the group consisting of polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate latex, ethyl cellulose, methacrylic acid/methylmethacrylate copolymers, and mixtures thereof.

40. The pharmaceutical composition of any one of claims 32-39, wherein the enteric polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, pH-sensitive methacrylic acid/methylmethacrylate copolymers, hydroxypropyl methylcellulose acetate succinate, and mixtures thereof.

41. The pharmaceutical composition of any one of claims 36-40, wherein the water-soluble polymer is selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (hypromellose), povidone, polyethylene glycol or mixtures thereof.

42. The pharmaceutical composition of any one of claims 31-41, wherein the TPR coating further comprises a plasticizer selected from the group consisting of triethyl citrate, triacetin, substituted glycerides, glyceryl monostearate, diethyl phthalate, triethyl citrate, dibutyl sebacate, acetyltributyl citrate, polyethylene glycols, and vegetable oils.

43. The pharmaceutical composition of any one of claims 36-42, wherein the barrier coating further comprises a plasticizer selected from the group consisting of triethyl citrate, triacetin, substituted glycerides, glyceryl monostearate, diethyl phthalate, triethyl citrate, dibutyl sebacate, acetyltributyl citrate, polyethylene glycols, and vegetable oils.

44. The pharmaceutical composition of any one of claims 31-43, wherein, in the TPR coating, the water insoluble polymer is ethylcellulose, the enteric polymer is hypromellose phthalate, and the plasticizer is diethyl phthalate or triethyl citrate.

45. The pharmaceutical composition of any one of claims 31-38, wherein the water insoluble polymer is an ammonio methacrylate copolymer, or a mixture thereof, and the enteric polymer is a mixture of pH-sensitive methacrylic acid/methylmethacrylate copolymers.

46. The pharmaceutical composition of any one of claims 1-45, wherein the composition comprises about 5 mg to about 125 mg of methylphenidate or a pharmaceutically acceptable salt thereof.

47. The pharmaceutical composition of claims 29 or 30, wherein the IR particles are coated with the seal coat.

48. The pharmaceutical composition of any one of claims 1-47, wherein the composition is a capsule.

49. A method of treating ADHD in a subject in need thereof, comprising orally administering a pharmaceutical composition of any one of claims 1-48.

50. The method of claim 49, wherein the composition is administered in the morning.

51. The method of any one of claims 49 or 50, wherein after said administering, the patient experiences a substantial reduction in ADHD compared to prior to said administering.

52. The method of claim 51, wherein after said administering, the patient experiences a reduction of ADHD that is characterized by an at least two point decline in DSM-IV Attention-Deficit/Hyperactivity Disorder Rating (DSM-IV ADHD) Scale value.

53. The method of claim 52, wherein after said administering, the patient experiences a reduction of ADHD that is characterized by an at least 20% reduction in DSM-IV ADHD Scale value.

54. The method of claim 52, wherein after said administering, the patient experiences a reduction of ADHD that is characterized by an at least two point decline in Adult Self- Report Scale (ASRS vl . l) for ADHD Scale value.

55. The method of claim 52, wherein after said administering, the patient experiences a reduction of ADHD that is characterized by an at least 20% reduction in DSM-V ADHD Scale value.

56. The method of claim 52, wherein after said administering, the patient experiences a reduction of ADHD that is characterized by an at least two point decline in Swanson, Kotkin, Agler, M-Flynn, and Pelham Rating Scale (SKAMP) value.

57. The method of claim 52, wherein after said administering, the patient experiences a reduction of ADHD that is characterized by an at least 20% reduction in SKAMP Scale value.

58. The method of claim 52, wherein after said administering, the patient experiences a reduction of ADHD that is characterized by an at least two point decline in Daily Parent Rating of Evening and Morning Behavior, Revised (PREMB-R) value.

59. The method of claim 52, wherein after said administering, the patient experiences a reduction of ADHD that is characterized by an at least 20% reduction in PREMB-R value.

60. The method of claim 52, wherein after said administering, the patient experiences a reduction of ADHD that is characterized by an at least one point decline in Before School Functioning Questionnaire (BSFQ) value.

61. The method of any one of claims 51-60, wherein after said administering, the patient experiences a substantial reduction of ADHD and does not experience a substantial increase in insomnia compared to prior to said administering.

62. The method of claim 61, wherein after said administering, the patient experiences an increase in Insomnia Severity Index scale value of not more than one point compared to prior to said administering.

63. The method of claim 61, wherein after said administering, the patient experiences an increase in Global Pittsburgh Sleep Quality Index of not more than one point compared to prior to said administering.

64. The method of claim 61, wherein after said administering, the patient experiences an increase in Epworth Sleepiness Scale of not more than one point compared to prior to said administering.

65. The method of claim 61, wherein after said administering, the patient does not experience an increase in Dysfunctional Beliefs and Attitudes about Sleep-16 (DBAS-16) of more than 1 point compared to prior to said administering.

66. The method of any one of claims 51-60, wherein after said administering, the patient experiences a substantial reduction of ADHD and does not experience a substantial reduction in appetite compared to prior to said administering.

67. The method of claim 66, wherein after said administering, the patient does not experience a decrease in Council on Nutrition appetite questionnaire (CNAQ) scale value of more than 1 point compared to prior to said administering.

68. The method of claim 66, wherein after said administering, the patient does not experience a decrease in simplified nutritional appetite questionnaire (SNAQ) scale value of more than 1 point compared to prior to said administering

69. The method of claim 66, wherein after said administering, the patient does not experience a decrease in body weight of more than about 5% compared to prior to said administering.

70. The method of claim 66, wherein after said administering, the patient does not experience a decrease in appetite hunger and sensory perception questionnaire (AHSP) scale value of more than about 20% compared to prior to said administering.

71. The method of claim 66, wherein after said administering, the patient does not experience a decrease in appetite hunger and sensory perception questionnaire (AHSP) scale value of more than about two points compared to prior to said administering.

72. The pharmaceutical composition of claim 1, wherein the composition is orally administered once a day.

73. The pharmaceutical composition of any one of claims 1-45, 47, and 72, wherein the composition comprises about 5 mg to about 200 mg of methylphenidate or a pharmaceutically acceptable salt thereof.

74. Methylphenidate for use in treating ADHD, comprising administering the pharmaceutical composition of any one of claims 1-48, 72, and 73 to a subject in need thereof.

75. The pharmaceutical composition for use according to claim 74, wherein the subject experiences a substantial reduction in ADHD compared to prior to said administering, as measured according to claims 52-71.

76. The pharmaceutical composition for use according to claim 74 or claim 75, wherein the composition is administered in the morning.