WO2019071272A1 - Compositions pharmaceutiques pour le traitement du trouble du déficit de l'attention avec hyperactivité (tdah) - Google Patents

Compositions pharmaceutiques pour le traitement du trouble du déficit de l'attention avec hyperactivité (tdah) Download PDF

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Publication number
WO2019071272A1
WO2019071272A1 PCT/US2018/055018 US2018055018W WO2019071272A1 WO 2019071272 A1 WO2019071272 A1 WO 2019071272A1 US 2018055018 W US2018055018 W US 2018055018W WO 2019071272 A1 WO2019071272 A1 WO 2019071272A1
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Prior art keywords
pharmaceutical composition
methylphenidate
administering
pharmaceutically acceptable
particles
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PCT/US2018/055018
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English (en)
Inventor
Gopi M. Venkatesh
Ana C. FERREIRA ARROYO
Chinmay Maheshwari
Peng Guo
Jin-Wang Lai
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Adare Pharmaceuticals, Inc.
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Publication of WO2019071272A1 publication Critical patent/WO2019071272A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine

Definitions

  • 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.
  • 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.
  • This invention relates to an oral pharmaceutical composition
  • 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.
  • the present disclosure provides a pharmaceutical composition for the treatment of ADHD comprising:
  • IR immediate release
  • TPRi timed, pulsatile release particles comprising methylphenidate or a pharmaceutically acceptable salt thereof
  • TPR2 timed, pulsatile release particles comprising methylphenidate or a pharmaceutically acceptable salt thereof
  • oral administration of the composition to a patient in need thereof provides treatment of ADHD for between about 16 hours to about 24 hours.
  • 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.
  • 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.
  • the IR particles comprise methylphenidate or a pharmaceutically acceptable salt thereof as a layer onto the outer surface of an inert core.
  • the inert core is selected from sugar spheres or microcrystalline cellulose spheres.
  • the average particle size of the inert core ranges from about 20 ⁇ to about 300 ⁇ .
  • the IR particles further comprise a polymeric binder.
  • the IR particles comprise a binder selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (hypromellose), povidone, polyethylene glycol, or a mixture thereof.
  • 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).
  • the TPRi and TPR2 particles comprise an IR particle coated with a TPR coating.
  • at least one population of particles further comprise a seal coating layer.
  • the seal coating layer comprises one or more hydrophilic polymers.
  • the IR particles are coated with the seal coat.
  • the TPR coating comprises one or more pharmaceutically acceptable water insoluble polymers and one or more pharmaceutically acceptable enteric polymers.
  • 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.
  • 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%.
  • 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).
  • the water insoluble polymer is ethylcellulose
  • the enteric polymer is hypromellose phthalate
  • the plasticizer is diethyl phthalate or triethyl citrate.
  • the water insoluble polymer is ammonio methacrylate copolymer (EUDRAGIT RSPO) or a mixture thereof
  • the enteric polymer is a mixture of pH-sensitive methacrylic acid/methylmethacrylate copolymers.
  • the pH-sensitive methacrylic acid/methylmethacrylate copolymer is anionic.
  • 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.
  • 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.
  • EUDRAGIT ® RS and RL polymers and their dispersions EUDRAGIT ® RS30D and EUDRAGIT ® RL30D, EUDRAGIT RSPO
  • EUDRAGIT ® E30D AQUACOAT ®
  • SURELEASE ®
  • 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.
  • AQUASOLVE HPMC-AS HPMC-AS LG, HPMC-AS MG, HPMC-AS HG
  • the water-soluble polymer is selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (hypromellose), povidone, polyethylene glycol or mixtures thereof.
  • 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).
  • 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).
  • 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.
  • 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.
  • 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 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 composition upon oral administration to a patient in need thereof 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.
  • 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.
  • the composition is administered in the morning.
  • the patient experiences a substantial reduction in ADHD compared to prior to said administering.
  • the subject experiences a substantial reduction in ADHD compared to prior to 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.
  • DSM-IV ADHD Attention-Deficit/Hyperactivity Disorder Rating
  • 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.
  • ASRS vl . l Adult Self-Report Scale
  • SKAMP Pelham Rating Scale
  • 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.
  • BSFQ Before School Functioning Questionnaire
  • the patient experiences a substantial reduction of ADHD and does not experience a substantial increase in insomnia compared to prior to 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.
  • the patient experiences an increase in Global Pittsburgh Sleep Quality Index of not more than one point compared to prior to said administering.
  • the patient experiences an increase in Epworth Sleepiness Scale of not more than one point compared to prior to 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.
  • DBAS-16 Dysfunctional Beliefs and Attitudes about Sleep-16
  • the patient experiences a substantial reduction of ADHD and does not experience a substantial reduction in appetite compared to prior to 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.
  • CNAQ Council on Nutrition appetite questionnaire
  • SNAQ simplified nutritional appetite questionnaire
  • the patient does not experience a decrease in body weight of more than about 5% compared to prior to 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.
  • AHSP appetite hunger and sensory perception questionnaire
  • 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. 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 + TPR 4 -hr,i-hr + TPR 8 -hr,i-hr] beads, [IR + TPR 4 -hr,i-hr + TPR 8- hr,3-hr] beads, and [IR + TPR 4-h r, 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 ' ⁇ ', 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 TPR 2 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 TPR 2 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 + TPR 2 (8,2) 5mg; MER-B: IR(0,0.5) 5mg + TPRi(5,4) 5mg + TPR 2 (9,4) 5mg; and MER-C: IR(0,0.5) 4mg + TPRi(5,2) 4mg + TPR 2 (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.
  • EUDRAGIT RSPO water- insoluble Ammonio Methacrylate Copolymer
  • EUDRAGIT LI 00 enteric methacrylic acid copolymer
  • 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. 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a water-soluble polymer includes a mixture of one or more water-soluble polymers.
  • the amount of coatings or layers described herein is expressed as the percentage weight gain provided by the coating, relative to the initial weight of the particles or beads prior to coating.
  • a 10% coating weight refers to a coating, which increases the weight of a particle or bead by 10%.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Gastric juice i.e. relatively insoluble at the low pH levels found in the stomach
  • Foreign 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.
  • an "immediate release” refers to a component that releases at least about 90% (e.g.
  • 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).
  • USP United States Pharmacopeia
  • 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.
  • Methods of methylphenidate 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).
  • drug micro-particulates or “drug micro-particles” refer to drug particles with particle size in the micrometer range.
  • 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.
  • “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.
  • 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.
  • the amount of coatings or layers described herein is expressed as the percentage weight gain provided by the coating, relative to the initial weight of the particles or beads prior to coating.
  • a 10% coating weight refers to a coating which increases the weight of a particle or bead by 10%.
  • the present disclosure provides a pharmaceutical composition
  • 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.
  • the composition is orally administered once a day.
  • the composition is orally administered once a day in morning.
  • 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 methylphenidate or a pharmaceutically acceptable salt thereof is d,l- methylphenidate hydrochloride.
  • the methylphenidate or a pharmaceutically acceptable salt thereof is dex-methylphenidate hydrochloride.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical composition of the present disclosure is a capsule, an orally disintegrating tablet, or a hot melt extruded or spray-congealed composition.
  • 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.
  • pharmaceutically acceptable water-soluble polymers e.g., as hypromellose, hydroxypropylcellulose, and polyvinylpyrrolidon
  • pH-sensitive methacrylic acid/methylmethacrylate copolymers such as EUDRAGIT LI 00 polymer, and EUDRAGIT SI 00 polymer
  • EUDRAGIT LI 00 polymer pH-sensitive methacrylic acid/methylmethacrylate copolymers
  • EUDRAGIT SI 00 pH-sensitive methacrylic acid/methylmethacrylate copolymers
  • 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).
  • 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.
  • 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.
  • 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.
  • the population of IR particles comprises about 20% to about 30%) by weight of the total dose of methylphenidate or pharmaceutically acceptable salt thereof.
  • the population of IR particles comprises about 30% to about 40% by weight of the total dose of methylphenidate or pharmaceutically acceptable salt thereof.
  • the IR particles comprise methylphenidate (MPH)-containing particles in the form of crystals, beads, pellets or mini-tablets.
  • the beads are sugar spheres or microcrystalline cellulose spheres layered with MPH and optionally a polymeric binder.
  • the IR particles comprise methylphenidate or a pharmaceutically acceptable salt thereof as a layer onto the outer surface of an inert core.
  • the average particle size of the inert core ranges from about 20 ⁇ to about 300 ⁇ (e.g., about 20 ⁇ , about 50 ⁇ , about 100 ⁇ , about 150 ⁇ , about 200 ⁇ , about 250 ⁇ , or about 300 ⁇ , inclusive of all values and subranges therebetween).
  • the IR particles further comprise a polymeric binder.
  • polymeric binders include cellulose derivatives such as methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyethylene glycol, and the like.
  • the IR particles comprise a binder selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (hypromellose), povidone, polyethylene glycol, or a mixture thereof.
  • 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.
  • 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.
  • TPR particles having the desired lag-time 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the drug load in TPR2 is higher than in TPRi, i.e., greater than a weight ratio of about 1:1.
  • 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.
  • 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.
  • 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.
  • the TPR coating comprises a combination of water-insoluble polymers (as described herein) and enteric polymers (as described herein).
  • the TPR coating is present as a layer containing a mixture of water-insoluble polymers and enteric polymers.
  • 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.
  • the TPR coating comprises one or more water-insoluble polymers and one or more enteric polymers.
  • 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.
  • 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.
  • 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.
  • 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.
  • the ratio of the water-insoluble polymer to the enteric polymer is from about 7:3 to about 1 : 1.
  • the ratio is from about 7:3 to about 6:4, inclusive of all ranges and values therebetween.
  • the ratio is from about 1 : 1 to about 2:3, inclusive of all ranges and values therebetween.
  • 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.
  • 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).
  • 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.
  • the coating weight is from about 5% to about 20%). In other embodiments, the coating weight is from about 10% to about 25%.
  • the coating weight is from about 20% to about 30%.
  • 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.
  • the coating weight of the TPR2 coating is from about 20% to about 50%).
  • the coating weight is from about 20% to about 35%.
  • 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.
  • 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).
  • the pH-sensitive methacrylic acid/methylmethacrylate copolymer is anionic.
  • 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.
  • 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.
  • 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.
  • plasticizer ranges 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.
  • the plasticizer range is from about 3% to about 20% by weight of the total coating weight.
  • the plasticizer range is from about 3%) to about 5% by weight of the total coating weight.
  • 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.
  • 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.
  • 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).
  • 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.
  • the water-insoluble polymer is ethylcellulose
  • the enteric polymer is hypromellose phthalate
  • the plasticizer is diethyl phthalate or triethyl citrate.
  • the present disclosure provides a pharmaceutical composition
  • 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.
  • 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%.
  • compositions disclosed herein can be orally administered once a day. In some embodiments, the composition is orally administered once a day in morning.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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%>.
  • tri ethyl citrate may conveniently be used as a plasticizer in an amount of about 10-15%) by weight of the total coating weight.
  • 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.
  • an immediate release particle population 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.
  • the present disclosure describes a pharmaceutical composition
  • 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
  • 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.
  • At least one population of particles further comprises a seal coating layer.
  • the IR particles are coated with a seal coating layer.
  • the seal coating layer comprises one or more pharmaceutically acceptable hydrophilic polymers.
  • 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.
  • 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).
  • SR sustained release
  • 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.
  • 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.
  • EUDRAGIT ® RS and RL polymers and their dispersions EUDRAGIT ® RS30D and EUDRAGIT ® RL30D, EUDRAGIT RSPO
  • EUDRAGIT ® E30D AQUACOAT ®
  • SURELEASE ® KOLL
  • 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.
  • AQUASOLVE HPMC-AS HPMC-AS LG, HPMC-AS MG, HPMC-AS HG
  • 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).
  • the water-soluble polymer is selected from the group consisting of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose (hypromellose), povidone, polyethylene glycol or mixtures thereof.
  • 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.
  • 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.
  • 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%
  • Lag-time and Release Profiles 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.
  • TID thrice-daily dosing
  • the timing of drug release and lag-times are designed to maintain therapeutically effective blood plasma concentrations of methylphenidate.
  • 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.
  • 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.
  • USP United States Pharmacopeia
  • 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.
  • 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.
  • 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.
  • 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.
  • USP United States Pharmacopeia
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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
  • 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.
  • 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
  • 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.
  • 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
  • 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
  • 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.
  • complete release is over about 0.5 h to about 6 h.
  • complete release is over about 2 h to about 10 h.
  • complete release is over about 2 h to about 8 h.
  • complete release is over about 1 h to about 4 h.
  • 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.
  • complete release is over about 2 h to about 10 h.
  • complete release is over about 2 h to about 8 h.
  • complete release is over about 2 h to about 10 h.
  • complete release is over about 2 h to about 8 h.
  • complete release is over about 1 h to about 4 h.
  • 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.
  • 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).
  • USP United States Pharmacopeia
  • 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.
  • EUDRAGIT ® RS and RL polymers and their dispersions EUDRAGIT ® RS30D and EUDRAGIT ® RL30D, EUDRAGIT RSPO
  • EUDRAGIT ® E30D AQUACOAT ®
  • SURELEASE ® KOLLICOAT
  • 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;
  • inert particles such as sugar spheres or cellulose spheres
  • 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.
  • ODT orally disintegrating tablet
  • 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 1500TM from Colorcon) and having an average particle size in the range of approximately 50-200 ⁇ , 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.
  • pregelatinized starch STARCH 1500TM from Colorcon
  • 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.
  • RDMs microgranules
  • 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.
  • a lubricant such as sodium stearyl fumarate (0.5-1.5% by weight)
  • 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.
  • 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.
  • 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.
  • the pharmaceutical composition upon oral administration of from about 5-125 mg of methylphenidate or a pharmaceutically acceptable salt thereof 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.
  • 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
  • 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 4
  • the composition 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.
  • the pharmaceutical composition 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.
  • the composition 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.
  • ng/mL about 3.5 ng/mL, about 4 ng/mL, about 4.5 ng/mL, about 5 ng/mL, about 5.5 ng/mL, about 6 ng/mL, about 6.5 ng/mL, about 7 ng/mL, about 7.5 ng/mL, about 8 ng/mL, about 8.5 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
  • the composition 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.
  • the pharmaceutical compositions of the present disclosure provide a blood plasma profile that is bioequivalent to that of FOQUEST ® .
  • 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).
  • 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 ® .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ® .
  • 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/
  • 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
  • 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
  • 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.
  • the T1/2- eiim is about 1 h. In other specific embodiments, the ⁇ /2-eiim is about 1.5 h. In other specific embodiments, the ⁇ /2-eiim is about 2 h. In other specific embodiments, the ⁇ /2-eiim is about 2.5 h. In other specific embodiments, the ⁇ /2-eiim is about 3 h. In other specific embodiments, the T1/2- eiim is about 3.5 h. In other specific embodiments, the ⁇ /2-eiim is about 4 h. In other specific embodiments, the ⁇ /2-eiim is about 4.5 h. In other specific embodiments, the ⁇ /2-eiim is about 5 h.
  • the ⁇ /2-eiim is about 5.5 h. In other specific embodiments, the T1/2- eiim is about 6 h. In other specific embodiments, the ⁇ /2-eiim is about 6.5 h. In other specific embodiments, the ⁇ /2-eiim is about 7 h. In other specific embodiments, the ⁇ /2-eiim is about 7.5 h. In other specific embodiments, the ⁇ /2-eiim is about 8 h. In other specific embodiments, the T1/2- eiim is about 8.5 h. In other specific embodiments, the ⁇ /2-eiim is about 9 h. In other specific embodiments, the ⁇ /2-eiim is about 9.5 h. In other specific embodiments, the ⁇ /2-eiim is about 10 h. In other specific embodiments, the ⁇ /2-eiim is about 10.5 h. In other specific embodiments, the T1/2- elim IS about 11 h.
  • 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.
  • Tmax maximum concentration
  • 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.
  • 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).
  • 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 ® .
  • 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.
  • 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,
  • 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
  • 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 ® .
  • 50% of a 100 mg dose i.e., 50 mg dose
  • 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
  • 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).
  • 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 3.7
  • 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
  • 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/m
  • 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 ⁇ . ⁇ !
  • 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. ⁇ !
  • 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 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. ⁇ ! 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 !
  • 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
  • Cmax maximum blood plasma concentration
  • 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
  • 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.
  • 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 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.
  • 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
  • 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.
  • each pulse can be considered to provide a Cmax.
  • Cmaxi is associated with the IR particles
  • Cmax2 is associated with the TPRi particles
  • Cmax3 is associated with the TPR3 particles.
  • the steady state blood plasma Cmaxi and the steady state blood plasma Cmax2 are substantially equivalent.
  • 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 7
  • the steady state blood plasma Cmax2 and steady state blood plasma Cmax3 are substantially equivalent.
  • 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%
  • 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
  • the steady state blood plasma Cmaxi and the steady state blood plasma Cmax3 are substantially equivalent.
  • 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
  • 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.
  • the present disclosure provides a method of treating ADHD in a subject in need thereof, comprising orally administering a pharmaceutical composition as disclosed herein.
  • 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.
  • a patient experiences a reduction in ADHD characterized by a decline in points or a percent reduction in scale value.
  • 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.
  • DSM-IV Attention-Deficit/Hyperactivity Disorder Rating
  • DSM-IV ADHD DSM-IV Attention-Deficit/Hyperactivity Disorder Rating
  • 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.
  • 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.
  • 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.
  • 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.
  • the patient experiences a reduction of ADHD that is characterized by an at least 20% reduction in DSM-V ADHD Scale value.
  • SKAMP Pelham Rating Scale
  • 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.
  • 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.
  • SKAMP Pelham Rating Scale
  • 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.
  • 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.
  • 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.
  • 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).
  • the patient experiences a reduction of ADHD that is characterized by an at least two point decline in Before School Functioning Questionnaire (BSFQ).
  • 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).
  • BSFQ Before School Functioning Questionnaire
  • 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.
  • prior to administering refers to a previous day in which the patient was not administered the present pharmaceutical compositions.
  • 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.
  • 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.
  • the Pittsburgh Sleep Quality Index 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.
  • 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 is also useful for determining the extent of insomnia upon treatment of ADHD with the presently disclosed compositions.
  • 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.
  • the patient 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.
  • 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.
  • 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.
  • 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.
  • the patient 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.
  • 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.
  • CNAQ Council on Nutrition appetite questionnaire
  • 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.
  • the pharmaceutical compositions disclosed herein provide a scope of greater than 28.
  • 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.
  • SNAQ simplified nutritional appetite questionnaire
  • 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.
  • the pharmaceutical compositions disclosed herein provide a scope of greater than 14.
  • AHSP appetite hunger and sensory perception questionnaire
  • 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.
  • AHSP appetite hunger and sensory perception questionnaire
  • 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.
  • AHSP appetite hunger and sensory perception questionnaire
  • 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).
  • a patient receiving treatment is able to maintain body weight.
  • 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.
  • the patient does not experience a decrease in body weight of more than about 5% compared to prior to said administering.
  • compositions and dosage forms of the present invention 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.
  • Pharmacokinetic/biopharmaceutical modeling and simulation was performed using GastroPlusTM (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).
  • 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).
  • 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
  • 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.
  • 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.
  • 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 + TPR 2 (8,2) 5mg], MER- B [IR(0,0.5) 5mg + TPRi(5,4) 5mg + TPR 2 (9,4) 5mg] and MER-C [IR(0,0.5) 4mg + TPRi(5,2) 4mg + TPR 2 (10,3) 7mg].
  • Table 4 summarizes the PK data for MER-A, MER-B, MER-C, and Concerta ® presented in FIG. 8.
  • 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.
  • 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.
  • 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.
  • 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.
  • TEC tri ethyl citrate
  • a Glatt GPCG 3 equipped with a 6" bottom spray Wurster 6" insert, ' ⁇ " 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 m 3 /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.
  • analytical testing i.e., HPLC assay and drug release
  • Example 2 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
  • Example 2. A. above 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.
  • analytical testing i.e., HPLC assay and drug release
  • 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%.
  • Dexmethylphenidate HCl IR beads drug load: 15%
  • Dexmethylphenidate HCl TPRi beads and either Dexmethylphenidate HCl TPRi beads or Dexmethylphenidate HCl TPR2 beads
  • 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).
  • 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.
  • 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
  • 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.
  • 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.
  • the spray system was rinsed with purified water for 3 minutes.
  • 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 Dexmethylphenidate HC1 TPR (Eudragit RSPO/L100/S100 at 2: 1 : 1) beads (drug load:
  • 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.
  • 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.
  • Eudragit LlOO (52.6 g)
  • Eudragit SlOO (52.6 g) were added sequentially to dissolve while constantly stirring.
  • 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.
  • 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.
  • the preheated GPCG 3 was charged with the IR beads (850 g) from Example 3.
  • 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.
  • the preheated GPCG 3 was charged with the IR beads (1400 g) from Example 5.
  • 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.
  • 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.
  • the spray system was rinsed with purified water for 3 minutes.
  • Methylphenidate HC1 TPR (Eudragit RSPO/L100/S100 at 1 :0.75:0.25) beads
  • the seal coated IR beads from Example 6. 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.
  • Example 7 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.
  • the spray system was rinsed with purified water for 5 minutes.
  • 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.
  • 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.
  • 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.
  • 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.
  • the spray system was rinsed with purified water for 3 minutes.
  • Methylphenidate HC1 TPR (Eudragit RSPO/L100/S100 at 1 :0.5:0.5) beads (drug load:
  • 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.
  • Methylphenidate HC1 TPR (Eudragit RSPO/L100/S100 at 1 :0.5:0.5) beads (drug load:
  • 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:
  • 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.
  • 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.
  • 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%>.
  • 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 20 ⁇ 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 175-300 ⁇ .
  • 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.
  • 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.
  • the spray system was rinsed with 0.5 kg of purified water.
  • 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.
  • EUDRAGIT RSPO 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.
  • 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
  • USP 2-stage dissolution-HPLC methodology 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.
  • 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.
  • Methylphenidate or the pharmaceutically acceptable salt thereof is released from the TPR2 particles over a period of about 10-14 hours following dissolution testing.

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Abstract

La présente invention concerne une composition pharmaceutique à libération prolongée pour une administration orale une fois par jour pour le traitement du TDAH, caractérisée par une libération pulsatile triphasique de méthylphénidate ou d'un sel pharmaceutiquement acceptable de celui-ci. La composition fournit un début d'action rapide lors d'une administration orale et maintient des concentrations de plasma appropriées pour maintenir l'efficacité tout en atténuant le potentiel pour des effets secondaires tels que l'insomnie et la suppression de l'appétit.
PCT/US2018/055018 2017-10-06 2018-10-09 Compositions pharmaceutiques pour le traitement du trouble du déficit de l'attention avec hyperactivité (tdah) WO2019071272A1 (fr)

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WO2022152863A1 (fr) * 2021-01-15 2022-07-21 Galventa Gmbh Formulation de caféine à libération pulsatile

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WO2020115709A1 (fr) * 2018-12-06 2020-06-11 Flamel Ireland Limited Composition pharmaceutique à libération modifiée
WO2022152863A1 (fr) * 2021-01-15 2022-07-21 Galventa Gmbh Formulation de caféine à libération pulsatile

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