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1. WO2020115709 - MODIFIED RELEASE PHARMACEUTICAL COMPOSITION

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

MODIFIED RELEASE PHARMACEUTICAL COMPOSITION

FIELD

[0001 ] The present disclosure generally relates to orally disintegrating or chewable pharmaceutical compositions comprising a bi-modal, mutiparticulate mixture of immediate release particles and modified release particles that provide a therapeutic effect over extended periods of time.

BACKGROUND

[0002] Extended release formulations of dexmethylphenidate HCI ( e.g ., FOCALIN® XR) are indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in patients aged 6 years and older. FOCALIN® XR utilizes a multiparticulate drug delivery system containing immediate release particles and modified release particles to deliver dexmethylphenidate HCI in a pulsatile manner. However, FOCALIN® XR capsules are large and either may be difficult for children to swallow or must be opened properly and sprinkled on food. In addition, the coating used in FOCALIN® XR isn’t compatible with tableting and the particle size is too large for palatability, creating undesirable organoleptic properties (e.g. an undesirable mouth feel that may be gritty/grainy).

[0003] Thus, there is a need for an alternate formulation of

dexmethylphenidate (e.g., dexmethylphenidate HCI) that provides effective treatment of ADHD for patients.

SUMMARY

[0004] One aspect of the present disclosure encompasses a

pharmaceutical composition including a multiparticulate mixture of immediate release particles and modified release particles for the delivery of an active ingredient in a pulsatile manner. The immediate release particles may include an inert core, a drug layer covering the inert core, and a taste-masking coating covering the drug layer. The drug layer of the immediate release particles includes a binder and an active ingredient selected from methylphenidate, dexmethylphenidate, structural analogs of

methylphenidate or dexmethylphenidate, pharmaceutical salts thereof, and mixtures thereof. The taste-masking coating of the immediate release particles includes a taste-masking polymer and a plasticizer. The modified release particles of the pharmaceutical composition may include an inert core, a drug layer covering the inert core, and a delayed-release coating covering the drug layer. The drug layer of the modified release particles includes the active ingredient and the binder (e.g., similar to that described above with respect to the immediate release particles). The modified release coating of the modified release particles includes a mixture of at least two polymers (e.g., polymer A and delayed release polymer B). In one aspect, the active ingredient in both the immediate and modified release particles is dexmethylphenidate hydrochloride

[0005] The multiparticulate mixture may be formulated in any appropriate matter; for example, as an orally disintegrating (e.g., dissolving) or chewable tablet. Another aspect of the present disclosure encompasses methods of treating a patient in need thereof. The method may include administering to the patient a therapeutically effective amount of a pharmaceutical composition described herein. In one aspect, the therapeutically effective amount administered to the patient treats attention deficit hyperactivity disorder.

[0006] Additional embodiments and features are set forth in the description that follows, and will become apparent to those skilled in the art upon examination of the specification or may be learned by the practice of the disclosed subject matter. A further understanding of the nature and advantages of the disclosure may be realized by reference to the remaining portions of the specification and the drawings, which forms a part of this disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] The disclosure contains at least one drawing executed in color. Copies of this disclosure with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0008] The description will be more fully understood with reference to the following figures and data graphs, which are presented as various embodiments of the disclosure and should not be construed as a complete recitation of the scope of the disclosure, wherein:

[0009] FIG. 1 is an illustration of the qualitative and quantitative composition of drug layered particles.

[0010] FIG. 2 is an illustration of the qualitative and quantitative composition of IR coated particles for taste-masking.

[0011 ] FIG. 3 is an illustration of the qualitative and quantitative composition of 25% MR particles.

[0012] FIG. 4 is an illustration of the qualitative and quantitative composition of 30% MR particles.

[0013] FIG. 5 is an illustration of the qualitative and quantitative composition of 35% MR particles.

[0014] FIG. 6 is the dissolution profile of IR coated particles (for taste-masking) in Phosphate 50mM pH 6.8 buffer.

[0015] FIG. 7 is the dissolution profile of MR coated particles in 0.1 N HCI medium (■ symbol MR25 coated particles,▲ symbols MR 30 coated particles, · symbols MR 35 coated particles).

[0016] FIG. 8 is the dissolution profile of MR coated particles in 50mM phosphate pH 6.8 medium (■ symbol MR25 coated particles,▲ symbols MR 30 coated particles, · symbols MR 35coated particles).

[0017] FIG. 9 is the Dissolution profile of ER Orally Disintegrating Tablets in 0.1 N HCL medium (■ symbol ER25 ODT,▲ symbols ER 30 ODT, · symbols ER 35 ODT). ODT refers to an orally disintegrating tablet.

[0018] FIG. 10 is the dissolution profile of ER Orally Disintegrating Tablets in 50mM phosphate pH 6.8 medium (■ symbol ER25 ODT,▲ symbols ER 30 ODT, · symbols ER 35 ODT).

[0019] FIG. 11 is the dissolution profile of IR coated particles (for taste-masking) with CA-based coating in 0.1 N HCI dissolution medium.

[0020] FIG. 12 is the dissolution profile of IR particles and CAB-based particles in 0.1 N HCI dissolution medium.

[0021 ] FIG. 13 presents the in vitro dissolution profiles of modified release particles with varying modified release coating amounts for medium (30% by weight of the modified release particle), fast (25% by weight of the modified release particle), and slow (35% by weight of the modified release particle) release, as disclosed herein, and a reference formulation.

[0022] FIG. 14 is an illustration of the qualitative and quantitative composition of 18% coated modified release particles.

[0023] FIG. 15 is an illustration of the qualitative and quantitative composition of 20% coated modified release particles.

[0024] FIG. 16 is an illustration of the qualitative and quantitative composition of 26% coated modified release particles.

[0025] FIG. 17A is the dissolution profile of MR coated particles in 50mM phosphate pH 6.8 medium (■ symbol MR18 coated particles,▲ symbols MR 20 coated particles, · symbols MR 26 coated particles).

[0026] FIG. 17B is the dissolution profile of MR 18% coated particles in 50mM phosphate pH 6.8 medium and 0.1 N HCL medium.

[0027] FIG. 17C is the dissolution profile of MR 20% coated particles in 50mM phosphate pH 6.8 medium and 0.1 N HCL medium.

[0028] FIG. 17D is the dissolution profile of MR 26% coated particles in 50mM phosphate pH 6.8 medium and 0.1 N HCL medium.

[0029] FIG. 18 is the dissolution profile of ER Orally Disintegrating Tablets in 0.1 N HCL medium (■ symbol ER 18 ODT, · symbols ER 26 ODT).

[0030] FIG. 19 is the dissolution profile of ER Orally Disintegrating Tablets in 50mM phosphate pH 6.8 medium (■ symbol ER 18 ODT, · symbols ER 26 ODT).

[0031 ] FIG. 20A is the dissolution profile of Orally Disintegrating Tablets with MR 18%, 20%, and 26% coated particles in 0.1 N HCL medium as compared to FOCALIN XR®.

[0032] FIG. 20B is the dissolution profile of Orally Disintegrating Tablets with MR 18%, 20%, and 26% coated particles in 50mM phosphate pH 6.8 medium as compared to FOCALIN XR®.

[0033] FIG. 21A is the dissolution profile of Orally Disintegrating Tablets with MR 18% coated particles in 0.1 N HCL medium and 50mM phosphate pH 6.8 medium after being stored for 3 months at 40°C and 75% relative humidity or being stored for 3 months at 25°C and 60% relative humidity.

[0034] FIG. 21 B is the dissolution profile of Orally Disintegrating Tablets with MR 20% coated particles in 0.1 N HCL medium and 50mM phosphate pH 6.8 medium after being stored for 3 months at 40°C and 75% relative humidity or being stored for 3 months at 25°C and 60% relative humidity.

[0035] FIG. 21C is the dissolution profile of Orally Disintegrating Tablets with MR 26% coated particles in 0.1 N HCL medium and 50mM phosphate pH 6.8 medium after being stored for 3 months at 40°C and 75% relative humidity or being stored for 3 months at 25°C and 60% relative humidity.

[0036] FIG. 22A is the dissolution profile of ER 40 Chewable Tablets (· symbol 50mM phosphate pH 6.8 medium, X symbols 0.1 N HCL medium).

[0037] FIG. 22B is the dissolution profile of ER 40 Chewable Tablets in 50mM phosphate pH 6.8 medium and 0.1 N HCL medium as compared to the particles alone.

DETAILED DESCRIPTION

[0038] The present disclosure may be understood more readily by reference to the following detailed description of embodiments of the formulation, methods of treatment using some embodiments of the formulation, and the Examples included therein.

[0039] The present disclosure provides orally disintegrating and chewable multiparticulate pharmaceutical compositions that provide extended release of an active ingredient in a pulsatile manner. The multi-phasic drug release profile is achieved by including multiple distinct components in the pharmaceutical composition which are designed to release the drug based on time and physiological pH in the gastrointestinal tract. The pulsatile release may substantially mimic the pharmacological and therapeutic effects produced by the administration of two or more immediate release dosage forms given sequentially. In some embodiments, the pulsatile release may mimic the effect produced by a single unit (capsule) of FOCALIN® XR. In some embodiments, the pharmaceutical composition may be bioequivalent to FOCALIN® XR.

(I) MULTIPARTICULATE PHARMACEUTICAL COMPOSITION

[0040] One aspect of the present disclosure provides extended release, multiparticulate pharmaceutical compositions having immediate release and modified release particles.

(a) Immediate Release Particles

[0041 ] The immediate release portion of the formulation may take any form capable of achieving immediate release of the active ingredient when ingested. In some embodiments, the immediate release portion may be immediate release particles. In some examples, the immediate release particles may not release the active ingredient in a small volume of saliva (e.g. in neutral conditions such as pH 6.8), may provide a quick release of the active ingredient in acidic conditions (e.g. in the stomach or at pH 1 .1 ), and/or may have a coating that is compatible with tableting. The immediate release particles may have desirable organoleptic properties.

[0042] The drug-loaded immediate release particles may be obtained by various techniques known in the art. For example, the immediate release particles may include a core with a drug layer or the drug may be incorporated into the core. In an embodiment, the immediate release particles of the pharmaceutical composition disclosed herein comprise an inert core, a drug layer covering the inert core, and a taste-masking coating covering the drug layer. The drug layer includes at least one active ingredient and a binder, and the taste-masking coating includes a taste-masking polymer and a plasticizer.

[0043] In other embodiments, the immediate release particles may be obtained by techniques including, but not limited to, agglomeration in the molten state, such as the Glatt ProCell™ technique, extrusion and spheronization, wet granulation, compacting, granulation and spheronization, where the spheronization is carried out (for example) in a fluidized bed apparatus equipped with a rotor, in particular using the Glatt CPS™ technique, spraying (for example) in a fluidized bed type apparatus equipped

with zig-zag filter, in particular using the Glatt MicroPx™ technique, or spraying (for example) in a fluidized bed apparatus optionally equipped with a partition tube or Wurster tube.

(i) Core

[0044] The inert core may be a sphere, particle, pellet, bead, or granule. In various embodiments, the inert core may be composed of a cellulose sphere, sugar sphere, or a non-pareil seed/bead. Non-limiting examples of the core include crystals or spheres of lactose, sucrose (such as Compressuc™ PS from Tereos), microcrystalline cellulose (such as Avicel™ from FMC Biopolymer, Cellet™ from Pharmatrans or Celphere™ from Asahi Kasei), sodium chloride, calcium carbonate (such as

Omyapure™ 35 from Omya), sodium hydrogen carbonate, dicalcium phosphate (such as Dicafos™ AC 92-12 from Budenheim) or tricalcium phosphate (such as Tricafos™ SC93-15 from Budenheim); composite spheres or granules, for example sugar spheres comprising sucrose and starch (such as Suglets™ from NP Pharm), spheres of calcium carbonate and starch (such as Destab™ 90 S Ultra 250 from Particle Dynamics) or spheres of calcium carbonate and maltodextrin (such as Hubercal™ CCG4100 from Huber); or combinations thereof. The core may also comprise other particles of pharmaceutically acceptable excipients such as particles of hydroxypropyl cellulose (such as Klucel™ from Aqualon Hercules), guar gum particles (such as Grinsted™ Guar from Danisco), xanthan particles (such as Xantural™ 180 from CP Kelco). According to specific embodiments, the cores are sugar spheres or microcrystalline cellulose spheres, such as Cellets™90, Cellets™100 or Cellets™127 marketed by Pharmatrans, or also Celphere™ CP 203, Celphere™ CP305, Celphere™ SCP 100. In one

embodiment, the inert core is a microcrystalline cellulose sphere.

[0045] The inert core may have a diameter in the range of about 50 pm to about 1500 pm. In some embodiments, the diameter of the inert core may range from about 50 pm to about 1500 pm, about 100 pm to about 300 pm, about 200 pm to about 400 pm, about 500 pm to about 700 pm, about 600 pm to about 800 pm, about 700 pm to about 900 pm, and about 800 pm to about 1000 pm. In one embodiment, the core has a diameter of 100 pm to 300 pm.

[0046] The inert core is about 10% to about 90% by weight of the immediate release particle. In some embodiments, the core is at least 10% by weight, at least 25% by weight, at least 35% by weight, at least 50% by weight, at least 60% by weight, at least 70% by weight, at least 80% by weight or less than or equal to 90% by weight of the immediate release particle. In an embodiment, the core is 25% to 35% by weight of the immediate release particle. In one embodiment, the inert core is about 32% by weight of the immediate release particle.

(ii) Drug Laver

[0047] In some embodiments, the immediate release particles of the pharmaceutical composition comprise a drug layer that is layered over the inert core. In an embodiment, the drug layer includes at least one active ingredient and a binder. In some embodiments, a drug laying medium of water and ethanol may be used to adhere the active ingredient to the inert core. In at least one example, the drug layering medium may include 50% water and 50% ethanol at room temperature. In some embodiments, the binder may be up to 10% of the dry content of the drug layering medium.

[0048] In one embodiment, the active ingredient is methylphenidate, dexmethylphenidate, a structural analog of methylphenidate or dexmethylphenidate, a pharmaceutically acceptable salt thereof, or mixtures thereof. In a specific example, the active ingredient is dexmethylphenidate HCI.

[0049] In general, the binder is a hydrophilic polymer or combination of hydrophilic polymers. Non-limiting examples of suitable binders include low molecular weight hydroxypropyl cellulose (ex. Klucel™ EF), low molecular weight hydroxypropyl methylcellulose (hypromellose) (ex. Methocel™ E3 or E5), low molecular weight methylcellulose (ex. Methocel™ A15), low molecular weight polyvinyl pyrrolidone (providone) (ex. Plasdone™ K29/32 or Kollidon™ 30), vinyl pyrrolidone and vinyl acetate copolymer (copovidone) (ex. Plasdone™ S630 or Kollidon™ VA 64), dextrose, pregelatinized starch, maltodextrin, and combinations thereof.

[0050] In specific embodiments, the binder may be low molecular weight hydroxypropyl methylcellulose (available under the tradename Klucel™ EF).

Hydroxypropyl cellulose has a strong binding capacity, which may aid in robust drug- layering processes. Low molecular weight hydroxypropyl cellulose corresponds to grades of hydroxypropyl cellulose having a molecular weight of less than 800,000 g/mol, preferably less than or equal to 400,000 g/mol, and in particular less than or equal to 100,000 g/mol. Low molecular weight hydroxypropyl methylcellulose (or hypromellose) corresponds to grades of hydroxypropyl methylcellulose the solution viscosity of which, for a 2% solution in water and at 20° C, is less than or equal to 1 ,000 mPa-s, preferably less than or equal to 100 mPa-s and in particular less than or equal to 15 mPa-s. Low molecular weight polyvinyl pyrrolidone (or povidone) corresponds to grades of polyvinyl pyrrolidone having a molecular weight of less than or equal to 1 ,000,000 g/mol, preferably less than or equal to 800,000 g/mol, and in particular less than or equal to 100,000 g/mol.

[0051 ] The active ingredient is present in an amount of 100% to 10% by weight of the drug layer of the immediate release particles. In various embodiments, the active ingredient is present in an amount of 100% to 95%, 100% to 90%, 95% to 90%, 95% to 85%, 80% to 70%, 70% to 60%, 60% to 50%, 50% to 40%, 40% to 30%, 30% to 20%, or 20% to 10% by weight of the drug layer of the immediate release particles. In an embodiment, the active ingredient is present in an amount of about 88% to about 96% by weight of the drug layer of the immediate release particles. In one embodiment, the active ingredient is about 90% by weight of the drug layer. The binder may be present in an amount of 0% to 90% by weight of the drug layer of the immediate release particles. In various embodiments, the binder is present in an amount of 0% to 5%, 0% to 10%, 5% to 10%, 5% to 15%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, or 80% to 90% by weight of the drug layer of the immediate release particles. For example, the binder may be present in an amount of 4% to 12% by weight of the drug layer of the immediate release particles. In one embodiment, the binder is about 10% by weight of the drug layer. In specific

embodiments, the drug layer of the immediate release particles comprises about 10% hydroxypropyl cellulose and about 90% active ingredient.

[0052] The drug layer is about 10% to about 90% by weight of the immediate release particle. In various embodiments, the drug layer is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% by weight of the immediate release particle. In some

embodiments, the drug layer is 40% to 50% by weight of the immediate release particle. In one embodiment, the drug layer may be about 48% by weight of the immediate release particle.

[0053] In general, the drug layer completely surrounds or encapsulates the inert core. A ratio of the drug layer to the inert core in the immediate release particles is about 0.1 to about 9. In some embodiments, the ratio of the drug layer to the inert core in the immediate release particles may be about 0.4 to about 0.6. In another

embodiment, the ratio of the drug layer to the inert core in the immediate release particles is about 0.35 to about 0.4.

[0054] The drug layer may have a thickness of about 10 pm to 50 pm. In an embodiment, the diameter of the drug layer may be about 26 pm. The core with drug layer may have a diameter in the range of about 50 pm to about 1500 pm. In some embodiments, the diameter of the inert core with drug layer may be about 370 pm to about 380 pm. In one embodiment, the diameter of the inert core with drug layer may be about 370 pm.

(iii) Taste-Masking Coating

[0055] The immediate release particles of the pharmaceutical composition disclosed herein further comprise a taste-masking coating layered over the drug layer.

In general, the taste-masking coating comprises a taste-masking polymer and a plasticizer.

[0056] The taste-masking polymer provides taste-masking and an immediate release dissolution profile. In various embodiments, the taste-masking polymer is a cellulosic derivative. In specific embodiments, the taste-masking polymer is cellulose acetate.

[0057] Examples of suitable plasticizers include, without limit, castor oil, triethyl citrate (TEC), acetyltriethyl citrate (ATEC), acetyl tri-n-butyl citrate (ATBC), dibutyl sebacate, diethyl phthalate, and triacetin. In one embodiment, the plasticizer is triethyl citrate. In another embodiment, the plasticizer is castor oil.

[0058] The taste-masking polymer is about 60% to about 98% by weight of the taste-masking coating. In various embodiments, the taste-masking polymer is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% by weight of the taste-masking coating. In some embodiments, the taste-masking polymer is 88% to 92% by weight of the taste-masking coating. In one embodiment, the taste-masking polymer is about 90% by weight of the taste-masking coating. The plasticizer is about 2% to about 40% by weight of the taste-masking coating. In various embodiments, the plasticizer is at least 5%, at least 10%, at least 15%, or at least 20% by weight of the taste-masking polymer. In an embodiment, the plasticizer is 8% to 12% by weight of the taste-masking coating. In an embodiment, the plasticizer is about 10% by weight of the taste-masking coating. In specific

embodiments, the taste-masking coating comprises about 10% triethyl citrate and about 90% cellulose acetate.

[0059] The taste-masking coating may be about 5% to about 50% by weight of the immediate release particle. In various embodiments, the taste-masking coating may be at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% by weight of the immediate release particle. In an embodiment, the taste-masking polymer is 5% to 25% by weight of the immediate release particle. In one embodiment, the taste-masking coating may be about 20% by weight of the immediate release particle.

[0060] In general, the taste-masking coating release coating completely surrounds or encapsulates the drug layer. The immediate release particles may have a diameter in the range of about 50 pm to about 1500 pm, about 100 pm to about 300 pm, about 200 pm to about 400 pm, about 500 pm to about 700 pm, about 600 pm to about 800 pm, about 700 pm to about 900 pm, and about 800 pm to about 1000 pm. The mean diameter of the immediate release particles may be less than 500 pm.

(b) Modified Release Particles

[0061 ] The modified release portion of the formulation may include drug-loaded particles with a modified release coating capable of achieving modified release of the active ingredient when ingested. In some examples, the modified release

particles may not release the active ingredient in a small volume of saliva (e.g. in neutral conditions such as pH 6.8), may provide an extended or delayed release of the active ingredient in acidic conditions (e.g. in the stomach or at pH 1.1 ), and/or may have a coating that is compatible with tableting. The modified release particles may have desirable organoleptic properties.

[0062] In an embodiment, each of the plurality of the modified release particles comprises an inert core, a drug layer over the inert core, and a modified release coating layered over the drug layer. The drug layer includes at least one active ingredient and a binder, and the modified release coating includes a polymer A, a delayed release polymer B, and optionally a plasticizer.

[0063] In other embodiments, the drug-loaded particles may be obtained by techniques including, but not limited to agglomeration in the molten state, such as the Glatt ProCellTM technique, extrusion and spheronization, wet granulation, compacting, granulation and spheronization, where the spheronization being carried out for example in a fluidized bed apparatus equipped with a rotor, in particular using the Glatt CPSTM technique, spraying for example in a fluidized bed type apparatus equipped with zig-zag filter, in particular using the Glatt MicroPxTM technique, or spraying, for example in a fluidized bed apparatus optionally equipped with a partition tube or Wurster tube.

(i) Core

[0064] The inert core may be a sphere, particle, pellet, bead, or granule. In various embodiments, the inert core may be a cellulose sphere, sugar sphere, or a non pareil seed/bead. Non-limiting examples of the core include crystals or spheres of lactose, sucrose (such as Compressuc™ PS from Tereos), microcrystalline cellulose (such as Avicel™ from FMC Biopolymer, Cellet™ from Pharmatrans or Celphere™ from Asahi Kasei), sodium chloride, calcium carbonate (such as Omyapure™ 35 from

Omya), sodium hydrogen carbonate, dicalcium phosphate (such as Dicafos™ AC 92-12 from Budenheim) or tricalcium phosphate (such as Tricafos™ SC93-15 from

Budenheim); composite spheres or granules, for example sugar spheres comprising sucrose and starch (such as Suglets™ from NP Pharm), spheres of calcium carbonate

and starch (such as Destab™ 90 S Ultra 250 from Particle Dynamics) or spheres of calcium carbonate and maltodextrin (such as Hubercal™ CCG4100 from Huber); or combinations thereof. The core may also comprise other particles of pharmaceutically acceptable excipients such as particles of hydroxypropyl cellulose (such as KlucelTM from Aqualon Hercules), guar gum particles (such as GrinstedTM Guar from Danisco), xanthan particles (such as XanturalTM 180 from CP Kelco). According to specific embodiments, the cores are sugar spheres or microcrystalline cellulose spheres, such as CelletsTM90, CelletsTMI OO or CelletsTM127 marketed by Pharmatrans, or also CelphereTM CP 203, CelphereTM CP305, Celphere™ SCP 100. In one embodiment, the inert core is a microcrystalline cellulose sphere.

[0065] The inert core may have a diameter in the range of about 50 pm to about 1500 pm. In some embodiments, the diameter of the inert core may range from about 50 pm to about 150 pm, about 100 pm to about 300 pm, about 200 pm to about 400 pm, about 500 pm to about 700 pm, about 600 pm to about 800 pm, about 700 pm to about 900 pm, and about 800 pm to about 1000 pm. In one embodiment, the core has a diameter of 100 pm to 300 pm.

[0066] The inert core is about 10% to about 90% by weight of the modified release particle. In some embodiments, the core is at least 10% by weight, at least 25% by weight, at least 35% by weight, at least 50% by weight, at least 60% by weight, at least 70% by weight, at least 80% by weight or less than or equal to 90% by weight of the modified release particle. In an embodiment, the inert core is about 25% to about 35% by weight of the modified release particle. In another embodiment, the inert core is about 25% to about 30% by weight of the modified release particle. In an embodiment, the inert core is at least 26% by weight of the modified release particle. In an

embodiment, the inert core is at least 27% by weight of the modified release particle. In an embodiment, the inert core is at least 28% by weight of the modified release particle. In an embodiment, the inert core is at least 29% by weight of the modified release particle. In an embodiment, the inert core is at least 30% by weight of the modified release particle. In an embodiment, the inert core is at least 31 % by weight of the modified release particle. In an embodiment, the inert core is at least 32% by weight of the modified release particle. In one embodiment, the inert core is about 26% by weight of the modified release particle. In one embodiment, the inert core is about 28% by weight of the modified release particle. In one embodiment, the inert core is about 29% by weight of the modified release particle. In one embodiment, the inert core is about 30% by weight of the modified release particle. In one embodiment, the inert core is about 32% by weight of the modified release particle. In one embodiment, the inert core is about 33% by weight of the modified release particle. In one embodiment, the inert core is about 35% by weight of the modified release particle.

[0067] The inert core in the modified release particles is substantially similar to the inert core in the immediate release particles, which is described above in section (l)(a). However, the size or weight percent of the cores in the immediate release particles and modified release particles may be the same or may be different in various embodiments.

(ii) Drug Laver

[0068] The modified release particles in the pharmaceutical composition comprise a drug layer that is layered over the inert core. In an embodiment, the drug layer includes at least one active ingredient and a binder. In some embodiments, a drug laying medium of water and ethanol may be used to adhere the active ingredient to the inert core. In at least one example, the drug layering medium may include 50% water and 50% ethanol at room temperature. In some embodiments, the binder may be up to 10% of the dry content of the drug layering medium.

[0069] The active ingredient may benefit from a pulsatile release over an extended period of time, such as to provide a once-daily administration. The controlled and modified release profile in terms of pH of the pharmaceutical composition may provide for the release of the active ingredient in the small intestine.

[0070] In one embodiment, the active ingredient is methylphenidate, dexmethylphenidate, structural analogs of methylphenidate or dexmethylphenidate, pharmaceutical salts thereof, and mixtures thereof. In a specific example, the active ingredient is dexmethylphenidate HCI.

[0071 ] In general, the binder is a hydrophilic polymer or combination of hydrophilic polymers. Non-limiting examples of suitable binders include low molecular weight hydroxypropyl cellulose (ex. Klucel™ EF), low molecular weight hydroxypropyl methylcellulose (hypromellose) (ex. Methocel™ E3 or E5), low molecular weight methylcellulose (ex. Methocel™ A15), low molecular weight polyvinyl pyrrolidone (providone) (ex. Plasdone™ K29/32 or Kollidon™ 30), vinyl pyrrolidone and vinyl acetate copolymer (copovidone) (ex. Plasdone™ S630 or Kollidon™ VA 64), dextrose, pregelatinized starch, maltodextrin, and combinations thereof.

[0072] In specific embodiments, the binder may be low molecular weight hydroxypropyl methylcellulose (available under the tradename Klucel™ EF).

Hydroxypropyl cellulose has a strong binding capacity, which may aid in robust drug layering processes. Low molecular weight hydroxypropyl cellulose corresponds to grades of hydroxypropyl cellulose having a molecular weight of less than 800,000 g/mol, preferably less than or equal to 400,000 g/mol, and in particular less than or equal to 100,000 g/mol. Low molecular weight hydroxypropyl methylcellulose (or hypromellose) corresponds to grades of hydroxypropyl methylcellulose the solution viscosity of which, for a 2% solution in water and at 20° C, is less than or equal to 1 ,000 mPa-s, preferably less than or equal to 100 mPa-s and in particular less than or equal to 15 mPa-s. Low molecular weight polyvinyl pyrrolidone (or povidone) corresponds to grades of polyvinyl pyrrolidone having a molecular weight of less than or equal to 1 ,000,000 g/mol, preferably less than or equal to 800,000 g/mol, and in particular less than or equal to 100,000 g/mol.

[0073] The active ingredient is present in an amount of 100% to 10% by weight of the drug layer of the modified release particles. In various embodiments, the active ingredient is present in an amount of 100% to 95%, 100% to 90%, 95% to 90%, 95% to 85%, 80% to 70%, 70% to 60%, 60% to 50%, 50% to 40%, 40% to 30%, 30% to 20%, or 20% to 10% by weight of the drug layer of the modified release particles. In an embodiment, the active ingredient is present in an amount of about 88% to about 96% by weight of the drug layer of the modified release particles. In one embodiment, the active ingredient is about 90% by weight of the drug layer. The binder may be present in an amount of 0% to 90% by weight of the drug layer of the modified release particles. In various embodiments, the binder is present in an amount of 0% to 5%, 0% to 10%, 5% to 10%, 5% to 15%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, or 80% to 90% by weight of the drug layer of the modified release particles. For example, the binder may be present in an amount of 4% to 12% by weight of the drug layer of the modified release particles. In one embodiment, the drug layer of the modified release particles comprises about 10% hydroxypropyl cellulose and about 90% active ingredient.

[0074] The drug layer is about 10% to about 90% by weight of the modified release particle. In various embodiments, the drug layer is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% by weight of the modified release particle. In some embodiments, the drug layer is 35% to 50% by weight of the modified release particle. In an

embodiment, the drug layer may be at least 39% by weight of the modified release particle. In an embodiment, the drug layer may be at least 42% by weight of the modified release particle. In an embodiment, the drug layer may be at least 44% by weight of the modified release particle. In an embodiment, the drug layer may be at least 46% by weight of the modified release particle. In an embodiment, the drug layer may be at least 48% by weight of the modified release particle. In an embodiment, the drug layer may be up to 50% by weight of the modified release particle. In one embodiment, the drug layer may be about 39% by weight of the modified release particle. In one embodiment, the drug layer may be about 42% by weight of the modified release particle. In one embodiment, the drug layer may be about 45% by weight of the modified release particle. In one embodiment, the drug layer may be about 46% by weight of the modified release particle. In one embodiment, the drug layer may be about 48% by weight of the modified release particle. In one embodiment, the drug layer may be about 50% by weight of the modified release particle.

[0075] In general, the drug layer completely surrounds or encapsulates the inert core. A ratio of the drug layer to the inert core in the modified release particles is about 0.1 to about 9. In an embodiment, the ratio of the drug layer to the inert core in the modified release particles is about 1 .5. In some embodiments, the ratio of the drug layer to the inert core in the modified release particles may be about 0.4 to about 0.6. In another embodiment, the ratio of the drug layer to the inert core in the modified release particles is about 0.35 to about 0.4.

[0076] The drug layer may have a thickness of about 10 pm to 50 pm. In an embodiment, the diameter of the drug layer may be about 26 pm. The core with drug layer may have a diameter in the range of about 50 pm to about 1500 pm. In some embodiments, the diameter of the inert core with drug layer may be about 370 pm to about 380 pm. In one embodiment, the diameter of the inert core with drug layer may be about 370 pm.

[0077] The drug layer in the modified release particles is substantially similar to the drug layer in the immediate release particles, which is described above in section (l)(a). However, the thickness or weight percent of the layers in the immediate release particles and modified release particles may be the same or may be different in various embodiments.

(iii) Modified Release Coating

[0078] The modified release particles of the pharmaceutical composition disclosed herein further comprise a modified release coating layered over the drug layer. In general, the modified release coating comprises a polymer A, a delayed release polymer B, and optionally a plasticizer.

[0079] The modified release coating provides for obtaining compressible particles having pH dependent properties and providing modified release of the active ingredient. In general, the modified release coating comprises mixture of a polymer A and a delayed release polymer B.

[0080] In an embodiment, polymer A is a polymer that is insoluble in gastrointestinal fluids. Polymer A may be a film forming non-water-soluble polymer to control water intake and ensure coating mechanical holding. Polymer A may include, but is not limited to ethylcellulose, cellulose acetate butyrate, or cellulose acetate.

Polymer B is a polymer carrying free carboxylic groups. In an embodiment, the delayed release polymer B may be an enteric polymer. For example, the delayed release

polymer B may be a pH-dependent enteric polymer. The pH-dependent enteric polymer may have a solubilization pH of 5 to 7. In an embodiment, delayed release polymer B is a polymer carrying free carboxylic groups ionized at pH 7.5. In some embodiments, delayed release polymer B may be a mixture of polymers. In a mixture, the different delayed release polymer B’s may have different solubilization pH’s. For example, a first delayed release polymer B may be non-water-soluble below pH 7 and soluble above pH 7 and a second delayed release polymer B may be non-water-soluble below pH 6 and soluble above pH 6. Non-limiting examples of the delayed release polymer B include (meth)acrylic acid/alkyl (e.g. methyl) (meth)acrylate copolymers or methacrylic acid copolymers type A, B or C, cellulose derivatives, preferably cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate,

carboxymethylethyl cellulose, cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, zein, shellac, alginate and mixtures thereof.

[0081 ] In various embodiments, the delayed release polymer B may be a combination of more than one delayed release polymer. For example, the modified release coating may include a mixture of polymer A, a first delayed release polymer B, and a second delayed release polymer B. In an embodiment, polymer A may be about 55% to about 65% of the modified release coating, the first delayed release polymer B may be about 10% to about 20% of the modified release coating, and the second delayed release polymer B may be about 5% to about 15% of the modified release coating. In specific embodiments, the modified release coating is a combination of cellulose acetate butyrate, Eudragit L100 (methacrylic acid - methylmethacrylate copolymer (1 :1 ) or methacrylic acid copolymer Type A) and Eudragit S100 (methacrylic acid - methylmethacrylate copolymer (1 :2) or methacrylic acid copolymer Type B).

[0082] The mixture of polymer A and delayed release polymer B is about 60% to about 100% by weight of the modified release coating. In various embodiments, the mixture of polymer A and delayed release polymer B is at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 100% by weight of the modified release coating. In an embodiment, the mixture of polymer A and delayed release

polymer B is 80% to 100% by weight of the modified release coating. In an embodiment, the mixture of polymer A and delayed release polymer B is about 85% by weight of the modified release coating.

[0083] The modified release coating optionally includes a plasticizer to render the polymer film slightly flexible. The plasticizer is about 0% to about 20% by weight of the modified release coating. In various embodiments, the plasticizer is 0%, greater than 0%, at least 5%, at least 10%, at least 15%, or at least 20% by weight of the modified release coating. In an embodiment, the plasticizer is 8% to 12% by weight of the modified release coating. In an embodiment, the plasticizer is about 15% by weight of the modified release coating. Examples of suitable plasticizers include, without limit, castor oil, triethyl citrate (TEC), acetyltriethyl citrate (ATEC), acetyl tri-n-butyl citrate (ATBC), dibutyl sebacate, diethyl phthalate, and triacetin. In one embodiment, the plasticizer is castor oil.

[0084] In one embodiment, the modified release coating comprises about 60% cellulose acetate butyrate, about 15% Eudragit L100, about 10% Eudragit S100, and about 15% castor oil.

[0085] The modified release coating may typically represent 10% to 50%, 15% to 45%, 20% to 40%, or 25% to 35% by weight of the total weight of the coated modified release particles. In various embodiments, the modified release coating is at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, or at least 50% by weight of the modified release particle. Preferably, the modified release coating represents 15% to 35% by weight of the total weight of the modified release particle. In one embodiment, the modified release coating may be about 18% by weight of the modified release particle. In one embodiment, the modified release coating may be about 20% by weight of the modified release particle. In one embodiment, the modified release coating may be about 22% by weight of the modified release particle. In one embodiment, the modified release coating may be about 26% by weight of the modified release particle. In one embodiment, the modified release coating may be about 30% by weight of the modified release particle. In one embodiment, the modified release coating may be about 35% by weight of the modified release particle. The greater the amount of modified release coating, the slower the release of the release of the active ingredient. For example, the modified release particles may have a coating ratio of 25% (fast), 30% (medium), or 35% (slow). In another example, the modified release particles may have a coating ratio of 18% (fast), 20% (medium), or 26% (slow). The coating ratio may depend on the solvent mixture used and/or the process conditions during spray drying.

[0086] In general, the modified release coating layer completely surrounds or encapsulates the drug layer of the modified release particles. The modified release particles may have a diameter in the range of about 50 pm to about 1500 pm, about 100 pm to about 300 pm, about 200 pm to about 400 pm, about 500 pm to about 700 pm, about 600 pm to about 800 pm, about 700 pm to about 900 pm, and about 800 pm to about 1000 pm. The mean diameter of the modified release particles may be less than 500 pm. In various embodiments, the diameter of the modified release particles may be about 400 pm to about 450 pm. In specific examples, the mean diameter of the modified release particles may be about 417 pm, about 423 pm, or about 435 pm.

[0087] The immediate release particles and modified release particles disclosed herein may be prepared using standard coating processes such as, spray coating, Wurster coating, fluidized bed coating, and the like. Additional guidance may be found, for example, in K. Masters, Spray Drying Handbook, 4th edition, Halsted Press, 1985. The drug layer, taste-masking coating, and modified release coating may be sprayed in the solute state i.e. in a solubilized form in a solvent medium. This solvent medium generally contains organic solvents mixed or not mixed with water. The coating thus formed proves homogeneous in terms of composition as opposed to a coating formed by a dispersion of these same polymers, in a mostly aqueous liquid. In an embodiment, the modified release coating may be spray coated using a mix of solvents including acetone, ethanol, and/or water. In at least one example, the mix of solvents may be 54% acetone, 36% ethanol, and 10% water. In another example, the mix of solvents may be 60% acetone, 35% ethanol, and 5% water. In yet another example, the mix of solvents may be 65% acetone, 35% ethanol, and 0% water. In other examples, the mix of solvents may be 80% acetone, 20% ethanol, and 0% water. The dry matter content for the spray drying process may range from about 8% to about 16%. During

coating, the inlet air humidity may be about 3 g/kg to 8 g/kg. In some examples, the inlet air may be about 50 m3/h, the product temperature may be about 36°C, the atomizing pressure may be about 1.6 bars to 2.5 bars, and the average solution rate may be about 15 g/min to 17 g/min.

(c) Dosage Forms

[0088] The multiparticulate mixture of the plurality of immediate release particles and the plurality of modified release particles may be formulated in a variety of dosage forms. In general, the dosage forms are orally disintegrating or chewable. In one embodiment, the pluralities of immediate release particles and modified release particles may be incorporated into an orally disintegrating tablet (ODT). In other embodiments, the pluralities of immediate release particles and modified release particles may be incorporated into a chewable tablet.

[0089] In general, the dose of the at least one active ingredient is equally distributed among the pluralities of immediate release particles and modified release particles. That is, each of the pluralities of immediate release particles and modified release particles comprises about 50% by weight of the at least one active ingredient. Alternatively, the ratio of the active ingredient in the immediate release particles to modified release particles is about 1. In other embodiments, the immediate release particles may comprise about 40% to about 60% by weight of the at least one active ingredient and the modified release particles may comprise about 60% to about 40% by weight of the at least one active ingredient, respectively. In this embodiment, the ratio of the active ingredient in the immediate release particles to modified release particles may range from 0.67 to 1.5.

[0090] The multiparticulate mixture of immediate release and modified release particles ranges from about 10% to about 70% by weight of the pharmaceutical composition. In various embodiments, the multiparticulate mixture is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, or at least 70% by weight of the pharmaceutical composition. In an embodiment, the multiparticulate mixture is 20% to 25% by weight of the pharmaceutical composition. In one

embodiment, the multiparticulate mixture is about 24.6% by weight of the

pharmaceutical composition. In general, the amount of active ingredient present in the pharmaceutical composition may range from about 1 mg to about 100 mg. In some embodiments, the amount of the active ingredient present in the pharmaceutical composition is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg. As described herein above, the active ingredient may be methylphenidate, dexmethylphenidate, structural analogs of methylphenidate or dexmethylphenidate, pharmaceutical salts thereof, or mixtures thereof.

[0091 ] In an embodiment, a pharmaceutical composition may include, but is not limited to, the multiparticulate mixture, a sugar alcohol, a disintegrant, a lubricant, and a filler.

[0092] In an embodiment, the pharmaceutical composition includes a sugar alcohol. Non-limiting examples of the sugar alcohol include mannitol, xylitol, or combinations thereof. In some embodiments, the pharmaceutical composition includes “ready-to-use” commercial sugar alcohol excipients such as Pearlitol® (mannitol), Pearlitol® Flash (mannitol/starch), Ludiflash® (mannitol-crospovidone-polyvinylacetate), F-melt® (inorganic excipients and desintegrants in a carbohydrate complex), or combinations thereof. In one embodiment, the sugar alcohol is mannitol. The sugar alcohol may be present in an amount of about 30% to about 75% by weight of the pharmaceutical composition. In various embodiments, the sugar alcohol is at least 30%, at least 40%, at least 50%, at least 60%, or at least 75% by weight of the

pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises about 33% by weight Pearlitol®. In another embodiment, the pharmaceutical composition comprises about 70.4% Pearlitol® Flash.

[0093] Examples of the disintegrant include, but are not limited to, crospovidone (Polyplasdone XL 10), croscarmellose sodium, and sodium starch glycolate. In one embodiment, the disintegrant is crospovidone (Polyplasdone XL 10). The disintegrant is present in an amount of 2% to 10% by weight of the pharmaceutical composition. In various embodiments, the disintegrant is present in an amount of at least 2%, at least 4%, at least 6%, at least 8%, or at least 10%. In an embodiment, the

pharmaceutical composition comprises about 3% to about 8% by weight crospovidone.

In specific embodiments, the pharmaceutical composition comprises 7.5% by weight crospovidone. In another embodiment, the pharmaceutical composition comprises 3% by weight crospovidone.

[0094] The pharmaceutical composition may further include a filler. Non limiting examples of fillers include microcrystalline cellulose (ex. Avicel), spray-processed lactose, dicalcium phosphate dehydrate, and spray-dried sucrose. In one embodiment, the filler is microcrystalline cellulose. The filler is present in an amount of about 0% to about 70% by weight of the pharmaceutical composition. In various embodiments, the filler comprises 0%, greater than 0%, at least 5%, at least 15%, at least 25%, at least 35%, at least 50%, at least 60%, or at least 70% by weight of the pharmaceutical composition. In an embodiment, the filler is 30% to 35% by weight of the composition. In one embodiment, the pharmaceutical composition comprises about 33% by weight microcrystalline cellulose, or Avicel.

[0095] The pharmaceutical composition may further comprise an excipient, such as a lubricant, gliding agent, and/or tacking agent. In some embodiments, the excipient may be magnesium stearate, colloidal silica, magnesium silicate, talc, or combinations thereof. Other excipients may include diluents, colorants, flavorings, and preservatives. In one embodiment, the excipient may be a lubricant selected from colloidal silicon dioxide, magnesium stearate, and combinations thereof. The excipient may function as an anti-caking agent, filler, flow agent, lubricant, or glidant in the pharmaceutical compositions disclosed herein. The pharmaceutical composition may comprise one or more excipients in a content ranging from 0.1 % to 5% by weight, in particular 0.5% to 2% by weight relative to the total weight of the pharmaceutical composition.

[0096] The orally disintegrating tablet may have a minimum hardness required for handling and packaging. The orally disintegrating tablet may have a maximum diameter of 10 mm to minimize the risk of choking if the tablet is swallowed intact without chewing. In some embodiments, the ODT may disintegrate within 30 seconds, such as about 15 seconds. The ODT may be about 400 mg and have a

harness of 70N to 90N. In some embodiments, the orally disintegrating tablet may be stored for up to 3 months, up to 6 months, or up to 1 year. In some examples, the orally disintegrating tablet may be stored at up to 40°C and 75% relative humidity, up to 30°C and 65% relative humidity, or up to 25°C and 60% relative humidity.

[0097] In other embodiments, the pharmaceutical composition may be a chewable composition that includes the components of the orally disintegrating tablet and further includes a gum. Examples of gums include xanthan gum, guar gum, and a mixture of guar gum and microcrystalline cellulose. In one embodiment, the gum is xanthan gum. The gum may be present in an amount of about 0% to about 3% by weight of the composition. In an embodiment, the gum is 0.25% to 1 % by weight of the pharmaceutical composition. If the pharmaceutical composition includes a gum, the amount of sugar alcohol and/or filler may be reduced by the respective amount of the gum.

[0098] The chewable composition may have a minimum hardness required for handling and packaging and a maximum hardness of 1 18 N. The chewable tablet may have a maximum diameter of 10 mm to minimize the risk of choking if the tablet is swallowed intact without chewing. In some embodiments, the chewable tablet may be stored for up to 6 months at up to 40°C and 75% relative humidity or up to 1 year at up to 25°C and 60% relative humidity.

[0099] The ODT or chewable tablet may be compressed, compacted, molded, or layered. Such dosage forms may be prepared using conventional methods known to those in the field of pharmaceutical formulation and described in pertinent texts, e.g., in Gennaro, A. R., editor.“Remington: The Science & Practice of

Pharmacy”, 21 st ed., 2006, Williams & Williams, and in the“Physician’s Desk

Reference”, 66th ed., 2014, PDR Staff.

(d) Pharmacokinetic Properties

[00100] In an embodiment, the active ingredient is released from the pharmaceutical composition in a pulsatile manner, such that a first portion of the active ingredient is immediately released upon administration and a second portion of the active ingredient is released after an initial delay period in a bimodal manner. This pulsatile release produces a plasma profile substantially similar to the plasma profile produced by the administration of two immediate release dosage forms given sequentially. For example, the pharmaceutical composition may be bioequivalent to FOCALIN® XR.

[00101 ] In some examples, 90% confidence intervals (Cls) of the geometric mean test/reference (T/R) ratios for one or more of the metrics (Cmax, AUC0-3h, AUC3-7h, AUC7-i2h, AUCo-inf) for the orally disintegrating tablet and/or the chewable tablet may fall within 80%-125% of the respective metrics for FOCALIN XR® when administered in a fasted condition, a fed condition, and/or a fasted condition with the contents sprinkled over a spoonful of applesauce. In at least one example the Cmax and AUC0-inffor the orally disintegrating tablet (with fast, medium, or slow MR particles) is within 80% to 152% of the Cmax and AUCo-inf of FOCALIN XR® in the fasted or fed state.

(e) In Vitro Dissolution Profiles

[00102] The release of the active ingredient from the immediate release particles is immediate, such that 80% to 100% of the active ingredient is released in vitro within at least 30 minutes or at least 1 hour. In one embodiment, 85% of the active ingredient is released at 1 hour when tested in a dissolution apparatus 2 according to USP 38 <71 1 > in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm. In another embodiment, 87% of the active ingredient is released at 30 minutes when tested in a dissolution apparatus 2 according to USP 38 <71 1 > in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37°C and a paddle speed of 75 rpm.

[00103] The release of the active ingredient from the modified release particles may be triggered by a change in pH. For example, the release from the modified release particles may be delayed in an acidic pH. The modified release particles may release more than 80% of the active ingredient in vitro within up to about 4 hours, up to about 6 hours, or up to about 16 hours of being in pH 6.8. In one embodiment, the modified release particles release less than 20% of the active ingredient at 2 hours when tested in a dissolution apparatus 2 according to USP 38

<71 1 > in 900 mL of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm. In another embodiment, the modified release particles release less than 20% of the active ingredient, preferentially less than 10% of the active ingredient at 1 hour when tested in a dissolution apparatus 2 according to USP 38 <71 1 > in 900ml of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37°C and a paddle speed of 75 rpm. In yet another embodiment, the modified release particles release more than 80% of the active ingredient at 18 hours when tested in a dissolution apparatus 2 according to USP 38 <71 1 > in 900ml of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37°C and a paddle speed of 75 rpm.

[00104] In a specific embodiment, the modified release fraction of the pharmaceutical composition releases more than 80% of the active ingredient at 4 hours when tested in a dissolution apparatus 2 according to USP 38 <71 1 > in 900ml of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37°C and a paddle speed of 75 rpm. In another specific embodiment, the modified release fraction of the pharmaceutical composition releases more than 80% of the active ingredient at 8 hours when tested in a dissolution apparatus 2 according to USP 38 <71 1 > in 900ml of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37°C and a paddle speed of 75 rpm.

[00105] In an embodiment, the modified release fraction of the

pharmaceutical composition may have a limited release (e.g. less than 20%) of the active ingredient at 2 hours in 0.1 N HCI, a limited release (e.g. less than 20%) of the active ingredient at 1 hour in pH 6.8, and a full release (e.g. more than 80%) of the active ingredient at 4 hours in pH 6.8. In another embodiment, the modified release fraction of the pharmaceutical composition may have a limited release (e.g. less than 20%) of the active ingredient at 2 hours in 0.1 N HCI, a limited release (e.g. less than 20%) of the active ingredient at 1 hour in pH 6.8, and a full release (e.g. more than 80%) of the active ingredient at 6 hours in pH 6.8.

[00106] In an embodiment, the pharmaceutical composition releases the active ingredient in a pulsatile manner, such that at least 80% of the active ingredient in the immediate release particles and less than 20% of the active ingredient in the

modified release particles is released at 2 hours when tested in a dissolution apparatus 2 according to USP 38 <71 1 > in 900 ml_ of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, and more than 80% of the active ingredient in the modified release particles is released at 4 hours when tested in a dissolution apparatus 2 according to USP 38 <71 1 > in 900ml of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37°C and a paddle speed of 75 rpm. In another embodiment, the pharmaceutical composition releases the active ingredient in a pulsatile manner, such that at least 80% of the active ingredient in the immediate release particles and less than 20% of the active ingredient in the modified release particles is released at 2 hours when tested in a dissolution apparatus 2 according to USP 38 <71 1 > in 900 ml_ of 0.1 N hydrochloric acid at a temperature of 37°C and a paddle speed of 75 rpm, and more than 80% of the active ingredient in the modified release particles is released at 6 hours when tested in a dissolution apparatus 2 according to USP 38 <71 1 > in 900ml of 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of 37°C and a paddle speed of 75 rpm. In yet another embodiment, at least about 40% of the active ingredient in the pharmaceutical composition is released at 2 hours in 0.1 N HCI, and at least about 80% of the active ingredient is released at 4 hours in pH 6.8 after being in the acidic pH for at least 2 hours.

(II) METHODS OF TREATMENT

[00107] Further provided herein is a method for treating a patient in need thereof by administering a therapeutically effective amount of the pharmaceutical composition. In an embodiment, the method may include treating attention deficit hyperactivity disorder (ADHD) by administering the pharmaceutical composition to a patient in need thereof. In at least one embodiment, the method may include treating ADHD in children above 6 years old by administering the pharmaceutical composition to the child in need thereof.

[00108] Administration of the pharmaceutical patient to a patient releases the active ingredient in a pulsatile manner. In various embodiments, the pharmaceutical composition is administered to the patient once daily.

DEFINITIONS

[00109] When a pharmacokinetic comparison is made between a

formulation described or claimed herein and a reference product, it will be understood that the comparison is performed in a suitable designed cross-over trial, although it will also be understood that a cross-over trial is not required unless specifically stated. It will also be understood that the comparison may be made either directly or indirectly.

For example, even if a formulation has not been tested directly against a reference formulation, it may still satisfy a comparison to the reference formulation if it has been tested against a different formulation, and the comparison with the reference formulation may be deduced therefrom.

[00110] When introducing elements of the present invention or the preferred embodiments(s) thereof, the articles "a", "an", "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and

"having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0011 1 ] The terms“about” or“substantially” or“approximately” will compensate for variability allowed for in the pharmaceutical industry and inherent in pharmaceutical products, such as differences in product strength due to manufacturing variation and time-induced product degradation. Particularly in reference to a given quantity,“about” is meant to encompass deviations of plus or minus five percent.

[00112] The term "enteric polymer" is used herein to represent a polymer, whose solubility is dependent on the pH in such a manner that it generally prevents the release of the drug in the stomach but permits the release of the drug at some stage after the formulation has emptied from the stomach.

[00113] The term“pulsatile” or“pulsatile profile” is meant to encompass the plasma profile associated with the administration of a drug where pulses of high active ingredient concentration are interspersed with low concentration troughs. A pulsatile profile with two peaks is“bimodal” or“multi-phasic”. A composition or a dosage form which produces a pulsatile profile upon administration may exhibit a“pulsed release” of the active ingredient.

[00114] The term“multiparticulate” as used herein means a plurality of discrete, or aggregated, particles, pellets, beads, granules or mixture thereof

irrespective of their size, shape or morphology.

[00115] The term“orally disintegrating,”“orodispersible,” or“dispersible” is used herein to represent formulations which are orally disintegrating, mouth-dissolving, rapid-dissolving, fast-disintegrating, or fast-dissolving.

[00116] The term“bioequivalence” means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives become available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.

[00117] “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use. The term“formulation” or “composition” refers to the quantitative and qualitative characteristics of a drug product or dosage form prepared in accordance with the current invention.

[00118] The term“modified-release (MR)” includes particles that lend to or support a particular MR pharmacokinetic characteristic. The modified release particles are designed to deliver drugs at a specific time or over a period of time after

administration, or at a specific location in the body. The USP defines a modified release system as one in which the time course or location of drug release or both, are chosen to accomplish objectives of therapeutic effectiveness or convenience not fulfilled by conventional IR dosage forms. More specifically, MR particles include extended release (ER) and delayed-release (DR) products. A DR product is one that releases a drug all at once at a time other than promptly after administration. Typically, coatings (e.g., enteric coatings) are used to delay the release of the drug substance until the dosage form has passed through the acidic medium of the stomach. An ER product is formulated to make the drug available over an extended period after ingestion, thus allowing a reduction in dosing frequency compared to a drug presented as a conventional dosage form, e.g. a

solution or an immediate release dosage form. For oral applications, the term “extended-release” is usually interchangeable with“sustained-release”,“prolonged-release” or“controlled-release”.

[00119] Traditionally, extended-release systems provided constant drug release to maintain a steady concentration of drug. For some drugs, however, zero-order delivery may not be optimal and more complex and sophisticated systems have been developed to provide multi-phase delivery. One may distinguish among four categories of oral modified release (MR) delivery systems: (1 ) delayed- release using enteric coatings, (2) site-specific or timed release (e.g. for colonic delivery), (3) extended-release (e.g., zero-order, first-order, biphasic release, etc.), and (4), programmed release (e.g., pulsatile, delayed extended release, etc.) See Modified Oral Drug Delivery Systems at page 34 in Gibaldi’s DRUG DELIVERY SYSTEMS IN

PHARMACEUTICAL CARE, AMERICAN SOCIETY OF HEALTH-SYSTEM

PHARMACISTS, 2007 and Rational Design of Oral Modified-release Drug Delivery Systems at page 469 in DEVELOPING SOLID ORAL DOSAGE FORMS:

PHARMACEUTICAL THEORY AND PRACTICE, Academic Press, Elsevier, 2009. As used herein,“modified release formulation” or“modified release portion” in one embodiment refers to a composition that releases its active substance according a multiphase delivery that is comprised in the fourth class of MR products, e.g. delayed extended release. As such it differs from the delayed release products that are classified in the first class of MR products.

EXAMPLES

[00120] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples represent techniques discovered by the inventors to function well in the practice of the invention. Those of skill in the art should, however, in light of the present disclosure, appreciate that many changes may be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention, therefore all matter set forth is to be interpreted as illustrative and not in a limiting sense.

Example 1: Dexmethylphenidate HCI Layered Particles

[00121 ] Dexmethylphenidate HCI layered particles were prepared as follows. 675g of Dexmethylphenidate HCI and 75 g of hydroxypropylcellulose (Klucel™ EF Pharm) were solubilized in 2125g of water and 2125g of ethanol. The solution was entirely sprayed onto 500g of microcrystalline cellulose spheres (CP 203®) in a fluid bed spray coater apparatus. Layered particles had a mean diameter of about 370pm. FIG. 1 and Table 1 provide the composition of the dexmethylphenidate HCI layered particles.

Table 1 : Composition of drug layered particles

Example 2: Dexmethylphenidate HCI Immediate Release Particles For Taste- Masking

[00122] Dexmethylphenidate HCI immediate release (IR) coated particles for taste-masking were prepared as follows. 72 g Cellulose Acetate (CA-398-10) and 8 g of Triethylcitrate were solubilized in 46g of ethanol and 874 g of ethanol. The solution was entirely sprayed onto 320g of dexmethylphenidate HCL layered particles of Example 1 in a fluid bed spray coater apparatus. The dexmethylphenidate immediate release (IR) coated particles had a mean diameter of about 400 pm. FIG. 2 and Table 2 provide the composition of the dexmethylphenidate, taste-masked immediate release particles.

Table 2: Composition of IR coated particles


Example 3: Dexmethylphenidate HCI Modified Release 25% Coated Particles

[00123] Dexmethylphenidate HCI modified release (MR) 25% coated particles were prepared as follows. 78 g cellulose acetate butyrate (Cellaburate, CAB- 171 -15), 19.5g methacrylic acid and methylmethacrylate copolymer (1 : 1 ), 13g methacrylic acid and methylmethacrylate copolymer (1 :2) and 19.5 g of castor oil were solubilized in 807g of acetone, 538.2 g of ethanol and 149.5g of water. The solution was entirely sprayed onto 390g of dexmethylphenidate HCI layered particles in a fluid bed spray coater apparatus. Dexmethylphenidate MR coated particles with mean diameters of 417 pm were obtained. FIG. 3 and Table 3 provide the composition of the 25% coated modified release particles.

Table 3: Composition of MR 25% coated particles



Example 4: Dexmethylphenidate HCI Modified Release (MR) 30% Coated Particles

[00124] Dexmethylphenidate HCL MR 30% coated particles were prepared as follows. 102.6 g cellulose acetate butyrate (Cellaburate, CAB-171 -15), 25.7g methacrylic acid and methylmethacrylate copolymer (1 :1 ), 17.1 g methacrylic acid and methylmethacrylate copolymer (1 :2) and 25.7 g of castor oil were solubilized in 1061 9g of acetone, 707.9 g of ethanol and 196.7g of water. The solution was entirely sprayed onto 399g of dexmethylphenidate HCI layered particles in a fluid bed spray coater apparatus. The dexmethylphenidate modified release coated particles had a mean diameter of 423 pm. FIG. 4 and Table 4 provide the composition of the 30% coated modified release particles.

Table 4: Composition of MR 30% coated particles


Example 5: Dexmethylphenidate HCL Modified Release 35% Coated Particles

[00125] Dexmethylphenidate HCL MR 35% coated particles were prepared as follows. 126 g cellulose acetate butyrate (Cellaburate, CAB-171 -15), 31.5g methacrylic acid and methylmethacrylate copolymer (1 :1 ), 21 g methacrylic acid and methylmethacrylate copolymer (1 :2) and 31.5 g of castor oil were solubilized in 1304.1 g of acetone, 869.4g of ethanol and 241 5g of water. The solution was entirely sprayed onto 390g of dexmethylphenidate HCI layered particles in a fluid bed spray coater apparatus. Dexmethylphenidate modified release coated particles with mean diameters of 435 pm were obtained. FIG. 5 and Table 5 provide the composition of the 30% coated modified release particles.

Table 5: Composition of MR 35% coated particles

Example 6: Dexmethylphenidate HCI Extended Release 25% Orally Disintegrating Tablet

[00126] A 40 mg dose dexmethylphenidate HCI extended release

(ER) 25% orally disintegrating tablet (ODT) was prepared as follows. Half of the dose was as an IR fraction and half as an MR fraction. 34.7g of IR coated particles, 37g of MR 25% coated particles, 101 .4g of cellulose microcrystalline (Avicel PH 102), 101.4g of mannitol (Pearlitol SD200), 22.5g of crospovidone (Polyplasdone XL-10), 0.6g of colloidal silicon dioxide (Aerosil 200) and 2.4g of magnesium stearate were mixed then tablets 10 mm in diameter and 400 mg mass were manufactured using a press. Table 6 provides the composition of the ER 25% ODT.

Table 6: Composition of ER 25% Orally Disintegrating Tablet


Example 7; Dexmethylphenidate HCI ER 30% Orally Disintegrating Tablets

[00127] A 40 mg dose dexmethylphenidate HCI ER 30% ODT was prepared as follows. Half of the dose was as an IR fraction and half as an MR fraction. 34.7g of IR coated particles, 39.7g of MR 30% coated particles, 100g of cellulose microcrystalline (Avicel PH102), 100g of mannitol (Pearlitol SD200), 22.5g of crospovidone (Polyplasdone XL-10), 0.6g of colloidal silicon dioxide (Aerosil 200) and 2.4g of magnesium stearate were mixed then tablets 10 mm in diameter and 400 mg mass were manufactured using a press. Table 7 provides the composition of the ER 30% ODT.

Table 7: Composition of ER 30% Orally Disintegrating Tablets



Example 8: Dexmethylphenidate HCI ER 35% Orally Disintegrating Tablets

[00128] A 40 mg dose dexmethylphenidate HCI ER 35% ODT was prepared as follows. Half of the dose was as an IR fraction and half as an MR fraction. 34.7g of IR coated particles, 42.75g of MR 35% coated particles, 98.5g of cellulose microcrystalline (Avicel PH102), 98.5g of mannitol (Pearlitol SD200), 22.5g of crospovidone (Polyplasdone XL-10), 0.6g of colloidal silicon dioxide (Aerosil 200) and 2.4g of magnesium stearate were mixed then tablet 10 mm of diameter and 400 mg mass were manufactured using a press. Table 8 provides the composition of the ER 35% ODT.

Table 8: Composition of ER 35% Orally Disintegrating Tablets


Example 9: In Vitro Dissolution Testing of IR Coated Particles

[00129] The dissolution profile of 92.6 mg of IR coated particles described in Example 2, corresponding to 40 mg of dexmethylphenidate HCL per vessel, is determined in phosphate 50mM buffer pH 6.8 using a USP II apparatus. Dissolution

medium is maintained at 37°C and the rotating speed is fixed at 75 RPM. The release profile of IR coated particles is shown in FIG. 6. All the dexmethylphenidate HCL is released after 1 hour.

Example 10: In Vitro Dissolution Testing of MR Coated Particles

[00130] The dissolution profile of the MR 25, 30 or 35% coated particles described in Examples 3-5 was performed as follows: 2.97g of MR coated particles from Examples 3-5 were lubricated with 0.03g of magnesium stearate. The dissolution profiles of the MR coated particles were determined using a USP II apparatus. The mass of lubricated MR particles corresponding to 40 mg of dexmethylphenidate HCL was 99.8 mg in the case of MR 25 coated particles lubricated, 107 mg in the case MR 30 coated particles lubricated and 1 15.1 mg in the case of MR 35 coated particles lubricated. The dissolution medium temperature was maintained at 37°C and the rotating paddle speed fixed at 75 RPM. The release profile of MR coated particles in 900 ml HCL 0.1 N buffer is shown in FIG. 7 and the release profile of MR coated particles in 900ml phosphate 50mM pH 6.8 buffer is shown in FIG. 8.

Example 11: In Vitro Dissolution Testing of ER Orally Disintegrating Tablets

[00131 ] The dissolution profile of 400 mg ER 25%, 30% or 35% orally disintegrating tablets described in Examples 6-8, corresponding to 40 mg of

dexmethylphenidate HCL was determined using a USP II apparatus. Dissolution medium was maintained at 37°C and the rotating speed fixed at 75RPM. The release profile of ER ODT in 900ml 0.1 N HCL buffer is shown in FIG. 9 and the release profile of ER ODT in 900 ml phosphate 50mM pH 6.8 buffer is shown in FIG. 10.

Example 12: IR Coated Particles For Taste-Masking

[00132] An alternative composition of dexmethylphenidate HCI IR coated particles using Cellulose Acetate for taste-masking was formed as follows. 180g of Dexmethylphenidate HCI and 20g of water soluble polymer hydroxypropylcellulose (Klucel™ EF Pharm) were solubilized in 566.7g of absolute ethyl alcohol and 566.7g of water. The solution was entirely sprayed onto 800g of microcrystalline cellulose spheres (Celphere™ CP203) in a fluid bed spray coater apparatus. Particles with a mean diameter of 291 pm were obtained.

[00133] 90. Og of Cellulose Acetate (CA-398-10), 10g of TriEthylCitrate

(TEC), were dissolved in 1092.5g of acetone and 57.5g of isopropanol. The solution was sprayed entirely on 400. Og of the drug-layered IR particles above in a fluid bed spray coater apparatus with an inlet temperature 53°C, spraying rate around 10g per min and atomization pressure 2.5b. Microparticles with a mean diameter of 327pm were obtained.

Example 13: In Vitro Release Profiles

[00134] The dissolution profile of 281 mg of taste-masked particles of Example 12, corresponding to 40mg of Dexmethylphenidate HCI per vessel, was determined in 0.1 N HCI dissolution medium using a USP II apparatus. Dissolution medium temperature was maintained at 37.0 ± 0.5°C, and the rotating paddle speed was fixed at 75 rpm. The release profile of the IR particles is shown in FIG. 11 A. All the dexmethylphenidate HCI was released after one hour.

Example 14: IR Coated Particles For Taste-Masking

[00135] An alternative composition of dexmethylphenidate HCI IR coated particles using Cellulose Acetate Butyrate for taste-masking was formed as follows.

180g of Dexmethylphenidate HCI and 20g of water soluble polymer

hydroxypropylcellulose (Klucel™ EF Pharm) were solubilized in 566.7g of absolute ethyl alcohol and 566.7g of water. The solution was entirely sprayed onto 800g of

microcrystalline cellulose spheres (Celphere™ CP203) in a fluid bed spray coater apparatus. Particles with a mean diameter of 289pm were obtained.

[00136] 67.1 g of Cellulose Acetate Butyrate (Cellaburate, CAB-171 -15),

3.5g of TriEthylCitrate (TEC), were dissolved in 771.4g of acetone and 40.6g of isopropanol. The solution was sprayed entirely on 400. Og of drug-layered IR particles above in a fluid bed spray coater apparatus with an inlet temperature 55°C, spraying

rate around 10g per min and atomization pressure 2.5b. Microparticles with a mean diameter of 305pm were obtained.

Example 15: In Vitro Release Profiles

[00137] The dissolution profile of 222mg of IR particles and of 264mg of taste-masked (TM) particles of Example 14, corresponding to 40mg of

dexmethylphenidate HCI per vessel, was determined in 0.1 N HCI dissolution medium using a USP II apparatus. Dissolution medium temperature was maintained at 37.0 ± 0.5°C, and the rotating paddle speed was fixed at 75 rpm. The release profile of the IR and TM microparticles is shown in FIG. 12. All the dexmethylphenidate HCI was released from the IR microparticles after 15 minutes. The API release is much slower from the CAB-based microparticles showing that they may not be suitable for taste-masked microparticles exhibiting an immediate-release profile.

Example 16: Dexmethylphenidate HCI Modified Release 18% Coated Particles

[00138] Alternative compositions that may be obtained by changing the solvents for the coating step of the modified release particles and/or the coating process conditions are described in Examples 16 to 18.

[00139] Dexmethylphenidate HCL modified release 18% coated particles were prepared as follows. 108 g cellulose acetate butyrate, 27g methacrylic acid-methylmetacrylate copolymer (1 : 1 ), 18g methacrylic acid- methylmetacrylate copolymer (1 :2) and 27 g of castor oil were solubilized in 1656g of acetone and 414g of ethanol. The solution was entirely sprayed onto 820g of dexmethylphenidate HCL layered particles in a fluid bed spray coater apparatus. Dexmethylphenidate IR coated particles with means diameter of 407 pm were obtained.

[00140] FIG. 14 and Table 9 provide the composition of the 18% coated modified release particles.

Table 9: Composition of 18% coated modified release particles


Example 17: Dexmethylphenidate HCI Modified Release 20% Coated Particles

[00141 ] Dexmethylphenidate HCL modified release 20% coated particles are prepared as follows. 120 g cellulose acetate butyrate, 30g methacrylic acid- methylmetacrylate copolymer (1 : 1 ), 20g methacrylic acid- methylmetacrylate copolymer (1 :2), and 30 g of castor oil were solubilized in 1840g of acetone and 460g of ethanol. The solution was entirely sprayed onto 800g of dexmethylphenidate HCL layered particles in a fluid bed spray coater apparatus. Dexmethylphenidate MR coated particles with means diameter of 412 pm were obtained.

[00142] FIG. 15 and Table 10 provide the composition of the 20% coated modified release particles.

Table 10: Composition of the 20% coated delayed release particles.



Example 18: Dexmethylphenidate HCL Modified Release 26% Coated Particles

[00143] Dexmethylphenidate HCL modified release 26% coated particles are prepared as follows. 156 g cellulose acetate butyrate, 39g methacrylic acid- methylmetacrylate copolymer (1 : 1 ), 26g methacrylic acid- methylmetacrylate copolymer (1 :2), and 39 g of castor oil were solubilized in 2392g of acetone and 598g of ethanol. The solution was entirely sprayed onto 740g of dexmethylphenidate HCL layered particles in a fluid bed spray coater apparatus. Dexmethylphenidate MR coated particles with means diameter of 421 pm were obtained.

[00144] FIG. 16 and Table 11 provide the composition of the 26% coated modified release particles.

Table 1 1 : composition of the 26% coated delayed release particles.


Example 19: Dexmethylphenidate HCI Extended Release 18% Orally

Disintegrating Tablet

[00145] A 40 mg dose dexmethylphenidate HCI extended release (ER) 18% orally disintegrating tablet was prepared as follows. Half of the dose was as an IR fraction and half was an MR fraction. 34.5g of IR coated particles, 33.9g of MR 18% coated particles, 103.05g of cellulose microcrystalline, 103.05g of mannitol, 22.5g of crospovidone, 0.6g of Colloidal silicon dioxide, and 2.4g of magnesium stearate were mixed. Then tablets 10 mm in diameter and 400 mg mass were manufactured using a press.

[00146] Table 12 provides the composition of the ER 18% ODT.

Table 12: Composition of the ER 18% ODT.

Example 20: Dexmethylphenidate HCI ER 26% Orally Disintegrating Tablet

[00147] A 40 mg dose dexmethylphenidate HCI ER 26% ODT was prepared as follows. Half of the dose was as an IR fraction and half was an MR fraction. 37.04g of IR coated particles, 40.04g of MR 26% coated particles, 107.86g of cellulose microcrystalline, 107.86g of mannitol, 24g of crospovidone, 0.64g of Colloidal silicon dioxide, and 2.56g of magnesium stearate were mixed. Then tablets 10 mm in diameter and 400 mg mass were manufactured using a press.

[00148] Table 13 provides the composition of the ER 26% ODT.

Table 13: Composition of the ER 26% ODT.


Example 21: In Vitro Dissolution Testing Of MR Coated Particles

[00149] The dissolution profiles of the MR 18%, 20% or 26% coated particles described in Examples 16-18 were performed as follows. 2.97g of MR coated particles from Examples 16-18 were lubricated with 0.03g of magnesium stearate. The dissolution profiles of the MR coated particles were determined using a USP II apparatus. The mass of lubricated MR particles corresponding to 40 mg of

dexmethylphenidate HCL was 91.2 mg in the case of MR 18% coated particles lubricated, 93.5 mg in the case MR 20% coated particles lubricated, and 101.1 mg in the case of MR 26% coated particles lubricated. The dissolution medium temperature was maintained at 37°C and the rotating paddle speed fixed at 75 RPM. The release profile of the MR coated particles in 900 ml phosphate 50mM pH 6.8 buffer is shown in FIG 17A. FIG. 17B shows the release profile for the MR 18% coated particles with a diameter greater than 315 pm in 900ml 0.1 N HCL buffer (pH 1.1 ) and 900 ml phosphate 50mM pH 6.8 buffer. FIG. 17C shows the release profile for the MR 20% coated particles with a diameter greater than 315 pm in 900ml 0.1 N HCL buffer (pH 1.1 ) and 900 ml phosphate 50mM pH 6.8 buffer. FIG. 17D shows the release profile for the MR 26% coated particles with a diameter greater than 315 pm in 900ml 0.1 N HCL buffer (pH 1.1 ) and 900 ml phosphate 50mM pH 6.8 buffer.

Example 22: In Vitro Dissolution Testing Of Orally Disintegrating Tablets

[00150] The dissolution profiles of 400 mg 18% or 26% orally disintegrating tablets described in Examples 19-20, corresponding to 40 mg of dexmethylphenidate HCL was determined using a USP II apparatus. Dissolution medium was maintained at 37°C and the rotating speed fixed at 75RPM. The release profile of ER 18% and 26% ODT in 900ml 0.1 N HCL buffer is shown in FIG. 18 and the release profile of ER 18% and 26% ODT in 900 ml phosphate 50mM pH 6.8 buffer is shown in FIG. 19.

[00151 ] FIG. 20A shows the release profile of 40 mg dose orally

disintegrating tablets with MR 18%, 20%, and 26% coated particles in 0.1 N HCL buffer as compared to FOCALIN® XR. FIG. 20B shows the release profile of 40 mg dose orally disintegrating tablets with MR 18%, 20%, and 26% coated particles in phosphate 50mM pH 6.8 buffer as compared to FOCALIN® XR.

Example 23: In Vitro Dissolution Testing Of Orally Disintegrating Tablets

[00152] The stability of orally disintegrating tablets with MR 18%, 20%, and 26% coated particles was tested after 3 months storage at either 40°C and 75% relative humidity or 25°C and 60% relative humidity. FIGS. 21 A, 21 B, and 21C show the release of the disintegrating tablets with MR 18%, 20%, and 26% coated particles, respectively, each in 0.1 N HCL buffer (pH 1.1 ) and in phosphate 50mM pH 6.8 buffer after the storage conditions.

Example 24: Chewable Tablet

[00153] To examine the manufacturing and the dissolution profile of a chewable tablet, the following was performed.

[00154] Dexmethylphenidate HCL modified release 40% coated particles were prepared as follows. 160 g cellulose acetate butyrate, 40g methacrylic acid-methylmetacrylate copolymer (1 : 1 ), 40g methacrylic acid- methylmetacrylate copolymer (1 :2), and 26.7 g of castor oil were solubilized in 1656g of acetone, 1 104g of isopropyl alcohol and 307g of water. The solution was entirely sprayed onto 400g of

dexmethylphenidate HCL layered particles in a fluid bed spray coater apparatus.

Dexmethylphenidate MR coated particles with means diameter of 462 pm were obtained.

[00155] Dexmethylphenidate HCI extended release (ER) 40% chewable tablet dose 40 mg (half as IR fraction and half as MR fraction) were prepared as follows. 20g of Dexmethylphenidate HCL, 61.6g of MR 40%coated particles, 67.6g of cellulose

microcrystalline, 210.7g of mannitol, 30g of crospovidone, 2.1 g of Xanthan gum, 0.8g of Colloidal silicon dioxide, 4.0g of talc, and 3.2g of magnesium stearate were mixed. Then tablets 10 mm in diameter and 400 mg mass were manufactured using a press.

[00156] Table 14 provides the composition of the ER 40% chewable tablet.

Table 14: Composition of the ER 40% chewable tablet.


[00157] The dissolution profile of 400 mg ER 40% chewable tablets corresponding to 40 mg of dexmethylphenidate HCL was determined using a USP II apparatus. Dissolution medium was maintained at 37°C and the rotating speed fixed at 75RPM. The release profile of the ER chewable tablet in 900ml 0.1 N HCL buffer and the release profile of the ER chewable tablet in 900 ml phosphate 50mM pH 6.8 buffer are shown in FIG. 22A.

[00158] An alternative chewable tablet was manufactured with a

composition as shown in Table 15. The resulting chewable tablets had a 40 mg dose of dexmethylphenidate HCL, a mass of 382 g, a diameter of 10 mm, a hardness of 50 N, a disintegrating time of 25 s, and a friability of 0.55%. The release profile of the alternative chewable tablet in 900ml 0.1 N HCL buffer and the release profile of the alternative chewable tablet in 900 ml phosphate 50mM pH 6.8 buffer are shown in FIG. 22B.

Table 15: Composition of the chewable tablet.



[00159] Having described several embodiments, it will be recognized by those skilled in the art that various modifications, alternative constructions, and equivalents may be used without departing from the spirit of the invention. Additionally, a number of well-known processes and elements have not been described in order to avoid unnecessarily obscuring the present invention. Accordingly, the above

description should not be taken as limiting the scope of the invention.

[00160] Those skilled in the art will appreciate that the presently disclosed embodiments teach by way of example and not by limitation. Therefore, the matter contained in the above description or shown in the accompanying drawings should be interpreted as illustrative and not in a limiting sense. The following claims are intended to cover all generic and specific features described herein, as well as all statements of the scope of the present method and system, which, as a matter of language, might be said to fall therebetween.