Compositions comprising methylphenidate complexed with ion-exchange resin particles
Inventors
Tengler, Mark • McMahen, Russell
Assignees
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Publication Number
US-9089496-B2
Publication Date
2015-07-28
Expiration Date
Abstract
Pharmaceutical compositions of methylphenidate complexed with ion-exchange resin particles to form drug-resin particles are provided. The compositions have a first plurality of drug-resin particles that are uncoated and a second plurality of drug-resin particles that are coated with a delayed release coating.
Core Innovation
The invention relates to a pharmaceutical composition comprising an ADHD effective agent complexed with ion-exchange resin particles to form drug-resin particles, wherein the ADHD effective agent is methylphenidate. The composition includes a first plurality of drug-resin particles that provide for immediate release and a second plurality of drug-resin particles that are coated with a delayed release coating, with the delayed release behavior produced by coating structure rather than by a single release population.
The second plurality is coated with a triggered-release coating triggered by a pH change and a diffusion barrier coating. The composition is defined by a specific weight split of methylphenidate between the immediate and delayed populations, where 20%-30% by weight of the methylphenidate is present in the first plurality and 70%-80% by weight of the methylphenidate is present in the second plurality.
The disclosed invention also provides an ADHD pharmaceutical system including methylphenidate in ion-exchange drug-resin particles, with a plurality of immediate release uncoated drug-resin particles and a delayed release fraction formed by drug-resin particles coated with a pH-triggered release coating. The delayed release fraction uses pH-triggered release polymer coatings such as EUDRAGIT L100 variants, with optional overcoating by diffusion barrier polymers, including ethylcellulose, to shape dissolution and to generate an ascending and/or bimodal in vivo plasma profile.
In the described pharmacokinetic performance requirement, administration to a human produces a mean plasma concentration profile for d-methylphenidate with one or more AUC parameters substantially similar to those of in vivo serum profiles of methylphenidate-containing drug-resin particle compositions shown in FIG. 20A, and in a human adult the composition produces an AUC0-∞ of about 160 ng hr/ml to about 180 ng hr/ml for total methylphenidate when the total methylphenidate dose is equivalent to that present in about a 60 mg total dose of methylphenidate hydrochloride.
Claims Coverage
The provided material includes two independent claims. Across the claims, the central inventive theme is an ADHD methylphenidate ion-exchange drug-resin composition with immediate-release and delayed-release populations defined by coating features, a methylphenidate weight split, and specified human pharmacokinetic or exposure profile constraints.
Methylphenidate ion-exchange drug-resin composition for ADHD
A pharmaceutical composition comprising an ADHD effective agent complexed with ion-exchange resin particles to form drug-resin particles, wherein the ADHD effective agent is methylphenidate.
Immediate and triggered pH-delayed release drug-resin populations
A composition comprising a first plurality of drug-resin particles that provide for immediate release and a second plurality of drug-resin particles that are coated with a delayed release coating, wherein the drug-resin particles of the second plurality are coated with a triggered-release coating triggered by a pH change and a diffusion barrier coating.
Methylphenidate weight split between immediate and delayed pluralities
20%-30% by weight of said methylphenidate is present in the first plurality of drug-resin particles and 70%-80% by weight of said methylphenidate is present in the second plurality of drug-resin particles.
Substantially similar human d-methylphenidate exposure parameters
Administration of the composition to a human produces a mean plasma concentration profile for d-methylphenidate with one or more AUC parameters substantially similar to those of the in vivo serum profiles of methylphenidate-containing drug-resin particle compositions shown in FIG. 20A.
Adult AUC0-∞ exposure for a 60 mg-equivalent methylphenidate dose
The composition would produce, in a human adult, a mean plasma concentration versus time curve having an AUC0-∞ of about 160 ng hr/ml to about 180 ng hr/ml for total methylphenidate when the composition contains a total methylphenidate dose equivalent to about a 60 mg total dose of methylphenidate hydrochloride.
Across the independent claims, the inventive features are an ADHD methylphenidate ion-exchange drug-resin composition, immediate-release and pH-triggered delayed-release populations, a specified methylphenidate weight distribution, and human AUC-based exposure constraints.
Stated Advantages
The coating structure is used to shape dissolution and to generate an ascending and/or bimodal in vivo plasma profile.
The system is evaluated for pharmacokinetic and bioequivalence performance relative to reference products such as ADDERALL XR and METADATE CD.
The disclosure reports ethanol and food-effect evaluations under fed and fasted conditions.
Documented Applications
ADHD pharmaceutical system.
Orally disintegrating tablets and liquid suspensions, including chewable compositions.
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