Pharmaceutical composition comprising amphetamines complexed with ion-exchange resin particles
Inventors
Tengler, Mark • McMahen, Russell
Assignees
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Publication Number
US-9265737-B2
Publication Date
2016-02-23
Expiration Date
Abstract
The invention relates to a pharmaceutical composition comprising amphetamines complexed with ion-exchanged resin particles to form drug-resin particles. The composition provides for prolonged therapy.
Core Innovation
The invention relates to pharmaceutical compositions comprising amphetamines complexed with ion-exchange resin particles to form drug-resin particles. The drug-resin particles are provided as a first plurality of immediate release drug-resin particles and a second plurality of drug-resin particles coated with a delayed release coating, and the composition includes an immediate-release portion and a delayed-release portion that together define the release behavior.
The disclosed compositions are structured to control in vivo exposure and release performance, including exposure reduction in the presence of ethanol and maintenance of controlled-release behavior under fed/fasted and ethanol conditions. In a mammal, the presence of ethanol results in reduced exposure to amphetamines compared to a composition without resin particles in the presence of ethanol.
In humans, the compositions are described as providing mean plasma concentration profiles for ADHD-related dosing requirements, including specified AUC and Cmax parameters over defined time windows and, for certain embodiments, a fasted serum profile with two peaks. The disclosed compositions include orally disintegrating tablet and liquid suspension formats, and include pharmacokinetic parameter constraints tied to bioequivalent reference compositions using 90% confidence interval bounds.
Claims Coverage
The provided set includes multiple independent claims covering 9 inventive features: the core drug-resin particle composition with immediate and delayed release fractions; ethanol-related exposure reduction; oral disintegrating tablet and liquid suspension compositions with quantified ADHD exposure windows; total amphetamine exposure AUC constraints; bioequivalence bounds for one or more pharmacokinetic parameters; food-timing exposure comparisons for a first 4 hours; and a fasted two-peak serum pharmacokinetic profile.
Immediate and delayed drug-resin particle composition with defined weight split
Amphetamines are complexed with ion-exchange resin particles to form drug-resin particles, wherein 30 to 50% by weight of the amphetamines are present in a first plurality of immediate release drug-resin particles and 50 to 70% by weight are present in a second plurality of drug-resin particles coated with a delayed release coating.
Ethanol exposure reduction with resin-particle composition and defined amphetamine mixture
A composition including a first plurality of immediate release drug-resin particles and a second plurality of drug-resin particles coated with a delayed release coating, where a mammal receiving the composition in the presence of ethanol is exposed to a reduced amount of amphetamines compared to when the mammal receives a composition without resin particles in the presence of ethanol, the composition comprising a mixture of dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate, and amphetamine sulfate.
Orally disintegrating tablet ADHD plasma profile with specified AUC and Cmax ranges
An orally disintegrating tablet composition comprising a first plurality of immediate release drug-resin particles and a second plurality of drug-resin particles coated with a delayed release coating, complexed dextro- and levo-amphetamines, effective to provide a mean plasma concentration profile in human ADHD patients with specified AUC and Cmax values for a 30 mg total dose across multiple time windows.
Liquid suspension ADHD plasma profile with specified AUC and Cmax ranges
A liquid suspension composition comprising a first plurality of immediate release drug-resin particles and a second plurality of drug-resin particles coated with a delayed release coating, complexed dextro- and levo-amphetamines, effective to provide a mean plasma concentration profile in human ADHD patients with specified AUC and Cmax values for a 30 mg total dose across multiple exposure windows.
Total amphetamine exposure AUC constraint for a 30 mg dose
A composition where, when containing about a total amphetamine dose of 30 mg, the human mean plasma concentration versus time curve for total amphetamines has an AUC0-∞ of about 1140 to about 1240.
Bioequivalence bounds for in vivo pharmacokinetic parameters
A composition comprising dextro-amphetamines, levo-amphetamines, or a racemic mixture complexed with ion-exchange resin particles to form drug-resin particles, including a first plurality of immediate release drug-resin particles and a second plurality coated with a delayed release coating, where one or more in vivo pharmacokinetic parameters selected from Cmax and specified AUC parameters have a 90% confidence interval whose upper and lower bounds are within a range from 90% to 115% of the value of the same parameter(s) for a bioequivalent reference composition.
Food-timed first-4-hours exposure comparison versus reference mixture
A liquid suspension composition where, when a human receives the composition substantially contemporaneously with food, the human is exposed to an increased amount of amphetamines in the first 4 hours compared to a human receiving a reference composition comprising a mixture of dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate, and amphetamine sulfate.
Fasted serum two-peak profile with peak timing windows
A composition with an in vivo fasted serum profile having a first and second peak, where the first peak occurs between 1 and 3 hours after ingestion and the second peak occurs between 4 and 7 hours after ingestion and is the Cmax.
50/50 immediate and delayed drug-resin particle distribution
A composition where about 50% by weight of the amphetamines are present in a first plurality of immediate release drug-resin particles and about 50% by weight are present in a second plurality coated with a delayed release coating.
Overall, the independent claims require amphetamines complexed with ion-exchange resin particles forming immediate-release and delayed-release coated drug-resin particle pluralities, with further constraints directed to ethanol exposure reduction, food/fasted exposure timing, orally disintegrating tablet or liquid suspension ADHD plasma exposure profiles, total exposure AUC limits, and bioequivalence-style 90% confidence interval bounds for selected pharmacokinetic parameters.
Stated Advantages
In the presence of ethanol, a reduced amount of amphetamines exposure compared to a composition without resin particles in the presence of ethanol.
In human ADHD patients, mean plasma concentration profiles with specified AUC and Cmax values for a 30 mg total dose across multiple time windows.
In humans, an orally disintegrating tablet embodiment providing specified mean plasma concentration profiles for dextroamphetamine and/or levoamphetamine.
In humans, a liquid suspension embodiment providing specified mean plasma concentration profiles for dextroamphetamine and/or levoamphetamine.
Bioequivalent pharmacokinetic performance, with selected in vivo parameters having 90% confidence intervals within 90%-115% of a bioequivalent reference composition.
Fasted serum profiles having two peaks with defined timing windows and the second peak being the Cmax.
Documented Applications
Pharmacokinetic evaluation and bioequivalence testing of controlled-release drug–resin formulations versus reference products (including methylphenidate and amphetamine formulations).
Ethanol and food/fed versus fasted studies evaluating exposure effects on methylphenidate (d+l) and amphetamine (mixed amphetamine polistirex) controlled-release ODT formulations.
Human ADHD-related pharmacokinetic studies, including pediatric ADHD cohorts (6–12 years) and related amphetamine formulations (including additional pediatric PK and amphetamine liquid suspension studies).
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