Composition comprising a mixture of dextro- and levo-amphetamines complexed with ion-exchange resin particles to form drug resin particles
Inventors
Tengler, Mark • McMahen, Russell
Assignees
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Publication Number
US-9017731-B2
Publication Date
2015-04-28
Expiration Date
Abstract
The invention relates to dosage forms that provide prolonged therapy. In particular, the invention relates to dosage forms including various pluralities of drug-containing resin particles. In a particular embodiment, the drug dosage form comprises a mixture of dextro- and levo-amphetamines complexed with ion-exchange resin particles to form drug resin particles. The invention also relates to methods of making these dosage forms and methods of treating using these dosage forms.
Core Innovation
The invention relates to a pharmaceutical composition for Attention Deficit Hyperactivity Disorder (ADHD) comprising a mixture of dextro- and levo-amphetamines complexed with ion-exchange resin particles to form drug-resin particles. The drug-resin particles are provided in a mixture of an uncoated first plurality and a second plurality that is coated with a delayed release coating.
A defined weight distribution places 30 to 50% by weight of the amphetamines in the first plurality of uncoated drug-resin particles and 50 to 70% by weight of the amphetamines in the second plurality of delayed-release coated drug-resin particles. In embodiments, the delayed release coating is configured as a triggered-release coating, where the triggered release is activated by a pH change.
The compositions are disclosed in multiple oral dosage forms and are evaluated by release/dissolution behavior and by in vivo pharmacokinetic exposure profiles. Reported targets and ranges include mean human plasma concentration profile metrics (AUC and Cmax) over specified time windows for ADHD patients for orally disintegrating tablets and liquid suspensions, as well as bioequivalence using 90% confidence intervals relative to a bioequivalent reference composition.
Claims Coverage
The independent claims collectively cover drug-resin particles formed from dextro- and levo-amphetamines complexed with ion-exchange resin, split into uncoated and delayed-release coated pluralities, combined with specific quantitative distribution, trigger-delayed coating concepts, and human pharmacokinetic/equivalence and dosing-form requirements.
Uncoated and delayed-release pluralities of drug-resin particles
A pharmaceutical composition comprising a mixture of dextro- and levo-amphetamines complexed with ion-exchange resin particles to form drug-resin particles, wherein a first plurality is uncoated and a second plurality is coated with a delayed release coating.
Weight distribution between uncoated and delayed-release pluralities
The composition in which 30 to 50% by weight of the amphetamines are present in the uncoated first plurality and 50 to 70% by weight of the amphetamines are present in the coated delayed release second plurality.
Triggered-release delayed coating activated by pH change
A composition where the second plurality of drug-resin particles has a triggered-release coating activated by a pH change.
Reduced amphetamine exposure in ethanol-treated mammal
A composition in which, when a mammal receiving the composition is exposed to ethanol, the mammal is exposed to a reduced amount of amphetamines compared to receiving a composition without resin particles in the presence of ethanol.
Orally disintegrating tablet plasma AUC/Cmax targets for ADHD patients
A composition that is an orally disintegrating tablet effective to provide a mean plasma concentration profile in human ADHD patients with specified AUC and Cmax values for a 30 mg total dose, or dose-proportional values for other doses.
Liquid suspension plasma AUC/Cmax targets for ADHD patients
A composition that is a liquid suspension effective to provide a mean plasma concentration profile in human ADHD patients with specified AUC and Cmax values for a 30 mg total dose, or dose-proportional values for other doses.
Fasted serum total-amphetamine AUC0-∞ range for 30 mg dose
A composition in which, when containing about a total amphetamine dose of 30 mg, a human mean plasma concentration-time curve has an area under the curve (AUC0-∞) of about 1140 to about 1240 for total amphetamines.
Bioequivalence of in vivo pharmacokinetic parameters using 90% confidence intervals
A composition in which one or more in vivo pharmacokinetic parameters selected from Cmax, AUC0-5, AUC5-12, AUC5-24, AUC5-t, AUC0-12, AUC0-24, AUC0-t, and AUC0-∞ have a 90% confidence interval with upper and lower bounds within 90%-115% of the value for a bioequivalent reference composition.
Food-associated exposure difference in first 4 hours for liquid suspension
A composition that is a liquid suspension wherein a human receiving the composition substantially contemporaneously with food is exposed to an increased amount of amphetamines in the first 4 hours compared to a human receiving a reference composition without resin particles under similar exposure to food.
Two-peak fasted serum profile timing
A composition with an in vivo fasted serum profile with a first and second peak, wherein 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.
The claims center on mixed dextro- and levo-amphetamines complexed with ion-exchange resin particles and split into uncoated and delayed-release-coated pluralities, with specified weight distributions and in vivo pharmacokinetic outcomes. Additional coverage includes ethanol-related reduced exposure, food-related increased first-4-hour exposure for a liquid suspension, orally disintegrating tablet and liquid suspension ADHD plasma AUC/Cmax targets, fasted two-peak serum timing, bioequivalence confidence interval bounds, and a total amphetamine AUC0-∞ range at a 30 mg dose.
Stated Advantages
When a mammal receives the composition in the presence of ethanol, the mammal is exposed to a reduced amount of amphetamines compared to a composition without resin particles in the presence of ethanol.
When a human receives the liquid suspension substantially contemporaneously with food, the human is exposed to an increased amount of amphetamines in the first 4 hours compared to a reference composition without resin particles.
Provides specified mean plasma concentration profile metrics (AUC and Cmax) for human ADHD patients, including AUC and Cmax target ranges for orally disintegrating tablets and liquid suspensions.
Achieves bioequivalence for selected in vivo pharmacokinetic parameters versus a bioequivalent reference composition using 90% confidence interval bounds within 90%-115%.
Produces an in vivo fasted serum profile with two peaks with defined timing after ingestion, where the second peak is the Cmax.
Documented Applications
Pharmaceutical compositions for Attention Deficit Hyperactivity Disorder (ADHD), including orally disintegrating tablets and liquid suspensions effective to provide defined human plasma concentration profiles.
Use of resin-containing compositions with a mammal receiving the composition in the presence of ethanol, evaluated as reduced amphetamine exposure compared to resin-free compositions with ethanol.
Use of a liquid suspension received by a human substantially contemporaneously with food, evaluated as increased first-4-hour amphetamine exposure versus a resin-free reference composition under similar exposure to food.
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