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-8709491-B2
Publication Date
2014-04-29
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 comprising a mixture of dextro- and levo-amphetamines complexed with ion-exchange resin particles to form drug-resin particles. The composition comprises a defined proportion of drug-resin particles that are uncoated and a defined proportion of drug-resin particles that are coated with a delayed release coating. The resin-based controlled-release design is used to provide comparable overall systemic exposure relative to reference products in human pharmacokinetic/bioequivalence studies.
The delayed release coating is a triggered-release coating associated with a pH change, and the coating is implemented using polymers and polymer mixtures that include cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters, co-polymerized methacrylic acid/acrylic acid ethyl esters, and mixtures thereof. The ion-exchange resin particles are strong acidic cation exchange resins selected from polistirex, polacrilex, cholestyramine, polacrilin, or mixtures thereof.
In described human studies, controlled-release orally disintegrating tablets and controlled-release oral liquid suspensions prepared from mixed amphetamine ion-exchange resin complexes are compared with reference products such as ADDERALL XR and METADATE CD. The studies evaluate bioequivalence using pharmacokinetic parameters including Cmax and AUC0-last/AUCinf, and report controlled-release characteristics with comparable AUC-based systemic exposure in some comparisons, limited food effect in certain comparisons, and ethanol effect on dissolution/drug release consistent with maintained controlled-release behavior.
Claims Coverage
The claim coverage centers on one independent composition claim with six inventive features, supported by dependent refinements that further define the release mechanism, coating polymers, resin selection, particle proportions, and dosage amount.
Defined uncoated versus delayed release coated drug-resin particle distribution
A pharmaceutical composition comprising a mixture of dextro- and levo-amphetamines complexed with ion-exchange resin particles to form drug-resin particles, wherein the composition comprises 20 to 50% of a first plurality of drug-resin particles that are uncoated and 50 to 80% of a second plurality of drug-resin particles that are coated with a delayed release coating.
PH-change-triggered delayed release coating on drug-resin particles
The composition includes a second plurality of drug-resin particles that have a pH-change-triggered release coating.
Selected polymers for triggered-release coating
The triggered-release coating is made from one of cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters, co-polymerized methacrylic acid/acrylic acid ethyl esters, or mixtures thereof.
Strong acidic cation exchange resin for forming drug-resin particles
The resin particles are strong acidic cation exchange resins selected from polistirex, polacrilex, cholestyramine, polacrilin, or mixtures thereof.
Tightened proportion ranges for uncoated and coated drug-resin particles
The composition contains 40% to 50% of a first plurality of drug-resin particles and 50% to 60% of a second plurality of drug-resin particles.
ADHD effective agent dosage amount range
The composition includes an ADHD effective agent in an amount of 2 to 60 mg.
The claim set is directed to complexing dextro- and levo-amphetamines with ion-exchange resin particles, specifying quantitative ratios of uncoated versus delayed-release coated drug-resin particles, and further defining the triggered-release coating, polymer options, resin selection, and an ADHD effective agent dosage amount range.
Stated Advantages
Controlled delayed/triggered release behavior is demonstrated.
Bioequivalence is described as comparable to references (ADDERALL XR and METADATE CD) in the disclosed comparisons.
Ethanol interaction and reduced dose-dumping exposure are discussed in the disclosed comparisons.
Overall systemic exposure (AUC-based) is comparable for some test products versus reference products despite differences in peak exposure.
Food effect is limited for resin-based orally disintegrating tablets in certain comparisons.
Controlled-release characteristics are maintained in the presence of food and ethanol.
Documented Applications
ADHD-effective pharmaceutical compositions using dextro- and levo-amphetamines complexed with ion-exchange resin particles are described.
Oral dosage forms are described including liquid suspensions, chewable compositions, and orally disintegrating tablets (ODT) for the disclosed compositions.
Human pharmacokinetic/bioequivalence studies comparing controlled-release ODTs and controlled-release oral liquid suspensions made from mixed amphetamine ion-exchange resin complexes versus reference products ADDERALL XR and METADATE CD.
Pediatric pharmacokinetic outcomes in ADHD children (age-related exposure trends, clearance/volume-of-distribution within target ranges).
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