Titre du document / Document title

In vitro dissolution and in vivo oral absorption of methylphenidate from a bimodal release formulation in healthy volunteers

Auteur(s) / Author(s)

YANFENG WANG ⁽¹⁾ ; LEE Lucy ⁽¹⁾ ; SOMMA Russell ⁽²⁾ ; THOMPSON Glenn ⁽²⁾ ; BAKHTIAR Ray ⁽³⁾ ; LEE James ⁽⁴⁾ ; GURVINDER SINGH REKHI ⁽⁵⁾ ; LAU Henry ⁽¹⁾ ; SEDEK Greg ⁽¹⁾ ; HOSSAIN Mohammad ⁽¹⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Clinical Pharmacology, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, ETATS-UNIS
⁽²⁾ Technical Research and Development, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, ETATS-UNIS
⁽³⁾ Bioanalytics, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, ETATS-UNIS
⁽⁴⁾ Biostatistics, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, ETATS-UNIS
⁽⁵⁾ Elan Drug Delivery, Inc., Gainesville, GA 30504, ETATS-UNIS

Résumé / Abstract

Purpose-The objective of this study was to evaluate the in vitro dissolution and in vivo absorption of D,L-threo-methylphenidate (MPH) from a novel bimodal release formulation (Ritalin® LA capsule) compared with an immediate-release formulation (Ritalin IR tablet) in healthy volunteers. Methods-The bimodal release formulation contains 50% of the dose in the immediate-release (IR) beads and 50% in polymethacrylate-coated, delayed-release (DR) beads. To better understand the impact of dissolution from the DR beads on oral absorption of MPH, three Ritalin LA formulations with different dissolution profiles for the DR beads (referred to as slow-, medium and fast-release formulations) were prepared, and tested together with the immediate-release formulation in 18 healthy male and female volunteers after a single oral dose under fasted conditions. The rate and extent of oral absorption of MPH were evaluated based on the overall C_max, t_max and AUC values, as well as the C_max, t_max and AUC values for each individual peak of the bimodal plasma concentration-time profile. The in vivo absorption-time profile was also examined by deconvolution. Results-All three Ritalin LA formulations demonstrated similar bimodal plasma concentration-time profiles with two peak concentrations observed at ∼2 and ∼6 h post dose, mimicking that of Ritalin IR tablets given 4 h apart. Deconvolution results showed that the absorption of MPH was biphasic, with a rapid absorption phase between 0 to ∼2 h, and a somewhat slower second absorption between ∼3-6 h, consistent with the in vitro bimodal release characteristics of Ritalin LA formulation. The three Ritalin LA formulations were bioequivalent to one another based on the overall C_max and AUC values and the corresponding values describing the first and second peaks, although their in vitro dissolution profiles for the DR beads were different. Compared with Ritalin IR, the Ritalin LA formulation demonstrated a similar rate of absorption for the first peak, a lower second C_max and a higher trough concentration between peaks, as well as similar overall plasma AUC. Conclusions-Following a single oral drug administration, Ritalin LA demonstrated a two-peak plasma concentration-time profile, similar to that of the IR formulation given 4 h apart, but with less fluctuation in the plasma concentration-time profile. The in vivo biphasic absorption of MPH appeared to be well correlated with the bimodal dissolution characteristics of this new Ritalin LA formulation, and some changes in the dissolution profiles for the DR beads appeared no to affect the overall bioavailability of MPH in humans.

Revue / Journal Title

Biopharmaceutics & drug disposition   ISSN 0142-2782   CODEN BDDID8 

Source / Source

2004, vol. 25, n^o2, pp. 91-98 [8 page(s) (article)] (18 ref.)

Langue / Language

Anglais

Editeur / Publisher

Wiley, Chichester, ROYAUME-UNI  (1979) (Revue)

Mots-clés anglais / English Keywords

Bioavailability ; CNS stimulant ; Psychotropic ; Human ; Formulation ; Methylphenidate ; Absorption ; Oral administration ; In vivo ; In vitro ; Dosage form ; Controlled release form ; Pharmacokinetics ;

Mots-clés français / French Keywords

Biodisponibilité ; Stimulant SNC ; Psychotrope ; Homme ; Formulation ; Méthylphénidate ; Absorption ; Voie orale ; In vivo ; In vitro ; Forme pharmaceutique ; Forme libération contrôlée ; Pharmacocinétique ;

Mots-clés espagnols / Spanish Keywords

Biodisponibilidad ; Estimulante SNC ; Psicotropo ; Hombre ; Formulación ; Metilfenidato ; Absorción ; Vía oral ; In vivo ; In vitro ; Forma farmacéutica ; Forma liberación controlada ; Farmacocinética ;

Mots-clés d'auteur / Author Keywords

Ritalin ; methylphenidate ; dissolution ; absorption ; human ;

Localisation / Location

INIST-CNRS, Cote INIST : 17959, 35400011671089.0060