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

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...

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Bibliographic Details
Published in:Biopharmaceutics & drug disposition 2004-03, Vol.25 (2), p.91-98
Main Authors: Wang, Yanfeng, Lee, Lucy, Somma, Russell, Thompson, Glenn, Bakhtiar, Ray, Lee, James, Rekhi, Gurvinder Singh, Lau, Henry, Sedek, Greg, Hossain, Mohammad
Format: Article
Language:English
Subjects:
absorption
Administration, Oral
Adult
Area Under Curve
Biological and medical sciences
Capsules
Central Nervous System Stimulants - administration & dosage
Central Nervous System Stimulants - blood
Central Nervous System Stimulants - pharmacokinetics
Cross-Over Studies
Delayed-Action Preparations
dissolution
Female
Half-Life
human
Humans
Male
Medical sciences
methylphenidate
Methylphenidate - administration & dosage
Methylphenidate - blood
Methylphenidate - pharmacokinetics
Neuropharmacology
Pharmacology. Drug treatments
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Ritalin
Solubility
Stereoisomerism
Tablets
Therapeutic Equivalency
Time Factors
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Summary: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 Cmax, tmax and AUC values, as well as the Cmax, tmax 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 Cmax 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 Cmax 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
ISSN:0142-2782
1099-081X
DOI:10.1002/bdd.390