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Effects of aqueous solubility and dissolution characteristics on oral bioavailability of entacapone
Author(s) -
Savolainen Jouko,
Forsberg Markus,
Taipale Hannu,
Männistö Pekka T.,
Järvinen Kristiina,
Gynther Jukka,
Jarho Pekka,
Järvinen Tomi
Publication year - 2000
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/1098-2299(200004)49:4<238::aid-ddr2>3.0.co;2-v
Subject(s) - entacapone , bioavailability , chemistry , solubility , dissolution , chromatography , pharmacology , pharmacokinetics , organic chemistry , medicine , levodopa , parkinson's disease , disease
Entacapone is a new catechol‐O‐methyltransferase (COMT) inhibitor used clinically in a triple combination therapy for Parkinson's disease (PD). The bioavailability of entacapone after oral administration is low and subject to large interindividual variation. The purpose of this study was to evaluate aqueous solubility/dissolution profiles of entacapone in vitro, and to evaluate their role in the poor oral bioavailability of entacapone in rats. The effect of the novel pharmaceutical excipient hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) on the aqueous solubility and dissolution of entacapone, and on entacapone bioavailability in rats, was also studied. The aqueous solubility of entacapone determined in this study is below 80 μg/ml at pH ≤5.0 and increases with increased pH. Due to its poor aqueous solubility, the dissolution of entacapone in an acidic environment is very slow. Complexation of entacapone with HP‐β‐CD (10% [w/v]) increases the aqueous solubility of entacapone 12‐fold and 85‐fold at pH 3.0 and at pH 5.0, respectively, and improves its bioavailability at the former pH about 2‐fold, compared to an entacapone suspension at that pH. The administration of entacapone as a pH 7.4 solution further increases the absolute bioavailability of entacapone, which is 1.8 and 3.3 times higher compared to the inclusion complex or suspension, respectively. In conclusion, it is possible to increase entacapone's bioavailability by improving its solubility and dissolution properties. However, the solubility and dissolution properties of entacapone do not fully explain its erratic bioavailability. Drug Dev. Res. 49:238–244, 2000. © 2000 Wiley‐Liss, Inc.