Bioavailability of sustained release propranolol formulations

Abstract

In this comparative bioavailability study two sustained release capsule formulations of propranolol, one a clinical trial formulation and the other the U.K. sales formulation ('Inderal' LA), were compared with a conventional 'Inderal' tablet. Twelve healthy adult male volunteers received, on cross-over basis, on three separate occasions, 160 mg oral doses of three formulations of 'Inderal'. Bioavailability was based on concentration of propranolol in whole blood. The peak blood level and area under the propranolol blood level curve fell as the dissolution time increased. The half-lives of the three formulations were inversely proportional to their dissolution rates, those of the sustained release formulations being considerably longer than that of the conventional tablet. The 160 mg 'Inderal' tablet produced a rapid 90-fold decline over 24 h in propranolol blood levels following a high initial peak. By comparison both sustained release formulations showed a less rapid fall in systemic levels and gave higher blood levels at the end of 24 h and plateau values between 8 and 14 ng ml-1. The 'Inderal' LA sustained release formulation gave consistently higher propranolol blood levels than the clinical trial sustained release formulation. This result is in good agreement with their dissolution profiles. The lowering of the systemic bioavailability as the dissolution time increases is thought to be due to an increased metabolism of propranolol.

Theoretical Michaelis — Menten elimination model for propranolol

“…A strong nonlinear dependence exists with the bioavailability dropping six-fold over the range of absorption half-life for conventional to 'Inderal' LA. This has been observed in practice and, furthermore, the absolute theoretical values are in good agreement with the observed experimental values (8,9). Thus Vm =100…”

“…Furthermore the calculated half-life for the linear elimination phase is equal to the value of the inputted absorption half-life indicating 'flip-flop' MichaelisMenten pharmacokinetics. The theoretical profiles for the 3 and 12 hours absorption half-lives are very similar to the experimentally obtained data for a 160 mg conventional 'Inderal' single dose and the 160 mg single dose of 'Inderal' LA, respectively (8,9). The calculated areas under the theoretical plasma level profiles as a function of the absorption half-life are illustrated in Fig.…”

“…Send reprint requests to: Dr. J. McAinsh, International Medical Affairs Department, Mereside, Alderly Park, Macclesfield, Cheshire, SKIO 4TG, U.K. tion that could be given once daily and produce both a steady propranolol blood level and a steady degree of beta blockade ('Inderal' LA) (7)(8)(9).…”

“…During the pharmacokinetic development of 'Inderal' LA it was found that the areas under the propranolol blood level curves were significantly reduced for the long-acting formulation in comparison with those achieved by conventional propranolol in single or divided doses (8,9). It was postulated that this difference could be due to either incomplete absorption across the gut wall, or to a higher degree of metabolism on the first pass through the liver due to the slower rate of absorption, from the long-acting formulation (8).…”

Guar Gum, Xanthan Gum, and HPMC Can Define Release Mechanisms and Sustain Release of Propranolol Hydrochloride

“…Although its oral absorption is almost complete (3), it undergoes hepatic metabolism, resulting in a 3-4-h elimination half-life (4). Sustained release matrix tablets containing propranolol hydrochloride have been prepared (5)(6)(7)(8), since oral sustained release formulations can provide a slower fall in plasma drug levels, maintaining plateau values between 8 and 14 ng/ml (9). In hypertensive patients, a constant therapeutic plasma drug level must be maintained to keep the blood pressure at adequate levels.…”