Abstract

EXTRUSION - A POTENTIAL KEYSTONE SOLUTION FOR PREPARATION OF CHRONOPHARMACEUTICAL DOSAGE FORMS

M. Dimitrov, T. Popova, V. Petkova* and Nikolai Lambov

Abstract

Bronchial asthma displays significant circadian variation at onset or exacerbation of symptoms (50-100 time more common between midnight and early morning hours with peak of bronchoconstriction at 4.00 am), which requires specific administration timing and creating chronopharmaceutical systems which can release the drug within a short/prolonged period of time, immediately after a predetermined lagtime – pulsatile-release drug delivery systems. The bronchodilating action of theophylline makes the drug useful in the chronic treatment of bronchial asthma, but its narrow therapeutic concentration range and variable pharmacokinetics make dosing management of the drug difficult which requires utilization of modified release drug dosage forms, like Contin® chronopharmaceutical technology, used in Uniphyl®/Uniphyllin® tablets. Unexpected, our recent in vitro study revealed that the release rate of theophylline from Uniphyllin® tablets is too slow and there is potential possibility that they could not provide satisfactory lag time. Utilization of multiple-unit pellet systems (MUPS) are one of ways that pulsatile-release or so called ―time clock systems‖ can be achieved. Multi-stage extrusion (two or three stages) approach technology gives the opportunity to achieve pulsatile release profile with simple reextrusion of the conventional or modified release pellets prepared by one stage extrusion. The present study compromises preparation and characterization of nine formulations tablets by tabletting of pellets prepared after single- (E1-1-E3-1), two-(E1-2-E3-2), or three-stages (E1- 3-E3-3) extrusion with application of different polymer blends. Formulations with HPMC release slower than formulations with CMC Na and increasing viscosity grade of HPMC, leads to decreasing in release rate. Moreover fastest is the release rate from single-extruded pellets and slowest – from three-stage extruded pellets. Among all formulations, formulation E3-3 (tablet prepared from pellets via three-stage extrusion) exhibits the desired chronopharmaceutical release profile. This system is designed, by taken before bedtime, to deliver API between midnight and early morning hours when asthma incidents are with higher frequency, which fully complies with the main principle of chronotherapy – synchronization of drug concentration to rhythms in disease activity.

Keywords: chronotherapy, extrusion, asthma.