Biomedical Engineering Reference
In-Depth Information
usually much longer than in case of SR and vary from days to years. Controlled
release may also incorporate methods to promote localization of drug at an active
site. Site-specific and targeted delivery systems are the descriptive terms used to
denote this type of control.
Programming the Release at a Defined Time
Approaches used for achieving programmed or pulsatile release may be physical
mechanisms such as swelling with bursting or chemical actions such as enzymatic
degradation. Capsules have been designed that burst after a predetermined expo-
sure to an aqueous environment. Physical factors that can be controlled are the
radius of the sphere, osmotic pressure of the contents and wall thickness, as well as
elasticity. Various pulsatile release methods for oral drug delivery include the Port
system (a semipermeable capsule containing an osmotic charge and an insoluble
plug) and Chronset System (an osmotically active compartment in a semipermeable
cap. Other systems have impermeable capsules and erodible plugs, which are formed
either by direct compression of various hydrophilic polymers, such as hydroxypropyl
methylcellulose and propylene oxide, or by solidification of a meltable material
directly into the capsule orifice.
Dosage Formulation of Calcium Channel Blockers
Although effective as antihypertensive agents, recent studies have suggested that
calcium channel blockers (CCBs) may be detrimental and may promote adverse
cardiovascular events. It is the rate of drug delivery into the systemic circulation
that produces profound effects on the hemodynamic and neurohumoral responses
to a dihydropyridine CCB drug. During chronic treatment with dihydropyridines,
major fluctuations in blood pressure (rapid onset and offset of antihypertensive
effects) during the dosing interval may persist for drugs and formulations that are
short acting. In contrast, slow-release formulations of otherwise rapidly absorbed
dihydropyridines achieve a more gradual and sustained antihypertensive effect. It
is probable that newer CCB formulations that do not provoke intermittent sympa-
thetic activation and do not evoke a cardioacceleratory response would be expected
not to promote adverse cardiovascular events. Comparison of sustained and con-
trolled release preparations of verapamil will be described as an example.
Sustained and Controlled Release Verapamil
With the immediate release formulation, more than 90% of the orally administered
dose of verapamil is absorbed. Because of rapid biotransformation of verapamil
during its first pass through the portal circulation, bioavailability ranges from 20%
to 35%. Peak plasma concentrations are reached between 1 and 2 h after oral
administration. Chronic oral administration of 120 mg of verapamil every 6 h
resulted in plasma levels of verapamil ranging from 125 to 400 ng/mL, with higher
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