Drug efficacy generally depends upon the ability of the drug to reach its target in sufficient quantity to maintain therapeutic levels for the desired time period. Orally administered drugs must overcome several obstacles to reach their desired targets. Before orally administered drugs enter the general circulation of the human body, they are absorbed into the capillaries and veins of the upper gastrointestinal tract and are transported by the portal vein to the liver. The pH and enzymatic activities found in gastrointestinal fluids may inactivate the drug or cause the drug to dissolve poorly. In addition, following their absorption in the intestine, orally administered drugs are often subject to a "first pass" clearance by the liver and excreted into bile or converted into pharmacologically inactive metabolites. Decreased bioavailability of orally administered drugs is a consequence of this first pass effect.
Orally administered drugs subject to the first pass effect generally exhibit non-linear pharmacokinetics. Until the liver's metabolic capacity has been exceeded, the amount of such drugs in the bloodstream is significantly lower than the amount administered. This metabolic elimination of the given dose results in reduced bioavailability. However, once the administered dose exceeds the liver's metabolic capacity, a significant increase in the drug concentration in the bloodstream may be obtained. The first pass phenomenon presents particular difficulties in the maintenance of therapeutic levels of an orally administered drug over an extended period such as 12 or 24 hours.
Drug delivery systems which have evolved with respect to orally administered drugs subject to the first pass effect include formulations capable of immediate drug release that are suitable for administration from 3-4 times daily, and formulations capable of immediate and sustained drug release that are suitable for once-daily administration. The second type of formulation is preferred because patient compliance with prescribed drug regimens involving once-daily administration is substantially higher than those involving multiple administrations. A sustained release formulation, however, may subject the patient to toxic drug levels over part of the dosing period and sub-therapeutic drug levels over other portions of the dosing period, if the drug release does not occur at appropriate time intervals. The maintenance of therapeutic levels of an orally administered drug over an extended period thus depends upon a drug delivery system capable of providing an appropriate release pattern.
Various drug delivery systems have been designed in attempts to ameliorate the first pass effect. U.S. Pat. No. 5,439,689 describes one such system designed to deliver the calcium antagonist diltiazem in a manner to maintain the drug in the bloodstream in therapeutic drug levels throughout the 24 hour period following oral administration. This formulation accomplishes its dosing profile through the use of a blend of immediate drug release beads and delayed drug release beads. One disadvantage of this system is the relatively complicated manufacturing scheme. In contrast to a formulation comprising the blend of two types of drug release beads, a single bead formulation could be manufactured more simply. A single bead formulation would not require the time and effort required by the separate production of two types of drug release beads to prepare a final dosage form. Moreover, concerns regarding blending or double-filling homogeneity would be eliminated.
U.S. Pat. No. 4,894,240 describes an extended release drug delivery system in a single bead formulation. This system was also designed to deliver diltiazem in therapeutic drug levels over a 24 hour period following oral administration. However, subsequent tests demonstrated that the commercial product based on this patent's teachings was unable to provide optimal diltiazem blood levels over the 24 hour period following oral administration because of significant variances between peak and trough levels.
A valuable contribution to the art therefore would be the development of a drug delivery system in a single bead formulation suitable for oral administration that facilitates an immediate yet sustained release of the active agent over the 24 hour period following oral administration while minimizing the variance between peak and trough levels.