TECHNOLOGY FOR ORAL DELIVERY OF FIRST-PASS DRUGS

STRATEGIES FOR REDUCING THE DOSING INTERVAL OF ORALLY ABSORBED DRUGS RELY ON CHANGING THE RELEASE PATTERN OF THE DRUG FROM THE DELIVERY SYSTEM SO THAT THE BLOOD LEVEL PROFILE OF THE DRUG FALLS WITHIN THE THERAPEUTIC WINDOW OVERTHE TIME OF THE DOSING INTERVAL. HOWEVER, FOR DRUGS THAT EXHIBIT FIRST-PASS METABOLISM, THE RELATIONSHIP BETWEEN EXTENT OF ABSORPTION AND BIOAVAILABILITY IS NONLINEAR, THEREBY LEADING TO REDUCED BIOAVAILABILITY WHEN DRUGS ARE ADMINISTERED AT A VERY LOW RATE INTO THE GI TRACT. THE SPECIFIC AIM OF THIS PROPOSAL IS THE DEVELOPMENT OF A DRUG DELIVERY STRATEGY TO REDUCE THE ORAL DOSING INTERVAL OF DRUGS EXHIBITING FIRSTPASS METABOLISM WHILE MAINTAINING BIOAVAILABILITY EQUIVALENT TO THE IMMEDIATE RELEASE DOSAGE FORM. THE STRATEGY ENTAILS THE DESIGN AND DEVELOPMENT OF A DOSAGE FORM STRATEGY THAT WILL RELEASE FRACTIONS OF THE TOTAL DOSE AT SPECIFIED TIMES/SITES IN THE GI TRACT. IN THIS MANNER, THE BIOAVAILABILITY WILL NOT BE COMPROMISED BY THE DECREASING RELEASE RATE, AS IS OFTEN SEEN IN CONVENTIONAL SUSTAINED-RELEASE DOSAGE FORMS. PROPRANOLOL HAS BEEN CHOSEN AS THE SPECIFIC DRUG TO BE STUDIED. PROPRANOLOL WAS CHOSEN BECAUSE ITS PHARMACOKINETICS ARE REASONABLY WELL UNDERSTOOD AND IT EXHIBITS DOSE-DEPENDENT BIOAVAILABILITY IN THE NORMAL THERAPEUTIC DOSAGE RANGE. FURTHERMORE, THERE HAVE BEEN REPORTS IN THE LITERATURE OF TECHNOLOGY DEVELOPED FOR THE CONTROLLED RELEASE OF PROPRANOLOL (FOR EXAMPLE, INDERAL-LA) THAT ARE NOT SATISFACTORY WITH RESPECT TO THEIR BIOAVAILABILITY.