Pharmacokinetic and pharmacodynamic evaluations of novel oral morphine sustained release granules

Pharmacokinetics and pharmacodynamics of novel oral sustained-release granules based on swelling polymer incorporation layer system (SPILA granules) containing morphine hydrochloride was evaluated. SPILA granules were designed to release morphine faster in neutral environment than in acidic one to keep higher plasma levels over a protracted period, especially after 12 h post dose. SPILA granules were orally administered to beagle dogs to compare the pharmacokinetics with commercially available twice-a-day dosage form, MS Contin®. Tmax and AUC0—24 h values of SPILA granules were 6 h and 191 μg·h/ml, respectively. Tmax and AUC0—24 h values of MS Contin® were 2 h and 146 μg·h/ml, respectively. Relative bioavailability following SPILA granules administration to twice-a-day MS Contin® (30 mg) administration was 131%. In rats, analgesic effect was evaluated over 24 h. SPILA granules and aqueous solutions were administered to rats to compare the analgesic effect. AUC0—24 h value for SPILA granules was 8.88 μg·h/ml, which was a little lower than that for the aqueous solution (10.1 μg·h/ml), whereas the analgesic effect after SPILA granules once-a-day administration expressed as AURC (1701% Analgesia·h) was similar to that after the aqueous solution 4 times-a-day administration (1603% Analgesia·h). These results indicate that SPILA granules based on the pH-dependent release regulating polymer system can be a good candidate for an oral once-a-day sustained-release dosage form.