Saburo Murata

Development of a Novel Drug Delivery System, Time-Controlled Explosion System (TES). IV. In Vivo Drug Release Behavior

Time-Controlled Explosion System (TES) has the time-controlled drug release property with a pre-designed lag time. The drug release from the system is initiated by destruction of the membrane. In this study, metoprolol tartrate was used as a model drug. After five types of TES with different in vitro lag times were orally administrated to dogs, plasma metoprolol concentration was monitored. There existed a good correlation between in vitro and in vivo lag time, while the extent of absorbed metoprolol decreased with prolongation of lag time. Next, the in vivo drug release behavior was directly investigated using five different colored TES with a lag time of two hours. Each TES was consecutively administrated to the fasted dogs at predetermined intervals. The amount of metoprolol released was monitored by recovering the administered TES from the gastrointestinal trace. The in vivo release profile corresponded with the in vitro one. It is demonstrated that TES can release the drug in in vivo conditions similarly to in vitro. Based on these results, the decrease of the absorption is suggested to be caused by increased hepatic first-pass metabolism of the drug due to the retarded release rate with longer lag time.

In vivo performance of time-controlled explosion system (TES) in GI physiology regulated dogs

Abstract In vivo oral absorption study of time-controlled explosion system (TES), using gastrointestinal (GI) physiology regulated dogs, was carried out to predict the feasibility in humans. TES is characterized by rapid drug release with a pre-programmed lag time, which can provide a programmed release system synchronized with circadian rhythm (e.g. asthma attack in the morning), a colon targeting system and a sustained release system with different lag times. In this study, TES containing diclofenac sodium with different lag times of 3 and 6 h (TES-3h and TES-6h) were prepared. TES-3h exhibited good performance in all six GI physiology regulated dogs without remarkable reduction of AUC. In the case of TES-6h, drug absorption was observed ∼6 h after administration in four of six dogs, but plasma level was low. Further, the location of the dosage forms after oral administration was estimated from the gastric emptying time (GET) and the small intestinal transit time (SITT) using a double marker method. As a result, in vivo performance of TES correlated with the intestinal location. It was concluded that TES-3h would perform well in humans and that the environmental water content in the GI tract affected the in vivo dissolution profile of TES when the drug release was initiated after entering the colon.

Physicochemical Characterization of Bisphosphonic Carboxyfluorescein for Osteotropic Drug Delivery

Disodium (fluorescein‐6−carbonyloxy)acetoaminomethylene bisphosphonate (CF‐BP), a prodrug of 6−carboxy‐fluorescein, is efficiently absorbed by the skeleton where it hydrolyses to carboxyfluorescein. An osteotropic drug‐delivery system based on this bisphosphonic prodrug has been developed as a novel method for site‐specific and controlled delivery of drugs to the bone. In this study the physicochemical properties of the prodrug have been characterized by investigating the affinity of CF‐BP for hydroxyapatite and the hydrolysis of the compound to carboxyfluorescein.