Fumio Shimojo

Osteotropic Drug Delivery System (ODDS) Based on Bisphosphonic Prodrug. I: Synthesis and in Vivo Characterization of Osteotropic Carboxyfluorescein

An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug was designed as a novel method for site-specific and controlled delivery of drugs to the bone. Due to the chemical adsorption of bisphosphonic promoiety to the mineral component, hydroxyapatite, a bisphosphonic prodrug is predominantly taken up into the bone. To verify the concept, bisphosphonic promoiety was chemically introduced into 6-carboxyfluorescein (CF) as a model compound and the disposition after intravenous injection was studied in rats. The bisphosphonic prodrug of CF, disodium (fluorescein-6-carbonyloxy) acetoaminomethylene bisphosphonate (CF-BP) was highly taken up to the skeleton (62.1% of dose) and the remainder was excreted into the urine (35.9% of dose). Subsequently, regeneration of CF by hydrolysis of CF-BP in the bone was observed. The microscopic observation showed that CF-BP was buried into the bone with a calcification of the bone. According to the remodeling of the bone, bisphosphonic prodrug buried was supposed to be released in the vicinity of the osteoclast or resorption surface of the bone. Thus, it is suggested that ODDS has a potential to achieve osteoclast-specific or resorption surface-specific targeting of the drugs.

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.

Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. III: pharmacokinetics and targeting characteristics of osteotropic carboxyfluorescein

An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug has been developed as a novel method for site-specific and controlled delivery of drugs to the bone. The pharmacokinetics and the targeting efficiency of a bisphosphonic prodrug of carboxyfluorescein (CF), disodium (fluorescein-6-carbonyloxy) acetoaminomethylene bisphosphonate (CF-BP), was investigated in rats. After intravenous injection, CF-BP was rapidly taken up into the skeleton, and subsequently cleared from the bone by hydrolysis of its ester linkage at a half-life of 3.2 days. On the other hand, the bone concentration of regenerated CF gradually increased to reach the maximum at 14 days and slowly decreased up to 56 days. Kinetical analysis revealed that bone tissue acts as a reservoir of regenerated CF to supply the parent compound into the systemic circulation. In contrast with CF-BP, CF injected intravenously showed rapid clearance from the plasma and extremely low bone distribution. Therapeutic availability (TA) and drug targeting index (DTI), which were calculated on the basis of the AUCs for CF in the bone and plasma after injection of CF-BP and CF, were 1551 and 6689, respectively. These results suggest that ODDS has a potential to improve not only apparent potency but also therapeutic index of the drugs which exhibit their pharmacological effects in the bone.

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.

Pharmacokinetics and pharmacodynamics of FK143, a nonsteroidal inhibitor of steroid 5α‐reductase, in healthy volunteers

The pharmacokinetics and pharmacodynamics of FK143, a new nonsteroidal inhibitor of steroid 5α‐reductase, were investigated in healthy volunteers, with use of plasma FK143 concentrations and serum dihydrotestosterone levels as an index for pharmacologic effects. The area under the plasma concentration‐time curve from zero to infinity [AUC(0‐∞)] and maximum plasma concentration [Cmax] were increased dose proportionally after oral administration (100 to 500 mg) while subjects were in the fed state. The AUC(0‐∞) and Cmax after 500 mg oral administration during fed conditions were significantly larger than those during the fasted state, suggesting an increase of the absorption of FK143. Dihydrotestosterone concentrations after a single administration of FK143 (100 to 500 mg) during fed conditions decreased to about 65% of predose values and thereafter slowly recovered to the same levels as predose values at 168 hours. A combined pharmacokinetic‐pharmacodynamic model was constructed with use of changes in dihydrotestosterone concentrations. The pharmacokinetic‐pharmacodynamic profiles of FK143 after repeated administration were predictable with use of the pharmacokinetic‐pharmacodynamic parameters obtained after a single administration of FK143.