Yoshiyuki Hirakawa

An organic acid-induced sigmoidal release system for oral controlled-release preparations.

To achieve time-controlled or site-specific drug delivery in the gastrointestinal tract, a sigmoidal release system (SRS) was developed, which achieved a prolonged lag time, followed by rapid release. The theophylline beads with a thick Eudragit RS film coating showed very low drug release in water, whereas the release rate increased considerably in organic acid solutions. A hydration study of Eudragit RS films suggested that the increase in drug release was attributable to structural changes of the film induced by polymer-acid interactions. When succinic acid was incorporated into the core of Eudragit RS-coated theophylline beads, the drug release profile showed a typical sigmoidal pattern. SRS beads containing acetaminophen were also prepared by the same technique. Again, a sigmoidal release pattern was observed in which the lag time was prolonged with an increase in the coating level, whereas the drug release rate thereafter was almost constant irrespective of the coating level. Acetaminophen-containing SRS beads with different coating thickness were orally administered to beagle dogs. The drug plasma concentration curves showed lag periods similar to the in vitro lag time.

Drug release behavior in gastrointestinal tract of beagle dogs from multiple unit type rate-controlled or time-controlled release preparations coated with insoluble polymer-based film

Abstract Drug release behaviors from two multiple unit types of controlled release systems were observed in the gastrointestinal (GI) tract of beagle dogs. Factors affecting the in vivo drug release are discussed. The in vivo drug release behaviors were directly predicted by measuring the residual amount of drugs in preparations recovered from the GI tract after oral administration. Theophylline (TP) and propranolol hydrochloride (PPL), which have markedly different solubility, were used as model drugs. A rate-controlled release preparation (porous ethylcellulose film-coated beads) and a time-controlled release preparation (SRS; sigmoidal release system) were examined. Although in vivo TP release from the rate-controlled release beads agreed considerably with in vitro release in the early stages, it was reduced by a lack of fluid in the lower region of the GI tract and the lower water-solublity of the drug. On the other hand, PPL release in vivo was in accord with the in vitro release, and the drug was released almost completely from the beads in the GI tract. In the case of PPL-SRS, although the in vivo release rate was slightly lower than that in vitro, sigmoidal drug release was also observed in the GI tract. TP was not released entirely from the SRS or the porous ethylcellulose film-coated beads in the GI tract. In conclusion, with respect to drug release from controlled release preparations coated with insoluble polymer based-film coating, a good in vitro/in vivo correlation was observed in the early stages of drug release, irrespective of drug properties, but solubility of the drugs was found to be an important factor that affected the drug release in the lower site of GI tract of dogs.

An organic acid-induced sigmoidal release system for oral controlled-release preparations. III. Elucidation of the anomalous drug release behavior through osmotic pumping mechanism

To provide a reasonable explanation for the unique S-shaped drug release profile of sigmoidal release system (SRS), which is a newly developed multiparticulate oral time-controlled drug delivery system, the release mechanism was investigated. The dissolution studies were conducted for the theophylline-loaded SRS in water or in glucose aqueous solutions with different concentrations to vary osmotic pressure. In water, the initial lag time was extended with increasing coating level, whereas less change was observed in the subsequent drug release rate. On the other hand, drug release behaviors in aqueous glucose solutions extensively changed depending on the glucose concentrations; extending the lag time and decreasing the drug release rate. All the results obtained in the present study indicated that the anomalous theophylline release from the device was brought about by two mechanisms:; duration of the initial osmotic water-influx to the system to produce a lag time and the subsequent osmotic pumping process to provide a steady-state rapid release.