Kazuo Murata

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.

Pharmacokinetic Analysis of an Oral Sustained-Release Diltiazem Preparation Using Multifraction Absorption Models

Application of multifraction absorption models to pharmacokinetic analysis of an oral sustained-release diltiazem preparation (HER-SR) was investigated. The plasma diltiazem concentrations after oral administration of the HER-SR preparation were analyzed using both the two-fraction absorption model and the two-step discontinuous absorption model. The two-fraction absorption model was suitable for the pharmacokinetic analysis of the HER-SR preparation, whereas the two-step discontinuous absorption model is often unsuitable for the analysis of sustained-release preparations which disintegrate into fractions with different release characteristics in the gastrointestinal tract. The two-step discontinuous absorption model is usually not applicable to plasma concentration data when the first peak is sharp. MFA-MULTI(V) was shown to be useful for the prediction of the bioavailability in each fraction of HER-SR. It was further demonstrated that a two-fraction absorption model is useful for the comparison of in vitro and in vivo release profiles or evaluating the influence of food on the absorption behavior of HER-SR. In addition, the application of a two-fraction absorption model to population pharmacokinetics of HER-SR was investigated.

Pharmacokinetics of Diltiazem and Its Metabolites in Dogs After Oral Administration of a Multiparticulate Sustained-Release Preparation

Pharmacokinetics of diltiazem and its six metabolites were compared after oral administration in dogs of a multiparticulate sustained-release diltiazem preparation (HER-SR, QD) and a conventional diltiazem preparation (HER, TID). The plasma concentration of diltiazem, its two active basic metabolites (Ml, N-monodesmethyl diltiazem; M2, deacetyl diltiazem), and four acidic metabolites [Al, ( + )-(2S,3S)-2-(4-methoxyphenyl)-3-acetoxy-4-oxo-2,3,4,5,-tetrahydro-l,5-benzothiazepin-5-acetic acid; A2, 3-deacetyl-Al; A3, O-demethyl-Al; A4, O-demethyl-3-deacetyl-Al] following several administration routes were determined using high-performance liquid chromatography with UV detector (UV-HPLC). Following the oral administration of HER to dogs, plasma concentrations were in the descending order of A2, diltiazem, Ml, and M2. The absolute bioavailability of diltiazem was about 30%. Diltiazem conversion to its metabolites (Ml, M2, A2) was 31.0, 2.1, and 14.6%, respectively. Following intraduodenal and mesenteric venous administration of diltiazem, Ml and A2 were produced mainly in the intestine and liver. Oral administration of HER-SR and HER to dogs resulted in almost-identical plasma concentrations of A2, diltiazem, Ml, and M2 (descending order). Supported evidence was the effective absorption of diltiazem from all gastrointestinal tract regions and similar formation ratios of diltiazem basic metabolites (Ml, M2) from the duodenum, ileum, and colon.

Radioimmunoassay for TA-0910, a new stable thyrotropin releasing hormone analogue and its metabolite, TA-0910 acid-type, in human plasma and urine

Radioimmunoassay (RIA) was investigated for the determination of TA-0910 and its main metabolite, TA-0910 acid-type, in human plasma and urine. TA-0910 is a new metabolically stable analogue of thyrotropin releasing hormone (TRH). Antiserum was raised in the rabbit against the 1-fluoro-2,4-dinitrophenyl derivative of TA-0910 or TA-0910 acid-type conjugated to keyhole limpet hemocyanin (KLH). The radioligand was prepared by iodination with 125I of the histidine imidazole ring of TA-0910 or TA-0910 acid-type. Cross-reactivities of anti-TA-0910 or TA-0910 acid-type antiserum for TA-0910, its metabolite and related compounds were low. The calibration range was 0.02-5 ng ml-1 using 100 microliters human plasma or urine. Inter-day variations of TA-0910 and TA-0910 acid-type assay in plasma were 3.5-15.5 and 1.8-9.4%, respectively. The variations of the assay in urine were the same as those in plasma. The recovery of TA-0910 and TA-0910 acid-type spiked in plasma or urine samples was approximately 100%. Furthermore, this method was applied to the determination of TA-0910 and TA-0910 acid-type in human plasma and urine samples, for the evaluation of the pharmacokinetics of TA-0910 in humans. From the results it was demonstrated that he developed RIA was useful for the determination of TA-0910 and TA-0910 acid-type in human plasma and urine, and was applicable to pharmacokinetic studies in humans.

Pharmacokinetic and pharmacodynamic study of imidaprilat, an active metabolite of imidapril, a new angiotensin-converting enzyme inhibitor, in spontaneously hypertensive rats

The pharmacokinetics and pharmacodynamics (PK/PD) of imidaprilat, an active metabolite of imidapril, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated. Imidapril was infused subcutaneously for 4 weeks via an osmotic pump implanted under the skin in the back of male spontaneously hypertensive rats (SHRs). Plasma concentration of imidaprilat, systolic blood pressure (SBP), and plasma ACE activity were determined periodically. The plasma concentration of imidaprilat increased in proportion to the infusion rates and was maintained for 4 weeks. The SBP and ACE activity did not decrease in proportion to the infusion rates due to the saturation of the pharmacologic effects, but these actions also were maintained for 4 weeks. The PK/PD of imidaprilat were not influenced by aging of SHRs. The antihypertensive action in subcutaneous infusion of imidapril was as potent as that in oral administration at the same dose, although the maximum plasma concentration of imidaprilat in subcutaneous infusion was one-eightieth times of that in oral administration. The action was also maintained 28 times longer than that in oral administration, indicating that subcutaneous infusion is useful as an administration route. Furthermore, good correlation between plasma imidaprilat concentration and SBP was observed in subcutaneous infusion, indicating that plasma concentration may be a useful marker of pharmacologic action.

Pharmacokinetics and pharmacodynamics of a sustained-release biodegradable pellet containing imidapril, a new angiotensin-converting enzyme inhibitor in spontaneously hypertensive rats.

The pharmacokinetics and pharmacodynamics (PK/PD) of a sustained-release biodegradable pellet containing imidapril, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated in comparison with those of an osmotic pump in male spontaneously hypertensive rats (SHRs). A pellet was prepared from copolymer of DL-lactic acid and glycolic acid by the melt-pressing technique. Imidapril was released in vitro from the pellet at an approximately zero-order rate and the release profile was similar to that of the osmotic pump. Imidapril was administered subcutaneously via a pellet or an osmotic pump implanted under the skin in the back of SHRs. Plasma concentrations of imidaprilat as an active metabolite of imidapril, plasma ACE activity and systolic blood pressure (SBP) were determined periodically. The plasma concentration of imidaprilat during the administration of a pellet was maintained for 4 weeks, and the plasma concentration profile was close to that of the osmotic pump. Both groups of pellet and osmotic pump significantly inhibited plasma ACE activity and reduced SBP for 4 weeks, and these action profiles were similar in both groups. In addition, in vivo release profile of the pellet was close to the in vitro release profile, and the in vivo release profiles of the pellet and the osmotic pump were similar to each other. From these results, it was found that the PK/PD of a biodegradable pellet were close to those of the osmotic pump, and it was shown that the pellet may be a useful system to maintain the plasma concentration of imidaprilat for a long time.