Toyohiro Sawada

Influence of water soluble fillers in hydroxypropylmethylcellulose matrices on in vitro and in vivo drug release.

The purpose of this study was to investigate the effect of fillers in gel-forming matrix on in vivo drug release after oral dosing. A further purpose was to predict the in vivo performance from in vitro dissolution test. Three controlled-release acetaminophen tablets containing hydroxypropylmethylcellulose (HPMC) with or without highly water soluble fillers, lactose or polyethylene glycol 6000 (PEG6000), were prepared. Water penetration into the matrix was enhanced by addition of fillers in the matrices, but the three tablets showed similar in vitro dissolution profiles, indicating that fillers in the HPMC matrices little affected the in vitro drug release. In contrast, the fillers in HPMC matrices did affect the in vivo performance in dogs. The absorption profile of HPMC matrix with PEG6000 was the fastest, followed by that with lactose and without water soluble filler, in that order. As the matrix with PEG6000 had a large amount of water and gelated a large portion of the matrix when in contact with water, the gel layer would be disintegrated by the gastrointestinal motility. It was found that dissolution of gel-forming HPMC matrices under mechanical stress by glass beads well correlated with the in vivo performance of the matrix, with little correlation by the conventional paddle method.

Role of Paracellular Pathway in Nonelectrolyte Permeation Across Rat Colon Epithelium Enhanced by Sodium Caprate and Sodium Caprylate

The enhancing effects of 0.25% sodium caprate (C10) and sodium caprylate (C8) on the paracellular permeation of seven water-soluble nonelectrolytes (inulin, polyethylene glycol 900, mannitol, erythritol, glycerol, thiourea, and urea) across the isolated rat colonic epithelium were examined using the Ussing-type chamber technique. The paracellular changes were also measured by impedance analysis. In both the presence and the absence of enhancers, the permeation clearances (Pm) for inulin (12–15 Å in molecular radius) to erythritol (3.2 Å) increased linearly with the increase in their free diffusion coefficients (Dfr), showing the existence of a paracellular shunt pathway unrestricted to any molecular size. Glycerol (2.9 Å), thiourea (2.6 Å), and urea (2.3 Å) had higher clearances than the expected linear values, showing the existence of a restricted paracellular or transcellular pathway. Both C10 and C8 increased the permeabilities in the two pathways, but C10 was more effective than C8. The increase in the permeabilities via the shunt pathway caused by the enhancers was greater than that via the restricted pathway, and thus, the two-phase pattern in the relationship of Pm and Dfr was similar to that in the absence of enhancers. The transcellular permeabilities for urea and thiourea, which were obtained from the efflux experiments, were increased by the enhancers. However, the relative increase caused by C10 was smaller than that of the paracellular-restricted permeabilities. The paracellular changes probably were due to the increase in pore area per unit diffusive path length. A decrease in the resistance of the intercellular junctions involving a simultaneous increase of membrane capacitance was observed in the presence of C10, corresponding to an increase of pore area per unit path length. The effect of C10 on the paracellular permeability was reversible, and the junctional resistance, membrane capacitance, and Pm of mannitol returned to the control level following the removal of C10.

Relationship Between Gelation Rate of Controlled-release Acetaminophen Tablets Containing Polyethylene Oxide and Colonic Drug Release in Dogs

AbstractPurpose. We hypothesized that sufficient gelation of orally administered hydrophilic matrix tablets before they reach the colon could, as a result of continuous erosion of the gelated matrix, prevent the decrease in colonic drug release which normally occurs here. The purpose of this study was to elucidate the effect of gelation of hydrophilic matrices containing polyethylene oxide on colonic drug release in dogs using controlled-release (CR) acetaminophen tablets. Methods. Two types of CR tablets were prepared, a slow gelling tablet (SG) and a rapid gelling tablet (RG) containing an extra highly water soluble filler. In vitro and in vivo performance were examined. Results. SG and RG showed similar drug release behavior in vitro. In oral administration to dogs, the two formulations showed similar gastrointestinal transit, reaching the colon within 2–4 h after oral dosing. Further, they showed similar maximum plasma levels (Cmax) and time to Cmax (Tmax). In contrast, however, the two tablets produced different plasma levels from 2 h post-dosing, with plasma levels of RG higher than those of SG and with smaller individual variation. Directly observed colonic drug release behavior of RG was similar to in vitro drug release, whereas that from SG was suppressed. Conclusions. Colonic drug release is closely related to the gelation of hydrophilic matrix, and rapid gelation provides continuous in vivo drug release.

Extended release of a large amount of highly water-soluble diltiazem hydrochloride by utilizing counter polymer in polyethylene oxides (PEO)/polyethylene glycol (PEG) matrix tablets.

The purpose of this study was to evaluate the feasibility of using a counter polymer in polyethylene oxide (PEO)/polyethylene glycol (PEG) polymeric matrices for the sustained release of a large amount of highly water-soluble drug. PEO/PEG matrix tablets (CR-A) containing four drugs with different water solubilities were prepared to investigate the effect of drug solubility on the drug-release and diffusion properties of PEO/PEG matrices. Cross-linked carboxyvinyl polymer (CVP)/PEO/PEG matrix tablets (CR-B) containing a water-soluble drug, diltiazem hydrochloride (DTZ), were also prepared, and their in vitro characteristics were compared with those of CR-A. Their in vitro drug release properties were evaluated using a dissolution test, and the polymeric erosion and drug diffusion properties of the matrices were also calculated. Drugs with higher solubility in water were released faster for the CR-A. The drug-release rate also increased with the amount of drug loaded. CR-A containing 50% DTZ (by weight) extended drug release by only 6h. This confirms the difficulty experienced when trying to formulate PEO/PEG matrices for the sustained release of a large amount of highly water-soluble drugs due to large drug diffusion. In an attempt to control this issue, a polymer bearing a charge opposite that of the drug was used to effectively decrease the diffusion of DTZ, resulting in sustained release for 24h or longer. These results suggested that including counter polymer in the PEO/PEG matrix tablet is a useful tool for achieving the sustained release of a large amount of highly water-soluble drug.

Differences in the enhancing effects of sodium caprate on colonic and jejunal drug absorption.

We examined the enhancing effect of sodium caprate (C10) on the jejunal absorption of a poorly absorbed drug, cefmetazole, in rats, in comparison with its colonic absorption (Pharm. Res. 5, 341–346, 1988). Jejunal absorption was significantly enhanced by C10, but to a smaller extent than colonic absorption. Membrane perturbation, caused by the interaction between C10 and membrane proteins or lipids, was shown to increase transcellular drug permeability, as reported in the colon. Paracellular permeabilities, obtained from the permeabilities of water-soluble nonelectrolytes of various molecular weights, showed a two-phase pattern against their free diffusion coefficients, suggesting the existence of at least two pore routes similar to those in the colon. C10 increased paracellular permeability in the colon but not in the jejunum. Impedance analysis and voltage clamp technique in the jejunum showed no significant effect of C10 on paracellular permeability, such as found in the colon. Accordingly, the difference in the effects of C10 on the jejunal and colonic absorption of cefmetazole was due mainly to the difference in its effects on the paracellular pathway.

A new index, the core erosion ratio, of compression-coated timed-release tablets predicts the bioavailability of acetaminophen

Although compression-coated tablets are a commonly used timed-release drug delivery technology, their utility is often limited by poor bioavailability. To try to improve the bioavailability of these tablets, the effect of their core composition of compression-coated tablet on in vivo pharmacokinetics was investigated. First, the extent of mass reduction of cores in different compression-coated tablet core formulations was used to establish a new index, the core erosion ratio. The data show that adding excipients with high water solubility to the core results in a greater core erosion ratio. Next, to elucidate the effect of core erosion ratio on in vivo acetaminophen (AAP) release, three compression-coated tablet formulations with similar in vitro AAP release profiles but different core erosion ratios were administered to four fasted dogs. The time for first appearance (TFA) of AAP in plasma did not differ significantly among formulations, indicating that the in vivo lag time was the same for all formulations. In separate experiments, necroscopy revealed that 3h after oral administration, the tablets were located in the ileum and colon and that all three formulations had identical GI transit times. However, the area under the AAP plasma concentration-time curve was greater in dogs given formulations with larger core erosion ratios. These results suggest that a formulation with a large core erosion ratio can significantly increase in vivo drug release from compression-coated tablets, leading to increased drug absorption from the lower GI tract.

A new stressed test to predict the foreign matter formation of minodronic acid in solution

A formulation containing 0.5 mg/ml minodronic acid, 40 mM citrate, pH 4.5, and sodium chloride, stored in regular flint glass ampoules, was stable without particulate increase under high temperature conditions, such as 40 degrees C for 6 months, or 50 or 60 degrees C for 3 months. However, when stored at 25 degrees C, there was an increase in >or=2 microm particles at the 5-month timepoint. This demonstrated that long-term stability cannot simply be predicted by the evaluation of samples just stored at higher temperatures. Therefore, a new stressed test was designed which is useful in the rapid selection of formulations that are stable and without particulate increase. Since the particulate matter is apparently a complex of minodronic acid and aluminum ions leaching from ampoules, samples were placed at 80 degrees C for up to 4 weeks to accelerate aluminum leaching. Although no particulate increase was observed directly after storage at 80 degrees C, 4 freeze-thaw cycles following the storage caused a drastic particulate increase. The evaluation of samples subjected to the freeze-thaw cycles indicated that the following formulation modifications have inhibitory effects on particulate generation: (1). addition of meglumine, diethanolamine, mannitol, or glycerol to the formulation; (2). increase of citric acid concentration; (3). decrease of minodronic acid concentration. These modifications also worked well for samples stored at 25 degrees C for 6 months, and particulate increase did not occur. This method is a powerful tool for predicting the stability of minodronic acid in solution.