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The improvement effect of the combined use of spermine (SPM), a polyamine, with sodium taurocholate (STC) on the pulmonary drug absorption was investigated utilizing poorly absorbable drugs with various molecular sizes in rats. The pulmonary absorption of rebamipide, a low molecular but poorly absorbable drug after oral administration, was significantly improved by the combined use of SPM with STC (SPM-STC formulation), while poly- L-lysine did not show a significant change in rebamipide absorption from the lungs. Furthermore, the safety of the SPM-STC formulation for the lungs was assessed in rats by the histopathological study and any local toxicity was not observed while poly-L-lysine, a typical chemical causing the toxicity for the epithelial cells, provided several histopathological changes. In addition, the SPM-STC formulation significantly improved the pulmonary absorption of fluorescein isothiocyanate dextran 4 (FD-4, Mw ca 4000) and interferon-α (IFN-α, Mw ca 25,000) as well. Our present results clearly indicated that the SPM-STC formulation significantly improved the pulmonary absorption of poorly absorbable small and large molecular drugs without any harmful effects on the lungs. Therefore, the SPM-STC formulation would be a useful one for the pulmonary absorption of drugs, specifically macromolecular ones, which are very difficult to be absorbed after oral administration. [ABSTRACT FROM AUTHOR]

Abstract: The synergetic improving effect of bile acids with spermine (SPM), a major polyamine, on the absorption of rebamipide, a poorly soluble and poorly absorbable drug (BCS Class IV), was evaluated in rats and beagle dogs. Although the absorption of rebamipide was improved by the addition of polyamines alone in normal rats, it was not improved in bile duct ligated (BDL) rats. The combinatorial use of sodium taurocholate (STC), a bile acid, with SPM improved the absorption of rebamipide even in BDL rats. In the beagle dogs, the oral administration of SPM alone did not enhance the absorption of rebamipide, but the combinatorial use of STC with SPM improved the absorption as well as in the BDL rats. These results indicate that bile acids are indispensable for the novel formulation containing SPM to improve the absorption of rebamipide after oral administration. [Copyright &y& Elsevier]

Abstract: In order to develop a novel oral formulation that can safely improve the intestinal absorption of poorly absorbable drugs, polyamines such as spermine (SPM) and spermidine (SPD) was examined as an absorption enhancing adjuvant in rats. The absorption of rebamipide, classified into BCS Class IV, from colon was significantly improved by SPM or SPD, and the enhancing ability of SPM was larger than that of SPD. As a possible mixing and/or interaction of polyamines with bile acids were expected, the combinatorial use of sodium taurocholate (STC) with polyamines was also examined. The absorption of rebamipide was drastically improved by the combinatorial use of SPM or SPD with STC. As STC itself did not enhance the absorption of rebamipide so much, it was considered that polyamines and STC had a synergistic enhancing effect. In-vivo oral absorption study was also performed to investigate the effectiveness and safety of polyamines and their combinatorial use with STC in rats. Although the enhancing effect slightly attenuated comparing with the in-situ loop study, the absorption of rebamipide was significantly improved and the combinatorial use of 10 mM SPM with 25 mM STC showed the largest enhancing effect. Histopathological studies clearly showed that any significant change in stomach and duodenum was not caused by SPM (10 mM), SPD (10 mM) or their combinatorial use with STC (25 mM) at 1.5 or 8.0 h after oral administration. Taken all together, polyamines, especially SPM, and its combinatorial use with STC could improve the absorption of poorly absorbable drugs without any significant changes in gastrointestinal tract after oral administration in rats. [Copyright &y& Elsevier]

The main focus of this study was to determine the optimal administration period concerning the toxic effects on ovarian morphological changes in the repeated dose toxicity study. In order to assess the morphological and functional changes induced in the ovary by cyclophosphamide (CP), the compound was administrated to female rats at dose levels of 0, 5, 10 and 20 mg/kg for the repeated dose toxicity study for 2 or 4 weeks, and at 0, 5, 10, and 20 mg/kg for the female fertility study from 2 weeks prior to mating to Day 7 of pregnancy. In the repeated dose toxicity study, increases in large sized atretic follicles, atrophy of corpora lutea were observed in the 20 mg/kg group in the 4-week study by the histopathological examination of the ovaries. There were no drug-related changes in the ovary in the 2-week study. In the female fertility study, the numbers of implantation were slightly decreased and the corpora lutea of pregnancy was not observed in the 20 mg/kg group. The dose-dependent increase in the incidence of post-implantation loss was observed, and no abnormalities were observed in the estrus cycle and mating in all treated groups. From these findings, the histopathological changes in the ovary are important endpoints for the evaluation of drug-induced ovarian damage as well as caesarean section. In conclusion, a 4-week administration period is sufficient to detect the ovarian toxicity of CP in the repeated dose toxicity study. [ABSTRACT FROM AUTHOR]

To develop the safe formulation that can safely improve bioavailability of poorly absorbable drugs and that is practically available, we prepared the suppositories of rebamipide, a poorly soluble and poorly absorbable antiulcer drug, by employing the combinatorial use of sodium laurate (C12), an absorption enhancer, with taurine (Tau) or l-glutamine (l-Gln), an adjuvant exerting the cytoprotective action. Although the dissolution of rebamipide from fatty base (FB) suppository prepared using Witepsol H-15 was very slow, it was remarkably improved by the addition of C12 and l-Gln or Tau into the suppository. On the other hand, the dissolution of rebamipide from water-soluble base (WB) suppository prepared using polyethylene glycol was very rapid and the addition of adjuvants did not influence its dissolution so much. Rectal absorption of rebamipide examined in rats was remarkably improved by FB suppository containing C12 or both C12 and Tau, while the enhancing effect of C12 was relatively small in the case of WB suppositories. Biochemical and histopathological studies have confirmed that FB suppository containing both C12 and Tau or l-Gln did not cause any serious local damage, while FB suppository containing C12 only caused the erosion and shrinkage for a lot of rectal epithelial cells. In conclusion, FB suppository employing the combinatorial use of C12 with Tau could be a promising formulation that is effective and safe enough for poorly absorbable drugs to be practically administered. [Copyright &y& Elsevier]