Hajime Toguchi

In vitro-in vivo correlation for wet-milled tablet of poorly water-soluble cilostazol.

The purpose of the present study was to investigate oral bioavailability of an immediate release tablet containing wet-milled crystals of a poorly water-soluble drug, cilostazol, and to establish in vitro-in vivo correlation. Sub-micron sized cilostazol (median diameter: 0.26 microm) was successfully prepared using a beads-mill in water in the presence of a hydrophilic polymer and an anionic surfactant. The milled suspension was solidified with a sugar alcohol as a water-soluble carrier by spray-drying method. The co-precipitate was compressed into an immediate release tablet with common excipients. Oral bioavailability of the wet-milled cilostazol tablet in male beagle dogs was 13-fold higher than the hammer-milled commercial tablet in fasted condition. Food did not increase the oral bioavailability of the wet-milled tablet, while 4-fold increase was found for the commercial tablet. Irrespective to the bioavailability enhancement, in vitro dissolution rate of the wet-milled tablet was even slower than the commercial tablet by the compendial method (USP Apparatus 2). On the other hand, a good correlation was found between the dissolution profiles obtained by a flow-through cell method (USP Apparatus 4, closed-loop system without outlet filter) using a large volume of water and sodium lauryl sulfate (SLS) solution at the concentration lower than the critical micellar concentration (cmc) as dissolution media corresponding to the fasted and fed conditions, respectively.

Sterility assurance of microspheres

The International Conference on Harmonization (ICH) provides a forum for constructive dialogues between regulatory authorities and the pharmaceutical industry on the real and perceived differences in the technical requirements for product registration in the EU, US and Japan. Achievement obtained so far is beyond expectation, having strong impacts both favorable and unfavorable on Japanese regulatory authorities and the pharmaceutical industry. The ICH guidelines are very science-oriented and little consideration seems to have been paid to the cultural and legal differences among the three regions. An example of such a difference is the interpretation of the guidelines between the US and Japan. In the US, they are generally recognized as good examples, whereas in Japan, they are usually taken as minimum and rigid requirements. A more flexible approach to guidelines will be necessary in the development of new dosage forms in Japan. In this paper, how to assure sterility of a new dosage form, that is, once-monthly injectable and biodegradable microspheres of Leuprorelin, a super agonist of LHRH, whose pharmaceutical development the author was in charge of at Takeda Chemical Industries, will be introduced.

Prediction of drug intestinal absorption in human using the Ussing chamber system: A comparison of intestinal tissues from animals and humans

&NA; An adequate evaluation system for drug intestinal absorption is essential in the pharmaceutical industry. Previously, we established a novel prediction system of drug intestinal absorption in humans, using the mini‐Ussing chamber equipped with human intestinal tissues. In this system, the TI value was defined as the sum of drug amounts transported to the basal‐side component (Xcorr) and drug amounts accumulated in the tissue (Tcorr), which are normalized by AUC of a drug in the apical compartment, as an index for drug absorption. In order to apply this system to the screening assay, it is important to understand the differences between animal and human tissues in the intestinal absorption of drugs. In this study, the transport index (TI) values of three drugs, with different levels of membrane permeability, were determined to evaluate the rank order of drug absorbability in intestinal tissues from rats, dogs, and monkeys. The TI values in small intestinal tissues in rats and dogs showed a good correlation with those in humans. On the other hand, the correlation of TI values in monkeys was lower compared to rats and dogs. The rank order of the correlation coefficient between human and investigated animal tissues was as follows: dog (r2 = 0.978), rat (r2 = 0.955), and monkey (r2 = 0.620). TI values in large intestinal tissues from rats (r2 = 0.929) and dogs (r2 = 0.808) also showed a good correlation. The obtained TI values in small intestinal tissues in rats and dogs were well correlated with the fraction of drug absorbed (Fa) in humans. From these results, the mini‐Ussing chamber, equipped with intestinal tissues in rats and dogs, would be useful as a screening tool in the drug discovery stage. In addition, the obtained TI values can be used for the prediction of the Fa in humans. Graphical abstract Figure. No caption available.

Evaluation of intestinal metabolism and absorption using the Ussing chamber system equipped with intestinal tissue from rats and dogs

Graphical abstract Figure. No Caption available. Abstract The purpose of this study was to evaluate the intestinal metabolism and absorption in a mini‐Ussing chamber equipped with animal intestinal tissues, based on the transport index (TI). TI value was defined as the sum of drug amounts transported to the basal‐side component (Xcorr) and drug amounts accumulated in the tissue (Tcorr), which are normalized by AUC of a drug in the apical compartment, as an index for drug absorption. Midazolam was used as a test compound for the evaluation of intestinal metabolism and absorption. The metabolite formulation of midazolam was observed in both rats and dogs. Ketoconazole inhibited the intestinal metabolism of midazolam in rats and improved its intestinal absorption to a statistically significant extent. Therefore, the mini‐Ussing chamber, equipped with animal intestinal tissues, showed potential to use the evaluation of the intestinal metabolism and absorption, including the assessment of species differences.

Arachidonic acid with taurine enhances pulmonary absorption of macromolecules without any serious histopathological damages

&NA; Therapeutic peptides and protein are being used in several indications; however, their poor permeability still remains to be solved. This study focused on the pulmonary route of macromolecules. First, the effects of arachidonic acid (AA) as an absorption enhancer on drug serum concentration, after intratracheal administration, were investigated in rats. Second, the safety of AA was assessed in rats in an acute toxicity study for 7 days. AA enhanced the exposure of both interferon‐&agr; (IFN‐&agr;) and fluorescein isothiocyanate 4000 (FD‐4). In addition, the histopathological analysis indicated that AA caused alveolitis and bronchitis in rats. In combination with Taurine (Tau), these lung injuries were prevented through the histopathological analysis. The combined use of Tau with AA did not show any changes in the pharmacokinetics of FD‐4. From these results, we suggest the combined use of AA with Tau as a novel formulation on the pulmonary route of macromolecule drugs. This formulation could improve the bioavailability of macromolecule drugs without any serious local damage to the lungs. Graphical abstract Figure. No caption available.