Improvement of Dissolution Rate and Oral Bioavailability of a Sparingly Water-Soluble Drug, (.+-.)-5-((2-(2 Naphthalenylmethyl)-5-benzoxazolyl)-methyl)-2,4-thiazolidinedione, in Co-ground Mixture with D-Mannitol.

We investigated the usefulness and efficiency of the co-grinding method with D-mannitol to improve the bioavailability of a sparingly water-soluble drug, (+/-)-5-[[2-(2-naphthalenylmethyl)-5-benzoxazolyl]methyl]-2, 4-thiazolidinedione (174), and compared it with those of the single-grinding method. The co-ground mixtures in drug/carrier weight ratios up to 1:5 gave fine particle sizes of less than about 3 microns, which showed a marked increase in the dissolution rate with reduction of particle size, compared with the single-ground powder, even with a similar particle size. The oral bioavailability study of co-ground powders in beagle dogs exhibited a dramatic increase, as did the dissolution rate, according to finer particle size. Finally, complete bioavailability was obtained at the finest particle size of 1.2 microns (drug/carrier ratio of 1:5, w/w) as was a solution of the drug. Bioavailability had a good linear correlation with the dissolution rate. These findings suggested that the co-grinding method with D-mannitol dramatically increased the available surface area, caused by a reduction of particle size, which not only accelerated the dissolution rate but also resulted in greater enhancement of the bioavailability of 174.