Abstract
To improve the rectal delivery of an anti-inflammatory drug, biphenylylacetic acid (BPAA), the use of 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) and heptakis (2, 6-di-O-methyl)-β-cyclodextrin (DM-β-CyD) was investigated. Inclusion complex formations of BPAA with both β-CyDs in a molar ratio of 1 : 1 in water were ascertained, and their stability constants were determined. The dissolution of BPAA in water and the release of BPAA from an oleaginous suppository (Witepsol H-5) were significantly increased by β-CyDs, depending on the magnitude of the stability constants of the water-soluble complexes. However, the serum levels of BPAA after rectal administration of the suppositories containing BPAA or its β-CyDs complexes in rats increased in the order of BPAA alone «DM-β-CyD⪈HP-β-CyD complex. The in situ recirculation study revealed that the greater the stability constant of the complex, the lesser was the absorption of BPAA from the rectal lumen of rats under the solution state. Both in vivo and in situ studies demonstrated that rather high amount of HP-β-CyD (about 20% of dose) was absorbable from the rat's rectum, compared with DM-β-CyD (less than 5% of dose), suggesting the possibility of the permeation of BPAA through the rectal membrane in the form of HP-β-CyD complex. Furthermore, DM-β-CyD and HP-β-CyD significantly reduced the irritation of the rectal mucosa caused by BPAA after the administration of the suppositories to rats. The above data suggest that water-soluble β-CyD derivatives are useful in the rectal formulation of BPAA, improving the bioavailability and local irritancy.
