betadex and 4-biphenylylacetic-acid-ethyl-ester

The effect of hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) on the cutaneous penetration and activation of ethyl 4-biphenylyl acetate (EBA), a prodrug of non-steroidal anti-inflammatory drug 4-biphenylylacetic acid (BPAA), from hydrophilic ointment was investigated, using hairless mouse skin in vitro. When the hydrophilic ointment containing a complex of EBA with HP-beta-CyD was applied to the full-thickness skin, HP-beta-CyD facilitated the penetration of EBA into the skin, the conversion of EBA to BPAA in the epidermis and the transfer of BPAA to the receptor phase. Under the present condition, pre- and post-application of the ointment containing HP-beta-CyD onto the skin did not affect the cutaneous penetration of EBA and its activation. When the ointment containing the EBA:HP-beta-CyD complex was applied to the skin, the flux of BPAA through the tape-stripped skin was greater than that through the full-thickness skin, while the activation of the prodrug in the skin was slowed down by the tape-stripping. When propylene glycol was used as a vehicle, HP-beta-CyD no longer enhanced the cutaneous permeation of BPAA through the full-thickness skin. These results suggest that the enhancing effect of HP-beta-CyD on the cutaneous penetration of EBA would be ascribable largely to an increase in effective concentration of EBA in the ointment. Furthermore, the slow diffusion of EBA solubilized in HP-beta-CyD through the stratum corneum, together with the vehicle effect, could make the prodrug more susceptible to the metabolic process that is active in the epidermis, eventually leading to the facilitated activation of the prodrug.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Excipients; Female; In Vitro Techniques; Mice; Mice, Hairless; Ointments; Phenylacetates; Skin; Skin Absorption; Time Factors

Cyclodextrins (CyDs) are known to be fermented to small saccharides by colonic microflora, whereas they are only slightly hydrolyzable and thus are not easily absorbed in the stomach and small intestine. This property of CyDs is particularly useful for colon-specific delivery of drugs. In this study, an antiinflammatory 4-biphenylylacetic acid (BPAA) was selectively conjugated onto one of the primary hydroxyl groups of alpha-, beta-, and gamma-CyDs through an ester or amide linkage, 6A-O-[(4-biphenylyl)acetyl[-alpha-, -beta-, and -gamma-CyDs (1-3) and 6A-deoxy-6A-[[(4-biphenylyl)acetyl]amino]-alpha-, -beta-, and -gamma-CyDs (4-6). In rat cecal and colonic contents (10%, w/v), 1 and 3 released more than 95% of BPAA within 1-2 h, and 2 released about 50% of the drug within 12 h. The amide prodrugs, 4-6, did not release BPAA in the cecal contents, but gave BPAA/maltose or BPAA/triose conjugates linked through an amide bond. On the other hand, these prodrugs were found to be stable in the contents of rat stomachs and small intestines, in intestinal or liver homogenates, and in rat blood. The serum levels of BPAA increased about 3 h after oral administration of 1 and 3 to rats, accompanying a marked increase in the serum levels, whereas 2 and 4-6 resulted in little increase of the serum levels. These facts suggest that BPAA is released after the ring opening of CyDs followed by the ester hydrolysis, and the BPAA activation takes place site-specifically in the cecum and colon. Therefore, the present CyD prodrug approach provides a versatile means of constructing a novel colon-specific drug delivery system.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbohydrate Sequence; Colon; Cyclodextrins; Digestive System; Drug Delivery Systems; Hydrogen-Ion Concentration; Male; Molecular Sequence Data; Phenylacetates; Prodrugs; Rats; Rats, Wistar

To improve the rectal delivery of ethyl 4-biphenylylacetate (EBA), a prodrug of the anti-inflammatory drug 4-biphenylylacetic acid (BPAA), the use of highly water-soluble 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD) was investigated and compared with the use of the parent beta-cyclodextrin (beta-CyD). Among the three beta-CyDs, HP-beta-CyD was best at improving the rectal bioavailability of EBA in rats after single and multiple administrations of oleaginous suppositories (Witepsol H-5) containing the complexes. To gain insight into the enhancing effect of beta-CyDs, the absorption behaviors of EBA (observed by monitoring BPAA as an active metabolite of EBA) and beta-CyDs themselves were examined in vitro, in situ, and in vivo. The in situ recirculation study revealed that the complexed form of EBA was less absorbable from the rectal lumen in the solution state, but this disadvantageous effect of beta-CyDs was compensated in part by the inhibition of the bioconversion of EBA to BPAA. When beta-CyDs were coadministered with EBA in vivo, however, rather high amounts of HP-beta-CyD (approximately 26% of dose) and DM-beta-CyD (approximately 21% of dose), compared with beta-CyD (approximately 5% of dose), were absorbed from the rat rectum. Thus, the enhancement of rectal absorption of EBA in vivo can be explained by the facts that the hydrophilic beta-CyDs increased the release rate of EBA from the vehicle and stabilized EBA in the rectal lumen and that the drug was partly absorbed in the form of the complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; beta-Cyclodextrins; Cyclodextrins; Drug Combinations; Hydrolysis; Intestinal Absorption; Male; Permeability; Phenylacetates; Rats; Rats, Wistar; Rectum; Suppositories

Ethyl 4-biphenylyl acetate (EBA) is a prodrug of the antiinflammatory 4-biphenylyl acetic acid (BPAA). The inclusion complexes of EBA with beta-cyclodextrin (beta-CyD), heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD), and 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) at a molar ratio of 1:2 (EBA:cyclodextrin) were prepared and used to make hydrophilic antiinflammatory ointments. The in vitro release of EBA from the ointments was enhanced by complexation in the order of beta-CyD less than DM-beta-CyD less than or equal to HP-beta-CyD. The improvement correlated with the improved solubility and not with the decreased diffusibility observed to occur upon the complexation of EBA. In vivo the complexation with cyclodextrin derivatives increased both the release of EBA from the vehicle and its conversion in the underlying tissue to BPAA, but the total of EBA and BPAA in the tissue was decreased. In vitro studies confirmed that the effects of cyclodextrin derivatives on the conversion were exerted indirectly. The combination of the enhanced release and of the enhanced prodrug hydrolysis by esterases in the site where the antiinflammatory action is required resulted in increased therapeutic effects. In the model of carrageenan-induced acute edema in rat paw, the complexation improved the therapeutic effects over those of EBA alone in the order of beta-CyD less than DM-beta-CyD less than HP-beta-CyD. HP-beta-CyD may be a particularly useful cyclodextrin derivative since it improves the topical availability and does not irritate tissues.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; beta-Cyclodextrins; Biotransformation; Carrageenan; Chromatography, High Pressure Liquid; Cyclodextrins; Edema; Hydrolysis; Male; Ointments; Phenylacetates; Prodrugs; Rats; Rats, Inbred Strains; Skin Absorption; Solubility