Inclusion Complexation of p-Hydroxybenzoic Acid Esters with 2-Hydroxypropyl-.BETA.-cyclodextrins. On Changes in Solubility and Antimicrobial Activity.

Abstract

To obtain a transparent and effective solution of p-hydroxybenzoic acid esters (parabens), the use of 2-hydroxypropyl-beta-cyclodextrins (2-HP-beta-CyDs) as solubilizers with different degrees of substitution (D.S.) was surveyed. 2-HP-beta-CyDs significantly increased the aqueous solubility of four kinds of parabens (methyl < ethyl < propyl < butyl esters), where the solubilizing ability decreased with an increase in the D.S. of the 2-hydroxypropyl group in beta-CyD. The antimicrobial activity of the parabens tended to decrease by complexation with 2-HP-beta-CyDs. However, the activity could be maintained by lengthening the alkyl chain of the parabens. 1H- and 13C-nuclear magnetic resonance and circular dichroism spectroscopic studies suggest that the hydrophobic alkyl moiety of butyl paraben is preferably included in the cavity, and the phenol group extrudes from the cavity. The present results suggest that a suitable combination of 2-HP-beta-CyDs and hydrophobic, longer alkyl parabens is useful for the preservation of liquid formulations.

Inclusion Complexation of Propofol with 2-Hydroxypropyl-β- cyclodextrin. Physicochemical, Nuclear Magnetic Resonance Spectroscopic Studies, and Anesthetic Properties in Rat

“…Similar inclusion modes with the hydroxy group at the wide cavity end were found for other phenol derivatives investigated. 23,24 The proposed inclusion mode III is also supported by computer-aided molecular modeling studies. In Figure 2, a minimized computer-generated structure of propofol-HP--CD complex is depicted; the hydroxyl and methyl groups pushed outside the HP--CD cavity are clearly shown.…”

Pharmaceutical Applications of Cyclodextrins. III. Toxicological Issues and Safety Evaluation

“…Other studies have proposed that various untoward effects observed after chronic large oral doses of HP--CD are not only caused by an increased excretion of some vital lipophiles but also by solubilization and increased absorption of lipophilic toxicants and carcinogens present in the gastrointestinal tract. 133 These results suggest that a suitable combination of HP--CD with longer chain alkyl parabens is useful for the preservation of ophthalmic liquid formulations. [123][124][125][126] One of the prerequisites for a new vehicle to be used in ophthalmic preparations is that it is not irritating to the ocular surface, because ocular damage should be avoided whenever possible and because the irritation causes reflex tearing and blinking, which result in a fast washout of the instilled drug.…”

Pharmaceutical Applications of Cyclodextrins. 2. In Vivo Drug Delivery

“…[191][192][193] To be used in multidose preserved preparations, new preservatives that do not interact with the cyclodextrins may have to be identified. Matsuda et al 191 did note, however, that the longer chain parabens, propyl and butyl, were solubilized by HP--CD so that it my be possible to use a combination of HP--CD and hydrophobic longer chain alkyl parabens for the preservation of liquid formulations.…”