The hydroxypropyl–β-cyclodextrin complexation of toltrazuril for enhancing bioavailability

Rabbit coccidiosis is a ubiquitous disease caused by one or more of 16 species of the apicomplexan genus Eimeria stiedae.14 General clinical symptoms of the disease are characterized by dullness, reduced food consumption, diarrhea or constipation, liver enlargement, ascites, icterus, abdominal distention, and death.3 Coccidiosis in rabbits can be prevented and treated using drugs.1,3,5,6 Toltrazuril (Tol), 1-[3-methyl-4-(4-trifluoromethylsulfanyl-phenoxy)-phenyl]-3-methyl-1,3,5-triazin-2,4,6-trione (Figure 1), is a symmetrical triazinetrione compound that is widely used to prevent and combat coccidiosis.710 However, due to poor aqueous solubility, Tol is difficult to be absorbed by the gastrointestinal (GI) tract. The clinical effects of Tol have been discounted because of its solubility in the GI tract.

Figure 1 Chemical structure of toltrazuril.

The poor aqueous solubility of Tol has been overcome by some techniques, such as solid dispersion, ultrafine power, and nanoemulsion.1113 As the currently most effective techniques for increasing solubility, Tol solid dispersion only increased the solubility of Tol to 2,000 times,11 which indicates that its solubility still needs to be enhanced significantly through other techniques. In addition, solid dispersion and nanoemulsion are unstable and inconvenient to store, while ultrafine power needs sophisticated equipment to produce.

β-cyclodextrin (β-CD) is in widespread use because of its unique cavity size, efficiency of drug complexation, and enhancements of drug stability, solubility, and bioavailability.14,15 For its regulatory status, β-CD is listed in numerous pharmacopoeia sources, including the US Pharmacopoeia/National Formulary, European Pharmacopoeia, and Japanese Pharmaceutical Codex.16,17 Hydroxypropyl–β-CD (HP-β-CD) is a hydroxyalkyl β-CD derivative that is studied extensively in drug inclusion complex because of its inclusion ability and high water solubility.1821 Toxicologic studies have reported on the safety of HP-β-CD in intravenous and oral administrations to the human body,22 and HP-β-CD has been used in clinical formulations to overcome poor solubility issues and enhance bioavailability.23

Not all drugs have properties to be made into complex with HP-β-CD. Tol was found to possess the properties based on a large number of screening research work. To increase the solubility and bioavailability of Tol by inclusion complex formation with HP-β-CD, toltrazuril–hydroxypropyl–β-cyclodextrin inclusion complex (Tol-HP-β-CD) was prepared by solution-stirring method in this study, and thin-layer chromatography (TLC), Fourier transform infrared (FTIR) spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy were employed to characterize the obtained Tol-HP-β-CD. The pharmacokinetic profiles of Tol and Tol-HP-β-CD in rabbits after oral administration were further compared in vivo.

Post time: Nov-11-2021