Nasal Absorption Enhancement of 17β-Estradiol by Dimethyl-β-Cyclodextrin in Rabbits and Rats

A new formulation for nasal administration containing 17-estradiol (E₂) with dimethyl--cyclodextrin (DMC) as a solubilizer and absorption enhancer is described. Nasal administration of this E₂-DMC formulation gave a significantly higher E₂ absorption than an E₂ suspension in both rabbits and rats. Relative to an intravenous injection of the E₂-DMC formulation, absolute bioavailabilities of 94.6 and 67.2% were calculated for the nasal E₂-DMC formulation in rabbits and rats, respectively. Differences in bioavailability may have resulted from differences in experimental animal conditions. The effects on human nasal ciliary activity of the E₂-DMC formulation were studied with an in vitro method. The formulation was found to exert only a minor effect on ciliary beat frequency. Thus, nasal delivery of E₂, using a cyclodextrin inclusion formulation, may have potential for clinical application, e.g., in the therapy of postmenopausal disorders.     

Bile Acid as an Effective Absorption Enhancer for Oral Delivery of Epidermal Growth Factor Receptor–Targeted Hybrid Peptide

The aim of this study was to improve the oral absorption of epidermal growth factor receptor–targeted hybrid peptide using bile acid as an absorption enhancer. The oral formulation of this peptide was formed through electrostatic interactions between the cationic peptide and anionic bile acid. Comparative studies of in vitro cell permeability and in vivo antitumor effects of peptide and peptide/bile acid complex were performed in Caco-2 cells and in a xenograft mouse model of human gastric cancer. The in vitro permeability of peptide/bile acid complex across Caco-2 cell monolayers was significantly enhanced to about 5.0-fold over those of peptide alone. Furthermore, in vivo mouse xenograft model treated with peptide/bile acid complex showed a 1.6-fold reduction in the mean tumor volume as compared with the peptide alone. A preliminary safety evaluation of blood cells counts, liver enzyme levels, and histopathology of gastrointestinal tissues and main organs showed that the peptide/bile acid complex did not induce any acute toxicity. These results suggest that bile acid is an effective absorption enhancer for improving the oral bioavailability and bioactivity of epidermal growth factor receptor–targeted hybrid peptide.     

Aerosolization,Drug Permeation and Cellular Interaction of Dry Powder Pulmonary Formulations of Corticosteroids with Hydroxypropyl-β-Cyclodextrin as a Solubilizer

Purpose

The purpose of this study was to assess the feasibility of hydroxypropyl-β-cyclodextrin as a solubilizer for the corticosteroids prednisolone and fludrocortisone acetate in dry powder inhalation formulations.

Methods

The dry particles were simultaneously produced and coated with nanosized L-leucine crystals using an aerosol flow reactor method. The aerosolization performances of carrier-free powders were studied using Easyhaler® and Twister? at 2 and 4 kPa pressure drops over the inhalers. Drug permeation properties of the formulations were tested across a Calu-3 cell monolayer. Toxicity and reactive oxygen species induction were tested against Calu-3 and A549 cell lines.

Results

The hydroxypropyl-β-cyclodextrin in the powders promoted the dissolution of fludrocortisone the most, followed by that of prednisolone. Fine particle fractions were 52–70% from emitted doses which showed good repeatability with a coefficient variation of 0.9–0.17. In addition, hydroxypropyl-β-cyclodextrin enhanced the permeation of the corticosteroids. The powders showed no statistically significant toxicity nor reactive oxygen species induction in the tested cell lines.

Conclusions

This study demonstrated the preparation and function of fine powder formulations which combine improved dissolution of poorly soluble drugs with good aerosolization performance. These results are expected to promote particle engineering as a way to develop new types of therapeutic pulmonary powders.