Cyclosporine A-Loaded Ternary Solid Dispersion Prepared with Fine Droplet Drying Process for Improvement of Storage Stability and Oral Bioavailability

Abstract

This study aimed to develop a cyclosporine A (CsA)-loaded ternary solid dispersion (tSD/CsA) to improve the storage stability of a solid dispersion (SD) system and the oral absorbability of CsA. Hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) were selected as carrier materials of tSD, and tSD/CsA was prepared with a fine droplet drying process, a powderization technology that employs an inkjet head. The physicochemical properties of tSD/CsA were evaluated in terms of morphology, storage stability, dissolution behavior, and mucoadhesive property. After the oral administration of CsA samples (10 mg-CsA/kg) to rats, the plasma concentration of CsA was monitored to estimate oral absorbability. tSD/CsA comprised uniform shriveled particles with a diameter of 3.4 mm and span factor of 0.4, which is a parameter to estimate the particle size distribution. Although HPC-based binary SD showed marked aggregation of the particles after storage under 40 °C/75% relative humidity, there were no significant aggregations of tSD/CsA, due to the relatively low hygroscopic property of HPMCAS. The pH-dependent release of CsA with improved dissolution was observed in tSD/CsA. In the in vitro mucoadhesive evaluation using a mucin disk, tSD/CsA exhibited a better mucoadhesive property than HPC-based SD, possibly leading to prolonged retention of tSD particles in the gastrointestinal tract after oral administration. Orally-dosed tSD/CsA in rats resulted in significantly improved oral absorption of CsA, as evidenced by a 27-fold higher bioavailability than amorphous CsA. tSD/CsA may be a promising dosage option to improve the storage stability of a SD system and the biopharmaceutical properties of CsA.

Keywords: cyclosporine A; fine droplet drying process; mucoadhesive particle; oral absorption; storage stability; ternary solid dispersion.

Figure 1

Particle size distribution and appearance of CsA-loaded solid dispersions. (A) Laser diffraction analysis of CsA samples to measure the particle size distribution. (A-I) SD/CsA and (A-II) tSD/CsA. Solid line, particle size distribution before storage; and dotted line, particle size distribution after storage at 40/75%RH for one week. (B) SEM observations of CsA samples. (B-I) SD/CsA and (B-II) tSD/CsA. (B-III,B-IV) after storage at 40/75%RH for one week. White bars represent 15 μm.

Figure 2

Dissolution behavior of CsA samples in (A) pH1.2 and (B) pH6.8 solutions. ×, amorphous CsA; ◯, tSD/CsA; △, SD/CsA. Each bar represents mean ± S.E. of three independent experiments.

Figure 3

Mucoadhesive property of CsA samples. Amount of CsA retained after the application of CsA samples to mucin disks. Each bar represents mean ± S.E. of three independent experiments.

Figure 4

Oral absorption profile of CsA samples after oral administration (10 mg-CsA/kg, p.o.) in rats. ×, amorphous CsA; ◯, tSD/CsA; and △, SD/CsA. Each bar represents mean ± S.E. of 5–6 independent experiments.