1. 静岡県立大学 薬学部 薬物動態学分野 Department of Pharmacokinetics and Pharmacodynamics School of Pharmaceutical Sciences, University of Shizuoka Hiroki Suzuki Tuesday, January 12, 2016 Data presentation

2. UNIVERSITY OF SHIZUOKA  Developing various powder formulation using fine droplet drying process for improvement in biopharmaceutical properties of drugs  Model compound:Cyclosporine A (CsA) 1. Potent immune suppression effect 2. Low solubility (ca. 20  g/mL in water) Collaborative study with RICOH company Working hypothesis HPC-SSL-based amorphous solid dispersion of CsA (ASD/CsA) with improved dissolution may show the enhanced oral absorption. 2 Main purpose This study mainly aims to clarify the feasibility of fine droplet drying process for the production of ASD formulation.

3. UNIVERSITY OF SHIZUOKA Characterization of ASD/CsA 3 Dissolution behavior Pharmacokinetic behavior in rats ▲ASD/CsA ■Amorphous CsA Mean±SE (n=3).Mean±SE (n=6). Test conditions Test solution: 100 mL of distilled water Applied sample: 3 mg-CsA/100 mL Rotation: 100 rpm Temperature: 37 º C

4. UNIVERSITY OF SHIZUOKA 3 Dissolution behavior Pharmacokinetic behavior in rats ▲ASD/CsA (10 mg-CsA/kg, p.o.) ■Amorphous CsA (10 mg-CsA/kg, p.o.) C max (ng/mL)T max (h)T 1/2 (h) AUC 0-inf (h·ng/mL) BA (%) ASD/CsA (10 mg-CsA/kg, p.o.) 1,000±1305.2±1.67.2±2.113,000±2,13014.6 Amorphous CsA (10 mg-CsA/kg, p.o.) 100±503.7±0.42.7±0.3560±2500.6 Pharmacokinetic parameters Mean±SE (n=6). Mean±SE (n=3).Mean±SE (n=6). Characterization of ASD/CsA

5. UNIVERSITY OF SHIZUOKA 3 Dissolution behavior Pharmacokinetic behavior in rats ▲ASD/CsA (10 mg-CsA/kg, p.o.) ■Amorphous CsA (10 mg-CsA/kg, p.o.) Mean±SE (n=3).Mean±SE (n=6). The ASD/CsA exhibited higher dissolution behavior and oral absorption of CsA than amorphous CsA. Characterization of ASD/CsA

6. UNIVERSITY OF SHIZUOKA 3 Dissolution behavior Pharmacokinetic behavior in rats ▲ASD/CsA (10 mg-CsA/kg, p.o.) ■Amorphous CsA (10 mg-CsA/kg, p.o.) Mean±SE (n=3).Mean±SE (n=6). Future plan Physicochemical stability of ASD/CsA Conditions:40ºC/75% relative humidity for 2, 4, and 8 weeks Assessments:Crystallinity Dissolution behavior Characterization of ASD/CsA