Category: Formulation and Quality
Purpose: Dutasteride is a potent 5α-reductase inhibitor which is used to treat benign prostatic hyperplasia (BPH) or androgenetic alopecia. Although a commercial product is available as a soft gelatin capsule on the market (Avodart®, GlaxoSmithKline Pharmaceuticals SA), it still has room for improvement in terms of bioavailability (approx. 40~60% in humans) due to its poor solubility. Further, considering that main target patient population is geriatrics, there is an evident clinical need for dosage forms with easy swallowing properties (e.g., powders or small-sized capsules) due to the large capsule size of the conventional product (19.13 mm in length). This study aimed to formulate a solid self-emulsifying drug delivery system (SEDDS) in order to enhance the dissolution rate of a poorly water-soluble drug, dutasteride.
Methods: Various placebo SEDDS formulations with different medium-chain lipids and surfactants were screened by visual observation and droplet size measurement after dilution (SEDDS: water, 1:99, w/w). The emulsion droplet size was measured using a dynamic light scattering technique. The formulation that requires the least amount of surfactant while maintaining clarity and small emulsion droplet size after dilution was chosen as the optimal SEDDS. The solid SEDDS were prepared by adsorbing the optimized SEDDS (100 mg) containing dutasteride (0.5 mg) to the adsorbent (magnesium aluminum silicate, Neusilin, Fuji Chemical Industries) at 1:0.7 w/w ratio. The solid SEDDS formulation containing dutasteride was evaluated for drug content, droplet size after dilution, flow properties (Carr’s index) and in vitro drug release (USP Apparatus II, simulated gastric fluid without enzyme, pH 1.2).
Results: It could be observed from the figures 1 and 2 that both the type of surfactant and the lipid significantly affected the droplet size of the SEDDS. In addition, the droplet size generally increased when the ratio of surfactant was decreased (from 1:1 to 1:0.5, w/w). The SEDDS formulations with significantly large droplet size (e.g., Peceol) were also highly turbid when observed with the naked eye. The optimized composition (Capmul MCM NF, Captex 355 EP/NF, Cremophor EL 1:1:2, w/w/w) which had the smallest droplet size showed no sign of phase separation (turbidity) after dilution and the droplet size was below 100 nm. The prepared solid SEDDS had the average droplet size of approx. 50 nm after dispersion, similar to that of SEDDS before the adsorption process. In addition, the solid SEDDS showed excellent flow properties (Carr’s Index: 6.98), with the drug content of 100.7±0.1%. In vitro dissolution test in a simulated gastric fluid indicated significantly improved dissolution rate for the optimized solid SEDDS over the conventional marketed soft capsule.
Conclusion: Solid SEDDS containing dutasteride, a poorly soluble drug, was successfully optimized in this study. The optimized solid SEDDS had an average droplet size below 100 nm with rapid in vitro dissolution profile whereas no drug was released for the commercial product in the same dissolution media, implying its potential for improved bioavailability. Furthermore, its excellent flowability suggests the system can be easily manufactured at commercial scale into various types of patient-friendly dosage forms (hard capsules, tablets, powders) and ultimately improve patient compliance.
Min-Seok Choi– Seoul, Seoul-t'ukpyolsi, Republic of Korea
Suk Lee– Seoul, Seoul-t'ukpyolsi, Republic of Korea
Min-Uk Cha– Seoul, Seoul-t'ukpyolsi, Republic of Korea
Ji-Min Hong– Seoul, Seoul-t'ukpyolsi, Republic of Korea
Kyu-Mok Hwang– Seoul, Seoul-t'ukpyolsi, Republic of Korea