Comparison of Three Different Aqueous Microenvironments for Enhancing Oral Bioavailability of Sildenafil: Solid Self-Nanoemulsifying Drug Delivery System, Amorphous Microspheres and Crystalline Microspheres

Background: The purpose of this study was to screen various drug delivery systems for improving the aqueous solubility and oral bioavailability of sildenafil. Three representative techniques, solid self-nanoemulsifying drug delivery systems (SNEDDS), amorphous microspheres and crystalline microspheres, were compared.

Methods: Both microspheres systems contained sildenafil:Labrasol:PVP at a weight ratio of 1:1:6. The amorphous microspheres were manufactured using ethanol, while crystalline microspheres were generated using distilled water. Liquid SNEDDS was composed of sildenafil:Labrasol:Transcutol HP:Captex 300 in the ratio of 1:70:15:15 (w:w:w:w). The solidification process in SNEDDS was performed using HDK N20 Pharma as a solid carrier.

Results: The amorphous microspheres appeared spherical with significantly decreased particle size compared to the drug powder. The crystalline microspheres exhibited a rough surface with no major particle-size difference compared with sildenafil powder, indicating that the hydrophilic excipients adhered to the sildenafil crystal. Solid SNEDDS presented a smooth surface, assuming that the oily liquid was adsorbed to the porous solid carrier. According to the physicochemical evaluation, the crystalline state maintained in crystalline microspheres, whereas the crystal state changed to amorphous state in other formulations. Amorphous microspheres, crystalline microspheres and solid SNEDDS produced about 79, 55, 82-fold increased solubility, compared to drug powder. Moreover, the prepared formulations provided a higher dissolution rate (%) and plasma concentration than did the drug powder (performance order; solid SNEDDS ≥ amorphous microspheres ≥ crystalline microspheres > drug powder). Among the formulations, solid SNEDDS demonstrated the highest improvement in oral bioavailability (AUC; 1508.78 ± 343.95 h·ng/mL).

Conclusion: Therefore, solid SNEDDS could be recommended as an oral dosage form for enhancing the oral bioavailability of sildenafil.

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Materials

Sildenafil (base) was supplied by Huons Pharm. Co. (Ansan, South Korea). Polyvinylpyrrolidone (PVP, K30), Solutol HS15 and Cremophor EL were purchased from BASF (Ludwigshafen, Germany). Dextran, polyvinyl alcohol (PVA), hydroxypropyl methylcellulose 2910 (HPMC), pyrogenic silica (HDK N20 Pharma), hydroxypropyl cellulose low viscosity (HPC-L), carboxymethyl cellulose sodium (Na-CMC), poloxamer 188, PEG 4000 and hydroxypropyl beta-cyclodextrin (HP-β-CD) were kindly offered from Hanmi Pharm. Co. (Suwon, South Korea). Soybean oil, sorbitan monooleate (Span 80), olive oil, polysorbate (Tween 80) and corn oil were provided by Daejung Chem. Co. (Siheugn, South Korea). Peceol, Capryol 90 (propylene glycol monocaprylate), Plurol diisosterarique, Labrafil M2125CS, Transcutol HP, Lauroglycol FCC and Labrasol were acquired from Gattefosse (Saint-Priest Cedex, France). Medium-chain triglycerides (Captex 300) were purchased from Abitec (Columbus, OH, USA). Mineral oil and linseed oil were obtained from Samchun Chemical Co. (Pyeongtaek, South Korea). Gelatin and sesame oil were purchased from Wako Chemicals Co. (Tokyo, Japan). All other chemicals and solvents were of reagent grade; they were used with or without further purification.

Kim JS, Din FU, Lee SM, Kim DS, Woo MR, Cheon S, Ji SH, Kim JO, Youn YS, Oh KT, Lim SJ, Jin SG, Choi HG. Comparison of Three Different Aqueous Microenvironments for Enhancing Oral Bioavailability of Sildenafil: Solid Self-Nanoemulsifying Drug Delivery System, Amorphous Microspheres and Crystalline Microspheres. Int J Nanomedicine. 2021;16:5797-5810
https://doi.org/10.2147/IJN.S324206