Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Int J Pharm. 2019 Apr 20;561:82-92. doi: 10.1016/j.ijpharm.2019.02.034. Epub 2019 Feb 26.
Drug-rich amorphous nanodroplets have great potential to improve intestinal absorption of poorly water-soluble drugs. Spray-dried samples (SPDs) of glibenclamide (GLB) with hypromellose (HPMC) or hypromellose acetate succinate (HPMC-AS, grade AS-LF and AS-HF) were prepared to investigate how GLB-rich amorphous nanodroplets form during the dissolution of solid dispersions. The co-spray drying of AS-LF significantly enhanced GLB dissolution from the SPD, leading to the temporary formation of GLB-rich amorphous nanodroplets. However, the droplets gradually coarsened as AS-LF fails to inhibit coarsening. In contrast, the addition of HPMC to the SPD failed to aid GLB-rich amorphous nanodroplet formation during dissolution. The failure of formation of GLB-rich amorphous nanodroplet was caused by slow GLB dissolution, due to the poor controllability of the GLB dissolution by HPMC. The addition of AS-HF to the SPD produced amorphous GLB particles that contained a large amount of AS-HF during dissolution. Gel-like particles formed instead of GLB-rich amorphous nanodroplets. When the SPD containing AS-LF was dissolved in AS-HF solution, stably-dispersed GLB-rich amorphous nanodroplets were successfully formed owing to rapid GLB dissolution from the SPD containing AS-LF and strong coarsening inhibition by AS-HF. Formulation optimization considering both aqueous dissolution of the solid dispersion and the inhibition of nanodroplet coarsening achieved stably-dispersed drug-rich amorphous nanodroplets.
富药物无定形纳米液滴在提高难溶性药物的肠道吸收方面具有很大的潜力。制备了格列本脲（GLB）与羟丙甲纤维素（HPMC）或羟丙甲纤维素醋酸琥珀酸酯（HPMC-AS，AS-LF 和 AS-HF 级）的喷雾干燥样品（SPD），以研究在固体分散体溶解过程中 GLB 富无定形纳米液滴是如何形成的。AS-LF 的共喷雾干燥显著提高了 SPD 中 GLB 的溶解，导致 GLB 富无定形纳米液滴的临时形成。然而，随着 AS-LF 无法抑制粗化，液滴逐渐变粗。相比之下，在 SPD 中添加 HPMC 无法促进 GLB 富无定形纳米液滴的形成。GLB 富无定形纳米液滴形成失败是由于 HPMC 对 GLB 溶解的控制能力差，导致 GLB 溶解缓慢。在 SPD 中添加 AS-HF 会在溶解过程中产生含有大量 AS-HF 的无定形 GLB 颗粒。形成凝胶状颗粒而不是 GLB 富无定形纳米液滴。当含有 AS-LF 的 SPD 溶解在 AS-HF 溶液中时，由于含有 AS-LF 的 SPD 中 GLB 的快速溶解和 AS-HF 的强烈粗化抑制作用，成功形成了稳定分散的 GLB 富无定形纳米液滴。考虑到固体分散体的水相溶解和纳米液滴粗化抑制的制剂优化，实现了稳定分散的富药物无定形纳米液滴。
