Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 561, Issue -, Pages 82-92Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijpharm.2019.02.034
Keywords
Amorphous nanodroplet; Solid dispersion; HPMC-AS; Coarsening inhibition; Dissolution rate
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Funding
- Japan Society for the Promotion of Sciences [16K18859]
- Grants-in-Aid for Scientific Research [16K18859] Funding Source: KAKEN
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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.
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