GLB flu xx

Amorphous solid dispersions enhance the dissolution and oral bioavailability of poorly water-soluble drugs. However, the link between polymer properties and formulation performance has not been fully clarified yet. We studied the effect of hydroxypropyl cellulose (HPC) polymers molecular weight (M_w) on the storage stability, dissolution kinetics and supersaturation stability of spray-dried amorphous glibenclamide (GLB) formulations. The solid-state stability of amorphous GLB during storage was significantly enhanced by both the 40 kDa (HPC-SSL) and 84 kDa (HPC-L) polymers, regardless of M_w differences. In contrast, HPC-SSL maintained significantly higher aqueous drug concentrations during dissolution, compared to HPC-L (its higher M_w analogue). Dedicated dissolution experiments, in situ optical microscopy and solid-state characterization revealed that aqueous drug concentrations were determined by the interplay between crystallization inhibition, drug ionization, wetting and solubilization effects: (1) HPC prevents surface nucleation, hence inhibiting crystallization, (2) intestinal colloids (bile salts and phospholipids) increase supersaturated drug concentrations via wetting and solubilization effects and (3) pH and drug ionization severely impact the degree of supersaturation. The better performance of the lower M_w HPC-SSL was due to its superior inhibition of surface crystallization during dissolution. These insights into the molecular mechanisms of dissolution and crystallization of amorphous solids provide foundation for rational formulation development.

Oral bioavailability of glibenclamide (Glb) was appreciably improved by the formation of an amorphous solid dispersion with Poloxamer‐188 (P‐188). Poloxamer‐188 substantially enhanced the solubility and thereby the dissolution rate of the biopharmaceutics classification system (BCS) class II drug Glb and simultaneously exhibited a better stabilizing effect of the amorphous solid dispersion prepared by the solvent evaporation method. The physical state of the dispersed Glb in the polymeric matrix was characterized by differential scanning calorimetry, X‐ray diffraction, scanning electron microscope and Fourier transform infrared studies. In vitro drug release in buffer (pH 7.2) revealed that the amorphous solid dispersion at a Glb–P‐188 ratio of 1:6 (SDE4) improved the dissolution of Glb by 90% within 3 h. A pharmacokinetic study of the solid dispersion formulation SDE4 in Wistar rats showed that the oral bioavailability of the drug was greatly increased as compared with the market tablet formulation, Daonil®. The formulation SDE4 resulted in an AUC0–24h ~2‐fold higher. The SDE4 formulation was found to be stable during the study period of 6 months.