II. Technological approaches to improve the dissolution behavior of nateglinide, a lipophilic insoluble drug: Co-milling

Nateglinide is an oral antidiabetic agent that should be administered 10–30 min before the meal, but it shows low and pH-dependent solubility that may reduce its oral bioavailability.To improve nateglinide dissolution rate, the active was co-milled with three different super-disintegrants or with some hydrophilic excipients, in 1:1, 1:2, and 1:4 drug to carrier ratio (w:w). The three super-disintegrants were crosslinked polyvinylpyrrolidone (PVPC), sodium starch glycolate (SSG) and crosslinked carboxymethyl cellulose (CMCC). The three hydrophilic excipient were amorphous silica (AS), mannitol (M) and Poloxamer (PO).A strong enhancement of drug dissolution rate was obtained from the nateglinide:super-disintegrant co-milled systems in 1:4 ratio, which can be explained by a combination of several factors: an increase in wettability, due to the hydrophilic nature of the carriers, a possible reduction of particle size and a more intimate dispersion of the drug onto the carrier, as a result of the mechanical treatment.

Graphical abstractEnhancement of the nateglinide dissolution rate obtained from drug:super-disintegrant co-milled (CM) systems in 1:4 w:w ratio, compared to physical mixtures and nateglinide alone (NH). Dose: 20 mg. Cross-linked polyvinylpyrrolidone (PVPC) and sodium starch glycolate (SSG) ensure a rapid and complete dissolution of the insoluble drug in very short times, in water.Figure optionsDownload full-size imageDownload high-quality image (119 K)Download as PowerPoint slide