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

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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 abstract

Enhancement 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.

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