I. Technological approaches to improve the dissolution behavior of nateglinide, a lipophilic insoluble drug: Nanoparticles and co-mixing

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Nateglinide is a non-sulphonylurea insulinotropic oral antidiabetic agent. The main problem in formulating an oral dosage form is its low solubility in aqueous media. This problem is particularly critical for an anti-diabetic drug because it should be administered just before the meals and be quickly bioavailable to cover the post-prandial glycemic peak. In this work, some technological approaches have been studied to improve the dissolution rate of nateglinide. Furthermore, two different polymorphs of nateglinide (H and B) have been tested to evaluate the influence of the crystal habitus on the dissolution behavior of the drug. The results have clearly demonstrated that wettability plays a key role in the dissolution behavior of nateglinide. As a matter of fact the physical dispersion of the drug with colloidal silica or hydrophilic swellable polymers strongly enhances the dissolution rate of nateglinide. The two polymorphs tested did not show significant differences in terms of dissolution behavior.

Graphical abstract

Dissolution profiles of nateglinide H samples of different particle size (NH = about 18 μm, 2 μm and 0.5 μm), alone, compared to the same samples co-mixed with amorphous silica (AS) in 1:4 (w:w) ratio, dose: 20 mg. By reducing the drug particle size no significant difference in dissolution rate can be evidenced as the particles tend to aggregate in water. The drug dissolution rate can be improved only when an hydrophilic excipient, amorphous silica, is used. The small hydrophilic silica particles produce a very fine dispersion of the binary system with the silica surrounding the drug particles, thus preventing their aggregation.

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