Enhancing the bioavailability of poorly soluble drugs

Mar 01, 2010

How many pharmaceuticals on the market exhibit poor solubility?

Peter G. Nielsen
Approximately half of the drugs on the market show poor solubility, but the use of modern solubilisation technologies can improve a drug product's bioavailability and performance. Applying a solubilisation technology will usually also reduce the food effect and variability of the absorption, which is often a direct consequence of low water solubility of the active molecule.

Although there is increased focus during the discovery process to select compounds not only based on their invitro biological properties, such as receptor binding studies, but also on physicochemical properties (i.e.,solubility), many poorly soluble drugs still reach the market. This can be attributed to the widespread use of combinatorial chemistry, which often provides products with low solubility.

Although effort is made in early R&D to select a drug substance based on solubility behaviour, this is not always possible if biological activity is to be maintained. If the drug has acidic or basic properties, a water-soluble counter ion can sometimes be selected to improve solubilisation; however, for neutral molecules and the lowest soluble molecules, a solubilisation technology is needed to obtain acceptable drug product performance.

For many years, Elan's Nanocrystal technology was the gold standard for improving the solubility of poorly soluble drugs. Using this technology, the active drug substance is milled down to particles in the nanosize range and incorporated with a surfactant to prevent aggregation of the nanoparticles. By reducing particle size and increasing the surface area for dissolution, the dissolution rate of the drug particles significantly increases. This technology has enhanced the performance of many poorly soluble drugs, but there are also a number of drawbacks in my opinion, relating to manufacturing and cost.

Another technique for improving solubilisation is to use lipid systems; namely, selfemulsifying drug delivery systems (SEDDS) and selfmicroemulsifying drug delivery system (SMEDDS) formulations, where the drug substance is dissolved in a self-emulsifying system that disperses in the intestine to form nanomicelles, which present the drug in a more absorbable form. These formulations are typically presented as soft or hard gelatine capsules, but comparability or leakage issues may sometimes give stability imitations. However, technologies, such as our liquidloaded tablet technology, are available that overcome these issues by enabling liquids to be administered in tablet forms.

In the last decade, a number of newer solubilisation technologies have been developed that offer improved performance and broader applicability compared with conventional approaches. Many of these technologies use various solid dispersion technologies, such as lyophilisation or melt extrusion. One of the advantages is that the drug substance can, in some cases, be stabilised in the amorphous state or presented as a solid solution, which presents the most drug in the most bioavailable form because no activation energy is needed to break up the crystal lattice structure before dissolution and absorption can take place.

The main difficulty in working with amorphous drug products relates to physical instability because there is an inherent risk of the drug product forming crystals during storage, which could impact drug bioavailability. The crystallisation behaviour is mainly guided by the glass transition temperature of the active and the matrix in which it is embedded. Various possibilities exist for stabilising the amorphous drug in the matrix by selecting appropriate polymeric exipients. MeltDose technology, a physical process for improving the bioavailability of poorly soluble compounds, is a good example of such a technology because the solid dispersion can, depending on the properties of the drug substance, be formed as either nanocrystals, amorphous particles or as a solid solution, offering large flexibility in the biodesign of a stable drug product.