Major advances have been made in the area of developing softgel formulations to address drug absorption issues (Ferdinando 2000, Perlman et al 2008, Aboul-Einien 2009). For poorly water-soluble drugs, ideally the dosage form would present the drug to the gastrointestinal tract in solution form, from which the drug can be rapidly absorbed. This can be achieved using a drug-solution matrix in a softgel formulation and such formulations can provide faster absorption than from other solid oral dosage forms, such as compressed tablets (Lissy et al 2010). This is probably because absorption of a poorly soluble drug from a tablet formulation requires time for disintegration of the tablet into granules, then drug dissolution into gastrointestinal fluid. With the solution-softgel approach, the shell ruptures within minutes to release the drug solution, which can be in a hydrophilic or highly dispersing vehicle that aids the rate of drug absorption. This may be beneficial for (a) therapeutic reasons, such as the treatment of migraine or acute pain, or (b) where there is a limited absorptive region or ‘absorption window’ high in the gastrointestinal tract. Figure 34.4 shows the faster absorption that can be achieved using a solution-softgel formulation of ibuprofen compared to a tablet (Saano et al 1991).

Increased bioavailability

As well as increasing the rate of absorption, softgels may improve the extent of absorption (Aboul-Einien 2009). This can be particularly effective for drugs with poor aqueous solubility and a relatively high molecular weight. An example of such a product is the protease inhibitor saquinavir, which was formulated as a solution-softgel product (Perry & Noble 1988). The solution-softgel formulation provided around three times greater bioavailability than a saquinavir hard-shell capsule formulation as measured by the area under the plasma – time curve (AUC).

In some cases a drug may be solubilized in vehicles that are capable of spontaneously dispersing into an emulsion on contact with gastrointestinal fluid. This is known as a self-emulsifying drug delivery system (SEDDS) (Gao et al 2006). Drug may be dissolved in an oil/surfactant vehicle that produces a micro-emulsion or a nano-emulsion on contact with gastrointestinal fluids. A nano-emulsion of progesterone has been developed whereby the vehicle consists of oils and surfactants in appropriate proportions. On contact with aqueous fluids, it produces an emulsion with an average droplet size less than 100 nm. The solubility of the drug is maintained as long as possible, delivering solubilized drug directly to the enterocyte membrane. This can increase bioavailability compared to formulations in which the drug is dosed in the solid state. Figure 34.5 shows the plasma concentration – time profile for progesterone absorbed from the nano-emulsion formulation (Ferdinando 2000).

Softgel formulations may contain excipients, for example one or more surfactants that can aid stability, wettability or even enhance permeability of the drug (Aungst 2000).

Decreased plasma variability

High variability in drug plasma levels is a common characteristic of drugs with limited bioavailability. By dosing drug optimally in solution, the plasma level variability of such drugs can be significantly reduced, particularly if absorption is limited by drug solubility. SEDDS have been shown to reduce variability of exposure to the lipophilic drug torcetrapib compared to a formulation in oil (Perlman et al 2008). The cyclic polypeptide drug ciclosporin (Sandimmune Neoral®) benefits from such an approach by using a micro-emulsion preconcentrate in a softgel (Drewe et al 1992, Meinzer 1993).