Development of viable dosage forms for poorly water soluble compounds continues to be a significant challenge to the formulation scientists in pharmaceutical industry and insufficient bioavailability of such compounds due to poor formulation design may result in delays in development or cause them to be dropped from the pipeline (1,2). Various solubilization techniques such as using surfactants, co-solvents and cyclodextrins, adjusting the formulation pH, and screening salts have been developed, but these conventional techniques are not always effective enough to achieve the desirable solubility enhancement for an increasing amount of difficult-to-formulate compounds. Recently several new solubilization technologies have advanced significantly with commercial successes. This article only focuses on two excipient-enabling techniques: lipid-based formulations and solid dispersion approach, and discusses how excipients play a critical role in these innovative solubilization technologies.
Lipid based formulations
With several commercial successes including Sandimmune® and Neroal®(Cyclosporine A), Norvir® (Ritonavir) and Fortovase® (Saquinavir), lipid-based formulations have drawn considerable interest and attention in pharmaceutical industry as effective ways to improve oral bioavailability of poorly water soluble compounds (3,4). In principle, this approach is to dissolve the lipohilic drug in oils, emulsify the oil phase in water, and maintain the drug in the solubilized state in the gastrointestinal tract until absorption has occurred. Very often the lipid formulation is designed in such way that it tends to generate and maintain a supersaturated drug concentration in vivo for improved oral absorption (5). In some cases nanoparticulate emulsions are formed. Excipients definitely play a most critical role in the formulation performance.One of the most critical criteria of the excipients used in lipid-based formulations is its solubilization capacity. The excipient or excipient blend must be able to fully solubilize the entire drug dose, preferably in a volume of a single oral dosage. This is often achieved by careful screening of appropriate oils, co-solvents and surfactants.
Both long-and medium-chain triglyceride oils with different degrees of saturation have been extensively investigated for the design of lipid-based formulations. Co-solvents have been also used to help dissolve the drug or a large amount of the hydrophilic surfactant in the formulations. Examples of such co-solvents include ethanol, propylene glycol and polyethylene glycol.
Surfactants with a relatively high hydrophilic/liphophilic balance (HLB) are often needed to provide a good dispersing/self-emulsifying performance. For example, polysorbates, Cremophor® (rebranded to Kolliphor® EL/ RH40) and Solutol® HS15 (rebranded to Kolliphor® HS15) are used as the surfactants due to their relatively low toxicity and excellent performance.
In addition to the solubilization capacity, excipients in the lipid-based formulations must maintain the drug in the solubilized state in the gastrointestinal tract, preferably in supersaturable high concentration, until absorption has occurred. Therefore excipient type/composition and excipient/drug ratio are the critical factors. For supersaturable lipid-based formulations, the metastable supersaturated drug concentration has to be maintained for a long enough time period sufficient for adsorption before drug precipitation occurs. This is often achieved by temporary inhibition of drug precipitation using excipients as precipitation inhibitors (6). For example cellulose derivatives and vinyl polymers have been widely studied as precipitation inhibitors. Examples of such polymers include hydroxypropyl methylcellulose (HPMC), methyl cellulose (MC), hydroxypropyl cellulose (HPC), hypromellose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), Polyvinyl alcohol (PVA), and vinylpyrrolidone/vinylacetate copolymers (PVPVA). The studies showed that HPMC and PVP were the effective precipitation inhibitors to prolong the supersaturable drug concentration for the significantly improved bioavailability of poorly water soluble compounds (7,8).