It is currently estimated that over 25% of all drug products in development have highly potent or highly toxic active pharmaceutical ingredients (API) and require some form of specialized handling. In oncology this figure is likely closer to 70%.1 These types of products represent a growing sector of investment in the pharmaceutical industry, with the market value from existing and new product launches expected to double between 2018 and 2025.2
New therapeutic treatments are frequently targeted to act locally at the site of therapy, which can reduce side effects and result in significantly lower dosages required. While these treatments offer huge benefits to the patient, the pharmaceutical industry faces the challenge of developing these API into safe and effective low-dose products – including consistently producing very low-dose products, e.g., microgram doses – while maintaining safety for operators during processing. Encapsulated liquid-based products offer a proven approach to overcome many of the challenges associated with the development, scale-up and commercial manufacturing for these highly potent API (HPAPI), from safer handling to producing more accurately dosed and homogeneous formulations for low-dose products.3
Liquid-fill technology is not new, and it benefits from a long history of continued innovation and market precedence. The original softgel patent dates from 1834, with the current process evolving from that created by RP Scherer in the 1930s. Hard-shell liquid-fill capsules were a further innovation from Cuine et al of the University of Strasbourg, producing several papers on the potential advantages of this technology in the 1970s. In the early 1980s, several additional publications from other authors presented the potential advantages for content uniformity and reduction of airborne contamination.
While commercially available products in the consumer health and nutrition sector were already utilizing softgel technology in the 1980s, key milestones for the technology in both hard and soft capsules in the pharmaceutical segment happened later that decade with the commercial approval and commercialisation of Vancocin® capsules. This product demonstrated the potential to produce an oral dosage form with a sensitive molecule that had been challenging for more traditional product approaches. Sandimmune’s® position as the first commercially successful lipid-based bioavailability-enhanced formulation further demonstrated the potential benefits of liquid-based technology (the product, containing the active ingredient cyclosporine, also represented a breakthrough in transplant management). A number of new products have since been launched using lipid-based formulations with softgel or liquid-filled hard capsule technology to address the continuing challenge of poor solubility.
Although liquid-fill capsule products continue to be seen principally as a mechanism to increase bioavailability for poorly soluble drugs;5 they are also increasingly evaluated to address lowdose HPAPI challenges.4 The technology allows the incorporation of an API powder into a liquid formulation as either a solution or as a suspended solid, which then removes the risk of subsequent airborne powder during manufacture and can also improve homogeneity for low-dose products. Market precedence is firmly established, as is the technology required for developing, scaling and manufacturing liquid-based capsule products with challenging, potent or toxic API. A few examples of marketed liquid-filled products with these challenging compounds in both hard capsule and softgel formats include hormones or related compounds, like promestriene, progesterone or dutasteride, vitamin A analogues such as isotretinoin and Vitamin D analogues like colecalciferol and ergocalciferol. Currently, it is estimated that 40% of liquid-filled hard capsule products in development utilize HPAPI.6