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FROM THE BOARD


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Bringing Poorly Soluble Molecules to Market with Bioavailability Enhancement Technologies


Ronak Savla Fellow of the Catalent Applied Drug Delivery Institute


Jeff Browne Director, Science & Technology, Rx Softgel


Vincent Plassat Scientific Affairs Manager


Introduction


According to the popularly cited study from Tufts Center for the Study of Drug Development, it costs $2.6 billion to receive a drug approval.1 Despite the increased investments and revolutionary therapies brought to market, return on investment from drug launches is near historical lows.2


Luckily, issues such as challenging physicochemical


properties and unfavorable absorption characteristics can be ad- dressed early in the development process. Screening formulation options in the pre-clinical setting has the potential to reduce both costs and risk of attrition.3


The routine use of high throughput screening and more targeted drugs have contributed to nearly 70% of pipeline drug candi- dates falling into Class II (poor solubility and good permeability) of the Biopharmaceutics Classification System (BCS). These compounds tend to have poor bioavailability, variable pharmacokinetics, and are subject to food effects. Therapies from non-optimized drug products developed with these compounds can range from sub-therapeutic pharmacotherapy, to cases where patients can be exposed to toxic levels of the drug. Butler and Dressman have proposed a newer Developability Classification System (DCS), which divides BCS Class II into two parts: drugs whose absorption is dissolution rate-limited (IIa); and for those whose absorption is solubility-limited (IIb).4


Whereas the


BCS was proposed primarily for use as a regulatory tool, the DCS was created as a developability tool to evaluate and address drug devel- opment issues at early development stages through the rational selection of appropriate formulation technologies for these challenging compounds.


10 | | May/June 2016


This trend for drug candidates to have similar characteristics has driven the increased use of bioavailability enhancement tech- nologies. The most successful approaches have been lipid form- ulations, solid amorphous dispersions, and particle size reduction.5 Certain API properties often favor one technology over another. Numerous groups have developed in silico prediction tools to choose an optimal formulation technology. However, this a priori approach should be taken more as guidance rather than a steadfast rule. A parallel screening approach at early clinical or pre-clinical stages, instead of a “fit-for-purpose” approach in Phase II, can accelerate development and potentially address efficacy and safety concerns sooner in development


Lipid-Based Drug Delivery System (LBDDS)


Of the above-mentioned bioavailability enhancement technologies, lipid-based formulations are perhaps the most studied and have the longest history of clinical and commercial success. This technology is, in many cases, a favorable option for DCS Class IIa, and preferably for IIb active pharmaceutical ingredients because the drug is both formulated to be in solution when delivered and maintained in solution in the gastrointestinal tract. Pouton et al. first proposed classification of lipid-based formulations into four different categories based on types and ratios of excipients.6


Porter et al. to include a fifth category of LBDDS.7


This was later expanded by The dynamic nature


of lipid-based formulations in-vivo requires specialized formulation expertise to perform pre-formulation screening and assessment in the


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