Biopharmaceutical classification of poorly soluble drugs with respect to “enabling formulations”

Abstract

The large number of drug candidates with poor dissolution characteristics seen in the past decade, has fostered interest in so-called "enabling formulations", i.e., formulations which shall make such drugs bio-available. Development of enabling formulations is currently being guided by the following (simplified) hypothesis: If a poorly soluble drug (BCS class II drug) can be transferred into a solubilized state, one can achieve an absorption profile close to that of a soluble drug (BCS class I drug). Thus, formulation development typically endeavors to achieve the most robust solubility enhancement. Here we critically review both common in vitro approaches and experimental data available in literature pertaining to the solubility and permeability of poorly soluble drugs from enabling formulations, and discuss their interplay. Recent in vitro data indicate, that commonly employed surfactants as well as endogenous surfactants present in the intestine, although enhancing drug solubility, mostly hamper drug permeation. Mechanistic studies demonstrate a direct correlation between passive transcellular diffusion and the concentration of molecularly dissolved drug. The latter may be reduced due to partitioning into micelles or other solubilizing carriers, but enhanced in supersaturating formulations. We conclude thus that biopharmaceutical assessment approaches that rely on the amount of molecularly dissolved drug should guide us towards successful enabling formulations.

Phospholipid-based solid drug formulations for oral bioavailability enhancement: A meta-analysis

“…However, results from meta-analysis revealed that the extent of enhancement of in vivo oral bioavailability was much lower than that of in vitro performance. This may be attributed to the fact that the in vivo system is much more complicated and prediction of oral bioavailability enhancement by enabling formulations may need to take into account the inter-relationship of commonly used parameters and/or additional factors (Buckley et al, 2013). Identification of key influence factors that could help optimizing the PL-based formulation is thus essential in order to increase the overall enhancement effect on bioavailability.…”

Gastrointestinal behavior of nano- and microsized fenofibrate: In vivo evaluation in man and in vitro simulation by assessment of the permeation potential

“…The absence of a positive systemic food effect demonstrates that estimating formulation performance based on simple dissolution experiments does not always capture the key intraluminal processes determining drug absorption from enabling strategies. In order to fully assess the performance of enabling formulations, the absorption-determining intraluminal processes should be identified and integrated into in vitro models (Buckley et al, 2013).…”

Thermal Processing of PVP- and HPMC-Based Amorphous Solid Dispersions

“…The dissolution of poorly soluble APIs is often the rate-limiting factor for oral bioavailability (1,2). Solubilityenhancing formulation strategies include particle size reduction and the use of pH modifiers, salts, co-crystals, pro-drugs, cyclodextrins, lipids, surfactants, self-emulsifying drug delivery systems, mesoporous drug delivery carriers, and amorphous solid dispersions (3)(4)(5)(6). The use of amorphous solid dispersions is of great interest in that these high-energy systems tend to lead to orders of magnitude increases in apparent solubility (7,8).…”