Development of a Biorelevant, Material-Sparing Membrane Flux Test for Rapid Screening of Bioavailability-Enhancing Drug Product Formulations

Bioavailability-enhancing formulations are often used to overcome challenges of poor gastrointestinal solubility for drug substances developed for oral administration. Conventional <i>in vitro</i> dissolution tests often do not properly compare such formulations due to the many different drug species that may exist in solution. To overcome these limitations, we have designed a practical <i>in vitro</i> membrane flux test, that requires minimal active pharmaceutical ingredient (API) and is capable of rapidly screening many drug product intermediates. This test can be used to quickly compare performance of bioavailability-enhancing formulations with fundamental knowledge of the rate-limiting step(s) to membrane flux. Using this system, we demonstrate that the flux of amorphous itraconazole (logD = 5.7) is limited by aqueous boundary layer (ABL) diffusion and can be increased by adding drug-solubilizing micelles or drug-rich colloids. Conversely, the flux of crystalline ketoconazole at pH 5 (logD = 2.2) is membrane-limited, and adding solubilizing micelles does not increase flux. Under certain circumstances, the flux of ketoconazole may also be limited by dissolution rate. These cases highlight how a well-designed <i>in vitro</i> assay can provide critical insight for oral formulation development. Knowing whether flux is limited by membrane diffusion, ABL diffusion, or dissolution rate can help drive formulation development decisions. It may also be useful in predicting <i>in vivo</i> performance, dose linearity, food effects, and regional-dependent flux along the length of the gastrointestinal tract

Impact of Drug-Rich Colloids of Itraconazole and HPMCAS on Membrane Flux <i>in Vitro</i> and Oral Bioavailability in Rats

Improving the oral absorption of compounds with low aqueous solubility is a common challenge that often requires an enabling technology. Frequently, oral absorption can be improved by formulating the compound as an amorphous solid dispersion (ASD). Upon dissolution, an ASD can reach a higher concentration of unbound drug than the crystalline form, and often generates a large number of sub-micrometer, rapidly dissolving drug-rich colloids. These drug-rich colloids have the potential to decrease the diffusional resistance across the unstirred water layer of the intestinal tract (UWL) by acting as rapidly diffusing shuttles for unbound drug. In a prior study utilizing a membrane flux assay, we demonstrated that, for itraconazole, increasing the concentration of drug-rich colloids increased membrane flux <i>in vitro</i>. In this study, we evaluate spray-dried amorphous solid dispersions (SDDs) of itraconazole with hydroxypropyl methylcellulose acetate succinate (HPMCAS) to study the impact of varying concentrations of drug-rich colloids on the oral absorption of itraconazole in rats, and to quantify their impact on <i>in vitro</i> flux as a function of bile salt concentration. When Sporanox and itraconazole/AFFINISOL High Productivity HPMCAS SDDs were dosed in rats, the maximum absorption rate for each formulation rank-ordered with membrane flux <i>in vitro</i>. The relative maximum absorption rate <i>in vivo</i> correlated well with the <i>in vitro</i> flux measured in 2% SIF (26.8 mM bile acid concentration), a representative bile acid concentration for rats. <i>In vitro</i> it was found that as the bile salt concentration increases, the importance of colloids for improving UWL permeability is diminished. We demonstrate that drug-containing micelles and colloids both contribute to aqueous boundary layer diffusion in proportion to their diffusion coefficient and drug loading. These data suggest that, for compounds with very low aqueous solubility and high epithelial permeability, designing amorphous formulations that produce colloids on dissolution may be a viable approach to improve oral bioavailability

Impact of Drug-Rich Colloids of Itraconazole and HPMCAS on Membrane Flux <i>in Vitro</i> and Oral Bioavailability in Rats

Improving the oral absorption of compounds with low aqueous solubility is a common challenge that often requires an enabling technology. Frequently, oral absorption can be improved by formulating the compound as an amorphous solid dispersion (ASD). Upon dissolution, an ASD can reach a higher concentration of unbound drug than the crystalline form, and often generates a large number of sub-micrometer, rapidly dissolving drug-rich colloids. These drug-rich colloids have the potential to decrease the diffusional resistance across the unstirred water layer of the intestinal tract (UWL) by acting as rapidly diffusing shuttles for unbound drug. In a prior study utilizing a membrane flux assay, we demonstrated that, for itraconazole, increasing the concentration of drug-rich colloids increased membrane flux <i>in vitro</i>. In this study, we evaluate spray-dried amorphous solid dispersions (SDDs) of itraconazole with hydroxypropyl methylcellulose acetate succinate (HPMCAS) to study the impact of varying concentrations of drug-rich colloids on the oral absorption of itraconazole in rats, and to quantify their impact on <i>in vitro</i> flux as a function of bile salt concentration. When Sporanox and itraconazole/AFFINISOL High Productivity HPMCAS SDDs were dosed in rats, the maximum absorption rate for each formulation rank-ordered with membrane flux <i>in vitro</i>. The relative maximum absorption rate <i>in vivo</i> correlated well with the <i>in vitro</i> flux measured in 2% SIF (26.8 mM bile acid concentration), a representative bile acid concentration for rats. <i>In vitro</i> it was found that as the bile salt concentration increases, the importance of colloids for improving UWL permeability is diminished. We demonstrate that drug-containing micelles and colloids both contribute to aqueous boundary layer diffusion in proportion to their diffusion coefficient and drug loading. These data suggest that, for compounds with very low aqueous solubility and high epithelial permeability, designing amorphous formulations that produce colloids on dissolution may be a viable approach to improve oral bioavailability

Millisecond Self-Assembly of Stable Nanodispersed Drug Formulations

We report the development of a new spray-drying and nanoparticle assembly process (SNAP) that enables the formation of stable, yet rapidly dissolving, sub-200 nm nanocrystalline particles within a high <i>T</i>_g glassy matrix. SNAP expands the class of drugs that spray-dried dispersion (SDD) processing can address to encompass highly crystalline, but modestly hydrophobic, drugs that are difficult to process by conventional SDD. The process integrates rapid precipitation and spray-drying within a custom designed nozzle to produce high supersaturations and precipitation of the drug and high <i>T</i>_g glassy polymer. Keeping the time between precipitation and drying to tens of milliseconds allows for kinetic trapping of drug nanocrystals in the polymer matrix. Powder X-ray diffraction, solid state 2D NMR, and SEM imaging shows that adding an amphiphilic block copolymer (BCP) to the solvent gives essentially complete crystallization of the active pharmaceutical ingredient (API) with sub-200 nm domains. In contrast, the absence of the block copolymer results in the API being partially dispersed in the matrix as an amorphous phase, which can be sensitive to changes in bioavailability over time. Quantification of the API–excipient interactions by 2D ¹³C–¹H NMR correlation spectroscopy shows that the mechanism of enhanced nanocrystal formation is not due to interactions between the drug and the BCP, but rather the BCP masks interactions between the drug and hydrophobic regions of the matrix polymers. BCP-facilitated SNAP samples show improved stability during aging studies and rapid dissolution and release of API <i>in vitro</i>