Effect of Amorphous Nanoparticle Size on Bioavailability of Anacetrapib in Dogs.

Amorphous solid dispersions (ASDs) are used as bioavailability-enhancing formulations on the premise of the increased solubility of the amorphous form over its crystalline counterpart. Recent studies have shown that ASDs can, during dissolution, generate amorphous nanoparticles that were initially postulated to serve as a source of rapidly dissolving compound during absorption. Researchers have proposed that nanoparticles, including crystalline nanoparticles, may provide additional benefits to absorption such as drifting in the mucous layer. However, there are limited published data on the impact of nanoparticle size on bioavailability in vivo and, to our knowledge, there have been no published examples looking at the impact of differential size of in situ-generated nanoparticles from an ASD. Anacetrapib, a highly lipophilic, Biopharmaceutics Classification System IV compound, formulated as an ASD that generates nanoparticles on dissolution, was used in the studies described in this article. A differential response in bioavailability was observed with ∼100 nm or smaller particles, resulting in higher average exposure compared to ∼200 nm or larger particles. This increase in bioavailability could not be fully accounted for by the improvement in dissolution rate and was not as pronounced as that achieved by improving solubilization by coadministration with a high-fat meal.

Incomplete Loading of Sodium Lauryl Sulfate and Fasted State Simulated Intestinal Fluid Micelles Within the Diffusion Layers of Dispersed Drug Particles During Dissolution.

Poorly water soluble drug candidates have been common in developmental pipelines over the last several decades. This has fueled considerable research around understanding how bile salt and model micelles can improve drug particle dissolution rates and human drug exposure levels. However, in the pharmaceutical context only a single mechanism of how micelles load solute has been assumed, that being the direct loading mechanism put forth by Cussler and coworkers (Am Inst Chem Eng J. 1976;22(6):1006-1012) 40 years ago. In this model, micelles load at the particle surface and will be loaded to their equilibrium loading values. More recently, Kumar and Gandhi and coworkers (Langmuir. 2003;19:4014-4026) developed a comprehensive theory of micelle solubilization which also features an indirect loading mechanism which they argue should operate in ionic surfactant systems. In this mechanism, micelles cannot directly load at the solute particle surface and thus may not reach equilibrium loading values within the particle diffusion layer. In this work, we endeavor to understand if the indirect micelle loading mechanism represents a plausible description in the pharmaceutical context. The overall data in SLS and FaSSIF systems obtained here, as well as several other previously published datasets, can be described by the indirect micelle loading mechanism. Implications for pharmaceutical development of poorly soluble compounds are discussed.

Comparing Dog and Human Intestinal Fluids: Implications on Solubility and Biopharmaceutical Risk Assessment.

Despite many documented differences in gut physiology compared to humans, the beagle dog has been successfully used as a preclinical model for assessing the relative bioavailability of dosage forms during formulation development. However, differences in pH and bile salt concentration and micellar structure between dog and human intestinal fluids may influence the solubility and dissolution behavior of especially BCS II/IV compounds. Recently, a canine fasted simulated intestinal fluid (FaSSIFc) mimicking the composition in the lumen of the beagle dog under the fasted state has been proposed. In this manuscript, we present the utilization of FaSSIFc to compare solubility of several preclinical candidates against human FaSSIF. While solubility of free bases and neutral compounds was easily predicted by the relative amounts of sodium taurocholate in the fluids, free acids were shown to be much more soluble in FaSSIFc owing to both the solubility at higher pH as well as the increased bile salt concentration. For one of the model compounds, we demonstrate that the high solubility necessitates the need for a formulation comparison at a relatively higher dose in the dog to mimic the outcome of a human relative bioavailability study. Finally, we show how using the solubility value in FaSSIFc for the same compound results in better predictability of the plasma concentration profiles in dogs from a physiologically based absorption model. The collective data indicate that caution and more detailed measurements are required if the dog is used as the preclinical model for the development of formulations of weak acids.

Mechanism of Dissolution-Induced Nanoparticle Formation from a Copovidone-Based Amorphous Solid Dispersion.

Amorphous solid dispersions (ASDs) have been increasingly used to maximize human exposures from poorly soluble drug candidates. One well-studied advantage of ASDs is the increased amorphous drug solubility compared to crystalline forms. This provides more rapid dissolution rates. An additional advantage of ASDs is that the dissolution process of the ASD particle may also rapidly transform much of the drug present in the ASD particle to small (<1 µm) amorphous drug nanoparticles which will have fast dissolution rates. This work examines the mechanism by which this nanoparticle formation occurs by studying an ASD consisting of 70-80% copovidone, 20% anacetrapib (a low solubility lipophilic drug), and 0-10% TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate, a surfactant). Nanoparticle formation is found to derive from a rapid amorphous drug domain formation within the ASD particle, driven by copovidone dissolution from the particle. The role of surfactant in the ASD particle is to prevent an otherwise rapid, local drug domain aggregation event, which we term "hydrophobic capture". Surfactant thus allows the amorphous drug domains to escape hydrophobic capture and diffuse to bulk solution, where they are reported as nanoparticles. This view of surfactant and nanoparticle formation is compared to the prevailing view in the literature. The work here clarifies the different roles that surfactant might play in increasing nanoparticle yields and extending the useful drug loading ranges in copovidone-based ASDs.

Direct probe of molecular polarization in de novo protein-electrode interfaces.

A novel approach to energy harvesting and biosensing devices would exploit optoelectronic processes found in proteins that occur in nature. However, in order to design such systems, the proteins need to be attached to electrodes and the optoelectronic properties in nonliquid (ambient) environments must be understood at a fundamental level. Here we report the simultaneous detection of electron transport and the effect of optical absorption on dielectric polarizability in oriented peptide single molecular layers. This characterization requires a peptide design strategy to control protein/electrode interface interactions, to allow peptide patterning on a substrate, and to induce optical activity. In addition, a new method to probe electronic, dielectric, and optical properties at the single molecular layer level is demonstrated. The combination enables a quantitative comparison of the change in polarization volume between the ground state and excited state in a single molecular layer in a manner that allows spatial mapping relevant to ultimate device design.

Quantification of internal electric fields and local polarization in ferroelectric superlattices.

Oxide heterostructure superlattices constitute a new family of materials with tunable ferroelectric properties. While theoretical models predict the presence of nanosized ferroelectric domains in these films, they had not been observed as the magnitude of the response functions challenges the limits of experimental detection. Here, a new protocol in a precise variant of piezoforce microscopy is used to image domains in BaTiO(3)/SrTiO(3) superlattices. Comparison of experimentally determined polarization to predictions of phase-field calculations is in quantitative agreement. Additionally, a combination of theory and experiment is used to determine the magnitude of internal electric field within the thin film, in a procedure that can be generalized to all ferroelectric films.