The inclusion of certain polymers within solid dispersion or lipid-based formulations can maintain drug supersaturation after dispersion and/or digestion of the vehicle, leading to improvements in bioavailability and variability in exposure. This review presents an overview of the fundamental principles that underpin drug precipitation mechanisms, describes the mechanisms by which precipitation may be inhibited, discusses the methods that can be used to identify polymeric precipitation inhibitors (PPIs), and summarizes current literature evidence of the most effective PPIs. Preliminary data from our laboratory is also presented, which describes the precipitation inhibition behavior of 53 polymeric materials using supersaturated solutions of danazol as a model, poorly water-soluble drug. These studies identify a group of PPIs with superior precipitation inhibition qualities, the majority of which are cellulose-based. These new results in combination with previous published data indicate that PPIs represent an appealing new technology with the potential to improve drug absorption for poorly water-soluble drugs. The molecular determinants of polymer utility, however, remain relatively poorly understood, although the cellulose derivates appear, in general, to provide the most benefit. More detailed studies are therefore required to define the parameters that most effectively predict and quantify the drug-polymer relationships that control precipitation inhibition.

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The role of the digestion of lipids in facilitating absorption of poorly water-soluble compounds, such as vitamins, is not only an important nutritional issue but is increasingly being recognized as an important determinant in the effectiveness of lipid-based drug formulations. It has been known for some time that lipids often form complex liquid crystalline structures during digestion and that this may impact drug solubilization and absorption. However, until recently we have been unable to detect and characterize those structures in real time and have been limited in establishing the interplay between composition, digestion, and nanostructure. Here, we establish the use of an in vitro lipid digestion model used in conjunction with synchrotron small-angle X-ray scattering by first confirming its validity using known, nondigestible liquid crystalline systems, and then extend the model to study the real time evolution of nanostructure during the digestion of common formulation lipids. The formation of liquid crystalline structures from unstructured liquid formulations is discovered, and the kinetics of formation and dependence on composition is investigated.

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Cyclosporins are natural or synthetic undecapeptides with a wide range of actual and potential pharmaceutical applications. Several members of the cyclosporin compound family have remarkably high passive membrane permeabilities that are not well-described by simple structural metrics. Here we review experimental studies of cyclosporin structure and permeability, including cyclosporin–metal complexes. We also discuss models for the conformation-dependent permeability of cyclosporins and similar compounds. Finally, we identify current knowledge gaps in the literature and provide recommendations regarding future avenues of exploration.

Bile components play a significant role in the absorption of dietary fat, by solubilizing the products of fat digestion. The absorption of poorly water-soluble drugs from the gastrointestinal tract is often enhanced by interaction with the pathways of fat digestion and absorption. These processes can enhance drug absorption. Thus, the phase behavior of bile components and digested lipids is of great interest to pharmaceutical scientists who seek to optimize drug solubilization in the gut lumen. This can be achieved by dosing drugs after food or preferably by formulating the drug in a lipid-based delivery system. Phase diagrams of bile salts, lecithin, and water have been available for many years, but here we investigate the association structures that occur in dilute aqueous solution, in concentrations that are present in the gut lumen. More importantly, we have compared these structures with those that would be expected to be present in the intestine soon after secretion of bile. Phosphatidylcholines are rapidly hydrolyzed by pancreatic enzymes to yield equimolar mixtures of their monoacyl equivalents and fatty acids. We constructed phase diagrams that model the association structures formed by the products of digestion of biliary phospholipids. The micelle-vesicle phase boundary was clearly identifiable by dynamic light scattering and nephelometry. These data indicate that a significantly higher molar ratio of lipid to bile salt is required to cause a transition to lamellar phase (i.e., liposomes in dilute solution). Mixed micelles of digested bile have a higher capacity for solubilization of lipids and fat digestion products and can be expected to have a different capacity to solubilize lipophilic drugs. We suggest that mixtures of lysolecithin, fatty acid, and bile salts are a better model of molecular associations in the gut lumen, and such mixtures could be used to better understand the interaction of drugs with the fat digestion and absorption pathway.

The prediction of surfactant phase behavior has applications in a wide range of areas. An accurate modeling of liquid phase behavior can aid our understanding of colloidal process or be used to design phases that respond in a defined way to their environment. In this work, we use molecular dynamics to model the phase behavior of the ternary sodium laurate/sodium oleate/water system and compare the simulation results to experimental data. Simulations were performed with the GROMOS 53A6 united-atom force field and cover the entire ternary phase diagram, producing micellar, hexagonal, and lamellar phases. The aggregate simulation time for the 33 simulations performed during this study is 4.4 μs. We find that the simulations were able to model the experimentally observed liquid phase behavior accurately, showing that the carboxylate and lipid parameters of the 53A6 force field give very good quality results for the in silico prediction of liquid system phase behavior.

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