Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.

Strategies to Address Low Drug Solubility in Discovery and Development

Engineering biocompatible implant surfaces

Mesoporous silicon in drug delivery applications.

Emerging trends in the stabilization of amorphous drugs

Recent advances in co-amorphous drug formulations

Surface functionalized mesoporous silicon (pSi) microparticles are reported as a solid dispersion carrier for improving dissolution and enhancing the orally administered pharmacokinetics (fasted ra...

Oxidized Mesoporous Silicon Microparticles for Improved Oral Delivery of Poorly Soluble Drugs

Nanostructuring materials can radically change their properties. Two interesting examples highlighted here are nanoscale porosity inducing biodegradability, and nanoscale confinement affecting the physical form of an entrapped drug. Mesoporous silicon is under increasing study for drug-delivery applications, and is the topic of this review. The authors focus on those properties of most relevance to this application, as well as those recent studies published on small molecule and peptide/protein delivery.

Mesoporous silicon: a platform for the delivery of therapeutics.

Porous silicon (p-Si) has been investigated as a novel delivery system for protein therapeutics. The loading of a model hydrophilic protein, Papain into anodised and stain etched p-Si powders has been investigated using X-ray photoelectron spectroscopy (XPS) and infrared spectroscopy (FTIR) and correlations made with the release kinetics. Variation in specific Papain (Amide I/II) and p-Si (Si–Hx) functional group absorbances with Papain loading level was characterised using FTIR, while the surface chemical distribution was assessed using XPS. A combination of burst release and sustained release of Papain was observed from p-Si powders; this was dependent on p-Si type and the Papain loading level. (© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Loading and release of a model protein from porous silicon powders

The influence of peptide/protein size and hydrophobicity on the physical and chemical aspects of loading within porous silicon (pSi) wafer samples has been determined using Atomic Force Microscopy (AFM) and Time-of-Flight Secondary Ion Mass Spectroscopy (ToF-SIMS). Both Gramicidin A (a small hydrophobic peptide) and Papain (a larger hydrophilic protein) were observed (ToF-SIMS) to penetrate across the entire pSi layer, even at low loading levels. AFM surface imaging of pSi wafers during peptide/protein loading showed that surface roughness increased with Papain loading, but decreased with Gramicidin A loading. For Papain, the loading methodology was also found to influence loading efficiency. These differences indicate more pronounced surface adsorption of Papain. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Peptide and protein loading into porous silicon wafers

Unlike the trace minerals iron, copper and zinc, the semiconductor silicon has not had its organoleptic properties assessed. Nanostructured silicon provides the nutrient orthosilicic acid through hydrolysis in the gastrointestinal tract and is a candidate for oral silicon supplements. Mesoporous silicon, a nanostructured material, is being assessed for both oral drug and nutrient delivery. Here we use taste panels to determine the taste threshold and taste descriptors of both solid and mesoporous silicon in water and chewing gum base. Comparisons are made with a metal salt (copper sulphate) and porous silica. We believe such data will provide useful benchmarks for likely consumer acceptability of silicon supplemented foodstuffs and beverages.

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Christian Barnett

Papers

Oxidized Mesoporous Silicon Microparticles for Improved Oral Delivery of Poorly Soluble Drugs

Mesoporous silicon: a platform for the delivery of therapeutics.

Loading and release of a model protein from porous silicon powders

Peptide and protein loading into porous silicon wafers

Taste and mouthfeel assessment of porous and non-porous silicon microparticles