Silver nanoparticles as antimicrobial agent: a case study on E. coli as a model for Gram-negative bacteria

A surprisingly large proportion of new drug candidates emerging from drug discovery programmes are water insoluble, and therefore poorly bioavailable, leading to abandoned development efforts. These so-called 'brickdust' candidates can now be rescued by formulating them into crystalline nanosuspensions. In the process of overcoming issues involving solubility, additional pharmacokinetic benefits of the drugs so formulated have come to be appreciated. As such, insolubility issues of the past have provoked a paradigm change, which now offers novel solutions for innovative drugs of the future.

Nanosuspensions in drug delivery

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

Solubility, the phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired (anticipated) pharmacological response. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. More than 40% NCEs (new chemical entities) developed in pharmaceutical industry are practically insoluble in water. Solubility is a major challenge for formulation scientist. Any drug to be absorbed must be present in the form of solution at the site of absorption. Various techniques are used for the enhancement of the solubility of poorly soluble drugs which include physical and chemical modifications of drug and other methods like particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant, complexation, and so forth. Selection of solubility improving method depends on drug property, site of absorption, and required dosage form characteristics.

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Drug Solubility: Importance and Enhancement Techniques

Formulation of poorly water-soluble drugs for oral administration: Physicochemical and physiological issues and the lipid formulation classification system ☆

Nanosizing: a formulation approach for poorly-water-soluble compounds.

Nanoparticulate crystalline therapeutic substances formulated with stabilizers and pharmaceutically acceptable clays to enhance contact between the crystalline therapeutic substances and the gastrointestinal tract and to provide extended therapeutic effect.

Formulations of oral gastrointestinal therapeutic agents in combination with pharmaceutically acceptable clays

The present invention is directed to nanoparticulate compositions comprising meloxicam particles having an effective average particle size of less than about 2000 nm.

Nanoparticulate meloxicam formulations

The present invention is directed to nanoparticulate compositions comprising one or more sterols or stanols, such as sitosterol or phytosterol The sterol particles of the composition have an effective average particle size of less than about 2000 nm In another aspect of this invention, novel combinations of sterols and other cholesterol lowering agents are described and methods of using same are taught

Nanoparticulate sterol formulations and sterol combinations

The present invention is directed to nanoparticulate compositions comprising one or more polycosanols. The polycosanol particles of the composition have an effective average particle size of less than about 2000 nm. In another aspect of this invention, novel combinations of polycosanols and other cholesterol lowering agents are described and methods of using same are taught.

Eugene R. Cooper

Papers

Nanosizing: a formulation approach for poorly-water-soluble compounds.

Formulations of oral gastrointestinal therapeutic agents in combination with pharmaceutically acceptable clays

Nanoparticulate meloxicam formulations

Nanoparticulate sterol formulations and sterol combinations

Nanoparticulate polycosanol formulations and novel polycosanol combinations