Pharmaceutical Research

Choy, Young; Prausnitz, Mark

doi: 10.1007/s11095-010-0292-6pmid: 20967491

The Rule of Five predicts suitability of drug candidates, but was developed primarily using orally administered drugs. Here, we test whether the Rule of Five predicts drugs for delivery via non-oral routes, specifically ophthalmic, inhalation and transdermal. We assessed 111 drugs approved by FDA for those routes of administration and found that >98% of current non-oral drugs have physicochemical properties within the limits of the Rule of Five. However, given the inherent bias in the dataset, this analysis was not able to assess whether drugs with properties outside those limits are poor candidates. Indeed, further analysis indicates that drugs well outside the Rule of Five limits, including hydrophilic macromolecules, can be delivered by inhalation. In contrast, drugs currently administered across skin fall within more stringent limits than predicted by the Rule of Five, but new transdermal delivery technologies may make these constraints obsolete by dramatically increasing skin permeability. The Rule of Five does appear to apply well to ophthalmic delivery. We conclude that although current non-oral drugs mostly have physicochemical properties within the Rule of Five thresholds, the Rule of Five should not be used to predict non-oral drug candidates, especially for inhalation and transdermal routes.

Liu, Xiangli; Testa, Bernard; Fahr, Alfred

doi: 10.1007/s11095-010-0303-7pmid: 21052797

In this review, we first summarize the structure and properties of biological membranes and the routes of passive drug transfer through physiological barriers. Lipophilicity is then introduced in terms of the intermolecular interactions it encodes. Finally, lipophilicity indices from isotropic solvent systems and from anisotropic membrane-like systems are discussed for their capacity to predict passive drug permeation across biological membranes such as the intestinal epithelium, the blood-brain barrier (BBB) or the skin. The broad evidence presented here shows that beyond the predictive power of lipophilicity parameters, the various intermolecular forces they encode allow a mechanistic interpretation of passive drug permeation.

Anton, Nicolas; Vandamme, Thierry

doi: 10.1007/s11095-010-0309-1pmid: 21057856

Much research has been done over the past years on self-emulsifying drug delivery systems, their main interest being the simplicity of the formulation processes, the great stability of the systems and their high potential in pharmaceutical applications and industrial scaling-up. Self-emulsifying drug delivery systems are generally described in the literature indiscriminately as either nano-emulsions or micro-emulsions. Although this misconception appears to be common, these two systems are fundamentally different, based on very different physical and physicochemical concepts. Their differences result in very different stability behaviors, which can have significant consequences regarding their applications and administration as nanomedicines. This paper aims at clarifying the problem, first by reviewing all the physical and physicochemical fundamentals regarding these two systems, using a quantitative thermodynamic approach for micro-emulsions. Following these clarifications, we show how the confusion between nano-emulsions and micro-emulsions appears in the literature and how most of the micro-emulsion systems referred to are actually nano-emulsion systems. Finally, we illustrate how to clear up this misconception using simple experiments. Since this confusion is well established in the literature, such clarifications seem necessary in order to improve the understanding of research in this important field.

Vader, Pieter; Aa, Leonardus; Engbersen, Johan; Storm, Gert; Schiffelers, Raymond

doi: 10.1007/s11095-010-0344-ypmid: 21181546

Poly(amido amine)s with minor fractions of protonatable fragments in the main chain are promising carriers for delivery of siRNA.

Gaowa, Arong; Motohashi, Hideyuki; Katsura, Toshiya; Inui, Ken-ichi

doi: 10.1007/s11095-010-0348-7pmid: 21161335

The decrease of renal excretion of anionic drugs during metabolic acidosis might be partly due to a reduction in the level of OAT3 protein.

Pinholt, Charlotte; Hostrup, Susanne; Bukrinsky, Jens; Frokjaer, Sven; Jorgensen, Lene

doi: 10.1007/s11095-010-0349-6pmid: 21190067

The influence of acylation on the adsorption behavior of insulin depends on the association degree of insulin, possibly due to a greater difference in hydrophobicity between monomeric insulin and acylated insulin than between the hexameric forms of these two proteins.

Kulinowski, Piotr; Dorożyński, Przemysław; Młynarczyk, Anna; Węglarz, Władysław

doi: 10.1007/s11095-010-0357-6pmid: 21181545

The temporal evolution of an HPMC-based tablet by means of noninvasive MRI integrated with USP Apparatus 4 was found to be consistent with both the theoretical model based on polymer disentanglement concentration and experimental VIS/FTIR studies.

Waard, Hans; Frijlink, Henderik; Hinrichs, Wouter

doi: 10.1007/s11095-010-0323-3pmid: 21086152