Recent developments in skin mimic systems to predict transdermal permeation

In recent years there has been a drive to create experimental techniques that can facilitate the accurate and precise prediction of transdermal permeation without the use of in vivo studies. This review considers why permeation data is essential, provides a brief summary as to how skin acts as a natural barrier to permeation and discusses why in vivo studies are undesirable. This is followed by an in-depth discussion on the extensive range of alternative methods that have been developed in recent years. All of the major ‘skin mimic systems’ are considered including: in vitro models using synthetic membranes, mathematical models including quantitative structure-permeability relationships (QSPRs), human skin equivalents and chromatographic based methods. All of these model based systems are ideally trying to achieve the same end-point, namely a reliable in vitro-in vivo correlation, i.e. matching non-in vivo obtained data with that from human clinical trials. It is only by achieving this aim, that any new method of obtaining permeation data can be acknowledged as a potential replacement for animal studies, for the determination of transdermal permeation. In this review the relevance, and potential applicability, of the various model systems will also be discussed

Ionisation effects on the permeation of pharmaceutical compounds through silicone membrane

Silicone membrane is frequently used as an in vitro skin mimic whereby experiments incorporate a range of buffered media which may vary in pH. As a consequence of such variability in pH there is a corresponding variability in the degree of ionisation which in turn, could influence permeation through the mainly hydrophobic-rich membrane structure. This study reports the effect of pH on the permeation of five model compounds (benzoic acid, benzotriazole, ibuprofen, ketoprofen and lidocaine). For the five compounds analysed, each at three distinct percentages of ionisation, it was found that the greater extent of permeation was always for the more ‘neutral’, i.e. more greatly unionised, species rather than the anionic or cationic species. These findings fit with the theory that the hydrophobic membrane encourages permeation of ‘lipid-like’ structures, i.e. the more unionised form of compounds. However, results obtained with an Inverse Gas Chromatography Surface Energy Analyser (iGC SEA) indicate the membrane surface to be an electron dense environment. In the knowledge that unionised forms of compounds permeate (rather than the charged species) this negatively charged surface was not anticipated, i.e. the basic membrane surface did not appear to affect permeation

A calorimetric investigation of doxorubicin-polymer bead interactions

Isothermal titration calorimetry (ITC) was utilised to investigate suitability of the technique to determine the stoichiometry and thermodynamics of the interactions that occur between a commonly used chemotherapeutic drug, namely doxorubicin, and a polymer bead-based drug delivery embolisation system (DC Bead™). Six temperatures were selected for drug-polymer titrations (293 to 313 K) and in all cases an initially exothermic signal reverted to an endothermic response upon the saturation of the beads with drug. From these experiments, and subsequent calculations, the molar ratio of drug to SO3- (polymer) was found to be 0.4:1 at all temperatures studied. Enthalpic data was calculated from the raw ITC data with an average enthalpy of drug-polymer binding of – 14.8 kJmol-1 at 293 K through to – 19.4 kJmol-1 at 313 K implying the process is enthalpically-driven yet only affected by an increase in experimental temperature to a limited extent whereby an increase in experimental temperature results in a small increase in the negativity in change in enthalpy recorded. The application of ITC in this study (with its unique ability to monitor real-time interactions and facilitate stoichiometric calculations) resolves the lack of knowledge regarding the thermodynamics of this specific drug-polymer interaction. This study confirms that ITC is not only useful for this specific system, but also highlights the potential use of ITC for more general studies in this area

Predicting human intestinal absorption in the presence of bile salt with micellar liquid chromatography

Understanding intestinal absorption for pharmaceutical compounds is vital to estimate bioavailability and therefore the in vivo potential of a drug. This study considers the application of micellar liquid chromatography (MLC) to predict passive intestinal absorption with a selection of model compounds. MLC is already known to aid prediction of absorption using simple surfactant systems however, with this study the focus was on the presence of a more complex, bile salt surfactant, as would be encountered in the in vivo environment. As a result, MLC using a specific bile salt has been confirmed as an ideal in vitro system to predict the intestinal permeability for a wide range of drugs, through the development of a quantitative partition-absorption relationship. MLC offers many benefits including environmental, economic, time-saving and ethical advantages compared with the traditional techniques employed to obtain passive intestinal absorption values

Permeation of pharmaceutical compounds through silicone membrane in the presence of surfactants

This study reports the effect of surfactant charge and concentration on the permeation of four model compounds (benzocaine, benzotriazole, ibuprofen and lidocaine). Surfactant charge was systematically varied using a range of surfactants that are known to possess specific head group charges, namely an anionic, a cationic, a zwitterionic and a neutral form over a series of surfactant concentrations, i.e. where possible, both above, and below, the critical micellar concentration for each surfactant. It was found that there was almost always a systematic reduction in permeation as the concentration of surfactant increased despite the wide range of physicochemical properties exhibited by the four model compounds studied. Overall, it was concluded that the presence of surfactant does generally seem to reduce permeation, regardless of the compound in question, and that the effect is surfactant concentration, as well as charge, dependent

Prediction of human intestinal absorption using micellar liquid chromatography with an aminopropyl stationary phase

The extent of human intestinal absorption (HIA) for a drug is considered to be an important pharmacokinetic parameter which must be determined for orally administered drugs. Traditional experimental methods relied upon animal testing and are renowned for being time consuming, expensive as well as being ethically unfavourable. As a result, developing alternative methods to evaluate a drug's pharmacokinetics is crucial. Micellar liquid chromatography (MLC) is considered to be one of these methods that can replace the use of animals in prediction of HIA. In this study, the combination of an aminopropyl column with the biosurfactant sodium deoxycholate (NaDC) bile salt were used in the experimental determination of micelle-water partition coefficients (log Pmw) for a group of compounds. Multiple linear regression (MLR) was then used for the prediction of HIA using the experimentally determined log Pmw along with other molecular descriptors leading to the construction of a model equation of R2= 85 % and a prediction power represented by R2Pred. =72 %. The use of MLC with an aminopropyl column in combination with NaDC was found to be a good method for the prediction of human intestinal absorption, providing data for a far wider range of compounds compared with previous studies

Effect of plasma surface treatment of poly (dimethylsiloxane) on the permeation of pharmaceutical compounds

This paper addresses the modification of poly(dimethylsiloxane), i.e. PDMS, using plasma surface treatment and a novel application of the membrane created. A set of model compounds were analysed to determine their permeation through PDMS both with, and without, plasma treatment. It was found that plasma treatment reduced permeation for the majority of compounds yet had little effect for some compounds, such as caffeine, with results indicating that polarity plays an important role in permeation, as is seen in human skin. Most importantly, a direct correlation was observed between plasma-modified permeation data and literature data through calculation of membrane permeability (Kp) values implying plasma-modified silicone membrane (PMSM) could be considered a suitable in vivo replacement to predict clinical skin permeatio

Pneumocystis pneumonia, a COVID-19 mimic, reminds us of the importance of HIV testing in COVID-19

While clinical environments are highly focused on COVID-19, reports of missed or delayed treatment for conditions that imitate COVID-19, such as pneumonia caused by the fungus Pneumocystis jirovecii, are emerging. Given the uncertain spectrum of COVID-19 presentations and variable sensitivity of laboratory tests for SARS-CoV-2, there is a risk that, without a high index of suspicion, alternative aetiologies may be overlooked while pursuing a diagnosis of COVID-19. The British HIV Association has been calling for the inclusion of HIV testing in all patients admitted to hospital with suspected COVID-19. In this article we reflect on the importance of including HIV testing to prevent avoidable morbidity and mortality in our patients.Publisher PDFPeer reviewe

The use of bile salt micelles for the prediction of human intestinal absorption

Human intestinal absorption (HIA) will dictate biopharmaceutical performance through its influence on absorption, distribution, metabolism, and elimination and can vary significantly depending upon the nature of the compound under consideration. In this study, an in vitro assay method is proposed for the prediction of HIA through the measurement of drug solubility in an aqueous phase containing micellar bile salt, namely sodium deoxycholate. A series of twenty compounds, displaying a range of physicochemical properties and known HIA values, were analyzed using UV spectroscopy to determine a solubilization ratio for each compound. A micelle/water partition coefficient (Kxm/a) was calculated and then used to develop an equation through simple linear regression; logit HIA = −0.919 + 0.4618 logKxm/a (R2 = 0.85). From this equation, a value for % HIA was determined which compared well with literature. Furthermore, 4 additional drugs were then analyzed using the developed equation and found to match well with literature, confirming the suitability of the method. Using a simple, economic, and robust UV bile salt assay allows prediction of HIA and avoids many of the disadvantages of other techniques, such as animal-based methods

Formation of a bile salt-drug hydrogel to predict human intestinal absorption

The unique character of bile salts to self-assemble into hydrogels in the presence of halide salts was exploited in this work to facilitate the prediction of human intestinal absorption (%HIA) for a set of 25 compounds. This was achieved by firstly incorporating each compound separately within the process of gel formation to create a series of gel-drug membranes. Scanning Electron Microscopy (SEM) analysis of the freeze-dried samples of the blank bile salt hydrogels and drug loaded bile salt hydrogels indicated a unique microstructure made of a network of intertwined fibrils. Drug-loaded sodium deoxycholate (NaDC) hydrogels were then utilised as the donor phase to study permeability using flow-through and static diffusion cells. The resulting values of the release-permeability coefficient (Kp) were then analysed, along with other molecular descriptors, for the prediction of human intestinal absorption (%HIA) using multiple linear regression (MLR). Overall, when comparing predicted values (using the systems presented in this study) with known literature values, it can be seen that both methods (i.e. using static and flow through cells) had good predictability with R2PRED. values of 79.8 % and 79.7 % respectively. This study therefore proposes a novel, accurate and precise way to predict human intestinal absorption for compounds of pharmaceutical interest using a simple in vitro permeation system. It is important to develop alternatives to the current methods used in prediction of HIA which are expensive and time consuming or include the use of animals. Therefore, the proposed method in this study being economic and time saving provides superiority over these current methods and suggests the possibility of its use as an alternate to such methods for prediction of HIA