Assessment of dermal bioavailability: predicting the input function for topical glucocorticoids using stratum corneum sampling.

Predicting the dermal bioavailability of topically delivered drugs is challenging. In this work, minimally invasive stratum corneum (SC) sampling was used to quantify the delivery of betamethasone valerate (BMV) into the viable skin. Betnovate® cream (0.1% w/w BMV) was applied at three doses (2, 5, and 10 mg cm-2) to the ventral forearms of 12 healthy volunteers. The mass of drug in the SC was measured using a validated tape-stripping method (a) after a 4-h "uptake" period, and (b) following a 6-h "clearance" period subsequent to cream removal. Concomitantly, the skin blanching responses to the same doses were assessed with a chromameter over 22 h post-application. BMV uptake into the SC was significantly higher for the 5 mg cm-2 dose compared to those of 2 and 10 mg cm-2. In all cases, ~30% of the drug in the SC at the end of the uptake period was cleared in the subsequent 6 h. From the SC sampling data, the average drug flux into the viable epidermis and its first-order elimination rate constant from the SC were estimated as 4 ng cm-2 h-1 and 0.07 h-1, respectively. In contrast, skin blanching results were highly variable and insensitive to the dose of cream applied. The SC sampling method was able to detect a 50% difference between two applied doses with 80% power; detection of a 20% difference would require a larger sample size. SC sampling enabled quantitative metrics describing corticosteroid delivery to the viable epidermis to be determined.

Skin Pharmacokinetics of Transdermal Scopolamine: Measurements and Modeling.

Prediction of skin absorption and local bioavailability from topical formulations remains a difficult task. An important challenge in forecasting topical bioavailability is the limited information available about local and systemic drug concentrations post application of topical drug products. Commercially available transdermal patches, such as Scopoderm (Novartis Consumer Health UK), offer an opportunity to test these experimental approaches as systemic pharmacokinetic data are available with which to validate a predictive model. The long-term research aim, therefore, is to develop a physiologically based pharmacokinetic model (PBPK) to predict the dermal absorption and disposition of actives included in complex dermatological products. This work explored whether in vitro release and skin permeation tests (IVRT and IVPT, respectively), and in vitro and in vivo stratum corneum (SC) and viable tissue (VT) sampling data, can provide a satisfactory description of drug "input rate" into the skin and subsequently into the systemic circulation. In vitro release and skin permeation results for scopolamine were consistent with the previously reported performance of the commercial patch investigated. New skin sampling data on the dermatopharmacokinetics (DPK) of scopolamine also accurately reflected the rapid delivery of a "priming" dose from the patch adhesive, superimposed on a slower, rate-controlled input from the drug reservoir. The scopolamine concentration versus time profiles in SC and VT skin compartments, in vitro and in vivo, taken together with IVRT release and IVPT penetration kinetics, reflect the input rate and drug delivery specifications of the Scopoderm transdermal patch and reveal the importance of skin binding with respect to local drug disposition. Further data analysis and skin PK modeling are indicated to further refine and develop the approach outlined.

Span poly-L-arginine nanoparticles are efficient non-viral vectors for PRPF31 gene delivery: An approach of gene therapy to treat retinitis pigmentosa.

Retinitis pigmentosa (RP) is the most common cause of inherited blindness in adults. Mutations in the PRPF31 gene produce autosomal dominant RP (adRP). To date there are no effective treatments for this disease. The purpose of this study was to design an efficient non-viral vector for human PRPF31 gene delivery as an approach to treat this form of adRP. Span based nanoparticles were developed to mediate gene transfer in the subretinal space of a mouse model of adRP carrying a point mutation (A216P) in the Prpf31 gene. Funduscopic examination, electroretinogram, optomotor test and optical coherence tomography were conducted to further in vivo evaluate the safety and efficacy of the nanosystems developed. Span-polyarginine (SP-PA) nanoparticles were able to efficiently transfect the GFP and PRPF31 plasmid in mice retinas. Statistically significant improvement in visual acuity and retinal thickness were found in Prpf31A216P/+ mice treated with the SP-PA-PRPF31 nanomedicine.

Structural analysis of nanosystems: Solid Sorbitan esters Nanoparticles (SSN) as a case study.

Innovative approaches in nanotechnology can provide drug delivery systems with a high potential in different fields. To avoid trial and error assays as a main driving force governing new designs and, furthermore, to develop successful nanosystem optimization strategies, it is of the greatest importance to develop specific characterisation techniques beyond conventional determinations of size, zeta potential and morphology. However, the application of techniques able to determine some key characteristics, such as nanostructure (i.e., solid structure vs vesicular), and the way in which the reorganization of components takes place on these structures has been scarcely explored. The present work has been devoted to provide some insights about the potential offered by some NMR techniques to those scientists working on nanotechnological approaches. For this purpose, we selected our nanosystems based on sorbitan monooleate as a case study. We used (1)H NMR methods, including a recently proposed method relying in the well-known Saturation Transfer Difference (STD) experiment for the observation of 'invisible signals' in large aggregates (Invisible State STD or ISSTD). Overall, these techniques revealed the presence in these nanosystems of a gradient of flexibility from an internal rigid core towards a more flexible region located on their surface, as well as the absence of water content in both regions. Such structure, corresponding to a solid nanostructure rather than a vesicular one, can explain some of the interesting properties previously observed for these innovative nanosystems, such as their high stability, and allows us to refer to these nanosystems with the term "Solid Sorbitan esters Nanoparticles" (SSN). On the basis of the valuable information provided by the mentioned characterisation techniques, it is our understanding that they could facilitate the future design of new drug delivery nanosystems as well as the improvement of existing ones and/or the development of new applications for classical drug delivery concepts.

Current strategies for DNA therapy based on lipid nanocarriers.

INTRODUCTION: Lipid based nanocarriers represent one of the most widely used strategies for the delivery of gene molecules. This review focuses on current strategies for the use of these nanocarriers that could open new horizons in DNA therapy and offer an opportunity to support the transition from resource-based approaches towards knowledge-based strategies. AREAS COVERED: The present review highlights the most promising approaches focusing on the development of safe, stable, and effective lipid-based carriers capable of delivering DNA to the proper target sites and cells. In addition, we intend to provide some insights in to future strategies that should be considered in order to break down barriers in the transformation of DNA basic-science breakthroughs into clinical applications. EXPERT OPINION: On the basis of the significant advances in the design of lipid nanocarriers our impression is that they are, with respect to other systems, in a 'pole' position in the DNA therapy development race.