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. Graphical abstract

Lipid Metabolic Events Underlying the Formation of the Corneocyte Lipid Envelope

Cornified cells of the stratum corneum have a monolayer of an unusual lipid covalently attached to the outer surface. This is referred to as the corneocyte lipid envelope (CLE). It consists of a monolayer of ω-hydroxyceramides covalently attached to the outer surface of the cornified envelope. The CLE is essential for proper barrier function of the skin and is derived from linoleate-rich acylglucosylceramides synthesized in the viable epidermis. Biosynthesis of acylglucosylceramide and its conversion to the cornified envelope is complex. Acylglucosylceramide in the bounding membrane of the lamellar granule is the precursor of the CLE. The acylglucosylceramide in the limiting membrane of the lamellar granule may be oriented with the glucosyl moiety on the inside. Conversion of the acylglucosylceramide to the CLE requires removal of the glucose by action of a glucocerebrosidase. The ester-linked fatty acid may be removed by an as yet unidentified esterase, and the resulting ω-hydroxyceramide may become ester linked to the outer surface of the cornified envelope through action of transglutaminase 1. Prior to removal of ester-linked fatty acids, linoleate is oxidized to an epoxy alcohol through action of 2 lipoxygenases. This can be further oxidized to an epoxy-enone, which can spontaneously attach to the cornified envelope through Schiff’s base formation. Mutations of genes coding for enzymes involved in biosynthesis of the CLE result in ichthyosis, often accompanied by neurologic dysfunction. The CLE is recognized as essential for barrier function of skin, but many questions about details of this essentiality remain. What are the relative roles of the 2 mechanisms of lipid attachment? What is the orientation of acylglucosylceramide in the bounding membrane of lamellar granules? Some evidence supports a role for CLE as a scaffold upon which intercellular lamellae unfold, but other evidence does not support this role. There is also controversial evidence for a role in stratum corneum cohesion. Evidence is presented to suggest that covalently bound ω-hydroxyceramides serve as a reservoir for free sphingosine that can serve in communicating with the viable epidermis and act as a potent broad-acting antimicrobial at the skin surface. Many questions remain.

Investigation of ex vivo Skin Penetration of Coenzyme Q10 from Microemulsions and Hydrophilic Cream

<b><i>Introduction:</i></b> Coenzyme Q10 (CoQ10) has been widely used in topical and cosmeceutical products due to its cutaneous antioxidant and energizer effects. CoQ10 is found in a higher concentration in the epidermis compared to dermis. The epidermal level of CoQ10 can be reduced due to several factors such as skin UV irradiation and photoaging. Various dermal nano-formulations have been investigated to overcome the skin barrier and enhance the poor penetration of CoQ10. The nanocarriers are designed to target and concentrate the CoQ10 in the viable epidermis. Most of these studies, however, failed to show the depth and extent of penetration of CoQ10 from the various carrier systems. <b><i>Objective:</i></b> The distribution of CoQ10 across the various skin layers has to be shown using skin slices representing the different skin layers. <b><i>Methods:</i></b> To realize this objective, a sensitive and selective HPLC method was developed and validated for the quantification of CoQ10 in the different skin slices. The method applicability to skin penetration (using excised human skin) as well as stability studies was investigated using CoQ10-loaded lecithin-based microemulsion (ME) and hydrophilic cream formulations. <b><i>Results:</i></b> It could be shown that the highest concentration of CoQ10 in the viable epidermis, the target skin layer for CoQ10, was observed after application of the CoQ10 in the hydrophilic cream. This cream contains 10% of 2-ethylhexyl laurate which works obviously as a penetration enhancer for CoQ10. In contrast, the penetration of CoQ10 was lower from the ME. Just in the deeper dermis, a certain amount of CoQ10 could be detected. <b><i>Conclusions:</i></b> The HPLC method quantified the trace quantities of the CoQ10 distributed across the various skin layers and, hence, can be used to investigate the skin penetration of CoQ10 from various dermal standard and nano-formulations.

RF-INDUCED TEMPERATURE INCREASE IN A STRATIFIED MODEL OF THE SKIN FOR PLANE-WAVE EXPOSURE AT 6–100 GHZ

This study assesses the maximum temperature increase induced by exposure to electromagnetic fields between 6 and 100 GHz using a stratified model of the skin with four or five layers under plane wave incidence. The skin model distinguishes the stratum corneum (SC) and the viable epidermis as the outermost layers of the skin. The analysis identifies the tissue layer structures that minimize reflection and maximize the temperature increase induced by the electromagnetic field. The maximum observed temperature increase is 0.4°C for exposure at the present power density limit for the general population of 10 W m −2 . This result is more than twice as high as the findings reported in a previous study. The reasons for this difference are identified as impedance matching effects in the SC and less conservative thermal parameters. Modeling the skin as homogeneous dermis tissue can underestimate the induced temperature increase by more than a factor of three.

Review of Microneedle based Transdermal Drug Delivery Systems

Transdermal drug delivery (TDD) provides an attractive and alternative drug delivery when compared to oral and other drug delivery as the former route offers several advantages like avoiding pre-systemic first pass metabolism of administered drugs, patient compliance, and avoiding gastric irritation. However, stratum corneum (SC), the upper most layer of skin, limits the permeation of number of drugs because of its barrier property. To breach or bypass this barrier, two approaches namely: chemical and physical are generally used. Physical approaches seem to be better as it does not involve the use of chemicals in the formulations, which could interact, with other component of formulations and more importantly may cause reversible damage to the skin. Microneedle technique is one of the most advanced physical techniques, which can easily by-pass, the SC and allow the drug to reach viable epidermis directly. The needles used in microneedle techniques are in hundreds of micron length range and when applied on skin generally produce little or no pain. The objective of this review is mainly focused on types of microneedles, various materials and fabrication techniques used in the preparation of microneedles. Furthermore, various techniques used in the application of microneedles and mechanism of action are described. In addition, this review also describes commercial products, patents on microneedle technology and recent works carried out on microneedles research and safety aspects of microneedles.