Current Pharmaceutical Design - Volume 21, Issue 20, 2015

Stratum corneum (SC), the outermost layer of the skin, constitutes an excellent protective physiological barrier, and is the main challenge in transdermal drug delivery. Many approaches have been used to enhance the penetration of drugs through this layer, covering passive and active methods or the combination of both. This opens the opportunity to broaden the spectrum of drugs that can be administered through the skin, providing alternatives to existing products, and filling gaps that conventional routes failed to occupy. In this review, an overview of the different permeation enhancing methodologies is carried out, focusing on the combination of lipid nanoparticles with conventional chemical enhancers, as a proof-of-concept of a successful development strategy.

Skin delivery is more advantageous for drug administration than other routes since it is more compliant and can avoid the first-pass metabolic effect. More importantly, it can ensure stable blood level of transdermal drugs for a long period of time, avoiding fluctuation and reducing side effects. However, it is restricted by the barrier function of the stratum corneum. Therefore, significant attention has been paid to developing methods to modify the kinetics of skin drug delivery and expand the range of drugs that can be used for transdermal delivery. Novel mechanisms of increasing the intercellular and appendages penetration pathways have also been developed. This review focuses on chemical penetration enhancers, physical permeabilization (sonophoresis, iontophoresis and microneedles) and novel nanocarriers for skin delivery. Recent developments on skin delivery are also discussed.

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 structurepermeability 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 models systems will also be discussed.

Supersaturated systems have attracted interest to enhance the skin penetration because of the low cost and reduced risks of irritation with respect to other approaches. The mechanism is simply based on the increased drug driving force for transit out of the dosage form and penetrate the stratum corneum. Supersaturated systems can be obtained by preparation of solvent/non-solvent mixtures; or mixtures containing a skin penetrating solvent or a volatile solvent, and quenching. All methods are described to obtain solutions or semisolid preparations; meanwhile the solvent evaporation and quenching can be used in the transdermal patch production. The adopted formulative strategies can increase the drug concentration in the vehicle 5-fold the solubility and the corresponding increment of the thermodynamic activity determines a significant increase of the drug flux through the skin, according to the Fick’s law. The main limitation of supersaturated systems is related to their thermodynamic instability that, leading to drug crystallization in the vehicle, affects the drug skin penetration. Among the possible strategies to avoid or retard this issue the use of polymeric materials appears the most efficacious. However, the crystallization of a drug during storage and/or application on the skin is driven by so many factors that the stability of supersaturated systems is unpredictable. This paper offers a comprehensive review of the literature with the aim to underline the “pros and cons” of the application of supersaturation in transdermal delivery in the light of the theoretical aspects.

Topically applied natural antioxidants can be an effective treatment for inhibiting oxidative damage and photoaging of the skin. Due to the barrier function of the stratum corneum (SC), it is necessary to use an enhancement approach to promote the cutaneous absorption of natural antioxidants. Some factors that should be considered when developing delivery systems for natural antioxidants include increased solubility, enhanced storage stability, improved permeability and bioavailability, skin targeting, and minimal side effects. This review describes the skin delivery systems for natural antioxidant permeation that have been developed during the last decade. The antioxidants introduced include vitamins, polyphenols, and carotenoids. Various types of formulations are employed to improve the skin penetration of the antioxidants, such as hydrogels, cyclodextrin, microemulsions, nanoparticles, liposomes and niosomes. This review focuses on the introduction of natural antioxidants used in skin protection, the mechanisms of antioxidant activity on the skin, and formulation designs for enhancing absorption and efficacy.

The skin remains an attractive area for drug delivery. The skin, however, often limits the ingress of drugs, because of its very low permeability. Much research, focusing on employing a variety of physical and chemical methods, aimed at reversibly altering skin permeability in favour of compounds, has been reported. Of the many chemical approaches that exist, one comprises the use of vesicular carriers for delivering drugs into and possibly through the skin. This review offers an overview of various vesicles that have been investigated during dermal and transdermal drug delivery research in recent years, with special emphasis on a relatively new carrier, namely the Pheroid™. The progress made to date by our research group with regards to the use of the Pheroid™ as transdermal delivery vector, is also discussed in detail.

Drug-in-adhesive transdermal drug delivery matrix exploits intimate contact of the carrier with stratum corneum, the principal skin barrier to drug transport, to deliver the actives across the skin and into the systemic circulation. The main application challenges of drug-in-adhesive matrix lie in the physicochemical properties of skin varying with age, gender, ethnicity, health and environmental condition of patients. This in turn poses difficulty to design a universal formulation to meet the intended adhesiveness, drug release and drug permeation performances. This review focuses on pressure-sensitive adhesives, and their adhesiveness and drug release/permeation modulation mechanisms as a function of adhesive molecular structure and formulation attributes. It discusses approaches to modulate adhesive tackiness, strength, elasticity, hydrophilicity, molecular suspension capability and swelling capacity, which contribute to the net effect of adhesive on skin bonding, drug release and drug permeation.

Dendritic nanoparticles have been developed with auspicious properties like high loading capacity for guest molecules, low polydispersity and tunable end groups. Demonstrating increased cellular uptake and bypassed efflux transporters, dendritic nanoparticles may offer new treatment options for therapy-resistant diseases. New core-shell architectures address the drawbacks of initial approaches. Especially tecto-dendrimers, bearing low-radii dendrimers on the surface of a bigger dendrimer, as well as the core-multishell architectures with an alkyl inner shell and a monomethylpoly(ethylene glycol) outer shell, gained interest for dermatotherapy. Moreover, the integration of e.g. pH labile groups into dendritic nanoparticles may offer triggered drug release. However, before declaring dendritic nanoparticles as an ultimate drug delivery system for skin penetration, dendritic nanoparticles need to prove their efficacy and safety in non-clinical, and subsequently in clinical studies. Here, we review major characteristics of human skin, and thus target structures for topical drug delivery systems. Focusing on the use as in vitro test system, we summarize the features of reconstructed human skin. Since drug delivery systems are intended to be applied to diseased skin, we additionally review latest insights into disease-related changes in the highly prevalent skin diseases such as atopic dermatitis, and cutaneous squamous cell carcinoma, as well as in their respective human cell-based skin disease models. We will conclude with the proposal of an integrated test strategy to promote the introduction of dendritic nanoparticles into medicinal products.

Nanogel nanoparticles loaded with active compounds are referred to as Drug-loaded polymeric colloidal nanogels (DPCNs). These nanogels are emerging as promising carriers for transdermal drug delivery applications. Much interest has been directed towards the potential use of DPCNs to deliver a variety of drugs for either controlled or sustained drug delivery systems. Transdermal drug delivery systems (TDDS) have shown a number of beneficial properties such as improving patients compliance as they are conveniently dosed compared to intravenous and oral therapy. The use of TDDS depends on the effectiveness of the drug formulation to accumulate in sufficient concentrations at the specific targeted sites, hence the therapeutic significance of DPCNs in TDDS. Nanogels have a high drug loading capacity, biodegradability and biocompatibility, which are the key points in designing an efficient TDDS. The advanced development of DPCN has led to stimuli responsive drug delivery systems that release the entrapped drug under variable environmental incentives. The development of these drug delivery systems has created room for further research to characterize the physical and chemical properties of theses nanogels as well as their in vitro and in vivo behavior. Therefore this review presents an insight on the basic fabrication methods, advanced developments, limitations and therapeutic significance of the DPCN in TDDS as well as forthcoming potential applications. Despite these numerous positive scientific findings, efficient TDDS remains a challenge for pharmaceutical scientists and significant amount of research is still directed toward the development of superior TDDS.

The skin presents several advantages as an administration route, including the possibility of localizing drugs in the tissue and overcoming the first-pass effect. However, its use is limited by the barrier function of the tissue, which is provided mainly (but not exclusively) by the stratum corneum. Various strategies to overcome this layer, have been considered over the years, ranging from the use of physical methods such as iontophoresis to wellknown conventional chemical penetration enhancers like oleic acid and DMSO. However, delivery of hydrophilic and large compounds remains a challenge. More recently, selected groups of peptides have attracted increasing attention due to their ability to penetrate into the skin promoting the transport of small and large molecules, including nanodispersed systems. Here, we will discuss the properties and application to cutaneous (into the skin) and transdermal (across the skin) delivery of three groups of peptides, namely protein-transduction domains, phagedisplayed peptides and antimicrobial peptides.

Lipid based drug delivery systems have been widely studied and reported over the past decade and offer a useful alternative to other colloidal drug delivery systems. Skin is a popular route of drug delivery for locally and systemically acting drugs and nanoparticles are reported as a potential formulation strategy for dermal delivery. Although the skin acts as a natural physical barrier against penetration of foreign materials, including particulates, opportunities exist for the delivery of therapeutic nanoparticles, especially in diseased and damaged skin and via appendageal routes such as the openings of hair follicles. The extent and ability of nanoparticles to penetrate into the underlying viable tissue is still the subject of debate although recent studies have identified the follicular route as the most likely route of entry; this influences the potential applications of these dosage forms as a drug delivery strategy. This paper reviews present state of art of lipid-based nanocarriers focussing on solid lipid nanoparticles, nanostructured lipid carriers and nanoemulsions, their production methods, potential advantages and applications in dermal drug delivery.

The skin has evolved to resist the penetration of foreign substances and particles. Effective topical drug delivery into and/or through the skin is hindered by these epidermal barriers. A range of physical enhancement methods has been developed to selectively overcome this barrier. This review discusses recent advances in physical drug delivery by broadly separating the techniques into two main areas; indirect and direct approaches. Indirect approaches consist of electrical, vibrational or laser instrumentation that creates pores in the skin followed by application of the drug. Direct approaches consist of mechanical disruption of the epidermis using techniques such as microdermabrasion, biolistic injectors and microneedles. Although, in general, physical techniques are yet to be established in a clinical setting, the potential gains of enhancing delivery of compounds through the skin is of great significance and will no doubt continue to receive much attention.

Transdermal drug delivery is impeded by the natural barrier of epidermis namely stratum corneum. This limits the route to transport of drugs with a log octanol-water partition coefficient of 1 to 3, molecular weight of less than 500 Da and melting point of less than 200°C. Nanotechnology has received widespread investigation as nanocarriers are deemed to be able to fluidize the stratum corneum as a function of size, shape, surface charges, and hydrophilicity-hydrophobicity balance, while delivering drugs across the skin barrier. This review provides an overview and update on the latest designs of liposomes, ethosomes, transfersomes, niosomes, magnetosomes, oilin- water nanoemulsions, water-in-oil nanoemulsions, bicontinuous nanoemulsions, covalently crosslinked polysaccharide nanoparticles, ionically crosslinked polysaccharide nanoparticles, polyelectrolyte coacervated nanoparticles and hydrophobically modified polysaccharide nanoparticles with respect to their ability to fuse or fluidize lipid/protein/tight junction regimes of skin, and effect changes in skin permeability and drug flux. Universal relationships of nanocarrier size, zeta potential and chemical composition on transdermal permeation characteristics of drugs will be developed and discussed.

Topical administration is an appealing method for drug delivery due to its non-invasiveness, selfcontrolled application, avoidance of first-pass metabolism in the liver and reduction of systemic side effects compared to other conventional routes such as oral and parenteral. However, topical administration must overcome the permeable barriers that skin and mucosa represent for the drug to achieve its desired therapeutic effect. Penetration of drugs through human skin is mainly impaired by the stratum corneum— the uppermost keratinized skin layer. In contrast, the stratified squamous epithelium (a nonkeratinized tissue) represents the major physical barrier for transbuccal drug administration in humans. Different technologies have been studied to enhance the bioavailability or local effects of drugs administered through skin and buccal mucosa. Those technologies involve the use of physical or chemical enhancers and new dosage forms such as vesicles, cyclodextrins, nanoparticles and other complex systems. Combinations of these technologies may further increase drug delivery in some cases. As analgesia is one of the main therapeutic effects sought through topical administration, this paper focuses on the review of drug delivery systems to improve the topical and transdermal/transbuccal drug delivery of substances with known analgesic action. A discussion of their possibilities and limitations is also included.

Proniosomes are liquid crystalline-compact niosomal hybrid that can be hydrated to form niosomal dispersion instantly before use. It is a promising drug carrier with better physical and chemical stability than niosomes. Proniosomes have the potential to be scaled up for industrial purposes. They have been remarkably considered for transdermal drug delivery because of their competences, including the penetration enhancing ability of surfactants and their non-toxic characteristics. This review offers current approaches in the research and development of proniosomal formulations for the transdermal delivery of drugs with a focus on therapeutic applications.

The prevalence of fungal infections of skin has increased rapidly, affecting approximately 40 million people across the globe. A wide variety of antifungal drugs has been utilized in the effective management of numerous dermatological infections. Topical treatment of fungal infections has proved to be quite advantageous due to various factors like targeting the site of infection, minimizing systemic side effects, enhanced efficacy of treatment, and improved patient compliance. In spite the fact that these agents are therapeutically active on topical application, these have restricted drug delivery across the skin resulting in insufficient therapeutic index and may exert local as well as systemic side effects. The accomplishment of topical drug delivery needs to pacify two anomalous aspects, first the barrier nature of stratum corneum, and second, deposition of drug within the skin should be ideally achieved with limited percutaneous absorption. Thus, to facilitate the delivery of antifungal drugs and improve the treatment aspects, various novel delivery carriers have been developed. This article attempts to provide an in-depth knowledge of nanoparticulate and vesicular carriers. This article focuses on the different aspects of fungal infections and their effective treatment with antifungal drugs. Efficacy of various carrier systems (nanoparticulate and vesicular carriers) in delivering antifungal drugs topically has also been discussed. Besides, compiling various research reports, this article also includes formulation considerations inclusive of regulatory aspects of excipients used, the mechanisms of penetration, and patents reported.