Current aspects of formulation efforts and pore lifetime related to microneedle treatment of skin

Importance of the field: The efficacy of microneedles in the area of transdermal drug delivery is well documented. Multiple studies have shown that enhancement of skin permeation by means of the creation of microscopic pores in the stratum corneum can greatly improve the delivery rates of drugs. However, skin pretreatment with microneedles is not the only factor affecting drug transport rates. Other factors, including drug formulation and rate of micropore closure, are also important for optimizing delivery by this route.

Areas covered in this review: This review aims to highlight work that has been done in these areas, with an emphasis on drug formulation parameters that affect transdermal flux.

What the reader will gain: This review creates an appreciation for the many factors affecting microneedle-enhanced delivery. Most results clearly indicate that microneedle skin pretreatment by itself may have different effects on drug transport depending on the formulation used, and formulation characteristics have different effects on the transport through untreated skin and microneedle-treated skin. Several formulation approaches are reported to optimize microneedle-enhanced drug delivery, including co-solvent use, vesicular, nanoparticulate and gel systems.

Take home message: In addition to well-established factors that affect microneedle-assisted delivery (geometry, type of microneedle, etc.), formulation and pore viability are also critical factors that must be considered.     

Spray-on transdermal drug delivery systems

Introduction: Transdermal drug delivery possesses superior advantages over other routes of administration, particularly minimizing first-pass metabolism. Transdermal drug delivery is challenged by the barrier nature of skin. Numerous technologies have been developed to overcome the relatively low skin permeability, including spray-on transdermal systems.

Areas covered: A transdermal spray-on system (TSS) usually consists of a solution containing the drug, a volatile solvent and in many cases a chemical penetration enhancer. TSS promotes drug delivery via the complex interplay between solvent evaporation and drug–solvent drag into skin. The volatile solvent carries the drug into the upper layers of the stratum corneum, and as the volatile solvent evaporates, an increase in the thermodynamic activity of the drug occurs resulting in an increased drug loading in skin.

Expert opinion: TSS is easily applied, delivering flexible drug dosage and associated with lower incidence of skin irritation. TSS provides a fast-drying product where the volatile solvent enables uniform drug distribution with minimal vehicle deposition on skin. TSS ensures precise dose administration that is aesthetically appealing and eliminates concerns of residual drug associated with transdermal patches. Furthermore, it provides a better alternative to traditional transdermal products due to ease of product development and manufacturing.     

Charged liposomes as carriers to enhance the permeation through the skin

Introduction: In recent years, there has been increased interest in developing charged liposomes as carriers for transdermal drug delivery. It is necessary to modify the basic composition of the liposomes in order to enhance the penetration properties of the vesicles through the skin. Charged liposomes offer several advantages compared with previous drug delivery systems.

Areas covered: This paper provides a brief overview of the different drug delivery systems that exist which aim to improve the permeation of drugs through the skin, focusing on the use of charged liposomes for transdermal delivery. We propose a classification of such liposomes based on the origin of the charge given to the vesicles.

Expert opinion: Despite the advances that are occurring in the design of charged liposomes for transdermal drug delivery, the long-term stability continues to be a drawback in such systems. The presence of charge on the surface of the vesicles favors the electrostatic repulsion among them, creating a ζ potential positive or negative that prevents their aggregation and flocculation. However, there is loss of the encapsulated drug, which limits the in vivo use of these systems. It should be emphasized that charged liposomes are indeed a promising candidate for use in gene therapy and vaccine targeting, in a great diversity of diseases, for which drugs are administered by the percutaneous route.     

Biomaterials as novel penetration enhancers for transdermal and dermal drug delivery systems

Abstract

The highly organized structure of the stratum corneum provides an effective barrier to the drug delivery into or across the skin. To overcome this barrier function, penetration enhancers are always used in the transdermal and dermal drug delivery systems. However, the conventional chemical enhancers are often limited by their inability to delivery large and hydrophilic molecules, and few to date have been routinely incorporated into the transdermal formulations due to their incompatibility and local irritation issues. Therefore, there has been a search for the compounds that exhibit broad enhancing activity for more drugs without producing much irritation. More recently, the use of biomaterials has emerged as a novel method to increase the skin permeability. In this paper, we present an overview of the investigations on the feasibility and application of biomaterials as penetration enhancers for transdermal or dermal drug delivery systems.     

An Investigation of the Role of Cavitation in Low-Frequency Ultrasound-Mediated Transdermal Drug Transport

Purpose. Low-frequency ultrasound (20 kHz) has been shown to increase the skin permeability to drugs, a phenomenon referred to as low-frequency sonophoresis (LFS). Many previous studies of sonophoresis have proposed that ultrasound-induced cavitation plays the central role in enhancing transdermal drug transport. In this study, we sought to definitively test the role of cavitation during LFS, as well as to identify the critical type(s) and site(s) of cavitation that are responsible for skin permeabilization during LFS. Methods. Pig full-thickness skin was treated by 20 kHz ultrasound, and the effect of LFS on the skin permeability was monitored by measuring the increase in the skin electrical conductance. A high-pressure LFS cell was constructed to completely suppress cavitation during LFS. An acoustic method, as well as chemical and physical dosimetry techniques, was utilized to monitor the cavitation activities during LFS. Results. The study using the high-pressure LFS cell showed definitively that ultrasound-induced cavitation is the key mechanism via which LFS permeabilizes the skin. By selectively suppressing cavitation outside the skin using a high-viscosity coupling medium, we further demonstrated that cavitation occurring outside the skin is responsible for the skin permeabilization effect, while internal cavitation (cavitation inside the skin) was not detected using the acoustic measurement method under the ultrasound conditions examined. Acoustic measurement of the two types of cavitation activities (transient vs. stable) indicates that transient cavitation plays the major role in LFS-induced skin permeabilization. Through quantification of the transient cavitation activity at two specific locations of the LFS system, including comparing the dependence of these cavitation activities on ultrasound intensity with that of the skin permeabilization effect, we demonstrated that transient cavitation occurring on, or in the vicinity of, the skin membrane is the central mechanism that is responsible for the observed enhancement of skin permeability by LFS. Conclusions. LFS-induced skin permeabilization results primarily from the direct mechanical impact of gas bubbles collapsing on the skin surface (resulting in microjets and shock waves).     

Future of the transdermal drug delivery market – have we barely touched the surface?

ABSTRACT

Introduction: Transdermal drug delivery is the movement of drugs across the skin for absorption into the systemic circulation. Transfer of the drug can occur via passive or active means; passive transdermal products do not disrupt the stratum corneum to facilitate delivery whereas active technologies do. Due to the very specific physicochemical properties necessary for successful passive transdermal drug delivery, this sector of the pharmaceutical industry is relatively small. There are many well-documented benefits of this delivery route however, and as a result there is great interest in increasing the number of therapeutic substances that can be delivered transdermally.

Areas Covered: This review discusses the various transdermal products that are currently/have been marketed, and the paths that led to their success, or lack of. Both passive and active transdermal technologies are considered with the advantages and limitations of each highlighted. In addition to marketed products, technologies that are in the investigative stages by various pharmaceutical companies are reviewed.

Expert Opinion: Passive transdermal drug delivery has made limited progress in recent years, however with the ongoing intense research into active technologies, there is great potential for growth within the transdermal delivery market. A number of active technologies have already been translated into marketed products, with other platforms including microneedles, rapidly progressing towards commercialisation.     

弹性脂质囊泡在经皮给药系统的研究进展

目的 对近年来弹性脂质囊泡在经皮给药系统的研究与应用进行文献整理和归纳,为以后该领域的研究提供借鉴。方法 查阅近5年弹性脂质囊泡在经皮给药系统的相关文献,总结弹性脂质囊泡的分类、制备方法、促透机制、应用的研究进展,提出其今后研究的重点方向。结果 弹性脂质囊泡具有较好的变形性、皮肤渗透性,可以通过角质层,更利于药物到达毛细血管被吸收,提高生物利用度,更有利于皮肤用药。结论 弹性脂质囊泡经皮给药系统是一种安全、有效的给药途径,其顺应性更好,在经皮给药方面有很好的应用前景。     

Biomedical applications of microneedles in therapeutics: recent advancements and implications in drug delivery

Introduction: The skin, as the largest organ, is a better option for drug delivery in many diseases. However, most transdermal delivery is difficult due to the low permeability of therapeutics across the various skin layers. There have been many innovations in transdermal drug delivery to enhance the therapeutic efficacy of the drugs administered. Microneedles (MN), micron sized needles, are of great interest to scientists as a new therapeutic vehicle through transdermal routes, especially for vaccines, drugs, small molecules, etc.

Areas covered: This review covers new insights into different types of MNs such as solid, hollow, coated and dissolving MNs (SMNs, HMNs, CMNs, and DMNs) for selected biomedical applications in detail. Specific focus has been given to CMNs and DMNs for vaccine and drug delivery applications with recent developments in new MNs covered.

Expert opinion: This review explores the feasibility of innovative MNs used as a drug delivery carrier. Because most of the SMNs and HMNs have many limitations, it is difficult to achieve therapeutic efficacy. Therefore, many scientists are investigating functional modifications of MNs through covalent and non-covalent methods, especially for CMNs and DMNs. The biomedical applications of MNs are growing and new exciting improvements could be achieved, thus resulting in better micro/nano technologies in the near future.     

Chemical permeation enhancers for transbuccal drug delivery

Importance of the field: The buccal drug delivery system has been accepted as a potential non-invasive route of drug administration, with the advantages of avoidance of the first-pass metabolism, sustained therapeutic action and better patient compliance. However, transmucosal delivery of drugs by means of the buccal route is still very challenging. The main obstacles derive from the limited absorption area and from the barrier properties of the mucosa that have to be overcome for successful delivery drug molecules to the systemic circulation by this route.

Areas covered in this review: One long-standing approach for improving buccal drug delivery uses buccal absorption promoters, also called permeation enhancers. This requisite has fostered the study of permeation enhancers that will safely alter the permeability restrictions of the buccal mucosa. This review includes various classes of transmucosal chemical permeation enhancers and their mechanism of action. As enhancers influence drug delivery, further exploration of these compounds is required to understand their modifying action on the properties of buccal mucosa.

What the reader will gain: This review will help the readers in the selection of a suitable enhancer(s) for improving the buccal drug delivery for future endeavor.

Take home message: The authors imagine new buccal formulations bearing permeation enhancer(s) being commercialized in the coming years.     

Lasers as an approach for promoting drug delivery via skin

Introduction: Using lasers can be an effective drug permeation-enhancement approach for facilitating drug delivery into or across the skin. The controlled disruption and ablation of the stratum corneum (SC), the predominant barrier for drug delivery, is achieved by the use of lasers. The possible mechanisms of laser-assisted drug permeation are the direct ablation of the skin barrier, optical breakdown by a photomechanical wave and a photothermal effect. It has been demonstrated that ablative approaches for enhancing drug transport provide some advantages, including increased bioavailability, fast treatment time, quick recovery of SC integrity and the fact that skin surface contact is not needed. In recent years, the concept of using laser techniques to treat the skin has attracted increasing attention.

Areas covered: This review describes recent developments in using nonablative and ablative lasers for drug absorption enhancement. This review systematically introduces the concepts and enhancement mechanisms of lasers, highlighting the potential of this technique for greatly increasing drug absorption via the skin. Lasers with different wavelengths and types are employed to increase drug permeation. These include the ruby laser, the erbium:yttrium-gallium-garnet laser, the neodymium-doped yttrium-aluminum-garnet laser and the CO₂ laser. Fractional modality is a novel concept for promoting topical/transdermal drug delivery. The laser is useful in enhancing the permeation of a wide variety of permeants, such as small-molecule drugs, macromolecules and nanoparticles.

Expert opinion: This potential use of the laser affords a new treatment for topical/transdermal application with significant efficacy. Further studies using a large group of humans or patients are needed to confirm and clarify the findings in animal studies. Although the laser fluence or output energy used for enhancing drug absorption is much lower than for treatment of skin disorders and rejuvenation, the safety of using lasers is still an issue. Caution should be used in optimizing the feasible conditions of the lasers in balancing the effectiveness of permeation enhancement and skin damage.     

Macromolecules as Novel Transdermal Transport Enhancers for Skin Electroporation

Purpose. Macromolecules were investigated as chemical enhancers of transdermal transport by skin electroporation. Although unable to enhance passive or iontophoretic transport, macromolecules are proposed to enhance electroporation-assisted delivery by stabilizing the increased permeability caused by high-voltage pulses. Methods. To test this hypothesis, we examined the timescale of transport, the influence of electrical protocol and the influence of macromolecule size, structure, and charge on enhancement of transdermal mannitol transport in vitro by heparin, dextran-sulfate, neutral dextran, and poly-lysine. Results. Skin electroporation increased transdermal mannitol delivery by approximately two orders of magnitude. The addition of macromolecules further increased transport up to five-fold, in support of the proposed hypothesis. Macromolecules present during pulsing enhanced mannitol transport after pulsing for hours, apparently by a macromolecule-skin interaction. No enhancement was observed during passive diffusion or low-voltage iontophoresis, suggesting that macromolecules interact specifically with transport pathways created at high voltage. Although all macromolecules studied enhanced transport, those with greater charge and size were more effective. Conclusions. This study demonstrates that macromolecules can be used as trandermal transport enhancers uniquely suited to skin electroporation.     

Permeation enhancer strategies in transdermal drug delivery

Abstract

Today, ～74% of drugs are taken orally and are not found to be as effective as desired. To improve such characteristics, transdermal drug delivery was brought to existence. This delivery system is capable of transporting the drug or macromolecules painlessly through skin into the blood circulation at fixed rate. Topical administration of therapeutic agents offers many advantages over conventional oral and invasive techniques of drug delivery. Several important advantages of transdermal drug delivery are prevention from hepatic first pass metabolism, enhancement of therapeutic efficiency and maintenance of steady plasma level of the drug. Human skin surface, as a site of drug application for both local and systemic effects, is the most eligible candidate available. New controlled transdermal drug delivery systems (TDDS) technologies (electrically-based, structure-based and velocity-based) have been developed and commercialized for the transdermal delivery of troublesome drugs. This review article covers most of the new active transport technologies involved in enhancing the transdermal permeation via effective drug delivery system.     

Site-specific drug delivery in the skin for the localized treatment of skin diseases

ABSTRACT

Introduction: Due to the well-organized structure and barrier function of the skin, it is generally difficult for drugs applied directly on the surface of skin to reach their expected site of action. Accordingly, site-specific drug delivery in the skin has been increasingly explored to facilitate the treatment of skin diseases and reduce the systemic toxicity.

Area covered: An overview of the generally used sites for drug delivery in the skin is herein presented. Different strategies including particle-based carriers, physical technologies, and chemical approaches are discussed with regards to their potential application in site-specific drug delivery in the skin.

Expert opinion: Particle-based carriers are of particular significance for the enhancement of drug delivery in the skin. Although no recommendation can be made regarding which type of carriers can provide better skin penetration, the lipid-based colloidal systems appear to be favored due to their compatibility. In addition, the physical technologies provide unique advantages in delivering hydrophilic macromolecules for the skin immunization. As a new class of permeation enhancers, skin penetrating peptides are gaining more attention in drug delivery to skin cells. For the design of robust site-specific drug delivery systems, the impacts of diseased state and drug properties should not be disregarded.     

A Theoretical Analysis of Low-Frequency Sonophoresis: Dependence of Transdermal Transport Pathways on Frequency and Energy Density

Purpose. Application of low-frequency ultrasound has been shown to increase skin permeability, thereby facilitating delivery of macromolecules (low-frequency sonophoresis). In this study, we seek to determine the dependence of transport pathways during low-frequency sonophoresis on ultrasound parameters. Methods. Pig skin is exposed to low-frequency ultrasound over a range of frequencies to achieve different skin resistivities. The porous pathway model is used to study the dependence of average pore size, porosity, and tortuosity on ultrasound parameters. Imaging experiments are also carried out to visualize the transport pathways created by ultrasound. Results. The data show that the average pore size, determined from the porous pathway model, does not depend on application frequency. Both in the presence and absence of ultrasound the average pore size determined from mannitol delivery is the same (28 ± 12 Å). With the application of ultrasound the skin porosity could be increased by up to 1700-fold. The effect of ultrasound on skin is heterogeneous thereby creating localized transport pathways (LTP). The porosity of these transport pathways is of the same order of magnitude as that of the dermis. Conclusions. With this study it is shown that low-frequency ultrasound increases skin permeability by increasing skin porosity rather than by increasing the size of the pores that are responsible for permeant delivery.     

Emerging trend in nano-engineered polyelectrolyte-based surrogate carriers for delivery of bioactives

Importance of the field: In recent decades a new colloidal drug delivery system based on layer-by-layer (LbL) technology has emerged, which offers promising means of delivering bioactive agents, specifically biological macromolecules including peptides and DNA. Nano-engineered capsules specifically fabricated from biocompatible and biodegradable polyelectrolytes (PEs) can provide a better option for encapsulation of cells thereby protecting cells from immunological molecules in the body, and their selective permeability can ensure the survival of encapsulated cells.

Areas covered in this review: This review encompasses a strategic approach to fabricate nano-engineered microcapsules through meticulous selection of polyelectrolytes and core materials based on LbL technology. The content of the article provides evidence for its wide array of applications in medical therapeutics, as indicated by the quantity of research and patents in this area. Recent developments and approaches for tuning drug release, biocompatibility and cellular interaction are discussed thoroughly.

What the reader will gain: This review aims to provide an overview on the development of LbL capsules with specific orientation towards drug and macromolecular delivery and its integration with other drug delivery systems, such as liposomes.

Take home message: Selection of PEs for the fabrication of LbL microcapsules has a profound effect on stability, drug release, biocompatibility and encapsulation efficacy. The release can be easily modulated by varying different physicochemical as well as physiological conditions. Scale-up approaches for the fabrication of LbL microcapsules by means of automation must be considered to improve the possibility of application of LbL microcapsules on a large scale.     

Nanoemulsions as potential vehicles for transdermal and dermal delivery of hydrophobic compounds: an overview

Introduction: In recent years, nanoemulsions have been investigated as potential drug delivery vehicles for transdermal and dermal delivery of many compounds especially hydrophobic compounds in order to avoid clinical adverse effects associated with oral delivery of the same compounds. Droplet size and surface properties of nanoemulsions play an important role in the biological behavior of the formulation.

Areas covered: In this review, current literature of transdermal and dermal delivery of hydrophobic compounds both in vitro as well as in vivo has been summarized and analyzed.

Expert opinion: Nanoemulsions have been formulated using a variety of pharmaceutically acceptable excipients. In many cases of dermal and transdermal nanoemulsions, the skin irritation or skin toxicity issues on human beings have not been considered which needs to be evaluated properly. In the last decade, much attention has been made in exploring new types of nanoemulsion-based drug delivery system for dermal and transdermal delivery of many hydrophobic compounds. This area of research would be very advantageous for formulation scientists in order to develop some nanoemulsion-based formulations for their commercial exploitation and clinical applications.     

Advances in oral macromolecular drug delivery

Introduction: Various macromolecules including polypeptides, proteins, genes and polysaccharides have been drawing attention for their therapeutic potential. The passage through intestinal epithelium is the major barrier for the oral delivery of macromolecules, by either paracellular or transcellular pathways. However, most macromolecules are poorly absorbed in oral route due to their high molecular weight and low stability in the gastrointestinal (GI) tract. Nonetheless, advancing in oral macromolecular drug delivery will be significant in expanding the clinical use of therapeutic macromolecules.

Areas covered: Technologies using chemical conjugation, absorption enhancers and nano-/micro-particulate systems have been developed to improve oral bioavailability of macromolecules, and some of them are in the process of clinical trials. In this review, they are discussed in the context of their progression states, hurdles and modes of action.

Expert opinion: According to the better understanding of receptor or transporter structure and transport mechanisms in the GI tract, the progress ineffective oral delivery systems for therapeutic macromolecules is anticipated over the next decades. In addition, the advent of numerous particulate systems will also speed up the development of novel drug delivery technologies. This offers an optimistic perspective on the potential clinical usage of oral macromolecular drugs.     

Microstructured bicontinuous phase formulations: their characterization and application in dermal and transdermal drug delivery

Introduction: The development of approaches to increase drug solubility and partitioning into the skin is an active area of research in topical and transdermal delivery. In addition to forming spherical aggregates, e.g., conventional oil in water or water in oil microemulsions, the combination of an oil, surfactant and water can create bicontinuous structures where the self-assembly properties of surfactants mean that the boundaries between oil and water are no longer random. This leads to the formation of specific microstructures whose intrinsic properties and interactions with the drug will determine the ability to formulate a given drug, its stability once formulated and its subsequent delivery.

Areas covered: The review explores the relationship between the microstructure of biphasic formulations, present in microemulsions and liquid crystalline phases, and drug delivery into the skin. An overview of possible internal microstructures is followed by a summary of the methods used for structure characterization. The final section presents the work to-date and discusses the efficacy of such vehicles in enhancing dermal and transdermal delivery.

Expert opinion: The combination of water, surface agent and oil generates a broad range of three dimensional structures differing in both chemical and physical proprieties. Knowledge of the microstructure is important in understanding the behavior of a formulation and its effect on drug delivery into the skin. Microstructure complexity, interactions between the drug and the vehicle (i.e., location and mobility) and those between the vehicle and the skin are key determinants of drug delivery.     

Skin tolerability of transdermal patches

Introduction: Transdermal patch systems are an effective method of administering active ingredients through the skin, with considerable advantages over other drug delivery routes, for example, maintenance of constant plasma drug levels and avoidance of first-pass metabolism. However, repeated epicutaneous application may be associated with local skin reactions.

Areas covered: This review addresses current issues regarding the effective/safe use of transdermal patch systems, and provides a critical analysis of the addition of ‘skin-caring’ ingredients to patch systems. Effective use of transdermal systems includes choosing an appropriate body area for application, maintaining regular skin care regimens before application and not replacing a patch in the same area (rotation) within 7 days. Another strategy, developed in an attempt to improve the tolerability of transdermal systems, is the addition of assumed ‘skin-caring’ ingredients (e.g., Aloe Vera) to patch systems. However, at present there is neither proof nor clinical evidence of any benefit. On the contrary, plant-derived ingredients might be associated with allergenic potential.

Expert opinion: Transdermal systems are generally well tolerated; physicians must adequately inform patients of the most effective ways to use these formulations for maximum therapeutic benefit, while minimising local adverse events. Skin-caring agents, including Aloe Vera, cannot be recommended until well-controlled clinical trials with standardised extracts are available.     

Dependence of Skin Permeability on Contact Area

Purpose. We report that experimentally measured skin permeability to hydrophilic solutes increases with decreasing contact area between the formulation and the skin. Our results suggest that an array of smaller reservoirs should thus be more effective in increasing transdermal drug delivery compared to a large single reservoir of the same total area. Methods. Experimental assessment of the dependence of skin permeability on reservoir size was performed using two model systems, an array of liquid reservoirs with diameters in the range of 2 mm to 6 mm and an array of gel disk reservoirs with diameters in the range of 3 mm to 16 mm. Full thickness pig skin was used as an experimental model. Two molecules, sodium lauryl sulfate (SLS) and oleic acid, were used as model penetration enhancers. Results. Mannitol transport per unit area into and across the skin increased with a decrease in the contact area between the skin and the formulation. Mannitol permeability increased approximately 6-fold with a decrease in the reservoir size from 16 mm to 3 mm in presence of 0.5% SLS in PBS (phosphate buffered saline) as a permeability enhancer. Similar results were obtained when oleic acid was used as an enhancer. Conclusions. To explain the observed dependence of transdermal transport on contact area a simple mathematical model based on skin geometry in the reservoir was developed. The model predicts a lateral strain in the skin due to preferential swelling of skin upon penetration of water. We propose that this lateral strain is responsible for the increased skin permeability at lower reservoir sizes.