Penetration enhancement of transdermal delivery--current permutations and limitations

In order to achieve enhanced topical drug delivery, it is necessary to make physical or biomolecular structural alterations to the stratum corneum by suitable techniques or by the use of specific chemical agents or drug carriers. The role of the chemical penetration enhancer is to reversibly alter the barrier properties of the stratum corneum by disruption of the membrane structures or by maximizing drug solubility within the skin. Alternatively, permeant delivery to the dermal vasculature using one of several physical methods to reduce diffusional resistance within the skin may be used to promote drug penetration. In the present article, we summarize the major facets of the diverse spectrum of penetration enhancement techniques that include modification of the stratum corneum, lipid-based delivery systems, drug/vehicle interactions, bypassing the stratum corneum, and electrical techniques of enhancement.     

Non-invasive administration of drugs through the skin: challenges in delivery system design

Vehicles designed to enhance drug delivery through the skin must incorporate specific elements that improve the ability of the delivery system to overcome the barrier posed by the stratum corneum. This review discusses several chemical penetration enhancers that have been investigated as potential tools to increase drug flux. In addition, lipid-based delivery systems offer an attractive alternative to traditional drug vehicles. The relationship between liposome composition and drug permeation is discussed, in addition to the possible mechanism of action of lipid vesicle-mediated drug delivery.     

Virtual design of chemical penetration enhancers for transdermal drug delivery

Traditional drug design is a laborious and expensive process that often challenges the pharmaceutical industries. As a result, researchers have turned to computational methods for computer-assisted molecular design. Recently, genetic and evolutionary algorithms have emerged as efficient methods in solving combinatorial problems associated with computer-aided molecular design. Further, combining genetic algorithms with quantitative structure-property relationship analyses has proved effective in drug design. In this work, we have integrated a new genetic algorithm and nonlinear quantitative structure-property relationship models to develop a reliable virtual screening algorithm for the generation of potential chemical penetration enhancers. The genetic algorithms-quantitative structure-property relationship algorithm has been implemented successfully to identify potential chemical penetration enhancers for transdermal drug delivery of insulin. Validation of the newly identified chemical penetration enhancer molecular structures was conducted through carefully designed experiments, which elucidated the cytotoxicity and permeability of the chemical penetration enhancers.     

Imaging drug delivery to skin with stimulated Raman scattering microscopy

Efficient drug delivery to the skin is essential for the treatment of major dermatologic diseases, such as eczema, psoriasis and acne. However, many compounds penetrate the skin barrier poorly and require optimized formulations to ensure their bioavailability. Here, stimulated Raman scattering (SRS) microscopy, a recently developed, label-free chemical imaging tool, is used to acquire high resolution images of multiple chemical components of a topical formulation as it penetrates into mammalian skin. This technique uniquely provides label-free, nondestructive, three-dimensional images with high spatiotemporal resolution. It reveals novel features of (trans)dermal drug delivery in the tissue environment: different rates of drug penetration via hair follicles as compared to the intercellular pathway across the stratum corneum are directly observed, and the precipitation of drug crystals on the skin surface is visualized after the percutaneous penetration of the cosolvent excipient in the formulation. The high speed three-dimensional imaging capability of SRS thus reveals features that cannot be seen with other techniques, providing both kinetic information and mechanistic insight into the (trans)dermal drug delivery process.     

微针与新型经皮给药载体结合的研究进展

经皮给药系统具有给药方便、血药浓度稳定、无首过效应等优点,但皮肤的屏障作用使得药物难以透过皮肤。近年来,出现了很多新型经皮给药的药物载体,如脂质体、醇质体、囊泡等,这些能通过化学方法促进药物的经皮渗透。而微针能穿透皮肤角质层形成微孔通道,通过物理方法促进药物的渗透,将微针与新型经皮给药载体结合能显著提高药物的经皮吸收的速率。本文对微针与新型经皮给药载体结合的最新研究进行了综述,并展望了微针辅助新型药物载体经皮给药的发展前景。     

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.     

驻极体及联用氮酮对环孢菌素A的体外透皮促渗作用

目的研究驻极体及联用氮酮对环孢菌素A的体外透皮促渗作用。方法采用常温电晕充电的-500V,-1 000 V、-2 000 V聚丙烯为驻极体,1%、3%、5%的氮酮为化学促渗剂,利用透皮实验仪和HPLC,研究驻极体、氮酮以及驻极体联用氮酮对环孢菌素A溶液的透皮促渗作用。结果不同表面电压的驻极体以及不同浓度的氮酮均能提高环孢菌素A的累积渗透量;-1 000 V驻极体与1%氮酮联用,环孢菌素A的累积渗透量较1%氮酮单独使用略有提高。结论负极性驻极体、氮酮对环孢菌素A均有促渗作用,负极性驻极体与氮酮联用对环孢菌素A没有明显联合促渗作用。     

Ocular prodrugs: Attributes and challenges

Ocular drug delivery is one of the most attention-grabbing and challenging endeavors among the numerous existing drug delivery systems. From a drug delivery point of view, eye is an intricate organ to investigate and explore. In spite of many limitations, advancements have been made with the intention of improving the residence time or permeation of the drug in the ocular region. Poor bioavailability of topically administered drugs is the major issue pertaining to ocular drug delivery. Several efforts have been made towards improving precorneal residence time and corneal penetration, e.g. iontophoresis, prodrugs and ion-pairing, etc. Prodrug approach (chemical approach) has been explored by the formulation scientists to optimize the physicochemical and biochemical properties of drug molecules for improving ocular bioavailability. Formulation of ocular prodrugs is a challenging task as they should exhibit optimum chemical stability as well as enzymatic liability so that they are converted into parent drug after administration at the desired pace. This review will encompass the concept of derivatization and recent academic and industrial advancements in the field of ocular prodrugs. The progression in prodrug designing holds a potential future for ophthalmic drug delivery.     

Dermal peptide delivery using colloidal carrier systems

The advancement in synthetic and molecular biology techniques over the past years has resulted in the application of peptides or peptide-like drugs becoming a growing field in therapeutics. Because of the unfavorable chemical properties of peptides, it poses a challenge to find an optimized way of drug administration. The transdermal route has attracted interest as a promising way to advance the delivery of these drugs. The objective of this review is to summarize the level of research of microemulsions as colloidal carrier for dermal peptide drug delivery. The presented studies resulted in enhanced drug delivery or superior penetration profiles of peptides incorporated in microemulsions in comparison to conventional vehicles. Due to their benefits like high solubilization capacity, enhanced drug delivery, noninvasive administration or easy preparation, microemulsions offer a suitable vehicle for dermal and transdermal drug delivery.     

Role of complexes formation between drugs and penetration enhancers in transdermal delivery

The use of chemical penetration enhancers (CPE) is growing due to their ability to improve drug delivery through the skin. A possible mechanism of penetration enhancement could involve the complex formation between drug and components in the pharmaceutical formulation, thus altering the physicochemical properties of the active substance. Here, modelling studies indicate that hydrocarbon and oxygen-containing terpenes (penetration enhancers) could form complexes with drugs. Satisfactory correlations have been obtained between the predicted molecular properties of enhancers and their enhancement effects.     

皮肤给药的经皮吸收与测量技术研究进展

经皮给药系统（TDDS）可避免首关效应、胃肠道破坏，为新型皮肤给药系统，可通过控制释放而延长治疗效果，成为药物制剂开发研究的热点之一。但是，药物的理化性质以及皮肤屏障影响药物的经皮吸收。综述了TDDS常用的促渗透技术，包括化学、物理、纳米、天然促渗透技术；介绍了促渗透能力的测定方法，包括体外、离体和体内评估皮肤渗透性的方法。通过对经皮药物递送系统和经皮吸收能力测定方法的归纳与总结，以期为TDDS的合理使用和快速发展提供参考。     

Structure-activity relationship of chemical penetration enhancers in transdermal drug delivery

Transdermal drug delivery (TDD) is the administration of therapeutic agents through intact skin for systemic effect. TDD offers several advantages over the conventional dosage forms such as tablets, capsules and injections. Currently there are about eight drugs marketed as transdermal patches. Examples of such products include nitroglycerin (angina pectoris), clonidine (hypertension), scopolamine (motion sickness), nicotine (smoking cessation), fentanil (pain) and estradiol (estrogen deficiency). Since skin is an excellent barrier for drug transport, only potent drugs with appropriate physicochemical properties (low molecular weight, adequate solubility in aqueous and non-aqueous solvents, etc) are suitable candidates for transdermal delivery. Penetration enhancement technology is a challenging development that would increase significantly the number of drugs available for transdermal administration. The permeation of drugs through skin can be enhanced by physical methods such as iontophoresis (application of low level electric current) and phonophoresis (use of ultra sound energy) and by chemical penetration enhancers (CPE). In this review, we have discussed about the CPE which have been investigated for TDD. CPE are compounds that enhance the permeation of drugs across the skin. The CPE increase skin permeability by reversibly altering the physicochemical nature of the stratum corneum, the outer most layer of skin, to reduce its diffusional resistance. These compounds increase skin permeability also by increasing the partition coefficient of the drug into the skin and by increasing the thermodynamic activity of the drug in the vehicle. This review compiles the various CPE used for the enhancement of TDD, the mechanism of action of different chemical enhancers and the structure-activity relationship of selected and extensively studied enhancers such as fatty acids, fatty alcohols and terpenes. Based on the chemical structure of penetration enhancers (such as chain length, polarity, level of unsaturation and presence of some special groups such as ketones), the interaction between the stratum corneum and penetration enhancers may vary which will result in significant differences in penetration enhancement. Our review also discusses the various factors to be considered in the selection of an appropriate penetration enhancer for the development of transdermal delivery systems.     

Transdermal drug delivery: penetration enhancement techniques

There is considerable interest in the skin as a site of drug application both for local and systemic effect. However, the skin, in particular the stratum corneum, poses a formidable barrier to drug penetration thereby limiting topical and transdermal bioavailability. Skin penetration enhancement techniques have been developed to improve bioavailability and increase the range of drugs for which topical and transdermal delivery is a viable option. This review describes enhancement techniques based on drug/vehicle optimisation such as drug selection, prodrugs and ion-pairs, supersaturated drug solutions, eutectic systems, complexation, liposomes, vesicles and particles. Enhancement via modification of the stratum corneum by hydration, chemical enhancers acting on the structure of the stratum corneum lipids and keratin, partitioning and solubility effects are also discussed. The mechanism of action of penetration enhancers and retarders and their potential for clinical application is described.     

Status of terpenes as skin penetration enhancers

Since its introduction, transdermal drug delivery has promised much but, in some respects has still to deliver on that initial promise, due to inherent limitations imposed by the percutaneous route. The greatest obstacle for transdermal delivery is the barrier property of the stratum corneum. Many approaches have been employed to breach the skin barrier, of which, the most widely used one is that of chemical penetration enhancers. Of the penetration enhancers, terpenes are arguably the most highly advanced and proven category and are classified as generally regarded as safe (GRAS) by the Food and Drug Administration. This paper presents an overview of the investigations on the feasibility and application of terpenes as sorption promoters for improved delivery of drugs through skin.     

微针的特点及其在黄褐斑治疗中的应用研究分析

黄褐斑是一种后天获得性色素沉着性疾病，困扰患者的工作和生活。外用经皮给药的主要挑战是药物透过角质层屏障的阻碍。微针作为物理促渗方法和新的递药系统，能够穿透角质层形成特定的药物输送通道，促进了药物的渗透，提高了药物的生物利用度。本文主要总结了微针的特点，并以黄褐斑为切入点，分析微针近年来在黄褐斑领域的应用研究，为后续黄褐斑微针产品的开发提供一定的参考。     

Enhancement of transdermal drug delivery: chemical and physical approaches

Transdermal drug delivery has been intensively studied over the last two decades because of the many advantages offered by this route of administration. However, the number of drugs used in transdermal drug delivery systems has been somewhat limited, in part resulting from the formidable barrier to drug permeation presented by the upper layer of the skin, the stratum corneum. In order to overcome this, different strategies have been implemented to render the skin more permeable to drugs. These strategies include both chemical and physical approaches. In this review, we outline the enhancing activities and mechanisms of action of some of the more extensively studied chemical penetration enhancers (oxazolidinones, propylene glycol, and epidermal enzymes). In addition, we discuss novel physical strategies, such as the use of microneedles or electroporation.     

Chemical modification and formulation approaches to elevated drug transport across cell membranes

Drug delivery across cellular barriers, such as intestinal, nasal, buccal, alveolar, vaginal, ocular and blood-brain, is a challenging task. Multiple physiological mechanisms, such as cellular organisation, efflux, and chemical and enzymatic degradation, as well as physicochemical properties of the drug molecule itself, determine the penetration of xenobiotics across epithelial cell layers. Limited intestinal absorption of many novel and highly potent lead compounds has stimulated an intense search for strategies that can effectively enhance permeation across these biological barriers. This review discusses some of the approaches that have been, and are currently being, investigated for transepithelial drug delivery. Transdermal drug delivery requires a separate discussion on its own and is thus outside the scope of this review article.     

Penetration enhancer-containing vesicles (PEVs) as carriers for cutaneous delivery of minoxidil: in vitro evaluation of drug permeation by infrared spectroscopy

Recently, we carried out a research on new liposomal systems prepared by using in their composition a few penetration enhancers which differ for chemical structure and physicochemical properties. The penetration enhancer-containing vesicles (PEVs) were prepared by using soy lecithin and different amounts of three penetration enhancers, 2-(2-ethoxyethoxy) ethanol (Transcutol^®), capryl-caproyl macrogol 8-glyceride (Labrasol^®), and cineole.To study the influence of the PEVs on (trans)dermal delivery of minoxidil, in vitro diffusion experiments were performed through new born pig skin and the results were compared with that obtained applying the vesicular system without enhancer (control) after pretreatment of the skin with the various enhancers. In this study, Fourier transform infrared spectroscopy (FTIR), attenuated total reflectance FTIR (ATR-FTIR) and FTIR imaging were used to evaluate the effective penetration of minoxidil in the skin layers and to discover the influence of the enhancer on the drug topical delivery. These analytical studies allowed us to characterize the drug formulations and to evaluate the vesicle distribution into the skin. Recorded spectra confirmed that the vesicle formulations with penetration enhancers promoted drug deposition into the skin.     

Drug delivery strategies for the treatment of malignant gliomas

As primary brain tumors, malignant gliomas are known to be one of the most insidious types of brain cancer afflicting the humans. The current standard strategy for the treatment of malignant gliomas includes the surgical resection of the tumor when possible, followed by a combination of radiotherapy and/or a certain chemotherapeutic protocol. However, due to the short mean survival, frequent recurrences, and poor prognosis associated with the tumors, new therapeutic strategies are investigated consecutively. These novel drug delivery approaches can be subdivided as systemic and local drug administration. This review focuses on localized drug delivery strategies for the treatment of malignant gliomas, including the injections, infusions, trans-nasal delivery systems, convection enhanced delivery (CED) systems, and various types of polymeric implants. Furthermore, systemic strategies to increase the drug penetration into the brain, such as temporary disruption of the blood brain barrier (BBB), chemical modification of the available therapeutic substances, and utilization of endogenous transport systems will be briefly discussed.     

离子电渗给药技术研究进展

离子电渗技术作为一种非入侵性、成熟的物理促渗方式,能有效解决药物经皮肤、角膜和黏膜转运速率低下和吸收量少的难题。相比其他促透方式而言,具有给药效率高和递送剂量可控等优势。本文介绍了该技术的装置组成、促渗机制以及影响因素,然后分析了近年来离子电渗技术在医药科学领域的应用方向,得出该技术可广泛用于小分子乃至大分子蛋白药物的递送及医疗诊断与监测的研究领域。同时本文简述了该技术与其他促渗方式联合应用的实例,表明联合促渗技术可起到药物跨屏障递送的协同作用,大幅度提高给药效率。虽然离子电渗给药技术现阶段仍存在设备要求高、用药成本高等问题,但其较高的医疗价值与良好的市场前景将会进一步推动该技术继续发展。