Skin permeabilization for transdermal drug delivery: recent advances and future prospects

Introduction: Transdermal delivery has potential advantages over other routes of administration. It could reduce first-pass metabolism associated with oral delivery and is less painful than injections. However, the outermost layer of the skin, the stratum corneum (SC), limits passive diffusion to small lipophilic molecules. Therefore, methods are needed to safely permeabilize the SC so that ionic and larger molecules may be delivered transdermally.

Areas covered: This review focuses on low-frequency sonophoresis, microneedles, electroporation and iontophoresis, and combinations of these methods to permeabilize the SC. The mechanisms of enhancements and developments in the last 5 years are discussed. Potentially high-impact applications, including protein delivery, vaccination and sensing are presented. Finally, commercial interest and clinical trials are discussed.

Expert opinion: Not all permeabilization methods are appropriate for all applications. Focused studies into applications utilizing the advantages of each method are needed. The total dose and kinetics of delivery must be considered. Vaccination is one application where permeabilization methods could make an impact. Protein delivery and analyte sensing are also areas of potential impact, although the amount of material that can be delivered (or extracted) is of critical importance. Additional work on the miniaturization of these technologies will help to increase commercial interest.     

Dermal and transdermal delivery: prodrugs

Attempts to deliver drugs into and through the skin (dermal and transdermal delivery) have not been very successful because the physicochemical properties of drugs are often not optimal. Prodrugs can be used to optimize those physicochemical properties of drugs and optimize their delivery by transiently masking their polar functional groups. For a drug to cross the rate-limiting barrier to delivery (the stratum corneum) it must dissolve in and cross multiple lipid and aqueous phases within the stratum corneum. Prodrugs can be designed to exhibit increased lipid and aqueous solubilities resulting in increased delivery. In order to identify the optimal prodrugs, they must be evaluated as saturated solutions where their thermodynamic activities are maximal in the solution and in the skin. If prodrugs are evaluated at concentrations less than at saturation, inaccurate conclusions about the optimal physicochemical properties may result. Prodrugs must be designed to optimize both their lipid and aqueous solubilities to optimize their delivery into and through the skin.     

Clinical efficacy of current transdermal drug delivery systems: a retrospective evaluation

In spite of intensive research on transdermal drug delivery systems (TDDSs), only four--nitroglycerin, clonidine, estradiol, and scopolamine--have reached the market, and the clinical effectiveness of these systems has yet to be clearly demonstrated. Ideally, a candidate for transdermal drug delivery should demonstrate clinical significance within a wide therapeutic range for a well-documented indication for use. Continuous administration of a drug should result in better control of the disease with fewer side effects and a marked increase in patient compliance than when traditional dosage forms are used. It appears that nitroglycerin is a poor candidate for transdermal drug delivery by virtue of the ambiguity associated with its clinical pharmacology, substantial interpatient variation in dose-response relationship, and development of tolerance with potential toxicity risks in chronic administration. Clonidine's well-defined indication for use coupled with its high potency and low molecular weight with high lipid solubility is well suited to transdermal therapy. Because estradiol is unsuitable for use in people who smoke and has dermatotoxic potential, it is a marginal candidate for use in TDDSs. Transdermal scopolamine was not reviewed because it is a unique entity (no conventional dosage forms of this product are available) intended for short-term use. Its use is dictated more by the patient's unique circumstances, such as travel requirements, than by physiological condition. Although TDDSs provide a convenient and effective means of administering medications, the aforementioned clinical constraints need to be evaluated in depth before more widespread application of TDDSs can be recommended. In particular; conclusive demonstration of biocompatibility of a TDDS is warranted.     

Passive transdermal drug delivery systems

The skin has evolved as a formidable barrier against invasion by external microorganisms and against the prevention of water loss. Notwithstanding this, transdermal drug delivery systems have been designed with the aim of providing continuous controlled delivery of drugs via this barrier to the systemic circulation. There are numerous systems now available that effectively deliver drugs across the skin. These include reservoir devices, matrix diffusion-controlled devices, multiple polymer devices, and multilayer matrix systems. This review article focuses on the design characteristics and composition of the main categories of passive transdermal delivery device available. Mechanisms controlling release of the active drug from these systems as well as patch size and irritation problems will be considered. Recent developments in the field are highlighted including advances in patch design as well as the increasing number of drug molecules now amenable to delivery via this route. From the early complex patch designs, devices have now evolved towards simpler, matrix formulations. One of the newer technologies to emerge is the delivery-optimized thermodynamic (DOT) patch system, which allows greater drug loading to be achieved in a much smaller patch size. With the DOT technology, drug is loaded in an acrylic-based adhesive. The drug/acrylic blend is dispersed through silicone adhesive, creating a semi-solid suspension. This overcomes the problem with conventional drug-in-adhesive matrix patches, in which a large drug load in the adhesive reservoir can compromise the adhesive properties or necessitate a large patch size. Transdermal drug delivery remains an attractive and evolving field offering many benefits over alternative routes of drug delivery. Future developments in the field should address problems relating to irritancy and sensitization, which currently exclude a number of therapeutic entities from delivery via this route. It is likely that further innovations in matrix composition and formulation will further expand the number of candidate drugs available for transdermal delivery.     

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.     

Current status and future potential of transdermal drug delivery

The past twenty five years have seen an explosion in the creation and discovery of new medicinal agents. Related innovations in drug delivery systems have not only enabled the successful implementation of many of these novel pharmaceuticals, but have also permitted the development of new medical treatments with existing drugs. The creation of transdermal delivery systems has been one of the most important of these innovations, offering a number of advantages over the oral route. In this article, we discuss the already significant impact this field has made on the administration of various pharmaceuticals; explore limitations of the current technology; and discuss methods under exploration for overcoming these limitations and the challenges ahead.     

Pressure-sensitive adhesives for transdermal drug delivery systems

Adhesives are a critical component in transdermal drug delivery (TDD) devices. In addition to the usual requirements of functional adhesive properties, adhesives for TDD applications must have good biocompatibility with the skin, chemical compatibility with the drug, various components of the formulation, and provide consistent, effective delivery of the drug. This review discusses the three most commonly used adhesives (polyisobutylenes, polyacrylates and silicones) in TDD devices, and provides an update on recently introduced TDD products and recent developments of new adhesives.     

Pulmonary drug delivery systems: recent developments and prospects

Targeting drug delivery into the lungs has become one of the most important aspects of systemic or local drug delivery systems. Consequently, in the last few years, techniques and new drug delivery devices intended to deliver drugs into the lungs have been widely developed. Currently, the main drug targeting regimens include direct application of a drug into the lungs, mostly by inhalation therapy using either pressurized metered dose inhalers (pMDI) or dry powder inhalers (DPI). Intratracheal administration is commonly used as a first approach in lung drug delivery in vivo. To convey a sufficient dose of drug to the lungs, suitable drug carriers are required. These can be either solid, liquid, or gaseous excipients. Liposomes, nano- and microparticles, cyclodextrins, microemulsions, micelles, suspensions, or solutions are all examples of this type of pharmaceutical carrier that have been successfully used to target drugs into the lungs. The use of microreservoir-type systems offers clear advantages, such as high loading capacity and the possibility of controlling size and permeability, and thus of controlling the release kinetics of the drugs from the carrier systems. These systems make it possible to use relatively small numbers of vector molecules to deliver substantial amounts of a drug to the target. This review discusses the drug carriers administered or intended to be administered into the lungs. The transition to CFC-free inhalers and drug delivery systems formulated with new propellants are also discussed. Finally, in addition to the various advances made in the field of pulmonary-route administration, we describe new systems based on perfluorooctyl bromide, which guarantee oxygen delivery in the event of respiratory distress and drug delivery into the lungs.     

The skin compliance of transdermal drug delivery systems

This review examines transdermal drug delivery systems (TDS) and focuses on the specific side effects they can have on the skin and how these may be avoided. After a general overview of the structure of skin and its functions, an outline is given of how TDS are composed and how they operate. Upon basic treatment of relevant skin irritation and sensitization phenomena, techniques are described for monitoring them. Subsequently, various specific skin reactions are dealt with; these can be evoked by TDS on both short- and long-term application. Suggestions are then put forward for improving the skin compliance of TDS. For example, it is proposed that hydrogel patches may prove to be a useful alternative for current systems in that they are suitable for long-term applications, having minimal side effects because they are less occlusive.     

Current landscape and trends in transdermal drug delivery systems

"Generic pharmaceutical marketers are increasingly keen to have a presence in generic patches as they represent high-margin, high entry-barrier opportunities with a smaller field of competition".     

Ethosomes: new prospects in transdermal delivery

Ethosomes are noninvasive delivery carriers that enable drugs to reach the deep skin layers and/or the systemic circulation. Although ethosomal systems are conceptually sophisticated, they are characterized by simplicity in their preparation, safety, and efficacy--a combination that can highly expand their application. Ethosomes are soft, malleable vesicles tailored for enhanced delivery of active agents. This article reviews work carried out in vitro, in vivo, in animal models, and in humans with various ethosomal systems incorporating a wide range of drugs. Because of their unique structure, ethosomes are able to encapsulate and deliver through the skin highly lipophilic molecules such as cannabinoids, testosterone, and minoxidil, as well as cationic drugs such as propranolol and trihexyphenidil. Results obtained in a double-blind two-armed randomized clinical study showed that treatment with the ethosomal acyclovir formulation significantly improved all the evaluated parameters. Preliminary studies with plasmids and insulin revealed that the ethosomal carrier may be used for enhanced delivery of these agents. In further work, the ethosomal technology was broadened to introduce agents into cultured cells and microorganisms. Enhanced delivery of bioactive molecules through the skin and cellular membranes by means of an ethosomal carrier opens numerous challenges and opportunities for the research and future development of novel improved therapies.     

Helicobacter pylori: past,current and future treatment strategies with gastroretentive drug delivery systems

Helicobacter pylori have been subject to intense investigation since its discovery from gastric biopsy in 1982. This gastropathogen has been regarded as serious public health problem due to its association with dyspepsia, gastritis, gastroduodenal ulcers, mucus-associated lymphoid tissue lymphoma and gastric carcinoma. In vivo eradication of established H. pylori infections is difficult due to several factors such as gastric niche, coccoid form due to sub-minimum inhibitory concentration of antimicrobials, bacterial load, primary antibiotic resistance, patient compliance and stability of therapeutics in gastric acid secretion. Considering these factors, a logical way to improve the outcome of the treatment is to develop dosage forms which are able to deliver the anti-helicobacter agents in the gastric niche for both local and systemic actions, simultaneously taking care of stability of therapeutics in acidic environment. Such dosage forms, which are popularly known as gastro retentive drug delivery systems (GRDDS), have the immense potential to effectively counter the problem of high bacterial load; prevent induction of coccoid bacteria thereby improving treatment outcome and compliance. This review describes efficacy of various therapeutic agents, treatment strategies and status of different GRDDS until now.     

Modulating apoptosis: current applications and prospects for future drug development

Agents modulating apoptosis are of extraordinary promise for the treatment of several states of disease including cancer, AIDS, neurodegenerative and ischemic diseases. In this review a brief summary of cellular pathways relevant to programmed cell death first is given and potential therapeutic targets therein are emphasized. Current efforts in drug development are discussed from a mechanistic, biochemical point of view and pro- and anti-apoptotic strategies are related to the respective diseases. Therapeutic approaches addressed in this paper include the design and activity of novel low molecular weight agents (e.g. caspase inhibitors) as well as gene therapy (e.g. p53, adenovirus as vector in cancer treatment). In final sections, the latest findings in the field of apoptosis are highlighted and future applications are outlined.     

Pulsed release of nitroglycerin from transdermal drug delivery systems

Non-ionic surfactant vesicles (niosomes) formed by a hexadecyl diglycerol ether (C16G2) and a series of polyoxyethylene alkyl ethers exhibit a variety of shapes dependent on their membrane composition. These surfactants form with an equimolar amount of cholesterol a mixture of largely spherical and tubular niosomes. In the absence of cholesterol, they form faceted polyhedral structures. The physicochemical and biological differences between polyhedral and spherical/tubular niosomes were studied. Polyhedral niosomes undergo a reversible shape transformation into spherical structures on heating above their phase transition temperature (Tm). The viscosity of polyhedral niosomes at room temperature is higher than their spherical counterparts due to their faceted and relatively rigid shape, and is more dependent on temperature due to shape transformation. At room temperature, polyhedral niosomes possess more rigid gel phase membranes and are less osmotically sensitive; however, they are more permeable because of a lack of or low levels of cholesterol in their membranes. Polyhedral niosomes loaded with luteinising hormone releasing hormone (LHRH), nonetheless, slow the release of drug compared to solution, albeit to a small extent.     

Ultrasound and transdermal drug delivery

Transdermal drug delivery offers an attractive alternative to the conventional drug delivery methods of oral administration and injection. However, the stratum corneum acts as a barrier that limits the penetration of substances through the skin. Application of ultrasound to the skin increases its permeability (sonophoresis) and enables the delivery of various substances into and through the skin. This review presents the main findings in the field of sonophoresis, namely transdermal drug delivery and transdermal monitoring. Particular attention is paid to proposed enhancement mechanisms and future trends in the field of cutaneous vaccination and gene delivery.     

Modulating cell cycle: current applications and prospects for future drug development

The cell cycle is a highly conserved and ordered set of events, culminating in cell growth and division. It is tightly controlled by many regulatory mechanisms that either permit or restrain its progression. The main families of regulatory proteins that play key roles in controlling cell cycle progression are the cyclins, the cyclin dependent kinases (Cdks), their substrate proteins, the Cdk inhibitors (CKI) and the tumor suppressor gene products, p53 and pRb. Many cell cycle control genes, when deregulated, can cause cells that are not dividing to enter the cell cycle and begin to proliferate leading to cancer development. They do so by interfacing with the basic cell cycle regulatory machinery to activate cell cycle entry. There is at present much optimism about the possibility of finding anticancer drug treatment strategies that modulate cell cycle regulatory molecules. Candidate targets for such strategies include crucial cell cycle molecules involved in G(1) to S phase or G(2) to M phase transition. This review will outline the basic regulatory machinery responsible for catalyzing cell cycle entry and describe the latest advances made in the field of cell cycle regulation. The basis of targeting the cell cycle particularly the Cdks as an approach to developing novel, specific and perhaps more effective anticancer treatments will be discussed. Examples of novel cell cycle-targeting agents that are in, or are close to being in clinical trials will be provided.