Yogeshvar N. Kalia

Iontophoretic drug delivery

The composition and architecture of the stratum corneum render it a formidable barrier to the topical and transdermal administration of therapeutic agents. The physicochemical constraints severely limit the number of molecules that can be considered as realistic candidates for transdermal delivery. Iontophoresis provides a mechanism to enhance the penetration of hydrophilic and charged molecules across the skin. The principal distinguishing feature is the control afforded by iontophoresis and the ability to individualize therapies. This may become significant as the impact of interindividual variations in protein expression and the effect on drug metabolism and drug efficacy is better understood. In this review we describe the underlying mechanisms that drive iontophoresis and we discuss the impact of key experimental parameters-namely, drug concentration, applied current and pH-on iontophoretic delivery efficiency. We present a comprehensive and critical review of the different therapeutic classes and molecules that have been investigated as potential candidates for iontophoretic delivery. The iontophoretic delivery of peptides and proteins is also discussed. In the final section, we describe the development of the first pre-filled, pre-programmed iontophoretic device, which is scheduled to be commercialized during the course of 2004.

Transdermal drug delivery: overcoming the skin's barrier function.

The skin represents an extraordinary evolutionary feat. Not only does it physically encapsulate the organism and provide a multifunctional interface between us and our surroundings, but it is perpetually engaged in the assembly of a highly efficient homeostatic barrier to the outward loss of water(1). In so doing, it furnishes a membrane that is equally adept at limiting molecular transport both from and into the body. Overcoming this barrier function then, for the purpose of transdermal drug delivery, has been a necessarily challenging task for the pharmaceutical scientist, and one that boasts significant progress.

Passive skin penetration enhancement and its quantification in vitro

The poor penetration of drugs into the skin (and, partially, the permeation across the stratum corneum) often limits the efficacy of topical formulations. Basically, skin penetration can be enhanced by the following strategies: (i) increasing drug diffusivity in the skin; (ii) increasing drug solubility in the skin, and/or (iii) increasing the degree of saturation of the drug in the formulation. In this article, we review the literature with respect to: (i) chemical penetration enhancers, which have been shown to influence the diffusivity and/or solubility of the drug in the skin and (ii) supersaturated formulations, in which the degree of saturation of the drug is increased compared to conventional formulations. In addition, three different in vitro methods, specifically, classic diffusion cell studies, attenuated total-reflectance-Fourier transform infrared spectroscopy, and tape stripping in conjunction with an appropriate analytical technique, are considered, emphasizing their application to obtain quantitative values for skin transport parameters and to separate the kinetic or thermodynamic effects of an enhancement strategy.

Iontophoresis: electrorepulsion and electroosmosis.

Over the last 10-15 years, the electrical enhancement of drug delivery across the skin has undergone intense investigation. During this period, considerable amounts of experimental data have been generated, and the successful enhancement of a diverse array of molecules has been achieved. Indeed, the commercial exploitation of the method can be envisaged within the next few years. Despite this progress, however, the mechanistic understanding of iontophoresis remains a challenging scientific question that is yet to be fully resolved. The routes of permeation under the influence of an applied electrical potential, and the molecular interactions of the transporting drug with these pathways, have resisted unequivocal and unambiguous identification. Equally, the relative contributions of electrorepulsion and electroosmosis to the total iontophoretic flux have proven difficult to quantify, due to the difficulty of designing appropriate experiments. The situation is further complicated by the fact that it has now been established that certain lipophilic cations, in particular, can associate strongly with the skin during their iontophoretic delivery, thereby altering the electrical properties of the membrane, and changing the mechanism of transport. In this short communication, the roles of electrorepulsion and electroosmosis have been reconsidered from a simple theoretical point of view, and experimental approaches by which their relative importance may be estimated have been proposed and subjected to initial evaluation.

Enhancement of topical delivery from biodegradable nanoparticles

AbstractPurpose. To determine whether and how encapsulation of lipophilic compounds in polymeric nanoparticles is able to improve topical delivery to the skin. Methods. The penetration of octyl methoxycinnamate (OMC; Parsol MCX), a highly lipophilic sunscreen, into and across porcine ear skin in vitro was investigated, subsequent to encapsulation in poly(∈-caprolactone) nanoparticles, using tape-stripping. Confocal laser scanning microscopy (CLSM) was used to visualize the distribution of nanoparticles, charged with Nile red (NR), a lipophilic and fluorescent dye. Results. Quantification of OMC in the skin using tape-stripping demonstrated that nanoparticulate encapsulation produced a 3.4-fold increase in the level of OMC within the stratum corneum (SC), although the use of nanoparticles did not appear to increase skin permeation (it was not possible to detect OMC in the receiver compartment after 6 h). The confocal images showed that the fluorescence profile observed in the skin after application of NR-containing nanoparticles was clearly different from that seen following application of NR dissolved in propylene glycol. Two hours post-application of NR-containing nanoparticles, fluorescence was perceptible at greater depths (up to 60 μm) within the skin. Conclusions. i) Nanoparticulate encapsulation of OMC increased its “availability” with the SC. ii) The altered distribution of NR when delivered via nanoparticles was due, at least in part, to its altered thermodynamic activity (relative to that in propylene glycol) and, as a result, an increase in its partition coefficient into the SC.

Homogeneous transport in a heterogeneous membrane: water diffusion across human stratum corneum in vivo.

The objective of this study was to determine whether a structurally heterogeneous biomembrane, human stratum corneum (SC), behaved as a homogeneous barrier to water transport. The question is relevant because the principal function of the SC in vivo is to provide a barrier to the insensible loss of tissue water across the skin. Impedance spectra (IS) of the skin and measurements of the rate of transepidermal water loss (TEWL) were recorded sequentially in vivo in human subjects as layers of the SC were progressively removed by the serial application of adhesive tape strips. The low-frequency (< or = 100 rad s-1) impedance of skin was much more significantly affected by tape stripping than the higher frequency values; removal of the outermost SC layer had the largest effect. In contrast, TEWL changed little as the outer SC layers were stripped off, but increased dramatically when 6-8 microns of the tissue had been removed. It follows that the two noninvasive techniques probe SC barrier integrity in somewhat different ways. After SC removal, recovery of barrier function, as assessed by increasing values of the low-frequency impedance, apparently proceeded faster than TEWL decreased to the prestripping control. The variation of TEWL as a function of SC removal behaved in a manner entirely consistent with a homogeneous barrier, thereby permitting the apparent SC diffusivity of water to be found. Skin impedance (low frequency) was correlated with the relative concentration of water within the SC, thus providing an in vivo probe for skin hydration. Finally, the SC permeability coefficient to water, as a function of SC thickness, was calculated and correlated with the corresponding values of skin admittance derived from IS.

Factors and strategies for improving buccal absorption of peptides

Peptides and polypeptides have important pharmacological properties but only a limited number (e.g. insulin, oxytocin, vasopressin) have been exploited as therapeutics because of problems related to their delivery. The buccal mucosa offers an alternative route to conventional, parenteral administration. Peptides are generally not well absorbed through mucosae because of their molecular size, hydrophilicity and the low permeability of the membrane. Peptide transport across buccal mucosa occurs via passive diffusion and is often accompanied by varying degrees of metabolism. This review describes various approaches to improve the buccal absorption of peptides including the use of penetration enhancers to increase membrane permeability and/or the addition of enzyme inhibitors to increase their stability. Other strategies including molecular modification with bioreversible chemical groups or specific formulations such as bioadhesive delivery systems are also discussed.

Modeling transdermal drug release

The stratum corneum forms the outermost layer of the skin and is essentially a multilamellar lipid milieu punctuated by protein-filled corneocytes that augment membrane integrity and significantly increase membrane tortuosity. The lipophilic character of the stratum corneum, coupled with its intrinsic tortuosity, ensure that it almost always provides the principal barrier to the entry of drug molecules into the organism; the only exceptions being highly lipophilic species which might encounter problems at the stratum corneum-viable epidermis interface where they must partition into a predominantly aqueous environment. Drugs can be administered either as suspensions or as solutions and the formulation can range in complexity from a gel or an ointment to a multilayer transdermal patch. In this review we describe the theoretical principles used to describe transdermal release and we show that relatively simple membrane transport models based on the appropriate solution to Ficks second law of diffusion can be used to explain drug release kinetics into this complex biological membrane.

In Vivo Methods for the Assessment of Topical Drug Bioavailability

This paper reviews some current methods for the in vivo assessment of local cutaneous bioavailability in humans after topical drug application. After an introduction discussing the importance of local drug bioavailability assessment and the limitations of model-based predictions, the focus turns to the relevance of experimental studies. The available techniques are then reviewed in detail, with particular emphasis on the tape stripping and microdialysis methodologies. Other less developed techniques, including the skin biopsy, suction blister, follicle removal and confocal Raman spectroscopy techniques are also described.

Contributions of Electromigration and Electroosmosis to Iontophoretic Drug Delivery

AbstractPurpose. To determine the electromigration and electroosmotic contributions to the iontophoretic delivery of lidocaine hydrochloride, in addition to the more-lipophilic quinine and propranolol hydrochlorides, in the presence and absence of background electrolyte.Methods: In vitro experiments, using excised pig ear skin and both vertical and side-by-side diffusion cells, were performed as a function of drug concentration and with and without background electrolytes in the anodal formulation. Concomitantly, the contribution of electroosmosis in each experimental configuration was monitored by following the transport of the neutral, polar marker molecule, mannitol. Results. Electromigration was the dominant mechanism of drug iontophoresis (typically representing ∼90% of the total flux). In the presence of background electrolyte, lidocaine delivery increased linearly with concentration as it competed more and more effectively with Na+ to carry the charge across the skin. However, iontophoretic delivery of quinine and propranolol increased non-linearly with concentration. Without electrolytes, on the other hand, electrotransport of the three drugs was essentially independent of concentration over the range 1-100 mM. Transport efficiency of lidocaine was ∼10%, whereas that of the more lipophilic compounds was significanly less, with the major charge carrier being Cl− moving from beneath the skin into the anodal chamber. Both quinine and propranolol induced a concentration-dependent attenuation of electroosmotic flow in the normal anode-to-cathode direction. Conclusion. Dissecting apart the mechanistic contributions to iontophoretic drug delivery is key to the optimization of the formulation, and to the efficient use of the drug substance.