Nanotechnology and the transdermal route: A state of the art review and critical appraisal.

The skin is refractive to most molecules, especially hydrophilic ones, despite the existence of trans-barrier pathways. It is essential to maintain this protective barrier even after breaching skin surface for purposes of transdermal drug delivery to cope with cutaneous microbiota. Mechanical abraders or local energy dischargers (porators) or else hard, sharp objects (perforators, micro-needles) can punch a limited number (approximately 10(2)cm(-2)) of relatively wide (> or =10(3)nm) openings in the skin barrier, which then lets transiently (approximately 1 day) small drug quantities (< or =10 mg) and even large molecules (and pathogens?) pass. Microscopic (> or =10(3)nm) ballistic droplets or particles also insert small drug amounts (approximately 1mg) into the upper skin through the > or =10(6)cm(2) pores they create. The latter "skin breaching" method is approved for use in humans, whereas the hard nano-sized (5 nm-10 microm) skin perforators are still in development for transdermal drug delivery. Alternatively, controlled and reliable drug delivery across skin barrier can be achieved with sufficiently deformable and stable nano-sized carriers. Such "soft" skin penetrators are typically composite colloids. As such they must obtain, or retain, their ability to act as drug carriers on, in, and ideally below skin barrier(s). If properly designed and applied, such self-regulating, ultra-adaptable, and stable hetero-aggregates can open spontaneously and carry drugs through < or =10(9)cm(-2) cutaneous pores in the primary skin barrier and minimise cutaneous drug clearance; this permits deep/targeted deposition and prolonged action of the carrier-transported drugs. Therapeutic products based on ultra-adaptable, self-regulating, nano-sized (approximately 10(2)nm) carriers are under development. The first one is already approved in Switzerland.

Efficacy of epicutaneous Diractin (ketoprofen in Transfersome gel) for the treatment of pain related to eccentric muscle contractions.

OBJECTIVE: To investigate the effect of epicutaneously applied Diractin (ketoprofen in Transfersome gel) on pain induced by eccentric muscle contractions. METHODS: Three pilot studies which were subsequently pooled for a meta-analysis compared the efficacy of a single application of 25 mg ketoprofen in Diractin to 25 mg oral ketoprofen and placebo for the treatment of pain induced by 50 eccentric contractions of the elbow flexor muscles. In addition, the effect of multiple usage of up to 100 mg ketoprofen in Diractin bid over seven days on pain induced by walking down stairs with a total altitude of 200 meters was investigated. RESULTS: A single dose of 25 mg ketoprofen in Diractin after the elbow flexion exercise was significantly superior to placebo from 5 to 12 hours after treatment and also to oral ketoprofen at some time points after treatment. In contrast, oral ketoprofen was not different to placebo at any time after treatment. Multiple doses of up to 100 mg ketoprofen Diractin provided significant more pain relief than placebo on muscle pain induced by walking down stairs. CONCLUSIONS: Eccentric exercise-induced muscle soreness was shown to be an appropriate acute pain model to evaluate the efficacy of nonsteroidal anti-inflammatory drugs applied epicutaneously with Transfersome carriers. Diractin proved to be efficacious in relieving pain from eccentric muscle contractions and muscle over-exercise, respectively. The effect needs to be confirmed in a larger prospective clinical trial.

Accurate potentiometric determination of lipid membrane-water partition coefficients and apparent dissociation constants of ionizable drugs: electrostatic corrections.

PURPOSE: Potentiometric lipid membrane-water partition coefficient studies neglect electrostatic interactions to date; this leads to incorrect results. We herein show how to account properly for such interactions in potentiometric data analysis. MATERIALS AND METHODS: We conducted potentiometric titration experiments to determine lipid membrane-water partition coefficients of four illustrative drugs, bupivacaine, diclofenac, ketoprofen and terbinafine. We then analyzed the results conventionally and with an improved analytical approach that considers Coulombic electrostatic interactions. RESULTS: The new analytical approach delivers robust partition coefficient values. In contrast, the conventional data analysis yields apparent partition coefficients of the ionized drug forms that depend on experimental conditions (mainly the lipid-drug ratio and the bulk ionic strength). This is due to changing electrostatic effects originating either from bound drug and/or lipid charges. A membrane comprising 10 mol-% mono-charged molecules in a 150 mM (monovalent) electrolyte solution yields results that differ by a factor of 4 from uncharged membranes results. CONCLUSION: Allowance for the Coulombic electrostatic interactions is a prerequisite for accurate and reliable determination of lipid membrane-water partition coefficients of ionizable drugs from potentiometric titration data. The same conclusion applies to all analytical methods involving drug binding to a surface.

Adaptability and elasticity of the mixed lipid bilayer vesicles containing non-ionic surfactant designed for targeted drug delivery across the skin.

Novel potential carriers for non-invasive drug delivery were prepared from polyoxyethylene(20) oleyl ether (C(18:1)EO(20)) and soybean phosphatidylcholine (SPC) in different relative molar ratios, R(e); this produced stiff SPC liposomes (2r(ves) approximately 120 nm) at one end and much smaller (2r(mic) or= R(e)(sat) = 0.25 in the bilayer. The surfactant-saturated bilayers exhibit bending rigidity of kappa(c) approximately 2.1 k(B)T, as determined with an improved vesicle adaptability assay involving analysis of normalised flux density through a nano-porous barrier as an activated transport process. Pore penetrability vs. driving pressure data measured with the mixed amphiphat vesicles resemble results of computer simulation of deformable vesicles penetrating a constriction [Gompper G, Kroll DM. 1995. Driven transport of fluid vesicles through narrow pores. Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics. 52:4198-4208], confirming basic similarity of both processes. The improved assay can reveal partial lipid solubilisation at R(e)>R(e)(sat), which is linearly proportional to R(e) - R(e)(sat). C(18:1)EO(20)-SPC mixed vesicles that can cross narrow pores are arguably suitable for targeted drug delivery across intact skin.

Occlusion effect on transcutaneous NSAID delivery from conventional and carrier-based formulations.

We studied skin occlusion effects in vitro and in vivo on local and systemic delivery of ketoprofen across the organ, using the drug in a conventional non-occlusive topical gel (Togal Mobil-Gel), an occlusive tape (Mohrus), and the new targeted analgesic (Diractin), comprising ultradeformable, hydrophilic carriers in the form of a Transfersome vesicle. In vitro occluded skin permeability to ketoprofen from the tape (0.086cmh(-1)) marginally exceeds the value for the drug from carriers in a gel (0.058cmh(-1)), which resembles conventional gel on open excised skin (0.057cmh(-1)); smallness of occlusion-induced permeation enhancement ( approximately 1.5x) may be due to the high tested applied dose. In contrast, open skin permeability to the drug from the carriers in vitro is approximately 15xlower (0.004cmh(-1)). The benefit of ketoprofen association with the carriers for targeted transcutaneous delivery only shows-up in vivo after an non-occlusive epicutaneous application: the area under the curve (AUC) in peripheral deep muscle for the carrier-based gel then exceeds AUC for conventional gel approximately 35-fold. The AUC for occluded ultradeformable, hydrophilic carriers measured in living pigs is conversely approximately 10x lower, being 1.4-2.2x below that of the tape that is inferior to non-occluded carriers formulation (normalised cmax: approximately 200x). Occlusion thus disables ultradeformable, hydrophilic carriers by eliminating transcutaneous hydration gradient that normally drives the carriers across the skin. Compared with other non-steroidal anti-inflammatory agents (NSAIDs) for local usage, Diractin is thus evidently well differentiated and innovative.

Spatial distribution of cutaneous microvasculature and local drug clearance after drug application on the skin.

We analysed quantitatively blood microvessels distribution in normal skin. We conclude that the segmental area of blood vessels peaks approximately 0.1 mm below the skin surface, where the upper cutaneous blood plexus resides. Total blood vessels area then decreases quasi-exponentially to a depth of approx. -0.75 mm, with a decay length of approximately 0.1 mm, which is site and skin condition dependent, but at greater depths the decrease is approx. 6-times less steep. The corresponding permeability sink exhibits a similar, but superficially steeper, depth-profile. The lateral localisation of superficial blood vessels is such that ensures maximum diffusion from and into the capillaries, which affects transdermal drug delivery: each hairpin-like loop is in the centre of a papilla that corresponds to a cluster of corneocytes surrounded by main diffusion pathways. The aggregate area of blood vessels in the skin is >or=2.5-fold greater than total organ surface area under normal physiological conditions. The molecules diffusing through the skin barrier are thus largely cleared in outermost 20% of the organ, which may create a drug concentration maximum in the dermis, if clearance increases significantly with time. Skin microdialysis data are therefore extremely sensitive to cutaneous blood flow (distribution) and sampling. Skin microvasculature and its distribution must consequently be considered in all topical or transdermal drug transport studies, for example, by including suitably formulated clearance term into generalised diffusion equation.