Purpose. To study at the ultrastructural level which part of the skin is associated with percutaneous iodide transport by passive diffusion and iontophoresis.

The skin barrier function can be evaluated by measuring the rate of transepidermal water loss (TEWL). This technique can also be used to elucidate the effect of enhancers on the skin barrier. In this in vivo study the effect of oleic acid in propylene glycol (OA/PG) has been investigated on 10 human volunteers of both sexes (age: 20–40 years). A 3-h and a 24-h occlusion of 0.16 M OA/PG resulted in a 2-fold increase in TEWL, whereas PG alone only increased TEWL with a ratio of 1.1. An optimal enhancement of TEWL has thus been achieved from the synergistic working of OA and PG. Furthermore, the enhancing effect lasted long: for a 3-h and a 24-h application, the TEWL increase could be monitored up to 25 and 72 h, respectively. The results indicate that OA remains inside the stratum corneum and is able to maintain its effect for a relatively long, yet limited, period of time. Another in vivo technique, attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) has been employed to follow the effect at a molecular scale. Following the absorbances at 1710 and 1740 cm−1, representing the carboxyl group of the free acid and of the ester, respectively, it was observed that the absorbance ratio of both wavenumbers is levelled off to that of an untreated condition already 3 h after the removal of OA/PG application system. These results may indicate either the migration of OA into lower cell layers or lateral spreading within the stratum corneum. Comparing the enhancement ratios from TEWL measurements of the OA/PG applied sites to the untreated sites with the ratio of absorbance at 1710 and 1740 cm−1 in time, there is a congruency with the disappearance of free acid in the uppermost layers of SC and the stabilization of the increased TEWL value (`steady-state' water diffusion). This suggests that the barrier perturbation by OA `outlives' its presence in the superficial cell layers in the free acidic form.

Purpose. This study aims to elucidate the skin permeation enhancement and the skin perturbation effects of a number of fatty acids, i.e. straight-chain saturated (SFA), monounsaturated (MUFA) and polyunsaturated acids (PUFA).

It is known that the fluorescence of p-aminobenzoic acid (PABA) is pH-dependent. However, recent observations showed that the fluorescence of PABA dissolved in water and in buffered solutions at physiological pH (7.4) decreases with time. A study was therefore performed to investigate these changes and find solutions for the problem. The first part of this study was to investigate the interdependence of the fluorescence intensity and the pH of a PABA solution in various acid-base mixtures. It turned out that this dependence is sigmoid, i.e. the fluorescence intensity is very low below pH 4, and it maximizes at pH 6 and beyond. In the second part, the fluorescence intensity was studied as a function of time. PABA was dissolved at the concentrations of 10, 50, 100 ng/ml and 1 μg/ml in various standard solutions: 0.1 N HCl, phosphate buffered saline (PBS) (pH 7.4), TRIS buffer (pH 7.4), borate buffer (pH 9.0) and 1 N NH4OH. PABA did not show any fluorescence at all in 0.1 N HCl, while showing stable fluorescence up to 7 days in borate buffer (pH 9.0) and in 1 N NH4OH. In water, PBS and TRIS buffer, the fluorescence of PABA decreased with time, with a higher decay rate in more diluted solutions. After 4 days, the fluorescence intensity of 10 and 50 ng/ml PABA in these solutions was practically zero. When concentrated NaOH was added to those solutions at time zero, the fluorescence intensity could be maintained. Apparently, at any pH below 9.0, a transformation of the fluorescent form of PABA to the unionized form takes place. Hence, pH should be taken into careful consideration when analysing PABA in aqueous solutions using fluorescence spectrometry.

Purpose. Transdermal transport rates of the dopamine agonist R-apomorphine were determined in patients with idiopathic Parkinson's disease (IPD). Apomorphine was applied by iontophoresis at two current densities.

Purpose. To investigate the feasibility of transdermal iontophoretic delivery of apomorphine in patients with Parkinson's disease, transdermal transport rates were optimized and validated across human stratum corneum and freshly dermatomed human skin in vitro.

Purpose. To study the potential of buccal delivery of the peptide drug in pigs.

Purpose. 1. The assessment of the role of hair follicles and sweat glands in skin resistance and percutaneous iontophoretic flux of 9-desglycinamide, 8-arginine vasopressin (DGAVP) by comparing two skin species: human stratum corneum which contained hair follicles, sweat and sebaceous glands, and shed snake skin which lacked all appendages. 2. The effect of l-dodecylazacycloheptan-2-one (dodecyl-Azone, a lipid perturbing agent) on the iontophoretic DGAVP flux.

The thermal behaviour of human stratum corneum was studied using differential thermal analysis within the temperature range of −130°C to 120°C. Aside from thermal transitions at around 40°C, 70°C, 85°C and 100°C, which have been reported before, a particular transition below 0°C (subzero), at approx. −9°C (264 K), was noticed. This transition was present in the analysis curves of dehydrated as well as hydrated stratum corneum sheets and could be distinguished from the water peak found only in hydrated stratum corneum samples. To further characterize this transition, thermal analysis was performed on stratum corneum sheets: (i) after lipid extraction, (ii) after pre-treatment of propylene glycol and (iii) after pretreatment of oleic acid/propylene glycol solution. From the results, it was concluded that the subzero transition (−9°C) belongs to low melting lipid components of stratum corneum.

The permeation of estradiol from vesicular formulations through human stratum corneum was studied in vitro. The vesicles were composed of nonionic n-alkyl polyoxyethylene ether surfactants (CnEOm). The thermodynamic activity of estradiol present in each formulation was kept constant by saturating all formulations with estradiol. The effects of both the particle size and the composition of the formulation on estradiol permeation across excised human stratum corneum were investigated. Stratum corneum that was pre-treated with empty surfactant carriers allowed for significantly higher estradiol fluxes compared with untreated stratum corneum. However, estradiol fluxes obtained in these pretreatment experiments appeared to be significantly lower than those obtained by the direct application of the estradiol-saturated carrier formulation on top of the stratum corneum. Furthermore, in the case of pretreatment of the stratum corneum, an increase in carrier size resulted in a decrease in estradiol flux. For direct application the opposite was found. Two mechanisms are proposed to play an important role in vesicle–skin interactions, i.e., the penetration enhancing effect of surfactant molecules and the effect of the vesicular structures that are most likely caused by adsorption of the vesicles at the stratum corneum–suspension interface.

The barrier properties of human epidermis grafted for 1-3 months onto nude mice are compared with normal human skin. Beside penetration studies with tritiated water and measurements of transepidermal water loss (TEWL), we analyzed the epidermal lipids by high-performance thin layer chromatography and evaluated the ultrastructure of the intercorneocyte lipid arrangement by freeze fracture electron microscopy (FFEM). The permeability of human skin for tritiated water and the TEWL exhibit no significant changes after grafting onto nude mice. FFEM analysis showed that grafted epidermis has the same morphological pattern as normal human epidermis. Regular desmosomes and lamellar lipid structures are present. Grafting did not qualitatively affect the lipid composition of human epidermis. Ceramides which contribute largely to the barrier function, have the same distribution profile.

The aim of this study was to characterize transport of FITC-labeled dextrans of different molecular weights as model compounds for peptides and proteins through buccal mucosa. The penetration of these dextrans through porcine buccal mucosa (a nonkeratinized epithelium, comparable to human buccal mucosa) was investigated by measuring transbuccal fluxes and by analyzing the distribution of the fluorescent probe in the epithelium, using confocal laser scanning microscopy for visualizing permeation pathways. The results revealed that passage of porcine buccal epithelium by hydrophilic compounds such as the FITC-dextrans is restricted to permeants with a molecular weight lower than 20 kDa. The permeabilities of buccal mucosa for the 4- and 10-kDa FITC-dextran (of the order of 10−8 cm/sec) were not significantly different from each other or from the much smaller compound FITC. The confocal images of the distribution pattern of FITC-dextrans showed that the paracellular route is the major pathway through buccal epithelium.

Mucoadhesion refers to the adhesion of polymeric materials to mucosal tissues. Some mucoadhesive polymers show appreciable binding to mucus even when hydrated and in the presence of an interstitial aqueous medium. The mucoadhesive performance (i.e. binding strength) is expected to depend on the interfacial energy thermodynamics in a three phase (solid-liquid-solid) system. According to known theories, such a system can be described in terms of spreading coefficients which are given by the free surface energy of each phase. Dispersion (α) and polar (β) surface energy parameters were available from previously reported contact angle measurements of captive air/octane bubbles on polymeric hydrogels and pig intestinal mucosa immersed in aqueous test media. It was found that individual spreading coefficients, as calculated from these surface energy parameters by the geometric mean equation, can be combined to one single parameter, called combined spreading coefficient SC. The latter is defined by the geometric mean of the polymer spreading coefficient and the Griffith fracture energy. This criterion provided a good correlation between predicted and measured mucoadhesive performance under various experimental circumstances. In its present form, this approach is based only on dispersion and polar surface energy components, without taking into account other forces due to ionic interactions, hydrogen bonding or acid-base interactions and eventual polymer chain interpenetration. Nevertheless, correct predictions were obtained. It is therefore concluded that the formation of a mucoadhesive bond is primarily governed by the aforementioned surface energy effects and spreading processes. The surface energy concept provides useful information for the search for better mucoadhesive materials and the identification of favored target sites in the human body for mucoadhesive drug delivery systems.

The possible role of surface energy thermodynamics in mucoadhesion was investigated with Polycarbophil and pig intestinal mucosa. In separate experiments, the surface energy parameters of the substrate (mucosa) and the adhesive (polymer film) were determined by contact angle measurements on captive air/octane bubbles in three physiologically relevant test fluids (isotonic saline, artificial gastric fluid, and artificial intestinal fluid). Whereas the swollen Polycarbophil films were relatively hydrophilic as indicated by small water contact angles (22, 23, and 16°), the water contact angles measured on mucosal tissue were significantly larger (61, 48, and 57°). Hence, mucus was found to possess an appreciable hydrophobicity. The measured adhesive performance (force of detachment) between Polycarbophil and pig small intestinal mucosa was highest in non-buffered saline medium, intermediate in gastric fluid, and minimal in intestinal fluid. In agreement with this trend, the mismatch in surface polarities between substrate and adhesive, calculated from the contact angle data, increased in the same order.

Bioadhesive carrier systems for example for transnasal, transbuccal or peroral drug delivery are being developed and studied with ever increasing intensity. The major objective of this approach is to increase the bioavailability of potent, unstable drugs such as peptides by shortening the required diffusion pathway and shielding the compound from degradative enzymes. Successful development of bioadhesive carriers requires fundamental knowledge of the mechanisms which govern the behaviour of bioadhesive polymers. This paper describes both thermodynamic and kinetic factors which contribute to bioadhesion, with reference to recent experimental data, and explains these within the framework of an adsorption‐interdiffusion theory. Attention is given to the (primary) adsorption step in a bioadhesive event, applying a surface energy analysis. An attempt is made to make up for what the authors claim to be an imperfection in current surface energy analyses and a new criterion for bioadhesion is proposed, based on t...