J. Blanco-Méndez

Delivery of a hydrophilic solute through the skin from novel microemulsion systems

Five microemulsions were prepared with a mean radius of the internal phase droplets varying from 10 to 70 nm. The microemulsions were evaluated for their ability to deliver a model hydrophilic solute (sucrose) across hairless mouse skin in vitro. Maximum sucrose fluxes, following application of the different microemulsions for 9 h, were similar and were about an order of magnitude greater than that from a 20 mM sucrose aqueous solution. The five (unloaded) formulations and three controls (water, propylene glycol and 5% oleic acid in propylene glycol) were applied for 3 h to the ventral forearm of six volunteers. Transepidermal water loss (TEWL) and relative skin blood flow (SBF) were measured immediately after removing the formulations and repeatedly over a further 3 hour period. SBF increased significantly only after application of the oleic acid/propylene glycol positive control; for all other treatments, SBF remained at the pretreatment value. Immediately after removing all the formulations, TEWL was elevated. However, these values quickly recovered to the pretreatment control except in the case of oleic acid/propylene glycol. Overall, this preliminary study indicates that microemulsion formulations can be used to improve the delivery of hydrophilic solutes while eliciting insignificant effects on human skin in vivo.

Microemulsions for topical delivery of 8-methoxsalen

8-Methoxsalen (8-MOP) and related furocumarins have been extensively used for the treatment of hyperproliferative skin diseases in association with long-wavelength UVA light. In order to develop alternative formulations for the topical administration of 8-MOP, microemulsions were evaluated as delivery vehicles. Six microemulsion formulations were prepared using water, isopropyl myristate (IPM) and Tween((R)) 80: Span((R)) 80: 1,2-Octanediol (3:1:1.2 w/w). The microemulsions were characterized using conductimetric and dynamic light scattering analyses. The ability of the systems to deliver 8-MOP into and through the skin was evaluated in vitro using newborn pig-skin. The in vitro permeation data showed that the novel microemulsions increased the 8-MOP total penetration through the skin by order of 1.9-4.5, as compared with IPM. In general, the accumulation of 8-MOP into the skin was increased by a factor of 1.5-4.5 by the microemulsion systems with respect to their total amount of drug delivered across the skin. These results suggest that the studied microemulsion systems may be appropriate vehicles for the topical delivery of 8-MOP.

Transdermal delivery of methotrexate: iontophoretic delivery from hydrogels and passive delivery from microemulsions.

In vitro assays were performed to investigate the effectiveness of transdermal administration of methotrexate (MTX) by iontophoretic delivery from two types of hydrogel and passive delivery from two types of microemulsion. Both iontophoretic delivery of MTX from hydrogels and passive delivery from microemulsions were more effective than passive delivery from aqueous solutions of the drug. In the iontophoretic delivery assays, the type of hydrogel used and the concentration of the drug in the loading solution had little influence on effectiveness of delivery. In the passive delivery assays, we used both water/oil (w/o) and oil/water (o/w) microemulsions: effectiveness of delivery was higher from o/w systems. At the end of all assays, significant amounts of MTX were detected in the skin. These results suggest that both hydrogels and microemulsions may be of value for the topical administration of MTX in the treatment of psoriasis.

Passive and iontophoretic transdermal penetration of methotrexate

The in vitro iontophoretic transdermal delivery of methotrexate (MTX) across pig skin was investigated. Cathodal iontophoresis considerably increased MTX skin permeation and accumulation as compared to the passive controls. The effect of NaCl and MTX concentrations in the vehicle were also studied. As expected, MTX iontophoretic transport decreased with NaCl content. On the other hand, MTX concentration did not modify its electrotransport in the range of concentrations considered (4.4-6.6 mM). The influence of the current density (0.25-0.5 mA/cm2) was also investigated. The iontophoretic transport of MTX tends to increase with current density although this effect was not always statistically significant. Finally, the possibility of using anodal iontophoresis from an acid (pH 4.0-5.0) donor solution to deliver MTX was explored. This was limited due to the low solubility of MTX in acid pH. On the whole, this work that iontophoresis may be used to improve the topical application of MTX for the treatment of psoriasis.

In-vitro bioadhesion of carbopol hydrogels

Abstract The main goal of this work was to study the adhesive capacity of hydrogels obtained from carbopol, this was achieved using a tensile tester in which adhesion work was the main parameter. The intended use of these hydrogels was the buccal administration of propanolol HC1. The adhesion assays were carried out under two hydration conditions, in order to evaluate the influence of water on adhesion. Results showed that adhesion capacity was considerably increased when water was limited in the system. The influence exerted on adhesion work by the polymer molecular weight and the crosslinking percentage were also studied and results showed that an increase in either of the mentioned parameters gave rise to a decrease in adhesion. Finally, propranolol HC1 was included into the hydrogels. It was observed that when water was limited in the system there was an increase in adhesion due to the increase in elasticity caused by the formation of a complex between the polymer and the drug. However, when there was no water limitation there was a slight decrease in adhesion caused by the precipitation of the complex carbopol-propranolol HC1.

A proton nuclear magnetic resonance study of the inclusion complex of naproxen with β-cyclodextrin

We report a 1H-NMR study of the complex formed between naproxen (NAP) and β-cyclodextrin (β-CD) in aqueous medium. Our results confirm that inclusion occurs. Analysis of our data by the continuous variation method shows that the complex has 1 : 1 stoicheiometry. Using Scotts modification of the Benesi-Hildebrand method, we estimate the apparent stability constant of the complex at 298 K in alkaline medium to be 420 M−1. Finally, with the aid of a molecular modelling program, we have determined the most probable structure of the complex. In general our results confirm those of previous studies, although our estimate of the apparent stability constant differs slightly from that reported on the basis of phase solubility results.

Iontophoretic delivery of ropinirole hydrochloride:effect of current density and vehicle formulation

AbstractPurpose. The objectives of this work were 1) to establish the feasibility of the transdermal iontophoretic delivery of ropinirole hydrochloride; 2) to investigate the possibility of delivering therapeutic doses of this drug; and 3) to determine the key factors that control ropinirole electrotransport. Methods. A series of in vitro transdermal iontophoretic experiments were instituted to study the effects of drug concentration, co-ion concentration, intensity of current, and application time on ropinirole flux. The convective contribution to ropinirole electrotransport was evaluated by following the transport of the electroosmotic marker mannitol. Results. Ropinirole flux decreased dramatically in the presence of competing ions. This effect was observed even when the molar fraction of the two competing cations was kept constant. Anodal flux of mannitol decreased with drug concentration, indicating a possible alteration of the skin permselectivity. In the absence of competing co-ions, ropinirole transport number reached a maximum value (8-13%). In these conditions, the main factor controlling drug delivery was the intensity of current applied. Conclusions. Transdermal iontophoresis allowed the delivery of therapeutic doses of ropinirole. The dose administered and the input rate were controlled by the judicious choice of the key delivery factors here described.

Cyclodextrins in drug delivery systems

Cyclodextrins are one of the most versatile aids in pharmaceutical technology, being of interest for the formulation of a wide range of delivery devices from the most classical dosage forms to the newest drug carriers. Their unique structural conformation together with the variety of substituents which can replace some of their hydroxyl groups endow cyclodextrins with versatile physicochemical features and the ability to form inclusion complexes with a wide range of drugs and macromolecules. Better knowledge of the reactivity of the cyclodextrins on forming supramolecular structures with a variety of architectures (self-assembled systems, poly(pseudo)rotaxanes, cross-linked networks, drug-conjugates) makes it possible to use cyclodextrins not only as drug solubilizers but also as true delivery systems. This review aims to summarize examples of the performance of cyclodextrins mainly in solid and semi-solid drug delivery systems, from the macro to the nanoparticulate scale, focusing on the information reported over the last 15 years.

Iontophoretic permselectivity of mammalian skin:characterization of hairless mouse and porcine membrane models

AbstractPurpose. To evaluate the transport number of Na+, and the isoelectric point, of two skin membranes frequently used for iontophoreticin vitroresearch. Methods. Na+ transport numbers were determined by the Hittorf method or by the measurement of membrane potential. The skin isoelectric point was deduced from the electroosmosis of mannitol (a polar non-electrolyte) as a function of pH. Results. The Na+ transport number across porcine skin, like that for hairless mouse, indicated a modest cation permselectivity. Consistent with this observation, the isoelectric points of porcine and hairless mouse skin were determined to be in the ranges of 3.5−3.75 and 4.5−4.6, respectively. That is, at physiological pH, both of these model membranes supports a net negative charge. Conclusions. The permselective properties of porcine and hairless mouse skin are similar (but with the porcine membrane having apparently fewer basic or more weakly-acidic groups than that of the mouse) and consistent with the characteristics, which have been deduced elsewhere, of human skin.

Interaction of naproxen with β-cyclodextrin in solution and in the solid state

Abstract The behaviour of the inclusion complex of naproxen with β-cyclodextrin was studied by molecular modelling using interactive computer graphics, solubility diagrams at different temperatures and pH values, infrared spectroscopy and differential scanning calorimetry. The complex was prepared by freeze-drying, spray-drying and kneading. Three-dimensional modelling shows that naproxen lies totally enclosed in the interior of the β-cyclodextrin cavity. The energy calculated for the model indicates a high stability. The dependency of the stability in solution on pH and temperature, and the thermodynamic parameters calculated show the possible existence of intermolecular hydrogen bonds that are less stable with increasing pH. Infrared spectra show a shift to lower wavenumber in the carbonyl-stretching bands of naproxen for the products prepared by freeze-drying and spray-drying. This may be due to the formation of hydrogen bonds between the host and guest. Thermal analysis confirmed that freeze-drying and spray-drying led to complex formation. The kneading method, however, gives poor drug complexation; only one-third of the naproxen penetrates the cyclodextrin cavity, the rest remaining freely dispersed between uncomplexed host and inclusion compound.