Advanced Inorganic Nanosystems for Skin Drug Delivery.

On/into/through the skin drug delivery represents an attractive alternative for the oral route, providing local and/or systemic drug delivery. Due to its complex and well-organised structure, most of the drugs show difficulties to penetrate the human skin. Therefore, enormous efforts have been invested to develop intelligent drug delivery systems overcoming the skin barrier with particular emphasis on increasing therapeutic activity and minimizing undesirable side-effects. Most of these strategies require the use of singular materials with new properties. In particular, and on the basis of their inherent properties, including biocompatibility, biodegradability and relative low-cost, inorganic nanoparticles are ideal candidates for the development of skin drug delivery systems. This review provides an updated and comprehensive overview of the state of the art in the trends towards skin drug delivery with a particular focus in the attractive alternative offered by inorganic-based nanosystems.

New magnetostratigraphic evidence for the age of Acheulean tools at the archaeo-palaeontological site "Solana del Zamborino" (Guadix - Baza Basin, S Spain).

The sedimentary record in the Guadix-Baza Basin (southern Spain) has proved to be a great source of information for the Miocene through the Pleistocene periods, due to the abundant faunal remains preserved, in some cases associated with lithic tools. The Solana del Zamborino (SZ) section has been the subject of controversy ever since a magnetostratigraphic analysis resulted in an age of 750-770 Kyr for Acheulean tools, a chronology significantly older than the ~600 Kyr established chronology for the first Acheulean record in Europe. Although recent findings at the "Barranc de la Boella" site (north-east of the Iberian Peninsula) seem to indicate that an earlier introduction of such technique in Europe around 0.96-0.781 Ma is possible, the precise age of the classical site at SZ is still controversial. The aim of this paper is to constrain the chronology of the site by developing a longer magnetostratigraphic record. For this purpose, we carried out an exhaustive sampling in a new succession at SZ. Our results provide a ~65 m magnetostratigraphic record in which 4 magnetozones of normal polarity are found. Our new magnetostratigraphic data suggest an age range between 300-480 Kyr for the lithic tools, closer to the age of traditional Acheulean sites in Europe.

Assessment of halloysite nanotubes as vehicles of isoniazid.

Equilibrium and thermodynamic aspects of the adsorption of isoniazid (INH) onto halloysite nanotubes (HLNTs) and characteristics of the resultant drug/nanocarrier systems are investigated. Equilibrium studies were performed in aqueous medium at different times, temperatures and drug concentrations. The overall adsorption process was explained as the result of two simple processes: adsorption on the activated sites of HLNTs and precipitation of INH on HLNTs surface. Formation of the INH-loaded HLNTs was spontaneous, endothermic and endoentropic, increasing the thermodynamic stability of the system (ΔH=70.40kJ/mol; ΔS=0.2519kJ/molK). Solid state characterization corroborated the effective interaction between the components that was also described by modeling at molecular level by quantum mechanics calculations along with empirical interatomic potentials. Transmission electron microphotographs confirmed the double allocation and homogeneous distribution of INH in the nanohybrids. FTIR spectra revealed the interaction via hydrogen bonds between the inner hydroxyl groups of HLNTs and N in INH molecules. Loading of INH in the nanohybrids was approximately 20% w/w. Effective loading of INH and activation energies of the interactions enable to propose the designed nanohybrids in the development of modified drug delivery systems.

Carvacrol/clay hybrids loaded into in situ gelling films.

The aim of the present work was the development of polymer films loaded with a carvacrol (CVR)/clay hybrid (HYBD) for the delivery of CRV in infected skin ulcer treatment. Different clays were considered: montmorrilonite, halloysite and palygorskite (PHC). CRV incorporation in PHC reduced its volatility. HYBD showed 20% w/w CRV loading capacity and was able to preserve CRV antioxidant properties. HYBD was characterized by improved antimicrobial properties against S. aureus and E. coli and cytocompatibility towards human fibroblasts with respect to pure CRV. Films were prepared by casting an aqueous dispersion containing poly(vinylalcohol) (PVA), poly(vinylpyrrolidone) (PVP), chitosan glutamate (CS), sericin and HYBD. Optimization of film composition was supported by a Design of Experiments (DoE) approach. In a screening phase, a full factorial design (FFD) was used and the following factors were investigated at two levels: PVA (12-14%w/w), PVP (2-4%w/w) and CS (0.134-0.5%w/w) concentrations. For the optimization phase, FFD was expanded to a "central composite design". The response variables considered were: elongation, tensile strength and buffer absorption of films, durability of the gels formed after film hydration. Upon hydration, the optimized film formed a viscoelastic gel able to protect the lesion area and to modulate CRV release.

Release kinetics of 5-aminosalicylic acid from halloysite.

This paper investigates desorption of 5-aminosalicilyc acid (5-ASA) adsorbed onto halloysite (HL). Desorption isotherms were fitted according to kinetic laws obtained considering release of 5-ASA from HL as the phase of desorption of the previously adsorbed drug molecules both inside the nanotubes of HL as onto the surface of clay particles and/or in the inter-particle spaces of their aggregates. Desorption isotherms has been also fitted with other equations frequently used in drug release kinetics studies. The best fitting corresponded to the kinetic model proposed; in agreement with the results of adsorption.

Polyelectrolyte-drug complexes of lambda carrageenan and basic drugs: relevance of particle size and moisture content on compaction and drug release behavior.

The interaction between polyelectrolytes (PE) and oppositely charged drugs (D) results in complexes (PE-D) that can be exploited in controlled release drug delivery systems. The aim of this work is to better understand the relevance of some preparative parameters such as moisture content and particle size on the performance of two PE-D complexes to be used in oral controlled release tablets. PE-D complexes containing diltiazem HCL (DTZ) or metoprolol tartrate (MTP) and lambda carrageenan were obtained at two particle size levels (<45 microm and 75-105 microm), maintained at different values of relative humidity (RH) (11, 52, 75, and 93%), and compressed. The tablets were characterized for porosity, hardness, moisture content, and contact angle. Drug release profiles were fitted to the Weibull equation, and a factorial design was used to understand the relevance of particle size and RH% on release rate as a function of medium pH. The results indicated that the hydrophobic character of the complex between PE and D depended on the drug and in the present case was more pronounced for DTZ than for MTP. This in turn affected the possible release mechanism and therefore the importance of particle size and RH%.

One-dimensional filtration of pharmaceutical grade phyllosilicate dispersions.

The filtration behaviour of some clay-water dispersions was studied. Two Spanish fibrous phyllosilicates (sepiolite from Vicálvaro and palygorskite from Turón) and a commercial bentonite (Bentopharm UK) with similar sizes and different morphologies (fibrous and/or laminar) were selected as model clays. Sepiolite from Vicálvaro is an almost pure fibrous sample, Bentopharm presents a high amount of laminar particles and palygorskite from Turón is made up of similar percentages of laminar and fibrous particles. The disperse systems were made up using a rotor-stator mixer working at two different mixing rates (1000 and 8000 rpm), for periods of 1 and 10 min. Filtration measurements were taken and the corresponding filtration curves obtained. Finally, the desorptivity (S) of the filtration cakes was calculated and correlated to the textural characteristics of the materials, the solid fraction and mixing conditions. Filtration behaviour of the dispersions depended on all three of these factors. Laminar dispersions presented lower S values than fibrous dispersions. In the 2% w/v dispersions the bridging forces between particles did not permit formation of an interconnected network as in 10% w/v dispersions and, consequently, filtration times increased with the solid fraction (i.e. S values decreased). Regarding stability to pH changes, the results showed that filtration behaviour was highly sensitive to basic pH in the fibrous clay dispersions and almost insensitive in the laminar clay dispersions.

Characteristics of pharmaceutical grade phyllosilicate powders.

The purpose of this paper was to evaluate the possible use of three types of pharmaceutical grades of phyllosilicates as pharmaceutical excipients. Seven samples (two smectites, three palygorskites, and two sepiolites) were studied. A complete mineralogical and chemical characterization of each material was made and powder texture was established by image analysis of scanning electron micrographs. Powder flow properties were then determined and the influence of textural characteristics on powder rheology and particle packing was assessed. Mineral contents were adequate for the sepiolites (> 90% of main mineral) and smectites (78 and 95%), but should be improved on the palygorskite samples (around 50% of main mineral in two of the studied samples). According to the textural characterization, the samples presented almost equal size distributions, but exhibited two different morphologies (i.e., laminar for smectites and fibrous for sepiolites and palygorskites). Both sepiolites possessed high flowability, whereas this factor varied from medium to low in the other materials. The compressibility of smectites was adequate, whereas that of palygorskites was high and that of the sepiolites was low. All of the samples studied would be useful as solid dosage form excipients (some samples would require improvement of their flow properties or treatment to reduce the amount of mineral impurities).

Characteristics of pharmaceutical grade phyllosilicate compacts.

The purpose of this paper was to determine the possible employment of three groups of phyllosilicates (two smectites, three palygorskites, and two sepiolites) as direct-compression tablet excipients. Compact lots of each material were obtained after application of three different compression loads and the elastic recoveries and tensile strengths of each lot were then determined. The results showed that, in comparison with laminar minerals (smectite samples), fibrous minerals (palygorskites and sepiolites) were found to have lower elastic recovery, regardless of the compression load. Almost all elastic recovery happened immediately after the ejection of the compacts. Then, and at least during the next 24 hr, smectite compacts maintained their dimensions without any significant variation, whereas fibrous compacts tended to continue increasing slightly their dimensions. On the other hand, compacts made with laminar particles had higher mechanical strength than those made with fibrous particles, except for one sepiolite sample in which the strength was similar. Both particle morphologies and the presence or absence of hydration water molecules were taken into account in order to explain these differences. According to the compact properties measured, at least two of the noncommercial samples (smectite from Gádor, Spain, and sepiolite from Vicálvaro, Spain) would be useful as direct-compression tablet excipients.

Pharmaceutical grade phyllosilicate dispersions: the influence of shear history on floc structure.

The effect of mixing conditions on the flow curves of some clay-water dispersions was studied. Two Spanish fibrous phyllosilicates (sepiolite from Vicálvaro and palygorskite from Turón) and a commercial bentonite (Bentopharm Copyright, UK) were selected as model clays. The disperse systems were made up using a rotor-stator mixer working at two different mixing rates (1000 and 8000 rpm), for periods of 1 and 10 min. Rheological measurements were taken and the corresponding flow curves obtained immediately after interposition and then after a period of 24 h under low shear caused by a roller apparatus. Aqueous sepiolite dispersions showed the highest viscosity and were easily interposed, whereas palygorskite dispersions were more difficult to obtain, resulting in low to medium viscosity gels. Bentonite dispersions provided medium viscosity systems, which greatly increased their viscosity after the low shear treatment (as a result of swelling), whereas the viscosity of the fibrous clays stayed at approximately the same values or even decreased. A linear relation was found between mixing energy and apparent viscosity in the bentonite systems, while apparent viscosity in the sepiolite samples was related to mixing power, with minor influence of mixing times. All the systems studied had thixotropic behaviour, changing from clearly positive to even negative thixotropy in some palygorskite systems. Finally, we studied the effect of drastic pH changes on the system structure. Results showed that rheological properties were highly sensitive to pH in the fibrous dispersions, but less sensitive behaviour was found in the laminar clay systems.