SAR interferometry monitoring of subsidence in a detritic basin related to water depletion in the underlying confined carbonate aquifer (Torremolinos, southern Spain).

This research underlines the need to improve water management policies for areas linked to confined karstic aquifers subjected to intensive exploitation, and to develop additional efforts towards monitoring their subsidence evolution. We analyze subsidence related to intensive use of groundwater in a confined karstic aquifer, through the use of the InSAR technique, by the southern coast of Spain (Costa del Sol). Carbonates are overlain by an unconfined detritic aquifer with interlayered high transmissivity rocks, in connection with the Mediterranean Sea, where the water level is rather stable. Despite this, an accumulated deformation in the line-of-sight (LOS) direction greater than -100 mm was observed by means of the ERS-1/2 (1992-2000) and Envisat (2003-2009) satellite SAR sensors. During this period, the Costa del Sol experienced a major population increase due to the expansion of the tourism industry, with the consequent increase in groundwater exploitation. The maximum LOS displacement rates recorded during both time spans are respectively -6 mm/yr and -11 mm/yr, respectively. During the entire period, there was an accumulated descent of the confined water level of 140 m, and several fluctuations of more than 80 m correlating with the subsidence trend observed for the whole area. Main sedimentary depocenters (up to 800 m), revealed by gravity prospecting, partly coincide with areas of subsidence maxima; yet ground deformation is also influenced by other factors, the main ones being the fine-grained facies distribution and rapid urbanization due to high touristic pressure.

Expanding Transdermal Delivery with Lipid Nanoparticles: A New Drug-in-NLC-in-Adhesive Design.

A monolithic drug-in-NLC-in-adhesive transdermal patch, with a novel design, was developed for codelivery of olanzapine (OL) and simvastatin (SV). Nanostructured lipid carriers (NLC) and enhancers were used as passive strategies, while the pretreatment of the skin with Dermaroller was tested as an active approach. The formulation was optimized for composition in a quality by design basis, in terms of enhancer and adhesive, with focus on permeation behavior, adhesion properties, and cytotoxicity. Propylene glycol promoted the best permeation rate for both drugs, with enhancement ratios of 8.1 and 12.9 for OL and SV, respectively, relative to the corresponding Combo-NLC patch without enhancer. Molecular dynamics results provided a rationale for these observations. The adhesive type displayed an important role in skin permeation, reinforced by the presence of the enhancer. Finally, Dermaroller pretreatment did not promote a significant improvement in permeation, which highlights the role of the combination of NLC with chemical enhancer in the transdermal patch as the main driving force in the process. It is also observed that NLC are able to reduce cytotoxicity, especially that associated with SV. This work provides a promising in vitro-in silico basis for a future in vivo development.

Can lipid nanoparticles improve intestinal absorption?

Lipid nanoparticles and their multiple designs have been considered appealing nanocarrier systems. Bringing the benefits of these nanosystems together with conventional coating technology clearly results in product differentiation. This work aimed at developing an innovative solid dosage form for oral administration based on tableting nanostructured lipid carriers (NLC), coated with conventional polymer agents. NLC dispersions co-encapsulating olanzapine and simvastatin (Combo-NLC) were produced by high pressure homogenization, and evaluated in terms of scalability, drying procedure, tableting and performance from in vitro release, cytotoxicity and intestinal permeability stand points. Factorial design indicated that the scaling-up of the NLC production is clearly feasible. Spray-drying was the method selected to obtain dry particles, not only because it consists of a single step procedure, but also because it facilitates the coating process of NLC with different polymers. Modified NLC formulations with the polymers allowed obtaining distinct release mechanisms, comprising immediate, delayed and prolonged release. Sureteric:Combo-NLC provided a low cytotoxicity profile, along with a ca. 12-fold OL/3-fold SV higher intestinal permeability, compared to those obtained with commercial tablets. Such findings can be ascribed to drug protection and control over release promoted by NLC, supporting them as a versatile platform able to be modified according to the intended needs.

Skin cancer and new treatment perspectives: a review.

Skin cancers are by far the most common malignancy of humans, particularly in the white population. The growing incidence of cutaneous malignancies has heralded the need for multiple treatment options. Although surgical modalities remain the mainstay of treatment, new research and fresh innovation are still required to reduce morbidity and mortality. Approaches for skin cancer may pass through new technological methods instead of new molecules. The first part of this paper provides a review of the state of the art regarding skin cancer disease as well as epidemiology data. Then, it describes the gold standards of the current recommended therapies worldwide and the actual needs of these patients. This is the first paper that highlights the novel and future therapeutic perspectives for the treatment of skin malignancies, new therapeutic agents and promising technological approaches, from nanotechnology to immunotherapy.

Study of polymorphic variants of the serotonin 2A receptor gene (5-HT2A) and its possible effects on smoking habits of a population from northeastern Brazil.

Previous studies have revealed a genetic component, including genetic polymorphisms in the serotonergic pathway, particularly in the serotonin receptor gene (5-HT2A). The aim of this study was to investigate associations of the T102C (rs6313) and A-1438G (rs6311) polymorphisms with tobacco use in a population from northeastern Brazil. We evaluated these polymorphisms in 135 nonsmokers and 135 smokers using polymerase chain reaction-restricted fragment length polymorphism. The distribution of allele and genotype frequencies and associations of polymorphisms with smoking were assessed with the chi-squared (χ(2)) test, the Fisher exact test, and odds ratio (OR) with a 95% confidence interval (CI). There were no differences in the distribution of genotype and allele frequencies between nonsmokers and smokers for A-1438G (P = 0.80) and T102C (P = 0.35). However, these polymorphisms were significantly associated with habit frequency (A/G: P = 0.02, OR = 6.87, 95%CI = 1.23-38.31, P = 0.04; A/G+G/G: P = 0.04, OR = 3.67, 95%CI = 1.06-12.75, P = 0.07), age of onset (C/C: P = 0.02, OR = 3.26, 95%CI = 1.17-9.07, P = 0.03, and nicotine dependence level (A/G: P = 0.02, OR = 3.28, 95%CI = 1.17-9.18, P = 0.04; A/G+G/G: P = 0.04, OR = 2.81, 95%CI = 1.13-6.99, P = 0.04; T/C: P = 0.03, OR = 3.12, 95%CI = 1.13-8.57, P = 0.04; T/C+C/C: P = 0.02, OR = 3.06, 95%CI = 1.22-7.70, P = 0.02). Therefore, these polymorphisms may not contribute significantly to smoking initiation, they do appear to be associated with habit maintenance.

Pseudomonas aeruginosa infection in cystic fibrosis lung disease and new perspectives of treatment: a review.

Cystic fibrosis (CF) is a complex inherited disease which affects many organs, including the pancreas and liver, gastrointestinal tract and reproductive system, sweat glands and, particularly, the respiratory system. Pseudomonas aeruginosa is the main cause of chronic airway infection. In order to reduce morbidity and mortality due to lung infection by P. aeruginosa, aerosol antibiotics have been used to achieve high local concentrations in the airways and to reduce systemic toxicity. In the course of this review, the current treatments to control CF lung infections by P. aeruginosa are presented. Some innovative aerosol formulations such as liposomes and microspheres are herein reviewed, which may improve the efficiency of anti-pseudomonal agents, and ensure patients' compliance to treatments, by reducing dosing frequency and/or drug dose, while maintaining therapeutic efficacy, preventing the occurrence of bacterial resistance and/or reducing adverse effects due to their controlled-release properties.

Gamma scintigraphy in the analysis of ketoprofen behaviour from matrix tablets.

The aim of this work was to study in vitro and in vivo the behaviour of matrix tablets (quick and extended release) containing ketoprofen (KTP) as a model drug and cellulose ether polymers, using gamma scintigraphy. The matrix tablets were prepared by the direct compression method and labelled by incorporating a drop of technetium ((99m)Tc). It was spectrophotometricaly confirmed that the radioisotope inclusion did not modify the kinetics of KTP release. In vitro studies were carried out for the tablets using the paddle method of the USP 35/NF30. The images were processed by defining regions of interest over the tablet (99m)Tc and the percentage of remaining activity/time curves were generated for both formulations. In vitro gamma scintigraphy studies showed significant differences (p<0.05) between both formulations. Identical results were obtained from the in vivo studies. In vivo tests were performed on five healthy volunteers. The scintigraphy images were acquired during 2.5 and 7.5h for quick and extended release formulations, respectively. The position of the extended release formulation tablet along the gastrointestinal tract (GIT) was assessed. The described results demonstrate the in vitro/in vivo correlation for the drug release profile and exhibit the importance of gamma scintigraphy for the drug location through the GIT.

Co-encapsulating nanostructured lipid carriers for transdermal application: from experimental design to the molecular detail.

Co-encapsulation of drugs directed at commonly associated diseases provides a convenient means for administration, especially if transdermally delivered. In this work, a comprehensive study for the co-encapsulation of drugs with a differential lipophilicity, olanzapine and simvastatin, and their transdermal delivery in a formulation containing nanostructured lipid carriers (NLC) is presented. Focus is given to the evaluation of a strategy in which NLC and chemical permeation enhancers are combined. It comprises in vitro, in silico and cellular viability approaches. The optimization and rationalization of the systems are carried out using a two-step factorial design. It is shown that the external medium in the NLC dispersion strongly influences permeation. It is also seen that the use of NLC determines a synergistic effect with selected permeation enhancers, thus promoting marked flux enhancement ratios (48 and 21, respectively for olanzapine and simvastatin) relative to the drugs in solution. The developed formulations can be considered non-irritant. A correlation between enhancer positioning in a lipid bilayer, partially governed by a H-bonding phenomenon, and enhancement effect is suggested from molecular dynamics studies and experimental observations.

In vitro release of ketoprofen from hydrophilic matrix tablets containing cellulose polymer mixtures.

The effect of cellulose ether polymer mixtures, containing both hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC K15M or K100M), on ketoprofen (KTP) release from matrix tablets was investigated. In order to evaluate the compatibility between the matrix components, Raman spectroscopy, scanning electron microscopy (SEM), and X-ray powder diffraction (XRPD) experiments were performed. The results evidence the absence of significant intermolecular interactions that could eventually lead to an incompatibility between the drug and the different excipients. Formulations containing mixtures of polymers with both low and high viscosity grades were prepared by a direct compression method, by varying the polymer/polymer (w/w) ratio while keeping the drug amount incorporated in the solid dispersion constant (200 mg). The hardness values of different matrices were found within the range 113.8 to 154.9 N. HPLC analysis showed a drug content recovery between 99.3 and 102.1%, indicating that no KTP degradation occurred during the preparation process. All formulations attained a high hydration degree after the first hour, which is essential to allow the gel layer formation prior to tablet dissolution. Independent-model dissolution parameters such as t(10%) and t(50%) dissolution times, dissolution efficiency (DE), mean dissolution time (MDT), and area under curve (AUC) were calculated for all formulations. Zero-order, first-order, Higuchi, and Korsmeyer-Peppas kinetic models were employed to interpret the dissolution profiles: a predominantly Fickian diffusion release mechanism was obtained - with Korsmeyer-Peppas exponent values ranging from 0.216 to 0.555. The incorporation of HPC was thus found to play an essential role as a release modifier from HPMC containing tablets.

Stratum corneum hydration: phase transformations and mobility in stratum corneum, extracted lipids and isolated corneocytes.

The outermost layer of skin, stratum corneum (SC), functions as the major barrier to diffusion. SC has the architecture of dead keratin filled cells embedded in a lipid matrix. This work presents a detailed study of the hydration process in extracted SC lipids, isolated corneocytes and intact SC. Using isothermal sorption microcalorimetry and relaxation and wideline (1)H NMR, we study these systems at varying degrees of hydration/relative humidities (RH) at 25 degrees C. The basic findings are (i) there is a substantial swelling both of SC lipids, the corneocytes and the intact SC at high RH. At low RHs corneocytes take up more water than SC lipids do, while at high RHs swelling of SC lipids is more pronounced than that of corneocytes. (ii) Lipids in a fluid state are present in both extracted SC lipids and in the intact SC. (iii) The fraction of fluid lipids is lower at 1.4% water content than at 15% but remains virtually constant as the water content is further increased. (iv) Three exothermic phase transitions are detected in the SC lipids at RH=91-94%, and we speculate that the lipid re-organization is responsible for the hydration-induced variations in SC permeability. (v) The hydration causes swelling in the corneocytes, while it does not affect the mobility of solid components (keratin filaments).

Influence of cellulose ether mixtures on ibuprofen release: MC25, HPC and HPMC K100M.

The influence of cellulose ether derivatives on ibuprofen release from matrix tablets was investigated. Raman spectroscopy and differential scanning calorimetry (DSC) experiments were used, in order to examine the compatibility between the matrix components: both excipients and ibuprofen. While both the DSC and Raman results did not detect any incompatibilities, DSC revealed the existence of some drug:excipient interactions, reflected by variations in the hydration/dehydration processes. Formulations containing mixtures of polymers with both low and high viscosity grades-methylcellulose (MC25) or hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC K100M), respectively--were prepared by a direct compression method (using 20, 25, and 30% of either MC25 or HPC). The tablets were evaluated for their drug content, weight uniformity, hardness, thickness, tensile strength, friability, porosity, surface area, and volume. Parameters such as the mean dissolution time (MDT) and the dissolution efficiency (DE) were calculated in all cases. The solid formulations presently studied demonstrated a predominantly Fickian diffusion release mechanism.

Thermal behaviour of human stratum corneum. A differential scanning calorimetry study at high scanning rates.

PURPOSE: To use high-speed differential scanning calorimetry (DSC) in the identification of transitions in human stratum corneum (SC). Several scanning rates (100 degrees C/min to 400 degrees C/min) are used. RESULTS: Eight transitions from 0 to 120 degrees C are detected in a significant number of samples. Most of these transitions have already been identified in previous studies, but have been labeled considering essentially that only four are present. Results also indicate some degree of reversibility for transitions occurring at temperatures above 90 degrees C. Dehydrated SC samples displayed slightly more defined transition peaks and a less frequent presence of the transitions below 50 degrees C. In turn, the delipidised SC matrix showed two major endothermic signals, centered around 55 and 100 degrees C, in conjunction with other much less marked features. CONCLUSIONS: The interpretation of DSC traces in terms of four main transition temperatures must be complemented having in mind the occurrence of other transitions, some of them at physiological temperatures. This work further suggests that transitions at temperatures above 90 degrees C may to a large degree be associated to lipids, while transition at approx. 55 degrees C is probably related to lipids covalently linked to proteins, as previously suggested.

Study of human stratum corneum and extracted lipids by thermomicroscopy and DSC.

A study on the thermal behavior of human stratum corneum and lipids is described. The use of high scanning rate DSC for both SC and extracted lipids allows the consistent determination of transition temperatures, including those of lower energy. Changes are found both at physiological and higher temperatures. There is a clear correspondence between the thermotropic behavior of these two systems. However, one of the transitions found in human SC (approximately 55 degrees C) is absent in extracted lipids and may be ascribed to those covalently-linked to corneocytes. Lipidic thermotropic behavior is clearly found above 100 degrees C, in which proteins do not play an exclusive role. Changes related to most transitions are observed directly by polarized light thermal microscopy in extracted lipids. This technique also allowed for the observation of large segregated domains in the extracted lipids. A drastic change is observed at approximately 60 degrees C, corresponding to the disruption of the lamellar structure.

Conformational study of ketoprofen by combined DFT calculations and Raman spectroscopy.

A conformational study of ketoprofen was carried out by both density functional theory (DFT) calculations and Raman spectroscopy. Nine different geometries were found to correspond to energy minimum conformations but only one of them was experimentally detected in the condensed phase spectra. Those rotations which interconvert the five most stable conformers were studied and the intramolecular interactions governing the corresponding conformational preferences were assessed. A thorough vibrational analysis was performed, leading to the assignment of both the solid and liquid spectra. Evidence for formation of intermolecular hydrogen bonds between carboxylic groups of adjacent ketoprofen molecules, leading to dimeric entities, was obtained.

Compatibility studies between ibuprofen or ketoprofen with cellulose ether polymer mixtures using thermal analysis.

Differential scanning calorimetry (DSC) was used to investigate and detect incompatibilities between drugs such as: ibuprofen (IBU) or ketoprofen (KETO) with cellulose ether derivatives, which are frequently applied on controlled release dosage forms. Binary mixtures concerning methylcellulose (MC25) or hydroxypropylcellulose (HPC) with hydroxypropylmethylcellulose (HPMC) K15M or K100M in different ratios were prepared and evaluated by the appearance, shift, or disappearance of peaks and/or variations in the corresponding DeltaH values. According to the DSC results, binary mixtures between those polymers were found to be compatible, but their mixture with IBU or KETO, promotes a solid-solid interaction mainly with 1:1:1 (w/w) ratio (drug-excipient). However, when the drug:excipient interactions were detected, they were not found to affect the drug bioavailability. DSC was successfully employed to evaluate the compatibility of the drugs with the selected polymers.

Role of cellulose ether polymers on ibuprofen release from matrix tablets.

Cellulose derivatives are the most frequently used polymers in formulations of pharmaceutical products for controlled drug delivery. The main aim of the present work was to evaluate the effect of different cellulose substitutions on the release rate of ibuprofen (IBP) from hydrophilic matrix tablets. Thus, the release mechanism of IBP with methylcellulose (MC25), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC K15M or K100M) was studied. In addition, the influence of the diluents lactose monohydrate (LAC) and beta-cyclodextrin (beta-CD) was evaluated. Distinct test formulations were prepared containing: 57.14% of IBP, 20.00% of polymer, 20.29% of diluent, 1.71% of talc lubricants, and 0.86% of magnesium stearate as lubricants. Although non-negligible drug-excipient interactions were detected from DSC studies, these were found not to constitute an incompatibility effect. Tablets were examined for their drug content, weight uniformity, hardness, thickness, tensile strength, friability, porosity, swelling, and dissolution performance. Polymers MC25 and HPC were found to be unsuitable for the preparation of this kind of solid dosage form, while HPMC K15M and K100M showed to be advantageous. Dissolution parameters such as the area under the dissolution curve (AUC), the dissolution efficiency (DE(20 h)), dissolution time (t 50%), and mean dissolution time (MDT) were calculated for all the formulations, and the highest MDT values were obtained with HPMC indicating that a higher value of MDT signifies a higher drug retarding ability of the polymer and vice-versa. The analysis of the drug release data was performed in the light of distinct kinetic mathematical models-Kosmeyer-Peppas, Higuchi, zero-, and first-order. The release process was also found to be slightly influenced by the kind of diluent used.

Influence of cellulose ether polymers on ketoprofen release from hydrophilic matrix tablets.

The present work reports the study of different ketoprofen:excipient formulations, in order to determine the effect of the polymer substitution and type of diluent on the drug-release mechanism. Substituted cellulose-methylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose were used as polymers, while lactose monohydrate and beta-cyclodextrin were tested as diluents. Distinct test formulations were prepared, containing 57.14% of ketoprofen, 20.00% of polymer, 20.29% of diluent, and 1.71% of talc/0.86% of magnesium stearate as lubricants. The tablets were tested for their drug content, weight variation, hardness, thickness, tensile strength, friability, swelling and release ratio. Polymers MC25 and HPC were found not to be appropriate for the preparation of modified release ketoprofen hydrophilic matrix tablets, while HPMC K15M and K100M showed to be advantageous. The analysis of the release profiles in the light of distinct kinetic models (zero-order, first-order, Higuchi and Korsmeyer-Peppas) led to the conclusion that the type of polymer did not influence the release mechanism of the drug. The mean dissolution time (MDT) was determined, the highest MDT value being obtained for HPMC formulations. Moreover, the drug-release process was found to be slightly influenced by the type of diluent, either lactose or beta-cyclodextrin.

Analysis of formulation effects in the dissolution of ibuprofen pellets.

In this work the effects of citric acid and of two common fillers, lactose (soluble) and tricalcium phosphate (insoluble) are examined on the release profiles from pellets, using ibuprofen as a model drug with pH-dependent solubility. Also studied is the dependence of these profiles on the specific surface area, bulk density, apparent density, porosity and porosity parameters (pore size distribution, total pore surface area, mean pore diameter and pore shape), as determined by mercury intrusion porosimetry. Pellets with high porosity and total pore surface area but small median pore diameter (tricalcium phosphate pellets-IPM) are found to produce similar dissolution results to those of low porosity and low total pore surface area, but having a high median pore diameter (lactose pellets-ILM), irrespective of the solubility of excipients. Addition of citric acid causes a delay in the initial dissolution for both formulations. During dissolution, however, citric acid reduces the median pore diameter of lactose-based pellets. In contrast, in tricalcium phosphate/citric acid pellets (CIPM), this parameter increases considerably during dissolution, when compared to the IPM formulation. These findings may justify the contrasting dissolution behaviors of CIPM and CILM (lactose/citric acid) pellets, after their common behavior in the initial stages, and show that porosity and its related parameters, along with physical properties of excipients such as solubility, density and specific surface area, are helpful to predict pellet behavior in drug release profiles.

Comparison of dissolution profiles of Ibuprofen pellets.

In this work we use both model dependent and independent techniques to assess the difference between dissolution profiles in which ibuprofen, in the form of uncoated pellets, is used as a model drug. The choice of a proper regression function, the relevance of the estimated parameters and the influence of the choice of dissolution points in the assessment of differences is discussed. The results obtained via mean dissolution times (MDT) and fit-factors (f(1) and f(2)) are also discussed and a non-quantitative method based on profiles correlation with graphical representation (concentration vs. concentration and rate vs. rate) presented. The tested methods discriminate similarly between curves, although not in all cases, but those based on modeling, MDT and fit-factors have shown to be less informative than the correlation approach.

The influence of core materials and film coating on the drug release from coated pellets.

The objective of this study was to analyse the influence of the composition of the core of the pellets on the in vitro drug release profile. The different materials (drugs and fillers) were chosen according to their relative solubility. Pellets were prepared by a standardised process of extrusion/spheronisation. A selected fraction size (1-1.4 mm diameter) of pellets of each preparation was coated with Surelease (an aqueous dispersion of ethyl cellulose) to give 5% weight gain. The dissolution studies were performed and data analysed in terms of the Area under the Curve (AUC) of the % dissolved as function of time and Mean Dissolution Time (MDT). ANOVA was applied in order to identify the influence factors and the relationship of cross effects. Canonical analysis and multiple regression were employed to quantify these relationships. The film coat was found to be the major factor controlling the drug release. The results however, show that both drug and filler solubility influenced the drug release profile. Some of the unusual results could only be explained if consideration was given to the physical characteristics of both powder and pellets. In particular, the specific surface area of calcium phosphate compared with other fillers played an important role on the release profile of the model drug.