J.J.S. Sousa

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.

Aggregation and gelation in hydroxypropylmethyl cellulose aqueous solutions

In this work we present an analysis of the thermal behavior of hydroxypropylmethyl cellulose aqueous solutions, from room temperature to higher temperatures, above gelation. We focus on significant aspects, essentially overlooked in previous work, such as the correlation between polymer hydrophobicity and rheological behavior, and the shear effect on thermal gelation. Micropolarity and aggregation of the polymer chains were monitored by both UV/vis and fluorescence spectroscopic techniques, along with polarized light microscopy. Gel formation upon heating was investigated using rheological experiments, with both large strain (rotational) tests at different shear rates and small strain (oscillatory) tests. The present observations allow us to compose a picture of the evolution of the system upon heating: firstly, polymer reptation increases due to thermal motion, which leads to a weaker network. Secondly, above 55 degrees C, the polymer chains become more hydrophobic and polymer clusters start to form. Finally, the number of physical crosslinks between polymer clusters and the respective lifetimes increase and a three-dimensional network is formed. This network is drastically affected if higher shear rates, at non-Newtonian regimes, are applied to the system.

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.

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.

Physical properties of chitosan pellets produced by extrusion-spheronisation: influence of formulation variables

Pellets comprising chitosan, cellulose microcrystalline, povidone, filler excipient and diclofenac sodium as model drug were prepared by extrusion-spheronisation. The effects of chitosan load (zero, 0%, low, 4% and high, 16% levels), type of filler (lactose, tribasic calcium phosphate and beta-cyclodextrin) and composition of the binding liquid (ethanol/water mixtures 20 and 50%) on physical characteristics of pellets were evaluated. A three-factor factorial design was employed in the study. Analysis of variance (ANOVA) indicated that single factors had significant effect on the physical characteristics of the pellets. The type of filler followed by polymer load markedly affected the density. The type of binding liquid had negligible effect on the shape and surface roughness of the pellets. Increase in the chitosan load resulted in pellets of lower porosity values. This could be attributed to the binding capacity of chitosan and povidone leading to more compacted structures. Chitosan load and type of filler had significant influence on the surface roughness. The surface of pellets became rougher as the chitosan load increased, however, there was no significant difference between zero and low contents of chitosan. Pellets prepared using tribasic calcium phosphate showed a smoother surface when compared with formulations including lactose or beta-cyclodextrin. Chitosan was useful to provide pellets of acceptable physical characteristics when employing an alcohol/water mixture 50% (v/v) as binding liquid for the extrusion-spheronisation process.

An investigation into the role of mucus thickness on mucoadhesion in the gastrointestinal tract of pig

Mucoadhesion in the gastrointestinal tract is a complex phenomenon and both formulation and physiological features need to be well understood and considered. Mucus thickness has been inferred to play a role in this process; however no definitive influence has been established. This study aimed to investigate the influence of mucus thickness on the mucoadhesion process, using a large animal (pig) as a model to closely resemble the human physiological features. The mucus thickness of different regions of the gastrointestinal tract of pig was fully measured by means of a histochemical method (hematoxilin/eosin) employing cryostat sections. Mucoadhesion was evaluated ex vivo on porcine mucosa by tensiometry using a polyacrylic acid polymer (Carbopol 974P NF) as a mucoadhesive model material, both in a dry and swollen state. Mucus was thickest in the stomach (body 67.9+/-54.7 microm) and mucus thickness increased from proximal to distal segments in both the small intestine (duodenum 25.9+/-11.8 microm, ileum 31.0+/-15.7 microm) and large intestine (caecum 19.4+/-8.7 microm, ascending colon 31.9+/-17.2 microm, descending colon 35.1+/-16.0 microm and rectum 40.8+/-12.5 microm). Swollen polymer exhibited lower mucoadhesion than the dry form in all sections analysed. Mucus thickness plays a role on the mucoadhesion, as thicker mucus provides deeper polymer chain diffusion and entanglements; however, other factors are also involved in this complex process.

Mucus thickness in the gastrointestinal tract of laboratory animals

Objectives  The objective of this study was to systematically assess the mucus thickness in the gastrointestinal tract of laboratory animals commonly used in preclinical studies.

Drug release from lipid liquid crystalline phases: relation with phase behavior

Introduction: We studied the release of propranolol hydrochloride (PHCl), a water-soluble amphiphilic drug, from monoolein (MO)/water and phytantriol/water systems. Methods: We related the dissolution profiles with phase behavior and viscosity of the different liquid crystalline phases. Diolein has been added aiming to stabilize the cubic phases and thus preventing formation of less viscous (lamellar) phases. Results: Formulations display first-order release rates and diffusion release mechanism. Some formulations (mostly MO) were close to zero-order release in the first 120 minutes. Discussion: Release mechanism can be influenced by phase changes during dissolution. Conclusions: Both MO and phytantriol show good potential to be used for propranolol hydrochloride sustained drug release.

A combination of nonionic surfactants and iontophoresis to enhance the transdermal drug delivery of ondansetron HCl and diltiazem HCl.

The present work reports the evaluation of three nonionic ether-monohydroxyl surfactants (C(12)E(1), C(12)E(5,) and C(12)E(8)) as skin permeation enhancers in the transdermal drug delivery of two drugs: ondansetron hydrochloride and diltiazem hydrochloride, formulated as hydrogels. The enhancers are used alone, or in combination with iontophoresis (0.3 mA - 8h). After 1h of pre-treatment with 0.16 M enhancer solutions in propylene glycol (PG), passive and iontophoretic 24 h in vitro studies across dermatomed porcine skin were performed using vertical Franz diffusion cells. Data obtained showed that the nonionic surfactant C(12)E(5) was the most effective permeation enhancer, both for the passive process as well as for samples subjected to iontophoresis, resulting in cumulative amounts of ondansetron HCl after 24h of approximately 93 μg/cm(2) and 336 μg/cm(2), respectively. Data obtained using diltiazem HCl showed a similar trend. The use of the nonionic surfactant C(12)E(5) resulted in higher enhancement ratios (ER) in passive studies, but C(12)E(8) yielded slightly higher values of drug permeated (2678 μg/cm(2)) than C(12)E(5) (2530 μg/cm(2)) when iontophoresis was also employed. Skin integrity studies were performed to assess potential harmful effects on the tissues resulting from the compounds applied and/or from the methodology employed. Skin samples used in permeation studies visualized by light microscopy and Scanning Electron Microscopy (SEM) at different levels of magnification did not show significant morphological and structural changes, when compared to untreated samples. Complementary studies were performed to gain information regarding the relative cytotoxicity of the penetration enhancers on skin cells. MTS assay data using human epidermal keratinocytes (HEK) and human dermal fibroblasts (HDF) indicated that HEK are more sensitive to the presence of the enhancers than HDF and that the toxicity of these compounds is enhancer molecular weight dependent.

Optimization of levofloxacin-loaded crosslinked chitosan microspheres for inhaled aerosol therapy.

The aim of this work was the development of innovative levofloxacin-loaded swellable microspheres (MS) for the dry aerosol therapy of pulmonary chronicPseudomonas aeruginosainfections in Cystic Fibrosis patients. In a first step, a factorial design was applied to optimize formulations of chitosan-based MS with glutaraldehyde as crosslinker. After optimization, other crosslinkers (genipin, glutaric acid and glyceraldehyde) were tested. Analyses of MS included aerodynamic and swelling properties, morphology, drug loading, thermal and chemical characteristics,in vitroantibacterial activity and drug release studies. The prepared MS presented a drug content ranging from 39.8% to 50.8% of levofloxacin in an amorphous or dispersed state, antibacterial activity and fast release profiles. The highest degree of swelling was obtained for MS crosslinked with glutaric acid and genipin. These formulations also presented satisfactory aerodynamic properties, making them a promising alternative, in dry-powder inhalers, to levofloxacin solution for inhalation.