Flávia Chiva Carvalho

Mucoadhesive drug delivery systems

Drug actions can be improved by developing new drug delivery systems, such as the mucoadhesive system. These systems remain in close contact with the absorption tissue, the mucous membrane, releasing the drug at the action site leading to a bioavailability increase and both local and systemic effects. Mucoadhesion is currently explained by six theories: electronic, adsorption, wettability, diffusion, fracture and mechanical. Several in vitro and in vivo methodologies are proposed for studying its mechanisms. However, mucoadhesion is not yet well understood. The aim of this study was to review the mechanisms and theories involved in mucoadhesion, as well as to describe the most-used methodologies and polymers in mucoadhesive drug delivery systems.

Rheological, mechanical, and bioadhesive behavior of hydrogels to optimize skin delivery systems

Background: Hydrogels are widely used for cutaneous formulations; thereby comparing the bioadhesive properties of polymers with a view to prolong the residence time of topical drugs on the skin would be very useful to design novel topical drug delivery systems. Aim: The objective of this study was to correlate data from rheological studies and texture profile analysis, with bioadhesion on the skin. Methods: Polyacrylic acid polymers used were carbomer homopolymer type A (C971) and type B (C974), and polycarbophil (PP) dispersed in water at various concentrations (0.1, 0.5, 1.0, 1.5, 2.0, 3.0, 5.0%, w/v). Rheological, texture, and bioadhesive properties were determined to compare the hydrogels. Results: Rheological analysis showed that all samples exhibited pseudoplastic behavior with thixotropy. Texture profile analysis showed that compressibility, hardness, and adhesiveness of the hydrogels were dependent on the polymer concentration, and the cohesion values were high. Bioadhesion of C974 and PP at 0.5 and 2% was of the same magnitude, while all samples of C971 had lower values. The bioadhesion of 5% C974 was the highest, while that 5% PP was lower, possibly because PP showed the greatest hardness and this rigidity may decrease the interaction of the polymer with the skin. Conclusion: A comprehensive comparative rheological and textural analyses of several polymers for topical systems were undertaken in terms of their bioadhesion. Therefore, it is possible to conclude that these polymers can be used for optimization of drug delivery systems on the skin.

Development and in vitro evaluation of surfactant systems for controlled release of zidovudine

The development of a controlled-release dosage form of zidovudine (AZT) is of crucial importance, in view of the pharmacokinetics of its toxic activity. A suitable drug delivery system could increase AZT bioavailability, reducing its dose-dependent side effects. In this study, systems composed of polyoxypropylene (5) polyoxyethylene (20) cetyl alcohol as surfactant (S), oleic acid as oil phase (O), and water (W) were developed, as possible AZT control release systems. They were characterized by polarized light microscopy (PLM), SAXS, and rheological analysis, followed by in vitro release assay. PLM and SAXS results indicated that the mixtures of S/O/W in the proportions 55/35/10 and 55/25/20 formed microemulsion (ME) systems, while 55/20/25 formed lamellar phase. The incorporation of AZT in these systems was greater than in water or oil; moreover, AZT incorporation did not significantly change the phase behavior of the mixtures. MEs behave as Newtonian fluids in flow rheological analysis and the lamellar phase as a pseudoplastic fluid. The release profile indicated that AZT could be released in a controlled manner, since an exponential pattern governs AZT diffusion, as demonstrated by the Weibull mathematical model. These systems are potential carriers for AZT and could have advantages over conventional pharmaceutical forms.

Surfactant systems for nasal zidovudine delivery: structural, rheological and mucoadhesive properties

Objectives Zidovudine is the antiretroviral drug most frequently used for the treatment of AIDS. Although its effectiveness is recognized, it undergoes extensive first‐pass metabolism and exhibits poor oral bioavailability. The nasal route is an option for enhanced therapeutic efficacy and to reduce the extent of the first‐pass effect. There are some mechanisms that limit intranasal absorption, such as mucociliary clearance, which rapidly removes the formulation from the nasal cavity. To improve the nasal residence time of zidovudine on the nasal mucosa, we aimed to develop a mucoadhesive surfactant system for zidovudine nasal administration.

Surfactant-based transdermal system for fluconazole skin delivery

The development of a controlled-release dosage form of antifungals is of crucial importance in view of the side-effects of conventional oral and intravenous treatments of Sporotrichosis. In this study, systems composed of polyoxypropylene (5) polyoxyethylene (20) cetyl alcohol (PPG-5-CETETH-20) as a surfactant, oleic acid as an oil phase, and water were developed as a possible fluconazole transdermal drug delivery system. The systems were characterised by polarised light microscopy (PLM), SAXS, and rheological analysis, followed by cellular and histological analyses, in vitro release assays, and ex vivo skin permeation and retention studies using porcine ear tissue and a Franz diffusion cell. PLM and SAXS results indicated that the mixtures of surfactant, oil and water formed micellar and lamellar phases. The incorporation of fluconazole in these systems was greater than in water and conventional dosage forms. Micellar systems behave as Newtonian fluids, being more viscous than elastic in rheological analysis, and lamellar phases behave as pseudoplastic fluids with high elastic moduli. In vitro and in vivo biological assays showed that the formulations did not affect normal cell macrophages and did not promote skin irritation. The release profile indicated that fluconazole could be released in a controlled manner. It was found that the systems enhanced drug permeation and skin retention by changing only the composition of the components in the formulations. Therefore, PPG-5-CETETH-20- based systems have great potential as transdermal systems with different structural and rheological characteristics for Sporotrichosis treatment using antifungal drugs.

Corrositex®, BCOP and HET-CAM as alternative methods to animal experimentation

Tests in animals are used as models in toxicological and investigative studies. However, such tests have been considered inhumane because they can cause pain and suffering to experimental animals, while these methods can often be subjective. Protests calling for animal protection have questioned the effectiveness of in vivo tests and suggest the introduction of alternative, in vitro methods. International organizations, such as the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), the National Institute of Health (NIH), the Organization for Economic Co-operation and Development (OECD), that regulate and develop new alternative animal models, have indicated the running of preliminary assays and execution of sequential tests, which consider physical-chemical properties and data of in vitro assays, before performing in vivo studies. Towards this background, the objective of the present article was to select promising alternative methods such as Corrositex®, BCOP and HET-CAM, intended to refine or replace the use of animals and reduce their suffering.

Development and In Vitro Evaluation of Lyotropic Liquid Crystals for the Controlled Release of Dexamethasone

In this study, amphiphilic polymers were investigated as biomaterials that can control dexamethasone (DXM) release. Such materials present interfacial properties in the presence of water and an oily phase that can result in lyotropic liquid crystalline systems (LLCS). In addition, they can form colloidal nanostructures similar to those in living organisms, such as bilayers and hexagonal and cubic phases, which can be exploited to solubilize lipophilic drugs to sustain their release and enhance bioavailability. It was possible to obtain lamellar and hexagonal phases when combining polyoxyethylene (20) cetyl ether (CETETH-20) polymer with oleic acid (OA), N-methylpyrrolidone (P), isopropyl myristate (IM), and water. The phases were characterized by polarized light microscopy (PLM), small-angle X-ray scattering (SAXS), rheological, textural, and bioadhesion analyses followed by an in vitro release assay. All samples showed elastic behavior in the rheology studies and hexagonal samples containing P and IM showed the highest adhesiveness. The drug release profile of all LLCS presented an average lag time of 3 h and was best fitted to the Korsmeyer-Peppas and Weibull models, with controlled release governed by a combination of diffusion and erosion mechanisms. These systems are potential carriers for DXM and can be explored in several routes of administration, providing potential advantages over conventional pharmaceutical forms.

Development of Cutaneous Bioadhesive Ureasil-Polyether Hybrid Films

The hydrolysis and condensation reactions involved in synthesis of ureasil-polyether films influence the film formation time and the number of chemical groups able to form hydrogen bonds, responsible for the bioadhesion, with the biological substrate. The objective of this work was to study the influence of the use of an acid catalyst (hydrochloric acid) and a basic catalyst (ammonium fluoride) in the hydrolysis and condensation reactions on the time formation and bioadhesion of ureasil-polyether films. The toxicity of the films was evaluated. The MTT assay has shown cell viability of human skin keratinocytes higher than 70% of all analyzed materials suggesting low cytotoxicity. The bioadhesion of the films is strongly dependent on the viscosity and hydrophilic/hydrophobic balance of the polyether chains used to synthetize the hybrid molecules. The use of acid catalyst promotes the formation of less viscous films with higher bioadhesion. The hybrids formed by more hydrophilic PEO chains are more bioadherent, since they can interact more efficiently with the water present in the stratum corneum increasing the bioadhesion. Due to their low toxicity and high bioadhesion, the ureasil-PEO films obtained by using HCl as catalyst agent are good candidates for application to the skin as bioadhesive films.

An HPLC-UV Method for the Quantification of Zidovudine in Rat Plasma

This work aims to develop and validate a simple methodology to quantify the most used antiretroviral, zi- dovudine (AZT), in rat plasma for preclinical studies. Some assays have been previously reported to quantify AZT in plasma; however, the majority of these methods uses complicated extraction methods. This method uses only 100 �L plasma samples, which were precipitated with 100 �L acidified acetonitrile containing an internal standard (IS). The plasma extracts were injected directly in a chromatographic system consisting of a UV-Vis detector (set at 266 nm) and an RP-C18 column. The mobile phase was an isocratic mixture of acetonitrile, methanol and 0.01% v/v aqueous formic acid (20:20:60 v/v/v) at a flow rate of 0.8 mL/min. Intra- and inter-day assay precision and accuracy variability were lower than 20% for the limit of quantification and 15% for higher concentrations. The applicability of the method was demonstrated by an in vivo study performed in rats. They were treated orally with an AZT-containing syrup and intrave- nously with an AZT solution. The calculated bioavailability of the syrup (56.7%) was in accordance with the literature. Therefore, this method can be used as an alternative to quantify plasma AZT in preclinical studies.