Pedro Barata

Module assemblage technology for floating systems: In vitro flotation and in vivo gastro-retention

The aim of this research was to study, in vitro by resultant-weight measurement and in vivo by gamma-scintigraphy experiments in humans, the floatation behavior of systems obtained by modules assembled in void configuration. The assembled system technology allowed the manufacturing of a system characterized by the presence of an internal void space that provided an apparent density lower than water. The gastro-retention times of floating assembled systems were determined in comparison with non-floating systems having the same mass and composition. In vitro the floatation of the system started immediately after immersion in water and lasted for more than 5 h. The in vivo studies confirmed that the in vitro floating ability of void configuration was maintained also in the human stomach where the system stayed for periods of time ranging from 2.5 to 5.0 h, depending on the food regimen and the sex of the subject. Reiterate eating and drinking further prolonged the stomach residence time.

Overview on gastroretentive drug delivery systems for improving drug bioavailability.

In recent decades, many efforts have been made in order to improve drug bioavailability after oral administration. Gastroretentive drug delivery systems are a good example; they emerged to enhance the bioavailability and effectiveness of drugs with a narrow absorption window in the upper gastrointestinal tract and/or to promote local activity in the stomach and duodenum. Several strategies are used to increase the gastric residence time, namely bioadhesive or mucoadhesive systems, expandable systems, high-density systems, floating systems, superporous hydrogels and magnetic systems. The present review highlights some of the drugs that can benefit from gastroretentive strategies, such as the factors that influence gastric retention time and the mechanism of action of gastroretentive systems, as well as their classification into single and multiple unit systems.

Pure insulin highly respirable powders for inhalation.

The aim of the present research was to investigate the possibility to obtain by spray drying an insulin pulmonary powder respirable and stable at room temperature without the use of excipients. Several insulin spray-dried powders were prepared with or without the addition of excipients (mannitol, bovine serum albumin, aspartic acid) from water dispersions or from acidic aqueous solutions. Each formulation was characterized using laser diffraction, scanning electron microscopy and in vitro aerosol performance with a Turbospin DPI device. Stability was assessed by the quantification of impurities with a molecular mass greater than that of insulin (HMWP) and related proteins (A21+ORP). Insulin powders prepared without excipients from an acid solution showed a shrivelled, raisin-like shape of non-aggregated microparticles and a high respirability (FPF>65%). The optimal result with respect to respirability and stability was reached when the pH of the insulin acetic acid solution to spray dry was adjusted at pH 3.6 with ammonium hydroxide. The median volume diameter of the obtained powder was 4.04 μm, insulin content 95%, emitted dose of 89.5%, MMAD 1.79 μm and fine particle fraction of 83.6%. This powder was stable at room temperature over a period of eighteen months with respect to the content of A21+ORP. As far as the HMWP content was concerned, the powder complied with the specification limits for a period of five months. The insulin acetic powder opens up the possibility of a more effective pulmonary therapy less dependent on refrigerated storage.

Physical and Chemical Stimuli-Responsive Drug Delivery Systems: Targeted Delivery and Main Routes of Administration

In the area of drug delivery, novel tools and technological approaches have captured the attention of researchers in order to improve the performance of conventional therapeutics and patient compliance to pharmacological therapy. Stimuli-responsive drug delivery systems (DDS) appear as a promising approach to control and target drug delivery. When these DDS are administered, the drug release is activated and then modulated through some action or external input and facilitated by the energy supplied externally. The stimuli responsible to activate the drug release can be classified into three types according to their nature or the type of energy applied: physical (e.g. magnetic field, electric field, ultrasound, temperature and osmotic pressure); chemical (e.g. pH, ionic strength and glucose); and biological (enzymes and endogenous receptors). The present review gives an overview of the most significant physical and chemical stimuliresponsive DDS and elucidates about their current and relevant applications in controlled and targeted drug delivery attending different routes of administration.

Artesunate-clindamycin multi-kinetics and site-specific oral delivery system for antimalaric combination products

The aim of this work was to study a multi-kinetics and site-specific oral antimalaria drug delivery system (MKS_DDS), containing artesunate and clindamycin, based on the Dome Matrix module assembly technology. The MKS_DDS assembled system comprises of four modules, i.e., two controlled release (CR) modules for delivery of 160 mg of clindamycin phosphate, one immediate release module containing 50 mg of artesunate and one immediate release module containing 80 mg of clindamycin phosphate. These modules have been assembled in stacked and void configurations. The void configuration is able to float and showed gastro-retentive behavior. The MKS_DDS was investigated for its mechanical characteristics, system behavior during release, drug release rate and mechanism. A bioavailability study (dogs) showed that the clindamycin plasma curve of the MKS_DDS system exhibited a quasi constant release rate, up to 8 h. The MKS_DDS system containing clindamycin and artesunate allows the use of one tablet containing one immediate release dose of artesunate and of clindamycin and a portion of clindamycin released over a prolonged time, by exploiting the gastro-retentive properties of a floating system.

Hyperbaric oxygen effects on sports injuries

In the last decade, competitive sports have taken on a whole new meaning, where intensity has increased together with the incidence of injuries to the athletes. Therefore, there is a strong need to develop better and faster treatments that allow the injured athlete to return to competition faster than with the normal course of rehabilitation, with a low risk of re-injury. Hyperbaric therapies are methods used to treat diseases or injuries using pressures higher than local atmospheric pressure inside a hyperbaric chamber. Within hyperbaric therapies, hyperbaric oxygen therapy (HBO) is the administration of pure oxygen (100%) at pressures greater than atmospheric pressure, i.e. more than 1 atmosphere absolute (ATA), for therapeutic reasons. The application of HBO for the treatment of sports injuries has recently been suggested in the scientific literature as a modality of therapy either as a primary or an adjunct treatment. Although results have proven to be promising in terms of using HBO as a treatment modality in sports-related injuries, these studies have been limited due to the small sample size, lack of blinding and randomization problems. HBO seems to be promising in the recovery of injuries for high-performance athletes; however, there is a need for larger samples, randomized, controlled, double-blinded clinical trials combined with studies using animal models so that its effects and mechanisms can be identified to confirm that it is a safe and effective therapy for the treatment of sports injuries.

Floating modular drug delivery systems with buoyancy independent of release mechanisms to sustain amoxicillin and clarithromycin intra-gastric concentrations

Abstract Release modules of amoxicillin and clarithromycin combined in a single dosage form designed to float in the gastric content and to sustain the intra-gastric concentrations of these two antibiotics used for the eradication of Helicobacter pylori have been studied. The modules having a disc shape with curved bases were formulated as hydrophilic matrices. Two modules of clarithromycin were assembled by sticking the concave base of one module to the concave base of the other, creating an internal void chamber. The final dosage form was a floating assembly of three modules of clarithromycin and two of amoxicillin in which the drug release mechanism did not interfere with the floatation mechanism. The assembled system showed immediate in vitro floatation at pH 1.2, lasting 5 h. The in vitro antibiotics release profiles from individual modules and assembled systems exhibited linear release rate during buoyancy for at least 8 h. The predicted antibiotic concentrations in the stomach maintained for long time levels significantly higher than the respective minimum inhibitory concentrations (MIC). In addition, an in vivo absorption study performed on beagle dogs confirmed the slow release of clarithromycin and amoxicillin from the assembled system during the assembly’s permanence in the stomach for at least 4 h.

Stimuli-responsive nanosystems for drug-targeted delivery

Abstract Although scientific and technological advances have been achieved in recent decades to produce promising drug delivery systems, the continuous discovery and therapeutic needs of bioactive molecules requires a constant development of novel tools and technological approaches. Stimuli-responsive nanosystems appear as a promising strategy to control the delivery and release of encapsulated therapeutic agents, specifically at required site of action (i.e., targeting delivery). In order to design an optimized system, it is necessary to understand the different stimulus mechanisms that active the drug release, such as physical (e.g., magnetic field, electric field, ultrasound, temperature, light, radiation) or chemical (e.g., pH, redox potential enzymes, temperature). This chapter gives an overview of the most significant physical and chemical stimuli-responsive nanosystems and elucidates their current and relevant applications in controlled and targeted drug delivery attending different routes of administration.