An appraisal of the scientific current situation and new perspectives in the treatment of cutaneous leishmaniasis.

Leishmaniasis is a Neglected Tropical Diseases caused by protozoan parasites of the genus Leishmania. It is a major health problem in many tropical and subtropical regions of the world and can produce three different clinical manifestations, among which cutaneous leishmaniasis has a higher incidence in the world than the other clinical forms. There are no recognized and reliable means of chemoprophylaxis or vaccination against infections with different forms of leishmaniasis. In addition, chemotherapy, unfortunately, remains, in many respects, unsatisfactory. Therefore, there is a continuing and urgent need for new therapies against leishmaniasis that are safe and effective in inducing a long-term cure. This review summarizes the latest advances in currently available treatments and improvements in the development of drug administration. In addition, an analysis of the in vivo assays was performed and the challenges facing promising strategies to treat CL are discussed. The treatment of leishmaniasis will most likely evolve into an approach that uses multiple therapies simultaneously to reduce the possibility of developing drug resistance. There is a continuous effort to discover new drugs to improve the treatment of leishmaniasis, but this is mainly at the level of individual researchers. Undoubtedly, more funding is needed in this area, as well as greater participation of the pharmaceutical industry to focus efforts on the development of chemotherapeutic agents and vaccines for this and other neglected tropical diseases.

Dual Release Model to Evaluate Dissolution Profiles from Swellable Drug Polyelectrolyte Matrices.

BACKGROUND: Mathematical modeling in modified drug release is an important tool that allows predicting the release rate of drugs in their surrounding environment and elucidates the transport mechanisms involved in the process. OBJECTIVE: The aim of this work was to develop a mathematical model that allows evaluating the release profile of drugs from polymeric carriers in which the swelling phenomenon is present. METHODS: Swellable matrices based on ionic complexes of alginic acid or carboxymethylcellulose with ciprofloxacin were prepared and the effect of adding the polymer sodium salt on the swelling process and the drug release was evaluated. Experimental data from the ciprofloxacin release profiles were mathematically adjusted, considering the mechanisms involved in each stage of the release process. RESULTS: A proposed model, named "Dual Release" model, was able to properly fit the experimental data of matrices presenting the swelling phenomenon, characterized by an inflection point in their release profile. This entails applying the extended model of Korsmeyer-Peppas to estimate the percentage of drug released from the first experimental point up to the inflection point and then a model called Lumped until the final time, allowing to adequately represent the complete range of the drug release profile. Different parameters of pharmaceutical relevance were calculated using the proposed model to compare the profiles of the studied matrices. CONCLUSION: The "Dual Release" model proposed in this article can be used to predict the behavior of complex systems in which different mechanisms are involved in the release process.

Benznidazole/Poloxamer 407 Solid Dispersion as a New Strategy to Improve the Treatment of Experimental Trypanosoma cruzi Infection.

Benznidazole and nifurtimox are the only drugs specifically approved for the treatment of Chagas disease. Both compounds are given orally in tablets, but occasionally are ineffective and cause adverse effects. Benznidazole, the first-line treatment in many countries, is a compound with low solubility in water that is administered at high doses for long periods of time. To improve its solubility, we developed a new liquid formulation on the basis of solid dispersions (SD) using the amphiphilic polymer poloxamer 407. Herein we present data on its trypanocidal performance in mouse models of acute and chronic Trypanosoma cruzi infection. SD at doses of 60 or 15 mg/kg per day given with different administration schedules were compared with the commercial formulation (CF; 50 mg/kg per day) and vehicle. The SD performance was assessed by direct parasitemia, total anti-T. cruzi antibodies, and parasitic burden in tissues after 4 or 6 mo posttreatment. The efficacy of the SD was equivalent to the CF but without manifest side effects and hepatotoxicity. Considering our previous data on solubility, together with these on efficacy, this new liquid formulation represents a promising alternative for the treatment of Chagas disease, particularly in cases when dosing poses a challenge, as in infants.

Films based on the biopolymer poly(3-hydroxybutyrate) as platforms for the controlled release of dexamethasone.

Controlled drug delivery aims to achieve an effective drug concentration in the action site for a desired period of time, while minimizing side effects. In this contribution, biodegradable poly(3-hydroxybutyrate) films were evaluated as a reservoir platform for dexamethasone controlled release. These systems were morphological and physicochemically characterized. In vitro release assays were performed for five different percentages of drug in the films and data were fitted by a mathematical model developed and validated by our research group. When the profiles were normalized, a single curve properly fitted all the experimental data. Using this unique curve, the dissolution efficiency (DE), the time to release a given amount of drug (tX% ), and the mean dissolution time were calculated. Furthermore, the dissolution rate, the initial dissolution rate (a%) and the intrinsic dissolution rate were determined. The a% mean value was 1.968 × 10-2% released/min, t80% was about 14 days, and the DE was 59.6% at 14 days and 66.5% at 20 days. After 2 days, when approximately 40% of the drug was released, the dissolution rate decreased about 60% respect to the initial value. The poly(3-hydroxybutyrate) platforms behaved as an appropriate system to release and control the dexamethasone delivery, suggesting that they could be an alternative to improve drug therapy.

Solid dispersion technology as a strategy to improve the bioavailability of poorly soluble drugs.

Over the last half-century, solid dispersions (SDs) have been intensively investigated as a strategy to improve drugs solubility and dissolution rate, enhancing oral bioavailability. In this review, an overview of the state of the art of SDs technology is presented, focusing on their classification, the main preparation methods, the limitations associated with their instability, and the marketed products. To fully take advantage of SDs potential, an improvement in their physical stability and the ability to prolong the supersaturation of the drug in gastrointestinal fluids is required, as well as a better scientific understanding of scale-up for defining a robust manufacturing process. Taking these limitations into account will contribute to increase the number of marketed pharmaceutical products based on SD technology.

Development and in vitro evaluation of solid dispersions as strategy to improve albendazole biopharmaceutical behavior.

AIM: Solid dispersions using Poloxamer 407 as carrier were developed to improve albendazole (ABZ) solubility and dissolution profiles. METHODS: ABZ/poloxamer solid dispersions were prepared, and dissolution profiles were mathematically modeled and compared with physical mixtures, pharmaceutical ABZ and a commercial formulation. RESULTS: Poloxamer 407 increased exponentially ABZ solubility, in about 400% when 95% w/w of polymer compared with its absence. Solid dispersions initial dissolution rate was three to 20-fold higher than physical mixtures, the drug and the commercial formulation. All the solid dispersions required less than 2.2 min to reach an 80% of ABZ dissolution, while the commercial formulation needed around 40 min. CONCLUSION: Solid dispersions improved ABZ solubility and dissolution rate, which could result in a faster absorption and an increased bioavailability.

Validation of kinetic modeling of progesterone release from polymeric membranes.

Mathematical modeling in drug release systems is fundamental in development and optimization of these systems, since it allows to predict drug release rates and to elucidate the physical transport mechanisms involved. In this paper we validate a novel mathematical model that describes progesterone (Prg) controlled release from poly-3-hydroxybutyric acid (PHB) membranes. A statistical analysis was conducted to compare the fitting of our model with six different models and the Akaike information criterion (AIC) was used to find the equation with best-fit. A simple relation between mass and drug released rate was found, which allows predicting the effect of Prg loads on the release behavior. Our proposed model was the one with minimum AIC value, and therefore it was the one that statistically fitted better the experimental data obtained for all the Prg loads tested. Furthermore, the initial release rate was calculated and therefore, the interface mass transfer coefficient estimated and the equilibrium distribution constant of Prg between the PHB and the release medium was also determined. The results lead us to conclude that our proposed model is the one which best fits the experimental data and can be successfully used to describe Prg drug release in PHB membranes.