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To date, the treatment for cysticercosis and neurocysticercosis consists of a single oral intake of praziquantel (5-10 mg/kg), which since it is only available as tablets, hinders its administration to pediatric patients. Praziquantel is a poorly water-soluble drug which represents a challenge for its formulation in solution, particularly for the pediatric population. Thus, this study aimed to develop a palatable solution for praziquantel using pharmaceutical-accepted co-solvent systems. A design of experiments approach was applied to identify the optimal conditions for achieving a suitable amount of praziquantel in solution using co-solvent mixtures. Thus, praziquantel solubility increased from 0.38 up to 43.50 mg/mL in the optimized system. A taste masking assay in healthy human volunteers confirmed a successful reduction of drug bitterness after the addition of selected flavors and a sweetener. Stability studies were also conducted at different temperatures (4, 25, and 40 °C) for 12 months Even though the presence of the three known impurities of praziquantel was observed, their amounts never exceeded the acceptance criteria of the USP. Thus, this novel approach should be considered a valuable alternative for further preclinical studies considering the high prevalence of this infection worldwide.
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It is well known that the splitting of tablets can bring serious risks to the health of the treated animals, e.g., the possible adverse reactions caused by overdoses of fenbendazole or aspirin. In this regard, this work aimed to evaluate, for the first time, the splitting behavior of commercial veterinary tablets and identifying the technological aspects that interfere in this process. Tablets were cut in halves using a tablet splitter and were analyzed regarding mass variation, mass loss, friability, and hardness. Microstructural and morphological evaluations were also performed. For most of the tablets, organic flavor additives provided more uniformity and cohesive matrix, which preserved its hardness after the cut and led to subdivision results within acceptable limits for mass measurements and friability. Apart from the microstructure, the most critical technological aspect for a correct splitting performance in such tablets was the presence of a score. Thus, the results presented here allow us to guide the manufacturing of veterinary drug products in order to produce tablets more adapted to the splitting process.
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Comprimidos/química , Medicina Veterinária , Animais , Composição de Medicamentos/métodos , DurezaRESUMO
Chagas disease is a serious parasitic infection caused by Trypanosoma cruzi. Unfortunately, the current chemotherapeutic tools are not enough to combat the infection. The aim of this study was to evaluate the trypanocidal activity of benznidazole-loaded microparticles during the acute phase of Chagas infection in an experimental murine model. Microparticles were prepared by spray-drying using copolymers derived from esters of acrylic and methacrylic acids as carriers. Dissolution efficiency of the formulations was up to 3.80-fold greater than that of raw benznidazole. Stability assay showed no significant difference (P > 0.05) in the loading capacity of microparticles for 3 years. Cell cultures showed no visible morphological changes or destabilization of the cell membrane nor haemolysis was observed in defibrinated human blood after microparticles treatment. Mice with acute lethal infection survived 100% after 30 days of treatment with benznidazole microparticles (50 mg kg-1 day-1). Furthermore, no detectable parasite load measured by quantitative polymerase chain reaction and lower levels of T. cruzi-specific antibodies by enzyme-linked immunosorbent assay were found in those mice. A significant decrease in the inflammation of heart tissue after treatment with these microparticles was observed, in comparison with the inflammatory damage observed in both infected mice treated with raw benznidazole and untreated infected mice. Therefore, these polymeric formulations are an attractive approach to treat Chagas disease.
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Doença de Chagas/tratamento farmacológico , Nanopartículas/administração & dosagem , Nitroimidazóis/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Doença Aguda/terapia , Animais , Modelos Animais de Doenças , Feminino , CamundongosRESUMO
Neglected tropical diseases (NTDs) constitute a group of infectious diseases prevalent in countries with tropical and subtropical climate that affect the poorest individuals and produce high chronic disability associated with serious problems for the health system and socioeconomic development. Chagas disease or American trypanosomiasis is included on the NTDs list. However, even though this disease affects more than 10 million people, mostly in Latin America, causing the death of over 10,000 people every year, only two drugs are approved for its treatment, benznidazole and nifurtimox. These antiparasitic agents were developed almost half a century ago and present several biopharmaceutical disadvantages such as low aqueous solubility and permeability limiting their bioavailability. In addition, both therapeutic agents are available only as tablets and a liquid pediatric formulation is still lacking. Therefore, novel pharmaceutical strategies to optimize the pharmacotherapy of Chagas disease are urgently required. In this regard, nanotechnological approaches may be a crucial alternative for the delivery of both drugs ensuring an effective pharmacotherapy although the successful bench-to-bedside translation remains a major challenge. The present work reviews in detail the formulation and in-vitro/in-vivo analysis of different nanoformulations of nifurtimox and benznidazole in order to enhance their solubility, dissolution, bioavailability and trypanocidal activity.
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Doença de Chagas/tratamento farmacológico , Nanoestruturas , Nifurtimox/uso terapêutico , Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêutico , Formas de Dosagem , Humanos , Nifurtimox/administração & dosagem , Nifurtimox/química , Nitroimidazóis/administração & dosagem , Nitroimidazóis/química , Tripanossomicidas/administração & dosagem , Tripanossomicidas/químicaRESUMO
Benznidazole (BNZ) is the drug of choice for the treatment of Chagas disease in many countries. However, its low water solubility produces low and/or variable oral bioavailability. Thus, the aim of this work was to formulate micro- and nanoparticles based on Eudragit® RS PO and Eudragit® RL PO as a convenient approach to increase the dissolution rate of BNZ. The microparticles were obtained by means of spray-drying process while the nanoparticles were prepared through the nanoprecipitation technique and further freeze-drying. The results indicated that nanoparticles were obtained in 86% yield while microparticles were obtained in 68% yield. In both cases, the encapsulation efficiency of particles was greater than 78% while drug loading capacity was nearly 24% w/w and 18% w/w, after spray-drying and freeze-drying procedures, respectively. Images of scanning electron microscopy showed that the particles obtained by spray-drying and freeze-drying were in the micrometer and nanometer scale, respectively. FT-IR spectra of BNZ-loaded particles obtained by both methods showed characteristic bands of BNZ confirming that part of drug remained on their surface. Thermal analysis revealed that the drug crystallinity after both methods decreased. Physical stability evaluation of the nanoparticles confirmed that Pluronic® F68 was suitable to keep the particles size in a range of 300 nm after 70 days storage at 4 ± 2 °C. In-vitro release studies showed increased dissolution rate of drug from the particles obtained by both methods respect to untreated BNZ. The kinetics of drug release in acid media followed the Higuchi kinetics indicating drug diffusion mechanism from particles.
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Doença de Chagas/tratamento farmacológico , Imunossupressores/química , Imunossupressores/uso terapêutico , Nanopartículas/química , Nitroimidazóis/química , Nitroimidazóis/uso terapêutico , Criança , Liberação Controlada de Fármacos , Humanos , Hidrodinâmica , Imunossupressores/síntese química , Cinética , Nitroimidazóis/síntese química , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
The goal of this study was to investigate the electrohydrodynamic atomization (EHDA) technology to encapsulate the water-soluble antiretroviral didanosine (ddI) within poly(epsilon-caprolactone) (PCL) particles and stabilize it in the gastric medium where it undergoes fast degradation. A preliminary study employing a one-needle setup enabled the adjustment of the critical process parameters. Then, a configuration of two concentric needles named coaxial electrohydrodynamic atomization (CEHDA) led to the formation of ddI-loaded PCL microcapsules. Scanning electron microscopy analysis showed that the microparticles were spherical and with narrow size distribution. Attenuated total reflectance/Fourier transform infrared spectroscopy confirmed that most of the drug was efficiently encapsulated within the particles, whereas differential scanning calorimetry and X-ray powder diffraction revealed that the drug was preserved mainly in crystalline form. The loading capacity was relatively high (approximately 12% w/w), and the encapsulation efficiency was approximately 100%. In vitro release assays (PBS pH = 7.4) indicated that ddI was released almost completely within 2 h. Moreover, the delayed release was expected to isolate ddI from the biological fluids during the gastric transit. Finally, pharmacokinetics studies in rats showed that ddI-loaded particles lead to a statistically significant increase of the oral bioavailability of almost 4 times and a 2-fold prolongation of the half-life with respect to a ddI aqueous solution, supporting the use of CEHDA as a promising reproducible, scalable and cost-viable technology to encapsulate water-soluble drugs within polymeric particles.
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Didanosine (ddI) is a water-soluble antiretroviral used in the treatment of HIV that undergoes fast gastric degradation to an inactive hypoxanthine. Therefore, its oral bioavailability is relatively low (20-40%). In this work, we investigated for the first time a scalable open-loop spray-drying method with co-current flow for the encapsulation of ddI (model drug) within particles of the biocompatible polyester poly(epsilon-caprolactone). The average diameter of the particles was 36-118 µm and the morphology spherical. The encapsulation efficiency ranged from 60% to 100% with yields of up to 65%. ATR/FT-IR analysis indicated that most of the drug was encapsulated within the particles. In vitro release assays showed that the particles released the drug within 120 min. Finally, oral administration to rats led to a statistically significant 2.5-fold increase of the bioavailability with respect to a ddI aqueous solution, highlighting the potential of this technology to encapsulate efficiently other hydrophilic antiretrovirals and, by doing so, to overcome different biopharmaceutical drawbacks associated with the oral administration.
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Materiais Biocompatíveis/química , Didanosina/química , Polímeros/química , Administração Oral , Animais , Disponibilidade Biológica , Interações Hidrofóbicas e Hidrofílicas , Masculino , Ratos , Ratos WistarRESUMO
The design of simple and scalable drug delivery systems to target the central nervous system (CNS) could represent a breakthrough in the addressment of the HIV-associated neuropathogenesis. The intranasal (i.n.) route represents a minimally invasive strategy to surpass the blood-brain barrier, though it demands the use of appropriate nanocarriers bearing high drug payloads and displaying sufficiently long residence time. The present work explored the development of submicron particles made of poly(ε-caprolactone) (PCL), Eudragit(®) RS 100 (RS a copolymer of ethylacrylate, methylmethacrylate and methacrylic acid esterified with quaternary ammonium groups) and their blends, loaded with the first-choice antiretroviral efavirenz (EFV) as an approach to fine tune the particle size and the release kinetics. Particles displaying hydrodynamic diameters between 90 and 530 nm were obtained by two methods: nanoprecipitation and emulsion/solvent diffusion/evaporation. In general, the former resulted in smaller particles and narrower size distributions. The encapsulation efficiency was greater than 94%, the drug weight content approximately 10% and the yield in the 72.5-90.0% range. The highly positive surface (>+30 mV) rendered the suspensions physically stable for more than one month. In vitro release assays indicated that the incorporation of the poly(methacrylate) into the composition reduced the burst effect and slowed the release rate down with respect to pure poly(ε-caprolactone) particles. The analysis of the release profile indicated that, in all cases, the kinetics adjusted well to the Higuchi model with R(adj)(2) values >0.9779. These findings suggested that the release was mainly controlled by diffusion. In addition, when data were analyzed by the Korsmeyer-Peppas model, n values were in the 0.520-0.587 range, indicating that the drug release was accomplished by the combination of two phenomena: diffusion and polymer chain relaxation. Based on ATR/FT-IR analysis that investigated drug/polymer matrix interactions, the potential role of the hydrophobic interactions of C-F groups of EFV with carbonyl groups in the backbone of PCL and poly(methacrylate) could be ruled out. The developed EFV-loaded particles appear as a useful platform to investigate the intranasal administration to increase the bioavailability in the CNS.
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Antivirais/química , Benzoxazinas/química , Portadores de Fármacos/química , Poliésteres/química , Ácidos Polimetacrílicos/química , Alcinos , Antivirais/administração & dosagem , Benzoxazinas/administração & dosagem , Cromatografia Líquida de Alta Pressão , Ciclopropanos , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
INTRODUCTION: Due to a lack of approved drugs and formulations, children represent the most vulnerable patients. Magistral, unlicensed formulations obtained by the manipulation of solid forms should undergo clinical evaluation to ensure bioequivalence. The development of new pediatric medicines is complex and faces technological, economic and ethical challenges. This phenomenon has contributed to the emergence of an adult-children gap. To improve the situation, the World Health Organization launched the global campaign 'Make medicines child size' and a number of international initiatives have been established. The situation is more critical in the case of poverty-related diseases (PRDs) that mainly affect poor countries. AREAS COVERED: This review critically discusses different strategies to develop pediatric formulations and drug delivery systems (DDS) in PRDs and their potential implementation in the current market. Readers will gain an updated perspective on the development of pediatric medicines for the treatment of PRDs and the proximate challenges and opportunities faced to ensure an effective pharmacotherapy. EXPERT OPINION: There is an urgent need for the development of innovative, scalable and cost-viable formulations to ensure pediatric patients have access to appropriate medications for PRDs. The guidelines of the International Conference on Harmonisation constitute a very good orientation tool, as they emphasize physiological and developmental aspects that need to be considered in pediatric research. It is important to consider cultural, economic and ethical aspects that make developing nations facing PRDs different from the developed world. Thus, the best strategy would probably be to conceive and engage similar initiatives in the developing world, to address unattended therapeutic niches.