Novel Dry Hyaluronic Acid-Vancomycin Complex Powder for Inhalation, Useful in Pulmonary Infections Associated with Cystic Fibrosis.

Polyelectrolyte-drug complexes are interesting alternatives to improve unfavorable drug properties. Vancomycin (VAN) is an antimicrobial used in the treatment of methicillin-resistant Staphylococcus aureus pulmonary infections in patients with cystic fibrosis. It is generally administered intravenously with a high incidence of adverse side effects, which could be reduced by intrapulmonary administration. Currently, there are no commercially available inhalable formulations containing VAN. Thus, the present work focuses on the preparation and characterization of an ionic complex between hyaluronic acid (HA) and VAN with potential use in inhalable formulations. A particulate-solid HA-VAN25 complex was obtained by spray drying from an aqueous dispersion. FTIR spectroscopy and thermal analysis confirmed the ionic interaction between HA and VAN, while an amorphous diffraction pattern was observed by X-ray. The powder density, geometric size and morphology showed the suitable aerosolization and aerodynamic performance of the powder, indicating its capability of reaching the deep lung. An in vitro extended-release profile of VAN from the complex was obtained, exceeding 24 h. Microbiological assays against methicillin-resistant and -sensitive reference strains of Staphylococcus aureus showed that VAN preserves its antibacterial efficacy. In conclusion, HA-VAN25 exhibited interesting properties for the development of inhalable formulations with potential efficacy and safety advantages over conventional treatment.

Fluorescent Multifunctional Organic Nanoparticles for Drug Delivery and Bioimaging: A Tutorial Review.

Fluorescent organic nanoparticles (FONs) are a large family of nanostructures constituted by organic components that emit light in different spectral regions upon excitation, due to the presence of organic fluorophores. FONs are of great interest for numerous biological and medical applications, due to their high tunability in terms of composition, morphology, surface functionalization, and optical properties. Multifunctional FONs combine several functionalities in a single nanostructure (emission of light, carriers for drug-delivery, functionalization with targeting ligands, etc.), opening the possibility of using the same nanoparticle for diagnosis and therapy. The preparation, characterization, and application of these multifunctional FONs require a multidisciplinary approach. In this review, we present FONs following a tutorial approach, with the aim of providing a general overview of the different aspects of the design, preparation, and characterization of FONs. The review encompasses the most common FONs developed to date, the description of the most important features of fluorophores that determine the optical properties of FONs, an overview of the preparation methods and of the optical characterization techniques, and the description of the theoretical approaches that are currently adopted for modeling FONs. The last part of the review is devoted to a non-exhaustive selection of some recent biomedical applications of FONs.

Improved efficacy and safety of low doses of benznidazole-loaded multiparticulate delivery systems in experimental Chagas disease therapy.

Benznidazole (BZ) is a first-line drug for the treatment of Chagas disease; however, it presents several disadvantages that could hamper its therapeutic success. Multiparticulate drug delivery systems (MDDS) are promising carriers to improve the performance of drugs. We developed BZ-loaded MDDS intended for improving Chagas disease therapy. To assess their efficacy and safety, Trypanosoma (T) cruzi infected BALB/c mice were orally treated with free BZ or BZ-MDDS at different regimens (doses of 50 and 100 mg/kg/day, administered daily or at 2- or 5-days intervals) and compared with infected non-treated (INT) mice. At 100 mg/kg/day, independent of the administration regimen, both treatments were able to override the parasitemia, and at 50 mg/kg/day significantly reduced it compared to INT mice. BZ-MDDS at a dose of 100 mg/kg/day administered every 5 days (BZ-MDDS 100-13d) induced the lowest cardiac parasite load, indicating an improved efficacy with lower total dose of BZ when loaded to the MDDS. Reactive oxygen species produced by leukocytes were higher in INT and mice treated with BZ at 50 mg/kg/day compared to 100 mg/kg/day, likely because of persistent infection. BZ-MDDS treatments markedly reduced heart and liver injury markers compared to INT mice and those receiving the standard treatment. Therefore, BZ-MDDS exhibited enhanced activity against T. cruzi infection even at lower doses and reduced administration frequency compared to free BZ while increasing the treatment safety. They likely avoid undesired side effects of BZ by keeping a sustained concentration, avoiding plasmatic drug peaks. BZ-MDDS evidenced significant improvements in experimental Chagas disease treatment and can be considered as a potential improved therapeutic alternative against this illness.

Evaluation of the Drug Release Kinetics in Assembled Modular Systems Based on the Dome Matrix Technology.

Mathematical models are an important tool in pharmaceutical formulations development, to evaluate in vitro and in vivo drug release processes and to optimize the design of new systems. Dome Matrix technology allows the combination of modules with different types of drugs, doses, and releases kinetics. This work aimed to design drug release systems based on Dome Matrix technology, with different swelling and erosion properties, to obtain complex drug release profiles and analyze them with simple mathematical models. Most of the release profiles followed a sigmoid curve, with an inflection point corresponding to a change in the release rate behavior. The experimental data were fitted with a simple model recently developed, named the Dual Release model, which consists in the combination of a modified Korsmayer-Peppas model from the beginning to the inflection point and the Lumped model from there until the end. This approach allowed determining relevant pharmaceutical parameters, such as the maximum release rate and the dissolution efficiency, among others. The use of the Dual Release model and the pharmaceutical parameters that characterize the different Dome Matrix modules allows optimizing the choice of the composition and the configuration during the development of a drug delivery system.

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.

Thermally self-assembled biodegradable poly(casein-g-N-isopropylacrylamide) unimers and their application in drug delivery for cancer therapy.

In this work, we report the synthesis of graft copolymers based on casein and N-isopropylacrylamide, which can self-assemble into biodegradable micelles of approximately 80 nm at physiological conditions. The obtained copolymers were degraded by trypsin, an enzyme that is overexpressed in several malignant tumors. Moreover, graft copolymers were able to load doxorubicin (Dox) by ionic interaction with the casein component. In vitro release experiments showed that the in situ assembled micelles can maintain the cargo at plasma conditions but release Dox immediately after their exposition at pH 5.0 and trypsin. Cellular uptake and cytotoxicity assays revealed the efficient delivery to the nucleus and antiproliferative efficacy of Dox in the breast cancer cell line MDA231. Both delivery and therapeutic activity were enhanced in presence of trypsin. Overall, the prepared micelles hold a great potential for their utilization as dual responsive trypsin/pH drug delivery system.

Preclinical pharmacokinetics of benznidazole-loaded interpolyelectrolyte complex-based delivery systems.

Benznidazole (BZ), first-line drug for Chagas treatment, is available as immediate-release tablets. High frequency of administration, long-term therapy, and side effects of BZ conspire against treatment adherence, and negatively impact in therapeutic success. We have developed BZ-loaded interpolyelectrolyte complexes (IPECs) composed of polymethacrylates (EE-EL-BZ) or polysaccharides (Ch-AA-BZ) for controlled BZ release. This work aimed to evaluate their preclinical pharmacokinetics compared to Abarax® (reference treatment) and to correlate them with the in vitro BZ release. A randomization schedule with a 3 × 2 cross-over design was used. Each healthy dog received a single oral dose of 100 mg of BZ from EE-EL-BZ, Ch-AA-BZ or Abarax®. BZ quantification was performed in plasma by a validated HPLC-UV method. Moreover, in silico simulations using the pharmacokinetic software PK Solutions 2.0™ were calculated for the multiple-dose administration at two dose regimens: 100 mg of BZ administered every 12 and 24 h. Also, the relationship between in vitro dissolution and in vivo plasma BZ concentration profiles in a single step was model for IVIVC analysis. BZ was rapidly absorbed from all formulations. The Cmax value for Ch-AA-BZ was 32% higher than reference (p < 0.05) and an earlier Tmax (4.2 h) was observed as compared to EE-EL-BZ (6.0 h). For both IPECs, the Tmax values were higher (p < 0.05) and the areas under the curve were 25% greater than those of Abarax® (p < 0.01). Despite these variations in pharmacokinetics parameters, simulations of once or twice daily dosing showed that all formulations reached a steady-state range concentration above of the minimum therapeutic dose while avoiding high BZ concentrations related to increased side effects. A linear level A IVIVC model was established using plasma concentration profiles and dissolved data obtained. Thus, BZ-loaded IPECs prolonged drug release and formulated as capsules showed improved in vivo performance, in terms of bioavailability and Tmax values, which were significantly higher compared to Abarax®. These BZ carrier systems would be useful for oral administration in the treatment of Chagas disease.

Polysaccharides-based multiparticulated interpolyelectrolyte complexes for controlled benznidazole release.

Polysaccharides-based delivery systems and interpolyelectrolyte complexes (IPECs) are interesting alternatives to control the release of drugs, thereby improving therapies. Benznidazole (BZ) is the selected drug for Chagas disease pharmacotherapy. However, its side effects limit its efficacy and safety. We developed novel multiparticulated BZ-loaded IPECs based on chitosan and alginic acid, and investigated their physicochemical and pharmacotechnical properties. IPECs were obtained using the casting solvent method, followed by wet granulation. They presented ionic interaction between the biopolymers, revealed that free BZ was uniformly distributed and showed adequate flow properties for hard gelatin-capsule formulation. The multiparticles exhibited mucoadhesion properties and revealed modulation of BZ release, depending on the release media, in accordance with the fluid uptake. The IPECs developed possess interesting properties that are promising for the design of novel alternatives to improve Chagas disease pharmacotherapy, which would diminish BZ's adverse effects and/or allow a reduction in the frequency of BZ administration.

Multi-kinetic release of benznidazole-loaded multiparticulate drug delivery systems based on polymethacrylate interpolyelectrolyte complexes.

Interpolyelectrolyte complexes (IPEC) formulated as multiparticulate drug delivery systems (MDDS) are interesting carriers to improve drug' performance. Benznidazole (BZ) is the first-line drug for Chagas treatment; however, it presents side effects and toxicity, conditioning its efficacy and safety. The goal of this work was to obtain novel MDDS composed by IPEC based on different polymethacrylate carriers loaded with BZ and to investigate in vitro drug delivery performance for oral administration. Physicochemical characterizations were studied and preclinical studies in a murine model of acute Chagas disease were also performed. The MDDS composed by BZ-loaded IPEC based on polymethacrylates were obtained by casting solvent followed by wet granulation methods with yields >83%. FT-IR demonstrated ionic interaction between the polyelectrolytes. Confocal microscopy, DSC and PXRD revealed a fraction uniformly distributed of free BZ on the multiparticles. The rheological evaluation of the MDDS showed adequate flow features for their formulation in hard gelatin-capsules. The type and composition of IPEC conditioned the modulation of BZ release and fluid uptake results. MDDS based on more hydrophylic Eudragit® showed very fast dissolution (Q15min > 85%), while an extended release (Q120min ≤ 40%) for the hydrophobic ones was observed. Capsules containing a combination of two MDDS with different release profile of BZ showed promising properties to improve Chagas disease pharmacotherapy in the preliminary in vivo assay performed, in which the BZ-loaded MDDS exhibited efficacy to reduce parasitemia, while decreasing the levels of liver injury markers in comparison to BZ conventional treatment. Multi-kinetic BZ delivery systems developed are interesting pharmaceutical alternatives to improve the treatment of Chagas disease.

Bioadhesive and biocompatible films as wound dressing materials based on a novel dendronized chitosan loaded with ciprofloxacin.

The bioadhesive polymeric films as topical drug delivery systems are interesting alternatives to improve the pharmacotherapy and patient compliances. New derivate biomaterials based on weisocyanate- dendronized PVP- crosslinked chitosan and loaded with ciprofloxacin (CIP), as model drug, were used to prepare bioadhesive films. Relevant in vitro/in vivo attributes to define main physicochemical and biopharmaceutical characteristics for topical wound-healing applications were evaluated. A high proportion of CIP, uniformly dispersed along throughout the film, was loaded. An extended release of CIP and different behaviors of release profiles, depending on the presence of dendron, were observed. The films loaded with CIP were effective in inhibiting the growth of both Gram positive and Gram negative bacteria. In addition, biocompatibility and bioadhesion into conjuntival-sacs of the rabbits suggests that these films have good properties to be applied over skin wounds for topical applications, allowing a reduction of the frequency of administration and improving the residence time of the films.

Study of the Influence of Formulation Variables in Bioadhesive Emulgels Using Response Surface Methodology.

The aim of the present work was to study the main formulation variables that influence attributes of bioadhesive emulgels based on a combination of polymers, using response surface methodology (RSM). Bioadhesive products continue to gain attention in topical cutaneous administration as they allow long residence times on the application site, which is important when a long dermal action and a reduced product administration frequency are desired. A Box-Behnken design of experiments (DoE) was introduced to study the effect of formulation variables on quality attributes of the emulgels. The effects of concentration of carbomer interpolymer type A (Polym1), xanthan gum (Polym2) and mineral oil (Oil) on detachment force (Fdetch), spreadability (Spread), and phase separation by mechanical stress (PhSep) were investigated. RSM and desirability functions were applied for data analysis. Emulgels were further characterized by viscosity and extrudability measurements. Polym1 showed a positive effect on Fdetch, while the increase in concentrations of Polym2 and Oil decreased this property. Polym1 and Polym2 favored emulgel PhSep. However, their interaction effect decreased it. The combination of 0.4-0.6% of carbomer and 0.2-0.3% of gum was able to produce easy-to-spread bioadhesive emulgels with mineral oil as discontinuous phase in the presence of a low surfactant concentration. Based on the DoE results, value ranges for the variables, which could achieve for the experimental domain to get the critical quality attributes of emulgels jointly within the specification limits, were able to be identified using RSM supported by desirability functions.

In vitro intestinal permeability studies, pharmacokinetics and tissue distribution of 6-methylcoumarin after oral and intraperitoneal administration in Wistar rats

ABSTRACT 6-Methylcoumarin (6MC) is a semisynthetic coumarin with important in vitro and in vivo anti-inflammatory activity. In order to continue the pre-clinical characterization of this molecule, in vitro intestinal permeability, plasma profile and tissue distribution after oral administration in rats were studied. The permeability of 6MC was evaluated by the Caco-2 cellular model in both the apical-basal (A-B) and basal-apical (B-A) directions. The pharmacokinetics and biodistribution were evaluated in rats after oral and intraperitoneal administration at doses of 200 mg/kg. Transport experiments with Caco-2 cells showed that 6MC presented high permeability at all concentrations evaluated. This finding suggested that 6MC could be transported across the gut wall by passive diffusion. The plasma concentration-time curve showed that the maximum concentration (Cmax) was 17.13 ± 2.90 µg/mL at maximum time (Tmax) of 30 min for the oral route and Cmax 26.18 ± 2.47 µg/mL at 6.0 min for the intraperitoneal administration, with elimination constant of (Ke ) 0.0070 min-1 and a short life half time of (T1/2 ) lower that 120 min. The distribution study showed that 6MC has high accumulation in the liver, and widespread distribution in all the organs evaluated.

A novel gel based on an ionic complex from a dendronized polymer and ciprofloxacin: Evaluation of its use for controlled topical drug release.

The development and characterization of a novel, gel-type material based on a dendronized polymer (DP) loaded with ciprofloxacin (CIP), and the evaluation of its possible use for controlled drug release, are presented in this work. DP showed biocompatible and non-toxic behaviors in cultured cells, both of which are considered optimal properties for the design of a final material for biomedical applications. These results were encouraging for the use of the polymer loaded with CIP (as a drug model), under gel form, in the development of a new controlled-release system to be evaluated for topical administration. First, DP-CIP ionic complexes were obtained by an acid-base reaction using the high density of carboxylic acid groups of the DP and the amine groups of the CIP. The complexes obtained in the solid state were broadly characterized using FTIR spectroscopy, XRP diffraction, DSC-TG analysis and optical microscopy techniques. Gels based on the DP-CIP complexes were easily prepared and presented excellent mechanical behaviors. In addition, optimal properties for application on mucosal membranes and skin were achieved due to their high biocompatibility and acute skin non-irritation. Slow and sustained release of CIP toward simulated physiological fluids was observed in the assays (in vitro), attributed to ion exchange phenomenon and to the drug reservoir effect. An in vitro bacterial growth inhibition assay showed significant CIP activity, corresponding to 38 and 58% of that exhibited by a CIP hydrochloride solution at similar CIP concentrations, against Staphylococcus aureus and Pseudomonas aeruginosa, respectively. However, CIP delivery was appropriate, both in terms of magnitude and velocity to allow for a bactericidal effect. In conclusion, the final product showed promising behavior, which could be exploited for the treatment of topical and mucosal opportunistic infections in human or veterinary applications.

Clomipramine and Benznidazole Act Synergistically and Ameliorate the Outcome of Experimental Chagas Disease.

Chagas disease is an important public health problem in Latin America, and its treatment by chemotherapy with benznidazole (BZ) or nifurtimox remains unsatisfactory. In order to design new alternative strategies to improve the current etiological treatments, in the present work, we comprehensively evaluated the in vitro and in vivo anti-Trypanosoma cruzi effects of clomipramine (CMP) (a parasite-trypanothione reductase-specific inhibitor) combined with BZ. In vitro studies, carried out using a checkerboard technique on trypomastigotes (T. cruzi strain Tulahuen), revealed a combination index (CI) of 0.375, indicative of a synergistic effect of the drug combination. This result was correlated with the data obtained in infected BALB/c mice. We observed that during the acute phase (15 days postinfection [dpi]), BZ at 25 mg/kg of body weight/day alone decreased the levels of parasitemia compared with those of the control group, but when BZ was administered with CMP, the drug combination completely suppressed the parasitemia due to the observed synergistic effect. Furthermore, in the chronic phase (90 dpi), mice treated with both drugs showed less heart damage as assessed by the histopathological analysis, index of myocardial inflammation, and levels of heart injury biochemical markers than mice treated with BZ alone at the reference dose (100 mg/kg/day). Collectively, these data support the notion that CMP combined with low doses of BZ diminishes cardiac damage and inflammation during the chronic phase of cardiomyopathy. The synergistic activity of BZ-CMP clearly suggests a potential drug combination for Chagas disease treatment, which would allow a reduction of the effective dose of BZ and an increase in therapeutic safety.

Extemporaneous benznidazole oral suspension prepared from commercially available tablets for treatment of Chagas disease in paediatric patients.

OBJECTIVE: To develop an extemporaneous 1% benznidazole (BNZ) suspension, with masked taste and adequate stability starting from available commercial tablets. The quality of compounding was evaluated through content uniformity measurement and physical and microbiological stability evaluation, under different storage conditions during 90 days. METHODS: Six batches of 1% BNZ suspension were prepared using safe excipients currently available in a galenic area of Hospital Pharmacy and then stored at 5 and 25 °C for 90 days. The BNZ content was determined by UV spectrophotometry. Physical stability was defined as the absence of colour, odour and/or flavour changes and the re-suspension of solid phase by a reasonable amount of simple 15-s shaking. The compliance with microbiological attributes of non-sterile pharmaceutical products was also evaluated. RESULTS: An oral liquid suspension, containing 1% of BNZ, was developed from commercially available BNZ tablets. The formulations stored for 90 days were easily re-dispersed after a simple 15-s shaking, ensuring the pouring of a liquid volume containing the desired dose of BNZ. All samples were within the acceptable range of BNZ concentration with minimal standard deviations. There were no detectable changes in colour, odour, viscosity, pH and microbial growth, complying with official quality requirements. The quality attributes were not affected by storage, room or refrigeration conditions or by the frequent opening or closing of the multidose containers. CONCLUSION: Paediatric oral liquid suspension containing 1.0% of BNZ was easily prepared starting from commercial tablets, being an interesting alternative for optimising the paediatric treatment of Chagas disease.

Novel poly(NIPA-co-AAc) functional hydrogels with potential application in drug controlled release.

The synthesis, characterization and properties of pH/thermosensitive hydrogels based on acrylic acid (AAc) and N-isopropylacrylamide (NIPA) using (+)-N,N'-diallyltartramide (DAT) as cross-linking agent and water as solvent, are presented in this article. Subsequently, the incorporation of ofloxacin (OFL) as model drug to evaluate the drug load capacity of hydrogels and the in vitro release from OFL-polymer conjugate are presented in order to define potential pharmaceutical applications. Interestingly, the incorporation of AAc diversified the properties of NIPA-based hydrogels allowing ionic interaction of these new materials with drugs of opposite charge and produced different release profiles at pH 1.2 and 6.8 simulated physiological media.

Diseño y preparación de formas farmacéuticas sólidas de Benznidazol para el tratamiento de la Enfermedad de Chagas / Design and Preparation fo Pharmaceutical Solid Dosage Forms of Benznidazole for the Treatment of Chagas Disease

INTRODUCCION: En Argentina se emplea el benznidazolcomo terapéutica de primera línea para el tratamiento etiológico del Chagas. Desde su lanzamiento (hace más de 40 años), sólo se dispone de comprimidos convencionales de 100 mg; no se han desarrollado nuevas formas farmacéuticas que aumenten la eficacia y seguridad, ni alternativas con dosis pediátricas. OBJETIVOS: Desarrollar formas farmacéuticas de benznidazol que ofrezcan ventajas farmacoterapéuticas. METODOS: Preformulación y diseño de nuevas formulaciones de benznidazol, con caracterización físico-química y selección de las formulaciones más favorables. Frente a la discontinuidad de producción del ingrediente activo benznidazol, se desarrolló una metodología de extracción a partir de 8520/8520/nica alternativa comercial disponible. RESULTADOS: Se obtuvieron nuevas formulaciones de comprimidos de 50 y 100 mg debenznidazol, con una rápida disolución del producto de referencia. Además, se obtuvieron formulaciones masticables de 50 mg bajo la forma de hidrogeles azucarados, con un efectivo enmascaramiento del mal sabor. Todas las formulaciones cumplieron los ensayos de evaluación de las propiedades farmacotécnicas y biofarmacéuticas, superando los perfiles de referencia. CONCLUSIONES: Se desarrollaron nuevas alternativas farmacéuticas de benznidazol de rápida disolución, que podrían mejorar el tratamiento etiológico de la enfermedad(especialmente en pediatría) y convertirse en herramientas aptas para su explotación comercial (AU)

INTRODUCTION: In Argentina, benznidazole is the drug of choice for the etiological treatment of Chagas disease. Since it was launched (more than 40 years ago), there are only 100 mg tablets available; the development included neither new pharmaceutical forms improving efficacy and safety, nor a pediatric dosage option. OBJECTIVES: To develop pharmaceutical form sof benznidazole with pharmacotherapeutic advantages. METHODS: Preformulation and design of new formulation sof benznidazole, with physicochemical characterization and selection of the most favorable formulations. Due to the discontinuity in the production of the active ingredient benznidazole, a specific methodology was developed in order to obtain it from the only commercially available alternative. RESULTS: New benznidazole tablet formulations were obtained (50 and 100 mg), with a rapid dissolution of the reference product, as well as chewable formulation sof 50 mg as sugar hydrogels featuring an effective taste masking. All formulations passed the evaluation tests for pharmacotechnical and biopharmaceutical properties, out performing the reference profiles. CONCLUSIONS:New fast-dissolving pharmaceutical dosage forms of benznidazole were developed, which could improve the etiological treatment of the disease (especially in the pediatric field) and become a proper tool for its commercial exploitation (AU)

Diseño y preparación de formas farmacéuticas sólidas de Benznidazol para el tratamiento de la Enfermedad de Chagas / Design and Preparation fo Pharmaceutical Solid Dosage Forms of Benznidazole for the Treatment of Chagas Disease

INTRODUCCIÓN: En Argentina se emplea el benznidazolcomo terapéutica de primera línea para el tratamiento etiológico del Chagas. Desde su lanzamiento (hace más de 40 años), sólo se dispone de comprimidos convencionales de 100 mg; no se han desarrollado nuevas formas farmacéuticas que aumenten la eficacia y seguridad, ni alternativas con dosis pediátricas. OBJETIVOS: Desarrollar formas farmacéuticas de benznidazol que ofrezcan ventajas farmacoterapéuticas. MÉTODOS: Preformulación y diseño de nuevas formulaciones de benznidazol, con caracterización físico-química y selección de las formulaciones más favorables. Frente a la discontinuidad de producción del ingrediente activo benznidazol, se desarrolló una metodología de extracción a partir de 8520/8520/nica alternativa comercial disponible. RESULTADOS: Se obtuvieron nuevas formulaciones de comprimidos de 50 y 100 mg debenznidazol, con una rápida disolución del producto de referencia. Además, se obtuvieron formulaciones masticables de 50 mg bajo la forma de hidrogeles azucarados, con un efectivo enmascaramiento del mal sabor. Todas las formulaciones cumplieron los ensayos de evaluación de las propiedades farmacotécnicas y biofarmacéuticas, superando los perfiles de referencia. CONCLUSIONES: Se desarrollaron nuevas alternativas farmacéuticas de benznidazol de rápida disolución, que podrían mejorar el tratamiento etiológico de la enfermedad(especialmente en pediatría) y convertirse en herramientas aptas para su explotación comercial

INTRODUCTION: In Argentina, benznidazole is the drug of choice for the etiological treatment of Chagas disease. Since it was launched (more than 40 years ago), there are only 100 mg tablets available; the development included neither new pharmaceutical forms improving efficacy and safety, nor a pediatric dosage option. OBJECTIVES: To develop pharmaceutical form sof benznidazole with pharmacotherapeutic advantages. METHODS: Preformulation and design of new formulation sof benznidazole, with physicochemical characterization and selection of the most favorable formulations. Due to the discontinuity in the production of the active ingredient benznidazole, a specific methodology was developed in order to obtain it from the only commercially available alternative. RESULTS: New benznidazole tablet formulations were obtained (50 and 100 mg), with a rapid dissolution of the reference product, as well as chewable formulation sof 50 mg as sugar hydrogels featuring an effective taste masking. All formulations passed the evaluation tests for pharmacotechnical and biopharmaceutical properties, out performing the reference profiles. CONCLUSIONS:New fast-dissolving pharmaceutical dosage forms of benznidazole were developed, which could improve the etiological treatment of the disease (especially in the pediatric field) and become a proper tool for its commercial exploitation

Stability evaluation of 7 % chloral hydrate syrup contained in mono and multi-dose bottles under room and refrigeration conditions.

PURPOSE: To evaluate the stability of an extemporaneously prepared 7% chloral hydrate syrup under different conditions of storage and dispensing. METHODS: Three batches of 7% chloral hydrate syrup were prepared. Each batch was stored in 50 light-resistant glass containers of 60 mL with child-resistant caps and in two bottles of 1000 mL to simulate two forms of dispensing, mono and multi-dose, respectively. Twenty five mono-dose bottles and a multi-dose bottle of each batch were stored under room conditions (20 ± 1 °C) and the rest of the samples were stored in the fridge (5 ± 2 °C). The physical, chemical and microbiological stability was evaluated for 180 days. Stability was defined as retention of at least 95% of the initial concentration of chloral hydrate, the absence of both visible particulate matter, or color and/or odor changes and the compliance with microbiological attributes of non-sterile pharmaceutical products. RESULTS: At least 98% of the initial chloral hydrate concentration remained throughout the 180-day study period. There were no detectable changes in color, odor, specific gravity and pH and no visible microbial growth. These results were not affected by storage, room or refrigeration conditions or by the frequent opening or closing of the multi-dose containers. CONCLUSIONS: Extemporaneously compounded 7% chloral hydrate syrup was stable for at least 180 days when stored in mono or multi-dose light-resistant glass containers at room temperature and under refrigeration.

Stability evaluation of 7% chloral hydrate syrup contained in mono and multi-dose bottles under room and refrigeration conditions

Purpose: To evaluate the stability of an extemporaneously prepared 7% chloral hydrate syrup under different conditions of storage and dispensing. Methods: Three batches of 7% chloral hydrate syrup were prepared. Each batch was stored in 50 light-resistant glass containers of 60 mL with child-resistant caps and in two bottles of 1000 mL to simulate two forms of dispensing, mono and multi-dose, respectively. Twenty five mono-dose bottles and a multi-dose bottle of each batch were stored under room conditions (20 ± 1oC) and the rest of the samples were stored in the fridge (5 ± 2oC). The physical, chemical and microbiological stability was evaluated for 180 days. Stability was defined as retention of at least 95% of the initial concentration of chloral hydrate, the absence of both visible particulate matter, or color and/or odor changes and the compliance with microbiological attributes of non-sterile pharmaceutical products. Results: At least 98% of the initial chloral hydrate concentration remained throughout the 180-day study period. There were no detectable changes in color, odor, specific gravity and pH and no visible microbial growth. These results were not affected by storage, room or refrigeration conditions or by the frequent opening or closing of the multi-dose containers. Conclusions: Extemporaneously compounded 7% chloral hydrate syrup was stable for at least 180 days when stored in mono or multi-dose light-resistant glass containers at room temperature and under refrigeration (AU)

Objetivo: Evaluar la estabilidad de un jarabe extemporáneo de hidrato de cloral al 7% bajo diferentes condiciones de almacenamiento y dispensación. Métodos: Se prepararon tres lotes de hidrato de cloral. Cada lote se almacenó en 50 contenedores de vidrio resistentes a la luz de 60 ml con tapones de protección infantil y en dos botes de 1000 ml para simular dos formas de dispensación, mono y multidosis, respectivamente. Veinticinco envases monodosis y un envase multidosis de cada lote se almacenaron en condiciones ambiente (20 ± 1oC)y el resto de las muestras se almacenaron en el frigorífico (5 ± 2oC). Se evaluaron las estabilidades física, química y microbiológica durante 180 días. Se definió la estabilidad como la retención de al menos el 95% de la concentración inicial del hidrato de cloral, la ausencia de partículas visibles y de cambios en el color y/o el olor, así como el cumplimiento de los requisitos microbiológicos de los productos farmacéuticos no estériles. Resultados: Al menos el 98% de la concentración inicial de hidrato de cloral se mantuvo a lo largo de los 180 días del periodo de estudio. No se apreciaron cambios detectables en el olor, el color ni la densidad o el pH y tampoco se apreció crecimiento microbiológico. Estos resultados no se vieron influidos por las condiciones de almacenamiento, estar a temperatura ambiente o refrigerada ni por la frecuencia de apertura y cierre de los contenedores multidosis. Conclusiones: El compuesto de jarabe de hidrato de cloral extemporáneo al 7% fue estable durante al menos 180 días en envases de vidrio mono o multidosis, resistentes a la luz, a temperatura ambiente y con refrigeració (AU)