Lívia Cristina Lira de Sá-Barreto

Solid effervescent formulations as new approach for topical minoxidil delivery.

&NA; Currently marketed minoxidil formulations present inconveniences that range from a grease hard aspect they leave on the hair to more serious adverse reactions as scalp dryness and irritation. In this paper we propose a novel approach for minoxidil sulphate (MXS) delivery based on a solid effervescent formulation. The aim was to investigate whether the particle mechanical movement triggered by effervescence would lead to higher follicle accumulation. Preformulation studies using thermal, spectroscopic and morphological analysis demonstrated the compatibility between effervescent salts and the drug. The effervescent formulation demonstrated a 2.7‐fold increase on MXS accumulation into hair follicles casts compared to the MXS solution (22.0 ± 9.7 &mgr;g/cm2 versus 8.3 ± 4.0 &mgr;g/cm2) and a significant drug increase (around 4‐fold) in remaining skin (97.1 ± 29.2 &mgr;g/cm2) compared to the drug solution (23.5 ± 6.1 &mgr;g/cm2). The effervescent formulations demonstrated a prominent increase of drug permeation highly dependent on the effervescent mixture concentration in the formulation, confirming the hypothesis of effervescent reaction favoring drug penetration. Clinically, therapy effectiveness could be improved, increasing the administration interval, hence, patient compliance. More studies to investigate the follicular targeting potential and safety of new formulations are needed. Graphical abstract Figure. No caption available.

Simultaneous determination of benznidazole and itraconazole using spectrophotometry applied to the analysis of mixture: A tool for quality control in the development of formulations

The aim of this work was the development of an analytical procedure using spectrophotometry for simultaneous determination of benznidazole (BNZ) and itraconazole (ITZ) in a medicine used for the treatment of Chagas disease. In order to achieve this goal, the analysis of mixtures was performed applying the Lambert-Beer law through the absorbances of BNZ and ITZ in the wavelengths 259 and 321 nm, respectively. Diverse tests were carried out for development and validation of the method, which proved to be selective, robust, linear, and precise. The lower limits of detection and quantification demonstrate its sensitivity to quantify small amounts of analytes, enabling its application for various analytical purposes, such as dissolution test and routine assays. In short, the quantification of BNZ and ITZ by analysis of mixtures had shown to be efficient and cost-effective alternative for determination of these drugs in a pharmaceutical dosage form.

Preparation of benznidazole pellets for immediate drug delivery using the extrusion spheronization technique

Abstract Recent advances in the treatment of Chagas disease have followed combinations of drugs that act synergistically against infection, predominantly including benznidazole (BNZ) and azoles derivatives. Possible incompatibilities between these drugs, slow dissolution of BNZ and dose adjustment difficulties are technological obstacles to the development of multidrug formulations. Thus, in the present study, BNZ pellets were developed using extrusion spheronization for immediate drug delivery. Preformulation studies were then performed using thermal analysis and infrared spectroscopy and compatibility between the drug and selected excipients (polyethylene glycol 6000, sodium starch glycolate, microcrystalline cellulose and sodium croscarmellose) was investigated. No chemical decomposition of BNZ was observed, even in samples submitted to wet granulation and thermal stress. Subsequently, formulations were elaborated according to a simplex lattice experimental design using polyethylene glycol, sodium starch glycolate and sodium croscarmellose as disintegrating agents. In these experiments, BNZ pellets showed appropriate physicochemical characteristics, including high drug load capacity and excellent flow properties. The mixture experimental design allowed identification of adequate compositions of disintegrating agents and achieved rapid disintegration and dissolution of pellets. Optimum performance was achieved using polyethylene glycol and sodium croscarmellose at 5.0% w/w each. The present BNZ pellets are versatile alternatives to treat Chagas disease and provide insights into the preparation of multidrug systems.

Key Technical Aspects Influencing the Accuracy of Tablet Subdivision

Tablet subdivision is a common practice used mainly for dose adjustment. The aim of this study was to investigate how the technical aspects of production as well as the method of tablets subdivision (employing a tablet splitter or a kitchen knife) influence the accuracy of this practice. Five drugs commonly used as subdivided tablets were selected. For each drug, the innovator drug product, a scored-generic and a non-scored generic were investigated totalizing fifteen drug products. Mechanical and physical tests, including image analysis, were performed. Additionally, comparisons were made between tablet subdivision method, score, shape, diluent composition and coating. Image analysis based on surface area was a useful tool as an alternative assay to evaluate the accuracy of tablet subdivision. The tablet splitter demonstrates an advantage relative to a knife as it showed better results in weight loss and friability tests. Oblong, coated and scored tablets had better results after subdivision than round, uncoated and non-scored tablets. The presence of elastic diluents such as starch and dibasic phosphate dehydrate conferred a more appropriate behaviour for the subdivision process than plastic materials such as microcrystalline cellulose and lactose. Finally, differences were observed between generics and their innovator products in all selected drugs with regard the quality control assays in divided tablet, which highlights the necessity of health regulations to consider subdivision performance at least in marketing authorization of generic products.

Taste masking and rheology improvement of drug complexed with beta-cyclodextrin and hydroxypropyl-β-cyclodextrin by hot-melt extrusion

This study aimed to mask fluconazole (FLU) taste and improve its rheological properties by an efficient process of cyclodextrin complexation. For this, hot-melt extrusion (HME) was used to obtain extrudates composed of FLU, hydroxypropylcellulose, and one of two different cyclodextrins (β-cyclodextrin or hydroxypropyl-β-cyclodextrin) maintaining the drug:cyclodextrin molar ratio at 1:0.3 or 1:0.2, respectively. Samples were characterized by physicochemical tests, palatability using e-tongue and antifungal assays. Drug stability was preserved after HME, according to spectroscopy test (correlation coefficient >0.9) and HPLC-assay (100-107%). Flowability was improved in HME systems with compressibility of <12%. Similarly, floodability exhibited significant enhancement (dispersibility <10%). Whereas extrudates of FLU containing only the polymeric matrix led to a slow drug dissolution efficiency (18.6%) and a partial drug taste masking; extrudates containing cyclodextrin accelerated FLU dissolution (dissolution efficiency approx. 30%) and provided a complete drug taste masking. Moreover, HME process could produce drug complexes with high complexation efficiency and preserve its antifungal activity.

Development and physical evaluation of Maytenus ilicifolia effervescent granules using factorial design

The medicinal plant Maytenus ilicifolia is a commonly used phytomedicine for the treatment of gastritis. The high dose required and low density of these extracts make necessary a daily intake of several capsules, hindering adherence to the medication. The purpose of this work was to develop a suitable dosage form for the administration of Maytenus ilicifolia using effervescent granules. A 23 factorial design was used to study the physical characteristics of the granules (particle size distribution, repose angle, Carr index, scanning electron microscopy and disintegration time). Moisture stability was also determined. According to the experimental design, granule size is the most important factor in determining the flow characteristics of effervescent granules. In turn, the disintegration time is controlled by the content of sodium bicarbonate present in the effervescent mixture as well as the granule size. The stability of formulations when exposed to moisture is strongly influenced by the percentage of effervescent mixture present in the vegetal granules. Precautions in handling and storage should be taken to ensure the stability of these preparations. The effervescent granules produced from Maytenus ilicifolia met the pharmacopoeial quality parameters, with appropriate mechanical and physical characteristics and proved to be a promising vehicle for plant extracts.

Preformulation studies of finasteride to design matrix systems for topical delivery

Graphical abstract Figure. No Caption available. HighlightsPreformulation of finasteride was performed using a simplex centroid mixture design.Drug interaction with polymers and cyclodextrin were identified by thermal analysis.Hydroxypropyl cellulose facilitated cyclodextrin‐drug inclusion complex formation.Chemical stability of the different mixtures was preserved after thermal treatment.Interaction with excipients suggest s a stabilization of the original drug crystalline phase. ABSTRACT A preformulation study with finasteride (FIN) was conducted to enable the development of a topical matrix system to treat androgenic alopecia. The compatibility of the drug with hidroxypropyl‐&bgr;‐cyclodextrin (HP&bgr;CD) and the hydrophilic polymers Klucel EXF (KLU) and Soluplus (SOL) were evaluated according to a simplex centroid mixture design. An extensive analytical arsenal was used to encompass the stability of the drug in the different mixtures. The selected excipients showed to have intense thermal interaction with FIN, which was dependent on the composition of the sample, shifting FIN melting peak to reduced temperatures along with the decrease of its associated enthalpy. The mixture design allowed measuring the interactions between components, showing that KLU enhanced the ability of the drug to form inclusion complexes with HP&bgr;CD, while SOL exhibited the opposite effect. The stability of samples was preserved even after a thermal treatment used to simulate pharmaceutical processing. Indeed, no drug content decaying was observed, which corroborates the chemical stability of the systems as indicated by thermogravimetry, chromatographic, morphological and spectroscopic assays. The original crystalline phase of the drug (orthorhombic form I) did not change after the heating treatment of the samples, demonstrating its physical stability. Thus, these series of experiments may guide the development of delivery systems for topical use of FIN, showing which combinations and proportions of components can lead to better results in terms of stability and drug delivery.

Subdivision of Tablets Containing Modified Delivery Technology: the Case of Orally Disintegrating Tablets

PurposeClinical practice suggests orally disintegrating tablets (ODTs) may be subdivided for dose adjustments, however there are no studies evaluating the effect of this practice in ODTs quality parameters. This work was therefore dedicated to elucidating the impact of the tablet subdivision on ten selected ODTs produced by different technologies.MethodsStructural properties were assessed using weight; dimensions; image analysis; moisture content and porosimetry evaluations. Functional evaluations were also performed by disintegration and wetting assays. Tablets were evaluated just after subdivision and after an accelerated aging.ResultsOutcomes suggest the manufacturing method plays an important role in the suitability of ODTs for subdivision. While tablets containing granules immersed in a powdered matrix structure showed poor subdivision performance, with high weight variation and weight loss, tablets obtained by freeze-drying or direct compression of powder mixtures showed acceptable levels of these parameters and could be subdivided for immediate use. Aged tablets revealed structural and/or functional damages for all analyzed drug products, which includes softening of their matrices, water uptake and darkening, with loss of their disintegration and wetting capacities, which suggest inadequacy of ODTs subdivision for later use.ConclusionsThe results exposed in this study could be useful for the clinical decision on the subdivision of this tablets category.