Claudio J. Salomon

First Century of Chagas' Disease: An Overview on Novel Approaches to Nifurtimox and Benznidazole Delivery Systems

Hundred years after the discovery of Chagas disease, there is a lack of effective treatment to control this neglected disease caused by the parasite Trypanosoma cruzi. The transmission is primarily through vector-borne blood transfusion or during pregnancy, producing high mortality and morbidity among poor people in many countries of Latin America. In the last decades, the efforts have been focused mainly on the elimination of vectors. At the same time, screening of blood donors in order to avoid transfusional transmission has been improved all over the world. However, Chagas disease is still a major public health problem, with estimates of nearly 90 million people at risk of infection and more than eight million infected in 18 endemic countries. Despite the high incidence in endemic regions and the dissemination of neglected diseases in North America and Europe, to date, there are only two drugs developed and prescribed for the treatment of Chagas disease, nifurtimox (tablets of 120 mg) and benzonidazole (tablets of 100 mg). In this review, different approaches carried out in the last decades for developing novel pharmaceutical formulations for the delivery of nifurtimox and benznidazole are discussed.

Development of prednisone: Polyethylene glycol 6000 fast-release tablets from solid dispersions: Solid-state characterization, dissolution behavior, and formulation parameters

The aim of the current study was to design oral fast-release polymeric tablets of prednisone and to optimize the drug dissolution profile by modifying the carrier concentration. Solid dispersions were prepared by the solvent evaporation method at different drug:polymer ratios (wt/wt). The physical state and drug:carrier interactions were analyzed by X-ray diffraction, infrared spectroscopy, and scanning electron microscopy. The dissolution rate of prednisone from solid dispersions was markedly enhanced by increasing the polymer concentration. The tablets were prepared from solid dispersion systems using polyethylene glycol (PEG) 6000 as a carrier at low and high concentration. The results showed that PEG 6000-based tablets exhibited a significantly higher prednisone dissolution (80% within 30 minutes) than did conventional tablets prepared without PEG 6000 (<25% within 30 minutes). In addition, the good disintegration and very good dissolution performance of the developed tablets without the addition of superdisintegrant highlighted the suitability of these formulated dosage forms. The stability studies performed in normal and accelerated conditions during 12 months showed that prednisone exhibited high stability in PEG 6000 solid dispersion powders and tablets. The X-ray diffraction showed that the degree of crystallinity of prednisone in solid dispersions decreased when the ratio of the polymer increased, suggesting that the drug is present inside the samples in different physical states. The Fourier transform infrared spectroscopic studies showed the stability of prednisone and the absence of well-defined drug:polymer interactions. Scanning electron microscopy images showed a novel morphology of the dispersed systems in comparison with the pure components.

Development of novel formulations for Chagas' disease: optimization of benznidazole chitosan microparticles based on artificial neural networks.

Benznidazole (BZL) is one of the two therapeutic agents used for the treatment of Chagas disease. However, the use of BZL in most pharmaceutical preparations and research experiments is still limited due to its low water solubility (0.4mg/mL). To overcome the dissolution rate-limiting step in oral absorption, chitosan microparticles prepared by the coacervation method were chosen, owing to non-toxicity of the polymer and mild conditions of the method. The influence of process parameters such as encapsulation efficiency, size, yield, and dissolution rate was optimized by using artificial neural networks (ANNs). The optimal conditions were found to be 1.5% (w/v) for the polymer concentration, 6.0% (w/v) for the coacervation agent concentration, 1400.0rpm for the stirring rate, and 5.0mL/min for the spraying rate. Confirmation experiments showed good agreement between predicted and experimental values of the optimized properties. These results indicate that ANNs is a valuable tool for the development of optimized BZL chitosan microparticles. To our knowledge it is the first report based on the development of optimized BZL microparticles.

Bis (tributyltin) oxide. A mild, neutral and selective reagent for cleavage of esters. Scope and limitation of the reaction

Abstract Bis(tributyltin)oxide acts as a mild, neutral and chemoselective ester cleavage reagent for a variety of carboxylic esters with good to excellent yields. The acyl-oxygen cleavage mechanism of (−)-(1R) menthyl acetate is discussed.

Development and Evaluation of Buccal Films Based on Chitosan for the Potential Treatment of Oral Candidiasis

In this work, chitosan films were prepared by a casting/solvent evaporation methodology using pectin or hydroxypropylmethyl cellulose to form polymeric matrices. Miconazole nitrate, as a model drug, was loaded into such formulations. These polymeric films were characterized in terms of mechanical properties, adhesiveness, and swelling as well as drug release. Besides, the morphology of raw materials and films was investigated by scanning electron microscopy; interactions between polymers were analyzed by infrared spectroscopy and drug crystallinity studied by differential scanning calorimetry and X-ray diffraction. In addition, antifungal activity against cultures of the five most important fungal opportunistic pathogens belonging to Candida genus was investigated. Chitosan:hydroxypropylmethyl cellulose films were found to be the most appropriate formulations in terms of folding endurance, mechanical properties, and adhesiveness. Also, an improvement in the dissolution rate of miconazole nitrate from the films up to 90% compared to the non-loaded drug was observed. The in vitro antifungal activity showed a significant activity of the model drug when it is loaded into chitosan films. These findings suggest that chitosan-based films are a promising approach to deliver miconazole nitrate for the treatment of candidiasis.

13C and 15N solid-state NMR studies on albendazole and cyclodextrin albendazole complexes

(13)C and (15)N solid-state nuclear magnetic resonance (NMR) spectra were recorded from albendazole (ABZ) and from ABZ:β-cyclodextrin, ABZ:methyl-β-cyclodextrin, ABZ:hydroxypropyl-β-cyclodextrin and ABZ:citrate-β-cyclodextrin, which were prepared by the spray-drying technique. ABZ signals were typical of a crystalline solid for the pure drug and of an amorphous compound obtained from ABZ:cyclodextrin samples. Relevant spectral differences were correlated with chemical interaction between ABZ and cyclodextrins. The number and type of complexes revealed a strong dependence on the cyclodextrin group substituent. Solid-state NMR data were consistent with the presence of stable inclusion complexes.

Unexpected solvent impact in the crystallinity of praziquantel/poly(vinylpyrrolidone) formulations. A solubility, DSC and solid-state NMR study.

The saturation solubility of PVP:PZQ physical mixtures (PMs) and solid dispersions (SDs) prepared from ethanol (E/E) or ethanol/water (E/W) by the solvent evaporation method at 1:1, 2:1 and 3:1 ratio (w/w) was determined. The presence of PVP improves the solubility of PZQ (0.31±0.01mg/mL). A maximum of 1.29±0.03mg/mL of PZQ in solution was achieved for the 3:1 SD (E/E). The amount of PZQ in solution depends on the amount of polymer and on the preparation method. Solid-state NMR (ssNMR) and DSC were used to understand this behavior. Results show that PMs are a mixture of crystalline PZQ with the polymer, while SDs show different degrees of drug amorphization depending on the solvent used. For E/W SDs, PZQ exists in amorphous and crystalline states, with no clear correlation between the amount of crystalline PZQ and the amount of PVP. For E/E SDs, formulations with a higher percentage of PZQ are amorphous with the components miscible in domains larger than 3nm ((1)H ssNMR relaxation measurements). Albeit its higher saturation solubility, the 3:1 E/E PVP:PZQ sample has a significant crystalline content, probably due to the water introduced by the polymer. High PVP content and small crystal size account for this result.

Recent Trends in the Development of Chitosan-Based Drug Delivery Systems

The 2015 12th International Conference of the European Chitin Society jointly with 13th International Conference on Chitin and Chitosan (EUCHIS/ICCC 2015) was held from August 30th to September 2nd in Münster, Germany. This was the first ICCC held in Germany and the first one to be cosponsored by AAPS and AAPS PharmSciTech journal, the International Union of Pure and Applied Chemistry (IUPAC), the European Chitin Society (EUCHIS), the University of Münster, along with several companies. With more than 300 attendees from all over the world, it was also probably the largest ever chitin and chitosan conference and the first one with a sizeable industrial exhibition. A Young Researcher Symposium preceded the conference, and it was followed by three parallel postconference workshops, namely on Chitosan Analysis, Mucoadhesion, and Electrospinning, the latter sponsored by the COST Action MP1206. The AAPS PharmSciTech journal sponsored the Award to the Best Poster in the Pharmaceutical Sciences. The poster prize was awarded to Ayben Işılay Doğan, Gulcin Akça, and Sevda Şenel from Hacettepe University (Turkey) for their work on Chitosan based formulations of atorvastatin for periodontal delivery. Chitosan has long been recognized as one of the most promising functional biopolymers, with potential applications in areas as diverse as material, food, agricultural, biomedical, and pharmaceutical sciences. Research of the past decade or so has paved the way for today’s Bsecond generation^ chitosans with better-defined structures and more reliable functions than the early ill-defined Bfirst-generation^ materials. This special volume of AAPS PharmSciTech, entitled BTheme: Recent Trends in the Development of ChitosanBased Drug Delivery Systems,^ includes a topical collection of a total of 14 papers including both articles from EUCHIS/ ICCC 2015 plus others freely contributed manuscripts that successfully passed the normal rigorous peer review process addressing a diversity of topics. The first article describes the advantages of chitosan matrices for the development of buccal mucoadhesive devices. These types of biopolymeric formulations generate hydrophilic networks that contain numerous polar functional groups that interact with biological structures. Tejada et al. [1] describe the formulation of miconazole nitrate buccal films using chitosan, pectin, and hydroxypropylmethyl cellulose to form such polymeric matrices. Chitosan:hydroxypropylmethyl cellulose films were found to be the most appropriate formulations in terms of folding endurance, mechanical properties, and adhesiveness. The in vitro antifungal activity showed a significant activity of the model drug loaded into those films. Reduction of particle size is an attractive and widely used technique to improve the aqueous solubility of poorly watersoluble compounds belonging to the class II of the Biopharmaceutical Classification System. Herein, Priotti et al. [2] reported the preparation of albendazole microcrystals using the bottom-up technology based on chitosan and cellulose derivatives. The concentration of polymers, the influence of surfactant in the crystals, the variables area under the curve, albendazole microcrystal solubility, and drug released were analyzed with a three-way ANOVA. The in vitro studies demonstrated the suitability of this approach for further in vivo studies. Microencapsulation is still one of the most suitable procedures to prepare controlled drug delivery systems, and the type of selected polymers used as carrier is one of the key 1 Facultad de Cs. Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, IQUIR-CONICET, Suipacha 531, 2000, Rosario, Argentina. 2 School of Food Science and Nutrition, University of Leeds, Leeds, LS2 9JT, UK. 3 Institut für Biologie und Biotechnologie der Pflanzen Westfälische Wilhelms-Universtät Münster, Schlossgarten 3, 48149, Münster, Germany. 4 To whom correspondence should be addressed. (e-mail: csalomon@fbioyf.unr.edu.ar) AAPS PharmSciTech (# 2017) DOI: 10.1208/s12249-017-0764-7

First solid-state NMR spectroscopy evaluation of complexes of benznidazole with cyclodextrin derivatives

Complexation of benznidazole (BZL), a drug of choice for the treatment of Chagasneglected disease, with cyclodextrin (CD) derivatives was analyzed by solid-state NMR. (13)C cross polarization/magic angle spinning spectra were recorded from BZL and from BZL:β-CD, BZL:methyl β-CD and BZL:hydroxypropyl β-CD complexes, which were obtained by the solvent evaporation technique. No significant evidence was obtained on BZL inclusion complexes involving either β-CD or hydroxypropyl β-CD. Conversely, BZL:methyl β-CD displayed BZL resonances characteristic of an amorphous drug and data analysis confirmed the presence of stable BZL:methyl β-CD inclusion complexes, with benzene encapsulated into the host cavity. Further evidences on complex structure and dynamics were obtained from proton and carbon spin-lattice relaxation times in the rotating frame. These data are consistent with a common guest-host spin reservoir. The BZL interaction with methyl β-CD provided a route to stabilize amorphous BZL. Physical mixtures with identical BZL and CD compositions were also studied for comparison.

The 1st International Meeting on Pharmaceutical Sciences (1er RICiFa)

Dear Colleagues n nFirst of all we would like to wish you all the best for 2010! n nThe First International Meeting on Pharmaceutical Sciences (1erRICiFa) will be held in Cordoba on the 24th and 25th June 2010, bringing together a high number of scientists from the academy as well as members of the pharmaceutical industry to exchange new knowledge and best practices and to discuss several issues related with the pharmaceutical sciences. n nThis conference is devoted to established topics such as advanced drug delivery systems, pharmaceutical biotechnology, micro and nanotechnology, natural products, pharmacology, and many more which will be dealt with in short oral and poster presentations. n nIn addition, a Workshop on Pharmacy Practice and Education is going to be organized during this meeting. As you know, education plays an extremely important role in preparing pharmacy students for several professional activities. It serves to ensure knowledge, skills, attitudes, and behavior required of pharmacists in order to contribute to communities and health systems in the best possible ways. Whether you are a student pharmacist, this meeting will provide educational programming and networking to keep you on track in your day-to-day practice. n nThis meeting will give you the opportunity to generate novel ideas, practices, cultural diversity, and practices in order to promote positive changes in pharmacy education and for pharmacy to progress globally as a profession. n nThe AAPS PharmSciTech Journal [http://www.pharmagateway.net/PharmSciTech] will publish an editorialized version of the proceedings including the presentation abstracts and presenters biographies. n nThe details on the scientific program, registration, and other useful information about the conference will be presented next month. n nThe versatile program of the congress as well as an attractive social program in this beautiful and historical city will enable you to share your experience with colleagues, discuss interesting topics with the experts on a highly professional level, establish new business connections, and meet new and old friends. n nThe chairs of the conference cordially invite you to join the First International Meeting and would be glad to welcome you in Cordoba! n nOn behalf of the organizing committee n nChairs of the Conference n nProf. Dr. Santiago Palma, University of Cordoba (Argentina) n nProf. Dr. Claudio Salomon, University of Rosario (Argentina) n nContact information:ricifa2010@gmail.com n nFor additional details on this event, visit: www.fbioyf.unr.edu.ar