Synthesis and characterization of a new cyclodextrin derivative with improved properties to design oral dosage forms.

This work aimed to synthesize a novel ß-cyclodextrin derivative, itaconyl-ß-cyclodextrin to evaluate whether albendazole inclusion complexes with the new ß-cyclodextrin derivative-improved albendazole dissolution efficiency and its anthelminthic activity. The new derivative was thoroughly evaluated and characterized, and an average degree of substitution of 1.4 per cyclodextrin molecule was observed. Albendazole:itaconyl-ß-cyclodextrin complexes were prepared by spray drying procedures and investigated using phase solubility diagrams, dissolution efficiency, X-ray diffraction, differential scanning calorimetry, Fourier transform infrared, scanning electronic microscopy, mass spectrometry, and nuclear magnetic resonance spectroscopy. Phase solubility diagrams and mass spectrometry studies showed that the inclusion complex was formed in an equimolar ratio. Stability constant values were 602 M-1 in water, and 149 M-1 in HCl 0.1 N. Nuclear magnetic resonance experiments of the inclusion complex showed correlation signals between the aromatic and propyl protons of albendazole and the itaconyl-ß-cyclodextrin inner protons. The studies indicated solid structure changes of albendazole included in itaconyl-ß-cyclodextrin. The maximum drug release was reached at 15 min, and the inclusion complex solubility was 88-fold higher than that of the pure drug. The in vitro anthelmintic activity assay showed that the complex was significantly more effective than pure albendazole.

Repositioning of Anti-parasitic Drugs in Cyclodextrin Inclusion Complexes for Treatment of Triple-Negative Breast Cancer.

Drug repositioning refers to the identification of new therapeutic indications for drugs already approved. Albendazole and ricobendazole have been used as anti-parasitic drugs for many years; their therapeutic action is based on the inhibition of microtubule formation. Therefore, the study of their properties as antitumor compounds and the design of an appropriate formulation for cancer therapy is an interesting issue to investigate. The selected compounds are poorly soluble in water, and consequently, they have low and erratic bioavailability. In order to improve their biopharmaceutics properties, several formulations employing cyclodextrin inclusion complexes were developed. To carefully evaluate the in vitro and in vivo antitumor activity of these drugs and their complexes, several studies were performed on a breast cancer cell line (4T1) and BALB/c mice. In vitro studies showed that albendazole presented improved antitumor activity compared with ricobendazole. Furthermore, albendazole:citrate-ß-cyclodextrin complex decreased significantly 4T1 cell growth both in in vitro and in vivo experiments. Thus, new formulations for anti-parasitic drugs could help to reposition them for new therapeutic indications, offering safer and more effective treatments by using a well-known drug.

Modified ß-cyclodextrin inclusion complex to improve the physicochemical properties of albendazole. complete in vitro evaluation and characterization.

The potential use of natural cyclodextrins and their synthetic derivatives have been studied extensively in pharmaceutical research and development to modify certain properties of hydrophobic drugs. The ability of these host molecules of including guest molecules within their cavities improves notably the physicochemical properties of poorly soluble drugs, such as albendazole, the first chosen drug to treat gastrointestinal helminthic infections. Thus, the aim of this work was to synthesize a beta cyclodextrin citrate derivative, to analyze its ability to form complexes with albendazole and to evaluate its solubility and dissolution rate. The synthesis progress of the cyclodextrin derivative was followed by electrospray mass spectrometry and the acid-base titration of the product. The derivative exhibited an important drug affinity. Nuclear magnetic resonance experiments demonstrated that the tail and the aromatic ring of the drug were inside the cavity of the cyclodextrin derivative. The inclusion complex was prepared by spray drying and full characterized. The drug dissolution rate displayed exceptional results, achieving 100% drug release after 20 minutes. The studies indicated that the inclusion complex with the cyclodextrin derivative improved remarkably the physicochemical properties of albendazole, being a suitable excipient to design oral dosage forms.

Recentes avanços no tratamentoda doença de Chagas / Recent advances in the treatment of Chagas disease

Descoberta há cem anos, a doença de Chagas afetaa mais de quinze milhões de pessoas em toda aAmérica Latina e, ainda hoje, não há tratamentoeficaz. O fármaco benznidazol, utilizado como únicaopção de tratamento no Brasil, é ineficaz na fasecrônica da doença. Problemas relacionados à biodisponibilidadedo medicamento comercial limitam suaeficácia, principalmente na fase crônica, quando osparasitos estão confinados em tecidos profundos eem lenta replicação. Nesse contexto, pesquisas lideradaspor grupos brasileiros e argentinos vêm sendoconduzidas com o objetivo de desenvolver formulaçõesde benznidazol mais eficientes. Diversas formasfarmacêuticas sólidas e líquidas foram propostas nosúltimos anos com resultados pré-clínicos promissores,sendo descritas melhorias acentuadas nas característicasfarmacocinéticas desse fármaco. Espera-seque as formas inovadoras apresentadas possam seravaliadas em ensaios clínicos e incorporadas à produçãoindustrial em breve.

Discovered about a hundred years ago, Chagas diseasecurrently affects more than fifteen million people in LatinAmerica, and it still remains without any effective treatment.Although benznidazole has been used as the onlypharmacotherapeutic option to treat Chagas disease inBrazil, it is ineffective in the chronic phase of the disease,when the parasites are confined to deep tissue layers andslowly replicate. This happens mainly due to problems related to the bioavailability of the drug, which is currentlyin the market. In this context, Brazilian and Argentineanresearch groups have conducted studies to develop moreefficient benznidazole formulations. Several solid andliquid formulations have been proposed over the last fewyears with promising preclinical results. Improvementsin the pharmacokinetic properties of this drug have beendescribed. Therefore, it is expected, that such innovative drugs and formulations be assessed in clinical trials andsoon incorporated to industrial production.

Preparation, characterization and dissolution studies of fast release diclofenac sodium tablets from PVP solid dispersions.

Diclofenac sodium is a non-steroidal anti-inflammatory drug widely used in the treatment of ankylosing spondylitis, rheumatoid arthritis and osteoarthritis. In this context, a rapid onset of action is required. Thus, the aim of this study was to formulate diclofenac sodium-PVP K-30 fast release tablets from solid dispersions. The physical state and drug:carrier interactions were analyzed by X-ray diffraction and scanning electron microscopy and stability upon storage was also studied. Dissolution rate of diclofenac sodium from solid dispersions was markedly enhanced by increasing the polymer concentration.

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.

Desarrollo de nuevas formulaciones coloidales para el tratamiento de la enfermedad del Chagas

Actualmente, no existe en forma comercial ninguna forma farmacéutica líquida (oral o inyectable) para la administración de BZL. Desde el punto de vista clínico y tecnológico es fundamental contar con una alternativa a las formas farmacéuticas sólidas, sobre todo en tratamientos sistémicos continuados para infantes (gotas y solución bebible). Los coadyuvantes de solubilidad empleados en este trabajo no son tóxicos, y permiten que la forma farmacéutica líquida sea estable en el tiempo. En el caso de las formulaciones inyectables, no se presentan incompatibilidades con el envase, ni problemas de precipitación y/o degradación luego del proceso de esterilización. La gran ventaja que presentan las formulaciones liquidas en comparación con las sólidas, es un incremento de la biodisponibilidad de los principios activos poco solubles en agua, posibilitando, una absorción mas rápida y la posibilidad de emplear menores dosis, disminuyendo de esta manera los efectos secundarios que presenta la droga. Estos resultados son muy promisorios y demuestran que los ensayos realizados permiten la solubilización y posterior formulación de soluciones orales y parenterales de BZL, de potencial administración en humanos.

Desarrollo de nuevas formulaciones coloidales para el tratamiento de la enfermedad del Chagas

Actualmente, no existe en forma comercial ninguna forma farmacéutica líquida (oral o inyectable) para la administración de BZL. Desde el punto de vista clínico y tecnológico es fundamental contar con una alternativa a las formas farmacéuticas sólidas, sobre todo en tratamientos sistémicos continuados para infantes (gotas y solución bebible). Los coadyuvantes de solubilidad empleados en este trabajo no son tóxicos, y permiten que la forma farmacéutica líquida sea estable en el tiempo. En el caso de las formulaciones inyectables, no se presentan incompatibilidades con el envase, ni problemas de precipitación y/o degradación luego del proceso de esterilización. La gran ventaja que presentan las formulaciones liquidas en comparación con las sólidas, es un incremento de la biodisponibilidad de los principios activos poco solubles en agua, posibilitando, una absorción mas rápida y la posibilidad de emplear menores dosis, disminuyendo de esta manera los efectos secundarios que presenta la droga. Estos resultados son muy promisorios y demuestran que los ensayos realizados permiten la solubilización y posterior formulación de soluciones orales y parenterales de BZL, de potencial administración en humanos.

Desarrollo de nuevas formulaciones coloidales para el tratamiento de la enfermedad del Chagas

Actualmente, no existe en forma comercial ninguna forma farmacéutica líquida (oral o inyectable) para la administración de BZL. Desde el punto de vista clínico y tecnológico es fundamental contar con una alternativa a las formas farmacéuticas sólidas, sobre todo en tratamientos sistémicos continuados para infantes (gotas y solución bebible). Los coadyuvantes de solubilidad empleados en este trabajo no son tóxicos, y permiten que la forma farmacéutica líquida sea estable en el tiempo. En el caso de las formulaciones inyectables, no se presentan incompatibilidades con el envase, ni problemas de precipitación y/o degradación luego del proceso de esterilización. La gran ventaja que presentan las formulaciones liquidas en comparación con las sólidas, es un incremento de la biodisponibilidad de los principios activos poco solubles en agua, posibilitando, una absorción mas rápida y la posibilidad de emplear menores dosis, disminuyendo de esta manera los efectos secundarios que presenta la droga. Estos resultados son muy promisorios y demuestran que los ensayos realizados permiten la solubilización y posterior formulación de soluciones orales y parenterales de BZL, de potencial administración en humanos.