Cavitandos naturales y de síntesis: desafíos y respuestas en química y tecnología farmacéutica / Natural and synthetic cavitands: challenges in chemistry and pharmaceutical technology

La química supramolecular es la base para numerosas aplicaciones en síntesis, catálisis, separaciones quirales, diseño de sensores químicos, así como en procesos de señalización, vehiculización y trasporte de fármacos. Ciertas supramoléculas pueden combinarse y auto-ensamblarse dando lugar a entidades con geometría y topología exclusiva.Se denominan cavitandos al conjunto de supramoléculas que tiene una cavidad central capaz de reconocer y alojar en su interior una variedad de especies. Entre los cavitandos de síntesis sobresalen los éteres corona, calixarenos, y los cucurbiturilos, presentando indudables cualidades ventajosas las porfirinas y las ciclodextrinas. Las ciclodextrinas ofrecen numerosas ventajas comparados con otros cavitandos, ya que ya que son productos naturales obtenidas a partir del almidón, lo cual las hace muy atractivas desde el punto de vista de la química sostenible. Se producen a escala industrial a través de un proceso enzimático relativamente sencillo y a un precio razonable. Los efectos secundarios o tóxicos a que pueden dar lugar son prácticamente inexistentes, por lo que se utilizan en la industria farmacéutica, cosmética y alimentaria.En este trabajo se revisa la utilidad las ciclodextrinas en el campo de la tecnología farmacéutica, incrementando la solubilidad y estabilidad de fármacos y mejorando sus propiedades farmacocinéticas. (AU)

Supramolecular chemistry involves non-covalent interactions and specific molecular recognition of molecules/analytes by host molecules or supramolecules. These events are present in synthesis, catalysis, chiral separations, design of sensors, cell signaling processes and drug transport by carriers. The typical behavior of supramolecules is derived from their ability to build well-structured self-assembled and self-organized entities.Cavitands are a particular group of supramolecules possessing a cavity able to include a variety of compounds thanks to host-guest non-covalent interactions developed among cavitands and analytes. Some typical cavitands are crown ethers, calixarenes, cucurbiturils, porphyrins and cyclodextrins. The two latter families are natural product cavitands that are generally considered models for molecular recognition of cations and organic and inorganic guest molecules, being attractive host molecules from the sustainability point of view. The natural cyclodextrins (𝛼-, 𝛽- and 𝛾-CD) are obtained with reasonable cost by enzymatic treatment of starch under adequate temperature conditions. They are profusely used in pharmaceutical, food and cosmetic industries due to their very low toxicity and side effects.This review is focused on the relevance and applications of cyclodextrins in pharmaceutical technology for their ability to increase solubility and stabilize drug molecules, thereby enhancing their bioavailability. The association of cyclodextrins with diverse nanostructured materials, i.e. carbon nanotubes, magnetic nanoparticles, silica and molecularly imprinted polymers, allows to synergize the properties of cyclodextrins and these nanostructured materials to reach highly specific molecular recognition of analytes. (AU)

Cavitandos naturales y de síntesis: desafíos y respuestas en química y tecnología farmacéutica / Natural and synthetic cavitands: challenges in chemistry and pharmaceutical technology

La química supramolecular es la base para numerosas aplicaciones en síntesis, catálisis, separaciones quirales, diseño de sensores químicos, así como en procesos de señalización, vehiculización y trasporte de fármacos. Ciertas supramoléculas pueden combinarse y auto-ensamblarse dando lugar a entidades con geometría y topología exclusiva.Se denominan cavitandos al conjunto de supramoléculas que tiene una cavidad central capaz de reconocer y alojar en su interior una variedad de especies. Entre los cavitandos de síntesis sobresalen los éteres corona, calixarenos, y los cucurbiturilos, presentando indudables cualidades ventajosas las porfirinas y las ciclodextrinas. Las ciclodextrinas ofrecen numerosas ventajas comparados con otros cavitandos, ya que ya que son productos naturales obtenidas a partir del almidón, lo cual las hace muy atractivas desde el punto de vista de la química sostenible. Se producen a escala industrial a través de un proceso enzimático relativamente sencillo y a un precio razonable. Los efectos secundarios o tóxicos a que pueden dar lugar son prácticamente inexistentes, por lo que se utilizan en la industria farmacéutica, cosmética y alimentaria. (AU)

Supramolecular chemistry involves non-covalent interactions and specific molecular recognition of molecules/analytes by host molecules or supramolecules. These events are present in synthesis, catalysis, chiral separations, design of sensors, cell signaling processes and drug transport by carriers. The typical behavior of supramolecules is derived from their ability to build well-structured self-assembled and self-organized entities.Cavitands are a particular group of supramolecules possessing a cavity able to include a variety of compounds thanks to host-guest non-covalent interactions developed among cavitands and analytes. Some typical cavitands are crown ethers, calixarenes, cucurbiturils, porphyrins and cyclodextrins. The two latter families are natural product cavitands that are generally considered models for molecular recognition of cations and organic and inorganic guest molecules, being attractive host molecules from the sustainability point of view. The natural cyclodextrins (𝛼-, 𝛽- and 𝛾-CD) are obtained with reasonable cost by enzymatic treatment of starch under adequate temperature conditions. They are profusely used in pharmaceutical, food and cosmetic industries due to their very low toxicity and side effects.This review is focused on the relevance and applications of cyclodextrins in pharmaceutical technology for their ability to increase solubility and stabilize drug molecules, thereby enhancing their bioavailability. The association of cyclodextrins with diverse nanostructured materials, i.e. carbon nanotubes, magnetic nanoparticles, silica and molecularly imprinted polymers, allows to synergize the properties of cyclodextrins and these nanostructured materials to reach highly specific molecular recognition of analytes. The exploitation of these benefits for analytical sample pre-treatment and chiral chromatographic separations are described. (AU)

Atorvastatin calcium loaded chitosan nanoparticles: in vitro evaluation and in vivo pharmacokinetic studies in rabbits / Atorvastatina de cálcio carregadas nanopartículas de quitosana: avaliação farmacocinética in vitro e in vivo em estudos de coelhos

In this study, we prepared atorvastatin calcium (AVST) loaded chitosan nanoparticles to improve the oral bioavailability of the drug. Nanoparticles were prepared by solvent evaporation technique and evaluated for its particle size, entrapment efficiency, zeta potential, in vitro release and surface morphology by scanning electron microscopy (SEM). In addition, the pharmacokinetics of AVST from the optimized formulation (FT5) was compared with marketed immediate release formulation (Atorva^(r)) in rabbits. Particle size of prepared nanoparticles was ranged between 179.3 ± 7.12 to 256.8 ± 8.24 nm with a low polydispersity index (PI) value. Zeta potential study showed that the particles are stable with positive values between 13.03 ± 0.32 to 46.90 ± 0.49 mV. FT-IR studies confirmed the absence of incompatibility of AVST with excipient used in the formulations. In vitro release study showed that the drug release was sustained for 48 h. Results of pharmacokinetics study showed significant changes in the pharmacokinetic parameter (2.2 fold increase in AUC) of the optimized formulation as compared to marketed formulation (Atorva^(r)). Thus, the developed nanoparticles evidenced the improvement of oral bioavailability of AVST in rabbit model...

No presente estudo, preparamos nanopartículas de quitosana com atorvastatina cálcica (AVST) para melhorar a biodisponibilidade oral do fármaco. As nanopartículas foram preparadas pela técnica de evaporação de solvente, avaliando-se a granulometria, a eficiência de encapsulamento, o potencial zeta, a liberação in vitroe a morfologia da superfície, por meio da microscopia eletrônica de varredura (MEV). Além disso, a farmacocinética da formulação otimizada de AVST (FT5) foi comparada com a formulação comercial, de liberação imediata, comercializada (Atorva(r)), em coelhos. O tamanho das das nanopartículas variou na faixa de 179,3 a 256,8 ± 7,12 ± 8,24 nm, com baixo índice polidispersibilidade (PI). O estudo do potencial Zeta mostrou que as partículas são estáveis, com valores positivos entre 13,03 ± 0,32 a 46,90 ± 0,49 mV. Os estudos de FT-IR confirmaram a ausência de incompatibilidade de AVST com o excipiente utilizado nas formulações. O estudo de liberação in vitro mostrou que liberação sustentada do fármaco por 48 horas. Os resultados do estudo farmacocinético mostraram alterações significativas nos parâmetros (aumento de 2,2 vezes na ASC) da formulação otimizada em relação à comercializada (Atorva(r) ). Assim, o desenvolvimento de nanopartículas evidenciou a melhora da biodisponibilidade oral de AVST em coelhos...

Effects of polyethylene glycols on intestinal efflux pump expression and activity in Caco-2 cells

The present study was planned to investigate the influence of polyethylene glycols (PEGs) on the activity and expression of P-glycoprotein (P-gp). Sub-toxic concentrations of PEGs in Caco-2 cells were determined using the MTT test assay. Then the measurement of Rhodamine-123 (Rho-123) uptake, a P-gp fluorescence substrate, in Caco-2 cells confronting PEG 400 (1% and 2% w/v), PEG 4000 (2% and 4% w/v), PEG 6000 (2% and 4% w/v), PEG 10000 (2% and 4% w/v), PEG 15000 (1% and 2% w/v), and PEG 35000 (2% and 4% w/v) overnight was taken to elucidate whether non-toxic concentrations of PEGs are able to impact P-gp activity. Furthermore, western blotting was carried out to investigate P-gp protein expression. The results showed that PEG 400 at concentrations of 1% (w/v) and 2% (w/v) and PEG 6000 at the concentration of 4% (w/v) are notably capable of blocking P-gp. Based on the obtained results it is concluded that the mentioned excipients could be used to obstruct P-gp efflux transporter in order to increase the bioavailability of co-administered substrate drug.

O presente estudo foi planejado para investigar a influência de polietileno glicóis sobre a atividade e expressão da P- glicoproteína (P-gp) . Concentrações sub-tóxicas de PGPs e em células Caco-2 foram determinadas por meio do ensaio de MTT. Em seguida, efetuou-se a a medida de captura de Rodamina-123 (Rho-123), um substrato fluorescente de P-gp, em células Caco-2, confrontando com PEG 400 (1% e 2% m/v), PEG 4000 (2% e 4% m/v) e PEG 6000 (2% e 4% m /v), PEG 10000 (2% e 4% w/v), PEG 15000 (1% e 2% m/v), e PEG 35000 (2% e 4% m/v). Essa medida foi efetuada durante a noite, para saber se as concentrações não tóxicas de excipientes são capazes de influenciar a actividade da P-gp. Além disso, realizou-se o western blotting para investigar a expressão da proteína P-gp. Os resultados mostraram que o PEG 400, nas concentrações de 1% (m/v) e 2% (m/v), e PEG 6000, na concentração de 4% (m/v) são capazes de bloquear P-gp. Com base nos resultados conclui-se que os excipientes mencionados poderiam ser utilizados para obstruir o efluxo por P-gp, a fim de aumentar a biodisponibilidade de do fármaco co-administrado.