Correlación entre modelos in vitro, in situ e in vivo en estudios de absorción

Predecir la magnitud y la velocidad de absorción de una sustancia es crucial en el diseño de medicamentos. En este campo se han empleado distintas metodologías, como modelos in vitro o ensayos in situ o in vivo en animales. Este trabajo analiza modelos matemáticos empleados para estudiar la absorción intestinal y analizar la influencia de tensioactivos en la permeabilidad intestinal; predecir la fracción de dosis absorbida; caracterizar parámetros de absorción pasiva y activa; y establecer correlaciones entre parámetros obtenidos in vitro e in situ. Cuanto más complejo es el modelo tanto mejor se correlaciona con los valores en humanos, pero resultan más difíciles de implementar. Los modelos in vitro resultan bastante adecuados para predecir la absorción cuando se produce por difusión pasiva, pero deficitarios cuando se produce por transporte activo. Se pone de manifiesto la necesidad de continuar desarrollando modelos que permitan el escalado a humanos. Palabras clave: Modelado matemático de la absorción. Predicción de la absorción. Modelos experimentales para la absorción. Correlaciones in vitro-in vivo.      &nbsp

“Development of Fixed Dose Combination Products” Workshop Report: Considerations of Gastrointestinal Physiology and Overall Development Strategy

The gastrointestinal (GI) tract is one of the most popular and used routes of drug product administration due to the convenience for better patient compliance and reduced costs to the patient compared to other routes. However, its complex nature poses a great challenge for formulation scientists when developing more complex dosage forms such as those combining two or more drugs. Fixed dose combination (FDC) products are two or more single active ingredients combined in a single dosage form. This formulation strategy represents a novel formulation which is as safe and effective compared to every mono-product separately. A complex drug product, to be dosed through a complex route, requires judicious considerations for formulation development. Additionally, it represents a challenge from a regulatory perspective at the time of demonstrating bioequivalence (BE) for generic versions of such drug products. This report gives the reader a summary of a 2-day short course that took place on the third and fourth of November at the Annual Association of Pharmaceutical Scientists (AAPS) meeting in 2018 at Washington, D.C. This manuscript will offer a comprehensive view of the most influential aspects of the GI physiology on the absorption of drugs and current techniques to help understand the fate of orally ingested drug products in the complex environment represented by the GI tract. Through case studies on FDC product development and regulatory issues, this manuscript will provide a great opportunity for readers to explore avenues for successfully developing FDC products and their generic versions

Biopharmaceutical optimization in neglected diseases for paediatric patients by applying the provisional paediatric biopharmaceutical classification system

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146268/1/bcp13650.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146268/2/bcp13650_am.pd

Ionic Hydrogel Based on Chitosan Cross-Linked with 6-Phosphogluconic Trisodium Salt as a Drug Delivery System

[EN] In this work, 6-phosphogluconic trisodium salt (6-PG(-)Na(+)) is introduced as a new aqueous and nontoxic cross-linking agent to obtain ionic hydrogels. Here, it is shown the formation of hydrogels based on chitosan cross-linked with 6-PG(-)Na(+). This formulation is obtained by ionic interaction of cationic groups of polymer with anionic groups of the cross linker. These hydrogels are nontoxic, do not cause dermal irritation, are easy to extend, and have an adequate adhesion force to be applied as polymeric film over the skin. This AWN formulation exhibits a first order release kinetic and can be applied as drug vehicle for topical administration or as wound dressing for wound healing. The primary goal of this communication is to report the identification and utility of 6-phosphogluconic trisodium salt (6-PG(-)Na(+)) as a nontoxic cross-linker applicable for cationic polymers.The authors acknowledge partial financial support to project SAF2016-78756 from MINECO (Spanish Ministry of economy, industry and competitiveness). Maria Teresa Martinez Martinez received a grant from the Ministry of Education and Science of Spain (FPU13-01105). The product was patented in Spain in 2016 by authors of this paper. Patent application 201631463.Martínez Martínez, M.; Rodríguez Berna, G.; Gonzalez-Alvarez, I.; Hernández, MJ.; Corma Canós, A.; Bermejo, M.; Merino Sanjuán, V.... (2018). Ionic Hydrogel Based on Chitosan Cross-Linked with 6-Phosphogluconic Trisodium Salt as a Drug Delivery System. Biomacromolecules. 19(4):1294-1304. https://doi.org/10.1021/acs.biomac.8b00108S1294130419

New Insights of Oral Colonic Drug Delivery Systems for Inflammatory Bowel Disease Therapy

[EN] Colonic Drug Delivery Systems (CDDS) are especially advantageous for local treatment of inflammatory bowel diseases (IBD). Site-targeted drug release allows to obtain a high drug concentration in injured tissues and less systemic adverse effects, as consequence of less/null drug absorption in small intestine. This review focused on the reported contributions in the last four years to improve the effectiveness of treatments of inflammatory bowel diseases. The work concludes that there has been an increase in the development of CDDS in which pH, specific enzymes, reactive oxygen species (ROS), or a combination of all of these triggers the release. These delivery systems demonstrated a therapeutic improvement with fewer adverse effects. Future perspectives to the treatment of this disease include the elucidation of molecular basis of IBD diseases in order to design more specific treatments, and the performance of more in vivo assays to validate the specificity and stability of the obtained systems.The authors want to thank the Spanish Government (project RTI2018-100910-B-C41 (MCUI/AEI/FEDER, UE)) and the Generalitat Valenciana (project PROMETEO/2018/024) for support. This work was also supported by the project "MODELOS IN VITRO DE EVALUACION BIOFARMACEUTICA" SAF2016-78756(AEI/FEDER, EU) funded by Agencia Estatal Investigacion and European Union, through FEDER (Fondo Europeo de Desarrollo Regional).Hernández Teruel, A.; Gonzalez-Alvarez, I.; Bermejo, M.; Merino Sanjuán, V.; Marcos Martínez, MD.; Sancenón Galarza, F.; Gonzalez-Alvarez, M.... (2020). New Insights of Oral Colonic Drug Delivery Systems for Inflammatory Bowel Disease Therapy. 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Cyclometalated Iminophosphorane Gold(III) and Platinum(II) Complexes. A Highly Permeable Cationic Platinum(II) Compound with Promising Anticancer Properties

New organometallic gold(III) and platinum(II) complexes containing iminophosphorane ligands are described. Most of them are more cytotoxic to a number of human cancer cell lines than cisplatin. Cationic Pt(II) derivatives 4 and 5, which differ only in the anion, Hg2Cl62– or PF6– respectively, display almost identical IC50 values in the sub-micromolar range (25–335-fold more active than cisplatin on these cell lines). The gold compounds induced mainly caspase-independent cell death, as previously reported for related cycloaurated compounds containing IM ligands. Cycloplatinated compounds 3, 4, and 5 can also activate alternative caspase-independent mechanisms of death. However, at short incubation times cell death seems to be mainly caspase dependent, suggesting that the main mechanism of cell death for these compounds is apoptosis. Mercury-free compound 5 does not interact with plasmid (pBR322) DNA or with calf thymus DNA. Permeability studies of 5 by two different assays, in vitro Caco-2 monolayers and a rat perfusion model, have revealed a high permeability profile for this compound (comparable to that of metoprolol or caffeine) and an estimated oral fraction absorbed of 100%, which potentially makes it a good candidate for oral administration

Estudio cualitativo sobre las barreras y los factores facilitadores en la demanda de los Servicios Profesionales Farmacéuticos Asistenciales en las farmacias comunitarias españolas

Introducción: según estudios recientes, los Servicios Profesionales Farmacéuticos Asistenciales (SPFA) demostraron sus beneficios en la calidad de vida de pacientes y sistemas de salud. Los SPFA son actividades sanitarias prestadas desde la farmacia comunitaria (FC) para la prevención de enfermedades y la mejora de la salud mediante la optimización del uso y del resultado de los tratamientos. Sin embargo, en España existe un bajo porcentaje de farmacias comunitarias que ofrecen SPFA, a excepción de la dispensación, indicación farmacéutica, medida de parámetros clínicos, la educación/información sanitaria y la formulación magistral, ya arraigados en la profesión desde hace tiempo. Objetivo: analizar los factores facilitadores y barreras en la demanda de determinados SPFA por parte de usuarios potenciales, desde el enfoque del producto según las 4Ps del Marketing Mix. Material y métodos: estudio cualitativo de tipo explicativo-interpretativo y exploratorio basado en la teoría fundamentada, mediante análisis inductivo aplicado a entrevistas semi-estructuradas, individuales y grupales. Resultados: las barreras y facilitadores son similares en todos los SPFA analizados, salvo algunas excepciones. Estas barreras y facilitadores son multifactoriales, porque están vinculados con la farmacia, el usuario, factores externos y el farmacéutico. Conclusiones: las barreras en la demanda de los SPFA son la baja adaptación a las necesidades del usuario, los nombres poco entendibles, la falta de integración de la FC en el sistema sanitario, el desconocimiento sobre los SPFA, las insuficientes evidencias de éxito y la satisfacción en servicios percibidos como similares realizados fuera de la FC. Por el contrario, los facilitadores que ayudan al aumento de la demanda de los SPFA son la actitud y aptitud del farmacéutico, el buen trato al paciente, la accesibilidad, cercanía y confortabilidad de la FC y la necesidad del paciente por mejorar su estado de salud

Permeability Study of Polyphenols Derived from a Phenolic-Enriched Hibiscus sabdariffa Extract by UHPLC-ESI-UHR-Qq-TOF-MS

Previous findings on the capacity of Hibiscus sabdariffa (HS) polyphenols to ameliorate metabolic disturbances justify the necessity of studies oriented to find the potential metabolites responsible for such an effect. The present study examined the intestinal epithelial membrane permeability of polyphenols present in a phenolic-enriched Hibiscus sabdariffa extract (PEHS), free and encapsulated, using the Caco-2 cell line. Additionally, selected polyphenols (quercetin, quercetin-3-glucoside, quercetin-3-glucuronide, and N-feruloyltyramine) were also studied in the same absorption model. The powerful analytical platform used ultra-high-performance liquid chromatography coupled with ultra-high-resolution quadrupole time-of-flight mass spectrometry (UHPLC-ESI-UHR-Qq-TOF-MS), and enabled the characterization of seven new compounds in PEHS. In the permeation study, only a few compounds were able to cross the cell monolayer and the permeability was lower when the extract was in an encapsulated form. Pure compounds showed a moderate absorption in all cases. Nevertheless, these preliminary results may need further research to understand the complete absorption mechanism of Hibiscus polyphenols.This work was supported by projects AGL2011-29857-C03-02 and AGL2011-29857-C03-03 (Spanish Ministry of Science and Innovation), in addition to P10-FQM-6563 and P11-CTS-7625 (Andalusian Regional Government Council of Innovation and Science), PROMETEO/2012/007 and ACOMP/2013/093 (Generalitat Valenciana), and CIBER (CB12/03/30038, Fisiopatología de la Obesidad y la Nutrición, CIBERobn, Instituto de Salud Carlos III). The authors are grateful to the Spanish Ministry of Science and Innovation for the grant FPI (BES-2009-028128), and the Spanish Ministry of Economy and Competitiveness (MINECO) in association with the European Social Fund (FSE) for the contract PTQ-13-06429. MH is a recipient of a VALi + D fellowship from GV (ACIF/2010/162). The authors are especially grateful to Bruker Daltonik GmbH (Bremen, Germany) for their help and support during this research

Global testing of a consensus solubility assessment to enhance robustness of the WHO biopharmaceutical classification system

The WHO Biopharmaceutical Classification System (BCS) is a practical tool to identify active pharmaceutical ingredients (APIs) that scientifically qualify for a waiver of in vivo bioequivalence studies. The focus of this study was to engage a global network of laboratories to experimentally quantify the pH-dependent solubility of the highest therapeutic dose of 16 APIs using a harmonized protocol. Intra-laboratory variability was ≤5 %, and no apparent association of inter-laboratory variability with API solubility was discovered. Final classification “low solubility” vs “high solubility” was consistent among laboratories. In comparison to the literature-based provisional 2006 WHO BCS classification, three compounds were re-classified from “high” to “low-solubility”. To estimate the consequences of these experimental solubility results on BCS classification, dose-adjusted in silico predictions of the fraction absorbed in humans were performed using GastroPlus®. Further expansion of these experimental efforts to qualified APIs from the WHO Essential Medicines List is anticipated to empower regulatory authorities across the globe to issue scientifically-supported guidance regarding the necessity of performing in vivo bioequivalence studies. Ultimately, this will improve access to affordable generic products, which is a critical prerequisite to reach Universal Health Coverage