Uso y optimización de una metodología para la priorización de la validación de métodos analíticos basada en la evaluación de riesgos en Servicios de Farmacia Hospitalaria / Implementation and optimisation of a tool for the prioritisation of analytical method validation based in risk management in Hospital Pharmacies

Objetivo: Poner en práctica y optimizar una metodología para evaluar los riesgos implicados en la elaboración de medicamentos en Servicios de Farmacia Hospitalaria con el fin de priorizar la validación de métodos analíticos de control de calidad. Método: Se han diseñado dos métodos para el cálculo del Número de Prioridad de Riesgo. Para el análisis y comparación entre ambos, se seleccionaron 3 parámetros a evaluar en cada medicamento: vía de administración, frecuencia de dispensación y complejidad del proceso de elaboración. A cada uno se asignó 4 niveles de gravedad, siendo 1 el más bajo y 4 el más alto. Se modificaron los criterios para la asignación de la gravedad en cada parámetro evaluado en el Método 2 con respecto al Método 1. Ambos métodos se han ensayado sobre 65 fórmulas. Resultados: El Método 1 segrega las formulaciones en 8 grupos según su Número de Prioridad de Riesgo. El Método 2 las separa en 14 grupos de 16 posibles. La frecuencia, en el Método 1 agrupa el 92,31% de las fórmulas en el primer nivel; la complejidad acumula el 86,15% en los niveles 2 y 4. Mientras el Método 2 separa el 25% de fórmulas en cada nivel según frecuencia, al segregar por cuartiles. La complejidad, al diferenciar las fórmulas asépticas con esterilización final de las elaboradas mediante llenado aséptico, separa las formulaciones en grupos más homogéneos. Conclusiones: El Método 2 es capaz de priorizar de forma más eficaz la validación de los métodos analíticos de las fórmulas analizadas, mejorando la consecución del objetivo propuesto. (AU)

Aim: To implement an optimise a methodology to evaluate the risks involved in the compounding of drug products in Hospital Pharmacy Services with the objective of prioritise the validation of analytical methods for quality control. Method: Two different methods were designed to assess the Risk Priority Number. For their analysis and comparison, 3 parameters were evaluated in each drug product: administration route, dispensing rate and compounding process complexity. To each parameter 4 levels of severity were allotted, being 1 the lowest and 4 the highest. The criteria to assign the level of severity for each parameter differ in both methods used. 65 drug products were evaluated with each method. Results: The use of Método 1 segregates drug products in 8 groups as per the Risk Priority Number, whilst Método 2 separates them in 14 groups out of the 16 feasible ones. Dispensing rate in Método 1 lumps together in the first level 92,31% of the drug products; complexity, by its side, clusters 86,15% in levels 2 and 4. On the other hand, Método 2 divides drug products in groups of 25% per severity level according to dispensing rate, since they are distributed in quartiles. Complexity, since it separates aseptic drug products exposed to final sterilisation from the ones compounded by aseptic processing, sets products apart in a more homogeneous groups. Conclusions: Método 2 is capable to prioritise in a more effective way the validation of analytical methods for quality control of analysed drug products; with a slightly higher convolution, it accomplishes the aim of these methods to a larger extent. (AU)

Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats.

Ivermectin is a widely used antiparasitic drug with known efficacy against several single-strain RNA viruses. Recent data shows significant reduction of SARS-CoV-2 replication in vitro by ivermectin concentrations not achievable with safe doses orally. Inhaled therapy has been used with success for other antiparasitics. An ethanol-based ivermectin formulation was administered once to 14 rats using a nebulizer capable of delivering particles with alveolar deposition. Rats were randomly assigned into three target dosing groups, lower dose (80-90 mg/kg), higher dose (110-140 mg/kg) or ethanol vehicle only. A toxicology profile including behavioral and weight monitoring, full blood count, biochemistry, necropsy and histological examination of the lungs was conducted. The pharmacokinetic profile of ivermectin in plasma and lungs was determined in all animals. There were no relevant changes in behavior or body weight. There was a delayed elevation in muscle enzymes compatible with rhabdomyolysis, that was also seen in the control group and has been attributed to the ethanol dose which was up to 11 g/kg in some animals. There were no histological anomalies in the lungs of any rat. Male animals received a higher ivermectin dose adjusted by adipose weight and reached higher plasma concentrations than females in the same dosing group (mean Cmax 86.2 ng/ml vs. 26.2 ng/ml in the lower dose group and 152 ng/ml vs. 51.8 ng/ml in the higher dose group). All subjects had detectable ivermectin concentrations in the lungs at seven days post intervention, up to 524.3 ng/g for high-dose male and 27.3 ng/g for low-dose females. nebulized ivermectin can reach pharmacodynamic concentrations in the lung tissue of rats, additional experiments are required to assess the safety of this formulation in larger animals.

Stability of poly(epsilon-caprolactone) microparticles containing Brucella ovis antigens as a vaccine delivery system against brucellosis.

In previous works, our research group has successfully proved the use of subcellular vaccines based on poly(epsilon-caprolactone) (PEC) microparticles containing an antigenic extract of Brucella ovis (HS) against experimental brucellosis in both mice and rams. However, the successful exploitation of pharmaceutical products, and therefore of this product as veterinary vaccine, requires preservation of both biological activity and native structure in all steps of development from purification to storage. In this context, we have carried out an accelerated stability study to evaluate the relative stability of HS when loading in PEC microparticles. For this purpose, freeze-dried microparticles were stored at 40 +/- 1 degrees C and 75% RH as a preliminary analysis of a stability testing. The results showed that both physico-chemical (size, morphology, antigen content, release profile) and biological (integrity and antigenicity of the HS) properties were preserved after 6 months of storage. On the contrary, after 1 year of storage, the HS release profile was dramatically affected probably due to a progressive loss of the polymer microstructure. In addition, the degradation and loss of the antigenicity of the HS components was also evident by SDS-PAGE and immunoblotting analysis. In fact, after 12 months of storage, only the integrity and antigenicity of two of the major protective proteins of the HS antigenic complex were preserved.