Achieving High Excipient Efficiency with Elastic Thermoplastic Polyurethane by Ultrasound Assisted Direct Compression

Ultrasound assisted compression (USAC) is a manufacturing technique which applies thermal and mechanical energy to the powder bed, producing tablets with improved characteristics compared to the direct compression process. This technology is ideal for thermoplastic materials, as polyurethanes, whose particles usually undergo a sintering process. Thermoplastic polyurethanes are widely used in sustained drug release systems but rarely seen in tablets due to their elastic properties. The aim of this work is to investigate the ability of USAC to manufacture sustained release matrix tablets based on elastic thermoplastic polyurethanes (TPU), overcoming the limitations of direct compression. The technological and biopharmaceutical characteristics of the TPU matrices have been evaluated, with special focus on the porous structure due to the implications on drug release. For the first time, USAC has been successfully employed for manufacturing elastic thermoplastic polyurethanes-based matrices. TPU tablets show an inert character with a sustained drug release governed by a diffusional mechanism. Initial porosity of matrices was similar in all batches studied, with no influence of drug particle size, and a fractal nature of the pore network has been observed. SEM microphotographs show the continuum medium created by the sintering of the polymer, responsible for the high excipient efficiency.España, Ministerio de Economía y Competitividad Grant MAT2016- 77345-C3-3-PEspaña, Junta de Andalucía Grant 2017/0000043

Printfills: 3D printed systems combining fused deposition modeling and injection volume filling. Application to colon-specific drug delivery

Three-dimensional printing has become a feasible manufacturing technique for pharmaceutical products providing cheap and accurate freeform systems with a great potential for personalized-dose drugs. Fused Deposition Modeling (FDM) highlights among other 3D technologies due to its low cost and easy to operate but, until now, it has the drawbacks of the low drug loaded and the impossibility to print thermosensitive drugs. So, intermediate processes such as hot melt extrusion are frequently associated with FDM. Here, pharmaceutical dosage forms have been manufactured for the first time with a 3D printer combining two different printing technologies: FDM and injection volume filling (IVF), performing customized extruded scaffolds in which a liquid or semisolid system can be injected at room temperature. A model drug and a pH-sensitive polymer were successfully incorporated during the construction of the extruded backbone of the systems, called printfills (printed systems filled with a liquid or semisolid). SEM microphotographs of printfills show the sealing of the structure in the perimeter and the homogeneity of the colonic film formed in the upper side. Thus, the addition of the pH-sensitive polymer does not need an additional process in a fluidized bed or coating pan. Results from drug release studies performed at different pH confirm the ability of printfills for colon-specific drug delivery. Therefore, IVF technology complements FDM, solving its main limitations providing an easy, automatized and versatile technology to manufacture tailored drug delivery platforms, avoiding other intermediate processes.Ministerio de Economía y Competitividad (MAT2016-77345-C3-3-P

Critical points for predicting 3D printable filaments behaviour

Fractal dimension has been employed for the first time to provide key information about the behaviour of extruded filaments. High drug loaded filaments made of thermoplastic polyurethane and anhydrous theophylline (10–70% w/w of drug content) have been obtained by using a single screw extruder. Fractal analysis was carried out based on the measures of the perimeter of the filaments at different magnification levels, using the box-counting technique approach. The fractal dimension values showed a critical point at 37.8% w/w of drug, which agrees with the behaviour of the printability of the filaments by FDM. The drug percolation threshold derived from drug release results was also in agreement with this critical point. Thus, both approaches concur in the estimation of a critical point around 38% w/w of drug, where printability and dissolution behaviour dramatically change. Therefore, the Fractal Dimension analysis could be considered as a non-destructive, non-expensive and fast method for estimating a crucial parameter for FDM 3D printing as is printability of the filament.MCIN/AEI RTI2018-095041-B-C3

Critical points in ethylcellulose matrices: Influence of the polymer, drug and filler properties

Percolation theory has been applied to study the drug release behaviour in multicomponent inert matrices containing ethylcellulose as a matrix forming polymer. Global influence of major formulation factors such as polymer viscosity, polymer particle size, drug and filler solubility and porosity of the tablets in drug release kinetics has been studied for the first time. Batches containing three viscosity grades of Ethocel™, microcrystalline cellulose (MCC) and lactose as fillers, a lubricant and flow aid mixture and three drugs with different solubility have been manufactured. For some batches, compression pressure was varied in order to obtain matrices with five levels of initial porosity. The behaviour of inert matrices was explained based on the percolation ranges of the main components of the formulation. The effect of the porosity percolation threshold was observed and the existence of a tricoherent drug-polymer-filler system is hypothesized

Assessment of the Extrusion Process and Printability of Suspension-Type Drug-Loaded AffinisolTM Filaments for 3D Printing

Three-dimensional (3D) printing technology enables the design of new drug delivery systems for personalised medicine. Polymers that can be molten are needed to obtain extruded filaments for Fused Deposition Modelling (FDM), one of the most frequently employed techniques for 3D printing. The aim of this work was to evaluate the extrusion process and the physical appearance of filaments made of a hydrophilic polymer and a non-molten model drug. Metformin was used as model drug and Affinisol™ 15LV as the main carrier. Drug-loaded filaments were obtained by using a single-screw extruder and, subsequently, their printability was tested. Blends containing up to a 60% and 50% drug load with 5% and 7.5% of auxiliary excipients, respectively, were successfully extruded. Between the obtained filaments, those containing up to 50% of the drug were suitable for use in FDM 3D printing. The studied parameters, including residence time, flow speed, brittleness, and fractal dimension, reflect a critical point in the extrusion process at between 30–40% drug load. This finding could be essential for understanding the behaviour of filaments containing a non-molten component

3D printed drug delivery systems based on natural products

In the last few years, the employment of 3D printing technologies in the manufacture of drug delivery systems has increased, due to the advantages that they offer for personalized medicine. Thus, the possibility of producing sophisticated and tailor-made structures loaded with drugs intended for tissue engineering and optimizing the drug dose is particularly interesting in the case of pediatric and geriatric population. Natural products provide a wide range of advantages for their application as pharmaceutical excipients, as well as in scaffolds purposed for tissue engineering prepared by 3D printing technologies. The ability of biopolymers to form hydrogels is exploited in pressure assisted microsyringe and inkjet techniques, resulting in suitable porous matrices for the printing of living cells, as well as thermolabile drugs. In this review, we analyze the 3D printing technologies employed for the preparation of drug delivery systems based on natural products. Moreover, the 3D printed drug delivery systems containing natural products are described, highlighting the advantages offered by these types of excipients.Ministerio de Ciencia, Innovación y Universidades RTI2018-095041-B-C3

Collaboration between HPMC and NaCMC in order to Reach the Polymer Critical Point in Theophylline Hydrophilic Matrices

Percolation theory has been applied in order to study the existence of critical points as well as the possibility to find a “combined percolation threshold” for ternary hydrophilic matrices prepared with HPMC, NaCMC, and theophylline. For this purpose, different batches of ternary as well as binary hydrophilic matrices have been prepared. Critical points have been found for binary hydrophilic matrices between 21.5 and 31.3% (v/v) of HPMC and between 39 and 54% (v/v) of NaCMC, respectively. In a previous work carried out with the same polymers but a much more soluble drug (KCl), it was demonstrated the existence of a partial collaboration between the polymers in order to establish the gel layer. In this work, it has been observed for the first time the need of a minimum concentration of one of the matrix-forming polymer (between 10 and 20% v/v, approximately) for establishing an effective collaboration

Design of crossed and nested Gauge R&R studies for the validation of the Heckel and Ryshkewitch Duckworth mathematical models

Introducción: Los estudios gauge permiten ganar información sobre el desempeño de procesos y son de utilidad para control de calidad, así como identificación de fuentes de variación. El objetivo del presente estudio, fue diseñar y analizar sistemas de medición para los modelos de Heckel y Ryshkewitch-Duckworth para caracterizar materiales, a través de estudios Gauge R&R. Método: Estudio Gauge R&R cruzado para evaluar el sistema de medición del peso y estudio Gauge R&R anidado para el sistema de la resistencia a la fractura. Resultados: Ambos estudios cumplieron con los supuestos de normalidad, varianza constante e independencia de los datos, por lo que fue posible determinar la significación de las fuentes de variación (factores) mediante un ANOVA así como su porcentaje de contribución. Para el estudio Gauge R&R cruzado los punzones evaluados contribuyen a la variación de la medición de manera significativa y en un 97,38% de la variación total; los operadores contribuyen en menos del 1% y de manera no significativa y no existió interacción parte-operador. Respecto al estudio Gauge R&R anidado, se identificó que el operador no influyó de manera significativa en la variabilidad de la medición y que ésta es atribuible en un 95% a las diferencias existentes entre las tabletas evaluadas. Conclusiones: Se realizó el diseño, ejecución y análisis de los sistemas de medición, destacando que en ambos estudios la principal fuente de variación fueron las partes evaluadas y que los operadores no contribuyen en la variabilidad de las mediciones, por lo que los estudios pueden usarse para evaluar los modelos matemáticos y durante el control estadístico de un proceso.Introduction: Gauge studies allow gaining information about the performance of processes and are very useful tools for quality control and identification of variability sources. The objective of the present study was design and analyzes measurement systems for the Heckel and Ryshkewitch-Duckworth models for characterizing materials, through Gauge R&R studies. Method: Crossed Gauge R&R study for the evaluation of weight measurement system and nested Gauge R&R study for the system of tablet hardness. Results: Both studies fulfilled with the assumptions of normality, constant variance and data independence, there fore it was possible to estimate the significance of variation sources (factors) through ANOVA and their contribution percentage. The crossed Gauge R&R study showed that the flat punches contributed to variability of the measure ment in a significant manner in 97.38% of the total variation of the study; operators did it in less than 1% and they were not statistically significant and there was no Part-Operator interaction. With respect to the nested Gauge R&R study, it was found that the operator did not influence in a statistically significant way in the variability of the mea surement and it was attributable in 95% to the existing differences between the tablets evaluated. Conclusions: Design, run and analysis of the measurement systems was performed, we remark that in both of the studies the main source of variability were the parts evaluated and that operators did not contribute to variability in the measurements; therefore, both studies could be used to evaluate the Heckel and Ryshkewitch-Duckworth mathematical models and also for statistical process control

Sistema de liberación controlada de morfina y otros fármacos solubles en agua por complejación con sustancias poliméricas

Sistema de liberación controlada de morfina y otros fármacos solubles en agua por complejación con sustancias poliméricas. Método de obtención de un sistema de liberación controlada de fármacos de elevada solubilidad acuosa por complejación con sustancias poliméricas, consistente en hacer reaccionar químicamente una resina acrílica, p.ej. Eudragit L 30D, con la sal del fármaco en cuestión, p.ej. morfina. Primero se neutraliza parcialmente un volumen determinado de suspensión acuosa de Eudragit L 6D, a la que posteriormente se le añade la solución acuosa de la sal del fármaco a complejar, produciéndose la reacción entre el fármaco y la resina y se obtiene un precipitado que, secado en estufa, da lugar al complejo fármaco Eudragit. Es de aplicación en la Industria Farmacéutica para la fabricación de formas sólidas de administración oral que permitan alcanzar rápidamente concentraciones plasmáticas terapéuticas y mantenerlas, posteriormente, durante un período prolongado hasta la total liberación del principio activo, optimizando así la terapia medicamentosa.Españ

Composición farmacéutica y medicamento de liberación controlada de morfina basado en un complejo de morfina con un polímero acrílico

Composición farmacéutica y medicamento de liberación controlada de morfina basado en un complejo de morfina con un polímero acrílico. La composición farmacéutica comprende un complejo de liberación controlada de morfina que contiene morfina complejada con un polímero acrílico, una sal farmacéuticamente aceptable de morfina libre, y uno o más excipientes inertes respecto a la liberación controlada. Dicha composición es útil para elaborar un comprimido oral de liberación controlada de morfina para el tratamiento del dolor crónico severo sin necesidad de tener que administrar simultáneamente morfina vía parenteral.Españ