Mechanically promoted lipid-based filaments via composition tuning for extrusion-based 3D-printing.

Lipid excipients are favorable materials in pharmaceutical formulations owing to their natural, biodegradable, low-toxic and solubility/permeability enhancing properties. The application of these materials with advanced manufacturing platforms, particularly filament-based 3D-printing, is attractive for personalized manufacturing of thermolabile drugs. However, the filament's weak mechanical properties limit their full potential. In this study, highly flexible filaments were extruded using PG6-C16P, a lipid-based excipient belonging to the group of polyglycerol esters of fatty acids (PGFAs), based on tuning the ratio between its major and minor composition fractions. Increasing the percentage of the minor fractions in the system was found to enhance the relevant mechanical filament properties by 50-fold, guaranteeing a flawless 3D-printability. Applying a novel liquid feeding approach further improved the mechanical filament properties at lower percentage of minor fractions, whilst circumventing the issues associated with the standard extrusion approach such as low throughput. Upon drug incorporation, the filaments retained high mechanical properties with a controlled drug release pattern. This work demonstrates PG6-C16 P as an advanced lipid-based material and a competitive printing excipient that can empower filament-based 3D-printing.

Influence of PLGA End Groups on the Release Profile of Dexamethasone from Ocular Implants.

The present study deals with the development of dexamethasone (DM)-loaded implants using ester end-capped Resomer RG 502 poly(lactic acid-co-glycolic acid) (PLGA) (502), acid end-capped Resomer RG 502H PLGA (502H), and a 502H:502 mixture (3:1) via hot melt extrusion (HME). The prepared intravitreal implants (20 and 40% DM loaded in each PLGA) were thoroughly investigated to determine the effect of different end-capped PLGA and drug loading on the long-term release profile of DM. The implants were characterized for solid-state active pharmaceutical ingredient (APIs) using DSC and SWAXS, water uptake during stability study, the crystal size of API in the implant matrix using hot-stage polarized light microscopy, and in vitro release profile. The kinetics of PLGA release was thoroughly investigated using quantitative 1H NMR spectroscopy. The polymorph of DM crystal was found to remain unchanged after the extrusion and stability study. However, around 3 times reduction in API particle size was observed after the HME process. The morphology and content uniformity of the RT-stored samples were found to be comparable to the initial implant samples. Interestingly, the samples (mainly 502H) stored at 40 °C and 75% RH for 30 d demonstrated marked deformation and a change in content uniformity. The rate of DM release was higher in the case of 502H samples with a higher drug loading (40% w/w). Furthermore, a simple digital in vitro DM release profile derived for the formulation containing a 3:1 ratio of 502H and 502 was comparable with the experimental release profile of the respective polymer mixture formulation. The temporal development of pores and/or voids in the course of drug dissolution, evaluated using µCT, was found to be a precursor for the PLGA release. Overall, the release profile of DM was found to be dependent on the PLGA type (independent of subtle changes in the formulation mass and diameter). However, the extent of release was found to be dependent on DM loading. Thus, the present investigation led to a thorough understanding of the physicochemical properties of different end-capped PLGAs and the underlying formulation microstructure on the release profile of a crystalline water-insoluble drug, DM, from the PLGA-based implant.

SEDEX-Self-Emulsifying Delivery Via Hot Melt Extrusion: A Continuous Pilot-Scale Feasibility Study.

The aim of this study was to develop a continuous pilot-scale solidification and characterization of self-emulsifying drug delivery systems (SEDDSs) via hot melt extrusion (HME) using Soluplus® and Kollidon® VA-64. First, an oil-binding capacity study was performed to estimate the maximal amount of SEDDSs that the polymers could bind. Then, HME was conducted using a Coperion 18 mm ZSK18 pilot plant-scale extruder with split-feeding of polymer and SEDDS in 10, 20, and 30% w/w SEDDSs was conducted. The prepared extrudates were characterized depending on appearance, differential scanning calorimetry, wide-angle X-ray scattering, emulsification time, droplet size, polydispersity index, and cloud point. The oil-binding studies showed that the polymers were able to bind up to 50% w/w of liquid SEDDSs. The polymers were processed via HME in a temperature range between 110 and 160 °C, where a plasticizing effect of the SEDDSs was observed. The extrudates were found to be stable in the amorphous state and self-emulsified in demineralized water at 37 °C with mean droplet sizes between 50 and 300 nm. A cloud point and phase inversion were evident in the Soluplus® samples. In conclusion, processing SEDDSs with HME could be considered a promising alternative to the established solidification techniques as well as classic amorphous solid dispersions for drug delivery.

Filament-based 3D-printing of placebo dosage forms using brittle lipid-based excipients.

In order to expand the limited portfolio of available polymer-based excipients for fabricating three-dimensional (3D) printed pharmaceutical products, Lipid-based excipients (LBEs) have yet to be thoroughly investigated. The technical obstacle of LBEs application is, however their crystalline nature that renders them very brittle and challenging for processing via 3D-printing. In this work, we evaluated the functionality of LBEs for filament-based 3D-printing of oral dosage forms. Polyglycerol partial ester of palmitic acid and polyethylene glycols monostearate were selected as LBEs, based on their chemical structure, possessing polar groups for providing hydrogen-bonding sites. A fundamental understanding of structure-function relationship was built to screen the critical material attributes relevant for both extrusion and 3D-printing processes. The thermal behavior of lipids, including the degree of their supercooling, was the critical attribute for their processing. The extrudability of materials was improved through different feeding approaches, including the common powder feeding and a devised liquid feeding setup. Liquid feeding was found to be more efficient, allowing the production of filaments with high flexibility and improved printability. Filaments with superior performance were produced using polyglycerol ester of palmitic acid. In-house designed modifications of the utilized 3D-printer were essential for a flawless processing of the filaments.

Can Liposomes Survive Inkjet Printing? The Effect of Jetting on Key Liposome Attributes for Drug Delivery Applications.

Purpose: Inkjet printing has the potential to enable novel personalized and tailored drug therapies based on liposome and lipid nanoparticles. However, due to the significant shear force exerted on the jetted fluids, its suitability for shear-sensitive materials such as liposomes, has not been verified. We have conducted a proof-of-concept study to examine whether the particle concentration and size distribution of placebo liposomes are affected by common inkjet/dispensing technologies. Methods: We have subjected three types of liposome-containing fluids ("inks") to two different commercial dispensing/jetting technologies, which are relevant to most drug printing approaches. The liposome jetting processes were observed in real-time using strobographic imaging techniques. The phospholipid concentrations and particle size distributions were determined before and after jetting via enzymatic colorimetric and dynamic light scattering methods, respectively. Results: Our results have shown that the jetting dynamics of the liposome inks are well predicted by the established inkjet printing regime map based on their physical properties and the jetting conditions. Importantly, although significant shear forces were confirmed during jetting, the liposome concentrations and particle size distributions in the collected samples remain largely unaffected. Conclusion: These findings, we believe, provide the essential proof-of-concept to encourage further development in this highly topical research area.

In-vial printing and drying of biologics as a personalizable approach.

This study addressed the need for a flexible (personalizable) production of biologics, allowing their stabilization in the solid state and processing of small batch volumes. Therefore, inkjet printing into vials followed by a gentle vacuum drying step at ambient temperature was investigated by screening different formulations with a 22-full factorial design of experiments regarding printability. Human Serum Albumin (HSA) was used as a model protein in a wide range of concentrations (5 to 50 mg/ml), with (10 w/v%) and without the surfactant polysorbate 80 (PS80). PS80 was identified to positively affect the formulations by increasing the Ohnesorge number and stabilizing the printing process. The dispensed volumes with a target dose of 0.5 mg HSA were dried and analyzed concerning their residual moisture (RM) and protein aggregation. All investigated formulations showed an RM < 10 wt% and no significant induced protein aggregation as confirmed by Size Exclusion Chromatography (<2.5%) and Dynamic Light Scattering (Aggregation Index ≤ 2.5). Additionally, long-term printability and the available final dose after reconstitution were investigated for two optimized formulations. A promising formulation providing ∼93% of the targeted dose and a reconstitution time of 30 s was identified.

Towards predicting the product quality in hot-melt extrusion: Pilot plant scale extrusion.

Following our study on the impact of hot melt extrusion (HME) process conditions on the product quality, we expanded our investigation to assessing the effect of scale-up on the product quality. To this end, we studied the influence of process settings and different scale-up variants on the active pharmaceutical ingredient (API) degradation in a pilot plant scale extruder. Six scale-up variants were investigated and none of them could replicate the product quality from the original process setup on a lab-scale extruder. By analyzing several process-dependent and -independent variables and cross referencing them to the experiments in the lab-scale extruder, we identified certain patterns. The results of the reduced order mechanistic 1D HME simulation of various process states made it possible to establish a correlation between the achieved API degradation and the local melt temperature and the exposure time in specific zones along the screw configuration. Since the same melt temperature and exposure time correlations were also valid for the lab scale-extruder, such an approach could be used in the future to predict the product quality as a function of processing conditions fully in silico prior to the first extrusion trials.

Towards predicting the product quality in hot-melt extrusion: Small scale extrusion.

In product development, it is crucial to choose the appropriate drug manufacturing route accurately and timely and to ensure that the technique selected is suitable for achieving the desired product quality. Guided by the QbD principles, the pharmaceutical industry is currently transitioning from batch to continuous manufacturing. In this context, process understanding and prediction are becoming even more important. With regard to hot melt extrusion, the process setup, optimization and scale-up in early stages of product development are particularly challenging due to poor process understanding, complex product-process relationship and a small amount of premix available for extensive experimental studies. Hence, automated, quick and reliable process setup and scale-up requires simulation tools that are accurate enough to capture the process and determine the product-process relationships. To this end, the effect of process settings on the degradation of the active pharmaceutical ingredient (API) in a lab-scale Leistritz ZSE12 extruder was investigated. As part of the presented study, the limitations of traditional process analysis using integral process values were investigated, together with the potential that simulations may have in predicting the process performance and the product quality. The results of our investigation indicate that the average melt temperatures and the exposure times in specific zones along the screw configuration correlate well with the API degradation values and can be used as potent process design criteria to simplify the process development.

Estudio descriptivo acerca del modelo de abordaje, postura teorica y rol del fonoaudiologo en el area de aprendizaje. Fonoaudiologos y licenciado en fonoaudiologia de la ciudad de San Nicolas. Año 2001 / Description study about of the model of boarding, theoric posture and rol of the phonoaudiology in the area of the apprentice. Phonoaudiology and licenciaty in phonoaudiology of the city of San Nicolas. Year 200l

En esta investigacion, se procuro conocer las relaciones entre el Modelo de Abordaje y la Postura Teorica, que se establecen en el area de aprendizaje, en los profesionaes foñnoaudiologos que ejercen en la ciudad de San Nicolas y se encuentran matriculados en la Delegacion Pergamino del Colegio de Fonoaudiologos de la Provincia de Buenos Aires. Se intento ademas, despertar la reflexion acerca del Rol DEl Fonoaudiologo en el area que se investiga, solicitando a los profesionales la definicion y caracterizacion del mismo. Para la recoleccion de la informacion, se empleo una entrevista con preguntas cerradas y abiertas. Las primeras preguntas estuvieron orientadas a establecer las acciones y estrategias que los fonoaudiologos consideran pertinentes en el area del aprendizaje, las concepciones de sujeto de aprendizaje y las vinculaciones entre lenguaje y aprendizaje, propuestas desde tres corrientes teoricas de referencia (Conductismo, Constructivismo e Interaccionismo), para obtener informacion respecto de las variables Modelo de Abordaje y Postura Teorica. Las preguntas abiertas posibilitaron recoger las definiciones de los profesionales respecto de la variable Rol, y analizar sus dimensiones. La poblacion estuvo constituida por 27 Licenciados en Fonoaudiologia, 13 Fonoaudiologos y un Doctor en Fonoaudiologia. Los resultados obtenidos se pueden sintetizar estableciendo que, de la totalidad de profesionales entrevistados, en 21 fonoaudiologos se pudo identificar un Modelo de Abordaje Parcial, mientras que en 20 profesionales la modalidad fue Integral. La Postura Teorica asumida fue Combinada en 29 casos, 8 fonoaudiologos adhirieron a la corriente Constructivista y 4 entrevistados relejaron asumir la perpectiva Interaccionista. En relacion a la variable Rol del Fonoaudiologo en el Aprendizaje, se evidencio que el 80,49 por ciento de los profesionales incluyo en sus conceptualizaciones las dimensiones actuado, subjetivo y prescripto del rol. Los restantes entrevistados, incluyeron dos o solo una de estas dimensiones