Extrusion-based technologies for 3D printing: a comparative study of the processability of thermoplastic polyurethane-based formulations.

Thermoplastic polyurethanes (TPU) offer excellent properties for a wide range of dosage forms. These polymers have been successfully utilized in personalized medicine production using fused deposition modeling (FDM) 3D printing (3DP). However, direct powder extrusion (DPE) has been introduced recently as a challenging technique since it eliminates filament production before 3DP, reducing thermal stress, production time, and costs. This study compares DPE and single-screw extrusion for binary (drug-TPU) and ternary (drug-TPU-magnesium stearate [MS]) mixtures containing from 20 to 60% w/w of theophylline. Powder flow, mechanical properties, fractal analysis, and percolation theory were utilized to analyze critical properties of the extrudates. All the mixtures could be processed at a temperature range between 130 and 160 °C. Extrudates containing up to 50% w/w of drug (up to 30% w/w of drug in the case of single-screw extrusion binary filaments) showed toughness values above the critical threshold of 80 kg/mm2. MS improved flow in mixtures where the drug is the only percolating component, reduced until 25 °C the DPE temperature and decreased the extrudate roughness in high drug content systems. The potential of DPE as an efficient one-step additive manufacturing technique in healthcare environments to produce TPU-based tailored on-demand medicines has been demonstrated.

Benefits of Fractal Approaches in Solid Dosage Form Development.

Pharmaceutical formulations are complex systems consisting of active pharmaceutical ingredient(s) and a number of excipients selected to provide the intended performance of the product. The understanding of materials' properties and technological processes is a requirement for building quality into pharmaceutical products. Such understanding is gained mostly from empirical correlations of material and process factors with quality attributes of the final product. However, it seems also important to gain knowledge based on mechanistic considerations. Promising is here to study morphological and/or topological characteristics of particles and their aggregates. These geometric aspects must be taken into account to better understand how product attributes emerge from raw materials, which includes, for example, mechanical tablet properties, disintegration or dissolution behavior. Regulatory agencies worldwide are promoting the use of physical models in pharmaceutics to design quality into a final product. This review deals with pharmaceutical applications of theoretical models, focusing on percolation theory, fractal, and multifractal geometry. The use of these so-called fractal approaches improves the understanding of different aspects in the development of solid dosage forms, for example by identifying critical drug and excipient concentrations, as well as to study effects of heterogeneity on dosage form performance. The aim is to link micro- and macrostructure to the emerging quality attributes of the pharmaceutical solid dosage forms as a strategy to enhance mechanistic understanding and to advance pharmaceutical development and manufacturing processes.

Novel Polyurethane Matrix Systems Reveal a Particular Sustained Release Behavior Studied by Imaging and Computational Modeling.

The aim of the present work was to better understand the drug-release mechanism from sustained release matrices prepared with two new polyurethanes, using a novel in silico formulation tool based on 3-dimensional cellular automata. For this purpose, two polymers and theophylline as model drug were used to prepare binary matrix tablets. Each formulation was simulated in silico, and its release behavior was compared to the experimental drug release profiles. Furthermore, the polymer distributions in the tablets were imaged by scanning electron microscopy (SEM) and the changes produced by the tortuosity were quantified and verified using experimental data. The obtained results showed that the polymers exhibited a surprisingly high ability for controlling drug release at low excipient concentrations (only 10% w/w of excipient controlled the release of drug during almost 8 h). The mesoscopic in silico model helped to reveal how the novel biopolymers were controlling drug release. The mechanism was found to be a special geometrical arrangement of the excipient particles, creating an almost continuous barrier surrounding the drug in a very effective way, comparable to lipid or waxy excipients but with the advantages of a much higher compactability, stability, and absence of excipient polymorphism.

A new deferiprone controlled release system obtained by ultrasound-assisted compression.

OBJECTIVES: This study implements the design of an innovative dosage form using ultrasound-assisted compression of thermoplastic polymers and the development of controlled release tablets for the oral administration of deferiprone in two doses per day. METHODS: Binary matrix tablets containing deferiprone and thermoplastic polymers have been prepared using an ultrasound-assisted tableting machine. Scanning electron microscopy has been employed to determine a sintering phenomenon of the excipients. Water uptake and drug release studies have been carried out to evaluate the ability of the polymers to control the drug release. RESULTS: SEM micrographs showed that some polymers underwent the sintering process and the in vitro dissolution test showed good fit of the release data from these tablets to the zero-order kinetic model. CONCLUSIONS: Carbopol 974P and 971P have been selected as matrix forming polymers for the final formulation. The polymer percolation threshold has been exceeded with 15% w/w of polymer. Therefore, sustained release tablets have been developed with only 15% of excipient. This implies that matrix tablets containing 750 mg of API, intended for two administrations a day, can be obtained with a similar weight to those existing in the market containing 500 mg of API for three administrations a day.

3D Printing Direct Powder Extrusion in the Production of Drug Delivery Systems: State of the Art and Future Perspectives.

The production of tailored, on-demand drug delivery systems has gained attention in pharmaceutical development over the last few years, thanks to the application of 3D printing technology in the pharmaceutical field. Recently, direct powder extrusion (DPE) has emerged among the extrusion-based additive manufacturing techniques. It is a one-step procedure that allows the direct processing of powdered formulations. The aim of this systematic literature review is to analyze the production of drug delivery systems using DPE. A total of 27 articles have been identified through scientific databases (Scopus, PubMed, and ScienceDirect). The main characteristics of the three types of 3D printers based on DPE have been discussed. The selection of polymers and auxiliary excipients, as well as the flowability of the powder mixture, the rheological properties of the molten material, and the printing temperatures have been identified as the main critical parameters for successful printing. A wide range of drug delivery systems with varied geometries and different drug release profiles intended for oral, buccal, parenteral, and transdermal routes have been produced. The ability of this technique to manufacture personalized, on-demand drug delivery systems has been proven. For all these reasons, its implementation in hospital settings in the near future seems promising.

Amorphous solid dispersion of a binary formulation with felodipine and HPMC for 3D printed floating tablets.

This study focuses on the combination of three-dimensional printing (3DP) and amorphous solid dispersion (ASD) technologies for the manufacturing of gastroretentive floating tablets. Employing hot melt extrusion (HME) and fused deposition modeling (FDM), the study investigates the development of drug-loaded filaments and 3D printed (3DP) tablets containing felodipine as model drug and hydroxypropyl methylcellulose (HPMC) as the polymeric carrier. Prior to fabrication, solubility parameter estimation and molecular dynamics simulations were applied to predict drug-polymer interactions, which are crucial for ASD formation. Physical bulk and surface characterization complemented the quality control of both drug-loaded filaments and 3DP tablets. The analysis confirmed a successful amorphous dispersion of felodipine within the polymeric matrix. Furthermore, the low infill percentage and enclosed design of the 3DP tablet allowed for obtaining low-density systems. This structure resulted in buoyancy during the entire drug release process until a complete dissolution of the 3DP tablets (more than 8 h) was attained. The particular design made it possible for a single polymer to achieve a zero-order controlled release of the drug, which is considered the ideal kinetics for a gastroretentive system. Accordingly, this study can be seen as an advancement in ASD formulation for 3DP technology within pharmaceutics.

Study of the properties of the new biodegradable polyurethane PU (TEG-HMDI) as matrix forming excipient for controlled drug delivery.

The purpose of this work is to study the ability of a new biodegradable polyurethane PU(TEG-HMDI) obtained by reaction of triethylene glycol (TEG) with 1,6-hexamethylene diisocyanate (HMDI) to act as matrix forming polymer for controlled release tablets and to estimate its percolation threshold in a matrix system. Matrix tablets weighing 250 mg were prepared by direct compression with 10-30% wt/wt of PU(TEG-HMDI) and anhydrous theophylline as model drug. Release studies were carried out using the paddle method. The results were analyzed using the kinetics models of Higuchi, Korsmeyer-Peppas, and Peppas and Sahlin. These studies confirm the existence of an excipient percolation threshold between 10 and 20 % wt/wt of PU(TEG-HMDI) for the different batches prepared. It has been observed that the new biodegradable polyurethane PU(TEG-HMDI) shows adequate compatibility as well as a high ability to control the drug release.

Development of 3D-Printed Bicompartmental Devices by Dual-Nozzle Fused Deposition Modeling (FDM) for Colon-Specific Drug Delivery.

Dual-nozzle fused deposition modeling (FDM) is a 3D printing technique that allows for the simultaneous printing of two polymeric filaments and the design of complex geometries. Hence, hybrid formulations and structurally different sections can be combined into the same dosage form to achieve customized drug release kinetics. The objective of this study was to develop a novel bicompartmental device by dual-nozzle FDM for colon-specific drug delivery. Hydroxypropylmethylcellulose acetate succinate (HPMCAS) and polyvinyl alcohol (PVA) were selected as matrix-forming polymers of the outer pH-dependent and the inner water-soluble compartments, respectively. 5-Aminosalicylic acid (5-ASA) was selected as the model drug. Drug-free HPMCAS and drug-loaded PVA filaments suitable for FDM were extruded, and their properties were assessed by thermal, X-ray diffraction, microscopy, and texture analysis techniques. 5-ASA (20% w/w) remained mostly crystalline in the PVA matrix. Filaments were successfully printed into bicompartmental devices combining an outer cylindrical compartment and an inner spiral-shaped compartment that communicates with the external media through an opening. Scanning electron microscopy and X-ray tomography analysis were performed to guarantee the quality of the 3D-printed devices. In vitro drug release tests demonstrated a pH-responsive biphasic release pattern: a slow and sustained release period (pH values of 1.2 and 6.8) controlled by drug diffusion followed by a faster drug release phase (pH 7.4) governed by polymer relaxation/erosion. Overall, this research demonstrates the feasibility of the dual-nozzle FDM technique to obtain an innovative 3D-printed bicompartmental device for targeting 5-ASA to the colon.

Hydrophilic High Drug-Loaded 3D Printed Gastroretentive System with Robust Release Kinetics.

Three-dimensional printing (3DP) technology enables an important improvement in the design of new drug delivery systems, such as gastroretentive floating tablets. These systems show a better temporal and spatial control of the drug release and can be customized based on individual therapeutic needs. The aim of this work was to prepare 3DP gastroretentive floating tablets designed to provide a controlled release of the API. Metformin was used as a non-molten model drug and hydroxypropylmethyl cellulose with null or negligible toxicity was the main carrier. High drug loads were assayed. Another objective was to maintain the release kinetics as robust as possible when varying drug doses from one patient to another. Floating tablets using 10-50% w/w drug-loaded filaments were obtained by Fused Deposition Modelling (FDM) 3DP. The sealing layers of our design allowed successful buoyancy of the systems and sustained drug release for more than 8 h. Moreover, the effect of different variables on the drug release behaviour was studied. It should be highlighted that the robustness of the release kinetics was affected by varying the internal mesh size, and therefore the drug load. This could represent a step forward in the personalization of the treatments, a key advantage of 3DP technology in the pharmaceutical field.

Redox-Responsive Polymersomes as Smart Doxorubicin Delivery Systems.

Stimuli-responsive polymersomes have emerged as smart drug delivery systems for programmed release of highly cytotoxic anticancer agents such as doxorubicin hydrochloride (Dox·HCl). Recently, a biodegradable redox-responsive triblock copolymer (mPEG-PDH-mPEG) was synthesized with a central hydrophobic block containing disulfide linkages and two hydrophilic segments of poly(ethylene glycol) methyl ether. Taking advantage of the self-assembly of this amphiphilic copolymer in aqueous solution, in the present investigation we introduce a solvent-exchange method that simultaneously achieves polymersome formation and drug loading in phosphate buffer saline (10 mM, pH 7.4). Blank and drug-loaded polymersomes (5 and 10 wt.% feeding ratios) were prepared and characterized for morphology, particle size, surface charge, encapsulation efficiency and drug release behavior. Spherical vesicles of uniform size (120-190 nm) and negative zeta potentials were obtained. Dox·HCl was encapsulated into polymersomes with a remarkably high efficiency (up to 98 wt.%). In vitro drug release studies demonstrated a prolonged and diffusion-driven release at physiological conditions (~34% after 48 h). Cleavage of the disulfide bonds in the presence of 50 mM glutathione (GSH) enhanced drug release (~77%) due to the contribution of the erosion mechanism. Therefore, the designed polymersomes are promising candidates for selective drug release in the reductive environment of cancer cells.

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 Fractal-like Structures with High Percentage of Drug for Zero-Order Colonic Release.

Colonic drug delivery of drugs is an area of great interest due to the need to treat high prevalence colonic local diseases as well as systemic conditions that may benefit from the advantages associated to this route of drug administration. In the last decade, the use of 3D printing technologies has expanded, offering the possibility of preparing personalized medicines in small batches directly at the point of care. The aim of this work is to design a high drug loaded 3D printed system prepared by a combination of Fused Deposition Modelling (FDM) and Injection Volume Filling (IVF) techniques intended for zero-order colonic drug release. For this purpose, different batches of binary and ternary filaments based on the thermoplastic polyurethane Tecoflex EG-72D (TPU), theophylline anhydrous (AT) as model drug, and magnesium stearate as lubricant have been developed and characterized. Filaments with the highest drug load and the best rheological properties were selected for the manufacture of a printed fractal-like structure based on multiple toroids. This design was proposed to provide high surface area, leading to increased drug release and water uptake in the colonic region. This structure was 3D printed by FDM and then coated in a unique step by IVF technology using the enteric polymer DrugCoat S 12.5. This way, an additional coating process is avoided, reducing costs and production time. Studies of drug release confirmed the ability of the structures to provide a five-hour period of constant drug delivery in the colonic region.

3D printed systems for colon-specific delivery of camptothecin-loaded chitosan micelles.

The use of 3D printing technology in the manufacturing of drug delivery systems has expanded and benefit of a customized care. The ability to create tailor-made structures filled with drugs/delivery systems with suitable drug dosage is especially appealing in the field of nanomedicine. In this work, chitosan-based polymeric micelles loaded with camptothecin (CPT) were incorporated into 3D printing systems (printfills) sealed with an enteric layer, aiming to protect the nanosystems from the harsh environment of the gastrointestinal tract (GIT). Polymeric micelles and printfills were fully characterized and, a simulated digestion of the 3D systems upon an oral administration was performed. The printfills maintained intact at the simulated gastric pH of the stomach and, only released the micelles at the colonic pH. From there, the dissolution media was used to recreate the intestinal absorption and, chitosan micelles showed a significant increase of the CPT permeability compared to the free drug, reaching an apparent permeability coefficient (Papp) of around 9×10-6 cm/s in a 3D intestinal cell-based model. The combination of 3D printing with nanotechnology appears to have great potential for the colon-specific release of polymeric micelles, thereby increasing intestinal absorption while protecting the system/drug from degradation throughout the GIT.

A Biodegradable Copolyester, Poly(butylene succinate-co-ε-caprolactone), as a High Efficiency Matrix Former for Controlled Release of Drugs.

A biodegradable copolyester, poly(butylene succinate-co-ε-caprolactone) (PBS_CL), was used for first time as an excipient for pharmaceutical dosage forms using direct compression and hot processing techniques (ultrasound-assisted compression (USAC) and hot melt extrusion (HME)). Robust binary systems were achieved with hot processing techniques, allowing a controlled release of the drug. With only 12% v/v of PBS_CL, controlled release forms were obtained using USAC whereas in HME over 34% v/v of excipient is necessary. Amounts over 23% v/v allowed a long-extended release for more than 72 h following diffusional kinetic. Thanks to the high melting point of theophylline and the physicochemical properties of PBS_CL selected and synthesized, the structure of the excipient inside the USAC tablets and HME filaments corresponds to a continuum medium. A percolation threshold around 23% v/v was estimated, which agrees with a continuum percolation model. The polymer shows a high excipient efficiency value using HME and USAC. A nanostructured matrix with wall thicknesses lower than 0.1 µm was obtained. This leads to a very effective coating of the drug particles by the excipient, providing a slow and reproducible release. The present study therefore supports the use of PBS_CL, for the preparation of controlled release dosage forms using hot processing techniques.

Polymer percolation threshold in HPMC extended release formulation of carbamazepine and verapamil HCl.

The principles of the percolation theory were applied to further understand and design hydroxypropyl methylcellulose (HPMC) extended release matrix tablets containing carbamazepine and verapamil HCl. This statistical theory studies disordered or chaotic systems where the components are randomly distributed in a lattice. The application of this theory to study the hydration and drug release of hydrophilic matrices allows describing the changes in hydration and drug release kinetics of swellable matrices. The aim of this work was to study and develop extended release matrix formulations for carbamazepine and verapamil HCl, containing hypromellose (HPMC, METHOCEL Premium K100M CR) as rate controlling polymer using the concepts of percolation theory. The knowledge of the percolation threshold of the components of the matrix formulations contributes to improve their design. First, reducing the time to market and second, avoiding to formulate in the nearby of the percolation threshold, which will result in a lower variability. Therefore these formulations will be more robust when they are prepared at industrial scale. The HPMC percolation threshold for drugs with very different water solubilities was determined and it was shown that there was no significant influence of drug solubility on the HPMC critical concentration threshold (excipient percolation threshold). This may be related to the versatility and broad functionality of the swelling hydrophilic matrices.

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.

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.

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.

Thermoplastic polyurethane as matrix forming excipient using direct and ultrasound-assisted compression.

Thermoplastic polyurethanes (TPU) are block copolymers utilized in a wide variety of applications due to their superior characteristics as resistance, flexibility and biocompatibility. However, the use of TPU as a matrix tablet forming excipient is more limited. For the first time, matrix tablets based on TPU have been developed by direct compression and ultrasound-assisted compression (USAC) allowing a comparison between these two methods. TPU powder has been rheologically characterized according to SeDeM method, demonstrating the suitability of the polymer (Pearlbond™ 523) to be compressed. TPU matrices have shown an inert behavior and a sustained drug release with a very low quantity of excipient. The better drug release control of matrices obtained by USAC has been explained based on the sintering of the TPU particles, resulting in lower porous structures and a quasi-continuum medium instead of particulate systems. The Excipient Efficiency values show the high ability of this TPU to control drug release by both methods. Finally, the estimation of the percolation threshold of TPU by both methods has contributed to the deep knowledge of the systems and allows defining the Design Space of a formulation.

Application of percolation theory in the study of an extended release Verapamil hydrochloride formulation.

The percolation theory studies the critical points or percolation thresholds of the system, where one component of the system undergoes a geometrical phase transition, starting to connect the whole system. The objective of the present paper was to study the existence of critical points governing the water and drug transport inside hydroxypropylmethylcellulose (HPMC) hydrophilic matrix systems obtained with different polymer viscosity grades. For this purpose, extended release formulations of Verapamil HCl, have been prepared and studied. The percolation theory has been applied for the first time to multi-component hydrophilic matrices. The materials used to prepare the tablets were Verapamil HCl, four different viscosity grades of HPMC, microcrystalline cellulose, lactose, magnesium stearate and colloidal silicon dioxide NF. In order to estimate the percolation threshold, the behaviour of the kinetic parameters with respect to the volumetric fraction of each component at time zero, was studied. From the point of view of the percolation theory, the optimum concentration for all the studied polymers, to obtain a hydrophilic matrix system for the controlled release of Verapamil HCl is higher than 20% (v/v) HPMC. Above 20% (v/v) HPMC, an infinite cluster of excipient would be formed, ensuring uniform hydration, maintaining integrity of the system and controlling the drug release.