3D printed polymeric drug-eluting implants for personalized therapy

Conventional oral drug delivery systems, such as tablets, capsules and solutions, are widely used today and is the most commonly selected mode of administration for patient treatment. These systems can, however, demonstrate limitations, including the need for their frequent administration so that drug therapeutic levels can effectively be achieved and maintained. This can lead to reduced patient compliance, especially in populations having multiple and multiplex conditions, that need to be treated with several active ingredients contained in different formulations - in the UK, patients over 65 years of age take on average 5 to 8 different medications per week. For certain clinical needs, this requirement for frequent administration can be avoided by the use of long-acting implants. In addition, personalised medicine is a new approach that can reduce medication burden, since the fabrication of bespoke dosage forms is based on an individual’s health status, needs, genetic and physical factors. Implants represent formulations with great potential to be applied in patient-centric therapies and can be manufactured with a variety of materials and processing technologies. 3D Printing is a manufacturing technology with increasing popularity in various fields, including pharmaceuticals. Its versatility and the high degree of design freedom make feasible the production of different types of personalised formulations with unique attributes matching each patient characteristics, needs and preferences. In the present study, the fabrication of sustained drug release dosage forms using a solvent-free method at a relatively low printing temperature by a pressure assisted microsyringe 3D printer is demonstrated. The selected materials for the implant manufacture were polycaprolactone (PCL) – a polymer that is considered promising due to its properties; biodegradability, biocompatibility and processability – and lidocaine (LDC) – the model drug with a melting point close to the polymer’s. The first stage of this work was the investigation of the printability of PCL with two molecular weights - 25 kDa and 50 kDa - using a pressure assisted microsyringe (PAM) 3D printer and a Fused Deposition Modelling (FDM) 3D printer. FDM polymeric filaments for printing were produced by a Hot Melt Extruder (HME). The impact of the extrusion on the thermal and crystalline properties of the polymer was explored. The next step in this study was the manufacture of lidocaine loaded PCL implants, with and without a PCL barrier-shell with various lidocaine loading using the PAM 3D printer. Physical and chemical characterization (SEM, DSC, XRD, FTIR, Raman) in the printed formulations have been performed to investigate potential changes in their thermal and crystalline properties, their chemical structure or potential interactions after their mixing and 3D printing process. In the final phase of this work, the drug release rate of the differently printed implants was evaluated using a USP4 flow-through cell apparatus. The structural integrity of the studied dosage forms after the four-day long dissolution studies was explored by SEM. Drug release kinetics were studied by fitting the drug release data to four standard mathematical models; zero-order, first-order, Higuchi model and Korsmeyer-Peppas model. PCL extrudability in an HME was demonstrated with the addition of 1% w/w plasticizer, triethyl citrate, and by a suitable combination of the extrusion parameters, temperature in heat zones and screw speed. Both molecular weight PCLs have been extruded in fine filaments at low temperatures, close to the polymer melting point. The printability of these filaments has subsequently been investigated in an FDM 3D printer. After optimization of the printing parameters – print temperature, print speed, nozzle diameter – applied, a basic triangle geometry, with a high printing resolution has been manufactured. The printability of PCL was shown to be successful without the addition of any other material – excipient or solvent – when a pressure-assisted microsyringe (PAM) 3D printer was used. Optimization of the printing procedure was also needed due to the high viscosity of the polymer, especially of the 50 kDa molecular weight PCL. In this 3D printer type, though, the fabrication of a predetermined shape with PCL has been achieved at a lower print temperature (110 oC) compared to the temperature applied during the FDM 3D printing (180 oC). DSC and XRD characterization of the filaments, as well as, of the 3D printed test shapes showed that the polymers were crystalline after the extrusion and 3D printing. The crystalline nature of the investigated materials was not affected by the various extrusion and printing parameters applied. The fabrication of encased and non-encased lidocaine loaded PCL implants has successfully been achieved using the Pressure Assisted Microsyringe 3D printer. Optimization of the printing process, regarding the print temperature, print speed, bed temperature, extrusion width and pressure, was required to accommodate the impact of formulation changes. Specifically, the addition of lidocaine led to a decreased formulation viscosity. The versatility of the selected 3D printing method was proven by the successful manufacture of a PCL barrier–shell lidocaine loaded polymeric implant without any particular material preparation prior to their loading to the cartridge of the printer or any post–printing processing. DSC and XRD characterization of the 3D printed PCL lidocaine implants revealed that the blending and extrusion processes did not significantly affect the thermal behaviour of the materials used with PCL and that lidocaine crystals were present in the fabricated formulations at a low level indicating the formation of solid dispersion for the majority of the drug in the polymer matrix. FTIR and Raman analysis demonstrated that the blending and printing processing did not result in detectable modifications in the materials chemical structures or interactions between PCL and LDC. Moreover, Raman spectra indicated the presence of both materials on the surface of the printed formulations. Nevertheless, this did not lead to a significant burst drug release suggesting that the active agent remained sufficiently physically associated with the polymer to control release. Sustained lidocaine release has been attained both when PCL was used as a matrix or as a barrier-shell in the fabricated dosage forms due to its slow degradation rate. The use of the PCL barrier enabled delayed and slower drug release that can be tuned by control of barrier size. The Korsmeyer-Peppas model was shown as the best fit to drug release profiles for all the produced encased and non-encased implants indicating that drug release was controlled by combined transportation mechanisms, diffusion and polymeric chain relaxation. The early stages of PCL degradation were also shown by SEM imaging of the lidocaine loaded and lidocaine free PCL formulations after four days of dissolution, where the appearance of some surface holes was detected. This work has demonstrated that PCL has a significant potential for the production of prolonged drug release formulations by 3D printing, both as a matrix and as a barrier-shell to enable predictable and programmable delayed drug release. Solid drug dispersions can successfully be manufactured with hot melt extrusion-based 3D printing broadening its applications in the pharmaceutical field. It has, also, been shown that drug loading can be varied in a bespoke fashion for each implant, showing that personalisable implants can be manufactured by 3D printing and, thereby, address some limitations of conventional pharmaceutical dosage forms