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Title: On demand manufacturing of solid dosage forms via fused deposition modelling (FDM) 3D printing
Author: Okwuosa, Tochukwu Chijioke
ISNI:       0000 0004 7970 1335
Awarding Body: University of Central Lancashire
Current Institution: University of Central Lancashire
Date of Award: 2018
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There is an increased emphasis on personalised treatment in a patient-centred health care. Personalising dosage forms are often carried out by tablet splitting, which could be inaccurate and risky. The industrial platform for tablet manufacturing is geared to mass productions, therefore, impractical and too expensive for small batch productions. Fused deposition modelling (FDM) 3D printing in solid dosage form manufacturing provides a flexible technique suitable for dose modification at a low cost. However, it was limited to non-pharmaceutical grade and extended release polymers, and often uses relatively high temperature (230 oC). Therefore, this research aims at tackling these limitations by producing 3D printed immediate and modified release tablets and liquid-filled capsules using pharmaceutical grade polymers for small and large molecule (peptides and protein) drug models. Bridging 3D printing processes with hot melt extrusion (HME) in the presence of a thermostable filler, talc and pharmaceutical grade polymers enabled the fabrication of tablets and capsules shells using FDM 3D printing. The first example of immediate release 3D printed tablets using polyvinyl pyrrolidone (PVP)-based filaments was demonstrated, with suitability for different actives (aspirin, dipyridamole and theophylline). This was achieved at a relatively low temperature of 110 oC. Thermogravimetric analysis (TGA) demonstrated that the excipients and actives were stable within the HME and 3D printing temperatures apart from aspirin as observed from further high-pressure liquid chromatography (HPLC). The hygroscopic nature of the polymer had a major impact in the glass transition temperature (Tg) of the PVP-filament and its compatibility with FDM 3D printers. Furthermore, for the first time, enteric release tablets were fabricated using a dual FDM 3D printer, using Eudragit L100-55-based shell and PVP-based drug loaded core filaments. This was achieved in a single process, requiring a shell layer thickness ≥0.52 mm to achieve adequate acid resistance. British Pharmacopoeia (BP) criteria for enteric release was met by replacing talc with tribasic phosphate (TBP). This however, resulted in the degradation of the active pharmaceutical ingredient (API), emphasising the superiority of talc (non-melting component) for filament formulations. The system also demonstrated suitability for other actives (budesonide, diclofenac and theophylline). By coordinating FDM 3D printing and liquid dispensing, immediate and extended liquid-filled capsules were fabricated using Eudragit EPO and RL respectively. The syringe-based liquid dispenser demonstrated a linear relationship between the estimated and actual doses obtained (R2 =0.9985). The integrity of the shell was maintaining during the filling process by using a multi-phase 3D printing approach, 1.6 mm shell thickness, 100 % shell infill and concentric infill pattern. This process avoided thermal exposure during the capsule filling which prompted investigations into the encapsulation of antimicrobial peptides (AMPs). Aurein 2.6 and LL-37 demonstrated a concentration and time dependent increase in anticancer activities against HT-29 and only the former against Caco-2 colon cancer cell lines. The solution structure of the peptides was maintained during encapsulation. As a proof of concept to demonstrate colon targeting, a Eudragit S100-based capsule shell and theophylline solution model core was presented. Accelerated stability studies indicated that the PVP-based filament was only stable when stored at 5 oC. However, Eudragit L100-55 and S100 remained stable in all the investigated storage conditions. By adapting these pharmaceutical grade polymers for FDM 3D printing and the modification of the FDM 3D printer head, it was possible to fabricate immediate, enteric, extended and colonic release tablets and liquid-filled capsules. These demonstrated suitability for thermostable and thermolabile actives. In a clinical setting, health care staffs will be able to rapidly manufacture varied doses of tablets and small volume liquid-filled capsules with individualised dose contents and release pattern in response to specific patient's needs.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: B950 - Paramedical science