Alvaro Goyanes

Fused-filament 3D printing (3DP) for fabrication of tablets.

The use of fused-filament 3D printing (FF 3DP) to fabricate individual tablets is demonstrated. The technology permits the manufacture of tablets containing drug doses tailored to individual patients, or to fabrication of tablets with specific drug-release profiles. Commercially produced polyvinyl alcohol (PVA) filament was loaded with a model drug (fluorescein) by swelling of the polymer in ethanolic drug solution. A final drug-loading of 0.29% w/w was achieved. Tablets of PVA/fluorescein (10 mm diameter) were printed using a 3D printer. It was found that changing the degree of infill percentage in the printer software varied the weight and volume of the printed tablets. The tablets were mechanically strong and no significant thermal degradation of the active occurred during printing. Dissolution tests were conducted in modified Hanks buffer. The results showed release profiles were dependent on the infill percentage used to print the tablet. The study indicates that FF 3DP has the potential to offer a new solution for fabricating personalized-dose medicines or unit dosage forms with controlled-release profiles. In addition, the low cost of FDM printers means the paradigm of extemporaneous or point-of-use manufacture of personalized-dose tablets is both feasible and attainable.

3D printing of medicines: Engineering novel oral devices with unique design and drug release characteristics

Three dimensional printing (3D printing) was used to fabricate novel oral drug delivery devices with specialized design configurations. Each device was loaded with multiple actives, with the intent of applying this process to the production of personalized medicines tailored at the point of dispensing or use. A filament extruder was used to obtain drug-loaded--paracetamol (acetaminophen) or caffeine--filaments of poly(vinyl alcohol) with characteristics suitable for use in fused-deposition modeling 3D printing. A multinozzle 3D printer enabled fabrication of capsule-shaped solid devices containing the drug with different internal structures. The design configurations included a multilayer device, with each layer containing drug, whose identity was different to the drug in the adjacent layers, and a two-compartment device comprising a caplet embedded within a larger caplet (DuoCaplet), with each compartment containing a different drug. Raman spectroscopy was used to collect 2-dimensional hyper spectral arrays across the entire surface of the devices. Processing of the arrays using direct classical least-squares component matching to produce false color representations of distribution of the drugs was used. This clearly showed a definitive separation between the drug layers of paracetamol and caffeine. Drug release tests in biorelevant bicarbonate media showed unique drug release profiles dependent on the macrostructure of the devices. In the case of the multilayer devices, release of both paracetamol and caffeine was simultaneous and independent of drug solubility. With the DuoCaplet design, it was possible to engineer either rapid drug release or delayed release by selecting the site of incorporation of the drug in the device; the lag-time for release from the internal compartment was dependent on the characteristics of the external layer. The study confirms the potential of 3D printing to fabricate multiple-drug containing devices with specialized design configurations and unique drug release characteristics, which would not otherwise be possible using conventional manufacturing methods.

Effect of geometry on drug release from 3D printed tablets

The aim of this work was to explore the feasibility of combining hot melt extrusion (HME) with 3D printing (3DP) technology, with a view to producing different shaped tablets which would be otherwise difficult to produce using traditional methods. A filament extruder was used to obtain approx. 4% paracetamol loaded filaments of polyvinyl alcohol with characteristics suitable for use in fused-deposition modelling 3DP. Five different tablet geometries were successfully 3D-printed-cube, pyramid, cylinder, sphere and torus. The printing process did not affect the stability of the drug. Drug release from the tablets was not dependent on the surface area but instead on surface area to volume ratio, indicating the influence that geometrical shape has on drug release. An erosion-mediated process controlled drug release. This work has demonstrated the potential of 3DP to manufacture tablet shapes of different geometries, many of which would be challenging to manufacture by powder compaction.

3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets

The aim of this study was to explore the potential of fused-deposition 3-dimensional printing (FDM 3DP) to produce modified-release drug loaded tablets. Two aminosalicylate isomers used in the treatment of inflammatory bowel disease (IBD), 5-aminosalicylic acid (5-ASA, mesalazine) and 4-aminosalicylic acid (4-ASA), were selected as model drugs. Commercially produced polyvinyl alcohol (PVA) filaments were loaded with the drugs in an ethanolic drug solution. A final drug-loading of 0.06% w/w and 0.25% w/w was achieved for the 5-ASA and 4-ASA strands, respectively. 10.5mm diameter tablets of both PVA/4-ASA and PVA/5-ASA were subsequently printed using an FDM 3D printer, and varying the weight and densities of the printed tablets was achieved by selecting the infill percentage in the printer software. The tablets were mechanically strong, and the FDM 3D printing was shown to be an effective process for the manufacture of the drug, 5-ASA. Significant thermal degradation of the active 4-ASA (50%) occurred during printing, however, indicating that the method may not be appropriate for drugs when printing at high temperatures exceeding those of the degradation point. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of the formulated blends confirmed these findings while highlighting the potential of thermal analytical techniques to anticipate drug degradation issues in the 3D printing process. The results of the dissolution tests conducted in modified Hanks bicarbonate buffer showed that release profiles for both drugs were dependent on both the drug itself and on the infill percentage of the tablet. Our work here demonstrates the potential role of FDM 3DP as an efficient and low-cost alternative method of manufacturing individually tailored oral drug dosage, and also for production of modified-release formulations.

Fabrication of controlled-release budesonide tablets via desktop (FDM) 3D printing

The aim of this work was to explore the feasibility of using fused deposition modelling (FDM) 3D printing (3DP) technology with hot melt extrusion (HME) and fluid bed coating to fabricate modified-release budesonide dosage forms. Budesonide was sucessfully loaded into polyvinyl alcohol filaments using HME. The filaments were engineered into capsule-shaped tablets (caplets) containing 9mg budesonide using a FDM 3D printer; the caplets were then overcoated with a layer of enteric polymer. The final printed formulation was tested in a dynamic dissolution bicarbonate buffer system, and two commercial budesonide products, Cortiment® (Uceris®) and Entocort®, were also investigated for comparison. Budesonide release from the Entocort® formulation was rapid in conditions of the upper small intestine while release from the Cortiment® product was more delayed and very slow. In contrast, the new 3D printed caplet formulation started to release in the mid-small intestine but release then continued in a sustained manner throughout the distal intestine and colon. This work has demonstrated the potential of combining FDM 3DP with established pharmaceutical processes, including HME and film coating, to fabricate modified release oral dosage forms.

3D scanning and 3D printing as innovative technologies for fabricating personalized topical drug delivery systems.

Acne is a multifactorial inflammatory skin disease with high prevalence. In this work, the potential of 3D printing to produce flexible personalised-shape anti-acne drug (salicylic acid) loaded devices was demonstrated by two different 3D printing (3DP) technologies: Fused Deposition Modelling (FDM) and stereolithography (SLA). 3D scanning technology was used to obtain a 3D model of a nose adapted to the morphology of an individual. In FDM 3DP, commercially produced Flex EcoPLA™ (FPLA) and polycaprolactone (PCL) filaments were loaded with salicylic acid by hot melt extrusion (HME) (theoretical drug loading - 2% w/w) and used as feedstock material for 3D printing. Drug loading in the FPLA-salicylic acid and PCL-salicylic acid 3D printed patches was 0.4% w/w and 1.2% w/w respectively, indicating significant thermal degradation of drug during HME and 3D printing. Diffusion testing in Franz cells using a synthetic membrane revealed that the drug loaded printed samples released <187μg/cm(2) within 3h. FPLA-salicylic acid filament was successfully printed as a nose-shape mask by FDM 3DP, but the PCL-salicylic acid filament was not. In the SLA printing process, the drug was dissolved in different mixtures of poly(ethylene glycol) diacrylate (PEGDA) and poly(ethylene glycol) (PEG) that were solidified by the action of a laser beam. SLA printing led to 3D printed devices (nose-shape) with higher resolution and higher drug loading (1.9% w/w) than FDM, with no drug degradation. The results of drug diffusion tests revealed that drug diffusion was faster than with the FDM devices, 229 and 291μg/cm(2) within 3h for the two formulations evaluated. In this study, SLA printing was the more appropriate 3D printing technology to manufacture anti-acne devices with salicylic acid. The combination of 3D scanning and 3D printing has the potential to offer solutions to produce personalised drug loaded devices, adapted in shape and size to individual patients.

Stereolithographic (SLA) 3D printing of oral modified-release dosage forms.

The aim of this work was to evaluate the suitability of stereolithography (SLA) to fabricate drug-loaded tablets with modified-release characteristics. The SLA printer creates solid objects by using a laser beam to photopolymerise monomers. In this work polyethylene glycol diacrylate (PEGDA) was used as a monomer and diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide was used as a photo-initiator. 4-aminosalicylic acid (4-ASA) and paracetamol (acetaminophen) were selected as model drugs. Tablets were successfully printed and formulations with different properties were fabricated by adding polyethylene glycol 300 (PEG 300) to the printing solution. The loading of paracetamol and 4-ASA in the printed tablets was 5.69% and 5.40% respectively. In a realistic dynamic dissolution simulation of the gastrointestinal tract, drug release from the tablets was dependent on the composition of the formulations, but independent of dissolution pH. In conclusion SLA 3DP technology allows the manufacture of drug loaded tablets with specific extended-release profiles. In the future this technology could become a manufacturing technology for the elaboration of oral dosage forms, for industrial production or even for personalised dose.

Fused-filament 3D printing of drug products: Microstructure analysis and drug release characteristics of PVA-based caplets.

Fused deposition modeling (FDM) 3-Dimensional (3D) printing is becoming an increasingly important technology in the pharmaceutical sciences, since it allows the manufacture of personalized oral dosage forms by deposition of thin layers of material. Here, a filament extruder was used to obtain filaments of polyvinyl alcohol (PVA) containing paracetamol or caffeine appropriate for 3D printing. The filaments were used to manufacture caplets for oral administration by FDM 3D printing, with the aim of evaluating the effect of the internal structure (micropore volume), drug loading and composition on drug dissolution behaviour. Micropore volume of the caplets was primarily determined by the presence of large pores due to gaps in the printed layers/net while printing, and the porosity of the caplets was 10 fold higher than the porosity of the extruded filament. Dynamic dissolution drug release tests on the caplets in biorelevant bicarbonate media revealed distinctive release profiles, which were dependent on drug solubility and drug loading. Porosity of the caplets did not help to predict the different drug release profiles. This study confirms the potential of 3D printing to fabricate caplets and helps to elucidate which factors influence drug release from this type of new dosage form.

Development of modified release 3D printed tablets (printlets) with pharmaceutical excipients using additive manufacturing

The aim of this study was to manufacture 3D printed tablets (printlets) from enteric polymers by single filament fused deposition modeling (FDM) 3D printing (3DP). Hot melt extrusion was used to generate paracetamol-loaded filaments from three different grades of the pharmaceutical excipient hypromellose acetate succinate (HPMCAS), grades LG, MG and HG. One-step 3DP was used to process these filaments into enteric printlets incorporating up to 50% drug loading with two different infill percentages (20 and 100%). X-ray Micro Computed Tomography (Micro-CT) analysis revealed that printlets with 20% infill had cavities in the core compared to 100% infill, and that the density of the 50% drug loading printlets was higher than the equivalent formulations loaded with 5% drug. In biorelevant bicarbonate dissolution media, drug release from the printlets was dependent on the polymer composition, drug loading and the internal structure of the formulations. All HPMCAS-based printlets showed delayed drug release properties, and in the intestinal conditions, drug release was faster from the printlets prepared with polymers with a lower pH-threshold: HPMCAS LG > HPMCAS MG > HPMCAS HG. These results confirm that FDM 3D printing makes it possible not only to manufacture delayed release printlets without the need for an outer enteric coating, but it is also feasible to adapt the release profile in response to the personal characteristics of the patient, realizing the full potential of additive manufacturing in the development of personalised dose medicines.

Selective laser sintering (SLS) 3D printing of medicines

Selective laser sintering (SLS) 3-dimensional printing is currently used for industrial manufacturing of plastic, metallic and ceramic objects. To date there have been no reports on the use of SLS to fabricate oral drug loaded products; therefore, the aim of this work was to explore the suitability of SLS printing for manufacturing medicines. Two thermoplastic pharmaceutical grade polymers, Kollicoat IR (75% polyvinyl alcohol and 25% polyethylene glycol copolymer) and Eudragit L100-55 (50% methacrylic acid and 50% ethyl acrylate copolymer), with immediate and modified release characteristics respectively, were selected to investigate the versatility of a SLS printer. Each polymer was investigated with three different drug loadings of paracetamol (acetaminophen) (5, 20 and 35%). To aid the sintering process, 3% Candurin® gold sheen was added to each of the powdered formulations. In total, six solid formulations were successfully printed; the printlets (3D printed tablets) were robust, and no evidence of drug degradation was observed. In biorelevant bicarbonate dissolution media, the Kollicoat formulations showed pH-independent release characteristics, with the release rate dependent on the drug content. In the case of the Eudragit formulations, these showed pH-dependent, modified-release profiles independent of drug loading, with complete release being achieved over 12h. In conclusion, this work has demonstrated that SLS is a versatile and practical 3D printing technology which can be applied to the pharmaceutical field, thus widening the armamentarium of 3D printing technologies available for the manufacture of modern medicines.