Promising, personalised and printed: A new era of medicine

Cheap 3D printers have truly opened up access to additive manufacturing – when combined with a more personalised approach to healthcare the scene is set for a new era of medicine says Katherine Triffitt 

Personalised medicine is already making a significant impact in clinical practice, with a number of health specialities already adopting individualised treatment strategies. With respect to this, the future of medicine design will inevitably take into account patient genetic and proteomic factors, in combination with the prospect of formulating a wide-range of individualised medicines made available to the patient at the point of prescription.

Additive manufacture is one promising area for development with regard to the manufacture of personalised medicines

However promising this looks to the evolution of disease treatment, applying the concept of personalised medicine to the pharmaceutical industry presents a number of challenges. For example, production of drug doses tailored to individual needs may in the future require novel manufacturing technologies capable of producing small scale numbers of dosage forms¹ available to the patient at the point of prescription presentation (i.e. community pharmacy). Current commercial medicines formulation technology only operates efficiently on a large scale¹, and therefore will only have limited future use in producing common dosage forms required in large percentage groups of the population. Manufacture therefore may move away from such industrial production, and instead towards in situ formulation of individually tailored unit dosage forms and drug combinations².

Additive manufacture is one promising area for development with regard to the manufacture of personalised medicines¹. Since its initial development and utilisation as a production tool for rapid prototyping¹ in the late 80’s, early 90’s³, additive manufacture has been adopted in many industry settings as a novel and highly efficient means of development. Binder Jetting is one form of additive manufacture that follows the principle of binding solution deposition from a print head onto a powdered substrate layer to allow ¹. The desired object is subsequently built up in the same fashion, layer by layer. Such technology is now seen in a diverse number of manufacturing fields, including architecture, nanosystems, aerospace industry, fashion and biomedical research². Medical researchers have also utilised additive manufacture to create bones and functional organs?,?,?, bringing such potential in the medical field to light, with the pharmaceutical field potentially to follow.

Using associated desktop technology in a pharmaceutical care setting could potentially allow the production of personalised medicine guided by their respective prescription?. Possibilities include single blend tablets made of a specific drug and dose to suit individual need? (e.g. for drugs that present with a narrow therapeutic index such as warfarin), multi-layer tablets to provide combinatorial therapy of different strengths or release profiles of the same drug, or a combination of two or more separate drugs? with the aim to reducing tablet load. Fused-deposition modelling (FDM) is another recent approach in additive manufacture, in which an extruded polymer filament is softened by passing through a heated printing tip?. Once deposited on the printers build plate, the polymer will harden and can then have subsequent polymer layer built on top in identical fashion to produce the desired 3D object?. In order to manufacture a pharmaceutically relevant tablet via FDM, it is necessary to incorporate the drug of interest into a polymer filament in order for feeding into the print stock¹. Such has traditionally been achieved via soaking of the polymer in alcoholic solutions containing the active drug?. Although relative success has been seen in drugs such as 4-aminosalicylic acid (4-ASA), 5-aminosalicylic acid (5-ASA)? and prednisolone¹?, the process relies upon passive diffusion and as such requires extended manufacture time, including additional drying steps with often only a low overall drug load achieved?.

The use of hot melt extrusion is a far more feasible and proven effective alternative methodology. It can be described as a process by which raw materials (i.e. drug and excipients) are forced to mix in a rotating screw² at elevated temperatures, and then converted into a product of uniform shape and density via extrusion through a die under defined conditions?,¹¹. The use of hot melt extrusion to produce drug-loaded filaments required for additive manufacture has already been shown to be achievable for water-soluble filaments when producing oral formulations²,¹². For example, Goyanes et al² successfully prepared both paracetamol and caffeine-loaded poly(vinyl) alcohol (PVA) filaments via a Noztec Pro hot melt extruder (Noztec, UK) at 180°C. The attempt to incorporate higher drug loading percentages reduced filament quality (via possible polymer crystallinity alterations²) and thus additive manufacturing potential in this instance; however drug loading percentages above 10% w/w were subsequently achieved via the addition of plasticising excipients². Alongside its success in the literature, hot melt extrusion offers further advantages in additive manufacture including (as previously mentioned) the possibility of working without solvents and thus avoiding the need for subsequent drying steps¹¹,¹³, low cost, fast production and availability for continuous production¹¹.

Using associated desktop technology in a pharmaceutical care setting could potentially allow the production of personalised medicine guided by their respective prescription

The nature hot melt extrusion dictates that both the excipients and more importantly the drug of interest are stable at high temperatures. Long residency time and high glass transition temperatures have often been described as potential drawbacks to the hot melt extrusion process¹?, however there are a number of ways to overcome this limitation should the drug of interest be thermally unstable. One such example could be the formulation and subsequent production of drug salts (e.g. through the reaction of an acid drug with an amine to form an ionic salt) which are known to remain stable at high temperatures, or to co-crystallise the drug with a co-former that could potentially provide desired stability.

There is a currently huge pharmaceutical interest in crystal engineering as a means to optimise chemical and physical drug properties such as solubility, hygroscopicity and dissolution rate¹?,¹?,¹?, therefore the consideration to also alter glass transition temperature may be reasonable. The use of co-crystal engineering in this sense however is only speculative, as there is currently no research to support the suggestion that addition of a second entity or co-former during the process would alter the glass transition of a specified drug. No conclusions therefore can be drawn regarding the use of co-crystallisation to provide thermally stable drug products for hot melt extrusion; however the process may be taken into consideration for future development in the area. Once fed into the print stock, the drug-loaded polymer filament is ready for commencement of fused deposition modelling. It is at this point that associated print software is utilised to adjust parameters of the manufacture, which will subsequently lead to the production of desired dose forms. Printing parameters such as deposition rate, tip size, push-out, suck-back and path-speed have all been used successfully to alter and control tablet shape within satisfactory limits?.

One specific parameter of interest in formulating tablets for individualised doses is infill percentage. In order to increase the mechanical strength of the desired tablet, a greater infill percentage would be selected which would raise the degree to which the printer will pack the void space with polymer¹. This parameter can vary from 0% (empty) to 100% (solid) and therefore has the potential not only to modify the structure of the tablet (i.e. 0% infill will result in a hollow tablet), but in doing so also modify the physical properties of the resultant formulation, such as its dissolution profile¹. For example, tablets with lower percentage infills demonstrated faster drug release in studies undertaken by Goyanes et al¹ (i.e. 6 and 15 hour timeframes for complete drug release in 10% and 50% infill tablets, respectively). This study also demonstrated a linear relationship between infill percentage and tablet weight, suggesting that drug dose could be controlled via selection of appropriate infill percentage¹. This has vast potential in the area of individualised medicine, where tablets could be manufactured at specific doses for an individual via calculation of the appropriate infill percentage.

The research field associated with global additive manufacturing is not only currently wide open, but is also gaining significant momentum, with many industrial sectors across the world participating in its development. Indeed, it is forecast to be a key enabler in high value manufacturing with a worldwide market estimation of £67 billion by 2020³,¹?. The UK is currently among the global leaders in both knowledge development and successful application of additive manufacturing technology³, with considerable capacity for further research including the involvement of 81 organisations (24 universities and 57 companies) since 2007³. Significant public and private sector investments totalling approximately £90million has been placed within the UK to expand the Technology Readiness Level of additive manufacturing, with the Government Office for Science’s Manufacturing Foresight Report 2013 claiming “advances in technologies such as additive manufacture will take place closer to the customer, with a much greater range of products becoming more personalised and tailored to specific needs”¹?.

Within the pharmaceutical industry, GlaxoSmithKline Research & Development have expressed interest in exploring the use of additive manufacture in the production of oral solid dosage formulations, with the future intent to distribute cartridge-based printing machines in local pharmacies and hospitals in the hope of providing patients with customised medicines at the point of prescription³. Given the current literature and financial support for research, the future of pharmaceutical additive manufacture looks both exciting and incredibly promising. Goyanes et al² describe perfectly the concept that ‘theoretically, computer aided design could leave imagination and the resolution of technology as the only limits to the design and manufacture of complex, multifaceted tablets’. With such in mind, it is a fair assumption to make that additive manufacture indeed holds the key to a new era of medicines manufacture.

References 1. Goyanes, A., Buanz, A.B.A., Basit, A.W., Gaisford, S., (2014), Fused-filament 3D printing (3DP) for fabrication of tablets, International Journal of Pharmaceutics, 476:88-92 2. Goyanes, A., Wang, J., Buanz, A., Martínez-Pacheco, R., Telford, R., Gaisford, S., Basit, A.W., (2015), 3D Printing of Medicines: Engineering Novel Oral Devices with Unique Design and Drug Release Characteristics, Molecular Pharmaceutics, 12:4077-4084 3. AM National Strategy, Positioning Paper: The Case for Additive Manufacturing, March 2015, Available athttp://www.amnationalstrategy.uk/wp-content/uploads/2015/05/AM-Strategy-Positioning-Paper.pdf 4. Jones, N., (2012) Science in Three Dimensions: The Print Revolution, Nature, 487(7405):22-23 5. Mannoor, M.S., Jiang, Z., James, T., Kong, Y.L., Malatesta, K.A., Soboyejo, W.O., Verma, N., Gracias, D.H., McAlpine, M.c., (2013), 3D Printed Bionic Ears, Nano Letters, 13(6):2634-2639 6. Kolesky, D.B., Truby, R.L., Gladman, A.S., Busbee, T.A., Homan, K.A., Lewis, J.A., (2014), 3D bioprinting of vascularised heterogenous cell-laden tissue constructs, Advanced Materials, 26(19)3124-3130 7. Khaled, S.A., Burley, J.C., Alexander, M.R., Roberts, C.J., (2014), Desktop 3D printing of controlled release pharmaceutical bilayer tablets, International Journal of Pharmaceutics, 461:105-111 8. Goyanes, A., Chang, H., Sedough, D., Hatton, G.B., Wang, J., Buanz, A., Gaisford, S., Basit, A.W., (2015), Fabrication of controlled-release budesonise tablets via deasktop (FDM) 3D printing, International Journal of Pharmaceutics, (article in press) available at http://dx.doi.org/10.1016/j.ijpharm.2015.10.039 9. Goyanes, A., Buanz, A.B., Hatton, G.B., Gaisford, S., Basit, A.W., (2015) 3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets, European Journal of Pharmaceutics and Biopharmaceutics, 89:157-162 10. Skowyra, J., Pietrzak, K., Alhnan, M.A., (2015) Fabrication of extended-release patient-tailored prednisolone tablets via fused deposition modelling (FDM) 3D printing, European Journal of Pharmaceutical Science, 68:11-17 11. Thiry, J., Krier, F., Evrard, (2015), A review of pharmaceutical extrusion: Critical process parameters and scaling-up, International Journal of Pharmaceutics, 479:227-240 12. Goyanes, A., Martínez, P.R., Buanz, A., Basit, A., Gaisford, S., (2015) Effect of geometry on drug release from 3D printed tablets, International Journal of Pharmaceutics, 494:657 13. Bruce, L.D., Shah, N.H., Waseem Malick, A., Infeld, M.H., McGinity, J.W., (2005), Properties of hot-melt extruded tablet formulations for the colonic delivery of 5-aminosalicylic acid, European Journal of Pharmaceutics and Biopharmaceutics, 59:85-97 14. Breitenbach, J., (2002), Melt extrusion: from process to drug delivery technology, European Journal of Pharmaceutics and Biopharmaceutics, 54:107-117 15. Chen, J.A., Li, S., Lu, T.B., (2014), Pharmaceutical Cocrystals of Ribavirin with Reduced Release Rates, Crystal Growth and Design, 14:6399-6408 16. Vishweshwar, P., McMahon, J.A., Bis, J.A., Zaworotko, M.J., (2006), Pharmaceutical Co-Crystals, Journal of Pharmaceutical Sciences, 95:499-516 17. Steed, J.W., (2012), The role of co-crystals in pharmaceutical design, Trends in Pharmacological Sciences, 34(3):185-193 18. Innovate UK (formerly TSB), (2012), Shaping our National Competency in Additive Manufacturing: A technology innovation needs analysis, Swindon: Innovate UK (formerly TSB) 19. Foresight, (2013), The Future of Manufacturing: A new era of opportunity and challenge for the UK, Summary Report, The Government Office for Science, London

Author

Katherine Triffitt is a third year undergraduate pharmacy student from Durham University, UK, with a keen interest in genetics and medicines personalisation.

Katherine was shortlisted for the United Kingdom and Ireland Controlled Release Society (UKICRS) essay copmpetition. The Society has a membership of scientists, predominantly based in the UK and from both academia and industry that are interested in Drug Delivery.

www.ukicrs.org