3D printing in pharmaceutics: a new avenue for fabricating therapeutic drug delivery systems

Abstract

Personaal- ehk täppismeditsiini abil soovitakse haiguseid ennetada, diagnoosida ja ravida viisil, mis saavutaks parima tulemuse konkreetsel patsiendigrupil. Mitmekülgsete teadmiste kasutamine sobivaima raviaine, annuse ja ravimvormi valimisel aitab kaasa oodatud ravitulemuse saavutamisele. Neid teadmisi aitab rakendada kolmemõõtmeline (3D) printimine. Tegu on meetodiga, kus arvuti abil disainitud mudel ehitatakse kiht kihi haaval soovitud objektiks. Sõltuvalt kihi lisamise viisist jaguneb 3D printimine erinevateks meetoditeks. Meetodi valik aga omakorda võib seada materjalide valikule lisatingimusi. 3D printimine sai alguse 1980ndatel ning on viimastel aastatel jõudnud ka meditsiinivaldkonda. Kirjandusest leiab põhjalikke ülevaateid selle kasutamisest nt kardioloogias, hambaravis, plastilises kirurgias, bioprintimisel. Ravimitööstuses nähakse 3D printimises võimalikku abimeest personaliseeritud ravimite tootmisel. Aastal 2015 sai müügiloa esimene 3D prinditud ravim Spritam®. Doktoritöös kasutati mikroekstrusioonil ning sulatatud sadestusega modelleerimisel põhinevaid printimistehnoloogiaid. Mõlema meetodi jaoks disainiti sobilik ravi- ja abiainete kombinatsioon. Sobivateks kandurpolümeerideks osutusid polüetüleenoksiid ja polükaprolaktoon, raviaineteks indometatsiin ja teofülliin. Sarnaselt klassikalisele ravimiarendusele vajab ka uudsete tehnoloogiate kasutuselevõtt põhjalikku eeltööd, et õppida tundma kasutatavate materjalide omadusi ning võimalikke protsessi ajal toimuvaid muutuseid. Seetõttu uuritigi doktoritöös nii materjalide printimiseelseid omadusi, näiteks viskoossus, füüsikalised omadused, sobivus filamentide tootmiseks jt kui ka saadud ravimkandursüsteemi printimisjärgseid omadusi nagu raviaine vabanemine, reageerimine kuumutamisele ja kiiritamisele. Lisaks töötati välja uudne meetod pooltahkete materjalide 3D-prinditavuse hindamiseks. Töö tulemused kinnitavad, et 3D printimine on farmaatsiateaduse jaoks paljulubav abimees tulevikuravimite arendamisel.

Precision medicine is an approach to enhance the prevention, diagnosis, and treatment of diseases to benefit a specific group of patients. Using this knowledge to select the most suitable active pharmaceutical ingredients (APIs) and doses enables us to achieve the optimal therapeutic efficiency. Three-dimensional (3D) printing is an additive manufacturing technique that has been proposed as tool for the application of these principles. In 3D printing, previously designed model is then layer-by-layer formed into desired object. 3D printing methods differ from each other based on layer formation and can dictate additional material considerations. 3D printing has been studied since 1980s and has been widely used in medicine these previous years. In pharmaceutics, 3D printing can be seen as a possible aid for fabricating personalised drug delivery systems. In 2015 the first 3D printed medicine Spritam® was authorised. In this dissertation, micro-extrusion-based and fused deposition modelling 3D printing methods were used. Suitable active substance and excipient(s) formulations were designed for both methods. Polymers used were polyethylene oxide and polycaprolactone, active substances indomethacin and theophylline. As classical does development, so does the implementation of novel technologies need thorough knowledge of material and process characteristics. Therefore, bulk material properties such as viscosity, physical characteristics, suitability for filament extrusion etc, and final drug delivery system characteristics such as drug release, reaction to heat and radiation were studied. In addition, a novel method for evaluating the 3D printability was designed. We can conclude from the results of this work, that 3D printing promises great aid in developing novel drug delivery systems.