Development of formulations and 3D printing process of tablets with targeted release of paracetamol made by fused deposition modelling technique

Trodimenzionalna (3D) štampa je revolucionarna tehnika proizvodnje u farmaceutskojindustriji kojom se može skratiti vreme proizvodnje farmaceutskih preparata, smanjiti troškovii omogućiti personalizovana terapija. Kao nova tehnika, 3D štampa je u svetu farmacije jošuvek nedovoljno poznata, te je ovakav način razvoja i proizvodnje lekova jedan odnajistraživanijih oblasti današnjice. Jedna od najpoznatijih tehnika 3D štampe jeste tehnikadeponovanja istopljenog filamenta (engl. Fused deposition modelling, FDM).Cilj istraživanja u okviru ove disertacije bio je razvoj i optimizacija formulacija i procesaštampe FDM 3D tableta paracetamola. Eksperimentalni rad je podeljen u 3 faze.U prvoj fazi eksperimentalnog rada ispitivanje uticaja formulacionih i procesnih parametara namogućnost ekstruzije/štampanja i karakteristike dobijenih filamenata/tableta sprovedeno jeprimenom tri različite vrste osnovnog polimera (kompolimera metakrilne kiseline (Eudragit®),polikaprolaktona (PCL) i polietilenoksida (PEO)). Prvi tip formulacija činile su formulacije sasmešom osnovnih polimera (Eudragit® i PEO), gde je pokazano da ovakva kombinacijaosnovnih polimera nije pogodna za dobijanje filamenata i 3D štampanje tableta paracetamola.Drugu grupu činile su formulacije na bazi PCL gde je pokazana laka ekstruzija filamenataujednačenog izgleda i jednostavna štampa FDM 3D tableta. Međutim, u ovim filamentimauočen je najveći gubitak sadržaja u odnosu na ostale formulacije, zbog neujednačenog prolaskasmeše kroz hranilicu ekstrudera usled razlika u veličini čestica. FDM 3D tablete na bazi PCLsu pokazale izrazito sporo oslobađanje lekovite supstance, gde se nakon 8 sati ispitivanjaoslobodilo između 36,83% i 42,79% paracetamola. Treći tip formulacija činile su formulacijesa PEO (PEO molekulske mase 200000 g/mol (PEO 200 K) i PEO molekulske mase 100000g/mol (PEO 100 K)), pri čemu nije uočen uticaj molekulske mase osnovnog polimera namogućnost ekstruzije i printabilnost filamenata. Ovi filamenti su bili manje prikladni za daljuštampu, koja je bila praćena čestim zapušavanjem mlaznice štampača. Tablete na bazi PEO supokazale znatno brže oslobađanje paracetamola (potpuno oslobađanje paracetamola nakon 4sata ispitivanja) u odnosu na tablete na bazi PCL. U prvoj fazi istraživanja je primećeno da jesa porastom koncetracije paracetamola u formulaciji bila potrebna i viša temperatura zaekstruziju, a da je štampanje filamentima bilo moguće kada je procenat paracetamola uformulacijama bio do 60%.U drugoj fazi eksperimentalnog rada ispitane su mogućnosti ubrzanja oslobađanjaparacetamola iz FDM 3D odštampanih tableta i mogućnosti dobijanja tableta kod kojih brzinaoslobađanja i predviđeni obim apsorpcije lekovite supstance odgovaraju tabletama sa trenutnimoslobađanjem. Ispitivane su FDM 3D tablete odštampane od istog osnovnog polimera,polivinilalkohola (PVA), u kombinaciji sa plastifikatorom Affinisol™ HPMC HME 4MHYPROMELLOSE®, na kojima su primenjene četiri strategije za ubrzanje oslobađanjalekovite supstance. Ekstruzija filamenata sa PVA je bila jednostavna, a naknadno dodavanjerazličitih pomoćnih supstanci u cilju ubrzanja oslobađanja paracetamola iz tableta nije uticalona mogućnost ekstruzije i printabilnost filamenata, ukoliko je udeo osnovnog polimera bioiznad 45%. Rezultati in vitro ispitivanja brzine oslobađanja paracetamola iz formulacije saPVA i Affinisol™ HPMC HME 4M HYPROMELLOSE® su pokazali da se za 5 sati ispitivanjaoslobodilo 58% paracetamola...Three-dimensional (3D) printing is a revolutionary technique in pharmaceutical industry thatcan shorten drug products production time, reduce costs and enable personalized therapy. As anew and still not fully explored technique, 3D printing in pharmacy has been intensivelyresearched in recent years. One of the best known 3D printing techniques is fused depositionmodelling (FDM).The aim of this dissertation was to develop and optimize formulation and 3D printing processof paracetamol-loaded tablets via FDM 3D printing technique. The research was divided into3 phases.The first phase of the research focused on providing basic information about the experimentalconditions of FDM 3D printing of paracetamol-loaded tablets. Evaluation of the influence offormulation and process parameters on the extrudion/printing potential and characteristics ofthe obtained filaments/tablets was carried out using three different types of the main polymer(methacrylic acid copolymers (Eudragit®), polycaprolactone (PCL) and polyethylene oxyde(PEO)). The first type of formulations consisted of a combination of the main polymers(Eudragit® and PEO) and the results showed that this combination is not suitable for obtainingfilaments by melt extrusion process and for 3D printing of paracetamol-loaded tablets. Thesecond group were formulations with PCL as the main polymer, where facile extrusion ofuniformed filaments and effortless FDM 3D tablets printing were demonstrated. However,these filaments exhibited the greatest loss of content in comparison to the other formulations,due to the uneven feeding of the mixture through the extruder caused by differences in particlesize. PCL-based FDM 3D tablets showed rather slow drug release, with 36.83-42.79%paracetamol released after 8 hours of testing. The third type of formulations were formulationswith PEO (PEO with molecular weight of 200000 g/mol (PEO 200 K) and PEO with molecularweight of 100000 g/mol (PEO 100 K)), and in this case there was no observable effect of thepolymer molecular weight on extrudability and printability of the filaments. These filamentswere less suitable for consequent 3D printing process, which was demonstrated by frequentclogging of the printer nozzle. However, PEO-based 3D printed tablets showed notably fasterdrug release rate (complete paracetamol release after 4 hours of testing) compared to PCLbasedtablets. In this research phase, it was noticed that increase in paracetamol concentrationin the formulation required a higher extrusion temperature. Also, printing with filaments waspossible only when the percentage of paracetamol in the formulations was up to 60%.The second phase of the research aimed to investigate possibilities of increasing the drugrelease rate from FDM 3D printed tablets to comply with drug release and consequentabsorption rate that correspond to immediate release tablets. FDM 3D printed tablets containingthe same main polymer, polyvinyl alcohol (PVA), in combination with a plasticizer Affinisol™HPMC HME 4M HYPROMELLOSE® were tested, and four different strategies were appliedto increase the drug release. The extrusion of filaments with PVA as the main polymer wassimple. Subsequent addition of various excipients, in order to increase the drug release fromtablets, did not affect extrudability and printability of the filaments when the percentage of themain polymer in formulations was above 45%. In vitro dissolution test results revealed that theformulation containing PVA and Affinisol™ HPMC HME 4M HYPROMELLOSE® released58% of paracetamol within 5 hours of testing..