Razvoj formulacija i postupka 3D štampe tableta sa ciljanim profilima oslobađanja paracetamola izrađenih tehnikom deponovanja istopljenog filamenta

Abstract

Trodimenzionalna (3D) štampa je revolucionarna tehnika proizvodnje u farmaceutskoj industriji kojom se može skratiti vreme proizvodnje farmaceutskih preparata, smanjiti troškovi i omogućiti personalizovana terapija. Kao nova tehnika, 3D štampa je u svetu farmacije još uvek nedovoljno poznata, te je ovakav način razvoja i proizvodnje lekova jedan od najistraživanijih oblasti današnjice. Jedna od najpoznatijih tehnika 3D štampe jeste tehnika deponovanja istopljenog filamenta (engl. Fused deposition modelling, FDM). Cilj istraživanja u okviru ove disertacije bio je razvoj i optimizacija formulacija i procesa štampe FDM 3D tableta paracetamola. Eksperimentalni rad je podeljen u 3 faze. U prvoj fazi eksperimentalnog rada ispitivanje uticaja formulacionih i procesnih parametara na mogućnost ekstruzije/štampanja i karakteristike dobijenih filamenata/tableta sprovedeno je primenom tri različite vrste osnovnog polimera (kompolimera metakrilne kiseline (Eudragit®), polikaprolaktona (PCL) i polietilenoksida (PEO)). Prvi tip formulacija činile su formulacije sa smešom osnovnih polimera (Eudragit® i PEO), gde je pokazano da ovakva kombinacija osnovnih polimera nije pogodna za dobijanje filamenata i 3D štampanje tableta paracetamola. Drugu grupu činile su formulacije na bazi PCL gde je pokazana laka ekstruzija filamenata ujednačenog izgleda i jednostavna štampa FDM 3D tableta. Međutim, u ovim filamentima uočen je najveći gubitak sadržaja u odnosu na ostale formulacije, zbog neujednačenog prolaska smeše kroz hranilicu ekstrudera usled razlika u veličini čestica. FDM 3D tablete na bazi PCL su pokazale izrazito sporo oslobađanje lekovite supstance, gde se nakon 8 sati ispitivanja oslobodilo između 36,83% i 42,79% paracetamola. Treći tip formulacija činile su formulacije sa PEO (PEO molekulske mase 200000 g/mol (PEO 200 K) i PEO molekulske mase 100000 g/mol (PEO 100 K)), pri čemu nije uočen uticaj molekulske mase osnovnog polimera na mogućnost ekstruzije i printabilnost filamenata. Ovi filamenti su bili manje prikladni za dalju štampu, koja je bila praćena čestim zapušavanjem mlaznice štampača. Tablete na bazi PEO su pokazale znatno brže oslobađanje paracetamola (potpuno oslobađanje paracetamola nakon 4 sata ispitivanja) u odnosu na tablete na bazi PCL. U prvoj fazi istraživanja je primećeno da je sa porastom koncetracije paracetamola u formulaciji bila potrebna i viša temperatura za ekstruziju, a da je štampanje filamentima bilo moguće kada je procenat paracetamola u formulacijama bio do 60%. U drugoj fazi eksperimentalnog rada ispitane su mogućnosti ubrzanja oslobađanja paracetamola iz FDM 3D odštampanih tableta i mogućnosti dobijanja tableta kod kojih brzina oslobađanja i predviđeni obim apsorpcije lekovite supstance odgovaraju tabletama sa trenutnim oslobađanjem. Ispitivane su FDM 3D tablete odštampane od istog osnovnog polimera, polivinilalkohola (PVA), u kombinaciji sa plastifikatorom Affinisol™ HPMC HME 4M HYPROMELLOSE®, na kojima su primenjene četiri strategije za ubrzanje oslobađanja lekovite supstance. Ekstruzija filamenata sa PVA je bila jednostavna, a naknadno dodavanje različitih pomoćnih supstanci u cilju ubrzanja oslobađanja paracetamola iz tableta nije uticalo na mogućnost ekstruzije i printabilnost filamenata, ukoliko je udeo osnovnog polimera bio iznad 45%. Rezultati in vitro ispitivanja brzine oslobađanja paracetamola iz formulacije sa PVA i Affinisol™ HPMC HME 4M HYPROMELLOSE® su pokazali da se za 5 sati ispitivanja oslobodilo 58% paracetamola...

Three-dimensional (3D) printing is a revolutionary technique in pharmaceutical industry that can shorten drug products production time, reduce costs and enable personalized therapy. As a new and still not fully explored technique, 3D printing in pharmacy has been intensively researched in recent years. One of the best known 3D printing techniques is fused deposition modelling (FDM). The aim of this dissertation was to develop and optimize formulation and 3D printing process of paracetamol-loaded tablets via FDM 3D printing technique. The research was divided into 3 phases. The first phase of the research focused on providing basic information about the experimental conditions of FDM 3D printing of paracetamol-loaded tablets. Evaluation of the influence of formulation and process parameters on the extrudion/printing potential and characteristics of the 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 obtaining filaments by melt extrusion process and for 3D printing of paracetamol-loaded tablets. The second group were formulations with PCL as the main polymer, where facile extrusion of uniformed 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 particle size. 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 formulations with PEO (PEO with molecular weight of 200000 g/mol (PEO 200 K) and PEO with molecular weight of 100000 g/mol (PEO 100 K)), and in this case there was no observable effect of the polymer molecular weight on extrudability and printability of the filaments. These filaments were less suitable for consequent 3D printing process, which was demonstrated by frequent clogging of the printer nozzle. However, PEO-based 3D printed tablets showed notably faster drug release rate (complete paracetamol release after 4 hours of testing) compared to PCLbased tablets. In this research phase, it was noticed that increase in paracetamol concentration in the formulation required a higher extrusion temperature. Also, printing with filaments was possible 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 drug release rate from FDM 3D printed tablets to comply with drug release and consequent absorption rate that correspond to immediate release tablets. FDM 3D printed tablets containing the same main polymer, polyvinyl alcohol (PVA), in combination with a plasticizer Affinisol™ HPMC HME 4M HYPROMELLOSE® were tested, and four different strategies were applied to increase the drug release. The extrusion of filaments with PVA as the main polymer was simple. Subsequent addition of various excipients, in order to increase the drug release from tablets, did not affect extrudability and printability of the filaments when the percentage of the main polymer in formulations was above 45%. In vitro dissolution test results revealed that the formulation containing PVA and Affinisol™ HPMC HME 4M HYPROMELLOSE® released 58% of paracetamol within 5 hours of testing...