Vrednotenje kritičnih lastnosti in stabilnosti 3D-tiskanih tablet, pripravljenih s tehnologijo ciljnega nalaganja

Potočnik, Luka (author), Dreu, Rok (mentor), Lavrič, Zoran (co-mentor)

Tehnologija ciljnega nalaganja je ena izmed tehnik tridimenzionalnega tiskanja. Predstavlja inovativen način izdelave personaliziranih peroralnih dostavnih sistemov, s katerimi lahko priredimo sproščanje učinkovine. To lahko storimo s spreminjanjem oblike in volumna tablet, sestave pomožnih snovi v formulaciji ter s spremembami v deležu polnjenosti jedra natisnjenih tablet. Tehnologija ciljnega nalaganja namreč omogoča izdelavo tablet, katerih jedro je zgrajeno iz plasti rešetk, kar prispeva k visoki poroznosti in v veliko primerih tudi k takojšnjemu sproščanju učinkovine. V okviru magistrske naloge smo vrednotili dejavnike, ki vplivajo na kakovost natisnjenih tablet in na njihovo kemijsko stabilnost. V tablete smo kot modelno učinkovino vgradili ketoprofen. V prvem delu smo izdelali 17 različnih formulacij filamentov, sestavljenih iz učinkovine enega ali dveh izbranih polimerov, manitola in silicijevega dioksida, kar je predstavljalo sestavo ogrodja tablete. Uporabili smo enovijačni ekstrudor za izdelavo filamentov, ki so vstopali v 3D tisklanik. Delež polnjenosti jedra tablete je znašal 50 %. Natisnjenim tabletam smo določili dimenzije, čas razpadnosti ter vrednotili sproščanje učinkovine. Temu je sledila HPLC analiza nečistoč. Izbrali smo formulaciji z najpočasnejšim in najhitrejšim sproščanjem učinkovine ter ju uporabili za izdelavo tablet, ki omogočajo takojšnje in podaljšano sproščanje učinkovine. V drugi fazi poskusov tiskanja tablet smo z izbranima formulacijama izdelali tablete s spremenjeno obliko tako, da smo v strukturo tablete vgradili eno ali dve odprtini, s čimer smo povečali razmerje med površino in volumnom. Z izbranimi formulacijami smo prav tako izdelali tablete z 20 in 80 odstotki polnjenosti jedra. Tako smo ovrednotili vpliv spremembe oblike tablete in deleža polnjenosti jedra na hitrost sproščanja učinkovine. V tretji fazi pa smo vzorec tablet vsake formulacije za 3 mesece izpostavili stresnim pogojem – temperaturi 40 °C in 75 % relativne vlage. Po treh mesecih smo ponovno izvedli preizkus raztapljanja učinkovine in analizo nečistoč ketoprofna z metodo HPLC. Med sedemnajstimi formulacijami smo izbrali tiste, katerih vsebnost nečistoč in odstopanje dimenzij je po treh mesecih ostala znotraj specifikacijskih mej. 6 od 17 formulacij se je izkazalo kot ustreznih. Tri od 17 formulacij so se po treh mesecih izpostavljenosti stresnim pogojem izkazale kot neustrezne, saj jim je kot posledica absorpcije vlage padla temperatura steklastega prehoda in je prišlo do deformacije oblike. Štirje vzorci so izkazali previsoko vsebnost nečistoč, vzorci štirih formulacij pa so izkazali previsoko odstopanje dimenzij tablete. Dva vzorca sta pri 50 % polnjenosti in nespremenjeni obliki izkazala takojšnje sproščanje učinkovine.

• Language: Slovenian
• Keywords: tehnologija ciljnega nalaganja, sproščanje učinkovine, analiza nečistoč, ketoprofen, stabilnost, čas razpadnosti
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2023
• PID: 20.500.12556/RUL-147199
• Publication date in RUL: 25.06.2023

Secondary language

• Language: English
• Title: Assessment of critical quality attributes and stability of 3D printed tablets prepared by Fused Deposition Modelling

Abstract

Fused deposition modelling is a three-dimensional printing process. It represents an innovative way of manufacturing personalised oral dosage forms. By altering their shape, the constitution of their formulations and their infill percentages, we can modify their release. This is possible, as fused deposition modelling creates tablets composed of layers of grids, that enable high levels of porosity and in many cases also immediate release. We evaluated the key factors that impact the tablets quality and stability. These tablets were ketoprofen-based and were developed from 17 sorts of filaments that have been developed. They were composed of one or two polymers, mannitol and silicon dioxide. The infill percentage of the printed tablets was 50%. The filaments were created with holt melt extrusion and then inserted into the three-dimensional printer. We first measured the dimensions of the printed tablets and then proceeded with dissolution studies. This was followed by disintegration studies and purity profile determination. We selected the formulation with the fastest and slowest dissolution rate and used them for the creation of a single tablet, that combined both types of modified release. We then proceeded to the second phase in which we designed tablets with altered shapes. These tablets had holes built in their structure which enhanced the surface to volume ratio. We also designed tablets with a 20 and 80 infill percentage. This was done so we could evaluate the impact of tablet shapes and infill percentages on the dissolution rate. We then concluded our studies with phase three in which we exposed a sample of tablets made out of each formulation to a temperature of 40°C and 75% relative humidity for 3 months. This was followed by a dissolution test and a HPLC analysis of impurities that have developed. Out of all 17 formulations, we chose the ones that do not exhibit impurity levels and dimension deviations that exceed specification. 6 out of 17 were deemed suitable. 3 out of 17 formulations caused tablet deformation after 3 months due to lowered glass transition temperatures, which was caused by water absorption 4 out of 17 formulations contained too much impurities after 3 months. 4 out of 17 formulations caused excessive dimension deviations. 2 formulations were developed into regular shaped tablets with immediate release at 50% infill.

• Keywords: fused deposition modelling, drug dissolution, impurity analysis, ketoprophen, stability, disintegration time