Razvoj formulacija i postupka 3D štampe tableta sa ciljanim profilima oslobađanja paracetamola izrađenih tehnikom deponovanja istopljenog filamenta
Development of formulations and 3D printing process of tablets with targeted release of paracetamol made by fused deposition modelling technique
Докторанд
Đuranović, MarijaМентор
Cvijić, SandraЧланови комисије
Ibrić, SvetlanaParojčić, Jelena
Grujić, Branka
Метаподаци
Приказ свих података о дисертацијиСажетак
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 polie...tilenoksida (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®), pol...ycaprolactone (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...