Z načrtovanjem eksperimentov vodena optimizacija nanostrukturiranih lipidnih nosilcev s težko topno učinkovino

Bauer, Klavdija (author), Zupančič, Špela (mentor)

Nanostrukturiani lipidni nosilci (NLC) predstavljajo obetaven dostavni sistem za težko topne učinkovine. Tekoči lipid poveča možnosti vgradnje NLC z učinkovino, saj omogoči nastanek amorfne mreže v ogrodju iz trdnega lipida, kar je glavna prednost pred trdnimi lipidnimi nanodelci. V pretekli študiji so bili razviti NLC z vgrajeno modelno učinkovino X z nizko stabilnostjo. Zato je bil namen te magistrske naloge ugotoviti razlog za nestabilnost in optimizirati sestavo NLC tako, da bodo v izotoničnem okolju ohranili vsebnost učinkovine vsaj 7 dni. NLC smo izdelali iz Compritola 888 ATO, Captexa 200, PEG 2000 DSPE in modelne učinkovine X s homogenizacijsko metodo in vrednotili parametre velikost, polidisperzni indeks (PI), zeta potencial (ZP), učinkovitost vgradnje (EE) in dejansko vsebnost. Pri načrtovanju eksperimentov (DOE) smo spreminjali parametre Captex 200, Kolliphor HS 15 ter učinkovino z namenom optimizacije sestave NLC. Pri DOE2 smo v NLC vgrajevali manjše količine Captexa 200, Kolliphorja HS 15 ter učinkovine v primerjavi z DOE1. Pri obeh eksperimentih smo preverjali stabilnost NLC in njihovih parametrov. NLC v izotoničnem mediju so bili po pripravi podobnih velikosti kot v demineralizirani vodi, pri obeh vzorcih pa smo opazili znatno znižanje EE po 4 dneh shranjevanja. Ugotovili smo, da je učinkovina začela izkristalizirati iz NLC že v prvem dnevu po izdelavi in da gre za fizikalno nestabilnost NLC z ZU. Na uspešnost vgradnje znatno vplivajo pomožne snovi, zato smo vrednotili topnost učinkovine v različnih lipidih in ugotovili, da ima učinkovina najvišjo topnost v zmesi Captexa 200 in Kolliphorja HS 15 v razmerju 1:3, drugo največjo pa v Captexu 200. Vzorci DOE1 so bili veliki do 179,5 nm s PI pod 0,3 in ZP do – 20,71 mV ter EE od 70 do 80 %. Ker je pri vseh vzorcih vgradnja znatno padla že po prvem dnevu, smo pri DOE2 zmanjšali količino vgrajenih pomožnih snovi. Pri tem so nastali manjši delci z višjo EE, ki je znašala tudi do 95,87 %, in so bili stabilni 7 dni. Ugotovili smo, da NLC lahko sprejmejo določeno količino učinkovine in ko je količina le-te presežena, se v nekaj dneh izkristalizira in izpade iz NLC. Z optimizirano sestavo smo izdelali NLC z velikostjo pod 100 nm, s PI pod 0,3, ZP okoli –16 mV ter EE od 90 do 97 %. Delci so bili stabilni po 2 dnevih, EE pa se je znižala za približno 3 %.

• Language: Slovenian
• Keywords: nanostrukturirani lipidni nosilci, težko topna učinkovina, tekoči lipidi, načrtovanje eksperimentov, stabilnost
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2024
• PID: 20.500.12556/RUL-159342
• Publication date in RUL: 06.07.2024

Secondary language

• Language: English
• Title: Experimental design-guided optimization of nanostructured lipid carrier with a poorly soluble drug

Abstract

Nanostructured lipid carriers (NLCs) represent a promising delivery system for poorly soluble drugs. Liquid lipids enhance the drug loading capacity of NLCs by enabling the formation of an amorphous matrix within the solid lipid, which is the main advantage over solid lipid nanoparticles. In a previous study, NLCs with incorporated model active pharmaceutical ingredient X (API X) were developed, but they were not stable. Therefore, the purpose of this master's thesis was to determine the reason for the instability and to optimize the composition of NLCs so that they retain drug loading in an isotonic environment for at least 7 days. NLCs were made from Compritol 888 ATO, Captex 200, PEG 2000 DSPE, and API X using the homogenization method. The parameters size, polydispersity index (PI), zeta potential (ZP), encapsulation efficiency (EE), and drug loading were evaluated. In the design of experiments (DOE), we varied the parameters Captex 200, Kolliphor HS 15, and API X with the aim of optimizing the NLC composition. In DOE2, smaller quantities of Captex 200, Kolliphor HS 15, and API X were incorporated into NLCs compared to DOE1. In both experiments, the stability of NLCs and their parameters were characterized. NLCs in an isotonic medium were similar in size to those prepared in demineralized water, and a significant decrease in EE was observed for both samples after 4 days of storage. We found that API X started to crystallize from the NLCs within one day and that NLC are physically unstable. The success of incorporation is significantly influenced by excipients, so we evaluated the solubility of API X in various lipids and found that it has the highest solubility in a mixture of Captex 200 and Kolliphor HS 15 in a ratio of 1:3, and the second highest in Captex 200. The DOE1 samples were as large as 179.5 nm with a PI below 0.3, a ZP of up to –20.71 mV, and an EE of 70–80%. Since the EE dropped significantly in all samples after the first day, we reduced the amount of excipients used in DOE2. This resulted in smaller particles with a higher EE of up to 95.87%, which were stable for 7 days. We found that NLCs can incorporate a certain amount of drug, and when this amount is exceeded, it crystallizes within a few days and precipitates out of the NLCs. With the optimized composition, we produced NLCs with a size below 100 nm, a PI below 0.3, a ZP of around –16 mV, and an EE of 90–97%. Particles were stable after 2 days, with EE decreasing by approximately 3%.

• Keywords: nanostructured lipid carriers, poorly soluble drug, liquid lipids, design of experiments, stability