Razvoj in vrednotenje liotropnih tekočih kristalov na osnovi glicerol monooleata za subkutano aplikacijo

Mikuž, Lara (author), Gosenca Matjaž, Mirjam (mentor), Vitek, Mercedes (co-mentor)

Liotropni tekoči kristali, ki se tvorijo v ustreznih zmeseh vode, lipidne faze in površinsko aktivnih snovi, se na področju farmacije proučujejo kot aktualni dostavni sistemi za različne poti dostave. Z vidika mikrostrukture ločimo lamelarne, heksagonalne in kubične mezofaze, med katerimi so zaradi obsežne medfazne površine zlasti kubične in heksagonalne sposobne zagotoviti podaljšano sproščanje zdravilnih učinkovin. Nastanek posameznih ali mešanih mezofaz je pogojen z izbiro in deležem izhodiščnih sestavin. Glicerol monooleat je amfifilen lipid, ki je zaradi svoje nizke toksičnosti, biorazgradljivosti, biokompatibilnosti in sposobnosti tvorbe različnih mezofaz primeren za razvoj tekočih kristalov za subkutano aplikacijo. Subkutana aplikacija v sklopu parenteralne poti dostave izkazuje številne prednosti, v primerjavi s klasičnimi peroralnimi farmacevtskimi oblikami pa lahko dosežemo večjo biološko uporabnost učinkovin. V porastu so dostavni sistemi s podaljšanim sproščanjem, ki bi tekom daljšega časovnega obdobja zagotovili terapevtski učinek, z manjšo frekvenco odmerjanja ter pojavnostjo neželenih učinkov. V sklopu magistrske naloge smo sprva izdelali dva (psevdo)trikomponentna diagrama na osnovi glicerol monooleata ter etanola oz. zmesi etanola in lecitina ter na podlagi organoleptičnih lastnosti ocenili področja nastanka tekočih kristalov. S polarizacijsko mikroskopijo smo nadalje vrednotili mikrostrukturo izbranih sistemov, kjer so se kot optimalne izkazale formulacije (E/L)Go20, (E/L)Go30, (E/L)Go40 in (E/L)Go50, iz katerih so ob stiku z vodo pretežno nastali heksagonalni oz. kubični tekoči kristali. V nadaljevanju smo izbranim formulacijam vrednotili injektabilnost, čas geliranja, sposobnost geliranja in privzem vode ter preučili reološke lastnosti. Vrednotenja smo izvedli pri sobni (25 °C) in telesni (37 °C) temperaturi. Za potrebe subkutane aplikacije se je z vidika hidratacije sistema in reološkega obnašanja kot optimalna izkazala formulacija (E/L)Go50. Tekoča prekurzorska formulacija ob stiku z vodo nemudoma gelira in tvori kompaktno poltrdno strukturo. Njena začetna viskoznost dovoljuje injiciranje, nastali gel pa je izrazito elastičen in tvori visoko urejeno, čvrsto strukturo, ki razpada počasi in enakomerno. Na podlagi pridobljenih ugotovitev lahko sklepamo, da bi na glicerol monooleatu osnovani tekoči kristali za subkutano aplikacijo ne le dosegli terapevtskih ciljev, temveč tudi omogočili pacientu prijaznejšo terapijo in zato predstavljajo obetaven dostavni sistem za nadaljnje raziskovanje.

• Language: Slovenian
• Keywords: heksagonalni tekoči kristali, kubični tekoči kristali, glicerol monooleat, subkutana aplikacija, podaljšano sproščanje
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2023
• PID: 20.500.12556/RUL-151661
• Publication date in RUL: 14.10.2023

Secondary language

• Language: English
• Title: Development and characterization of glycerol monooleate-based lyotropic liquid crystals for subcutaneous application

Abstract

Lyotropic liquid crystals form in different mixtures of water, lipid phase and surfactants. In the field of pharmacy they are investigated as delivery systems for various routes of delivery. Based on their microstructure we distinguish between lamellar, hexagonal and cubic mesophases, among which, due to their extensive interfacial area, hexagonal and cubic mesophases are especially suitable for sustained release of active ingredients. The formation of individual or mixed mesophases depends on the type and ratio of ingredients. Glycerol monooleat is an amphiphilic lipid and is, due to its low toxicity, biodegradability, biocompatibility and the ability to form different types of liquid crystals, suitable for the development of liquid crystals for subcutaneous application. Subcutaneous application is a parenteral route of delivery with many advantages and can provide greater bioavailability of drugs compared to classic oral dosage forms. Sustained-release delivery systems have gained much attention as they assure therapeutic effect over a longer period of time with fewer adverse effects and less frequent dosing. As part of laboratory research we firstly created two ternary-phase diagrams using glycerol monooleate and ethanol or mixture of ethanol and lecithin, then based on organoleptic properties outlined the areas of formation of liquid crystals. Using polarized light microscopy we further evaluated the microsctructure of chosen samples with optimal formulations being (E/L)Go20, (E/L)Go30, (E/L)Go40 and (E/L)Go50 where upon contact with water, hexagonal or cubic liquid crystals were predominantly formed. Afterwards we evaluated the injectability, gelation time, water uptake and rheological properties of the selected samples and performed a gelation test. Samples were evaluated at 25 °C and 37 °C. Due to its suitable water uptake profile and rheological properties (E/L)Go50 was found optimal system for subcutaneous application. Its precursor solution displayed good injectability and, upon contact with water, immediately formed a compact, semi-solid gel that showed desired highly elastic behaviour. Its structure was firm and stable, allowing a slow and constant rate of disintegration. Based on our findings, it can be concluded that liquid crystals based on glycerol monooleate for subcutaneous application could not only achieve the desired therapeutic goals, but also provide a more patient-friendly treatment and therefore represent a promising delivery system for further research.

• Keywords: hexagonal liquid crystals, cubic liquid crystals, glycerol monooleat, subcutaneous application, sustained release