Naslov (srp)

Preklinička ispitivanja disperzija nanokristala i lipidnih nanočestica deuterisanih pirazolohinolinonskih liganada – fizičkohemijski i biološki aspekti : doktorska disertacija

Autor

Mitrović, Jelena, 1992-

Doprinosi

Ranđelović, Danijela, 1970-
Petković, Miloš, 1980-
Pantelić, Ivana, 1982-
Savić, Snežana, 1971-
Savić, Miroslav M., 1973-
Savić, Sanela, 1987-

Opis (eng)

Recent trends in the discovery of new potential drug canidates have led to the synthesis ofsubstances with low solubility which usually leads to the low bioavailability after administration.This often results in the discontinuation of the drug development. Because of that, the usage ofadvanced formulation approaches already in early stages of drug development could help toovercome the unfavorable physicochemical properties of new chemical entities and enablefarmacological and toxicological preclinical studies. Deuterated pyrazoloquinolinones represent thenew, patent protected ligands for GABAA receptors, with high selectivnost, efficacy and metabolicstability but very low solubility in water, oils and many organic solvents.Therefore, the main aim of this doctoral thesis was the development of nanoparticle formulations oftwo pyrazoloquinolinone ligands, DK-I-56-1 (7-Methoxy-2-(4‑methoxy‑d3-phenyl)−2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one) and DK-I-60-3 (7-Methoxy-d3-2-(4-methoxyd3-phenyl)-2,5-dihydro-3Hpyrazolo[4,3-c]quinolin-3-one), as well as the estimation of the application of developedformulations in preclinical studies of the mentioned substances. The selection of formulationstrategies to overcome the low solubility was guided by the physicochemical properties of thementioned substances taking into account the intended administration routes. Two types offormulations were developed: nanocrystals and lipid nanoparticles. Their comprehensivecharacterization included the assessment of the physicochemical properties significant for thestability during storage and after administration as well as the analysis of their behavior after oraland parenteral administration in context of the prospective pharmacokinetic and pharmacodynamicstudies. While the main advantage of nanocrystals was the simple composition and lowconcentration of stabilizers, lipid nanoparticles with more complex structure provided the additionalincrease of bioavailability thanks to lecithin and polysorbate 80 as stabilizers. In addition, thestability of nanocrystal dispersion during storage was successfully enhanced by lyophilization andin that way the first step to overcome the main disadvantage of these systems was made.It was shown that the selected formulations could contribute to the investigation ofpyrazoloquinolinone ligands through their delivery within the biocompatible formulations whichenable bioavailability enhancement, at the same time keeping the basic characteristics of ligandsduring distribution in the body as well as providing pharmacological effects monitoring without theeffects of excipients traditionally used to dissolve low solubility drug candidates during theirpreclinical studies.

Opis (srp)

Trenutni trendovi u otkriću novih potencijalnih kandidata za lek doveli su do sinteze supstanci saniskom rastvorljivošću, što uglavnom vodi ka niskoj bioraspoloživosti nakon primene i time možezaustaviti njihov dalji razvoj. Iz tog razloga, uključivanje savremenih pristupa formulaciji već uranoj fazi razvoja leka može omogućiti prevazilaženje nepovoljnih fizičkohemijskih osobinanovosintetisanih supstanci i sprovođenje farmakoloških i toksikoloških prekliničkih studija.Deuterisani pirazolohinolinoni predstavljaju nove, patentno zaštićene ligande za GABAA receptorekoje odlikuje visoka selektivnost, efikasnost i metabolička stabilnost, ali i niska rastvorljivost uvodi, uljima i mnogim organskim rastvaračima.Stoga je osnovni cilj ove doktorske disertacije bio razvoj nanočestičnih formulacija dvapirazolohinolinonska liganda, DK-I-56-1 (7-metoksi-2-(4‑metoksi‑d3-fenil)−2,5-dihidro-3Hpirazolo[4,3-c]hinolin-3-on) i DK-I-60-3 (7-metoksi-d3-2-(4-metoksid3-fenil)-2,5-dihidro-3Hpirazolo[4,3-c]hinolin-3-on), kao i procena mogućnosti primene razvijenih formulacija uprekliničkim ispitivanjima navedenih supstanci. Izbor formulacionih strategija za prevazilaženjeslabe rastvorljivosti bio je vođen fizičkohemijskim karakteristikama liganada uzimajući u obzirplaniran put primene. Razvijena su dva tipa formulacija: nanokristali i lipidne nanočestice. Njihovasveobuhvatna karakterizacija uključila je procenu kritičnih fizičkohemijskih osobina značajnih zastabilnost tokom čuvanja i nakon primene, kao i procenu njihovog ponašanja nakon oralne ipareneteralne primene u kontekstu sprovođenja farmakokinetičkih i farmakodinamskih studija. Dokse kao osnovna prednost nanokristalnih formulacija izdvojio jednostavan sastav i niskakoncentracija stabilizatora, lipidne nanočestice kompleksnije strukture obezbeđuju dodatnopovećanje oralne bioraspoloživosti zahvaljujući lecitinu i polisorbatu 80 kao stabilizatorima.Dodatno, liofilizacijom uspešno je povećana stabilnost nanokristalnih disperzija i načinjen prvikorak ka prevazilaženju osnovnog nedostatka ovih sistema.Pokazano je da odabrane formulacije mogu doprineti ispitivanju pirazolohinolinonskih liganadakroz omogućavanje njihove primene u sastavu biokompatibilnih formulacija koje dovode dopovećanja biološke raspoloživosti, ali i zadržavanja osnovnih osobina liganada tokom distribucijekroz organizam, kao i obezbeđenja praćenja farmakoloških efekata bez uticaja ekscipijenasatradicionalno korišćenih za rastvaranje slabo rastvornih kandidata za lekove tokom njihovogprekliničkog istraživanja.

Opis (srp)

Farmacija - Farmaceutska tehnologija / Pharmacy- Pharmaceutical Technology Datum odbrane: 30.09.2023.

Jezik

srpski

Datum

2023

Licenca

Ovo delo je licencirano pod uslovima licence
Creative Commons CC BY-NC-ND 3.0 AT - Creative Commons Autorstvo - Nekomercijalno - Bez prerada 3.0 Austria License.

http://creativecommons.org/licenses/by-nc-nd/3.0/at/legalcode

Predmet

OSNO - Opšta sistematizacija naučnih oblasti, Farmaceutska tehnologija i kozmetologija

nanocrystals, lipid nanoparticles, lyophilization, poor solubility, pyrazoloquinolinones , parenteral administration, oral administration, nuclear magnetic resonance, pharmacokinetics, spontaneous locomotor activity assay

OSNO - Opšta sistematizacija naučnih oblasti, Farmaceutska tehnologija i kozmetologija

nanokristali, lipidne nanočestice, liofilizacija, niska rastvorljivost, pirazolohinolinoni, parenteralna primena, oralna primena, nuklearna magnetna rezonanca, farmakokinetika, test spontane lokomotorne aktivnosti

615.015:543.51(043.3)