Vrednotenje stabilnosti hidrokortizonsukcinata v raztopinah za infundiranje

Gaál, Enikő Éva (author), Roškar, Robert (mentor), Temova Rakuša, Žane (comentor)

Kortizol je glukokortikoidni hormon, ki nastaja zaradi odziva na stres in deluje pri imunskem odzivu in uravnavanju vnetja. Naša študija se je osredotočila na hidrokortizonsukcinat, ki se zaradi večje vodotopnosti in vazopresornega delovanja uporablja v obliki raztopin za injekcije in infuzije v terapiji hemodinamsko nestabilnih bolnikov. Ker je učinkovina v vodnem mediju izredno nestabilna, se nahaja v obliki liofilizata, ki se tik pred uporabo raztopi. Osrednji namen naloge je bil ovrednotiti stabilnost hidrokortizonsukcinata v raztopinah za infundiranje pri različnih pogojih shranjevanja, ki posnemajo realne pogoje in na osnovi dobljenih rezultatov podati priporočila za njegovo uporabo v bolnišnicah. Za namen vrednotenja stabilnosti smo najprej preizkusili nekaj literaturnih HPLC-UV metod. Izbrali in optimizirali smo metodo s kratkim časom analize, kateri smo na osnovi stresnih vzorcev potrdili stabilnostno indikativnost in jo nato ustrezno ovrednotili v skladu s smernicami ICH. Nato smo preverili vpliv različnih dejavnikov na stabilnost učinkovine v vodnih raztopinah, ki smo jo tudi kvantitativno ovrednotili na osnovi konstant reakcijske hitrosti 1. reda. Ugotovili smo, da na stabilnost hidrokortizonsukcinata bistveno vpliva temperatura in potrdili zelo dobro skladanje z Arrheniusovo premico. pH raztopine ima prav tako velik vpliv - najbolj stabilen je pri pH med 6 in 7, najmanj pa v bazičnem mediju. V vodnem mediju je njegova obstojnost slabša kot v organskem topilu, medtem ko ima koncentracija učinkovine manjši vpliv na stabilnost. V sklopu stabilnostne študije na raztopinah za infundiranje smo pripravili štiri raztopine učinkovine, pri dveh različnih koncentracijah (1 in 4 mg/mL) in v dveh topilih (fiziološka in glukozna raztopina), ki smo jih shranjevali zaščitene in nezaščitene pred svetlobo ter pri sobni temperaturi in 30 °C. Ugotovili smo, da že majhna sprememba v temperaturi bistveno vpliva na upad koncentracije učinkovine. Svetloba, vrsta topila in razlike v pH vrednostih infuzijskih raztopin pa niso znatno vplivale na stabilnost učinkovine. Nekoliko boljšo stabilnost smo zaznali pri glukozni raztopini s koncentracijo 1 mg/mL, medtem ko v fiziološki raztopini ni bilo zaznati razlik v stabilnosti med obema koncentracijama učinkovine. Ugotovljeni rok uporabnosti (upad 5 % učinkovine) z upoštevanjem intervala zaupanja raztopin za infundiranje je med 22 in 26 ur pri sobni temperaturi oz. med 5 in 7 ur pri 30 °C.

• Language: Slovenian
• Keywords: hidrokortizonsukcinat, raztopine za infundiranje, HPLC-UV, stabilnost
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2019
• PID: 20.500.12556/RUL-112776
• Publication date in RUL: 13.11.2019

Secondary language

• Language: English
• Title: Stability evaluation of hydrocortisone succinate in infusion solutions

Abstract

Cortisol is a glucocorticoid hormone produced in the adrenal cortex of the human body as a response to stress. Our study focused on hydrocortisone succinate, which has high water solubility, and is used in form of injections and infusions as a vasopressor in the treatment of hemodynamically unstable patients. Since it is extremely unstable in aqueous solutions, it is formulated as a lyophilisate, which is dissolved shortly before use. The aim of the master's thesis was to evaluate the stability of hydrocortisone succinate in solutions for infusion under various storage conditions, which mimic real usage conditions, and to provide evidence based recommendations for its use in hospitals. Selected literature HPLC-UV methods were tested and the most suitable was additionally optimized in order to achieve stability-indicative method with short run times. The method was evaluated in accordance with the ICH guidelines and confirmed by stress samples. The established method was applied to study the influence of various factors on the stability of hydrocortisone succinate in aqueous solutions, which was quantitatively evaluated by 1st order reaction rate constants. The stability of hydrocortisone succinate was significantly influenced by temperature, which showed very good agreement with the Arrhenius plot. The pH of the solution also had a major influence on stability - it was found most stable at pH between 6 and 7 and least stable in alkaline medium. Its stability in aqueous solutions was lower than in organic solvent, whereas the concentration had no significant effect on its stability. In the stability study on solutions for infusion, hydrocortisone succinate solutions with concentration of 1 and 4 mg/mL in physiological saline and glucose were prepared, and stored protected and unprotected from light, at room temperature and at 30 °C. We found that even a small change in temperature has an extremely high influence on the decay rate. On the other hand, exposure to light, the solvent, the concentration and the small difference in the pH value did not significantly affect the stability of hydrocortisone succinate. Slightly higher stability was noticed in glucose solution at a concentration of 1 mg/mL, whereas no difference in its stability was observed between the two concentrations in physiological saline. The estimated shelf life (5 % decrease of the active substance), taking into account the confidence interval is between 22 and 26 hours in infusion solutions stored at room temperature and between 5 and 7 hours if stored at 30 °C.

• Keywords: hydrocortisone succinate, infusion solutions, HPLC-UV, stability