Razvoj in optimizacija izdelave liofilizata z ibuprofenom za parenteralno uporabo : doktorska disertacija

Preskar, Maja (author), Gašperlin, Mirjana (mentor), Vrečer, Franc (co-mentor)

Protivnetna nesteroidna zdravila (NSAID) so široko uveljavljena skupina zdravil predvsem za peroralno aplikacijo, medtem ko jih je za parenteralno uporabo na tržišču zelo malo. Parenteralne oblike so primernejše predvsem za bolnike s težavami prebavnega trakta in z oteženim požiranjem peroralno apliciranih trdnih farmacevtskih oblik (FO) ter v primerih postoperativnih indikacij, kjer je zahtevano hitro analgetično, protivnetno in antipiretično delovanje. V eksperimentalnem delu doktorske disertacije smo kot modelno učinkovino uporabili ibuprofen (IBP) kot predstavnika široko uporabljene slabo topne zdravilne učinkovine (ZU), ki jo uvrščamo v skupino NSAID. Na seznamu zdravil, ki so odobrena s strani Ameriške agencije za hrano in zdravila (FDA), je le ena parenteralna oblika z IBP s koncentracijo > 10 mg/ml, kar je vsekakor posledica fizikalno-kemijskih lastnosti molekule, predvsem slabe vodotopnosti (< 1 mg/ml), ki poleg visokega odmerka (peroralno maks. 800 mg dnevno) predstavlja velik izziv za razvoj farmacevtske oblike z IBP. Številne objave opisujejo različne tehnike za izboljšanje topnosti predvsem za trdne peroralne FO, medtem ko je za paranteralne oblike to področje slabše raziskano. Eksperimentalno delo v doktorski disertaciji smo razdelili na dva dela. V prvem delu smo največ pozornosti namenili razvoju parenteralnega liofiliziranega izdelka z IBP, ki bo povečal topnost ZU ter hkrati omogočal izotoničnost končno pripravljene raztopine, ki nastane po raztapljanju liofilizata z vodo za injekcije (VZI). Pri tem smo se osredotočili na vrednotenje raztopine pred liofilizacijo za definiranje ključnih procesnih parametrov ter na izbor pomožnih snovi. V nadaljevanju smo predstavili pristop k optimizaciji energetsko in časovno potratnega liofilizacijskega procesa. Vpliv formulacijskih in procesnih parametrov na ključne lastnosti končnega izdelka smo vrednotili z multivariantno analizo podatkov (z metodo odzivnih površin) ter določili optimalno kombinacijo formulacijskega in procesnega parametra. V drugem delu doktorskega dela smo ovrednotili uporabnost procesne analizne tehnologije (PAT), in sicer bližnje infrardeče (NIR) in ramanske spektroskopije za merjenje ključnih karakteristik liofilizata, kot so vsebnost vode (RMC), specifična površina (SSA) in rekonstitucijski čas (RT). Pri obdelavi obsežnih podatkov smo si pomagali z multivariantno analizo podatkov (MVA), in sicer z metodo glavnih komponent (PCA) in regresijo delnih najmanjših kvadratov (PLS). Doktorsko delo predstavljajo uvodno poglavje in tri poglavja z raziskovalnimi rezultati v obliki člankov, ki smo jih objavili ali poslali v objavo v priznane znanstvene publikacije.

• Language: Slovenian
• Keywords: parenteralne oblike, liofilizirani izdelki, pomožne snovi, analizni pristopi, ibuprofen
• Work type: Dissertation
• Typology: 2.08 - Doctoral Dissertation
• Organization: FFA - Faculty of Pharmacy
• Place of publishing: Ljubljana
• Publisher: [M. Preskar]
• Year: 2021
• Number of pages: 171 str.
• PID: 20.500.12556/RUL-137072
• UDC: 615.212(043.3)
• COBISS.SI-ID: 63708419
• Publication date in RUL: 01.06.2022

Secondary language

• Language: English
• Title: Development and process optimization of freeze dried powder with ibuprofen for parenteral application

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for oral, while there are just a few for parenteral administration on the market. Parenteral forms are preferred in cases of postoperative indications, where rapid analgesic, anti-inflammatory and antipyretic action is required especially in patients with gastrointestinal problems and in patients with swallowing difficulties. Ibuprofen (IBP), which is classified in the NSAID group and is a representative of the widely used poorly soluble active pharmaceutical ingredient (API), was used in the experimental part of the doctoral thesis. US Food and Drug Administration (FDA) approved only one parenteral form with IBP with a concentration > 10 mg/mL, which is certainly due to the physicochemical properties of the molecule, especially poor water solubility (< 1 mg/mL), which in addition to the high dose (max. 800 mg daily) presents a great challenge to formulating dosage form with IBP. Numerous publications describe various techniques for IBP solubilization for solid dosage forms, while for parenteral forms solubility enchancment is less researched. The work of the doctoral thesis was divided into two parts. Firstly, the main focus was to develop a parenteral lyophilized product with enhanced solubility of IBP and isotonicity of the finally prepared solution after dissolving the lyophilisate with water for injections (WFI). We focused on the evaluation of the solution before lyophilization to define key process parameters and on the selection of excipients. Furtermore, as lyophilization is energy and time consuming technological process, its optimization was investigated. The influence of formulation and process parameters on the critical attributes of the final product was evaluated by multivariate data analysis (using the response surface method) and the optimal combination of formulation and process parameters was determined accordingly. In the second part of this thesis, the applicability of process analysis technology (PAT), namely near- infrared (NIR) and Raman spectroscopy for evaluation of critical attributes of the lyophilisate such as residual moisture content (RMC), specific surface area (SSA) and reconstitution time (RT) was evaluated. Multivariate data analysis (MVA), namely the principal components method (PCA) and partial least squares regression (PLS) were used for evaluation of the collected process data. The doctoral thesis consists of introduction part and three research papers that already are or will be published in recognised scientific journals.