Razvoj disolucijsko-permeabilnostne metode za vrednotenje sproščanja slabo topne učinkovine iz trdne disperzije hidroksipropilmetilceluloze acetat sukcinata v majhnih volumnih

Zakrajšek, Jan (author), Janković, Biljana (mentor), Huzjak, Tilen (comentor)

Farmacevtska industrija stremi k proizvodnji peroralnih farmacevtskih oblik (FO) zaradi enostavnega načina aplikacije. Ker pa je število slabo topnih zdravilnih učinkovin (ZU), ki se vgrajujejo v omenjene FO v porastu, je razumljiva tudi potreba po razvoju naprednih metod za njihovo vrednotenje, s ciljem obvladanja bioekvivalenčnega tveganja. Namen magistrske naloge je razvoj disolucijsko-permeabilnostne metode za vrednotenje sproščanja šibko bazične, slabo topne ZU, vgrajene v amorfno trdno disperzijo (ASD) s hidroksipropilmetilceluloznim acetat sukcinatom. Razvili smo biorelevantno bifazno metodo v posodicah z majhnim volumnom na sistemu MicroFLUXTM, pri čemer smo testirali različne načine izvedbe s štirimi kombinacijami medijev: sončnično olje – FaSSIF pH 6,5, oktanol – FaSSIF pH 6,5, oktanol – fosfatni pufer pH 6,5 in oktanol – SGF pH 1,6 + FaSSIF(x3) (trikratni koncentrat medija FaSSIF). Za končno vrednotenje preiskovanih vzorcev smo izbrali medij oz. metodo, ki je predstavljala kompromis med enostavnostjo izvedbe, ponovljivostjo, diskriminatornostjo in primerljivostjo s podatki iz bioekvivalenčnih študij. Kot najboljša se je na podlagi teh kriterijev izkazala kombinacija oktanol – FaSSIF pH 6,5, na kateri smo testirali skupno 15 različnih vzorcev ASD s preiskovano ZU, pripravljenih pri različnih procesnih pogojih s tehnologijo iztiskanja talin (HME). Po izvedbi eksperimentov z bifazno metodo smo 2 vzorca, ki izkazujeta največjo primerljivost s testiranim inovatorskim izdelkom, in 3 vzorce, katerih podatki in vivo so dostopni, analizirali tudi z MicroFLUXTM metodo z membrano z medijem SGF pH 1,6 in FaSSIF pH 6,5 na donorski in 20 mM HEPES 1% SLS pH 7,4 na akceptorski strani. Metodi sta pomembno prispevali k opredelitvi kritičnosti in vpliva vrednotenih procesnih parametrov (temperatura, hitrost vrtenja polžev in količina uporabljenega polimera pri tehnologiji iztiskanja talin ter proces mletja iztiskancev) na profil sproščanja ZU iz ASD ter k razvoju končne generične formulacije. Pripomogli sta tudi k razumevanju biorelevantnih disolucijsko-permeabilnostnih procesov (precipitacija, tvorba prenasičenja in koloidnih struktur) in vzpostavitvi in vitro – in vivo korelacije.

• Language: Slovenian
• Keywords: amorfna trdna disperzija, biorelevantne metode, bifazna metoda, MicroFLUXTM, prenasičenje
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2022
• PID: 20.500.12556/RUL-141629
• Publication date in RUL: 03.10.2022

Secondary language

• Language: English
• Title: Development of dissolution-permeability method for evaluating release of poorly soluble drug from solid dispersion hydroxipropylmethylcelulose acetate succinate in small volumes

Abstract

The pharmaceutical industry is striving to develop oral pharmaceutical dosage forms to improve patient compliance. As the number of poorly soluble active ingredients included in oral pharmaceutical dosage forms increases, the development of advanced methods to evaluate their release is also required to successfully mitigate the risk of bioequivalence. The objective of this master's thesis is to develop a dissolution-permeability method to evaluate the release of weakly basic, poorly soluble active ingredient contained in an amorphous solid dispersion (ASD) containing hydroxypropyl methylcellulose acetate succinate. We developed a biphasic method in microdissolution vessels on the MicroFLUXTM system, testing different method approaches and 4 different combinations of dissolution media: Sunflower oil – FaSSIF pH 6,5, Octanol – FaSSIF pH 6,5, Octanol – Phosphate buffer pH 6,5 and Octanol – SGF pH 1,6 + FaSSIF(x3) (triple concentrated medium FaSSIF). For the final evaluation of the studied samples, we chose a method that is at the same time simple to perform, repeatable, has adequate discriminatory power and biological relevance. The combination of the media octanol – FaSSIF 6,5 proved to be optimal, and we tested 15 ASD samples prepared under different process parameters using the hot-melt extrusion (HME) method. After performing all experiments using the biphasic method, we selected two samples that showed the greatest comparability with the original product and three samples for which in vivo data were available and also analysed them using the MicroFLUXTM membrane method with SGF pH 1,6 and FaSSIF pH 6,5 as donor media and 20 mM HEPES 1% SLS as acceptor media. Both methods contributed significantly to elaborate the influence of critical process parameters (temperature, screw speed, amount of polymer used at HME and extrudate miling process) on the release profile of the drug in the form of ASD and the development of the final dosage form. In addition, the methods also contribute to the understanding of biorelevant dissolution-permeability processes (precipitation, supersaturation and colloidal structures) and to the establishment of an in vitro – in vivo correlation.

• Keywords: amorphous solid dispersion, biorelevant methods, biphasic method, MicroFLUXTM, supersaturation