Evaluation of process parameters’ influence on the release of poorly soluble drug from solid dispersion

Večina novih zdravilnih učinkovin (ZU) je slabo vodotopnih, kar vodi v razvoj novih, bolj kompleksnih dostavnih sistemov. Primer takšnih dostavnih sistemov so med drugim amorfne trdne disperzije (ASD). Zaradi kompleksnosti procesov, ki se odvijajo med sproščanjem in absorpcijo ZU v nekaterih primerih s klasičnimi metodami za spremljanje sproščanja ne moremo zadovoljivo preučiti in opisati vseh procesov, ki nanju vplivajo. Posledično je razvoj metod, ki se bolj približajo pogojem prebavnega trakta in vivo, nujen (t. i. biorelevantne metode). Predmet magistrske naloge je bila ASD, pripravljena s tehnologijo iztiskanja talin, ki je sestavljena iz slabo topne ZU razreda BCS II in polimera. V nalogi smo preučevali vpliv procesne temperature in hitrosti vrtenja polžev v ekstrudorju pri pripravi iztiskanca ter razmerje med ZU in polimerom na kinetiko sproščanja ZU iz različno pripravljenih ASD. Teste sproščanja smo izvedli v različnih biorelevantnih medijih (0,3 % SLS v vodi, FaSSIF pH 6,5 in FaSSIF pH 5,8) na napravi USP2. Glavni namen je bil razviti formulacijo oz. ASD, ki bi se po kinetiki sproščanja najbolj približala sproščanju ZU iz referenčnega produkta. Za preverjanje skladnosti s specifikacijskimi mejami smo izvedli eksperimente po QC (angl. »Quality control«) metodi sproščanja, ki sestoji iz kisle in nevtralne faze. Za dotično učinkovino smo poskusili razviti tudi bolj biorelevantne metode (bifazna metoda in MicroFLUXTM metoda). S pomočjo naštetih medijev oz. metod smo pokazali, da procesna parametra pri izdelavi iztiskanca (temperatura iztiskanja talin in hitrost vrtenja polžev) vplivata na profil sproščanja. V mediju z 0,3 % SLS v vodi smo v primeru vseh formulacij z višjim deležem ZU v iztiskancu opazili višje profile sproščanja kot v primeru formulacij z nižjim deležem ZU. V obeh FaSSIF medijih pa so po drugi strani formulacije z višjim deležem ZU v iztiskancu imele višje profile sproščanja v primeru, da so bile pripravljene pri višji temperaturi ekstruzije in višjih obratih polžev v ekstrudorju. V primeru formulacij z nižjim deležem ZU smo vpliv na sproščanje opazili samo pri spremembi hitrosti vrtenja polžev. Glede na dostopne in vivo podatke predhodno izvedenih bioekvivalenčnih študij smo ocenili, da se je za najbolj biorelevantno metodo izkazala MicroFLUXTM metoda. SLS in FaSSIF rezultati niso ekvivalentni in da je vsak občitljiv na druge kritične parametre. Na podlagi naših eksperimentov smo zaključili, da je za usmerjanje razvoja bioekvivalentnega produkta smiselno uporabiti kombinacijo opisanih metod.Most of the new active pharmaceutical ingredients (API) are poorly soluble in water, leading to the development of new, more complex delivery systems such as amorphous solid dispersions (ASD). Due to the complexity of the processes that take place during release and absorption of API, in some cases with the classical dissolution methods it is not possible to satisfactorily describe all the processes that affect them. Consequently, the development of methods that simulate the conditions of the digestive tract in vivo is necessary (so-called biorelevant methods). The subject of the master\u27s thesis was ASD, prepared by extrusion from poorly soluble active pharmaceutical ingredient BCS II class and polymer. In this paper, we studied the influence of process temperature and speed of rotation of the extruder during extrudate preparation and the ratio between API and polymer on the kinetics of API release from differently prepared ASD. Dissolution tests were performed in various biorelevant media (0.3% SLS in water, FaSSIF pH 6.5 and FaSSIF pH 5.8) on a USP2 device. The main purpose was to develop a ASD, which would assure the same relese kinetics as reference product under biorelevant conditions. To check compliance with the specification limits, we performed experiments according to the QC ("Quality control") method, which consists of an acidic and a neutral phase. We also tried to develop more biorelevant methods for the active substance (biphasic method and MicroFLUX method). With the help of the listed media and methods, we showed that the extruson process parameters (melt extrusion temperature and speed of rotation) affect the API release from the final formulation. In the medium with 0.3 % SLS in water, higher release profiles were observed in the case of all formulations with a higher API content in the extrudate than in the case of formulations with a lower API content. In both FaSSIF media, on the other hand, formulations with a higher API content in the extrudate had higher release profiles in case they were prepared at a higher extrusion temperature and higher speed of rotation in the extruder. In the case of formulations with a lower API content, only the effect of the speed of rotation was observed on the release profiles. Based on the available in vivo data from the performed bioequivalence studies, we estimated that the MicroFLUX method proved to be the most biorelevant method. SLS and FaSSIF results are not equivalent and that each is sensitive to other critical parameters. Based on our experiments, we concluded that it makes sense to use a combination of the described methods to guide the development of a bioequivalent product