Ovrednotenje različnih medijev za izvedbo preskusa sproščanja ogrodne tablete na napravi za posnemanje črevesnega gibanja : enoviti magistrski študij farmacije

Jamnik, Jani (author), Trontelj, Jurij (mentor), Klančar, Uroš (comentor)

Preskus sproščanja peroralnih farmacevtskih oblik se običajno izvaja bodisi za namene kontrole kakovosti, kjer preverjamo skladnost izdelka, bodisi za namene raziskav in razvoja, kjer si želimo poustvariti čim bolj biorelevantno okolje, ki nam omogoča visoko stopnjo in vitro-in vivo korelacije. V ta namen se poslužujemo uporabe kompleksnih in vitro modelov in metod, s katerimi lahko dosegamo visoko in vivo napovedno moč. Glavni cilj magistrske naloge je bil opredeliti uporabnost novega in vitro modela, razvitega v podjetju Lek d.d. Ljubljana, ki posnema črevesno gibanje, za sproščanje trdnih peroralnih farmacevtskih oblik v črevesu. S tem namenom smo preskusili sproščanje učinkovine iz treh formulacij hidrofilnih ogrodnih tablet z različnimi kinetikami sproščanja (hitra, srednje hitra, počasna formulacija) in iz referenčnega zdravila. Pri ogrodni tableti je učinkovina porazdeljena v ogrodju, ki nam, v primerjavi z oblikami s takojšnjim učinkom, omogoča nadzorovano sproščanje skozi daljše časovno obdobje. Ovrednotili smo pet različnih metod za izvedbo preskusa sproščanja. V acetatnem pufru pH-4,5 (program P03), kjer smo preverjali vpliv pH na sproščanje učinkovine, je le-to potekalo hitreje kot pri drugi primerljivi metodi (fosfatni pufer pH-6,8, program P04) zaradi večje topnosti oziroma hitrosti raztapljanja modelne učinkovine. V umetnem črevesnem soku, ki posnema pogoje na tešče (FaSSIF), smo dosegli najmanjša razlikovanja med formulacijami z različnimi kinetikami sproščanja in najmanjše ujemanje z in vivo opaženo kinetiko (razmerja med deleži sproščene učinkovine iz testnih formulacij in reference). Dodatek NaCl fosfatnemu pufru oziroma povišanje ionske jakosti je zaradi izsoljevanja upočasnilo sproščanje učinkovine v primerjavi s pufrom brez dodatka NaCl. Pri vseh preskušenih medijih oziroma metodah smo z modelom uspeli doseči razlikovanja med formulacijami z različnimi kinetikami sproščanja. Kot najboljša za izbrano formulacijo se je izkazala metoda s kalijevim fosfatnim pufrom pH-6,8 in programom P12, saj smo na ta način dosegli največje ujemanje z in vivo opaženo kinetiko. Prav tako smo z metodo dosegli boljše ujemanje z in vivo razmerji kot s klasično napravo z vesli (USP II). S predstavljenim primerom želimo prikazati uporabnost in fleksibilnost naprave oziroma novega in vitro modela, za katerega pričakujemo, da bo lahko uspešno simuliral sproščanje tudi drugih podobnih formulacij.

• Language: Slovenian
• Keywords: sproščanje učinkovin in vitro model vrste ogrodnih tablet tanko črevo ionska jakost preskusi sproščanja
• Work type: Master's thesis/paper
• Typology: 2.09 - Master's Thesis
• Organization: FFA - Faculty of Pharmacy
• Place of publishing: Ljubljana
• Publisher: [J. Jamnik]
• Year: 2016
• Number of pages: V, 54 f.
• PID: 20.500.12556/RUL-87409
• UDC: 543:615.011(043.3)
• COBISS.SI-ID: 4107633
• Publication date in RUL: 07.12.2016

Secondary language

• Language: English
• Title: Evaluation of different media for implementation of dissolution testing of a matrix tablet on an apparatus simulating the movement of human intestine

Abstract

Dissolution testing of oral dosage forms is usually performed either for quality control purposes testing the compliance of batches or for research and development purposes simulating a biorelevant environment that allows high degree of in vitro-in vivo correlation. For this purpose we use complex in vitro models and methods that reach a high level of in vivo prediction. The main objective of this master’s thesis has been to assess the efficacy of a new in vitro model developed at Lek d.d. Ljubljana simulating the movement of human intestine for evaluation of dissolution of oral dosage forms in human intestine. Therefore, we performed dissolution testing of three different hydrophilic matrix tablets with different release kinetics (fast, medium and slow release) and a reference product. In a matrix tablet the active ingredient is distributed in the matrix allowing for a controlled release over a longer time period compared to an immediate release form. We evaluated five different methods for dissolution testing. Acetate buffer pH-4,5 (program P03) where we examined the influence of pH on the release of the active ingredient showed a faster release rate in comparison to the other equivalent method (phosphate buffer pH-6,8, program P04) due to its higher solubility in acidic environment. Fasted state simulated intestinal fluid showed the least discrimination between formulations with different release rates as well as the greatest discrepancy to in vivo observed kinetics (test formulations/reference ratios from in vivo study). Due to salting out, addition of NaCl to phosphate buffer (increase in ionic strength) reduced release rates as compared to a buffer without addition of NaCl. The model was able to show discrimination between formulations with different release kinetics in all tested media. Owing to the greatest correlation with in vivo observed kinetics the method with phosphate buffer pH-6,8 and program P12 was established as the best formulation. Compared to the conventional USP II paddle method, the aforementioned method showed better correlation to observed in vivo ratios. The presented case aims to show efficacy and flexibility of the method and the novel in vitro model which is expected to successfully simulate dissolution of other similar formulations.

• Keywords: dissolution testing in vitro model biorelevant matrix tablet ionic strength