Proučevanje sproščanja dipiridamola iz tablet na pretočnem sistemu s posnemanjem pH vzdolž celotnega prebavnega trakta

Javornik, Janez (author), Bogataj, Marija (mentor), Felicijan, Tjaša (co-mentor)

Da bi ugotovili, kakšnemu mehanizmu bo podvrženo sproščanje določene farmacevtske oblike (FO), je bilo razvitih mnogo in vitro testov, s katerimi lahko posnemamo pogoje vzdolž prebavnega trakta bolje kot s farmakopejskimi metodami. S tem namenom smo v tej magistrski nalogi preučevali sproščanje dipiridamola (DIP) iz tablet na pretočnem sistemu s steklenimi kroglicami v zaporedju medijev, ki ponazarjajo individualne in vivo profile pH. Izbrani profili pH, ki so bili predhodno že ponazorjeni, predstavljajo različne vrednosti pH in različne čase zadrževanja v posameznih delih prebavnega trakta. Profile pH smo morali le optimizirati z zamenjavo medijev v tolikšni meri, da smo dosegli ustrezno stopnjo ujemanja s profilom in vivo iz študije pH na prostovoljcih, vzete iz literature. Izdelali smo tablete z različnimi sestavami in na podlagi testiranja sproščanja na USP II izbrali ustrezno končno sestavo, s katero smo izvedli teste sproščanja v pretočnem sistemu. Končna FO je vsebovala 25,0 % dipiridamola in 75,0 % hidroksipropilmetilceluloze (HPMC, Pharmacoat 603). Tekom poskusov sproščanja v pretočnem sistemu je prišlo do obarjanja DIP zaradi prenasičenja pri dvigu pH, ki je ponazarjal prehod iz želodca v duodenum. Zaradi tega smo se poslužili dvojnega vzorčenja, s katerim smo istočasno določili celokupno koncentracijo sproščenega DIP in delež raztopljenega DIP. Deleži sproščenega DIP so se med celokupnim in raztopljenim vzorcem razlikovali, saj je zaradi dviga pH po ponazoritvi prehoda v dvanajstnik prišlo do obarjanja. V primeru celokupnega vzorca je zaradi izpiranja oborine iz odvodne cevke prišlo do lomov na krivulji sproščanja. Glede na rezultate sproščanja smo ugotovili, da različen čas zadrževanja v kislini in koncentracija uporabljene kisline vplivata na delež sproščenega DIP v največji meri. Daljši kot je bil čas zadrževanja v kislini, večja koncentracija DIP se je sprostila iz tablete. Ugotovili smo tudi, da obstaja možnost vplivov pH, hitrosti naraščanja pH tekom profila pH, razpada tablete in medija, ki sledi po ponazoritvi prehoda v dvanajstnik, na hitrost sproščanja DIP v pretočnem sistemu. Izvesti bi bilo potrebno nadaljnje raziskave, da bi določili ključne faktorje sproščanja DIP v pretočnem sistemu.

• Language: Slovenian
• Keywords: dipiridamol, pretočni sistem s steklenimi kroglicami, profili pH celotnega prebavnega trakta, testiranje sproščanja, supersaturacija
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2019
• PID: 20.500.12556/RUL-111444
• Publication date in RUL: 01.10.2019

Secondary language

• Language: English
• Title: Evaluation of dipyridamole release from tablets on flow-through dissolution system with pH simulation of the whole gastrointestinal tract

Abstract

Many in vitro tests that can simulate gastrointestinal conditions in vitro more closely than pharmacopoeial methods have been developed. With this purpose we have evaluated in this thesis the release of dipyridamole (DIP) from tablets using the flow-through system with glass beads in a sequence of media that illustrates individual pH profiles. Selected pH profiles, that have been simulated before, represent different pH values and different retention times along the gastrointestinal tract. pH profiles had to be optimised by slightly changing the media sequence in order to achieve a certain degree of analogy with the in vivo pH profiles from study on volunteers from the literature. We made tablets with different compositions and, based on the dissolution test in USP II, selected the formulation with a suitable composition, which was tested in the flow-through system. The final formulation contained 25.0% of dipyridamole and 75.0% of hydroxypropyl methylcellulose (HPMC, Pharmacoat 603). During dissolution tests in the flow-through system precipitation was observed due to supersaturation of DIP after the increase in pH value, which simulated the passage from the stomach to the duodenum. For this reason, the collected samples were prepared in two different ways, which enabled us to simultaneously determine the total concentration of the released DIP and the percentage of the dissolved DIP. The proportions of the dissolved and total released DIP in the samples differed from each other because the increase in pH value that simulated the passage from the stomach to the duodenum produced drug precipitation. In the case of the total DIP release profiles broken curve of drug release occurred due to the transfer of the accumulated precipitate in the drainage tube in the cylinders with collected samples. Based on the results, we determined that different retention times in the acid and acid concentration influenced the release of DIP the most. The longer the retention time, the higher the concentration of the total released DIP. An observation made during this research suggests, that the pH, the rate of pH increase along the profile, the disintegration of the tablet and the medium that simulates the passage through small intestine could all influence the dissolution rate of DIP in the flow-through system. Further research would be required to determine the key factors of DIP release in the flow-through system.

• Keywords: dipyridamole, flow-through system with glass beads, whole gastrointestinal tract, pH profiles, dissolution test, supersaturation