Evaluation of the pH gradient in a gel layer of matrix tablets and its influence on the poorly soluble drug release

Večina zdravilnih učinkovin (ZU) je šibkih baz/kislin ali njihovih soli, za katere je značilna pH-odvisna topnost, ki lahko vodi v omejeno absorpcijo in biološko uporabnost zdravila. Z vgradnjo pH modifikatorjev v farmacevtsko obliko (FO) lahko v neposredni bližini delcev ZU prilagodimo pH mikrookolja (pHM), s tem pa izboljšamo topnost ZU in vplivamo na sproščanje. Hidrofilne ogrodne tablete se vzdolž GIT premikajo v enoviti obliki, izpostavljene mehanskim vplivom, ki jih v klasičnih napravah za sproščanje ne moremo posnemati. V podjetju Lek d.d. so razvili biorelevantni in vitro napravi za sproščanje, katerih prednost je izboljšana anatomska podobnost s človeškimi prebavili ter sposobnost stiskanja vsebine s krožnimi peristaltičnimi kontrakcijami, podobno kot in vivo. To sta umetni želodčni (AGSang: »advacend gastric simulator«) in črevesni (IMSPAang. »intestinal model for simulation of peristaltic action«) simulator. V prvem delu magistrske naloge smo opazovali sproščanje ZU s pH-odvisno topnostjo (natrijev diklofenakat, propranololijev klorid in dipiridamol) iz HPMC ogrodnih tablet v klasičnem (USP2) in biorelevantnem (AGS+IMSPA) sistemu za sproščanje. Z menjavo medija po 2 urah smo simulirali prehod iz želodca v tanko črevo. Vse modelne ZU so pričakovano izkazovale pH-odvisen profil sproščanja. V AGS+IMSPA smo zaradi dodatnih mehanskih obremenitev dosegli hitrejše in obsežnejše sproščanje. Ko smo v obstoječe FO vgradili pH modifikatorje, smo v primeru dipiridamola z vgradnjo fumarne kisline dosegli hitrejše in značilno obsežnejše sproščanje v obeh sistemih, propranololijev klorid pa se je ob prisotnosti vinske kisline sproščal hitreje in obsežneje le v AGS+IMSPA. Obseg in hitrost sproščanja natrijevega diklofenakata se nista povečala, ker je bil uporabljen delež pH modifikatorja Eudragita E najverjetneje prenizek. S kriostatsko metodo smo v plasteh hidrogela ogrodnih tablet brez pH modifikatorjev ob menjavi medija opazovali pH gradient. Opazili smo povečan vpliv želodčnega medija na pHM v gelskih plasteh po mehanski obdelavi v AGS v primerjavi z USP2, kar je sovpadalo s pospešeno kinetiko sproščanja obeh bazičnih učinkovin. pHM v gelskem območju tablet smo opazovali tudi vizualno z barvnim pH indikatorjem metiloranžem in potrdili vpliv pH vstopajočega medija, prisotnosti ZU in pH modifikatorjev na pHM v FO. S sočasno uporabo obeh metod smo lahko ovrednotili vpliv dinamičnega spreminjanja pHM po simuliranem prehodu iz želodca v črevo na kinetiko sproščanja ZU.Most of the drugs are either weak bases/acids or salts thereof, which exhibit pH-dependent solubility that can lead to insufficient absorption and bioavailability. pH modifiers can optimise pH (pHM) in the pharmaceutical dosage form in the intimate vicinity of the drug and therefore, improve pH-dependent solubility and release. Hydrophilic matrices travel along the GIT in non-disintegrated form being exposed to mechanical stress, that cannot be mimicked appropriately by the pharmacopeial dissolution apparatuses, like USP2. In Lek d.d. two biorelevant in vitro dissolution apparatuses were developed - AGS (»advanced gastric simulator«) and IMSPA (»intestinal model for simulation of peristaltic action«). Their main advantages are anatomical similarity with human digestive system and ability to mimic gastric and intestinal peristaltic action. Initially dissolution profiles of 3 model drugs with pH-dependent solubility (dipyridamole, Na diclofenac and propranolol HCl) from HPMC matrix tablets were generated in two dissolution systems – USP2 and combination of biorelevant apparatuses AGS and IMSPA incubating tablets for 2 hours in acidic media, followed by dissolution media replacement with neutral pH, simulating transition from stomach to small intestine. All model drugs showed pH-dependent release profiles. As expected, in AGS+IMSPA, due to stronger mechanical stress and hydrodynamics, all drugs were released from matrices faster and to a greater extent in comparison to USP2. When pH modifiers were added to initial formulations, we observed faster and greater extent of released dipyridamole in the presence of fumaric acid in both dissolution systems, while added tartaric acid improved dissolution behaviour of propranolol HCl only in AGS+IMSPA. In contrast, presumably due to insufficient amount of basic Eudragit E, its addition did not result in faster or more extensive release of Na diclofenac. Cryostatic method was used to evaluate pH gradient in the gel layer of matrix tablets with no added pH modifiers. A more pronounced effect of acidic media on pHM in the gel layer was observed in AGS, where stronger mechanical stress was applied in comparison to USP2. Additionally, pHM was also observed visually by the use of pH indicator methyl orange, where we confirmed the influence of penetrating media pH, presence of drugs and pH modifiers on the pHM. By the use of both methods for observing pHM we could evaluate the influence of dynamic changes of pHM after simulated transition from stomach to small intestine on the kinetics of model drug release