AbstractsChemistry

Low oral bioavailability and general delivery problems related to poorly water soluble drugs are major challenges in pharmaceutical formulation development. Nanocrystal technologies have been introduced as advantageous formulation approaches for these molecules. Nanocrystals, with greater surface to volume ratio, can effectively increase both the dissolution rate and saturation solubility of active ingredients. The aim of this thesis was to obtain detailed knowledge about the dissolution characteristics of drug nanocrystals, and to develop feasible nanocrystal applications for ocular and oral drug delivery purposes. Hence, develop-ability issues from the analytical difficulties of the drug dissolution behavior to the scale-ability of the nanocrystals were covered. A new approach in dissolution testing of nanocrystals, UV imaging, was introduced and applied in order to obtain detailed understanding of the real-time dissolution behavior of different nanosized particle fractions. Moreover, both liquid and solid nanocrystal dosage forms were formulated and studied in vitro and in vivo. High-quality nanocrystal suspensions were prepared using the rapid and industrially relevant top-down wet milling technique. Detailed, real-time dissolution analyses of the nanocrystals enabled a close level insight into the occurring phenomena. With regards to the formulation development, an in vivo effective nanocrystal suspension formulation was developed for ocular delivery, to treat elevated intraocular pressure. Furthermore, nanocrystal suspensions were converted into dry powders, by both freeze-drying and granulating technique, and further processed into tablet and capsule formulations. By screening both powder and tablet properties, optimal compositions for nanocrystalline solid formulations were indicated with regards to the higher scale process-ability. The formulations were studied both in vitro and in vivo. As a result, the great difficulty of predicting the in vivo behavior based on the in vitro results and the importance of in vivo studies in the early development phase, were addressed. It was concluded that the methods applied and studied provided valuable knowledge and important tools for the pharmaceutical formulation development in order to solve the current problems related to the delivery of poorly soluble drugs. Lääkeainemolekyylin alhainen vesiliukoisuus on suuri haaste farmaseuttiselle lääkekehitykselle. Huonot liukenemisominaisuudet johtavat alhaiseen imeytymisasteeseen elimistössä ja tekevät lääkkeestä epätehokkaan. Nanokideteknologia tarjoaa yhtenä lupaavimmista lähestymistavoista niukkaliukoisille lääkeainemolekyyleille hyödyllisiä formulaatioratkaisuja. Nanokiteytyksen avulla pystytään parantamaan huomattavasti lääkeaineen liukenemisominaisuuksia ja näin ollen myös sen tehoa elimistössä. Tämän väitöskirjatyön tavoitteena oli etsiä ratkaisuja liukenemisongelmaan nanokiteytyksen avulla. Työssä pyrittiin saamaan yksityiskohtaista tietoa niukkaliukoisten lääkeaineiden nanokiteiden liukenemiskäyttäytymisestä…