Formulation and in vitro/in silico characterization of modified release dry powers for inhalation with drugs of diferent biopharmaceutical properties

[J. S Ignjatović]

237 str.

Farmacija - Farmaceutska tehnologija / Pharmacy - Pharmaceutical technology

Inhalacioni put primene lekova pokazuje brojne prednosti, no broj registrovanih preparata za ovaj put primene je relativno ograničen u odnosu na ostale vrste preparata. Dodatno, svi do sada registrovani preparati za inhalaciju predstavljaju preparate sa trenutnim oslobađanjem lekovite supstance. Poslednjih godina se intenzivno radi na razvoju preparata za inhalaciju sa modifikovanim oslobađanjem lekovite supstance, koji bi mogli da doprinesu povećanju komplijanse pacijenata i efikasnosti terapije. U skladu sa tim, cilj ove disertacije je razvoj formulacije čvrstih lipidnih mikročestica u obliku praškova za inhalaciju, odgovarajućih aerodinamičkih karakteristika i sa modifikovanim oslobađanjem lekovite supstance, kao i in vitro/in silico karakterizacija praškova za inhalaciju sa modifikovanim oslobađanjem lekovitih supstanci različih biofarmaceutskih svojstava, salbutamol-sulfata i budesonida. Metodom emulgovanja na povišenoj temperaturi, u kombinaciji sa sušenjem raspršivanjem, izrađeni su praškovi za inhalaciju u obliku čvrstih lipidnih mikročestica, koji su pokazali odgovarajuće aerodinamičke karakteristike i modifikovanu (produženu) brzinu oslobađanja salbutamol-sulfata u odnosu na prašak čistog salbutamol-sulfata. Rezultati sprovedenih ispitivanja su ukazali na značaj primene in silico modela zasnovanih na računarskoj dinamici fluida i čestica u razvoju praškova za inhalaciju, jer su na ovaj način određene karakteristike ispitivanih formulacija koje nije moguće utvrditi in vitro metodama. Fiziološki-zasnovano farmakokinetičko (PBPK) modelovanje pokazalo je da bi se inhalacionom primenom mukoadhezivnog praška sa modifikovanim oslobađanjem budesonida postiglo sporije rastvaranje i produžena apsorpcija budesonida. Takođe, rezultati PBPK modelovanja ukazali su na to da bi inhalacionom primenom praškova čvrstih lipidnih mikročestica mogla da se produži apsorpcija salbutamola u plućima. Pri tome je predviđeno da se, nakon primene praškova čvrstih lipidnih mikročestica, veći procenat salbutamola apsorbuje putem pluća, a manji iz gastrointestinalnog trakta, u odnosu na registrovani preparat sa trenutnim oslobađanjem lekovite supstance. Dobijeni rezultati ukazuju na to da bi inhalaciona primena praškova čvrstih lipidnih mikročestica potencijalno mogla obezbediti veću efikasnost i bezbednost inhalacione terapije.

Pulmonary drug delivery has many advantages, but the number of marketed inhalation products is still limited, in comparison to the other types of drug products. In addition, all currently marketed inhalation medicines represent immediate release drug products. The development of modified-release inhalation products has received widespread attention over the last few years, since they can improve patient compliance and treatment efficacy. Therefore, the aim of this dissertation was to develop solid lipid microparticles as dry powders for inhalation (DPIs) with adequate aerodynamic characteristics and modified drug release, as well as in vitro/in silico characterization of modified-release DPIs with drugs of different biopharmaceutical properties, salbutamol-sulphate and budesonide. DPIs comprised of solid lipid microparticles were successfully formulated and prepared using the melt emulsification process coupled with spray drying. The obtained formulations exhibited suitable aerodynamic characteristics and modified (prolonged) drug release in comparison to the raw salbutamol-sulphate powder. The results of in silico characterization studies highlighted the importance of computational fluid and particle dynamics models in the DPI development, considering that these models enabled the assessment of certain DPI characteristics which cannot be determined using in vitro methods. Physiologically-based pharmacokinetic (PBPK) modeling indicated that inhalation administration of mucoadhesive modified-release DPI may provide prolonged budesonide dissolution and absorption in the lungs. Also, PBPK modeling results implied that inhalation of DPI comprised of solid lipid microparticles may lead to prolonged salbutamol pulmonary absorption. In addition, the model predicted increased salbutamol absorption in the lungs, together with decreased absorption in the gastrointestinal tract, following inhalation administration of solid lipid microparticles, in comparison to the marketed immediate release drug product. The obtained results implied that inhalation administration of DPIs containing solid lipid microparticles could potentially improve therapeutic efficacy and safety of inhaled drugs.

praškovi za inhalaciju, modifikovano oslobađanje, čvrste lipidne mikročestice, aerodinamičke karakteristike, modeli zasnovani na računarskoj dinamici fluida i čestica, fiziološki-zasnovano farmakokinetičko (PBPK) modelovanje, salbutamol-sulfat, budesonid

dry powders for inhalation (DPIs), modified release, solid lipid microparticles, aerodynamic characteristics, computational fluid and particle dynamics models, physiologically-based pharmacokinetic (PBPK) modeling, salbutamol-sulphate, budesonide

615.453.2.015(043.3)

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