The use of microfluidics for production of particles in dry powder inhalation systems : doctoral dissertation

Saboti, Denis (author), Planinšek, Odon (mentor), Chan, Hak-Kim (co-mentor)

Respiratory devices such as metered dose inhalers (MDI), nebulizers and dry powder inhalers (DPI) have been used to administer active pharmaceutical ingredients to treat lung diseases. Inhalable drug particles for DPI formulation are conventionally produced by a top down approach through crystallization followed by milling. This approach tends to generate partially amorphous materials that require post-processing to improve the formulations’ stability. Other methods involve homogenization or precipitation and often require the use of stabilizers, mostly surfactants. The purpose of our work was therefore to develop a novel method for preparation of fine drug particles using a microfluidic reactor and to find an appropriate particle isolation method, in this case ultrasonic spray freeze drying, hence avoiding the need of additional homogenization step or use of a stabilizer. Different active pharmaceutical ingredients and excipients were tested for compatibility with budesonide and beclomethasone dipropionate found to be the most appropriate for further characterization. In the final developed method, a commercial T-junction microfluidic reactor was employed to produce the particle suspension (using an ethanol–water, methanol-water and an acetone–water systems), which was directly fed into an ultrasonic atomization probe, followed by direct feeding to liquid nitrogen. Freeze drying was the final step in the process. The result were fine crystalline budesonide and beclomethasone dipropionate powders that were characterized by the following analytical techniques: optical microscopy, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), dynamic light scattering (DLS), dynamic vapor sorption (DVS), thermal gravimetric analysis (TGA), X-ray powder diffraction (XRD) and aerosol performance with Next Generation Impactor (NGI). When blended with lactose and dispersed using an Aerolizer at 100 L/min air flow rate, budesonide generated fine particle fraction in the range 47.6±2.8% to 54.9±1.8%, thus exhibiting a good aerosol performance. Drug product formulations were compared to commercially available products and showed comparable aerosol performance. Subsequent sample analysis confirmed the suitability of the developed method to produce inhalable drug particles without additional homogenization or stabilizers. The developed method provides a general viable solution for particle isolation from microfluidic reactor.

• Language: English
• Keywords: farmacevtska tehnologija, pljučne bolezni, zdravljenje, inhalatorji, inhalatorji s suhim prahom, zdravilne učinkovine, nosilni delci, priprava, izolacija, mikrofluidni reaktorji, sušenje z razprševanjem, budezonid, beklometazon dipropionat, disertacije
• Work type: Dissertation
• Typology: 2.08 - Doctoral Dissertation
• Organization: FFA - Faculty of Pharmacy
• Place of publishing: Ljubljana
• Publisher: [D. Saboti]
• Year: 2017
• Number of pages: 126 str.
• PID: 20.500.12556/RUL-143798
• UDC: 661.12:615.458(043.3)
• COBISS.SI-ID: 293101056
• Publication date in RUL: 12.01.2023

Secondary language

• Language: Slovenian
• Title: Uporaba mikrofulidnega [!] reaktorja za izdelavo nosilnih delcev zdravilne učinkovine v praških za inhaliranje

Abstract

Pri zdravljenju pljučnih bolezni učinkovine običajno doziramo z uporabo inhalacijskih naprav kot so inhalatorji pod tlakom (MDI), inhalatorji s suhim prahom (DPI) in nebulatorji. Običajno se delci za DPI formulacije pripravljajo s “top-down” pristopom, kjer s kristalizacijo in nato mletjem dosežemo ustrezno velikost delcev. S tem pristopom običajno dobimo amorfen material, ki za izboljšanje fizikalne stabilnosti potrebuje dodatne tehnološke korake. Druge sorodne tehnike vsebujejo homogenizacijo ali obarjanje in običajno zahtevajo uporabo stabilizatorjev oziroma površinsko aktivnih snovi. Namen našega dela je bil razviti novo metodo za pripravo delcev za inhaliranje z uporabo mikrofluidnega reaktorja, hkrati pa poiskati primerno metodo za izolacijo teh delcev. Sušenje z razprševanjem in zamrzovanjem se je izkazalo za najbolj primerno, saj smo se na ta način lahko izognili uporabi dodatne homogenizacije in uporabe stabilizatorjev. Med testiranimi učinkovinami in ekscipienti, sta se kot najprimernejša izkazala Budezonid in Beklometazon dipropionat. Metoda izdelave delcev je vsebovala komercialno dostopen mikrofluidni reaktor s T-stikom (uporabili smo etanolno-vodni, metanolno-vodni ter aceton-vodni sistem), ki je bil neposredno sklopljen z ultrazvočno šobo za razprševanje, usmerjeno v čašo s tekočim dušikom. Sušenje z razprševanjem in zamrzovanjem je predstavljalo zadnji procesni korak. Pridobljene mikronizirane delce smo analizirali z mnogimi analitskimi tehnikami kot: optična mikroskopija, vrstična elektronska mikroskopija (SEM), diferenčna dinamična kalorimetrija (DSC), dinamično sipanje svetlobe (DLS), dinamična sorpcija pare (DVS), termogravimetrija (TGA), rentgenska praškovna difrakcija (XRD) in določanje aerodinamskih lastnosti z NGI. Pripravili smo DPI formulacijo tako pripravljenega budezonida in komercialne laktoze, ter jo z uporabo Aerolizerja pri pretoku zraka 100 L/min analizirali z NGI. Delež delcev z aerodinamičnim premerom manjšim od 5 μm je bi med 47.6±2.8% in 54.9±1.8%, kar je pomenilo dobre aerodinamske lastnosti za inhalacije. Izdelane formulacije so bile primerjane s komercialno dostopnimi izdelki in izkazale podobne aerodinamske lastnosti kot referenčni izdelki. Analize so potrdile primernost nove metode za izdelavo delcev, ki se lahko uporabijo v inhalacijah brez dodatne homogenizacije ali stabilizatorjev. Razvita metoda izolacije je prav tako splošno uporabno rešitev za izolacijo delcev v mikrofluidiki.