Ambrus, Rita

Szabó, B.

Szabóné Révész, P.

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R. Ambrus*, B.Szabó, P. zabó RévészS -Department of Pharmaceutical Technology, University of Szeged, Szeged, Hungary*e-mail: arita@pharm.u-szeged.hu!!!The effectiveness of inhalation therapy, especially for a drugdry powder formulation (DPI), is dependent on factors that arerelated to the patient, the device and the characteristics of theformulation.The engineered drug particles theirselves are typicallyhighly cohesive and display poor aerosolization properties,necessitating the addition of a coarse carrier particle to themicronized drug.Our aims were to develop mannitol-based carrier systemscontaining aqueous and ethanolic solution during co-spray-drying procedures and application of different types ofadditives could help the DPI formulation of also watersolubleand insoluble drug.Mannitol (M), a hydrophilic carrier, was obtained fromHungaropharma Budapest, Hungary; PVA3-88 is ordere fromISPCustomer ServiceGmBH,Cologne,Germany; amino acidsuch as L-leucine (LEU) is from Applichem, Germany.Hydroxypropyl beta cyclodextrin as complex former andpermeability improving agent is from Cylolab Ltd (Budapest,Hungary).The procedure of spray-drying (spd) was from a aqueous(w)and ethanolic solution (10% of EtOH and 90 % of water (mix))of M, LEU with/without CD or PVA using a Büchi MiniDryer B-191. The amount of additives was determinedaccording to our preliminary work. The amount of CD wascalculated according its complex former ratio e.g. 1:1 2:1 4:1.(Fig. 1 ).The particle size distribution of themicrocomposites was alsoestimated by laser diffraction (Malvern Mastersizer Scirocco2000, Malvern Instruments Ltd., Worcestershire, UK). Themorphology of the microcomposites was examined by SEM(Hitachi S4700,Hitachi Scientific Ltd., Tokyo, Japan).Andersen Cascade Impactor (ACI) (Copley Scientific Ltd.,Nottingham, UK) is used for measuring the mass distributionof pharmaceutical aerosols via the aerodynamic diameterusing 60Lmin-1 flow rate. The products were filled into hardgelatine capsules (size 3). The inhaler device applied was aplasticRS01 (Plastiape, Italy).XRPD was carried out in order to determine the crystallineformand crystallinity of the producedmaterials. Samplesweremeasured with a Bruker D8 Advance diffractometer (BrukerAXS GmbH, Karlsruhe, Germany). Thermoanaliticalmeasurements were also applied (Mettler Toledo, StareprogramW9,Mettler Inc. SwerzenbachSwitzerland)In our present work three suitable ways were applied todeveloped pulmonary drug delivery systems (PDDS) ofdifferent drugs. During spray-drying procedure aqueous andethanolic solution of the excipients could be applied, whichhelp to solve or disperg the drug. If the drug is very poorlysoluble in water or ethanol/water mixture, the present of CDcan help by formation of inclusion complex. According to themorphology, the size, size distribution and fine particle fraction(FPF) calculation of the samples, they are applicable asPDDS(Fig. 2).Particle characterization5 andomogenous distribution (Table 1). According to theaerodynamicmeasurements the FPFare higher comparewiththe maketed products.The crystal morphology is a criticalparameter for DPI development, because the particle shapeaffects the aerodynamic behaviour and thus lung deposition.The effect of spray-drying procedure on the morphology ofparticles was determinative. The spherical form of themicrocomposites could be advantageous for suitablepulmonary depositions (Figs. 3-4).Structural investigationsEvaluation of the structural analysis usingDSCandXRPD,wecan conclude that the raw M is crystalline and additives aresemi-crystalline/amorphous materials. The samples aremainly crystalline, the degree of the crystallinity decreasedand because of the increased concentration of CD turned toamorphous character. (Figs. 5-8).MaterialsParticle characterizationStructural investigationsSample preparationLEU or; ;-2The particle sizes of the samples satisfied the pharmacopoeialrequirements, the average size was between 2.5- .5 μmresulted hFigure 2. Development-protocol Table 1. Size and Aerodynamic propertiesFigure 8. XRPD patterns of the samplescontaining cyclodextrinsFigure 4. Morphology of the productsFigure 7. XRPD patterns of the samplescontaining mannitolFigure 5. DSC curves of the samplescontaining PVAFigure 6. DSC curves of the samplescontaining LEUIntroduction, aimExperimental methodsResultsFigure 1. Materials and preparation procedureCo-spray-drying procedure:Inlet temperature: 140 °CFeed rate: 75 %Apirator air: 600 L/minAspirator rate: 5 %Development of dry powder carrier systemsfor pulmonary applicationFigure 3. Morphology of the productsSample D 0.1 (µm) D 0.5 (µm) D 0.9 (µm)FPF(%)M-w 1.38 2.91 4.63 81.45M-mix 1.51 2.79 4.57 70.27M-PVA-w 2.95 6.36 10.18 25.85M-PVA-mix 2.41 4.72 9.49 38.91M-LEU-w 2.27 4.05 8.32 72.33M-LEU-mix 1.38 2.83 5.57 59.51M-LEU-CD0.9 1.61 3.30 6.46 46.52M-LEU-CD1.8 2.35 5.47 10.22 40.78M-LEU-CD3.6 3..95 8.25 12.10 36.91Sample M PVA LEU CD solventM-w 5 - - - waterM-mix 5 - - - mixM-PVA-w 5 0.2 - - waterM-PVA-mix 5 0.2 - - mixM-LEU-w 5 - 0.4 - waterM-LEU-mix 5 - 0.4 - mixM-LEU-CD0.9 5 - 0.4 0.9 mixM-LEU-CD1.8 5 - 0.4 1.8 mixM-LEU-CD3.6 5 - 0.4 3.6 mix“This project was supported by the János Bolyai ResearchScholarship of the HungarianAcademy of Sciences (2014-2017).”Mannitol LeucinPVA Hydroxypropyl betacyclodextrin Büchi Mini Dryer B-191M-w M-mixM-wMM-mixM-LEU-mixM-LEU-wM-PVA-w M-PVA-mixM-LEU-CD 0.9M-LEU-CD 1.8M-LEU-CD 3.6M-LEU-CD 3.6M-LEU-CD 1.8M-LEU-CD 0.9MMannitol-based Carrier SystemsCarrier: MannitolSolvent: WaterAdditives: LEU or PVACarrier: MannitolSolvent: 90 %Water and10% EthanolAdditives: LEU or PVACarrier: MannitolSolvent: Water-EthanolAdditives: LEU and CDAPI could be dissolvedAPI could be suspendedAPI could be dissolved API could be dissolvedby form inclusion complex

Development of dry powder carrier systems for pulmonary application

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