Ambrus, Rita

Chvatal, A.

Pomázi, A.

SZabóné Révész, P.

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Aerodynamicand structural evaluation of microcompositescontaining meloxicam potassiumR. Ambrus*, A.Chvatal, A. Pomazi P. zabó Révész,Department of Pharmaceutical Technology, University of Szeged, Szeged, HungaryS -*e-mail: arita@pharm.u-szeged.hu!!!A new tendency in the development of dry powder inhalers(DPIs) is the design of carrier-basedmicrocomposites particlesize (3-5 µm) as pulmonary drug delivery systems involvingdifferent carriers and adjuvants. The adjuvants are applied insmall amounts in the microcomposites in order to promotephysicochemical stability, wettability, dispersibility andaerodynamic properties.A new possibility in drug formulation is applying Meloxicamin a salt form (Meloxicam Potassium (MXP)) to develop DPI.Using its salt form could be a novel application, troughalternative routes, because it has never used before in thedrug therapy.Meloxicam Potassium (MXP) purchased from EGIS Ltd.,Budapest, Hungary, PVA 3-88 from ISP Customer ServiceGmBH, Cologne, Germany, Leucin (LEU) fromHungaropharma, Budapest, Hungary.The heated solutions containing MXP, , werespray-driedwith aBüchiMini Dryer B-191 (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).Evaluation of the structural analysis usingDSCandXRPD,wecan conclude that the rawMXP is crystalline and additives aresemi-crystalline materials. The crystalline form of MXP turnedto amorphous character in the presence of PVA(crystallizationinhibitor effect). When LEU was applied the characteristicpeaks of MXP on the XRPD patterns and its melting on theDSCcurveswere detected(Figs. 5-7).Our aims were therefore to apply aqueous solution of MXPcontaining additives in different concentrations (using one-step green technology), which help to improve theaerodynamic properties of the product.LEU and/or PVAAndersen Cascade Impactor (ACI) (Copley Scientific Ltd.,Nottingham, UK) is used for measuring the mass distributionof pharmaceutical aerosols via the aerodynamic diameterusing 60Lmin 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)The particle sizes of the samples satisfied the pharmacopoeialrequirements, the ave .Moreover, the particle size distribution of MXP and manyproducts was heterodispers only MXPspd, MXP-PVA0.1 andMXP-LEU2-PVA0.1 resulted homogenous distribution (Fig. 2-3 and Table 1). The crystal morphology is a critical parameterfor DPI development, because the particle shape affects theaerodynamic behaviour and thus lung deposition. The effect ofspray-drying procedure on the morphology of particles wasdeterminative. The nearly spherical form of themicrocomposites could be advantageous for suitablepulmonary depositions.Fig. 4 and Table 2 show the amounts of drug deposited on thethroat, on stages 7 and on the filter of ACI, expressed aspercentages of the total amount of powder recovered. All ofthe products exhibited favourable aerolisation characteristics,these powder particles impacting on stages 2-5. Biggerconcentration of PVA without LEU resulted only pooraerodynamic character, because of the sticky of the particles.But PVA in small concentration shown an excellent result. TheMMAD values were around 3 , and 46-66 % FPF could beacceptable for pulmonary application and presented betterresult comparewith themarketedDPI products.-1rage size was between 2.5-4.5 μmμmThe goal of our study was to find the optimized co-spray dryingparameters, sample compositions for the preparation of DPIform of a novel MXP salt monohydrate. The MXP-PVA0.1 andMXP-LEU2-PVA0.1 could be an innovative products whichmay be considered suitable for scaled-up processes andpulmonary application. It is a novel possibility in anti-inflammatory treatment and for the mono- and combinationtherapy of cancer, pulmonary fibrosis and pain.®®®®®MaterialsParticle characterizationStructural investigationsParticle characterizationStructural investigationsPreparation of products®“This project was supported by the János Bolyai Research Scholarship oftheHungarianAcademyof Sciences (2014-2017).”Figure 2. Particle size distributionTable 1. Particle size analyses Table 2. Aerodynamic propertiesFigure 7. XRPD patterns of the samplesFigure 3. Morphology of the productsFigure 6. DSC curves of the samplesFigure 4. Aerodynamic-patternby Cascade impactorFigure 5. Structure of the raw samplesIntroduction, aimExperimental methodsResultsFigure 1. Compositions and preparation procedureCo-spray-drying procedure:Inlet temperature: 140 °CFeed rate: 005 %Aspirator air: 600 L/minAspirator rate: 75 %FPD: Fine Particle DoseFPF: Fine Particle FractionMMAD: Median Mass Aerodynamic DiameterSamples MXP PVA LEUMXPSPD 1 - -MXP-LEU1 1 - 1MXP-LEU2 1 - 2MXP-PVA0.1 1 0.1 -MXP-PVA0.25 1 0.25 -MXP-LEU1-PVA0.251 0.25 1MXP-LEU2-PVA0.11 0.1 2Meloxicam-Potassium(MXP)Structure: C H KN O SM : 407.5Egis Company, BudapestPattent: WO2006064298A1water solubility: 13.1 ± 0,015 mg/mL14 13 3 5 2w7.123.211.38MXP-LEU2-PVA0.110.244.422.07MXP-LEU1-PVA0.259.033.831.75MXP-PVA0.254.692.441.24MXP-PVA0.18.343.661.16MXP-LEU28.803.391.53MXP-LEU16.163.011.40MXPSPD993.7558.433.35MXPD(0.9) [µm]D(0.5) [µm]D(0.1) [µm]Samples57.582.83MXP-LEU2-PVA0.146.633.05MXP-LEU1-PVA0.2521.537.23MXP-PVA0.2566.323.04MXP-PVA0.154.783.67MXP-LEU249.103.91MXP-LEU155.973.18MXPSPD10.5012.11MXPFPF (%)MMAD (µm)Samples051015202530354045505560651 2 3 4 5 6 7 8StagesM XPM XP-SPDM XP-LEU1M XP-LEU2M XP-PVA0.1M XP-PVA0.25M XP-LEU1-PVA0.25M XP-LEU2-PVA0.1MXP-SPDMXPMXP-LEU2-PVA0.1MXP-PVA0.1

Aerodynamic and structural evaluation of microcomposites containing meloxicam potassium

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