Abdelhakim, Hend EEA

Coupe, Alastair

Craig, Duncan QM

Edirsinghe, Mohan

Tuleu, Catherine

English

UCL Discovery

Taste-masked fibres for paediatric drug deliveryHend E. E. A. Abdelhakim1*; Catherine Tuleu1; Mohan Edirisinghe2  ; Alastair Coupe3 ; Duncan Q. M. Craig11 UCL, School of Pharmacy, 29-39 Brunswick Square, London, WC1N 1AX, UK,  2 UCL, Mechanical Engineering Department, London, WC1E 7JE, UK, 3 Pfizer Ltd, Sandwich, CT13 9ND, UK*hend.abdelhakim.16@ucl.ac.ukIntroductionAims & ObjectivesResults & DiscussionElectrospinningUsing the DoE definitive screening design, E-EPO concentration wasfound to be the most statistically significant factor affecting the productionof smooth nanofibres with a p-value of 0.004 for reduction of beading,and a p-value of 0.008 for reduction of diameter. Using this knowledge,drug loaded fibres were electrospun at concentrations ranging from 30-40% E-EPO in ethanol. Process parameters used were appled voltagesof 10-15 kV, gap distances of 150-175 mm, and flow rates of 0.5-1.0mL/h. At drug-to-polymer ratios between 1:2 and 1:4, particles wereobserved due to a change in conductivity and viscosity. At ratios of 1:6onwards smooth fibres form.SEMThe XRD patterns shown in Figure 1 shows the diffraction peaks for thecrystalline CPM alone and the amorphous halo for E-EPO, as expected,while the drug loaded fibres showed no drug peaks, suggesting amolecular dispersion of the drug in the polymer matrix.Figure 2. SEM images of electrospun fibres; Left: 35% E-EPO, processed at 15kV, gapdistance of 175 mm, and flow rate of 1.0 mL/h. Mean diameter 893 ± 341 nm. T:26oC.RH: 32%. Right: 35% E-EPO, 1:8 CPM to E-EPO, processed at 15kV, gap distance of175 mm, and flow rate of 1.0 mL/h. Mean diameter 1507 ± 392 nm. T:23oC, RH: 49%.Figure 1: An XRD diffraction pattern of (a) Pure E-EPO (b) Pure CPM (c) Placebo 30% E-EPO fibre; Active fibres (d) 30% E-EPO , 1:6 CPM (e) 40% E-EPO, 1:6 CPM (f) 35% E-EPO,1:6 CPM (g) 35% E-EPO, 1:8 CPM (h) 35% E-EPO, 1:7 CPMXRDFigure 3 – PCA biplot of drug loaded fibres compared to the physical mixture,placebo fibre, pure E-EPO and pure CPM.ConclusionThe DoE approach was used to identify and optimise the most influential factors for electrospinning smooth, non-beaded E-EPO fibres. 35% E-EPO is theoptimum percentage of drug that allows for the transfer of process conditions from placebo to drug loaded fibres. 35% E-EPO fibres that have drug loads of1:6, 1:7 and 1:8 yielded reproducible smooth, non-beaded fibres. XRD indicated that CPM was incorporated as a molecular dispersion, while SEM showedthe fibres to be of satisfactory morphology and diameter. The E-tongue indicated good taste masking of CPM when incorporated into the fibres, compared tothe physical mixture. The study has demonstrated it is possible to manufacture taste-masked nanofibers of CPM embedded in E-EPO.AcknowledgmentsThis study is funded by MRC iCASE award No. 170156, andPfizer Ltd. award No. 173803.Methodology The aim of this study was to explore the potential of using electrospinningas a technique for generating taste-masked dosage forms.The objectives were to reliably manufacture CPM-loaded E-EPO fibres,assess their morphology and their ability to mask the bitter taste of CPM,assessed by an electronic tasting system.E-tongueThe larger the Euclidean distance between CPM and a formulation,the better the taste masking. Figure 3 shows a PCA biplotillustrating the distances from pure CPM.-4 -2 0 2 4-1.0-0.50.00.51.0-0.5 0.0 0.5-1.0-0.8-0.6-0.4-0.20.00.20.40.60.81.0AC0AN0C00AE11mg CPM1:6 CPM, 30% E-EPO1:6 CPM, 35% E-EPO1:6 CPM, 40% E-EPO1:7 CPM, 35% E-EPO1:8 CPM, 35% E-EPO1:6 E-EPO1:7 E-EPO1:8 E-EPO1:6 PM1:7 PM1:8 PM1:6 Placebo, 30% E-EPOPrincipal Component 2Principal Component 1Drug loaded fibresPure E-EPOPhysical mixturesPlacebo fibrePure CPMElectrospinning is being explored as an approach for oral drug delivery,particularly as historical issues of large scale production are now beingbetter understood. Here we explore the manufacture of taste-maskedfibres loaded with the bitter antihistamine drug chlorpheniramine maleate(CPM). We use a Design Of Experiment (DoE) definitive screeningapproach to optimise the manufacturing conditions for fibres composed ofEudragit E PO (E-EPO) loaded with CPM. A biosensor (E-tongue)approach was then used to asses the bitterness of the fibres producedcompared to the drug alone.Solutions of 25% to 45% E-EPO were prepared in either ethanol orethanol and 10-20% water. A DoE approach was used to screen the mostinfluential factors in producing smooth E-EPO fibres and the findings usedto optimise the manufacturing process. JMP Pro 12.0.1 was used tocreate the screening design. Process parameters controlled were appliedvoltage (10-25 kV), flow rate (0.5-2.0 mL/h), and working distance (150-250 mm). CPM was added in a range of amounts as a ratio to E-EPO (1:2to 1:8). Spraybase® electrospinning apparatus was used to manufacturethe fibres. A Scanning Electron Microscope (SEM) FEI Quanta 200FEG,was used to image the fibre morphology. ImageJ 1.46R was used tomeasure diameters. Characterisation of solid state was undertaken usinga Rigaku MiniFlex 600 X-Ray Diffractometer. Patterns were recorded overthe 2θ range 3º - 90º at a scan rate of 3º/min, with an interval of 0.02 º.The data was viewed on X’Pert Data Viewer 1.2F. TS-5000Z E-tonguewas used for taste assessment. OriginPro 2017 was used to complete amultivariate principal component analysis (PCA) and Euclidean distanceswere calculated from cluster centres.2 Theta (o)abcdefgh0 5 10 15 20 25 30 35 40 45Placebo and drug-loaded smooth non-beaded fibres were producedunder the conditions shown in Figure 2.

Taste-masked nanofibres for paediatric drug delivery

https://discovery.ucl.ac.uk/id/eprint/10153606/1/2018%20PBP%20Taste%20masked%20nanofibres%20for%20paediatric%20drug%20delivery.pdf

Taste-masked nanofibres for paediatric drug delivery

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