Biophysical properties of experimental compositions of a synthetic pulmonary surfactant synsurf® for aerosolisation

Agenbag, Chris-Mare (2018-03)

Thesis (MScMedSc)--Stellenbosch University, 2018.

Thesis

ENGLISH ABSTRACT: Synthetic pulmonary surfactant consists of phospholipid mixtures, free fatty acids and/or sterols, as well as specific protein constructs that mimic the functions of surfactant associated proteins B and/or C. Treatment of neonatal respiratory distress syndrome with surfactant replacement therapy consists of an invasive technique of endotracheal intubation and administration into the airway. For this reason, a less invasive approach such as nebulisation in these frail patients would be beneficial. Formulations of synthetic pulmonary surfactants intended for use, require that the in vitro-aerosolisation behaviour with regards to optimal particle size generation and conservation of surface tension, are ideal in order to maintain proper lung function. The objective of this study was to evaluate the suitability of different formulations of a new peptide-containing synthetic pulmonary surfactant Synsurf® during aerosolisation in comparison with the natural surfactants, Curosurf® (porcine) and Liposurf® (bovine). Synsurf®, was synthesised with and without alterations in key components that included cholesterol (1 % and 2 %), palmitic acid (11 %) and tripalmitin (7 %). An extrusion method through polycarbonate membranes with different pore sizes was also included during synthesis of the different formulations. Surfactants were aerosolised with the use of Aeroneb®Pro vibrating mesh nebuliser and particles generated were assessed with a Malvern Zetasizer® and visualised by scanning electron microscopy. Surface tension analyses was determined with a Drop Shape Analyser (DSA25). The main findings of this study showed that nebulisation of non-extruded Synsurf® formulations as well as Curosurf® and Liposurf®, produced a decrease of ± 80 % - 90 % in particle size, that is below the desired distribution range of 1 - 3 d.μm for inhaled particles. However, extrusion included in the synthesis of Synsurf®, generated larger particles post-nebulisation, within the desired range. Nebulisation also significantly influenced the density and viscosity of most Synsurf® preparations and natural surfactants. Additionally, an increase in cholesterol concentration showed a marked increase in viscosity of Synsurf®. With the exception of the original Synsurf® formulation, nebulisation diminished the surface tension lowering ability of all other surfactant preparations. Addition of palmitic acid/tripalmitin and 1 % cholesterol to the original Synsurf® formulation showed an overall pronounced reduction in surface tension in comparison to other formulations. In conclusion, the data of this study indicate that the original formulation of Synsurf® with addition of palmitic acid/tripalmitin and low concentrations of cholesterol, aid in the conservation of the surface tension properties and ideal particle size generation of the surfactant during nebulisation with a vibrating mesh nebuliser.

AFRIKAANSE OPSOMMING: Sintetiese pulmonêre surfaktant bestaan uit fosfolipiedmengsels, vry vetsure en/of sterole, sowel as spesifieke proteïenkonstrukte wat die funksies van surfaktant geassosieerde proteïene B en/of C naboots. Behandeling van neonatale respiratoriese-nood-sindroom behels surfaktantvervangingsterapie, ’n ingrypende tegniek van endotrageale intubasie en toediening in die lugpyp. ’n Minder ingrypende benadering soos nebulisering sal gevolglik voordeliger vir hierdie tingerige pasiënte wees. Formulerings van sintetiese pulmonêre surfaktante wat vir gebruik bedoel is, vereis ideale in vitro-aërosoliseringswerking ten opsigte van die ontwikkeling van optimale partikelgrootte en die behoud van oppervlakspanning ten einde behoorlike longfunksie te handhaaf. Die doel van hierdie studie was om die geskiktheid tydens aërosolisering van verskillende formulerings van ’n nuwe peptiedbevattende sintetiese pulmonêre surfaktant, genaamd Synsurf®, teenoor die natuurlike surfaktante Curosurf® (vark) en Liposurf® (bees) te evalueer. Synsurf® is met en sonder veranderings in sleutelkomponente soos cholesterol (1 % en 2 %), palmitiensuur (11 %) en tripalmitien (7 %) gesintetiseer. Ekstrusie by wyse van polikarbonaatmembrane met verskillende poriegroottes is tydens die sintese van die verskillende formulerings toegepas. Surfaktante is met behulp van ’n Aeroneb®Pro- vibrerende “mesh”-nebuliseerder geaërosoliseer, terwyl die partikels wat ontwikkel is aan die hand van ’n Malvern Zetasizer® geëvalueer en deur middel van ’n skandeer elektronmikroskoop gevisualiseer is. ’n Druppelvormontleder (Eng. drop shape analyser, die DSA25) is gebruik om oppervlakspanning te ontleed. Die hoofbevindings van hierdie studie toon dat nebulisering van Synsurf®-formulerings, asook Curosurf® en Liposurf® die partikelgrootte met ± 80 % - 90 % verminder het. Dit is benede die verlangde verdelingspektrum van 1 – 3 d.μm vir geïnhaleerde partikels is. In die geval van Synsurf®, egter, het die ekstrusie tydens sintetisering na nebulisering groter partikels opgelewer, maar steeds binne die verlangde spektrum. Nebulisering het ook die digtheid en viskositeit van die meeste Synsurf®-preparate en natuurlike surfaktante aansienlik beïnvloed. Daarbenewens het ’n toename in cholesterolkonsentrasie ’n duidelike toename in die viskositeit van Synsurf® getoon. Nebulisering het alle sufaktantpreparate buiten die oorspronklike Synsurf®-formulering se vermoë om oppervlakspanning te verlaag, verminder. Wanneer palmitiensuur/tripalmitien en 1 % cholesterol by die oorspronklike Synsurf®-formulering gevoeg is, was die totale vermindering in oppervlakspanning duidelik in vergelyking met ander formulerings. Ten slotte dui die studiedata aan dat die oorspronklike Synsurf®-formulering met die byvoeging van palmitiensuur/tripalmitien en lae konsentrasies cholesterol daartoe bydra dat die surfaktant se oppervlakspanningeienskappe en die ontwikkeling van ideale partikelgroottes behoue bly tydens nebulisering met ’n vibrerende “mesh”-nebuliseerder.

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