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Melatonin loaded polyanhydride nanoparticles for oromucosal application

Melatonin (MEL), a circadian synchronizing hormone, could provide a valid therapeutic strategy for treatment of gingivitis and periodontitis due to its antioxidant, antiinflammatory, immunomodulatory and osteogenic actions. To further enhance its therapeutic potential, MEL was loaded into PEGylated nanoparticulate (NP) delivery system based on poly(methyl vinyl ether-co-maleic acid) anhydride (PVM/MA). This water-insoluble, mucoadhesive, non-toxic, synthetic co-polymer is able to form NP by simple solvent displacement and could be easily functionalized with different ligands. NPs densely coated with low molecular weight polyethylene glycol (PEG) are able to readily penetrate the mucus layer, thus overcoming its barrier properties and rapid NP clearance from the application site. PEGylated NPs were prepared by solvent displacement method and functionalised with PEG 4000, 6000 and 10 000 at 1:0.15 PVM/MA to PEG ratio, while MEL loading was performed at 1:10 and 1:5 MEL to PVM/MA ratio. NPs were characterised in terms of the particle size and zeta potential. The level of PEGylation was determined by HPLC, while MEL encapsulation efficiency was calculated after UV/VIS quantification of unloaded MEL. NPs in the solid state were prepared by freeze-drying using sucrose, trehalose and glycine at 1-5 % (w/v) as cryoprotectors.Unloaded PEG coated NPs were monodisperse with an average size in the range of 195.8 (NPPEG 4000) up to 219.3 nm (NPPEG 10000) and negative zeta potential of -40 mV. Sucrose at 5% (w/v) concentration appeared as the best cryoprotector. The NPs production yield varied from 51.9 – 56.5%. The highest PEGylation level of 93.0% was obtained for PEG 6000 coated NPs after 1h of incubation. The highest encapsulation efficiency of MEL in such NPs of 11.45% was obtained at indole to PVM/MA ratio of 1:5, resulting in particles of 164.3 nm in size and negative zeta-potential of -37.7 mV. MEL loaded PVM/MA NPs coated with PEG 6000 showed of acceptable size and surface characteristics for mucopenetration and can be considered as a potential novel oromucosal delivery system for gingivitis and periodontitis treatment.

Melatonin, mucopenetrative nanoparticles, poly(methyl vinyl ether-co-maleic acid) anhydride, freeze-drying

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