Solid Lipid Nanoparticles Modified With Amphipathic Hyaluronic Acid Derivatives

Solid lipid nanoparticles(SLNs)are ideal systerm for application of oral drug delivery.However,Limitations are also excite: on the one side,there will be transformations long-term storage in which case espulsion of drug will happen.Furthermore,the glycerides,usually used as the lipid matrix materials in SLNs,tend to be degraded in the gastrointestinal tract due to hydrosis catalyzed by lipase enzyme,which leads to the precipitate of drug of SLNs in the gastrointestinal tract.In order to tackle these hurdles,alkyl hyaluronic acid(AHA)were synthesized used as emulsifiers,Tween-80 and Poloxamer 188 used as controlled group,to develop AHA-SLNs.N-octyl hyaluronic acid(C8,OHA),n-dodecyl hyaluronic acid(C12,DHA),n-hexadecyl hyaluronic acid(C16,HHA)were synthesized and alkly structure were confirmedby infrared spectroscopy(IR)and proton nuclear magnetic resonance spectroscopy(1H-NMR).Their substitution degrees of alkyl group were 15.01%,24.72%,and 30.36%,respectively.SLNs were prepared by melt-emulsification and ultrasonication method.AHA as the surfactant,Compritol 888 ATO as lipid and simvastatin(SV)as model drug.SLNs prepared by Tween-80 or poloxamer 188(P188)as the surfactant as the control.SLNs prepared by OHA,DHA,HHA were compared to investigate the influence of the length of acyl chain on long-term storage of SLNs.The mean particle sizes(PS)of optimal Tween-SLNs,P188-SLNs,OHA-SLNs,DHA-SLNs,HHA-SLNs,were213.4±6.3,188.4±7.7,511.3±20.9,600.8±22.1,623.2±11.8 nm respectively.Their zeta-potentials(ZP)were-38.6±1.0,-32.1±1.9,-46.5±0.5,-41.1±1.8,-59.3.5±1.2 m V,respectively.The PS of optimal Tween-SV-SLNs,OHA-SV-SLNs,DHA-SV-SLNs,HHA-SV-SLNs,were 178.2±6.7 nm,449.4±7.6,522.5±10.9,590.5±14.9.ZP were-28.9±1.2,-52±1.0,-62.0±1.3,-53.8±1.84 m V.Entrapment efficiencies(EE)were25.31%,45.12%,35.78%,26.43%,respectively.Vitro release results confirmed that SV released from Tween-SV-SLNs,OHA-SV-SLNs,DHA-SV-SLNs,HHA-SLNs were about 10% of encapsulated drug after 24 h.The DSC and XRD analyses confirmed that SV was dispersed in SLNs at amorphous or molecular status.Compared with Tween-80,AHA cuold decrease degree of crystallinity.Besides,OHA obtained the best results.The stability studies conformed that blank SLNs prepared by Tween and P188 performed non-ideal results compared with AHA-SLNs.Its particle size increased as well as the absolute value of ZP decreased,which indicated that crystalline in SLNs transformed gradually at storage conditions whenas blank AHA-SLNs performed more stable state when stored at same conditions,although the PS of DHA-SLNs,HHA-SLNs changed a lot than newly prepared SLNs.Drug loaded SLNs confirmed similiar results.Tween-SV-SLNs showed more unstable transformation of lipid crystalline compared with AHA-SLNs.Its particle size changed slightly when absolut zeta-position of Tween-SV-SLNs decreased sharply which indicated the apperance of particle generation.Changes can obsreved from DSC and XRD results.The metastable α-modification gradually transformed to more stable β′-modification duating long-tem storage of.Tween-SV-SLN showed dramatically transformation from unstableα-modification to more stable β′-modification.whereas AHA-SLNs showed slightly transformation of crystalline polymorphism.OHA-SLNs indicated the smallest transformation,and the next was HHA-SV-SLNs,and DHA-SV-SLNs showed the fastest transformation of crystalline among AHA-SLNs.The results mentioned illustrated SLNs prepared by AHA as surfactents performed better stability than that prepared by Tween-80 and P188-SLNs,and OHA-SLNs is the best one,which followed by DHA-SLNs and HHA-SLNs.The in vitro lipolysis study demonstrated that the degree of lipolysis of Tween-SV-SLNs,P188-SLNs,OHA-SLNs were almost up to 100%,while HHA-SLNs was 63.5%,and OHA-SLNs was 10.5%.The preliminary toxicity assessment confirmed AHA-SLNs as well as Tween-SLNs and P188-SLNs,with cell viabilityall more than 85%.