Development of in situ gel containing asiaticoside-cyclodextrin complex for periodontal tissue regeneration

Abstract

Asiaticoside (AS) is active herbal compound isolated from Centella asiatica. It has the potential benefit in promoting type I collagen (COL I) synthesis and osteogenic differentiation in human periodontal ligament cells. However, it has low aqueous solubility which may hamper the bioavailability. Thus, the main objective of this study was to develop the thermoresponsive in situ gels containing AS by using cyclodextrin (CD). To determine the solubility enhancement of AS, phase-solubility profiles were investigated and revealed that CDs enhanced the aqueous solubility of AS. Hydroxypropyl-beta-CD (HPβCD) and sulfobutyl-ether-beta-CD (SBEβCD) were selected due to highly solubilization enhancement of AS. The mucoadhesive polymer i.e., chitosan (CS) or thermogelling agent i.e., poloxamer 407 (P407) was added to investigate the effect of polymer to AS/SBEβCD binary complex. The resulted ternary systems synergistically improved the solubility of AS. Solution-state characterization (1H-NMR) and solid-state characterization (DSC, FT-IR and PXRD) of binary complex (AS/HPβCD or AS/SBEβCD) as well as ternary complex (AS/SBEβCD/CS or AS/SBEβCD/P407) were performed. It indicated that there were some interactions and possibly formed AS/CD inclusion complex. The enhancement of AS dissolution was achieved in both binary and ternary system when compared with intact AS alone. The morphology and particle size were analyzed by TEM and DLS techniques. The large aggregate size provided the evidence that AS solubility was enhanced through the AS/CD aggregate formation or micelle-like behavior. AS loaded nanoparticles were prepared via ionic gelation using anionic SBEβCD and cationic CS. Thermally triggered in situ gels containing AS with the proper SBEβCD/CS weight ratio were developed. The physicochemical and chemical characterizations i.e., appearance, pH, viscosity, gelation temperature, gelation time, in vitro gelling capacity, drug content and entrapment efficiency were within acceptable range. In vitro mucoadhesion and the in vitro release studies revealed that nanoencapsulated in situ gels had excellent mucoadhesive property and performed the sustained release of AS. These formulations somewhat negative effect to ligament cells. However, the CD encapsulated platforms containing AS at low content could express the COL I synthesis. Therefore, it may be promising candidate that can deliver AS for periodontal tissue regeneration.