Development of Metronidazole Microemulsion gel for Periodontal use

Abstract

Various pharmaceutically acceptable components were investigated the possibility to form microemulsion gel (MEG) and liquid crystal (LC). Spontaneous formation was obtained by mixing four components. Isopropyl myristate (IPM), castor oil (CO) and soybean oil (SBO) were used as an oil phase; tween 80 (T₈₀), cremophor EL (CEL) and cremophor RH (CRH) as surfactant; Lutrol F-68 (L₆₈), Brij 72 (B₇₂), Brij 721S (B721s), Brij 35 (B₃₅), cetyl alcohol (C), butanol (B), glycerin (G) and propylene glycol (PG) as cosurfactant and ultrapure water were used. Pseudo-ternary phase diagrams were constructed from various combinations of these excipients to evaluate the MEG and LC existing area. Polarized light microscope was used to elucidate the formation, structure and microscopic pattern of the obtained MEG and LC. Transmission electron microscope (TEM) and SemAfore computerized program were used to determine the particle size and size distribution of system. The physicochemical properties were also investigated both before and after stability testing including visual observation, MEG type, conductivity, pH, syringeability, viscosity, loading capacity of selected MEG and LC. The potential of MEG and LC to prolong the release of 1.5% w/w metronidazole was accordingly evaluated in vitro using modified Franz diffusion cell whereas the possibility to use MEG and LC as periodontal drug delivery was studied on the antimicrobial activity against Porphyromonas gingivalis. The results indicated that types and ratios of surfactant, cosurfactant and oil used had pronounced effect on the existing region of MEG and LC. MEG area could be produced by specific type and ratio of component in a narrow range. B, C, B₇₂ and G as cosurfactant could not form MEG at any ratio. The areas of MEG in pseudo-ternary phase diagrams were mostly increased with the decreasing oil to surfactant radio. The results from dilution test and dye solubility test including conductivity test confirmed that most MEG and LC were o/w type. Results from TEM revealed that the mean droplet diameters of the system were in the range of 25-85 nm and increased after freeze-thawing. The type and amount of oil, surfactant and cosurfactant also affected the viscosity of system. Furthermore, the assessment of the possibility of using these systems as periodontal drug delivery showed that selected formulations could hold a maximum of 1.5% w/w metronidazole. Most systems exihibited birefringent property under cross-polarizing microscope. The non-newtonian and shear-thinning flow behaviors could be obtained indicating the good syringeability and injectability of the systems. The drug diffusion from MEG and LC systems was sustained to more than 24 hours and was best fitted with first order kinetic and Higuchi model. Antimicrobial activity of selected formulation showed the strong inhibition zone against P. gingivalis. by agar diffusion method. After accelerated and Thai FDA stability testing, MEG and LC still showed good physicochemical stability.