Development of parenteral peptide drug delivery system via microemulsion technology

Abstract

Various microemulsions were prepared using pharmaceutically acceptable components. Phospholipid (PC), tween 80 (TW) were used as surfactants; propylene glycol (PG), polyethylene glycol 400 (PEG), glycerol (GR), and caproic acid (CA) as cosurfactants; isopropyl myristate (IPM), ethyl oleate (EO), medium chain triglyceride (MCT), and soybean oil (SBO) as oils. Partial pseudo-ternary phase diagrams were constructed to evaluate the microemulsion existing area. The effects of ingredients and ratios on microemulsion types, viscosity, and appearance were investigated. The obtained systems were also compared to systems containing butanol (BT) as cosurfactant. The potentials of microemulsions to prolong the release of buserelin acetate were accordingly evaluated both in vitro using modified Franz diffusion cell and in vivo in rabbits. Types and ratios of surfactants, cosurfactants, and oils used had a pronounced effect on the existing region of microemulsions, likely due to their molecular structures and geometric packing which consequently affected the curvature of droplets. In PC-based systems, microemulsion regions could be produced only from the systems containing cosurfactants of BT, PG, and CA. All TW-based systems yielded microemulsion regions except when SBO was used as oil. Oil of larger molecule size evidently resulted in smaller microemulsion regions. In addition, microemulsion regions were mostly increased when Em /oil ratio increased. PC-based microemulsions were mostly water-in-oil type while TW-based microemulsions with high percentage of internal phase were oil-in-water type. Negative stained transmission electron micrographs (TEM) revealed seemingly that the droplet size of the system was in the range of microemulsion. Increasing the amount of surfactant would increase the viscosity of the system. The obtained microemulsion systems were stable except when GR was used as cosurfactant. Buserelin acetate has partition coefficient (C0/Cw) in octanol-water system 0.01. Most TW-based systems prolonged the release of drug during 1-6 days of the experiment. The drug released from PC-based systems was much slower and quite low with less than 10% while the amount of drug release from buffer solution was about 80% within two days. In vivo study by subcutaneous injection of 3.3 mg/ml buserelin acetate both PC-based and TW-based microemulsions would not clearly conclude the effects of drug on testosterone levels over 30 days.