| Parenteral drug delivery took a major leap after successful development of the submicronic parenteral fat emulsion (Intralipid) in 1960s. Quick commercialization of submicron emulsion based products, such as Diazemuls (Diazepam) and Diprivan (Propofol), was the indicator of the interest of pharmaceutical industry.In this study, a novel monostearin lipid nanosphere (LNS) suitable for parenteral administration was prepared. The purpose of this study was to produce an oil-in-water lipid-nano spheres with different compositions of the continuous and dispersed phases. The technique utilizing a two stage high pressure homogenizer could yielded a very fine monodispersed LNS.To produce LNS, either a large amount of energy or surfactant is required. Using different kinds of surfactant could affect the HLB of the system. It was much safer and better tolerated by combined use of egg yolk phospholipid and non-ionic emulsifier(F68 and Tween-80) as a complex emulsifier since lowing each of surfactant content. Droplet diameter was evaluated in terms of the mixture oil phase consisted of three components, monostearin and medium-chain triglycerides (MCT) and soya oil. The mean droplet size of LNS ranged from 90-150 nm was successfully achieved. Drug release experiments showed these LNS were a good anticancer drug delivery vehicle for parenteral administration.The reconstitution of lyophilised LNS was one of the most important factors in the whole process of the preparation and practical application of nanospheres. For long-term storage considerations, aqueous suspensions of LNS were essentially required for lyophilisation and must be reconstituted into physiological suspensions as the original aqueous suspensions before use. As acetic acid was used against drug hydrolysis during the formulation preparation process, the optimised LNS were readjusted to neutral pH with 0.1M sodium hydroxide before lyophilisation. To optimise the cryoprotectants for the LNS dispersion during the freeze-drying process, mannite, lactose, glucose, sorbitol, trehalose and mannose were chosen with regards to an intravenous application. Various amounts of cryoprotectants were added to the LNS dispersions, and then freeze-drying was carried out in a refrigerator. The optimizing i.v.-injectable LNS cryoprotectant was 7.5% sucrose and 7.5% mannitol, which could preserve their small particle size (LD50) approximately 129nm after reconstitution.After the intravenous administration of 10 mg/kg of drug, blood samples were obtained from the retro-orbital sinus at 5,15,30,45,60 and 90 min. Three groups of 54 kunming mice were used to evaluate the pharmacokinetics of chlorambucil lipid nanospheres (CHL-LNS), PEG 40 chlorambucil lipid nanospheres (PEG-CHL-LNS) and, chlorambucil injections.Chlorambucil in CHL-LNS and PEG-CHL-LNS were rapidly eliminated following intravenous injection based on in vivo data. The following three factors should be considered in complex LNS formulation development:small particle size, a certain type of lipid matrix and optimised drug solubility (drug/lipid ratio). Small particle sizes led to large surface areas on the nanospheres, and some amount of drug might be adsorbed on the surface of the lipid matrix; structurally different complex lipid matrices were also incorporated into each other. These in vitro formulation factors allowed the interaction of LNS with lipases for more efficient hydrolysis and led to rapid in vivo drug release. The drug/lipid ratio was the main formulation parameter in LNS formulation development responsible for enhancing the drug concentration distributions in the mice’s tissues.The results of the experiments showed that this novel lipid nanosphere complex developed by our research group was a useful anticancer drug delivery vehicle for parenteral administration. This formulation strategy might create additional delivery possibilities for a wide variety of anticancer drugs. |
PDF Full Text Request