Studies On Solid Lipid Nanoparticles Loaded With Alprostadil

Alprostadil also named prostaglandin E₁（PGE₁）,an important intrinsic substance, has extensive biological function such as vessel dilation,blood pressure regulation, platelet congregation inhibition,microcirculation improvement,arteriosclerosis delaying and immune regulation.Thus,it is extensively used to treat periphery vessel disease, ischemic heart disease,hyperlipidemia and erection dysfunction,and also used in treating hepatitis,diabetes and renal failure as assistant therapy method.However,low solubility and instability of PGE₁ leads to need a long infusion and more than 80%of intravenously administered PGE₁ is metabolized and inactivated during the first passage through the lungs,which makes the oral administration ineffective.Alprostadil injection,a dosage form in market,which encapsulates PGE₁ into 0.12～0.38μm emulsion,improves the stability of PGE₁ and prolongs its half-life.However,the emulsion including soybean oil is unstable during storage.Solid lipid nanoparticles（SLNs） is a drug delivery system with solid lipid as drug carriers,diameters ranging between 50 and 1000 nanometers.The object of this paper was to prepare stable PGE₁-loaded SLNs with high activity and low side effects.The ultrafiltration method was developed to separate free PGE₁ and PGE₁-loaded SLNs.The PGE₁,encapsulation efficiency and related substances in formulation were determined by HPLC method with post column derivatization.Film dispersing followed by high pressure homogenization method was adopted to prepare PGE₁-SLNs.Single factor experiments and orthogonal design were applied to optimize its formulation and technology with encapsulation efficiency and particle size as indexes.The cryoprotectants and process parameters of lyophilization which was employed to improve the stability of PGE₁-SLNs were optimized with appearance,redispersibility and mean particle size as indexes.The quality and primary stability of PGE₁-SLNs prepared by optimized technology and formulation were evaluated.The pharmacokinetics and tissue distribution were investigated in rats. The results indicated that the analysis methods were precise,simple and reliable. PGE₁-SLNs were composed of alprostadil/stearic acid/soybean phospholipid in the weight ratio of 1:150:300,5%Poloxamer 188,10%sucrose and 5%mannitol.The main process parameters of lyophilization were as follow:prefreezing temperature of-40℃, prefreezing time of 8h,sublimation time of 36h and temperature programming.The obtained PGE₁-SLNs were spherical,smooth particles with rapid redispersibility,PGE₁ content of 104.55%,related substance of 6.44%,encapsulation efficiency of 94.9%and mean particle size of 125.9nm.The amount of accumulative release was 45.7%in 24h and the release curve was fitted with Weibull equation.There were no obvious changes of physiochemical characteristics within 12 months at（6±2）℃,which indicated that PGE₁-SLNs were stable during the storage after freeze-drying.The results of pharmacokinetics and tissue distribution showed that there were no significant difference between PGE₁-SLNs and PGE₁ injection.Increased concentrations in liver,spleen and lung were also observed after i.v.administration of PGE₁-SLNs.These results indicated that solid lipid nanoparticles would be a promising durg delivery system for alprostadil.