Studies On Prostagladin E₁ Intravenous Lipid Emulsion

Prostaglandin E₁ (alprostadil, PGE₁), 9-oxo-11α, 15S-dihydroxy-1a, 1b-dihomoprost-13E-en-1-oic acid, molecular formula is C₂₀H₃₄O₅.Prostaglandin E₁ (PGE₁) belongs to the family of arachidonic acid, it is foundin many mammals' tissue, and the concentration of prostaglandin E₁ in thesemen is extremely high. In 1930's, Euler showed that the mysterioussubstance in semen affected blood pressure, and the substance was so calledprostaglandin. When the cells were stimulated with prostaglandin E₁, the Ca2+signal increased abruptly, and then rapidly fell back to baseline. In contrast,total cAMP (assayed biochemically in the cells prelabeled with rose rapidly toa plateau and then remained elevated for some time. Prostaglandin E₁ is usedfor the treatment of peripheral vascular disorders including arteriosclerosisobliterans, thromboangiitis obliterans and Burger's disease.At present, there is PGE₁ powder for injection on sale. It suffers fromhigh-dose and low clinical compliance.The price of PGE₁ is too high andPGE₁ is hardly dissoluble, but can be dissolved in ethanol and oil. The meltingpoint, the stabilities under the high temperature and strong light were tested,therefore this article choose the intravenous emulsion to be the carrier of PGE₁.At first common lipid emulsion is blank;it can offer nutrition for patients whohave been operated just now. With the development of pharmacy, the lipidemulsion becomes a new vehicle for poorly soluble drugs. It not only improvethe stability, but avoid bringing more organic impregnant. At the same time,concentration of drug in out-water-phase is very low, it can reduce possibilityof phlebitis. In addition intravenous emulsion has high target ability. It canarrive at the RES of liver, kidney, spleen, lung, heart and marrow. So theconcentration of other tissues is lower correspondingly. Intravenous emulsionis used for the treatment of cancer and vascular disorders. PGE1 is developedto give it a target-directed nature by modifying the conventional PGE1, whichhas been used and found to be useful in clinical practice. The drug was shownto be significantly more active and longer acting than PGE1 in powder forinjection. When incorporated in emulsion, PGE1 appeared to be more stable,longer acting and more efficacious than PGE1 alone.The recipe of PGE1 for intravenous emulsion is: intravenous soybean oil,lecithin and glycerin, which was designed by orthogonal design method.Traditional intravenous emulsion was prepared by using ultrasonic, high speedmix round machine, colloid milling etc. An advanced nano-machine was usedto prepare the intravenous emulsion and the particle size of emulsion is about200 nm. The particle size of emulsion was measured by photon correlationspectroscopy. The best technique for producing the highest quality emulsion is:the original emulsion was prepared by mixing 5 min in a pulsator, and thensecondary P 1000 bar and first P 100 bar were used, 5 times. Finally, theemulsion was adjusted pH to 5.0 and sterilized.Analytical methods for the determination of PGE1 and PGA1 in emulsionby HPLC were developed. This paper describes fast, specific and sensitivemethods for direct determination of PGE1 and PGA1 in emulsion. It alsoprovides excellent reproducibility, which makes it suitable for pharmacystudies. The distribution of prostaglandin E1 in a lipid emulsion has beenshown to be consistent with a three-phase model which assumes that solutemay reside in the bulk aqueous and oil phases and at the oil/waterinterface.PGE1 exist predominantly at the interface (88.63%-94.37%).Determination of peroxide value, free fatty acid and bacteria endotoxin suitedto certify the conformance to relevant standards of Pharmacopoeia of People'sRepublic of China. The acceleration test was conducted at 25±2℃ for 6months. The result showed that the particle size of emulsion was gettingbigger, but all the indexes of emulsion were in the control. So the date ofexpiration of emulsion is atleast 1 year.The study on the stability of PGE1emulsion in injection solution showed: the solutions prepared were compatibleand clinical applicable, the PGE1 emulsion in injection solution in 2 hours wasstable.Pharmic effectiveness test on animals showed: a significantly increase inpulmonary blood flow (PBF) and a significantly decrease in pulmonaryvascular resistance by the injection of PGE1;PGE1 has the ability to inhibitthrombus formation and blood platelet aggregation, prolong OT in rat. Theemulsion is more effective than powder injection. Local irritation test,atiguability test and Hemolysis Test showed the PGE1 emulsion had no sideeffect. Because of the solubility of PGE1 and PGA1, we could not obtain theLD50 concentrations. But through our work, the result showed the PGE1 andPGA1 are extremely safe.The PGE1 intravenous emulsion we had studied on the formulation andproducing technique, stability of physico-chemical properties , Pharmiceffectiveness test. It's safe and effective, it will be well used in future.