Studies On Submicron Emulsions Of Pyritinol Ester Prodrugs

Pyritiniol is a derivative of vitamin B₆. A variety of pharmacological effects had been reported for pyritinol, which could accelerate the intracerebral uptake and metabolism of glucose and amino acids, increase the energy metabolism of brain cell as well as blood flow through A. carotis, also improve the assimilation of all over the body. Pyritinol was a good medicine in curing AD, cerebral concussion、post-traumatic brain syndrome, etc. In clinical, it was used in the form of pyritinol hydrochloride injection, but often caused very serious pain and blood vessel irritation when injected, so that it was used less and less. In this study, two ester prodrugs of pyritinol were synthesized. The physico-chemical properties and stability of the two prodrugs were investigated. Emulsion formulations of two prodrugs were studied. Security and pharmacokinetics of optimized prodrug emulsion were studied to develop a more effective and less painful prodrug preparation.Pyritinol tetraacetate ester（I-A） and Pyritinol tetrapropionate ester（I-P） were synthesized by origanic acid esterification method by using pyritinol as raw material. The structure of prodrugs were identified by IR, UV, ¹HNMR、¹³C-NMR and MS respectively.HPLC method were developed for the assay of prodrugs in vitro. The hydrolysis kinetics and plasma degradation of prodrugs were studied. The results showed that the hydrolysis process was specifically catalyzed by acid, base and water. The prodrugs were stable at pH 3～7, while the most stable range was pH 5～6. Two prodrugs degraded to pyritinol fast in 80% rat plasma, the half time were 0.987min for I-A and 1.012min for I-P.The solubility of prodrugs varied with pH of buffer solutions. The solubility was independent of pH between pH value 4～7. The lgP were 2.17 and 4.82 respectively for I-A and I-P. Obviously I-P was more lipophilic. Two prodrugs showed good stability by the results of the experiments under high temperature, humidity and strong light.The formulations of emulsion were composed by Soybean oil or MCT as oil, soybean lipid and poloxamer as emulsifier, oleic acid as stabilizer and glycerin as isoosmotic adjusting agent. The particle size and distribution, zeta potential and Ke were the main evaluation parameters to optimize the formulation and preparation process. The physicochemical properties of prodrug submicron emulsions were studied. The results showed that the mean particle size were 208±26 nm and 136±18 nm,ζ-potential were -44.5 mV and -27.5 mV, resectively for I-A submicron emulsion and I-P submicron emulsion. Both were slightly hypertonic, pH were 5.5～6.0, drug contents were 90～110%, encapsulation efficiency were above 90%.The I-P submicron emulsion was safe within 8 hours after compatibility test with glucose injection （5%） and sodium chloride injection （0.9%）.The pharmaceutical safety test results indicated that I-P submicron emulsion caused no hemolysis and no stimulation on vein. LD₅₀ of I-P submicron emulsion was 210.2mg/kg.The pharmacokinetics of I-P submicron emulsion in rats was studied compared with pyritinol hydrochloride injection. The serum concentration-time data were analyzed by non-compartmental model. The relative AUC value of I-P submicron emulsion for injection was 137.8%.