Lipid Material Lipolysis And Pancreatic Lipase Trigger A New Type Of Pulse Preparation Feasibility Study

Pulsed drug delivery systems (PDDS) could overcome the disadvantages of traditional formulations, which have low compliance resulting from complicated administration. Based on chronobiological and chronopharmacokinetic characteristics, PDDS are designed to release drug quickly and completely after a lag-time when necessary.In this issue, the feasibility of a novel oral pH-sensitive pulsed formulation was investigated. The formulation was established to improve the inconveniences and compliance of oral hypoglycemic drugs according to high level of pancreatic lipase after meal enhancing lipolysis on lipid excipients which would result in the increase of lipid products, such as fatty acids, and the change of pH in the intestinal microenvironment.In order to study the feasibility of this novel pulsed formulation, it is necessary to investigate pH change during lipolysis of lipid excipients catalyzed by different concentration of pancreatic lipase, and then to select the appropriate lipid excipient which could stimulate drug release quickly by lipolysis under the condition of high level pancreatic lipase in fed state. This paper aims to investigate the relationship among lipid type, the release amount of fatty acids and pH change. Moreover, it is another key to choose a pH responsive polymer as drug carrier for this intelligent drug delivery system. Consequently, in this paper, we investigate as follows:(1) Lipolysis pattern of lipid excipient:it was found that the concentration of pancreatic lipase was significantly different between fasted and fed state. In vitro lipolysis model was used to determine the lipolysis of common lipid excipients. The results showed that more fatty acids were produced under the condition of higher pancreatic lipase in fed state resulting in the significant decrease of environmental pH. In the same way, lipolysis on pure glycerides with different chain length and number of ester bonds were investigated in fasted and fed state. The results would help to choose the appropriate lipid excipient for novel pH-sensitive pulsed formulation.(2) The synthesis and characterization of poly (β-amino esters):poly (β-amino esters) was synthesized in laboratory and determined by using NMR and GPC methods. The results showed that the desired poly (β-amino esters) was synthesized successfully. Glipizide was as a model drug and the drug-loaded nanoparticles were prepared by self-emulsifying solvent diffusion method. The formulation was optimized by Box-Behnken design and results showed that the average particle size of nanoparticles was225.6nm, the polydispersity index (PDI) was0.206and the zeta potential was3.27mV. The in vitro drug release characteristics of nanoparticles were investigated by dialysis method at pH5.0and pH7.8respectively and results showed that at pH5.0the drug was released faster than that at pH7.8. It suggested that poly (β-amino esters) was dissolved quickly when pH<7and could be solved more easily in acidic environment.This subject mainly involved the evaluation of the feasibility of the novel pancreatic lipase stimulated pulsed formulation. In present work, the change patterns of environmental pH were studied and the results showed that more fatty acids were produced from lipolysis since higher concentration of pancreatic lipase in fed state, resulting in environment pH significantly decreased. The lipid excipient with shorter chain length and more ester bonds would be catalyzed fast and produced more fatty acids to form acidic environment, which was benefit to drug release. In future, detailed study on lipid excipients such as its type and dosage should be carried out. On the other hand, a pH-responsive polymer as drug carrier for the intelligent drug delivery system, poly (β-amino esters) was synthesized, drug-loaded nanoparticles were prepared and drug release characteristics in vitro were also investigated. In future, the pancreatic lipase stimulated pulsed formulation should be prepared by suspending pH-sensitive nanoparticles in lipid carrier suspension and drug release behavior and pharmacokinetic characteristics should be investigated.