Research On The Withdrawal Of Pioglitazone In Alcohol Addiction And Its Formulation Optimization

Pioglitazone(PIO)is a synthetic agonist of peroxisome proliferator-activated receptor gamma(PPARγ)receptor,which can protect damaged nerve cells by activating PPARγreceptor.Pioglitazone can treat neurodegenerative diseases caused by alcohol addiction.This suggests that pioglitazone may be a potential drug for the treatment of alcohol addiction,but relevant preclinical evidence is still lacking.Pioglitazone is insoluble in water and has low bioavailability.Patients often need to take large doses of drugs to achieve efficacy,which also increases the possibility of bladder cancer.In view of the above reasons,this paper designed preclinical experiments to provide more evidence for the potential efficacy of pioglitazone in alcohol addiction,and used the polymer material crospovidone(PVPP)to prepare pioglitazone solid dispersion with excellent dissolution.The main work and results are as follows:First,we investigated whether the PPARγ agonist pioglitazone could help counteract neurodegeneration and cognitive impairment caused by alcohol addiction.Adult Wistar rats underwent a 4-day binge-drinking procedure to simulate excessive alcohol intake in humans.The effect of pioglitazone on neurodegeneration was determined in brain regions by fluoro-jade B(FJ-B)immunostaining,and the effect of pioglitazone on cognitive function was assessed in the reverse learning task and the Morris water maze task.The study found that binge drinking led to degeneration of selective neurons in the dentate gyrus and adjacent entorhinal cortex of the hippocampus.Treatment with pioglitazone decreased the expression of FJ-B positive cells.Pioglitazone also rescued alcohol-impaired inverse learning during manipulation tasks and spatial learning deficits in the Morris water maze.These findings confirmed that activation of PPARγ prevents neuronal and cognitive degeneration caused by binge drinking.Subsequently,the dosage form of pioglitazone was optimized by using the polymer carrier material PVPP.The preparation conditions of the carrier were first explored.The polymerization was initiated by the water-soluble azo initiator 2,2’-azabis[2-(2-imidazoline-2-yl)propane]dihydrochloride(AIBI),which can effectively reduce the energy required for the reaction.The dosage was only need 1%,and the reaction was carried out at60℃.It can be completed within 60 minutes.The post-treated carrier was combined with pioglitazone by a solvent method to prepare PIO-PVPP solid dispersions with different ratios.The dissolution results showed that the PIO-PVPP solid dispersion prepared with a ratio of 1: 4 had the best effect,and the cumulative drug release rate reached 68% within120 minutes,which was much higher than that of the PIO.At the same time,observed by optical microscope,PIO formed non-crystalline amorphous in the carrier PVPP,and was highly dispersed.