Evaluation of Poloxamer as a Slow Release Carrier for Morphine
Abstract
This study evaluates the use of poloxamer as a slow release carrier for morphine to prolong its duration of effect. The thermoresponsive nature of poloxamer enables it to be injected in solution, and form a drug depot once it gels in the patient. The study largely divides into in-vitro and in-vivo phases. Aims of the in-vitro phase of the study were to 1) investigate the effects of poloxamer concentrations (20, 25, 30%), temperature and pH of the media solution on morphine release rate, 2) compare the flow characteristic (rheology), dissolution rate and surface morphology of poloxamer alone compared to poloxamer-morphine mixture. We hypothesized that the concentrations of poloxamer, temperature, and pH of the media solution, would affect the morphine release rate from poloxamer; and the poloxamer-morphine will have observable changes of surface morphology. Results revealed poloxamer concentrations and temperature, but not pH of media affected morphine release rate. Rheology results showed an inverse relationship between poloxamer concentrations and the sol-gel temperatures. There was no significant difference in the dissolution rates between poloxamer and poloxamer-morphine, in contrary to its surface characterization from scanning electron microscopy. All the findings demonstrated that 25% of poloxamer was an ideal carrier for morphine. It was then tested in-vivo; where we aimed to 1) compare the kinetic of morphine release with and without poloxamer as a carrier; 2) investigate histopathology reaction of the treatment group compared to control, and show good biocompatibility. A kinetic study was performed by administration of subcutaneous injection of treatments on rats and plasma samples were withdrawn at 10, 30, 45 minutes, 2, 4, 6, 8, 12, 24 and 48 hours to monitor the plasma morphine concentrations over time. Liquid chromatography-mass spectrometry (LC-MS) bioanalysis was employed to determine morphine concentrations. It was shown that poloxamer-morphine mixture was able to produce plasma morphine concentrations within the therapeutic window for up to 8 hours compared to control morphine group at only 2 hours. The mean elimination half-life (t½) was significantly higher in poloxamer-morphine at 5.53hr compared to only 0.94hr in morphine group. In contrast, morphine group showed significantly higher mean maximum plasma concentrations (Cmax) at 716.77ng/ml compared to 242.81ng/ml in the poloxamer-morphine group. Although we found no significant difference between the mean pain/ behavior scores after injections with both poloxamer-morphine and morphine, there is a trend for lower scores in the poloxamer-morphine group compared to morphine control group beginning 4 hours post injection. Histopathology results showed no foreign body reaction. Data were analyzed using Statistical Package for the Social Sciences (SPSS) software with statistical significance level set at 0.05. All our findings suggested that poloxamer-morphine at 25% injected subcutaneously is biocompatible and successfully provide a slow release of morphine.
Degree
Ph.D.
Advisors
Ko, Purdue University.
Subject Area
Pharmaceutical sciences|Veterinary services
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