Bioavailability Enhanced Formulation Of Mitragynine With Better Analgesic Activity
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Date
2015-01
Authors
PARTHASARATHY, SUHANYA
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Abstract
Mitragynine the principal alkaloid of M. speciosa leaf has been reported responsible for most of its pharmacological effects. However a large dose variation was encountered in mitragynine analgesic (33 to 200 mg/kg), pharmacokinetic (20 to 50 mg/kg) and toxicity (477 to 920 mg/kg) studies in animal models. Mitragynine sub optimal physicochemical properties may have contributed to the large dose variation observed in the preclinical studies. As the drug poor water solubility is evident, work was undertaken to establish the physicochemical properties of MG. This physicochemical properties of MG was further used as the basis to develop a new MG formulation in order to achieve uniformity in oral absorption .This was carried out by incorporation of mitragynine into a lipid carrier Gelucire 44/14. Two HPLC methods were developed and validate for determination of MG. HPLC-DAD (LOQ: 0.5 μg/mL; r2 >0.999) was used to determine MG in ketum juice. The HPLC-UV (LOQ (solution): 0.16 μg/mL; r2 >0.999) (LOQ (plasma): 39.1 ng/mL; r2 >0.999) method was employed to analyse samples from formulation and bioavailability studies. Mitragynine is both hydrophobic (<100 μg/mL) and lipophilic (log P: 1.70), weak base (pKa: ~8.1) and acid degradable (10-20%). Using heat infusion method, the drug was dispersed into Gelucire 44/14 (1:2) and the dispersion was filled in a self-made capsule for bioavailability study in rats. Mitragynine dispersion physicochemical properties were further characterized. DSC study indicated that mitragynine is molecularly dispersed in Gelucire 44/14 (amorphous solid solution). The FTIR spectrum and mitragynine content analysis studies showed that the mitragynine dispersion was stable at storage temperature 4oC for the studied period (2 months). The dispersion was also found stable in both simulated
gastric (SGF) and intestinal fluid (SIF) when compared to the pure amorphous drug .The in vitro drug release of mitragynine from capsule filled with the dispersion was almost complete in both SIF (97%) and SGF (104%); The new formulation was finally tested for its oral bioavailability in rats. The dispersion resulted in a 4.5 fold increase in mitragynine bioavailability when compared to the conventional mitragynine solution. When the dispersion was tested for analgesic activities, mitragynine dispersion (10 mg/kg) repeatedly gave the highest and longest duration of analgesic effect, when compared to morphine and mitragynine solution. This mitragynine new formulation could be used to conduct a more realistic assessment of its pharmacological effects especially toxicity before one can make a correct inference of animal studies for human safety risk prediction.
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Bioavailability Enhanced Formulation , Of Mitragynine With Better Analgesic Activity