Journal of pharmaceutical and biomedical analysis
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J Pharm Biomed Anal · Dec 2012
Clinical TrialAnalysis of total and unbound hydromorphone in human plasma by ultrafiltration and LC-MS/MS: application to clinical trial in patients undergoing open heart surgery.
A method for a sensitive and specific analysis of hydromorphone total and unbound drug concentrations in human plasma was developed and validated. Sample preparation was preceded with an ultrafiltration step to separate the unbound drug from the protein bound fraction of hydromorphone. Both the ultrafiltrate and plasma samples were extracted with solid-phase extraction and substituted with stable isotope-labeled hydromorphone that was used as internal standard. ⋯ Intra- and interassay reproducibility and inaccuracy did not exceed 10%. Hydromorphone was on the average 14% bound to plasma proteins, supporting the previously published unreferenced statements that the protein binding of hydromorphone is low. Method was applied to a clinical trial in patients undergoing open heart surgery to generate a target controlled infusion model for the postoperative patient controlled analgesia with hydromorphone.
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J Pharm Biomed Anal · Dec 2012
Comparative analysis of zaleplon complexation with cyclodextrins and hydrophilic polymers in solution and in solid state.
The aim of this work was to investigate the potential synergistic effect of water-soluble polymers (hypromellose, HPMC and polyvinylpyrrolidone, PVP) on zaleplon (ZAL) complexation with parent β-cyclodextrin (βCD) and its randomly methylated derivative (RAMEB) in solution and in solid state. The addition of HPMC to the complexation medium improved ZAL complexation and solubilization with RAMEB (K(ZAL/RAMEB)=156±5M(-1) and K(ZAL/RAMEB/HPMC)=189±8M(-1); p<0.01), while such effect was not observed for βCD (K(ZAL/βCD)=112±2M(-1) and K(ZAL/βCD/HPMC)=119±8M(-1); p>0.05). Although PVP increased the ZAL aqueous solubility from 0.22 to 0.27mg/mL, it did not show any synergistic effects on ZAL solubilization with the cyclodextrins tested. ⋯ The in vitro dissolution rate followed the rank order ZAL/RAMEB/HPMC>ZAL/RAMEB=ZAL/βCD/HPMC>ZAL/βCD≫ZAL, clearly demonstrating the superior performance of RAMEB on ZAL complexation in the solid state and its synergistic effect with HPMC on drug solubility. Surprisingly, when loaded into tablets made with insoluble microcrystalline cellulose, RAMEB complexes had no positive effect on drug dissolution, because HPMC and RAMEB acted as a binders inside the tablets, prolonging their disintegration. Oppositely, the formulation with mannitol, a soluble excipient, containing a ternary RAMEB system, released the complete drug-dose in only 5min, clearly demonstrating its suitability for the development of immediate-release oral formulation of ZAL.