Assessment of compatibility of rhIGF-1/rhIGFBP-3 with neonatal intravenous medications.

BACKGROUND: Recombinant human (rh)IGF-1/IGFBP-3 protein complex, administered as a continuous intravenous infusion in preterm infants, is being studied for the prevention of complications of prematurity. METHODS: We conducted in vitro studies to evaluate the physical and chemical compatibility of rhIGF-1/IGFBP-3 with medications routinely administered to preterm neonates. In vitro mixing of rhIGF-1/IGFBP-3 drug product with small-molecule test medications plus corresponding controls was performed. Physical compatibility was defined as no color change, precipitation, turbidity, gas evolution, no clinically relevant change in pH/osmolality or loss in medication content. Chemical compatibility of small molecules was assessed using liquid chromatography (e.g., reverse-phase HPLC and ion chromatography), with incompatibility defined as loss of concentration of ≥ 10%. A risk evaluation was conducted for each medication based on in vitro compatibility data and potential for chemical modification. RESULTS: In vitro physical compatibility was established for 11/19 medications: caffeine citrate, fentanyl, fluconazole, gentamicin, insulin, intravenous fat emulsion, midazolam, morphine sulfate, custom-mixed parenteral nutrition solution (with/without electrolytes), parenteral nutrition solution + intravenous fat emulsion, and vancomycin (dosed from a 5 mg/mL solution), but not for 8/19 medications: amikacin, ampicillin, dopamine, dobutamine, furosemide, meropenem, norepinephrine, and penicillin G, largely owing to changes in pH after mixing. Small-molecule compatibility was unaffected post-mixing, with no loss of small-molecule content. For physically compatible medications, risk analyses confirmed low probability and severity of a risk event. CONCLUSION: Co-administration of rhIGF-1/rhIGFBP-3 drug product with various medications was assessed by in vitro studies using case-by-case risk analyses to determine the suitability of the products for co-administration.

Pharmacokinetic applicability of a validated liquid chromatography tandem mass spectroscopy method for orally administered curcumin loaded solid lipid nanoparticles to rats.

A simple and sensitive validated LC-MS/MS analytical method was used for determination of curcumin in rat plasma, using nimesulide as internal standard. Analyses were performed on an Agilent LC-MS/MS system using a Chromolith rod™ and isocratic elution with acetonitrile:10 mM ammonium acetate buffer (pH 3.5) (80:20, v/v) at a flow rate of 0.8 ml/min with a total run time of 3 min and an overall recovery of 77.15%. A triple quadrupole mass spectrometer, equipped with an electrospray ionization interface, operated in the negative mode was used. Calibration curve in plasma spiked with varying concentration of curcumin were linear over the concentration range of 10-2000 ng/ml with determination coefficient >0.99. The lower limit of quantification was 10 ng/ml. Intra and inter-day variability's (RSD) for extraction of curcumin from plasma were less than 10% and 15% respectively and accuracy was 102.43-108.5%. Multiple reaction monitoring was used to monitor the transition for curcumin (m/z; 367/217 [M-H](-)) and IS (m/z; 307/229). The method was applied for determining curcumin concentration in plasma after peroral administration of 50 mg/kg of free curcumin (C-S) or curcumin loaded solid lipid nanoparticles (C-SLNs) to rats. Results established selectivity and suitability of the method for pharmacokinetic studies of curcumin from C-SLNs.