ABSTRACT
PURPOSE: The stability of aprepitant injectable emulsion is evaluated in various admixture bags and solutions, under different storage conditions, and when combined with other antiemetics. METHODS: A volume of 18 mL aprepitant injectable emulsion was added to infusion bags (either non-di-(2-ethylhexyl) phthalate [DEHP], polyvinyl chloride [PVC]-containing bags or non-DEHP, non-PVC bags) containing 100, 130, or 250 mL of 0.9% normal saline solution (NSS) or 5% dextrose in water (D5W). Bags were stored at controlled room temperature (20-25°C) for up to 12 hours or refrigerated (2-8°C) for up to 72 hours. Compatibility/stability was also assessed in admixtures combined with either dexamethasone or palonosetron. At specified time points, bags were tested for appearance, pH, assay for aprepitant (ie, percent label claim of aprepitant) and aprepitant-related substances, Z-average particle size, globule size distribution, particulate matter, and DEHP content (PVC bags). In separate analyses to assess microbial burden, bags containing aprepitant were inoculated with seven different organisms and assessed for microbial growth. RESULTS: There was no detectable impact on the physicochemical properties or potential to promote microbial growth of aprepitant when diluted with various amounts of either NSS or D5W and when admixed with either dexamethasone or palonosetron at room temperature for at least 6 hours or during refrigeration for up to 72 hours in either PVC- or non-PVC-containing bags. CONCLUSION: Aprepitant-containing admixtures are stable under these conditions, a finding that may improve patient and provider convenience and reduce medication wastage.
Subject(s)
Antiemetics/chemistry , Aprepitant/chemistry , Dexamethasone/chemistry , Palonosetron/chemistry , Antiemetics/administration & dosage , Aprepitant/administration & dosage , Dexamethasone/administration & dosage , Diethylhexyl Phthalate/chemistry , Drug Combinations , Drug Incompatibility , Drug Packaging , Drug Stability , Drug Storage , Emulsions , Hydrogen-Ion Concentration , Palonosetron/administration & dosage , Polyvinyl Chloride/chemistry , Refrigeration , Temperature , Time FactorsABSTRACT
Inaccurately perceived as niche drugs, antiemetics are key elements of cancer treatment alleviating the most dreaded side effect of chemotherapy. Serotonin 5-HT3 receptor antagonists are the most commonly prescribed class of drugs to control chemotherapy-induced nausea and vomiting. These antagonists have been clinically successful drugs since the 1980s, yet our understanding of how they operate at the molecular level has been hampered by the difficulty of obtaining structures of drug-receptor complexes. Here, we report the cryoelectron microscopy structure of the palonosetron-bound 5-HT3 receptor. We investigate the binding of palonosetron, granisetron, dolasetron, ondansetron, and cilansetron using molecular dynamics, covering the whole set of antagonists used in clinical practice. The structural and computational results yield detailed atomic insight into the binding modes of the drugs. In light of our data, we establish a comprehensive framework underlying the inhibition mechanism by the -setron drug family.
Subject(s)
Antiemetics/chemistry , Antiemetics/metabolism , Palonosetron/metabolism , Receptors, Serotonin, 5-HT3/chemistry , Receptors, Serotonin, 5-HT3/metabolism , Animals , Binding Sites , Cryoelectron Microscopy , Hydrogen Bonding , Mice , Molecular Dynamics Simulation , Palonosetron/chemistry , Protein Conformation , Serotonin/chemistry , Serotonin/metabolism , Serotonin 5-HT3 Receptor Antagonists/chemistry , Serotonin 5-HT3 Receptor Antagonists/metabolismABSTRACT
Efficient encapsulation of hydrophilic drugs was substantially challenging when using emulsion solvent evaporation approach. The aim of present study was to design palonosetron hydrochloride-loaded PLGA microspheres (Pal-MS) with high encapsulation efficiency (EE) to sustain drug release for over several days. Pal-MS were prepared using emulsion-solvent evaporation method. Results showed that the pH of external phase could significantly affect the EE and the drug release rate of Pal-MS. By increasing the pH of external phase from 5.0 to 10.0, EE of Pal-MS increased from 55.64% to 94.33%. When the pH of external phase was 7.0, an ideal Pal-MS with EE of 86.51% and a zero-order drug release profile was obtained. The improved EE and drug release performance was proved to be associated with possible PLGA degradation, enhanced drug-PLGA interaction and reduced drug diffusion from organic phase to aqueous phase. After subcutaneous injection, such Pal-MS showed more steady drug plasma concentration (0.207-1.238 ng/ml) over the entire 6-day in comparison with those of multiple-day-dosing intravenous palonosetron hydrochloride solution. It was concluded that Pal-MS were successfully designed by the adjustment of the pH of external phase and could be promising for preventing both acute and delayed chemotherapy-induced nausea and vomiting (CINV).
