生物学的同等性とバイオアベイラビリティのジャーナル

概要

Non-Invasive Nasal Hydromorphone with High Bioavailability for Rapid Onset and Non-Dissociative Acute Pain Control: A Feasibility Study

Cunningham G and Maggio ET

Aim: To test the hypothesis that intranasal hydromorphone could mimic IV administration parameters for use in acute pain situations such as battle field injury, EMS first response and breakthrough cancer pain.
Methods: A single healthy volunteer was recruited to a monocentric, open label, randomized, four-way crossover pharmacokinetic study, with 7 days washout period between treatments (more than 70 times the terminal elimination half-life). The use of a single subject minimized the effect of person to person variability in metabolism. For small molecule drugs (i.e., MW<1,000 Daltons) nasal bioavailability in the presence of alkylsaccharide absorption enhancers is predominantly a function of molecular weight and is expected to be high. Unexpected impediments to nasal delivery are likely due to local mucosal irritation or vasoconstriction, which can reduce bioavailability. According to an analysis of FDA data by eHealthMe, of 18,420 people reported to have side effects when taking hydromorphone, only 1 person reported vasoconstriction.
The subject received 2 mg oral hydromorphone vs. 3 different formulations of 2 mg intranasal hydromorphone administered using a 100 μl Aptar multidose spray pump (Aptar Group, Crystal Lake, IL). Hydromorphone concentrations were evaluated by HPLC-MS/MS. Bioavailability was calculated using trapezoidal methodology to determine area under the curve.
Results and conclusion: Moderate euphoria was observed for all dosage forms, nasal and oral. Oral concentrations were fairly low at all reportable time periods, with Tmax at minute 60 and Cmax 1.5 ng/mL. All intranasal formulations exhibited a greatly improved Tmax of 10 minutes and improved Cmax values. IN-3 had a significantly better Cmax value of 6.6 ng/ml respectively and drug effect was noted as early as minute 1, experienced as a moderate euphoria which lasted until minute 120, then tapering off. We believe the proprietary formulations of intranasal hydromorphone should be further investigated and developed.