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Naloxone and nalmefene absorption delivered by hollow microneedles compared to intramuscular injection
Mark G Papich1, Roger J Narayan2
1College of Veterinary Medicine, Department of Molecular Biomedical Sciences, North Carolina State University, 1060 William Moore Drive, Raleigh, NC, 27607, USA. mgpapich@ncsu.edu.
Naloxone and nalmefene were administered to seven research beagle dogs (mean weight approximately 12 kg) at doses of 0.04 mg/kg and 0.014 mg/kg for naloxone and nalmefene, respectively. Each dose was administered intramuscularly (IM) with a standard IM injection and with a hollow microneedle device array using needles of 1 mm in length. The IM injection was delivered in the epaxial muscles, and the microneedle injection was delivered in the skin over the shoulder of each dog. Each dog received the same injections in a crossover design. Following the injection, blood samples were collected for plasma analysis of naloxone and nalmefene by high-pressure liquid chromatography with mass spectrometry detection (LCMS). The plasma sample concentrations were plotted for observed patterns of absorption and analyzed with non-compartmental pharmacokinetic methods (NCA). The results showed that the injection of naloxone from the microneedle device produced a higher peak concentration (CMAX) by 2.15 × compared the IM injection of the same dose, and time to peak concentration (TMAX) was similar. For the nalmefene injection, the peak was not as high (lower CMAX) by 0.94 × for the microneedle injection compared to the IM injection of the same dose. The microneedle produced an exposure, measured by area under the curve (AUC), that was 0.85 × and 0.58 × as high for naloxone and nalmefene, respectively, than the injection by the IM route. We also observed that although the dose for naloxone was approximately 3 × higher for naloxone compared to nalmefene, the mean peak concentration achieved from the naloxone injection was more than 12 × higher than that from the nalmefene injection. These studies were designed to test the feasibility of using the hollow microneedle array as an effective method of naloxone and nalmefene delivery for emergency treatment of opioid-induced respiratory depression (OIRD). The results of these studies will form the basis of future studies, using the dog as a model, for development of hollow microneedle microarray devices to deliver opioid antagonists for treatment of OIRD in people.
Naloxone and nalmefene were administered to seven research beagle dogs (mean weight approximately 12 kg) at doses of 0.04 mg/kg and 0.014 mg/kg for naloxone and nalmefene, respectively. Each dose was administered intramuscularly (IM) with a standard IM injection and with a hollow microneedle device array using needles of 1 mm in length. The IM injection was delivered in the epaxial muscles, and the microneedle injection was delivered in the skin over the shoulder of each dog. Each dog received the same injections in a crossover design. Following the injection, blood samples were collected for plasma analysis of naloxone and nalmefene by high-pressure liquid chromatography with mass spectrometry detection (LCMS). The plasma sample concentrations were plotted for observed patterns of absorption and analyzed with non-compartmental pharmacokinetic methods (NCA). The results showed that the injection of naloxone from the microneedle device produced a higher peak concentration (CMAX) by 2.15 × compared the IM injection of the same dose, and time to peak concentration (TMAX) was similar. For the nalmefene injection, the peak was not as high (lower CMAX) by 0.94 × for the microneedle injection compared to the IM injection of the same dose. The microneedle produced an exposure, measured by area under the curve (AUC), that was 0.85 × and 0.58 × as high for naloxone and nalmefene, respectively, than the injection by the IM route. We also observed that although the dose for naloxone was approximately 3 × higher for naloxone compared to nalmefene, the mean peak concentration achieved from the naloxone injection was more than 12 × higher than that from the nalmefene injection. These studies were designed to test the feasibility of using the hollow microneedle array as an effective method of naloxone and nalmefene delivery for emergency treatment of opioid-induced respiratory depression (OIRD). The results of these studies will form the basis of future studies, using the dog as a model, for development of hollow microneedle microarray devices to deliver opioid antagonists for treatment of OIRD in people.
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