Development of nalbuphine pressurized metered-dose inhaler and its characterization through gamma scintigraphy in human subjects: an approach for instant pain management in traumatic conditions

Nalbuphine is well-recognized agonist/antagonist analgesics from others in having greater antagonist activity and less behavioral effects at analgesic doses than buprenorphine pentazocine and butorphanol. Pressurized metered-dose inhaler (pMDI) is an effective choice to deliver drug in the anterior lobe of lungs from where drug can distribute fast and obtain maximum plasma level and reach to the pain suppress receptors. The objective of the contemporary study was to develop a novel nalbuphine pMDI and characterization using gamma scintigraphy in healthy human volunteers. The toxicity of Nalbuphine pMDI was also determined and found safe at 1X and toxic at higher doses, i.e., 4X. Nalbuphine was successfully radiolabeled and found stable up to 24 h in normal saline and serum as confirmed by instant thin-layer chromatography-silica gel chromatography. pMDI was prepared by filling 134-hydrofluoroalkane propellant and ^99mTc-nalbuphine in an aluminum canister under sterilized environment. The repairable fraction and aerodynamic particle size distribution of the ^99mTc-nalbuphine was determined using Anderson Cascade Impactor (ACI) and calculated by radiometry. Radiolabeled nalbuphine puff was evaluated in 12 healthy human volunteers by ventilation scintigraphy. Nalbuphine pMDI provided a consistent delivered dose is 22% ± 3.2%. The mass median aerodynamic diameter and geometric standard deviation for an aerodynamic particle size distribution determined with an ACI was 4.71 μ and 1.69, respectively. In vivo uptake of the ^99mTc-nalbuphine was considered in real time and activity in lungs and body as the internalized fraction in terms of milligrams as well as percentage. Scintigraphy data showed significant uptake of radiolabeled nalbuphine in the lungs and brain up to 4 h. Results obtained through study provide important insight to develop instant acting pMDI inhaler of nalbuphine for the management of sever/traumatic pain. (author)