In vitro and in vivo studies of subcutaneous hydromorphone implants designed for the treatment of cancer pain

Unrelieved cancer pain remains a significant problem worldwide. Patients receive inadequate analgesia for a variety of complex and multifactorial reasons. Limited availability of opioids secondary to concerns about potential diversion of these medications for illicit use and poor compliance with oral regimens are significant factors in many countries. This study was designed to develop and test an implantable opioid delivery device capable of releasing a potent opioid subcutaneously at a continuous rate for 4 weeks. A low temperature solvent casting technique was used to formulate ethylene vinyl acetate (EVA) copolymer disks containing 50% hydromorphone by weight. The release characteristics of disks of different height and diameter, coated and uncoated, and with and without a central uncoated channel were studied. The effect of temperature and pH were also evaluated. In vitro assessments were conducted in phosphate buffer using UV spectrophotometry. In vivo studies employed New Zealand White Rabbits and a radioimmunoassay. Plasma levels following hydromorphone delivery by polymer, osmotic pump, and intravenous administration were compared. In vitro, uncoated EVA polymer disks measuring 1.05 cm in diameter and 0.27 cm in height released an initial large burst of hydromorphone. Coating the disks with 100-200 microM of poly(methyl-methacrylate) prevented drug egress from the polymer. A central uncoated channel measuring 1.25 mm in diameter in an otherwise coated polymer virtually eliminated the initial burst of drug release and provided near zero-order hydromorphone release at an average rate of 164 micrograms per hour for 4 weeks. Doubling the height of the polymer approximately doubled the release rate while doubling the diameter of the polymer extended the duration of drug release to over 8 weeks. In rabbits, stable plasma hydromorphone concentrations (23-37 ng/ml) were sustained for 4 weeks following implantation of 2 polymers with an uncoated central channel. No initial burst of hydromorphone release was noted. Increasing the number of polymers produced sustained and predictable increases in plasma hydromorphone concentrations. Plasma levels were similar with subcutaneous hydromorphone delivered by polymer and osmotic pump and much less variable than with intravenous bolus hydromorphone. A uniquely configured implantable drug delivery device has been developed using materials which are approved for human use. It safely and reproducibly releases hydromorphone for weeks in vitro and in vivo without an initial burst of drug release. Varying the thickness, diameter, and number of implants provides flexibility in the release rate and duration of release. This implantable opioid delivery device could provide a sustained subcutaneous infusion of hydromorphone to patient with cancer pain in developed and developing nations without pumps, catheters, or extensive outpatient support services. In addition, it should improve compliance and reduce concern regarding illicit diversion of opioids.