Precision Particle Fabrication Microsphere Depot Sustains Tramadol Blood Levels with Minimal ‘ Burst ’

SUMMARY Most analgesics require multiple oral administrations per day which frequently leads to poor compliance and insufficient control over pharmacokinetic profiles. In addition, the increased reliance on analgesic opioids for chronic pain management has led to increased levels of dependence and abuse. While injectable formulations offer improved compliance and reduced risk of abuse, they typically result in drug ‘burst’, followed by imprecise pharmacokinetics resulting in a lack of tight control over the concentration of these drugs in the blood. Here, we explore the possibility of developing a safer, more effective extended pain reliever using Orbis Biosciences’ controlled release technology to reformulate tramadol into a long-acting injectable depot. INTRODUCTION Approximately 130 million people in the United States suffer from chronic pain with approximately sixty percent of patients reporting daily breakthrough pain 1,2 . Drug delivery systems that allow for long-term release of pain relievers, including analgesics and opioids, reduce the risk of patient non-compliance and abuse, but often result in difficult to control drug release kinetics. Attempts to sustain and control the concentration of these drugs in the blood via controlled release formulations have typically resulted in drug ‘burst’, followed by marginal control over the ensuing pharmacokinetics. Precision Particle Fabrication technology was used to produce uniform microspheres encapsulating the μ-opioid receptor agonist, tramadol 3,4 . Following subcutaneous injections in canines, plasma concentrations of tramadol were sampled and found to have a smooth ramp to the maximum concentration followed by a steady decline until day 7. Importantly, there was little measurable ‘burst’ associated with this sustained release delivery system. EXPERIMENTAL METHODS Uniform microspheres were prepared using Orbis’ Melt-Spray Precision Particle Fabrication technology. Briefly, Tramadol-HCL (“tramadol”) was first dissolved in dichloromethane (DCM) and then dispersed into molten Generally Accepted As Safe (GRAS) wax matrix material. DCM was subsequently evaporated to create a fine tramadolwax solid dispersion. Tramadol-loaded wax suspensions were sprayed through a coaxial Precision Particle Fabrication nozzle. Simultaneously, the wax matrix jet was acoustically excited using an ultrasonic transducer (Sonics and Materials, Newtown, CT) controlled by a frequency generator (Agilent, Santa Clara, CA) that produced regular disruptions in the wax-tramadol jet. Waxtramadol particles air-cooled and were collected in an empty vessel positioned approximately 4 feet below the nozzle. The dried particles were either stored at -20oC or used immediately for dissolution testing. In vitro tramadol release from the microsphere/sesame oil ‘vehicle’ (exactly as it was given to the dogs) was injected into Slide-A-Lyzer Dialysis cassettes with a 10,000 MW cutoff. The cassettes were submerged in DI water in a glass beaker at 37oC and sampled daily after the first 12 and 24 hour time points. Cumulative release was found by normalizing incremental release to total loaded drug, both determined by HPLC. In vivo studies were designed for testing the controlled release of tramadol from wax microspheres. All pharmacokinetic studies were conducted using beagle dogs. The tramadol-loaded microspheres, having an average particle size of 150 μm diameter and 7 wt% drug loading, were compared to injection of free tramadol and to Ultram ® tablets. Both free tramadol and tramadolloaded microspheres were suspended in an oil ‘vehicle’ immediately prior to injection. After delivery, plasma samples were taken with decreasing frequency during the first 24 hours, then every 8 hours for 7 days. RESULTS AND DISCUSSION In vitro tramadol release from Precision Particle Fabrication wax microspheres demonstrated low initial burst (<10%), followed by steady release until day 7 (Figure 1A). Only 20% of the loaded drug was released over 7 days. Uniform microspheres (Figure 1B) were produced in a single-step process – requiring no additional lyopholization or postprocessing steps, which are typically required with traditional encapsulation techniques. The performance of the tramadol-loaded wax microspheres was then compared in vivo to free tramadol injection and to Ultram ® tablets dosed orally. At the onset of administration, dogs dosed with Ultram ® and free tramadol experienced a spike in plasma concentrations well beyond the therapeutic window, whereas this ‘burst’ was minimized with the microsphere formulation (Figure 2). By the end of the first 24-hour period, tramadol was undetectable in dogs administered the free drug or tablets; however, dogs with the microsphere injection showed a steadily declining plasma concentration through 7 days. Pharmacokinetic analysis (table not shown) supported the observed profiles, revealing a tramadol half-life of the microsphere formulation that was 13 times longer than the free drug injection, with an average burst concentration approximately 3 times lower. The microencapsulated tramadol also exhibited a slightly higher AUC, which suggested near complete release in vivo – an interesting observation considering the lack of complete release observed in vitro (Figure 1A). Compared to the Ultram ® group, the microspheres were able to achieve faster action while minimizing the ‘burst’ release. In addition, the microspheres were able to outperform both free tramadol and Ultram ® groups by sustaining blood levels via slow release of tramadol from the microspheres. CONCLUSION Melt-Spray Precision Particle Fabrication was successfully used to create uniform wax-tramadol microsphere depots that eliminated ‘burst’ and sustained drug plasma concentrations. Future studies will focus on optimizing the microsphere formulation and dose to maintain therapeutic blood concentrations for five days. REFERENCES 1. Fishbain D, Johnson S, Webster L, Greene L, Faysal J. J Manag Care Pharm. 2010;16(4):27687. 2. Voices of Chronic Pain. National Study: American Pain Foundation; 2006. 3. Berkland C, Kim K, Pack DW. J Control Release.