The Impact of Extrusion Processes on Drug Burst Release from PLGA Ocular Implants Studied by Confocal Raman Mapping Kiomars Karami1, Hongwen Rivers1, Michelle Luu1, Patrick Hughes1 and Scott Smith1 Physical Chemistry, Pharmaceutical Development1, Allergan, Inc., Irvine CA PURPOSE Figure 1. Raman Spectra of AGN-217951, Ocular Implant with 30% Drug Load and Placebo. Figure 3. Comparison of Raman Maps on the Ocular Implant Formulations (Cross Sections) This study was conducted to evaluate the effect of extrusion processes on the observed drug-release rate from PLGA ocular implants. In particular, the impact of the drug distribution on the initial burst release of the implants was investigated by using confocal Raman spectroscopy. INTRODUCTION A hydrophilic drug was mixed with PLGA (poly- D,L-lactide-co-glycolide) polymers to manufacture a solid implant formulation by using two different hot- melt extrusion processes. The drug-release profiles were obtained at 37°C in phosphate buffer saline (PBS) solution. Process 1 generated variation in drug release profiles including 95% burst release within the first 24 hours, whereas Process 2 resulted implants with consistent slow release of the drug over period of 90 days. The 95% initial burst release was considered a potential serious risk for developing a controlled release implant. To investigate the cause of the high initial burst, Confocal Raman Microscopy (CRM) was applied to compare the drug distribution and phase separation of the drug and polymer within implants with and w/o burst release. CRM maps were obtained in order to locate distribution of the drug and polymer on the outer surface and cross-section surfaces of the implants. To calculate the drug-polymer ratios in the Raman maps, the peak area of the Raman shift at 643 cm-1 (for the drug) and at 1769 cm-1 (for the PLGA polymers) were used. Table 1. Average Drug/Polymer Ratios calculated from Raman Maps on Cross Section of the Ocular Implants using OMNIC Software Raman mappings of the implants were conducted at a map size about100x100 sq. microns, 100% laser power was applied at 780 nm . Mapping conditions: 3 sec. exposure, 2 exposures/scan at step size of 3 microns/scan. For calculation of drug/polymer ratios in the Raman maps, the peak area of Raman shift at 643 cm-1 (for drug) and 1769 cm-1 (for polymers) were used. Release testing was conducted on implants with size of 6mm in length, placed in 0.01M PBS solution (pH7.4) at 37°C in a shaking water bath set at 50 rpm. At predetermined time-points, the solution containing released AGN-217951 was removed and analyzed by HPLC. The removed solution was subsequently replaced with fresh PBS solution. Figure 2 presents the in-vitro release profile of the formulations extruded by Process 1 (Lot 9749-002-I6RR with high initial burst release (95%) and Lot 9097-087-I6R with low initial burst) compared to the formulation manufactured by Process 2 (Lot 9749-026-I6R5). Figure 4. Comparison of Raman Maps on the Ocular Implant Formulations (Outer Surface ) MATERIALS Figure 2. In-vitro Release Profiles of Implant Formulations in PBS Solution at 37°C The PLGA polymers used in this study were provided from Boehringer Ingelheim. The drug substance used was Allergan compound with assignment: AGN-217951. The hot-melt extrusions were performed at 70°C. Table 2. Average Drug/Polymer Ratios calculated from Raman Maps on Outer Surface of the Ocular Implants using OMNIC Software METHODS The feasibility of Raman analysis for identifying drug in the implant formulations was assessed using a Thermo-Scientific CRM. Raman spectra of the pure drug, implant formulation and placebo (extruded PLGA polymers w/o drug) were acquired at laser wavelength of 780nm and100% laser intensity. The laser exposure was 3 sec. at two exposures per data collection. The calculated drug-polymer ratios (D/P ratios) in the drug-rich areas (DRA) were 3-6 fold larger than those in the polymer-rich areas (PRA), which indicated no homogeneous molecular dispersion or solid solution of the drug and PLGA polymers (Table 1 and Table 2). . RESULTS CONCLUSIONS The image analysis of CRM maps estimated a drug content of 26.3%-33.3% (w/w), which is consistent with the theoretical drug load in the implant formulations (i.e. 30 w/w%). Phase separation between the drug-rich and polymer-rich areas was visually observed in the maps (Figure 3-4). There were larger drug regions on the outer surface compare to the interior section of the formulation with the high initial burst release (compare Figure 3 with Figure 4). The drug substance found to have a specific peak at Raman shift of 643 cm-1, while PLGA polymers shown an specific peak at 1769 cm-1 (see Figure 1). The drug specific peak at 643 cm-1 was also traceable in the implant formulations and had no interference with the Raman peaks for the PLGA polymers. The extrusion processes affect distribution of the drug in the ocular implants. Process 1 resulted in a higher fraction of the drug on outer surface which presumably caused a high initial burst release. Confocal Raman spectroscopy proved to be useful in characterizing phase distribution of the drug and PLGA polymers within the ocular implant. Further studies are needed to understand how the process affects drug distribution within the matrix. REFERENCE: Thermo-Scientific user Guide and Manual for Dispersive Raman Spectroscopy.