Freeze-drying of bupivacaine lipospheres: preparation, characterization, and evaluation of anti-microbial properties.

Abstract

To prepare freeze-dried bupivacaine lipospheres intended for topical application in burn injuries. The aim was improving the storage stability and developing a prolonged release pattern to tackle the adverse reactions resulting from the frequent administration of bupivacaine. The lipospheres were prepared by hot-melt dispersion method employing bupivacaine base at 1.5 and 3%w/w, tristearin 6% w/w as the core while dipalmitoyl phosphatidylcholine (DPPC) and soy phosphatidylcholine (SPC) as the coat at 0.75, 1.5 and 3% w/w. The lotion was then freeze-dried and cryoprotected by sucrose 3% w/w. Evaluation was carried out through loading and release analysis, storage study, particle characterization including morphology, zeta potential and particle size as well as anti-microbial assessment. The highest loading, (87.6 ± 0.1%), was achieved using bupivacaine 3% and SPC 0.75%. After 6 months of storage at 4 ͦC, the loading in the lotion and the freeze-dried samples were 17.4 ± 0.2 and 87.2 ± 0.3%, respectively. In vitro dissolution test demonstrated 94.5% and 95% of bupivacaine release from lotion and freeze-dried samples, after 24h. The respective zeta potential of -1.30 and 26 mV was recorded for lotion and solid-state bupivacaine. Micromeritic evaluation of freeze-dried powder exhibited particle size of 35.23 ± 2.02μm and highly-wrinkled-irregular morphology without detectable needle structures related to drug free crystals. The powder had rapid reconstitution property and antibacterial activity. Freeze- drying holds a promising potential to improve the storage stability of bupivacaine lipospheres with well- preserved release pattern and particle properties for further topical application.