Periodontal therapy using antimicrobials that are topically applied requires slow or controlled release devices. The in vitro antimicrobial activity of biodegradable polymer formulations that contain a new minocycline lipid complex (P-MLC) was evaluated. The new P-MLC formulations that contained 11.5% minocycline were compared with pure minocycline or an existing commercial formulation, which included determination of minimal inhibitory concentration (MIC) values against two oral bacteria and activity on six-species periodontal biofilm. Moreover, the flow of gingival crevicular fluid (GCF) was modeled up to 42 days and the obtained eluates were tested both for MIC values and inhibiting biofilm formation. In general, MICs of the P-MLC formulations were slightly increased as compared with pure minocycline. Biofilm formation was clearly inhibited by all tested formulations containing minocycline with no clear difference between them. In 3.5 day old biofilms, all formulations with 250 µg/mL minocycline decreased bacterial counts by 3 log10 and metabolic activity with no difference to pure antimicrobials. Eluates of experimental formulations showed superiority in antimicrobial activity. Eluates of one experimental formulation (P503-MLC) still inhibited biofilm formation at 28 days, with a reduction by 1.87 log10 colony forming units (CFU) vs. the untreated control. The new experimental formulations can easily be instilled in periodontal pockets and represent alternatives in local antimicrobials, and thus warrant further testing.