Abstract
Minocycline (MNC) is a tetracycline antibiotic capable of associating with cyclodextrin (CD), and it is a frontline drug for many instances of implant infection. Due to its broad-spectrum activity and long half-life, MNC represents an ideal drug for localized delivery; however, classic polymer formulations, particularly hydrogels, result in biphasic release less suitable for sustained anti-microbial action. A polymer delivery system capable of sustained, steady drug delivery rates poses an attractive target to maximize the antimicrobial activity of MNC. Here, we formed insoluble hydrogels of polymerized CD (pCD) with a range of crosslinking densities, and then assessed loading, release, and antimicrobial activity of MNC. MNC loads between 5–12 wt % and releases from pCD hydrogels for >14 days. pCD loaded with MNC shows extended antimicrobial activity against S. aureus for >40 days and E. coli for >70 days. We evaluated a range of water/ethanol blends to test our hypothesis that solvent polarity will impact drug-CD association as a function of hydrogel swelling and crosslinking. Increased polymer crosslinking and decreased solvent polarity both reduced MNC loading, but solvent polarity showed a dramatic reduction independent of hydrogel swelling. Due to its high solubility and excellent delivery profile, MNC represents a unique drug to probe the structure-function relationship between drug, affinity group, and polymer crosslinking ratio.
Highlights
Minocycline (MNC) is a second generation tetracycline that has longer half-life than first generation combined with better oral availability and fewer resistance concerns [1]
MNC has a broad spectrum of activity, including coverage of common Gram positive bacteria, such as Staphylococcus aureus (S. aureus), and coagulase-negative Staphylococci (CoNS), such as
This work focused on the antimicrobial activity of MNC released from polymerized cyclodextrin (pCD), determining the effect of increasing cross link density upon affinity-based release and the impact of solvent polarity on loading and swelling. pCD swelling in water decreased with increasing crosslink density for pCD-α, -β, and -γ (Figure 1)
Summary
Minocycline (MNC) is a second generation tetracycline that has longer half-life than first generation combined with better oral availability and fewer resistance concerns [1]. MNC has a broad spectrum of activity, including coverage of common Gram positive bacteria, such as Staphylococcus aureus (S. aureus), and coagulase-negative Staphylococci (CoNS), such as. MNC has activity against both community-acquired and nosocomial methicillin-resistant S. aureus (MRSA) [1,2,3]. In addition to its broad-spectrum activity, MNC has several properties that make this drug ideal for localized delivery, including long half-life and time-dependent killing. The ratio of MNC’s area-under-the-curve to minimum inhibitory concentration (AUC/MIC) is the best predictor of antimicrobial activity [1]. A polymer delivery system capable of sustained, steady drug delivery rates poses an attractive target to maximize the antimicrobial activity of MNC
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