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Pharmacokinetics of DepoFoam gentamicin delivery system and effect on soft tissue infection
L S Grayson1, J F Hansbrough, R L Zapata-Sirvent
1Department of Surgery, University of California, San Diego Medical Center 92103.
Abstract:
Infections of burn and soft tissue wounds are often difficult to treat with systemic antibiotics since drug delivery to the wound may be suboptimal and high doses may result in toxicity. DepoFoam particles, a novel lipid-based drug delivery system, are composed of phospholipid membranes, enclosing multiple aqueous chambers into which pharmacologic agents can be encapsulated for local drug delivery. We encapsulated gentamicin (GENT) in DepoFoam particles with an average yield of 81% +/- 8 SD for 10 preparations. Encapsulated GENT was incubated in human plasma with t1/2 of 21 days, demonstrating stability in vitro. In vivo pharmacokinetics were determined by injecting CF-1 mice subcutaneously (sc) with a single dose of 0.5 mg of free (nonencapsulated drug) or DepoFoam GENT. At intervals postinjection the sc tissue was excised and blood was obtained by inferior cava puncture and both were assayed for GENT levels. At 0.5, 2, 6, and 24 hr following drug administration there was a significant difference between GENT levels in the tissue achieved with the encapsulated drug and free drug with n = 3-4 at each time point for each group (P < 0.01). By 24 hr following administration of free drug there was minimal detectable GENT in the tissues, while therapeutic levels of GENT remained in tissue at 24 hr following DepoFoam GENT injection. Serum GENT peaked at 30 min for both the DepoFoam (5 micrograms/ml) and free drug (10 micrograms/ml) and was undetectable by 2 hr (n = 3 each group).(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
DepoFoam particles effectively deliver gentamicin to soft tissues for extended periods, improving local antibiotic concentrations and potentially reducing toxicity compared to free drug administration.
Area of Science:
- Biomedical Engineering
- Pharmacology
- Drug Delivery Systems
Background:
- Systemic antibiotic delivery for wound infections faces challenges with suboptimal drug concentrations and potential toxicity.
- Novel drug delivery systems are needed to improve local antibiotic efficacy in wound treatment.
Purpose of the Study:
- To evaluate the efficacy of DepoFoam particles for local delivery of gentamicin (GENT) in soft tissues.
- To assess the in vitro stability and in vivo pharmacokinetics of encapsulated gentamicin.
Main Methods:
- Gentamicin was encapsulated in DepoFoam particles, achieving an 81% yield.
- In vitro stability was assessed by incubating encapsulated GENT in human plasma.
- In vivo pharmacokinetics were determined in mice by subcutaneous injection of free or encapsulated GENT, followed by tissue and serum GENT level analysis.
Main Results:
- DepoFoam-encapsulated gentamicin demonstrated stability in human plasma with a half-life of 21 days.
- Subcutaneous administration of DepoFoam GENT resulted in significantly higher local tissue drug levels compared to free GENT at 0.5, 2, 6, and 24 hours post-injection.
- While free GENT was undetectable in tissues by 24 hours, therapeutic levels of DepoFoam GENT persisted.
Conclusions:
- DepoFoam particles provide a viable platform for sustained local delivery of gentamicin.
- This novel drug delivery system shows potential for enhanced treatment of soft tissue infections by maintaining therapeutic drug concentrations at the wound site.