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Evaluation of PLGA microsphere size effect on myotoxicity using the isolated rodent skeletal muscle model
G A Brazeau1, M Sciame, S A al-Suwayeh
1Department of Pharmaceutics, University of Florida, College of Pharmacy, J. Hillis Miller Health Center, Gainesville 32610, USA.
Abstract:
The present work investigated the magnitude of microsphere-induced acute myotoxicity and determined whether this myotoxicity is related to microsphere size and/or reconstitution solvent. Using a high molecular weight poly(dl-lactide-co-glycolide) copolymer, the myotoxicity of two different size microsphere formulations (3.6 microns and 19 microns) in normal saline or distilled water was quantified using a previously validated isolated rat muscle system. Overall, microspheres were found to be relatively nontoxic compared to known myotoxic agents (e.g., phenytoin) and control muscles. The smaller microspheres were found to be significantly more myotoxic than larger microspheres. Furthermore, the myotoxicity was lower in large microspheres reconstituted with normal saline or normal saline with 0.5% (w/v) carboxymethylcellulose (to prevent aggregation) compared to those reconstituted with distilled water. Smaller microspheres were found to be extremely difficult to inject, due to aggregation, which could not be prevented by the addition of carboxymethylcellulose. This study suggests that larger microspheres are less myotoxic than smaller microspheres.
Insights
This study found that larger microspheres are less myotoxic than smaller ones. Microsphere size and reconstitution solvent impact acute myotoxicity in muscle tissue.
Area of Science:
- Biomaterials Science
- Toxicology
- Pharmacology
Background:
- Microspheres are widely used in drug delivery systems.
- Understanding their potential myotoxicity is crucial for safe clinical application.
- Poly(dl-lactide-co-glycolide) (PLGA) microspheres are common, but their biocompatibility requires thorough investigation.
Purpose of the Study:
- To quantify the acute myotoxicity induced by PLGA microspheres.
- To determine the influence of microsphere size on myotoxicity.
- To assess the effect of reconstitution solvent on microsphere myotoxicity.
Main Methods:
- Utilized an isolated rat muscle system to assess myotoxicity.
- Investigated two sizes of PLGA microspheres (3.6 µm and 19 µm).
- Reconstituted microspheres in normal saline, distilled water, or saline with carboxymethylcellulose.
Main Results:
- Microspheres exhibited relatively low myotoxicity compared to controls and known myotoxic agents.
- Smaller microspheres (3.6 µm) demonstrated significantly higher myotoxicity than larger ones (19 µm).
- Larger microspheres showed reduced myotoxicity when reconstituted in normal saline or saline with carboxymethylcellulose compared to distilled water.
Conclusions:
- Microsphere size is a critical factor influencing acute myotoxicity.
- Larger microspheres are associated with lower myotoxicity.
- Reconstitution solvent choice can modulate microsphere myotoxicity, with saline-based solutions being preferable to distilled water.