Mapping in vivo microclimate pH distribution in exenatide-encapsulated PLGA microspheres

Area of Science:

• Biomaterials Science
• Drug Delivery Systems
• Pharmacokinetics

Background:

• The microclimate pH (μpH) within poly(lactic-co-glycolic acid) (PLGA) microspheres is often detrimental to encapsulated pH-labile drugs in vitro.
• The in vivo relevance of these in vitro μpH findings remains largely unaddressed.

Purpose of the Study:

• To quantitatively map the in vivo μpH distribution kinetics within degrading PLGA microspheres.
• To compare in vivo μpH with established in vitro conditions.
• To correlate μpH with the stability of encapsulated pH-labile drugs.

Main Methods:

• Utilized a cage implant system and confocal laser scanning microscopy to map in vivo μpH in rats.
• Administered PLGA microspheres (with and without exenatide) subcutaneously for up to 6 weeks.
• Compared in vivo μpH with two distinct in vitro conditions (low and high microsphere concentrations).
• Assessed exenatide stability using mass spectrometry.

Main Results:

• In vivo μpH kinetics closely resembled in vitro conditions with low microsphere concentrations (nylon bags).
• In vivo μpH significantly differed from high microsphere concentration in vitro conditions.
• Exenatide degradation showed a trend paralleling the observed μpH changes, primarily via pH-dependent acylation.
• Improved external pH stability in release media may influence in vitro μpH outcomes.

Conclusions:

• The study provides the first quantitative mapping of in vivo μpH kinetics in PLGA microspheres.
• In vitro models using low microsphere concentrations appear more predictive of in vivo μpH than high concentration models.
• The developed methodology can aid in understanding in vivo drug instability and refining predictive in vitro models for PLGA microsphere performance.