Effects of Drug Physicochemical Properties on In-Situ Forming Implant Polymer Degradation and Drug Release Kinetics

Jordan B Joiner; Alka Prasher; Isabella C Young; Jessie Kim; Roopali Shrivastava; Panita Maturavongsadit; Soumya Rahima Benhabbour

doi:10.3390/pharmaceutics14061188

Effects of Drug Physicochemical Properties on In-Situ Forming Implant Polymer Degradation and Drug Release Kinetics

Pharmaceutics. 2022 Jun 1;14(6):1188. doi: 10.3390/pharmaceutics14061188.

Authors

Jordan B Joiner¹, Alka Prasher², Isabella C Young¹, Jessie Kim³, Roopali Shrivastava², Panita Maturavongsadit¹, Soumya Rahima Benhabbour^{1

2}

Affiliations

¹ Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, Chapel Hill, NC 27599, USA.
³ Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Abstract

In-situ forming implants (ISFIs) represent a simple, tunable, and biodegradable polymer-based platform for long-acting drug delivery. However, drugs with different physicochemical properties and physical states in the polymer-solvent system exhibit different drug release kinetics. Although a few limited studies have been performed attempting to elucidate these effects, a large, systematic study has not been performed until now. The purpose of this study was to characterize the in vitro drug release of 12 different small molecule drugs with differing logP and pKa values from ISFIs. Drug release was compared with polymer degradation as measured by lactic acid (LA) release and change in poly(DL-lactide-co-glycolide) (PLGA) molecular weight (MW) measured by size exclusion chromatography with multi-angle laser light scattering (SEC-MALS). Drug physical state and morphology were also measured using differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). Together, these results demonstrated that hydrophilic drugs have higher burst release at 24 h (22.8-68.4%) and complete drug release within 60 days, while hydrophobic drugs have lower burst release at 24 h (1.8-18.9%) and can sustain drug release over 60-285 days. Overall, drug logP and drug physical state in the polymer-solvent system are the most important factors when predicting the drug release rate in an ISFI for small-molecule drugs. Hydrophilic drugs exhibit high initial burst and less sustained release due to their miscibility with the aqueous phase, while hydrophobic drugs have lower initial burst and more sustained release due to their affinity for the hydrophobic PLGA. Additionally, while hydrophilic drugs seem to accelerate the degradation of PLGA, hydrophobic drugs on the other hand seem to slow down the PLGA degradation process compared with placebo ISFIs. Furthermore, drugs that were in a crystalline state within the ISFI drugs exhibited more sustained release compared with amorphous drugs.

Keywords: biodegradable implants; controlled drug release; drug delivery; drug physicochemical properties; in-situ; injectable; long-acting; poly(lactic-co-glycolic acid).

Abstract

Grants and funding