TY - JOUR

T1 - An in vitro gel-based system for characterizing and predicting the long-term performance of PLGA in situ forming implants

AU - Li, Zhuoxuan

AU - Mu, Huiling

AU - Weng Larsen, Susan

AU - Jensen, Henrik

AU - Østergaard, Jesper

N1 - Publisher Copyright: © 2021 The Authors

PY - 2021

Y1 - 2021

N2 - In situ forming implants are exposed to an extracellular matrix resembling a gel rather than aqueous solution upon subcutaneous administration. The aim of study was to develop a gel-based release testing system for characterizing the long-term in vitro behavior of in situ forming implants. The gel-based system consisted of an agarose gel mimicking the subcutaneous injection site and a receiver layer comprising phosphate buffer. Poly(D,L-lactide-co-glycolide) in situ forming implants containing leuprolide acetate as the model peptide and N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO) or triacetin as co-solvent were investigated. The gel-based release testing system discriminated between the formulations. Accelerated release data obtained at elevated temperatures were able to predict real-time release applying the Arrhenius equation. Monitoring of the microenvironmental pH of the implants was performed by UV–Vis imaging in the gel-based system at 50 °C. A pH drop (from pH 7.4 to 6.7 for the NMP and DMSO implants, to pH 5.5 for the triacetin implants) within the first day was observed, followed by an increase to pH ∼7.4. The gel-based system coupled with UV imaging offered opportunity for detailed evaluation and prediction of the in vitro performance of long-acting injectables, facilitating future development of in situ depot forming delivery systems.

AB - In situ forming implants are exposed to an extracellular matrix resembling a gel rather than aqueous solution upon subcutaneous administration. The aim of study was to develop a gel-based release testing system for characterizing the long-term in vitro behavior of in situ forming implants. The gel-based system consisted of an agarose gel mimicking the subcutaneous injection site and a receiver layer comprising phosphate buffer. Poly(D,L-lactide-co-glycolide) in situ forming implants containing leuprolide acetate as the model peptide and N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO) or triacetin as co-solvent were investigated. The gel-based release testing system discriminated between the formulations. Accelerated release data obtained at elevated temperatures were able to predict real-time release applying the Arrhenius equation. Monitoring of the microenvironmental pH of the implants was performed by UV–Vis imaging in the gel-based system at 50 °C. A pH drop (from pH 7.4 to 6.7 for the NMP and DMSO implants, to pH 5.5 for the triacetin implants) within the first day was observed, followed by an increase to pH ∼7.4. The gel-based system coupled with UV imaging offered opportunity for detailed evaluation and prediction of the in vitro performance of long-acting injectables, facilitating future development of in situ depot forming delivery systems.

KW - Accelerated release

KW - In situ forming implants

KW - In vitro release testing model

KW - microenvironmental pH

KW - Solvent induced phase inversion

KW - UV–Vis imaging

U2 - 10.1016/j.ijpharm.2021.121183

DO - 10.1016/j.ijpharm.2021.121183

M3 - Journal article

C2 - 34653562

AN - SCOPUS:85117611761

VL - 609

JO - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

SN - 0378-5173

M1 - 121183

ER -