(W0930-08-54) Long Acting In Situ Forming Implants – Hydrogel Phantom Approach and Comparative In Vitro Release Studies

Purpose: In-situ forming implants (ISFIs) offer controlled and extended drug release, minimally invasive administration, and improved patient compliance, utilizing simple manufacturing with biocompatible, biodegradable polymers such as poly (lactic-co-glycolic acid) (PLGA). Drug release from these implants typically exhibits a triphasic pattern: an initial burst during formation, sustained release from the solidified matrix, and accelerated release upon polymer erosion, with kinetics strongly influenced by polymer molecular characteristics. However, current in vitro release testing methods often do not reflect physiologically relevant conditions¹. Purpose of this study to develop a tissue-mimetic phantom that replicates subcutaneous tissue properties including elastic modulus, stiffness, and viscoelasticity using a hydrogel-based phantom (proprietary natural polymer-based hydrogel) featuring solvent resistance, low water solubility, and biomimetic microchannels. Using atazanavir as a model antiretroviral agent, we systematically characterize drug release kinetics and implant microstructure, correlating chemical interaction analysis with physiologically relevant in vitro dissolution models.

Methods: Formulations were prepared by dissolving PURASORB® PDLG 7502 (75/25 DL-lactide/glycolide copolymer) in NMP solvent at ratios equivalent to those in commercial PERSERIS®, followed by solubilization of atazanavir (ATZ). Drug content uniformity and rheological characterization—including amplitude, time, temperature, and frequency sweeps—were performed using an MCR 301 rheometer. In vitro release testing (IVRT) assessed burst and comparative release profiles using the sample-and-separation method, semi-solid adapter with molecular weight cut-off membrane, and a hydrogel-based phantom. Drug was quantified with the sensitive and robust HPLC method. Solid implants were prepared by gel incubation in media and subsequent freeze drying, then analyzed by FT-IR, DSC, and chemical imaging to characterize molecular interactions and drug distribution in the polymer matrix. All experiments were performed in triplicate, and data are reported as mean ± SD.

Results: FT-IR spectra confirmed distinct peaks for PLGA’s ester carbonyl (1750 cm⁻¹) and atazanavir’s N–H (3350 cm⁻¹) functional groups, providing evidence of molecular interactions within the implant matrix². Burst release studies showed initial drug release was less than 0.5% using the semi-solid adapter method and greater than 2% with the sample-and-separation method. In comparative dissolution testing, both the hydrogel-based phantom and semi-solid adapter with a cut-off membrane maintained cumulative release below 2% over 90 hours, while the sample-and-separation method exceeded 15% cumulative release within the same period.

Conclusion: FT-IR data shows a 6–7 cm⁻¹ red-shift of PLGA’s carbonyl (from 1750 → 1743 cm⁻¹) band and a 60% loss of atazanavir’s N–H stretch, confirming strong hydrogen bonding that embeds the drug in the polymer network. Constrained dissolution setups using hydrogel phantom or semi-solid adapter, mimic subcutaneous condition (restricted surface exposure, volume of exposure) unlike sample and separation method reveal this interaction, limiting release to < 2% over 90 h, whereas the sample-and-separation method disrupts the bonds and exceeds 15% release within 48 h (ANOVA, p< 0.001). Together, these findings link the spectroscopically verified drug-polymer complex to the implant’s long-acting, low-burst release.

References: 1. Wang, X., & Burgess, D. J. (2021). Drug release from in situ forming implants and advances in release testing. Advanced Drug Delivery Reviews, 178, 113912.
2. Ogueri, K. S., Ogueri, K. S., Allcock, H. R., & Laurencin, C. T. (2020). A regenerative polymer blend composed of glycylglycine ethyl ester-substituted polyphosphazene and poly (lactic-co-glycolic acid). ACS applied polymer materials, 2(3), 1169-1179.

Figure 1: FT-IR Spectrum of drug, polymer, physical mixture and Implant.

Figure 2: Burst and Comparative release profiles of atazanavir (Represented as Average and SD, n=3)