(W1130-11-64) Reverse Engineering of the Sublocade^® Buprenorphine In Situ Forming Implant

Purpose: Sublocade® is a biodegradable, in-situ forming implant designed for the sustained delivery of buprenorphine, a partial mu-opioid receptor agonist, with monthly dosing to treat moderate to severe opioid use disorder (OUD) patients. It is a viscous, semi-solid clear-yellowish liquid consisting of 18% w/w buprenorphine free base (BUP), 32% w/w poly(lactide-co-glycolide) (PLGA) and 50% w/w N-Methyl-2-Pyrrolidone (NMP) based on Atrigel® technology.¹ Buprenorphine is a Schedule III controlled substance, so Sublocade® is a proprietary prescription-based medicine administered by trained medical practitioners. The heterogeneous nature of PLGA and the absence of a standardized in vitro release testing system make the generic product development challenging. In this study, we focus on the comprehensive characterization of Sublocade® in situ forming implant in terms of PLGA’s molecular weight (MW), lactide/glycolide (L/G) ratio, end groups, and blockiness, and understanding the release of buprenorphine over time, which will guide the development of generic products.

Methods: The purification of PLGA from Sublocade® was conducted according to the method described by Garner et al. (2015), with some modification.² We further optimized the purification process to achieve the highest recovery of PLGA polymers by adjusting the solvent dichloromethane (DCM) to non-solvent (Hexane: Ethanol) ratio. The purity of the extracted PLGA in terms of MW was confirmed using Multi-angle Light Scattering Detector (MALS) coupled with Gel Permeation Chromatography (GPC), and the L/G ratio, end groups, and blockiness of purified PLGA were evaluated using Nuclear Magnetic Resonance Spectroscopy (NMR, ¹H, ¹³C, 400 MHz).³ To understand the release of buprenorphine from the in-situ depot, different dissolution setups were employed, including a platform shaker and USP II apparatus. Various methods of depot formation, such as direct injection, paddle over the basket, and a novel adapter with a PVA thin film, were investigated.⁴

Results: The recovery percentage of PLGA purified from Sublocade® using a non-solvent mixture (Hexane: Ethanol, 80/20 v/v) was 92%. The highest recovery was attributed to the solubilizing ability of DCM and its miscibility with the non-solvents used. GPC-MALS analysis demonstrated that the PLGA extracted from Sublocade® had a number-average and weight-average MW of 11.7 kDa and 12.2 kDa, respectively. Quantitative ¹H-NMR analysis revealed an L/G ratio of 52/48 (Fig. 1A). Analysis of the ¹³C-NMR spectrum indicated a blockiness (G-G sequencing) of 2.03 and carboxyl-terminal groups (Fig. 1B, C). Furthermore, our in vitro drug release studies showed that the platform shaker and paddle-over-basket methods were unable to consistently reproduce the shapes of the in-situ forming implant. The hydrodynamics in the platform shaker were insufficient, resulting in only 35% of the BUP being released over three months. However, the release of buprenorphine over three months is 70% which is contributed by reducing Sublocade® weight to one-fourth, and agitation of the dissolution media (Fig. 2A). Additionally, it was observed that during the phase inversion process, NMP diffused out from polymer matrix which in turns crystallizes buprenorphine base due to its very low aqueous solubility. The use of a novel adapter (1.5 ml internal volume, windows on both sides) in the USP II apparatus revealed biphasic release, with 80% of buprenorphine released within 2.5 months (Fig. 2B).

Conclusion: This study reports the reverse engineering of Sublocade® in situ forming implant. Sublocade® was successfully characterized using analytical techniques focusing on identifying PLGA attributes. Our preliminary in vitro release study with a novel adapter present reproducible data and serves as a useful tool to understand the drug release mechanism of in situ forming implants.

References: (1) https://www.sublocaderems.com/#Main/Home. Sublocade product.
(2) Garner, J.; Skidmore, S.; Park, H.; Park, K.; Choi, S.; Wang, Y. A Protocol for Assay of Poly(Lactide-Co-Glycolide) in Clinical Products. Int J Pharm 2015, 495 (1), 87–92.
(3) Sun, J.; Walker, J.; Beck-Broichsitter, M.; Schwendeman, S. P. Characterization of Commercial PLGAs by NMR Spectroscopy. Drug Deliv Transl Res 2022, 12 (3), 720–729.
(4) Suh, M. S.; Kastellorizios, M.; Tipnis, N.; Zou, Y.; Wang, Y.; Choi, S.; Burgess, D. J. Effect of Implant Formation on Drug Release Kinetics of in Situ Forming Implants. Int J Pharm 2021, 592.

Acknowledgements: This work was funded by a U.S. Food and Drug Administration grant (75F40123C00196).


Fig. 1. A) Lactic acid content; B) Blockiness determination; C) End-group analysis with 13 C-NMR of PLGA in Sublocade®.


Fig. 2. In vitro release study with A) USP paddle over basket apparatus; B) USP II with adapter of Sublocade® (mean ± SD, n=3)