Design and in vivo evaluation of a microparticulate depot formulation of buprenorphine for veterinary use

Abstract

Buprenorphine is a frequently used analgetic agent in veterinary medicine. A major drawback, however, is the short duration of action requiring several daily administrations. We therefore designed a poly-lactic-co-glycolic acid (PLGA) based microparticulate drug formulation for sustained parenteral drug release. Particles were designed to allow for a fast onset of action and a duration of the analgesic effect of at least two days in laboratory mice. Microparticles were produced using a solvent evaporation technique. Release rate was dependent on polymer type and particle size. Spherical particles used for subsequent animal studies had a mean size of 50 µm and contained 4.5% of buprenorphine. Drug release was characterized by an initial burst release of 30% followed by complete release over seven days. In vivo pharmacokinetic experiments in female C57BL/6 J mice confirmed prolonged exposure in plasma and brain tissue and correlated with the pharmacological effect in the hot plate assay or after minor abdominal surgery. No adverse side effects with respect to food and water intake, body weight, local tolerability, or nesting behavior were observed. Our formulation is an attractive alternative to established immediate release formulations. A use for prolonged pain management in laboratory animals is proposed.

A Buprenorphine depot formulation provides effective sustained post-surgical analgesia for 72h in mouse femoral fracture models

“…Binding concentrations of less than 3 ng/g at 48h injection (BUP-Depot) – which is comparable to levels observed 12h after Temgesic injection – still resulted in high, but not significantly increased withdrawal latencies compared to a single injection with Temgesic or NaCl. Schreiner et al therefore suggests that alleviation of strong pain through the BUP-Depot might require the administration every 24h (Schreiner et al, 2020). However, based on our assessment of the clinical, behavioral, and model-specific parameters, we can postulate that the analgesic properties of the BUP-Depot are sufficient for 72h post-operative analgesia in our specific mouse-osteotomy model of moderate severity.…”

“…We evaluated the analgesic efficacy and possible side-effects of a newly developed sustained-release Buprenorphine (BUP-Depot) in comparison to an already established protocol (Tramadol in the drinking water) after a pre-operative injection of Buprenorphine in two mouse-osteotomy models with different fixation stiffnesses (Schreiner et al, 2020; Schreiner et al, 2021; Jirkof et al, 2019; Rapp et al, 2015). The BUP-Depot delivered reliable pain relief over 72h post-surgical without side effects on fracture healing outcome, comparable to Tramadol applied with the drinking water.…”

“…Studies specified therapeutic effective concentrations of Buprenorphine in plasma at a threshold of around 1 ng/ml or 1 ng/g in mice and rats (Yassen et al, 2005; Yun et al, 2010; Guarnieri et al, 2012). However, Buprenorphine works through the μ-, κ- and δ-opioid receptors in the brain (Villiger and Taylor, 1981; Lutfy and Cowan, 2004) and it can be hypothesized that reliable pain alleviation is more reliant on specific binding concentration values in the brain than specific plasma concentrations (Schreiner et al, 2020). Ohtani et al also demonstrated a correlation between analgesic effects and specific binding concentrations of Buprenorphine in the brain of rats (Ohtani et al, 1995).…”

“…The BUP-Depot was injected once at the end of both interventions. The PLGA based BUP-Depot (RG 502 H-Big) was prepared at the University of Basel, Switzerland, as described previously by Schreiner et al (Schreiner et al, 2020; Schreiner et al, 2021). The BUP-Depot was imported in accordance with national regulations for controlled substances (BtM import authorization No.…”

“…Four different batches of BUP-Depot were used during the study. Each batch was analyzed before shipment with respect to drug content, reconstitution time, and drug release kinetics as described previously (Schreiner et al, 2020; Schreiner et al, 2021). The-BUP-Depot was stored as a lyophilizate in crimped glass vials at 4°C.…”