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.
Highlights
Buprenorphine is a frequently used analgetic agent in veterinary medicine
The results showed that stirring speed had a major influence on particle size
The same tendency could be seen with the higher molecular weight polymer RG 503 H, where particles produced with a higher stirring speed were only half the size of the particles produced with 600 rpm, namely 14.7 μm compared to 34.5 μm
Summary
Buprenorphine is a frequently used analgetic agent in veterinary medicine. A major drawback, is the short duration of action requiring several daily administrations. The lack of available sustained-release buprenorphine formulations on the European market impede effective pain management and induce considerable stress on animals through the need of recurring injections and repeated animal handling[12]. There is an urgent need to develop a biocompatible sustained-release formulation to prolong analgesic effect in laboratory animals. Both formulations are depot formulations with a duration of action of at least 12–72 h in mice[25,26,27] and 48–72 h in rats[28,29,30] They are legally marketed unapproved animal drugs for minor species. It was the aim of the current study to provide an alternative for the European market These existing products are based on in situ forming implants or liquid suspensions and have certain limitations. The novelty of our approach consists in the use of a lyophilisate with a proposed extended shelf-life, a reduced risk for injection site reactions, a lower dose and a reduced risk for side effects as compared to Animalgesics for Mice®, and a lower viscosity as compared to Buprenorphine SR-Lab® allowing for convenient handling
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