Intra-articular injection of morphine to the horse: establishment of an in vitro–in vivo relationship.

Abstract

Background: In the area of parenteral depots, a strong need exists for the development of suitable in vitro drug release models that might enable establishment of in vitro–in vivo relations (IVIVRs).

Aim: The objective of this study was to investigate the possibility of establishing an IVIVR between morphine disappearance from the joint cavity and in vitro release data obtained employing the rotating dialysis cell model.

Method: In vitro release experiments were conducted using the rotating dialysis cell model. For establishment of an IVIVR, data from a previous study on pharmacokinetics of intra-articular (IA) morphine in horses with lipopolysaccharide-induced synovitis were used (Lindegaard et al., (2009). Vet Anaesth Analg, 37, 186–195).

Results: A rate constant of morphine disappearance from the donor phase of the in vitro model of 1.8 × 10⁻² min⁻¹ was calculated, independently of the different release media used. The in vivo synovial fluid disappearance rate constants were in the range of 1.0 × 10⁻²–1.7 × 10⁻² min⁻¹. An IVIVR (R² = 0.89) was established between the calculated disappearance data and the joint disappearance data.

Conclusion: The results indicate that the IA fate of morphine administered in the form of a solution can be predicted from the in vitro release data obtained in the rotating dialysis cell model. Thus, this model might be a valuable tool in the establishment of IVIVRs after IA administration of drugs with similar properties.

Keywords::

• Intra-articular administration
• in vitro in vivo relations
• IVIVR
• morphine
• pharmacokinetics