In-vitro release of bupivacaine from injectable lipid formulations investigated by a single drop technique--relation to duration of action in-vivo.
The aim of this study was to develop an in-vitro release method suitable for injectable slow-release lipid formulations of local anaesthetics (or other drugs). We also aimed that the results of the in-vitro measurements should have a clear relationship to duration of action in-vivo. Six formulations of bupivacaine base in medium-chain triglyceride-glyceryl dilaurate mixtures were developed. A new apparatus was constructed for determination of their in-vitro release profiles. A bulbous glass tube was fixed inside a standard glass bottle, which was then filled with release medium. A stirring magnet was enclosed in the perforated polypropylene cylinder holding the glass tube. The stirring created a continuous, rotating downward flow of medium inside the tube, which kept the lipid phase, introduced by means of a syringe, suspended as a single, free drop. Release profiles were obtained by sampling of the release medium for up to 72 h and analysis by gas-liquid chromatography. The duration of action in-vivo of the respective formulations was tested by the hot-plate method in rats. The release profiles of bupivacaine in-vitro were mono-exponential for four formulations and bi-exponential for the other two. There was a positive correlation between the proportion of glyceryl dilaurate in the formulation and the slow half-life of release of bupivacaine. All formulations showed prolonged duration of action in-vivo, median values within the range 4.5-12 h, as compared with a 2-h effect of bupivacaine hydrochloride solution. A comparison of in-vitro release curves and durations of action in-vivo suggested that to maintain nerve blockade in-vivo the formulations must release bupivacaine at a rate of approximately 350 microg h(-1) under the in-vitro conditions. To conclude, we designed and tested a novel apparatus for measuring release of a local anaesthetic (or other drug) from a fluid or semi-solid formulation in-vitro. Release rates obtained in-vitro by means of this technique may be used to guide the development of formulations with suitable durations of action in-vivo. The apparatus is, however, as yet a prototype. Rigorous evaluation of performance should be carried out on devices built to specific standards according to their intended application.
Söderberg
Lars
L
Hospital Pharmacy, Malmö University Hospital, Sweden.
Dyhre
Henrik
H
Roth
Bodil
B
Björkman
Sven
S
D000779:Anesthetics, Local / Q000008:administration & dosage* / Q000737:chemistry*; D000818:Animals; D002045:Bupivacaine / Q000008:administration & dosage* / Q000737:chemistry*; D003692:Delayed-Action Preparations; D007267:Injections; D008055:Lipids / Q000737:chemistry; D008297:Male; D009407:Nerve Block; D011237:Predictive Value of Tests; D051381:Rats; D017207:Rats, Sprague-Dawley
D000779:Anesthetics, Local; D003692:Delayed-Action Preparations; D008055:Lipids; D002045:Bupivacaine