In-vitro release of bupivacaine from injectable lipid formulations investigated by a single drop technique — relation to duration of action in-vivo

Abstract

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.

Local Anesthetics in Lipid-Depot Formulations—Neurotoxicity in Relation to Duration of Effect in a Rat Model

“…However, because depot formulations of local anesthetics are mainly designed to produce reversible nerve blocks for postoperative pain, the findings were troubling and raised the question of whether long duration of action with such formulations must be bought at the price of more or less severe neurotoxicity. This question prompted a second study on formulations that mainly contain bupivacaine as the active substance, in concentrations higher than in licensed preparations, as well as a test of the possible neurotoxicity of some earlier reported formu-lations 21,22 with otherwise promising pharmaceutical and pharmacologic characteristics.…”

“…Aqueous solutions of bupivacaine HCl were prepared in 0.5%, 1.0%, and 2.0% concentrations (corresponding to base). Furthermore, four previously described formulations were studied: 4.2% and 7.0% of bupivacaine base in MCT, 22 20% lidocaine base in SPC/GD, and pure SPC/GD vehicle. 21 The MCT formulations were prepared by mixing the components in a glass vial and melting to a homogenous transparent liquid, at a maximum temperature of 90°C.…”

“…21,22,28,29 The animals were briefly anesthetized with halothane, 2% to 3% in oxygen, by facemask. The sciatic nerve on one side was surgically exposed.…”

“…In the absence of nerve block, the rats withdrew the paw within 3 seconds. 21,22,28,29 Consequently, partial block was defined as a withdrawal latency of 4 to 10 seconds. The duration of sensory block is given as the time from injection of the test formulation to the last occurrence of full and partial block, respectively.…”

“…6,7,10,14,16,17,20,[23][24][25][26]31 Other recently presented depot formulations of local anesthetics are based on oily vehicles prepared from natural lipids. 21,22,28,29,33 The possibility that depot formulations of local anesthetics may be neurotoxic has not received adequate attention in the literature. Ample theoretical reason suggests that they might be.…”