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

Söderberg, Lars LU ; Dyhre, Henrik LU ; Roth, Bodil LU and Björkman, Sven (2002) In Journal of Pharmacy and Pharmacology 54(6). p.747-755
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... (More)
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 mug 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. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
keywords
Injections, Delayed-Action Preparations, Comparative Study, Bupivacaine: chemistry, Bupivacaine: administration & dosage, Lipids: chemistry, Rats, Nerve Block, Predictive Value of Tests, Male, Sprague-Dawley, Animal, Local: chemistry, Local: administration & dosage, Anesthetics
in
Journal of Pharmacy and Pharmacology
volume
54
issue
6
pages
747 - 755
publisher
Pharmaceutical Press
external identifiers
  • pmid:12078990
  • wos:000176204000002
  • scopus:0035997889
ISSN
0022-3573
language
English
LU publication?
yes
id
66619830-a0fa-4696-a43a-9b5fdbf08e41 (old id 115206)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12078990&dopt=Abstract
date added to LUP
2007-07-30 11:06:13
date last changed
2017-01-01 07:23:36
@article{66619830-a0fa-4696-a43a-9b5fdbf08e41,
  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 mug 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.},
  author       = {Söderberg, Lars and Dyhre, Henrik and Roth, Bodil and Björkman, Sven},
  issn         = {0022-3573},
  keyword      = {Injections,Delayed-Action Preparations,Comparative Study,Bupivacaine: chemistry,Bupivacaine: administration & dosage,Lipids: chemistry,Rats,Nerve Block,Predictive Value of Tests,Male,Sprague-Dawley,Animal,Local: chemistry,Local: administration & dosage,Anesthetics},
  language     = {eng},
  number       = {6},
  pages        = {747--755},
  publisher    = {Pharmaceutical Press},
  series       = {Journal of Pharmacy and Pharmacology},
  title        = {In-vitro release of bupivacaine from injectable lipid formulations investigated by a single drop technique--relation to duration of action in-vivo.},
  volume       = {54},
  year         = {2002},
}