| 1. |
- Dyhre, Henrik, et al.
(författare)
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Local anesthetics in lipid-depot formulations--neurotoxicity in relation to duration of effect in a rat model
- 2006
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Ingår i: Regional anesthesia and pain medicine. - : BMJ. - 1098-7339 .- 1532-8651. ; 31:5, s. 401-408
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: The aim of this study was to investigate the possible local neurotoxicity of a number of lipid-depot formulations of local anesthetics in relation to their duration of action in sciatic-nerve block. METHODS: Formulations that contain 2%, 4%, 8%, 16%, 32%, or 64% of a mixture of bupivacaine and lidocaine base 4:1 in medium-chain triglyceride were prepared and evaluated, together with 0.5%, 1.0%, and 2.0% bupivacaine HCl solutions, bupivacaine 4.2% or 7.0% in medium-chain triglyceride, and 20% lidocaine base in a polar lipid vehicle. The duration of sensory and motor sciatic-nerve block was determined in rats. A week later, the sciatic nerves were dissected and removed for histopathologic examination by light microscopy. RESULTS: The duration of sensory and motor-nerve block was prolonged almost 4 times with the 32% and 13 times with the 64% bupivacaine:lidocaine formulation, in comparison to the 0.5% aqueous solution. The 64% formulation was applied by injection and also placed directly on the nerve with similar results. Slight to moderate signs of neurotoxicity were only found after administration of the 64% formulation. CONCLUSIONS: The findings suggest that depot formulations of local anesthetics with advantageous pharmaceutical and pharmacologic properties can be prepared by use of bupivacaine as the active component and natural lipids as carriers. A favorable balance between effects and toxicity may conceivably be obtained. After supplemental testing in more sensitive models for toxicity, such formulations could be candidates for clinical trials.
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| 2. |
- Dyhre, Henrik
(författare)
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Long acting local anaesthetics - a study in rats
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Local anaesthetics provide excellent pain relief after central and peripheral nerve blocks. However, in many clinical situations there is an insufficient duration of action to allow effective treatment of long-term pain with single injection techniques. This problem became the focus of the present studies. The natives in South America used to chew the leaves from Erythroxylon Coca and were well aware of the numbness in the mouth after chewing it, as well as the centrally stimulating effect. Niemann described the purification process and named it cocaine in 1860. The eye surgeon Koller described in 1884 cocaine as a topical local anaesthetic of the eye. The toxic effects of cocaine were soon identified since they had resulted in many deaths among both patients and addicted persons. Development via modern organic chemistry led to new local anaesthetics. The nerve impulses flow along the nerve by small electrical changes. The two most important ions in this process are sodium (Na+) and potassium (K+). Local anaesthetics inhibit the sodium-influx (by blocking the Na+-channels). In a local anaesthetic solution two forms of the drug are in equilibrium with each other, the ionised (BH+) and the non-ionised (B) form. Both forms are necessary for the action; the base form (B) penetrates the membrane of the nerve axon and the protonated form (BH+) is the active part and blocks the Na+- channels intracellularly. The concentration relationship between these two forms depends on the pKa of the drug and the tissue (and solution) pH. It has been stated that an increase of pH (alkalinization) increases the non-ionised form that gives a higher penetration rate and leads to a prolonged duration of action in a local anaesthetic block. In Paper I, this could not be concluded in the infraorbital nerve block (IONB) in rats after pH modulation by dissolving lidocaine or pethidine in normal saline and varying their pH by adding HCl or NaCO3. However, after dissolving the tested drugs in a buffer (THAM) at physiological pH the duration of nerve block was prolonged. This was presumable due to the inherent low buffer capacity in the original solution. Many local anaesthetics exist as two enantiomers, i.e. as two molecules that are mirror images of each other. According to their geometrical configuration these are named S (sinister) and R (rectus). Another description is how the enantiomer rotates the plane of polarized light; l or (-) as in levo and d or (+) as in dextro. When applied intradermally, the S(-)-enantiomers levobupivacaine and ropivacaine show vasoconstrictive properties over a wide range of concentrations, whereas similar concentrations of the racemate (R,S)- bupivacaine and its R(+)-enantiomer induce vasodilatation. Braun showed already in 1903 that vasoconstrictive properties (for example inclusion of adrenaline) of local anaesthetic solutions enhanced the duration of the nerve block. Still today adrenaline is used for this purpose. In Paper II the hypothesis was that the S(-)-enantiomers could produce long durations of blocks. However, similar duration of blocks were produced by S-enantiomers and the racemate (R,S)-bupivacaine. This could be because of injections into a presumably richly vascularized area where the vasoconstriction cannot affect the local anaesthetics. The two used blocks (IONB and SNB) are more comparable to a peripheral nerve block than what an intradermal weal test is. Inclusion of local anaesthetics into various formulations has been tried in the attempt to prolong the duration of block. In this Thesis two different lipid systems were used with the aim to make a slow-release formulation with prolonged nerve blocking properties without toxic side effects. In Paper III the local anaesthetic lidocaine, at maximum of 20%, was dissolved into a polar lipid system, SPC/GD. In SNB in rats the 20% lidocaine in lipid formulation prolonged the duration of the block three times compared to clinically used 2% lidocaine HCl aqueous solution. The in vitro release of lidocaine from the 200 mg/ml (20%) lidocaine in SPC/GD showed a sustained release. Blood concentrations of lidocaine in arterial blood in rats after SNB with 0.1 ml of 20% lidocaine in lipid formulation or 2% lidocaine HCl aqueous solution were measured. The AUC (area under the curve) of the blood concentrations was 8.8 times higher after the tenfold higher dose but the Cmax did not like AUC increase in proportion to the tenfold difference in dose. Another lipid formulation (non-polar) was used in Papers IV and V, namely MCT (medium-chain triglycerides). MCT are already used in other available medications, i.e. the injectable depot neuroleptic drug flupentixol decanoate (Fluanxol® Depot, Lundbeck). The preparation has been in clinical use for decades. The well-known eutectic mixture of local anaesthetics (EMLA®; developed at AstraZeneca Inc.), which consists of a 1:1 mixture of lidocaine and prilocaine, proved to be freely soluble in MCT at any concentration, Paper IV. The duration of SNB was prolonged three times with 20% and about 180 times with 60% formulation, in comparison to 2% aqueous HCl solution. Formulations 60% and ethanol produced neurotoxic signs as shown by light microscopy. There is a possibility to use the high-concentration formulations as an alternative to ethanol for neurolytic long-term nerve blocks. The mean Cmax values of the local anaesthetics in blood were only about twice as high after 20% formulation in comparison with 2% aqueous HCl solution in spite of the tenfold higher dose. The terminal half-lives and the calculated times for 50% release into the circulation attested to the depot characteristics of this formulation. In the attempt to further prolong nerve block, the long acting bupivacaine was mixed with lidocaine in MCT. The function of lidocaine in the mixture was to increase the solubility of bupivacaine in MCT. Concentrations between 2 and 64% were prepared. The duration of nerve block was prolonged almost four times with the 32% and 13 times with the 64% in comparison to the clinically used 0.5% aqueous bupivacaine HCl solution. Slight to moderate signs of neurotoxicity were seen only after administration of the 64% formulation. The findings in this Thesis suggest that MCT as carrier of local anaesthetics has advantageous pharmaceutical and pharmacological properties. A favourable balance between effects and toxicity may conceivably be obtained. After supplemental testing in more sensitive models for toxicity such formulations could be candidates for clinical trials.
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| 3. |
- Söderberg, Lars, et al.
(författare)
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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.
- 2002
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Ingår i: Journal of Pharmacy and Pharmacology. - 0022-3573. ; 54:6, s. 747-755
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Tidskriftsartikel (refereegranskat)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.
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| 4. |
- Söderberg, Lars, et al.
(författare)
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The "inverted cup" : a novel in vitro release technique for drugs in lipid formulations
- 2006
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Ingår i: Journal of Controlled Release. - : Elsevier BV. - 0168-3659 .- 1873-4995. ; 113:1, s. 80-88
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to develop a membrane-free in vitro release method for drugs in lipid formulations. It was intended to be applicable to as wide a range as possible of preparations, independently of their polarity and viscosity. The principle of the novel technique is to keep the sample suspended in the release medium in an inverted glass cup, allowing a possible phase transition or swelling. Thirteen formulations containing bupivacaine, lidocaine and/or prilocaine in lipid vehicles with different physical properties were prepared and examined. When possible, in vitro release profiles obtained by the new method were compared to profiles obtained by earlier techniques. For three formulations of either bupivacaine or lidocaine in polar lipid formulations, in vitro release profiles were evaluated in relation to in vivo data, from nerve block and pharmacokinetic studies in rats. Preparations that could be investigated both by the "inverted cup" and by the earlier published "single drop" technique generally showed good agreement between the two release profiles. In the case of the polar lipid formulations, arterial blood concentration curves in rats could reasonably be predicted from the in vitro release profiles. In conclusion, the "inverted cup" technique should potentially be applicable to a wide range of lipid formulations of drugs, both for physico-chemical characterisation and for obtaining in vitro - in vivo correlations.
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| 5. |
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