Bupivacaine-loaded Microspheres Research Articles

Assessing the Use of 50% Enantiomeric Excess Bupivacaine-Loaded Microspheres after Sciatic Nerve Block in Rats

To achieve better therapeutic benefits of local anesthetics in the control of postoperative pain through controlled-release carrier. The objective of this study was to compare the characteristics of sensory and motor blockade between microspheres without local anesthetic: racemic bupivacaine-loaded microspheres; 50% enantiomeric excess bupivacaine-loaded microspheres; and free 50% enantiomeric excess bupivacaine. Wistar rats were distributed into four groups: A (Microsphere); B (S50-R50 bupivacaine-loaded microsphere); C (50% enantiomeric excess bupivacaine-loaded microsphere); and D (50% enantiomeric excess bupivacaine). Inhalation anesthesia was performed before the sciatic nerve block (2% halothane and 100% O(2)). Sensorial blockade was measured by the time required for each rat to withdraw its paw from a hot plate at 56°C (positive>4 sec). Motor blockade was measured by the time between drug injection until recovery of a motor score of 2 on the established criterion. The sensory response was significantly more frequent in groups B, C, and D than in group A (p<0.001). There were no statistically significant differences in the response to the sensory test in groups B, C, and D (p>0.05). The response to the motor test was also significantly more frequent in groups B, C, and D than in group A (p=0.02). A tendency to greater positivity in the motor test was more frequently found in groups B and D than in group C (p=0.10). Controlled-release of 50% enantiomeric excess bupivacaine-loaded microspheres showed similar results regarding analgesia and less motor blockade when compared to other anesthetic formulations.

Preparação, caracterização e avaliação in vitro de microesferas de bupivacaína em excesso enantiomérico de 50% (S75-R25)

Microspheres can be used as a controlled delivery system to prolong the duration of action of local anesthetics. The objective of this study was the preparation, characterization and analysis of the in vitro release of 50% enantiomeric excess bupivacaine (S75-R25)-loaded microspheres. Microspheres were prepared using the copolymer of polylactide-co-glycolic acid by the spray-dryed method. Characterization of microspheres regarding their size and content were similar to the theoretical values. The in vitro release demonstrated a biphasic pattern. Manufacturing of 50% enantiomeric excess bupivacaine-loaded microspheres by the spray-dryed method with results similar to bupivacaine-loaded microspheres can be done.

Nerve Conduction Blockade in the Sciatic Nerve Prevents but Does Not Reverse the Activation of p38 Mitogen-activated Protein Kinase in Spinal Microglia in the Rat Spared Nerve Injury Model

Current evidence indicates that p38 mitogen-activated protein kinase activation in spinal microglia contributes to the development of neuropathic pain. However, how nerve injury activates p38 in spinal microglia is incompletely unknown. Nerve injury-induced ectopic spontaneous activity is essential for the generation of neuropathic pain. The authors examined whether peripheral neural activity is necessary for p38 activation in spinal microglia. To examine whether spinal microglia activation depends on peripheral activity in the rat spared nerve injury (SNI) model, the authors blocked conduction in the sciatic nerve before or 2 days after SNI. The block was produced by applying bupivacaine-loaded microspheres above the nerve injury site. The p38 activation was examined by p38 phosphorylation using a phosphorylated p38 antibody, and neuropathic pain-related behavior was evaluated before and after intrathecal infusion of a p38 inhibitor. Three days after SNI, there was a marked p38 activation in the medial two thirds of the dorsal horn, where the injured tibial and peroneal nerves terminated and where isolectin B4 staining was lost. Phosphorylated p38 was only colocalized with the microglial surface marker OX-42, indicating a microglial localization of phosphorylated p38 in the SNI model. Bupivacaine microspheres produced persistent block (loss of sensory and motor function) of the sciatic nerve for the whole period of the study (3 days). This blockade prevented but did not reverse p38 activation in spinal microglia. Intrathecal infusion of the p38 inhibitor FR167653 prevented and reversed mechanical allodynia on post-SNI day 3. After nerve injury, activity in the peripheral nerve is required for the induction but not the maintenance of p38 activation in spinal microglia.

Contralateral effect of amitriptyline and bupivacaine for sciatic nerve block in an animal model of inflammation

Using a carrageenan inflammation rat model, we evaluated two experimental approaches to prolong sciatic nerve block on contralateral hyperalgesia. Method. We performed ipsilateral sciatic nerve block on the inflamed hind paw with bupivacaine-loaded microspheres suspended in dexamethasone (bupivacaine 12.5 mg) and with amitriptyline (6.25 and 12.5 mg) as ultralong-acting local anaesthetics. Bupivacaine (1.25 mg) was used as long-acting local anaesthetic and saline was used as a control. The sixth group received amitriptyline 6.25 mg intraperitoneally (n=10 for each group). The duration of ipsilateral nerve block was 2 h for bupivacaine, 7 h for amitriptyline 6.25 mg, 11 h for amitriptyline 12.5 mg and 21 h for bupivacaine-loaded microspheres in suspension with dexamethasone. Whereas contralateral hyperalgesia was not observed during block produced by bupivacaine-loaded microspheres, contralateral hyperalgesia was observed with sciatic nerve block using amitriptyline. Because of the differential effect observed on the contralateral side, the mechanism underlying the prolongation of ipsilateral block with amitriptyline may not result only from a prolonged Na(+) channel blockade but might be explained by a local toxic effect or lack of systemic actions.

Effect of dexamethasone on motor brachial plexus block with bupivacaine and with bupivacaine-loaded microspheres in a sheep model

Effect of dexamethasone on motor brachial plexus block with bupivacaine and with bupivacaine-loaded microspheres in a sheep model

Preparation of bupivacaine-loaded poly(ɛ-caprolactone) microspheres by spray drying: drug release studies and biocompatibility

Poly(ε-caprolactone) microspheres containining bupivacaine were prepared by the spray-drying process. The average size of drug loaded microspheres was less than 3 μm in diameter, and the percentage of entrapment efficiency was 91±3%. In vitro drug release kinetic in phosphate buffer at 37°C showed a hyperbolic profile, with a burst-effect during the first hour. Subcutaneous injection of bupivacaine-loaded microspheres in the back of rats caused an increase in drug concentration in plasma. Maximum bupivacaine concentration in plasma was 237±58 ng/ml at 105 h, and drug was detected in plasma for 16 days. The half-life time of the drug was increased by more than 125 times with regard to that of the drug administered in a solution by intraperitoneal injection. After 30 days of injection, a mass formed by microspheres surrounded by a thin fibrous capsule was observed. Small blood vessels and multinucleate foreign body giant cells with macrophagic function around microspheres were detected. After 60 days of injection a subcutaneous mass was also observed, which was formed of more degraded dispersed microspheres in conjunctive tissue, which had a normal structure. Thus, bupivacaine-loaded poly(ε-caprolactone) microspheres could be considered as a device to be used in the treatment of severe pain that is not responsive to opioids for example in cancer-related syndromes or in intractable herpetic neuralgia.

Preparation of bupivacaine-loaded poly(ε-caprolactone) microspheres by spray drying: drug release studies and biocompatibility

Poly(ε-caprolactone) microspheres containining bupivacaine were prepared by the spray-drying process. The average size of drug loaded microspheres was less than 3 μm in diameter, and the percentage of entrapment efficiency was 91±3%. In vitro drug release kinetic in phosphate buffer at 37°C showed a hyperbolic profile, with a burst-effect during the first hour. Subcutaneous injection of bupivacaine-loaded microspheres in the back of rats caused an increase in drug concentration in plasma. Maximum bupivacaine concentration in plasma was 237±58 ng/ml at 105 h, and drug was detected in plasma for 16 days. The half-life time of the drug was increased by more than 125 times with regard to that of the drug administered in a solution by intraperitoneal injection. After 30 days of injection, a mass formed by microspheres surrounded by a thin fibrous capsule was observed. Small blood vessels and multinucleate foreign body giant cells with macrophagic function around microspheres were detected. After 60 days of injection a subcutaneous mass was also observed, which was formed of more degraded dispersed microspheres in conjunctive tissue, which had a normal structure. Thus, bupivacaine-loaded poly(ε-caprolactone) microspheres could be considered as a device to be used in the treatment of severe pain that is not responsive to opioids for example in cancer-related syndromes or in intractable herpetic neuralgia.

The Effect of Local Anesthetics and Amitriptyline on Peroxidation In Vivo in an Inflammatory Rat Model: Preliminary Reports

We studied the inhibition of peroxidation by local anesthetics in an inflammatory animal model. Inflammatory lipid peroxidation was assessed by the thiobarbituric assay in plasma from rats injected or not injected with carrageenan (Carra) and killed 1, 2, 4, 6, 12, and 24 h thereafter. Thiobarbituric acid reactive substances (TBARS) values in inflammatory animals were maximal 6 h after Carra administration. This result, in accordance with the evolution of paw edema width during time, supports that TBARS reflect the intensity of inflammation. Local anesthetics (bupivacaine, lidocaine, ropivacaine, or bupivacaine-loaded microspheres) or amitriptyline were injected in clinically relevant concentrations as a sciatic nerve block or intraperitoneally in inflamed animals. Ropivacaine did not exhibit any protective effect on Carra-induced lipid peroxidation in rats. With all the other drugs administered as a sciatic nerve block, the maximal TBARS increase was not observed at 6 h. Our conclusion is that bupivacaine (plain or encapsulated), lidocaine, and amitriptyline in clinically relevant concentrations administered via the sciatic nerve showed antioxidant properties toward lipid peroxidation induced by Carra inflammation. Intraperitoneal injection of those drugs gave the same effect as nerve block; this result suggests that their mechanism of action is not strictly limited to the nerve.

Sciatic Nerve Blocks with Amytriptiline, Bupivacaine, and Bupivacaine-Loaded Microspheres

Sciatic Nerve Blocks with Amytriptiline, Bupivacaine, and Bupivacaine-Loaded Microspheres

Spray-dryed bupivacaine-loaded microspheres: in vitro evaluation and biopharmaceutics of bupivacaine following brachial plexus administration in sheep

Microspheres could be used as a drug delivery system to prolong the duration of action of bupivacaine and to reduce its systemic absorption leading to high plasma concentrations related to central nervous and cardiovascular toxicity. Bupivacaine-loaded microspheres were made by spray-drying using polylactide-co-glycolide polymers from different sources and with different bupivacaine–polymer ratio. The characterization of microspheres concerned the shape and size, the bupivacaine drug-content (DC) and the cumulative release profiles. We evaluated in sheep the bupivacaine pharmacokinetics: (i) after short intravenous infusion of 75 mg bupivacaine solution; and (ii) following brachial nerve plexus injections of 75 mg bupivacaine solution alone, with the addition of 75 μg epinephrine, with the addition of 150 μg epinephrine and of bupivacaine (750 mg)-loaded microspheres. Release profiles showed a biphasic pattern whatever the DC. After i.v. infusion the mean clearance value was 1.53±0.53 l/min and the mean elimination half-life was 120.5±73.1 min. Following brachial plexus nerve injection, bupivacaine C max were lower than 100 ng/ml following either solution or microspheres administration. Ninety percent of the 75 mg bupivacaine given as a solution were absorbed in 5.8±1.0 h (bupivacaine alone) compared to 24.6±1.2 h following microsphere administration.

The pharmacokinetics and pharmacodynamics of bupivacaine-loaded microspheres on a brachial plexus block model in sheep.

We evaluated bupivacaine-loaded microspheres (B-Ms) using a brachial plexus block model in sheep. In the first step, pharmacokinetic characterization of 75 mg bupivacaine hydrochloride (B-HCl) (IV infusion and brachial plexus block) was performed (n = 12). In the second step, a brachial plexus block dose response study of B-HCl was performed with 37.5 mg, 75 mg, 150 mg, 300 mg, and 750 mg. As a comparison, evaluations were performed using a 750-mg bupivacaine base (B). In the third step, evaluations of brachial plexus block were performed with B-Ms (750 mg of B as B-Ms) using two formulations, 60/40 and 50/50 (w/w %); drug-free microspheres were also evaluated. Toxicity evaluations were also performed after IV administration of B-HCl (750 mg and 300 mg), B-Ms (750 mg), and drug-free microspheres (30 mL over 1 min). As the B-HCl dose increased, the time of onset of block decreased and the duration of complete motor blockade increased at the expense of an increase in bupivacaine plasma concentrations. The time of maximum concentration appeared to be independent of the B-HCl dose. In brachial plexus block, a 37.5-mg dose of B-HCl did not induce motor blockade whereas a dose of 750 mg of B-HCl was clinically toxic. In the case of IV administration, doses of 300 mg of B-HCl were as toxic as 750 mg of B-HCl. Compared with the 75 mg of B-HCl administration for brachial plexus block, administration of 750 mg of B as B-Ms increased the duration of complete motor blockade without significant difference in maximum concentration. No significant clinical difference between the two formulations of B-Ms was demonstrated. The IV administration of B-Ms was safe. We conclude that the controlled release of bupivacaine from microspheres prolonged the brachial plexus block without obvious toxicity. Administration of 750 mg of bupivacaine as loaded-microspheres resulted in prolongation of brachial plexus block in sheep. The peak plasma concentration was not significantly larger than that obtained with 75 mg of plain bupivacaine. The motor blockade was increased more than six times compared with 75 mg plain bupivacaine.

The Pharmacokinetics and Pharmacodynamics of Bupivacaine-Loaded Microspheres on a Brachial Plexus Block Model in Sheep

The Pharmacokinetics and Pharmacodynamics of Bupivacaine-Loaded Microspheres on a Brachial Plexus Block Model in Sheep

Room A, 10/17/2000 2: 00 PM - 4: 00 PM (PS) Intravenous and Brachial Plexus Administration of Bupivacaine Loaded-Microspheres Lack Systemic Toxicity in Sheep Model

<b>Room A, 10/17/2000 2: 00 PM - 4: 00 PM (PS) Intravenous and Brachial Plexus Administration of Bupivacaine Loaded-Microspheres Lack Systemic Toxicity in Sheep Model</b>

In vitro controlled release of bupivacaine from albumin microspheres and a co-matrix formed by microspheres in a poly(lactide-co-glycolide) film

Albumin microspheres cross-linked with glutaraldehyde and loaded with bupivacaine, a local anaesthetic, were synthesized (138 +/- 59 microm diameter). A matrix formed by bupivacaine-loaded microspheres in a poly(lactide-co-glycolide) film was prepared in order to improve the controlled release of the drug. In vitro release of the drug was determined in phosphate buffer at 37 degrees C in the absence and in the presence of protease type VIII to mimic a biological system. The effect of temperature and protease on bupivacaine as a function of time was examined; both of them cause a degradative effect on the drug. A rapid release (60 +/- 8% of the drug) takes place at 1 h, and maximum release is found at 50 +/- 6 h from microspheres with swelling. In the presence of protease, maximum release of bupivacaine from microspheres is found at 28 +/- 2 h; the microspheres disappear at 8 days. Inclusion of bupivacaine-loaded microspheres in a poly(lactide-co-glycolide) film causes a slower release of the drug, up to 18 days, with swelling. In the presence of protease, the polymer protects bupivacaine-loaded microspheres from degradation, which takes place at 20 days.

Bupivacaine-loaded comatrix formed by albumin microspheres included in a poly(lactide-co-glycolide) film: in vivo biocompatibility and drug release studies.

Bupivacaine-loaded comatrix, formed by bupivacaine-loaded microspheres included in a poly(lactide-co-glycolide) film, was assayed for the controlled release of the drug 'in vivo'. The comatrix, with 66.37 microg of bupivacaine, signifying a dose of 265.5 microg/kg, was subcutaneously implanted in the back of rats. Maximum plasma bupivacaine concentration was 147.6 +/- 5.0 ng/ml 95 h after the device implantation, and the drug was detected in plasma for 17 days. The half-life time of bupivacaine improves by more than 50 times with regard to that of the drug administered in a solution by intraperitoneal injection. After 15 days of implantation the comatrix was included in a thin fibrous capsule and degradation of the microspheres was observed. The histological studies show good biocompatibility of this comatrix. After 50 days the comatrix was degraded and its remains were almost indistinguishable from the surrounding tissue. Small number of microspheres was observed and they were surrounded by conjunctive tissue. Nerve packets and small blood vessels were also observed in the periphery of the implant.

Extradural bupivacaine‐loaded microspheres and spinal cord bloodflow in the chronically instrumented rabbit

The local anaesthetic agent bupivacaine decreases spinal cord blood flow. This study documents the effect of bupivacaine-loaded polylactic acid microspheres, a formulation allowing sustained release, in the awake rabbit. Animals received at random extradural injection (1 ml) of either 5 mg of plain bupivacaine (n = 6) or 5 mg of bupivacaine-loaded microspheres (n = 6). Arterial blood pressure, cardiac output and spinal cord blood flow, using radioactive microspheres, and arterial blood gas tensions were measured before (T0) and 30 (T30) and 120 (T120) min after the extradural injection. Motor blockade was assessed on a four-point scale every 5 min until complete recovery. All rabbits experienced paralysis of hindlimbs. Those receiving bupivacaine recovered completely before T120, and the block duration was 86 +/- 23 min (mean +/- SD), whereas the block duration was 210 +/- 60 min (P < 0.05) in those receiving the microsphere formulation. Left renal blood flow baseline was 470 +/- 179 (mean +/- SD) and right renal blood flow was 464 +/- 177 ml min(-1) 100g(-1) and did not vary significantly throughout the experiment. Lumbar spinal cord blood flow decreased in both groups, at T30 with bupivacaine (-16 +/- 7%) and at T120 with microspheres (-12 +/- 8%). Arterial blood pressure decreased more rapidly with bupivacaine (-20 +/- 14% within 15 min) than with microspheres (-19 +/- 11% within 30 min) and returned to baseline at T120 in both groups. Cardiac output and arterial blood gas tensions did not change significantly. We conclude that polylactic acid microspheres can prolong motor blockade from bupivacaine. Whatever its formulation, and independently of systemic haemodynamic and blood gas variables, bupivacaine leads to a decrease in spinal cord blood flow, which persists for the duration of motor blockade. This suggests that motor block must be avoided in clinical practice when extradural bupivacaine is used for pain relief.

Antinociceptive effect of bupivacaine encapsulated in poly(D,L)-lactide-co-glycolide microspheres in the acute inflammatory pain model of carrageenin-injected rats.

Encapsulating bupivacaine in poly(D,L)-lactide-coglycolide microspheres may prolong analgesia and diminish systemic toxicity. The antinociceptive effect of bupivacaine-loaded microspheres (1, 2.5, and 5 mg) and plain bupivacaine solutions (1, 2.5, and 5 mg) were compared using the vocalization threshold to paw pressure test (VTPP) in rats. Local anesthetic solutions were injected subcutaneously in the plantar hindpaw. First, the biological inactivity of the vehicle and drug-free microspheres (DFM) was evaluated in normal (n = 8) or carrageenin-injected rats (n = 24). Second, onset of antinociception was evaluated in normal rats (n = 16). We then evaluated the duration of antinociception induced by the different local anesthetic solutions in carrageenin-injected rats (n = 56). Neither the vehicle nor the DFM induced any modification of the VTPP. Onset of antinociception was 5 min for all local anesthetic solutions. Duration of antinociception was 60 min with plain bupivacaine (1 mg) and increased to 90, 120, and 180 min, respectively, for the different doses of bupivacaine-loaded microspheres (1, 2.5, and 5 mg). Larger doses of plain bupivacaine (2.5 and 5 mg) induced systemic toxicity. The encapsulation of bupivacaine in microspheres induced a dose-dependent increase in duration of antinociception as compared with plain bupivacaine.

Prolongation of Spinal Anesthesia with Bupivacaine-Loaded (DL-Lactide) Microspheres

ESTEBE, J. -P.; CORRE, P. LE; MALLÉDANT, Y.; CHEVANNE, F.; LEVERGE, R. Author Information

Motor and Blood Pressure Effects of Epidural Sustained-Release Bupivacaine from Polymer Microspheres

The incorporation of local anesthetics into injectable polymer microspheres can be useful in providing prolonged regional effects. This randomized study was designed to compare the effects of bupivacaine and bupivacaine-loaded microspheres on the time course of motor block in rabbits injected epidurally. Bupivacaine-loaded microspheres and drug-free microspheres 1-10 microns in size were devised from poly-d,l-lactic acid by using a solvent evaporation/extraction method. The effects of bupivacaine and of similar amounts of bupivacaine-loaded microspheres were studied in 26 rabbits as follows: 0.9% sodium chloride, followed by drug-free microspheres, then 1.25 mg of bupivacaine and 1.25 mg of bupivacaine-loaded microspheres (Group I; n = 8); 2.5 mg of bupivacaine, then 2.5 mg of bupivacaine-loaded microspheres (Group II; n = 8); and 5 mg of bupivacaine and 5 mg of bupivacaine-loaded microspheres (Group III; n = 10). Motor block was evaluated blindly by observation of walking disturbances, using a scale from 0 (free movements) to 3 (total limb paralysis). A period of 3 days elapsed between each injection. No limitation on movements was observed after 0.9% sodium chloride and drug-free microsphere injection. With 5 mg, both bupivacaine solutions provided complete motor block which was significantly more prolonged (+244% +/- 129%, mean +/- SD) with bupivacaine-loaded microspheres than bupivacaine. With 2.5 and 1.25 mg, block intensity was less marked, and block duration was shorter after administration of bupivacaine-loaded microspheres than after bupivacaine. We concluded that blocks resulting from bupivacaine-loaded microspheres are highly influenced by the amount of drug initially released by the polymer.

Motor and Blood Pressure Effects of Epidural Sustained-Release Bupivacaine from Polymer Microspheres

The incorporation of local anesthetics into injectable polymer microspheres can be useful in providing prolonged regional effects.This randomized study was designed to compare the effects of bupivacaine and bupivacaine-loaded microspheres on the time course of motor block in rabbits injected epidurally. Bupivacaine-loaded microspheres and drug-free microspheres 1-10 micro meter in size were devised from poly-d,l-lactic acid by using a solvent evaporation/extraction method. The effects of bupivacaine and of similar amounts of bupivacaine-loaded microspheres were studied in 26 rabbits as follows: 0.9% sodium chloride, followed by drug-free microspheres, then 1.25 mg of bupivacaine and 1.25 mg of bupivacaine-loaded microspheres (Group I; n = 8); 2.5 mg of bupivacaine, then 2.5 mg of bupivacaine-loaded microspheres (Group II; n = 8); and 5 mg of bupivacaine and 5 mg of bupivacaine-loaded microspheres (Group III; n = 10). Motor block was evaluated blindly by observation of walking disturbances, using a scale from 0 (free movements) to 3 (total limb paralysis). A period of 3 days elapsed between each injection. No limitation on movements was observed after 0.9% sodium chloride and drug-free microsphere injection. With 5 mg, both bupivacaine solutions provided complete motor block which was significantly more prolonged (+244% +/- 129%, mean +/- SD) with bupivacaine-loaded microspheres than bupivacaine. With 2.5 and 1.25 mg, block intensity was less marked, and block duration was shorter after administration of bupivacaine-loaded microspheres than after bupivacaine. We concluded that blocks resulting from bupivacaine-loaded microspheres are highly influenced by the amount of drug initially released by the polymer. (Anesth Analg 1995;81:519-24)