Pascal Le Corre

Spray-dried redispersible oil-in-water emulsion to improve oral bioavailability of poorly soluble drugs.

A physically stabilized dry emulsion dosage form reforming the original emulsion after rehydration was developed by spray-drying a liquid oil-in-water emulsion containing maltodextrin as carrier and sodium caseinate as emulsifying agent. Several oil:water as well as maltodextrin:water ratios were tested, the homogenization and spray-drying processes and the reconstitution properties were investigated and an optimum formulation was selected for poorly soluble drug incorporation, having an identical oil:water and carrier:water ratio of 10% (w/w) and a load of solid material of 20% (w/w). Lipophilic 5-phenyl-1,2-dithiole-3-thione (5-PDTT) was selected as a model drug. 5-PDTT release from the solid state emulsion was studied using an in vitro two-phase stirred model and the relative bioavailability of 5-PDTT in the dry emulsion was obtained in the rabbit after oral administration of the reconstituted emulsion, compared to a 5-PDTT-sulfobutyl ether 7 beta-cyclodextrin complex in solution. Incorporation of 5-PDTT in the oil phase neither affects the surface morphology of the powder nor the reconstitution, the droplet size or the drug releasing properties and, furthermore, allows a 3-fold improvement of 5-PDTT relative bioavailability in rabbit after oral administration. These results indicate that dry emulsions may be considered as relevant dosage forms to improve bioavailability of poorly absorbable lipophilic drugs.

Specific and non-specific phagocytosis of ligand-grafted PLGA microspheres by macrophages.

We evaluated the influence of ligand grafting on the rate and intensity of uptake of poly(d,l-lactide-co-glycolide) microparticles by alveolar macrophages. Microspheres with a mean diameter of 2.5 microm were obtained by spray drying. Three ligands (WGA, an RGD containing peptide and mannose-PEG(3)-NH(2)) and a cationic molecule (PLL) were covalently grafted on the particle surface using the carbodiimide method. Their grafting efficiency was quantified, and WGA grafting was characterized by confocal laser scanning microscopy (CLSM) and by atomic force microscopy (AFM). The uptake by macrophages of surface-modified microspheres was quantified by CLSM. This work showed that the uptake of negatively charged ligand-grafted microspheres (-26 to -51 mV) was increased up to two to four times according to the ligand compared to ungrafted microspheres (-81 mV) and displayed saturation as opposed to the cationic PLL-grafted microspheres. Moreover, a specific receptor-mediated phagocytosis mechanism was suggested based on free ligand, cytochalasin D and +4 degrees C incubation that decreased the microparticle uptake. Furthermore, this work clearly showed that the relative contribution of specific and non-specific processes to the overall uptake varied greatly according to the ligands, and was dependent on the particle-to-cell ratio. In conclusion, this work showed that ligand grafting can enhance the uptake of microparticles, with a variable relative contribution of specific and non-specific uptake mechanism.

Intrathecal bupivacaine in humans: influence of volume and baricity of solutions.

BACKGROUND The effects of volume and baricity of spinal bupivacaine on block onset, height, duration, and hemodynamics were studied. METHODS Ninety patients undergoing endoscopic urologic procedures were randomized to receive 10 mg of intrathecal bupivacaine at L2-L3 level in sitting position. In the operating room, commercial products were diluted as needed with NaCl 0.9% to obtain isobaric solutions (density, 1.005-1.008) or with NaC 10.9% and glucose 30% to obtain hyperbaric solutions (density, 1.031-1.037) of 2, 5, or 10 ml (six groups of 15 patients each). Three minutes after spinal injection the patients were placed in lithotomy position. Sensory blockade was assessed using pinprick and cold sensation tests, and motor blockade was assessed using a four-point scale. RESULTS Onset times to maximal cephalad spread of spinal blockade were similar with isobaric and hyperbaric solutions. A greater maximal cephalad spread of anesthesia was obtained with diluted isobaric bupivacaine but was not associated with more hypotension. Volume had no effect on cephalad extent of anesthesia with hyperbaric bupivacaine. Times for regression of anesthesia to L2 and offset of motor block were longer with isobaric than with hyperbaric solutions of bupivacaine. The intensity of motor blockade was decreased with diluted hyperbaric bupivacaine. No patient reported back pain. CONCLUSION In this study, volume had no significant influence on either cephalad spread or duration of sensory blockade for either isobaric or hyperbaric bupivacaine. Time for offset of anesthesia was shorter with hyperbaric bupivacaine compared with isobaric solutions.

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 microg epinephrine, with the addition of 150 microg 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.

Alkalinization of intracuff lidocaine improves endotracheal tube-induced emergence phenomena.

UNLABELLED We sought to evaluate the effect of filling an endotracheal tube cuff with 40 mg lidocaine alone (Group L) or alkalinized lidocaine (Group LB) in comparison to an Air Control group (Group C) on adverse emergence phenomena in a randomized controlled study (n = 25 in each group). The incidence of sore throat was decreased for Group LB in comparison to Group L during the 24 postextubation hours. The difference between Group L and Group C remained significant in the two postextubation hours only. Plasma lidocaine levels increased when lidocaine was alkalinized (C(max) were 62.5 +/- 34.0 ng/mL and 3.2 +/- 1.0 ng/mL for Groups LB and L, respectively). Cough and restlessness before tracheal extubation were decreased in Group LB compared with Group L and in Group L compared with Group C. Nausea, postoperative vomiting, dysphonia, and hoarseness were increased after extubation in Group C compared with the liquid groups, and a better tolerance was recorded with Group LB compared with Group L. The increase of arterial blood pressure and cardiac frequencies during the extubation period was less in the liquid groups than in the control group and less in Group LB compared with Group L. We concluded that use of intracuff alkalinized lidocaine is an effective adjunct to endotracheal intubation. IMPLICATIONS Use of 40 mg of alkalinized lidocaine, rather than lidocaine or air, to fill the endotracheal tube cuff reduces the incidence of sore throat in the postoperative period. This approach also decreases hemodynamic effects, restlessness, dysphonia, and hoarseness.

Ex vivo and in situ PLGA microspheres uptake by pig ileal Peyer's patch segment.

We investigated the ability of pig ileal Peyers patch segments to transport intestinal poly (D,L-lactide-co-glycolide) microspheres (PLGA MS) from intestinal lumen across the mucosae using in situ and ex vivo segments with confocal laser scanning microscopy (CLSM) and transmission electronic microscopy (TEM). From a global aspect, CLSM suggested that PLGA MS were translocated by M cells labelled with a FITC-conjugated anti-cytokeratin peptide 18, and transported through the follicle-associated epithelium (FAE) in the dome area in both types of experiments. At the ultrastructural level, TEM showed the traffic of PLGA MS throughout M cells, their transport into the basolateral invaginations of the M cells and their subsequent migration into the dome area and the follicular area in contact with macrophages and lymphatic vessels. Although in situ experiments allowed following the migration of PLGA MS until mesenteric lymph nodes, an ex vivo model could be used as a useful tool to study the targeting ability of PLGA MS formulations to the gut-associated lymphoid tissue (GALT).

PLGA microspheres phagocytosis by pig alveolar macrophages: influence of poly(vinyl alcohol) concentration, nature of loaded-protein and copolymer nature.

The study aimed to investigate on a pig alveolar macrophage culture model the influence of: (1) poly(D,L-lactide-co-glycolide) characteristics, (2) the residual poly(vinyl alcohol) (PVA) and (3) the nature of encapsulated proteins, immunoglobulin Y (IgY) or bovine serum albumin, on the microspheres phagocytosis efficiency. The phagocytosis evaluation was performed by flow cytometry and has allowed a screening of microspheres formulations. The hydrophilicity of microspheres resulting from the nature of the polymer and/ or from the residual hydrophilic surface agent (PVA) led to a decrease of phagocytosis intensity. The phagocytosis results of IgY-loaded microspheres strongly suggested that the phagocytosis was increased when the phagocytic cell possessed a receptor for this protein on its surface.

Intrathecal ropivacaine in rabbits: pharmacodynamic and neurotoxicologic study.

Background Ropivacaine is available for spinal or intrathecal use in humans, although data on neurotoxicity after spinal injection are not yet available. The authors experimentally determined the relationship between doses of intrathecal ropivacaine and spinal effects and local neurotoxic effects. Methods Eighty rabbits equipped with an intrathecal lumbar catheter were studied. Sixty were randomly assigned to receive 0.2 ml of intrathecal solutions as a sole injection of: 0.2%, 0.75%, 1.0%, and 2.0% ropivacaine (doses from 0.4–4.0 mg; groups R0.2 to R2.0), 5.0% lidocaine (10 mg; group L), or 0.9% NaCl as control (group C). Twenty other rabbits received either repeated injections of 0.2 ml of 0.2% ropivacaine every 2 days during 2 weeks (total dose of 2.8 mg; group RINT); or a continuous intrathecal infusion of 0.2% ropivacaine at the rate of 1.8 ml/h over 45 min (2.7 mg; group RCONT). Injection rate was 30 s in all groups except Rcont. Time to onset, duration and extent of motor block, and variations of mean arterial blood pressure were recorded in all groups. Somatosensory evoked potentials were also recorded in group RCONT and RINT. Seven days after the last intrathecal injection spinal cord and nerves were sampled for histopathologic study. Results In groups R0.2 and RINT, the lowest dose of ropivacaine induced a clinically visible spinal block in only 50% of rabbits, but SEPs recorded in group RINT were decreased by 70% in the lumbar dermatome. Complete motor block was observed with doses greater than 1.5 mg of ropivacaine (group RCONT and R0.75 to R2.0). Onset time was shorter and duration of block increased as doses of ropivacaine increased. Significant hypotension was observed only with 4.0 mg of ropivacaine (concentration of 2.0%). Complete paralysis and hypotension were observed with 5.0% lidocaine. No neurologic clinical lesion was observed in rabbits receiving saline or ropivacaine within the 7 days after the last intrathecal injection, and histopathologic study revealed no sign of neurotoxicity in these groups. In contrast, intrathecal lidocaine induced clinical and histopathologic changes. Conclusion Ropivacaine induced dose-dependent spinal anesthesia, and did not induce any neurotoxicologic lesion in this experimental animal model.

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.

A dose-response study of epidural liposomal bupivacaine in rabbits.

Liposomes are drug delivery systems used to prolong local effects of bupivacaine. We studied the relationships between motor and hemodynamic changes and epidural doses of plain bupivacaine (P) and liposomal bupivacaine (L) in rabbits equipped with chronical lumbar epidural and femoral arterial catheters. Liposomal (phosphatidylcholine-cholesterol) suspensions contained 20 mg ml-1 of lipid, and different doses of bupivacaine (Lipo 7.5=7.5-; Lipo 3.7=3. 75-; Lipo 2.5=2.5-; Lipo 1.2=1.25-; and Lipo 0.7=0.65-mg of bupivacaine per ml). Forty rabbits were randomly assigned to five groups to receive epidural anesthesia (1 ml) as follows: Groups I to V received 0.65 to 7.5 mg of bupivacaine as P then as L. Release rate of bupivacaine from liposome was significantly slower using Lipo 3.7 than after Lipo 2.5 (Td was 3.9 h and 1.7 h respectively). Increasing the doses of L and P resulted in faster onset time for complete motor blockade and in a prolonged duration of motor effects. Liposomal formulation appears to be a powerful delivery system to prolong the motor effects of bupivacaine since E50 was lower and Emax higher than after the use of plain solution (E50 4.49+/-1.81 mg and Emax 152+/-40 min for P; and E50 2.61+/-0.23 mg and Emax 202+/-9 min for L). Hemodynamic changes were linearly related to doses of bupivacaine injected. The best bupivacaine-to-lipid ratio to prolong motor effects using our model was 3.75 mg and 20.0 mg respectively (Lipo 3.7).