Gilles Dollo

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.

Alkalinization of intra‐cuff lidocaine and use of gel lubrication protect against tracheal tube‐induced emergence phenomena

BACKGROUND We sought to determine the benefits of using alkalinized lidocaine 40 mg to fill the cuff of a tracheal tube (ETT) in combination with water-soluble gel lubrication to prevent post-intubation sore throat. METHODS The work included an in vitro study of the diffusion of alkalinized lidocaine solution through the low-pressure, high-volume cuff of an ETT. We also performed a randomized controlled study (n=20 patients in each group) that included a group who received an alkalinized lidocaine-filled ETT cuff with lubrication of the tube using water-soluble gel (Group G), and two control groups who received an alkalinized lidocaine-filled cuff with ETT lubrication with water (Group W) or an air-filled cuff with ETT lubrication with water (Group C). RESULTS Water-soluble gel lubrication (Group G) produced a lower incidence of sore throat during the 24-h post-extubation period than lubrication with water alone in the cuffs filled with alkalinized lidocaine (Group W), and compared with the air control group. The ability of lidocaine to pass through the cuff of an ETT when water-soluble gel and/or water alone was used as a lubricant was similar, as determined by lidocaine plasma concentrations (C(max) 45 ng x ml(-1)). Cough and restlessness before tracheal extubation were decreased in patients with the alkalinized lidocaine-filled cuffs compared with the air-filled cuffs. After extubation, nausea, vomiting, dysphonia and hoarseness were greater for patients with air-filled cuffs compared with the lidocaine-filled cuffs. No significant difference between the groups was recorded in arterial blood pressure and heart rate. In vitro data suggest that the lower the NaHCO(3) injection volume, the greater the release of lidocaine across a low-pressure, high-volume cuff. CONCLUSIONS These data show benefits of using an alkalinized lidocaine-filled ETT cuff in combination with water-soluble gel lubrication in preventing post-intubation sore throat.

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.

Inclusion complexation of amide-typed local anaesthetics with β-cyclodextrin and its derivatives. I. Physicochemical characterization

Qualitative aspects of the inclusion complexation of two local anaesthetics of the amide-type (LAs), bupivacaine (BVC) and lidocaine (LDC) with three cyclodextrins (CDs), β-cyclodextrin (βCD) and its alkylated derivatives 2-hydroxypropyl-β-cyclodextrin (HPβCD) and heptakis (2,6-di-o-methyl)-β-cyclodextrin (DMβCD), were studied in the solid state by infrared spectroscopy (IR) and differential scanning calorimetry (DSC). The LDC-βCD couple was also investigated in aqueous solution by nuclear magnetic resonance (1H-NMR and 13C-NMR). This first part of a study dealing with improvement in LA administration provided clear indications about LA-CD complexation. Qualitative modifications in a number of peaks or bands obtained from spectral methods as well as thermal analysis signed the inclusion, showing that the freeze-drying method was suitable for obtaining inclusion complexes of LAs with CDs.

Inclusion complexation of amide-typed local anesthetics with β-cyclodextrin and its derivatives. III. Biopharmaceutics of bupivacaine-SBE7-βCD complex following percutaneous sciatic nerve administration in rabbits

Abstract The effect of a new modified β -cyclodextrin derivative, sulfobutylether7- β -cyclodextrin (SBE7- β CD) on the biopharmaceutics of local anesthetic bupivacaine (BVC) was studied in a rabbit sciatic model. Phase-solubility study revealed the formation of a 1:1 complex of the Al type between BVC and SBE7- β CD, with an apparent stability constant of 149±7 M −1 . Then, BVC hydrochloride (BVC-HCl) and BVC complexed with SBE7- β CD (BVC-SBE7- β CD) were administered around the sciatic nerve both as solutions, in a randomized cross-over design in six New Zealand rabbits. The plasma concentrations of BVC, the onset and duration of motor blockade were evaluated. For the dose of BVC injected (5 mg in 2.5 ml), complexation with SBE7- β CD led to a decrease in the maximum plasma concentration ( C max ) of BVC, while the time to reach C max ( T max ) was increased. Complexation also delayed the onset of motor block and did not modify its duration. This decrease in absorption rate of BVC following complex administration was confirmed by Loo-Riegleman absorption analysis. The effect of SBE7- β CD concerned mainly the faster absorption phase, responsible for side effects, but had also an impact on the slower phase, even if not stastistically significant, shown by a flip-flop in the elimination constant. Complexation may be useful to improve the therapeutic index of local anesthetics, allowing greater amounts of drug to be injected in order to prolong nerve blockade.

Biopharmaceutics and metabolism of yohimbine in humans

The biopharmaceutics of yohimbine (YO) and the pharmacokinetics of 10-hydroxy-yohimbine (10-OH-YO) and 11-hydroxy-yohimbine (11-OH-YO) were investigated in healthy subjects following i.v. (5 mg) and oral (8 mg) dosing. One subject was found as a slow hydroxylator of YO. The mean (+/-S.D.) oral absolute bioavailability of YO was 22.3+/-21. 5%. Total plasma clearance (CL) and renal clearance (CL(r)) of YO following i.v. dosing were 0.728+/-0.256 ml/min and 0.001+/-0.002 ml/min, respectively. Based on the steady-state volume of distribution (V(ss)), YO had a relatively low distribution (V(ss) = 32.2+/-12.1 l). The overall renal excretion of YO, 10-OH-YO and 11-OH-YO, expressed as percent of the dose of YO administered, were not different following i.v. and oral dosing, and were around 0.1, 0.2 and 14%, respectively. Following i.v. dosing of YO, the mean apparent terminal half-life of 11-OH-YO (347+/-63 min) was almost four times higher than that of YO (91.0+/-33.6 min) suggesting an elimination rate-limited kinetics for 11-OH-YO.

In vitro and in vivo microdialysis calibration using retrodialysis for the study of the cerebrospinal distribution of bupivacaine

Microdialysis coupled to HPLC was used to study the disposition of local anesthetics in the cerebrospinal fluid (CSF) because of the difficulty in sampling CSF. A retrodialysis method for the microdialysis calibration was investigated in vitro and in vivo. Calibration by retrodialysis was simultaneously validated through the use of the zero net flux method. Two local anesthetics (bupivacaine and ropivacaine), which differ structurally by only one methyl group, were respectively utilized as substance of interest and as internal standard. Different parameters were tested in vitro to compare the relative recovery (RR) of bupivacaine and the relative loss (RL) of ropivacaine. Several flow rates were tried to select an optimal in vivo flow rate (1 microliter/min). the RR and RL values were not influenced by the variation of bupivacaine concentration. A significant variability among different probes within a batch was established (RR ranging from 41.1-65.3%; RL ranging from 30.7-61.0%). The K-factor values, defined as RLropivacaine/RLbupivacaine, were calculated in vitro and in vivo. This ratio decreased in vivo but was constant (K in vitro = 1.06 +/- 0.04, K in vivo = 0.87 +/- 0.03). The extracellular tissue concentration of the compound of interest was again in vitro and no deterioration of probe during the in vivo experiment was found. After administration of bupivacaine in the epidural space of rabbits, plasma and microdialysis CSF samples were simultaneously collected. Plasma and CSF disposition of bupivacaine displayed different kinetics. The maximum CSF concentration of B averaged 394 +/- 170 micrograms ml-1 with a mean Tmax of 3.8 +/- 1.8 min. The maximum CSF concentration of B averaged 0.44 +/- 0.09 micrograms ml-1 with a mean Tmax occurring at 1 min. Microdialysis, combined with accurate calibration, should be a reliable technique to gain further insight in the spinal disposition of local anesthetics.

Controlled Systemic Absorption and Increased Anesthetic Effect of Bupivacaine Following Epidural Administration of Bupivacaine-Hydroxypropyl-β-Cyclodextrin Complex

AbstractPurpose. To investigate the influence of complexation between bupivacaine and hydroxypropyl-β-cyclodextrin (HP-β-CD) on the systemic absorption and on the pharmacodynamic effect of bupivacaine following epidural administration in a rabbit model. Methods. Bupivacaine and bupivacaine-HP-β-CD complex were administered according to a randomized and cross-over design in six rabbits chronically instrumented with an epidural catheter. The plasma concentrations of bupivacaine and the duration and intensity of the motor blockade were evaluated. Results. Complexation with HP-β-CD led to a decrease in the maximum plasma concentration of bupivacaine. Individual absorption kinetics evaluated by Loo-Riegelman absorption analysis indicated that systemic absorption resulted from two parallel first-order processes. Only the faster absorption phase was slowed by complexation with HP-β-CD. The duration of the motor blockade was increased almost twice but the intensity was not modified. Conclusions. Complexation with HP-β-CD could be a promising drug delivery system to improve the therapeutic index of bupivacaine.

Epidural, intrathecal and plasma pharmacokinetic study of epidural ropivacaine in PLGA-microspheres in sheep model.

BACKGROUND Microparticulate local anesthetics-loaded delivery systems are known to provide a controlled release of drug and to reduce systemic toxicity resulting from transient high plasma concentrations. The aim of this study was to evaluate epidural, intrathecal and plasma pharmacokinetics of ropivacaine following epidural administrations of repeated boluses or infusions and to compare them with the epidural administration of polylactide-co-glycolide ropivacaine-loaded microspheres. METHODS In the first step, the epidural and intrathecal pharmacokinetics was evaluated in 3 Lacaunes ewes, receiving epidural continuous infusion of ropivacaine with increasing doses (20, 50 and 100mg/h). Then, six animals received an epidural administration of ropivacaine-loaded microspheres (500 mg), three others received ropivacaine in epidural bolus (30 mg) followed by infusion (2mg/ml during 6h), and the last three animals received three successive epidural boluses of ropivacaine (50mg) at 2h interval. A simultaneous microdialysis technique was used to measure epidural and intrathecal concentrations of ropivacaine. RESULTS After epidural administration of ropivacaine-loaded microspheres, Cmax in plasma was around 100 ng/ml while epidural and intrathecal Cmax of ropivacaine were close to 600 and 150 microg/ml, respectively. The ratios of intrathecal to epidural AUC (AUCit/AUCepi) for bolus administration, bolus+infusion administration, and for microspheres were 13.4+/-2.4; 14.1+/-6.1 and 33.9+/-22.6%, respectively. This suggested that administration of ropivacaine as microspheres increased the transmeningeal passage of ropivacaine in comparison to other administration regimens. CONCLUSIONS Epidural administration of ropivacaine-loaded microspheres led to the sustained levels of ropivacaine in the intrathecal space compared to the boluses of ropivacaine solution. Moreover, epidural administration of microspheres resulted in the highest efficiency in intrathecal uptake of ropivacaine compared to administration in solution.

Alkalinization of Intracuff Lidocaine: Efficacy and Safety

When alkalinized lidocaine instead of air is used to fill the endotracheal tube (ETT) cuff, coughing, and bucking are decreased during extubation when ventilation is controlled with N2O. However, sodium bicarbonate (NaHCO3) used to transform lidocaine hydrochloride (L-HCl) to lidocaine base induces a pH increase that could be irritating for mucosa in the case of cuff rupture. Therefore, we determined, in a randomized controlled study with controlled patient ventilation without N2O, whether the smallest concentrations of NaHCO3 (1.4% versus 8.4%) reduced diffusion (in vitro evaluation) and other secondary clinical benefits. After pH determination of different solutions (2 mL of 2% L-HCl and 2 to 6 mL of 8.4%, or 1.4% NaHCO3), an in vitro lidocaine diffusion through the ETT cuffs was evaluated (2 mL of 2% L-HCl and 3 mL of 8.4% or 1.4% NaHCO3). Then, adult patients scheduled for total thyroidectomy surgery were consecutively enrolled (n = 20 for each group). The ETT cuff was filled with air (group air) or with alkalinized lidocaine (2 mL of 2% L-HCl) using 8.4% (group large dose) or 1.4% (group small dose) of NaHCO3. After tracheal extubation, sore throat was evaluated by visual analog scale as the main end-point of the study. Hoarseness, bucking, dysphonia, dysphagia, cough, restlessness, and postoperative nausea and vomiting were also evaluated. There was a slight tendency toward a slower release when a small concentration of NaHCO3 was used (i.e., 1.4%). Compared with group air, the alkalinized-lidocaine groups had a significant reduction in sore throat during the 24-h postoperative period (P < 0.0001). The difference was not significant between the two alkalinized lidocaine groups. This increase in ETT tolerance was confirmed by the analysis of secondary end-points. No laryngospasm, rupture of ETT cuff, or depression of the swallowing reflex were recorded. A decrease in sore throat during the postoperative period was recorded when the cuff was inflated with a small dose of alkalinized lidocaine (i.e., 40 mg of L-HCl and 1.4% of NaHCO3) rather than with air when ventilation was controlled without N2O.