Evaluating the influence of particle morphology and density on the viscosity and injectability of a novel long-acting local anesthetic suspension.

Proper pain management is well understood to be one of the fundamental aspects of a healthy postoperative recovery in conjunction with mobility and nutrition. Approximately, 10% of patients prescribed opioids after surgery continue to use opioids in the long-term and as little as 10 days on opioids can result in addiction. In an effort to provide physicians with an alternative pain management technique, this work evaluates the material properties of a novel local anesthetic delivery system designed for controlled release of bupivacaine for 72 hours. The formulation utilizes solid-lipid microparticles that encapsulate the hydrophobic molecule bupivacaine in its free-base form. The lipid microparticles are suspended in a non-crosslinked hyaluronic acid hydrogel, which acts as the microparticle carrier. Two different particle manufacturing techniques, milling and hot homogenization, were evaluated in this work. The hot homogenized particles had a slower and more controlled release than the milled particles. Rheological techniques revealed that the suspension remains a viscoelastic fluid when loaded with either particle type up to 25% (w/v) particles densities. Furthermore, the shear thinning properties of the suspension media, hyaluronic acid hydrogel, were conserved when bupivacaine-loaded solid-lipid microparticles were loaded up to densities of 25% (w/v) particle loading. The force during injection was measured for suspension formulations with varying hyaluronic acid hydrogel concentrations, particle densities, particle types and particle sizes. The results indicate that the formulation viscosity is highly dependent on particle density, but hyaluronic acid hydrogel is required for lowering injection forces as well as minimizing clogging events.

Evaluation of the Efficacy, Biocompatibility, and Permeation of Bupivacaine-Loaded Poly(epsilon-caprolactone) Nano-Capsules as an Anesthetic.

In this study bupivacaine (BVC) was encapsulated in Nano-capsules of poly-ε-caprolactone (PCL) and its cytotoxicity in HaCaT (MTT) cells, its permeability in the oesophageal epithelium of pigs, as well as its anesthetic effect in the incision model of rat's hind paw (electronic von Frey anesthesiometer) were evaluated. BVC and epinephrine-associated bupivacaine (BVC-Epi) have been compared to BVC-Nano and it was demonstrated that BVC-Nano had high physicochemical properties and remained stable for 120 days; also, encapsulation of bupivacaine did not affect its toxicity to HaCaT cells, but epinephrine reduced its toxicity. Although both methods of combination with epinephrine and encapsulation in nanocapsules resulted in an extended time of anesthesia, the efficacy of epinephrine was more favorable. The permeation evaluation indicated that encapsulation increased both the permeability coefficient and the steady-state flux of bupivacaine across the esophageal epithelium. BVC permeation was enhanced by encapsulation into Nano-capsules, as a new novel therapeutic strategy, facilitating future research as a topical anesthetic.

Determination of bupivacaine tissue concentration in human biopsy samples using high-performance liquid chromatography with mass spectrometry.

In the present study, we developed a simple and rapid analytical method for the quantification of bupivacaine hydrochloride in human biopsy samples of adipose, muscle, neural, connective and cartilage tissue using liquid chromatography-mass spectrometry. Anesthetics were extracted from the tissue samples using 0.1% formic acid in acetonitrile for protein denaturation and hexane for removal of lipophilic impurities. Analytes were separated adequately on Phenomenex Luna Omega polar C18 column using a gradient mobile phase 0.1% formic acid in water and 0.1% formic acid in acetonitrile. The lower limits of quantification were ≤ 97 ng g-1 tissue for all studied tissues. Intra-day recoveries were between 48.2% and 82.1% with relative standard deviations (RSDs) between 1.47% and 14.28%, whereas inter-day recoveries were between 52.2% and 77.6% with RSDs between 2.98% and 14.79%. The calibration curve showed a linear fit with R2 higher than 0.99 in the concentration range from 0.16 to 100 µg g-1 . Lidocaine hydrochloride was tested as internal standard because its recoveries and matrix effects were comparable to bupivacaine hydrochloride. Post-analytical corrections of measured bupivacaine tissue concentrations can accordingly be made based on recovery of lidocaine as internal standard, with recoveries between 51.2% and 86.9% and RSDs between 1.99% and 16.88%. The developed method could be used to study time-dependent spread of bupivacaine locally or to more distant locations across tissue barriers.

Enhancement of the Mechanical and Drug-Releasing Properties of Poloxamer 407 Hydrogels with Casein.

PURPOSE: Topical therapy of local disease (e.g. skin) is advantageous over oral therapy since there is less systemic drug distribution (so fewer side-effects), no first-pass effect, etc. However, patient compliance with topical therapy can be poor as it may require many applications a day and can last months. Here we propose a topical controlled release formulation with thermoresponsive gelation at body temperature and improved adhesiveness, making it easier to remain in contact with the body. METHODS: The formulation contains two excipients, poloxamer 407 (P407) and casein. Casein can modify the properties of the hydrogel through molecular entanglement. In addition, tissue reaction and drug release profile were evaluated. RESULTS: Changes in casein concentration affected adhesive strength, viscosity, mechanical properties and drug release, presumably by hydrophobic interactions between casein and P407. Two different concentrations of P407 were tested with two different concentrations of casein. Formulations containing 5% and 10% casein released 80% of model drug in 48 h, while formulations without casein released the same fraction in around 24 h hours. Formulations with 10% casein had almost twice the adhesive strength of those without casein. CONCLUSIONS: Addition of casein modified the mechanical properties and drug release rate of the hydrogel. There was no inflammation or injury after brief exposure in vivo.

A prospective randomized trial comparing liposomal bupivacaine vs standard bupivacaine wound infiltration in open gynecologic surgery on an enhanced recovery pathway.

BACKGROUND: Value in healthcare is reflected by patient-centered outcomes of care per health dollar expended. Although liposomal bupivacaine is more expensive, it has been shown to provide prolonged analgesia (up to 72 hours). OBJECTIVE: This study aimed to evaluate whether the addition of liposomal bupivacaine to standard bupivacaine could decrease opioid intake and improve pain control after laparotomy for gynecologic surgery compared with standard bupivacaine alone in an enhanced recovery after surgery pathway. STUDY DESIGN: A prospective randomized controlled single-blinded trial of wound infiltration with liposomal bupivacaine plus 0.25% bupivacaine (study arm) vs 0.25% bupivacaine (control arm) was performed at a National Cancer Institute-designated tertiary referral cancer center. Participants were patients aged ≥18 years undergoing exploratory laparotomy for a gynecologic indication. All patients were treated on an enhanced recovery pathway including local wound infiltration before closure. In this study, 266 mg of liposomal bupivacaine (free base; equal to 300 mg bupivacaine HCL)+150 mg of bupivacaine mixed in the same syringe was used in the study arm, and 150 mg of bupivacaine was used in the control arm. The primary outcome was the proportion of patients who were opioid-free within 48 hours after surgery. Secondary outcomes included number of opioid-free days from postoperative day 0 to postoperative day 3, days to first opioid administration, morphine equivalent daily dose, and patient-reported outcomes collected with the MD Anderson Symptom Inventory. The MD Anderson Symptom Inventory was administered as a preoperative baseline, daily while hospitalized, and at least weekly for 8 weeks after discharge. All outcomes were prespecified before data collection. RESULTS: In this study, 102 patients were evaluated. Among them, 16.7% of patients in the study arm received no opioids up to 48 hours compared with 14.8% in the control arm (P=.99). There were no significant differences in the amount of intraoperative opioids administered or days to first opioid use. There was no significant difference between the 2 arms in median cumulative morphine equivalent daily dose (21.3 [study arm] vs 33.8 [control arm]; P=.36) or between the groups in morphine equivalent daily dose per individual day. There were no significant differences in patient-reported pain or interference with walking between the 2 arms or other patient-reported outcomes. CONCLUSION: Within an enhanced recovery after surgery pathway, adding liposomal bupivacaine to 0.25% bupivacaine wound infiltration did not decrease the proportion of patients who were opioid-free within 48 hours after surgery, did not decrease opioid intake, or did not improve patient's self-reported pain and functional recovery compared with standard bupivacaine.

Efficacy of liposomal bupivacaine vs. traditional anaesthetic infiltration for pain management in total hip arthroplasty: a systematic review and meta-analysis.

In this review, we assess the effectiveness of liposomal bupivacaine against the traditional bupivacaine infiltration in the postoperative management of total hip arthroplasty (THA). Various databases including PubMed Central, Medline, Scopus, Embase, Google Scholar, Cochrane library and ScienceDirect (inception date till August 2020) were searched. The quality of published trials was assessed using Cochrane risk of bias tool, and a random-effects model was used for meta-analysis. We report pooled Risk ratios (RR) or pooled Standardized Mean difference (SMD) with 95% confidence intervals (CIs). We analyzed a total of 13 studies with 62,582 participants. The majority of the studies were retrospective with lower bias risks. Liposomal bupivacaine was significantly associated with the reduction in opioid requirement at 48 hours (SMD = -0.25; 95% CI: -0.40 to -0.09; p=0.002) and length of hospital stay (SMD = -0.25; 95% CI: -0.43 to -0.07, p=0.006) following THA compared with the control group. However, there was no statistically significant difference between the effect of liposomal bupivacaine and other agents for pain score (24 and 48 hours), opioid requirement at 24 hours and incidence of nausea. Liposomal bupivacaine has selective benefits in terms of opioid consumption and length of hospital stay against the traditional bupivacaine among the patients undergoing THA.

Studying the effect of vasopressors on therapeutic drug monitoring of two local anesthetics using hybrid micelle liquid chromatography as an analysis tool.

A hybrid micelle based mobile phase was used to develop and validate a liquid chromatographic method for the separation and quantification of two local anesthetics namely; lidocaine hydrochloride (LID), and bupivacaine hydrochloride (BPV) in presence of the frequently co administered vasopressors phenyl ephrine (PHR) and ephedrine (EPH). Optimization of chromatographic separation conditions was performed applying experimental one factor at a time tool, and design of experiment, where the retention behavior of all analytes using both optimization protocols was in accordance. Chromatographic separation was carried on a C8 column operating at 40 °C at a flow rate of 1.5 mL/min. using a mobile phase consisting of 0.18 M sodium dodecyl sulphate, 10% acetonitrile, containing 0.3% triethyl amine and adjusted to pH 7 using 2 M ortho phosphoric acid, adopting UV detection at 230 nm. The proposed method was fully validated and applied to both in vitro and in vivo analysis of rat blood samples. The pharmacokinetics of both LID and BPV was followed when they were solitary injected or when co administered with either PHR or EPH. Moreover, the in vitro spiked experiment was also subjected to documented bio-analytical validation procedures.

Entrapping bupivacaine-loaded emulsions in a crosslinked-hydrogel increases anesthetic effect and duration in a rat sciatic nerve block model.

The purpose of this research was to evaluate a novel long-acting bupivacaine delivery system for control of postoperative pain. Bupivacaine-loaded lipid emulsion (BLE) droplets were created by high-speed homogenization. The BLE droplets were then entrapped into a crosslinked-hyaluronic acid hydrogel system to create an injectable composite gel formulation (HA-BLE). Dynamic light scattering, rheological, and drug release techniques were used to characterize the formulations. A rat sciatic nerve block with a thermal nociceptive assay was used to evaluate the anesthetic effect in comparison to controls, bupivacaine HCl and liposomal bupivacaine. The BLE droplets had a zeta potential, droplet size, and polydispersity index of -40.8 ± 0.66 mV, 299 ± 1.77 nm, and 0.409 ± 0.037, respectively. The HA-BLE formulation could be injected through 25 g needles and had an elastic modulus of 372 ± 23.7 Pa. Approximately 80% and 100% of bupivacaine was released from the BLE and HA-BLE formulations by 20 and 68 h, respectively. The HA-BLE formulation had a 5-times greater anesthetic area under the curve and an anesthetic duration that was twice as long as controls. Results indicate that incorporating the BLEs into the hydrogel significantly increased anesthetic effect by protecting the BLE droplets from the in vivo environment.

Integration of Solid-Phase Extraction and Reversed-Phase Chromatography in Single Protein-Coated Columns for Direct Injection of Bupivacaine in Human Serum.

A rapid, reliable and precise integrated solid-phase extraction (SPE) and reversed-phase liquid chromatography method was developed and validated to determine bupivacaine in human serum using single protein-coated analytical columns. The protein-coated columns were packed with four different sorbents: TSK-ODS, LiChrosorb RP-8, LiChrosorb RP-2 and µ-Bondapak CN-bonded silica. The method involved direct injection of serum sample onto the columns for trapping of the analyte, clean-up from weakly retained serum endogenous components, as well as the final separation. The protein-coated columns operated in two different chromatographic modes. Serum proteins were extracted and cleaned up by SPE, whereas the final separation of bupivacaine was based on reversed-phase chromatography. The protein-coated TSK-ODS column resulted in more accurate peak integration and more reproducible results. A linear relationship between the concentrations of drug and peak areas was confirmed in the range of 100-2000 ng/mL. Detection and quantification limits were 24.85 and 85.36 ng/mL, respectively. The average recovery for bupivacaine ranged from 96.48% to 98.81%. The present methodology was successfully applied, with a high degree of confidence, to analyze clinical samples obtained from patient receiving 0.5% bupivacaine therapy.

Injectable in situ forming nanogel: A hybrid Alginate-NLC formulation extends bupivacaine anesthetic effect.

Finding an ideal anesthetic agent for postoperative pain control, with long action and low side effects, is still a challenge. Local anesthetics have potential for such application if their time of action is improved. This work introduces a new hybrid formulation formed by the association of a nanostructured lipid carrier with a biopolymeric system to encapsulate bupivacaine (BVC). The hybrid formulation was physicochemical and structurally characterized by DLS, TEM, DSC, XRD and FTIR-ATR, and it remained stable for 12 months at room temperature. In vivo analgesia and imaging tests showed that the hybrid system was able to modulate the release, and to increase the concentration of BVC at the site of action, by forming a nanogel in situ. Such nanogel improved over 5 times (>24 h) the anesthesia duration, when compared to free BVC at clinical (0.5%) doses. Therefore, this novel in situ-forming nanogel shows great potential to be used in postsurgical pain control, improving the action of BVC, without losing its versatility of (infiltrative) application.

Stability study of hydromorphone and bupivacaine mixture by HPLC-UV.

Objectives: The objective of this study was to evaluate the physical and chemical stability of hydromorphone hydrochloride and bupivacaine hydrochloride in concentrations of 15 mg.ml-1 and 10 mg.mL-1 in 0.9% sodium chloride injection. Test samples of hydromorphone/bupivacaine mixtures were stored at 37°C, body temperature encounterd during continuous intrathecal infusion, for 90 days. The solutions were packaged in 20 ml plastic syringes. Evaluations for physical and chemical stability were performed initially and throughout the storage periods. Physical stability was assessed by visual observation. The chemical stability of the drug was evaluated by means of a stability-indicating high-performance liquid chromatographic (HPLC) analytical technique. In addition, pH and osmolarity were measured electronically. Methods: This study determines the stability and compatibility of hydromorphone (15 mg.ml-1) and bupivacaine (10 mg.ml-1) mixture after 3 months at 37°C using a validated method by HPLC-UV. A simple, precise, specific and accurate reversed phase high performance liquid chromatographic (RP-HPLC) method was developed and validated. The different analytical performance parameters such as linearity, accuracy, specificity, precision and sensitivity (limit of detection and limit of quantitation) were determined according to International Conference on Harmonisation ICH Q2 (R1) guidelines. RP-HPLC was conducted on a nucleoshell RP18plus (C18 150×4.6 mm with 2.7 µm particle size) column. The mobile phase consisted of buffer A (phosphate buffer (0.05M) pH 4.5) and acetonitrile B. The gradient used for the elution is the following one: time (min)/% of B: 0 min/20%; 1.9 min/50%; 2.5 min /40%; 4.5 min/40%; 5.5 min/20%; and 8 min /20%, and the flow rate was maintained at 1.0ml.min-1 and performed at 35°C. The molecules were monitored using Dionex ultimate 3000, equipped with photo diode array detector (λ=210 nm). Linearity was observed in concentration range of 9-21 mg.l-1 for hydromorphone and 6-14 mg.l-1 for bupivacaine. All the system suitability parameters were found within the range. Results: The degradation study shows a photolytic degradation compound for hydromorphone and an oxidative degradation compound found for bupivacaine. The stability study shows no visible haze or particulate formation or gas evolution. pH and osmolarity were stable during the 3 months. Colour changed after 2 months, although this colouring is due to hydromorphone, proportional to hydromorphone concentrations and increases with time but it is a well known modification. The quantitative study by HPLC method revealed no significant change in hydromorphone and bupivacaine concentration. There is less than 5% of variability during the 3-month period. Conclusions: Hydromorphone (15 mg.ml-1) and bupivacaine (10 mg.ml-1) were physically and chemically compatible and analysed with HPLC, which revealed no significant change in hydromorphone and bupivacaine concentration in this simulated compatibility study.

Transcutaneous anaesthetic nano-enabled hydrogels for eyelid surgery.

Local anaesthetics are administered as a diffuse superficial slow injection in blepharoplasty. Current transcutaneous local anaesthetic formulations are not licensed for use on the face due to safety concerns. Here we report for the first time the permeation of local anaesthetics (lidocaine, bupivacaine loaded SNEDDS and their hydrogels) across human eyelid and mouse skin as a novel and ocular safe formulation for eyelid surgery. SNEDDS were loaded with high levels of anaesthetics and incorporated within carbomer hydrogels to yield nano-enabled gels. Lidocaine hydrogels have a significantly reduced lag time compared to EMLA, while they enhance lidocaine flux across human eyelid skin by 5.2 fold. Ex vivo tape stripping experiments indicated localisation of anaesthetics within the stratum corneum and dermis. Initial histopathological studies have shown no apparent signs of skin irritation. These results highlight the potential clinical capability of nano-enabled anaesthetic hydrogels as a non-invasive anaesthetic procedure for eyelid surgery.

Liposomal bupivacaine and novel local anesthetic formulations.

Novel preparations allowing for the extended duration of action of local anesthetics have many clinically relevant benefits. With regard to this, the development of liposomal bupivacaine has the potential to significantly impact patient care by improving perioperative pain control. The unique liposomal bilayer that encapsulates bupivacaine allows for a sustained release of local anesthetic for up to 72 h after a single use and can significantly decrease postoperative opioid consumption. SABER-bupivacaine is another depot formulation that helps in sustained release of bupivacaine from an encapsulated bupivacaine in a biodegradable sucrose acetate isobutyrate biolayer. HTX-011 is an investigational extended-release local anesthetic formulation currently undergoing Phase 3 clinical trials. HTX-011 is composed of a bioerodible polymer with bupivacaine and low-dose meloxicam in which the polymer undergoes hydrolysis and allows for sustained release of bupivacaine and meloxicam for 3 days. The present investigation reviews pharmacologic considerations related to the formulation of liposomal bupivacaine, current FDA-approved indications for its use, and future extended-release local anesthetic formulations currently under investigation.

Citrem-phosphatidylcholine nano-self-assemblies: solubilization of bupivacaine and its role in triggering a colloidal transition from vesicles to cubosomes and hexosomes.

Improvement of pain management strategies after arthroscopic surgery by multimodal analgesia may include the use of long-acting amide local anesthetics. Among these anesthetics, the low molecular weight local anesthetic agent bupivacaine (BUP) is attractive for use in postoperative pain management. However, it has a relatively short duration of action and imposes a higher risk of systemic toxicity at relatively large bolus doses. Bupivacaine encapsulation in lipid-based delivery systems is an attractive strategy for prolonging its local anaesthetic effect and reducing the associated undesirable systemic side effects. Here, we discuss the potential development of liquid crystalline nanocarriers for delivering BUP by using a binary lipid mixture of citrem and soy phosphatidylcholine (SPC) at different weight ratios. The produced safe-by-design family of citrem/SPC nanoparticles is attractive for use in the development of nanocarriers owing to the previously reported hemocompatibility. BUP encapsulation efficiency (EE), depending on the lipid composition, was in the range of 65-77%. In this study, nanoparticle tracking analysis (NTA) and synchrotron small-angle X-ray scattering (SAXS) were employed to gain insight into the effect of BUP solubilization and lipid composition on the size and structural characteristics of the produced citrem/SPC nanodispersions. BUP loading led to a slight change in the mean sizes (diameters) and size distributions of citrem/SPC nanoparticles. However, we found that BUP accommodation into the self-assembled interiors of nanoparticles, triggers significant structural alterations in BUP concentration- and lipid composition-dependent manners, which involve vesicle-cubosome and vesicle-hexosome transitions. The structural tunability of citrem/SPC nanoparticles and the implications for potential applications in intra-articular BUP delivery are discussed.

Delivery of bupivacaine from UHMWPE and its implications for managing pain after joint arthroplasty.

Total joint replacement is a widely used and successful surgical approach. Approximately 7 million US adults are currently living with a hip or knee replacement. However, the surgical procedures for total joint replacement are associated with significant postoperative pain, and current strategies do not adequately address this pain, which leads to patient dissatisfaction, reduced mobility, and increased risk of opioid addiction. We hypothesized that the ultra-high-molecular-weight polyethylene (UHMWPE) bearing surfaces used in total joint prosthetics could provide sustained release of the local anesthetic bupivacaine to provide relief from joint pain for an extended period of time after surgery. In this paper, we describe the production of bupivacaine-loaded UHMWPE (BPE) and measure the in vitro bupivacaine release kinetics of BPE. We found that bupivacaine could be released from BPE at clinically relevant rates for up to several days and that BPE possesses antibacterial effects. Therefore, bupivacaine-loaded UHMWPE is a promising material for joint replacement prostheses, and future studies will evaluate its safety and efficacy in in vivo models. STATEMENT OF SIGNIFICANCE: Total joint replacement is associated with significant pain and risk of infection. In our paper, we introduce bupivacaine-loaded ultra-high-molecular-weight polyethylene (BPE), which releases bupivacaine, a pain-treating drug, at doses comparable to currently used doses. Additionally, BPE inhibits the growth of infection-causing bacteria. Therefore, BPE may be able to reduce both postsurgical pain and risk of infection, potentially treating two of the most prominent complications associated with total joint replacement. To our knowledge, this is the first development of a material that can address both complications, and devices incorporating BPE would represent a significant advancement in joint arthroplasty prosthetics. More generally, the incorporation of therapeutic agents into ultra-high-molecular-weight polyethylene could impact many orthopedic procedures owing to its ubiquity.

Involvement of TREK-1 Channel in Cell Viability of H9c2 Rat Cardiomyoblasts Affected by Bupivacaine and Lipid Emulsion.

Lipid emulsion (LE) therapy has been used to reduce overdose of bupivacaine (BPV)-induced cardiotoxicity. The TWIK-related potassium channel-1 (TREK-1) is inhibited by BPV and activated by polyunsaturated fatty acids, which are the main component in LE. These pharmacological properties inspired us to investigate whether the TREK-1 channel is associated with cell viability of H9c2 cardiomyoblasts affected by BPV and LE. Consistent with previous studies, BPV-induced cell death was reduced by LE treatment. The reduction in the TREK-1 expression level by BPV was alleviated by LE. The BPV cytotoxicity highly decreased in TREK-1 overexpressed cells but was the opposite in TREK-1 knocked-down cells. TREK-1 channel activators and inhibitors increased and decreased cell viability, respectively. BPV-induced depolarization of the plasma and mitochondrial membrane potential and increase in intracellular Ca2+ level were blocked by LE treatment. BPV-induced depolarization of membrane potential was reduced in TREK-1 overexpressed cells, indicating that TREK-1 channels mediate setting the resting membrane potentials as a background K+ channel in H9c2 cells. These results show that TREK-1 activity is involved in the BPV cytotoxicity and the antagonistic effect of LE in H9c2 cells and suggest that TREK-1 could be a target for action of BPV and LE.

Investigation into spinal anesthetic failure with hyperbaric bupivacaine: the role of cold exposure on bupivacaine degradation.

PURPOSE: Hyperbaric bupivacaine (0.75% in dextrose) is used for spinal obstetric anesthesia. Occasional clusters of anesthetic failures occur in this setting, not readily attributable to clinical factors. We hypothesized that cold temperature exposure is related to bupivacaine instability. METHODS: An electronic survey was distributed to Canadian anesthesiologists to determine consistencies in spinal anesthesia practice, and to invite submission of failed bupivacaine samples for analysis. Another survey for hospital pharmacists focused on bupivacaine logistics. Ultraviolet (UV) spectrometry, differential scanning calorimetry, and high performance liquid chromatography were used to evaluate the effect of temperature on bupivacaine chemical stability. Mass spectrometry (MS) was used to observe bupivacaine and dextrose degradation in laboratory samples of hyperbaric 0.75% bupivacaine in dextrose. Hyperbaric bupivacaine that failed to produce adequate anesthesia in labour and delivery patients was subject to tandem MS/MS analysis on commonly observed ions to look for ion patterns consistent with bupivacaine degradation products and to compare with laboratory samples subjected to cold temperatures. RESULTS: Canadian obstetric anesthesiologists report similar practices and use hyperbaric bupivacaine for spinal anesthesia. Pharmacists surveyed indicated facility storage at room temperature but variable temperatures during shipping. No standard procedure for failure reporting was identified. Analysis of bupivacaine showed a slight decrease in bupivacaine concentration or UV spectral changes after incubation at temperatures ≤ 4°C. Mass spectrometric analysis of hyperbaric bupivacaine from failed spinal anesthesia cases showed complex and inconsistent patterns of ion formation, and different from the ion patterns observed for cooled vs uncooled bupivacaine solutions. Temperature-related changes were noted for dextrose in cooled samples in which dextrose-related ions were formed. CONCLUSIONS: Canadian clinical practice and handling of hyperbaric bupivacaine is consistent. Most respondents indicated an interest in a formal reporting and collection process. Cold exposure did not degrade bupivacaine. A complex and possibly inconsistent reaction involving dextrose was identified that requires further analysis of a larger sample size to elucidate the mechanisms.

RéSUMé: OBJECTIF: La bupivacaïne hyperbare (0,75 % dans du dextrose) est utilisée pour l'anesthésie obstétricale rachidienne. Il arrive parfois que plusieurs anesthésies rapprochées soient inefficaces dans cette situation, et ces échecs ne sont pas nécessairement attribuables à des facteurs cliniques. Nous avons émis l'hypothèse qu'une exposition de la bupivacaïne au froid expliquerait son instabilité. MéTHODE: Un sondage électronique a été distribué aux anesthésiologistes canadiens afin de déterminer les similitudes dans la pratique de la rachianesthésie, et nous avons invité les médecins à nous envoyer des échantillons de bupivacaïne à des fins d'analyse lorsque leur anesthésie était inefficace. Un autre sondage, envoyé aux pharmaciens hospitaliers, mettait l'emphase sur la logistique entourant la manutention de la bupivacaïne. Nous avons utilisé une spectrométrie de rayons ultraviolets (UV), une analyse calorimétrique différentielle et une chromatographie liquide à haute performance afin d'évaluer l'effet de la température sur la stabilité chimique de la bupivacaïne. Une spectrométrie de masse (SM) a été utilisée pour observer la dégradation de la bupivacaïne et du dextrose dans des échantillons de laboratoire de bupivacaïne hyperbare 0,75 % dans le dextrose. La bupivacaïne hyperbare qui n'a pas procuré une anesthésie adéquate chez des patientes en travail ou en accouchement a été sujette à une analyse de SM/SM en tandem sur les ions fréquemment observés afin d'identifier des modèles ioniques correspondant aux produits de dégradation de la bupivacaïne et les comparer à des échantillons de laboratoire soumis au froid. RéSULTATS: Les anesthésiologistes obstétricaux canadiens font état de pratiques semblables et utilisent de la bupivacaïne hyperbare pour réaliser une rachianesthésie. Les pharmaciens interrogés ont indiqué que la bupivacaïne était entreposée à température ambiante au sein de leur établissement mais qu'elle était exposée à des températures variables pendant l'expédition. Aucune procédure standardisée n'a été identifiée pour rapporter les échecs d'anesthésie. L'analyse de la bupivacaïne a montré une légère réduction dans la concentration de bupivacaïne ou des changements spectraux UV après une période d'incubation à des températures ≤ 4°C. L'analyse par spectrométrie de masse des échantillons de bupivacaïne hyperbare utilisés lors d'échecs de la rachianesthésie a révélé des types de formation des ions complexes et incohérents, lesquels différaient des modèles des ions observés dans les solutions de bupivacaïne refroidies vs non refroidies. Les changements liés à la température ont été notés sur le dextrose dans les échantillons refroidis dans lesquels des ions liés au dextrose se sont formés. CONCLUSION: La pratique clinique canadienne et la manutention de la bupivacaïne hyperbare est homogène. La plupart des répondants ont indiqué être intéressés par un processus formel d'enregistrement et de récolte des données. L'exposition au froid n'a pas dégradé la bupivacaïne. Une réaction complexe et possiblement inconstante ayant un rapport avec le dextrose a été identifiée; elle requiert des analyses approfondies sur un échantillonnage plus important afin d'en élucider les mécanismes.

Pain control using liposomal bupivacaine versus bupivacaine for robotic assisted thoracic surgery.

Background Despite a trend towards minimally invasive thoracic surgeries over thoracotomies, patients can still experience significant post-operative pain. Literature on the use of liposomal bupivacaine in patients undergoing robotic surgeries is lacking. Objective To compare pain control via intercostal nerve block with liposomal bupivacaine to bupivacaine for patients undergoing robotic assisted thoracic surgery. Setting A 455 bed community hospital. Methods This was a prospective observational study with a historical control group of 96 patients who underwent robotic lung resection. Patients in the control group received bupivacaine, while the intervention group received liposomal bupivacaine. Main outcome measure Average pain scores 24, 48, and 72 h after surgery. Results There were no significant differences in average pain scores between groups. The frequency of ketorolac use on the first post-operative day was lower for those who received liposomal bupivacaine. There were no significant differences in opioid requirements, length of stay, or rate of complications. Conclusions There was no significant difference in post-operative pain control between patients receiving liposomal bupivacaine and bupivacaine for robotic assisted surgery.

Probing the mechanism of bupivacaine drug release from multivesicular liposomes.

The mechanism of drug release from complex dosage forms, such as multivesicular liposomes (MVLs), is complex and oftentimes sensitive to the release environment. This challenges the design and development of an appropriate in vitro release test (IVRT) method. In this study, a commercial bupivacaine MVL product was selected as a model product and an IVRT method was developed using a modified USP 2 apparatus in conjunction with reverse-dialysis membranes. This setup allowed the use of in situ UV-Vis probes to continuously monitor the drug concentration during release. In comparison to the traditional sample-and-separate methods, the new method allowed for better control of the release conditions allowing for study of the drug release mechanism. Bupivacaine (BPV) MVLs exhibited distinct tri-phasic release characteristics comprising of an initial burst release, lag phase and a secondary release. Temperature, pH, agitation speed and release media composition were observed to impact the mechanism and rate of BPV release from MVLs. The size and morphology of the MVLs as well as their inner vesicle compartments were analyzed using cryogenic-scanning electron microscopy (cryo-SEM), confocal laser scanning microscopy and laser diffraction, where the mean diameters of the MVLs and their inner "polyhedral" vesicles were found to be 23.6 ±â€¯11.5 µm and 1.52 ±â€¯0.44 µm, respectively. Cryo-SEM results further showed a decrease in particle size and loss of internal "polyhedral" structure of the MVLs over the duration of release, indicating erosion and rearrangement of the lipid layers. Based on these results a potential MVL drug release mechanism was proposed, which may assist with the future development of more biorelevant IVRT method for similar formulations.