Rationalizing the Structural Properties of Bupivacaine Base—A Local Anesthetic—Directly from Powder X-Ray Diffraction Data

Cheung, Eugene; Harris, Kenneth D. M.; Johnston, Roy L.; Kitchin, Simon J.; Hadden, Kelly L.; Zakrzewski, Marek

doi:10.1002/jps.10551

Cited by 13 publications

(4 citation statements)

References 15 publications

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“…In contrast, BUP showed a flat, needle-like morphology with <1 μm dimension ( Figure 1 A ). The morphology and size of the BUP prepared in this study were changed after base precipitation and showed highly anisotropic shapes, which were similar to those observed in a previous study, suggesting success of the alkali precipitation 47 .…”

Section: Resultssupporting

confidence: 87%

Precision-guided long-acting analgesia by hydrogel-immobilized bupivacaine-loaded microsphere

Zhang¹,

Cong²,

Xu³

et al. 2018

Theranostics

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Peripheral nerve blockade (PNB) is a conventional strategy for the management of acute postoperative pain. However, the short duration of the associated analgesia and the potential systemic toxicity due to the low molecular weights of local anesthetics limit their application.Methods: An in situ forming injectable Gel-microsphere (Gel-MS) system consisting of PLGA-PEG-PLGA Gel (Gel) and Gel-immobilized bupivacaine-loaded microsphere (MS/BUP) was prepared for precision-guided long-acting analgesia. A series of in vitro characterizations, such as scanning electron microscopy, rheology analysis, confocal laser scanning microscopy, drug release, and erosion and degradation, were carried out. After that, the in vivo analgesia effect of the Gel-MS system, the immobilization effect of Gel on the MS, and biocompatibility of the system were evaluated using a sciatic nerve block model.Results: The BUP release from the Gel-MS system was regulated by both the inner MS and the outer Gel matrix, demonstrating sustained BUP release in vitro for several days without an initial burst release. More importantly, incorporation of the Gel immobilized the MS and hindered the diffusion of MS from the injection site because of its in situ property, which contributed to a high local drug concentration and prevented systemic side effects. In vivo, a single injection of Gel-MS/BUP allowed rats to maintain sensory and motor blockade significantly longer than treatment with MS/BUP (P < 0.01) or BUP-loaded Gel (Gel-BUP, P < 0.01). Histopathological results demonstrated the excellent biodegradability and biocompatibility of the Gel-MS system without neurotoxicity.Conclusion: This precision-guided long-acting analgesia, which provides an in situ and sustained release of BUP, is a promising strategy for long-acting analgesia, and could represent a potential alternative for clinical pain management.

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Section: Resultssupporting

confidence: 87%

Precision-guided long-acting analgesia by hydrogel-immobilized bupivacaine-loaded microsphere

Zhang¹,

Cong²,

Xu³

et al. 2018

Theranostics

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“…In this report, we utilized the solvent evaporation method to encapsulate BP within PLGA microparticles, as previously reported 13 . To support this approach, BP-HCl was first converted to the base form 12 , 25 , and using PLGA with a molecular weight of 7–17 kDa, microparticles were generated that exhibited a smooth and predominantly spherical morphology, with diameters between approximately 1–20 µm. As shown by the SEM images (Fig.…”

Section: Resultsmentioning

confidence: 99%

A moldable sustained release bupivacaine formulation for tailored treatment of postoperative dental pain

Shepherd

O'Buckley

Harrington

et al. 2018

Sci Rep

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A moldable and biodegradable dental material was designed for customized placement and sustained delivery of bupivacaine (BP) within an extraction cavity. Microparticles comprising poly(lactic-co-glycolic acid) (PLGA) containing BP were generated via solvent-evaporation and combined with absorbable hemostat Gelfoam®. Kinetics of drug release were evaluated by in vitro dialysis assays, showing higher release within the first 24 hours, with subsequent tapering of release kinetics. Formulations of Gelfoam® and BP-PLGA microparticles (GelBP), with three targeted dosing profiles (0.25, 0.5, and 1 mg/kg/day), were evaluated alongside acute subcutaneous BP injections (2 mg/kg) to determine analgesic efficacy in a rat model of tooth extraction pain. Molar extraction resulted in mechanical and thermal cold hyperalgesia in male and female rats. GelBP outperformed acute BP in blocking post-surgical dental pain, with the 0.25 mg/kg GelBP dose preventing hypersensitivity to mechanical (p < 0.01) and thermal cold stimuli (p = 0.05). Molar extraction also resulted in decreased food consumption and weight. Males receiving acute BP and 0.25 mg/kg GelBP maintained normal food consumption (p < 0.002) and weight (p < 0.0001) throughout 7 days. Females, receiving 0.25 mg/kg GelBP maintained weight on days 5–7 (p < 0.04). Customized, sustained release formulation of anesthetic within a tooth extraction cavity holds potential to eliminate post-operative dental pain over several days.

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“…These peaks decreased in intensity when beeswax was incorporated into the NLC systems without (NLC-L and NLC-M) or with BVC S75 (NLC-L-B and NLC-M-B), showing that incorporation of the liquid lipids (LO and MO) or BVC S75 amorphized the structural organization of the solid lipid, as expected of NLC formulations 15 and corroborating the DSC results. Moreover, the diffraction pattern of BVC S75 , with a peak of greater intensity at 10°c orresponding to the racemic mixture, 60 proved the crystallinity of the anesthetic. When bupivacaine was incorporated into the NLC, this peak practically disappears, which is compatible with drug insertion in the lipid matrix.…”

Section: Transmission Electron Microscopy (Tem) Dsc and Xrd Measurementsmentioning

confidence: 89%

Development of S75:R25 bupivacaine‐loaded lipid nanoparticles functionalized with essential oils for treating melanoma

Geronimo

Silva

Moura

et al. 2021

J of Chemical Tech & Biotech

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BACKGROUND: A new role as an antitumoral agent has been proposed for the local anesthetic bupivacaine (BVC), considering its toxic effects on cancer cells. However, such drug repositioning requires an improvement in drug available concentrations and sustained release profiles to surpass BVC short action and narrow therapeutic window. Nanostructured lipid carriers (NLC) may provide bupivacaine with sustained release, and they can be formulated with essential oils, whose intrinsic therapeutic properties may act synergistically with BVC. This study reports the development of two NLC formulations prepared with lavender or melaleuca oils and enantiomeric excess S(−)75:R(+)25 bupivacaine (BVC S75 ). The nanoparticles were characterized by dynamic light scattering, nanotracking analysis, transmission electron microscopy, differential scanning calorimetry and X-ray diffraction, and their stability was followed for 1 year. Encapsulation efficiency and in vitro BVC S75 release profile were also measured. Additionally, the effect on the viability of mice (B16-F10) and human (SK-MEL-25) melanoma cells was determined, as was in vivo anesthesia assessed by the tail flick test in mice. RESULTS:The two formulations optimized by factorial design (NLC-L-B and NLC-M-B) showed robust physical and chemical properties, 1-year stability and sustained release in vitro. Cytotoxicity tests revealed a decrease in IC 50 values, relative to free BVC S75 , of~80% and 62% (NLC-L-B) and 80% and 25% (NLC-M-B) in mice and human melanoma cells, respectively. Encapsulation in both formulations doubled the anesthesia time of BVC S75 .CONCLUSION: Combining the effects of bupivacaine and NLC excipients, the two optimized NLC formulations containing BVC S75 may be interesting nanosystems for the treatment of melanomas after further in vivo tests.

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Rationalizing the Structural Properties of Bupivacaine Base—A Local Anesthetic—Directly from Powder X-Ray Diffraction Data

Cited by 13 publications

References 15 publications

Precision-guided long-acting analgesia by hydrogel-immobilized bupivacaine-loaded microsphere

Precision-guided long-acting analgesia by hydrogel-immobilized bupivacaine-loaded microsphere

A moldable sustained release bupivacaine formulation for tailored treatment of postoperative dental pain

Development of S75:R25 bupivacaine‐loaded lipid nanoparticles functionalized with essential oils for treating melanoma

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