RESUMEN
RATIONALE: Anesthetics are widely used for optimizing surgical conditions, postoperative pain management, and treating various chronic pain conditions. Tetracaine and decamethonium are representative drugs of local anesthetics and neuromuscular blocking agents, respectively. However, overdose and toxicity of the drugs always lead to serious adverse events. Thus, there is a strong demand for effective antidotes. METHODS: The binding interactions of amide naphthotubes with tetracaine and decamethonium were systematically studied using 1H NMR, ITC, and DFT calculations. The antidotal effects of amide naphthotube to tetracaine toxicity were assessed in vitro and in vivo, and the mechanism of detoxification was explored at a cellular level. Additionally, mouse models were established to evaluate the reversal activities of amide naphthotube on decamethonium-induced mortality and muscle relaxation, and the reversal mechanism was investigated through pharmacokinetic experiments. RESULTS: We have demonstrated that the anti-isomer of amide naphthotube exhibits significant binding affinities towards tetracaine (K a = 1.89×107 M-1) and decamethonium (K a = 1.01×107 M-1) in water. The host displayed good biocompatibility both in vitro and in vivo. The administration of amide naphthotube following tetracaine overdose in mouse models notably increased the overall survival rate, indicating its effective antidotal properties. The host could reverse the tetracaine-induced Na+ channels blockage at the cellular level. Moreover, the injection of amide naphthotube also reversed the mortality and paralysis induced by decamethonium in mouse models following a pharmacokinetic mechanism. CONCLUSION: An emerging artificial receptor, amide naphthotube, has strong binding affinities towards tetracaine and decamethonium. It functions as a supramolecular antidote for tetracaine poisoning and a reversal agent for decamethonium by selectively sequestering these compounds in vivo.
Asunto(s)
Antídotos , Tetracaína , Animales , Tetracaína/farmacología , Tetracaína/química , Ratones , Antídotos/farmacología , Antídotos/química , Amidas/química , Amidas/farmacología , Masculino , Anestésicos Locales/farmacología , Anestésicos Locales/química , Humanos , Bloqueantes Neuromusculares/química , Bloqueantes Neuromusculares/farmacologíaRESUMEN
Local anesthesia is essential in dental practices, particularly for managing pain in tooth socket wounds, yet improving drug delivery systems remains a significant challenge. This study explored the physicochemical characteristics of lidocaine hydrochloride (LH) incorporated into a polyelectrolyte complex and poloxamer thermosensitivity hydrogel, assessing its local anesthetic efficacy in mouse models and its onset and duration of action as topical anesthetics in clinical trials. The thermoresponsive hydrogel exhibited a rapid phase transition within 1-3 minutes and demonstrated pseudo-plastic flow behavior. Its release kinetics followed Korsmeyer-Peppas, with 50% of biodegradation occurring over 48 h. In mouse models, certain thermogels showed superior anesthetic effects, with rapid onset and prolonged action, as evidenced by heat tolerance in tail-flick and hot plate models. In clinical trials, the LH-loaded thermoresponsive hydrogel provided rapid numbness onset, with anesthesia (Ton) beginning at an average of 46.5 ± 22.5 seconds and lasting effectively (Teff) for 202.5 ± 41.0 seconds, ranging from 120 to 240 seconds, indicating sustained release. These results highlight the promising properties of these formulations: rapid onset, prolonged duration, mucoadhesion, biodegradability, and high anesthesia effectiveness. This study demonstrates the potential for advancing local anesthesia across various medical fields, emphasizing the synergy between material science and clinical applications to improve patient care and safety.
Asunto(s)
Anestésicos Locales , Sistemas de Liberación de Medicamentos , Hidrogeles , Lidocaína , Poloxámero , Lidocaína/administración & dosificación , Lidocaína/química , Animales , Hidrogeles/química , Anestésicos Locales/administración & dosificación , Anestésicos Locales/química , Ratones , Poloxámero/química , Sistemas de Liberación de Medicamentos/métodos , Polielectrolitos/química , Masculino , Liberación de Fármacos , Humanos , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinéticaRESUMEN
Regional analgesia based on the local anesthetic ropivacaine plays a crucial role in postoperative pain management and recovery; however, the short duration of analgesia limits its clinical potential. Various drug delivery systems such as microparticles and lipid carriers have been used to prolong the analgesic effect, yet most of them are prone to abrupt release from the site of administration or have poor analgesic effects of less than 48 h, which fail to meet the needs of postoperative analgesia. In this study, a low-molecular-weight gelator sodium deoxycholate-based hydrogel loaded with ropivacaine (DC-ROP gel) was designed for long-acting analgesia. The noncovalent interaction between ropivacaine and sodium deoxycholate helps to improve the stability and sustained release performance of the gel. This internal drug-binding hydrogel also avoids experiencing the burst release effect commonly seen in polymer hydrogels previously reported for the slow release of local anesthetics. DC-ROP gel exhibited the dual advantages of self-healing after compression and long-term controlled release. In mice with inflammatory pain, DC-ROP gel achieved peripheral nerve block for more than 1 week after a single injection. Histological and blood biochemical analyses confirmed that the DC-ROP gel did not produce systemic toxicity, and cytotoxicity experiments demonstrated that the DC-ROP gel resulted in low irritation. These results suggest that DC-ROP gel provides a promising strategy for local anesthetics in long-term postoperative pain management, broadening the potential of bile salt-based low-molecular-weight hydrogels for drug delivery.
Asunto(s)
Anestésicos Locales , Ácido Desoxicólico , Hidrogeles , Ropivacaína , Ropivacaína/química , Ropivacaína/farmacología , Hidrogeles/química , Hidrogeles/farmacología , Animales , Ácido Desoxicólico/química , Ratones , Anestésicos Locales/química , Anestésicos Locales/administración & dosificación , Anestésicos Locales/farmacología , Analgesia/métodos , Masculino , Peso MolecularRESUMEN
Local anesthetics (LA), as part of multimodal analgesia, have garnered significant interest for their role in delaying the initiation of opioid therapy, reducing postoperative opioid usage, and mitigating both hospitalization duration and related expenses. Despite numerous endeavors to extend the duration of local anesthetic effects, achieving truly satisfactory long-acting analgesia remains elusive. Drawing upon prior investigations, vesicular phospholipid gels (VPGs) emerge as promising candidates for extended-release modalities in small-molecule drug delivery systems. Therefore, we tried to use the amphiphilicity of phospholipids to co-encapsulate levobupivacaine hydrochloride and meloxicam, two drugs with different hydrophilicity, to obtain a long-term synergistic analgesic effect. Initially, the physicochemical attributes of the formulation were characterized, followed by an examination of its in vitro release kinetics, substantiating the viability of extending the release duration of the dual drugs. Sequentially, in vivo investigations encompassing pharmacokinetic profiling and assessment of analgesic efficacy were undertaken, revealing a prolonged release duration of up to 120 h and attainment of optimal postoperative analgesia. Subsequently, inquiries into the mechanism underlying synergistic analgesic effects and safety evaluations pertinent to the delivery strategy were pursued. In summation, we successfully developed a promising formulation to achieve long-acting analgesia.
Asunto(s)
Anestésicos Locales , Preparaciones de Acción Retardada , Liberación de Fármacos , Levobupivacaína , Meloxicam , Dolor Postoperatorio , Dolor Postoperatorio/tratamiento farmacológico , Anestésicos Locales/administración & dosificación , Anestésicos Locales/farmacocinética , Anestésicos Locales/química , Animales , Meloxicam/administración & dosificación , Meloxicam/farmacocinética , Masculino , Levobupivacaína/administración & dosificación , Fosfolípidos/química , Fosfolípidos/administración & dosificación , Ratas Sprague-Dawley , Bupivacaína/administración & dosificación , Bupivacaína/farmacocinética , Bupivacaína/química , Bupivacaína/análogos & derivados , Analgésicos/administración & dosificación , Analgésicos/química , Analgésicos/farmacocinética , Geles , Sinergismo FarmacológicoRESUMEN
Nanostructured lipid carriers (NLC) have emerged as innovative drug delivery systems, offering distinct advantages over other lipid-based carriers, such as liposomes and solid lipid nanoparticles. Benzocaine (BZC), the oldest topical local anesthetic in use, undergoes metabolism by pseudocholinesterase, leading to the formation of p-aminobenzoic acid, a causative agent for allergic reactions associated with prolonged BZC usage. In order to mitigate adverse effects and enhance bioavailability, BZC was encapsulated within NLC. Utilizing a 23 factorial design, formulations comprising cetyl palmitate (solid lipid), propylene glycol monocaprylate (liquid lipid), and Pluronic F68 as surfactants were systematically prepared, with variations in the solid/liquid lipid mass ratios (60:40-80:20%), total lipid contents (15-25%), and BZC concentrations (1-3%). The optimized formulation underwent characterization by dynamic light scattering, differential scanning calorimetry, Raman imaging, X-ray diffraction, small-angle neutron scattering, nanotracking analysis, and transmission electron microscopy (TEM)/cryo-TEM, providing insights into the nanoparticle structure and the incorporation of BZC into its lipid matrix. NLCBZC exhibited a noteworthy encapsulation efficiency (%EE = 96%) and a 1 year stability when stored at 25 °C. In vitro kinetic studies and in vivo antinociceptive tests conducted in mice revealed that NLCBZC effectively sustained drug release for over 20 h and prolonged the anesthetic effect of BZC for up to 18 h. We therefore propose the use of NLCBZC to diminish the effective anesthetic concentration of benzocaine (from 20 to 3% or less), thus minimizing allergic reactions that follow the topical administration of this anesthetic and, potentially, paving the way for new routes of BZC administration in pain management.
Asunto(s)
Anestésicos Locales , Benzocaína , Portadores de Fármacos , Lípidos , Benzocaína/administración & dosificación , Benzocaína/química , Anestésicos Locales/administración & dosificación , Anestésicos Locales/química , Anestésicos Locales/farmacocinética , Anestésicos Locales/farmacología , Portadores de Fármacos/química , Animales , Lípidos/química , Ratones , Nanoestructuras/química , Liberación de Fármacos , Masculino , Nanopartículas/químicaRESUMEN
Depot-type drug delivery systems are designed to deliver drugs at an effective rate over an extended period. Minimizing initial "burst" can also be important, especially with drugs causing systemic toxicity. Both goals are challenging with small hydrophilic molecules. The delivery of molecules such as the ultrapotent local anesthetic tetrodotoxin (TTX) exemplifies both challenges. Toxicity can be mitigated by conjugating TTX to polymers with ester bonds, but the slow ester hydrolysis can result in subtherapeutic TTX release. Here, we developed a prodrug strategy, based on dynamic covalent chemistry utilizing a reversible reaction between the diol TTX and phenylboronic acids. These polymeric prodrugs exhibited TTX encapsulation efficiencies exceeding 90 % and the resulting polymeric nanoparticles showed a range of TTX release rates. In vivo injection of the TTX polymeric prodrugs at the sciatic nerve reduced TTX systemic toxicity and produced nerve block lasting 9.7±2.0â h, in comparison to 1.6±0.6â h from free TTX. This approach could also be used to co-deliver the diol dexamethasone, which prolonged nerve block to 21.8±5.1â h. This work emphasized the usefulness of dynamic covalent chemistry for depot-type drug delivery systems with slow and effective drug release kinetics.
Asunto(s)
Polímeros , Profármacos , Tetrodotoxina , Profármacos/química , Profármacos/farmacología , Tetrodotoxina/química , Tetrodotoxina/toxicidad , Tetrodotoxina/administración & dosificación , Polímeros/química , Animales , Anestesia Local/métodos , Anestésicos Locales/química , Anestésicos Locales/administración & dosificación , Ácidos Borónicos/química , Sistemas de Liberación de Medicamentos , Nanopartículas/química , Nervio Ciático/efectos de los fármacos , Liberación de Fármacos , RatonesRESUMEN
Currently, to overcome the short half-life of the local anesthetic ropivacaine, drug delivery systems such as nanoparticles and liposomes have been used to prolong the analgesic effect, but they are prone to abrupt release from the site of administration or have poor slow-release effects, which increases the risk of cardiotoxicity. In this study, injectable lipid suspensions based on ropivacaine-docusate sodium hydrophobic ion pairing (HIP) were designed to significantly prolong the duration of analgesia. The resulting ion-paired lipid suspension (HIP/LIPO) had a micrometer scale and a high zeta potential, which facilitates stable in situ retention. The strong interaction between docusate sodium and ropivacaine was verified using thermal and spectroscopic analyses, and the formation of micron-sized polymorphic vesicles was attributed to the mutual stabilizing interactions between ropivacaine-docusate sodium HIP, docusate sodium and lecithin. The HIP/LIPO delivery system could maintain drug release for more than 5 days in vitro and achieve high analgesic efficacy for more than 10 days in vivo, reducing the side effects associated with high drug doses. The stable HIP/LIPO delivery system is a promising strategy that offers a clinically beneficial alternative for postoperative pain management and other diseases.
Asunto(s)
Anestésicos Locales , Preparaciones de Acción Retardada , Liberación de Fármacos , Ropivacaína , Ropivacaína/administración & dosificación , Ropivacaína/farmacocinética , Ropivacaína/química , Anestésicos Locales/administración & dosificación , Anestésicos Locales/química , Animales , Masculino , Ratas Sprague-Dawley , Anestesia Local/métodos , Ácidos Decanoicos/química , Ácidos Decanoicos/administración & dosificación , Tamaño de la Partícula , Liposomas , Sistemas de Liberación de Medicamentos , Amidas/química , Amidas/administración & dosificación , Ratas , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/prevención & control , Lípidos/química , Interacciones Hidrofóbicas e Hidrofílicas , Lecitinas/química , InyeccionesRESUMEN
Ropivacaine hydrochloride (RPL) is a local anesthetic agent that has been widely used for the treatment of pain during or after surgery. However, this drug is only available in parenteral dosage form and may contribute to the infiltration of RPL into the plasma, causing some undesirable side effects. Intradermal delivery of RPL using dissolving microneedles may become a promising strategy to deliver such drugs into the skin. This research aimed to develop RPL-loaded dissolving microneedles (DMN-RPLs) as a proof of the concept of intradermal delivery of a local anesthetic. The DMN-RPLs were fabricated using either centrifugation or air-pressurized chamber methods. Several polymers, such as poly(vinyl pyrrolidone) (PVP), poly(vinyl alcohol) (PVA), and sodium hyaluronate (SH), were utilized for manufacturing the DMN-RPLs. The prepared DMN-RPLs were assessed for their thermal properties, chemical bonds, mechanical strength, insertion ability, skin-dissolution study, and drug content. Furthermore, in-skin deposition and dermatokinetic studies were also performed. The results showed that F9 (30 % w/w PVP-4 % w/w SH) and F10 (30 % w/w PVP-5 % w/w PVA) containing 5 % w/w of RPL were the most promising formulations, as shown by their needle height reduction (<10 %) and insertion depth (â¼400 µm). Both formulations were also able to deliver more than 60 % of the RPL contained in the DMNs into the epidermis, dermis, and receiver compartment. This study, for the first time, has provided a proof concept to deliver RPL as a local anesthetic using DMNs and the intradermal route, aiming to minimize pain and discomfort during administration and improve the patient's experience.
Asunto(s)
Anestésicos Locales , Sistemas de Liberación de Medicamentos , Agujas , Ropivacaína , Piel , Ropivacaína/administración & dosificación , Ropivacaína/farmacocinética , Anestésicos Locales/administración & dosificación , Anestésicos Locales/farmacocinética , Anestésicos Locales/química , Animales , Piel/metabolismo , Administración Cutánea , Liberación de Fármacos , Absorción Cutánea , Povidona/química , Prueba de Estudio Conceptual , Solubilidad , Ácido Hialurónico/química , Ácido Hialurónico/administración & dosificación , Microinyecciones/métodos , Masculino , Ratas Sprague-Dawley , Alcohol Polivinílico/químicaRESUMEN
Lidocaine is generally recognized and preferred for local anaesthesia, but in addition, studies have described additional benefits of lidocaine in cancer therapy, inflammation reduction, and wound healing. These properties contribute to its increasing importance in dermatological applications, and not only in pain relief but also in other potential therapeutic outcomes. Therefore, the purpose of our study was to enhance lidocaine delivery through the skin. A stable nanostructured lipid carrier (NLC), as a passive permeation enhancer, was developed using a 23 full factorial design. The nanosystems were characterized by crystallinity behaviour, particle size, zeta potential, encapsulation efficiency measurements, and one of them was selected for further investigation. Then, NLC gel was formulated for dermal application and compared to a traditional dermal ointment in terms of physicochemical (rheological behaviour) and biopharmaceutical (qualitative Franz diffusion and quantitative Raman investigations) properties. The study also examined the use of 3D printed solid microneedles as active permeation enhancers for these systems, offering a minimally invasive approach to enhance transdermal drug delivery. By actively facilitating drug permeation through the skin, microneedles can complement the passive transport achieved by NLCs, thereby providing an innovative and synergistic approach to improving lidocaine delivery.
Asunto(s)
Administración Cutánea , Anestésicos Locales , Lidocaína , Permeabilidad , Absorción Cutánea , Piel , Lidocaína/administración & dosificación , Lidocaína/farmacocinética , Lidocaína/química , Absorción Cutánea/efectos de los fármacos , Anestésicos Locales/administración & dosificación , Anestésicos Locales/farmacocinética , Anestésicos Locales/química , Animales , Piel/metabolismo , Lípidos/química , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Nanoestructuras/química , Nanoestructuras/administración & dosificación , Porcinos , Agujas , Tamaño de la Partícula , GelesRESUMEN
Therapeutic deep eutectic solvents (THEDES) have been attracting increasing attention in the pharmaceutical literature as a promising enabling technology capable of improving physicochemical and biopharmaceutical properties for difficult-to-deliver drug compounds. The current literature has explored amide local anaesthetics and carboxylic acid nonsteroidal anti-inflammatories (NSAIDs) as commonly used THEDES formers for their active hydrogen-bonding functionality. However, little is known about what happens within the "deep eutectic" region where a range of binary compositions present simply as a liquid with no melting events detectable across experimentally achievable conditions. There is also very limited understanding of how parent compounds' physicochemical properties could impact upon the formation, interaction mechanism, and stability of the formed liquid systems, despite the significance of these information in dose adjustment, industrial handling, and scaling-up of these liquids. In the current work, we probed the "deep eutectic" phenomenon by investigating the formation and physicochemical behaviours of some chosen lidocaine-NSAID systems across a wide range of composition ratios. Our data revealed that successfully formed THEDES exhibited composition dependent Tg variations with strong positive deviations from predicted Tg values using the Gordon-Taylor theory, suggesting substantial interactions within the formed supramolecular structure. Interestingly, it was found that the parent compound's glass forming ability had a noticeable impact upon such profound interaction and hence could dictate the success of THEDES formation. It has also been confirmed that all successful systems were formed based on charge-assisted hydrogen bonding within their THEDES network, affirming the significant role of partial protonisation on achieving a profound melting point depression. More importantly, the work found that within the "deep eutectic" region there was still an ideal, or thermodynamically preferrable "THEDES point", which would exhibit excellent stability upon exposure to stress storage conditions. The discoveries of this study bring the literature one step closer to fully understanding the "therapeutic deep eutectic" phenomenon. Through correlation between parent reagents' physicochemical properties and the synthesised products' characteristics, we establish a more educated process for the prediction and engineering of THEDES.
Asunto(s)
Antiinflamatorios no Esteroideos , Lidocaína , Lidocaína/química , Lidocaína/administración & dosificación , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/administración & dosificación , Solventes/química , Anestésicos Locales/administración & dosificación , Anestésicos Locales/química , Enlace de Hidrógeno , Química Farmacéutica/métodos , Estabilidad de MedicamentosRESUMEN
Rationale: To meet the need of long-acting analgesia in postoperative pain management, slow-releasing formulations of local anesthetics (LAs) have been extensively investigated. However, challenges still remain in obtaining such formulations in a facile and cost-effective way, and a mechanism for controlling the release rate to achieve an optimal duration is still missing. Methods: In this study, nanosheets formed by a self-assembling peptide were used to encapsulate ropivacaine in a soft-coating manner. By adjusting the ratio between the peptide and ropivacaine, ropivacaine particles with different size were prepared. Releasing profile of particles with different size were studied in vitro and in vivo. The influence of particle size and ropivacaine concentration on effective duration and toxicity were evaluated in rat models. Results: Our results showed that drug release rate became slower as the particle size increased, with particles of medium size (2.96 ± 0.04 µm) exhibiting a moderate release rate and generating an optimal anesthetic duration. Based on this size, formulations at different ropivacaine concentrations generated anesthetic effect with different durations in rat sciatic nerve block model, with the 6% formulation generated anesthetic duration of over 35 h. Long-acting analgesia up to 48 h of this formulation was also confirmed in a rat total knee arthroplasty model. Conclusion: This study provided a facile strategy to prepare LA particles of different size and revealed the relationship between particle size, release rate and anesthetic duration, which provided both technical and theoretical supports for developing long-acting LA formulations with promising clinical application.
Asunto(s)
Anestésicos Locales , Nanopartículas , Tamaño de la Partícula , Péptidos , Ropivacaína , Ropivacaína/administración & dosificación , Ropivacaína/química , Ropivacaína/farmacocinética , Animales , Anestésicos Locales/administración & dosificación , Anestésicos Locales/química , Ratas , Nanopartículas/química , Péptidos/química , Péptidos/administración & dosificación , Dolor Postoperatorio/tratamiento farmacológico , Ratas Sprague-Dawley , Masculino , Analgesia/métodos , Preparaciones de Acción Retardada/química , Liberación de Fármacos , Amidas/química , Amidas/administración & dosificación , Nervio Ciático/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
PURPOSE: To prepare freeze-dried bupivacaine lipospheres intended for topical application in burn injuries. The aim was improving the storage stability and developing a prolonged release pattern to tackle the adverse reactions resulting from the frequent administration of bupivacaine. METHODS: The lipospheres were prepared by hot-melt dispersion method employing bupivacaine base at 1.5 and 3%w/w, tristearin 6% w/w as the core while dipalmitoyl phosphatidylcholine (DPPC) and soy phosphatidylcholine (SPC) as the coat at 0.75, 1.5 and 3% w/w. The lotion was then freeze-dried and cryoprotected by sucrose 3% w/w. Evaluation was carried out through loading and release analysis, storage study, particle characterization including morphology, zeta potential and particle size as well as anti-microbial assessment. RESULTS: The highest loading, (87.6 ± 0.1%), was achieved using bupivacaine 3% and SPC 0.75%. After 6 months of storage at 4 ͦC, the loading in the lotion and the freeze-dried samples were 17.4 ± 0.2 and 87.2 ± 0.3%, respectively. In vitro dissolution test demonstrated 94.5% and 95% of bupivacaine release from lotion and freeze-dried samples, after 24 h. The respective zeta potential of -1.30 and 26 mV was recorded for lotion and solid-state bupivacaine. Micromeritic evaluation of freeze-dried powder exhibited particle size of 35.23 ± 2.02 µm and highly-wrinkled-irregular morphology without detectable needle structures related to drug free crystals. The powder had rapid reconstitution property and antibacterial activity. CONCLUSION: Freeze- drying holds a promising potential to improve the storage stability of bupivacaine lipospheres with well- preserved release pattern and particle properties for further topical application.
Asunto(s)
Anestésicos Locales , Bupivacaína , Estabilidad de Medicamentos , Liofilización , Liposomas , Tamaño de la Partícula , Bupivacaína/química , Bupivacaína/farmacología , Bupivacaína/administración & dosificación , Anestésicos Locales/química , Anestésicos Locales/farmacología , Anestésicos Locales/administración & dosificación , Liposomas/química , Antibacterianos/química , Antibacterianos/farmacología , Composición de Medicamentos/métodos , Liberación de Fármacos , Almacenaje de MedicamentosRESUMEN
Controlled release systems for prolonged duration local anesthesia have long been an area of research interest, and now are entering clinical practice, in part driven by the opioid epidemic. We discuss the design considerations and material properties of systems for controlled release of local anesthetics, from relatively simple systems to covalent binding of drugs to materials and delivery triggered by external stimuli.
Asunto(s)
Anestésicos Locales , Sistemas de Liberación de Medicamentos , Anestésicos Locales/farmacología , Anestésicos Locales/química , Anestésicos Locales/uso terapéutico , Preparaciones de Acción Retardada/químicaRESUMEN
Local analgesia is one of the most desirable methods for postoperative pain control, while the existing local anesthetics have a short duration of analgesic effect. Nano-drug carriers have been widely used in various fields and provide an excellent strategy for traditional drugs. Although the existing liposomes for local anesthetics have certain advantages, their instability and complexity of the preparation process still cannot be ignored. Here, we developed novel ropivacaine hydrochloride liposomes with improved stability and sustained release performance by combining ropivacaine hydrochloride with sodium oleate in liposomes via hydrophobic ion-pairing (HIP). The liposomes are easy to prepare, inexpensive, and suitable for mass production. The infrared (IR), particle size, and Zeta potential measurements adequately characterized the complex, which showed a diameter of 81.09 nm and a zeta potential of -83.3 mV. Animal behavioral experiments, including the hot plate test and von Frey fiber test, demonstrated that the liposome system had a prolonged analgesic effect of 2 h versus conventional liposome preparations, consistent with the results of in vitro release experiments. In addition, in vitro cytotoxicity evaluations in RAW264.7 cells and in vivo evaluations revealed the biocompatibility and safety of the ropivacaine-sodium oleate ion-paired liposome (Rop-Ole-Lipo) system as a suitable local anesthetic for local pain management. Our findings provide a new idea for the preparation of local anesthetics.
Asunto(s)
Anestésicos Locales , Liposomas , Analgésicos , Anestésicos Locales/química , Animales , Manejo del Dolor , Ropivacaína/químicaRESUMEN
Microneedles offer a convenient transdermal delivery route with potential for long term sustained release of drugs. However current microneedle technologies may not have the mechanical properties for reliable and stable penetration (e.g. hydrogel microneedles). Moreover, it is also challenging to realize microneedle arrays with large size and high flexibility. There is also an inherent upper limit to the amount and kind of drugs that can be loaded in the microneedles. In this paper, we present a new class of polymeric porous microneedles made from biocompatible and photo-curable resin that address these challenges. The microneedles are unique in their ability to load solid drug formulation in concentrated form. We demonstrate the loading and release of solid formulation of anesthetic and non-steroidal anti-inflammatory drugs, namely Lidocaine and Ibuprofen. Paper also demonstrates realization of large area (6 × 20 cm2) flexible and stretchable microneedle patches capable of drug delivery on any body part. Penetration studies were performed in an ex vivo porcine model supplemented through rigorous compression tests to ensure the robustness and rigidity of the microneedles. Detailed release profiles of the microneedle patches were shown in an in vitro skin model. Results show promise for large area transdermal delivery of solid drug formulations using these porous microneedles.
Asunto(s)
Anestésicos Locales/química , Antiinflamatorios no Esteroideos/química , Portadores de Fármacos , Sistemas de Liberación de Medicamentos/instrumentación , Ibuprofeno/química , Lidocaína/química , Agujas , Polímeros/química , Administración Cutánea , Anestésicos Locales/administración & dosificación , Anestésicos Locales/metabolismo , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/metabolismo , Composición de Medicamentos , Liberación de Fármacos , Dureza , Ibuprofeno/administración & dosificación , Ibuprofeno/metabolismo , Lidocaína/administración & dosificación , Lidocaína/metabolismo , Miniaturización , Porosidad , Absorción Cutánea , Sus scrofa , Resistencia a la TracciónRESUMEN
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.
Asunto(s)
Bupivacaína , Poliésteres , Anestésicos Locales/química , Animales , Bupivacaína/química , Caproatos , Lactonas , Ratas , PorcinosRESUMEN
Various techniques have been explored to prolong the duration and improve the efficacy of local anaesthetic nerve blocks. Some of these involve mixing local anaesthetics or adding adjuncts. We did a literature review of studies published between 01 May 2011 and 01 May 2021 that studied specific combinations of local anaesthetics and adjuncts. The rationale behind mixing long- and short-acting local anaesthetics to hasten onset and extend duration is flawed on pharmacokinetic principles. Most local anaesthetic adjuncts are not licensed for use in this manner and the consequences of untested admixtures and adjuncts range from making the solution ineffective to potential harm. Pharmaceutical compatibility needs to be established before administration. The compatibility of drugs from the same class cannot be inferred and each admixture requires individual review. Precipitation on mixing (steroids, non-steroidal anti-inflammatory drugs) and subsequent embolisation can lead to serious adverse events, although these are rare. The additive itself or its preservative can have neurotoxic (adrenaline, midazolam) and/or chondrotoxic properties (non-steroidal anti-inflammatory drugs). The prolongation of block may occur at the expense of motor block quality (ketamine) or block onset (magnesium). Adverse effects for some adjuncts appear to be dose-dependent and recommendations concerning optimal dosing are lacking. An important confounding factor is whether studies used systemic administration of the adjunct as a control to accurately identify an additional benefit of perineural administration. The challenge of how best to prolong block duration while minimising adverse events remains a topic of interest with further research required.
Asunto(s)
Anestesia de Conducción/métodos , Anestésicos Locales/administración & dosificación , Anestésicos Locales/química , Analgésicos Opioides/administración & dosificación , Anestesia de Conducción/normas , Anestesia Local/métodos , Anestesia Local/normas , Anestésicos Locales/farmacocinética , Antiinflamatorios no Esteroideos/administración & dosificación , Quimioterapia Combinada , Humanos , Magnesio/administración & dosificación , Bloqueo Nervioso/métodos , Bloqueo Nervioso/normasRESUMEN
Tetracaine (TTC) is a local anesthetic broadly used for topical and spinal blockade, despite its systemic toxicity. Encapsulation in nanostructured lipid carriers (NLC) may prolong TTC delivery at the site of injection, reducing such toxicity. This work reports the development of NLC loading 4% TTC. Structural properties and encapsulation efficiency (%EE > 63%) guided the selection of three pre-formulations of different lipid composition, through a 23 factorial design of experiments (DOE). DLS and TEM analyses revealed average sizes (193-220 nm), polydispersity (< 0.2), zeta potential |- 21.8 to - 30.1 mV| and spherical shape of the nanoparticles, while FTIR-ATR, NTA, DSC, XRD and SANS provided details on their structure and physicochemical stability over time. Interestingly, one optimized pre-formulation (CP-TRANS/TTC) showed phase-separation after 4 months, as predicted by Raman imaging that detected lack of miscibility between its solid (cetyl palmitate) and liquid (Transcutol) lipids. SANS analyses identified lamellar arrangements inside such nanoparticles, the thickness of the lamellae been decreased by TTC. As a result of this combined approach (DOE and biophysical techniques) two optimized pre-formulations were rationally selected, both with great potential as drug delivery systems, extending the release of the anesthetic (> 48 h) and reducing TTC cytotoxicity against Balb/c 3T3 cells.
Asunto(s)
Anestésicos Locales/farmacología , Proliferación Celular , Portadores de Fármacos/química , Composición de Medicamentos/métodos , Liberación de Fármacos , Nanoestructuras/administración & dosificación , Tetracaína/farmacología , Anestésicos Locales/química , Animales , Células 3T3 BALB , Ratones , Nanoestructuras/química , Tetracaína/químicaRESUMEN
Voltage-gated sodium channels play a vital role in nerve and muscle cells, enabling them to encode and transmit electrical signals. Currently, there exist several classes of drugs that aim to inhibit these channels for therapeutic purposes, including local anesthetics, antiepileptics and antiarrhythmics. However, sodium-channel-inhibiting drugs lack subtype specificity; instead, they inhibit all sodium channels in the human body. Improving understanding of the mechanisms of binding of existing nonselective drugs is important in providing insight into how subtype-selective drugs could be developed. This study used molecular dynamics simulations to investigate the binding of the antiepileptics carbamazepine and lamotrigine and the local anesthetic lidocaine in neutral and charged states to the recently resolved human Nav1.4 channel. Replica exchange solute tempering was used to enable greater sampling of each compound within the pore. It was found that all four compounds show similarities in their binding sites within the pore. However, the positions of the carbamazepine and lamotrigine did not occlude the center of the pore but preferentially bound to homologous domain DII and DIII. The charged and neutral forms of lidocaine positioned themselves more centrally in the pore, with more common interactions with DIV. The best localized binding site was for charged lidocaine, whose aromatic moiety interacted with Y1593, whereas the amine projected toward the selectivity filter. Comparisons with our previous simulations and published structures highlight potential differences between tonic and use-dependent block related to conformational changes occurring in the pore.
Asunto(s)
Anestésicos Locales , Canales de Sodio Activados por Voltaje , Anestésicos Locales/química , Anestésicos Locales/metabolismo , Anestésicos Locales/farmacología , Antiarrítmicos/farmacología , Anticonvulsivantes , Sitios de Unión , Humanos , Lidocaína/química , Lidocaína/metabolismo , Lidocaína/farmacología , Canal de Sodio Activado por Voltaje NAV1.4 , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/metabolismo , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio Activados por Voltaje/metabolismoRESUMEN
The activity of local anesthetics (LAs) has been attributed to the inhibition of ion channels, causing anesthesia. However, there is a growing body of research showing that LAs act on a wide range of receptors and channel proteins far beyond simple analgesia. The current concept of ligand recognition may no longer explain the multitude of protein targets influenced by LAs. We hypothesize that LAs can cause anesthesia without directly binding to the receptor proteins just by changing the physical properties of the lipid bilayer surrounding these proteins and ion channels based on LAs' amphiphilicity. It is possible that LAs act in one of the following ways: They 1) dissolve raft-like membrane microdomains, 2) impede nerve impulse propagation by lowering the lipid phase transition temperature, or 3) modulate the lateral pressure profile of the lipid bilayer. This could also explain the numerous additional effects of LAs besides anesthesia. Furthermore, the concepts of membrane-mediated activity and binding to ion channels do not have to exclude each other. If we were to consider LA as the middle part of a continuum between unspecific membrane-mediated activity on one end and highly specific ligand binding on the other end, we could describe LA as the link between the unspecific action of general anesthetics and toxins with their highly specific receptor binding. This comprehensive membrane-mediated model offers a fresh perspective to clinical and pharmaceutical research and therapeutic applications of local anesthetics. SIGNIFICANCE STATEMENT: Local anesthetics, according to the World Health Organization, belong to the most important drugs available to mankind. Their rediscovery as therapeutics and not only anesthetics marks a milestone in global pain therapy. The membrane-mediated mechanism of action proposed in this review can explain their puzzling variety of target proteins and their thus far inexplicable therapeutic effects. The new concept presented here places LAs on a continuum of structures and molecular mechanisms in between small general anesthetics and the more complex molecular toxins.