Encapsulation of ropivacaine in a combined (donor-acceptor, ionic-gradient) liposomal system promotes extended anesthesia time (original) (raw)
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J. Braz. Chem. …, 2010
O objetivo do presente estudo foi determinar os parâmetros farmacocinéticos da ropivacaína encapsulada em lipossomas após anestesia local em 14 voluntários sadios. Neste estudo randomizado, cruzado e duplo-cego, os voluntários receberam anestesia infiltrativa na maxila de ropivacaína a 0,5% encapsulada em lipossomas e ropivacaína 0,5% com epinefrina a 1:200.000 em duas sessões distintas. Amostras de sangue foram coletadas antes e após (de 15 a 1440 min) a administração das formulações de ropivacaína. A quantificação da concentração plasmática de ropivacaína foi feita por meio de HPLC com detecção por UV. Os parâmetros farmacocinéticos AUC 0-24 (área sob a curva de concentração × tempo do tempo 0 até 24 horas) , AUC 0-∞ (área sob a curva de concentração x tempo do tempo 0 até o infinito), C max (concentração máxima da droga), CL (clearance renal), T max (tempo em que ocorre a concentração máxima); t 1/2 (meia vida de eliminação) e V d (volume de distribuição) foram analisados pelo teste de Wilcoxon. Nenhuma diferença (p > 0,05) foi observada entre as duas formulações em cada parâmetro farmacocinético avaliado e as concentrações plasmáticas de ropivacaína, considerando cada período de tempo. Ambas as formulações apresentaram perfil farmacocinético semelhante, indicando que a formulação lipossomal poderia ser uma opção mais segura para o uso deste anestésico local, devido à ausência de vasoconstritor.
Journal of Pharmacy and Pharmacology, 2019
Objectives To evaluate whether a ternary system composed of hydroxypropyl-β-cyclodextrin (HP-βCD) further encapsulated into egg phosphatidylcholine liposomes (LUV) could prolong the action and reduce the toxicity of ropivacaine (RVC). Methods Dynamic light scattering and NMR were used to characterize the inclusion complex (RVC : HP-βCD), liposomal (RVC : LUV) and ternary (LUV : RVC : HP-βCD) systems containing 0.25% RVC. Their encapsulation efficiency, release kinetics, in-vitro cytotoxicity and in-vivo anaesthetic effect (paw-withdraw tests in mice) were also evaluated. Key findings 1 : 1 RVC : HP-βCD inclusion complex was encapsulated in liposomes (220.2 ± 20.3 nm size, polydispersity <0.25, zeta potentials = −31.7 ± 1.4 mV). NMR (diffusion-ordered spectroscopy (DOSY)) revealed stronger anaesthetic binding to LUV : RVC : HP-βCD (Ka = 342 m−1) than to RVC : HP-βCD (Ka = 128 m−1) or liposomal formulation (Ka = 22 m−1). The formulations promoted in-vitro sustained drug release and...
Journal of Liposome Research, 2015
Context: Ropivacaine (RVC) is an aminoamide local anesthetic widely used in surgical procedures. Studies with RVC encapsulated in liposomes and complexed in cyclodextrins have shown good results, but in order to use RVC for lengthy procedures and during the postoperative period, a still more prolonged anesthetic effect is required. Objective: This study therefore aimed to provide extended RVC release and increased upload using modified liposomes. Materials and methods: Three types of vesicles were studied: (i) large multilamellar vesicle (LMV), (ii) large multivesicular vesicle (LMVV) and (iii) large unilamellar vesicle (LUV), prepared with egg phosphatidylcholine/cholesterol/a-tocopherol (4:3:0.07 mol%) at pH 7.4. Ionic gradient liposomes (inside: pH 5.5, pH 5.5 + (NH 4) 2 SO 4 and pH 7.4 + (NH 4) 2 SO 4) were prepared and showed improved RVC loading, compared to conventional liposomes (inside: pH 7.4). Results and discussion: An high-performance liquid chromatography analytical method was validated for RVC quantification. The liposomes were characterized in terms of their size, zeta potential, polydispersion, morphology, RVC encapsulation efficiency (EE(%)) and in vitro RVC release. LMVV liposomes provided better performance than LMV or LUV. The best formulations were prepared using pH 5.5 (LMVV 5.5 in) or pH 7.4 with 250 mM (NH 4) 2 SO 4 in the inner aqueous core (LMVV 7.4 in + ammonium sulfate), enabling encapsulation of as much as 2% RVC, with high uptake (EE(%) 7070%) and sustained release (7025 h). Conclusion: The encapsulation of RVC in ionic gradient liposomes significantly extended the duration of release of the anesthetic, showing that this strategy could be a viable means of promoting longer-term anesthesia during surgical procedures and during the postoperative period.
Journal of Pharmacy and Pharmacology, 2008
This study reports an investigation of the pharmacological activity, cytotoxicity and local effects of a liposomal formulation of the novel local anaesthetic ropivacaine (RVC) compared with its plain solution. RVC was encapsulated into large unilamellar vesicles (LUVs) composed of egg phosphatidylcholine, cholesterol and -tocopherol (4:3:0.07, mole %). Particle size, partition coefficient determination and in-vitro release studies were used to characterize the encapsulation process. Cytotoxicity was evaluated by the tetrazolium reduction test using sciatic nerve Schwann cells in culture. Local anaesthetic activity was assessed by mouse sciatic and rat infraorbital nerve blockades. Histological analysis was performed to verify the myotoxic effects evoked by RVC formulations. Plain (RVC PLAIN ) and liposomal RVC (RVC LUV ) samples were tested at 0.125%, 0.25% and 0.5% concentrations. Vesicle size distribution showed liposomal populations of 370 and 130 nm (85 and 15%, respectively), without changes after RVC encapsulation. The partition coefficient value was 132 26 and in-vitro release assays revealed a decrease in RVC release rate (1.5 fold, P 0.001) from liposomes. RVC LUV presented reduced cytotoxicity (P 0.001) when compared with RVC PLAIN . Treatment with RVC LUV increased the duration (P 0.001) and intensity of the analgesic effects either on sciatic nerve blockade (1.4-1.6 fold) and infraorbital nerve blockade tests (1.5 fold), in relation to RVC PLAIN . Regarding histological analysis, no morphological tissue changes were detected in the area of injection and sparse inflammatory cells were observed in only one of the animals treated with RVC PLAIN or RVC luv at 0.5%. Despite the differences between these preclinical studies and clinical conditions, we suggest RVC LUV as a potential new formulation, since RVC is a new and safe local anaesthetic agent.
Liposomes for entrapping local anesthetics: A liposome electrokinetic chromatographic study
ELECTROPHORESIS, 2010
Bupivacaine is a lipophilic, long-acting, amide class local anesthetic commonly used in clinical practice to provide local anesthesia during surgical procedures. Several cases of accidental overdose with cardiac arrest and death have been reported since bupivacaine was introduced to human use. Recent case reports have suggested that Intralipid (Fresenius Kabi) is an effective therapy for cardiac toxicity from high systemic concentrations of, e.g. bupivacaine, even though the mechanism behind the interaction is not fully clear yet. Our long-term aim is to develop a sensitive, efficient, and non-harmful lipid-based formulation to specifically trap harmful substances in vivo. In this study, the in vitro interaction of local anesthetics (bupivacaine, prilocaine, and lidocaine) with Intralipid or lipid vesicles containing phosphatidylglycerol, phosphatidylcholine, cardiolipin, cholesterol, and N-palmitoyl-D-erythro-sphingosine (ceramide) was determined by liposome electrokinetic chromatography. The interactions were evaluated by calculating the retention factors and distribution constants. Atomic force microscopy measurements were carried out to confirm that the interaction mechanism was solely due to interactions between the analytes and the moving pseudostationary phase and not by interactions with a stationary lipid phase adsorbed to the fused-silica wall. The heterogeneity of the liposomes was also studied by atomic force microscopy. The liposome electrokinetic chromatography results demonstrate that there is higher interaction between the drugs and negatively charged liposome dispersion than with the commercial Intralipid dispersion.
Liposomes for the Drug Delivery: A Review
2021
Quick Response Code Abstract: Formulation of drugs in liposomes has provided an opportunity to enhance the therapeutic indices of various agents mainly through alteration in their bio distribution. Liposomes are a novel drug delivery system (NDDS), they are vesicular structures consisting of bilayer which form spontaneously when phospholipids are dispersed in water. They are microscopic vesicles in which an aqueous volume is entirely enclosed by a membrane composed of lipid bilayers. The goal of any drug delivery system is spatial placement and temporal delivery of the medicament. Research works are going on to prepare an ideal drug delivery system which satisfies these needs. Liposomes are small vesicles (100 nm) composed various lipid molecules which build their membrane bilayers. These formulations are mainly composed of phosphatidylcholine and other constituents such as cholesterol and lipidconjugated hydrophilic polymers. Liposomes are biodegradable and biocompatible in nature.