Physico-chemical characterization of benzocaine-beta-cyclodextrin inclusion complexes

Local anesthetics are able to induce pain relief by binding to the sodium channel of excitable membranes, blocking the influx of sodium ions and the propagation of the nervous impulse. Benzocaine (BZC) is a local anesthetic whose low water-solubility limits its application to topical formulations. The present work focuses on the characterization of inclusion complexes of BZC in P-cyclodextrin (P-CD). Differential scanning calorimetry and electron microscopy gave evidences of the formation and the morphology of the complex. Fluorescence spectroscopy showed a BZC/beta-CD 1:1 stoichiometry. Phase-solubility diagrams allowed the determination of the association constants between BZC and P-CD (549 M-1) and revealed that a three-fold increase in BZC solubility can be reached upon complexation with P-CD. The details of BZC/beta-CD molecular interaction were analyzed by H-1 2D NMR allowing the proposition of an inclusion model for BZC into P-CD where the aromatic ring of the anesthetic is located near the head of the P-CD cavity. Moreover, in preliminary toxicity studies, the complex seems to be less toxic than BZC alone, since it induced a decrease in the in vitro oxidation of human hemoglobin. These results suggest that the BZC/beta-CD complex represents an effective novel formulation to enhance BZC solubility in water, turning it promising for use outside its traditional application, i.e., in infiltrative anesthesia. (c) 2005 Elsevier B.V. All rights reserved.39595696

Influence of liposomal local anesthetics on platelet aggregation in vitro

We assessed the effect of local anesthetics (LA) from different families such as esters (benzocaine), linear aminoamides (lidocaine) and cyclic aminoamides (bupivacaine) on the platelet aggregation induced by ADP. Liposomal formulations of the three LA, prepared with egg phosphatidylcholine: cholesterol a-tocopherol, were also tested. The three LA were able to inhibit platelet aggregation induced by ADP, in the following order: bupivacaine > lidocaine > benzocaine. After encapsulation into liposomes the inhibitory effect increased for all anesthetics studied, showing that aggregation tests could be used to assess the toxicity of new drug formulations.1441671515

Encapsulation of mepivacaine prolongs the analgesia provided by sciatic nerve blockade in mice

Purpose: Liposomal formulations of local anesthetics (LA) are able to control drug-delivery in biological systems, prolonging their anesthetic effect. This study aimed to prepare, characterize and evaluate in vivo drug-delivery systems, composed of large unilamellar liposomes (LUV), for bupivacaine (BVC) and mepivacaine (MVC). Methods: BVC and MVC hydrochloride were encapsulated into LUV (0.4 mum) composed of egg phosphatidylcholine, cholesterol and a-tocopherol (4:3:0.07 molar ratio) to final concentrations of 0.125, 0.25, 0.5% for BVC and 0.5, I, 2% for MVC. Motor function and antinociceptive effects were evaluated by sciatic nerve blockade induced by liposomal and plain formulations in mice. Results: Liposomal formulations modified neither the intensity nor the duration of motor blockade compared to plain solutions. Concerning sensory blockade, liposomal BVC (BVLUV) showed no advantage relatively to the plain BVC injection while liposomal MVC (MVCLUV) improved both the intensity (1.4-1.6 times) and the duration of sensory blockade (1.3-1.7 times) in comparison to its plain solution (P < 0.001) suggesting an increased lipid solubility, availability and controlled-release of the drug at the site of injection. Conclusion: MVCLUV provided a LA effect comparable to that of BVC. We propose MVCLUV, drug delivery as a potentially new therapeutic option for the treatment of acute pain since the formulation enhances the duration of sensory blockade at lower concentrations than those of plain MVC.51656657

Alternatives for the Treatment of Schistosomiasis: Physico-Chemical Characterization of an Inclusion Complex Between Praziquantel and Hydroxypropyl-beta-Cyclodextrin

Alternatives for the Treatment of Schistosomiasis: Physico-Chemical Characterization of an Inclusion Complex Between Praziquantel and Hydroxypropyl-beta-Cyclodextrin. Praziquantel (PZQ) is the drug of choice commonly used for the treatment of shistosomiasis. However, it has low aqueous solubility, which could limit its bioavailability in the body. To circumvent these features, an inclusion complex with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was prepared. Thus, the objective of this work was to prepare and characterize the PZQ/HP-beta-CD inclusion complex. Morphological, spectroscopic, and calorimetric analysis showed the first signs of the guest/host interaction. The complexation kinetic analysis was used to determine the kinetic constant and, besides that, it was possible to establish the time consumed to reach equilibrium. Using the solubility isotherm, it was observed that the interaction with HP-beta-CD increased 2.4 fold the aqueous solubility of plain PZQ. In vitro cytotoxicity tests, using fibroblast cells, evidenced no toxicity for these cells at the concentrations tested. These results demonstrated that there is a potential use of PZQ in formulations with HP-beta-CD.2971067107

A new look at the hemolytic effect of local anesthetics, considering their real membrane/water partitioning at pH 7.4

The interaction of local anesthetics (LA) with biological and phospholipid bilayers was investigated regarding the contribution of their structure and physicochemical properties to membrane partition and to erythrocyte solubilization. We measured the partition into phospholipid vesicles-at pH 5.0 and 10.5-and the biphasic hemolytic effect on rat erythrocytes of., benzocaine, chloroprocaine, procaine, tetracaine, bupivacaine, mepivacaine, lidocaine, prilocaine, and dibucaine. At pH 7.4, the binding of uncharged and charged LA to the membranes was considered, since it results in an ionization constant (pK(app)) different from that observed for the anesthetic in the aqueous phase (pK(w)). Even though it occurred at a pH at which there is a predominance of the charged species, hemolysis was greatly influenced by the uncharged species, revealing that the disrupting effect of LA on these membranes is mainly a consequence of hydrophobic interactions. The correlation between the hemolytic activity and the LA potency shows that hemolytic experiments could be used for the prediction of activity in the development of new LA molecules. (C) 2004 Elsevier B.V. All rights reserved.110321322