Liposomal formulations of prilocaine: effect of complexation with hydroxypropyl-ß-cyclodextrin on drug anesthetic efficacy

Abstract

A combined strategy, based on cyclodextrin complexation and loading in liposomes, has been investigated to develop a new delivery system with improved therapeutic activity of the local anesthetic, prilocaine (PRL). In order to evaluate the actual effectiveness and advantages of this approach compared to the traditional drug-in-liposome one, four different liposomal formulations were prepared: (1) liposomes loaded with PRL base as complex with hydroxypropyl-β-cyclodextrin (HP CD) in the aqueous phase; (2) liposomes loaded with PRL hydrochloride in the aqueous phase; (3) liposomes loaded with PRL base in the lipophilic phase; and (4) "double-loaded" liposomes, containing free PRL base in the membrane bilayer and its HP CD complex in the aqueous compartment. All batches were characterized for particle size, charge, deformability, and entrapment efficiency from using, respectively, light scattering, extrusion, and dialysis techniques, while the anesthetic effect was evaluated in vivo on Guinea pigs, according to the test of dorsal muscle contraction. All drug liposomal dispersions showed enhanced analgesic duration with respect to the corresponding aqueous solutions, but significant differences were observed between the different formulations. In particular, cyclodextrin complexation not only allowed an efficient encapsulation of PRL base in the aqueous vesicle core, but also increased the anesthetic effect duration and reduced the initial lag time, in comparison with the corresponding formulations containing, respectively, free PRL in the lipophilic phase or PRL hydrochloride in the aqueous vesicle core. The technique of double loading was the most effective, giving rise to the shortest onset time and longest duration of anesthetic effect.

Preparation of drug-in-cyclodextrin-in-liposomes at a large scale using a membrane contactor: Application to trans -anethole

“…Furthermore, for all formulations, the presence of CD did not affect the size distribution, which is in agreement with other studies (Sebaaly, Charcosset, Stainmesse, Fessi, & Greige-gerges 2016;Cavalcanti, et al, 2011;Ascenso, et al, 2013;Bragagni, Maestrelli, Mennini, Ghelardini, & Mura, 2010;Maestrelli, Gonzalez-Rodriguez, Rabasco, Ghelardini, & Mura, 2010).…”

“…This approach can be useful to increase drug solubility and stability (Loukas, Vraka, & Gregoriadis, 1998) and to avoid the rapid release of poorly aqueous soluble drugs incorporated in the lipid bilayer of conventional liposomes (McCormack & Gregoriadis, 1994, 1998. Further advantages can be obtained using a double-loading technique, by preparing liposomes loaded with the free drug in the lipophilic phase and its CD inclusion complex in the aqueous phase, resulting in both a fast onset action and a prolonged effect (Bragagni, Maestrelli, Mennini, Ghelardini, & Mura, 2010).…”

Development and Characterization of Niosomal Formulations of Doxorubicin Aimed at Brain Targeting

“…Encapsulation efficiency was indirectly determined by using the size exclusion chromatography and dialysis methods, which both allowed separation of the unloaded drug from niosomes (25)(26)(27)(28).…”

Local Toxicity from Local Anesthetic Polymeric Microparticles

“…32,[38][39][40] Reporting of local tissue injury from local anesthetic controlled release formulations has been variable, in both animal and human studies. Most do not describe myotoxicity [2][3][4][5][7][8][9][11][12][13][14][15]18,[22][23][24] (including the liposomal formulation undergoing human trials 16,17 ), while some others document mild muscle injury comparable to single injections of unencapsulated drug. 10,25,26 In our own work, we have found muscle injury to be a ubiquitous finding in a wide range of extended-release bupivacaine formulations independent of the delivery vehicle 6,19,21,41 or co-encapsulated agent, 32,37,42,43 and it is sometimes severe.…”

“…A very broad range of controlled release formulations have been developed to provide prolonged duration local anesthesia, including polymeric microspheres, [1][2][3][4][5][6][7] surgically implantable pellets, 8 microcrystals, 9 liposomes, [10][11][12][13][14][15] (including a formulation undergoing human clinical trials 16,17 ) lipospheres, 18 cross-linkable hyaluronic acid matrices, 19 lipidprotein-sugar particles, 20,21 cyclodextrin complexes, 22,23 liposomes loaded with cyclodextrin complexes 24 and implantable membrane matrices. 25,26 Such systems have extended the duration of nerve block to varying degrees ranging from hours to weeks, but have not been widely adopted clinically.…”