Many drugs used to treat schizophrenia lack an effective uptake into the brain, and need either passive or facilitated transport to pass through the blood-brain-barrier (BBB). The development of nanoparticles (NPs) is a valid strategy to enhance drug delivery and permeation through BBB. The capacity of the drug to pass BBB depends on the drug carrier’s shape and molecular size [1]. NPs could improve drug delivery to the CNS and also reduce adverse effects caused by the free drug. The aim of this work was to prepare and characterize freeze-dried surfactant-free PLGA- PEG NPs loaded with three different antipsychotic drugs: Clozapine, Buspirone and Haloperidol, with the aim at obtaining suitable formulations to perform in vivo studies in rats. Surfactant-free PLGA-PEG NPs were prepared using a nanoprecipitation method. The PLGA-PEG copolymer increases the half-life of the NPs in the bloodstream, due to reduced non-specific interaction with biological components. The PEG shell has been demonstrated to prevent the NPs aggregation, typically seen with uncoated PLGA NPs, and to prolong NPs circulation time by inhibiting their uptake by the mononuclear phagocytic system. Because in vivo studies can be hampered if the nanosuspension volume is too high to reach useful therapeutic drug concentrations, nanoparticle suspensions should be concentrated. A freeze-drying process was used to concentrate the produced nanosuspensions into dry powders and to increase storage stability. To help retaining the desired nanometer particle size after lyophilisation, sucrose was used as a cryoprotectant [2]. Colloidal nanocarriers were characterized by photon correlation spectroscopy (PCS) in terms of mean size, PDI, Zeta potential, and thermal analysis (DSC). The latter experiments showed that all drugs were efficiently encapsulated into the colloidal systems as suggested by the disappearance of the drugs melting peak. We demonstrated that each drug influence the cryoprotective effect of sucrose on surfactant-free PLGA-PEG NPs as suggested by the Sf/Si values (ratio of the final to initial NP mean size). Because cryoprotective action is a surface phenomenon, the possible presence of drug molecules on the NP surface could influence sucrose deposition during the drying process and consequently its efficacy, as suggested by PCS data. Difference in Zeta potential values confirmed our hypotesis, probably due to the different logP and chemical structure of the encapsulated drugs. We obtained a prolonged release profile for clozapine-loaded NPs. In vivo studies on murine models of schizophrenia are in course to compare the efficacy of IV administered nano-encapsulated vs. neat drugs.

PLGA-PEG NANOPARTICLES LOADED WITH ANTIPSYCHOTIC AGENTS: INFLUENCE OF DRUG MOLECULES ON THE CRYOPROTECTIVE EFFECT OF SUCROSE.

MUSUMECI, TERESA;CARBONE, CLAUDIA;LEGGIO, GIAN MARCO;SALOMONE, Salvatore;PIGNATELLO, Rosario;PUGLISI, Giovanni
2016

Abstract

Many drugs used to treat schizophrenia lack an effective uptake into the brain, and need either passive or facilitated transport to pass through the blood-brain-barrier (BBB). The development of nanoparticles (NPs) is a valid strategy to enhance drug delivery and permeation through BBB. The capacity of the drug to pass BBB depends on the drug carrier’s shape and molecular size [1]. NPs could improve drug delivery to the CNS and also reduce adverse effects caused by the free drug. The aim of this work was to prepare and characterize freeze-dried surfactant-free PLGA- PEG NPs loaded with three different antipsychotic drugs: Clozapine, Buspirone and Haloperidol, with the aim at obtaining suitable formulations to perform in vivo studies in rats. Surfactant-free PLGA-PEG NPs were prepared using a nanoprecipitation method. The PLGA-PEG copolymer increases the half-life of the NPs in the bloodstream, due to reduced non-specific interaction with biological components. The PEG shell has been demonstrated to prevent the NPs aggregation, typically seen with uncoated PLGA NPs, and to prolong NPs circulation time by inhibiting their uptake by the mononuclear phagocytic system. Because in vivo studies can be hampered if the nanosuspension volume is too high to reach useful therapeutic drug concentrations, nanoparticle suspensions should be concentrated. A freeze-drying process was used to concentrate the produced nanosuspensions into dry powders and to increase storage stability. To help retaining the desired nanometer particle size after lyophilisation, sucrose was used as a cryoprotectant [2]. Colloidal nanocarriers were characterized by photon correlation spectroscopy (PCS) in terms of mean size, PDI, Zeta potential, and thermal analysis (DSC). The latter experiments showed that all drugs were efficiently encapsulated into the colloidal systems as suggested by the disappearance of the drugs melting peak. We demonstrated that each drug influence the cryoprotective effect of sucrose on surfactant-free PLGA-PEG NPs as suggested by the Sf/Si values (ratio of the final to initial NP mean size). Because cryoprotective action is a surface phenomenon, the possible presence of drug molecules on the NP surface could influence sucrose deposition during the drying process and consequently its efficacy, as suggested by PCS data. Difference in Zeta potential values confirmed our hypotesis, probably due to the different logP and chemical structure of the encapsulated drugs. We obtained a prolonged release profile for clozapine-loaded NPs. In vivo studies on murine models of schizophrenia are in course to compare the efficacy of IV administered nano-encapsulated vs. neat drugs.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/110275
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