Andrade, Claudia Marlise Balbinotti

Dalla Costa, Teresa Cristina Tavares

Guterres, Silvia Stanisçuaski

Haas, Sandra Elisa

Sansone, Pedro Ernesto da Silva

English

Lume 5.8

ISSN 0102-6593 caderno do farmácia Órgão Oficial da Faculdade de Farmácia da Universidade Federal do Rio Grande do Sul volume 26, Suplemento, 2010 TECNOLOGIA FARMACÊUTICA E BIOFARMÁCIA 226 ___________ ')-__j_~___,__!CS _ _,=--Y_._)--"-. _____ Ph~rmaceutical technology and biopharmacy NEW OIL CORE SELF-ORGANIZED NANOPARTICLES PREPARED WITH CHITOSAN ANO LECITHIN: DEVELOPMENT, CHARACTERIZATION ANO PHARMACOKINETIC EVALUATION USING CLOZAPINE AS DRUG MODEL Haas 8.E.' 1 ; Andrade C. 1 ; 8ansone P.E.8. 1 ; Guterres 8.8. 1 ; Dalla Costa T. 1 1 Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, UFRG8. *Doutoranda -Início: 2009/1 lntroduction: Chitosan is a cationic polysaccharide, biodegradable, biocompatible, low toxicity, mucoadhesive that has demonstrated to improve the absorption and biodistribution of drugs1• In this context, we propose the development of innovative oily core self-organized nanoparticle prepared by the interaction between chitosan and lecithin, to allow the encapsulation of different drugs. Clozapine (CZP) has low bioavailabilit/ and was used as a drug model. Objectives: The aims of this work were: a) to develop and physico-chemically evaluate the influence of isopropyl myristate, chitosan and lecithin on the properties of the self-organized nanoparticles; and b) to develop, physico-chemically evaluate the self-organized chitosan nanoparticles loaded with CZP, and to investigate the drug pharmacokinetics (PK) in rodents. Materiais and Methods: Nanoparticles suspensions were obtained by injecting through a funnel 4 ml of a Lipoid 845 in ethanol and isopropyl myristate solution into 46 ml of a chitosan aqueous solution mechanically stirred through Ultraturrax (3). A 33 factorial design was applied varying chitosan viscosity (30, 60 and 90 cP), percentage of isopropyl myristate (1, 2 and 4%) and concentration of Lipoid 845 in the ethanolic solution (25, 50 and 100 mg/ml). The obtained systems were characterized by particle size (laser diffractometry, Mastersizer 2000, Malvern lnstruments, London, UK), zeta potential (electrophoresis, Nanosizer®), pH and viscosity (using Brookfield® rheometer). The characterization was conducted right after the preparation. The results were analyzed using 8tat graphics ® Plus v. 5.1. CZP (2 mg/ml) was incorporated in the system consisting of 100 mg/ml of Lipoid 845®, 1% of isopropyl myristate and chitosan aqueous solution (30 cP). Physico-chemical evaluation was carried out by determining particle size, polydispersity index (PDI) and zeta potential. 8tability evaluation of nanosystems was performed by optical analyzer Turbiscan® Lab (25 ºC, 1 h, scan every 5 min). Transmission electron microscopy (TEM) was evaluated after nanosuspensions fixation with uranyl acetate. PK investigation was conducted in Wistar rats (300-350 g) after 1 O mg/kg oral dosing of free and nanoencapsulated CZP (n = 6/group). Blood samples were withdrawn from the lateral tail vein at pre-determined time points and plasma samples were analyzed by LC-M8/M8 using a previously validated method. Results and Discussion: Content of chitosan influences the pH values, which ranged from 3.5 to 4.2, using 0.4% and 0.8% of the cationic polymer, respectively. Viscosity showed values between 39 and 127 cP. Zeta potential was strongly positive (+41 to +52 mV), and lower values were obtained with 25 mg/ml of Lipoid 845 concentration. 8imultaneous increase of surfactant and isopropyl myristate increased the zeta potential. Besides that, it was observed single peaks of zeta potential for each formulation, indicating the absence of other type of particle, only nanocapsules. Nanocapsules presented a wide range of particles size (0.422 to 3.755 11m). The increase of isopropyl myristate increased this parameter, while the concentration of Lipoid 845 was important for the reduction of nanocapsules size. The formulation with 100 mg/ml of Lipoid 845®, 1% of isopropyl myristate and chitosan aqueous solution (30 cP) showed the smallest diameter and PDI and it was chosen for the incorporation of clozapine. CPZ-Ioaded and blank nanocapsules presented mean diameter of 181 ± 3 and 470 ± 2, nm, acid pH values (3.67 ± 0.01 and 3.75 ± 0.03), positive zeta potentials (+42 ± 1 and + 48 ± 2 mV) and IPD bellow 0.2 and 0.3, respectively. Backscattering analyses demonstrated slight alteration of diameter for CZP-Ioaded nanocapsule. The TEM evaluation revealed the presence of nanometric, spherical and oval nanoparticles in both suspensions. After Wistar rats oral dosing, an increased AUC was observed encapsulated CZP indicating an increased drug bioavailability. Conclusions: The results demonstrated the biological applicability of this new self-organized chitosan nanoparticle for improving drugs oral bioavailability. References: 1. R.J. Freddo. Tese de Doutorado. PPG em Ciências Farmacêuticas, UFRG8, , 2009. 2. K. Manjunath, V.Venkateswarlu, J Contrai Release. 107, 215 (2005). 3. F. 8onvico et ai., lnt J Pharm. 324, 67 (2006). 

New oil core self-organized nanoparticles prepared with chitosan and lecithin : development, characterization and pharmacokinetic evaluation using clozapine as drug model

https://lume.ufrgs.br/bitstream/10183/267772/1/000770547.pdf

New oil core self-organized nanoparticles prepared with chitosan and lecithin : development, characterization and pharmacokinetic evaluation using clozapine as drug model

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