Estudo da estabilidade e produção piloto de lipossomas pH-sensíveis furtivos de cisplatina

Abstract

Cisplatin (CDDP) is an antineoplasic drug used for the treatment of ovary, testicle, head, neck and lung carcinoma. The CDDP entrapment into liposomes is an alternative to circumvent severe side effects and the appearance of drug resistance which limit its use. However, thephysical (aggregation/fusion) and chemical (hydrolysis/peroxidation) instabilities limit the use of these drug carriers as pharmaceutical products. The preparation of freeze-dried pharmaceuticals is a strategy used to improve the stability of these formulations. Moreover, the development of an economically feasible and reproducible process of liposome production on a large scale becomes necessary. Therefore, the aim of this work was the study of different factors related to the chemical and physico-chemical stability of stealth pH-sensitive liposomecontaining CDDP (SpHL-CDDP) as well as the establishment of an efficient process for its production in a pilot scale. SpHL-CDDP were produced in a pilot scale using three stages, namely: reverse phase evaporation, homogenization under high pressure and ultrafiltration(REV/HAP/UF). The optimization of factors related to the homonogenization under high pressure (pressure and number of cycles) and ultrafiltration (number of cycles) was evaluated in this process of pilot production. The pressure of 500 Bar and number of cycles equal to 9were adopted for the production of SpHL-CDDP which presented a mean diameter of 99.0 ± 3.9 nm and encapsulation percentage of 12.9 ± 2.30. Two cryoprotectants, sucrose and trehalose, were investigated about their effectiveness to control the vesicles diameter and retention of encapsulated CDDP after the freeze-drying/rehydration step. The trehalose showed a higher ability to the formation of smaller vesicles than the sucrose. The long-term storage of SpHL-CDDP was evaluated by the alterations of the diameter, zeta potential and encapsulation of CDDP. After 135 days of storage, freeze-dried or diluted SpHL-CDDP didnot show any alteration of the vesicle diameter and zeta potential. However, the freeze-dried SpHL-CDDP were superior on the CDDP retention than the liposomal dispersion.