Study of the pilot production process of long-circulating and pH-sensitive liposomes containing cisplatin.
Long-circulating and pH-sensitive liposomes, containing cisplatin (SpHL-CDDP), have been developed as an alternative aimed at avoiding severe side effects as well as the appearance of resistance, which can limit the use of free cisplatin. However, physical (i.e., aggregation/fusion) and chemical instabilities limit the use of these drug carriers as pharmaceutical products. The preparation of freeze-dried pharmaceuticals has proven to be a successful strategy implemented to improve the stability of these formulations. In addition, the development of an economically feasible, reproducible process of liposome production, on a large scale, has also become necessary. A pilot production process, using three stages (i.e., reverse-phase evaporation, homogenization under high pressure, and ultrafiltration), was used to prepare SpHL-CDDP. The optimization of factors related to the homonogenization under high pressure (i.e., pressure and number of cycles), ultrafiltration (i.e., number of cycles), and storage stability at 4°C were assessed by means of particle size, zeta potential, and encapsulation percentage. A 500-bar pressure and 9 cycles were adopted as measures for the production of SpHL-CDDP, which presented a mean diameter of 99.0 ± 3.9 nm and an encapsulation percentage of 12.9 ± 2.3. The use of trehalose as a cryoprotectant was investigated, regarding its effective ability to control the vesicle diameter and retain encapsulated CDDP after the freeze-drying/rehydration step. After 135 days of storage, freeze-dried or liquid SpHL-CDDP showed no significant change in mean diameter. However, the freeze-dried SpHL-CDDP proved to be more efficient, in terms of CDDP retention, than did the liposomal liquid dispersion.
dos Santos Giuberti
Cristiane
C
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brasil.
de Oliveira Reis
Eduardo Cássio
EC
Ribeiro Rocha
Talita Guieiro
TG
Leite
Elaine Amaral
EA
Lacerda
Rodrigo Gribel
RG
Ramaldes
Gilson Andrade
GA
de Oliveira
Mônica Cristina
MC
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006863:Hydrogen-Ion Concentration; D008081:Liposomes; D010316:Particle Size; D010865:Pilot Projects; D012867:Skin / Q000378:metabolism
D000970:Antineoplastic Agents; D008081:Liposomes; D002945:Cisplatin