Solid state characterization and cytotoxicity evaluation of inhalatory microparticles based on indomethacin-polylysine complex

NAZARETH ELIANA CESCHAN; VERÓNICA BUCALÁ; HUGH SMYTH; MARÍA VERÓNICA RAMIREZ-RIGO

Río de Janeiro

Congreso; XVIII Congresso da Federación Farmacéutica SUdamericana (FEFAS)- 8 RioPharma (Congresso da Ciências Farmacêuticas); 2015

FEFAS-ABF

IntroductionIndomethacin (IN) is a non-steroidal anti-inflammatory drug that reduces pain and inflammation in rheumatoid arthritis. When administered by the oral route, IN exhibits variable bioavailability and produces undesirable gastrointestinal side effects. To overcome these problems, IN has been proposed for pulmonary administration (1). In the design of new inhalable materials, lung accessibility and absence of toxicity are important challenges. Microparticles based on IN and polylysine (PL, a cationic polymer) were previously obtained by spray drying (SD)(2). The SD process parameters were selected in order to obtain particles with aerosolization-deposition properties suitable for IN inhalatory delivery(2). The aim of the work is to characterize the solid state of the particulate material and to study the cytotoxic effect on a model lung cell line. MethodsPL (raw material was a physical mixture with dextrin (DX) in a 50:50 ratio) was dissolved in water and IN was added in an adequate amount in order to neutralize the 50% of the available amino groups of PL. The 1.3% w/v solution obtained was then processed by SD. The solid state characterization was performed by FT-IR spectroscopy, powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM). The cytotoxicity of the raw materials and the MP was assayed by the MTT colorimetric assay in A549 cells (adenocarcinomic human alveolar basal epithelial cells).ResultsIn the FT-IR spectra, the stretching band of COOH group and out of plane stretching band of O-H group of carboxylic acid characteristic of the IN completely disappeared in the SD microparticles (MP), due to the ionic interaction between IN and PL. The IN-PL complex was amorphous (by XRPD), a favorable characteristic for low solubility drugs, and the MP were rounded with smooth surfaces. PL cytotoxicity has been previously related to the interactions between cationic groups of the polymer and cytoplasmic membrane and/or negatively charged cellular proteins(3). However, the cytotoxic level of MP did not show a statistically significant difference with respect to the control at the selected therapeutic concentrations. The neutralization of PL by IN improved the material cytotoxicity profile.ConclusionNovel MPs were produced by SD of PL-IN solutions that exhibited amorphous structure and was not cytotoxic to alveolar model cells. Keywords: Spray-dried particles, Ionic interaction, Indomethacin, Polylysine, A549 cell culture. Acknowledgements CONICET, Bec.ar and Fulbright commission for the financial support. Lic F Cabrera for the technical assistance. References: 1. Onischuk A, Tolstikova TG, Sorokina IV, Zhukova N, Baklanov AM, Karasev VV, et al. Anti-inflammatory effect from indomethacin nanoparticles inhaled by male mice. Journal of aerosol medicine and pulmonary drug delivery. 2008;21(3):231?43.2. Ceschan NE, Bucalá V, Ramírez-Rigo MV. Polymeric microparticles containing indomethacin for inhalatory administration. Powder Technology. 2015; In Press.3. Gu Q, Lin R-L, Vanaman TC, Lee L-Y. Hypersensitivity of pulmonary chemoreflex induced by poly-L-lysine: role of cationic charge. Respiratory physiology & neurobiology. 2006;151(1):31?43.