Production of didanosine-loaded poly(epsilon-caprolactone) microparticles by spray-drying: From design to in vivo evaluation

SEREMETA, KP; HOCHT, C; TAIRA, C; REYES TUR, MI; LÓPEZ HERNÁNDEZ, OD; SOSNIK, A

Rosario, Santa Fé

Congreso; 8vo Congreso Latinoamericano de Órganos Artificiales, Biomateriales e Ingeniería de Tejidos; 2014

Sociedad Latinoamericana de Biomateriales, Organos Artificiales e Ingenieria de Tejidos (SLABO)

The Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) is the most deadly infectious disease of our times with approximately 35 million infected people worldwide. The High Activity Antiretroviral Therapy (HAART) has improved the therapeutic outcomes. However many antiretroviral drugs have biopharmaceutical drawbacks resulting in reduced oral bioavailability. Didanosine (ddI) is a first-line anti-HIV agent approved by the US-FDA that displays short plasma half-life (1-2 h) and low oral bioavailability (20-40%) due to its fast hydrolysis under gastric pH conditions to the corresponding inactive hypoxanthine. Therefore, ddI is often administered in buffered formulations, though the addition of basic salts may provoke intestinal and renal adverse effects. In this context, the encapsulation of ddI within polymeric particles would be a useful strategy to stabilize it in the gastric environment and to improve its oral bioavailability. Spray-drying is a one-step process that involves the transformation of a material from a fluid state into dried particulate form by spraying the liquid into a hot drying gas medium. The speed of the process and the consequently short processing time enables the drying of even temperature-sensitive products without thermal degradation. Furthermore, the possibility to scale-up the production of pharmaceuticals without major modifications of the experimental conditions has promoted a growing interest in this method. In the present work, we developed microparticles made of poly(epsilon-caprolactone) (PCL) of molecular weight 40,000 g/mol loaded with ddI by spray-drying. The equipment used was a Mini Spray Dryer Büchi B-191 (BÜCHI Labortechnik AG, Suiza) operated in an open-loop mode with compressed air as the drying gas. Precursor solid-in-oil (s/o) suspensions or water-in-oil (w/o) emulsions with four different drug cargos (50, 100, 150 and 200 mg) were spray-dried and the fine powders produced thoroughly characterized. Drug-loaded particles displayed diameters between 36-118 µm with spherical morphology and smooth surface. In addition, free ddI crystals were barely observed. The encapsulation was confirmed by ATR/FT-IR analysis that show only a very low amount of drug on the surface. Encapsulation efficiency varied from 60 to 100%. DSC analysis showed that the degree of crystallinity of ddI in the particles was between 46 and 99% (being undetectable in a case). XRD analysis was in agreement with DSC. In vitro release assays (PBS pH = 7.4) showed the relatively fast release of drug from particles. Finally, pharmacokinetics studies in Wistar rats showed that ddI-loaded particles lead to a statistically significant increase of the oral bioavailability of approximately 2.5-fold with respect to a ddI aqueous solution. These results supporting the use of spray-drying as a useful technology to encapsulate sensitive drugs within of polymer particles.