Abstract
The lyoprotective effects of mannitol and lactose have been evaluated in the production of sildenafil citrate liposomes. Liposomes were prepared by mixing the components under ultrasonic agitation, followed by a transmembrane pH gradient for remote drug loading. Mannitol and lactose, as compared to sucrose and trehalose, were used as the stabilizing agents, and different freeze-drying cycles were assayed. The remaining moisture and the thermal characteristics of the lyophilized samples were analyzed. Size, entrapment efficiency, biocompatibility, and cell internalization of original and rehydrated liposomes were compared. The type of additive did not affect the biocompatibility or cell internalization, but did influence other liposome attributes, including the thermal characteristics and the remaining moisture of the lyophilized samples. A cut-off of 5% (w/w) remaining moisture was an indicator of primary drying completion—information useful for scaling up and transfer from laboratory to large-scale production. Lactose increased the glass transition temperature to over 70 °C, producing lyoprotective effects similar to those obtained with sucrose. Based on these results, formulations containing liposomes lyophilized with lactose meet the FDA’s requirements and can be used as a biocompatible and biodegradable vehicle for the pulmonary delivery of therapeutic doses of sildenafil citrate.
Highlights
Among colloidal carriers, liposomes are safe for pulmonary administration in humans and animals [1,2,3,4], and much progress has been made in the formulation of liposomal drugs
The application of a transmembrane pH gradient to liposomes without any additive led to an EE% > 60%
The sildenafil citrate (SC) liposomes obtained in this study showed the following critical attributes: (A) biocompatibility and biodegradability, since Egg L-α-phosphatidylcholine (EPC) and Ch are both components of the pulmonary surfactant; (B) no risk of solvent residuals, since liposomes were prepared in the absence of organic solvents; (C) the size and zeta potential accorded with those values recommended for particles used for pulmonary administration; (D) the drug loading (DL) values were high enough to enable a level of pulmonary drug exposure higher than that achieved with the current administration routes used for pulmonary hypertension
Summary
Liposomes are safe for pulmonary administration in humans and animals [1,2,3,4], and much progress has been made in the formulation of liposomal drugs. The lyophilization of liposomes is considered the best approach for avoiding drug leaking and vesicle fusion/aggregation, as well as for protecting the lipid bilayer from oxidation [6,7,8,9]. Much work has been carried out in this field and, as a result, different lyoprotectants have been proposed as stabilizing agents, with sugars being considered the best option [5,10]. Studies on the administration route for liposomal formulations have been carried out Pharmaceutics 2021, 13, 1164.
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