# Sildenafil Citrate Liposomes for Pulmonary Delivery by Ultrasonic Nebulization
## 1 Introduction  
Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by a progressive increase in pulmonary vascular resistance, leading to right heart failure and premature death [1]. Therapies for PAH target the prostacyclin, endothelin, or nitric oxide pathways, and are believed to be effective by reversing or diminishing vasoconstriction, vascular endothelial cell proliferation, smooth muscle cell proliferation, and endothelial dysfunction [2]. Approved drugs currently used in the treatment of PAH include the orally administered 5-phosphodiesterase (PDE-5) inhibitors--sildenafil and tadalafil. Sildenafil was first approved in 1998 for erectile dysfunction, but additional uses for the drug have since been found [3]. In 2005, its use was approved for PAH in adults, and, in 2011, sildenafil received approval for the treatment of pediatric patients aged 1-17 years [4]. Intravenous injection of sildenafil is also approved for patients who are unable to take sildenafil orally [5]. Sildenafil increases the level of cyclic guanosine monophosphate (cGMP) in the body, where the accumulation of cGMP leads to a series of cellular changes that cause decreased intracellular calcium levels and the relaxation of smooth muscles [6; 7]. PDE-5 inhibitors have been associated with ocular side effects [8], but other unwanted effects, such as systemic hypotension, are expected, since PDE-5 is found in the corpus cavernosum, retina, platelets, smooth muscles of the vascular system, and pulmonary circulation [7]. In 2012, the FDA issued a warning against the use of sildenafil in pediatric patients, based on the results of a clinical trial showing a higher risk of mortality after 2 years of treatment among children randomized to high-dose treatment, versus those receiving low doses [9]. Pulmonary drug delivery is an efficient method for passive drug targeting, with relevant advantages compared to oral or intravenous administration. Direct access to the respiratory system and the avoidance of extensive systemic exposure are some of the most interesting features of this route for PDE-5 inhibitors used in PAH treatment. Antibiotics are among the drugs considered for pulmonary administration [10; 11], and nanocarrier-mediated drug delivery to the lungs proved beneficial over conventional inhalation in handling various pulmonary diseases [12]. Studies with isolated rat lung proved that vancomycin nebulization produced much higher drug levels in respiratory tissue and bronchoalveolar fluids than those achieved in systemic fluid [13]. Also, nebulization of liposomes facilitated the drug uptake in the lungs, compared to the drug solution [14]. Among colloidal carriers, liposomes have been shown to be safe for pulmonary administration in animals and humans. Inhalation of hydrogenated soy phosphatidylcholine liposomes did not cause pathological effects on alveolar macrophages or physiological abnormalities in the lungs of sheep, even after prolonged administration. Also, liposomal insulin formulations delivered to the lungs by nebulization have been reported to be safe in animal models [15]. Moreover, some studies have established that the inhalation of liposomes is safe for humans, and that inhaled liposome-entrapped becometasone is well tolerated by humans when administered in therapeutic doses [16]. Arikace(r), an anti-pseudomonal liposome formulation, has been shown to be safe and suitable for inhalation by humans suffering from cystic fibrosis [17]. Liposomes are known for their sustained drug release capability, as shown by [PERSON] et al. [18]. These authors found that an aerosolized liposomal formulation of terbutaline produced a prolonged anti-asthmatic effect, in comparison to the solution aerosol. Sustained drug release avoids the high peaks associated with side effects and reduces the dose frequency required for maintaining therapeutic levels. Accordingly, the inhalation of drugs entrapped in liposomes is likely to produce safer and more efficacious kinetic profiles than the inhalation of free drugs.