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BIOCOMPATIBILITY AND FATE OF LIPOSOMES IN THE LUNG

Surfactant and lipids, including both cholesterol and phospholipids, are endogenous to the lung. Of the phospholipids, PC is the major component in the lung and for this reason many inhaled liposomal formulations utilize a form of PC in their composition. Thus, it is expected that liposomes that are composed of sterols and natural phospholipids should be biocompatible. There is a long history of safe and efficacious administration of inhaled or instilled formulations of surfactants, lipids, and liposomes. Synthetic dipalmitoyl PC (DPPC) was delivered by aerosol to infants with respiratory distress syndrome (RDS) as early as 1964. This was followed by studies that demonstrated an improvement in symptoms for babies and infants with RDS after inhalation of DPPC and dipalmitoyl phosphatidylglycerol (DPPG) [24].

Schematic of nebulization of liposomes

FIGURE 8.2 Schematic of nebulization of liposomes. During nebulization, many of the primary droplets impact within the nebulizer and form smaller droplets or are exposed to shear during droplet formation. This process may be deleterious to the large multilamellar vesicles but unilamellar liposomes have a greater likelihood of being uncompromised. The drug molecules are represented by the dots. (From Cipolla, D. et al., Ther. Deliv., 4(8), 1047, 2013. With permission.)

Effect of jet, mesh, and ultrasonic nebulization on the release of encapsulated drug

FIGURE 8.3 Effect of jet, mesh, and ultrasonic nebulization on the release of encapsulated drug (or marker) as a function of liposome vesicle size. The black circles represent the release of carboxyfluorescein from liposomes comprised of soyPC and dipalmitoyl phosphatidylglycerol of different sizes. (From Cipolla, D. et al., Pharm. Res, 11(4), 491, 1994. With permission.)

A number of instilled or inhaled surfactant products are now on the market and have become the standard of care for RDS [86].

Transitioning from the biocompatibility of individual lipids to that of liposomes, even though biocompatible lipids were used in the composition of liposomes, questions remained about the ultimate fate of liposomes in the lung [5]. Inhaled liposomes will deposit both in the conducting airways and in the deep lung. Liposomes depositing in the central airways will be transported by the mucociliary escalator out of the lungs in time spans similar to those for insoluble particles [5]. This time frame allows an opportunity for the encapsulated drug to be released while mitigating concerns about long-term accumulation in the central airways. In contrast, the primary clearance mechanisms for liposomes depositing in the peripheral airways are incorporation into the surfactant phospholipid pool and uptake by alveolar macrophages [5]. In a study of lung transplant patients who inhaled liposomal amphotericin B aerosols over a median of 24 weeks, there were no changes in the lipid content in their lungs compared to control patients who did not receive inhaled treatment [47]. In summary, inhaled liposomes do not appear to accumulate in the lungs and their lipids are most likely processed and recycled similar to that for endogenous surfactant.

The safety of inhaled empty liposomes (without drug) has been assessed in a number of studies in animals and humans and no changes in lung function have been reported [5,24]. Other subjective measures of safety and tolerability have also been monitored and found to be acceptable [5,24]. For inhaled products to proceed into human clinical trials, inhalation toxicity studies in animals must be completed at doses severalfold higher than those in humans. While no inhalation toxicity studies have been published for the inhaled liposomal products in late-stage development due to their proprietary nature, presumably they have been reviewed by the regulators and the liposomal products have been deemed adequately safe to continue their evaluation in human clinical trials.

 
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