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PULMONARY RATIONALE AND HISTORY

The primary rationale to develop an inhaled liposomal product has not changed in the past 25 years since the development of inhaled liposomal formulations were first considered [4,5,29]. Similar to most inhaled products, the goal is to combat lung disease by delivering high concentrations of the therapeutic agent directly to the treatment site [3,24,30-32]. In contrast to oral or IV administration, which requires much higher doses to achieve the same drug concentration in the lung, the inhalation route of delivery results in lower systemic exposure [30,33]. The benefits described earlier for the IV-administered liposomal products may also apply to liposomal formulations delivered as aerosols to the respiratory tract—modified PK and reduced side effects.

The modified release profile of small molecule drugs from liposomes may allow for less frequent dosing compared to that of the unencapsulated form that would be rapidly absorbed from the lungs and need to be replaced more often (by more frequent administration events). In addition, for compounds that are bitter, cause cough, or have vesicant properties (e.g., cancer compounds), inhaled liposomal formulations may reduce local irritation in the airways and thus increase their tolerability, allowing for higher doses to be delivered, thus increasing the likelihood of achieving efficacy [32]. Furthermore, to treat intracellular pathogens, including nontuberculous mycobacteria (NTM), or bioterrorism threats like tularemia and pneumonic plague, appropriately designed liposomal formulations may be more effective due to their propensity to accumulate in alveolar macrophages [34].

Researchers targeting lung disease have used liposomes to encapsulate a wide variety of agents including small molecule drugs, peptides, proteins, and nucleic acids [24]. Initial efforts included attempts to improve asthma therapy by formulating steroids [35-37], bronchodilators [38,39], and cromolyn [40] in liposomes with the goal to extend their duration of effect. Additionally, oncology drugs (e.g., 9-nitrocamptothecin [41,42], IL-2 [43], and cisplatin [44]) were encapsulated in liposomes to treat lung cancer more effectively by allowing higher doses to be administered with reduced side effects. Some of these inhaled liposomal products were evaluated in human subjects or patients, but none remained in clinical development, for a variety of reasons. For asthma treatment, long-acting beta agonists (e.g., salmeterol [Serevent Diskus®, Advair®] and formoterol [Foradil Aerolizer®]) and long-acting muscarinic antagonists (e.g., tiotropium, Spiriva®) were developed with a greater duration of effect, thus reducing the business proposition for formulation strategies using liposomes in this therapeutic area.

During the 1990s, after safety concerns arose with the use of viral vectors for the delivery of gene therapy products, interest in the use of liposomes and lipid complexes for gene therapy applications exploded. However, the interest was relatively short-lived due to the difficulties in showing correlations between in vitro transfection and in vivo effect, as well as toxicities associated with some of these charged lipid complexes [32].

The development activity of inhaled liposomal products waned for a period of time in the early 2000s, but interest in using these formulations to address unmet needs in the field of lung infection and lung transplantation gradually emerged. AmBisome, a liposomal amphotericin B, is used off-label by nebulizer to treat patients with fungal infections in the lung and was found to be better tolerated than formulations of “free” amphotericin B [32]. As a prophylactic therapy, AmBisome is also inhaled to prevent fungal infections in lung transplant patients [45-47].

Cyclosporine, an immunosuppressive, has been delivered by nebulizer to prevent rejection in lung transplant patients. Due to cyclosporine’s poor aqueous solubility, the nebulizer formulation contained propylene glycol, which was irritating and may have contributed to its failure in the clinic [48]. Liposomal formulations of cyclosporine have been developed and found to be well tolerated by inhalation [49,50]; however, the clinical failure of the propylene glycol formulation—possibly due to poor compliance in response to its poor tolerability, rather than a true lack of efficacy—may have blunted enthusiasm for continued development of a liposomal cyclosporine product [32].

There are now two liposomal products in the late stages of clinical evaluation to treat lung infection and these will be described more thoroughly later in this chapter: liposomal amikacin [51-55] and liposomal ciprofloxacin [30,56-59].

 
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