Acyl Carbon Number of Phospholipid

AAC = area above curve (hypoglycemic response)

Figure 3 Influence of the length of the phospholipid acyl side chain on the pulmonary absorption of insulin.

Various glucocorticoids have also attracted attention for delivery using liposomes as a vehicle [71,76-81]. These are highly potent molecules normally delivered from pressurized metered-dose inhalers or dry powder inhalers for treatment of asthma. Young children with asthma or infants with inflammatory lung conditions cannot be treated using pMDls or DPIs. The alternative is to use a nebulizer, but this has, until recently, required that the drug be soluble in an aqueous environment—an issue for all the major inhaled steroids. Dilauryl PC in combination with beclomethasone diproprionate has been evaluated using a variety of nebulizers [76], with a view to identifying those devices best suited for aerosol delivery. A subsequent adult volunteer study was completed, and no adverse responses were reported after using reservoir doses of 1 mg beclomethasone and 25 mg dilauryl PC/mL. Dexamethasone entrapped in liposomes has also been tested in animal models [81,82] and found to be better retained in the lungs than "free" dexamethasone, signifying that the liposomes have a role in modulating absorption [82]. Triamcinolone acetonide (TA) and the phosphate (TAP) have also been incorporated in DSPC and DSPG lipsomes, where it was found that pulmonary residence time was a function of liposome size for TAP-containing but not the TA-containing liposomes. The conclusions that can be drawn from these studies is that there is a role for lipid-based steroid therapy but that much has yet to be learned about how they should best be formulated and used in the clinical setting. Furthermore, any liposome formulation worthy of commercial development will have to compete with the nebulizer-compatible budesonide suspensions (now available as Pulmicort Respules®) that are now in widespread use [83-86].

Antibiotics have also been aerosolized with lipids [87]. This combination has come about to deliver therapeutic agents that might otherwise not be used because of low solubility or toxicity. There are a variety of antibacterials, antifungals, and antivirals that demonstrate excellent in vitro activity but are not effective because of their systemic toxicity and/or poor penetration into the lung tissue. It is also believed that liposomes might be a means to deliver drug to macrophages harboring infections such as tuberculosis or other mycobacteria [88,89]. However, it has been known for many years that although alveolar macrophages will happily phagocytose liposomes, the phagosomes remain excluded from the cystol [90]. Unless the antibiotic is capable of diffusing across the internalized membranes, the liposome-drug targeting ability is compromised.

The main concern with delivering antibiotics to the lungs is the dose required. Recommended doses of most antibiotics via inhalation (e.g., colistin or tobramycin) are in the range of 250-500 mg daily. The drugs require delivery via nebulizer or some form of continuous delivery device. Drug concentrations as high as possible are necessary to deliver the maximum concentration of antibiotic to the lung surface, to minimize the dosing time, and thus, hopefully, to maximize compliance. Combined with lipids, the absolute mass dosed may exceed gram quantities, amounts that may be intolerable even if successful formulations could be created.

Formulations will increasingly become more complex as the content of the antibiotic is raised within the liposomes [91], and stability is a general concern: Dispersions may exhibit aqueous stability of only a matter of days. This issue has partially been addressed through the use of reconstituted lyophilized preps, and a formulation of anamycin has demonstrated over 3 months' stability in the solid state [56]. Beauloac et al. [58] have taken this one step further by aerosolizing a dry powder of lyophilized liposome-tobramycin to administer to mice infected with Pseudomonas aeruginosa. [58]. However, the use of powdered preparations does not address the dosing problem.

The merits of liposome antibiotic therapy vs. antibiotic alone seem rarely to have been compared directly. Studies have shown benefit of using some liposome antifungals [92], but the formulations were either under development or were commercialized as a liposome product for administration by injection [93]. So the debate must continue. Although liposomal formulations can be generated and aerosolized and have proved effective in combination with various drugs, do the benefits ultimately outweigh the issues developing these kinds of formulations [94]?

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