Around 1990, the pulmonary delivery of liposomes was largely an academic exercise [43-46] and at best at an early stage of commercial development . However, these and earlier efforts demonstrated the utility of liposomes, and interest has continued to flourish. This has been reinforced by greater acceptance of the dosage form, since there are now several injectable liposomal products on the market [e.g., Ambisome®, Fungisome®, Myocet®]. The specific use of lipid-based vehicles to deliver plasmid-based DNA has attracted much attention [48 - 51]. These developments have indirectly helped improve the quality and variety of
Figure 2 In vitro release profiles of rifampicin and rifampicin coated with PLGA or PLA.
lipids now available, and for similar reasons better analytical technology to study liposome characteristics and biology has emerged.
Nebulization can cause disruption or "processing" of multilameller vesicles . Fortunately, these issues can be addressed, and, through manipulation of the composition, buffer and environment liposomes have been aerosolized without causing loss of entrapped drug [53-55]. Liposomes have also been prepared as spray-dried and lyophilized powders [56-59]. The former may be aerosolized directly as a powder, but in both cases reconstitution in an aqueous environment results in liposome formation. However, it is not understood if this is just spontaneous reformation of original liposomes (pre-spray-drying) or the creation of de novo liposomes in an aqueous environment.
With respect to safety and the use of phospholipids, no NDA-supporting chronic inhalation studies have been conducted except for those found in commercial pulmonary surfactants. These studies presumably will have involved intratracheal instillation and not aerosolization, since the primary indication is respiratory distress syndrome of the newborn. Nevertheless, the fact that these products are available suggests that synthetic versions of natural lipids such as dipalmitoyl phosphatidylcholine (DPPC) and dipalmitoyl phosphatidylglycerol (DPPG) are likely to be well tolerated. This assumption has been supported from subchronic aerosol studies in mice  and acute single-dose aerosol studies in man, the latter involving soy-derived phosphatidylcholines .
A variety of other small molecules and proteins have also been incorporated with liposomes. In all cases, modulation of absorption or the response has been distinguished due to the presence of the phospholipids. A brief discussion on selected molecules now follows.
The potential of liposomes as extended delivery vehicles for beta-agonists has been investigated [62-65]. The rationale is logical because the short duration of action of compounds like terbutaline and albuterol requires frequent dosing (1-2 actuations four times daily). A less frequent dosing regime would be welcomed by patients and may lead to better compliance and less abuse of these drugs. Results with metoproterenol proved disappointing, but animals receiving albuterol  and terbutaline  resisted a challenge from a bronchocontstrict-ing agent for an extended period relative to the drug alone. To some degree, interest in this approach has waned with the introduction of longer-acting beta-2 agonists such as salmeterol  and formoterol . However, these newer drugs do not satisfy the need for immediate relief that the short-acting beta-agonists can provide.
An intriguing 1996 study conducted by Li and Mitra  examined the length of the acyl side chain of the lipids on the absorption of insulin from the lungs and observed an unusual parabolic relationship between glucose lowering and the length of the acyl side chain (Fig. 3). In a 2001 paper  they expand on this finding and note that DPPC mixtures with insulin produce higher circulating levels of insulin than liposomes alone after intratracheal instillation. Together, these results highlight the importance of phospholipid type and structure on biological effects.
Cyclosporine A is indicated for the prophylaxis of organ rejection associated with allogeneic transplants. It has not been indicated for lung allografts, because systemic therapy does not provide the necessary level of imunosuppression at tolerable doses . It is poorly water-soluble and has been formulated in various solvents, including alcohol, oil, and even Cremophor EL. Issues concerning inhaled therapy relate to the narrow therapeutic index of the drug, the high doses that will be necessary for transplant rejection, possible irritation in sensitive and diseased tissue, the increased risk of infection and, importantly, the identification of a suitable formulation . Although cyclosporine has been nebulized using nonaqueous intravenous formulations [72,73], this is hardly an optimized medium. Not surprisingly, cyclosporine has been successfully formulated as a liposome aerosol  and has been tested in normal volunteers . Some irritation was noted, which appears to have been related to the drug and not the lipids. This apparently was lessened through the use of a face mask. The pharmacokinetics of the liposome formulation has been studied in dogs via inhalation, and, as expected, lung concentrations were substantially higher than those of the other major organs .
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Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...