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Inhaled Liposomes

David Cipolla


Liposomes are supramolecular aggregates possessing one or more closed lipid bilayers and thus can vary in a number of attributes, including bilayer thickness, number of lamellae, and overall size and shape (usually spherical) depending upon their composition and how the formulation has been processed [1]. These lipid vesicles are typically composed of phospholipids and sterols in which both hydrophobic fatty acid tails of each phospholipid molecule are oriented toward the center of the bilayer, while the hydrophilic head group, for example, the phosphatidylcholine (PC) moiety, is oriented toward the internal or external aqueous phases [1,2]. The formation and stabilization of these bilayers is driven both by entropic factors related to the sequestration of the hydrophobic fatty acid tails from the aqueous medium as well as enthalpic elements due to hydrogen bonding between the hydrophilic head groups and van der Waals interactions between the aligned acyl groups of the fatty acid chains. Even for a specific liposomal formulation manufactured under controlled conditions, a range of liposome sizes and shapes will be present. The selection of the manufacturing processes, the controls over the various processing steps, and the ingredients that constitute the liposome as well as the solvents and buffers used during manufacturing will determine the extent of this heterogeneity and the reproducibility from batch to batch.

The pharmaceutical interest in liposomes arises because these lipid vesicles can be utilized to package drug molecules with superior pharmacologic properties relative to the unencapsulated drug alone. Two key attributes of liposomes are their size and morphology; liposomes can be produced spanning two orders of magnitude in size with unilamellar liposomes typically around 100 nm or smaller, while multilamellar liposomes can be as large as a few microns in size [1]. Another important parameter for liposomes is the ratio of drug to lipid; larger liposomes have the potential to encapsulate a greater amount of drug relative to lipid, but this advantage can be undermined if the larger liposomes are not stable or do not release drug at the appropriate rate to achieve safe and efficacious levels in the target organ. Thus, many liposomal products on the market or in development utilize unilamellar liposomes even though the potential drug payload on a per weight basis (and per liposome) is smaller [1].

The formulation development and the manufacturing process for liposomes are more complex and costly than for standard pharmaceutical products and so would not be utilized unless liposomal formulations provided an inherent advantage over that for the free drug alone. In spite of these challenges, liposomes are now well accepted as drug delivery vehicles with the potential to change the in vivo distribution of the encapsulated drug relative to that of the unencapsulated drug [1,3-5]. However, it is important to recognize that the drug can only assert its effect once it is released from the liposome, so the rate of release of the drug is a critical parameter that determines whether the liposome composition will be pharmaceutically efficacious.

More than ten pharmaceutical products utilizing liposomes have been approved in the United States for intravenous (IV) or subcutaneous administration [1]. The first one, liposomal amphotericin B (AmBisome®, Gilead Sciences) [6-8], was approved for the treatment of fungal infections in 1990 (in Europe), 29 years after Dr. Alec Bangham and colleagues first discovered liposomes [9]. AmBisome was followed in 1995 by liposomal doxorubicin HCl (DOXIL®, Centocor), which is now labeled for the treatment of ovarian cancer, Kaposi’s sarcoma, and myeloma [10-12]. A liposomal formulation of vincristine (Marqibo®, Talon Therapeutics) was approved in 2012 to treat a leukemia indication, Philadelphia chromosomenegative acute lymphoblastic leukemia, given via IV administration [1,13-16]. For these products, the liposomes provide an altered pharmacokinetic (PK) profile that leads to improved safety and efficacy and a reduction in side effects. For AmBisome, the liposomes also serve as a solubilizing matrix with the amphiphilic amphotericin B intercalated within the membrane bilayer. While hydrophobic drugs can be “solubilized” within the lipid bilayer, hydrophilic drugs can be compartmentalized within the interior of the liposome, either by passive encapsulation or by active transport [17], and in some cases form precipitates that can lead to a depot effect upon release [18].

The physicochemical properties of liposomes, and in particular their drug release profile, can be engineered into the formulation via a variety of strategies, including the following:

• Modification of the liposomal composition: An increase in the acyl chain length of PC can reduce the drug release rate of a liposomal formulation as was observed for liposomal vincristine [19].

  • • Addition of sterol: The presence of moderate amounts of cholesterol (e.g., 30%) reduces membrane permeability [20], leading to a slower drug release rate for many liposomal formulations, including adriamycin [21] and doxorubicin [22]. Cholesterol also increases membrane rigidity and thus the liposomes are more likely to retain their physical integrity in response to stress encountered during nebulization [23,24].
  • • Surface modification with polyethyleneglycol (PEG): The presence of covalently attached PEG groups can lead to longer circulation half-lives and slower release as was observed for doxorubicin from hydrogenated soy phosphatidylcholine (HSPC)/cholesterol liposomes containing PEG (DOXIL) versus egg PC/cholesterol liposomes without PEG (Myocet®) [12].
  • • Liposomal size and lamellarity: Unilamellar liposomes typically release their contents at a faster rate than multilamellar vesicles because each bilayer represents a barrier to transport or diffusion.
  • • Drug to lipid ratio: Higher drug to lipid ratios reduced the release rate of liposomal vincristine that was associated with an increase in efficacy [25].
  • • State of the drug inside the vesicle: Liposomes can be designed with drug in either a soluble or a precipitated form resulting in different release rates. For example, liposomes containing precipitated doxorubicin had slower release than those with doxorubicin in solution [18]. Similarly, liposomes containing ciprofloxacin in nanocrystalline form also had slower release than those with ciprofloxacin in solution [26,27].
  • • Choice of drug loading method: A larger transmembrane pH gradient reduced the release rate of liposomal doxorubicin [28].
  • • Other factors can influence the release rate, including osmolarity, pH, and choice of buffer and excipients encapsulated within the liposome.

For liposomes given systemically, other features have been exploited, including the addition of antibodies on the surface to target-specific receptors or PEG groups (producing “stealth” liposomes) to prevent uptake by the mononuclear phagocyte system. Stealth liposomes have a longer circulating half-life and enhanced localization in tumors and other pathological tissues with increased vascular permeability [1]. A good example of a product adopting this strategy is pegylated liposomal doxorubicin [10-12].

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