Liposomes as Drug Delivery Vehicles
By Tony Nakhla, N/A
It was reported almost 40 years ago that when phospholipids are subjected to aqueous environments, closed bilayer structures called liposomes spontaneously form that can encapsulate part of the aqueous medium in their interior.
Initially, liposomes were attractive to biophysicists as model systems for biological membranes. The lipid bilayer structures of liposomes mimic the barrier properties of biomembranes, and therefore, they offered the potential of examining the behavior of membranes of known composition. Thus, by altering the lipid composition of the bilayer or the material incorporated, it was possible to establish differences in membrane properties. Model membranes have facilitated the study of the lipid-protein interactions occurring in biological membranes and have been used in a multitude of research projects concerning membrane structure and function.
Liposomes may differ in their size, composition, charge, and lamellarity, and accordingly, a wide range of compounds may be incorporated into either the lipid or trapped aqueous space. Such flexibility has presented several potential applications to scientific investigators and liposomes have since been adapted to numerous other potential applications. Because of their biodegradable and non-toxic nature, liposomes can be safely administered without serious side effects and are frequently used as drug delivery vehicles.
Liposomes are regarded as suitable carriers because they can serve as a depot system for the sustained release of an associated compound. One of the basic goals of chemical therapeutics is to deliver the drug efficiently and specifically to the site of disease. Some drugs may be delivered in their free form whereas others require a carrier in order to reach and enter their final destination because a) they are rapidly cleared from the area of introduction or the circulation or b) they are obstructed by biological barriers which they cannot permeate. Liposomes can alter the biodistribution of entrapped substances and protect the enclosed materials from inactivation by the host defense mechanisms. Therefore, liposomes can be used as vehicles to achieve specific delivery of therapeutic drugs to target organs. In addition, liposomes can reduce toxicity of antimicrobial, antiviral and chemotherapeutic agents and have demonstrated the ability to modulate or potentiate the immunogenicity of antigenic substances, that is, function as immunological adjuvants. Accordingly, myriad drugs and antigens have been incorporated into liposomes to achieve those objectives. More recently, liposomes have been demonstrated to be efficient vehicles for gene therapy.
With the many potential uses presented by these model membranes, the therapeutic applications of liposomes are dependent on the physical integrity and stability of the lipid bilayer structure. There are numerous techniques for liposome preparation and the resulting vesicles may be large, or small, and of unilamellar or multilamellar nature. Multilamellar vesicles (MLV), composed of numerous concentric bilayers, are produced from mechanical agitation of a dispersion of dried lipid with an aqueous phase. Mechanical agitation is the simplest method forproduction of MLV that produces a suspension of large liposomes that are very heterogeneous in size and exhibit a relatively low level of aqueous encapsulation. However, homogenous liposome formulations that exhibit reduced vesicle diameters are advantageous with respect to extended circulation half-life, and consequently, enhanced uptake by tissues and organs. These parameters are critical to the in vivo behavior of liposomal drug delivery systems. Large unilamellar vesicles (LUV) can be prepared from MLV to exhibit the characteristics that are beneficial for enhanced delivery of the incorporated material.
The most common method for LUV preparation is extrusion of MLV under pressure through membranes of known pore sizes. These LUVs' are utilized to optimize the incorporation of a desired compound within liposomes, to limit the permeability of the membrane to the entrapped material and to alter half-life in circulation in attempts to enhance the therapeutic efficiency of a liposomal formulation.
However, making liposome formulations exhibiting narrow size distribution has been a formidable challenge under the demanding conditions and large volumes required for pharmaceutical production. At moderate volumes, size reduction is often not consistent and unpredictable membrane clogging occurs. To manufacture lipid-based drug delivery systems on a commercial scale the extrusion process must work with 10–1,000 L volumes.
As a result of the encouraging data that has been generated by several laboratories, liposome therapy has moved into the clinic. Accordingly, an efficient, robust system that can reproducibly generate homogenous unilamellar liposome formulations which exhibit diameters in the 100–200 nm range, and limit the amount of lost material is a necessity for the pharmaceutical, biotechnology, and cosmetic industries. In addition, sterility and processing are critical issues in the development of large volume liposomal formulations under cGMP conditions.
Anthony Nakhla is senior scientist in R&D at SP Pharmaceuticals. His doctoral thesis in biochemistry from Memorial University involved the development and characterization of liposomal vaccines to strengthen immune responses against bacterial endotoxin. His industrial experience with Lipex Biomembranes included development of anti-cancer formulations and scale-up of lipid based delivery systems.
For more information: Arthur C. Solomon, Vice President of Business Development, SP Pharmaceuticals, 4272 Balloon Park Road NE, Albuquerque, NM 87109. Tel: 505-761-9230. Fax: 505-761-9229.
Visit SP Pharmaceuticals' Storefront on Pharmaceutical Online.