MLs have Demonstrated Appreciable Potential and Promises to Overcome the CL Drawbacks
The ideal drug delivery system delivers the drugs at the target site and in a controllable manner to achieve the site-specific drug delivery. Today, various types of vesicular and particulate systems like liposomes, emulsion, nanoparticle etc. are developed to achieve controlled drug delivery. But, lipid vesicles (liposomes) are one of the most researched means of drug delivery carriers. Starting with the application of liposome as a therapeutic device in the mid-1950s, it seemed to be an attractive candidate as a drug delivery system. Liposomes resemble cell membranes in structure and composition. They are made of natural, biodegradable, nontoxic and nonimmunogenic lipid molecules and can encapsulate a large variety of both hydrophilic and hydrophobic compounds. Their utilization is based on their properties (dimensions, lamellarity, loading efficiency, surface properties, stability) as well as their biological interactions with the cells.
Liposomes are sealed sacs in the micron and sub micron range dispersed in an aqueous environment. In last three decades, a few liposomal formulations have already reached in market. E.g. Doxil, DaunoXone, AmBisome.
The conventional liposomes (CLs; first generation liposomes) and previously developed drug-delivery carrier liposomes including cationic liposomes, fusogenic liposomes, pH sensitive liposomes, long circulating liposomes, immuno liposomes etc. are impractical for delivery of several drugs, toxins, enzymes and protein/peptides. Typically, liposomes as a drug delivery carrier offer some advantages, but are simultaneously capable of having some drawbacks. CLs are highly susceptible to destruction via uptake by reticulo-endothelial system (RES), which can result in under-utilization and wastage of the entrapped drug. Also, CLs are rapidly eliminated from human body. For drug delivery, CLs can be administrated either topically or parenterally. Furthermore, liposomal phospholipids can undergo chemical degradation, such as oxidation and hydrolysis, which may result in aggregation, fusion or leakage of interior contents. Also, the variability of liposomes in storage temperature, leads to instability problems. In addition, CLs are highly unstable in biological fluids leading to a rapid release of encapsulated molecules. Thus, CLs have limited application in the development of controlled drug delivery system.
After numerous and various studies, new formulations of liposomes with increased stability were designed. Liposomes that can tolerate specifically induced modifications of the bilayers or can be covered with different molecules were constructed. Liposomes include pH-sensitive liposomes, which are able to avoid lysosomal degradation, proteoliposomes containing fusogenic proteins, cationic liposomes form complexes with DNA, target sensitive liposomes disintegrate after binding to a target cell and release the content in the cell vicinity, and immunoliposomes which direct toward specific sites by coupling antibodies to their surface. At present, several researchers continue to develop and refine the advanced controlled release technologies particularly in the development of polymer/membrane technology. Within this technology, microencapsulated liposomes (MLs) target a specific site in a microencapsulated polymer. The MLs have been studied as stable, adaptable and targetable drug carriers. MLs are composed of a wide range of phospholipids such as phosphatidylcholine, phosphatidylglycerol, and dipalmitoyl phosphatidylcholine, in conjunction with polymers such as alginate, acacia gelatin, Chitosan and gelatin alone.
Liposomes were first encapsulated in alginate by Wheatley et al. Again alginate is the first choice because it has been widely used to encapsulate various cell lines and is also easy to process. Generally, encapsulation of liposomes in a polymer matrix provides two control points for drug release; the first being the release of drug from the liposomes into the polymer matrix and the second being the diffusion of drug across the matrix and into the surrounding medium. Liposomal microcapsules were prepared by encapsulating a liposome suspension in a nylon wall formed by the interfacial polymerization technique. Also, the encapsulation of polymer within or association of drugs with liposomes may alter the drug pharmacokinetics and the alteration of liposome surface, which may be exploited to achieve targeted therapies. Thus, MLs are requisites of optimized liposomal drug targeting. To encapsulate the drug containing liposomes in a polymer matrix is in the form of a microcapsule called MLs. Such MLs systems have been studied for different purposes.
As mentioned above, the rapid uptake of liposomes referred as CLs by the RES has limited their use for targeting to other cells. As a result, the development of liposomes as drug delivery vehicles relied on attempts to construct vesicles that avoid the RES uptake and of regulating the release profile. Thus, the uptake of liposomes by the RES limits the duration for which the liposome circulate and can release the entrapped drug into the blood stream. To protect the liposomes from the RES and regulating the release profile, such approach would be advantageous for a drug that targets the particular system. In case of vaccine delivery, prolonging the release of the vaccine into the blood stream would help in evoking a stronger immune response and thus, a way of protecting the liposomes from immune system is to encapsulate the drug containing liposomes in a polymer matrix in the form of a microcapsule.
Also, MLs have been shown to extend in vivo drug retention times and also to elicit higher response as compared to liposomes alone. A significantly higher immune response was observed by the release of Hepatitis B surface antigen from liposome encapsulated in alginate compared to liposomes alone. In another study, liposomes bearing antigens are encapsulated within alginate lysine microcapsules and reportedly control antigen release and improve the antibody response. Liposomes of acetyl salicylic acid have been microencapsulated by acacia gelatin. Such liposomes exhibit greater stability and a potential for oral drug delivery system more than the corresponding one. Thus, MLs facilitate the oral liposome drug delivery. Also, the change in temperature, pH and use of surfactant, all promote the disintegration and leakage of the liposome. Thus, as a way to protect the liposome from external stimuli, liposomes are formulated as MLs.
Furthermore, such MLs systems have been studied by several investigators for the delayed or pulsed release of biologically active substances. A collagen matrix has been used to entrap liposomes for delivering insulin and growth hormones.
In liposomes, generally the tendency of the bilayer components of the different vesicles is to mix during preparation. Mcphail et al, 2000 have developed polymeric vesicles based on chitosan and prove that prepared MLs have least tendency to mix/aggregation during storage conditions. Liposomal microcapsules could be stored in the dry state as a free-flowing powder.
Liposomes are one of the most studied in the modern drug delivery system. To overcome some difficulties with respect to the liposome stability and the MPS uptake, MLs systems have been developed. Such approach is also being provided for improvement of stability, to protect the liposomes from rapid elimination in human body, and regulating the release profile. However, MLs demonstrated appreciable potential and promises to overcome the drawbacks of CLs. �
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