Liposome Controlled Release Systems

Polyelectrolytes have recently found application in the development of pH sensitive liposomal controlled release systems. This application arises from the fact that polyelectrolytes may be used both to stabilize liposomes, and to disrupt liposomes in a pH dependent manner. Although the use of liposomes in oral pharmaceutical compositions has been discussed [424], liposomes generally suffer from poor stability and are therefore prone to leakage of the entrapped active agents. To overcome this problem, several authors have stabilized the liposomes using polyelectrolytes. For example, Tirrell and coworkers have employed ionene [425], and polyethylene imine) [426] to stabilize liposomes. Similarly, Sato and coworkers have studied maleic acid copolymers [427], and Sumamoto and coworkers have studied liposomes [428] coated with polysaccharides. In related work, Kondo and coworkers have emphasized the use of carboxymethyl chitin to produce artificial red blood cells [429-435]. 

Seki and Tirrell [436] studied the pH-dependent complexation of poly(acrylic acid) derivatives with phospholipid vesicle membranes. These authors found that polyfacrylic acid), poly(methacrylic arid) and poly(ethacrylic acid) modify the properties of a phospholipid vesicle membrane. At or below a critical pH the polymers complex with the membrane, resulting in broadening of the melting transition. The value of the critical pH depends on the chemical structure and tacticity of the polymer and increases with polymer hydro-phobicity from approximately 4.6 for poly(acrylic acid) to approximately 8 for poly(ethacrylic acid). Subsequent photophysical and calorimetric experiments [437] and kinetic studies [398] support the hypothesis that these transitions are caused by pH dependent adsorption of hydrophobic polymeric carboxylic acids 

Similarly comb-like copolymers of vinyl pyrollidone and vinyl alkyl amines were shown [446] to influence the permeability of negatively charged phospholipid liposomes containing encapsulated carboxyfluorescein. At a pH of approximately 7, the copolymers allowed permeability and solute release due to polymer/liposome complex formation and disruption of the phospholipid membrane. 

Polymeric phospholipids based on dioctadecyldimethylammonium methacrylate were formed by photopolymerization to give polymer-encased vesicles which retained phase behavior. The polymerized vesicles were more stable than non-polymerized vesicles, and permeability experiments showed that vesicles polymerized above the phase transition temperature have lower permeability than the nonpolymerized ones [447-449]. Kono et al. [450,451] employed a polypeptide based on lysine, 2 aminoisobutyric acid and leucine as the sensitive polymer. In the latter reference the polypeptide adhered to the vesicular lipid bilayer membrane at high pH by assuming an amphiphilic helical conformation, while at low pH the structure was disturbed resulting in release of the encapsulated substances. 

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The rate of liposome accumulation in alveolar type-II cells is dependent on lipid composition. It is therefore possible to select liposome compositions displaying minimal interaction with these cells and thereby function as controlled-release systems for entrapped solutes. For example, liposomes composed of dipalmitoylphosphatidylcholine and cholesterol and containing entrapped sodium cromoglycate will provide sustained delivery of the drag for over 24 hours. Conversely other liposome compositions could be utilized for enhanced epithelial interaction and transport of the drug (e g. cationic lipids for the cellular delivery of the CFTR gene). 

Polyhedral niosomes were found to be thermoresponsive Fig. 7 (a). Above 35 °C, there was an increase in the release of CF from these niosomes even though the polyhedral shape was preserved until these vesicles were heated to 50 °C. Solulan C24-free polyhedral niosomes do not exhibit this thermoresponsive behavior [160] due to a decrease in the interaction of the polyoxyethylene compound solulan C24 with water at this temperature (due to decreased hydrogen bonding) as identified by viscometry [161]. This observed thermoresponsive behavior was used to design a reversible thermoresponsive controlled release system Fig. 7 (b). Thermoresponsive liposomal systems which rely on the changing membrane permeability, when the system transfers from the gel state (La) to the liquid crystal state (L 3) [162], are not reversible. This is not unex-... 

In the area of controlled release, the preparation of indomethacin sustained-release microparticles from alginic acid (alginate)-gelatin hydrocolloid coacervate systems has been investigated. In addition, as controlled-release systems for liposome-associated macromolecules, microspheres have been produced encapsulating liposomes coated with alginic... 

Echogenic liposomes seem to constitute one of the most sensitive ultrasound-controlled release systems yet described, with ultrasound having been used to trigger release from several different echogenic liposomal drug delivery preparations such as tissue plasminogen activator (tPA) and papaverin (22, 23). 

Drug Delivery. Philadelphia Taylor Francis. ISSN 1071-7544. Covers basic research, development, and application principles of drug delivery and targeting at molecular, cellular, and higher levels. Topics covered include all delivery systems and modes of entry, such as controlled release systems microcapsules, liposomes, vesicles, and macromolecular conjugates antibody targeting and protein/peptide delivery. Peer-reviewed. 

The use of liposomes has received special attention in clinical applications. Especially as carriers of drugs to treat cancer, with the advantage of being less toxic to patients and improve treatment efficacy [57]. Also, controlled release systems have been proposed based on liposomes targeted to the oral cavity [66]. In addition. Complexes of liposome-biopolymer-bioceramics in the regeneration of bone tissue have also been used [103]. 

Other surface-active compounds self-assemble into bilayer structures (schematically illustrated in Fig. 10b), which normally spherilize into structures termed vesicles. When vesicles are formed from phospholipids, the term liposome is used to identify the structures, which also provide useful drug delivery systems [71]. Solutes may be dispersed into the lipid bilayer or into the aqueous interior, to be subsequently delivered through a variety of mechanisms. Liposomes have shown particular promise in their ability to act as modifiers for sustained or controlled release. 

FIGURE 13.7 Reconstituted CLSM optical slices of the stratum corneum of the skin following skin delivery of FITC-Bac in vivo in SD rats. Comparison of skin permeation routes from systems containing 0.1% FITC-Bac following an 8 h skin exposure ethosomes vs. liposomes and hydroethanolic solution. (Reproduced from Godin, B. Touitou, E., J. Control. Release, 94, 365, 2004. With permission from Elsevier.)... 

Knepp, V.M., F.C. Szoka, and R.H. Guy. 1990. Controlled drug release from a novel liposome delivery system. II. Transdermal delivery characteristics. J Control Release 12 25. 

Knepp, V. M., Hinz, R. S., Szoka, F. C., and Guy, R. H. (1988), Controlled drag release from a novel liposomal delivery system. I. Investigation of transdermal potential, /. Controlled Release, 5,211-221. 

Paveli, Z., Skalko-Basnet, N., Filipovi -Gr i, J., Martinac, A., and Jalsenjak, I. (2005), Development and in vitro evaluation of a liposomal vaginal delivery system for acyclovir, /. Controlled Release, 106, 34-43. 

Liposomes have been used for years as components of drug delivery systems, and as transdermal carriers of active ingredients in the cosmetic industry (307, 308). More recently, liposomes have found use in the food and nutritional supplement industries. Keller (308) lists more than a dozen nutritional products on the market that have been formulated with novel liposome-based delivery systems. In the food area, hposomes have been studied for their ability to encapsulate and provide controlled release of enzymes (309, 310), and liposome-encapsulated enzymes have been used to accelerate the ripening of cheese (311). 

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