Current Pharmaceutical Design - Volume 8, Issue 6, 2002

The antifungal agents for systemic mycoses are only a few in number. Among them amphotericin-B is still the most widely used drug, but substantial side effects including nephrotoxicity limits its clinical usefulness. Efforts to lower the toxicity are synthesis of AMPH-B analogues such as AMPH-B esters and encapsulation in lipid vesicles in the forms of liposomal AMPH-B (AmBisome), amphotericin-B lipid complex (Abelcet), amphotericin-B colloidal dispersion (Amphocil) and intralipid AMPH-B. The newer formulations are effective against wide range of fungi, may be given in higher doses and nephrotoxicity is lowered. Although all of them showed comparable efficacies, a standard formulation is yet to be determined. In Japan, studies on efficacies of lipid nanosphere-encapsulated AMPH-B are in progress. Special drug career systems and dosage forms, such as nanoparticles and liposomes hold the promise of overcoming the pharmacokinetic limitations. Nanoparticles are stable, solid colloidal particles consisting of macromolecular material and vary in size. Nanoparticles represent an interesting carrier system for the specific enrichment in macrophage containing organs like liver and spleen. Injectable nanoparticle carriers have important potential applications as in sitespecific drug delivery. Modifications of liposomes in order to avoid uptake by RES, thus increase targetability has been attempted. A novel targetable liposome 34A-PEG-L modified with polyethylene glycol conjugated with MoAb, 34A specific to murine pulmonary epithelia has been evaluated in murine pulmonary aspergillosis. 34A-PEG-L-AmB showed higher tissue concentration and comparable efficacy than other AMPH-B formulations.

From the point of view of pharmaceutical design, development of carrier system of antimicrobial agents with functional properties should be required. We introduced here the development process of liposomal formulations of polyene macrolide antibiotics, amphotericin B (AmB) and nystatin as injectable dosage forms. Both development of the effective encapsulation method of these drugs in liposomes and investigation of the encapsulation mechanism and the molecular states of them are important to determine the optimum lipid composition for therapeutic uses. Enhanced encapsulation of these hydrophobic drugs, longcirculation in blood and high targetability are the required functional properties for the carrier system. Low encapsulation of AmB in liposomes has been overcome by the incorporation of polyethylene glycol-lipid derivatives, DSPE-PEG. Both the hydration with 9% sucrose solution and the complex formation between AmB and DSPE-PEG contribute not only to the enhanced encapsulation of AmB in liposomes but also to the stability and long-circulation properties in blood. Encapsulation mechanism and the molecular states of AmB in liposomes were also investigated by several methods. AmB-encapsulating PEG liposomes (PEG-L-AmB) with optimum lipid composition also showed reduced toxicity and higher therapeutic efficacy on murine model of pulmonary aspergillosis than that of conventionally used AmB formulations. Further enhanced therapeutic effects was observed by using AmB-encapsulating PEG immunoliposomes (34A-PEG-L-AmB) carrying monoclonal antibodies at the distal ends of the PEG chains. On the contrary to AmB, encapsulation characteristics of nystatin were apparently different from that of AmB, though the chemical structure is very similar. Self-association of nystatin with sterol-free lipid membrane dominantly influences on the encapsulation characteristics. Many experiments about the encapsulation of antimicrobial agents in liposomes have been demonstrated by many researchers, but there are not so much drugs developed for commercially used. Optimization of the formulation of functional drug-carrier system should be important for the practical uses.

Viral replication takes place only in the host cell. From this intrinsic characteristics of virus, therapeutics agents specifically target to the virus genome is quite difficult. However, genetic medicine toward viral gene is promising in terms of selective toxicity for viral infection. Genetic medicine including antisense DNA, ribozyme, aptamer, triplex and gene itself has been enthusiastically studied in the past decades. At the early age of genetic medicine research, there were many skepticisms about clinicla usage. However, the first antisense DNA is on the market in the USA and Europe. Although the mechanism of antisense manner is still controversial, it was clearly epoch-making in the human application of genetic medicine. Genetic medicine opens the possibility to combat virus replication in a sequence specific way.Virus utilizes the specific receptor on the host cells for entry this is the reason why virus has organ specificity (tropism). Since life cycle of each virus is unveiled, target for the therapeutic agent's reveals in a molecular level. Furthermore, decipher of viral genome has been carried out rapidly and inexpensively. Once we hand entire sequences of viral genome, more theoretical way to design genetic medicine targeted viral infection could be main stream in the development of antiviral agents. Furthermore, efficient drug delivery system (DDS) to deliver antiviral agents to the infectious site is highly needed. In this article, we will address the target molecule of antiviral agents and possible DDS for the infectious disease.

In recent years, a Drug Delivery System (DDS), a preparative approach attracts the attention in the development of new drugs. DDS focuses on the regulation of the in vivo dynamics, such as absorption, distribution, metabolism, and elimination, thereby improving the effectiveness and the safety of the drugs by an applicable use of drug preparation technologies. A conventional intravenous dosage form of Amphotericin B (AmB), Fungizone, is the most effective clinically available for treating fungal infections. However, the clinical efficacy of AmB is limited by its adverse effects. Several lipid formulations, such as Liposomal AmB (L-AmB), AmB lipid complex (ABLC), and AmB colloidal dispersion (ABCD), with reduced side effects have been developed. These formulations are reported to have excellent safety and efficacy. However, comparable efficacy can be achieved only when they are administered at high doses than AmB. One of the problems of using these formulations is that they are easily taken up by the reticuloendothelial system (RES). An artificial lipoprotein-like particles, a novel drug carrier Lipid Nano-Sphere (LNS), which is 25 - 50 nm in size and is composed of phospholipids and simple lipid. LNS show a higher plasma concentration of drugs and lower uptake by RES-tissue different forms other lipid base drug carriers. In vitro and in vivo, LNS incorporating AmB, NS-718, shows reduced toxicity, while maintaining activity against fungi. LNS have a unique characteristic as an effective carrier of AmB for treatment of fungal infection.

Liposome-encapsulated drugs often exhibit reduced toxicity and have also been shown to enhance retention of drugs in the tissues. Thus, encapsulation of drugs in liposomes has often resulted in an improved overall therapeutic efficacy. The results of efficacy of liposome-encapsulated ciplofloxacin or azithromycin for therapy of intracellular M. avium infection show enhanced cellular delivery of liposome-encapsulated antibiotics and suggest that efficiency of intracellular targeting is sufficient to mediate enhanced antimycobacterial effects. The antitubercular drugs encapsulated in lung specific stealth liposomes have enhanced efficacies against tuberculosis infection in mice. These results from stealth liposome study indicate that antitubercular drugs encapsulated in liposome may provide therapeutic advantages over the existing chemotherapeutic regimen for tuberculosis. Liposomes with encapsulated amikacin are able to protect collagen almost completely from adherence of bacterial cells of all strains examined and prevent from invading of bacteria.