A number of antimicrobial agents have been developed since penicillin was discovered. In spite of the strong antimicrobial activity, some of them are difficult to be used clinically due to their various side effects including the organ toxicity. On the other hand, some of them are not suitable for oral administration because of their poor absorbability. To overcome these problems, DDS technology has been applied. Some poorly absorbable drugs became to be used as the oral dosage form by converting to the well-absorbable prodrugs. Lipid-dispersed formulations, such as liposomes and lipid-nanospheres, of amphotericin B could make the antifungal drug less toxic and more effective. Recently, extensive studies are conducted to treat or protect against the virus infections. Oral vaccine delivery is one of the most attractive objectives. The use of the particulate dosage form has been investigated to deliver the vaccine to M cells. However, the most suitable properties of the carrier particles for the extensive binding to M cells and the sequential uptake remain to be clarified. To protect against influenza virus infection, the nasal applications of influenza vaccine were examined. The high protection against the viral challenge by the administration of influenza vaccine with sodium polystyrene sulfonate resin or CT 112 K, a mutant of cholera toxin, as the adjuvant was shown by the experiments in mice. The plasmid DNA could also protect against in influenza virus infection in mice while the method of effective introduction of the plasmid DNA to mucosal cells should be developed. The optimal DDS technology will lead the success of these novel approaches.

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Amphotericin B(AmB), polyene macrolide antibiotics, has been used for the treatment of systemic fungal infections. It is necessary to administer at higher dosage to treat pulmonary aspergillosis, however, its clinical use is limited by toxic side effects. Several kinds of carrier system, such as liposomes, microsphere and polymer micelles, have been developed to resolve the problems. Liposomal formulations of AmB, which make it possible to reduce its toxicity and improve the therapeutic efficacy, have been developed and now on the market in USA and Europe. But, further improvements of the encapsulation of AmB in liposomes and therapeutic efficacy have still been required, Enhanced encapsulation of AmB in liposomes by complex formation between AmB and polyethylene glycol-lipid derivatives, DSPE-PEG, has clearly solved the problems, which have been investigated by us. Hydration by 9% sucrose solution and incorporation of DSPE-PEG are required for the high encapsulation efficacy. AmB-encapsulating PEG liposomes showed not only high encapsulation of AmB but also high retention of AmB in Liposomes in vitro and long-circulation property in vivo. We also prepared the novel AmB-encapsulating PEG-immunoliposomes carrying monoclonal antibodies at the distal ends of the PEG chains. AmB-PEG-immunoliposomes and AmB-PEG liposomes showed the higher therapeutic effects on murine model of pulmonary aspergillosis than that of commercially used liposomes. Many experiments on the encapsulation of antimicrobial agents in liposomes have been demonstrated, but there are not so much drugs-carrier system applied for therapy. Determination of the optimum functional carrier system should be important for the practical uses.

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Virus infections are divided according to organ level such as respiratory apparatus infection, upper respiratory infection, lower respiratory tract infection, hepatitis, urinary tract infection and etc. since virus has organ specificity (tropism) Obvious locus of infection would make it convenient to design targeting pharmaceutical drug. However, antigen of influenza virus and human acquired immune deficiency virus (HIV) are frequently altered as well as others. Because of frequent alteration of target molecule, cellular targeting is never easy. Current available anti viral drugs are made targeted toward metabolic products of virus. Other type of and viral drugs are designed targeted viral gene like antisense drugs. Gene medicine itself would be categorized as target therapeutic agent. I will address the gene medicine which have been enthusiastically developed in addition to the current anti viral drugs.

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Fungal infection is an important opportunistic infection occurred in the patients with immunocompromised. Amphotericin B is an antifungal agents against Aspergillosis, however, the adverse effects is a problem for the treatment. The antifungal agents of amphotericin B drug delivery system are successful of the antifungal activity and safety. Liposomai amphotericin B (AmBisome) shows an efficacy against invasive pulmonary aspergillosis in the patients with neutropenia. Liposomal amphotericin B reduced the nephrotoxity after the therapy for the patients with invasive pulmonary aspergillosis. NS-718, a novel lipid formulation of amphotericin B, evaluated the efficacy against aspergillosis and cryptococcosis in an animal models. And NS-718 reduced the nephrotoxity in the evaluation of the cell damage to renal calls in vitro. Drug delivery system of antifungal agents is estimated the effective antifungal agents in the future.

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Since the discovery of Helicobacter pylori (H. pylori) in 1982 and subsequent understanding of its aetiological role in gastrointestinal diseases, importance of H. pylori eradication has been recognized. One of currently recommended regimens is based on proton pump inhibitor in combination with two antimicrobial agents, because none of antimicrobial agents can completely eradicate H. pylori by monotherapy. One of the reasons why antimicrobial agents having low MIC value cannot provide strong eradication in vivo is inefficient delivery following oral administration to the gastric mucus and epitherial cell surface where H. pylori exists. We have developed mucoadhesive microspheres, Adhesive Micromatrix System (AdMMS), containing a drug and a cross-linked poly (acrylic) acid powder dispersed in a waxy base, which has the ability to strongly adhere to gastric wall and to reside in the gastrointestinal tract for an extended period. AdMMS containing an anti-H. pylori agent, amoxicillin, adhered to H. pylori-infected mongolian gerbil stomach, completely eradicated H. pylori and cured gastritis. After AdMMS administration, the required dose of arnoxicillin to clear H. pylori was reduced by a factor of 10 compared to that of after suspension administration. AdMMS is expected to be a useful oral targeting drug delivery system for H. pylori eradication.

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Gels formed in situ following oral administration of aqueous solutions of sodium alginate to rabbits were evaluated as sustained-release vehicles. The formulation contained calcium ions in complexed form, the release of which in the acidic environment of the stomach caused gelation of the sodium alginate. Plasma levels of theophylline after oral administration of sodium alginate and a commercial oral sustained-release liquid dosage form were compared in rabbits. Bioavailability of theophylline from sodium alginate gels formed by in situ gelation in the animal stomach was increased by 3-fold in rabbits compared with that from the commercial oral formulation. There was no significant difference in the mean residence times of theophylline when administered by these two vehicles.

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Hairless animals have been frequently used for in vivo and in vitro skin penetration experiments. The flux and enzymatic activity are obviously influenced by the species of animal used. In this paper, we have investigated the penetration and metabolism of prednisolone(PN) and prednisolone 21-acetate (PNA) in the skin using two different strains of hairless mouse. The abdominal skin of hairless mouse, inbred (HOS : HR-1 and Hr/Kud) and closed-colony (BALB/cA hr/hr) mice, was mounted between in vitro side-by-side penetration systems or homogenized by Polytrone^® and Potter-Elvehjim type homogenizer. The thickness of whole skin (227 μm) and stratum corneum(29 μm) of HOS : HR-1 mouse was same as that of Hr^-/Kud mouse. The diffusion and partition coefficients in stratum corneum of PN for Hr^-/Kud mouse were 0.45 and 2.80 times as these for HOS : HR-1 mouse, respectively. The kinetic constants, V_max and K_m, for skin enzyme also differ between HOS : HR-1 and Hr^-/Kud mice.

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