Trends and future perspectives in drug delivery research are discussed. Recently research on movement and fate of various compounds including drugs attracts great interest not only in the field of therapeutics but also in all fields of life science. In order to elucidate and control in vivo fate of drugs, its disposition features should be analyzed based on a pharmacokinetic model. Based on obtained information about relationship between physicochemical and biological properties of drugs and their in vivo disposition, total performance of drugs in the body can be controlled deductively. Progress in drug delivery technology would develop new era in medicine.

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The recent rapid progress in molecular biology makes it possible to produce peptides in sufficient quantities at reasonable cost. The development of the oral peptides delivery system is highly desirable ; however, poor absorbability and low stability of peptides in the gastrointestinal(GI) tract make it difficult. In order to develop successful strategies for enhancement of the oral bioavailability of peptide drugs, we have investigated various pharmaceutical approaches using insulin, one of the typical peptide drugs. As the first step, insulin absorption from various sites in the rat intestine was compared using the in situ ligated loop technique. The results suggest that the ileum seems to be the most useful region in the small intestine for insulin absorption ; however, insulin must be protected from proteolysis to enhance its absorption. Further, we evaluated the effectiveness of an oral administration of Eudragit insulin microspheres (IMS) containing a protease inhibitor. A significant continuous hypoglycemic effect was obtained after the oral administration of IMS containing aprotinin or Bowman-Birk inhibitor in both normal and diabetic rats. However, the efficacy of oral administration, relative to i, v., remains low. Thus, as the next step we prepared water-in-oil-in-water (w/o/w) emulsions by a two-step emulsification procedure and liposomes by a reverse-phase evaporation method. These preparations were expected to protect insulin against proteolysis in the GI tract. A significant hypoglycemic effect was observed at the ileum and colon loops after administration of the filtered emulsions containing 5% w/w gelatin in the inner phase. In the colon, the hypoglycemic effect of the emulsion containing fatty acids such as oleic acid, linoleic acid or linolenic acid in the oily phase was markedly increased. After enteral or oral administration of liposomes prepared with dipalmitoylphosphatidylcholine and cholestelol, a significant continuous hypoglycemic effect was observed. Our findings suggest that these pharmaceutical approaches offer much improvement bioavailability of insulin via oral route.

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Prostaglandin E₁ (PGE₁), a vasodilator and platelet aggregation inhibitor, effectively treats many diseases. However, PGE₁ is generated locally and acts locally to regulate physiological responses, thereby suppressing the progress of disease. Therefore, the therapeutic use of PGE₁ necessitates the targeting of specific sites to maximize local action and prevent systemic side effects. The authors have developed a PGE₁ preparation, using lipid microspheres (LM) with a 0.2 μ diameter (o/w emulsion) as carriers for passive targeting of sites of vascular lesions ; the preparation is called lipo-PGE₁. Favorable preclinical and clinical results have been achieved with preparation. The intravascular distribution of lipo-PGE₁ injected intravenously in spontaneously hypertensive rats(SHR) was investigated using electron microscopy. LM were accumulated in the subendothelial space of vascular walls, particularly in vascular lesions associated with hypertension. Laser confocal imaging revealed the marked uptake of PGE₁ by endothelial cells of diseased or newly developed vessels treated with lipo-PGE₁. On the other hand, free PGE₁ showed trace accumulation in the endothelial cells. The control cells incubated with normal mouse IgG instead of anti-PGE₁ antibody did not show any fluorescence. Lipo-PGE₁ is delivered preferentially to the site of vascular lesions, and PGE₁ becomes less irritant because it is incorporated into the microspheres. In addition, its inactivation in the lungs is slightly reduced for the same reason. All these features of the preparation strongly suggest that it would be very valuable in clinical practices. We performed the Phase III clinical trial of lipo-PGE₁ conducted in Japan which clearly showed that lipo-PGE₁ is safe and effective in patients with arteriosclerotic vascular disease, diabetic neuropathy, peripheral vascular disease secondary to diffuse connective tissue diseases, vibration disease, or ductus arteriosusdependent congenital heart disease.

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Reactive oxygen species have been postulated to underlie the pathogenesis of various diseases. Since these species rapidly react with various molecules, they should be scavenged appropriately at their site of generation. Superoxide dismutase (SOD) and related antioxidants have been expected to protect tissues from oxygen toxicity. However, because of their unfavorable pharmacokinetic properties, they often failed to inhibit oxidative tissue injury. In case of Cu/Zn-SOD, it disappeared from the circulation with a half-life of 5 min and underwent urinary excretion. Hence, intravenously administered SOD failes to dismutate superoxide radicals in vivo. The present work describes the chemical and genetic methods for targeting SOD to the site of generation and/or pathologic action of superoxide radical. Some SOD derivatives (SM-SOD, FA-SOD) reversibly bind to endogenous albumin thereby remain in the circulation with a half-life of 6 hr. Other derivatives (GSL-SOD, MAN-SOD, AH-SOD) selectively accumulate in hepatocytes, reticuloendothelial cells of liver, spleen and other tissues and renal proximal tubule cells, respectively. The fusion SOD (HB-SOD) preferentially binds to vascular endothelial cells thereby dismutates superoxide radicals in and around vascular walls. Pathophysiological role of superoxide and related free radicals, such as nitric oxide, were studied using these site-directed SODs.

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Poly(N-isopropylacrylamide) (PIPAAm) is well-known to change its structure in response to temperature in aqueous solutions. Polymer chains of IPAAm hydrate to form expanded structures in water at lower solution temperatures (<32°C). At temperatures above 32°C, however, the chains form compact structures by dehydration manifested as a lower critical solution temperature (LUST). Telomerization chemistry is expected to control oligomer molecular weight and create synthetic routes to semitelechelic oligomers averaging one functional end group per oligomer chain. Thiol compounds having functional groups as telogens are known to be effective in introducing functional groups to the ends of growing polymeric chains and regulating polymer molecular weight by radical telomerization via chain-transfer reactions. The research described in this paper is directed toward development and funda mental studies of biomedically relevant modulation systems using the temperature-responsive polymer, PIPAAm with a functional end group, as switching sequence. Temperature responsive semitelechelic PIPAAm polymer was attached to biomolecules, crosslinked hydrogels and solid surfaces to create new, modified bioconjugates, graft type gels and grafted surfaces, respectively.

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Drug targeting is currently a great challenge in biomedical research. Many strategies have been undertaken toward this goal utilizing various types of vehicle systems. For a promising candidate as an ideal drug carrier, we have prepared AB block copolymer micelles. Amphiphilic block copolymers in aqueous milieu form micellar structures through the association of hydrophobic segments. These micelles have several advantageous features as drug carrier systems due to their considerable thermodynamic stability as well as to the formation of a hydrophobic core separated from the outer aqueous milieu by the corona of hydrophilic segments. The core acts as the micrccontainer of drugs, which can be introduced into the core either through chemical linkage to core-forming segment or by a simple physical entrapment. This review presents a concept and strategy for using a block copolymer micelle as a nanometric virus-mimicking carrier of anti-cancer drugs to treat solid tumors. Further, formation of novel micelles system (polyion complex micelle) from a pair of oppositely charged block copolymers with poly(ethylene glycol) segment was described as a novel carrier for peptides and nucleotides.

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Gene transfer vectors play critical roles in human gene therapy. These vectors are different from existing drug delivery systems, because they deliver DNA, a fragile macromolecule, directly into cells. In addition, DNA should he delivered into a nucleus by an active transport mechanism, as the nuclear membrane is a tight harrier for macromolecules. To satisfy these requirements, gene transfer vectors should be developed based on biological phenomena. In this review, I describe a new vector system called “hybrid vectors”. Hybrid vectors use the mechanism of infection of animal viruses for gene transfer and have the advantages of both viral vectors and non-viral vectors.

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