薬物のターゲティング - 基礎および臨床での証明 -

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Prostaglandin E<SUB>1</SUB> (PGE<SUB>1</SUB>), a vasodilator and platelet aggregation inhibitor, effectively treats many diseases. However, PGE<SUB>1</SUB> is generated locally and acts locally to regulate physiological responses, thereby suppressing the progress of disease. Therefore, the therapeutic use of PGE<SUB>1</SUB> necessitates the targeting of specific sites to maximize local action and prevent systemic side effects. The authors have developed a PGE<SUB>1</SUB> preparation, using lipid microspheres (LM) with a 0.2 <I>μ</I> diameter (o/w emulsion) as carriers for passive targeting of sites of vascular lesions ; the preparation is called lipo-PGE<SUB>1</SUB>. Favorable preclinical and clinical results have been achieved with preparation. The intravascular distribution of lipo-PGE<SUB>1</SUB> 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 PGE<SUB>1</SUB> by endothelial cells of diseased or newly developed vessels treated with lipo-PGE<SUB>1</SUB>. On the other hand, free PGE<SUB>1</SUB> showed trace accumulation in the endothelial cells. The control cells incubated with normal mouse IgG instead of anti-PGE<SUB>1</SUB> antibody did not show any fluorescence. Lipo-PGE<SUB>1</SUB> is delivered preferentially to the site of vascular lesions, and PGE<SUB>1</SUB> 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-PGE<SUB>1</SUB> conducted in Japan which clearly showed that lipo-PGE<SUB>1</SUB> 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.
日本DDS学会の論文
1995-09-10

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