The chemotherapeutic utility of polymeric prodrugs has recently been the focus of intense research because of the possible reduction of undesirable side-effects and their utility as a sustained release system. We describe a novel polymeric prodrug preparation by mechanochemical solid state polymerization. The results include that solid vinyl monomers, methacryloyl derivatives of bioactive compounds, synthesized along the line of structural criteria derived from the quantum chemical considerations can undergo the mechanochemical polymerization to give the corresponding polymers essentially quantitatively. One of the most striking properties observed in such polymers is that the resulting polymeric prodrugs are of very low heterogeneity (narrow molecular weight distribution). Further, the molecular weight of the polymers can be controlled by the operational conditions. Thus, the mechanochemical solid-state polymerization provides a novel and simple methodology for syntheses of highly functionalized polymeric prodrugs through a totally dry process.

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Superoxide dismutase(SOD)is a hopeful candidate as a therapeutic agent against inflammatory disease. However, for such use a serious drawback must be overcome, i. e., exogenously supplied SOD fails to exhibit activity in vivo mainly due to its short half-life. To increase the half-life of the enzyme, we conjugated SOD with a copolymer of divinyl ether and maleic anhydride (DIVEMA). The half-life of DIVEMA-SOD was examined in vitro and in vivo based on the enzymatic activity of SOD. The enzymatic activity of SOD decrease to 50% within 139 min in human plasma in vitro. On the contrary that of DIVEMA-SOD showed no decrease in 24 hrs. Afte injection of mice with the enzyme via a caudal vein, blood was collected periodically, and the serum was examined for its SOD activity. SOD injected alone lost 50% of its activity within 6 min, whereas DIVEMA-SOD showed a biphasic decrease in activity, with the half-life of the β phase being 69 min. Pharmacokinetic analysis revealed that the AUC (area under the curve) of DIVEMA-SOD was 5.8 times greater than that of SOD. Such dramatic improvement of the phamacokinetic parameters should contribute to the increased anti-inflammatory activity of DIVEMA-SOD in vivo.

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To prevent first pass metabolism of dopamine (DA) in the intestinal absorption process, DA-dipeptide derivatives, in which the amino group of DA was protected by dipeptides containing Phe and Pro, were synthesized, and the hydrolysis of these compounds by rat liver, jejunum and ileum homogenates, 10, 000 g supernatant and precipitate (ppt), were investigated. Significant differences were not found between the DA-releasing rates from Phe-Phe-DA and Pro-Phe-DA by the homogenates and that from Phe-DA, because Phe-Phe and Pro-Phe were hydrolyzed rapidly by the homogenates. On the other hand, the DA-releasing rates from Phe-Pro-DA and Pro-Pro-DA by the homogenates ppt were much larger than that from Pro-DA, suggesting that the existence of Phe and Pro at the P2 site in the DA-dipeptide derivatives promote the DA-releasing rates from these derivatives. The results indicate the feasibility that the dipeptides containing Pro at the P₁ site may be useful promoieties for the control of the DA-releasing rate from the DA-dipeptide derivatives.

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The double-labeled lipid microspheres with ³H-dipalmitoylphosphatidylcholine (DPPC) and ¹⁴C-tripalmitin (TP) having various particle sizes : small ; 50 nm, medium ; 130 nm, large ; 215 nm in mean diameters, were prepared by a Microfluidics homogenizer. After intravenous administration of microspheres to rats, plasma levels of radioactivities were measured from 1 to 360 min periodically. The smaller the particle size of lipid microsphere was, the faster the elimination of radioactivities from plasma was ; which was contrary to the results of liposomes. Elimination of ¹⁴C-TP from plasma was faster than that of ³H-DPPC in any microspheres, particularly in small and medium microspheres. This result suggested that triglyceride in microsphere core was hydrolysed and eliminated from circulation, while phospholipid was remained in the surface lipid monolayer of microsphere. Sucrose step-density gradient fractionation of the rat plasma samples showed that a large part of the radioactivity moved to the high-density fraction from the low-density (microshere's) fraction. The transported radioactivity of ¹⁴C was much in the smaller microsheres. These results suggested that clearance of microsphere from plasma was much influenced by the interaction with apoproteins and lipases rather than the uptake by reticuloendotherial system. A part of this work was supported by a grant from Human Science Foundation

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GSH was covalently attached to dextran (T-40) by both the CNBr activation method and the NaIO₄, oxidation method. The conjugates, D-GSH (CNBr) and D-GSH (NaIO₄), were water-soluble powder containing 10 and 25 w/w% of GSH, respectively. Mice were depleted of GSH by treatment with buthionine sulfoximine, a potent inhibitor of γ-glutamylcysteine synthetase. Intravenous administration of D-GSH (CNBr) led to a marked increase in the level of GSH. However, administration of D-GSH (NaIO₄)or free GSH had no significant effect on the hepatic GSH. In mice given a lethal dose of acetaminophen, the survival rate increased progressively with coadministration of D-GSH (CNBr), whereas little improvement was found when D-GSH (NaIO₄) or free GSH was given. This was due to the distinction of the linkage structure between the conjugates ; D-GSH(NaIO₄) was too stable to release free GSH. The conjugate was transported into hepatic cells and, in the case of D-GSH (CNBr), was intracellulary hydrolyzed to free form, which protected mice from hepatotoxicity of acetaminophen. These results suggested that the linkage structure would be the most critical in the delivery of GSH, as a dextran conjugate, into the liver.

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An adriamycin (ADM)-oxidized dextran conjugate, which may act as a potential anticancer drug with reduced side effects, was synthesized by binding of adriamycin as Schiff's base with periodate-modified dextran, preparated by partial periodate oxidation, glycylation followed second periodate oxidation. This paper has been concerned with structure of starting dextran, having one (1→43)-linked branch point per 21 α(1→6)-linked glucose resides, its periodate-modified, and glycylated derivative, and that of the final product, Adriamycin-oxidized dextran conjugate (ADM-OXD). The structure of ADM-OXD and that of intermediates at each reactive step, were elucidated mainly by methylation, periodate oxidation, Smith degradation, and also NMR. Thus, ADM-OXD was shown to consist of 1 mole of branching glucose residue, 1 mole of morpholine derivative, 4 moles of periodate-oxidized glucose residues (aldehyde groups), 12 moles of glycylating residues at C-4 and/or C-2 positions of periodate-oxidized glucose residues, and 3 moles of adriamycin conjugating oxidized-glucose residues, respectively, per repeating units(21 glucose residues) of dextran T-70.

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[in Japanese]

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Eudispert hv hydrogel and xerogel preparations containing ONO-4057(5-[2-carboxyethyl)3-{6-(4-methoxyphenyl)-5E-hexenyl}oxyphenoxy]valeric acid), a new leukotriene B₄ antagonist, were prepared, and evaluated in rats following rectal administration of these preparations. For rectal administration of gel preparations, the absolute bioavailability of ONO-4057 was almost the same (approximately 30%) as that for oral administration (31%) and also quite low compared with those of Witepsol H-15 or PEG 2000 suppositories (37% and 56%). The residual amounts in the intestine and rectum tubes and the accumulative amounts in the intestine and rectum tissues of ONO-4057 following oral and rectal administrations of various preparations were measured. The results indicate that the residual and accumulative amounts of ONO-4057 for eudispert hv gel preparations increased 2∼5 folds compared with administration of oral and two conventional suppositories. Accordingly, it is assumed that eudispert hv hydrogel and xerogel preparations have excellent staying properties in the lower part of rectum and can directly act to focus parts of ulcerative colitis by raising ONO-4057 concentrations in rectum and its tissue.

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