New concept of inflammation responsive drug delivery system by biodegradable hydrogels of hyaluronic acid (HA) is reviewed. HA has been well known to be degraded specifically by the presence of hydroxyl radicals, which are produced locally at an inflammatory site. Our system is established by constructing a heterogeneous-structured device of drug microreservoirs (lipid microspheres) dispersed into the degradable matrices of crosslinked HA gel. The most attractive characteristics of this device are : (1) to performe the release of lipid microspherers in proportion to surface-controlled degradation of crosslinked HA gels, and (2) to be quantitatively inflammation-responsive degradable. These unique features of the device are favorable to regulated drug delivery to several inflammatory related diseases, where lipid microspheres can be released in response to inflammation-induced degradation although being stable under normal health conditions.

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A plasmid carrying antisense human myc DNA and the gene encoding E. coli xanthine—guanine phosphoribosyltransferase (Ecogpt) was introduced into human promyelocytic leukemia cell line HL-60 by protoplast fusion. High-level expression of antisense myc RNA was obtained by selecting cells resistant to progressively higher levels of mycophenolic acid. The constitutive production of myc protein in clones producing high levels of antisense myc RNA was reduced by 90% compared with parental HL-60 cells, and these cells showed increased commitment toward monocytic differentiation. Inhibition of myc expression was seen at both the translational and the transcriptional levels, implying that antisense RNA can regulate transcription of the myc gene. However, since monocytic differentiation is associated with downregulation of c-myc expression, it cannot be ruled out that the induction of the 74 kD protein and reduction of c-myc transcription are secondary events, triggered by an initial reduction in c-myc expression by “conventional” antisense regulation at the posttranscriptional level. The TCC-CACC repeats in the c-myc leader sequence are the primary transcriptional target of the antisense RNA. The 74 kD nuclear protein, which appears to be induced in the antisense myc transformants, was able to bind to this sequence in these transformants. The suppression of endogenous myc gene expression by either antisense RNA or this 74 kD protein decreases cell proliferation and triggers monocytic differentiation.

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Intra-arterial injection therapy with multi-anticancer drug for hepatocellular carcinoma has been conducted frequently. We prepared Cisplatin (CDDP)-Epirubicin(EPI)-Lipiodol Emulsion (CELE)in 1990 and have used in this therapy ever since. We examined clinical evaluation for CELE including survival rate, while pharmaceutical evaluation for stability and size of particles of CELE with image analyzer lately. These average particle diameters of CELE were as follows : Iopamiron 300, a non-ionic contrast medium, 1.4 μm : Urografin 76, an ionic contrast medium, 10∼150 μm, respectively. CELE used Iopamiron 300 was retained emulsification over three hours after preparation. CDDP and EPI in CELE were taken into liver 85% and 35% of total dose, respectively. Two years survival rate treated transcatheter arterial embolization with CELE was improved from about 10% to 70% as compared with Cisplatin-Lipiodol-suspension. No severe side effects were observed with CELE.

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Angio-CT was employed via an intraarterial or intraportal infusion port system for the treatment or prevention of malignant hepatic tumors in 7 and 6 cases respectively to observe the flow pattern of Iopamidol in the liver. The homogenous distribution of the contrast medium was observed in 3 of the 13 cases. The heterogenous distribution was observed in 5 of the 13 cases. Catheter occulusion or thrombus formation of the hepatic artery was not evident in these 5 cases. Therefore it is surmised that this heterogenous distribution may be influenced by the laminar flow. No contrast medium enhancement was observed in the liver owing to the occulusion of the hepatic artery, ileum vein or portal vein in the remaining 5 cases. In 4 of the 5 cases, CDDP was infused via the port system. Therefore these occlusions may be due to drug induced angitis, which can happen in case of the infusion of CDDP. Angio-CT via an infusion port system is useful for the assesment of the patency of the catheter and blood distribution in the liver and thus may predict the effect of chemotherapy.

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This study was undertaken to examine the effect of bile salt on lymphatic absorption of vitamin D₃ emulsified by milk fat globule membrane(MFGM) and to examine the mechanism of promotion of lymphatic drug absorption by MFGM. A soybean oil emulsion containing vitamin D₃ which was prepared using MFGM as an emulsifier, was administered to rats. It was found that MFGM emulsion significantly enhanced lymphatic absorption of vitamin D₃. The recovered percentage of vitamin D₃ in lymph, administered in MFGM emulsion form, was 2.5 times higher than that in oil solution form. The percentage decreased to 1/32 when bile duct of the rat was fistulizated, and this recovered completely when taurocholate was infused in duodenum constantly. However, infusion of other surface active substance, such as tween 80, hardly increased lymphatic absorption of vitamin D₃ in biliary fistula rats. MFGM emulsion, after diluted with taurocholate solution, tween 80 solution or water, was separated by ultracentrifugation. The fraction of microemulsion was collected and was administered to biliary fistula rats. Lymphatic absorption of vitamin D₃ in the microemulsion with taurocholate was much greater than that in the microemulsion with tween 80 or with water. Furthermore, we confirmed that the ability of vitamin D₃ transport to microemulsion by taurocholate was 2 times higher than that by tween 80 in vitro. These results suggest that promotion of lymphatic absorption of vitamin D₃ by MFGM is partly due to the microemulsion formation in the presence of bile salt.

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Poly(vinyl alcohol) gel sphere(PVA -GS)was prepared and the GI transit-time was examined in rats following the oral administration by monitoring unabsorbable phenol red contained in the dosage form. While more than 90% of the aqueous solution was transferred to the large intestine 6 h after the administration, about 40% of PVA-GS still remained in the ileum. Thus, PVA-GS can provide drugs prolonged residence in the small intestine, the major site of drug absorption. The prolonged plasma concentration-time profile of cephalexin was observed following oral administration of the antibiotic as the PVA-GS dosage form. Although the maximum concentration became the half of the aqueous solution, the constant plasma level was maintained from 3 h to at least 12 h after the administration. The usefulness of PVA-GS as a GI transit-time controlling type dosage form was demonstrated.

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The therapeutic gain factor(TGF)of ¹⁰B-neutron capture therapy(NCT)was analyzed using transplanting Greene's melanoma and normal skin of hamster. The Kyoto University Research Reactor, which has a very low contamination of γ rays and fast neutrons, was used as a thermal neutron source. Boron-10-paraboronophenylalanine hydrochloride(¹⁰B-BPA), which can highly concentrate ¹⁰B into melanoma cells, was administered to the hamsters eight hours before thermal neutron irradiation. Then the tumor or the normal skin was irradiated under a condition of 5 MW for 90 minutes. The absorbed dose from NCT was calculated by method of Fairchild(1966). The tumor RBE of NCT obtained by the tumor growth delay time method was 2.2 at 11.5 Gy of NCT. Early skin reactions were recorded two or three times a week after irradiation, according to an arbitrary scale. The maximum skin reaction score was used in the determination of the skin RBE. The skin RBE was 2.1 at 11.1 Gy of NCT. On the bases of these date, the TGF of NCT was calculated as 1.1 (2.2/2.1). There is a significant difference in absorbed dose distribution between the melanoma and the surrounding normal skin on NCT. In consideration of these condition, a “practical” TGF value for pre-clinical evaluation becomes higher.

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Percutaneus absorption of a drug with enzymatic metabolism in the hairless mouse skin was demonstrated using an in vitro skin permeation apparatus. Prednisolone(PN)and its prodrug, Prednisolone 21- (2E, 6E-Farnesirate)(PNF), were seleced as model drugs. Either intact skin or stripped skin, from which the stratum corneum removed completely, was mounted between the half cells of in vitro skin permeation system. Percutaneous absorption of PN was found to be controlled by permeation in the stratum corneum. The appearance rate of the metabolite(PN)was controlled by the rate of metabolism of PNF in the viable skin rather than by the permeation rate in the stratum corneum. Permeation profiles of PNF for the stripped skin were analyzed by a diffusion model accompanied by enzymatic reaction ; the rate constant of enzymatic reaction was determined to be 0.87 hr^-1. The caluculated profiles for PN in donor and receptor solutions well agreed with the experimental results.

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We have conducted interstitial chemotherapy for malignant brain tumors with slowly releasing anticancer drugs-polymer composites. We administerd either ACNU-composite or 5Fu-composite at the time of the operation in treating of 123 cases of malignant tumors. In 5Fu-composite cases, a severe local brain edema was seen in and around composite. It is thougt that this edema is due to the occurence of focal leucoencephalopathy of cause of 5Fu. This study presents the morphological change of glioma after local treatment with anticancer drugs-polymer. 6 cases of malignant gliomas, 5 glioblastoma and 1 anaplastic astrocytoma, were reoperated after this treatment. Histological exsamination revealed, (1) marked tumor tissue necrosis and no tumor cell around the drugs-polymer, (2) The viable tumor cells were seen around the tumor vessels.

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