The transport of 5-fluorouracil (5-FU) and its prodrugs across the duodenum, jejunum, ileum, colon, and rectum of the albino rabbits was examined using the modified Ussing Chamber. 5-FU penetrated the jejunum, most readily, followed by the duodenum, ileum, rectum, and colon in that order. This may be due to an active transport mechanism taking place in the small intestine whereas a simple diffusion process is responsible for the transport across the membranes in the large intestine. By the use of prodrugs, it is feasible to promote the transport of 5-FU across the colon and rectum. On the other hand, the prodrugs showed a decreased total transport of 5-FU across the small intestine, although the mechanism remains to be investigated. These results indicated that the transport of 5 -FU in the lower region of the gastrointestinal tract was improved by the prodrug approach.

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New hydrogels containing pentoxifylline were prepared by adding NaOH solution to Eudragit L, S, Eudispert hv, mv and lv (acrylic resins) at various concentrations. The in vitro release rate of pentoxifylline from hydrogels was much the same as that found for Witepsol S-55 suppository and could he controlled by modifying the milliequivalent (mEq) of NaOH per unit weight of the polymer materials and the percentages of the polymer materials added to the hydrogels. Furthermore, the xerogel newly prepared by freeze-drying 10% Eudispert by hydrogel added 5 mEq of NaOH resulted in the slowest release of pentoxifylline. In in vivo evaluation using rabbits, it was found that 15% Eudispert by hydrogel and xerogel prepared from 10% Eudispert by hydrogel adding 5 mEq of NaOH were useful as rectal controlled release preparations of pentoxifylline. The relative bioavailability of Eudispert by hydrogels and xerogels increased to 1.3-1.5 fold compared with Witepsol S-55 suppository. From the results of the statistical moment analysis for Eudispert hv hydrogels and xerogels, it became clear that there were statistically significant correlations between the in vitro mean dissolution time (MDT_{in vitro}) and the in vivo mean residence time (MRT).

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The tissue distribution of aclarubicin(ACR)was studied and compared between the two dosage forms, namely the new dosage form (ACR-CH) and the aclarubicin aqueous solusion (ACR-sol). ACR-CH comprises 50 mg/ml of activated carbon (Mitsubisi #1500AA) and 5 mg/ml of aclarubicin in saline. Aclarubicin at 5 mg/kg was injected intrapritoneally in the form of ACR-CH or ACR-sol, and the tissues (the greater omentum, the liver, the spleen, the heart. the lung and the intracardial blood) were taken upto 7 days later. The organs and the blood was subjected to measuring aclarubicin level through the high pressure liquid chromatography(HPLC)method. The experiment showed that ACR-CH distributed higher level (2 to 10 times) of ACR concentration to the greater omentum for a long period, and lower level to the heart, the lung and intracardial blood than those of ACR-sol. These results leads to think that intraperitoneal ACR-CH distributes a large amount of ACR to the intraperitoneal tissues and small amount to the tissues of extraperitoneal organs.

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Three liposoluble platinum complexes, chelate compounds of saturated fatty acids and Cyclohexane-1, 2-diammineplatinum (II)(DACH), have been developed for intra-arterial chemotherapy of the hepatocellular carcinoma using Lipiodol. We studied the anticancer effect of Lipiodol containing these platinum complexes after injection into the hepatic artery of rabbit bearing VX-2 tumor in the liver. The anticancer effect of trans-1-DACH (Myr)₂ (DACH C14), leaving group of which was myristic acid, was stronger and more selective than those of the untreated group and the group given Lipiodol alone. The effect depended on content of DACH C14 in Lipiodol. The anticancer effects of trans-1-DACH (Lau)₂ (DACH C12) and trans-1-DACH (Dec)₂ (DACH C10), leaving groups of which were lauric acid and decanoic acid, respectively, tended to be similar to that of DACH C14. Platinum concentrations in the tumor 7 days after injection into the hepatic artery of rabbits were selectively higher than those in other parts of the liver in all platinum complexes. These results suggest that three liposoluble platinum complexes in Lipiodol are applicable to intra-arterial chemotherapy of hepatocellular carcinoma.

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The antitumor effect of an interleukin 2 (IL-2) mini-pellet on liver metastases of Colon-26 adenocarcinoma has been evaluated. After the administration of the IL-2 mini-pellet containing I × 10⁶u of IL-2, the serum concentration of IL-2 was detectable for 72 hours. The administration of the IL-2 mini-pellet into the spleen, which was translocated to the subcutaneous position, after the intraportal injection of Colon-26 tumor cells was significantly effective in reducing the number of metastatic nodules and could also prolong the survivals. The lytic activity of splenocytes against YAC-1 cells and Colon-26 cells on day 2 after the administration of the IL-2 mini-pellet were augmented. These findings demonstrated that the IL-2 mini-pellet could be applied to the immunotherapy of hepatic metastases in human.

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We have developed an adriamycin-oxidized dextran conjugate (ADM-OXD) which was found to possess not only higher antitumor activity but also less animal toxicity than ADM. It appeared that improvement of the therapeutic index of ADM-OXD was due to its bio-distribution. Therefore, we examined the tissue distribution of [¹⁴C]-OXD and [¹⁴C] ADM in tumor bearing rats and mice. ADM-OXD gave much higher blood levels than ADM. It was also found that ADM-OXD was more highly concentrated in the tumor tissues than ADM in both rats and mice. However, heart tissues showed lower concentration of ADM-OXD. On the other hand, ADM-OXD tended to remain in the liver, kidney and spleen. Approximately 50% of the administered ADM-OXD was excreted into the urine within 6 hours after its administration.

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Liposomes were investigated as a carrier for the delivery of therapeutic agents to target brain tumors. We have developed the coating of liposomes with pullulan derivative and compared with conventional neutral liposome. When pullulan-coated liposome labeled with ¹⁴C was intracarotidly administrated into the 9L cells implanted brain tumor rats, brain tumor uptake increased 4.5 times and spleen uptake decrease compared with the neutral liposome. The cytotoxity of cisplatin against 9L-glioma cells was not inhibited by encapsulation of pullulan-coated liposomes. The median survival times were 35.3 days for pullulan-coated liposome-encapsulated cisplatin-treated rats and 20.3 days for untreated rats. The difference was statisticall significant (P<0.05). These findings suggest that pullulan-coated liposome-encapsulated cisplatin could be utilized for targeting the chemotherapy of brain tumors, however in order to increase the targetability of liposome to brain tumors, we must have developed the conjugating of liposome with the specific sensory device.

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We have reported that temperature-sensitive liposomes containing adriamycin (TS-Lip-ADM) mainly delivered ADM to heated tumors with local hyperthermia and enhanced antitumor effect. TS-Lip-ADM composed of DPPC (Tc= 41°C) (type-I) released considerable amount of ADM in the blood stream, making its clinical application difficult. To raise the stability of the liposomes, we included various ratio of DSPC (Tc = 54°C) and/or cholesterol (Chol) in the liposomal membrane and assessed temperature sensitivity. Addition of DSPC reduced ADM leakage from the liposomes at lower than 40°C and raised the maximal releasing temperature. Chol makes liposomes more stable in the presence of serum. TS-Lip-ADM including Chol up to 20 mol% remained temperature-sensitive. Inclusion of 30 mol% Chol abolished this characteristic. We made TS-Lip-ADM composed of DPPC, DSPC and Chol, in the molar ratio 7 : 1 : 2 (type-II), and investigated the selective delivery of ADM from type-II to NUE human hepatoma cells inoculated in nude mice and antitumor effect evaluated by the tumor weights, compared with type-I. NUE tumor uptake of ADM was increased by local hyperthermia at 42 °C for 30 min. ADM concentration in heated type-II tumors was about three times as high as in heated free ADM tumors, but not different from type-I significantly. Hyperthrarmia enhanced the antitumor effect.

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Conventional monolithic devices in which drug is uniformally dispersed shows a first order release. More specifically, the drug release rate from the monolithic devices continuously diminishes with time. To achieve zero order release, monolithic device having heterogeneous polymer structure was synthesized and drug release pattern in phosphate buffer saline solution from these devices were compared to homogeneous monolithic devices. Heterogeneous devices that poly(acrylamide) (PAAm) beads were dispersed in poly (2-hydroxy ethyl methacrylate) (HEMA) or random copolymer of HEMA with butyl methacrylate(BMA) were synthesized. These devices were soaked in sodium salicylate solution. Drug was selectively loaded into PAAm beads for the difference of partition coefficient between PAAm beads and surrounding polymeric matrices, At low loading, the release pattern from heterogeneous devices approached to zero order release. This can be explained in terms of release regulating function of polymeric matrices surrounding PAAm beads. At high loading, burst release was observed due to an increase in water content by hydrophilicity of the drug. It was concluded that zero order release could be achieved by regulating hydrophilicity of the drug and polymeric matrices, beads content, drug loading amount and drug distribution in the polymeric devices.

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Poly(N-isopropyl acrylamide) (IPAAm) has characteristics to exhibit a remarkable swelling change in aqueous system in response to a change of temperature. Random copolymers of IPAAm with alkyl methacrylate (RMA) having different length of alkyl chain were systhesized to clarify the effect of the hydrophobic structure on thermo-sensitive swelling behaviors. Indomethacin was loaded into these polymers and drug relase experiment was performed. At constant temperature, release pattern was observed as zero order release pattern when temperature was low. This can be explained in terms of a permeability increase in polymeric matrices after the durg was released, because the loaded hydrophobic drug suppress the swelling of polymeric matrices. New equation based on the swelling change in the process of the drug releasing was derived and a good agreement was found between the experimental results and the theoretical release simulation. Pulsatile release patterns were found to be regulated by temperature flactuation between 20°C and 30°C. This ON-OFF release mechanism is due to surface shrinking layer with an increase in temperature. The formation process of these shrinking layers were dependent on alkyl chain length of RMA. When the period of OFF drug release state was enlarged, drug release rate in ON state was maintained constant before and after OFF state. The results suggested that loaded drug in polymeric matrices migrated to the surface during OFF state even if the drug release was completely stooped.

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