Controlled-release tablet can be obtained by oxygen plasma irradiation(radio-frequency discharges operating at 13.56 MHz) on the outermost layer of the double-compressed tablet which was fabricated from theophylline as a core material and a mixture of plasma-degradable polyoxymethylene (POM) and plasma-cross-linkable polystyrene (PST) as a wall material. Insulin controlled-release tablet can be obtained similarly by use of a mixture of POM and polylactic acid (PLA) as a wall material. Polycarbonate (PC) derived from bisphenol A can be considered to be of intramolecular bifunctionality, crosslinkable and degradable, as a plasma irradiation effect. Thus, theophylline controlled-release tablet can also be obtained by use of PC as a single wall material of the double-compressed tablet. The dissolution profiles are capable of being varied so as to cause release of drugs at different rates, depending on the set of conditions chosen for tablet fabrication as well as plasma operational conditions. SEM observation of the tablet surface clearly indicated that the theophylline has been released from the tablet through the resulting micropores. There are several obvious advantages of the present approach over other methods for fabrication of DDS device : The first is the avoidance of direct plasma-exposure to the drug. The present method is totally dry process, which eliminates the need for any workup such is required in the method in conventional wet processes. Further, one of the characteristics of plasma irradiation is the fact that it is surface-limited so that it does not affect the bulk properties of the polymeric pharmaceutical aids.

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Superoxide anion (O₂^-) acts as an exacerbating factor in various disease conditions. Superoxide dismutase(SOD), a scavenger of O₂^-, has been expected to become a therapeutic tool for treating many diseases. However, to attain an adequate clinical effect, it is necessary to prolong the biological half-life of SOD and to increase its affinity for cell membrane by using a drug delivery system. Several chemically modified forms of SOD, including polyethylene glycol binding SOD and pyran-SOD, have not yet been approved for clinical use. In the present study, we lecithinized recombinant human SOD by covalently binding four molecules of a lecithin derivative to each SOD dimer. The blood half-life after the intravenous(i.v.)injection of lecithinized-SOD into rats was doubled compared to that of unmodified SOD. Lecithinized-SOD also had a 10-fold higher affinity for several cells. The i. v. injection of Forssman antiserum is known to induce a biphasic airway resistance and it is suggested that O₂^- is involved in the second phase of this response. We examined the effects of lecithionized-SOD on this phase of respiratory resistance using guinea pigs. Unmodified SOD was ineffective at i. v. doses of 1, 000∼30, 000 U/kg, whereas over a dose range of 10∼1, 000 U/kg, lecithinized-SOD demonstrated a dose-dependent inhibitory effect. Therefore, we expect PC-SOD to be safe and pharmacologically very potent in humans, with the potential for use in various clinical applications.

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Ganglioside GMI-thermosensitive liposomes (GM1-TSL) were prepared from DPPC/DSPC (9 : 1 in molar ratio) and appropriate amount of GM1 by reverse-phase evaporation method. Doxorubicin (DXR)was encapsulated into GM1-TSL with> 98% in trapping efficiency by pH gradient method. The incorporation of 3 or 6 mol% of GM1 to TSL did not affect the temperature-dependent release of DXR from liposomes in vitro. Inclusion of 6 mol% of GM1 endowed TSL with prolonged circulation ability, resulting in increased blood levels of liposomes and decreased RES uptake over 6 hours after i. v. injection to mice. Concomitantly, DXR levels in blood remained high for long time. The combination of DXR-GM1-TSL and the local hyperthermia have been tested for their utility as a temperature sensitive release for DXR in colon 26 tumor-bearing mice. The accumulation of DXR into tumor by local hyperthermia (42°C, 20 min) after injection of DXR-GM1-TSL(GM1 6mol%) was 7 or 2.4 times greater than that after treatment with free DXR or DXR-TSL in combination with hyperthermia, respectively. These results indicate that long-circulating ability is effective for thermosensitive liposomal drug delivery in combination with hyperthermia. This system is expected to be very useful for antitumor therapy.

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Binding affinities of several drugs for microfibrous collagen (Avitene) were determined applying dialysis measurement, and binding potential was calculated from the efflux rate of drugs. Bromophenolblue showed the strongest affinity for collagen. Released amount of bromophenolblue for 5 hrs from collagen was about 20% and almost constant during 24 hrs. Comparatively weak binding was observed in salicylic acid, chloramphenicol, epirubicin HC1, and 5-FU. There were considerable time lags in the release profiles of all these drugs when the release profiles were compared with those of the control. Only the release behavior of amikacin sulfate was similar to that of the control. On the other hand, release behaviors of cisplatin and mitomicin C were quite different from those of other drugs. They failed to reach to 100% release even in a prolonged incubation period, suggesting a part of these drugs bound to collagen irreversibly. It was supposed that the affinity of drugs for collagen was dependent on its chemical structure, especially electro-resonance structure, and electro-negative charges.

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An ester compound (Ada-Enk) of [D-Ala²] Leu-enkephalin(Enk) with 1-adamantanol was evaluated as a prodrug for the improved brain delivery using rats as the experimental animal. The tissue-to-plasma concentration ratio (Kp) of Ada-Enk at steady state during the intravenous infusion was 4.5 times larger than that of Enk, indicating the improved delivery to the brain. The distribution of Ada-Enk to the other organs was also increased in comparison with Enk, but the degree of the enhanced distribution was much higher in the brain. The distribution of Ada-Enk was similar in all the regions in the brain. In addition, Enk was found in the brain during the intravenous infusion of Ada-Enk. The in vitro metabolic study showed that Ada -Enk was metabolized in both plasma and brain while Enk was formed in the brain homogenates much more than in the plasma.

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EGF-labeled reverse phase evaporation vesicles (EGF-REV) encapsulating bleomycin (BLM) have been prepared and their selective uptake and cytotoxic activity have been evaluated using A431 and Swiss/3T3 cells which are over-expressing EGF-receptors on cell surface and no EGF-receptor, respectively. EGF has been bound to REV surface as active form, and EGF-REV has been taken up selectively by A431 cells via EGF-receptors, but not by Swiss/3T3 cells. Cytotoxic activity of EGF-REV encapsulating BLM (EGF-REV-BLM) for A431 cells was superior to that of normal liposomes containing BLM, and this effect was dependent on the treatment time. However, this cytotoxic activity of EGF-REV-BLM could not be observed in Swiss/3T3 cells, These findings suggested that EGF-REV is a useful drug carrier for squamous carcinoma which are over-expressing EGF-receptors on cell surface.

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[in Japanese]

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Recently, thyrotropin-releasing hormone (TRH) has attached much attention as a potential drug for the management of various neurogic and neuropsychiatric disorders including depression, brain injury, acute spinal trauma, schizophrenia and Alzheimer's disease. However, the absolute bioavailability of TRH is very low in man (1∼2%) due to their low lipophilicity. In order to improve the intestinal absorption of TRH, we synthesized a novel lipophilic derivative of TRH (Lau-TRH) by chemical attachment of lauric acid to the N-terminal pyroglutamyl group of TRH. The permeation of TRH and Lau-TRH across the rat upper small intestine was studied using an in vitro modified everted gut technique. Lau-TRH was more permeable than TRH in the rat upper small intestine and most of Lau-TRH were converted to TRH during permeation across the rat upper small intestine. In addition, Lau-TRH was gradually converted to TRH in mucosal side. Furthermore, the acylation of TRH with lauric acid was more effective than the absorption enhancers such as EDTA, sodium caprate, and lauryl maltoside in enhancing the upper small intestinal absorption of TRH. These results indicated that chemical modification of TRH with fatty acid might be a useful approach for improving the upper small intestinal transport of TRH.

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[in Japanese]

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Blood flow of I-87 human lung carcinoma was measured using hydrogen clearance method. I-87 tumors were transplanted to the subcutis of nude rats(F344/Njcl). When the mean arterial blood pressure(BP)was elevated from 111.1±7.2 mmHg (mean±SD : normatension)to 155.7±5.9 mmHg (hypertension induced by angiotensin II : AII), blood flow of I-87 significantly induced from 8.2±4.9 ml/min/100 g to 38.2±30.7 ml/min 100 g(mean increse rate ; 6.3). A model of lung metastasis of rats (Donryu/Crj) was made by intravenous inoculation of AH100 (moderately sensitive to adriamycin) cells. Using these models in which metastatic foci of lung were histologically detected on day 3 after the inoculation, growth inhibitory effect were compared. In AH100b model, growth inhibitory effects were investigated by the ratio of area of tumor/ lung (%T/L) on photomontage of microscopicalsections. In day 10-samples of each treatment schedule, % T/L for AII induced hypertension chemotherapy (IHC), was significantly low comparing with that for non-IHC (P<0.05), and control (P<0.01). But in day 14-samples, there was no significant differences between groups because of regrowth of tumors. In a series of AH 100 B-bearing rats treated with adriamycin, no obvious prolongation of survival days was shown in all treatment groups. Under AII-IHC, chemoterapeutic effects on lung metastasis was augmented on the basis of selective increase of blood flow of lung carcinoma and enhancement of drug delivery to lung metastasis.

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