Liposomes are artificial phospholipid vesicles consisting of lipid bilayers. They can be used as drug-carriers for drug delivery system (DDS), by entrapping antitumor drugs in the vesicles. We conducted basic experiments and clinical trials of 3 types of DDS using adriamycin (ADM) entrapped in liposomes (Lip-ADM). (1) As the liposomes were prepared from egg yolk phosphatidylcholine, cholesterol and dipalmitoyl phosphatidic acid, Lip-ADM has a character of lymphatic tissue affinity. Gastroendoscopic submucosal injection of Lip-ADM revealed therapeutic lymphnodes delivery of ADM for the treatment of cancer metastases. (2) Liposomes have own liquid-crystalline phase transition temperature(Tc), at which they release entrapped drugs. The temperature-sensitive liposomes encapsulating ADM (TS-Lip-ADM) prepared from dipalmitoylphosphatidylcholine (Tc : 41°C) and cholesterol, showed the temperature-sensitive release of ADM and the enhanced antitumor effect by combination of local hyperthermia of the tumor. (3) Lip-ADM conjugated with anti α-fetoprotein (AFP)monoclonal antibodies showed the selective delivery of ADM and the targeted antitumor effect against AFP-producing xenograft Li-7 in vivo. A possibility of missile therapy using antitumor drugs entrapped in liposomes conjugated with tumor associated monoclonal antibodies was revealed.

抄録全体を表示

Interpenetrating polymer network (IPN)s composed of poly(acrylamide(AAm)-co-butyl methacrylate(BMA)) and poly (acrylic acid) (PAAc) were investigated in terms of temperature dependence of swelling and drug release behavior to achieve effective thermo-responsive drug delivery system. The two polymers used as ingredients for the IPNs form interpolymer complex by hydrogen bonding and precipitate at lower temperatures in water, and at higher temperatures the complex dissociates and the polymers are solubilized. The IPNs constructed from the polymers showed low swelling ratio in a lower temperature range and high swelling in a higher temperature range, exhibiting drastic swelling change at around 25°C. It is explained that such temperature-dependent swelling behavior with transition of the IPNs was attributed to drastic formation/dissociation alteration of polymer complex induced by a zipper effect with temperature. The IPNs also demonstrated reversible swelling/shrinking changes with temperature fluctuations. Further, drug release from the IPNs was conducted using ketoprofen as a model drug. On-off releases responding temperature change, i. e “on” release at high temperature and “off” release at low temperature, were observed for IPNs containing proper amounts of BMA. Release rate in “on” state could be regulated by changing BMA content.

抄録全体を表示

A cow milk fat globule membrane (MFGM) has an excellent emulsifying ability against lipids. In this study we examined the effect of oil phase on emulsifying ability of MFGM and on stability of its emulsion and comparison with other surface active substances. In addition to that there was no significant differences of diameter of MFGM emulsions among those with various oils : triolein, ethyl eicosapentanoate, butter oil and soybean oil, they also did not greatly affect the stability of those emulsions which was determined by their turbidity. Although MFGM exerted less solubilizing ability against lipid soluble drug, its emulsifying ability was almost equal as sucrose fatty acid esters having good emulsifying ability and no toxicity. In relation of the emulsifying ability of MFGM to other substances in milk : casein (isoelectric pH 4.7), a major protein in milk but not included in MFGM, showed pH dependent its emulsion stability as well as MFGM, that is stable in weak alkaline and unstable in weak acidic solution. It was reported that the mean isoelectric point of whole MFGM is close to pH 5. These facts suggest the possibility that proteins in MFGM might contribute to its emulsifying ability.

抄録全体を表示

The effect of polyethyleneglycol (PEG, 1800, 5000 and 12000 in molecular weight) on biodistribution of liposomes composed of egg phosphatidylcholine/cholesterol (PC/CH=1 : 1 in molar ratio) was examined in mice. PC/CH liposomes have been cleared from blood(3.5% of dose)and taken up by liver and spleen (60.0% and 6.6% of dose, respectively)3h post injection. Incorporation of lipophilic PEG derivatives or ganglioside GM1 increased the liposome concentration in blood and avoided the uptake by reticuloendothelial system. Liposomes composed of PEG with 5000 in molecular weight showed the highest blood concentration with 59.1% of injected dose at 3h post injection. This PEG's activity to increase the liposome concentration is greater than that of the ganglioside GM1, a well described glycolipid with this activity. PEG with 12000 in molecular weight also played liposomes to increase their concentration in blood with a similar level of GM1. PEG with low molecular weight such as 1800 showed relatively lower activity than above mentioned PEG and GM1. Present data indicate that lipophilic PEG can significantly avoid RES uptake, concomitantly enhance the liposome concentration in the circulation.

抄録全体を表示

Oxygen plasma-irradiation(radio frequency discharges operating at 13.56 MHz with less than 10 W) on the compressed tablet of one of the bioerodible polymers, polylactic acid(PLA), was found to cause only low efficiency in its degradation to such an extent as has been observed with polystyrene. Thus, controlled-release tablets have been obtained by oxygen plasma irradiation on the outermost layer of the double-compressed tablet which were fabricated from theophylline tablet as a core materials and a mixture of plasma-degradable polyoxymethylene (POM) and bioerodible PLA as a wall material. Dissolution test clearly indicated that the theophylline has been released from the tablet through the resulting micropore, while the release from untreated tablets was negligible. It was also found that dissolution profiles are capable of being varied so as to cause release of theophylline at different rates, depending on the set of conditons chosen for tablet fabrication as well as plasma operational conditions.

抄録全体を表示

Three kinds of eptazocine hydrobromide(EP) suppositories were prepared by fusion method : oleaginous-base conventional type (C-type), oleaginous hollow type (H-type) and polyethylene glycol type (PEG-type). Release tests in vitro were carried out according to Muranishi's method, and rectal absorptions of EP contained in three kinds of suppositories were investigated using four rabbits. The release rate of EP from H-type was larger than those from the other two kinds of suppositories in early phase, whereas the cumulative release percentage from PEG-type showed the highest value at 300 min. In the rectal absorption studies, the maximum plasma concentration (C_max) of PEG-type was about a fourth of those of the other suppositories. And the other two kinds of oleaginous base suppositories gave significantly shorter T_max (the time to reach C_max) than that of PEG-type. The mean bioavailability of C-type, H-type and PEG-type was 61.1%, 36.6% and 18.2% respectively. These results suggest that C-type and H-type may be put to good use as a rectal dosage form of EP.

抄録全体を表示

Effects of intratumoral drug injection on tumor growth and lung metastases were studied using Lewis lung carcinoma. Puncture to the tumor from 4 directions, saline administration in the edge of tumors, or lipiodol administration in the center of tumors promoted tumor growth and lung metastases. However, intratumoral administration of ACR or DWA2114R inhibited tumor growth better than intraperitoneal administration (i. p) and inhibited lung metastases almost the same as i. p. Administration of DWA2114R in the center of tumors inhibited tumor growth more than that in the edge of tumors. Fractionated administration of DWA2114R was more effective on inhibition of tumor growth and less effective on lung metastases than single administration. Intratumoral administration of PEP or PEP-emulsion was effective on growth inhibition and lung metastases as well as i. p of PEP. We conclude that intratumoral administration of anti-cancer drugs inhibit tumor growth and lung metastases.

抄録全体を表示

Effect of various vehicles on the ocular absorption of insulin was examined in the albino rabbits. The vehicles used in this study were 5% polyvinylalcohol(PVA), 0.1% polyacrylic acid (PAA), 0.2% hyaluronic acid (HA) and 1% Na-glycocholate was chosen as a model absorption promoter. Plasma glucose concentration was measured in a glucose analyzer whereas plasma insulin concentration was measured using radioimmunoassay. Of the vehicles, 0.1% PAA appeared to be more effective to enhance the ocular absorption of insulin than 5% PVA and 0.2% HA. The bioavailability of insulin from the ocular route without vehicle was about 1%, whereas in the presence of 0.1% PAA reached more than 5% based on both glucose and insulin measurements. Coadministration of 1% Na-glycocholate with 0.1% PAA tended to further hypoglycemic response and insulin absorption. The bioavailability of insulin with these additives was 13.6% based on glucose measurement and 7.4% based on insulin measurement. These findings indicated that it is feasible to obtain hypoglycemia from ocularly administered insulin with these additives.

抄録全体を表示

Colchicine transdermal tapes were prepared for the treatment of gout, using segmented polyurethane adhesives (SPUA) as the drug reservoir. Drug-releasing properties of SPUA were examined, together with the absorption properties of the drug in rats. As a control, hydroxypropyl cellulose (HPC) was used as the drug reservoir. The release rate of colchicine from the SPUA tape was higher than that from the HPC tape. The percent drug released from the SPUA tape was 90% and about 40% higher than that from the HPC tape, when compared at a drug concentration of 5%, 75 mimutes after the start of the experiment. The colchicine concentration in skin and muscles increased with time and the drug concentration, when the SPUA tape was used. However, the colchicine concentration in plasma became constant after 1 hour, and remained the same level 10 hours later. The colchicine concentration in plasma was not dependent on the drug concentration.

抄録全体を表示

The concept of “intracellular hyperthermia” is local inductive heating of cancer cells after administration of submicron particles producing magnetic excitation, These particles were taken in the cancer cells intracellularly by phagocytosis, resulting in selective destruction of cancer cells with little effect on normal cells and tissues. We examined effects of intracellular hyperthermia on Meth-A, AH60C and VX-2 tumor cells and a phagocytosis of DM in various tumor cells. Dextran magnetite was used as the submicron particle. DM particles are not simple mixture of dextran and ferrate but submicron complex. The heating unit was a 7 kW generator of 500 kHz with a pancake type coil creating electromagnetic field. DM particles were injected in animals with tumor cells intraperitoneally or intratumorously. These animals were exposed to the external inductive field for 20 min. at a temperature of more than 43°C. The phagocytosis of tumor cells was examined microscopically. DM particles were taken intracellularly in tumor cells at 24 hours after administration. The survival rate of rats and mice and the inhibition for growth of VX-2 tumor were most evident in the each groups of 2 times of hyperthermia. DM particles were very promising in inductive heating of 500 kHz.

抄録全体を表示