Prospect for the clinical application of transdermal DDS from the viewpoints of safety, usefulness and effectiveness is described in this review. Development of the more safe materials and improvement of the dosage form itself and package should be required for the popularization of transdermal DDS in the future. Patient compliance instruction is important for getting the better compliance and for a prevention of misuse. Problems of the poor transdermal absorption might be solved by a finding of safe and potent absorption enhancer. Results of our recent studies on enhancing effects and safety of cyclic monoterpenes such as d-limonene are also described.

抄録全体を表示

Effectiveness of a hepatic targeting system utilizing carbohydrate recognition mechanism was evaluated. Three types of bovine serum albumin (BSA)derivatives with 1-thiogalactoside(Gal-BSA), 1-thioglucoside(Glc-BSA), and 1-thiomannoside (Man-BSA) were synthesized by the amidation method and their disposition characteristics in mice were studied. Gal-BSA and Glc-BSA were rapidly taken up by the liver parenchymal cells, while Man-BSA was accumulated in the non-parenchymal cells due to receptor-mediated endocytosis. Similar results were observed in glycosylated superoxide dismutase and carboxymethyldextran, suggesting wide applicability of this methodology.

抄録全体を表示

The present study was undertaken to examine potential value of cetlymannosides-modified multilamellar liposomes(Man-MLV)as vehicle of recombinant human macrophage colony-stimulating factor (M-CSF) to human blood monocytes. Man-MLV was taken effectively by monocytes as compared with liposomes without cetylmannoside (PC-MLV). Addition of D-mannose(50 mM) inhibited about 50% of uptake of Man-MLV by monocytes, but not significantly uptake of PC-MLV by monocytes. These results suggest that mannose redisues of Man-MLV contributes to uptake of Man-MLV by monocytes. We examined effect of encapsulation of M-CSF in Man-MLV on survival prolongation of monocytes. Blood monocytes that had been incubated for 7 days in medium with M-CSF encapsulated in Man-MLV were effective in prolongation of monocytes survival. This enhancing effect by M-CSF encapsulated in Man-MLV showed about 5-10 times higher than that in PC-MLV, in spite of the uptake of Man-MLV by monocytes was only about 2-fold different from that of PC-MLV. It was suspected that this effect contributes to not only effective uptake by monocytes, but also the difference of intracellular disposition of liposomes in monocytes. These results suggest that Man-MLV may be effective carrier vehicle in in vivo delivery of M-CSF to human blood monocytes.

抄録全体を表示

There are two problems in the application of Auger electrons derived from ¹²⁵IUdR for cancer treatment. One is cell cycle dependency (effective only for S phase cells), the other is side effects for the cell renewal systems(e. g. bone marrow, intestine). We tried intratumoral injection of ¹²⁵IUdR oil suspension using Ehrlich ascites tumors in the thighs of mice. Oil suspension was more effective in tumor growth delay than saline solution. Single injection of oil suspension at the dose of 0.46 MBq resulted in 21.5 days growth delay while 1.85 MBq of saline solution resulted in 11.5 days growth delay relative to control growth delay. At 40 days after treatment, higher radioactivities were observed in the tumor and the skin of the mice treated with oil suspension, which represented prolongation of ¹²⁵IUdR oil suspension within the tumors. No normal tissue toxicities were observed. This method can be a new treatment for brain tumors and radioresistant head and neck tumors by further improvements of drug delivery systems

抄録全体を表示

We investigated the therapeutic effects of activated charcoal microparticles(CH) (specific surface area=1, 480 m²/g, diameter=20 mm), which have high capacity to retain anti-cancer agents, on perconeal dissemination of gastric cancer in 7 cases without liver metastasis, the primary tumor of which were resected surgically. The composition of MMC-CH was as followed : MMC : CH =1 : 8.3 (weight ratio). MMC solved into saline solution was shaked to mix up with 2% polyvinylpyrrolidone K-30 containing CH (50 mg/l ml saline), and the mixture was scattered into the abdominal cavities just before the closure of abdominal walls. MMC was given at 20 mg to 2 cases, at 30 mg to 3 cases, at 40 mg to one case and at 50 mg to one case respectively. The survival rate of the MMC-CH administration group, calculated by Kaplan-Meier's method, was higher than that of the control group

抄録全体を表示

The in vitro release of aclarubicin (ACR) from the microspheres (MS) and the lymphotropic delivery of ACR were studied using a different molecular weight of lactic acid-oligomers and a different size of microspheres (MS). The more sustained release of ACR was observed with an increase of molecular weight of lactic acid-oligomers, while a size of MS did not so influence. The pronounced delivery into lymph nodes was observed after intramuscular injection of ACR-MS but not after subcutaneous injection. The ACR-MS with small size was effectively targeted to lymph nodes, where ACR was prolonged retained. The largest molecular weight, 10, 000, and small size of MS showed the most effective lymph targeting and longest retention in the regional lymph node.

抄録全体を表示

A new form (ACR-CH) of anticancer drug administration for treatment of breast cancer is prepared, the new dosage form of ACR-CH comprised 12.5 mg/ml of activated carbon, 5 mg/ml of polyvinylpyrrolidone and 5 mg/ml of aclarubicin (ACR) in saline. ACR-CH distributes less amount of ACR in blood and systemic organs than ACR aqueous solutionin (ACR-SOL) does. ACR-CH and ACR-SOL were studied on the acute toxicity. Some doses of ACR-CH and ACR-SOL were injected subcutaneously into the back of mice. Survival rate and general conditions were observed during 14 days after the injection. The mice were subjected to autopsy. The LD₅₀ values of ACR-CH and ACR-SOL calculated following Litchfield-Wilcoxon method were 83.5 mg/kg and 43.5 mg/kg, respectively. Except for the recovery of body weight, there was no difference between the two dosage form in the intoxication symptomes and the autopsy findings. It was concluded that ACR-CH was adimistrated more safely than ACR-SOL.

抄録全体を表示

We attempted to deliver adriamycin (ADM) to lymph nodes by using sulfatide-inserted liposomes, which consist of phosphatidylcholine, cholesterol, and sulfatide (molar ratio, 5 : 4 : 1) (Lip-ADM). We measured the concentrations of ADM in regional lymph nodes of the stomach after the injection of Lip-ADM or free ADM into the gastric mucosa of dogs, and found that in the case of Lip-ADM, ADM levels in all regional nodes were significantly higher than those in the case of free ADM and these high levels were maintained for 48h. Then, we transplanted a mammary tumor into foot pads of mice to make inguinal lymph node metastases. Upon subcutaneous injection into the femur, Lip-ADM brought about a higher concentration of the drug in the metastasized cells at 24 hours than did the free ADM. These data suggest that liposomes entrapping ADM are effective for the treatment of lymph node metastases of gastric cancers.

抄録全体を表示

Adriamycin (ADR) was covalently conjugated with a copolymer of divinyl ether and maleic anhydride (DIVEMA). Either sole ADR or DIVEMA-ADR conjugate was injected intraperitoneally into mice, and the concentration of ADR in the serum and peritoneal fluid (PF) was measured by HPLC (high-performance liquid chromatography). A reversed phase liquid chromatography column enabled to measure the concentration of ADR as low as 6 ng/ml. In sole ADR administration, the ADR concentration in the PF reached 179 ng/ml at one hour then gradually decreased to 13 ng/ml at 24 hours after i.p. injection. In contrast, the concentration in the serum fell rapidly from 16.8 ng/ml at one hour to 6.6 ng/ml at 2 hours after the injection. In DIVEMA-ADR conjugate, the ADR concentration in the PF was elevated to 4, 057 ng/ml at one hour and decreased more slowly than in sole ADR. Even at 24 hours after i.p. administration of the conjugate, ADR was kept as high as 90 ng/ml in the PF. On the other hand, the serum concentration remained under the limit of detection at all times measured. Pharmacokinetic parameters were obtained based on the time-concentration curves of either sole ADR or DIVEMA-ADR administration, using two-compartment model. The results showed that the conjugate increased the AUC(area under the curve) of ADR in the PF by 15.4 times higher than that of sole ADR. These remarkable ability of DIVEMA conjugate on pharmacokinetics of ADR would be greatly contributable for improvement of cancer chemotherapy, especially for the treatment of peritoneal dissemination from intraabdominal malignancies.

抄録全体を表示

In an attempt to develop a transdermal therapeutic system for 2', 3'-didehydro-3'-deoxythymidine (D4T) and its lipophilic prodrugs, percutaneous penetration of the drugs was examined in rat skin. The ability of penetration enhancers (Azone and l-menthol) to increase transdermal delivery of the drugs was evaluated in excised rat skin. Azone and l-menthol showed a significant enhancing effect on the penetration of D4T and its 5'-acetate (C2-D4T) at a concentration of 3 % in water. The penetration of 5'-octanoate (C8-D4T) was, however, hardly observed even in the presence of the enhancers. A D4T suspension containing l-menthol (3 %) was applied on rat abdominal skin, and the plasma concentration was measured. D4T was detected in plasma at 12 hours after the application, and a constant plasma concentration (1-3 μM ) was maintained for 8 hours.

抄録全体を表示

Several tape formulations containing a possible drug, dopamine hydrochloride and a useful penetration-enhancer, glyceryl monocaprylate were prepared, and the release rate and skin permeation rate were measured. Skin permeation was measured in vitro by using the excised hairless rat skin and diffusion cell. Release rate from the drug-suspended adhesive was rapider than that from the drug-dissolved one. Acrylvinyl-type adhesive showed the best skin permeation of the drug among the adhesives tested in the present study. The higher were the drug concentration and enhancer concentration, the higher was the skin permeation. The blood concentration after application the formulation could be predicted by the in vitro skin permeation data and elimination pharmacokinetics.

抄録全体を表示