Transdermal delivery systems containing nitroglycerin, isosorbide dinitrate and estradiol have already been in the Japanese market, and those of eperizone hydrochloride and tulobuterol are coming. Separately, topical formulations like NSAID plasters are also in the market. Through the R&D on such formulations, criteria of designing the systems and selecting the pharmaceutical additives and materials have been established, resulting in development of potential skin-penetration enhancers and iontophoresis. In addition, non-needle syringes and skin-adhesive injections are producing, which may be similar to transdermal drug delivery systems. Thus, skin will be a potential site of drug administration of many kinds of drugs to improve quality of life especially for aged patients, together with the GI tract, an absorption site of oral formulations.

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Historical aspects of antibiotic and anticancer drug development were briefly reviewed. Based on the authors experience with highly tumor targeting anticancer agents especially SMANCS, several proposals are made to change old paradigm to new paradigm in cancer chemotherapy. Firstly, the dose setting based on maximum tolerable dose to that based on tumor size or tumor volume. When tumor takes up anticancer agents (usually polymeric drug) 10 times or more of the concentration in blood, then tumor with a weight of 1 kg will be equivalent to 10 kg volume (10 L) equivalent, which will be 2 fold larger than blood volume (of body weight of 65 kg). The dose of drug such as SMANGS/Lipiodol should be most reasonably calculated based on the tumor weight, i. e., tumor of 300 g should be given at least 10 times of tumor of 3 g, and perhaps administered more frequently in the larger tumor. Secondly, present criteria of efficacy (or response) for so called “no effect” include no tumor growth (no change) or to tumor size regression less than 50% reduction of the original size. If the drug is not toxic and beneficial to a patient, especially in view of QOL, such marginal or no reduction, if not progressive tumor growth, should be counted as a favorable effect. Prolonged period of no change, e.g. 3 months, should be counted as effective. Thirdly, other beneficial effect for patients such as suppression of ascitic or pleural fluid accumulation, suppression of metastasis, or recurrent rate should be counted beneficial. QOL of the patients should be evaluated more seriously. For instance, any prolongation of survival period of a patient, who is free of bed-confinement, should be taken into the account.

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The feasibility of a new chemotherapy of the brain tumor which utilizes the direct transport pathway from the nasal cavity to the cerebrospinal fluid (CSF) was evaluated using three anticancer drugs with small MW, cisplatin analogue pyridoxatodiammineplatinum (II) (P-PtB), mitomycin C (MMC) and methotrexate (MTX). In vitro anticancer activity of MTX against 9L glioma cells was particularly potent compared with P-PtB and MMC. The pharmacokinetic studies following nasal and intravenous applications revealed that P-PtB and MTX, which are relatively hydrophilic, archived significantly high concentration in the CSF following nasal application, while lipophilic MMC was not detected following both nasal and intravenous applications. Therefore, the low lipophilic anticancer drugs are suitable for the strategy. The investigations on the enhancement and duration of the drug concentration in the CSF indicated that the most favorable dosage forms of P-PtB and MTX are nebulization of the powder and instillation of a viscous CMC (carboxymethyl cellulose) solution, respectively. It was also shown that acetazoleamide, which is used clinically to reduce the renal side effect by MTX, enhanced the MTX level in the CSF and reduced the plasma MTX level. The in vivo therapeutic potencies of P-PtB and MTX applied as favorable dosage forms as shown above were evaluated using 9L-bearing animals. Compared with the non-treated animals, P-PtB neither increased the survival nor reduced the tumor weight at the death. On the contrary, the tumor weight of the rats receiving four nasal applications of MTX was significantly reduced as compared to the non-treated group and the intraperitoneal group. It was clarified that efficient chemotherapy of the brain tumor and the reduction of systemic side effects are enabled by nasal application of anticancer agents. Our strategy is thought to be clinically significant.

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Ceramide is well known as a regulator of cell apoptosis and cell growth suppression. In this study, we synthesized more lipophilic ceramide derivatives in order to incorporate into lipid microsphere (LM), and their activity was evaluated in vivo. Cera 03, diacetylated form of C₂-ceramide showed a potent cell growth inhibition and potently induced apoptosis in both U 937 cells and Meth A-T tumor cells in vitro, with a similar potency as cell membrane-permeable C₂-ceramide. Diacetylated form of natural type ceramide (Ger), Cera 02, also suppressed the in vitro cell growth with a similar potency as that of Cer, which was much lower than that of C₂-ceramide and Cera 03. LM preparation of Cera 03 (Lipo-Cera 03, 1 mg/ml) was stable, and inhibited the murine experimental pulmonary metastasis employed with Meth A-T cells. Intravenous injection of lipo-Cera 03 (1 mg/kg of Cera 03) showed over 35% inhibition in the experimental metastasis model. In while, LM preparation of Cera 02 (Lipo-Cera 02, 1 mg/ml) was also stable, however, a significant efficacy was not observed. Therefore, LM emulsion of a ceramide derivative (Cera 03) has a potential for an anti-metastatic injectable drug, and also would be an useful tool for researching the role of ceramide in vivo.

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We have developed a novel sustained-release system for protein drugs using silicone. The silicone formulation is an injectable dosage form, and designed to maintain the protein drug effects for months by sustained-release. Since the silicone formulation can be prepared without heating nor organic solvents, various protein drugs, which are generally unstable, can be applied to the silicone formulation. The purposes of the study are (1) to investigate the drug release from the silicone formulation in vivo, and (2) to improve the release profiles. In this study, interferon (IFN) was used as an example of the protein drugs. The IFN silicone formulation was prepared and investigated IFN release profiles in vitro for 30 days. The IFN silicone formulation released IFN through this period in a first-order profile. When the IFN silicone formulations were administered into nude mice which bore human renal cell carcinoma, the IFN silicone formulation significantly inhibited the growth of the tumor. From these results, it is found that IFN was released from silicone without loss of its bioactivity. For these experiments, matrix type IFN silicone formulation was used, and its release profile was first-order as above mentioned. In order to achieve zero-order release, a covered-rod type IFN silicone formulation has been developed. We found that the covered-rod silicone formulation released IFN in a zero-order profile for 60 days in vitro. In addition, it maintained serum IFN concentration for 30 days in nude mice. The half life of the serum IFN concentration after the administration of the IFN covered-rod formulation was about 158 hrs, which was 26 folds longer than that of IFN aqueous solution. From these results, the silicone formulation is thought to be especially effective for the treatment of chronic diseases and for preventive treatment of high risk patients.

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We developed a novel w/o/w emulsion formulation containing medium-chain triglyceride (MCT) as an oily phase and lomeron 300 as an aqueous phase with functions of embolizing and sustaining drug-release in trans-catheter arterial embolization (TAE) therapy for hepatocellular carcinoma. The various formulations with various kinds of surfactants were applied to the MCT w/o/w emulsion to improve its stability. The most stable w/o/w emulsion was obtained when the mixture of HCO-10 and CO-3 (1 : 1) of 3% in oily phase and HCO-60 of 5% in aqueous phase were formulated. The stability of emulsion was also evaluated by a drug release test with Spin-Biodialyser^™ Double-sided for the emulsions encapsulating epirubicin hydrochloride (EPI), doxorubicin hydrochloride (DOX) or Evans blue in an inner aqueous phase. The drug release profiles suggested the sustained drug release property of the emulsions. When normal rats were treated with the hepatic arterial injection of the MCT w/o/w emulsion encapsulating EPI, there was non dysfunction trans aminase of GOT and GPT in normal liver. The increased drug retention in liver after the arterial administration of EPI in a w/o/w emulsion form in rats bearing a hepatic tumor revealed the usefulness of this device for the drug targeting to the hepatic tumor.

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A liposome formulation study was performed to prepare a sustained release system of the cationic amphiphilic antitumor agent, N'-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-N-(2-chloroethyl)-N-nitrosourea hydrochloride (ACNU). Liposomes were prepared with dipalmitoylphosphatidylcholine as the main lipid component with addition of dipalmitoylphosphatidylglycerol (DPPG) and/or cholesterol, and then extruded for size control. The ACNU-loaded liposomes could be stably dispersed provided cholesterol was formulated as one of the lipid components. The dependence of the encapsulation efficiency on the kind of lipids, and concentration of either ACNU or other additional electrolytes was investigated to obtain information on the mode of encapsulation. The encapsulation efficiency was much higher than the calculated captured volume ratio within the liposomes regardless of presence or absence of DPPG, an anionic lipid, but not strongly affected by the ratio of ACNU/DPPG in feed. These results indicated that ACNU was mainly embedded inside the lipid bilayer according to its partition between the lipid bilayers and aqueous phase. By comparing the chemical stability of ACNU encapsulated in liposomes of different sizes, it was found that the larger the size, the higher the stability. This was consistent with the encapsulation mode speculated above. Furthermore, the larger liposomes resulted in ACNU release with a more sustained manner. It is expected that the ACNU-loaded liposome is applicable as a chemoembolization agent as well as a sustained release reservoir for intratumor, intramuscular and subcutaneous administrations.

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Cis[((1 R, 2 R)-1, 2-cyclohexanediamine-N, N')bis(myristato)]platinum(II) (SM-11355) is a platinum complex under development that targets primary hepatocellular carcinoma using Lipiodol as a carrier. The present study attempted to clarify the relationship between the sustained release of SM-11355 suspended in Lipiodol (SM-11355/Lipiodol) and the adduct formation of the released compound to nuclear DNA as a target, using an assay system capable of coexisting with the drugs contained in Lipiodol and tumor cells. SM-11355/Lipiodol and CDDP suspended in Lipiodol (CDDP/Lipiodol) showed cytotoxic activity against rat ascite hepatoma AH-109 A cells in a dose-dependent manner. SM-11355/Lipiodol showed a sustained release into the culture medium over the course of a 7-day drug exposure. Following the exposure of CDDP/Lipiodol, the platinum concentration in the culture medium was at its maximum on the first day and remained constant thereafter. Intracellular platinum uptake and adduct formation to nuclear DNA were dependent on the release characteristic of each drug suspension. Although cyclohexane-1, 2-diamineplatinum(II) diiodide (DPI) and cyclohexane-1, 2-diamineplatinum(II) dichloride (DPC), which are hypothesized as the release compound from SM-11355/Lipiodol, were taken up by cells, only DPC detected DNA adduct formation. Thus, this study observed that SM-11355/Lipiodol shows a sustained release of cytotoxic compounds, like DPC that bind to DNA and subsequently show the cytotoxic activity as SM-11355/Lipiodol.

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Peritoneal recurrence is one of the most important disease after surgery of the gastrointestinal cancer. We have reported that dextran surfate prevents malignant cells from adhering mesothelium and attenuates peritoneal metastases when malignant cells are seeded into abdominal cavity. In this report, we examined acute toxicity of dextran sulfate in mice (BDF 1, strain, male). The mice, bred in specific pathogen free, were divided into 11 groups. One was the group of mice that was given nothing, another was the group of mice that was injected physiological saline, the rest 9 groups were the groups of mice that were received dextran sulfate in abdominal cavity. Dextran sulfate was dissolved at a range of 2-8 mg/ml in saline solution in 9 stages, and was injected into abdominal cavity of the mice. Survival rate and general conditions were observed during 14 days after injection. The number of dead mice increased as the dose of dextran sulfate become large. The death was seen within 3 days after injection. Body weight turned into increasing phase and the toxic symptoms were improved 4 days later. The LD₅₀ value of dextran sulfate, calculated following the Probit method, was 0.341 mg/g, which dose is much greater than the dose effectively prevents cancer cells from adhering.

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