For substitution of oxygen transporting ability in blood stream, artificial red cells have been widely developed for recent years. Since the role of the other blood components can be replaced by synthetic molecules (chemical regents), the realization of artificial O₂-infusion leads to complement of the artificial blood based on the present transfusion techniques. This review describes the recent topics of the development of artificial red cells, especially on hemoglobin (Hb) based materials and totally synthetic lipidhemes. The Hb vesicles (HbV, cellular type) with appropriate O₂-binding ability have several advantages in comparison to the acellular types such as crosslinked Hb. The results of animal tests clearly represented the in vivo oxygen delivery by HbV. On the other hand, molecular assemblies of synthetic lipidhemes act as O₂-carrier under physiological conditions, More recently, albumin heme hybrid has also been developed as a new type of the O₂-infusion series.

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2'-C-Cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine (CNDAC) has been developed as a novel antitumor nucleoside. 5'-Dipalmitoylphosphatidyl derivative of CNDAC (DPP-CNDAC) also has a significant antitumor activity and is readily incorporated in liposomes. Therefore, to reduce the side effects and to enhance the antitumor activity, we incorporated DPP-CNDAC into reticuloendothelial systems (RES)-avoiding, long circulating, liposomes modified with palmityl-D-glucuronide (PGlcUA), which tend to accumulate passively in tumor tissues. When liposomal DPP-CNDAC modified with PGlcUA was injected intravenously into Meth A sarcoma-bearing mice, it showed higher antitumor activities and increased more the life span of mice, compared to those obtained by injection of DPP-CNDAC only or by liposomal DPP-CNDAC without PGlcUA. Thus, the incorporation of DPP-CNDAC into liposoma membrane modified with PGlcUA may be useful as a formulation of this anticancer agent.

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Stratum corneum which is the uppermost layer of skin acts as its barrier. Therefore, scarcely any kind of drug can be delivered into and through skin. In order to settle this problem, many agents and technology have been developed, for example transdermal absorption enhancers. In the field of cosmetics, high performance products containing moisturizers, or whitening agents have recently been developed. Regarding these products, the penetration of these cosmetic ingredients into skin have become of major importance for cosmetic developer. However, most of absorption enhancers cannot be utilized for cosmetics because of their tendency to cause skin roughness. We need a way in which no-irritation for skin is caused and therefore can be practically used for cosmetics. The purpose of this study is to increase accumulative quantity of cosmetic ingredients into stratum corneum/epidermis utilizing on for absorption carrier. Yucatan micropig (YMP) skin is used for this examination for it resembles the human skin histologically. dl-α-Tocopheryl nicotinate and butyl parahydroxybenzoate are used for oil soluble agents. From our experiments, we found that the oils which increase accumulative quantity of oil soluble agents were divided into two groups. The oils we call group A have high solubility parameter. The solubility parameter of these oils was in correlation with their accumulative quantity of the oil soluble agents. Another group of oils, group B, have specific solubility parameter from 16.0 to 17.5. The affinity of stratum corneum's keratin protein and these two groups of oils were investigated utilizing three dimensional solubility parameter.

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The poor oral bioavailability (BA) of clinically effective peptides requires that these agents be administrated primarily by parenteral routes, Non-invasive systems for peptide delivery are therefore very attractive and have long been studied. Iontophoresis is one such system where macromolecules are delivered with high potency. Pulse depolarization systems are iontophoretic systems that depolarize the skin (i. e., neutralize the charge stored in the skin capacitance) after each pulse of an applied current. In this study, we evaluated a pulse depolarization iontophoretic system (PDP-IP) as a peptide delivery system. The evaluation involved measuring the BA of a model peptide, salmon calcitonin (sCT), at various dosages and currents using either transdermal or transbuccal administration in dogs. The BA in transbuccal iontophoresis against intramuscular administration, with a constant transport current of 0.2 mA for 1 hour, was about 10 times higher than the BA in transdermal iontophoresis (1% vs 10%). In transbuccal iontophoresis, with a constant voltage of 8 V, there was a liner relationship between dosage and AUC of sCT serum concentration. Furthermore, electrically induced transport of sCT depended on the total transport current(mA × min). The difference in electrical characteristics between skin and buccal mucosa may be the reason for the difference in iontophoretic peptide delivery between these two membranes : buccal resistance is lower than skin resistance, although buccal impedance is similar to skin impedance. Other possible factors include site differences in enzymatic activity and non-specific binding. PDP-IP effectively enhanced the peptide delivery in both transbuccal and transdermal administration. However, the enhancement in macromolecular drug delivery was greater for the transbuccal iontophoresis (faster delivery rate and higher amount of drug absorption) than for the transdermal iontophoresis. Although further experiments are needed to clarify possible local irritation, PDP-IP is very attractive as a transbuccai delivery system for macromolecular drugs.

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Distribution of phosphorothioate antisense oligonucleotide (S-oligo), S-oligo/lipofectin complex and S-oligo/PEG lipid complex in Hela cells was observed by a confocal laser scanning microscope. The S-oligo localized to endosome/lysosome in a punctate fluorescence pattern. In the presence of lipofectin, the S-oligo was accumulated in the nucleus of Hela cells. The S-oligo/PEG lipid complex showed both punctate fluorescence and diffuse fluorescence in the cyoplasm, but not in the nucleus. These result clearly demonstrated that the subcellular distribution of S-oligo depended on the delivery system.

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Patients with metastatic hepatocelluiar carcinoma (HCC) and impossibility to cut out primary HCC were treated carcinostatic transcatheter arterial embolization (TAE) combinated intra-arterial injected chemo-lipiodolization therapy. In this study, we were investigated constituents THP-emulsion using non-ionic contrast media (NCM), iopamidol (IOP) and iohexol (OMN), in pirarubicin (THP) emulsion, to use TAE combinated chemo-lipiodolization therapy for HCC. In these emulsion, water phase was NCM used as solvents for THP, oily phase was lipiodol ultrafluid (LPN). THP-emulsion was prepared by high pressure homogenization using two syringes jointed three-way cock. Stable w/o and o/w types of THP-emulsion were uniform at particle size, independent on kind of NCM. The OMN used to THP-emulsion was easier to decompose into doxorubicin. Therefore, water phase of THP-emulsion was suitable to more TOP than OMN. Stability of THP in NCM was examined and IOP was selected as the solvent. Further, there was non disfunction, transaminase of GOT and GPT in normal liver when rats were received intra arterial injection of each THP-emulsion. We could propose THP-emulsion using IOP and LPD as constituents to carry pre clinical study for TAE combinated chemo-lipiodolization therapy for HCC.

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The solubility of cyclosporin A (CYA), an immunosuppressive drug, in water increased with a rise in hydrophilic cyclodextrin (CyD) concentrations, forming higher-order complexes. The solubilizing ability of hydrophilic CyDs for CYA increased in the order γ-CyD<β-CyD<α-CyD<<2, 6-dirnethyl-β-CyD(DM-β-CyD)≈DM-α-CyD. The oral bioavailability of CYA was increased about 4.5-fold by the complexation with DM-CyDs, and the variation of CYA absorption from gastrointestinal tracts was significantly decreased. On the other hand, the lymphatic transfer of CYA was hardly affected by the hydrophilic CyDs including DM-CyDs. Acylated β-CyDs that all hydroxyl groups of β-CyD are substituted with acetyl, butanoyl and octanoyl groups, were used as slow release carriers for CYA. When CYA/acylated β-CyDs complexes were administered orally, both plasma and lymph concentrations of CYA were prolonged up to at least 36 h, although the bioavailability decreased particularly for the butanoyl and octanoyl β-CyDs complexes. Interestingly, triacetyl-β-CyD complex increased both plasma and lymph concentrations of CYA compared with drug alone. The oral administration of CYA as an olive oil solution significantly enhanced the lymph levels of CYA. The CYA/olive oil solution in combination with HP-CyDs, especially HP-γ-CyD, further increased plasma and lymph levels of CYA. These results suggest that DM-CyDs are particularly useful in improving the oral bioavailability of CYA, while hydrophobic acylated β-CyDs are useful as a prolonged-release carrier for CYA. The CYA/olive oil solution in combination with HP-γ-CyD was proved to facilitate the lymphatic transfer of CYA.

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