Drug Delivery System
Online ISSN : 1881-2732
Print ISSN : 0913-5006
ISSN-L : 0913-5006
10 巻, 6 号
選択された号の論文の8件中1~8を表示しています
  • 高倉 喜信, 橋田 充
    1995 年 10 巻 6 号 p. 391-398
    発行日: 1995/11/10
    公開日: 2009/02/23
    ジャーナル フリー
    Recently, DNA medicines have attracted great interest as a novel class of therapeutic agents against various kinds of inherited and acquired disorders. These medicines involves antisense oligonucleotides and plasmid DNA, which enable us to treat the diseases at gene expression level. However, the therapeutic potentials of the DNA medicines are limited due to their physicochemical and biological characteristics as nucleic acids. Therefore, it is virtualy necessary to develop desirable drug delivery systems for DNA medicines. In vivo disposition property of DNA medicines is one of the most critical issues to be considered in developing DNA delivery systems. Based upon the understanding of their in vivo disposition characteristics, rational design of delivery systems, which can realize desirable disposition profiles of DNA medicines in the body, would be possible. In this paper, we will review our pharmacokinetic studies using model oligonucleotides and plasmid DNA in order to constract the startegy for DNA delivery systems. Basic pharmacokinetic characteristics and mechanisms involved in disposition processes have been studied at whole body level in mice and at organ level employing organ perfusion experimental systems.
  • 水野 正明, 吉田 純
    1995 年 10 巻 6 号 p. 399-403
    発行日: 1995/11/10
    公開日: 2009/02/23
    ジャーナル フリー
    Liposomes, artificial generated lipid vesicles, that can entrap drugs within their aqueous compartment and/or in their lipid bilayer have been regarded as a useful drug delivery system ; their potentials for in vivo gene transfection has been reported. In 1987, Feigner and his colleagues demonstrated that a cationic liposomes provide a highly efficient and convenient means to deliver nucleic acids and proteins into various cell types, and that they have a lot of advantages in in vivo gene transfection. Our research of cationic liposomes was initiated in 1988 and we found by collaboration of Yagi and his colleagues that cationic liposomes consisting of N-(α-trimethylammonioacety1)-didodecyl-D-glutamate chloride (TMAG), dilauroyl phosphatidylcholine (DLPC), and dioleoyl phosphatidylethanolamine (DOPE) (1 : 2 : 2 or 1 : 2 : 3, molar ratio) provide high efficiency of DNA entrapping and high potentiality to DNA transfer to human glioma cells. Our cationic liposomes were at first prepared by an improved procedure of reverse-phase evaporation method. However, the improved procedure had some problems for clinical application. Namely, it was complicate and reverse-phase evaporation vesicles were not easy to sterilize and prepare in large quantities. To elucidate these problems, we developed further simple method and characterized the liposomes. Another advantage of cationic liposomes is targeting of the liposomes to specific cells by conjugating the Iiposomes with monoclonal antibodies or ligands. On the monoclonal antibody conjugating Iiposomes, many successful experimental achievements have been reported in the medical application of liposomes. Here, we described simpler method for the association of a monoclonal antibody to target the gene to specific tissues. Further, we also reported the characterization of the liposomes associating a monoclonal antibody (immunoliposomes). We found the immunoliposomes to transfer the entrapped genes more effectively than control liposomes. A β-galactosidase activity was about 2 to 3-fold higher when Lac Z gene was transfected to human glioma cells, and the production of human interferon-β (HuIFN β) was 2 to 7-fold higher when HuIFN β gene was done, than that of control liposomes. Liposomes appear to be more safe than viral vectors because liposomes are non-infectious and appear non-immunogenic. We thought that non viral gene transfer like liposomes would be needed in near future. Furthermore, the immunoliposomes conjugating a glioma-associated monoclonal antibody may become effective carriers for gene transfer to human glioma cells and various cells.
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    加藤 智啓, 山本 一彦
    1995 年 10 巻 6 号 p. 405-411
    発行日: 1995/11/10
    公開日: 2009/02/23
    ジャーナル フリー
    Recently, a great advance has been achieved in creating bioactive molecules using combinatorial selection from a shape library. The library which contains a large number of molecular variants are prepared at the start of the selection, then a subset of the library is selected to bind a target molecule on the basis of shape. This library can include polymers consisting of natural or modified amino acids, nucleotides, carbohydrates and other organic materials. Directing molecular evolution in the test tube, this selection strategy would be useful to elucidate natural molecular interaction and to create novel bioactive molecules. Here, principles and applications of this method were described to create artificial ligands composed of DNA and RNA.
  • 木村 聰城郎, 小野川 雅英, 柳本 恵理, 黒崎 勇二, 中山 太二, 溝渕 憲子, 小西 良士, 北川 幸己
    1995 年 10 巻 6 号 p. 413-417
    発行日: 1995/11/10
    公開日: 2009/02/23
    ジャーナル フリー
    Five azidothymidine (AZT) prodrugs conjugated with the 1-adamantane moiety or the acyl group via an ester bond were evaluated as the brain-directed prodrug in rats. All the prodrugs showed the high lipophilicity and four of them were rapidly degraded to AZT in both plasma and brain homogenates. Adamantanecarbonyl-AZT (Ada-AZT2) was stable in both plasma and brain homogenates. After intravenous bolus administration of the prodrugs, improved brain AZT levels were observed only in acetyl-AZT (C2-AZT) and decanoyl-AZT (C10-AZT). Ada-AZT2 was highly delivered to the brain in the early time point but was rapidly cleared and the generation of AZT was not observed in the brain. The favorable nature for brain-targeted prodrugs was discussed.
  • 佐々木 定之, 高橋 俊雄, 咲田 雅一, 萩原 明於, 辻本 洋行
    1995 年 10 巻 6 号 p. 419-423
    発行日: 1995/11/10
    公開日: 2009/02/23
    ジャーナル フリー
    Pathological changes were compared between two dosage formulations of cisplatin microcrystals suspended in oil (CDDP-Oil), and cisplatin aqueous solution(CDDP-Sol), by intraperitoneal administration in mice. Main toxic findings such as decreasement of the organ weights and histopathological degenerations were seen in the kidney, liver, and hematologic tissues of the spleen, lymph nodes and bonemarrow. Those changes were more heavy in mice died by the toxicity than in mice surviving during the observation period. Thus, the toxic changes were principally similar in the two dosage formulations, and there were no aditional toxic effects in the CDDP-Oil.
  • 案田 岳夫, 山下 弘己, 藤田 英志, 徳永 能治, 柴田 尚武
    1995 年 10 巻 6 号 p. 425-430
    発行日: 1995/11/10
    公開日: 2009/02/23
    ジャーナル フリー
    Liposomes have been proved to be effective as carriers of water-soluble drugs into the central nervous system, but the mechanisms by which water-soluble drugs encapsulated in liposomes permeate the blood-brain barrier(BBB) are not clear. In order to elucidate the mechanisms, the authors investigated the permeability of liposome encapsulated cisplatin [cis-diamminedichloroplatinum (II), CDDP] across in vitro BBB model compared with that of free CDDP. This in vitro BBB model is consisted of primarily cultured bovine brain microvessel endothelial cell (BMEC) monolayer onto the collagen-coated polycarbonate membrane which is put in side by side diffusion cells. This in vitro BBB model matches in vitro BBB in morphology and enzymatic activity, and has been used in many transport studies. The result showed that liposome encapsulated CDDP permeated across BMEC monolayers and the permeability was significantly attenuated by metabolic inhibitor, 2-deoxyglucose treatment (p<0.05 by Student's t-test). Our findings confirmed that CDDP encapsulated in liposomes could be transported through BBB by way of energy-dependent transcellular pathway.
  • 長田 孝司, 山村 恵子, 矢野 亨治, 鍋島 俊隆, 岩田 久, 四ッ柳 智久
    1995 年 10 巻 6 号 p. 431-435
    発行日: 1995/11/10
    公開日: 2009/02/23
    ジャーナル フリー
    Synthesis hydroxyapatite (HAP), similar to bone or tooth mineral composition, was developed for bone grafts in dental and orthopedic applications. Common skin microorganisms, such as Staphylococcus aureus and Staphylococcus epidermidis, have been associated with bone graft-related infections. We investigated whether an antibiotic controlled-releasing HAP device would reduce bacterial organisms at the operated site. Cefotiam (CTM) was used as a model antibiotic since it possesses activity against Staphylococcus aureus and Staphylococcus epidermidis. To control the release rate of CTM, egg phosphatidylcholine (EPC) was loaded into a HAP bead (diameter : 8.48 mm, weight : 531 mg). The EPC-HAP beads were placed in CTM aqueous solutions(4-25 mg/ml) under atmospheric pressure. A bead containing CTM solution in its intemal pores was referred to as a “wet CTM-EPC-HAP bead”. In vitro release studies demonstrated that the release rate of CTM decreased with the increase of EPC load. One wet CTM-EPC-HAP bead was implanted in the skin pocket made in a rat, and inoculated with Staphylococcus aureus or Staphylococcus epidermidis (107 CFU/ml). Wet CTM-EPC-HAP beads showed less Staphylococcus aureus and Staphylococcus epidermidis in comparison with the control HAP beads two days after inoculation. These studies suggest that antibiotic controlled-releasing HAP delivery can decrease infections at the operated site of patients undergoing bone grafts.
  • Chong Su Cho, Seung Ho Choi, You Han Bae, Sung-Wan Kim
    1995 年 10 巻 6 号 p. 437-444
    発行日: 1995/11/10
    公開日: 2009/02/23
    ジャーナル フリー
    Phase separated composite membranes composed of pressure sensitive adhesive polymers and non adhesive polymers were prepared by interpenetrating each polymer component as an alternative approach in the design of a transdermal delivery device. Acrylic polymers were used for an adhesive polymer domain and crosslinked polyethers, such as poly (ethylene oxide)-poly(propylene oxide) block copolymer or crosslinked poly(propylene oxide), were utilized as a non adhesive polymers. The Tg study of the composite membranes revealed a phase separated structure with partial mixing. The membrane adhesiveness was linearly proportional to the amount of adhesive component in the membranes. The tested drugs of β-estradiol, testosterone, hydrocortisone, and nicotine showed preferential permeation through one domain in the membranes. This permeation specificity could be related to the experimental conditions (solvent compositions in diffusion cell compartments) and the interactions between polymer components and drugs for the particular systems used in this study. These results indicate that controlled permeability and adhesive strength can be obtained by a composite membrane.
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