Recent Aspects of Pharmaceutical Application of Cyclodextrins

Because of the multi-functional characteristics and bioadaptability, cyclodextrin (CyD) is capable of alleviating the undesirable properties of drug molecules through the formation of inclusion complexes. This paper outlines the current application of natural and chemically modified CyDs in the various pharmaceutical formulations including peptide and protein drugs. Furthermore, potential use of CyD/drug conjugates in site-specific drug delivery is discussed.     

Preparation and evaluation of polyamidoamine dendrimer (G2)/branched-��-cyclodextrin conjugate as a novel gene transfer carrier

The purpose of this study is to evaluate the potential use of polyamidoamine (PAMAM) starburst dendrimer (generation 2, G2) conjugates with 6-O-??-(4-O-??-d-glucuronyl)-d-glucosyl-??-cyclodextrin (GUG-??-CDE (G2)) having glucose as a spacer between dendrimer and cyclodextrin (CyD) as a novel gene transfer carrier. GUG-??-CDE (G2) was found to have lower hemolytic activity than dendrimer (G2), suggesting that GUG-??-CDE (G2) had lower local irritation than dendrimer (G2). Of GUG-??-CDEs (G2) having the various average degree of substitution (DS) of a glucuronylglycoside group, GUG-??-CDE (G2, DS 1.8) possessed much higher gene transfer activity than ??-CDE (G2, DS 1.2) and ??-CDE (G2, DS 1.3) in A549 and RAW264.7 cells, suggesting the crucial role of a spacer between dendrimer and CyD for high gene transfer activity of GUG-??-CDE (G2, DS 1.8). In sharp contrast to linear polyethyleneimine (10 kDa, PEI), GUG-??-CDE (G2, DS 1.8) had negligible cytotoxicity. These results suggest that GUG-??-CDE (G2, DS 1.8) could have the potential for a novel gene transfer carrier, compared to ??-CDE (G2, DS 1.2), ??-CDE (G2, DS 1.3) and PEI.     

Prostaglandins and their cyclodextrin complexes

Generally, prostaglandins (PG) are unstable and insoluble in water, though they exhibit strong biological activities in minute amount. The most difficult problem in developing PG preparations is how to stabilize and solubilize PG without loss of their activities. We have successfully developed the pharmaceutical preparations contaning PG complexes with cyclodextrins (CD). These preparations are already on the market, namely PGE₂ ·-CD Tablet and PGE₁ ·-CD Injection. Moreover, PG and PGI₂ derivatives are now under development as a form of CD complex.     

The contribution of fructose and nitric oxide to oxidative stress in hamster islet tumor (HIT) cells through the inactivation of glutathione peroxidase

Reducing sugars, such as glucose and fructose, are known to play a role in the initiation of apoptosis in pancreatic beta-cells. The data collected in this study show that fructose increases H2O2 levels and lipid peroxidation of hamster islet tumor (HIT) cells, which originated from hamster pancreatic beta-cells. In an attempt to clarify the mechanism of this oxidative stress, we were able to show that glutathione peroxidase (GPx) is inactivated by fructose, and that mRNA expression of GPx is suppressed by fructose. Nitric oxide (NO) is also known to bring about apoptosis. The presence of NO increases intracellular peroxide levels in HIT cells as judged by flow cytometric analysis. These data suggest that fructose and nitric oxide suppress the activity or expression of GPx, and, as a result, permit an increase in intracellular peroxides or lipid peroxidation. This represents a major contribution to the main mechanism of apoptosis by fructose and NO.     

Improvement of dissolution properties of a new Helicobacter pylori eradicating agent (TG44) by inclusion complexation with beta-cyclodextrin

The interaction of a newly developed Helicobacter pylori eradicating agent (TG44, 4-methylbenzyl-4'-[trans-4-(guanidinomethyl)cyclohexylcarbonyloxy]biphenyl-4-carboxlylate monohydrochloride) with beta-cyclodextrin (beta-CyD) in aqueous solution and in solid state was studied to gain insight into the high in-vivo H. pylori eradicating activity of TG44/beta-CyD complex. The interaction was studied by the solubility method, spectroscopic methods, powder X-ray diffractometry and differential scanning colorimetry (DSC). TG44 gave A(L)-type phase solubility diagram with beta-CyD in water, showing a linear increase in solubility of the drug up to 8 mM beta-CyD concentration. The solubility of TG44 (0.04 mM in water at 25 degrees C) increased about 70-folds at 8 mM beta-CyD. Ultraviolet, circular dichroism, fluorescence and (1)H-nuclear magnetic resonance spectroscopic studies indicated that TG44 forms the inclusion complex with beta-CyD in a 1:1 stoichiometry and the biphenyl moiety of TG44 is preferably included in the beta-CyD cavity in water. The Giordano plot made by monitoring changes in the fusion enthalpy of TG44 (about 184 degrees C) suggested that TG44 forms the 1:1 complex with beta-CyD in the solid state. The TG44/beta-CyD solid complex in a 1:1 stoichiometry was prepared by the grinding and spray-drying methods and confirmed by powder X-ray diffractometry and DSC that the complex is in an amorphous state. The initial dissolution rate of TG44/beta-CyD complex was significantly faster than those of the drug alone and the physical mixture of both components, maintaining higher supersaturated concentrations of the drug for a long time. The results suggested that the higher eradicating activity of TG44/beta-CyD complex to Helicobacter pylori, compared with that of the drug alone, is attributable at least partly to the faster dissolving property of the complex and its ability to maintain the supersaturated state of the drug in the gastric fluid.     

Application Of Insulator-Metal Transition Of Conducting Polymers

As example of application of the insulator-metal transition in conducting polymers, electro-optic device utilizing electrochemical doping and radiation induced doping are discussed in detail.     

Tubular linear actuators using conducting polymer, polypyrrole

Conducting polymers show an electrochemomechanical deformation (ECMD), which is able to be utilized as soft actuators. A tubular linear actuator of polypyrrole film is fabricated and the characteristics are examined. The film was electrochemically prepared on an acryl resin rod in an aqueous electrolyte solution of pyrrole and dodecylbenzensulfonic acid (DBS), followed by removing the rod. The actuations of tubular polypyrrole film due to ECMD in various conditions have been examined to clarify the mechanism. It has been found that the tubular actuator elongates upon reduction with the strain of 7%, which is more than twice of that observed in a rectangular film. The facts indicate that cations play the role of dopants instead of large DBS anion and the tubular structure gives the better performance for large strain.     

In vitro gene delivery mediated by lactosylated dendrimer (generation 3, G3)/��-cyclodextrin conjugates into hepatocytes

The purpose of this study is to evaluate in vitro gene delivery efficiency of polyamidoamine (PAMAM) starburst dendrimer (generation 3, G3) conjugates with ??-cyclodextrin (??-CDE (G3)) bearing lactose (Lac-??-CDE) with various degrees of substitution of the lactose moiety (DSL) as a novel hepatocyte-selective carrier. Lac-??-CDE (G3, DSL 1.2) was found to have much higher gene transfer activity than ??-CDE (G3), Lac-??-CDE (G2, DSL 2.6) and Lac-??-CDEs (G3, DSL 2.6, 4.1 and 6.1) in HepG2 cells, which are dependent on the expression of cell-surface asialoglycoprotein receptor (ASGP-R). Lac-??-CDE (G3, DSL 1.2) provided negligible cytotoxicity up to a charge ratio of 100 (carrier/pDNA) in HepG2 cells. These results suggest the potential use of Lac-??-CDE (G3, DSL 1.2) as a non-viral vector for gene delivery toward hepatocytes.