Isao Kaetsu

Stimulus responsive drug release from polymer gel.: Controlled release of ionic drug from polyampholyte gel

Abstract 2-(Dimethylamino)ethyl methacrylate or Methacryloyloxyethyltrimethylammonium chloride as a cationic monomer was copolymerized by UV with anionic monomer such as acrylic acid (AAc), into a polyampholyte. The pH responsive swelling behaviour and the pH and electro-responsive drug release functions of polyampholyte were investigated. The result showed that a copolymer of cation rich composition swelled at acidic condition, and shrank at alkaline condition. On the other hand, an anion rich copolymer showed a reverse phenomenon. Polyampholyte proved to interact with an ionic drug both by ionic binding and physical adsorption.

The synthesis and the electric-responsiveness of hydrogels entrapping natural polyelectrolyte

Abstract A mixture of vinyl monomer, a natural polyelectrolyte—hyaluronic acid—and crosslinker was polymerized and crosslinked to entrap the natural polymer into the synthetic gel. The controlled release of the model drug from the obtained gel was studied under the on–off switching of electric field. It was proved that electric-responsive drug releases were possible using hyaluronic acid entrapping gel and the electro-responsiveness was greatly affected by various factors such as degree of swelling, crosslinking density, kind and composition of vinyl monomer and crosslinkers.

Intelligent biomembrane obtained by irradiation techniques

Abstract An intelligent biomembrane for environment-responsive feedback releases has been developed using radiation techniques. Various fine-porous base membranes (polyester, polycarbonate, silicon) were prepared by hole fabrication techniques with excimer-laser, ion-beam etching and photo-lithography etching. Then, various monomeric mixture of stimuli-sensitive hydrogels with or without immobilized enzymes were coated and polymerized on the porous membrane by UV, γ -ray or electron beam. The product showed the intelligent feedback release functions of model substance (methylene blue) in response to the on–off switching of signals such as pH changes and introduction of electric field. The responsiveness was remarkably improved by radiation induced IPN (interpenetrating polymer network) formation. Intelligent release controlled by a computer program was also studied and proved.

Intelligent type controlled release systems by radiation techniques

Intelligent controlled release systems have been designed and constructed. The systems have a sensor-actuator gate consisting of polyelectrolyte hydrogel layer with immobilized enzymes inside fine holes of polyethylene terephthalate (PET) film and silicon wafer as base materials. Excimer-laser or ion-beam irradiation was used for the etching of holes in PET film and photo-lithography was used for the etching of silicon wafer. U.V. and γ-ray irradiations were used for the polymerization and immobilization of electrolyte layers in the holes. Various kinds of signal responsive release systems such as pH responsive, substrate responsive, Ca2+ responsive, photo-responsive and electric field responsive systems have been developed using those techniques. Some integrated systems have been designed and constructed by combination of unit systems in series and in parallel and proved the selective signal transfer and the successive signal responsive release functions.

Ipsilateral Dominance of Human Olfactory Activated Centers Estimated from Event‐Related Magnetic Fields Measured By 122‐Channel Whole‐Head Neuromagnetometer Using Odorant Stimuli Synchronized with Respirations

ABSTRACT: The aim of this study was to measure and analyze olfactory event‐related magnetic fields using a whole‐cortex biomagnetometer (122‐channel SQUID gradiometer). Amyl‐acetate gas (approx. 1%) was administered for 300 msec into either the right or left nostril in synchronization with respiration using a mask and an optical fiber sensor. Clear olfactory event‐related magnetic fields were asymmetrically obtained on both sides of the forehead in all six subjects. The generators of olfactory magnetic fields were estimated at two regions located fairly asymmetrivally near the bilateral frontal deep areas. The goodness‐of‐fit was better for the two‐dipole model than the one‐dipole model in all experiments.

Biomedical materials, devices and drug delivery systems by radiation techniques

The study of radiation polymerization in a super-cooled state started in 1966 and has been applied to the immobilization of biofunctional materials since 1973. In the last twenty years, application has been concentrated to the immobilization of drugs and hormones for the purpose of drug delivery systems. Very recently, the author has proposed a concept of environmental signal responsive chemical delivery system, as a new generation of controlled release and delivery systems. The study and development of materials, devices and systems is described. The signal responsive delivery system consists of a sensor part and a controlled delivery part. Therefore, the use of immobilization techniques for the biochip sensor and the hydrogel actuator has been investigated. As a future goal, systems for the brain research are to be designed and studied.

Synthesis of electro-responsive hydrogels by radiation polymerization of sodium acrylate

Abstract Sodium acrylate-crosslinker (polyethyleneglycol dimethacrylate or diethyleneglycol dimethacrylate) copolymers were synthesized by photopolymerization and γ-ray-induced polymerization. The copolymer gels had large hydrophilicity. The electrically-responsive changes in weight were studied by sandwiching them between the two electrodes and applying repeatedly the electric field. Both the copolymer gels showed the reversible weight change in response to the on-off switching of the electric field. The response of the copolymer gel with polyethyleneglycol dimethacrylate is sharper than that of the copolymer with diethyleneglycol dimethacrylate. Release of methylene blue a model drug from the copolymer gels was found to occur intermittently in response to the on-off switching. The intermittent release was attributed to the squeezing effect due to the shrinkage of polyelectrolyte gels caused by electrophoretic movement of polymeric anions.

Preparation of poly-lactic acid microspheres containing the angiogenesis inhibitor TNP-470 with medium-chain triglyceride and the in vitro evaluation of release profiles

TNP-470 (AGM-1470, 6-0-(N-chloroacetylcarbamoyl)-fumagillol), a derivative of fumagillin, is a promising angiogenesis inhibitor. However, as TNP-470 is very unstable in in vitro and in vivo, it has been difficult to verify its pharmacological efficacy in the clinical medicine. The preparation of a drug delivery system (DDS) in a microsphere form was studied for the stable inclusion and controlled release of TNP-470. Medium-chain triglyceride (MCTG) as an effective stabilizer and poly-lactic acid (PLA) as a biodegradable carrier were used for this purpose. The release of TNP-470 from the MCTG containing DDS continued for approximately 2 weeks, while the release of TNP-470 from the one without MCTG stopped after only 5 days. It was proved that TNP-470 could be released much more stable for much longer period from the MCTG containing DDS compared to the one without DDS.

Temperature and pH responsiveness of poly-(DMAA-co-unsaturated carboxylic acid) hydrogels synthesized by UV-irradiation

Abstract Stimuli-responsive polyampholyte hydrogels were synthesized by the copolymerization of dimethylaminoethyl methacrylate (DMAA) and acrylic acid (AAc) or itaconic acid (IAc) by UV-irradiation. Temperature and pH responsiveness of these hydrogels were studied. The temperature responsiveness of poly-(DMAA-co-AAc, IAc) hydrogels shown in change of water content became dull compared to that of DMAA homo-polymer hydrogel. The water content of the poly-(DMAA-co-AAc, IAc) hydrogels showed a minimum at pH 8, and increased in more acidic and alkaline regions. This fact can be attributed to the coexistence of anions and cations in the poly-(DMAA-co-AAc, IAc) hydrogels. The poly-(DMAA-co-AAc, IAc) hydrogels were polyampholyte having both temperature responsiveness and pH responsiveness.

Signal responsive chemical delivery systems by radiation techniques and the use for brain research

Signal responsive chemical delivery systems consisting of a biosensor, actuator and reservoir were prepared partly using radiation means. The sensor unit was constructed by immobilization of enzyme or receptor on the ISFET (Ion Sensitive Field Effect Transistor) gate. The actuator and reservoir unit was prepared from an electro-responsive hydrogel (polyelectrolyte) or by lithography-etching of a semiconductor. Controlled release of smell substances and neurotransmitters was investigated using signal responsive chemical delivery systems. Application of the system to brain research was studied by connecting the smell release system with electroencephalogram (EEG) equipment and measuring the effect of smell on α and θ waves of EEG under various mental actions. It was found that the controlled release of smell substance affected remarkedly the EEG profiles of mental actions.