JP2011177242A - Method and device for manufacturing hydrogen-containing biocompatible solution - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method and apparatus for easily manufacturing a hydrogen-containing biocompatible solution used for injection, drip, infusion, organ preservation, or the like. <P>SOLUTION: Hydrogen molecules are brought into contact with a biocompatible solution in a hydrogen-permeable container 2i from the outer side of the container without opening the container. Thus, the hydrogen molecules are contained in the biocompatible solution easily without working over an existing manufacture process. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a method and apparatus for producing a hydrogen-containing biological fluid.

  As means for transporting hydrogen molecules as a medical substance into a living body, inhalation of hydrogen gas, drinking of hydrogen-containing water, injection of a liquid containing a hydrogen-containing living body, and the like are known. Injection of a hydrogen-containing biological application liquid is considered as an ideal transportation means without the danger of handling as in the case of inhaling hydrogen gas.

JP 2005-126384 A

  However, a hydrogen-containing biological fluid that is administered to a living body for the purpose of maintaining and improving biological functions and preventing or treating diseases and disorders is a strict liquid from the viewpoint of ensuring physicochemical purity and combating bacteria and microorganisms. Quality control is required. Therefore, when the manufacturing process is completed and the container in which the biological application liquid is sealed is opened, there is a problem that the liquid quality guarantee performance cannot be guaranteed. Therefore, a means for extrapolating hydrogen from the outside of the container without opening the container is desirable.

  The problem to be solved by the present invention is to provide a production method and a production apparatus capable of producing an oral bioapplication liquid containing hydrogen without opening a container in which the bioapplication liquid is sealed.

  The present invention solves the above problems by bringing a gas or liquid containing hydrogen from the outside of the container into contact with a container having hydrogen molecule permeability, in which an oral biomedical solution is enclosed.

  ADVANTAGE OF THE INVENTION According to this invention, hydrogen can be easily contained in an oral living body applicable liquid, without modifying an existing manufacturing process.

It is the top view, front view, and partial enlarged view which show the manufacturing apparatus of the hydrogen containing biological application liquid which concerns on one embodiment of this invention. It is a block diagram which shows notionally the manufacturing apparatus of the hydrogen containing biological application liquid shown in FIG. It is a block diagram which shows notionally the manufacturing apparatus of the hydrogen containing biological application liquid which concerns on other embodiment of this invention. It is a block diagram which shows notionally the manufacturing apparatus of the hydrogen containing biological application liquid which concerns on other embodiment of this invention. It is a block diagram which shows notionally the manufacturing apparatus of the hydrogen containing biological application liquid which concerns on other embodiment of this invention. It is a block diagram which shows notionally the manufacturing apparatus of the hydrogen containing biological application liquid which concerns on other embodiment of this invention. It is a block diagram which shows notionally the manufacturing apparatus of the hydrogen containing biological application liquid which concerns on other embodiment of this invention.

Embodiments of the present invention will be described below. FIGS. 1-7 is a figure which shows the manufacturing apparatus of the hydrogen containing biological application liquid which concerns on embodiment of this invention, FIG.1 and FIG.2 is 1st Embodiment and each of FIGS. It is a figure which shows the manufacturing apparatus of the hydrogen containing biological application liquid which concerns on other embodiment.
For example, referring to the example shown in FIG. 2, the manufacturing apparatus of this example has an appropriate size capable of storing the biological application liquid held in a container 2 i such as an infusion (infusion) bag together with the biological application liquid. And a liquid or gas containing hydrogen molecules is supplied to the separate container 2g (hereinafter referred to as a hydrogen reservoir). In the hydrogen storage 2g, the biological application liquid and the hydrogen molecules in the hydrogen storage 2g are separated from each other through the biological application liquid container 2i. However, as time passes, the hydrogen molecules in the hydrogen storage 2g gradually increase. Permeates into the biological fluid.

  A suitable container for biological application liquid 2g (FIG. 2) is a plastic container made of polyethylene, polypropylene, polystyrene or the like used for the above-mentioned infusion bag or infusion bag, but is a container (membrane) that is permeable to hydrogen. This is not limited to this. Even in a container characterized by oxygen gas barrier properties and water vapor barrier properties, in many cases, hydrogen molecules, which are the smallest molecules, can permeate without problems. The biologically applied liquid container adsorbs / separates and permeates hydrogen (preferably selectively permeates), while hydrogen once permeated and contained in the biologically applied liquid is stable in the liquid. It is further desirable that the hydrogen permeation direction is irreversibly controlled so that the hydrogen permeation direction is maintained. Moreover, in order to confirm the consumption of the biologically applied liquid in infusion or the like, it is desirable that the container be a translucent or transparent container that is more than the extent that the water level of the contents can be confirmed from the outside.

  The present invention, which can contain hydrogen molecules from the outside of a container with respect to an existing biological application liquid, is “non-destructively (without opening)” hydrogen without modifying the contents of the container. It is characterized by containing molecules. That is, the present invention is basically a container that is closed (or sealed) to the outside world and opened for the first time during use, or even if it is once opened, it is closed when the present invention is implemented. It is used.

  Furthermore, the biological application liquid containing hydrogen molecules can be frozen together with the container to prevent the hydrogen molecules from coming out of the container. Considering the loss of hydrogen molecules during the freezing process, the freezing time is preferably as short as possible. Specifically, at least 80% of the hydrogen-containing biological fluid is within 10 hours, more preferably within 5 hours. At least 80% volume of the hydrogen-containing bioapplication liquid, more preferably at least 80% volume of the hydrogen-containing bioapplication liquid within 3 hours, more preferably at least 80% of the hydrogen-containing bioapplication liquid within 1 hour. % Volume, more preferably at least 80% of the hydrogen-containing bioapplication fluid within 0.5 hours, should be frozen, and hydrogen content immediately after thawing part or all after 24 hours The concentration of dissolved hydrogen in the biological application liquid is preferably at least 0.05 ppm or more, preferably 0.1 ppm or more, preferably 0.2 ppm or more. 0.3 ppm or more, more preferably 0.4 ppm or more, more preferably 0.5 ppm or more, more preferably 0.6 ppm or more, more preferably 0.7 ppm or more. It is preferably 0.8 ppm or more, more preferably 0.9 ppm or more, more preferably 1.0 ppm or more.

  In general, the “hydrogen reservoir” and “container for biological application liquid” of the present invention are divided according to the hydrogen permeability of the reservoir or container. A suitable hydrogen storage container is a container that does not have high hydrogen permeability, and a suitable container for a biological fluid is a container that has high hydrogen permeability. However, strictly speaking, as described above, the hydrogen molecule, which is the smallest molecule, can permeate many containers over a long period of time. ~ High container. Here, the hydrogen-permeable medium container stably maintains a saturated concentration (1.6 ppm at a water temperature of 20 ° C. and 1 atm.) In 20 times the volume of the hydrogen-dissolved water in the container. When the physiological saline solution is fully or substantially filled with water and immersed in the container for 5 hours, the dissolved hydrogen concentration of the physiological saline solution is 1 ppb or more, preferably 10 ppb or more, particularly preferably 100 ppb or more and less than 0.8 ppm. I can say that there is. If the bioappliance fluid container has moderate or higher hydrogen permeability, it can be considered that the bioappliance fluid can reach the desired dissolved hydrogen concentration after a certain time using the present invention. A container having high hydrogen permeability can be said to be a container in which the concentration of dissolved hydrogen in the physiological saline becomes 0.8 ppm or more when the container holding the physiological saline is immersed for 5 hours. A container having low hydrogen permeability means a container in which the concentration of dissolved hydrogen in the physiological saline is less than 100 ppb, preferably less than 10 ppb, and particularly preferably less than 1 ppb when the container containing the physiological saline is immersed for 5 hours. It can be said that.

  Biologically applied fluids include saline, water, nutrients, electrolyte replenishment for injections, infusions, infusions, fluids for injection, oral fluids, drugs (vasodilators such as prostaglandins, Injectable solution and physiological saline solution (including anticancer drugs), liquid drugs, transfusion preparations used for blood transfusion (blood for transfusion), autologous blood, enteral fluid, and for organ preservation Maintenance and improvement of biological functions and diseases including prepared organ preservation solution, biologically applied solution containing lymphocytes and vaccine used in cancer immunotherapy and vaccine therapy, peritoneal dialysis solution, dialysis solution, myocardial protective agent, etc. -It is a concept that indicates all liquids that are applied to living bodies orally or parenterally for the purpose of preventing or treating diseases. In the present specification, the term “biologically applied liquid” may refer to biological biological fluid or biological water itself. In the case of injecting a bioapplied solution, a non-destructive hydrogen-containing treatment of the present invention is performed on the bioapplied solution using a hydrogen-permeable container such as an infusion bag, and then a syringe is placed in the bag mouth. Can be used by sucking the required amount into a syringe.

  The hydrogen reservoir refers to all containers that can hold hydrogen supplied into the vessel from the outside or hydrogen supplied into the vessel through means provided in the reservoir itself for a certain period of time. Although it is possible to supply hydrogen in consideration of the decay of hydrogen, in order to keep the supplied hydrogen for a longer time, a container having a relatively low gas permeability is basically desired. Similarly, in order to prevent the hydrogen supplied into the vessel from being dissipated into the atmosphere, it is desirable that the inside of the vessel is designed to be closed or sealed as required by an openable top lid or the like. Also, in order to increase the permeation or penetration efficiency of hydrogen into the biological application liquid, or to select the dissolved hydrogen concentration of the biological application liquid, a pressurization (pressure adjustment) device, a cooling (temperature adjustment) device, a hydrogen concentration adjustment It is desirable to have a device (or instructions for it) and a dipping / exposure time adjustment device (or instructions for it). In the case of pressurizing the hydrogen reservoir, it is desirable to apply a pressure of 1.0 atm or higher, preferably 1.2 atm or higher, more preferably 1.5 atm or higher, and particularly preferably 2.0 atm or higher.

  Such a hydrogen reservoir is not limited by the size of the container, and a room to which hydrogen molecules are supplied can be regarded as one hydrogen reservoir, such as a repressure chamber generally used for treating decompression sickness. .

  As a hydrogen carrier to be supplied to the hydrogen reservoir, a liquid containing hydrogen molecules such as “hydrogen-containing water”, a gas containing hydrogen molecules such as “hydrogen-containing gas”, or a solid containing hydrogen molecules such as a hydrogen storage alloy However, the present invention is not limited to this, and does not exclude other possible intermediate phases such as liquid crystal. In the present specification, the term “hydrogen-containing water” may be simply described regardless of the intentions of the inventors and the like indicating “a liquid containing hydrogen molecules”. However, since the liquid carrier containing hydrogen according to the present invention is not limited to water, “hydrogen-containing water” may be “liquid containing hydrogen molecules” or “hydrogen-containing” as appropriate depending on the context. It can be read as “liquid”.

  Here, “hydrogen-containing water” means that hydrogen gas is bubbled into water, hydrogen gas is dissolved in water under pressure, water is electrolyzed, and a chemical reaction (for example, magnesium, zinc, etc. has a higher ionization tendency than hydrogen). It is produced through means such as generation of hydrogen in water by a metal and water hydrogen generation reaction), but is not limited thereto. The dissolved hydrogen concentration in the hydrogen-containing water should be at least equal to or higher than the biological application liquid that is to contain hydrogen, but considering the work efficiency, etc., at a water temperature of 20 ° C. and 1 atm, 0.01 mg / L or more, more preferably 0.05 mg / L or more, more preferably 0.1 mg / L or more, more preferably 1.0 mg / L or more, more preferably saturation concentration, more Preferably, it is desirable that the concentration is stably saturated (mainly saturated at least 3 hours or more). Such a hydrogen-containing liquid has an advantage that it is easier to handle than a hydrogen-containing gas described later, which requires safety considerations.

In addition, in order to keep a high concentration (0.05 mg / L or more) of hydrogen in contact with the container for biological application liquid stably, the hydrogen reservoir supplies hydrogen gas to a liquid such as water supplied into the vessel. Or an electrolyzed water generating device capable of continuously electrolyzing a liquid such as water supplied into the vessel (or a part of such an electrolyzed water generating device (cathode chamber). It is desirable that In the embodiment shown in FIG. 2, it can be realized by circulating the hydrogen-containing water generated in the cathode chamber of the electrolytic cell housing 2d into the hydrogen reservoir 2g. In the embodiment shown in FIGS. 3 and 4, the cathode chambers of the electrolytic cell housings 3d and 4d constitute the hydrogen reservoir itself.
It is also desirable that the hydrogen storage device is provided with an apparatus intended to maintain and manage the hydrogen gas concentration or dissolved hydrogen concentration in the hydrogen storage device within a certain range. As an example, based on the dissolved hydrogen amount measuring instrument and its measurement signal, when the hydrogen gas concentration or dissolved hydrogen concentration in the hydrogen reservoir falls below a certain value, the electrolytic treatment starts (restarts) or supplies hydrogen gas An apparatus characterized by (re-supply) is conceivable.
It is also desirable that the hydrogen reservoir is equipped with a device intended to control the immersion time of the biological application liquid. As an example, the timer time is set according to the target value of dissolved hydrogen to be contained in the biological application liquid and / or the container characteristics (material, thickness, hydrogen permeability, etc.) of the biological application liquid. A device can be considered.
In addition, it is desirable that the hydrogen storage device is provided with a device that non-destructively monitors the concentration of dissolved hydrogen in the biological application liquid using a laser, infrared rays, or the like without sampling the biological application liquid. .
In addition, it is desirable that the hydrogen storage device includes a device for controlling the liquid temperature or the air temperature in the hydrogen storage device.

  In addition, in order to achieve a sufficient efficacy effect on the living body, the dissolved hydrogen (hereinafter referred to as DH) concentration of the hydrogen-containing living body application liquid is 0.01 mg / L or more at the time of manufacture at a temperature of 20 ° C. and 1 atmosphere. More preferably 0.05 mg / L or more, more preferably 0.1 mg / L or more, more preferably 0.2 mg / L or more, more preferably 0.4 mg / L or more, more preferably It is desirable to be 0.6 mg / L or more, more preferably 0.8 mg / L or more, and even more preferably 1.0 mg / L or more.

Diseases / disorders that can be applied to hydrogen-containing biological fluids include liver damage caused by drugs and harmful substances, ischemic reperfusion injury, cardiovascular diseases such as arteriosclerosis, gastrointestinal diseases such as gastric ulcer and gastric mucosal injury , Respiratory diseases, diabetic complications (eg hypertension, cerebral infarction, myocardial infarction, etc.), renal diseases, cataracts, skin diseases, various inflammatory diseases, neurological diseases, cancer, aging, free radicals and lipid peroxides It is suitable for diseases involving acute oxidative stress, such as ischemic reperfusion injury, but is not limited thereto.
Many of the side effects associated with cancer treatment involve active oxygen, but a hydrogen-containing biological fluid (or hydrogen-containing anticancer agent) should be administered to patients during or before cancer treatment. Thus, treatment can be performed while suppressing side effects.
In order to enhance the reactivity of hydrogen molecules, a catalyst such as a noble metal colloid (platinum, palladium, etc.) may be added in a very small amount to the biological application liquid as necessary.

  In order to add a new effect to the original effect of an existing biological application liquid, the present invention contacts a hydrogen permeable non-opened container holding the biological application liquid from the outside of the container. In other words, the biological application liquid contains hydrogen molecules in a non-destructive manner.

  Although the method of incorporating the hydrogen gas in the air through the hydrogen permeable membrane into the ultrapure water is known in the technical field such as the surface cleaning of the semiconductor substrate, it has hydrogen permeability with a living body application liquid. There has never been considered a method in which hydrogen molecules are contained in a biological application liquid by bringing hydrogen gas into contact with an unopened container from the outside of the container. The reason is that the fact that the container is permeable to hydrogen means that hydrogen easily enters and exits easily, so that the “hydrogen” -containing biological application liquid contained in the “hydrogen” -permeable container is In addition, a certain amount of the active ingredient must be delivered to the living body (including humans, animals such as dogs, cats, and competing horses) at the time of use while maintaining the active ingredient stably for at least the effective period of the product. It was obvious that it was not possible to satisfy the request.

  In fact, according to the observations by the inventors, the biological application liquid containing hydrogen varies depending on the material and thickness of the container, or the contact area with the atmosphere, but the rate is approximately 20% to 30% or more per hour. The hydrogen molecules that are the active ingredient are attenuated. That is, even if it is a biological application liquid containing hydrogen molecules up to a saturated concentration (1.6 ppm at 20 ° C. and 1 atm), about 24/1 to 1 / 169-169 This is a calculation in which only hydrogen molecules of 0.0004 ·· ppm to 0.009 ·· ppm remain. And it is natural to judge that any pharmaceutical product cannot be put to practical use in such a pharmaceutical form that loses the active ingredient at such a decay rate.

  Even if a container that permeates hydrogen, the present invention attenuates the active ingredient as long as hydrogen decay is anticipated in advance, and the biological application liquid contains hydrogen molecules at the time of use in the medical field. However, it is possible to administer the drug, and as a result, "permeate hydrogen, so that the hydrogen molecule that is the active ingredient escapes" is described as "permeate hydrogen, physicochemical purity and sterility. This is based on the idea of the inventors, etc., that it can be converted into a “merit that hydrogen molecules can be contained in the biologically applied liquid without invading any commercially available biologically applied liquid that is guaranteed by .

  In addition, the idea of the inventors etc. is not limited to the medical field, but, for example, in the manufacturing plant of the liquid for biological application, the non-destructive feature of the present invention can be used in the post-process after the product packaging is completed. If the hydrogen-containing method is used, in addition to the effects and functions inherently possessed by all biologically applied liquids already on the market, new functions derived from hydrogen molecules can be additionally provided. It extends to where it can be done. The decay of hydrogen molecules in the distribution process after product shipment is as described above, in which the product is frozen before shipment, or the biological fluid container is covered with a hydrogen-permeable outer bag as described later. It can be solved through ingenuity.

That is, according to the present invention, hydrogen can be easily contained in the biological application liquid without modifying the existing manufacturing process. In other words, a very small amount of hydrogen-safe gas (1) from the outside of the container, without any modification to the contents (biologically applied liquid) manufactured under strict control based on the pharmacopoeia standards. Just by feeding in several micrograms to several milligrams per liter), a new effect can be added to the original effect of the contents.
In addition, when the hydrogen-containing biological application liquid is prepared at the time of use in the medical field or the like, there is no worry of wasting hydrogen during the distribution process or storage period.
Furthermore, the present invention can be used for the purpose of supplementing the biological application liquid already containing hydrogen molecules with hydrogen molecules.

  Examples of the present invention will be described below. Unless otherwise specified in the present application, various meters used for measuring various physical property values are pH meters (including thermometers) manufactured by HORIBA, Ltd. 13 ”, the probe type“ 9620-10D ”), and the ORP meter is an ORP meter manufactured by HORIBA, Ltd. (main body type“ D-25 ”, same probe type“ 9300-10D ”) The EC meter is an EC meter manufactured by HORIBA, Ltd. (main body model “D-24”, the same probe model “9382-10D”), and the DO meter is manufactured by HORIBA, Ltd. DH meter (dissolved hydrogen meter) is a DH meter (manufactured by Toa DK Corporation) (model “D-25”, model “9520-10D”). Integrated type "DHDI-1" is the same electrode (probe) Model, "HE-5321", the relay model "DHM-F2").

[Example 1]
A commercially available physiological saline (Otsuka Pharmaceutical Co., Ltd., “Japan Pharmacopoeia physiological saline Otsuka raw food injection”) contained in an infusion bag having a capacity of 500 mL was used as a biological application solution. A 2 L polypropylene container was used as the hydrogen reservoir. This container was filled with hydrogen-containing water having a DH concentration of 1.2 mg / L, and then an infusion bag containing physiological saline was immersed therein, and the container was closed with the top lid closed. The hydrogen-containing water was replaced with fresh water having the same DH concentration every hour. After 5 hours, the infusion bag was taken out from the hydrogen reservoir and opened, and the DH concentration and electrical conductivity (EC) of physiological saline were measured. At that time, the DH concentration of hydrogen-containing water was also measured. The details of the apparatus for producing a hydrogen-containing biological fluid will be described later.
The DH concentration of physiological saline was 0.6 mg / L, and EC was 1.2 S / m.
The DH concentration of hydrogen-containing water was 1.2 mg / L.

[Example 2]
A commercially available physiological saline (Otsuka Pharmaceutical Co., Ltd., “Japan Pharmacopoeia physiological saline Otsuka raw food injection”) contained in an infusion bag having a capacity of 500 mL was used as a biological application solution. A 2 L polypropylene container was used as the hydrogen reservoir. An infusion bag containing physiological saline was placed in the container, and hydrogen gas was passed through the tube from the opening of the gas supply container at a flow rate of 100 mL / min. After 5 hours, the infusion bag was taken out from the hydrogen reservoir and opened, and the DH concentration of physiological saline was measured.
The DH concentration of physiological saline was 0.46 mg / L.

[Example 3]
A commercially available physiological saline (Otsuka Pharmaceutical Co., Ltd., “Japan Pharmacopoeia physiological saline Otsuka raw food injection”) contained in an infusion bag having a capacity of 500 mL was used as a biological application solution. A 2 L polypropylene container was used as the hydrogen reservoir. This container was filled with hydrogen-containing water having a DH concentration of 0.9 mg / L, and then an infusion bag containing physiological saline was immersed therein, and the container was closed with the top lid closed. After 1 hour, the infusion bag was taken out from the hydrogen reservoir and opened, and the DH concentration of physiological saline was measured.
The DH concentration of physiological saline was 0.18 mg / L.

[Example 4]
A commercially available physiological saline (Otsuka Pharmaceutical Co., Ltd., “Japan Pharmacopoeia physiological saline Otsuka raw food injection”) contained in an infusion bag having a capacity of 500 mL was used as a biological application solution. A 10 L capacity polypropylene container connected to the electrolyzed water generator was used as the hydrogen reservoir.

  This electrolyzed water generating device is an electrolyzer and electrolyzed water generating device disclosed in the republished patent WO99 / 10286, which has been filed earlier and has already been published, and the contents of which are incorporated in this invention by this reference. That is, an electrolysis chamber into which raw water is introduced, and at least a pair of electrode plates provided with a diaphragm sandwiched between the electrolysis chamber and the outside of the electrolysis chamber, and an electrode plate outside the electrolysis chamber (open system) Is provided in contact with the diaphragm or through a slight gap, and the electrode plate provided in the electrolysis chamber is used as a cathode while the electrode plate provided outside the electrolysis chamber is used as an anode to apply a voltage between both electrodes. An electrolytic cell and an electrolyzed water generating device. The outline of the electrolyzed water generating apparatus is shown in FIG. 2 (hydrogen storage separated type) and FIG. 3 or FIG. 4 (hydrogen storage integrated type).

  As shown in FIG. 2, water is intermittently electrolyzed in a polypropylene container (hydrogen reservoir) 2g connected through a hose extending from the inlet / outlet of the electrolyzed water generator 2d and the electrolyzed water generator. While circulating, the water in the container 2g was stably kept at a saturated DH concentration (1.5 to 1.6 ppm at 20 ° C. and 1 atm).

The infusion bag containing physiological saline was immersed in the hydrogen-containing water in 2 g of the container, and the container was closed with the lid on the container closed. After 5 hours, the infusion bag was taken out from the container and opened, and the DH concentration, dissolved oxygen (DO) concentration, redox potential (ORP), and electrical conductivity (EC) of physiological saline were measured.
The DH concentration of physiological saline was 0.8 mg / L, the DO concentration was 4.6 mg / L, the ORP was −370 mV, and the EC was 1.6 S / m.

  In the above-described Examples 1 to 4, one biological application liquid is installed or immersed in the hydrogen reservoir. However, assuming practical use in a medical field, a plurality of biological applications are applied to one hydrogen reservoir. It is desirable that the liquids can be installed or immersed together. However, in order to supply a sufficient amount of hydrogen to each biological application liquid, it is not desirable that a large amount of biological application liquid is packed in one hydrogen reservoir. The capacity of the hydrogen reservoir is at least 1 time, preferably at least 2 times, more preferably at least 4 times the total volume of the biological fluid to be installed or immersed therein, considering practicality and processing efficiency. desirable.

[Example 5]
One commercially available physiological saline solution (Otsuka Pharmaceutical Co., Ltd., “Japanese Pharmacopoeia Saline Otsuka Raw Food Injection”) in a 500 mL volume infusion bag as a bio-applied solution, in a 100 mL volume infusion bag. Of two physiological saline (manufactured by Mylan Pharmaceutical Co., Ltd., “Japanese Pharmacopoeia Saline Saline MP”), a total of three. One of the 100 mL physiological saline was subjected to a head space air venting process from the bag mouth using a syringe.

A 10 L capacity polypropylene container (see FIG. 2) connected to the same electrolyzed water generator as in Example 4 was used as a hydrogen reservoir. As described above, the hydrogen-containing water in the container was kept at a DH concentration of 1.5 to 1.6 ppm. Three physiological saline solutions were immersed in hydrogen-containing water, and the container upper lid was closed and left standing. After 5.5 hours, each physiological saline was taken out from the container and opened, and each DH concentration was measured.
The DH concentration of physiological saline (500 mL) was 0.787 mg / L.
The DH concentration of physiological saline (100 mL) was 0.34 mg / L.
The DH concentration of physiological saline (100 mL, vented) was 0.810 mg / L.

This example includes an example in which air is vented from the headspace of the infusion bag prior to the hydrogen-containing treatment in the biological application solution, but more hydrogen than in the case where such treatment is not performed. Is contained.
That is, the air in the container head space of the biological application liquid and the dissolved gas (dissolved oxygen) contained in the biological application liquid are thought to be factors that prevent the biological application liquid from containing a certain amount of hydrogen molecules. . When it is desired to contain more hydrogen molecules in the biological application liquid, it is desirable to remove the dissolved gas (dissolved oxygen) in the biological application liquid by removing excess air from the biological application liquid container.

  In the present invention, whether the hydrogen molecule in the hydrogen reservoir is supplied as a gas or a liquid, prior to contacting the biological application liquid with the hydrogen molecule, the above means and means such as reduced pressure are used. It is desirable to remove the air and dissolved gas in the container for biological application liquid. However, among them, it is most desirable to deaerate non-destructively from the outside of the container through means such as decompression.

  The non-destructive hydrogen-containing treatment for the biologically applicable liquid of the present invention is carried out in the manufacturing process (mainly the post-packaging process) of the biologically applicable liquid manufacturing factory, etc. To be implemented. In that case, in order to prevent hydrogen once contained through the container from escaping again, the department in charge of nursing should ensure that the treatment containing hydrogen in the biomedical solution ends immediately before the scheduled administration start time. It is desirable that the person etc. start the hydrogen-containing treatment first. In this case, the nursing staff adjusts the conditions for the hydrogen-containing treatment (such as the immersion / exposure time of the biologically applied liquid and the DH concentration / hydrogen gas mixed concentration in the hydrogen reservoir) to the biologically applied liquid for each patient. The ability to select and determine the DH concentration to be contained is a great merit.

  By the way, it is desirable that the DH concentration of the biological application liquid is about 0.01 ppm, more preferably 0.05 ppm or more. If the DH concentration of the biological application liquid reaches about 0.01 ppm, for example, at the time of infusion, even if the preparation time until the start of infusion or the amount of hydrogen molecules attenuated in the process of passing through the infusion tube is subtracted This is because an effective amount of hydrogen molecules is considered to be secured when the blood vessels reach.

  The inventors of the present invention applied the biological application liquid in a plastic container for about 3 hours after immersing it in hydrogen-containing water having a substantially saturated DH concentration, while the biological application liquid rapidly dissolved hydrogen, While reaching a DH concentration of approximately 10 to 40% of the water DH concentration, it was confirmed that the hydrogen dissolution rate thereafter became relatively slow and gradually approached the DH concentration of the hydrogen-containing water.

  Also, after 10 hours have passed, when the DH concentration of the biological application liquid has reached approximately 60% to 90% of the DH concentration of the hydrogen-containing water, the hydrogen dissolution rate has become even slower, and 24 hours have passed. Even after the lapse of time, it was confirmed that the DH concentration of the hydrogen-containing water hardly changed.

  Therefore, in that sense, the hydrogen-containing water DH concentration in the present invention is preferably 50.0 ppb (0.05 ppm / 1) or more, more preferably 55.5 ppb (0.05 ppm / 0.9) or more, More preferably 62.5 ppb (0.05 ppm / 0.8) or more, more preferably 71.4 ppb (0.05 ppm / 0.7) or more, more preferably 83.3 ppb (0.05 ppm) /0.6) or more.

  By the way, a hydrogen-containing biological application liquid production apparatus can also be connected to peripheral devices such as an infusion (infusion) apparatus that is addressed to each patient during treatment. In this case, since it is assumed that the patient moves in the hospital together with an infusion (infusion) device, the equipment added to the device is preferably as small as possible, and the capacity of the hydrogen reservoir is basically 100 or 500 mL. Any volume plus alpha that can accommodate one volume of infusion (infusion) solution is sufficient. Specifically, referring to the above-described electrolyzed water generating apparatus and the republished patent WO99 / 10286, the electrolytic cell described therein can be used as a hydrogen reservoir. In Example 4 described above, a polypropylene container was used in addition to the electrolyzed water generating apparatus, and the biological application liquid was immersed in a container connected to the electrolyzer, but in this example, the electrolyzer of the electrolyzed water generating apparatus. Since it itself is used as a hydrogen reservoir having a hydrogen (hydrogen-containing water) supply function, the biological application liquid is immersed in the electrolytic cell itself (see FIGS. 3 and 4).

  Basically, there is no need to change the device configuration after the infusion line, but in order to prevent hydrogen molecules from decaying in the process of passing through the infusion line, the infusion line itself is a liquid containing hydrogen molecules. Or may be exposed to a gas containing hydrogen molecules. Moreover, it is a case where a hydrogen-containing biological application liquid is administered via a certain kind of (medical) device including not only the drip device but also a dialysis apparatus, which will be described later, and the hydrogen-containing biological application liquid reaches the living body. When hydrogen molecules are expected to decay, in the process, hydrogen is applied to the line through which the hydrogen-containing biological application liquid passes (where hydrogen molecules can permeate) using the above method or the like. It is desirable to complement the decay of hydrogen molecules through contacting the molecules.

  In the case of this example, it is also possible to infuse while supplying hydrogen to the biological application liquid via the electrolytic cell, so that the atmosphere from the container in the time lag from the hydrogen-containing treatment to the biological application liquid until the actual administration starts There is little need to worry about the dissipation of hydrogen into it or the attenuation of hydrogen in the drip line.

  In addition, the present invention can take the following configurations. That is, a biological hydrogen storage solution (hereinafter referred to as “outside container”) that is placed in a medium or high hydrogen permeability container (hereinafter referred to as “inner container”) such as a plastic bag. And the outer container is filled with a liquid or gas containing hydrogen molecules such as hydrogen-containing water. While hydrogen permeates the surface of the inner container and is contained in the biological application liquid, it is blocked by the outer container, and is hardly dissipated to the outside world during the distribution process and storage period. At the time of use, the inner container containing the biological application liquid may be taken out from the outer container and used, or both the outer container and the inner container may be opened and used without taking out the inner container. In general, plastic containers such as infusion bags are lightweight and have a low possibility of breakage and are convenient for transportation and storage, but they do not have gas barrier properties (oxygen barrier properties) that prevent chemical deterioration and oxidative degradation. In the case of using a chemical solution that is susceptible to alteration due to the above, it is secondarily packaged in an outer bag having an improved gas barrier property, but such an existing “bag-packaging” combination may be used as appropriate.

  In addition, the present invention can take the following configurations. That is, the hydrogen storage connected to the electrolyzed water generating device described in Example 4 and the example of the infusion (infusion) device described above, or the hydrogen storage incorporated in a part of the electrolyzed water generating device as an electrolytic cell Hydrogen supplied into the vessel through a hydrogen-containing liquid supplied into the vessel from the outside, or means provided in the reservoir itself, such as a hydrogen vessel or a hydrogen reservoir capable of continuously supplying the hydrogen gas described above A hydrogen permeable membrane characterized in that the first system having a hydrogen reservoir capable of stably maintaining the DH concentration of the contained liquid allows hydrogen to pass therethrough, preferably a gas that passes only gas without passing ions. A second tank having a tank for storing a biologically applied liquid such as an infusion solution, a dialysate, or a blood for transfusion, or a pipeline for circulating the biologically applied liquid, through a permeable membrane, more preferably a hydrogen permeable membrane that allows only hydrogen gas to pass through. Contact with the system A hydrogen permeable membrane integrated hydrogen-containing biological applicable fluid producing device comprising a. Here, the second system is characterized in that it is closed while including the hydrogen permeable membrane as a part of the boundary between the outside and the inside of the system. The hydrogen permeable membrane may actually be a part of the boundary as shown in FIG. 5 described in detail below, or may be connected to the second system via a closed line as shown in FIG. In this specification, both are expressed as being closed while including the hydrogen permeable membrane. Here, the term “closed” means that appropriate management is performed to limit the influence of physical / chemical conditions outside the system on the system. For example, unopened containers for the purpose of preventing contamination of microorganisms and microorganisms in biological fluids, and blood that has been introduced to a dialyzer for the purpose of removing waste products, etc. A recursive line that circulates is considered closed. If this apparatus is used, the hydrogen produced in the first system is transferred to the biological application fluid of the second system through the hydrogen permeable membrane, and the first system intended to produce hydrogen Since the second system for the purpose of incorporating hydrogen into the biological application liquid is a separable system, only the second system requiring stricter hygiene management can be installed in a clean room. Is easy to take. Also, here, a first system is provided by providing a hydrogen permeable membrane on the cathode chamber side of the anode diaphragm contact type single tank electrolyzer described in the republished patent WO 99/10286, and through the hydrogen permeable membrane, A gas exchange membrane integrated electrolytic cell characterized in that hydrogen gas in the cathode water of the first system is transferred to the biological application liquid of the second system can also be configured (see FIG. 5).

  Further, the carrier of hydrogen molecules supplied to the first system can be any phase such as gas or liquid. The production method also includes mixing hydrogen gas with other gas at an appropriate concentration, bubbling hydrogen gas into water, dissolving hydrogen gas in water under pressure, electrolyzing water, chemical reaction (for example, magnesium A method of generating hydrogen in water by a hydrogen generation reaction between a metal and water having a higher ionization tendency than hydrogen, such as zinc and zinc), but is not limited thereto.

  Here, in the second system, a pipeline for circulating the biologically applied liquid is connected to the living body, and the biologically applied liquid (such as self-blood or self-body fluid) that is derived from (or is to be introduced to) the living body. (Including body fluids and biological water) in the course of flowing through the line, while removing solutes such as wastes as necessary, while containing hydrogen of the first system through the hydrogen permeable membrane In addition, a hydrogen-containing biologically-applied liquid administration device similar to a dialysis apparatus, which is refluxed (or introduced) into a living body as a hydrogen-containing biologically-applied liquid, can also be configured.

  Further, considering the use of the present invention for dialysis in particular, the following configuration can be adopted. That is, in many cases, in a dialysis facility, the dialysate supplied to the patient's dialysis machine is managed centrally. That is, the dialysate is a “water treatment apparatus” for the purpose of preparing purified water (RO water) from tap water, and the “dialysis solution supply” for the purpose of diluting the dialysate stock solution with the obtained purified water. Manufactured in a dedicated facility within the facility with "equipment". Therefore, when considering the production of a hydrogen-containing dialysate, it is most efficient to collectively perform the hydrogen-containing treatment in such a water treatment apparatus or dialysate supply apparatus.

  On the other hand, however, in this case, the dialysis fluid of a patient who does not require the administration of hydrogen is indiscriminately supplied with the hydrogen-containing dialysis fluid, or the individual patient dialysis from the dialysis fluid supply device. In consideration of the possibility that hydrogen may escape during the process of supplying the hydrogen-containing dialysate to the device, the dialyzer (dialyzer (dialyzer) before the dialysate is introduced into the dialyzer through the supply line Before passing through the dialyzer), a device for allowing the dialysate to contain hydrogen may be provided. As such an apparatus, for example, a hydrogen-containing biological application liquid production apparatus using the above-described hydrogen permeable membrane can be used. That is, from a hydrogen-containing liquid having a stable DH concentration flowing through the first system, hydrogen is dialyzed from the hydrogen-permeable membrane through the second system (the dialysate supplied from the supply line to the dialyzer). ) Can be used as a hydrogen-containing dialysate production apparatus. Alternatively, the hydrogen-containing dialysate obtained by containing hydrogen by the above-described nondestructive method may be poured into a supply line or dialyzer before the dialyzer. After that, the hydrogen-containing dialysate flows around the semipermeable membrane such as the hollow fiber membrane in the dialyzer, and the concentration of the patient blood flowing through the membrane and the content of components through the membrane based on the principle of osmotic pressure and diffusion. In the process of equalization, a certain amount of hydrogen is transferred into the blood. When peritoneal dialysis is performed instead of hemodialysis, a commercially available peritoneal dialysis solution contained in a product package may be exposed to or immersed in a gas or liquid containing hydrogen molecules in a hydrogen reservoir. it can.

  In addition, hydrogen molecules in the dialysate can be treated by coating a part or all of a semipermeable membrane such as a hollow fiber membrane in a dialyzer through which hydrogen-containing dialysate passes with a hydrogen catalyst such as platinum or palladium. In the process of transferring to the patient's blood through the hydrogen catalyst, the antioxidant power of hydrogen molecules can be immediately exerted against the oxidative stress in the blood on the hydrogen catalyst.

  In addition, the present invention can take the following configurations. That is, as an application example of the hydrogen-permeable membrane-integrated hydrogen-containing biological application liquid production apparatus described above, hydrogen derived from the hydrogen-containing liquid produced in the first system is passed through a hydrogen-permeable membrane having hydrogen permeability. A hydrogen-containing bioapplied liquid production apparatus characterized by bringing the hydrogen permeable membrane into direct contact with a living body when transferring to a second system bioapplied liquid. In this case, the biological application liquid refers to biological liquid or biological water itself in which hydrogen is contained through the skin or mucous membrane through contact with the hydrogen permeable membrane. Specifically, the skin (mucosal) contact body such as a belt made of a hydrogen permeable membrane connected to the first system is brought into contact with an appropriate part of the living body, thereby moving to the skin contact body. Hydrogen derived from this system (if necessary, hydrogen contained in an appropriate carrier such as a liquid in the skin contact body or a hydrogen storage material) is contained in biological fluid or biological water via the skin or mucous membrane. Thus, a hydrogen-containing biological fluid generating device can be configured.

  Hereinafter, merits of using the present invention for biologically applied liquids manufactured from raw materials derived from organisms such as humans such as blood products including the above-mentioned blood transfusion products (blood for transfusion) will be described. Blood products usually include whole blood products containing all blood, blood component products obtained by physically separating blood components such as erythrocytes, plasma, and platelets by centrifugation, etc., and plasma components, particularly proteins, physicochemically. And separated into purified plasma fraction preparations. In many cases, such blood products contain a preservative solution such as a blood preservative solution (CPD solution) or a red blood cell preservative solution (MAP solution).

When hydrogen molecules are to be included in blood products, in addition to the method in which hydrogen molecules are added to the preservation solution and then mixed with whole blood, blood components, or plasma fractions, etc., and blood containing the preservation solution There is a method of including hydrogen molecules in the preparation. And it is desirable to include hydrogen molecules in whole blood, blood components, or plasma fractions together with the preservation solution. However, it contains hydrogen molecules directly in biologically-applied raw materials such as whole blood, blood components, or plasma fractions, or blood products containing them, or biologically applied fluids produced from biologically-derived raw materials. In order to prevent contamination, it is necessary to consider the prevention of contamination more than when hydrogen molecules are contained in physiological saline or the like. In that sense, the method for producing a hydrogen-containing bioapplication liquid of the present invention in which hydrogen molecules are extrapolated from the outside of a product package is particularly preferably used for a bioapplication liquid produced from biological materials such as blood products. It can be said that. Furthermore, in the sense that it is easy to accept the merit of the present invention, the ratio of the raw material derived from the organism in the preparation is 10 vol% or more, preferably 50 vol% or more, particularly preferably 80 vol% or more, or 5 wt% or more, It can be said that the method for producing a hydrogen-containing bioapplication liquid of the present invention is particularly preferably used for a bioapplication liquid of preferably 45 wt% or more, particularly preferably 75 wt% or more.
In addition, these hydrogen-containing blood products are manufactured for the purpose of medicinal effects by hydrogen molecules including suppression of oxidative stress when transfused into a living body, and the expiration date of blood products due to the physical and chemical effects of hydrogen molecules It may be produced for the purpose of prolonging, enhancing activity, suppressing side effects associated with blood transfusion, and the like. In addition, if the hydrogen-containing biological application liquid once containing hydrogen molecules to a saturated concentration is kept in contact with hydrogen from the outside of the container, it prevents the hydrogen from coming out of the container and stably dissolves in a high concentration. This is desirable from the viewpoint of maintaining the hydrogen concentration.

Additional examples are described below.
[Example 6]
A commercially available physiological saline (Otsuka Pharmaceutical Co., Ltd., “Japan Pharmacopoeia physiological saline Otsuka raw food injection”) contained in an infusion bag having a capacity of 500 mL was used as a biological application solution. A 1.5 L capacity water purification filter housing was used as a hydrogen reservoir. An infusion bag containing physiological saline was installed in the hydrogen reservoir, and 100% hydrogen gas was passed through the tube from the gas supply container opening at a flow rate of 100 mL / min. After 5 hours, the infusion bag was taken out from the hydrogen reservoir and opened, and the DH concentration of physiological saline was measured.
The DH concentration of physiological saline was 0.85 mg / L.

[Example 7]
A commercially available physiological saline (Otsuka Pharmaceutical Co., Ltd., “Japan Pharmacopoeia physiological saline Otsuka raw food injection”) contained in an infusion bag having a capacity of 500 mL was used as a biological application solution. A 1.5 L capacity water purification filter housing was used as a hydrogen reservoir. An infusion bag containing physiological saline was installed in the hydrogen reservoir, and 100% hydrogen gas was passed through the tube from the gas supply container opening at a flow rate of 100 mL / min. After 15 hours, the infusion bag was taken out from the hydrogen reservoir and opened, and the DH concentration of physiological saline was measured.
The DH concentration of physiological saline was 1.18 mg / L.

[Example 8]
A commercially available physiological saline (Otsuka Pharmaceutical Co., Ltd., “Japan Pharmacopoeia physiological saline Otsuka raw food injection”) contained in an infusion bag having a capacity of 500 mL was used as a biological application solution. A 1.5 L capacity water purification filter housing was used as a hydrogen reservoir. An infusion bag containing physiological saline was installed in the hydrogen reservoir, and 50% hydrogen gas was passed through the tube from the gas supply container opening at a flow rate of 100 mL / min. After 15 hours, the infusion bag was taken out from the hydrogen reservoir and opened, and the DH concentration of physiological saline was measured.
The DH concentration of physiological saline was 0.59 mg / L.

[Consideration of Additional Examples]
The biological application liquid in a plastic container with a capacity of 500 mL maintained in a hydrogen reservoir with a 100% hydrogen gas concentration at room temperature and normal pressure was obtained by dissolving hydrogen molecules over time. For example, the DH concentration of the biological application liquid that was 0 ppm immediately after the start of measurement became about 0.85 ppm after 5 hours (Example 6), and about 1.18 ppm after 15 hours (Example 7). ). On the other hand, when the hydrogen gas concentration in the hydrogen reservoir is 50% (half of 100%), the DH concentration of the biological application liquid is half that of Example 7 even after the same 15 hours have elapsed. It was 0.59 ppm which is.

  Thus, since the dissolved amount of hydrogen molecules in the biological application liquid is proportional to the hydrogen gas partial pressure in the atmospheric gas, in the final equilibrium state at 20 ° C. and 1 atmosphere, the atmospheric gas is 100% hydrogen ( If the partial pressure is 760 mmHG), the DH concentration of the biologically applied liquid is equilibrated at 1.6 ppm (saturated hydrogen concentration), and if the atmospheric gas is 3.125% hydrogen (partial pressure 23.75 mmHG), the DH concentration of the biologically applied liquid is Becomes equilibrium at 0.05 ppm (saturated hydrogen concentration). On the other hand, since it takes a long time for the atmospheric hydrogen gas to move into the biological application liquid through the container and reach an equilibrium state, in order to bring the biological application liquid to a predetermined DH concentration, It is desirable that the concentration (partial pressure) be equal to or higher than the concentration (partial pressure) that maintains equilibrium with the concentration. That is, in order to make the DH concentration of the biological application liquid 0.05 ppm, it is desirable that the atmospheric gas is 3.125% hydrogen (partial pressure 23.75 mmHG) or more. Further, in order to obtain a biological application solution having a higher DH concentration, the atmospheric gas is 0.625% (partial pressure 4.75 mmHG) or more, more preferably 3.125% (partial pressure 23.75 mmHG) or more, More preferably 6.25% (partial pressure 47.5 mmHG) or more, more preferably 25% (partial pressure 190 mmHG) or more, more preferably 50% (partial pressure 380 mmHG) or more, more preferably Is 75% (partial pressure 570 mmHG) or more, more preferably 100% (partial pressure 760 mmHG).

  Further, when the hydrogen reservoir is a sealed container, dissolved gas other than hydrogen pushed out from the biologically applied liquid container with the dissolved hydrogen gas in the biologically applied liquid is replaced with the atmospheric gas in the sealed container, The atmosphere gas cannot be kept at 100% hydrogen. Therefore, in order to keep the hydrogen in the atmosphere gas at a high concentration, a part of the atmosphere gas is continuously exhausted from the hydrogen reservoir in a range where the risk of explosion is low, and new hydrogen gas is continuously supplied. It is desirable to use a hydrogen reservoir having such a structure.

  The hydrogen gas supply method to the hydrogen reservoir is roughly divided into a method using a hydrogen gas cylinder, a method using hydrogen gas generated by electrolysis, a method using hydrogen gas generated by a chemical reaction, and the like. However, here, as an example, an embodiment related to a method using hydrogen gas generated by electrolysis will be described.

As shown in FIG. 6, the hydrogen-containing water produced by the anode diaphragm contact-type one-tank electrolyzer 6d described in the republished patent WO99 / 10286 is passed to the gas-liquid separator 6j having the hydrogen permeable membrane 6h. In addition, a hydrogen-containing biological application liquid can be produced by supplying the separated hydrogen gas to a hydrogen reservoir 6n having an arbitrary biological application liquid bag 6i. As another example, as shown in FIG. 7, the hydrogen-containing water produced by the anode diaphragm contact-type one-tank electrolyzer 7d is supplied to a hydrogen reservoir 7n, which is a separate container, and in accordance with the water replacement method. By appropriately collecting hydrogen gas in a container (preferably a container that does not have high hydrogen permeability), any biological application liquid installed in the container can contain hydrogen molecules. That is, by combining an anodic membrane contact type one-tank electrolyzer and a water displacement method, a hydrogen-containing bioapplication liquid can be produced relatively easily without the need for a gas-liquid separation membrane device or a pressure / adjustment device. Can do.
Additional examples are described below.
[Example 9]
As a biological application solution, a physiological saline solution filled with a 500 mL capacity polyethylene terephthalate container was used. A 10 L capacity polypropylene container (see FIG. 2) connected to the same electrolyzed water generator as in Example 4 was used as a hydrogen reservoir. As described above, the hydrogen-containing water in the container was stably maintained at a substantially saturated concentration (1.6 ppm at 20 ° C. and 1 atm). A physiological saline solution was immersed in hydrogen-containing water, and the upper lid of the container was closed and left standing. After 5 hours, the physiological saline solution was taken out from the container and opened, and its DH concentration was measured.
The DH concentration of the physiological saline was 0.152 mg / L.
[Example 10]
As the living body application liquid, a physiological saline solution filled with water in a 500 mL capacity polyethylene terephthalate container slightly thicker than Example 9 was used. A 10 L capacity polypropylene container (see FIG. 2) connected to the same electrolyzed water generator as in Example 4 was used as a hydrogen reservoir. As described above, the hydrogen-containing water in the container was stably maintained at a substantially saturated concentration (1.6 ppm at 20 ° C. and 1 atm). A physiological saline solution was immersed in hydrogen-containing water, and the upper lid of the container was closed and left standing. After 5 hours, the physiological saline solution was taken out from the container and opened, and its DH concentration was measured.
The DH concentration of the physiological saline was 0.115 mg / L.
[Example 11]
As a biological application solution, a physiological saline solution filled with a 500 mL capacity aluminum laminate container was used. A 10 L capacity polypropylene container (see FIG. 2) connected to the same electrolyzed water generator as in Example 4 was used as a hydrogen reservoir. As described above, the hydrogen-containing water in the container was stably maintained at a substantially saturated concentration (1.6 ppm at 20 ° C. and 1 atm). A physiological saline solution was immersed in hydrogen-containing water, and the upper lid of the container was closed and left standing. After 5 hours, the physiological saline solution was taken out from the container and opened, and its DH concentration was measured.
The DH concentration of the physiological saline was 0.006 mg / L.
[Example 12]
As a biological application solution, a physiological saline solution filled with a 500 mL capacity aluminum laminate container was used. A 10 L capacity polypropylene container (see FIG. 2) connected to the same electrolyzed water generator as in Example 4 was used as a hydrogen reservoir. As described above, the hydrogen-containing water in the container was stably maintained at a substantially saturated concentration (1.6 ppm at 20 ° C. and 1 atm). A physiological saline solution was immersed in hydrogen-containing water, and the upper lid of the container was closed and left standing. After 20 hours, the physiological saline solution was taken out from the container and opened, and its DH concentration was measured.
The DH concentration of the physiological saline was 0.016 mg / L.
[Example 13]
200 mL capacity containing 28 ml of blood preservation solution C (component (w / v%): sodium citrate hydrate 2.63, citric acid hydrate 0.327, glucose 2.32, sodium dihydrogen phosphate 0.251) The venous blood of a dog collected in a polyvinyl chloride container “Terumo Blood Bag CPD” (manufactured by Terumo Corporation) was used. A 10 L capacity polypropylene container (see FIG. 2) connected to the same electrolyzed water generator as in Example 4 was used as a hydrogen reservoir. As described above, the hydrogen-containing water in the container was stably maintained at a substantially saturated concentration (1.6 ppm at 20 ° C. and 1 atm). The blood bag was immersed in hydrogen-containing water, and the container upper lid was closed and left standing. After 5 hours, the blood bag is removed from the container and opened, and the DH concentration is measured by Unisense's dissolved hydrogen measuring device (including H2-N (Hydrogen Needle Sensor), PA2000 (2-Channel Picoammeter), ADC-216. (2-Channel A / D Converter)).
The DH concentration of blood was 0.85 mg / L.
[Example 14]
As a living body application liquid, dog vein blood collected in a 200 mL capacity polyvinyl chloride container “Terumo Blood Bag CPD” (manufactured by Terumo Corporation) containing 28 ml of the above-mentioned blood preservation solution C was used. A 1.5 L capacity water purification filter housing was used as a hydrogen reservoir. A blood bag was installed in the hydrogen reservoir, and 100% hydrogen gas was aerated at a flow rate of 100 mL / min through the tube from the opening of the gas supply container under a pressure of 0.01 MPa. After 5 hours, the blood bag is removed from the hydrogen reservoir and opened, and the DH concentration in the blood is measured by Unisense's dissolved hydrogen measuring device (including H2-N (Hydrogen Needle Sensor), PA2000 (2-Channel Picoammeter), It was measured using ADC-216 (2-Channel A / D Converter).
The DH concentration of blood was 0.87 mg / L.
Hereinafter, the free radical scavenging reaction of the hydrogen-containing blood product was simply measured using diphenylpicrylhydrazyl (DPPH) which is a free radical reagent.
[Example 15]
Using the apparatus described in Example 4, hydrogen molecules are contained in the above blood preservation solution C contained in a polyvinyl chloride container from the outside of the container, and a hydrogen-containing blood preservation solution C having a DH concentration of 1.0 ppm. Got. Next, 5 μg of platinum colloid (0.0005 wt% of 0.0005 wt%) as a catalyst was added to 20 cc of a hydrogen-containing blood product model solution obtained by diluting dog vein blood 1000 times with this hydrogen-containing blood preservation solution C. After adding 0.1 g of a platinum colloid solution), about 0.02 g of a 0.625 wt% DPPH ethanol solution (DPPH 0.25 g / ethanol 40 g) was added dropwise, and the color change was examined.
In the hydrogen-containing blood product model solution, 7 drops of DPPH having a purple color were changed to amber. That is, DPPH corresponding to 875 μg was erased.
In the hydrogen-containing blood product model solution diluted 1000 times, the red color derived from blood and the amber color derived from DPPH were mixed, and the color reaction after the 8th drop could not be confirmed. It was considered that the color reaction after the 8th drop could be confirmed by further dilution.
[Comparative Example 1]
To 20 cc of the blood product model solution obtained by diluting the venous blood of the dog 1000 times with the above blood preservation solution C, 5 μg of platinum colloid (0.0005 wt% platinum colloid solution as a catalyst was added to 0.1 ml). 1 g) was added, and a 0.625 wt% DPPH ethanol solution (DPPH 0.25 g / ethanol 40 g) was dropped about 0.02 g at a time, and the color change was examined.
The blood product model solution did not change the purple-colored DPPH to amber at all. That is, DPPH was not erased at all.
Hereinafter, an embodiment of a hydrogen-containing blood product comprising a combination of an inner container having hydrogen permeability and a portable hydrogen reservoir having lower hydrogen permeability than the inner container will be described.
[Example 16]
The venous blood of a dog collected in a 200 mL polyvinyl chloride container “Terumo Blood Bag CPD” (manufactured by Terumo Corporation) containing 28 ml of the above-mentioned blood preservation solution C is housed in a 550 mL capacity aluminum pouch container. After that, the space between the polyvinyl chloride container and the aluminum pouch container was filled with 1.5 ppm of dissolved hydrogen water, and the opening of the aluminum pouch container was heat sealed and left for 24 hours. Thereafter, the aluminum pouch container and the polyvinyl chloride container were opened, and the dissolved hydrogen concentration of the blood product in the polyvinyl chloride container was measured.
For the measurement, a dissolved hydrogen measuring device (including H2-N (Hydrogen Needle Sensor), PA2000 (2-Channel Picoammeter), ADC-216 (2-Channel A / D Converter)) manufactured by Unisense was used.
The dissolved hydrogen concentration of the blood product was 600 ppb.
[Comparative Example 2]
The hydrogen-containing blood product of the same lot as the hydrogen-containing blood product produced in Example 13 and having a DH concentration of 0.85 mg / L at the time of manufacture was left as it was for 24 hours without opening. Thereafter, the polyvinyl chloride container was opened, and the dissolved hydrogen concentration of the blood product in the polyvinyl chloride container was measured.
For the measurement, a dissolved hydrogen measuring device (including H2-N (Hydrogen Needle Sensor), PA2000 (2-Channel Picoammeter), ADC-216 (2-Channel A / D Converter)) manufactured by Unisense was used.
The dissolved hydrogen concentration of the blood product was 0 ppb or below the detection limit.

Claims (2)

A method for producing an oral bioapplication liquid containing hydrogen by substantially containing hydrogen molecules in an oral bioapplication liquid sealed in a hydrogen molecule-permeable container,
A hydrogen contact step in which hydrogen molecules are brought into contact from the outside of the container without opening the container in the container in which the oral bioapplication liquid is sealed; and
Through the container having hydrogen molecule permeability, the dissolved hydrogen concentration substantially contained in the oral biomedical solution after the hydrogen contact step is 0.01 mg / L or more at a temperature of 20 ° C. and 1 atm. A method for producing an oral bioapplication liquid containing hydrogen. An apparatus for producing an oral biological application liquid containing hydrogen by substantially containing hydrogen molecules in an oral biological application liquid sealed in a container having hydrogen molecule permeability,
A hydrogen reservoir that encloses the container filled with the oral biomedical solution without opening the container, and makes hydrogen molecules contact the container from the outside of the container;
A hydrogen molecule supply means for supplying hydrogen molecules to the hydrogen reservoir, and
The dissolved hydrogen concentration substantially contained in the oral biological fluid through the container having hydrogen molecule permeability is 0.01 mg / L or more at a temperature of 20 ° C. and 1 atm. An apparatus for producing an oral biological fluid containing hydrogen.

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