JPS5946186B2 - Human blood sugar control device - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a device for stabilizing blood sugar levels in the human body.

Diabetes is a disease that occurs in relatively elderly people, and is characterized by an abnormal increase in the amount of sugar in the blood.

One of the main reasons for this is that the beta cells of the islets of Langerhansch in the human pancreas lose their function, and the control of insulin secretion according to the amount of glucose in the blood stops, or the insulin present in the blood becomes inefficient. This is because they don't work well.

Therefore, transport of glucose from the blood to the cells of the body, which is part of the function of insulin in the body, is not carried out, resulting in an abnormal increase in the amount of glucose in the blood.

Conditions caused by this diabetes include brain or kidney damage, and many people die.

It is also well known that many patients suffer from this symptom, even if it does not lead to death.

Particularly in recent years, as eating habits have improved and there is a tendency to consume too many nutrients, the number of patients and deaths from this disease has increased rapidly both in Japan and overseas.

Generally known countermeasures include insulin injection and administration of hypoglycemic agents.

Although these methods have the effect of temporarily lowering the blood sugar level in the body, they are not sufficient as a method for stably maintaining it for a long period of time.

For example, current treatments include repeated injections every day or several days.

However, with this method, it is not possible to adjust the blood sugar level when it fluctuates abnormally due to disturbances such as meals during treatment, and there are many cases of death due to increased burden on other organs such as the kidneys. The reality is that many patients suffer from the complicated number of injections.

Also, injecting too much insulin at once can cause hypoglycemia.

Therefore, for patients who are unable to control autosecretion of insulin, insulin is given according to the amount of glucose in the blood by some method. In other words, when the amount of glucose in the blood increases compared to normal, insulin is given to patients who are unable to control autosecretion of insulin. There are many people in this field who are looking forward to a treatment method that does not require insulin in such cases.

As a result of intensive research aimed at solving the current problems, the present inventor found that a method of releasing insulin or its derivative solution into the blood through a polymer membrane can be effectively used for such treatment, and the present invention is presented. reached.

That is, the present invention includes a processing chamber between a blood inlet and an outlet that can be connected to a human blood vessel, and a discharger containing insulin or its derivative solution that is in contact with blood through a polymer membrane inside the processing chamber. This human body blood sugar level control device further includes a diaphragm that pressurizes the solution contained in the ejector in response to a command from a blood abnormality value sensor that detects an abnormality in the amount of glucose in the blood.

Generally, the abnormal glucose value of a diabetic patient fluctuates up to 400% compared to the average value of 100% to 100% for a normal person.

Ideally, this value should be lowered to the range of normal people and maintained at a stable value, but in reality it is extremely difficult to maintain such a state due to external effects.

However, as a method intended for such a purpose, the idea of linking a glucose sensor and an insulin syringe has been proposed, for example, in An Artificial Endocrin.
e Pancreas (Diabetes 23:
389, 1974).

This method maintains a stable glucose level in the body by expelling insulin from a syringe according to the amount of glucose detected by a glucose sensor.

However, since this method uses a special device called a syringe, insulin is administered discontinuously and the entire device is bulky, making it extremely difficult to put it to practical use.

However, the device of the present invention continuously and slowly releases insulin or its derivatives into the blood from a polymer membrane having a wide area in response to fluctuations in factors such as blood sugar level or pH, thereby reducing minute amounts of glucose. It controls the
Moreover, since it is lightweight and can be transported while being worn on the human body, it can respond slowly and stably, especially to disturbances such as eating.

An embodiment of the method of the present invention is shown in FIG. 1, and its outline will be explained.

In FIG. 1, abnormal values of glucose, PH, etc. detected by a sensor at the blood inlet are sensed as a generated current, and this current is amplified by an amplifier and linked to an electric motor.

At this time, if the current increases compared to the normal blood sugar value,
The air sent from the electric motor pushes the diaphragm valve installed in the emitter, allowing some of the insulin substance to be released from the emitter into the blood through the polymer membrane, which reduces the amount of glycose during metabolism in the body's circulation. After controlling and over time, the amount of glucose at the inlet of the device decreases.

Next, a specific example of the apparatus of the present invention is shown in FIG.

FIG. 2 shows the use of a holofiber as the emitter.

Blood that flows in through the inlet 1 passes through the processing chamber 2 and flows out through the outlet 3.

Inside the processing chamber, there are hollow fibers 4 and their liquid reservoirs 5,
There is an ejector with a solution 7 of insulin or its derivatives encapsulated in 6, which solution is in contact with blood only by a polymer membrane forming a hollow fiber.

Furthermore, there is an abnormal value sensor 8 in the blood flow path, and the current detected by the sensor is measured by a voltmeter 9. amplified by an amplifier 10,
Activates the electric motor 11 when the blood sugar level exceeds the level of a normal person,
The released air pushes the diaphragm 12.

The rotational speed of this sharpening motor is varied by the current sent from the amplifier, or it is activated when the current value exceeds a certain value.

When the diaphragm is pressed, the insulin liquid part is pressurized and insulin is released into the blood.

Note that the end of the liquid reservoir and hollow fiber is made of resin 13.
It is fixed at 14.

The material of the polymer membrane used in the present invention includes all natural and synthetic polymers, but preferably regenerated cellulose, acetyl cellulose, cuprophane, hydrochel, phoriacrylonitrile, etc., which have good affinity with blood, are particularly effective. It is.

Furthermore, the membrane morphology, ie, membrane surface area, membrane thickness, and pore size are important factors that determine the release ability.

These vary depending on the absolute amount of insulin required by the patient, but for treatment of general diabetic patients, the membrane surface area is 50-50 ocIri2, the membrane thickness is 20-80μ,
Membranes with a pore size of 0.5-10μ are used.

The shape of the membrane may be a hollow fiber or a simple flat membrane, but in the sense of effectively using the small housing volume,
Hollow fibers are effective because they can utilize a wide surface area.

The insulin or its derivative solution referred to in the present invention includes aqueous solutions or emulsion m solutions of regular insulin, semi-lenticulin insulin, clopurin insulin, isophane insulin, lenti insulin, protamine zinc insulin, ultra insulin, etc., which are generally used for diabetes treatment. .

The insulin concentration of the solution used depends on the type of insulin, but in the case of regular insulin, it is preferably between 50 and 100 Da.

The abnormal value sensor referred to in the present invention refers to an abnormal value in the blood associated with an increase in blood sugar level, such as glucose amount, pH (
The normal value for normal people is 7.4, and for people with severe diabetes 6.9). Abnormal changes due to cholesterol, etc. are sensed as a potential difference. An example of a glucose sensor is a glucose oxidase electrode.

When glucose oxidase acts on glucose, gluconic acid and H2O2 (formula 0) are produced.

When a platinum-silver electrode is installed in the reaction system, this H20
□ is oxidized by platinum and releases two electrons (formula 0)
.

Oxidized H2O2 is reduced with silver to become H2O (equation 0).

In this reaction system, a potential difference occurs between the platinum electrode (anode) and the silver electrode.

This potential difference increases as the amount of glucose in the blood increases, and glucose sensors utilize this principle.

The reaction formula is as follows. ■ Overall, H20□--raH20+i0□When this principle is used in the present invention, the sensor itself is miniaturized because it is used continuously in the blood flow, and the glucose oxidase part, which is the center of the reaction, is kept for a long time. It is optimal to use an enzyme-immobilized electrode in which glucose oxidase is immobilized on a carrier in order to withstand the use of

Although the electrode part is embedded in the blood, it can also be installed inside the processing chamber as shown in FIG. 2 to simplify the process.

Further, since the potential difference generated between these electrodes is usually 1 mV or less, it is necessary to install an amplifier between the potentiometer and the drive section in order to convert this potential difference into driving force for the motor.

On the other hand, as a pressurizing method, a method that does not use air but uses electric motor power to drive a piston to push the ejector can also be used.

Note that the best way to normally use the pressurizing section is to not perform the pressurizing operation when the sensor detects a normal blood sugar level, but to perform the pressurizing operation only when the blood glucose level exceeds the normal value.

In the present invention, the insulin substance necessary for human metabolism refers to the amount of insulin necessary for a diabetic patient to be treated to restore the blood sugar level to a normal state, and specifically, the basal insulin secretion level of a normal person is 217 W Unit/min (
IUSP insulin unit is the amount of insulin that supports 1.5g of glucose metabolism), and the amount of blood sugar is 3
In the case of 00 ■, it is about 80 mUs P which is 4 times the basal secretion amount.
The equipment is designed to supply 1/min as a guideline.

That is, when the amount of glucose in the blood detected by the sensor is 30 omy%, when an insulin aqueous solution containing about 80 mUSP is transferred from the polymer membrane to the blood side per minute by pressurizing the release device, the released insulin will be As it circulates through the body, it plays the role of moving glucose to the body's cells, reducing the body's blood sugar levels to normal levels.

When this blood sugar level returns to normal, the pressurizing operation of the ejector stops.

Incidentally, a phenomenon in some diabetic patients is that insulin is secreted sufficiently from the pancreas, but its function may be low.

In that case, an excessive amount of the drug would be required compared to a normal patient.

The present invention can compensate for this by increasing the insulin concentration or increasing the release capacity of the emitter.

As described above, the method of the present invention is a flexible treatment method that can be optimally designed depending on the behavior of blood sugar fluctuations of the patient.

Since the device of the present invention is applied by being attached to the human body, it is preferable that the material of the blood contacting part be an anticoagulant material such as silicone rubber, Teflon, or polyurethane to prevent blood clotting. If it is necessary to use other materials for reasons such as this, it is important to process the wall surface as smoothly as possible, since rough surfaces in the blood contacting part may cause blood clots.

The device of the present invention is used by being attached to the human body,
It can be adapted to any location where blood passes through the body.

An example of use when worn on the human body is shown in Fig. 3. In FIG. 3, the device is attached to the forearm of a human body, and 15 is the radial artery and 16 is the radial subcutaneous vein.

The device of the present invention is installed between 15 and 16.

Blood flowing out from the 15 arteries through chanters 17 and 18 installed in each blood vessel bypasses the device and returns to the 16 veins.

At that time, the sensor 19 is embedded in the same processing chamber,
The detected abnormality is transmitted through the amplifier 20 as a signal to operate the electric motor 21, which in turn operates the diaphragm 22.

At this time, commercially available small batteries such as AA to AA batteries can be used as the energy source for driving the electric motor.

The device of the present invention is lightweight and can be transported while attached to the human body, and can be made compact, for example, within 500 g.

In addition, since the absolute amount of insulin generally required by diabetic patients is low, the device of the present invention can be used for a long time.
For special patients who consume a large amount of insulin, additional insulin can be added during use.

Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto.

Example 1 This example is based on an in vitro test.

The experiment utilized the apparatus shown in FIG. 2 having the circuit shown in FIG.

The emitter consists of 45 hollow fibers made of cellulose acetate (inner diameter 230μ, thickness 30μ, average bore size approximately 5μ), the total length of the part in contact with blood is 5 cIrL, and the area where the emitter contacts the diaphragm is 1.5 cm. ,
'.

Hollow fiber and liquid tank have a concentration of 6omy%.
A regular insulin aqueous solution (PH = 3.2) was filled.

Both ends of the hollow fiber are held together with epoxy resin,
Blood contact parts such as the resin surface and the housing were coated with polyurethane (polyethylene oxide 1215 segment polyurethane urea).

At that time, the inner diameter of the housing was set to 1.5 CrrL.

Human blood that had been collected within 8 hours was allowed to flow in through the inlet 1 of the apparatus shown in FIG. 2 at a rate of 60 ml/min.

The diaphragm chamber was designed to push the discharge using air pressure from an electric motor.

Using this device, various potential differences (0.1 to 1.0 mV)
By artificially sending a signal to the amplifier and interlocking it with the electric motor, the amount of insulin released into the blood by the diaphragm pressurizing the ejector was determined.

The relationship between the potential difference and the amount of insulin released into the blood is
As shown in the table.

As a method for tracing the insulin substance, a tracer experiment was carried out in which insulin labeled with 125■ was mixed with unlabeled insulin and the amount of γ-ray irradiation in the blood was measured.

The potential difference range in Table 1 is the glucose fluctuation value of diabetic patients (
100-400%) was artificially generated to match the potential difference detected by the glucose oxidase electrode.

Therefore, Table 1 shows that within this range, the ejector has the ability to release insulin necessary for human body metabolism by pressurizing the electric motor.

Furthermore, in the housing of the same device as above, a platinum silver electrode as a glucose sensor is wrapped in an acetylcellulose membrane, the outer layer is wrapped in a membrane in which glucose oxidase is immobilized on regenerated cellulose with glutyraldehyde, and the outer layer is wrapped in a polycarbonate membrane. The amount of insulin released was measured by using an enzyme electrode covered with a cloth and interlocking it with an electric motor to pass blood with different glucose concentrations at a speed of 60 m/min.

Table 2 shows the results. Table 2 shows that when glucose-free blood is passed through the same device, the amount of insulin released is very small, and as the concentration increases, the amount released increases accordingly, resulting in a glucose concentration of 3001 nI? 90 near the station
It is clear that mUSP/1711 n has been reached.

This value is close to the amount of insulin required for human metabolism by a typical diabetic patient, indicating that the method of the present invention has the ability to slowly release the insulin required for metabolism according to the glucose concentration. There is.

Example 2 Using the device shown in FIG. 2, the insulin release ability of ejectors made from hollow fibers of various different shapes was investigated.

The sensor uses a glucose oxidase electrode, 201
Blood containing 1 and 398,172% glucose were respectively flowed into the device.

Table 3 shows the relationship between the type of hollow fiber and the measured insulin release amount.

Table 3 shows that the standard insulin release capacity according to the method of the present invention can be sufficiently changed by changing the derailment surface area, inner diameter, membrane thickness, and pore size, and that it can be designed according to the patient's blood sugar level. It shows.

From the above results, the method and device of the present invention release insulin into the blood, which is necessary to metabolize excess glucose according to the amount of glucose in the blood, and gradually reduce the amount of blood sugar as insulin circulates through the body. It is clear that it has the effect of reducing and maintaining a stable state.

[Brief explanation of drawings]

FIG. 1 is a diagram illustrating the invention in detail. Figure 2 shows the internal structure when a hollow fiber is used as an emitter as an example of the present invention.
indicates a processing chamber, and 4 indicates a hollow fiber. FIG. 3 is a schematic diagram when the device of the present invention is used on the forearm of a human body.

Claims (1)

[Claims] 1. A discharge device comprising a processing chamber between a blood inlet and an outlet that can be connected to a human blood vessel, and containing an insulin or its derivative solution that is in contact with blood through a polymer membrane inside the processing chamber. A human body blood sugar level control device, which has a diaphragm that pressurizes the solution contained in the discharger in response to a command from a blood abnormal value sensor that detects an abnormality in the amount of glycose in the blood. 2. The device according to claim 1, wherein the ejector is a hollow fiber containing insulin or its derivative.