JPH0568267B2 - - Google Patents

Description

RELATED APPLICATIONS This application is a continuation-in-part of applicant's US patent application Ser. No. 562,435, filed December 6, 1983.

BACKGROUND OF THE INVENTION The present invention relates to the ability of fuels (carbohydrates, proteins, and fats) to be processed (i.e., oxidized, stored, and converted into other substances) in chronically abnormal (e.g., diabetic patients) or impaired by acute disorders. The present invention relates to an insulin injection device for administering insulin to a person who has been injured (for example, an accident or surgical trauma patient).

The normal fuel processing capacity of the human body, such as the liver and other tissues such as muscles, can be disrupted by disease (eg diabetes) or trauma (accident or surgery).

Insulin is administered in large doses to diabetics, surgical patients, or accident (especially burn) victims to restore normal fuel handling capacity and prevent the breakdown of muscle proteins. Glucose is also injected because large doses of insulin lower blood sugar levels.

Established treatment programs for diabetic patients include administering insulin to regulate blood glucose levels.A pattern of insulin injections based directly on measured blood glucose levels was developed by Eisenberg et al. in U.S. Pat. No. 3,387,339, Klein US Pat. No. 4,206,755, Edelman US Pat. No. 4,073,292 and Chemical Abstracts 92:135345m. Insulin injection patterns based on predicted blood glucose concentrations and predicted changes in blood glucose calculated using measured blood glucose concentrations are described in U.S. Pat. Patent No. 4,253,456, U.S. Patent No. 4,151,845 to Clemens, U.S. Patent No. 4,151,845 to Clemens et al.
No. 4055175 and Chemical Abstracts 89:
39926u. In each type of program described above, both the amount of insulin injected and the duration of the injection are based on measurements of glucose concentration. That is, insulin is administered when the measured and/or predetermined glucose concentration rises to a certain limit. Insulin infusion continues until the glucose concentration reaches or falls below a certain concentration.

In addition to insulin injection patterns that constantly measure the glucose concentration as described above, insulin injection devices have also been developed that are capable of injecting insulin according to a predetermined profile of the patient's insulin requirements. for example,
The device disclosed in Frannetsky et al., U.S. Pat. ) can be called by the patient if necessary. Similarly, the device disclosed in U.S. Pat. No. 4,077,405 to Harton et al. is capable of delivering pulses of medication (e.g., insulin) on a constant baseline in response to preprogrammed or manually controlled signals. There is. These devices work to directly control the actual concentration of glucose in the bloodstream and administer insulin in a designed pattern, similar to the methods described above that constantly measure glucose concentrations.

SUMMARY OF THE INVENTION The present invention provides an insulin injection device for injecting insulin into a human body, which comprises: a unit for injecting insulin in pulses in accordance with the intake of a carbohydrate-containing meal; and a duration of the pulses. a programmable processing unit for controlling the interval between peaks of free insulin concentration in the blood of 50 to 3000 μU/ml with a minimum value between the peaks of 60 to 1000 μU/(ml blood); a programming unit for programming said programmable processing unit to deliver pulses of increasing intensity. Here, the free insulin concentration refers to insulin that is not bound to an antibody, and is measured by a conventional method. The method for measuring the amount of free insulin used in the present invention is a conventional method of separating free insulin from antibody-bound insulin, and is carried out as described below. That is, a blood sample is taken from either an artery or a vein;
The collected blood sample is immediately centrifuged at 15000G for 1 minute. Take out 0.5 ml of plasma obtained from this centrifugation process and dilute it with polyethylene glycol.
Mix 0.5 ml of 25% solution. Centrifuge the plasma/polyethylene glycol mixture for 1 minute at 15000G. Because the insulin bound to the antibody has a large molecular weight, it migrates to the bottom of the tube, leaving free insulin in the supernatant. A sample of the supernatant is then removed and the insulin content in the sample determined using a conventional two-antibody insulin assay. Since the supernatant contains only the supernatant, this assay provides a measure of the free insulin content of the raw blood sample.

In general, devices of the present invention useful in the treatment of diabetes or surgical disease (1) after a high carbohydrate concentration has been established in the patient's metabolic system, (2) by administering insulin to increase the carbohydrate concentration. activating the prandial carbohydrate processing capacity of the patient's liver by increasing the concentration of "free" insulin in the patient's metabolic system during at least a portion of the period of exhaustion, said insulin being administered in the form of a pulse; Insulin is injected into the patient's body such that a series of peaks in free insulin concentration is created.

In a preferred embodiment, the change in free insulin concentration is achieved by varying the insulin dose over time, the high carbohydrate concentration is established by ingestion or infusion of carbohydrate, the administration phase is initiated coincident with said establishment phase, and the insulin is pulsed. After the first series of insulin pulses, which produce sharp peaks over progressively increasing peak-to-peak concentrations, there is a rest period during which insulin administration is stopped, before the administration of the first series of pulses. After the rest period, a second series of insulin pulses is administered to create an insulin concentration that fluctuates above and below the baseline to maintain the fuel processing system in an active state. The average insulin amount for the second series of pulses is less than the average insulin amount for the first series of pulses,
The second series lasts for the entire period between carbohydrate ingestions or infusions.

Additionally, in a preferred embodiment, time-varying insulin doses are administered using an external or implantable programmable insulin infusion pump.

The insulin concentration change program of the present invention activates the body's ability to process fuels such as carbohydrates (glucose, fructose, sutucarose, galactose, starch and their analogs and derivatives), amino acids and lipids in diabetic and surgical patients; and maintain. In diabetic patients, this method of insulin administration addresses the underlying problem of diabetes, namely the metabolic system's defective ability to autoregulate glucose levels, and the resting state of the metabolic system through dietary carbohydrate processing, especially in the liver, including the muscles. It indirectly regulates blood glucose concentration by rapidly and effectively activating the body's processing system.

Other features and advantages of the invention will be apparent from the following preferred embodiments and from the claims.

Description of the preferred embodiment First, the drawings will be briefly explained.

Figure 1 shows the concentration of "free" insulin achieved with the device of the invention.

2 shows an enlarged view of section A of FIG. 1, FIG. 3 shows an enlarged view of section C of FIG. 1, and FIG. 4 shows an enlarged view of section C of FIG. Figure 5 shows a schematic block diagram of a programmable external insulin pump for delivering insulin to the device of the present invention.

DESCRIPTION The insulin concentration change program of the present invention matches the increase in carbohydrate concentration in human body tissue, for example by digestion of a carbohydrate-containing meal or infusion of carbohydrates (e.g. glucose), with the insulin concentration produced by the program, thereby increasing the fuel processing capacity of the human body. It is intended to be useful for activating and maintaining the system. Specifically, this program is designed to align hepatic and portal vein glucose concentrations with insulin concentrations to activate the dietary carbohydrate processing system. Based on studies of the enzymes involved in glucose metabolism and the distribution of exogenous and autogenous glucose in the metabolic system, this dietary carbohydrate processing system is thought to be located primarily in the liver and to a lesser extent in the muscles. Both the amount of insulin infused and the duration of insulin pulses are independent of blood glucose concentration.

In people who inject insulin (e.g., diabetics on insulin), insulin is bound to antibodies that can be used to regulate fuel processing capacity, particularly glucose levels in the blood. The insulin concentration that is possible is generally much lower than the total insulin concentration in the metabolic system. The concentration of insulin that can be used to regulate blood glucose levels in this manner is referred to as the "free" insulin concentration.

The first part of the program is designed to activate the body's fuel processing capacity, specifically the dietary carbohydrate processing system. In order to activate this system, human tissues, especially the hepatic glands (but also the muscles), are activated when glucose concentrations in the hepatic and portal veins become high, for example after the ingestion of carbohydrate-containing foods or by the infusion of carbohydrates. Later, at the same time, "free"
Insulin concentration should (ie, should) be seen to increase rapidly and gradually increase overall between the peaks of "free" insulin concentration. Figures 1 and 2
Part A of the diagram shows the required pattern of "free" insulin concentrations. These three factors, i.e., the gradual increase in ``free'' insulin concentration when intrahepatic or portal vein glucose concentration is high, as well as the sudden change in ``free'' insulin concentration, (and to a lesser extent) enzymes involved in glucose metabolism are synthesized and activated.

Once the metabolic system has been activated, varying amounts of insulin can be administered over time to achieve insulin concentrations near or near baseline, i.e., near the insulin concentration that existed before administration at the beginning of the program. It is possible to maintain "free" insulin levels that rise and fall. Part C of FIG. 1 and FIG. 3 show the "free" insulin concentration moving up and down.

Preferably, the time-varying insulin dose is a pulse of insulin, that is, an injection or infusion that starts and stops within a short period of time (on the order of seconds). However, any method can be used as long as it provides the time variation that provides the desired "free" insulin concentration pattern.

peak-to-peak insulin pulses by administering a first series of insulin pulses spaced sufficiently close together that the effects of one pulse (i.e., the "free" insulin concentration peak) do not completely disappear before the next pulse is applied. On top of the increase in concentration, the "free" insulin concentration can be changed rapidly. Referring to FIGS. 1 and 2, the time of ingestion of a carbohydrate-containing meal or infusion of carbohydrate when the "free" insulin concentration is X is shown at D, or time=0. X represents the "free" insulin concentration present in the patient's metabolic system prior to the application of the first series of insulin pulses, hereinafter referred to as the baseline concentration. For example, in the case of a diabetic patient, X is the lowest "free" insulin concentration in the patient's metabolic system after the last insulin injection of a typical treatment program. A typical baseline "free" insulin concentration is between 5 and 15 microunits of insulin per ml of serum (μU/ml).
It is.

Peak E is achieved by applying the first pulse of the first series of the insulin delivery program of the present invention at or shortly after a constant high carbohydrate concentration. This pulse is “free” in the blood
Peak insulin concentration is 50-3000μU/ml,
Preferably, the amount is sufficient to reach 100-2000 μU/ml. This “free” insulin concentration is approximately 90
% decrease to Y (ie, approximately 10% excess of the "free" insulin concentration at the time of administration of the first pulse), the second pulse of the first series is applied, resulting in peak F. When the "free" insulin concentration has again decreased by about 90% to Z, i.e. about 10% in excess of the "free" insulin concentration at the time of the second pulse administration, the next pulse of the first series is applied, It becomes peak G. As this operation is repeated, the peak-to-peak concentration of "free" insulin becomes progressively higher as shown by line H. The amount of insulin injected with each pulse in this first series of insulin pulses may be constant, but the peak "free" insulin concentration after each pulse is between 50 and 3000 μU/ml, preferably between 100 and 3000 μU/ml.
It may be changed as long as it is 2000μU/ml. The time between pulses may also be constant, but the next pulse is administered before the insulin concentration from the previous pulse has returned to the concentration that existed before the administration of the previous pulse, so that from one pulse to the next there is a peak-to-peak interval. may be varied so that the "free" insulin concentration increases by between 10 and 500 μU/ml. The duration of this first series, administered with each meal or carbohydrate infusion, should not exceed 3 hours, and is generally within about 6 to 180 minutes. A particularly useful result is a series of
10 pulses administered every 6 minutes, total time
Obtained when set to 56 minutes. It is desirable to administer the lowest amount of insulin that is consistent with the activation of the dietary fuel processing system, and the amount of insulin required to activate this system varies from patient to patient and even from day to day within the same patient. For this reason, the length of the first series, that is, the time, cannot be determined with certainty.

Predetermined first insulin pulse...
After the carbohydrate meal/infusion sequence is complete,
The pulse administration is discontinued to allow the "free" insulin concentration to return to the baseline concentration as shown in section B of FIG.

When the free insulin concentration reaches this baseline concentration,
or when it is near that point, administer a second series of smaller insulin pulses to replace the first.
As shown by the curve J in the C section of the figure and Fig. 3,
Have a "free" insulin concentration that varies above and below a concentration at or near the baseline concentration. This second series of insulin pulses is such that the peak "free" insulin concentration is between 10 and 300 μU/ml. The pulses (alone or in pairs) have peak-to-peak "free" insulin concentrations between individual pulses or pulse pairs of 5 to
They are separated from each other to be approximately constant at 15 μU/ml.
i.e. one pulse (or a pair of pulses)
The effect of is separated so that it dissipates before the next pulse (or pulse pair) is administered.

This second series of administrations (1) along with the first series, maintains the body's fuel processing capacity, particularly the dietary carbohydrate processing system, active, and (2) maintains hepatic storage between carbohydrate ingestion or infusion intervals. A cycle of glucose excretion and hepatic glucose absorption is enabled. In other words, when the "free" insulin concentration exceeds the baseline, the activated glucose production function of the liver is blocked, the liver absorbs glucose, and the "free" insulin concentration decreases toward or below the baseline. When this happens, the activated hepatic glands produce and release glucose.

The fuel processing system is activated by this series of first and second insulin injection programs and remains activated for a period of time (1-4 days) before it is able to function normally. In the case of diabetic patients, repeating this first and second series of administrations allows the liver (and muscles) to function normally and automatically regulate the body's glucose levels. Although it is impossible to permanently discontinue insulin injections or infusions in insulin-dependent diabetic patients, after approximately 1 to 4 days of administration in this program, the activated dietary fuel processing system simply All you need to do is make adjustments every 6 to 30 days or more. During this period, diabetic patients receive standard treatment (e.g., subcutaneous insulin, oral hypoglycemic agents,
can return to a therapeutic diet). However, when combined with conventional standard therapy, an activated fuel processing system means that diabetics are less likely to experience wide fluctuations in blood sugar concentrations, which may reduce the need for restrictive therapeutic diets as prescribed by the American Diabetes Association. will also decrease. Alternatively, the metabolic system may be given a first series of doses with a therapeutic diet and a second series administered at night for an indefinite period of time.

The insulin infusion program with the device of the invention consists of 10 to 100 g of therapeutic carbohydrate or 10 to 100 g of therapeutic carbohydrate.
For example, a first series of insulin pulses is administered immediately after ingestion of a mixed meal containing g of glucose or its analogues [e.g. Sustacal], or immediately after injection of a similar synthetic fuel combination [e.g. (intravenous injection, intraperitoneal administration, or subcutaneous administration). The first series of pulses administered every 6 to 30 minutes over a period of 60 to 180 minutes may be of the same or different doses, with an average dose of 1 kg of body weight.
0.01 to 0.05 units per kg (U/Kg), preferably 0.02
~0.04U/Kg can be achieved. As previously stated, it is desirable to use the lowest amount of insulin necessary to achieve the desired therapeutic effect. These pulses produce a corresponding series of peaks in "free" insulin concentration in arterial blood or arterialized venous blood with peak intensities of 50-3000 μU/ml, preferably 100-2000 μU/ml, at intervals of 6-30 minutes. Corresponding to these “free” insulin concentration peaks, peak-to-peak “free” insulin concentrations ranged from 6 to 30
Maximum peak-to-peak "free" insulin concentration increases by 10-500 μU/ml at minute intervals and peaks at 6-180 minutes
Reaching 60-1000 μU/ml. How to inject insulin so as to achieve a continuously increasing minimum between peaks of free insulin concentration becomes clear when the following is understood. After injecting insulin, the amount of insulin in the bloodstream is approximately 5.
It has a half-life of minutes. For example, if an amount of insulin is injected that produces a circulating insulin concentration of approximately 400 μU/ml, the insulin concentration will decrease in approximately 5 minutes.
It decreases to 200μU/ml. In about 6 half-lives (about 30 minutes) the free insulin concentration will approach the baseline of about 6 μU/ml. In order to gradually increase the peak-to-peak nadir of free insulin concentration, the time interval between pulses is selected such that each subsequent pulse is administered before the insulin concentration returns to baseline. Thus, for example, the time interval between pulses is 6
Assuming 4 half-lives (20 minutes) rather than half-lives, the second pulse
It is administered when the concentration decreases from 400 μU/ml to 25 μU/ml. Thus, an appropriate interval between pulses can be selected, or an appropriate pulse size can be selected, such that the subsequent pulse is administered before the subsequent pulse baseline is reached. This allows the peak-to-peak minimum value of free insulin concentration to gradually rise. The administration of insulin is then “free”
Interruption is interrupted for a sufficient period of time (eg, 90-120 minutes) for the insulin concentration to trickle back to the baseline "free" insulin concentration of 5-15 μU/ml.
After reaching this baseline "free" insulin concentration, the peak "free" insulin concentration in arterial or arterialized venous blood increases between 10 and 300 μU/ml between 2 and 90 minutes.
The same or variable amount of insulin pulses are administered every 2 to 90 minutes at an average dose of 0.001 to 0.02 U/Kg so that the This second pulse type continues for the entire period between carbohydrate ingestions or infusions.

The sequence described above is repeated at every meal or injection. Meals are ingested or injected frequently, eg, 2 to 8 times a day. Meals and infusions can be administered in any combination, such as meals alone, infusions alone, or meals and infusions alternating in a regular or irregular pattern.

After 8 to 96 hours, significant improvements in respiratory quotient and carbohydrate oxidation rate were seen after a carbohydrate-containing meal or an equivalent carbohydrate infusion, as in normal patients. Ingestion or similar infusion can be started.

The first and second series of insulin delivery programs described above can be delivered using a standard programmable external insulin pump, as shown schematically in FIG. Preferably, the external pump configuration is used for clinical purposes, such as outpatient therapy (e.g., "chune-up") for patients treated for accidental or surgical trauma, or for adjusting the patient's metabolic system prior to surgery. Referring to FIG. 4, the externally programmable pump 10 includes a programmable microprocessor 12, a pump section 14, and an infusion catheter 16. The programmable microprocessor 12 has a programming keyboard 18 and a display 20, such as an LCD.
Includes LED display. Pump part 14
includes a pump mechanism 22 and an insulin storage section 24. Infusion catheter 16 is connected to pump mechanism 2
2 and inserted into the patient's body, and insulin is supplied through veins (including the hepatic portal vein), peritoneum, or subcutaneously. In this configuration, for example, the programmable microprocessor 12 may (1)
Deliver the first series of insulin pulses every ~30 minutes, (2) interrupt the insulin infusion for 90-120 minutes, and (3) deliver a second series of small doses until the next first series begins. Programmed to deliver insulin pulses. The initiation of the first series can be automatically controlled or programmed to coincide with a preset carbohydrate injection, or manually controlled, such as by pressing a predetermined key on the keyboard 18 when the object is ingested. I can do it.
Alternatively, microprocessor 12 can be programmed (either manually or under automatic control) to supply only the first series.

Glucose concentration (levels) can be independently monitored using finger sticks, venipuncture, or glucose sensors. The glucose sensor or analyzer can also be designed in combination with an external programmable pump to issue an alarm when a predetermined glucose concentration, known to those skilled in the art, is reached, for example in an artificial beta cell. However, with this design, the glucose sensor cannot control when insulin is injected or its rate;
At best, it can be used to interrupt insulin infusion when the glucose concentration reaches a predetermined limit. Upon interruption of insulin infusion, an alarm alerts the patient (or caregiver) and the insulin infusion program (first series) can be manually restarted, if necessary, concurrently with carbohydrate administration.

The above program can also be performed using a standard implantable programmable insulin pump, as shown schematically in FIG. This implantable pump is preferred for long-term self-administration by diabetics. Referring to FIG. 5, implantable pump assembly 26 includes an external transmitter/receiver device 28 and an implantable pump device 30. Referring to FIG. The external transceiver 28 includes a programmable microprocessor 32 having a programmable keyboard 34 and a display 36, such as an LCD or LED display, and receives control signals from the microprocessor 32 to the buried device 30. a telemetry device 38 for transmitting and transmitting care signals received from implanted device 30 to microprocessor 32; The implantable pump device 30 includes a power source 40
a programmable microprocessor 42; a transmitting/receiving device 44 for transmitting information received from the microprocessor 42 to the external transmitting/receiving device 28 and transmitting control signals received from the external transmitting/receiving device 28 to the microprocessor 42; , pump mechanism 4
6 and an insulin container 48. Insulin catheter 50 extends from pump mechanism 46 into a vein (including the portal vein), peritoneum, or subcutaneously. The insulin container 48 has a syringe 5
2 can be used to refill. Implantable pump device 30 can be programmed from the beginning to administer first and second insulin series in the same manner as described for external insulin pump devices. If desired, an external transmitter/receiver unit 28 can also be used to initiate and/or change the insulin delivery pattern, eg, to deliver only the first series.

Glucose concentrations can also be independently monitored using finger sticks, venipuncture, or glucose sensors, as well as using the external pump devices described above. A glucose sensor can also be designed to be incorporated into an implantable insulin pump to communicate glucose concentrations to an external transceiver device 28, as is well known to those skilled in the art. The external transceiver device can be programmed to only issue an alarm when the glucose concentration reaches a predetermined limit, but it can also be programmed (similar to an external pump device) to interrupt insulin delivery and issue an alarm at the same time. can. With either external or implantable devices, it is important to note that glucose concentration alarms are primarily used to convey information and are not used independently to initiate insulin or glucose infusions. is important.

Additionally, it should be noted that administering carbohydrates at concentrations high enough to work in conjunction with the insulin infusion pattern described above is quite contrary to standard diabetic diets. . Furthermore, although the pulses are timed to match the expected high portal glucose concentration after ingestion of a carbohydrate-containing meal or after the initiation of carbohydrate infusion, the insulin infusion pattern according to the present invention and the resulting insulin concentration are normal. This is very different from what occurs in humans or in typical diabetic treatment programs.

The insulin infusion program described above provides a rapid and effective primary activation of the fuel processing system, particularly the processing system of dietary carbohydrates, and the administration of intravenous pulses of smaller doses of insulin for primary activation either immediately before or after meal intake. It can be used in diabetic patients to maintain the above system by administering it immediately. This insulin delivery pattern is important when acute care is required, i.e. in the liver and other tissues of both non-diabetic and diabetic patients, such as trauma patients (surgical patients, accident victims) and overnourished patients. It is also effective in maintaining and/or restoring the fuel (eg, glucose, amino acids, lipids) processing capacity of shrimp muscle.

The present invention includes embodiments other than those described above. For example, replacing the second series with standard insulin therapy by using long-acting (NPH) insulin or by continuous infusion of low-level insulin, administering the first series of pulses with meals, Intermeal (including overnight) "free" insulin concentrations can be maintained at or near baseline concentrations, with the first and/or second series being administered intravenously (including the portal vein), peritoneally, or subcutaneously. can be administered using multiple cycles of insulin injection therapy.

Claims (1)

[Scope of Claims] 1. An insulin injection device for injecting insulin into a human body, comprising: a unit for injecting insulin in pulses in accordance with the intake of a carbohydrate-containing meal; and the period and interval of the pulses. a programmable processing unit for controlling a series of peaks of free insulin concentration in the blood from 50 to 3000 μU/ml with a minimum value between the peaks of 60 to 1000 μU/(ml blood); a programming unit for programming said programmable processing unit to deliver successively increasing pulses. 2. The device of claim 1, wherein the programming unit is programmed to deliver pulses for a period of up to 3 hours. 3. The apparatus of claim 1, wherein the programming unit is programmed to deliver pulses for a period of 6 to 180 minutes. 4. The apparatus of claim 1, wherein each of the four pulses is in the range of 0.01 to 0.05 U/Kg. 5. The apparatus of claim 1, wherein each of the five pulses is in the range of 0.02 to 0.04 U/Kg. 6. The programming unit is programmed to deliver pulses every 6 to 30 minutes,
An apparatus according to claim 1. 7. The programming unit instructs the programmable processing unit to instruct the next set of pulses at which the next series of peaks of smaller magnitude than the first series will occur after the free insulin concentration resulting from the first series has returned to the baseline concentration. 2. The device of claim 1, further adjusted to initiate delivery of the device. 8. The apparatus of claim 1, wherein the next series of pulses is adjusted to produce a free insulin concentration that fluctuates above and below a baseline free insulin concentration. 9 Programming unit is 0.001~0.02U/Kg
8. The apparatus of claim 7, wherein the apparatus is programmed to produce the next pulse within the range of . 10 The programming unit will select the next pulse as 2.
programmed to be sent out every ~90 minutes,
An apparatus according to claim 7.