RU2784997C2 - Planning of refueling of dosing device - Google Patents

Abstract

FIELD: medical equipment.

SUBSTANCE: invention relates to medical equipment, namely to a method for planning of refueling of the first secondary reservoir of an ambulatory infusion system from the first primary reservoir, in which the first drug is stored, and planning of refueling of the second secondary reservoir of the ambulatory infusion system from the second primary reservoir, in which the second drug is stored, and which is separated from the first primary reservoir. The method includes periodic and automatic execution of a program for assessment of a refueling volume, which includes determination of the need for refueling of the first secondary reservoir and/or the need for refueling of the second secondary reservoir, performed in the current period of time, based on calculated infusion of the first drug and the second drug between the current period of time and the future evaluative period of time. A control unit of an ambulatory infusion device and an ambulatory infusion device made with the possibility of implementation of such a method are also proposed.

EFFECT: obtaining a method for planning of refueling of drug reservoirs.

15 cl, 3 dwg

Description

The technical field to which the invention belongs

The present invention relates to the field of infusion devices and infusion systems for combined infusion (infusion into the body) of two or more drugs. In particular, it refers to scheduling (timing) the filling of one or more secondary reservoirs from primary reservoirs for subsequent infusion from one or more secondary reservoirs over an extended period of time. A typical field of application of the invention is the treatment of diabetes by combined infusion of insulin and glucagon.

State of the art

Ambulatory infusion machines, also referred to as infusion devices or infusion devices, are widely known in the art, for example, in the treatment of diabetes mellitus by continuous subcutaneous insulin administration (CSII), also known as continuous subcutaneous injection, and in the treatment of pain or cancer, and are supplied nearby. manufacturers. The essence of the invention and the possibility of its implementation are discussed in the present description on the example of the design of the infusion apparatus, especially suitable for NVI.

Ambulatory infusion machines used for continuous subcutaneous administration of insulin are designed to be worn substantially continuously, day and night, by a diabetic patient, also referred to as a user. These devices are designed to be concealed, eg clipped to a waist belt or in a trouser pocket, and/or alternatively can be configured to be attached directly to the body via an adhesive backing. Ambulatory infusion machines allow infusion into the body of a drug, in particular insulin, at least two methods. First, they are designed to infuse the drug in a substantially continuous, basal regimen, which is usually pre-programmed and is time-varying and self-contained, ie. does not require special interaction with the user or actions on his part. Second, they are designed to infuse higher on-demand boluses of drug, for example to compensate for carbohydrate intake, and also to correct undesirably high blood glucose values. To control these, and if necessary, other functions, ambulatory infusion machines contain an electronic control unit, usually built on the basis of one or more microprocessors or microcontrollers. As used herein, the terms "ambulatory infusion set" and "ambulatory infusion system" refer to a device and system having at least the basic functionality described above, respectively.

In accordance with the classical and generally accepted design scheme, such outpatient infusion devices or systems are usually performed as a syringe pump, when the drug for infusion administration is displaced from the corresponding cartridge by means of a controlled and incremental (step by step) movement of the cartridge piston, i.e. displacement of the piston in discrete increments of its stroke. To move the cartridge piston, a screw gear with an electric motor is provided. Typical cartridges typically have volumes ranging from 1 to 3 ml, for example, and the drug, in particular insulin, is stored in the cartridge for several days to a week or longer. A number of disadvantages of such devices are known from the prior art. In particular, such devices have limited accuracy as they are used to deliver drugs in very small quantities, typically in the nanoliter range, by displacing the drug from a cartridge whose total usable volume is measured in milliliters. Therefore, additional ideas and architectures have been proposed, involving the use of a separate (remote) dosing device located in the drug delivery path after the drug reservoir, containing, for example, a diaphragm or piston micropump, configured to be connected to the drug reservoir and especially well suited for accurate dosing of small volumes. While several designs for such dispensing devices are known in the art, they are quite complex and most of them are expensive and/or critical on a large scale.

EP 1970677 A1 discloses a system with a miniaturized piston pump having a metering cylinder that is periodically connected to and filled from a larger reservoir, followed by connecting the metering cylinder to the infusion site and infusion into the body of the drug displaced from the metering cylinder, performed in a stepwise manner. mode, i.e. discrete increments of the piston stroke, over a long period of time. For alternate connection of the dosing cylinder to the tank and the infusion site, a hydraulic distribution system, or a hydraulic distributor, is proposed. An infusion is a metered infusion of controlled volumes or volume increments.

The possibilities of carrying out the present invention are illustrated in the present description on the example of the architecture corresponding to the principles described in EP 1970677 A1 of the technical solution, unless otherwise indicated. The larger reservoir, also referred to as the "primary" reservoir, contains a supply of drug stored there for a period ranging from a few days to a week or longer, as explained above. The internal volume of the dosing cylinder is called the "secondary" reservoir. From the dosing cylinder, the drug is infused into the body in essentially the same way as in the case of the classic syringe type design described above. The control of both the switching of the hydraulic valve and the movement of the piston in the metering cylinder, or secondary tank, is carried out by means of an electronic control unit.

In contrast to the classic syringe pump, the secondary reservoir has a relatively small filling volume and can be, for example, 70 microliters, which corresponds to 7 IU (international units) of a U100 standard concentration liquid insulin preparation.

Each time the secondary reservoir is emptied or about to empty, it must be refilled from the primary reservoir to continue infusion. It is advisable that the control of the filling status of the secondary reservoir and its refilling, when necessary, is a background process controlled and performed by the ambulatory infusion machine autonomously, without the need for user intervention. For a number of reasons, and due to certain limitations associated with the design of the apparatus and energy consumption, it is advisable to fill or top up the secondary reservoir relatively slowly, which can take, for example, a time of the order of one minute or more.

WO 2012/140063 A1 discloses an outpatient infusion machine and a method for controlling its operation, comprising the following steps: (a) determining a maximum refill level for a secondary reservoir based on external parameter data, wherein the maximum refill level does not exceed the maximum capacity of the secondary reservoir; (b) filling the secondary reservoir with the liquid drug from the primary reservoir to the maximum refill level; (c) dispensing a plurality of portions of liquid medicine and feeding them into a channel connected to the secondary reservoir; (d) refilling the secondary tank, performed when it is empty, as in step (b), and continuing with step (c).

The hormone glucagon is an insulin antagonist that causes a rapid increase in blood glucose levels in a diabetic patient. Although injection of glucagon is a common measure in the emergency treatment of diabetic patients in a state of severe hypoglycemia, the use of glucagon in the daily practice of treating diabetes is not accepted. However, it has been suggested that infusion of both the hormone insulin and its antagonist glucagon can improve the quality of therapy.

Disclosure of the essence of the invention

Accordingly, ambulatory infusion machines have been proposed that allow the infusion of both insulin and glucagon essentially using two separate syringe-type pumps. However, such devices are complex, bulky and expensive. Currently, there are no mass-produced devices and systems suitable for everyday use.

In addition to infusion of insulin and glucagon in the treatment of diabetes, there is a more general situation in other cases where the combined administration of two or more drugs to the body over a long period of time is required, for example, in various types of hormone therapy, cancer treatment or pain treatment. The possibilities of carrying out the present invention are illustrated in the present description mainly on the example of the infusion of insulin and glucagon, without excluding the implementation of the invention with the infusion of other drugs in addition to the infusion of insulin and glucagon or as an alternative to it.

In the context of insulin and glucagon infusion for the treatment of diabetes, insulin is typically administered in both the basal and bolus regimens discussed above, while glucagon administration is typically a bolus infusion performed in special situations. This application is assumed in the following text in the general case, unless otherwise indicated. In addition, for the case of infusion of insulin and glucagon, insulin is considered as the first drug, and glucagon is considered as the second drug.

In the context of an ambulatory infusion set and an ambulatory infusion set containing(s) a primary reservoir and a secondary reservoir, as explained above, unnecessary refilling operations should generally be avoided, since each refilling is associated with significant energy consumption and the potential introduction of some kind of error in dosing due to switching of the control valve and changes in the direction of movement of the piston. In addition, bolus infusion of drug is desirably done as far as possible so that the secondary reservoir does not have to be refilled during the process. That is, refilling the secondary reservoir should be avoided during bolus infusion.

The general objective of the present invention is to improve the means and methods of the prior art in the field of combined infusion of two or more drugs over a long period of time, carried out, in particular, by means of outpatient infusion machines and an outpatient infusion system, the principle of operation of which is generally based on the use of two or more primary reservoirs with various drugs in combination with one or more secondary reservoirs. Medicines are liquid.

It is a particular object of the present invention to control or schedule the refilling or refilling (refilling) of the secondary tank so that refilling occurs at appropriate times. Particularly suitable are times when refilling does not affect the therapeutically relevant functioning of the ambulatory infusion set, in particular basal and bolus infusion, or at least has only a small effect on such functioning. This avoids unnecessary refueling procedures.

This general task is solved by a set of essential features of independent claims. Considered as examples and expedient embodiments of the invention are given in the dependent claims, as well as in the description of the invention. In general, the problem is solved by predicting or predicting the volume of two or more drugs, which is calculated to be used for infusion in the near future, and determining the time points for refilling based on this forecast.

In the following, the invention is discussed in the general example of the infusion of two different drugs, called the first drug and the second drug. For purposes of illustrating the invention, the first drug is a liquid insulin formulation and the second drug is a liquid glucagon formulation.

In one aspect, this general problem is solved in a method for scheduling the refilling of the first secondary reservoir of the ambulatory infusion system from the first primary reservoir that stores the first drug, and scheduling the refilling of the second secondary reservoir of the ambulatory infusion system from the second primary reservoir that stores the second drug. The second primary reservoir is separate (different) from the first primary reservoir. The method includes periodically and automatically executing a refueling volume estimation program, which includes determining whether the first secondary tank needs to be topped up and/or the second secondary tank needs to be topped up, i. determining whether the respective secondary reservoir needs to be refilled, such determination being based on the estimated or expected infusion of the first drug and the second drug between the current time and a future estimated time.

The method according to the invention determines whether the first and/or the second secondary tank needs to be topped up immediately, i. at the current point in time to avoid having to refill it at a potentially inappropriate point in time in the future, in particular at a point in time when drug administration is to take place and the remaining filling capacity of the secondary reservoir is likely to be insufficient.

The method according to the invention is usually carried out as a computer-implemented method and is executed by one or more microcomputers and/or microcontrollers, in which the corresponding software or embedded program code is executed.

In one embodiment of the invention, the first secondary reservoir is physically separate from the second secondary reservoir, with the first primary reservoir communicating only with the first secondary reservoir, and the second primary reservoir communicating only with the second secondary reservoir.

However, in other embodiments of the invention, the first secondary reservoir and the second secondary reservoir are formed by one common secondary reservoir, which alternately serves as the first secondary reservoir and the second secondary reservoir. In such an embodiment of the invention, such a common secondary reservoir is the only physically available secondary reservoir and can be filled alternately with the first liquid drug for infusion of the first liquid drug and the second liquid drug for infusion of the second liquid drug. At a particular moment in time, the common secondary reservoir can be filled, or filled, either only with the first drug - in which case it serves as the first secondary reservoir, respectively, or only with the second drug, in which case it serves as the second secondary reservoir, respectively. Unless expressly stated otherwise, the terms "first secondary reservoir" and "second secondary reservoir" may refer to one common secondary reservoir, which in a particular context serves as the first secondary reservoir or the second secondary reservoir. In addition, the first secondary reservoir and the second secondary reservoir may be referred to simply as "secondary reservoir" only when it is unambiguous.

It should be noted that in addition to the first secondary reservoir and the second secondary reservoir, there may similarly be other secondary reservoirs, either other physically separate secondary reservoirs or a common secondary reservoir shared for infusion of different drugs. Each secondary tank has a physically separate primary tank.

The definition of estimated (expected) infusion is based on estimated infusion volumes as estimates of the amount of first drug and second drug administered between the current time and a future time.

The time interval between a reference point (reference point), such as the current point in time, and a subsequent point, such as the future point in time, for which the evaluation is performed, is called the estimated time interval. An estimated time interval is a time interval for which drug administration (first, second, or whatever) from the secondary reservoir is predictable, or estimated, with sufficient certainty, as explained in more detail below. It should be noted, however, that an accurate forecast is not necessary, since the secondary tank can be topped up from the primary tank at any time if necessary. In the context of the treatment of diabetes, the estimated time interval may be, for example, two hours. Longer or shorter time intervals may also be used, such as one hour or four hours. Typically, the estimated time interval is predetermined and constant. However, in other embodiments of the invention, the estimated time interval is not predetermined, but adaptive. As a general rule, the estimated time interval can be long if the predictability is high, i.e. if the basal and/or bolus infusion profile as a function of time of day remains constant or similar over an extended period of time, such as several days or weeks. If the predictability is low, it may be appropriate to use shorter evaluation time intervals. In one embodiment of the invention, the method includes periodically determining the variability in the profile of past basal and/or bolus infusions through statistical analysis, as well as refining the estimated time interval depending on the variability thus determined.

In some embodiments of the invention, the method provides that the filling volume estimation program is executed at time intervals less than the estimated time interval. The charge volume estimation program may be executed at a fixed time interval of, for example, 10 minutes. Longer or shorter time intervals may also be used, such as 5 minutes, 30 minutes, or 60 minutes. In exemplary embodiments of the invention, program steps are executed at specific predetermined times of the day under the control of the ambulatory infusion machine timing circuit. In alternative embodiments of the invention, the times of day at which the charge volume estimation program is executed are, at least in part, not predetermined, but are different for different times of day. As a general rule, the priming volume estimate program may be run less frequently during times of the day when the predictability of a basal and/or bolus infusion is high and more frequently during times of the day when said predictability is low. For example, the charge volume estimate program may run more frequently during the day and less frequently during the night. In addition, if necessary, the priming volume estimation program can be synchronized with a basal infusion, in particular a basal insulin infusion. For ambulatory infusion machines with the ability to provide substantially continuous basal insulin infusion delivered in incremental doses or bursts, as explained below, the priming volume estimation program can generally be performed, for example, substantially after the basal infusion of the incremental dose of drug is delivered, thereby providing the maximum available time interval for refilling the secondary reservoir, and therefore, the creation of interference with the delivery of the next next incremental dose in the basal infusion mode is excluded.

As an alternative to executing the fill volume estimate program according to a plan, or preferably in addition to such scheduled execution, the method may include executing the fill volume estimate program upon the occurrence of a trigger event. Such a trigger event may be, for example, temporary corrections (modifications) to the set basal infusion regimen at the user's command or the cancellation of such a correction, and / or the onset of a therapy-related event that affects the infusion, for example, the occurrence of a situation with a low glucose level in blood, as explained in more detail below. In addition, the programming of an on-demand bolus can serve as a trigger event.

The priming volume estimation program is a background program that runs at a certain interval of time, as discussed above, during normal operation of the ambulatory infusion system when basal and/or bolus infusions are performed. The times when the charge volume estimation program is executed are the current times.

In some embodiments of the invention, the fill volume estimate program includes determining a first estimated fill volume of the first secondary reservoir at a future estimated point in time and determining whether the first secondary tank needs to be topped up, i. determining whether the first secondary tank needs to be topped up depending on the first estimated charge amount.

The first estimated filling volume is the predicted filling volume and represents the filling volume of the first secondary reservoir that is expected at the estimated time point if the drug is infused from the secondary reservoir from the current time point to the estimated time point without refilling the first secondary reservoir. The same can be similarly referred to as an addition or alternative to the second secondary reservoir or any other secondary reservoir.

In some embodiments of the invention, the fill volume estimation program includes determining that the first secondary reservoir should be topped up if the first estimated fill volume is below a first threshold fill volume. Typically, the first charge threshold is predetermined. In some such embodiments of the invention, the first threshold filling volume is zero, i.e. the need to top up the first secondary reservoir at the current time is determined if the first estimated amount of topping up is negative. In this context, it should be borne in mind that a negative physical filling volume is not possible for technical reasons. Alternatively, the threshold filling volume is not zero, but positive and takes into account, for example, some margin of safety. In such an embodiment of the invention, the threshold filling volume for the case of NVI may be, for example, in the range from 10 to 50 microliters, respectively from 1 to 5 IU (international units) of a U100 standard concentration liquid insulin preparation. The positive threshold filling volume may correspond, in particular, to at least a back-dosing volume, as explained below. The same principles may similarly apply, in addition or alternatively, to a second secondary reservoir or any other secondary reservoir.

In some embodiments of the invention, the method includes, as part of the estimating priming volume program, determining that the secondary reservoir should not be refilled if the estimated priming volume is below a threshold priming volume, but the estimated length of time until the next next on-demand bolus delivery is greater than the time threshold. - bolus out. In such an embodiment of the invention, the secondary reservoir may not be topped up at the current time, although in principle, based on the assessment as explained above, it should be topped up. In particular, in such an embodiment of the invention, the secondary reservoir is not refilled if the time interval from the current time point to the predicted or expected time point for the next demanded bolus exceeds the bolus timeout threshold. The bolus timeout threshold is typically pre-set and in a particular example may be 20 minutes, for example. Such an embodiment of the invention avoids refilling, which in reality may be unnecessary due to the typical variability in drug infusion. In particular, the bolus timeout threshold corresponds to a time interval beyond which there is a significant likelihood of a significant change in the estimated volume of filling of the secondary reservoir, in particular a deviation in the upper side. A typical reason for this deviation may be a temporary decrease or suspension of basal infusion due to physical activity or sports, or low blood glucose. Also, if there is a long delay before the next expected bolus, there is some chance that the bolus will not actually be delivered as expected.

In some embodiments of the invention of the type described above, the method includes, as part of the estimating priming volume program, determining that the secondary reservoir should not be refilled if the estimated priming volume is below a threshold priming volume, the estimated length of time until the next next on-demand bolus delivery is not exceeds the bolus timeout threshold, but the estimated amount of the next next requested bolus does not exceed the bolus volume threshold. As explained above, in a situation where the Estimated Prime Volume is below the Threshold Prime Volume and the estimated time until the next next Prompt Bolus is less than the Bolus Timeout Threshold, the secondary reservoir should be refilled at all. However, in an embodiment of the type discussed herein, the secondary reservoir is not refilled under these conditions if the estimated volume of the next next on-demand bolus does not exceed the threshold bolus volume. In an exemplary embodiment of the invention, the threshold bolus volume corresponds to the fill level of the secondary reservoir at the current time, including a safety margin if necessary. The margin of safety may at least correspond to the amount of back-dosing. In such an embodiment, the secondary reservoir is not refilled at the current time if it can be expected that the refill volume without pre-refilling is sufficient to deliver the next next on-demand bolus.

In some embodiments of the invention, the priming volume estimation program includes determining a first estimated priming volume by subtracting from the first priming volume of the first secondary reservoir at the current time the first estimated infusion volume representing the estimate, i. the result of an estimate of the amount of drug estimated to be infused between the current time point and a future estimated time point. In the case of a combined basal-bolus infusion, as explained below, when a drug, such as insulin for diabetes, is infused in both basal and bolus modes, the first estimated infusion volume may include a separate estimate of the basal infusion volume and a separate estimate of bolus infusion volume. In addition, the estimated infusion volume may be a composite estimated infusion volume reflecting the total or cumulative infusion, both bolus and basal. The same principles may similarly apply, in addition or alternatively, to a second secondary reservoir or any other secondary reservoir.

In some embodiments, the method includes calculating a set of first baseline estimated infusion volumes, each of which is an estimate of the amount of the first drug estimated to be infused over an estimated time interval beginning at a corresponding predetermined time of day, and storing the set of first baseline estimated infusion volumes in memory. . For such embodiments of the invention, the priming volume estimation program includes retrieving from memory the first base estimated infusion volume related to the time of day that corresponds to the current time.

In some embodiments, the method includes calculating a set of second baseline estimated infusion volumes, each of which is an estimate of the amount of a second drug estimated to be infused over an estimated time interval beginning at a corresponding predetermined time of day, and storing the set of second baseline estimated infusion volumes in memory. . For such embodiments of the invention, the priming volume estimation program includes retrieving from memory a second base estimated infusion volume related to the time of day that corresponds to the current point in time.

The retrieved baseline estimated infusion volume at the current time is used as the estimated infusion volume for prediction. For example, baseline estimated infusion volumes can be calculated at ten minute time intervals, e.g. for 0:00 (midnight), 0:10, 0:20, 0:30, 0:40, 0:50, 1.00 (1 am) , and so on. The times of the day at which the charging volume estimation program is executed are also referred to as estimated times of day in the following.

The baseline estimated infusion volumes are preferably pre-calculated and do not need to be computed by a periodically executed priming volume estimation program, the steps of determining and storing a set of baseline estimated infusion volumes forming the infusion estimation program. However, such an infusion estimation program may be performed from time to time or periodically, resulting in an update or recalculation of a set of baseline estimated infusion volumes. Typically, the baseline estimated infusion volumes take into account both basal and bolus infusions, with both basal and bolus regimens injecting a drug into the body, such as insulin in the treatment of diabetes. Each base estimated infusion volume from the set of base estimated infusion volumes may include a base estimated basal infusion volume and/or a base estimated bolus volume, as discussed in more detail below. However, as an alternative, the estimated infusion volume may be explicitly calculated within the priming volume estimation program each time the priming volume estimation program is executed. The same principles regarding the calculation of baseline estimated infusion volumes may likewise be applied, in addition or alternatively, to a second secondary reservoir or any other secondary reservoir.

In some embodiments of the invention, the determination of the need to top up the first secondary tank, i.e. determining whether to top up the first secondary reservoir is based at least in part on the predetermined first basal infusion schedule of the first drug.

When conducting therapies involving essentially continuous infusion of the drug, such as NVI, basal infusion of the drug is usually performed in accordance with the basal regimen. The basal infusion regimen is usually set in advance and is variable over time, i.e. basal infusion rate changes as a function of time. Usually, but not necessarily, in NPVI, the basal infusion regimen is a cyclic daily (circadian) administration schedule having a period of 24 hours. In such a case, which is hereinafter taken as an example to illustrate the invention, unless otherwise stated, the rate of basal infusion is accordingly determined depending on the time of day. Typically, the parameters of the basal infusion regimen are stored in the memory of the outpatient infusion system, in particular the control unit of the outpatient infusion machine, by means of a lookup table containing the basal infusion rate for certain time intervals, for example, for every hour of the day or every half hour of the day. It should also be noted that in practice, basal infusion is often not carried out continuously in the strict sense of the word, but in incremental doses with a fixed time interval between successive incremental doses of, for example, 3 minutes or 6 minutes. As an alternative to such a schedule, an incremental dose is fixed, for example, equal to 0.05 IU, 0.1 IU or 0.2 IU, and the time interval between successive doses varies in accordance with the basal infusion regimen. In yet another embodiment, a combination or combination of the two approaches discussed above is used. In addition, the basal infusion regimen can be stored in memory not as a lookup table, but as a mathematical function or parameters of such a function. While the user is generally given the option to temporarily pause or adjust the basal infusion as explained below, typically the basal delivery is performed by the ambulatory infusion system autonomously under the control of the ambulatory infusion machine control unit without the need for user interaction.

Determining an estimated priming volume based at least in part on a given basal infusion schedule includes determining the total basal infusion volume (volume) for the estimated time interval and subtracting that value from the secondary reservoir priming volume at the current time. The total basal infusion value, determined in accordance with the given basal infusion regimen, serves as an estimate of the basal infusion volume.

Since the basal infusion regimen is usually predetermined, the estimated basal infusion volume may be pre-calculated within the infusion estimation program as mentioned above. In particular, for a given start time of day and a given end time of day, a base estimated basal infusion volume may be calculated by summing, or integrating, the basal infusion volume according to the basal infusion schedule for the time interval between the start time of day and the end time of day. Meanwhile, calculating the estimated fill volume within the fill estimate program simply involves retrieving the base estimated basal infusion volume from memory at the current time and subtracting that value from the secondary reservoir fill volume at the current time. The calculation of baseline estimated basal infusion volumes can be performed, for example, each time the basal infusion mode is reprogrammed or each time the secondary reservoir is changed. It may be performed, in particular, in conjunction with the calculation of estimated bolus volumes, as explained below.

Presetting a basal infusion regimen means that the parameters of this regimen are usually stored in memory and therefore known in advance, as explained above. Usually, the basal infusion regimen is programmed according to the individual needs of the patient, or user, by the healthcare professional, and in some cases, when required, by the patient himself, and can be reprogrammed if necessary. Since the basal infusion is usually pre-set, the secondary reservoir fill prediction is correct, provided that the basal infusion actually proceeds as planned. As discussed in more detail below, this is not always the case.

In some embodiments of the invention, when determining the estimated filling volume, time corrections (modifications) of a given basal infusion regimen in the time interval between the current time point and the estimated time point are taken into account. Temporary adjustment of the basal infusion regimen can usually be undertaken spontaneously and at any time. Modern ambulatory infusion systems allow the user to temporarily adjust the basal infusion for a time interval, typically several hours, such as up to 12 hours or 24 hours, to accommodate special or exceptional circumstances such as sports or illness, and/or to temporarily suspend basal infusion. infusion. The basal infusion regimen temporarily introduced as a result of this correction is called the adjusted basal infusion regimen. Depending on the specific ambulatory infusion system, the adjusted basal infusion rate may be determined by proportionally scaling the basal infusion determined by the preset rate using a scaling factor that can be greater than one (in the case of an increase in basal infusion) or less than one (in the case of a decrease in basal infusion). infusion). In yet another embodiment, an adjusted basal infusion rate is defined as a basal rate at a constant infusion rate, temporarily replacing a predetermined basal infusion rate. Accounting for temporal corrections of the given basal infusion rate is achieved by correcting the given basal infusion rate or replacing it with an adjusted basal infusion rate for the estimated time interval or part of the estimated time interval when the correction is active. As mentioned above, programming (applying) or ending the time offset can serve as a trigger event that initiates the immediate execution of the fill volume estimation program, usually asynchronous to the overall schedule. The same is true for time corrections based on measured and/or predicted blood glucose values, as explained below.

In some embodiments, the measured and/or predicted blood glucose level is taken into account when implementing the method for predicting the estimated filling volume. This kind of embodiment of the invention is advantageous, in particular in the context of NVI. The ambulatory infusion system may include a component that provides a substantially continuous measurement of glucose concentration in body fluid or tissue, or may be configured to be connected to such a component for functional interaction with it. The outpatient infusion system can also be configured to make temporary adjustments to the basal infusion schedule according to the measured blood glucose value. In particular, the ambulatory infusion system may be configured to temporarily suspend basal infusion or reduce basal infusion according to a predetermined threshold in the event of low blood glucose levels. The result of such a correction in the basal infusion regimen is the operation of the infusion system in the adjusted basal infusion regimen, which was discussed above in the context of user-initiated corrections and can be considered in a similar way.

It should be understood that the time correction of the basal infusion regimen can usually last for a predetermined time programmed by the user, for example, a time selected in accordance with the planned physical activity, in particular sports. In embodiments where the estimated basal volume is typically pre-calculated as explained above, appropriately adjusted estimated basal volumes considering temporal correction may be computed at the start of the correction for the entire time span spanning future estimated times that the programmed correction will affect. . The corrected estimated basal infusion volumes for the affected time period can then be used in volume estimation.

However, as an alternative to a time-fixed correction, the length of the time correction may not be known in advance. This may be the case, in particular, when time correction is applied to signals from a component for continuous glucose measurement, as explained above. In this case, accounting for temporary corrections of a given basal infusion regimen can be achieved by determining, within the framework of the volume estimation program, whether the correction is currently active, and in the case of an affirmative answer, by using a correspondingly adjusted estimated basal infusion volume. In such an embodiment of the invention, the corrected estimated basal infusion volume is accordingly calculated at the current time, and not at the beginning of the correction interval. It should be noted that this kind of embodiment of the invention can also be used even if the duration of the correction is known. It should also be noted that normally an active correction can be canceled by the user. In this case, operation is preferably continued based on the predetermined basal infusion regimen.

In some embodiments of the invention, determining the need to top up the first secondary tank, i.e. determining whether to top up the first secondary reservoir is based at least in part on the estimated infusion volume (value) of the first drug bolus on demand between the current time and a future estimated time.

In the context of NVI, boluses of insulin, considered as an example of the first drug, are infused on demand to compensate for food intake, in particular carbohydrates, and also to correct undesirably high blood glucose values. Unlike a basal infusion, on-demand boluses can typically be initiated at any time by a specific user command, and such a bolus can be of variable size. Boluses on demand are typically administered within a relatively short time interval, typically ranging from a few seconds or fractions of a second to several minutes. To handle special situations such as eating a certain type of food, the on-demand bolus can also be given over a longer period of time, such as an hour or up to several hours, and/or can be a combination of one serving delivered substantially all at once. , and another serving administered over a longer period of time. Typical modern infusion machines used, for example, in NVI, usually offer a number of predefined bolus profiles (called, for example, a multi-wave bolus, an extended bolus, etc.), from which the user can select the profile that he needs in a particular situation.

Due to the inherent variability in size and size of boluses, predicting on-demand boluses is not as straightforward as predicting a basal infusion. However, in practical applied scenarios, for example, with NVI, there is still a certain amount of predictability. Because meals often occur at approximately the same times of day on different days, and because the food taken is often similar in volume and/or composition, on-demand boluses also tend to be similar to each other.

Determining an estimated priming volume based at least in part on an estimated value, or estimated infusion volume, of an on-demand bolus delivered may include determining an estimated (expected) total bolus volume delivered from a start time to an end time, and subtracting that volume from the filling volume of the secondary tank at the current time. As explained above in the context of a basal infusion, the time difference between the end time and the start time corresponds to the estimated time interval, and the end time is defined as the start time plus the estimated time interval. The estimated bolus infusion value serves as an estimated bolus volume for the bolus infusion delivered between the start time and the end time.

Similar to the estimated basal volume, the estimated bolus volume can be determined online at the moment or can be preset. In the second case, the steps currently being performed within the Prime Volume Estimation program are to retrieve the corresponding estimated bolus volume from memory and subtract it from the secondary reservoir prime volume at the current time.

Accounting for basal infusion, bolus infusion, and basal-bolus combination infusion is described above with emphasis on insulin infusion as the first drug, in which case the estimated bolus volume is the first estimated bolus volume and the estimated basal volume is the first estimated bolus volume. basal infusion volume. However, the same principles can be similarly applied to all drugs administered by basal infusion, eg second drug, third drug, etc., i.e. to any other medicinal product, when applicable.

In some embodiments of the invention, the prediction of the estimated filling volume is based at least in part on the history of the actual infusion in the past. The history of the actual infusion in the past is usually stored in the corresponding memory of the ambulatory infusion system, in particular the control unit of the ambulatory infusion machine. In addition, the history of the actual infusion in the past may be stored in the memory of a structurally separate remote device, such as a remote controller or a diabetes management device. The remote device and the control unit of the ambulatory infusion machine are typically configured to interact and exchange data via appropriate communication interfaces.

In some embodiments of the invention, the history of the actual infusion in the past is stored in the memory of one or more external devices in one or more remote locations, such as on a server or in the cloud, and transferred directly to the ambulatory infusion machine and / or to a remote controller or device as necessary. diabetes management via internet connection. In addition, the estimated infusion volumes, in particular the baseline estimated infusion volumes, may be pre-calculated and stored in the memory of such an external device or external devices.

In some embodiments, within the aforementioned history, the time and volume of each drug infusion, whether it is an on-demand bolus infusion or an incremental basal infusion, is stored along with a time stamp (the time stamp provides information about the time of day, and preferably and about the date). Since, however, basal drug administration is typically delivered according to a given basal infusion schedule and at specified times (e.g., every three minutes starting at 0:00 a.m.), past basal infusion history can be determined from basal infusion parameters assuming no events occur. that have a temporary effect on basal infusion.

The on-demand bolus history is stored as a list of timestamps and bolus amounts (t _i , B _i ), where i is the index value, t _i is the time stamp of a past bolus infusion, and B _i is the corresponding bolus amount. If the ambulatory infusion set offers different types of on-demand boluses as explained above, other meaningful data such as the bolus type identifier, volumes delivered immediately and over a longer period of time, and the period of time during which infusion was performed.

The use of past actual infusion history is particularly advantageous for determining an estimated bolus infusion volume, as explained above. An estimated bolus volume for a given start time as time of day can be obtained by statistically estimating past actual bolus infusions over an interval starting at the start time and ending at the end time, i.e. at a point in time determined by the sum of the initial point in time and the estimated time. The statistical evaluation may include data for one day or, preferably, for several days. When determining the estimated volume of the bolus infusion, the last previous day or, preferably, several previous days, for example, 7, 14 or 30 days, may be taken into account. When determining an estimated bolus volume, it may be calculated directly from past bolus volumes or may be calculated by modifying a previously calculated estimate accordingly. In some embodiments of the invention, the data for all the past days used for the calculation are weighted equally. However, in alternative embodiments of the invention, data for different days are weighted differently. In particular, 24-hour data from the recent past can be considered to have a higher weight than 24-hour data from the more recent past.

The estimated bolus volume can be a given percentile of bolus volumes for the past day under consideration, such as the 80% percentile, or the 90% percentile, or the 100% percentile, where the 100% percentile corresponds to the maximum bolus volume for the past day under consideration and for the interval time from the start time to the end time. It should be noted that other statistical metrics known in the art may be used, such as those based on means and variance.

In some embodiments of the invention, when determining the estimated volume of the bolus infusion based on the history of the actual infusion in the past several days, a continuous sequence of past days is taken into account. However, as an alternative, only selected days can be taken into account. For example, estimated bolus volumes can be calculated separately for the entire day or week, or separately for weekdays and weekends. Such an embodiment of the invention may be advantageous if substantially different typical bolus infusion schedules are used for different days. In other embodiments of the invention, it may be possible for the user to enter a command to exclude specific days from the calculation, for example, days on which illness, travel, or generally exceptional circumstances occurred. Such an embodiment of the invention is particularly advantageous if only a small number of days of data are used in the calculation, whereby the infusion history for each day has a significant influence on the result of the calculation.

If the estimated bolus volume is not calculated online each time the Prime Volume Estimation program is executed, i.e. at the current time, it can be calculated, for example, once a day, once a week or when replacing the secondary tank.

It should be noted that similarly to calculating the estimated bolus infusion volume separately for different days, the estimated basal infusion volumes can also be calculated separately for different days. Typical current ambulatory infusion systems allow different basal infusion schedules to be set between which the user can switch or which the system can switch automatically to account for, for example, differences between day shift and night shift and/or between weekdays and weekends. Estimated basal infusion volumes can be determined separately for different basal infusion regimens.

As an alternative to determining the estimated bolus volume based on past history of actual infusion as explained above, the estimated bolus volume may be pre-calculated based on, for example, a diabetic meal plan, and may be stored in the ambulatory infusion system memory, for example, via a reference time-of-day tables at which the estimated bolus volume is determined, said individual times of day serving as starting points in time.

In yet another embodiment, a combination of the two approaches is contemplated, with estimated bolus volumes pre-set, for example, based on a meal plan, when setting up or initializing the ambulatory infusion machine after delivery to the user, or in the event of a fundamental change in the meal plan. Thereafter, the estimated volumes are changed or adjusted based on the history of the actual infusion in the past.

In embodiments involving calculating a set of baseline estimated basal infusion volumes for given estimated times of day, the set of baseline estimated basal infusion volumes may include an estimated basal infusion volume for each estimated time of day, such as for 0:00, 0:10, 0:20 and so on.

In embodiments of the invention that calculate a set of baseline estimated bolus volumes for given estimated times of day, as explained above, the estimated bolus volume may be calculated for each of the estimated times of day, for example, for 0:00, 0:10, 0:20 and so on, as for the basal infusion.

Accordingly, the set of pre-computed estimated basal infusion volumes can be represented by a table or list containing(s) triplets of values, each containing an estimated time of day, T _j , a corresponding pre-computed estimated basal infusion volume b ^* _j , and a corresponding pre-computed estimated basal infusion volume bolus infusion B ^* _j , where j is the index.

Since, however, on-demand bolus infusions are typically performed at approximately the same times of day (corresponding to mealtimes), albeit with some variability, the method may include determining typical times of day based on a history of actual bolus infusions in the past. bolus delivery and corresponding typical bolus volumes. Typical bolus times of day τ _j and typical bolus volumes B ^* _j can be determined from the history of actual bolus infusions in the past using a statistical or data dependency algorithm, which is per se known in the art. A set of typical times of day for bolus delivery and corresponding typical bolus volumes may be stored in memory as a list of pairs of values (τ _j , V ^* _j ), which for a typical day may contain, for example, three to five entries (corresponding to the number of meals/snacks ). Only those typical bolus volumes B ^* _j that are between the current time and a future estimated time, as indicated by the corresponding typical time of day bolus delivery τ _j , can be considered when executing the priming volume estimate program at the current time.

In some embodiments of the invention, including determining an estimated fill volume based at least in part on an estimated value, or estimated infusion volume, of a prompted bolus, the method may include ignoring selected past boluses. Thus, on-demand boluses to lower an elevated blood glucose value may be excluded from the evaluation process, since such boluses are given only sporadically and usually do not follow a predetermined pattern. To this end, along with the bolus volume and time stamp, as explained above, a corresponding marker can be stored in the history. Similarly, a bolus may be flagged as otherwise exceptional if necessary, and may also be ignored in the calculation, or excluded from the calculation.

In exemplary embodiments of the invention, both the estimated (expected) basal infusion and the estimated (expected) bolus infusion are accounted for by subtracting the respective infusions from the priming volume at the current time. At the same time, the current determination of the estimated volume of refilling of the secondary reservoir at the future estimated time includes subtracting the estimated basal infusion volume and the estimated bolus infusion volume from the current filling volume at the current time.

Accounting for past actual infusion history and calculation of estimated infusion volumes is described primarily in terms of basal and bolus infusions of insulin as first drug. For the case of glucagon infusion as a second drug, the same general principles may apply. However, infusion of glucagon as a second drug may be limited to a bolus infusion. In addition, the same principles may be applied, as appropriate, to the third, fourth and any other medicinal product.

In some embodiments of the invention, the fill volume estimate program includes determining that the second secondary reservoir should be topped up if the second drug infusion is expected to occur between the current time point and a future estimated time point and before the next next infusion of the on-demand bolus. first drug. This kind of embodiment is particularly advantageous in applications where the first drug is infused most of the time and generally on a basal basis, while the second drug is only occasionally infused as on-demand boluses. This is a typical case for combined infusion of insulin and glucagon, where insulin is considered as the first drug and glucagon as the second drug. In addition, this kind of embodiment of the invention may be suitable for use in the arrangement discussed above with a common secondary tank. In yet another embodiment of the invention, the refill volume estimation program includes determining that the second secondary reservoir should be refilled if the second drug infusion is expected to occur between the current time point and a future estimated time point and before the next next first drug infusion. .

In yet another aspect, the above general task is performed in a refueling scheduling node. The refueling time calculation unit is configured to implement a secondary tank refueling scheduling method according to any embodiment of the invention described above and/or described below. The refueling planning unit can be implemented or built on the basis of a microcomputer and/or a microcontroller. Although the computer-implemented embodiment is hereinafter taken as an example illustrating the possibilities of carrying out the invention, the use of such computer means is not essential. The refueling scheduling unit capable of implementing the method of the invention can also be implemented, in whole or in part, by other types of circuitry and can be built, for example, based on an application-specific integrated circuit (ASIC).

In yet another aspect, the above general task is performed in the control unit of the ambulatory infusion machine. The control unit of the outpatient infusion apparatus is configured to control the operation of the outpatient infusion apparatus. The control unit of the ambulatory infusion apparatus comprises a first hydraulic valve control unit configured to control actuation of the first hydraulic valve drive actuator to switch the first hydraulic valve between a filling state and an alternative supply state. The control unit of the ambulatory infusion machine also includes a second valve control unit configured to control actuation of the second valve drive actuator to switch the second valve between a filling state and an alternative supply state.

The control unit of the outpatient infusion apparatus also contains a control unit for the actuator of the drive of the first secondary reservoir, configured to control the operation of the actuator of the drive of the first secondary reservoir in the filling mode to increase the volume of the first secondary reservoir filled with liquid in the filling mode, as well as to control the operation of the actuator of the drive of the first secondary tank in the alternative fill mode supply mode to reduce the volume of the first secondary tank filled with liquid in the supply mode. The control unit of the outpatient infusion apparatus also contains a control unit for the actuator of the drive of the second secondary reservoir, configured to control the operation of the actuator of the drive of the second secondary reservoir in the refueling mode to increase the volume of the second secondary reservoir filled with liquid in the priming mode, as well as to control the operation of the actuator of the second secondary reservoir secondary tank in the alternative fill mode supply mode to reduce the liquid-filled volume of the second secondary tank in the supply mode.

The ambulatory infusion machine control unit also includes a refueling scheduling unit according to any of the embodiments of the invention discussed above and/or discussed below. The refueling planning unit is configured to operate in parallel with the operation of the first secondary tank drive actuator control unit and the second secondary tank drive actuator control unit in the feeding mode.

The control unit of the ambulatory infusion machine is also configured such that, upon determining that the first secondary reservoir needs to be refilled, it controls the execution of the first refilling procedure of the secondary reservoir. The first procedure for refilling the secondary reservoir includes the sequence of the following steps: (i) actuating the first valve actuator to switch the first valve to a prime state; (ii) actuating an actuator to drive the first secondary reservoir to increase the liquid-filled volume of the first secondary reservoir; (iii) actuating the first spool valve actuator to switch the first spool valve to a feed state. The control unit of the ambulatory infusion machine is also configured such that, upon determining that the second secondary reservoir is to be refilled, it controls the execution of a second refilling procedure of the secondary reservoir, which includes the sequence of the following actions: switching the second hydraulic valve to the filling state; (II) actuating an actuator to drive the second secondary reservoir to increase the liquid-filled volume of the second secondary reservoir; (III) actuating the second hydraulic valve actuator to switch the second hydraulic valve to a feed state.

The ambulatory infusion set control unit in this embodiment is particularly suitable for use in the context of ambulatory infusion sets with first and second secondary reservoirs physically separate from each other, the first secondary reservoir communicating only with the first primary reservoir and the second secondary reservoir communicating only with second secondary tank. Further, in this kind of outpatient infusion apparatus, the first valve actuator and the second valve actuator are physically separate, with the first valve actuator connected to the first valve, and the second valve actuator separately connected to the second valve. Furthermore, in this kind of ambulatory infusion machine, the first secondary reservoir actuator and the second secondary reservoir actuator are physically separate, wherein the first secondary reservoir actuator is connected to and controls the volume of the first secondary reservoir to be filled with liquid, and the second secondary reservoir actuator is of the secondary reservoir is separately connected to the second secondary reservoir and controls its liquid-filled volume. Due to this separation, the switching of the first and second control valves generally takes place independently of each other. Similarly, the liquid-filled volume of the first and second secondary tanks can be increased or decreased independently of each other.

Connection to the patient may be provided through a common infusion site interface (e.g., tubing), through completely separate infusion site interfaces for the first and second drugs, or through an infusion site (tube) interface with separate fluid paths (lumen) for the first and second drugs.

In yet another aspect, the above general problem is solved in another embodiment of the control unit of the ambulatory infusion machine. The control unit of the outpatient infusion apparatus is configured to control the operation of the outpatient infusion apparatus. The control unit of the outpatient infusion machine comprises a valve control unit configured to control actuation of the valve drive actuator to switch the valve between the first filling state, an alternative second filling state and an alternative delivery state.

In such an embodiment, the ambulatory infusion machine control unit also includes a secondary reservoir actuator control assembly. The secondary reservoir drive actuator control unit is configured to control the operation of the secondary reservoir drive actuator in the refueling mode to increase the volume of the common secondary reservoir filled with liquid in the priming mode. The secondary reservoir actuator control unit is also configured to control the operation of the secondary reservoir actuator in the alternative fill mode supply mode to reduce the liquid-filled volume of the common secondary reservoir in the supply mode.

In such an embodiment, the ambulatory infusion machine control unit also includes a refueling scheduling unit according to any of the embodiments of the invention discussed above and/or discussed below. The refueling planning unit is configured to operate in parallel with the operation of the secondary reservoir drive actuator control unit in the supply mode.

In such an embodiment, the control unit of the ambulatory infusion machine is also configured such that, upon determining that the first secondary reservoir is to be refilled, it controls the execution of the first refilling procedure of the secondary reservoir, which includes the sequence of the following actions: (ia) actuating the actuator actuator a valve for switching the valve to the first state of filling; (iia) actuating the secondary reservoir actuator to increase the liquid-filled volume of the common secondary reservoir; (iiiia) actuating the spool valve actuator to switch the spool valve to a supply state.

In such an embodiment, the control unit of the ambulatory infusion machine is also configured such that, upon determining that the second secondary reservoir is to be refilled, it controls the execution of a second refilling procedure of the secondary reservoir, which includes the sequence of the following actions: (ib) actuating the actuator actuator a valve for switching the valve to the second state of filling; (iib) actuating the secondary reservoir actuator to increase the liquid-filled volume of the common secondary reservoir; (iiib) actuating the spool valve actuator to switch the spool valve to a supply state.

In the context of such an embodiment of the invention, the first secondary reservoir and the second secondary reservoir are virtual, and only one common secondary reservoir is physically present, as explained above. If the common secondary reservoir is filled with the first drug, it serves as the first secondary reservoir. If the common secondary reservoir is filled with a second drug, it serves as the second secondary reservoir.

Since there is only a common secondary reservoir, the connection to the interface of the infusion site is realized in this case via a common tubing or a common infusion cannula.

In a particular case of the ambulatory infusion machine control unit described above, the first refilling procedure of the secondary reservoir includes a first emptying sequence before step (ia), including steps (ia') of actuating the spool actuator to switch the spool valve to the second a charging state; and (iia') actuating the secondary reservoir actuator to reduce the liquid-filled volume of the common secondary reservoir to a minimum volume. In addition, the second refilling procedure of the secondary reservoir may include a second emptying sequence performed prior to step (ib) including steps (ib') actuating the valve actuator to switch the valve to the first state of filling and (iib') actuating actuating the actuating mechanism of the drive of the secondary reservoir to reduce the volume of the common secondary reservoir filled with liquid to the minimum volume.

Since the common secondary reservoir serves alternately as the first secondary reservoir and the second secondary reservoir, emptying the common secondary reservoir of one of the drugs is necessary before it is refilled or refilled with another drug. This is achieved by performing the first and second emptying sequences described above. The same principle may be applied, as appropriate, to the third, fourth primary reservoir, and in general to any number of primary reservoirs.

The control unit of the ambulatory infusion machine in this further embodiment is particularly suitable for use in the context of ambulatory infusion machines with a common secondary reservoir, which can alternately serve as the first secondary reservoir or the second secondary reservoir, as explained above. Further, in this kind of ambulatory infusion machine, the spool drive actuator is a common spool actuator that can switch the spool valve being the common spool valve between the first filling state, the second filling state, and the supply state. While the previously described embodiment is advantageous with respect to the functional and fluid separation of the components associated with the infusion of the first and second drugs, the second additional embodiment of the invention is advantageous in terms of cost and compactness, since it has a (usually disposable) secondary reservoir and a hydrodispenser, as well as the spool drive actuator and the secondary reservoir actuator are used together to prime and dispense both medicines. In another embodiment of the invention, there is a common secondary reservoir as discussed above, but its fluid connection to the patient is implemented through separate channels. In this case, the valve may have five different states, namely: the first filling state, in which the first primary reservoir communicates with the common secondary reservoir through the first inlet; a second alternative filling state in which the second primary reservoir is in communication with the common secondary reservoir through the second inlet; a first alternative supply state in which the common secondary reservoir communicates with the first infusion site interface through the first outlet; a second, alternative, delivery state in which the common secondary reservoir communicates with a separate second infusion site interface through a second outlet. As in other embodiments of the invention, this option can be extended to a different number of drugs, for example, three or more drugs, each of which has a separate inlet and a separate outlet in a common secondary tank.

In some embodiments of the invention, the primary reservoirs are a cartridge, usually but not necessarily cylindrical and usually made of glass or plastic approved for medical use, in the body of which there is a tight sliding fit of a piston that is moved inside the cartridge body by emptying the primary tank. It is known that the plunger of such a drug cartridge, usually a rubber plunger, if left undisturbed or moved for a long time, tends to stick in place, after which a considerable pulling force is required to move it. In the context of the architecture discussed here, with primary reservoirs and one or more secondary reservoirs, the piston of the cartridge is only moved to top up the secondary reservoir. Depending on the user's individual need for treatment, the period of time between successive top-ups can be relatively long, typically a few hours, up to a day or longer. It should also be understood that when refilling the secondary reservoir, the drug is sucked from the primary reservoir and the cartridge piston moves only under the action of the retraction force resulting from the suction created by the impact of the drug on the front surface of the piston in contact with the liquid. Advantageously, no additional pushing force is applied to the cartridge piston, or only a small pushing force is applied. It should also be understood that the pulling force required to overcome piston sticking may be in the same range as the maximum suction force, or may even exceed this maximum force. Therefore, piston sticking is a problem.

In yet another aspect, it is a general object of the present invention to reduce, and preferably eliminate, the problem of cartridge piston sticking discussed above. In one aspect, this problem is solved in a method for preventing piston sticking. The method for preventing piston sticking includes, in a supply state, comparing the time elapsed after refilling the secondary reservoir with a predetermined back dosing time interval. The piston sticking prevention method also includes actuating the hydraulic distributor drive actuator to switch the hydraulic distributor from the supply state to the filling state, and then actuating the secondary reservoir actuator to reduce the volume of the secondary reservoir filled with liquid by a predetermined back-dosing amount, and then actuate the spool valve actuator to switch the spool valve back from the filling state to the supply state. In yet another aspect, the problem of preventing cartridge piston sticking is addressed in an ambulatory infusion machine control unit configured to implement a piston sticking prevention method.

By reducing the liquid-filled volume of the secondary reservoir, the amount of drug corresponding to the back-dosing volume is displaced from the secondary reservoir into the primary reservoir. In this case, the displaced drug creates a pushing force acting respectively on the piston of the cartridge, as a result of which the sticking friction and the force holding the piston in place are overcome. It should be noted that no infusion of the drug into the patient's body occurs during back dosing. The back-dosing volume is relatively small and may be, for example, in the range from 1 IU to 5 IU. Preferably, the back-dosing time interval is somewhat shorter than the time interval after which sticking of the piston can be expected, and in one embodiment of the invention, the back-dosing time interval can be, for example, 12 hours.

The piston sticking prevention method may be performed intermittently or continuously, in parallel with and independently of the refueling scheduling method. However, in alternative embodiments of the invention, it may be performed in coordination with the refueling scheduling method. In particular, it can be executed if it is determined that the secondary tank should not be topped up at the current time.

It should be noted that the described method for preventing piston sticking is in principle independent and different from the refueling scheduling method and, if necessary, can be implemented and can be performed without some or all of the steps of the refueling scheduling method. Similarly, the control unit of an ambulatory infusion machine may be configured to perform a method to prevent sticking of the piston, and such a control unit does not need to be able to perform some or all of the steps of the method of scheduling refilling.

The method discussed above for preventing piston sticking may be applied to some or all of the primary reservoirs, in particular to the first and second primary reservoirs.

In yet another aspect, the above general object is accomplished in a computer program product comprising a computer-readable storage medium in which computer program code is stored for causing a processor to execute a method according to any of the above and/or below embodiments of the invention and/or for the processor to operate as a node. scheduling refilling and/or as a control unit of an outpatient infusion machine according to any of the above and/or below discussed embodiment of the invention. The processor, in particular, can be implemented or formed by one or more microprocessors and/or microcontrollers.

In yet another aspect, this general task is performed in an outpatient infusion machine. The ambulatory infusion apparatus includes the control unit discussed above. The outpatient infusion apparatus also contains the first hydraulic distributor drive actuator, functionally connected with the first hydraulic distributor control unit, and the second hydraulic distributor drive actuator, functionally connected with the second hydraulic distributor control unit. The outpatient infusion apparatus also comprises a first secondary reservoir drive actuator operably connected to the first secondary reservoir drive actuator control unit, and a second secondary reservoir drive actuator operably connected to the second secondary reservoir drive actuator control unit. Valve actuators and secondary reservoir actuators are typically electrical actuators such as rotary actuators such as DC motors, brushless DC motors or stepper motors. Other types of electrical actuators can also be used, in particular shape memory alloy actuators, which can be used as hydraulic control actuators. The actuating mechanisms of the hydraulic distributor drive are made in such a way that they can be connected in a detachable way with the corresponding hydraulic distributors and interact with them. The actuator for driving each secondary reservoir is configured to be releasably connected to and cooperating with a piston located in the metering cylinder as explained below, the piston and the metering cylinder forming a metering pump. The dosing pump and the hydraulic distributor together form a dosing device and are structurally made in one piece. In addition, the metering cylinder and its piston form a secondary reservoir having a controlled variable volume.

Yet another type of ambulatory infusion machine has one spool actuator and a secondary reservoir actuator configured to connect to a common secondary reservoir as explained above and further described below.

The secondary reservoir drive actuator or secondary reservoir actuators of the ambulatory infusion machine, as well as the corresponding control units of the secondary reservoir actuators are preferably configured to increase and/or decrease (change) the volume of the secondary reservoir or secondary reservoirs by dosed, i.e. in a volumetrically controlled manner, in particular with the possibility of reducing the volume filled with liquid in incremental steps of a predetermined volume over a long period of time.

In general, the method of the present invention, in any embodiment disclosed herein, may be carried out by means of a corresponding embodiment of a refueling scheduling unit, an ambulatory infusion machine, an ambulatory infusion machine control unit, and/or a computer program product, also respectively disclosed in the description. Likewise, refueling scheduling units, ambulatory infusion machine controllers, ambulatory infusion machines, and computer software products of the embodiments disclosed herein can be used to implement a corresponding embodiment of the method of the invention, also suitably disclosed herein.

Brief description of the drawings

In FIG. 1 is a simplified functional diagram showing the main components of an ambulatory infusion system.

In FIG. 2 shows an algorithm for implementing the present invention.

In FIG. 3 shows another algorithm related to the refueling scheduling method according to the invention.

EXAMPLES OF CARRYING OUT THE INVENTION

In FIG. 1 shows a dispenser 100, an ambulatory infusion machine 200, as well as a first drug reservoir 300 and a second drug reservoir 300'. In the example considered to illustrate the possibilities of carrying out the invention, the first drug reservoir 300 contains insulin and the second drug reservoir 300' contains glucagon, both in the form of liquid preparations. It should be noted that the diagram shows only structural and functional units that are relevant in the context of the present invention.

The dosing device 100 includes a dosing pump 110 having a dosing cylinder with a cavity and a piston (these elements are not separately indicated in the diagram), as described in the above section of the description, revealing the essence of the invention. In the proximal (closest to the hydraulic distributor) end wall of the metering cylinder, a channel is made that communicates the cavity of the cylinder with the hole 127a facing the pump. The metering device also includes a spool valve 120, which may alternatively be in a first charging state 120b, a second charging state 120b', or a feeding state 120a. During operation, the control valve 120 periodically switches between these states, as explained in more detail below. The first drug reservoir 300 communicates with the hydraulic valve 120 through the first filling port 127b, and the second drug reservoir 300' communicates with the hydraulic valve 120 through a second filling port 127b' different from the first filling port 127b. The patient 900 is connected to the valve 120 through the outlet 127 c and through the infusion site interface 890, which can optionally be integrated into the fluid line, such as through a catheter. The metering device 100 also includes a valve actuator slave 125 for switching the valve 120 between a first charging state 120b, a second charging state 120b', and a supply state 120a. Similarly, the metering device 100 includes a driven element 115 of the pump drive for linear movement of the piston of the pump 110 within the metering cylinder. In one embodiment of the invention, the maximum fill volume of the dosing cylinder is 7 IU (international units) of a liquid insulin preparation with a concentration of U100, which corresponds to 70 microliters.

With regard to the valve 120, it should also be noted that in FIG. 1 shows only the states 120a, 120b, 120b' in which either one of the filling ports 127b, 127b' or the outlet port 127c communicates with the pump-facing port 127a. However, the valve may be in an optional intermediate state in which all orifices 127a, 127b, 127b', 127c may be blocked, resulting in the pump being locked.

The outpatient infusion apparatus includes a pump drive 217 connected to the pump drive drive element 215, and a valve drive 227 connected to the valve drive drive element 225. The pump drive 217 and the valve drive 227 are powered and controlled by the ambulatory infusion machine electronic control unit 250, typically based on one or more microcontrollers and/or microprocessors.

The metering cylinder and piston together form a common secondary reservoir, while the first drug reservoir 300 forms the first primary reservoir and the second drug reservoir 300' forms the second primary reservoir, as explained above in the summary section of the description. The first drug reservoir 300 and the second drug reservoir 300' may be in the form of a cylindrical cartridge with a sliding piston located therein, or may be wholly or partly a flexible reservoir such as a bag. In addition, the first drug reservoir 300 and the second drug reservoir 300' may be of the same or different design. Further, any of them may be supplied already charged at the factory or may be filled by the user. The ambulatory infusion machine control unit 250 also includes a secondary reservoir actuator control assembly (not shown separately in the diagram) that controls the operation of the pump actuator 217, in particular the secondary reservoir actuator. In addition, the control unit 250 of the ambulatory infusion machine contains a valve actuator control unit (not shown separately in the diagram) that controls the operation of the valve actuator 227, in particular the valve actuator. In accordance with the present invention, the control unit 250 of the ambulatory infusion machine also includes a refueling planning unit 251, the operation of which is explained in more detail below.

It should be noted that the drug reservoirs 300, 300' and the dispenser 100 are represented in the diagram as separate components from the ambulatory infusion machine 200. However, in an operative configuration, they may be mechanically connected to the ambulatory infusion machine 200 to form a single compact device and/or may be inserted into the appropriate compartments of the body of the ambulatory infusion apparatus, which is usually implemented. In addition, in some embodiments of the invention, the dispensing device 100 and one or both of the reservoirs 300, 300' drugs can be made in the form of a common unit.

Desirably, the ambulatory infusion set is in the form of a strap-on device designed to be attached directly to the body of the patient 900, such as on the abdomen, as is commonly known in the art, when in use. This has the advantage that the fluid-filled volume of the infusion site interface 890 is small and can preferably be ignored. If the fluid-filled volume of the infusion site interface is negligible, this is advantageous in terms of the necessary switching between insulin and glucagon infusion, or more generally between first and second drugs. If this liquid-filled volume is not negligible, it can be taken into account as explained below.

Next, FIG. 2 which illustrates an exemplary embodiment of the method according to the invention. The implementation of the method begins in step S1 when a user, such as a diabetic, is provided with a new outpatient infusion machine. The ambulatory infusion machine is designed to be used in combination with first and second primary reservoirs and a common secondary reservoir (referred to as a "secondary reservoir") as explained above. It should be noted that the implementation shown in FIG. 2, 3 methods is based on the use of a system comprising an ambulatory infusion machine 200 and a dispensing device 100 and its components shown in FIG. 1 and discussed above.

In the next parameter setting step S2, the ambulatory infusion machine is prepared and initialized for use by the user. This includes, in particular, the programming of a basal first drug regimen or several basal regimens designed for weekdays and weekends, for example, as explained above. In many current systems, the ambulatory infusion set includes, or is configured to connect to, a bolus recommender system. The bolus recommender system is designed to calculate and suggest to the user bolus volumes of drug, in particular insulin boluses, suitable to cover the amount of food consumed, in particular carbohydrates, and/or to reduce undesirably elevated blood glucose values. The bolus amount calculation is performed based on the amount of food, and possibly the type of food and/or blood glucose value, using a number of patient specific bolus advice parameters that are also set or programmed in step S2. If the ambulatory infusion set provided in step S1 is a replacement device for a previously used device, step S2 may include retrieving or retrieving one or more of the basal delivery schedules and bolus advice parameters from the memory of the previously used device, or from data file that stores these parameters.

In a subsequent service step S3, the dosing device with the secondary reservoir, as well as the first primary reservoir and the second primary reservoir, are inserted into the ambulatory infusion machine and connected to the infusion cannula directly or via an infusion tube. In addition, additional steps necessary in the context of replacing the dosing device and/or the secondary reservoir, such as pumping, are carried out. This assumes that both primary reservoirs and the dosing device with the secondary reservoir are usually replaced together with each other, for example after a period of time ranging from several days to several weeks, depending on the individual needs of the user. The dosing device and primary tanks can also be made as a single unit. However, as an alternative, they can be structurally separate and can also be replaced separately from each other. In addition, glucagon as the second drug can be infused in much smaller volumes compared to insulin as the first drug. Therefore, it may be possible to replace the first and second primary reservoirs independently of each other.

The next step S4 calculates baseline estimated infusion volumes for use during normal operation. The baseline estimated infusion volumes include a set of first baseline estimated infusion volumes for insulin and a set of second baseline estimated infusion volumes for glucagon. The set of first baseline estimated infusion volumes includes a set of baseline estimated basal infusion volumes and a set of baseline estimated bolus volumes. Since glucagon as the second drug is infused only as boluses, the set of second baseline estimated infusion volumes takes into account only the bolus infusion. For example, the estimated time interval is set as two hours, and for specific times of the day with an interval of 10 minutes, i.e. for 0:00 (midnight), 0:10, 0:20, 0:30, 0:40, 0:50, 1.00 (1 a.m.), etc., calculate the base bolus volume estimate and the base basal volume estimate for insulin, as well as the baseline estimated bolus volume for glucagon. A set of baseline estimated basal infusion volumes for insulin is calculated based on the basal infusion regimen. As an alternative to calculating from a programmed basal infusion schedule, estimated basal infusion volumes can be calculated from past actual basal insulin infusions stored in past infusion history memory. This approach has the advantage of also allowing for typical time corrections that have occurred in the past. A set of baseline estimated bolus infusion volumes for insulin is calculated based on a history of past actual bolus infusions stored in the appropriate memory of the ambulatory infusion machine itself and/or in an external device such as a remote controller or diabetes management device. For calculation, data is retrieved from said history memory (step S4'). For each time of day used as the starting point in time for which the calculation is performed, the corresponding estimated bolus infusion volume is calculated, for example, as an 80% percentile, as explained above in the disclosure section of the description. The calculation is performed, for example, on the basis of historical data for the past few days, in particular for the past three or seven days. Baseline estimated bolus volumes for glucagon are calculated according to the same principles as baseline estimated bolus volumes for insulin.

After steps S4, S4', routine drug infusion is performed. As a background process, the charging amount estimation procedure (steps S5, S5') is periodically and automatically performed, which will be explained in more detail below.

If during normal operation any of the primary tanks becomes empty, i.e. is emptied, the algorithm continues with the transition to step S6, where the infusion is stopped and an appropriate message is issued. From step S6, the algorithm returns to the service program S3. Preferably, one or more warnings are given well in advance of the actual emptying of the primary reservoir, which would allow the user to proceed to maintenance step S3 and replace the dispenser and primary reservoirs at their convenience.

Next, FIG. 3, which shows the flow of actions related to the planning (timing) of refueling, as well as another related action during normal operation of the ambulatory infusion machine.

At step S10, normal operation of the ambulatory infusion machine for infusion of insulin as the first drug, i. the ambulatory infusion set is operated for autonomous infusion, i. e. infusion administration in the body, insulin in the basal mode of administration, as well as infusion of additional boluses of insulin on demand.

In the next step S11, the current time is set as the time to perform the charge amount estimation. The next step S12 determines the estimated filling volume of the common secondary tank, which in this case serves as the first secondary tank.

In embodiments where sets of baseline estimated bolus volumes for insulin and glucagon and baseline estimated basal volumes for insulin infusion are precomputed, step S12 includes retrieving from memory the baseline estimated basal volume and baseline estimated bolus volumes associated with the current moment. time, and determining the estimated secondary reservoir fill volume by subtracting the baseline estimated basal infusion volume and the baseline estimated insulin bolus volume from the current secondary reservoir fill volume. In alternative embodiments of the invention, in which the base estimated infusion volumes are not pre-calculated, the estimated secondary reservoir fill volume can be calculated in step S12, as explained in the summary section of the description, using the current time as the initial time, and in as the end point of the current point in time plus the estimated time interval.

In the next step S13, it is determined if any insulin infusion time corrections are active. Data regarding such time correction can be retrieved (at step S5') from the device or device for continuous glucose level measurement and/or from the ambulatory infusion machine memory, which stores information about time corrections. If such a correction is active, step S13 further includes a corresponding change or update (updating) of the estimated filling volume of the secondary tank.

In the next step S13', it is determined whether a glucagon bolus infusion is expected in the estimated time interval between the current time point and the future time point, and depending on the result, the algorithm branches. If no glucagon bolus infusion is expected, the algorithm continues to step S14 as explained below.

If a glucagon bolus infusion is expected, the algorithm continues to step S101. In step S101, it is determined whether the glucagon bolus infusion is expected to occur before the next next insulin bolus infusion, or whether the glucagon bolus infusion is not expected to occur until the next next insulin infusion, and depending on the result, the algorithm branches. In yet another general implementation of step S13', it is determined whether the next infusion will be an insulin or glucagon infusion.

If it is determined in step S101 that the next next insulin infusion or insulin bolus infusion is expected before the actual time of glucagon infusion, the flow proceeds to step S14 again. Otherwise, the algorithm continues to step S102. In step S102, the second emptying sequence is first performed. During the second emptying sequence, the spool drive actuator is actuated to switch the spool valve to the first filling state, thereby communicating the metering cylinder as a common secondary reservoir with the first drug reservoir, after which the reservoir drive actuator is energized to reduce the liquid filled volume of the metering cylinder as a common secondary reservoir to a minimum volume. Thus, the dosing cylinder is emptied, displacing insulin from it. In embodiments where the fluid-filled volume of the infusion site interface 890 is not negligible, the second drain sequence may be provided prior to switching the valve from the supply state to the first prime state by increasing the liquid-filled volume of the secondary reservoir by the liquid-filled volume of the infusion site interface. performed by retracting the plunger in the metering cylinder and drawing the insulin present at the infusion site interface into the metering cylinder or secondary reservoir.

In the next step S103, the spool actuator is operated to switch the spool valve to the second filling state, thereby communicating the metering cylinder as a common secondary reservoir with the second drug reservoir containing glucagon. Further, in step S103, the secondary reservoir actuator is operated to increase the liquid filling volume of the metering cylinder as a secondary reservoir, thereby filling the metering cylinder with glucagon. Desirably, the amount of glucagon primed corresponds to the amount of glucagon calculated based on the estimated glucagon bolus infusion volume.

The next step S104 waits for the user to enter a specific command to infuse glucagon. Next, in step S104, when the user commands to infuse glucagon, the spool actuator is operated to switch the spool valve to the dispensing state, and then the secondary reservoir actuator is operated to reduce the filling volume of the metering cylinder as a secondary reservoir, followed by infusion. glucagon. Because the dosing cylinder has been primed with glucagon in advance, glucagon infusion can begin immediately when the appropriate command is entered, which is particularly effective. It should be noted that switching the spool valve to the supply state may alternatively be performed in step S103 after filling the metering cylinder with glucagon. At the end of the glucagon infusion, the dosing cylinder is empty; the liquid-filled volume of the secondary reservoir is minimal or zero, or at least negligible. The algorithm then returns to step S11 as explained above.

In embodiments of the invention in which the ambulatory infusion machine is operatively coupled to a continuous glucose monitoring sensor to operate as part of a closed loop feedback system, waiting for a specific command to infuse glucagon by the user may not be required.

In a practical implementation, the sequence of steps S102, S103 and S104, directly related to the infusion of glucagon as a second drug, may include a number of additional steps and branches of the algorithm, which for clarity and brevity in FIG. 3 are not shown. In particular, a situation may arise where a glucagon infusion that was expected based on the infusion history did not actually take place. In such a situation, the algorithm may involve expelling glucagon back into the second drug reservoir. In addition, a situation may arise where the user decides to administer glucagon, but as a bolus of a different volume than intended. If the actual bolus volume is less than expected, the dosing cylinder will not be empty at the end of the glucagon infusion. In this case, step S104 may include switching the spool valve to the second prime state and expelling the remaining glucagon back into the second drug reservoir. If the volume of the actual bolus given is greater than expected, the current prime volume can be delivered in the first dose, after which the dose cylinder primes with the remaining volume, which is then delivered to the body in the second dose, or the dose cylinder prime volume can be increased to the required volume first. , and glucagon infusion can be done in one go.

In embodiments where the fluid-filled volume of the infusion site interface 890 is not negligible, step S104 may include, after infusion of glucagon, increasing the fluid-filled volume of the dosing cylinder as a secondary reservoir by the fluid-filled volume of the infusion site interface, performed by retracting piston in the metering cylinder and accompanied by suction of the glucagon present at the interface of the infusion site into the metering cylinder or secondary reservoir, after which the spool valve is switched to the second prime state and expel the glucagon into the reservoir of the second drug.

In step S14, the algorithm forks depending on the estimated amount of insulin as the first drug.

If the estimated refueling amount at the future estimated time is positive, the flow continues with step S15. In this case, it is accordingly assumed that during the estimated time interval the secondary reservoir is not emptied. In this case, optional steps S15, S16, S17 are performed.

In step S15, the time elapsed since the last replenishment of the secondary tank is estimated by comparing it with a predetermined back-dosing time interval of, for example, 12 hours, and depending on the result of the comparison, the algorithm branches. If refueling was performed within the back-dosing time interval, the flow continues to step S16 where no action is required. Otherwise, in step S17, the reverse dosing sequence is performed.

During the reverse dosing sequence, the spool actuator is actuated to switch from the supply state to the charge state. The secondary reservoir actuator is then actuated while in the supply mode to reduce the liquid-filled volume of the secondary reservoir by a small amount of back-dosing. Thereafter, the spool actuator is actuated to switch back from the charging state to the supply state. By reducing the liquid-filled volume of the secondary reservoir, an amount of drug corresponding to the back-dosing volume is displaced from the secondary reservoir into the primary reservoir. For the case where the primary reservoir is a glass or plastic cartridge with a piston installed in the glass cartridge body in a close movable fit, this is due to the forced movement of the cartridge piston inside the cartridge body against the direction of its normal movement to empty the cartridge, and the forced movement of the cartridge piston is caused pushing force applied to the piston of the drug cartridge. In this way, the force of breakaway, or seizing, between the piston and the cartridge body is overcome, which usually increases if the piston has not been moved for a certain time. Such breakaway force can be significant and can substantially exceed the retraction force hydraulically applied to the piston by drawing fluid from the cartridge. It should be noted that the method steps associated with reverse dosing can also be implemented independently as a way to prevent piston sticking.

After step S16 or step S17, the algorithm continues to step S22 as explained below.

In alternative embodiments where the breakaway force is particularly low, or in embodiments where another type of primary reservoir is used, such as a bag, steps S15, S16, and S17 may not be necessary.

If the estimated filling amount at the end has a negative value, the flow after step S14 continues to step S18. At step S18, it is determined whether the next next bolus infusion is expected to be performed only after the time interval determined by the bolus timeout threshold has elapsed from the current time point. The bolus timeout threshold in this example could be 20 minutes, but higher or lower values could also be used. In the case of an affirmative answer, the algorithm continues with the transition to step S19, which establishes that there is no need to perform any actions at the moment. Otherwise, the algorithm proceeds to step S20, where it is determined whether the estimated (expected) volume of the next next bolus exceeds the threshold bolus volume. It is advisable that the threshold volume of the bolus is set dynamically according to the current filling volume of the secondary reservoir. In the case of a negative answer, the algorithm also continues with the transition to step S19. Otherwise, the algorithm continues to step S21, which initiates refilling of the secondary reservoir with insulin.

After performing step S19 or step S21, the flow continues to step S22. At step S22, the execution of the algorithm is suspended until the current time corresponds to the time for the next execution of the filling volume estimation program. In the next step S23, it is determined whether the primary reservoir is empty. If the answer is yes, the algorithm continues with the transition to step S6, where the algorithm ends and the program for replacing the primary reservoir and, if necessary, the dosing device with the secondary reservoir, is initiated. In the case of a negative answer, the algorithm returns to step S11 for the next execution of the filling volume estimation program.

It should be noted that, like steps S15, S16, S17, steps S18, S19, S20 are optional. Performing steps S18, S19 avoids refueling in situations where refueling would have to be initiated, but in reality may be unnecessary due to typical variability in drug infusion, as explained in the disclosure section of the description. The additional step S20 avoids a current refuel in situations where the next expected on-demand bolus can still be delivered without prior refueling.

Claims (31)

1. A method for planning the refilling of the first secondary reservoir (110) of the outpatient infusion system from the first primary reservoir (300) in which the first drug is stored, and planning the refilling of the second secondary reservoir (110) of the outpatient infusion system from the second primary reservoir (300'), in which the second medicinal product is stored and which is separate from the first primary reservoir (300), including periodic and automatic execution of the program for estimating the volume of refilling, which includes determining the need for refilling the first secondary tank and/or the need for refilling the second secondary reservoir at the current time based on the estimated infusion of the first drug and the second drug between the current time and a future estimated time. 2. The method of claim 1, wherein the fill volume estimate program includes determining a first estimated fill volume of the first secondary reservoir at a future estimated time point and determining whether the first secondary tank needs to be topped up depending on the first estimated fill volume. 3. The method of claim 2, wherein the fill volume estimate program includes determining that the first secondary tank should be topped up if the first estimated top-up volume is below the first threshold fill volume. 4. The method according to claim 2 or 3, in which the program for estimating the filling volume includes determining the first estimated filling volume by subtracting from the first filling volume of the first secondary reservoir at the current time the first estimated infusion volume, which is an estimate of the amount of the first drug, calculated infused between the current time and the future estimated time. 5. The method according to any one of the preceding claims, comprising calculating a set of first baseline estimated infusion volumes, each of which is an estimate of the amount of the first drug estimated to be infused over an estimated time interval starting at a corresponding predetermined time of day, and storing the set of first baseline estimated volumes infusion in memory, and the program for estimating the amount of filling includes retrieving from the memory the first base estimated infusion volume related to the time of day, which corresponds to the current point in time. 6. The method according to any one of the preceding claims, wherein the determination of the need to refill the first secondary reservoir is based at least in part on the predetermined first basal infusion rate of the first drug. 7. The method of any one of the preceding claims, wherein the determination of the need to refill the first secondary reservoir is based at least in part on the estimated infusion volume of the on-demand bolus of the first drug between the current time point and a future estimated time point. 8. The method of any one of the preceding claims, comprising calculating a set of second baseline estimated infusion volumes, each of which is an estimate of the amount of a second drug estimated to be infused over an estimated time interval starting at a corresponding predetermined time of day, and storing the set of second baseline estimated volumes infusion in the memory, wherein the priming volume estimate program includes retrieving from the memory a second base estimated infusion volume related to the time of day that corresponds to the current point in time. 9. The method according to any one of the preceding claims, wherein the first secondary reservoir and the second secondary reservoir are formed by one common secondary reservoir, which alternately serves as the first secondary reservoir and the second secondary reservoir. 10. The method of claim 9, wherein the fill volume estimate program includes determining that the second secondary reservoir should be topped up if the second drug infusion is expected to occur between the current time point and a future estimated time point and before the next next infusion of an on-demand bolus of the first drug. 11. Node (251) planning refueling outpatient infusion apparatus, configured to implement the method according to one of the previous paragraphs. 12. The control unit of the outpatient infusion apparatus, configured to control the operation of the outpatient infusion apparatus and containing: a first valve control unit configured to control actuation of the first valve drive actuator to switch the first valve between a filling state and an alternative supply state; - a second valve control unit configured to control actuation of the second valve drive actuator to switch the second valve between a filling state and an alternative supply state; - a control unit for the actuator of the drive of the first secondary reservoir, configured to control the operation of the actuator of the drive of the first secondary reservoir in the filling mode to increase the volume of the first secondary reservoir filled with liquid in the filling mode, as well as to control the operation of the actuator of the drive of the first secondary reservoir in the alternative filling mode a supply mode for reducing, in the supply mode, the liquid-filled volume of the first secondary reservoir; - a control unit for the actuator of the drive of the second secondary reservoir, configured to control the operation of the actuator of the drive of the second secondary reservoir in the refueling mode to increase the volume of the second secondary reservoir filled with liquid in the refueling mode, as well as to control the operation of the actuator of the drive of the second secondary reservoir in the alternative refueling mode a supply mode for reducing, in the supply mode, a liquid-filled volume of the second secondary reservoir; - refueling planning node according to clause 11; wherein the refueling scheduling unit is configured to operate in parallel with the operation of the first secondary reservoir actuator control unit and the second secondary reservoir actuator control unit in the feeding mode; moreover, the control unit of the ambulatory infusion machine is also configured so that, when determining that the first secondary reservoir should be refilled, it controls the execution of the first procedure for refilling the secondary reservoir, which includes the sequence of the following actions: (i) actuating the actuator of the drive of the first hydraulic distributor to switch the first valve to the filling state; (ii) actuating an actuator to drive the first secondary reservoir to increase the liquid-filled volume of the first secondary reservoir; (iii) actuating the first spool valve actuator to switch the first spool valve to a feed state, and moreover, the control unit of the ambulatory infusion machine is also configured so that, when determining that the second secondary reservoir should be refilled, it controls the execution of the second procedure for refilling the secondary reservoir, which includes the sequence of the following actions: (I) actuating the actuator of the second hydraulic distributor drive to switch the second hydraulic valve to the filling state; (II) actuating an actuator to drive the second secondary reservoir to increase the liquid-filled volume of the second secondary reservoir; (III) actuating the second hydraulic valve actuator to switch the second hydraulic valve to a feed state. 13. The control unit (250) of the outpatient infusion machine, configured to control the operation of the outpatient infusion machine (200) and containing: a spool control unit configured to control actuation of the spool valve actuator (227) to switch the spool valve between a first filling state, an alternative second filling state, and an alternative supply state; - a control unit for the actuating mechanism of the drive of the secondary reservoir, configured to control the operation of the actuating mechanism of the drive (217) of the secondary reservoir in the filling mode in order to increase the volume of the common secondary tank filled with liquid in the filling mode, as well as to control the operation of the actuating mechanism of the drive of the secondary tank in the alternative filling mode supply mode to reduce in the supply mode the liquid-filled volume of the common secondary reservoir (110); - node (251) scheduling refueling under item 11; moreover, the node (251) scheduling refueling is configured to work in parallel with the operation of the actuator actuator of the secondary reservoir in the supply mode; moreover, the control unit (250) of the ambulatory infusion apparatus is also configured in such a way that, when determining that the first secondary reservoir should be refilled, it controls the execution of the first procedure for refilling the secondary reservoir, which includes the sequence of the following actions: (ia) actuating the actuator actuator (227) valve to switch the valve in the first state of filling; (iia) actuating the secondary reservoir actuator (217) to increase the liquid-filled volume of the common secondary reservoir; (iiiia) actuating the spool valve actuator (227) to switch the spool valve to a feed state, and moreover, the control unit (250) of the ambulatory infusion apparatus is also configured in such a way that, when determining that the second secondary reservoir should be refilled, it controls the execution of the second procedure for refilling the secondary reservoir, which includes the sequence of the following actions: (ib) actuating the actuator actuator (227) valve to switch the valve in the second state of filling; (iib) actuating the secondary reservoir actuator (217) to increase the liquid-filled volume of the common secondary reservoir; (iiib) actuating the spool valve actuator (227) to switch the spool valve to a supply state. 14. The control unit (250) of the outpatient infusion apparatus according to claim 13, in which: - the first refilling procedure of the secondary reservoir includes, before step (ia), the first emptying sequence, including the steps of (ia') actuating the valve actuator to switch the valve to the second state of filling and (iia') actuating the actuator a mechanism for driving the secondary reservoir to reduce the liquid-filled volume of the common secondary reservoir to a minimum volume; and/or - the second procedure for refilling the secondary reservoir includes a second emptying sequence performed before step (ib), including steps (ib') actuating the valve actuator to switch the valve to the first state of filling and (iib') actuating the actuator mechanism for driving the secondary reservoir to reduce the liquid-filled volume of the common secondary reservoir to a minimum volume. 15. A computer-readable storage medium that stores a computer program code that enables the processor to execute the method according to one of paragraphs. 1-10 and/or operation of the processor as a refueling planning node (251) according to claim 11 and/or as a control unit (250) of an outpatient infusion machine according to one of claims. 12-14.

Images