Method and device utilizing insulin delivery protocols

A method of infusing liquid medicaments including insulin via an insulin pump, includes identifying an insulin delivery protocol associated with ingestion of carbohydrates wherein the insulin delivery protocol is likely to lead to a postprandial drop in blood glucose to a level below a basal level, then proposing at least one alternative insulin delivery protocol to inhibit the postprandial drop in blood glucose by delivering a metered amount of insulin that is appropriate to facilitate the metabolism of the carbohydrates without the postprandial blood glucose level drop. The invention further includes querying the patient as to whether to apply the alternative insulin delivery protocol, receiving instructions from the patient in response to the query, and applying the alternative insulin delivery protocol following receiving instructions from the patient to apply the alternative insulin delivery protocol.

FIELD OF THE INVENTION

The invention relates generally to insulin pumps that are utilized for controlled infusion of insulin into the human body. Insulin pumps may also include dual hormone therapy devices that infuse insulin and another hormone or medication into the body. More particularly, the invention relates to profiles that are used to control the infusion of insulin and other medicaments in the treatment of diabetes.

BACKGROUND OF THE INVENTION

There are many applications in academic, industrial, and medical fields, as well as others, that may benefit from devices and methods that are capable of accurately and controllably delivering fluids, including liquids and gases that have a beneficial effect when administered in known and controlled quantities. Such devices and methods may be particularly useful in the medical field where much of the treatments for a large percentage of patients includes the administration of a known amount of a substance at predetermined intervals.

Insulin-injecting pumps have been developed for the administration of insulin for those suffering from both type I and II diabetes. Recently continuous subcutaneous insulin injection and/or infusion therapy has been adapted for the treatment of diabetes. Such therapy may include the regular and/or continuous injection or infusion of insulin into or under the skin of a person suffering from diabetes and offers an alternative to multiple daily injections of insulin by an insulin syringe or an insulin pen.

Generally, present insulin pump therapy is based on the use and application of currently available, so-called, “rapid-acting” insulin analogues, including insulin lispro (marketed by Eli Lily & Company under the trademark Humalog®), insulin glulisine (marketed by Sanofi-Aventis under the trademark Apidra), and insulin aspart (marketed by Novo Nordisk under the trademark NovoLog). More recently, ultra-rapid acting insulins have been developed. Further, other drugs have been developed that either modify insulin action time or alter the rate of metabolism of food. These all change the way that post-prandial blood glucose levels behave in a somewhat similar fashion.

Currently, in presently available insulin pumps, an insulin bolus is delivered as rapidly as it can be. The delivery of an insulin bolus creates an abrupt rise in the level of insulin in the blood stream which encourages the rapid metabolism of glucose. The beginning of insulin appearance in the blood stream is delayed from the time of infusion because of the time required for insulin absorption and distribution in the circulation. With ultra-rapid acting insulins the delay time is less than for fast acting insulin. Thus, the delivery of such an insulin bolus according to a “normal” protocol may cause an excessive metabolism of glucose thereby causing a drop in blood glucose which can be dangerous. In extreme cases, the drop in blood glucose can lead to insulin shock, which is also known as hypoglycemic shock. In rare cases hypoglycemic shock can even cause death.

The use of pramlintide, (e.g., pramlintide acetate marketed by Bristol Myers-Squibb under the trademark Symlin) is becoming increasingly common in the treatment of type I diabetes. Pramlintide is synthetic amylin, an agent that acts to slow the rate of gastric emptying and therefore the rate at which food is released into the small intestine. Accordingly, this slows the rate at which food is metabolized. Glucagon-like peptide-1 (GLP-1) agonist therapy may also be used to slow the rate of gastric emptying which in turn slows the rate of absorption of food in the small intestine. The use of these agents results in a less pronounced rise in blood sugar after eating that also may last for a longer period of time.

The development of new insulins as well as adjunctive medicinal therapy for diabetes creates a need for new therapy protocols to be used with an insulin pump or a dual therapy insulin pump.

SUMMARY OF THE INVENTION

The present invention solves many of the above-indicated problems and assists individuals under treatment for diabetes in attaining the goal of as constant a blood sugar level as possible. The maintenance of a constant blood sugar level is expected to reduce the damaging sequelae of diabetes mellitus that include microvascular changes in the eyes and elsewhere in the body such as retinopathy, nephropathy and neuropathy as well cardiovascular disease.

According to the invention, current insulin pump based therapies in which a bolus of insulin is delivered as quickly as it can be, thus creating a rapid rise in insulin level, are modified to accommodate more rapidly acting insulins and complementary drug therapies, such as pramlintide, which cause a similar post-prandial effect by slowing the rate at which food is emptied from the stomach and thus the metabolism of carbohydrates. The invention is also useful with modified insulin that has insulin action time modifiers, such as hyaluronidase, added to it. Further, the invention also is well suited to be used along with insulin infusion site modifiers. For example, this includes but is not limited to, products that apply heat to the infusion site. If the insulin infusion site is heated, the absorption of insulin is facilitated. Other insulin infusion site modifiers are being developed as well.

In one embodiment, the invention includes a method of providing dual hormone therapy for diabetes in which two hormones are supplied from separate compartments in the same insulin pump and a controller is utilized to maintain a memory when pramlintide (or another agent that slows gastric emptying) has been administered and when it has not. Accordingly, based on this information, the pump can be activated to provide a standard insulin bolus or to provide an extended or other new type of insulin bolus as discussed herein. The extent to which a bolus is extended is governed by a new metric not currently used in prior art insulin pumps.

According to one embodiment of the invention, a ratio comparing minutes of bolus extension to the dose of pramlintide (or other agent) is used. Accordingly, if a sufficiently large amount of carbohydrate is ingested above a predetermined threshold, a dose of pramlintide (or other agent) may be given. In this case, a bolus of insulin may be infused along with an insulin bolus extension. According to an embodiment of the invention, the length of the extension is proportional to the dose of pramlintide. According to another embodiment of the invention, an extended bolus may be given if a dose of pramlintide exceeds a certain predetermined threshold.

According to another embodiment of the invention, a bolus whose shape can be represented in a graph is more similar to a single sine wave or a Gaussian distribution to approximate the expected post-prandial rise in blood glucose levels. Current insulin pumps deliver boluses that are either abrupt and immediate or where a fraction of the bolus is delivered immediately and a remaining fraction is delivered over an extended period of time. As the speed of insulin action increases it is desirable for the shape of the insulin infusion profile to more closely match the shape of the carbohydrate profile.

According to another embodiment of the invention, a small amount of insulin is delivered in a first dose followed by an increased second amount of insulin delivered following a period of time, again followed by a third decreased amount of insulin delivered.

According to another embodiment of the invention, metrics that are used are the time to peak bolus and the total bolus extension of time. According to the invention, these two metrics are used to govern the shape of a sine wave like bolus. The goal of therapy under the present invention is to provide the required amount of insulin at the right time relative to blood sugar control so that the blood sugar level may be maintained at a constant level as possible. Slower food movement into the small intestine as controlled by pramlintide and related medications and the utilization of ultra-rapid acting insulins, as controlled by the invention, may permit better overall blood sugar control than has previously been possible.

The goal of the invention is to match the rate at which food is metabolized to the rate at which insulin becomes active. A concern with ultra-rapid acting insulins is that the insulin may act faster than the food uptake that causes a rise in blood sugar. Accordingly, there even may be a postprandial drop in blood glucose level rather than the normally expected rise. According to the invention, with the use of ultra-rapid acting insulins, meal boluses are carbohydrates boluses that may be extended. According to one embodiment of the invention, the shape of the extension is similar to a sine wave or Gaussian curve.

According to the invention, with both pramlintide (or other like acting medicaments) use and ultra-rapid acting insulin use, it is likely that a correction bolus should be infused immediately. If the patient using the pump promptly enters meal boluses or carbohydrate boluses, the controller of the insulin pump can track delivery of a correction or a meal bolus and a particular bolus shape can be suggested to the patient.

According to the invention, even combination boluses where a part of the bolus is for correction and part of the boluses is intended to accommodate a future meal are calculated and delivered.

Another context in which the invention is applicable is in therapy where insulin action time modifiers are included as an adjunct to standard insulin therapy. For example, it is known that the inclusion of hyaluronidase to insulin causes the standard insulin to act more rapidly. According to the invention, with the use of insulin action time modifiers, either mixed directly with the insulin within the same injection or separately injected using a dual drug insulin pump. Insulin boluses are modified or extended as described herein.

According to one embodiment of the invention, the amount of extension is based on a ratio of insulin to the modifier that is injected. Thus, the invention also includes an additional metric that is used to calculate the proper insulin dose.

According to embodiments of the invention, the metric is based on a ratio of insulin to modifier or may be based on a number of minutes of bolus extension of insulin per dose of modifier. Thus the period of extension is proportional to the dose of modifier. According to another embodiment of the invention, a combination of the ratio of insulin to modifier and a period of extension per dose of modifier is used. Further, an alternative insulin delivery protocol may be appropriate if hyalouronidase or another insulin action modifier has been given over some predetermined earlier time span. For example, if the modifier has been used by the patient in the last 24 or 48 hours it may be appropriate to use an alternative insulin delivery protocol as described herein.

Further, if the dual drug pump is utilized, the pump controller can track when both drugs are pumped and therefore predict when to apply the correction.

Further, according to another embodiment of the invention, if insulin and the modifier are mixed, the mixing ratio is entered into the pump controller so that the pump can calculate how much to extend or modify boluses.

Rapid changes in blood glucose level can cause patients with diabetes to feel uncomfortable or emotionally out of balance in ways that patients find hard to describe. This can occur when an excessively large insulin bolus is delivered or if the patient engages in exercise with an excess of insulin in his system. With increasing speed of insulin action it may be desirable to extend even correction boluses to reduce the rate of change of blood sugar level. Thus, according to another embodiment, the invention includes an alternative insulin delivery protocol wherein a correction bolus is delivered that includes a correction bolus extension to moderate the rate at which blood glucose change occurs. According to another embodiment, the invention includes utilizing an alternative insulin delivery protocol that maintains the rate of change of blood glucose below a preselected level.

DETAILED DESCRIPTION

The invention generally applies to the operation and utilization of insulin infusion pumps. Included below is a description of an insulin infusion pump with which the methods of the invention may be used.

Provided herein are systems, devices and methods for identifying an insulin delivery protocol associated with ingestion of carbohydrates wherein the insulin delivery protocol is likely to lead to a postprandial drop in blood glucose to a level below a basal level that is likely to deprive a patient of sufficient blood glucose to function normally. The invention also includes proposing at least one alternative insulin delivery protocol to inhibit the postprandial drop in blood glucose by delivering a metered amount of insulin that is appropriate to facilitate the metabolism of the carbohydrates without the postprandial blood glucose drop. The inventions are usable in the context of an infusion pump and particularly in an insulin pump. Some embodiments may include advances in the internal components, the control circuitry, and improvements in a user interface of the systems and devices. The advances may allow for a safer and more accurate delivery of medicament to a patient than is currently attainable today from other devices, systems, and methods. Although embodiments described herein may be discussed in the context of the controlled delivery of insulin, delivery of other medicaments as well as other applications are also contemplated. Device and method embodiments discussed herein may be used for pain medication, chemotherapy, iron chelation, immunoglobulin treatment, dextrose or saline IV delivery, or any other suitable indication or application. Non-medical applications are also contemplated.

FIGS. 1A-1Dshows an embodiment of an infusion pump system110including an infusion cartridge112and pump device114. Infusion cartridge112can be a reversibly removable and interchangeable element that may be inserted into different pump devices. Referring toFIG. 1A, a front view of the pump device114is shown and includes a user friendly user interface116on a front surface118of the pump device114. The user interface116includes a touch sensitive screen120that may be configured to display a variety of screens used for displaying data, facilitating data entry by a patient, providing visual tutorials, as well as other interface features that may be useful to a patient operating the pump device114.FIG. 1Bis a rear view of the pump device114and illustrates the detachable installment of the infusion cartridge112in a slot122of the pump device114which is configured to accept the cartridge112.

FIG. 1Cis a schematic view of an open housing124of the pump device114which shows schematically some components that may be included in embodiments of the pump device114. The cartridge112may include a fluid interface configured to receive a fluid such as collapsible reservoir126. The collapsible reservoir126may be formed from a flexible material or membrane128that is disposed about an interior volume of the reservoir126. The cartridge112also includes a substantially rigid container130sealed around the flexible material of the collapsible reservoir126. A disposable delivery mechanism132is disposed within the disposable cartridge112and may have a fill port134with a re-sealable septum136sealed over the fill port134, a reservoir inlet port138in fluid communication with an interior volume140of the collapsible reservoir126, a fluid dispense port142in fluid communication with a bore144of the delivery mechanism132, a vent inlet port146and a vent outlet port148both in fluid communication with the bore144. The collapsible reservoir126may have a bag-like structure with flexible walls that can collapse and expand depending upon the amount of material in the volume of the reservoir. The interior volume of the reservoir may be in fluid isolation from the remaining interior volume of the rigid container130.

The cartridge112may be releasably and operatively secured to a housing124of the pump device114. The housing124may be configured to house a drive mechanism150including a motor152and gear box154disposed in the housing124and detachably coupled to a spool member156of the delivery mechanism132. At least one pressure sensor158may be disposed in a volume160between an outside surface162of the flexible material or membrane128of the collapsible reservoir126and an inside surface164of the substantially rigid shell or case130. The graphic user interface116may be operatively coupled to a controller168, which may include at least one processor170, a memory device172and connective circuitry or other data conduits that couple the data generating or data managing components of the device. A power storage cell in the form of a battery174that may be rechargeable may also be disposed within the housing124. Data generating or managing components of the device may include the processor(s)170, the memory device172, sensors158, including any pressure or temperature sensors, the GUI166and the like.

The pressure inside the infusion cartridge112, and particularly the vented volume160of the infusion cartridge112, may be measured by a pressure sensor158disposed in the infusion cartridge112or in the pump device114in a volume, such as pocket186as shown inFIG. 1D.

Pocket186is an interior volume disposed within the pump device114and in fluid communication with an interior volume of the fluid cartridge112. The pocket186is in sealed relation with the interior volume160of the cartridge. As such, a pressure sensor158disposed within the volume of the pocket186will read the pressure of the volume160in the cartridge, but can remain with the pump device114after disposal of the disposable cartridge112. This configuration lowers the cost of the cartridge while providing the means of pressure measurement within the cartridge112. In some embodiments, data from the pressure sensor158may be used to provide a measurement of how much insulin or other medicament is being delivered by the first pump device114. Alternatively, the pressure sensor158can be disposed within the cartridge directly in the vented volume160.

The pump device114can also include a thermistor or other temperature sensor188including an optical or infrared sensor that measures the temperature of the insulin or other medicament within the reservoir126upon coupling the infusion cartridge112with the pump device114. Taking the temperature of the air may be important in measuring how much insulin or other medicament is in the fluid reservoir. In some embodiments, the thermistor or other temperature sensor188is positioned in the pocket186such that it can measure the temperature of the air in the pocket186as shown inFIG. 1D. As noted above, the pocket186may also include a pressure sensor158coupled to the controller168for measuring pressure within the pocket186and volume160. Because the air in the pocket186is in fluid communication with the residual air within the chamber160, the temperature and pressure of the air in the infusion cartridge112surrounding the fluid reservoir126may be equal or approximately equal to the temperature and pressure of the air in contact with the temperature sensor188and pressure sensor158. In turn, the temperature sensor188may provide a relatively accurate measurement of the temperature of the insulin or other medicament within the reservoir126.

Referring toFIGS. 2-7, an embodiment of the delivery mechanism132is shown in a fluid delivery cycle sequence wherein fluid from the interior volume of the reservoir126is drawn into the bore220of the delivery mechanism132and dispensed from the dispense outlet port142.

Referring again toFIG. 2, a portion of the fluid reservoir cartridge112including a delivery mechanism132is shown in section as well as a portion of a drive mechanism150of an infusion pump. The disposable fluid cartridge112includes the delivery mechanism132which has a delivery mechanism body236and a bore220disposed in the delivery mechanism body236. The bore220, which may have a substantially round transverse cross section, includes a distal end238, a proximal end240disposed towards the drive mechanism150of the infusion pump114, an interior volume242, a reservoir inlet port138, a fluid dispense port142, a vent inlet port146and a vent outlet port148. The spool156, which may also have a substantially round transverse cross section, is slidingly disposed within the bore220and forms a collapsible first volume244and a vent second volume246between the bore220and an outside surface266of the spool156.

The collapsible first volume244of the delivery mechanism132may be positionable to overlap the reservoir inlet port138independent of an overlap of the fluid dispense port142. The collapsible first volume244may be formed between a first seal248around the spool156, a second seal250around the spool, an outer surface of the spool body between the first and second seal250and an interior surface252of the bore220between the first and second seal248and250. The first and second seals248and250are axially moveable relative to each other so as to increase a volume of the collapsible volume244when the first and second seals248and250are moved away from each other and decrease the collapsible volume244when the seals248and250are moved closer together.

The second seal250is disposed on a main section254of the spool156of the delivery mechanism132and moves in conjunction with movement of the rest of the spool. A proximal end196of the spool156is coupled to a ball portion194of a drive shaft190of the drive mechanism150of the pump device114. The drive mechanism150includes a rack and pinion192mechanism actuated by an electric motor152through a gear box154. As such, the second seal250moves or translates axially in step with axial translation of the spool156and drive shaft190. The first seal248, however, is disposed on a distal section258of the spool156which is axially displaceable with respect to the main section254of the spool156. The distal section of the spool156is coupled to the main section of the spool by an axial extension260that is mechanically captured by a cavity261in the main section254of the spool156. This configuration allows a predetermined amount of relative free axial movement between the distal section258of the spool and the nominal main section254of the spool156.

For some embodiments, a volume of a “bucket” of fluid dispensed by a complete and full dispense cycle of the spool156may be approximately equal to the cross section area of the bore220multiplied by the length of displacement of the captured axial extension of the spool156for the distal section258. The complete bucket of fluid may also be dispensed in smaller sub-volumes in increments as small as a resolution of the drive mechanism150allows. For some embodiments, a dispense volume or bucket defined by the complete collapsible volume244of the delivery mechanism132may be divided into about 10 to about 100 sub-volumes to be delivered or dispensed. In some cases, the maximum axial displacement between the distal section and main section of the spool may be about 0.01 inch to about 0.04 inch, more specifically, about 0.018 inch, to about 0.022 inch.

In use, once the reservoir cartridge112of the infusion pump system110has been installed or otherwise snapped into place in the slot122of the pump device114, the interior volume140of the collapsible reservoir126may then be filled with a desired fluid121for dispensing. In order to fill the reservoir126, the spool156may be translated by the drive mechanism150to a hard stop position226as shown inFIG. 2. In the hard stop position226the first seal248is disposed proximally of a relief port310, the relief port310being disposed in fluid communication between a distal end238of the bore220and the reservoir volume140. In the hard stop position, the first seal248is also disposed distally of the reservoir inlet port138. In the hard stop position, a distal end316of the spool156is contacting the distal end238of the bore220or a shoulder portion312of the distal end238of the bore220to prevent any further distal displacement of the spool156.

A reservoir fill port134is disposed on a top portion of the bore220substantially opposite the bore220of the reservoir inlet port138. With the spool156and seals248,250,262and264thereof so positioned, a patient may then obtain an amount of a desired fluid to be dispensed. In some cases, if the desired fluid to be dispensed is insulin or other suitable medicament, the patient127typically stores the insulin in a refrigerated glass container. The insulin is then accessed with a hypodermic needle222of a syringe device and drawn into an interior volume of the syringe (not shown). The tip of the hypodermic needle222of the syringe may then be pushed through a septum membrane136that seals the reservoir fill port134as shown and fluid manually dispensed from the interior volume of the syringe, through the hypodermic needle222, through a bubble trap volume314in the bore220of the delivery mechanism132and into the interior volume140of the collapsible reservoir126of the cartridge112as shown by the arrow318inFIG. 2.

As discussed above with regard to other embodiments of the delivery mechanism132, the vented volume160of the cartridge112disposed between an outside surface162of the flexible membrane128of the collapsible reservoir126and an inside surface164of the rigid shell130may include or be in operative communication with a pressure sensor158. The pressure sensor158may be used to monitor the pressure within the vented volume160during the filling of the collapsible reservoir126. The controller168of the pump system114may be programmed with information regarding the fixed volume of the rigid shell130of the cartridge112and configured to calculate the volume of fluid loaded into the collapsible reservoir126based on the pressure rise within the rigid shell130upon filling of the collapsible reservoir126. The data regarding the volume of fluid loaded into the collapsible reservoir126may be stored and used to calculate and display data later in the use cycle such as fluid remaining in the collapsible reservoir126and the like.

Once the collapsible reservoir126contains a desired amount of a fluid121to be dispensed, a dispense cycle may be initiated by driving the spool156with the drive mechanism150based on commands from a controller168of the pump device to a position with the collapsible first volume244in communication with the reservoir inlet port138. The hard stop position shown inFIG. 2is such a position. If the spool156has been driven to this hard stop position226in a distal direction from previous proximal position, the friction generated between the first seal248of the spool156and the inside surface252of the bore220will have collapsed the collapsible volume244of the delivery mechanism132with the first seal248and second seal250in a least axially separated state. In this state, the collapsible volume244has a minimum volume. Such a state of the delivery mechanism132is shown inFIG. 2. Once in this pre-fill position, the spool156may then be driven so as to axially separate the first and second seals248and250(and the main section254of the spool156and distal section258of the spool156) of the collapsible first volume244and draw fluid into the first volume244through the reservoir inlet port138from the reservoir126as shown by the arrow320inFIG. 3. As the fluid121is drawn into the collapsible volume244, the pressure within the vented volume160decreases. As previously discussed, this drop in pressure may be used in accordance with the ideal gas law to determine the amount of material taken from the collapsible reservoir126. An unexpected reading based on the magnitude of the translation of the main section254of the spool156may also be used to detect a failure of a portion of the delivery mechanism132in some cases.

The collapsible volume244of the delivery mechanism132may be completely filled by proximally retracting the main section254and second seal250of the spool156relative to the first seal248and distal section258of the spool156as shown by arrow322on spool156inFIG. 4. Once filled, the spool156may then be driven in a proximal direction as shown inFIG. 5wherein there are two seals248and250disposed in the bore220between the reservoir inlet port138and relief port310and the dispense port142. As shown by arrow323and arrow324inFIG. 5, both the main section254and distal section258of the spool156are proximally retracted together. The captured axial extension of the distal section258by the main section254pulls the distal section along without axial displacement between the main section254and distal section258of the spool156The dispense port may be in fluid communication with a subcutaneous portion of a patient's body. The delivery mechanism132always includes at least one seal248or250disposed in the bore220between the reservoir volume140and material121disposed therein and the dispense port142in order to prevent a free flow condition wherein the material121in the reservoir126is in uninterrupted communication with the patient's body.

Once filled, the spool156and filled collapsible volume244may be proximally displaced with the drive mechanism150to a position with the collapsible first volume244in communication with the fluid dispense port142of the bore220as shown inFIG. 6. Once the spool156is positioned as shown inFIG. 6, the main section of the spool156may then be axially driven in a distal direction by the drive mechanism150with the distal section258of the spool remaining stationary or substantially stationary. This axial distal movement of the main section254as indicated by arrow326on the spool156shown inFIG. 7, serves to at least partially collapse the collapsible first volume244. Collapsing the first volume244of the delivery mechanism132dispenses fluid from the collapsible first volume244through the fluid dispense port142as shown by the arrow328inFIG. 7. Once all fluid from the collapsible first volume244is dispensed in this manner, additional cycles as described above can be completed to provide additional insulin to the patient. Further details on the operation and configuration of such an infusion pump can be found in U.S. Pat. No. 8,287,495, which is hereby incorporated by reference herein in its entirety.

Some embodiments of an infusion system may include a portable infusion device, as described above and a remote commander device. In such an instance, the portable infusion device may include a suitably configured receiver and/or transmitter for communication with an external device such as a remote commander, as well as programming for directing the use of the device. The remote commander may additionally include a suitably configured receiver and/or transmitter for communication with an external device such as a portable infusion device, as well as programming for directing the use of the device. For instance, the remote commander may include one or more of the functionalities described herein above with respect to the portable infusion device.

FIG. 9Ais a graph schematically depicting a rise in blood glucose over time that occurs after ingestion of food; particularly, ingestion of carbohydrates. The rise in blood glucose occurs in people suffering from diabetes because of insufficient insulin production or production of insulin that is ineffectively used. This at least partially uncontrolled rise in blood glucose is a contributor to the sequelae of diabetes that include microvascular changes in the eyes and elsewhere in the body. Complications of diabetes include retinopathy, nephropathy and neuropathy as well as cardiovascular disease.

According to the invention, current insulin pump therapies in which a bolus of insulin is typically delivered abruptly and quickly, thus creating a rapid rise in insulin level, are modified to provide more effective blood sugar modulation—particularly in the case of the use of rapid-acting insulins and complementary drug therapies.

FIG. 9Bis a graph schematically depicting a more gradual rise in blood glucose over time, with the blood glucose level having a reduced amplitude and a lengthened time course as compared toFIG. 9A. This sort of postprandial rise in blood sugar occurs, for example, when gastric emptying is slowed. This occurs, for example, when a medication such as pramlintide or a GLP-1 agonist is used. Because gastric emptying is slowed, the absorption of food is slowed and the rise in blood sugar is in turn more gradual and has a lower peak amplitude over time.

FIG. 10is a graph schematically depicting an undesirable postprandial drop in blood glucose over time that can occur under certain circumstances that are addressed by embodiments of this invention. This atypical drop in blood glucose can occur, e.g., after an ingestion of carbohydrates in the presence of other circumstances.

Circumstances that can cause a postprandial drop in blood glucose include infusion of ultra-rapid-acting insulin, where the action of the insulin is faster than the expected rise in blood sugar. Thus, insulin is metabolized more quickly than are carbohydrates, and an undesirable drop in blood glucose may occur. Having an undesirable drop in blood glucose can lead to a circumstance where insufficient blood glucose is available for nutrition and can lead to problems. Such problems can include in extreme cases, insulin shock which can cause serious harm or in rare cases even death. Neuroglycopenia is another concern that can arise when blood glucose level drops to a level below that needed for normal physiological function. Neuroglycopenia occurs when the brain does not receive sufficient glucose to support brain metabolism and to function properly. Neuroglycopenia can present with a wide variety of neurological symptoms including confusion, ataxia, fatigue, anxiety, moodiness and depression.

Another circumstance that can cause an undesirable postprandial drop in blood glucose is the use of pramlintide or a GLP-1 agonist in combination with insulin therapy. If the rise in blood glucose has been modified as inFIG. 9B, a conventionally-used bolus of insulin may cause an undesirable quick metabolism of blood glucose, thus resulting in the aforementioned postprandial drop in blood glucose.

Thus, with the benefit of the invention and the embodiments discussed herein, it is expected that blood glucose can be maintained at a relatively constant level without an undesirable postprandial drop in blood glucose.

FIG. 11is a graph schematically depicting a typical prior art insulin bolus delivery profile, with a bolus extension, as a function of time. As can be seen, a bolus of insulin may be delivered quickly, causing a relatively large quantity of insulin to be infused and to be present in the blood stream relatively rapidly in anticipation of a blood glucose rise that would otherwise occur with ingestion of carbohydrates. The bolus extension is intended to cover the metabolism of insulin over time after the initial rise in blood glucose that would already occur.

Referring now toFIG. 12, an alternative insulin delivery protocol according to an example embodiment of the invention is depicted in schematic form as a function of time. According to this example embodiment of the invention, insulin is delivered at a basal level400, followed by a first small bolus402, followed by a larger bolus404and then a second small bolus406. After second small bolus406, insulin delivery returns to the basal level400. As can be seen, this delivery of insulin more closely aligns with the expected rise in blood glucose as depicted inFIG. 8. Accordingly, an insulin delivery protocol according to this embodiment of the invention is well suited to maintain blood glucose at a more constant level.

Referring now toFIG. 13, another insulin delivery protocol408is depicted in schematic form as a function of time. According to this embodiment of the invention, insulin is maintained at a basal level400followed by first small bolus410. This is then followed by first rest period412in which insulin delivery returns to a basal level400. This is then followed by a larger bolus414which in turn is followed by second rest period416during which insulin delivery returns to a basal level400. Finally, a second small bolus418is delivered followed by a return to basal level400. Again, it is expected in the circumstance of a blood sugar rise similar to that depicted inFIG. 8, a more constant blood glucose level would be maintained within this delivery protocol than prior art delivery protocols. The relative heights of the different insulin delivery levels inFIGS. 12 and 13are for example only. Those of ordinary skill in the art can adjust the size of the bolus deliveries in order to accommodate an expected blood glucose rise.

Referring now toFIG. 14, another insulin delivery protocol426is depicted in schematic form as a function of time. As can be seen by examination ofFIG. 14, in insulin delivery protocol426a Gaussian-shaped insulin bolus428is delivered. In other words, the delivery of insulin approximates a Gaussian curve. It should be understood that the insulin delivery in this protocol426does not necessarily have to be in the form of an exact Gaussian curve as mathematically defined; rather, it approximates a Gaussian curve in that there is a gradual rise in insulin delivery to a peak followed by a gradual decline in insulin delivery as time progresses. This curve is expected to approximate the expected rise in blood glucose over time as depicted inFIG. 8and thus is expected to provide a relatively constant level of blood glucose over the time of insulin delivery. Gaussian insulin bolus428may also have a lower peak in order to accommodate an expected blood glucose rise similar to that depicted inFIG. 9.

FIG. 15depicts another insulin delivery protocol460in schematic form as a function of time, including insulin bolus432and Gaussian extension434. According to this embodiment of the invention, an initial insulin bolus432is delivered followed by an extension that is not constant in insulin delivery but that gradually rises and falls over time, approximating a Gaussian curve. As discussed above, this is not intended to describe a curve that is precisely mathematically Gaussian in structure but a curve that gradually rises and then gradually falls. The curve may be, but need not be, generally symmetrical.

Referring now toFIG. 16, a flow chart depicting a method according to the invention is depicted. This method may be implemented in the operation of an insulin pump that includes a controller such as that described herein.

A method according to the invention for infusing liquid medicaments including insulin, via an insulin pump having at least one reservoir containing the liquid medicaments includes identifying an insulin delivery protocol associated with ingestion of carbohydrates wherein the insulin delivery protocol is likely to lead to a postprandial drop in blood glucose to a level below a basal level that is likely to deprive a patient of sufficient blood glucose to function normally436. The method may further include proposing at least one alternative insulin delivery protocol to inhibit the postprandial drop in blood glucose by delivering a metered amount of insulin that is appropriate to facilitate the metabolism of the carbohydrates without the postprandial blood glucose drop438. The method may further include querying the patient as to whether to apply the alternative insulin delivery protocol440and receiving instructions from the patient in response to the query442and applying the alternative insulin delivery protocol following receiving instructions from the patient to apply the alternative insulin delivery protocol444.

According to another embodiment of the invention, the invention may include delivering a first bolus of the liquid medicament having a first volume at a time t1446, delivering a second bolus of the liquid medicament having a second volume at a time t2448and delivering a third bolus of the liquid medicament having a third volume at a time t3440.

According to another embodiment of the invention, the invention may further include delivering an initial bolus followed by a bolus extension, the bolus extension rising and falling in volume in a cyclical wave fashion over a period of time452.

According to another example embodiment of the invention, the method may include delivering insulin over an extended period of time during which the volume of insulin delivered rises and falls in a cyclical wave fashion over a period of time and then declines to a basal level454.

According to another example embodiment of the invention, the method further includes delivering a volume of insulin at a volume rate based on the expected postprandial rise in blood glucose that mirrors the expected postprandial rise in blood glucose whereby blood glucose is metabolized such that blood glucose level is maintained to be substantially constant following the ingestion of carbohydrates456.

According to another example embodiment of the invention, the method further includes delivering a volume of insulin at a volume rate based on the expected postprandial rise in blood glucose that mirrors the expected postprandial rise in blood glucose such that the volume rate of infusion generally resembles a Gaussian curve458.

According to another embodiment of the invention, the method may include identifying the use of a dose of an agent that slows gastric emptying as a factor that is likely to lead to a postprandial drop in blood glucose to a level below a basal level that is likely to deprive a patent of sufficient blood glucose to function normally460.

According to another embodiment of the invention, the method may include conforming the volume rate of infusion to generally resemble the Gaussian curve that is flattened to conform with the slowed gastric emptying462.

According to another example embodiment, the method may include selecting the agent from a group of agents consisting of pramlintide, GLP-1 agonists and combinations thereof464.

According to another embodiment of the invention, the method may include delivering an initial bolus of insulin followed by a bolus extension, the bolus extension being delivered over a period of time that is directly proportional to the dose of the agent that slows gastric emptying468.

According to another embodiment of the invention, the method may include receiving an input from the patient that the patient has ingested or is about to ingest a quantity of carbohydrate and an input from the patient enumerating the quantity of carbohydrate; and applying the alternative insulin delivery protocol only if the enumerated quantity of carbohydrate exceeds a predetermined threshold470.

According to another embodiment of the invention, the method further includes delivering the dose of the agent that slows gastric emptying via a dual hormone therapy device472.

According to another embodiment of the invention, the method may include identifying use of an insulin action time modifier as a factor that is likely to lead to the postprandial drop in blood glucose to a level below a basal level that is likely to deprive the patient of sufficient blood glucose to function normally474.

This method may further include delivering an initial bolus of insulin followed by a bolus extension, the bolus extension being delivered over a period of time that is directly proportional to the dose of the insulin action time modifier476.

According to another embodiment, the method may further include identifying use of an ultra-rapid acting insulin as a factor that is likely to lead to the postprandial drop in blood glucose to a level below a basal level that is likely to deprive the patient of sufficient blood glucose to function normally478.

According to another embodiment, the method may further include delivering an initial bolus of insulin followed by a bolus extension only if the dose of the agent that slows gastric emptying exceeds a predetermined threshold480.

Rapid changes in blood glucose level can cause patients with diabetes to feel uncomfortable or emotionally out of balance in ways that patients find hard to describe. This can occur when an excessively large insulin bolus is delivered or if the patient engages in exercise with an excess of insulin in his system. With increasing speed of insulin action it may be desirable to extend even correction boluses to reduce the rate of change of blood sugar level. Thus, according to another embodiment, the invention includes an alternative insulin delivery protocol wherein a correction bolus is delivered that includes a correction bolus extension to moderate the rate at which blood glucose change occurs. According to another embodiment, the invention includes utilizing an alternative insulin delivery protocol that maintains the rate of change of blood glucose below a preselected level.

The present invention may be embodied in other specific forms without departing from the spirit of the essential attributes thereof; therefore, the illustrated embodiments should be considered in all respects as illustrative and not restrictive, reference being made to the appended claims rather than to the foregoing description to indicate the scope of the invention.