METHODS FOR TREATING CONGENITAL HYPERINSULINISM

Abstract

A method of treating congenital hyperinsulinism in a subject is disclosed. The method can include parenterally administering to the subject a first composition comprising a glucagon, a glucagon analogue, or a salt form of either thereof, and optionally administering to the subject a second composition comprising glucose, a glucose analogue, or a salt form of either thereof, wherein administration of the first composition sufficiently increases blood glucose level in the subject such that the second composition is not administered or the second composition is administered at a glucose infusion rate (GIR) of less than 8 mg/(kg*min).

Claims

1. A method of treating congenital hyperinsulinism in a subject, the method comprising: (a) parenterally administering to the subject a first composition comprising a glucagon, a glucagon analogue, or a salt form of either thereof; and (b) optionally administering to the subject a second composition comprising glucose, a glucose analogue, or a salt form of either thereof, wherein administration of the first composition sufficiently increases blood glucose level in the subject such that the second composition is not administered or the second composition is administered at a glucose infusion rate (GIR) of less than 20 mg/(kg*min).

2. The method of claim 1, wherein the second composition is administered to the patient.

3. The method of claim 2, wherein the GIR is less than 15, or less than 10 mg/(kg*min).

4. The method of claim 3, wherein the GIR is less than 8 mg/(kg*min).

5. The method of claim 2, wherein the GIR is at least 33% less than what would otherwise be needed had the subject not being administered the first composition.

6. The method of any one of claims 1 to 5, wherein the second composition is intravenously administered to the subject.

7. The method of any one of claims 1 to 6, wherein the subject is being treated with or has been previously treated with glucose injection at a second GIR prior to step (a), and wherein the second GIR is greater that the GIR.

8. The method of claim 6, wherein the glucose injection prior to step (a) is being or has been administered through a peripherally inserted central catheter.

9. The method of any one of claims 1 to 8, wherein the second composition is an aqueous composition comprising 5 w/w % to 60 w/w % d-glucose.

10. The method of claim 9, wherein the second composition comprises about 50 w/w % d-glucose.

11. The method of claim 9, wherein the second composition comprises about 10 w/w % d-glucose.

12. The method of any one of claims 1 to 11, wherein the first compositions is administered from a glucagon delivery apparatus.

13. The method of claim 12, wherein the glucagon delivery apparatus comprises: a reservoir containing the first composition; a sensor configured to measure a patient's blood glucose level; and an electronic pump configured to intradermally, subcutaneously or intramuscularly deliver at least a portion of the composition to a patient based on the patient's measured blood glucose level.

14. The method of claim 13, where the sensor is configured to transmit data wirelessly, via radio frequency, or via a wired connection, to a processor configured to control operation of the electronic pump.

15. The method of claim 14, where the processor is configured to control operation of the pump based at least in part on the data obtained by the sensor.

16. The method of claim 15, where the processor is configured to control operation of the pump to intradermally, subcutaneously or intramuscularly inject at least a portion of the composition if the data obtained by the sensor indicates a glucose level below a defined threshold.

17. The method of any one of claims 12 to 16, further comprising a monitor configured to communicate information indicative of the patient's glucose level.

18. The method of claim 17, where the monitor comprises a speaker or a display device, or both.

19. The method of any one of claims 17 to 18, where the monitor is configured to communicate an alert when a glucose level of the patient is estimated to be at a defined threshold.

20. The method of any one of claims 12 to 19, where the apparatus is configured to allow manual adjustment of at least one of a delivery rate and a dose of the composition intradermally, subcutaneously or intramuscularly delivered by the pump.

21. The method of any one of claims 12 to 20, where the composition does not include a drug capable of decreasing the blood glucose level in the patient and/or where the apparatus is not capable of injecting a composition comprising a drug capable of decreasing the blood glucose level in the patient.

22. The method of any one of claims 12 to 22, where the composition further includes a drug capable of decreasing the blood glucose level in the patient and/or where the apparatus is capable of injecting a composition comprising a drug capable of decreasing the blood glucose level in the patient.

23. The method of any one of claims 21 to 22, where the drug capable of decreasing the blood glucose level in the patient is insulin, an insulin mimetic peptide, incretin, or an incretin mimetic peptide.

24. The method of any one of claims 12 to 23, wherein the apparatus is a closed-loop system for delivering glucagon to the patient.

25. The method of any one of claims 12 to 24, wherein the apparatus is an open-loop system for delivering glucagon to the patient.

26. The method of any one of claims 12 to 25, wherein the apparatus is a no-loop system for delivering glucagon to the patient.

27. The method of any one of claims 1 to 26, wherein the first composition is a single-phase solution comprising the glucagon, glucagon analogue, or a salt form of either thereof, dissolved in a non-aqueous solvent.

27. The method of claim 27, wherein the first composition comprises glucagon, glucagon analogue, or a salt form of either thereof solubilized in an aprotic polar solvent.

28. The method of claim 27, wherein the first composition further comprises an ionization stabilizing excipient, wherein (i) the glucagon, glucagon analogue, or salt thereof is dissolved in the aprotic solvent in an amount from about 0.1 mg/mL up to the solubility limit of the glucagon, glucagon analogue, or salt thereof, and (ii) the ionization stabilizing excipient is dissolved in the aprotic solvent in an amount to stabilize the ionization of the glucagon peptide or salt thereof.

29. The method of claim 28, wherein the ionization stabilizing excipient is at a concentration of 0.1 mM to less than 100 mM.

30. The method of claim 29, wherein the ionization stabilizing excipient is a mineral acid.

31. The method of claim 30, wherein the mineral acid is hydrochloric acid.

32. The method of claim 28, wherein the aprotic solvent is DMSO.

33. The method of claim 28, wherein the aprotic solvent is a deoxygenated aprotic solvent.

34. The method of claim 28, wherein the ionization stabilizing excipient is HCl and the aprotic solvent is DMSO.

35. The method of claim 28, wherein the composition has a moisture content of less than 10, 5, or 3%.

36. The method of claim 28, wherein the composition further comprises a preservative at less than 10, 5, or 3% w/v.

37. The method of claim 36, wherein the preservative is trehalose.

38. The method of claim 28, wherein the composition further comprises a sugar alcohol at less than 10, 5, or 3% w/v.

39. The method of claim 38, wherein the sugar alcohol is mannitol.

40. The method of claim 27, wherein the first composition further comprises a carbohydrate, an amphoteric molecule, and optionally an acid.

41. The method of claim 40, wherein the aprotic polar solvent is DMSO, the carbohydrate is trehalose, the amphoteric molecule is glycine, and the optional acid is hydrochloric acid.

42. The method of any one of claims 40 to 41, wherein the first composition comprises at least 80 wt. % of the aprotic polar solvent, 3 to 7 wt. % of the carbohydrate, 0.001 to 0.1 wt. % of the amphoteric molecule, and 0 wt. % to less than 0.1 wt. % of the acid.

43. The method of any one of claims 40 to 42, where the first composition comprises, consists essentially of, or consists of glucagon, the glucagon analogue, or the salt form of either thereof, the aprotic polar solvent, the amphoteric molecule, the carbohydrate, and optionally the acid.

44. The method of any one of claims 1 to 43, where the first composition has a water content of 0 to less than 15 wt. %, 0 to less than 3 wt. %, 3 to 10 wt. %, or 5 to 8 wt. %.

45. The method of any one of claims 1 to 44, where the glucagon, glucagon analogue, or salt form of either thereof, has been previously dried from a buffer, wherein the dried glucagon, glucagon analogue, or salt form of either thereof, has a first ionization profile that corresponds to an optimal stability and solubility for the glucagon, glucagon analogue, or salt form thereof, wherein the dried glucagon, glucagon analogue, or salt form of either thereof, is reconstituted into an aprotic polar solvent and has a second ionization profile in the aprotic polar solvent, and wherein the first and second ionization profiles are within 1 pH unit of one another.

46. The method of claim 45, where the first or second or both ionization profiles correspond to the ionization profile of glucagon when solubilized in an aqueous solution having a pH range of about 1 to 4 or 2 to 3.

47. The method of any one of claims 1 to 46, where the first composition is a two-phase mixture of a powder dispersed in a liquid that is a non-solvent to the solid, where the powder comprises the glucagon, glucagon analogue, or a salt form of either thereof, and where the liquid is a pharmaceutically acceptable carrier, where the powder is homogeneously contained within a pharmaceutically acceptable carrier.

48. The method of claim 47, where the first composition is a paste, slurry, or suspension.

49. The method of any one of claims 47 to 48, where the powder has a mean particle size ranging from 10 nanometers (0.01 microns) to about 100 microns, with no particles being larger than about 500 microns.

50. The method of any one of claims 1 to 49, where the first composition has been stored in the reservoir for at least 1, 2, 3, 4, 5, 6, 7, 14, 21, 30, 45, or 60 days.

51. The method of any one of claims 1 to 50, where the first composition remains stable after being stored for one month or 6 months or 12 months or 18 months at room temperature.

52. The method of any one of claims 1 to 51, further comprising administering a third composition to the subject, wherein the third composition comprises diazoxide or octreotide, or a combination thereof.

53. The method of claim 52, wherein the third composition is administered before administration of the first composition, preferably within 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 hour before administration of the first composition.

54. The method of claim 52, wherein the third composition is administered simultaneously with the first composition.

55. The method of claim 52, wherein the third composition is administered after administration of the first composition, preferably within 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 hour after administration of the first composition.

56. The method of any one of claims 1 to 55, wherein the subject is a human.

57. The method of claim 56, wherein the human is less than 20 years old, preferably less than 10 years old, more preferably less than 5 years old, or even more preferably within 0 to 3 years old, or within 0 to 12 months old.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0080] The following drawings illustrate by way of example and not limitation. For the sake of brevity and clarity, every feature of a given structure is not always labeled in every figure in which that structure appears. Identical reference numbers do not necessarily indicate an identical structure. Rather, the same reference number may be used to indicate a similar feature or a feature with similar functionality, as may non-identical reference numbers. The figures are drawn to scale (unless otherwise noted), meaning the sizes of the depicted elements are accurate relative to each other for at least the embodiment depicted in the figures.

[0081] FIG. 1 is a perspective view of a first embodiment of the present glucagon delivery apparatuses.

[0082] FIG. 2 is a cross-sectional side view of various components of the glucagon delivery apparatus of FIG. 1 shown coupled to a patient.

[0083] FIG. 3 is a schematic depicting various components of the glucagon delivery apparatus of FIG. 1.

[0084] FIGS. 4A-4C are side views of reservoirs containing various compositions of the present disclosure that are suitable for use in some embodiments of the present glucagon delivery apparatuses.

[0085] FIG. 4D is a top view of a reservoir suitable for use in some embodiments of the present glucagon delivery apparatuses.

[0086] FIG. 5 depicts an illustrative flow chart of one example of closed-loop control of one embodiment of the present glucagon delivery apparatuses.

[0087] FIG. 6 provides data that indicates a clinically significant reduction in the amount of glucose that must be infused (i.e. the glucose infusion rate (GIR)) to maintain the patient's glucose levels in the euglycemic range when used with and without glucagon CSI.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0088] Prior to the present invention, the typical process of treating CH includes diazoxide or octreotide to block insulin release from the pancreas, but these drugs have significant side effects and are effective in less than half of all cases. The other CH therapy is continuous infusion of an aqueous solution of dextrose (for example, a 50% (w/v) dextrose solution referred to hereafter as D50). However, D50 therapy typically requires high glucose infusion rate (GIR) via a peripherally inserted central catheter, or PICC line, which must be implanted surgically. The PICC line is a source of infection for the patient and a high GIR can cause fluid overload, which can lead to heart failure, pulmonary edema, and cyanosis.

[0089] The present invention offers a solution to the current D50 treatment method for CH. The solution is premised, in part, on a discovery that a stable and flowable glucagon formulation delivered as a continuous subcutaneous infusion (CSI) can be administered before or during D50 treatment, which can then result in lowering the GIR of D50 over a shorter time period than without the use of glucagon CSI. In one non-limiting embodiment, use of a glucagon formulation of the present invention in combination with a patch-pump (e.g. OmniPod) can enable treatment via a more convenient subcutaneous administration rather than the current paradigm which requires a surgically implanted PICC line, followed by years of IV infusion of D50. Without wishing to be bound by theory, it is believed that glucagon CSI can result in lower level D50 administration or even complete removal/avoidance of D50 administration altogether.

[0090] These and other aspects of the present invention are provided in non-limiting detail in the following subsections.

A. Glucagon Delivery Apparatuses and Related Methods

[0091] Referring now to FIGS. 1-4, shown therein and designated by the reference numeral 100 is a first non-limiting embodiment of the present glucagon delivery apparatuses. In the depicted embodiment, apparatus 100 comprises a housing 104, which generally functions to locate and/or secure components of apparatus 100 relative to one another. In the embodiment shown, glucagon delivery apparatus 100 is configured to intradermally, subcutaneously or intramuscularly deliver a composition comprising glucagon to a patient.

[0092] In the depicted embodiment, apparatus 100 comprises a reservoir 108a, which in this embodiment, may be disposed and/or disposable within housing 104. For example, in this embodiment, housing 104 defines and/or is configured to allow access to a receptacle 112, which may be dimensioned to receive and/or allow removal and/or replacement of reservoir 108a within housing 104.

[0093] In this embodiment, reservoir 108a may comprise a composition (e.g., 116a, 116b, 116c, and/or the like) (sometimes referred to collectively as composition 116 or compositions 116). The present glucagon delivery apparatuses can be used with any suitable storage stable composition, such as, for example, the glucagon containing formulations described throughout the present application.

[0094] In the embodiment shown, reservoir 108a comprises a cap 120. In this embodiment, cap 120 includes a puncturable seal 124 (e.g., which may be punctured by a needle or other sharp object external to or within apparatus 100, for example, when reservoir 108a is inserted into receptacle 112, to allow for communication of composition 116 from reservoir 108a to pump 128). In this way, compositions 116 can be stored prior to use, which may be facilitated by the stability of the compositions.

[0095] While some embodiments of the present glucagon delivery apparatuses do not comprise a composition having a protein or peptide capable of decreasing the blood glucose level of a patient, other embodiments may comprise a composition including a glucose-reducing formulation (e.g., insulin, an insulin memetic peptide, incretin, an incretin mimetic peptide, and/or the like, as described above). For example, some embodiments may comprise a (e.g., additional to reservoir 108a) reservoir 108b containing the glucose-reducing formulation, and, in such embodiments, pump 128 (described in more detail below) may be configured to intracutaneously delivery at least a portion of the glucose-reducing formulation (an example of such a configuration is depicted in FIG. 3, which may include a valve to selectively place either reservoir 108a or reservoir 108b in communication with pump 128). In these and similar embodiments, housing 104 may comprise a receptacle (e.g., 112) dimensioned to receive and/or allow removal and/or replacement of reservoir 108b within housing 104.

[0096] In the embodiment shown, apparatus 100 comprises an electronic pump 128 configured to intracutaneously delivery at least a portion of the composition to a patient. Pumps of the present disclosure can comprise any suitable pump, such as, for example, positive displacement pumps (e.g., gear pumps, screw pumps, peristaltic pumps, piston pumps, plunger pumps, and/or the like), centrifugal pumps, and/or the like. In this embodiment, pump 128 is electronic (e.g., is configured to be actuated electrically, for example, by an electric motor with power supplied from a battery 132); however, in other embodiments, the pump may be actuated manually (e.g., via application of force by a user, for example, to a plunger, lever, crank, and/or the like). In this embodiment, pump 128 is in communication with a needle 136 via an (e.g., flexible) conduit 140 such that actuation of pump 128 may cause communication of composition 116 from reservoir 108a, through conduit 140, and into the patient via needle 136 (e.g., which, in some embodiments, may be configured to be received within an implanted port of the patient). An example of such composition communication is depicted in FIG. 3, in which composition communication is indicated by dashed lines 144, and electrical communication is indicated by dotted lines 148.

[0097] In the embodiment shown, apparatus 100 comprises a sensor 152 configured to obtain data indicative of a glucose level within interstitial fluid of the patient (e.g., by measuring a current generated as glucose oxidase (GOx) catalyzes the reaction of glucose in the interstitial fluid with oxygen). The level can then be used to determine the blood glucose level of the patient or can be used to determine how much of the glucagon formulation to administer to the patient. For example, and referring particularly to FIG. 2, in this embodiment, a portion of sensor 152 (e.g., which may include a needle, electrodes, and/or the like) is inserted into a patient's skin 156 and is in communication with the interstitial fluid.

[0098] In the embodiment shown, sensor 152 is configured to transmit data wirelessly. For example, in this embodiment, sensor 152 is configured to transmit data via radio frequency (e.g., whether in response to a signal generated by a reader 160 and/or facilitated by a battery in electrical communication with the sensor). However, in other embodiments, sensor 152 can be configured to transmit data via a wired connection.

[0099] In the embodiment shown, apparatus 100 comprises a monitor 164 configured to communicate information indicative of the glucose level within the interstitial fluid of the patient. Monitors 164 of the present disclosure can comprise any suitable monitor, and can be configured to communicate information audibly (e.g., via a speaker 164a), tactilely (e.g., via a vibratory motor), visually (e.g., via a display device 164b), and/or the like. For example, in this embodiment, monitor 164 comprises a speaker 164a and a display device 164b. While monitor 164 is depicted as attached to housing 104 of apparatus 100, in other embodiments, monitors (or components thereof, such as, for example, speaker 164a or display device 164b) may be physically separate from housing 104 (e.g., and in wireless and/or wired communication with other components of apparatus 100). In this way, by receiving information communicated by monitors 164, a patient using apparatus 100 may gain insight into how food intake, physical activity, medication, illness, and/or the like impact blood glucose levels.

[0100] In the embodiment shown, monitor 164 can be configured to communicate alerts under any suitable circumstance (e.g., triggers for which may be stored within a memory in electrical communication with processor 172). To illustrate, in this embodiment, apparatus 100 is configured such that monitor 164 communicates an alert when a glucose level within interstitial fluid of the patient is estimated to be at least one of: above a threshold (e.g., indicating an existing or impending hypoglycemic condition) and below a threshold (e.g., indicating an existing or impending hyperglycemic condition). Processor 172 may detect impending conditions by analyzing data received from sensor 152 over a time period to anticipate a patient's blood glucose level at a future time period (e.g., by determining trends within the patient's blood glucose level over time).

[0101] In this embodiment, apparatus 100 is configured to allow manual adjustment of at least one of a delivery rate and a dose of the composition intracutaneously delivered by pump 128. For example, in the embodiment shown, apparatus 100 comprises one or more user input devices (e.g., buttons) 168. User input devices 168 can be configured to allow a user to activate and/or deactivate apparatus 100 and/or pump 128, set a time and/or time period for activation and/or deactivation of apparatus 100 and/or pump 128, set a desired blood glucose level, set a desired composition delivery rate and/or dose (e.g., basal and/or bolus doses), and/or the like. User input devices 168 may work in conjunction with monitor 164 (or a display device 164b thereof) (e.g., to provide information to assist a user in interacting with apparatus 100, to provide for menu navigation, to display current parameters (e.g., target blood glucose level, composition delivery rate and/or dose, and/or the like), and/or the like). While in the depicted embodiment, user input devices 168 comprise buttons, in other embodiments, user input devices 168 can comprise any suitable structure, such as, for example, touch sensitive surface(s) of a display device 164b.

[0102] In the embodiment shown, apparatus 100 comprises a processor 172 configured to control operation of pump 128. In the embodiment shown, processor 172 control can be open-loop or closed-loop (e.g., based, at least in part, on data obtained by sensor 152). To illustrate, in this embodiment, processor 172 is configured to control operation of pump 128 to intracutaneously inject at least a portion of composition 116 if the data obtained by the sensor indicates a blood glucose level within interstitial fluid of the patient below a threshold (e.g., indicating an existing or impending hyperglycemic condition). FIG. 5 provides an illustrative flow chart of such closed-loop processor-based control. For example, at step 176, processor may receive data from sensor 152 indicative of the glucose level within interstitial fluid of the patient (e.g., through communication with reader 160). At step 180, in this embodiment, processor 172 may compare the received data to a targeted or threshold value. In the depicted embodiment, at step 184, if the data indicates a blood glucose level within interstitial fluid of the patient is below the targeted or threshold value, processor 172 may command pump 128 to actuate to cause intracutaneous delivery of composition 116 to the patient. Embodiments configured for such closed-loop control may require no input from a patient, and may be suited for treating patients having, for example, type II insulin dependent diabetes, post-bariatric surgery reactive hypoglycemia, hypoglycemia associated autonomic failure, insulinoma, and/or the like.

[0103] In some embodiments (e.g., 100), the present apparatuses can be configured to communicate (e.g., via a display 164b) data indicative of current blood glucose level to a patient, whereby the patient may adjust the delivery rate, dose, and/or the like of composition 116 (e.g., controlling apparatus 100 in an open-loop fashion). Embodiments configured for such open-loop control may be suited for treating patients having, for example, type I insulin dependent diabetes, type II insulin dependent diabetes, and/or the like.

[0104] Some embodiments may be configured to provide intradermal, subcutaneous or intramuscular delivery of composition 116 in a no-loop fashion. For example, some embodiments may be configured such that pump 128 actuates to deliver a fixed (e.g., basal) dose of composition 116. In these and similar embodiments, sensor 152, reader 160, monitor 164, user input devices 168, processor 172, and/or the like may be omitted. Such embodiments may be suitable for treating patients having, for example, congenital hyperinsulinism, post-bariatric surgery reactive hypoglycemia, and/or the like.

[0105] Some embodiments of the present methods for treating CH in a patient comprise using a glucagon delivery apparatus (e.g., 100) to intradermally, subcutaneously or intramuscularly deliver at least a portion of a composition (e.g., 116) to the patient. In some embodiments, the patient has been diagnosed as having a blood glucose level from 0 mg/dL to less than 50 mg/dL or has an indication of impending hypoglycemia before delivery of the composition, and the patient has a blood glucose level from 50 mg/dL to 180 mg/dL within 1 to 30 minutes after delivery of the composition. In some embodiments, the patient has been diagnosed as having a blood glucose level between from 10 mg/dL to less than 40 mg/dL. In some embodiments, the patient has a blood glucose level from 50 mg/dL to 180 mg/dL within 1 to 30 minutes after delivery of the composition. In some embodiments, the patient has a blood glucose level from 50 mg/dL to 180 mg/dL within 1 to 15 minutes after delivery of the composition. In some embodiments, the patient has been diagnosed with type I, type II, or gestational diabetes. Some embodiments comprise measuring, with a sensor (e.g., 152), the blood glucose level of the patient.

B. Commercially Available Glucagon Formulations

[0106] In addition to the glucagon formulations discussed above, it is also contemplated in the context of the present invention that commercially available glucagon formulations can be used in the context of the present invention for treating CH and ultimately reducing D50 GIR levels or even avoiding the need for D50 therapy. Non-limiting examples of commercially available glucagon formulations include the Glucagon Emergency Kit (Eli Lilly) and the GlucaGen rescue kit (Novo Nordisk), both of which are sold as powders that must be reconstituted with a diluent syringe at the time of administration and are prone to fibrillation and gelation during storage.

[0107] Determination of an effective amount or dose is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, the formulations to deliver these doses may contain a glucagon peptide present at a concentration from about 0.1 mg/mL up to the solubility limit of the peptide in the formulation to produce a solution, wherein the glucagon peptide is fully or completely solubilized in the aprotic polar solvent. This concentration is preferably from about 1 mg/mL to about 100 mg/mL, e.g., about 1 mg/mL, about 5 mg/mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, about 60 mg/mL, about 65 mg/mL, about 70 mg/mL, about 75 mg/mL, about 80 mg/mL, about 85 mg/mL, about 90 mg/mL, about 95 mg/mL, or about 100 mg/mL.

C. Treating Congenital Hyperinsulinism

[0108] Congenital hyperinsulinism (CH) is a genetic disorder of pancreatic (3-cell function characterized by failure to suppress insulin secretion in the presence of hypoglycemia, resulting in brain damage or death if inadequately treated. CHI is a relatively rare disease. For instance, it can affect 1 in 25,000 to 50,000 babies/infants. Germline mutations in several genes have been associated with congenital hyperinsulinism. These mutations can include, for example, the sulfonylurea receptor (SUR-1, encoded by ABCC8), an inward rectifying potassium channel (Kir6.2, encoded by KCNJ1 1), glucokinase (GCK), glutamate dehydrogenase (GLUD-1), short-chain L-3-hydroxyacyl-CoA (SCHAD, encoded by HADSC) and/or mitochondrial uncoupling protein 2 (UCP2). A non-limiting example of the application of the disclosed invention can include identifying a CHI patient that requires a glucose infusion rate (GIR) of 20 mg/(kg*min) to maintain a targeted euglycemic blood glucose level of 100 mg/dL. The patch-pump containing 5 mg/mL non-aqueous glucagon formulation can be turned on, delivering a continuous subcutaneous glucagon infusion rate of 5 mcg/(kg*hr). The glucose of the CHI patient will begin to rise, which will require the clinician to decrease the glucagon infusion rate to maintain the targeted 100 mg/dL blood glucose level. The infusion rate of the stable and soluble exogenous glucagon formulation can be increased (e.g. up to 25 mcg/(kg*hr)) to allow the GIR to drop sufficiently low (e.g. <8 mg/(kg*min)) such that the peripherally inserted central catheter may be removed from the patient.

EXAMPLES

[0109] Some embodiments of the present disclosure will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit any present invention in any manner. For example, those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results.

Example 1

Ionization Stabilized Glucagon Composition

[0110] As a non-limiting example of a stable and flowable glucagon formulation that may be used in the context of the present invention, the preparation of a stable, non-aqueous glucagon solution is described. In this example, glucagon solutions were prepared by dissolving glucagon peptide powder (Bachem AG) in acidified DMSO containing dissolved 5% (w/v) trehalose (from dihydrate) and optionally mannitol (2.9% (w/v)). The DMSO solution was acidified with 3.0-3.2 mM H.sub.2SO.sub.4 (from a 1.0 N sulfuric acid stock solution). Samples were stored in both glass and CZ (Crystal Zenith) vials (0.5-mL fill volume in 2-mL vials) and placed on stability 40 C./75% RH. Chemical stability of the samples was examined following 60 days using a glucagon stability indicating UHPLC-MS method.

[0111] The reversed-phase ultra-high-performance liquid chromatography-mass spectrometry (RP-UHPLC-MS) method used to assess chemical stability was a gradient method with mobile phases A and B respectively consisting of 1% (v/v) FA (Formic Acid) in water and 1% (v/v) FA in acetonitrile. A C8 column (2.1 mm I.D.100 mm length, 1.7 micron particle size) was used with a column temperature of 60 C., a 0.55 mL/min flow rate, 5-L sample injection volume and 280-nm detection wavelength. The chemical stability data provided in Table 1 indicate that the soluble non-aqueous glucagon formulation exhibits long-term stability at accelerated conditions in both glass and COP (CZ) container-closure systems.

TABLE-US-00001 TABLE 1 Chemical stability (provided as glucagon peak purity) for a soluble, non-aqueous 5 mg/mL glucagon formulation following 60 days at 40 C./75% RH. Data is provided as the average (standard deviation) for N = 3 sample replicates. Physical Glucagon Peak CCS Excipients Appearance Purity Glass 5% (w/v) Trehalose Clear, Colorless 90.2 (0.1)% 3.0 mM H.sub.2SO.sub.4 Solution CZ 5% (w/v) Trehalose Clear, Colorless 87.5 (0.4)% 3.0 mM H.sub.2SO.sub.4 Solution Glass 5% (w/v) Trehalose Clear, Colorless 90.1 (0.3)% 2.9% (w/v) Mannitol Solution 3.2 mM H.sub.2SO.sub.4 CZ 5% (w/v) Trehalose Clear, Colorless 88.0 (0.5)% 2.9% (w/v) Mannitol Solution 3.2 mM H.sub.2SO.sub.4

Example 2

Clinical Study Data On Effects of Glucagon CSI vis--vis Glucose D50 Treatment

[0112] An ongoing clinical trial is being performed to evaluate whether CSI-Glucagon (non-aqueous glucagon formulation in DMSO) can reduce or eliminate the glucose infusion requirement (administered IV) in infants with congenital hyperinsulinism (CHI). Patients <1 year of age with CHI that requires glucose infusion to prevent hypoglycemia and that are non-responsive to diazoxide. The patient will be given a randomized, blinded 48-hour continuous infusion treatment that will compare the glucose infusion rate (GIR) response between glucagon and placebo. This study will evaluate the effect of exogenous glucagon administered by continuous subcutaneously infusion via patch-pump (e.g. OmniPod) by measuring the rate of glucose that must be infused to maintain the blood sugar in the euglycemic range (>70 mg/dL). The lower the GIR, the greater the effect of the exogenous glucagon.

[0113] In the clinical trial, half the subjects are given placebo and the other half CSI glucagon during a 2-day blinded phase, while continuing D50. Following the blinded phase, subjects are eligible for open-label CSI glucagon. The blind has not been broken (as of Jul. 14, 2018), but open-label results from one study subject treated to-date are available. The CSI glucagon administered in this study was a non-aqueous glucagon formulation with a peptide concentration of 5 mg/mL with 5% (w/v) trehalose dissolved in dimethyl sulfoxide (DMSO).

[0114] As shown in FIG. 6, an infant receiving CSI glucagon experienced a clinically meaningful 65% reduction in GIR, comparing the average level during the last 12 hours of the blinded phase and the last 12 hours of open-label treatment. During CSI-glucagon treatment, glucagon infusion rate (GIR) was reduced to an average of 6.2 mg/(kg*min), a level that would allow removal of the PICC line for long-term maintenance. No side effects or signs of intolerance were observed.

[0115] In summary, the data indicates a clinically significant reduction in the amount of glucose that must be infused to maintain the patient's glucose levels in the euglycemic range.

[0116] All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this disclosure have been described in terms of some embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit, and scope of the disclosure. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope, and concept of any invention as defined by the appended claims.

[0117] Embodiments of the present disclosure have been described in an illustrative manner, and it is to be understood that the particular embodiments depicted in the figures and the terminology which has been used has been intended in a nature of words of description rather than of limitation. It is to be further understood that any combination of the ingredients/therapeutic agents described in the foregoing paragraphs are deemed to be encompassed by the appended claims. It is to be further understood that all specific embodiments of the delivery apparatus are deemed to be encompassed by the appended claims. Many modifications and variations of the present disclosure are possible in light of the above teachings. It is therefore to be understood that the obvious modifications are deemed to be encompass within the appended claims.

[0118] The above specification and examples provide a complete description of the structure and use of illustrative embodiments. Although certain embodiments have been described above with a certain degree of particularity, or with reference to one or more individual embodiments, those skilled in the art could make numerous alterations to the disclosed embodiments without departing from the scope of this disclosure. As such, the various illustrative embodiments of the methods and systems are not intended to be limited to the particular forms disclosed. Rather, they include all modifications and alternatives falling within the scope of the claims, and embodiments other than the one shown may include some or all of the features of the depicted embodiment. For example, elements may be omitted or combined as a unitary structure, and/or connections may be substituted. Further, where appropriate, aspects of any of the examples described above may be combined with aspects of any of the other examples described to form further examples having comparable or different properties and/or functions, and addressing the same or different problems. Similarly, it will be understood that the benefits and advantages described above may relate to one embodiment or may relate to several embodiments.

[0119] The claims are not intended to include, and should not be interpreted to include, means-plus- or step-plus-function limitations, unless such a limitation is explicitly recited in a given claim using the phrase(s) means for or step for, respectively.