TREATMENT OF EXERCISE-INDUCED HYPOGLYCEMIA IN TYPE 1 AND INSULIN USING TYPE 2 DIABETES
Certain embodiments are directed to methods for treating, ameliorating, or preventing exercise-induced or exercise-associated hypoglycemia comprising administration to a subject in need thereof a formulation(s) of glucagon or glucagon analog in an amount effective to treat, ameliorate, or prevent the condition. The subject can be administered a glucagon or a glucagon analog composition 1, 5, 10, 15 to 20, 25, 30 minutes prior to initiation of exercise.
1 .- 31 . (canceled)
32 . A method for preventing or treating exercise-induced hypoglycemia in a subject comprising administering a composition comprising glucagon or a glucagon analog 5 to 30 minutes prior to initiation of exercise.
33 . The method of claim 32 , wherein the subject is a diabetic subject.
34 . The method of claim 33 , wherein the diabetic subject uses exogenous insulin.
35 . The method of claim 32 , wherein the composition comprises 50 to 300 μg of glucagon or glucagon analog.
36 . The method of claim 35 , wherein the composition comprises 150 μg of glucagon or glucagon analog.
37 . The method of claim 32 , wherein the composition is administered as a bolus.
38 . The method of claim 32 , wherein the composition is administered as an infusion over 5 to 45 minutes.
39 . The method of claim 32 , wherein the composition is administered from a delivery apparatus, wherein the apparatus comprises: (i) a reservoir containing the glucagon or glucagon analog composition; and (ii) an electronic pump configured to intradermally, subcutaneously, or intramuscularly deliver at least a portion of the composition to a subject.
40 . The method of claim 39 , wherein the apparatus is a closed-loop, open-loop, or no loop system for delivering the composition to the subject.
41 . The method of claim 32 , wherein the composition is a single-phase solution comprising glucagon, a glucagon analog, or salt thereof, dissolved in a non-aqueous solvent.
42 . The method of claim 41 , wherein the non-aqueous solvent is an aprotic polar solvent.
43 . The method of claim 42 , wherein the aprotic polar solvent is DMSO.
44 . The method of claim 42 , wherein the aprotic polar solvent is a deoxygenated aprotic polar solvent.
45 . The method of claim 42 , wherein the composition further comprises an ionization stabilizing excipient, wherein (i) the glucagon, glucagon analog, or salts thereof is dissolved in the aprotic polar solvent in an amount from about 0.1 mg/mL up to the solubility limit of the glucagon, glucagon analog, or salt thereof, and (ii) the ionization stabilizing excipient is dissolved in the aprotic polar solvent in an amount sufficient to stabilize the ionization of the glucagon, glucagon analog, or salt thereof.
46 . The method of claim 45 , wherein the ionization stabilizing excipient is at a concentration of 0.1 mM to 100 mM.
47 . The method of claim 45 , wherein the ionization stabilizing excipient is a mineral acid.
48 . The method of claim 47 , wherein the mineral acid is sulfuric acid.
49 . The method of claim 45 , wherein the ionization stabilizing excipient is sulfuric acid and the aprotic polar solvent is DMSO.
50 . The method of claim 45 , wherein the composition has a moisture content of less than 10, 5, or 3%.
51 . The method of claim 45 , wherein the composition further comprises a preservative at less than 10, 5, or 3% w/v.
52 . The method of claim 51 , wherein the preservative is benzyl alcohol, methyl parabens, propyl parabens, or mixtures thereof.
53 . The method of claim 45 , wherein the composition further comprises a sugar alcohol at less than 10, 5, or 3% w/v.
54 . The method of claim 53 , wherein the sugar alcohol is mannitol or sorbitol.
55 . The method of claim 47 , wherein the composition further comprises one or more sugars or starches.
56 . The method of claim 55 , wherein the sugar is trehalose, glucose, or sucrose.
57 . The method of claim 55 , wherein the composition comprises at least 80 wt.% of the aprotic polar solvent, 3 to 7 wt. % of the sugar or starch, 0.001 to 0.1 wt. % of an amphoteric molecule, and 0 wt. % to less than 0.1 wt. % of the acid.
58 . The method of claim 32 , wherein the composition has a water content of less than 15 wt. %, less than 3 wt. %, 3 to 10 wt. %, or 5 to 8 wt. %.
59 . The method of claim 43 , wherein the glucagon, glucagon analog, or salts thereof, has (i) been previously dried from a buffer; (ii) has a first ionization profile that corresponds to an optimal stability and solubility for the glucagon, glucagon analog, or salt form thereof; (iii) is reconstituted into an aprotic polar solvent; and (iv) has a second ionization profile in the aprotic polar solvent, wherein the first and second ionization profiles are within 1 pH unit of one another.
60 . The method of claim 32 , wherein the composition has been stored in the reservoir for at least 1, 2, 3, 4, 5, 6, 7, 14, 21, 30, 45, or 60 days.