STABILIZED ULTRA-RAPID-ACTING INSULIN FORMULATIONS
Compositions and methods for enhancing the stability of rapid acting injectable insulin formulations have been developed for subcutaneous injection. The formulations contain insulin in combination with a zinc chelator such as ethylenediaminetetraacetic acid (“EDTA”), a dissolution/stabilization agent such as citric acid, a magnesium salt, a zinc compound and, optionally, additional excipients. New presentations include rapid acting concentrated insulin formulations and a way to enhance the absorption of commercially available rapid acting analog formulations while maintaining insulin stability.
1 . An injectable insulin formulation comprising an effective amount of a dissolution/stabilizing agent and an effective amount of a chelator to enhance the stability of the insulin as measured by loss of insulin potency of less than 5 IU at 7 days at 37° C.
2 . The formulation of claim 1 wherein the insulin is human recombinant insulin.
3 . The formulation claim 1 where the insulin is an insulin analog.
4 . The formulation of claim 1 wherein the insulin concentration is 100, 200, 400 or 500 U/mL.
5 . The formulation of claim 1 wherein the chelator is EDTA and the concentration of EDTA is between 0.1125 and 0.225 mg/ml of the formulation.
6 . The formulation of claim 5 , comprising sodium citrate at a concentration between 0.5 and 4.8 mg/ml of the formulation.
7 . The formulation of claim 1 comprising a zinc compound providing a zinc:insulin hexamer ratio between 0.4 and 2.6.
8 . The formulation of claim 7 wherein the zinc:insulin hexamer ratio is between 0.7 and 0.9.
9 . The formulation of claim 6 , wherein the dissolution agent is citrate or sodium citrate at a concentration between 0.6 mg/ml and 2.4 mg/ml of the formulation.
10 . The formulation of claim 1 , further comprising a nicotinic compound in a range between 25 mM and 250 mM.
11 . The formulation of claim 10 comprising about 50 mM nicotinamide.
12 . The formulation of claim 1 , further comprising one or more magnesium compounds are selected from the group consisting of inorganic magnesium salts, organic magnesium salts, and combinations thereof.
13 . The formulation of claim 12 , wherein the one or more magnesium compounds are Mg(OH) 2 , MgSO 4 , magnesium EDTA, or combinations thereof.
14 . The formulation of claim 1 , wherein the concentration of the one or magnesium compounds is about 0.1 to about 10 mg/ml, preferably from about 0.1 to about 5 mg/ml, more preferably from about 0.1 to about 2 mg/ml, most preferably from about 0.2 to about 2 mg/ml.
15 . The formulation of claim 1 wherein the dissolution/stabilization agent is selected from the group consisting of acetic acid, ascorbic acid, citric acid, glutamic, succinic, aspartic, maleic, fumaric, adipic acid, and salts thereof.
16 . The formulation of claim 1 wherein the dissolution/stabilization agent forms citric ions and the pH is about 7.
17 . The formulation of claim 1 further comprising calcium chloride.
18 . The formulation of claim 1 further comprising glycerine and m-cresol.
19 . The formulation of claim 1 , wherein the chelator is sodium EDTA.
20 . A method of treating a diabetic individual comprising injecting into the individual an effective amount of the formulations of claim 1 .
21 . A method of decreasing injection site pain a diabetic individual comprising injecting the individual with an effective amount of the formulation of claim 1 .