Buffered formulations of exendin (9-39)
Provided herein are liquid pharmaceutical formulations comprising exendin (9-39) or a pharmaceutically acceptable salt thereof and a tonicity modifier in a physiologically acceptable buffer having a pH in the range of about 5 to about 6. In some embodiments, the buffered liquid formulation comprises exendin (9-39) or a pharmaceutically acceptable salt thereof in an acetate buffer or a citrate buffer. Methods of treating or preventing hyperinsulinemic hypoglycemia in a subject comprising administering to the subject the buffered liquid formulation are also provided.
1 . A liquid pharmaceutical formulation comprising exendin (9-39) or a pharmaceutically acceptable salt thereof and a tonicity modifier in a physiologically acceptable buffer having a pH in from about 5.1 to about 6, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof does not exhibit detectable aggregation in the formulation.
2 . The liquid pharmaceutical formulation of claim 1 , wherein the pH is from about 5.5 to about 6.
3 . The liquid pharmaceutical formulation of claim 1 , wherein the pH is from 5.2 to 6.
4 . The liquid pharmaceutical formulation of claim 1 , wherein the physiologically acceptable buffer comprises an acetate buffer, a citrate buffer, a histidine buffer, a phosphate buffer, or a mixture of two or more thereof.
5 . The liquid pharmaceutical formulation of claim 1 , wherein the physiologically acceptable buffer comprises one or more of sodium acetate, potassium acetate, trisodium citrate, magnesium citrate, potassium citrate, and potassium phosphate.
6 . The liquid pharmaceutical formulation of claim 1 , wherein the tonicity modifier comprises mannitol, dextrose, glycerin, lactose, sucrose, or trehalose.
7 . The liquid pharmaceutical formulation of claim 1 , wherein the liquid pharmaceutical formulation is formulated as a single-use prefilled syringe, as a sterile isotonic solution in a vial or ampule, or as cartridge pen-injector device.
8 . The liquid pharmaceutical formulation of claim 1 , wherein the liquid pharmaceutical formulation further comprises one or more preservatives.
9 . The liquid pharmaceutical formulation of claim 1 , wherein the liquid pharmaceutical formulation further comprises one or more surfactants.
10 . The liquid pharmaceutical formulation of claim 1 , wherein the pharmaceutically acceptable salt of exendin (9-39) comprises sulfate, hydrochloride, phosphate, sulfamate, acetate, trifluoroacetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, or quinate.
11 . The liquid pharmaceutical formulation of claim 1 , wherein the detectable aggregation in the formulation is determined by whether the formulation remains as a non-gelatinous solution when stored at 50° C. for 18, 24, 36, 48 or 72 hours, and/or by visual or light microscopy inspection of the formulation for aggregation or precipitation when stored at 50° C. for 18, 24, 36, 48 or 72 hours.
12 . A method of treating hyperinsulinemic hypoglycemia in a human subject, comprising administering to the human subject a liquid pharmaceutical formulation comprising exendin (9-39) or a pharmaceutically acceptable salt thereof and a tonicity modifier in a physiologically acceptable buffer having a pH of from about 5.1 to about 6, wherein the exendin (9-39) or the pharmaceutically acceptable salt thereof does not exhibit detectable aggregation in the formulation, and wherein liquid pharmaceutical formulation is administered to the human subject in an amount effective to prevent or reduce symptoms of the hyperinsulinemic hypoglycemia.
13 . The method of claim 12 , wherein the liquid pharmaceutical formulation is administered by oral, intravenous, buccal, rectal, parenteral, intraperitoneal, intradermal, intramuscular, subcutaneous, or inhalational administration.
14 . The method of claim 12 , wherein the pH is from about 5.5 to about 6.
15 . The method of claim 12 , wherein the pH is from 5.2 to 6.
16 . The method of claim 12 , wherein the human subject previous had bariatric surgery and/or a related metabolic procedure.
17 . The method of claim 16 , wherein the bariatric surgery and/or the related metabolic procedure comprises Roux-en-Y Gastric Bypass, Vertical Sleeve Gastrectomy, placement of an endosleeve device, duodenal mucosal resurfacing, partial bypass of duodenum, vagal nerve blockade, or pyloroplasty.
18 . The method of claim 12 , wherein the human subject previous had a surgical procedure involving gastrointestinal system.
19 . The method of claim 18 , wherein the surgical procedure comprises esophagectomy, Nissen Fundoplication, or gastrectomy.
20 . The method of claim 12 , wherein the human subject is prediabetic and/or insulin resistant.
21 . The method of claim 12 , wherein treating hyperinsulinemic hypoglycemia reduces the risk, frequency, or severity of hypoglycemic episodes in the human subject.