Sustained release formulations using non-aqueous carriers

Abstract

The disclosure provides one-component, injectable, sustained release formulations which comprise microspheres containing active pharmaceutical ingredients (e.g., exenatide), wherein the microspheres are suspended in a non-aqueous carrier. The non-aqueous carrier can be an oil, a fractionated oil, triglycerides, diglycerides, monoglycerides, propylene glycol fatty acid diesters, and the like. The formulations offer distinct advantages of long shelf life for the stability and potency of the formulation and sustained release of active pharmaceutical ingredients to reduce the frequency of medication dosing and to increase patient compliance.

1 . (canceled) 
     
     
         2 . A manufactured pre-mixed formulation comprising a suspension of
 (i) a pharmaceutically acceptable non-aqueous carrier comprising one or more glycerol or propylene glycol esters of fatty acids, wherein the one or more esters comprise 0 to 2 wt %, C 6  fatty acid, 50 to 65 wt % C 8  fatty acid, 30 to 45 wt % C 10  fatty acid, 0 to 2 wt % C 12  fatty acid, and 0 to 2 wt % C 14  fatty acid based on the total fatty acid content of the one or more esters; and   (ii) microspheres comprising a biocompatible, biodegradable polymer and an active pharmaceutical ingredient.   
     
     
         3 - 11 . (canceled) 
     
     
         12 . The formulation of  claim 2 , wherein the one or more glycerol esters of the fatty acids are one or more monoglycerides, one or more diglycerides, one or more triglycerides, or a combination of two or more thereof. 
     
     
         13 . The formulation of  claim 2 , wherein the one or more propylene glycol esters of the fatty acids are propylene glycol diesters. 
     
     
         14 . The formulation of  claim 2 , wherein the fatty acids are saturated fatty acids. 
     
     
         15 . The formulation of  claim 12 , wherein the one or more glycerol esters of the fatty acids are one or more triglycerides which comprise esters of C 6  to C 12  fatty acids. 
     
     
         16 - 18 . (canceled) 
     
     
         19 . The formulation of  claim 15 , wherein the triglycerides further comprise ester of C 14  fatty acid. 
     
     
         20 . (canceled) 
     
     
         21 . The formulation of  claim 2 , further comprising a pharmaceutically acceptable excipient. 
     
     
         22 . The formulation of  claim 21 , wherein the pharmaceutically acceptable excipient is a sugar or a sugar alcohol. 
     
     
         23 . The formulation of  claim 21 , wherein the pharmaceutically acceptable excipient is sucrose, glucose, dextrose, galactose, maltose, trehalose, fructose, maltodextrin, glycol, glycerol, erythritol, threitol, arabitol, ribitol, sorbitol, dulcitol, iditol, isomalt, maltitol, lactitol, mannitol, xylitol, benzoic acid, sorbic acid, meta cresol, sodium benzoate, potassium sorbate, methylparaben, propylparaben, butylparaben, benzalkonium chloride, sodium metabisulfite, butylated hydroxy anisole, butylated hydroxy toluene, sodium sulfite, tocopherol thymol, ascorbate, propyl gallate, or a combination of two or more thereof. 
     
     
         24 . The formulation of  claim 23 , wherein the pharmaceutically acceptable excipient is sucrose. 
     
     
         25 . The formulation of  claim 2 , wherein the biocompatible, biodegradable polymer is a polylactide, a copolymer of a polylactide, a polyglycolide, a copolymer of a polyglycolide, a poly(lactide-co-glycolide) copolymer, a polylactic acid, a copolymer of a polylactic acid, a polyglycolic acid, a copolymer of a polyglycolic acid, a poly(lactic acid-co-glycolic acid) copolymer, a polycaprolactone, a copolymer of a polycaprolactone, a polycarbonate, a copolymer of a polycarbonate, a polyesteramide, a copolymer of a polyesteramide, a polyanhydride, a copolymer of a polyanhydride, a polyamino acid, a copolymer of a polyamino acid, a polyorthoester, a copolymer of a polyorthoester, a polycyanoacrylate, a copolymer of a polycyanoacrylate, a poly(p-dioxanone), a copolymer of a poly(p-dioxanone), a polyalkylene oxalate, a copolymer of a polyalkylene oxalate, a polyurethane, a copolymer of a polyurethane, or a combination of two or more thereof. 
     
     
         26 . The formulation of  claim 2 , wherein the biocompatible, biodegradable polymer is a poly(lactide-co-glycolide) copolymer. 
     
     
         27 - 29 . (canceled) 
     
     
         30 . The formulation of  claim 2 , wherein the active pharmaceutical ingredient is a GLP-1 receptor agonist. 
     
     
         31 . The formulation of  claim 2 , wherein the active pharmaceutical ingredient is exenatide. 
     
     
         32 . The formulation of  claim 2 , wherein the active pharmaceutical ingredient is GLP-1 (7-37) or GLP-1(7-36)-NH 2 . 
     
     
         33 . The formulation of  claim 2 , wherein the active pharmaceutical ingredient is pramlintide, davalintide, Val 27 -davalintide, metreleptin, insulin, a glucagon agonist or antagonist, a chimera of a GLP-1 receptor agonist and a glucagon agonist, bovine serum albumin, sodium salicylate, salicylic acid, minocycline HCl, insulin, or a small molecule organic compound. 
     
     
         34 - 46 . (canceled) 
     
     
         47 . The formulation of  claim 2 , wherein the microspheres are present in the formulation at a concentration of from 10 mg/ml to 500 mg/ml. 
     
     
         48 . The formulation of  claim 31 , wherein the exenatide is present in the microspheres in an amount of about 5 wt %. 
     
     
         49 . The formulation of  claim 21 , wherein the pharmaceutically acceptable excipient is sucrose, the biocompatible, biodegradable polymer is a poly(lactide-co-glycolide) copolymer, and the active pharmaceutical ingredient is exenatide. 
     
     
         50 - 66 . (canceled) 
     
     
         67 . A method for treating diabetes, stimulating insulin release; lowering plasma glucagon; reducing food intake; reducing appetite; decreasing gastric motility; delaying gastric emptying: lowering plasma lipid levels; treating impaired glucose tolerance; treating hyperglycemia: treating obesity: treating overweight; treating fatty liver disease: or treating non-alcoholic steatohepatitis in a patient in need thereof, the method comprising administering to the patient the formulation of  claim 2 . 
     
     
         68 - 89 . (canceled) 
     
     
         90 . The kit of claim  88 , wherein the container is a single-dose or multi-dose pen injector, a single-dose or multi-dose vial, or a single-dose or multi-dose cartridge. 
     
     
         91 - 118 . (canceled)