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.

What is claimed is: 
     
         1 . A manufactured pre-mixed formulation for injection comprising a suspension of:
 a pharmaceutically acceptable non-aqueous carrier comprising one or more esters of C 6 -C 12  fatty acids; and   microspheres comprising a biocompatible, biodegradable polymer and an active pharmaceutical ingredient;   wherein the one or more esters of C 6 -C 12  fatty acids are selected from the group consisting of:   (i) esters of three C 8  fatty acids;   (ii) esters of three C 10  fatty acids;   (iii)esters of two C 8  fatty acids and ester of one C 10  fatty acid;   (iv)esters of two C 10  fatty acids and ester of one C 8  fatty acid;   (v) esters of two C 8  fatty acids and ester of one C 6  fatty acid;   (vi)esters of two C 10  fatty acids and ester of one C 6  fatty acid;   (vii) esters of one C 8  fatty acid, ester of one C 10  fatty acid and ester of one C 6  fatty acid; and   (viii) any combination of esters of C 6 , C 8 , C 10  and C 12  fatty acids.   
     
     
         2 . The manufactured pre-mixed formulation of  claim 1 , wherein the one or more esters of C 6 -C 12  fatty acids comprise one or more monoglycerides of C 6 -C 12  fatty acids, one or more diglycerides of C 6 -C 12  fatty acids, one or more triglycerides of C 6 -C 12  fatty acids, or a combination thereof. 
     
     
         3 . The manufactured pre-mixed formulation of  claim 1 , wherein the one or more esters of C 6 -C 12  fatty acids comprise one or more propylene glycol esters of C 6 -C 12  fatty acids, one or more glycerol esters of C 6 -C 12  fatty acids, or a combination thereof. 
     
     
         4 . The manufactured pre-mixed formulation of  claim 1 , wherein the microspheres further comprise a sugar. 
     
     
         5 . The manufactured pre-mixed formulation of  claim 4 , wherein the sugar is selected from the group consisting of glucose, dextrose, galactose, maltose, fructose, mannose, sucrose, lactose, trehalose, raffinose, acarbose, glycol, glycerol, erythritol, threitol, arabitol, ribitol, sorbitol, dulcitol, iditol, isomalt, maltitol, lactitol, mannitol, xylitol, and a combination thereof. 
     
     
         6 . The manufactured pre-mixed formulation of  claim 5 , wherein the sugar is sucrose. 
     
     
         7 . The manufactured pre-mixed formulation of  claim 1 , wherein the biocompatible, biodegradable polymer is selected from the group consisting of 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, and a combination thereof. 
     
     
         8 . The manufactured pre-mixed formulation of  claim 7 , wherein the biocompatible, biodegradable polymer is a poly(lactide-co-glycolide) copolymer. 
     
     
         9 . The manufactured pre-mixed formulation of  claim 1 , further comprising a pharmaceutically acceptable excipient. 
     
     
         10 . The manufactured pre-mixed formulation of  claim 9 , wherein the pharmaceutically acceptable excipient is selected from the group consisting of a sugar, a sugar alcohol, an antioxidant, a preservative, and a combination thereof. 
     
     
         11 . The manufactured pre-mixed formulation of  claim 9 , wherein the pharmaceutically acceptable excipient is selected from the group consisting of 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, and a combination thereof. 
     
     
         12 . The manufactured pre-mixed formulation of  claim 9 , wherein the pharmaceutically acceptable excipient is sucrose. 
     
     
         13 . The manufactured pre-mixed formulation of  claim 1 , wherein the active pharmaceutical ingredient is selected from the group consisting of a GLP-1 receptor agonist, exenatide, GLP-1(7-37), GLP-1(7-36)-NH 2 , pramlintide, davalintide, Val 27 -davalintide, metreleptin, insulin, a glucagon agonist, a glucagon antagonist, a chimera of a GLP-1 receptor agonist and a glucagon agonist, bovine serum albumin, sodium salicylate, salicylic acid, minocycline HCl and a small molecule organic compound. 
     
     
         14 . The manufactured pre-mixed formulation of  claim 1 , wherein the active pharmaceutical ingredient is exenatide. 
     
     
         15 . The manufactured pre-mixed formulation of  claim 4 , wherein the microspheres comprise a poly(lactide-co-glycolide) copolymer as the biocompatible, biodegradable polymer; wherein the poly(lactide-co-glycolide) copolymer has dispersed therein 1% to 10% (w/w) exenatide and 0.1% to 5% (w/w) sugar. 
     
     
         16 . The manufactured pre-mixed formulation of  claim 6 , wherein the microspheres comprise a poly(lactide-co-glycolide) copolymer as the biocompatible, biodegradable polymer; wherein the poly(lactide-co-glycolide) copolymer has dispersed therein 5% (w/w) exenatide and 2% (w/w) sucrose. 
     
     
         17 . The manufactured pre-mixed formulation of  claim 1 , wherein the pharmaceutically acceptable non-aqueous carrier further comprises up to 2% C 14  fatty acids. 
     
     
         18 . The manufactured pre-mixed formulation of  claim 1 , wherein the microspheres are present in the formulation at a concentration of from 10 mg/ml to 500 mg/ml or from 20 mg/ml to 200 mg/ml. 
     
     
         19 . 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, comprising administering to the patient the manufactured pre-mixed formulation of  claim 1 . 
     
     
         20 . A kit comprising a container which comprises the manufactured pre-mixed formulation of  claim 1  and instructions for use; wherein the container is selected from the group consisting of a single-dose pen injector, a multi-dose pen injector, a single-dose vial, a multi-dose vial, a single-dose cartridge and a multi-dose cartridge.