Stable pharmaceutical formulations

Abstract

Stable pharmaceutical formulations and methods of making same are provided. In a general embodiment, the present disclosure provides a method of making a stable pharmaceutical formulation comprising adding one or more vitrifying additives to an aqueous pharmaceutical solution to raise the glass transition temperature of the aqueous pharmaceutical solution. The aqueous pharmaceutical solution can be cooled to a temperature of about −50° C. to about −10° C. The vitrifying additive enhances the formation of a glass or amorphous solid of the aqueous pharmaceutical solution at cryogenic temperatures (−50 to −10° C.), and the pharmaceutical formulation can be thawed to liquid form and administered to a mammalian subject.

1 . A method of stabilizing a pharmaceutical agent without lyophilization, the method comprising:
 combining a pharmaceutical agent with water and at least one vitrifying additive to form an aqueous pharmaceutical solution, the vitrifying additive being present in an amount ranging from about 1% to about 30% effective to enhance the formation of an amorphous solid of the aqueous pharmaceutical solution when the aqueous pharmaceutical solution is cooled to a temperature below a glass transition temperature of the aqueous pharmaceutical solution; and   cooling the aqueous pharmaceutical solution to a temperature of about −25° C. to about −10° C. to form the amorphous solid of the aqueous pharmaceutical solution.   
     
     
         2 . The method of  claim 1 , wherein the vitrifying additive is a polyalcohol selected from polyethylene glycol, mannitol, sorbitol, and combinations thereof. 
     
     
         3 . The method of  claim 1 , wherein the vitrifying additive is a disaccharide selected from the group consisting of sucrose, trehalose, lactose, and combinations thereof. 
     
     
         4 . The method of  claim 1 , wherein the vitrifying additive is raffinose. 
     
     
         5 . The method of  claim 1 , wherein the vitrifying additive is a dextran with an average molecular weight of about 40,000. 
     
     
         6 . The method of  claim 1 , wherein the pharmaceutical agent is an echinocandin antifungal agent. 
     
     
         7 . The method of  claim 1 , wherein the pharmaceutical agent comprises an antifungal agent selected from caspofungin, micafungin, anidulafungin, or a salt thereof. 
     
     
         8 . A method of making a shelf-stable pharmaceutical agent without lyophilization, the method comprising:
 combining a carbapenem with water and a dextran to form an aqueous carbapenem solution, the dextran being present in an amount ranging from about 1% to about 30% effective to give the carbapenem a shelf-life of at least 1 month; and   cooling the aqueous carbapenem solution to a temperature of about −25° C. to about −10° C. to form the amorphous solid of the aqueous carbapenem solution.   
     
     
         9 . The method of  claim 8 , wherein the shelf-stable carbapenem has a shelf-life of least 3 months. 
     
     
         10 . The method of  claim 8 , wherein the shelf-stable carbapenem has a shelf-life of least 6 months. 
     
     
         11 . A pharmaceutical formulation comprising:
 an aqueous pharmaceutical solution comprising water and a pharmaceutical agent that is unstable in aqueous solution at room temperature, and   at least one vitrifying additive, the vitrifying additive being present in an amount effective to enhance the formation of an amorphous solid of the aqueous pharmaceutical solution when the aqueous pharmaceutical solution is cooled to a temperature below a glass transition temperature of the aqueous pharmaceutical solution.   
     
     
         12 . The pharmaceutical formulation of  claim 11 , wherein the vitrifying additive is selected from the group consisting of polyalcohols, polysaccharides, monosaccharides, disaccharides, trisaccharides, aminosugars, amino derivatives of saccharides, and combinations thereof. 
     
     
         13 . The pharmaceutical formulation of  claim 11 , wherein the vitrifying additive comprises a polyalcohol selected from polyethylene glycol, mannitol, sorbitol, and combinations thereof. 
     
     
         14 . The pharmaceutical formulation of  claim 11  wherein the vitrifying additive comprises a monosaccharide selected from the group consisting of dextrose, fructose, and combinations thereof. 
     
     
         15 . The pharmaceutical formulation of  claim 11 , wherein the vitrifying additive comprises a disaccharide selected from the group consisting of sucrose, trehalose, lactose and combinations thereof. 
     
     
         16 . The pharmaceutical formulation of  claim 11 , wherein the vitrifying additive comprises raffinose. 
     
     
         17 . The pharmaceutical formulation of  claim 11 , wherein the vitrifying additive is a polysaccharide selected from the group consisting of dextrans, cyclodextrins, and combinations thereof. 
     
     
         18 . The pharmaceutical formulation of  claim 11 , wherein the vitrifying additive is a 2-hydroxypropyl-beta-cyclodextrin. 
     
     
         19 . The pharmaceutical formulation of  claim 11 , wherein the vitrifying additive is a dextran with an average molecular weight of about 40,000. 
     
     
         20 . The pharmaceutical formulation of  claim 11 , wherein the pharmaceutical agent is selected from the group consisting of antibiotics, antifungal agents, monoclonal antibodies, plasma proteins, and combinations thereof. 
     
     
         21 . The pharmaceutical formulation of  claim 11 , wherein the pharmaceutical agent is an antibiotic selected from the group consisting of trimethoprims, polymyxin B sulfate, beta-lactams, monobactams, oxazolidinones, macrolides, ketolides, tetracyclines, streptogramins, and combinations thereof. 
     
     
         22 . The pharmaceutical formulation of  claim 20 , wherein the antibiotic is a beta-lactam antibiotic selected from the group consisting of cephalosporins, penicillins, thienamycins, carbapenems, penems, cephems, trinems, and combinations thereof. 
     
     
         23 . The pharmaceutical formulation of  claim 11 , wherein the pharmaceutical agent is a carbapenem antibiotic. 
     
     
         24 . The pharmaceutical formulation of  claim 11 , wherein the pharmaceutical agent is an echinocandin antifungal agent. 
     
     
         25 . The pharmaceutical formulation of  claim 20 , wherein the antifungal agent comprises caspofungin, micafungin, anidulafungin, or a salt thereof. 
     
     
         26 . A pharmaceutical formulation comprising:
 an aqueous pharmaceutical solution comprising water and a pharmaceutical agent that is unstable in aqueous solution at room temperature, the pharmaceutical agent selected from the group consisting of antibiotics, antifungal agents, monoclonal antibodies, plasma proteins, and combinations thereof, and   at least one vitrifying additive selected from the group consisting of polyalcohols, polysaccharides, monosaccharides, disaccharides, trisaccharides, aminosugars, amino derivatives of saccharides, and combinations thereof, the vitrifying additive being present in an amount effective to enhance the formation of an amorphous solid of the aqueous pharmaceutical solution when the aqueous pharmaceutical solution is cooled to a temperature below a glass transition temperature of the aqueous pharmaceutical solution.