Methods and compositions for therapeutic agents

Abstract

The present disclosure provides inter alia compositions that comprise therapeutic agents (e.g., live attenuated viral antigens, therapeutic proteins, etc.) and a lipid component. The lipid component may comprise or consist of different types of lipid or lipids as described herein. In some embodiments the therapeutic agents are thermolabile. The present disclosure also provides methods for preparing compositions, including the aforementioned compositions (e.g., melt methods and spray injection methods among others).

What is claimed is: 
     
         1 . A thermostable lyophilized composition comprising:
 a therapeutic agent; and   a lipid component consisting of one or more non-ionic surfactants.   
     
     
         2 . The composition of  claim 1 , wherein the lipid component consists of 1-monopalmitoyl glycerol (MPG). 
     
     
         3 . A thermostable lyophilized composition comprising:
 a therapeutic agent; and   a lipid component consisting of one or more non-ionic surfactants and one or more steroids.   
     
     
         4 . The composition of  claim 3 , wherein the lipid component consists of 1-monopalmitoyl glycerol (MPG) and cholesterol (CHO). 
     
     
         5 . A thermostable lyophilized composition comprising:
 a therapeutic agent; and   pre-formed vesicles that comprise a non-ionic surfactant, a steroid and an ionic amphiphile.   
     
     
         6 . The composition of  claim 5 , wherein the ionic amphiphile is dicetylphospate (DCP). 
     
     
         7 . The composition of  claim 5 , wherein the ionic amphiphile is diphosphatidyl glycerol (DPPG). 
     
     
         8 . The composition of  claim 6  or  7 , wherein the non-ionic surfactant is 1-monopalmitoyl glycerol (MPG) and the steroid is cholesterol (CHO). 
     
     
         9 . A thermostable lyophilized composition comprising:
 a therapeutic agent; and   vesicles that comprise a non-ionic surfactant, a steroid and a phosphoglyceride.   
     
     
         10 . The composition of  claim 9 , wherein the phosphoglyceride is diphosphatidyl glycerol (DPPG). 
     
     
         11 . The composition of  claim 10 , wherein the non-ionic surfactant is 1-monopalmitoyl glycerol (MPG) and the steroid is cholesterol (CHO). 
     
     
         12 . The composition of any one of  claims 1 - 11 , wherein the therapeutic agent comprises an attenuated measles virus, an attenuated mumps virus, an attenuated rubella virus, an attenuated varicella virus, or a combination thereof. 
     
     
         13 . The composition of any one of  claims 1 - 11 , wherein the therapeutic agent comprises an attenuated virus selected from the group consisting of an attenuated rotavirus, an attenuated herpes zoster virus, an attenuated vaccinia virus, an attenuated yellow fever virus, and combinations thereof. 
     
     
         14 . The composition of any one of  claims 1 - 11 , wherein the therapeutic agent comprises a therapeutic protein. 
     
     
         15 . The composition of  claim 14 , wherein the therapeutic protein is an antibody. 
     
     
         16 . The composition of any one of  claims 1 - 11 , wherein the therapeutic agent comprises a polynucleotide or polysaccharide. 
     
     
         17 . The composition of any one of  claims 1 - 11 , wherein the therapeutic agent comprises a small molecule therapeutic. 
     
     
         18 . The composition of any one of the preceding claims, wherein the composition is more stable when stored for 4-12 weeks at 37±2° C. than a reference composition that lacks the lipid component. 
     
     
         19 . The composition of  claim 18 , wherein stability is based on potency. 
     
     
         20 . The composition of any one of  claims 1 - 19 , wherein the composition is prepared by a method that includes steps of:
 providing the lipid component in molten form;   combining the molten lipid component with an aqueous solution that includes the therapeutic agent; and   homogenizing the resulting product.   
     
     
         21 . The composition of  claim 20 , wherein the molten lipid component is added to the aqueous solution that includes the therapeutic agent. 
     
     
         22 . The composition of  claim 20 , wherein the aqueous solution that includes the therapeutic agent is added to the molten lipid component. 
     
     
         23 . The composition of any one of  claims 1 - 19 , wherein the composition is prepared by a method that includes steps of:
 providing the lipid component in dissolved form; and   injecting the dissolved lipid component into an aqueous solution that includes the therapeutic agent.   
     
     
         24 . The composition of  claim 23 , wherein the vesicle-forming lipids are dissolved in an organic solvent without any co-solvents. 
     
     
         25 . The composition of  claim 23 , wherein the lipid component is dissolved in an organic solvent with one or more co-solvents. 
     
     
         26 . The composition of  claim 23 , wherein the lipid component is dissolved in a water-free solvent system. 
     
     
         27 . The composition of any one of  claims 24 - 26 , wherein the organic solvent is a water-miscible solvent. 
     
     
         28 . The composition of any one of  claims 24 - 26 , wherein the organic solvent is a polar-protic organic solvent. 
     
     
         29 . The composition of  claim 28 , wherein the polar-protic organic solvent is an aliphatic alcohol having 2-5 carbon atoms. 
     
     
         30 . The composition of  claim 28 , wherein the polar-protic organic solvent is an aliphatic alcohol having 4 carbon atoms. 
     
     
         31 . The composition of  claim 28 , wherein the polar-protic organic solvent is tert-butanol. 
     
     
         32 . The composition of  claim 28 , wherein the polar-protic organic solvent is ethanol. 
     
     
         33 . The composition of any one of  claims 24 - 26 , wherein the organic solvent is diethyl ether. 
     
     
         34 . The composition of any one of  claims 1 - 33 , wherein the composition was prepared by a method that involved storing the composition in dried form. 
     
     
         35 . The composition of  claim 34 , wherein the composition in dried form was not stored under temperature-controlled conditions. 
     
     
         36 . The composition of  claim 34 , wherein the composition in dried form was stored at a temperature that at least temporarily exceeded 8° C. 
     
     
         37 . The composition of  claim 34 , wherein the composition in dried form was stored at a temperature that at least temporarily exceeded 15° C. 
     
     
         38 . The composition of  claim 34 , wherein the composition in dried form was stored at a temperature that at least temporarily exceeded 20° C. 
     
     
         39 . The composition of  claim 34 , wherein the composition in dried form was stored at a temperature that at least temporarily exceeded 25° C. 
     
     
         40 . A method of treating an individual the method comprising:
 providing a composition of  claim 34 , wherein the composition is in dried form and has been stored for a period of time at a temperature in excess of 8° C.;   rehydrating the composition with an aqueous solution; and   administering to the individual a therapeutically effective amount of the rehydrated composition.   
     
     
         41 . The method of  claim 40 , wherein the composition has been stored for a period of time at a temperature in excess of 25° C. 
     
     
         42 . The method of  claim 40 , wherein the composition has been stored for a period of time at a temperature in excess of 30° C. 
     
     
         43 . The method of  claim 40 , wherein the composition has been stored for a period of time at a temperature in excess of 35° C. 
     
     
         44 . The method of any one of  claims 40 - 43 , wherein the composition is administered by intramuscular injection. 
     
     
         45 . The method of any one of  claims 40 - 43 , wherein the composition is administered by subcutaneous injection. 
     
     
         46 . A method comprising:
 melting a lipid component consisting of one or more non-ionic surfactants;   combining the molten lipid component with an aqueous solution that includes a therapeutic agent; and   homogenizing the resulting product.   
     
     
         47 . The method of  claim 46 , wherein the lipid component consists of 1-monopalmitoyl glycerol (MPG). 
     
     
         48 . A method comprising:
 melting a lipid component consisting of one or more non-ionic surfactants and one or more steroids;   combining the molten lipid component with an aqueous solution that includes a therapeutic agent; and   homogenizing the resulting product.   
     
     
         49 . The method of  claim 48 , wherein the lipid component consists of 1-monopalmitoyl glycerol (MPG) and cholesterol (CHO). 
     
     
         50 . A method comprising:
 preparing vesicles that comprise a non-ionic surfactant, a steroid and an ionic amphiphile;   combining the vesicles with an aqueous solution that includes a therapeutic agent; and   homogenizing the resulting product.   
     
     
         51 . The method of  claim 50 , wherein the ionic amphiphile is dicetylphospate (DCP). 
     
     
         52 . The method of  claim 50 , wherein the ionic amphiphile is diphosphatidyl glycerol (DPPG). 
     
     
         53 . The method of  claim 51  or  52 , wherein the non-ionic surfactant is 1-monopalmitoyl glycerol (MPG) and the steroid is cholesterol (CHO). 
     
     
         54 . A method comprising:
 melting a lipid component that comprises a non-ionic surfactant, a steroid and phosphoglyceride;   combining the molten lipid component with an aqueous solution that includes a therapeutic agent; and   homogenizing the resulting product.   
     
     
         55 . The method of  claim 54 , wherein the phosphoglyceride is diphosphatidyl glycerol (DPPG). 
     
     
         56 . The method of  claim 55 , wherein the non-ionic surfactant is 1-monopalmitoyl glycerol (MPG) and the steroid is cholesterol (CHO). 
     
     
         57 . The method of any one of  claims 46 - 56 , wherein the molten lipid component is added to the aqueous solution that includes the therapeutic agent. 
     
     
         58 . The method of any one of  claims 46 - 56 , wherein the aqueous solution that includes the therapeutic agent is added to the molten lipid component. 
     
     
         59 . A method comprising:
 dissolving in an organic solvent a lipid component that consists of one or more non-ionic surfactants; and   injecting the dissolved lipid component into an aqueous solution that includes a therapeutic agent.   
     
     
         60 . The method of  claim 59 , wherein the lipid component consists of 1-monopalmitoyl glycerol (MPG). 
     
     
         61 . A method comprising:
 dissolving in an organic solvent a lipid component that consists of one or more non-ionic surfactants and one or more steroids; and   injecting the dissolved lipid component into an aqueous solution that includes a therapeutic agent.   
     
     
         62 . The method of  claim 61 , wherein the lipid component consists of 1-monopalmitoyl glycerol (MPG) and cholesterol (CHO). 
     
     
         63 . A method comprising:
 dissolving in an organic solvent a lipid component that comprises a non-ionic surfactant, a steroid and phosphoglyceride; and   injecting the dissolved lipid component into an aqueous solution that includes a therapeutic agent.   
     
     
         64 . The method of  claim 63 , wherein the phosphoglyceride is diphosphatidyl glycerol (DPPG). 
     
     
         65 . The method of  claim 64 , wherein the non-ionic surfactant is 1-monopalmitoyl glycerol (MPG) and the steroid is cholesterol (CHO). 
     
     
         66 . The method of any one of  claims 46 - 65 , wherein the therapeutic agent comprises an attenuated measles virus, an attenuated mumps virus, an attenuated rubella virus, an attenuated varicella virus, or a combination thereof. 
     
     
         67 . The method of any one of  claims 46 - 65 , wherein the therapeutic agent comprises an attenuated virus selected from the group consisting of an attenuated rotavirus, an attenuated herpes zoster virus, an attenuated vaccinia virus, an attenuated yellow fever virus, and combinations thereof. 
     
     
         68 . The method of any one of  claims 46 - 65 , wherein the therapeutic agent comprises a therapeutic protein. 
     
     
         69 . The composition of  claim 68 , wherein the therapeutic protein is an antibody. 
     
     
         70 . The method of any one of  claims 46 - 65 , wherein the therapeutic agent comprises a polynucleotide or polysaccharide. 
     
     
         71 . The method of any one of  claims 46 - 65 , wherein the therapeutic agent comprises a small molecule therapeutic.