Thermogel formulation for combination drug delivery

Abstract

The invention provides a drug delivery system for a combination of therapeutic agents. The system includes a water soluble biodegradable ABA-type triblock copolymer that possesses thermosensitive gelation properties. The system can form a stable thermogel that includes a combination of therapeutic agents including, for example, rapamycin, paclitaxel, and 17-AAG. After administration to a subject, the drugs are released at a controlled rate from the thermogel, which biodegrades into non-toxic components. The polymer system can also function to increase the solubility and stability of drugs in the composition.

What is claimed is: 
     
         1 . A composition comprising a PLGA-PEG-PLGA triblock copolymer, water, and a combination of therapeutic agents,
 wherein:
 the PLGA-PEG-PLGA triblock copolymer has an average molecular weight of about 3 kDa to about 5 kDa, 
 the combination of therapeutic agents comprises at least two of paclitaxel, 17-AAG, and rapamycin. 
   
     
     
         2 . The composition of  claim 1 , wherein the sum of the molecular weights of the PLGA blocks of the triblock copolymer is more than twice the molecular weight of the PEG block. 
     
     
         3 . The composition of  claim 1 , wherein the combination of therapeutic agents comprises at least two of about 4 mg/mL to about 8 mg/mL of paclitaxel, about 4 mg/mL to about 8 mg/mL of 17-AAG, and about 2 mg/mL to about 6 mg/mL of rapamycin. 
     
     
         4 . The composition of  claim 3 , wherein the combination of therapeutic agents is paclitaxel and rapamycin. 
     
     
         5 . The composition of  claim 1 , wherein a total PLGA content of about 50 wt % to about 85 wt % based on total weight of the PLGA-PEG-PLGA triblock copolymer, and a concentration range of about 3 wt % to about 30 wt %. 
     
     
         6 . The composition of  claim 5 , wherein the combination of therapeutic agents comprises about 4 mg/mL to about 8 mg/mL of paclitaxel and about 2 mg/mL to about 6 mg/mL of rapamycin. 
     
     
         7 . The composition of  claim 1 , wherein the composition is a non-flowing thermosensitive hydrogel at and above 22° C. and a free-flowing solution below about 10° C. 
     
     
         8 . The composition of  claim 7 , wherein the sum of the molecular weights of the PLGA blocks of the triblock copolymer is more than twice the molecular weight of the PEG block; and the drug release t 1/2  of the non-flowing thermosensitive hydrogel at 37° C. is about 10 hours, and each of the drugs of the non-flowing thermosensitive hydrogel at 37° C. has equivalent drug release kinetics. 
     
     
         9 . The composition of  claim 1 , wherein the drug release t 1/2  of the non-flowing thermosensitive hydrogel at 37° C. is about 10 hours, and each of the drugs of the non-flowing thermosensitive hydrogel at 37° C. has equivalent drug release kinetics. 
     
     
         10 . The composition of  claim 1 , wherein the concentration of therapeutic agents in the composition is about 9 mg/mL to about 20 mg/mL. 
     
     
         11 . The composition of  claim 10 , wherein the concentration of paclitaxel in the composition is about 4 mg/mL to about 8 mg/mL. 
     
     
         12 . The composition of  claim 10 , wherein the concentration of rapamycin in the composition is about 2 mg/mL to about 6 mg/mL. 
     
     
         13 . The composition of  claim 1 , wherein the PLGA-PEG-PLGA triblock copolymer is a PLGA 1.5K -PEG 1K -PLGA 1.5K  triblock copolymer. 
     
     
         14 . The composition of  claim 1 , wherein the composition has a polydispersity index of about 0.3 to about 0.5. 
     
     
         15 . The composition of  claim 1 , wherein the PLGA-PEG-PLGA triblock copolymer has a concentration range of about 10 wt % to about 30 wt %. 
     
     
         16 . A method for killing or inhibiting the growth of cancer cells comprising contacting cancer cells with an effective lethal or inhibitory amount of a composition of  claim 1 , wherein the composition is in the form of a non-flowing gel and each of the drugs of the non-flowing has equivalent drug release kinetics, thereby killing the cancer cells or inhibiting their growth;
 wherein the cancer cells are brain cancer cells, breast cancer cells, esophageal cancer cells, head and neck cancer cells, ovarian cancer cells, or pancreatic cancer cells.   
     
     
         17 . A method of treating a solid tumor comprising locally administering an effective anticancer amount of a composition of  claim 1  to a subject in need thereof, wherein the amount of therapeutic agents administered to the subject would cause systemic toxicity if administered orally or intravenously, and wherein the local administration does not cause systemic toxicity. 
     
     
         18 . A method of preparing a composition of  claim 1  comprising combining an aqueous solution of PLGA-PEG-PLGA triblock copolymer and an alcoholic solution comprising at least two of paclitaxel, 17-AAG, and rapamycin at a temperature above about 50° C. to form a mixture, lyophilizing the mixture to provide a powder or cake, and rehydrating the powder or cake with water at a temperature of less than about 10° C., to provide the free-flowing solution of  claim 1 . 
     
     
         19 . The method of  claim 16 , wherein the PLGA-PEG-PLGA triblock copolymer is a PLGA 1.5K -PEG 1K -PLGA 1.5K  triblock copolymer and the alcohol of the alcoholic solution is t-butanol. 
     
     
         20 . A composition comprising a PLGA-PEG-PLGA triblock copolymer, water, and a combination of therapeutic agents,
 wherein:
 the PLGA-PEG-PLGA triblock copolymer has an average molecular weight of about 3 kDa to about 5 kDa; and 
 the combination of therapeutic agents is about 4 mg/mL to about 8 mg/mL of paclitaxel and about 2 mg/mL to about 6 mg/mL of rapamycin.