Elp fusion proteins for controlled and sustained release

Abstract

The present disclosure provides pharmaceutical formulations for sustained release, and methods for delivering a treatment regimen with a combination of sustained release and long half-life formulations. The disclosure provides improved pharma-cokinetics for peptide and small molecule drugs.

1 - 28 . (canceled) 
     
     
         29 . A sustained release pharmaceutical formulation comprising:
 a therapeutic agent, the therapeutic agent comprising an active agent and an ELP amino acid sequence comprising [VPGXG] 144  or [XPGVG] 144 , where each X is selected from V, G, and A, and wherein the ELP exhibits a transition temperature between 26° C. and 37° C., and one or more pharmaceutically acceptable excipients.   
     
     
         30 . The pharmaceutical formulation of  claim 29 , wherein the formulation provides slow absorption from an injection site upon administration, wherein the absorption is characterized by a T max  of greater than 5 hours. 
     
     
         31 . The pharmaceutical formulation of  claim 30 , wherein the formulation provides a flat PK profile upon administration, as compared to the PK profile for the active agent in the absence of said amino acid sequence. 
     
     
         32 . (canceled) 
     
     
         33 . The pharmaceutical formulation of  claim 29 , wherein formation of a reversible matrix at body temperature reverses as protein concentration decreases. 
     
     
         34 . The pharmaceutical formulation of  claim 29 , wherein V, G, and A are at a ratio selected from the group consisting of
 a) 5:3:2;   b) 7:2:0;   c) 7:0:2;   d) 6:0:3;   e) 5:2:2; and   f) 5:0:4.   
     
     
         35 . The pharmaceutical formulation of  claim 29 , wherein the ELP comprises an ELP unit selected from [VPGXG] 144 , where each X is V. 
     
     
         36 . The pharmaceutical formulation of  claim 29 , wherein the active agent is a protein. 
     
     
         37 . The pharmaceutical formulation of  claim 36 , wherein the therapeutic agent is a recombinant fusion protein between the protein active agent and said amino acid sequence. 
     
     
         38 . The pharmaceutical formulation of  claim 36 , wherein the protein active agent has a circulatory half-life in the range of from about 30 seconds to about 10 hours, or about 30 second to about 1 hour. 
     
     
         39 . The pharmaceutical formulation of  claim 36 , wherein the active agent is a GLP-1 receptor agonist or derivative thereof, a VPAC2 selective agonist or a derivative thereof, a GIP receptor agonist or a derivative thereof, a glucagon receptor agonist or a derivative thereof, exendin-4 or a derivative thereof, or insulin or a derivative thereof. 
     
     
         40 . The pharmaceutical formulation of  claim 39 , wherein the formulation is a co-formulation comprising at least two of a GLP1 receptor agonist, a glucagon receptor agonist, a GIP receptor agonist, exendin-4, and insulin. 
     
     
         41 . The pharmaceutical formulation of  claim 29 , wherein the therapeutic agent is a chemical conjugate between the active agent and said amino acid sequence. 
     
     
         42 . The pharmaceutical formulation of  claim 41 , wherein the active agent is a chemotherapeutic agent, such as a chemotherapeutic agent selected from methotrexate, daunomycin, mitomycin, cisplatin, vincristine, epirubicin, fluorouracil, verapamil, cyclophosphamide, cytosine arabinoside, aminopterin, bleomycin, mitomycin C, democolcine, etoposide, mithramycin, chlorambucil, melphalan, daunorubicin, doxorubicin, tamoxifen, paclitaxel, vinblastine, camptothecin, actinomycin D, cytarabine, and combrestatin. 
     
     
         43 . The pharmaceutical formulation of  claim 42 , wherein the therapeutic agent is present in the range of about 0.5 mg/mL to about 200 mg/mL. 
     
     
         44 . (canceled) 
     
     
         45 . The pharmaceutical formulation of  claim 34 , wherein the therapeutic agent is present in the range of about 50 mg/mL to about 125 mg/mL, or the range of about 75 mg/mL to about 110 mg/mL. 
     
     
         46 - 47 . (canceled) 
     
     
         48 . The pharmaceutical composition of  claim 34 , wherein a storage temperature is less than about 40° C., or less than about 37° C., or less than about 30° C., or less than about 27° C., or less than about 25° C. 
     
     
         49 . The pharmaceutical formulation of  claim 29 , wherein the formulation comprises two or more of calcium chloride, magnesium chloride, potassium chloride, potassium phosphate monobasic, sodium chloride, sodium chloride, polysorbate 20, sodium phosphate, sodium phosphate monobasic, and sodium phosphate dibasic. 
     
     
         50 . The pharmaceutical formulation of  claim 49 , wherein the formulation comprises sodium phosphate, sodium chloride and polysorbate 20. 
     
     
         51 . (canceled) 
     
     
         52 . The pharmaceutical formulation of  claim 29 , wherein the formulation is packaged in the form of pre-dosed pens or syringes for administration once per week, twice per week, or from one to eight times per month. 
     
     
         53 . A method for delivering a sustained release regimen of a therapeutic agent, comprising, administering the formulation of  claim 29  to a subject in need, wherein the formulation is administered from about 1 to about 8 times per month. 
     
     
         54 - 57 . (canceled)