Formulations of active agents for sustained release

Abstract

The present invention provides pharmaceutical formulations for sustained release when administered at cold temperatures, and methods for delivering a treatment regimen with a combination of sustained release and long half-life formulations. The invention provides improved pharmacokinetics for peptide and small molecule drugs.

That is claimed is: 
     
         1 . A method for delivering a sustained release regimen of an active agent to a subject in need, comprising, administering a therapeutic agent for systemic administration, the therapeutic agent comprising an active agent and an amino acid sequence capable of forming a reversible matrix at the body temperature of a subject when administered as a cold formulation, the reversible matrix formed of hydrogen bonds and/or hydrophobic interactions, and one or more pharmaceutically acceptable excipients and/or diluents inducing the formation of the matrix upon administration. 
     
     
         2 . The method of  claim 1 , wherein the cold formulation is from about 2 to about 3° C., about 2 to about 4° C., about 2 to about 5° C., about 2 to about 6° C., about 2 to about 7° C., about 2 to about 8° C., about 2 to about 10° C., about 2 to about 12° C., about 2 to about 14° C., about 2 to about 15° C., about 2 to about 16° C., about 2 to about 20° C., about 10 to about 25° C., or from 15 to 22° C. 
     
     
         3 . The method of  claim 2 , wherein the formulation provides a flat PK profile upon administration, as compared to the PK profile for the active agent in the absence of the amino acid sequence forming a reversible matrix. 
     
     
         4 . The method of  claim 3 , wherein the PK profile has a shallow Cmax and/or low ratio of peak to trough and/or long Tmax. 
     
     
         5 . The method of any one of  claims 1  to  4 , wherein the formation of the matrix reverses as protein concentration decreases. 
     
     
         6 . The method of any one of  claims 1  to  5 , wherein the amino acid sequence capable of forming the matrix at or around body temperature is a repeating peptide sequence having repeating units of from four to ten amino acids. 
     
     
         7 . The method of  claim 6 , wherein the repeating unit forms one, two, or three hydrogen bonds in the formation of the matrix. 
     
     
         8 . The method of  claim 6 , wherein the amino acid sequence capable of forming the matrix at body temperature is an amino acid sequence of silk, elastin, collagen, or keratin, or mimic thereof. 
     
     
         9 . The method of any one of  claims 1  to  6 , wherein the amino acid sequence capable of forming the matrix at body temperature comprises [VPGXG] 90 , where each X is selected from V, G, and A, and wherein the ratio of V:G:A may be about 5:3:2. 
     
     
         10 . The method of  claim 9 , wherein the amino acid sequence capable of forming the matrix at body temperature comprises [VPGXG] 120 , where each X is selected from V, G, and A, and wherein the ratio of V:G:A may be about 5:3:2. 
     
     
         11 . The method of any one of  claims 1  to  6 , wherein the amino acid sequence capable of forming the matrix at body temperature comprises [VPGVG] 90 . 
     
     
         12 . The method of any one of  claims 1  to  6 , wherein the amino acid sequence capable of forming the matrix at body temperature is an elastin-like-peptide (ELP) sequence. 
     
     
         13 . The method of any one of  claims 1  to  5 , wherein the amino acid sequence capable of forming the matrix at body temperature forms a random coil or non-globular extended structure. 
     
     
         14 . The method of any one of  claims 1  to  5 , wherein the amino acid sequence capable of forming the matrix at body temperature is includes a random coil, or a non-globular extended structure. 
     
     
         15 . The method of any one of  claims 1  to  14 , wherein the subject is human. 
     
     
         16 . The method of any one of  claims 1  to  14 , wherein the subject is a non-human mammal. 
     
     
         17 . The method of any one of  claims 1  to  16 , wherein the active agent is a protein. 
     
     
         18 . The method of  claim 17 , wherein the therapeutic agent is a recombinant fusion protein between the protein active agent and the amino acid sequence capable of forming the matrix at the body temperature of the subject. 
     
     
         19 . The method of  claim 18 , wherein the protein active agent has a circulatory half-life in the range of from about 30 seconds to about 10 hour, or about 30 seconds to about 1 hour. 
     
     
         20 . The method of  claim 19 , 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 or a glucagon receptor agonist or a derivative thereof. 
     
     
         21 . The method of  claim 19 , wherein the formulation is a co-formulation comprising at least two of a GLP1 receptor agonist, a glucagon receptor agonist, and a GIP receptor agonist 
     
     
         22 . The method of  claim 19 , wherein the protein active agent is a clotting factor, where the clotting factor may be Factor VII, Factor VIII, or Factor IX. 
     
     
         23 . The method of any one of  claims 1  to  22 , wherein the active agent s selected from GLP-1 (A8G,7-37) ELP1-120 and GLP-1 (A8G,7-37) ELP4-120 (PB1046). 
     
     
         24 . The method of  claim 19 , wherein the protein active agent is insulin or a derivative thereof. 
     
     
         25 . The method of any one of  claims 1  to  17 , wherein the therapeutic agent is a chemical conjugate between the active agent and the amino acid sequence capable of forming the matrix at the body temperature of the subject. 
     
     
         26 . The method of  claim 25 , 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. 
     
     
         27 . The method of  claim 25 , wherein the agent is an immunogenic molecule, or is an immunomodulator, or is an anti-inflammatory agent. 
     
     
         28 . The method of any one of  claims 1  to  27 , wherein the therapeutic agent is present in the range of about 0.5 mg/mL to about 200 mg/mL. 
     
     
         29 . The method of  claim 28 , wherein the therapeutic agent is present in the range of about 5 mg/mL, to about 125 mg/mL. 
     
     
         30 . The method of  claim 28 , wherein the therapeutic agent is present in the range of about 10 mg/mL to about 50 mg/mL or about 15 mg/mL to about 30 mg/mL. 
     
     
         31 . The method of any one of  claims 1  to  30 , wherein the therapeutic agent does not form the phase-transitioned matrix at storage conditions. 
     
     
         32 . The method of  claim 31 , wherein the storage conditions are 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., or less than about 20° C., or less than about 15° C., or less than about 10° C., or less than about 5° C. 
     
     
         33 . The method of any one of  claims 1  to  32 , wherein the formulation has an ionic strength of at least that of 25 mM Sodium Chloride, or at least that of 30 mM Sodium chloride, or at least that of 40 mM Sodium Chloride, or at least that of 50 mM Sodium Chloride, or at least that of 75 mM Sodium Chloride, or at least that of 100 mM Sodium Chloride, or at least that of 150 mM Sodium Chloride. 
     
     
         34 . The method of any one of  claims 1  to  33 , wherein the formulation has an ionic strength of about 0.9% saline or less. 
     
     
         35 . The method of  claim 34 , wherein the formulation comprises two or more of calcium chloride, magnesium chloride, potassium chloride, potassium phosphate monobasic, sodium chloride, and sodium phosphate dibasic. 
     
     
         36 . The method of  claim 35 , wherein the formulation comprises the components listed in Table 4, Table 5, or Table 6. 
     
     
         37 . The method of any one of  claims 1  to  36 , 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 five times per month. 
     
     
         38 . The method of any one of  claims 1  to  37 , 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 five times per month. 
     
     
         39 . The method of any one of  claims 1  to  38 , wherein the formulation is administered from about 1 to about 8 times per month. 
     
     
         40 . The method of any one of  claims 1  to  39 , wherein the active agent is GLP-1 or an analog thereof, and is administered about 1 to about 8 times per month. 
     
     
         41 . The method of any one of  claims 1  to  40 , wherein the active agent is VIP or an analog thereof, and is administered about 1 to about 8 times per month. 
     
     
         42 . The method of any one of  claims 39  to  41 , wherein the formulation is administered about weekly. 
     
     
         43 . The method of any one of  claims 39  to  41 , wherein the formulation is administered subcutaneously or intramuscularly. 
     
     
         44 . The method of any one of  claims 39  to  41 , wherein the site of administration is not a pathological site. 
     
     
         45 . A sustained release pharmaceutical formulation comprising:
 a therapeutic agent, the therapeutic agent comprising an active agent and an amino acid sequence comprising [VPGXG] 90 , where each X is selected from V, G, and A, and one or more pharmaceutically acceptable excipients and/or diluents for formation of a reversible matrix from an aqueous form upon administration to a human subject as a cold formulation.   
     
     
         46 . The sustained release pharmaceutical formulation of  claim 45 , wherein the cold formulation is from about 2 to about 3° C., about 2 to about 4° C., about 2 to about 5° C., about 2 to about 6° C., about 2 to about 7° C., about 2 to about 8° C., about 2 to about 10° C., about 2 to about 12° C., about 2 to about 14° C., about 2 to about 15° C., about 2 to about 16° C., about 2 to about 20° C., about 10 to about 25° C., or from 15 to 22° C. 
     
     
         47 . A method for delivering a sustained release regimen of insulin to a subject in need, comprising: administering, about once weekly, a cold formulation of an insulin polypeptide fusion with an amino acid sequence capable of forming a reversible matrix at the body temperature of a subject, the reversible matrix formed of hydrogen bonds and/or hydrophobic interactions, and the formulation comprising a once weekly effective amount of the insulin fusion and one or more pharmaceutically acceptable excipients and/or diluents inducing the formation of the matrix upon administration to the subject. 
     
     
         48 . The method of  claim 47 , wherein the cold formulation is administered at from about 2 to about 22° C. 
     
     
         49 . The method of  claim 47 , wherein the cold formulation is administered at from about 2 to about 10° C. 
     
     
         50 . The method of any one of  claims 47  to  49 , wherein the amino acid sequence capable of forming a reversible matrix at the body temperature of a subject is [VPGXG] 120 , where each X is selected from V, G, and A, and wherein the ratio of V:G:A is about 5:3:2.