US2020230242A1PendingUtilityA1
METHODS OF USING CTLA4Ig SUBCUTANEOUS FORMULATIONS

Assignee: BRISTOL MYERS SQUIBB COPriority: Dec 20, 2005Filed: Mar 24, 2020Published: Jul 23, 2020
Est. expiryDec 20, 2025(expired)· nominal 20-yr term from priority
Inventors:Manisha P Desai Charles E. Dahlheim Sunita Borsadia Vijay H. Naringrekar Rajesh Gandhi Manoj Nerurkar
C07K 14/70521A61K 9/0019C07K 2319/30C07K 16/2827A61K 47/10A61K 38/1774
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References
Claims
Abstract

The present invention relates generally to stable formulations comprising CTLA4Ig molecules, including lyophilized, and liquid formulations for administration via various routes including, for example, routes such as intravenous (IV) and subcutaneous (SC) for treating immune system diseases and tolerance induction.
Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method of treating rheumatoid arthritis in a subject comprising administering to the subject an effective amount of a formulation comprising:
 a) a CTLA4Ig molecule comprising amino acid residues 26-382 of SEQ ID NO:2, amino acid residues 26-383 of SEQ ID NO:2, amino acid residues 27-382 of SEQ ID NO:2 and/or amino acid residues 27-383 of SEQ ID NO:2 at a concentration of about 125 mg/ml;   b) a sugar;   c) at least one buffering agent;   d) a surfactant; and   e) a pharmaceutically acceptable aqueous carrier;   wherein the sugar is sucrose, lactose, maltose, mannitol, trehalose or a mixture thereof;   wherein the pH is between 6 and 8;   wherein the viscosity is between 9 and 20 cps;   wherein the formulation is suitable for subcutaneous administration;   wherein the formulation is stable when stored at 2 to 8° C. for at least 12 months; and   wherein the formulation is administered once weekly in a volume of about 1 ml.   
     
     
         2 . The method of  claim 1 , wherein the CTLA4Ig molecule is abatacept. 
     
     
         3 . The method of  claim 1 , wherein the sugar is sucrose. 
     
     
         4 . The method of  claim 3 , wherein the concentration of sucrose is about 170 mg/ml. 
     
     
         5 . The method of  claim 1 , wherein the sugar is lactose. 
     
     
         6 . The method of  claim 1 , wherein the sugar is maltose. 
     
     
         7 . The method of  claim 1 , wherein the sugar is mannitol. 
     
     
         8 . The method of  claim 1 , wherein the sugar is trehalose. 
     
     
         9 . The method of  claim 1 , wherein the buffering agent is phosphate, glycinate, carbonate, citrate or a combination thereof. 
     
     
         10 . The method of  claim 1 , wherein the buffering agent is phosphate. 
     
     
         11 . The method of  claim 10 , wherein the concentration of the phosphate buffer is at least about 10 mM. 
     
     
         12 . The method of  claim 1 , wherein the surfactant is selected from the group consisting of a polysorbate, polysorbate 20, polysorbate 80, poloxamer, poloxamer 188, sorbitan ester, sorbitan derivative, Triton, sodium laurel sulfate, sodium octyl glycoside, lauryl-sulfobetadine, myristyl-sulfobetadine, linoleyl-sulfobetadine, stearyl-sulfobetadine, lauryl-sarcosine, myristyl-sarcosine, linoleyl-sarcosine, stearyl-sarcosine, linoleyl-betaine, myristyl-betaine, cetyl-betaine, lauramidopropyl-betaine, cocamidopropyl-betaine, linoleamidopropyl-betaine, myristamidopropyl-betaine, palmidopropyl-betaine, isostearamidopropyl-betaine, lauroamidopropyl-dimethylamine, myristamidopropyl-dimethylamine, palmidopropyl-dimethylamine, isostearamidopropyl-dimethylamine, sodium methyl cocoyl-taurate, and disodium methyl oleyl-tauratem, polyethylene glycol, polypropyl glycol, and a copolymer of ethylene and propylene glycol. 
     
     
         13 . The method of  claim 1 , wherein the surfactant is a poloxamer. 
     
     
         14 . The method of  claim 1 , wherein the surfactant is poloxamer 188. 
     
     
         15 . The method of  claim 14 , wherein the concentration of poloxamer 188 is about 8 mg/ml. 
     
     
         16 . The method of  claim 1 , wherein the pharmaceutically acceptable aqueous carrier is sterile water. 
     
     
         17 . The method of  claim 1 , wherein the formulation is stable when stored at 2 to 8° C. for at least 18 months. 
     
     
         18 . The method of  claim 1 , wherein the formulation is stable when stored at 2 to 8° C. for at least 24 months. 
     
     
         19 . The method of  claim 1 , wherein the percentage of CTLA4Ig high molecular weight species in the formulation is less than about 10%. 
     
     
         20 . The method of  claim 1 , wherein the percentage of CTLA4Ig high molecular weight species in the formulation is less than about 5%. 
     
     
         21 . The method of  claim 1 , wherein the percentage of CTLA4Ig high molecular weight species in the formulation is less than about 3%. 
     
     
         22 . The method of  claim 1 , wherein the pH is between 6 and 7.8. 
     
     
         23 . The method of  claim 1 , wherein the pH is between 6 and 7.2. 
     
     
         24 . The method of  claim 1 , wherein the viscosity is between 9 and 15 cps. 
     
     
         25 . The method of  claim 1 , wherein the viscosity is between 12 and 15 cps. 
     
     
         26 . The method of  claim 1 , wherein the formulation further comprises an osmolality between 250-800 mOsm/kgH 2 O. 
     
     
         27 . The method of  claim 26 , wherein the osmolality is between 700-800 mOsm/kgH 2 O. 
     
     
         28 . The method of  claim 26 , wherein the osmolality is between 750-800 mOsm/kgH 2 O. 
     
     
         29 . A method of treating a rheumatic disease in a subject comprising administering to the subject an effective amount of a formulation comprising:
 a) a CTLA4Ig molecule comprising amino acid residues 26-382 of SEQ ID NO:2, amino acid residues 26-383 of SEQ ID NO:2, amino acid residues 27-382 of SEQ ID NO:2 and/or amino acid residues 27-383 of SEQ ID NO:2 at a concentration of about 125 mg/ml;   b) a sugar;   c) at least one buffering agent;   d) a surfactant; and   e) a pharmaceutically acceptable aqueous carrier;   wherein the sugar is sucrose, lactose, maltose, mannitol, trehalose or a mixture thereof;   wherein the pH is between 6 and 8;   wherein the viscosity is between 9 and 20 cps;   wherein the formulation is suitable for subcutaneous administration;   wherein the formulation is stable when stored at 2 to 8° C. for at least 12 months; and   wherein the formulation is administered once weekly in a volume of about 1 ml.   
     
     
         30 . The method of  claim 29 , wherein the CTLA4Ig molecule is abatacept. 
     
     
         31 . The method of  claim 29 , wherein the sugar is sucrose. 
     
     
         32 . The method of  claim 31 , wherein the concentration of sucrose is about 170 mg/ml. 
     
     
         33 . The method of  claim 29 , wherein the sugar is lactose. 
     
     
         34 . The method of  claim 29 , wherein the sugar is maltose. 
     
     
         35 . The method of  claim 29 , wherein the sugar is mannitol. 
     
     
         36 . The method of  claim 29 , wherein the sugar is trehalose. 
     
     
         37 . The method of  claim 29 , wherein the buffering agent is phosphate, glycinate, carbonate, citrate or a combination thereof. 
     
     
         38 . The method of  claim 29 , wherein the buffering agent is phosphate. 
     
     
         39 . The method of  claim 38 , wherein the concentration of phosphate buffer is at least about 10 mM. 
     
     
         40 . The method of  claim 29 , wherein the surfactant is selected from the group consisting of a polysorbate, polysorbate 20, polysorbate 80, poloxamer, poloxamer 188, sorbitan ester, sorbitan derivative, Triton, sodium laurel sulfate, sodium octyl glycoside, lauryl-sulfobetadine, myristyl-sulfobetadine, linoleyl-sulfobetadine, stearyl-sulfobetadine, lauryl-sarcosine, myristyl-sarcosine, linoleyl-sarcosine, stearyl-sarcosine, linoleyl-betaine, myristyl-betaine, cetyl-betaine, lauramidopropyl-betaine, cocamidopropyl-betaine, linoleamidopropyl-betaine, myristamidopropyl-betaine, palmidopropyl-betaine, isostearamidopropyl-betaine, lauroamidopropyl-dimethylamine, myristamidopropyl-dimethylamine, palmidopropyl-dimethylamine, isostearamidopropyl-dimethylamine, sodium methyl cocoyl-taurate, and disodium methyl oleyl-tauratem, polyethylene glycol, polypropyl glycol, and a copolymer of ethylene and propylene glycol. 
     
     
         41 . The method of  claim 29 , wherein the surfactant is a poloxamer. 
     
     
         42 . The method of  claim 29 , wherein the surfactant is poloxamer 188. 
     
     
         43 . The method of  claim 42 , wherein the concentration of poloxamer 188 is about 8 mg/ml. 
     
     
         44 . The method of  claim 29 , wherein the pharmaceutically acceptable aqueous carrier is sterile water. 
     
     
         45 . The method of  claim 29 , wherein the formulation is stable when stored at 2 to 8° C. for at least 18 months. 
     
     
         46 . The method of  claim 29 , wherein the formulation is stable when stored at 2 to 8° C. for at least 24 months. 
     
     
         47 . The method of  claim 29 , wherein the percentage of CTLA4Ig high molecular weight species in the formulation is less than about 10%. 
     
     
         48 . The method of  claim 29 , wherein the percentage of CTLA4Ig high molecular weight species in the formulation is less than about 5%. 
     
     
         49 . The method of  claim 29 , wherein the percentage of CTLA4Ig high molecular weight species in the formulation is less than about 3%. 
     
     
         50 . The method of  claim 29 , wherein the pH is between 6 and 7.8. 
     
     
         51 . The method of  claim 29 , wherein the pH is between 6 and 7.2. 
     
     
         52 . The method of  claim 29 , wherein the viscosity is between 9 and 15 cps. 
     
     
         53 . The method of  claim 29 , wherein the viscosity is between 12 and 15 cps. 
     
     
         54 . The method of  claim 29 , wherein the formulation further comprises an osmolality between 250-800 mOsm/kgH 2 O. 
     
     
         55 . The method of  claim 54 , wherein the osmolality is between 700-800 mOsm/kgH 2 O. 
     
     
         56 . The method of  claim 54 , wherein the osmolality is between 750-800 mOsm/kgH 2 O. 
     
     
         57 . A method of treating a graft-related transplantation disease in a subject comprising administering to the subject an effective amount of a formulation comprising:
 a) a CTLA4Ig molecule comprising amino acid residues 26-382 of SEQ ID NO:2, amino acid residues 26-383 of SEQ ID NO:2, amino acid residues 27-382 of SEQ ID NO:2 and/or amino acid residues 27-383 of SEQ ID NO:2 at a concentration of about 125 mg/ml;   b) a sugar;   c) at least one buffering agent;   d) a surfactant; and   e) a pharmaceutically acceptable aqueous carrier;   wherein the sugar is sucrose, lactose, maltose, mannitol, trehalose or a mixture thereof;   wherein the pH is between 6 and 8;   wherein the viscosity is between 9 and 20 cps;   wherein the formulation is suitable for subcutaneous administration;   wherein the formulation is stable when stored at 2 to 8° C. for at least 12 months; and   wherein the formulation is administered once weekly in a volume of about 1 ml.   
     
     
         58 . The method of  claim 57 , wherein the graft-related transplantation disease is graft versus host disease (GVHD). 
     
     
         59 . The method of  claim 57 , wherein the graft-related transplantation disease is associated with a solid organ transplant, tissue transplant or bone marrow transplant. 
     
     
         60 . The method of  claim 57 , wherein the sugar is sucrose. 
     
     
         61 . The method of  claim 60 , wherein the concentration of sucrose is about 170 mg/ml. 
     
     
         62 . The method of  claim 57 , wherein the sugar is lactose. 
     
     
         63 . The method of  claim 57 , wherein the sugar is maltose. 
     
     
         64 . The method of  claim 57 , wherein the sugar is mannitol. 
     
     
         65 . The method of  claim 57 , wherein the sugar is trehalose. 
     
     
         66 . The method of  claim 57 , wherein the buffering agent is phosphate, glycinate, carbonate, citrate or a combination thereof. 
     
     
         67 . The method of  claim 57 , wherein the buffering agent is phosphate. 
     
     
         68 . The method of  claim 67 , wherein the concentration of phosphate buffer is at least about 10 mM. 
     
     
         69 . The method of  claim 57 , wherein the surfactant is selected from the group consisting of a polysorbate, polysorbate 20, polysorbate 80, poloxamer, poloxamer 188, sorbitan ester, sorbitan derivative, Triton, sodium laurel sulfate, sodium octyl glycoside, lauryl-sulfobetadine, myristyl-sulfobetadine, linoleyl-sulfobetadine, stearyl-sulfobetadine, lauryl-sarcosine, myristyl-sarcosine, linoleyl-sarcosine, stearyl-sarcosine, linoleyl-betaine, myristyl-betaine, cetyl-betaine, lauramidopropyl-betaine, cocamidopropyl-betaine, linoleamidopropyl-betaine, myristamidopropyl-betaine, palmidopropyl-betaine, isostearamidopropyl-betaine, lauroamidopropyl-dimethylamine, myristamidopropyl-dimethylamine, palmidopropyl-dimethylamine, isostearamidopropyl-dimethylamine, sodium methyl cocoyl-taurate, and disodium methyl oleyl-tauratem, polyethylene glycol, polypropyl glycol, and a copolymer of ethylene and propylene glycol. 
     
     
         70 . The method of  claim 57 , wherein the surfactant is a poloxamer. 
     
     
         71 . The method of  claim 57 , wherein the surfactant is poloxamer 188. 
     
     
         72 . The method of  claim 71 , wherein the concentration of poloxamer 188 is about 8 mg/ml. 
     
     
         73 . The method of  claim 57 , wherein the pharmaceutically acceptable aqueous carrier is sterile water. 
     
     
         74 . The method of  claim 57 , wherein the formulation is stable when stored at 2 to 8° C. for at least 18 months. 
     
     
         75 . The method of  claim 57 , wherein the formulation is stable when stored at 2 to 8° C. for at least 24 months. 
     
     
         76 . The method of  claim 57 , wherein the percentage of CTLA4Ig high molecular weight species in the formulation is less than about 10%. 
     
     
         77 . The method of  claim 57 , wherein the percentage of CTLA4Ig high molecular weight species in the formulation is less than about 5%. 
     
     
         78 . The method of  claim 57 , wherein the percentage of CTLA4Ig high molecular weight species in the formulation is less than about 3%. 
     
     
         79 . The method of  claim 57 , wherein the pH is between 6 and 7.8. 
     
     
         80 . The method of  claim 57 , wherein the pH is between 6 and 7.2. 
     
     
         81 . The method of  claim 57 , wherein the viscosity is between 9 and 15 cps. 
     
     
         82 . The method of  claim 57 , wherein the viscosity is between 12 and 15 cps. 
     
     
         83 . The method of  claim 57 , wherein the formulation further comprises an osmolality between 250-800 mOsm/kgH 2 O. 
     
     
         84 . The method of  claim 83 , wherein the osmolality is between 700-800 mOsm/kgH 2 O. 
     
     
         85 . The method of  claim 83 , wherein the osmolality is between 750-800 mOsm/kgH 2 O.
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