Highly Concentrated Pharmaceutical Formulations

Abstract

The present invention relates to a highly concentrated, stable pharmaceutical formulation of a pharmaceutically active anti-CD20 antibody, such as e.g. Rituximab, Ocrelizumab, or HuMab<CD20>, or a mixture of such antibody molecules for subcutaneous injection. In particular, the present invention relates to formulations comprising, in addition to a suitable amount of the anti-CD20 antibody, an effective amount of at least one hyaluronidase enzyme as a combined formulation or for use in form of a co-formulation. The said formulations comprise additionally at least one buffering agent, such as e.g. a histidine buffer, a stabilizer or a mixture of two or more stabilizers (e.g. a saccharide, such as e.g. α,α-trehalose dihydrate or sucrose, and optionally methionine as a second stabilizer), a nonionic surfactant and an effective amount of at least one hyaluronidase enzyme. Methods for preparing such formulations and their uses thereof are also provided.

1 . A highly concentrated, stable pharmaceutical formulation of a pharmaceutically active anti-CD20 antibody comprising:
 a. about 50 to 350 mg/ml anti-CD20 antibody;   b. about 1 to 100 mM of a buffering agent providing a pH of 5.5±2.0;   c. about 1 to 500 mM of a stabilizer or a mixture of two or more stabilizers;   d. about 0.01 to 0.1% of a nonionic surfactant; and   e. optionally an effective amount of at least one hyaluronidase enzyme.   
     
     
         2 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 1 , wherein the anti-CD20 antibody concentration is 100 to 150 mg/ml, preferably 120±20 mg/ml. 
     
     
         3 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 1 , comprising about 1,000 to 16,000 U/ml of a hyaluronidase enzyme, preferably about 2,000 U/ml or 12,000 U/ml. 
     
     
         4 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 1 , wherein the buffering agent is at a concentration of 1 to 50 mM. 
     
     
         5 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 1 , wherein the buffering agent provides a pH of 5.5 to 6.5, preferably selected from the group consisting of 5.3, 5.5, 6.0, 6.1 and 6.5. 
     
     
         6 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 1 , wherein the buffering agent is a histidine buffer. 
     
     
         7 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 1 , wherein the stabilizer is a saccharide, such as e.g. α,α-trehalose dihydrate or sucrose. 
     
     
         8 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 1 , wherein the stabilizer is at a concentration of 15 to 250 mM. 
     
     
         9 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 7 , wherein methionine is used as a second stabilizer. 
     
     
         10 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 9 , wherein methionine is present in a concentration of 5 to 25 mM. 
     
     
         11 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 1 , wherein the nonionic surfactant is a polysorbate, preferably selected from the group consisting of polysorbate 20, polysorbate 80, and polyethylene-polypropylene copolymer. 
     
     
         12 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 11 , wherein the concentration of the polysorbate is 0.02% (w/v) to 0.08% (w/v). 
     
     
         13 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 1 , wherein the hyaluronidase enzyme is rHuPH20. 
     
     
         14 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 1 , wherein the anti-CD20 antibody is Rituximab. 
     
     
         15 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 1 , wherein the anti-CD20 antibody is Ocrelizumab. 
     
     
         16 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 15 , wherein the anti-CD20 antibody is 2H7.v16. 
     
     
         17 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 1 , wherein the anti-CD20 antibody is HuMab<CD20>. 
     
     
         18 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 1 , which is stable upon freezing and thawing. 
     
     
         19 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 1 , which is for subcutaneous or intramuscular administration. 
     
     
         20 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 1  in liquid form. 
     
     
         21 . A highly concentrated, stable pharmaceutical anti-CD20 antibody formulation according to  claim 1  in lyophilized form. 
     
     
         22 . A method of treating a disease or disorder which is amenable to treatment with an anti-CD20 antibody, such as cancer or a non-malignant disease, in a subject comprising administering the formulation of  claim 1  to a subject in an amount effective to treat the said disease or disorder. 
     
     
         23 . The method according to  claim 22  wherein the anti-CD20 antibody comprises Rituximab. 
     
     
         24 . The method according to  claim 23  wherein the anti-CD20 antibody is administered subcutaneously at a fixed dose of about 1400 mg. 
     
     
         25 . The method according to  claim 24  wherein the fixed dose is administered approximately every 2 months or approximately every 3 months. 
     
     
         26 . The method according to  claim 24  wherein the disease or disorder is non-Hodgkin's lymphoma. 
     
     
         27 . The method according to  claim 22  wherein the formulation is co-administered concomitantly or sequentially with chemotherapy. 
     
     
         28 . The method according to  claim 27  wherein the chemotherapy is selected from the group consisting of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and CVP (cyclophosphamide, vincristine, and predisone). 
     
     
         29 . A method of treating non-Hodkin's lymphoma (NHL) in a human patient comprising administering a formulation comprising Rituximab subcutaneously to the subject, wherein the Rituximab is administered at a fixed dose of 1400 mg thereof. 
     
     
         30 . The method according to  claim 29  wherein the formulation comprising rituximab is administered approximately every 2 months or approximately every 3 months. 
     
     
         31 . The method according to  claim 30  further comprising administering chemotherapy to the patient. 
     
     
         32 . The method according to  claim 31  wherein the chemotherapy is selected from the group consisting of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and CVP (cyclophosphamide, vincristine, and predisone). 
     
     
         33 . The method according to  claim 29  wherein the formulation comprises about 50 to 350 mg/ml rituximab and at least one hyaluronidase enzyme.