Pharmaceutical formulations of c1 esterase inhibitor

Abstract

The present invention relates to pharmaceutical formulations comprising the C1 esterase inhibitor (C1-INH), exhibiting a higher stability for prolonged storage and a reduced formation of aggregates of said esterase inhibitor (C1-INH) upon storage for ameliorated use in treating or preventing disorders related to kinin formation.

1 . A stable pharmaceutical formulation comprising
 (a) C1-INH at a concentration of about 400 IU/mL-2,000 IU/mL; and   (b) histidine, preferably L-histidine, or a salt/salts thereof at a concentration of about 5-150 mM, preferably 10-80 mM,   wherein the formulation does not comprise citrate or phosphate.   
     
     
         2 . The pharmaceutical formulation according to  claim 1 , further comprising one or more amino acid, preferably an L-amino acid, or a salt thereof at a concentration of 2-150 mM each, preferably about 5-50 mM. 
     
     
         3 . The pharmaceutical formulation according to  claim 2 , wherein said one or more amino acid is arginine, glycin and/or lysine or a salt thereof. 
     
     
         4 . The pharmaceutical formulation according to any one of the preceding claims, further comprising saccharose at a concentration of about 5-250 mM, preferably 20-200 mM. 
     
     
         5 . The pharmaceutical formulation according to any one of the preceding claims, further comprising sodium chloride or sodium glutamate at a concentration of about 1-200 mM, preferably 20-150 mM. 
     
     
         6 . The pharmaceutical formulation according to any one of the preceding claims, wherein the pH of the formulation is between about 6.0 and about 8.0, preferably between 6.7 and 7.5. 
     
     
         7 . The pharmaceutical formulation according to any one of the preceding claims, wherein the formulation comprises
 (a) about 400-625 IU/mL C1-INH,   (b) about 10-200 mM sodium chloride,   (c) about 5-150 mM histidine,   (d) about 5-50 mM arginine or arginine*HCl, and   (e) about 100-200 mM saccharose.   
     
     
         8 . The pharmaceutical formulation according to any one of the preceding claims, wherein the formulation further comprises
 (a) a non-ionic detergent selected from the group consisting of PS80 (polysorbate 80) and PS20 (polysorbate 20); and/or   (b) a preservative and/or antioxidant selected from the group consisting of benzylalcohol, cresol, phenol, methionine and glutathione.   
     
     
         9 . The pharmaceutical formulation according to any one of the preceding claims, wherein the C1-INH is human C1-INH, preferably wherein the human C1-INH is derived from human plasma, or wherein the human C1-INH is recombinantly expressed. 
     
     
         10 . The pharmaceutical formulation according to any one of the preceding claims, wherein the formulation is
 (a) obtainable by reconstitution of a lyophilized powder with a suitable liquid, or   (b) provided as a liquid formulation.   
     
     
         11 . The pharmaceutical formulation according to any one of the preceding claims, wherein the formulation is provided as a lyophilized powder. 
     
     
         12 . The pharmaceutical formulation according to any one of the preceding claims, wherein the formulation can be administered via subcutaneous administration or via intravenous administration. 
     
     
         13 . The pharmaceutical formulation according to any one of the preceding claims, wherein a patient can self-administer the formulation. 
     
     
         14 . The pharmaceutical formulation according to any one of the preceding claims for use in the acute and/or prophylactic treatment of a disorder related to kinin formation, in particular hereditary angioedema (HAE), preferably HAE type I, HAE type II or HAE type III, secondary brain edema, edema of the central nervous system, hypotensive shock, or edema during or after contacting blood with an artificial surface; in the acute and/or prophylactic treatment of a disorder related to an ischemia-reperfusion injury (IRI), in particular wherein the IRI is due to surgical intervention, in particular vascular surgery, cardiac surgery, neurosurgery, trauma surgery, cancer surgery, orthopedic surgery, transplantation, minimally invasive surgery, or insertion of a device for delivery of a pharmacologically active substance or for mechanical removal of complete or partial obstructions; in the acute and/or prophylactic treatment of retinopathy or in preventing rejection of transplanted tissue in a patient. 
     
     
         15 . A kit comprising the pharmaceutical formulation according to one of  claims 1 - 14  as a lyophilized powder and a respective volume of a suitable liquid for reconstitution. 
     
     
         16 . A kit comprising the pharmaceutical formulation according to one of the  claims 1 - 15  and at least one syringe and/or one needle. 
     
     
         17 . A syringe prefilled with a liquid pharmaceutical formulation according to one of the  claims 1 - 14 .