Preparation and use of radium-223 to target calcified tissues for pain palliation, bone cancer therapy, and bone surface conditioning

Abstract

Processes for the preparation, prepared solutions, and the use of radium- 223 for the treatment of calcified tumors, bone tumors, treatment of bones, bone surfaces and soft tissues is described.

1 . Method to produce radium- 223  for biomedical uses, characterized in loading a mother nuclide on generator column containing AC-resin on an inorganic matrix, or comprising a step using AC-resin in a liquid/liquid extraction system.  
     
     
         2 . Method according to  claim 1 , characterized in that the generator column contains a methane bis-phosponic acid derivative on silica matrix and in the step of liquid/liquid extraction one or more P,P′ di-esterified methylene bis-phosphonic acid derivatives or combinations thereof are used as phase transfer agents.  
     
     
         3 . Method according to  claim 2 , characterized in that the generator column contains P,P′ di-octyl methane bis-phosphonic acid on a silica matrix and in the step of liquid/liquid extraction P,P′ di-octyl methylene bis-phosphonic acid or P,P′ di(2-ethyl-hexyl)methane bis-phosphonic acid or combinations thereof are used as phase transfer agents.  
     
     
         4 . Method according to claim  1 - 3 , characterized in that the generator column contains mineral acids which after neutralization gives physiological compatible solutions of their salts, preferably nitric acid or hydrocloric acid, and in the step of liquid/liquid extraction it is used a water phase consisting of a mineral acid, preferably nitric acid or hydrochloric acid.  
     
     
         5 . Method according to  claim 4 , characterized in that the concentration of the mineral acid in the said column is 0.01M-8M, preferably 0.1M-2M, more preferably 0.5M-1M, and the concentration of the mineral acid in the liquid/liquid extraction is 0.01M-8M, preferably 0.1M-2M, more preferably 0.8M-1.5M.  
     
     
         6 . Physiologically acceptable preparation for in vivo administration, characterized in comprising dissolved radium- 223  salt, with or without a single or a combination of several cations as stabilizing alkaline earth metal cation analogue carrier, with or without an agent to prevent precipitation and/or generation of colloids, in addition to pharmacologically acceptable carriers and adjuvans.  
     
     
         7 . Preparation according to  claim 6 , characterized in that the cation acting as stabilizing alkaline earth metal cation are selected from the group consisting of magnesium, calcium and strontium.  
     
     
         8 . Preparation according to claim  6 - 7 , characterized in that the agent to prevent precipitation and/or generation of colloids is a carboxylic acid or a combination of carboxylic acids.  
     
     
         9 . Preparation according to  claim 8 , characterized in that the carboxylic acids are selected from the group containing oxalic acid, oxaloacetic acid, tartaric acid, succinic acid, malic acid and malonic acid.  
     
     
         10 . Preparation according to claims  4 - 6 , characterized in that it is prepared for injection, infusion or ingestion, or a combination thereof.  
     
     
         11 . Use of radium- 223  to produce a pharmaceutically active preparation to treat diseased bone and bone surfaces.  
     
     
         12 . Use according to  claim 11  wherein the preparation is used in a combination therapy with another therapeutically active component, such as but not limited to, chemotherapy including biphosphonates, surgery, external beam irradiation, low-LET radiation emitting bone seeking radiopharmaceuticals and hormonal treatment.  
     
     
         13 . Use according to claims  11 - 12 , wherein the preparation is used for therapy and/or palliation related to non-malignant and malignant diseases affecting bones and/or soft tissues.  
     
     
         14 . Use according to claims  11 - 13 , wherein the malignant diseases are selected from the group consisting of prostate cancer, breast cancer, kidney and urinary cancer, primary bone cancer, lung cancer and multiple myeloma.  
     
     
         15 . Method for prophylactic or therapeutical treatment of non-malignant or malignant disease affecting bones and soft tissues in a mammal, characterized in comprising administrating to the mammal in need thereof a palliative or therapeutically effective amount of the preparation according to claims  6 - 10 .  
     
     
         16 . Method according to  claim 15 , characterized in that it is administered to the mammal a prophylactic effective amount.  
     
     
         17 . Method according to claims  14 - 16 , characterized in that the mammal is a dog or a human.  
     
     
         18 . Kit, characterized in containing  223 Ra produced according to claims  1 - 5 , cations as stabilizing alkaline earth metal cation analogue carrier according to  claim 7 , and an agent to prevent precipitation and/or generation of colloids according to claims  8 - 9 , pharmaceutically acceptable carriers and suitable administration equipment.