US2014274995A1PendingUtilityA1

Parenteral ceftolozane antibiotic compositions

Assignee: CUBIST PHARM INCPriority: Mar 15, 2013Filed: Mar 14, 2014Published: Sep 18, 2014
Est. expiryMar 15, 2033(~6.6 yrs left)· nominal 20-yr term from priority
A61P 31/04A61P 31/12A61P 31/00A61P 43/00A61K 47/183A61K 31/546A61K 47/12A61K 31/431A61K 47/02A61K 47/36A61K 9/0019A61K 47/26A61K 9/19A61K 31/433Y02A50/30
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Claims

Abstract

Parenteral pharmaceutical compositions including ceftolozane and tazobactam can be formulated to provide desired levels of osmolality, pH and ceftolozane stability.

Claims

exact text as granted — not AI-modified
1 . A method of treating an infection selected from the group consisting of Complicated Urinary Tract Infections (cUTI), Complicated Intra-Abdominal Infections (cIAI) and Hospital-Acquired Bacterial Pneumonia (HABP)/Ventilator-Associated Bacterial Pneumonia (VABP), the method comprising
 a. reconstituting a lyophilized unit dosage form composition comprising the following components   
       
         
           
                 
                 
               
                     
                 
                     
                   Nominal Composition 
                 
                   Component 
                   mg per 1 g ceftolozane active 
                 
                     
                 
                   Ceftolozane Sulfate 
                   about 1147 (providing 1,000 mg ceftolozane active) 
                 
                   Citric Acid 
                   21 
                 
                   Sodium Chloride 
                   450-500 
                 
                   L-Arginine 
                   500-700 
                 
                   Tazobactam 
                   about 537 (providing 500 mg tazobactam free acid 
                 
                   Sodium 
                   per 1,000 mg ceftolozane active) 
                 
                     
                 
             
                
                
                
                
               
               
                
                
                
                
                
                
                
               
            
           
         
         
           
             in one or more pharmaceutically acceptable liquid carriers selected from the group consisting of 0.9% sodium chloride aqueous solution for injection, 0.45% sodium chloride aqueous solution for injection, and 5% dextrose for injection and water for injection, to form a dissolved unit dosage form; 
           
         
         b. diluting the dissolved unit dosage form in one or more pharmaceutically acceptable liquid carriers selected from the group consisting of 0.9% sodium chloride aqueous solution for injection, 0.45% sodium chloride aqueous solution for injection, and 5% dextrose for injection and water for injection, to form a parenteral pharmaceutical formulation comprising a therapeutically effective amount of ceftolozane sulfate and tazobactam, and having an osmolality of about 400-600 mOsm/kg and a pH of about 5-7; and 
         c. intravenously administering to a patient in need thereof the parenteral pharmaceutical formulation comprising the therapeutically effective dose of ceftolozane sulfate and tazobactam; tazobactam in an amount providing 500 mg of tazobactam acid per 1,000 mg of ceftolozane active in the parenteral pharmaceutical formulation; 450 to 500 mg of sodium chloride per 1,000 mg of ceftolozane active in the parenteral pharmaceutical formulation; and L-arginine. 
       
     
     
         2 . The method of  claim 1 , further comprising intravenously administering the parenteral pharmaceutical formulation over a period of about 1 hour to the patient. 
     
     
         3 . The method of  claim 1 , further comprising administering a second and a third parenteral pharmaceutical formulation comprising ceftolozane and tazobactam to a patient in need thereof by repeating steps (a)-(c) three times a day. 
     
     
         4 . The method of  claim 1 , wherein the infection is a Complicated Urinary Tract Infections (cUTI) or Complicated Intra-Abdominal Infections (cIAI). 
     
     
         5 . The method of  claim 4 , wherein the parenteral pharmaceutical formulation contains a total of 1,000 mg of ceftolozane active present as ceftolozane sulfate. 
     
     
         6 . The method of  claim 5 , wherein the parenteral pharmaceutical formulation contains a total of 500 mg of tazobactam acid present as tazobactam sodium. 
     
     
         7 . The method of  claim 1 , wherein the lyophilized unit dosage form composition comprises 1,000 mg of ceftolozane active present as ceftolozane sulfate. 
     
     
         8 . The method of  claim 1 , wherein the lyophilized unit dosage form composition is obtained by a process comprising the steps of:
 a. lyophilizing a first aqueous solution in the absence of tazobactam, the first aqueous solution comprising ceftolozane, 450 mg to 500 mg of sodium chloride per 1,000 mg of ceftolozane active, at a pH of 6-7 prior to lyophilization to obtain a first lyophilized ceftolozane composition,   b. lyophilizing a second solution comprising tazobactam in the absence of ceftolozane to form a second lyophilized tazobactam composition; and   c. blending the first lyophilized ceftolozane composition and the second lyophilized tazobactam composition to obtain the antibacterial composition; and   d. packaging a portion of the antibacterial composition as the lyophilized unit dosage form composition.   
     
     
         9 . The method of  claim 8 , wherein the first aqueous solution further comprises L-arginine in an amount providing a pH of about 6-7. 
     
     
         10 . The method of  claim 8 , wherein the first aqueous solution comprises water and the following components: 
       
         
           
                 
                 
               
                     
                 
                     
                   Nominal Composition 
                 
                   Component 
                   mg per Vial 
                 
                     
                 
                   Ceftolozane Sulfate 
                   about 1147 (providing 1,000 mg ceftolozane active) 
                 
                   Citric Acid 
                    21 
                 
                   Sodium Chloride 
                   487 
                 
                   L-Arginine 
                   600 
                 
                     
                   Q.S. for pH adjustment 
                 
                   Nitrogen 
                   Q.S. 
                 
                     
                 
             
                
                
                
                
               
               
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         11 . A method of treating a bacterial infection in a subject comprising administering to a patient in need thereof a parenteral pharmaceutical antibiotic composition having an osmolality of 400-500 mOsm/kg at a pH of 5-7, the composition comprising
 a. an amount of ceftolozane sulfate providing 1,000 mg ceftolozane active,   b. about 450 mg to 500 mg sodium chloride per 1,000 mg ceftolozane active, and   c. an amount of tazobactam sodium providing 500 mg of tazobactam free acid;   
       in a pharmaceutically acceptable liquid carrier selected from the group consisting of 0.9% sodium chloride aqueous solution for injection, 5% dextrose for injection and water for injection. 
     
     
         12 . The method of  claim 11 , wherein the bacterial infection is a complicated urinary tract infection. 
     
     
         13 . The method of  claim 11 , wherein the bacterial infection is a complicated intra-abdominal infection. 
     
     
         14 . The method of  claim 11 , wherein the bacterial infection comprises a bacteria selected from the group consisting of:  Staphylococcus aureus, Escherichia coli, Acinetobacter  baumanii,  Haemophilus influenzae, Klebsiella pneumonia , and  Pseudomonas aeruginosa.    
     
     
         15 . The method of  claim 11 , further comprising the steps of
 a. reconstituting a unit dosage form of ceftolozane/tazobactam having the composition:   
       
         
           
                 
                 
               
                     
                 
                     
                   Nominal Composition 
                 
                   Component 
                   mg per Vial 
                 
                     
                 
                   Ceftolozane Sulfate 
                   about 1147 (providing 1,000 mg ceftolozane active) 
                 
                   Citric Acid 
                    21 
                 
                   Sodium Chloride 
                   487 
                 
                   L-Arginine 
                   600 
                 
                     
                   Q.S. for pH adjustment 
                 
                   Tazobactam 
                   about 537 (providing 500 mg tazobactam free acid 
                 
                   Sodium 
                   per 1,000 mg ceftolozane active) 
                 
                   Nitrogen 
                   Q.S. 
                 
                     
                 
             
                
                
                
                
               
               
                
                
                
                
                
                
                
                
                
               
            
           
         
         
           in a pharmaceutically acceptable liquid carrier to obtain a reconstituted antibiotic composition; 
         
         b. intravenously administering the reconstituted antibiotic composition within the parenteral pharmaceutical antibiotic composition. 
       
     
     
         16 . The method of  claim 15 , further comprising repeatedly intravenously administering separate doses of the parenteral pharmaceutical antibiotic composition to a patient in need thereof three times per day. 
     
     
         17 . The method of  claim 16 , wherein each separate parenteral pharmaceutical antibiotic compositions are administered to the patient over a 1 hour period.

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