Cyclooxygenase inhibitor and calcium channel antagonist compositions and methods for use in urological procedures

Abstract

Compositions of a cyclooxygenase inhibitor and a calcium channel antagonist in a liquid carrier. The composition may be administered the urinary tract during urological diagnostic, interventional, surgical and other medical procedures. One disclosed composition comprises ketoprofen and nifedipine in a liquid irrigation carrier, and includes a solubilizing agent, stabilizing agents and a buffering agent.

1 . A locally deliverable composition for inhibiting pain/inflammation and spasm, comprising a combination of ketoprofen and a calcium channel antagonist in a carrier, each of the ketoprofen and the calcium channel antagonist included in a therapeutically effective amount such that the combination inhibits pain/inflammation and spasm at a site of local delivery. 
     
     
         2 . The composition of  claim 1 , wherein the calcium channel antagonist comprises an L-type calcium channel antagonist. 
     
     
         3 . The method of  claim 2 , wherein the L-type calcium channel antagonist is selected from the group consisting of verapamil, diltiazem, bepridil, mibefradil, nifedipine, nicardipine, isradipine, amlodipine, felodipine, nisoldipine and nimodipine. 
     
     
         4 . The method of  claim 2 , wherein the L-type calcium channel antagonist comprises a dihydropyridine. 
     
     
         5 . The composition of  claim 4 , wherein the L-type calcium channel antagonist is selected from the group consisting of nifedipine, nicardipine, isradipine, amlodipine, felodipine, nisoldipine and nimodipine. 
     
     
         6 . The method of  claim 5 , wherein the L-type calcium channel antagonist comprises nifedipine. 
     
     
         7 . The composition of  claim 5 , wherein the L-type calcium channel antagonist has an onset of action of less than or equal to 10 minutes. 
     
     
         8 . The composition of  claim 1 , wherein the calcium channel antagonist comprises nifedipine. 
     
     
         9 . The composition of  claim 8 , wherein ketoprofen and nifedipine are included in the composition in a ketoprofen:nifedipine molar ratio of from 10:1 to 1:10. 
     
     
         10 . The composition of  claim 9 , wherein ketoprofen and nifedipine are included in the composition in a ketoprofen:nifedipine molar ratio of from 4:1 to 1:1. 
     
     
         11 . The composition of  claim 10 , wherein ketoprofen and nifedipine are included in the composition in a ketoprofen:nifedipine molar ratio of 3:1. 
     
     
         12 . The composition of  claim 8 , wherein ketoprofen is included in the composition at a concentration of no more than 500,000 nanomolar and nifedipine is included in the composition at a concentration of no more than 200,000 nanomolar. 
     
     
         13 . The composition of  claim 12 , wherein ketoprofen is included in the composition at a concentration of no more than 300,000 nanomolar and nifedipine is included in the composition at a concentration of no more than 100,000 nanomolar. 
     
     
         14 . The composition of  claim 13 , wherein ketoprofen is included in the composition at a concentration of no more than 50,000 nanomolar and nifedipine is included in the composition at a concentration of no more than 25,000 nanomolar. 
     
     
         15 . The composition of  claim 1 , wherein ketoprofen is included in the composition at a concentration of no more than 500,000 nanomolar and the calcium channel antagonist is included in the composition at a concentration of no more than 200,000 nanomolar. 
     
     
         16 . The composition of  claim 15 , wherein ketoprofen is included in the composition at a concentration of no more than 300,000 nanomolar and the calcium channel antagonist is included in the composition at a concentration of no more than 100,000 nanomolar. 
     
     
         17 . The composition of  claim 16 , wherein ketoprofen is included in the composition at a concentration of no more than 50,000 nanomolar and the calcium channel antagonist is included in the composition at a concentration of no more than 25,000 nanomolar. 
     
     
         18 . The composition of  claim 1 , wherein ketoprofen comprises the S-(+)-enantiomer, dexketoprofen. 
     
     
         19 . The composition of  claim 1 , wherein the composition is coated onto an implantable device or medical instrument. 
     
     
         20 . The composition of  claim 1 , wherein the composition is impregnated into an implantable device or medical instrument. 
     
     
         21 . A method of inhibiting pain/inflammation and spasm in the urinary tract, comprising:
 delivering to the urinary tract a composition including a combination of ketoprofen and a calcium channel antagonist in a carrier, each of the ketoprofen and the calcium channel antagonist included in a therapeutically effective amount such that the combination inhibits pain/inflammation and spasm in the urinary tract.   
     
     
         22 . The method of  claim 21 , wherein the composition is delivered periprocedurally to the urinary tract during a urological diagnostic, interventional, surgical and other medical procedure. 
     
     
         23 . The method of  claim 22 , wherein the composition is periprocedurally delivered during a cystoscopic procedure. 
     
     
         24 . The method of  claim 22 , wherein the composition is periprocedurally delivered during a ureteroscopic procedure. 
     
     
         25 . The method of  claim 22 , wherein the composition is periprocedurally delivered during a procedure to remove, fragment or dislodge a kidney or bladder stone. 
     
     
         26 . The method of  claim 22 , wherein the composition is periprocedurally delivered during a procedure that causes thermal injury to urinary tract tissue. 
     
     
         27 . The method of  claim 26 , wherein the composition is periprocedurally delivered during a laser, microwave ablation, radiofrequency ablation, electrocauterization or cryoblation procedure. 
     
     
         28 . The method of  claim 22 , wherein the composition is periprocedurally delivered during a transurethral resection of a prostate. 
     
     
         29 . The method of  claim 22 , wherein the composition is periprocedurally delivered transrectally or transperitoneally to the prostate. 
     
     
         30 . The method of  claim 21 , wherein the calcium channel antagonist in the composition comprises nifedipine. 
     
     
         31 . The method of  claim 21 , wherein the ketoprofen in the composition comprises the S-(+)-enantiomer, dexketoprofen. 
     
     
         32 . A method of inhibiting pain/inflammation and spasm in the urinary tract during a diagnostic, interventional, surgical or other medical urological procedure, comprising:
 periprocedurally delivering to the urinary tract during a urological procedure a composition including a combination of ketoprofen and nifedipine in a carrier, each of the ketoprofen and the nifedipine included in a therapeutically effective amount such that the combination inhibits pain/inflammation and spasm in the urinary tract.   
     
     
         33 . The method of  claim 32 , wherein the composition is during a cystoscopic procedure. 
     
     
         34 . The method of  claim 32 , wherein the composition is periprocedurally delivered during a ureteroscopic procedure. 
     
     
         35 . The method of  claim 32 , wherein the composition is periprocedurally delivered during a procedure to remove, fragment or dislodge a kidney or bladder stone. 
     
     
         36 . The method of  claim 32 , wherein the composition is periprocedurally delivered during a procedure that causes thermal injury to urinary tract tissue. 
     
     
         37 . The method of  claim 36 , wherein the composition is periprocedurally delivered during a laser, microwave ablation, radiofrequency ablation, electrocauterization or cryoblation procedure. 
     
     
         38 . The method of  claim 32 , wherein the composition is periprocedurally delivered during a transurethral resection of a prostate. 
     
     
         39 . The method of  claim 32 , wherein the composition is periprocedurally delivered transrectally or transperitoneally to the prostate. 
     
     
         40 . The method of  claim 32 , wherein the ketoprofen in the composition comprises the S-(+)-enantiomer, dexketoprofen. 
     
     
         41 . A method of inhibiting pain/inflammation and spasm in the urinary tract during a urological procedure, comprising:
 periprocedurally delivering to the urinary tract during a ureteroscopic procedure a composition including a combination of a cyclooxygenase inhibitor and a calcium channel antagonist in a carrier, each of the cyclooxygenase inhibitor and the calcium channel antagonist included in a therapeutically effective amount such that the combination inhibits pain/inflammation and spasm in the urinary tract.   
     
     
         42 . The method of  claim 41 , wherein the cyclooxygenase (COX) inhibitor in the composition comprises a nonselective COX-1/COX-2 inhibitor. 
     
     
         43 . A method of inhibiting pain/inflammation and spasm in the urinary tract during a urological procedure, comprising:
 periprocedurally delivering to the urinary tract during a procedure to remove, fragment or dislodge a kidney or bladder stone a composition including a combination of a cyclooxygenase inhibitor and a calcium channel antagonist in a carrier, each of the cyclooxygenase inhibitor and the calcium channel antagonist included in a therapeutically effective amount such that the combination inhibits pain/inflammation and spasm in the urinary tract.   
     
     
         44 . The method of  claim 43 , wherein the cyclooxygenase (COX) inhibitor in the composition comprises a nonselective COX-1/COX-2 inhibitor. 
     
     
         45 . A method of inhibiting pain/inflammation and spasm in the urinary tract during a urological procedure, comprising:
 periprocedurally delivering to the urinary tract during a procedure that causes thermal injury to urinary tract tissue a composition including a combination of a cyclooxygenase inhibitor and a calcium channel antagonist in a carrier, each of the cyclooxygenase inhibitor and the calcium channel antagonist included in a therapeutically effective amount such that the combination inhibits pain/inflammation and spasm in the urinary tract.   
     
     
         46 . The method of  claim 45 , wherein the cyclooxygenase (COX) inhibitor in the composition comprises a nonselective COX-1/COX-2 inhibitor. 
     
     
         47 . The method of  claim 45 , wherein the composition is delivered periprocedurally to the urologic structure during a laser, microwave ablation, radiofrequency ablation, electrocauterization or cryoblation procedure. 
     
     
         48 . A method of inhibiting pain/inflammation and spasm during a urological procedure, comprising:
 periprocedurally delivering transrectally or transperitoneally to the prostate a composition including a combination of a cyclooxygenase inhibitor and a calcium channel antagonist in a carrier, each of the cyclooxygenase inhibitor and the calcium channel antagonist included in a therapeutically effective amount such that the combination inhibits pain/inflammation and spasm.   
     
     
         49 . The method of  claim 48 , wherein the cyclooxygenase (COX) inhibitor in the composition comprises a nonselective COX-1/COX-2 inhibitor. 
     
     
         50 . A method of inhibiting pain, inflammation and/or spasm in the urinary tract during a urological procedure, comprising:
 periprocedurally delivering to the urinary tract during a ureteroscopic procedure a composition including a combination of a plurality of agents that inhibit pain/inflammation and/or spasm in a carrier, each agent included in a therapeutically effective amount such that the combination inhibits pain/inflammation and/or spasm in the urinary tract.   
     
     
         51 . A method of inhibiting pain, inflammation and/or spasm in the urinary tract during a urological procedure, comprising:
 periprocedurally delivering to the urinary tract during a procedure to remove, fragment or dislodge a kidney or bladder stone a composition including a combination of a plurality of agents that inhibit pain/inflammation and/or spasm in a carrier, each agent included in a therapeutically effective amount such that the combination inhibits pain/inflammation and/or spasm in the urinary tract.   
     
     
         52 . A method of inhibiting pain, inflammation and/or spasm in the urinary tract during a urological procedure, comprising:
 periprocedurally delivering to the urinary tract during a procedure that causes thermal injury to urinary tract tissue a composition including a combination of a plurality of agents that inhibit pain/inflammation and/or spasm in a carrier, each agent included in a therapeutically effective amount such that the combination inhibits pain/inflammation and/or spasm in the urinary tract.   
     
     
         53 . The method of  claim 52 , wherein the composition is delivered periprocedurally to the urologic structure during a laser, microwave ablation, radiofrequency ablation, electrocauterization or cryoblation procedure. 
     
     
         54 . A method of inhibiting pain, inflammation and/or spasm during a urological procedure, comprising:
 periprocedurally delivering transrectally or transperitoneally to the prostate a composition including a combination of a plurality of agents that inhibit pain/inflammation and/or spasm in a carrier, each agent included in a therapeutically effective amount such that the combination inhibits pain/inflammation and/or spasm.