Composition and method for controlling drug delivery from silicone adhesive blends

Abstract

Compositions and methods for controlling transdermal drug delivery, particularly of amine-functional and basic drugs, comprising a blend of a first silicone-based polymer having a reduced silanol concentration and a second silicone-based polymer have a substantial or high silanol concentration. The blend of such silicone-based polymers, particularly pressure-sensitive silicone adhesives, provides sufficient drug solubility and reduced initial drug delivery onset to permit a prolonged delivery duration at a substantially zero-order rate of delivery.

1 . A flexible, finite transdermal drug delivery composition, said composition comprising a blend of: 
 a matrix and at least one drug,    wherein said matrix comprises at least one first silicone-based polymer, said first silicone-based polymer having a reduced silanol concentration; and    at least one second silicone-based polymer, said second silicone-based polymer having a substantial silanol concentration; and    wherein said at least one drug excludes selegiline.    
     
     
         2 . The composition according to  claim 1 , wherein said first silicone-based polymer has a silicone-bonded hydroxyl content below about 13,000.  
     
     
         3 . The composition according to  claim 1 , wherein said first silicone-based polymer has a silicone-bonded hydroxyl content below about 7,700.  
     
     
         4 . The composition according to  claim 2 , wherein said second silicone-based polymer has a silicone-bonded hydroxyl content of greater than about 13,000.  
     
     
         5 . The composition according to  claim 3 , wherein said second silicone-based polymer has a silicone-bonded hydroxyl content of greater than about 13,000.  
     
     
         6 . The composition according to  claim 1 , wherein said at least one drug includes an amine-functional drug or basic drug.  
     
     
         7 . The composition according to  claim 5 , wherein said at least one drug is an amine-functional drug.  
     
     
         8 . The composition according to  claim 6 , wherein said at least one drug is selected from the group consisting of oxybutynin, scopolamine, clonidine, nicotine, ramipril, enalapril, fentanyl and analogs such as alfentanyl, carfentanyl, lofentanyl, remifentanyl, sufentanyl, and trefentanyl, fluoxetine, epinephrine, morphine, hydromorphone, atropine, cocaine, buprenorphine, chlorpromazine, imipramine, desipramine, methylphenidate, amphetamine, dextroamphetamine, phentermine, methamphetamine, lidocaine, procaine, benzocaine, tetracaine, pindolol, nadolol, carisoprodol, azelastine, tacrine, alprazolam, buspirone, paroxetine, pramipaxole, bupropion, clonazepam, timolol, cyclobenzaprine, granisetron, levorphanol, triptans, pergolide, ropinirole, rotigotine, testosterone, and pharmaceutically acceptable prodrugs and salts thereof.  
     
     
         9 . The composition according to  claim 1 , wherein said second silicone-based polymer is present in an amount from about 10% to about 80% by dry weight of said matrix.  
     
     
         10 . The composition according to  claim 1 , wherein said second silicone-based polymer is present in an amount from about 20% to about 75% by dry weight of said matrix.  
     
     
         11 . The composition according to  claim 1 , wherein said second silicone-based polymer is present in an amount from about 25% to about 60% by dry weight of said matrix.  
     
     
         12 . The composition according to  claim 7 , wherein said second silicone-based polymer is present in an amount below about 50% said matrix.  
     
     
         13 . The composition according to  claim 1 , further comprising at least one additive selected from the group consisting of enhancers and crystallization inhibitors.  
     
     
         14 . The composition according to  claim 13 , wherein said crystallization inhibitor is selected from the group consisting of polyvinylpyrrolidone, vinyl acetate/vinylpyrrolidone copolymer and cellulose derivatives.  
     
     
         15 . A flexible, finite transdermal drug delivery composition, said composition comprising a blend of: 
 a matrix and at least one amine-functional drug,    wherein said matrix comprises at least one first silicone-based polymer, said first silicone-based polymer having a silicone-bonded hydroxyl content of below about 13,000; and    at least one second silicone-based polymer, said second silicone-based polymer having silicone-bonded hydroxyl content of greater than about 13,000.    
     
     
         16 . The composition according to  claim 15 , wherein said at least one amine-functional drug is selected from the group consisting of oxybutynin, scopolamine, ephedrine, clonidine, nicotine, ramipril, enalapril, fentanyl and analogs such as alfentanyl, carfentanyl, lofentanyl, remifentanyl, sufentanyl, and trefentanyl, fluoxetine, epinephrine, morphine, hydromorphone, atropine, cocaine, buprenorphine, chlorpromazine, imipramine, desipramine, methylphenidate, amphetamine, dextroamphetamine, methamphetamine, lidocaine, procaine, tetracaine, pindolol, nadolol, carisoprodol, and acid addition salts thereof.  
     
     
         17 . The composition according to  claim 16 , wherein said at least one amine-functional drug includes fentanyl and analogs thereof.  
     
     
         18 . The composition according to  claim 17 , wherein said fentanyl is fentanyl or sufentanyl base.  
     
     
         19 . The composition according to  claim 18 , wherein said first silicone-based polymer is present in an amount of from about 22.5% to about 72.5% by dry weight of said composition.  
     
     
         20 . The composition according to  claim 26 , wherein said second silicone-based polymer is present in an amount of from about 25% to about 75% by dry weight of said composition.  
     
     
         21 . The composition according to  claim 15 , wherein said second silicone-based polymer is present in an amount below about 50% said matrix.  
     
     
         22 . The composition according to  claim 15 , further comprising at least one additive selected from the group consisting of enhancers and crystallization inhibitors.  
     
     
         23 . The composition according to  claim 22 , wherein said crystallization inhibitor agent is selected from the group consisting of polyvinylpyrrolidone, vinyl acetate/vinylpyrrolidone copolymer, and cellulose derivatives.  
     
     
         24 . A method of controlling transdermal drug delivery, comprising topically administering at least one drug in a flexible, finite matrix, said matrix comprising a blend of: 
 at least one first silicone-based polymer, said first silicone-based polymer having a silicone-bonded hydroxyl content below about 13,000; and    at least one second silicone-based polymer, said second silicone-based polymer having silicone-bonded hydroxyl content of greater than about 13,000,    wherein said at least one drug is present in an amount sufficient to achieve kinetics resulting in blood levels of drug that is approximately constant once steady state is attained, and wherein said at least one drug excludes selegiline.    
     
     
         25 . The method according to  claim 24 , wherein said first silicone-based polymer has a silicone-bonded hydroxyl content below about 7,700.  
     
     
         26 . The composition according to  claim 24 , wherein said at least one drug includes an amine-functional drug.  
     
     
         27 . The composition according to  claim 26 , further comprising at least one additive selected from the group consisting of enhancers and crystallization inhibitors.  
     
     
         28 . The composition according to  claim 27 , wherein said crystallization inhibitor is selected from the group consisting of polyvinylpyrrolidone, vinyl acetate/vinylpyrrolidone copolymer and cellulose derivatives.  
     
     
         29 . The composition according to  claim 28 , wherein said second silicone-based polymer is present in an amount below about 50% by dry weight of said composition.  
     
     
         30 . The method according to  claim 24 , wherein the blood levels of said patient do not vary more than up to 40% from the mean at steady state for delivery to the skin or mucosa of a patient in need thereof over a period of time of 24 hours or less.  
     
     
         31 . The method according to  claim 24 , wherein said at least one drug is selected from the group consisting of oxybutynin, scopolamine, clonidine, nicotine, ramipril, enalapril, fentanyl and analogs such as alfentanyl, carfentanyl, lofentanyl, remifentanyl, sufentanyl, and trefentanyl, fluoxetine, epinephrine, morphine, hydromorphone, atropine, cocaine, buprenorphine, chlorpromazine, imipramine, desipramine, methylphenidate, amphetamine, dextroamphetamine, phentermine, methamphetamine, lidocaine, procaine, benzocaine, tetracaine, pindolol, nadolol, carisoprodol, azelastine, tacrine, alprazolam, buspirone, paroxetine, pramipaxole, bupropion, clonazepam, timolol, cyclobenzaprine, granisetron, levorphanol, non-steroidal anti-inflammatory agents such as ketoprofen, triptans, pergolide, ropinirole, rotigotine, testosterone, and acid addition salts thereof.  
     
     
         32 . The composition according to  claim 30 , wherein said at least one drug includes fentanyl and analogs thereof.