Fentanyl suspension-based silicone adhesive formulations and devices for transdermal delivery of fentanyl

Abstract

Silicone adhesive formulations are provided, in which fentanyl particles are suspended one or more a solvated silicone adhesives. The formulations can be used for manufacturing improved, matrix-type transdermal devices for administering fentanyl.

1 . A monolithic patch for administering fentanyl transdermally to an individual, comprising: 
 (a) a backing layer substantially impervious to the fentanyl to be administered transdermally;    (b) a fentanyl-containing adhesive layer in contact with at least a portion of the backing layer, the adhesive layer being cast from a formulation comprising a blend of fentanyl particles suspended in one or more solvated silicone adhesives; and    (c) a removable release liner in contact with the adhesive layer.    
     
     
         2 . The patch of  claim 1 , wherein the one or more solvated silicone adhesives is a heptane-solvated silicone adhesive.  
     
     
         3 . The patch of  claim 2 , wherein the adhesive layer comprises about 1% to about 10% w/w fentanyl.  
     
     
         4 . The patch of  claim 3 , wherein the adhesive layer comprises about 3% to about 7% w/w fentanyl.  
     
     
         5 . The patch of  claim 4 , wherein the adhesive layer comprises about 4% w/w fentanyl.  
     
     
         6 . The patch of  claim 2 , wherein the adhesive layer comprises about 5% to about 15% w/w fentanyl.  
     
     
         7 . The patch of  claim 6 , wherein the adhesive layer comprises about 8% to about 12% w/w fentanyl.  
     
     
         8 . The patch of  claim 7 , wherein the adhesive layer comprises about 9.5% w/w fentanyl.  
     
     
         9 . The patch of  claim 8 , wherein the adhesive layer comprises about 9.1% w/w fentanyl.  
     
     
         10 . The patch of  claim 1 , wherein the fentanyl is the fentanyl free base.  
     
     
         11 . The patch of  claim 1 , wherein the backing layer is a polyolefin.  
     
     
         12 . The patch of  claim 1 , wherein the fentanyl is suspended uniformly in the solvated silicone adhesives as small particles.  
     
     
         13 . The patch of  claim 1 , wherein the fentanyl-containing adhesive layer is cast from a formulation comprising a blend of a slurry of fentanyl in a silicone fluid blended with one or more solvated silicone adhesives.  
     
     
         14 . The patch of  claim 13 , wherein the fentanyl-containing layer comprises up to about 25% w/w silicone fluid.  
     
     
         15 . The patch of  claim 14 , wherein the fentanyl-containing layer comprises about 2% to about 10% w/w silicone fluid.  
     
     
         16 . The patch of  claim 15 , wherein the fentanyl-containing layer comprises about 6.5% w/w silicone fluid.  
     
     
         17 . The patch of  claim 13 , wherein the silicone fluid comprises polydimethylsiloxane.  
     
     
         18 . The patch of  claim 1 , which further comprises a fentanyl-free adhesive layer between and in contact with said backing layer and said fentanyl-containing adhesive layer which extends at least partially beyond said fentanyl-containing adhesive layer.  
     
     
         19 . The patch of  claim 18 , wherein the fentanyl-containing adhesive layer is cast from a formulation comprising a blend of a slurry of fentanyl in a silicone fluid blended with one or more solvated silicone adhesives.  
     
     
         20 . The patch of  claim 19 , wherein the fentanyl-containing layer comprises up to about 25% w/w silicone fluid.  
     
     
         21 . A method for making a laminate, which is useful for making a monolithic patch for transdermal administration of fentanyl, comprising: 
 a) selecting a solvent that can substantially or fully solvate a silicone adhesive while keeping fentanyl, when blended with the solvated adhesive, suspended in the solvated adhesive;    b) blending fentanyl particles with one or more silicone adhesives which are solvated with the above solvent, to form a blend formulation in which fentanyl particles are suspended in the solvated adhesives;    c) casting the blend formulation onto a support material; and    d) removing the solvent, to produce a laminate containing the support material and a fentanyl suspension-containing adhesive layer.    
     
     
         22 . The method of  claim 21 , wherein the support material is a backing layer or release liner.  
     
     
         23 . The method of  claim 21 , wherein the blend formulation is treated prior to the casting step to disperse the fentanyl throughout the formulation and particle size is maintained by passing the formulation through a mixing device.  
     
     
         24 . The method of  claim 21 , wherein the solvent is heptane.  
     
     
         25 . The method of  claim 24 , wherein the silicone adhesive is solvated in about 20% to about 50% heptane.  
     
     
         26 . The method of  claim 25 , wherein the silicone adhesive is solvated in about 30% heptane.  
     
     
         27 . The method of  claim 21 , wherein the fentanyl is the fentanyl free base.  
     
     
         28 . The method of  claim 21 , wherein fentanyl particles are suspended uniformly in the solvated silicone adhesives as small particles.  
     
     
         29 . A method for making a laminate, which is useful for making a monolithic patch for transdermal administration of fentanyl, comprising: 
 a) selecting a solvent that can substantially or fully solvate a silicone adhesive while keeping fentanyl particles, when blended with the solvated adhesive, suspended in the solvated adhesive;    b) solvating said silicone adhesive in said solvent;    c) forming a slurry of fentanyl particles in a silicone fluid;    d) blending the slurry from step c) with the solvated silicone adhesive of step b) so as to form a blend formulation in which fentanyl particles are suspended in the solvated adhesive;    e) casting the blend formulation onto a support material; and    f) removing the solvent to produce a laminate containing the support material and a fentanyl suspension-containing adhesive layer.    
     
     
         30 . The method of  claim 29 , wherein the support material is a backing layer or release liner.  
     
     
         31 . The method of  claim 29 , wherein the solvated silicone adhesive is divided into a first portion and a second portion, the slurry of fentanyl particles is blended with a first portion of the solvated silicone adhesive, the resulting blend is passed through a mixing device to form a suspension, and the resulting suspension is blended with the second portion of the solvated silicone adhesive.  
     
     
         32 . The method of  claim 29 , wherein the solvent is heptane.  
     
     
         33 . The method of  claim 32 , wherein the silicone adhesive is solvated in about 20% to about 50% heptane.  
     
     
         34 . The method of  claim 29 , wherein the fentanyl is fentanyl free base.  
     
     
         35 . The method of  claim 29 , wherein fentanyl particles are suspended uniformly in the solvated silicone adhesive as small particles.  
     
     
         36 . A method for administering fentanyl transdermally to an individual in need of such administration, comprising applying to the skin of the individual a monolithic patch comprising: 
 (a) a backing layer substantially impervious to the fentanyl to be administered transdermally; and    (b) a fentanyl-containing adhesive layer in contact with the backing layer, the adhesive layer being cast from a formulation comprising a blend of fentanyl suspended in one or more solvated silicone adhesives.    
     
     
         37 . The method of  claim 36 , wherein the solvated silicone adhesives are heptane-solvated silicone adhesives.  
     
     
         38 . The method of  claim 37 , wherein the adhesive layer comprises about 1% to about 10% w/w fentanyl.  
     
     
         39 . The method of  claim 38 , wherein the adhesive layer comprises about 3% to about 7% w/w fentanyl.  
     
     
         40 . The method of  claim 39 , wherein the adhesive layer comprises about 4% w/w fentanyl.  
     
     
         41 . The method of  claim 40 , wherein the fentanyl is administered transdermally for a period of about 3 days.  
     
     
         42 . The method of  claim 37 , wherein the adhesive layer comprises about 5% to about 15% w/w fentanyl.  
     
     
         43 . The method of  claim 42 , wherein the adhesive layer comprises about 8% to about 12% fentanyl.  
     
     
         44 . The method of  claim 43 , wherein the adhesive layer comprises about 9.5% w/w fentanyl.  
     
     
         45 . The method of  claim 37 , wherein the adhesive layer comprises about 9.1% w/w fentanyl.  
     
     
         46 . The method of claims  44 , wherein the fentanyl is administered transdermally for a period of about 7 days.  
     
     
         47 . The method of claims  45 , wherein the fentanyl is administered transdermally for a period of about 7 days.  
     
     
         48 . The method of  claim 36 , wherein the fentanyl is the fentanyl free base.  
     
     
         49 . The method of  claim 36 , wherein the fentanyl-containing adhesive layer is cast from a formulation comprising a blend of a slurry of fentanyl in silicone fluid blended with one or more solvated silicone adhesives.  
     
     
         50 . The method of  claim 49 , wherein the fentanyl-containing adhesive layer comprises up to about 25% w/w silicone fluid.  
     
     
         51 . The method of  claim 50 , wherein the fentanyl-containing adhesive layer comprises about 2% to about 10% w/w silicone fluid.  
     
     
         52 . The method of  claim 51 , wherein the fentanyl-containing adhesive layer comprises about 6.5% w/w silicone fluid.  
     
     
         53 . The method of  claim 48 , wherein fentanyl particles are suspended uniformly in the solvated silicone adhesives as small particles.  
     
     
         54 . The method of  claim 36 , wherein the backing layer is a polyolefin.  
     
     
         55 . The method of  claim 23 , wherein said mixing device comprises a high shear colloid mill or homogenizer.