Method and device for transdermal delivery of fentanyl and sufentanil

Abstract

The invention provides an improved electrotransport drug delivery system for analgesic drugs, namely fentanyl and sufentanil. The fentanyl/sufentanil is provided as a water soluble salt (eg, fentanyl hydrochloride) dispersed in a hydrogel formulation for use in an electrotransport device ( 10 ). In accordance with one aspect of the invention, the concentration of fentanyl/sufentanil in the donor reservoir ( 26 ) solution is above a predetermined minimum concentration, whereby the transdermal electrotransport flux of fentanyl/sufentanil is maintained independent of the concentration of fentanyl/sufentanil in solution. In accordance with a second aspect of the present invention, the donor reservoir ( 26 ) of the electrotransport delivery device ( 10 ) is comprised of silver and the donor reservoir ( 26 ) contains a predetermined “excess” loading of fentanyl/sufentanil halide to prevent silver ion migration with attendant skin discoloration. In accordance with a third aspect of the present invention, a transdermal electrotransport delivered dose of fentanyl/sufentanil is provided which is sufficient to induce analgesia in (eg, adult) human patients suffering from moderate-to-severe pain associated with major surgical procedures.

1 - 23 . (canceled)  
     
     
         24 . A method for delivering an active agent through a body surface by electrotransport comprising the steps of: 
 a) providing an electrotransport delivery device having a silver anodic donor electrode, a cathodic counter electrode, and a donor reservoir containing a loading amount of the analgesic drug in electrical contact with the donor electrode, the device adapted to deliver up to only a predetermined maximum total amount of analgesic drug over a period of time, the loading amount prior to delivery being at least two times greater than the predetermined maximum total amount to prevent transient epidermal discoloration; and    b) delivering only up to the maximum total amount of the analgesic drug;    wherein the analgesic drug is selected from the group consisting of fentanyl halide salts and sufentanil halide salts thereby avoiding transient epidermal discoloration.    
     
     
         25 . The method of  claim 24 , wherein the donor reservoir comprises a hydrogel containing an aqueous fentanyl halide salt solution in a loading that is at least 3 times greater than the predetermined maximum total amount and wherein the donor reservoir is substantially free of sources of halide other than the selected analgesic drug halide salt.  
     
     
         26 . The method of  claim 24 , wherein the donor reservoir comprises a hydrogel containing an aqueous fentanyl salt solution in a loading that is at least 3 times greater than the predetermined maximum total amount, and during the delivery of the predetermined maximum total amount maintaining the fentanyl concentration above 6 mg/mL in the hydrogel, the body surface is skin.  
     
     
         27 . The method of  claim 24 , wherein the donor reservoir comprises a hydrogel containing an aqueous fentanyl salt solution or a sufentanil salt solution and the body surface is intact human skin and the period of time is at least 6 hours.  
     
     
         28 . The method of  claim 24 , comprising enabling the delivery of the analgesic drug through the body surface only up to the predetermined maximum total amount of the analgesic drug and wherein the drug delivery is substantially proportional to a level of current applied by the delivery method during the iontophoretic drug delivery.  
     
     
         29 . The method of  claim 24 , wherein the drug is a salt of fentanyl or salt of sufentanil and applying electrotransport current between about 150 μA to about 240 μA.  
     
     
         30 . The method of  claim 28 , wherein the drug is a salt of fentanyl or salt of sufentanil and applying electrotransport current between about 150 μA to about 190 μA.  
     
     
         31 . The method of  claim 28 , wherein the drug is a salt of fentanyl or salt of sufentanil and applying electrotransport current between about 190 μA to about 240 μA.  
     
     
         32 . The method of  claim 24 , comprising delivering only up to the predetermined maximum total amount of the analgesic drug in multiple predetermined dose amounts.  
     
     
         33 . The method of  claim 32 , comprising applying electrotransport current for delivery in multiple predetermined dose amounts with delivery interval of up to about 20 minutes.  
     
     
         34 . The method of  claim 32 , comprising applying electrotransport current for delivery in multiple predetermined dose amounts with delivery interval of about 8 to about 12 minutes.  
     
     
         35 . The method of  claim 32 , comprising delivery in about 10 to about 100 dose amounts.  
     
     
         36 . The method of  claim 32 , comprising delivery in about 20 to about 80 dose amounts.  
     
     
         37 . The method of  claim 36 , wherein the predetermined dose amount is about 20 to 60 μg fentanyl halide.  
     
     
         38 . The method of  claim 37 , wherein the predetermined dose amount is about 40 μg fentanyl halide.  
     
     
         39 . The method of  claim 32 , comprising deliverying multiple predetermined dose amounts over at least about 6 hours.  
     
     
         40 . The method of  claim 24 , wherein the analgesic drug comprises sufentanil hydrochloride and the loading amount is at least about 4 times greater than the predetermined maximum total amount.  
     
     
         41 . The method of  claim 24 , wherein the donor reservoir has a weight on a hydrated basis of about 0.5 g to 0.8 g and is loaded with at least about 9 mg of fentanyl hydrochloride.  
     
     
         42 . The method of  claim 24 , wherein the drug loading amount is such that the analgesic drug amount remaining after the delivery of the predetermined maximum total amount in the drug reservoir is at least two times the predetermined maximum total amount of the analgesic drug.  
     
     
         43 . A method for transdermally delivering an active agent by electrotransport comprising the steps of: 
 a) providing an electrotransport delivery device having a silver anodic donor electrode, a cathodic counter electrode, and a donor reservoir containing a loading amount of the analgesic drug in electrical contact with the donor electrode, wherein the donor reservoir comprises a hydrogel containing an aqueous fentanyl salt solution that has a weight on a hydrated basis of about 0.5 g to 0.8 g, is loaded with at least about 9 mg of fentanyl hydrochloride and is substantially free of sources of halide other than fentanyl salt, the device electronically adapted to deliver up to only a predetermined maximum total amount of analgesic drug over a period of time, the loading amount prior to delivery being at least two times greater than the predetermined maximum total amount to prevent transient epidermal discoloration by silver;    b) delivering only up to the predetermined maximum total amount of the analgesic drug by delivering about 10 to about 100 predetermined dose amounts, wherein the predetermined dose amount comprises about 20 to 60 μg fentanyl halide delivered by applying a current of about 150 μA to about 240 μA for a delivery interval of about 8 to about 12 minutes;    c) maintaining the solution fentanyl concentration above 6 mg/mL in the hydrogel.    
     
     
         44 . A method for transdermally delivering an active agent by electrotransport comprising the steps of: 
 a) providing an electrotransport delivery device having a silver anodic donor electrode, a cathodic counter electrode, and a donor reservoir containing a loading amount of the analgesic drug in electrical contact with the donor electrode, wherein the donor reservoir comprises a hydrogel containing an aqueous sufentanil halide solution, the device electronically adapted to deliver up to only a predetermined maximum total amount of analgesic drug over a period of time, the loading amount prior to delivery being at least about four times greater than the predetermined maximum total amount; and    b) delivering only up to the predetermined maximum total amount of the analgesic drug by delivering about 10 to about 100 predetermined dose amounts, wherein the predetermined dose amount comprises about 4 to 5.5 μg sufentanil halide delivered by applying a current of about 150 μA to about 240 μA for a delivery interval of up to about 20 minutes;    wherein the drug reservoir prior to delivery has a loading amount of the analgesic drug that is at least about four times greater than the maximum total amount to prevent transient epidermal discoloration.