Transdermal drug delivery system for ketamine

Abstract

Provided herein are transdermal delivery devices comprising ketamine, such as monolithic transdermal patches. Also provided herein are methods of preparing transdermal delivery devices. The transdermal delivery device and monolithic patch herein can have various uses, for example, for treating various diseases or disorders, such as depression, anxiety, and/or pain in a subject in need thereof.

1 - 10 . (canceled) 
     
     
         11 . A method of preparing an adhesive composition, the method comprising:
 (a) mixing ketamine, oleyl oleate, levulinic acid, a polyvinyl pyrrolidone-co-vinyl acetate, a carboxylate-functionalized polyacrylate-vinylacetate copolymer, and optionally an antioxidant in a solvent to form a homogenous mixture; and   (b) drying the homogenous mixture to remove the solvent, thereby providing the adhesive composition, wherein on a dry basis of the adhesive composition:
 (i) ketamine is in an amount of about 14-17% by weight; 
 (ii) oleyl oleate and levulinic acid are each in an amount of about 4-7% by weight; 
 (iii) the polyvinyl pyrrolidone-co-vinyl acetate is in an amount of about 15-25% by weight; 
 (iv) the carboxylate-functionalized polyacrylate-vinylacetate copolymer is in an amount of about 45-55% by weight; and 
 (v) the optional antioxidant, if present, is in an amount of about 0.01-1% by weight. 
   
     
     
         12 . A method of treating depression in a subject in need thereof, the method comprising administering to the subject a transdermal delivery device to transdermally deliver a therapeutically effective amount of ketamine:
 wherein the transdermal deliver device comprises a drug-in-adhesive layer, wherein the drug-in-adhesive layer comprises:
 (a) ketamine in an amount of about 14-17% by weight; 
 (b) oleyl oleate and levulinic acid, each in an amount of about 4-7% by weight; 
 (c) a polyvinyl pyrrolidone-co-vinyl acetate in an amount of about 15-25% by weight; 
 (d) a carboxylate-functionalized polyacrylate-vinylacetate copolymer in an amount of about 45-55% by weight; and optionally 
 (e) an antioxidant in an amount of about 0.01-1% by weight. 
   
     
     
         13 . The method of  claim 12 , wherein the transdermal delivery device is applied to the subject at a dosing frequency ranging from once a day to once a week, wherein each application of the transdermal delivery device has a duration of about 24 hours, wherein during the patch-on period, the transdermal delivery device delivers ketamine to the subject at a substantially constant rate ranging from about 0.1 mg/cm 2 /day to about 1 mg/cm 2 /day, wherein the therapeutically effective amount of ketamine is a dose of about 15 mg to about 150 mg delivered to the subject over about 24 hours. 
     
     
         14 . A method of treating depression in a subject in need thereof, the method comprising administering to the subject a transdermal delivery device to deliver a therapeutically effective plasma concentration of ketamine, hydroxynorketamine, and norketamine, wherein the therapeutically effective plasma concentration of ketamine, hydroxynorketamine, and norketamine during the period of 0-96 hours, is characterized by one or more of the following:
 (a) a C max  of ketamine of about 5-50 ng/mL such as about 10-30 ng/ml and/or a C max  of hydroxynorketamine of about 5-50 ng/mL such as about 10-30 ng/ml;   (b) a ratio of area under the curve from 0-96 hours of hydroxynorketamine to ketamine ranging from about 1 to about 3;   (c) a ratio of area under the curve from 0-96 hours of norketamine to ketamine ranging from about 1 to about 2;   (d) a ratio of C max  of hydroxynorketamine to ketamine during 0-96 hours ranging from about 0.7 to about 1.5; and   (e) a ratio of C max  of norketamine to ketamine during 0-96 hours ranging from about 0.7 to about 1.5,   wherein the transdermal deliver device comprises a drug-in-adhesive layer, wherein the drug-in-adhesive layer comprises:   (a) ketamine in an amount of about 14-17% by weight;   (b) oleyl oleate and levulinic acid, each in an amount of about 4-7% by weight;   (c) a polyvinyl pyrrolidone-co-vinyl acetate in an amount of about 15-25% by weight;   (d) a carboxylate-functionalized polyacrylate-vinylacetate copolymer in an amount of about 45-55% by weight; and optionally   (e) an antioxidant in an amount of about 0.01-1% by weight.   
     
     
         15 . The method of  claim 14 , wherein the transdermal delivery device is applied to the subject for a duration of about 24 hours, wherein during the patch-on period, the transdermal delivery device delivers ketamine to the subject at a substantially constant rate ranging from about 0.1 mg/cm 2 /day to about 1 mg/cm 2 /day. 
     
     
         16 . The method of  claim 14 , wherein the transdermal delivery device is applied to the subject at a dosing frequency ranging from once a day to once a week, wherein each application of the transdermal delivery device has a duration of about 24 hours. 
     
     
         17 . The method of  claim 14 , wherein the depression is selected from major depressive disorder, treatment resistant depression and bipolar depression. 
     
     
         18 - 30 . (canceled)