Non-sedating dexmedetomidine treatment regimens

Abstract

Disclosed herein are methods of administering relatively high doses of dexmedetomidine or a pharmaceutically acceptable salt thereof to a human subject, without also inducing significant sedation. The disclosed methods are particularly suitable for the treatment of agitation, especially when associated with neurodegenerative and/or neuropsychiatric diseases such as schizophrenia, bipolar illness such as bipolar disorder or mania, dementia, depression, or delirium.

1 - 431 . (canceled) 
     
     
         432 . A method of treating agitation in a human subject with schizophrenia or bipolar disorder, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose resulting in a total exposure of dexmedetomidine, as measured by plasma AUC 0-inf , from about 600 ng*h/L to about 12600 ng*h/L. 
     
     
         433 . The method of  claim 432 , wherein the dose is about 120 μg to about 240 μg. 
     
     
         434 . The method of  claim 432 , wherein the human subject has schizophrenia. 
     
     
         435 . The method of  claim 432 , wherein the human subject has bipolar disorder. 
     
     
         436 . The method of  claim 432 , wherein the AUC 0-inf  is about 2300 ng*h/L to about 3600 ng*h/L; and wherein C max  is about 300 ng/L to about 500 ng/L. 
     
     
         437 . The method of  claim 436 , wherein the C max  is within the range of about 80% to about 125% of about 400 ng/L. 
     
     
         438 . The method of  claim 436 , wherein the AUC 0-inf  is within the range of about 80% to about 125% of about 2900 ng*h/L. 
     
     
         439 . The method of  claim 432 , wherein the AUC 0-inf  is about 1100 ng*h/L to about 1800 ng*h/L; and wherein C max  is about 150 ng/L to about 300 ng/L. 
     
     
         440 . The method of  claim 439 , wherein the C max  is within the range of about 80% to about 125% of about 220 ng/L. 
     
     
         441 . The method of  claim 439 , wherein the AUC 0-inf  is within the range of about 80% to about 125% of about 1410 ng*h/L. 
     
     
         442 . The method of  claim 439 , wherein the plasma T max  is about 1 hour to about 8 hours. 
     
     
         443 . The method of  claim 439 , wherein the plasma T max  is about 5 minutes to about 4 hours. 
     
     
         444 . The method of  claim 432 , wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oromucosally, orally, intranasally or parenterally. 
     
     
         445 . The method of  claim 444 , wherein the administration is oromucosal. 
     
     
         446 . The method of  claim 445 , wherein the administration is sublingual. 
     
     
         447 . The method of  claim 445 , wherein the administration is buccal. 
     
     
         448 . The method of  claim 432 , wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in the form of a tablet, film, spray, gel or drops. 
     
     
         449 . The method of  claim 448 , wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered sublingually in the form of a film. 
     
     
         450 . The method of  claim 448 , wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally in the form of a film, patch or tablet. 
     
     
         451 . The method of  claim 432 , wherein said film is a self-supporting, dissolvable, film, comprising:
 (i) dexmedetomidine or a pharmaceutically acceptable salt thereof;   (ii) hydroxypropyl cellulose (40,000 MW);   (iii) hydroxypropyl cellulose (140,000 MW);   (iv) hydroxypropyl cellulose (370,000 MW); and   (v) polyethylene oxide (600,000 MW).   
     
     
         452 . The method of  claim 451 , wherein hydroxypropyl cellulose (40,000 MW) is present at about 3% to about 15% w/w of the total film weight, hydroxypropyl cellulose (140,000 MW) is present at about 3% to about 8% w/w of the total film weight, hydroxypropyl cellulose (370,000 MW) is present at about 10% to about 50% w/w of the total film weight, and a polyethylene oxide (600,000 MW) is present at about 40% to about 70% w/w of the total film weight. 
     
     
         453 . The method of  claim 432 , wherein the dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 180 μg. 
     
     
         454 . The method of  claim 432 , wherein the dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 120 μg. 
     
     
         455 . The method of  claim 432 , wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is dexmedetomidine hydrochloride. 
     
     
         456 . The method of  claim 432  further comprising administering a second dose after a period of time ranging from about 30 minutes to about 12 hours. 
     
     
         457 . The method of  claim 456 , wherein the second dose is about 60 μg or about 90 μg. 
     
     
         458 . The method of  claim 432 , wherein the agitation is reduced, as measured by a mean change in Positive and Negative Syndrome Scale Excited Component (PEC) scores relative to baseline of at least −4 points. 
     
     
         459 . The method of  claim 458 , wherein the reduction in agitation is maintained for about 2 hours to about 6 hours. 
     
     
         460 . The method of  claim 458 , wherein the agitation is reduced within about 20 minutes to about 1 hour. 
     
     
         461 . The method of  claim 432 , wherein the agitation is reduced, as measured by the Agitation-Calmness Evaluation Scale (ACES), wherein the ACES score is a 3 (mild agitation) or 4 (normal behavior). 
     
     
         462 . The method of  claim 461 , wherein the reduction in agitation is maintained for about 2 hours to about 6 hours. 
     
     
         463 . The method of  claim 461 , wherein the agitation is reduced within about 20 minutes to about 1 hour.