Methods and compositions for treatment with donepezil

Abstract

A method for delivering a therapeutic agent to a subject from a transdermal delivery system is described, where the therapeutic agent (i) has a half-life in the blood when delivered orally of greater than about 48 hours and (ii) is for the treatment of a chronic condition. The transdermal delivery system achieves transdermal delivery of the therapeutic agent at steady state that is bioequivalent to administration of the therapeutic agent orally, wherein bioequivalency is established by (a) a 90% confidence interval of the relative mean Cmax and AUC of the therapeutic agent administered from the transdermal delivery system and via oral delivery between 0.70 and 1.43 or between 0.80 and 1.25, or (b) a 90% confidence interval of the ratios for AUC and Cmax of the therapeutic agent administered from the transdermal delivery system and via oral delivery between 0.70 and 1.43 or between 0.80 and 1.25.

It is claimed: 
     
         1 . A method for treating Alzheimer's disease in a human subject, comprising:
 applying to skin of the subject a transdermal composition comprising a drug reservoir comprising a donepezil salt, an alkaline salt, a hydrophilic solvent in which the donepezil salt is soluble, and an adhesive matrix in which donepezil base is soluble; and   delivering donepezil base transdermally to the subject in an amount therapeutically effective for treatment of Alzheimer's disease, the donepezil base generated in the drug reservoir by reaction therein of the donepezil salt and the alkaline salt.   
     
     
         2 . The method of  claim 1 , wherein the therapeutically effective amount of donepezil base is generated for a period of at least about 3 days. 
     
     
         3 . The method of  claim 1 , wherein the therapeutically effective amount of donepezil base is sufficient to achieve a plasma concentration of donepezil that is bioequivalent to administration of donepezil hydrochloride orally at a dose of up to approximately 10 mg/day. 
     
     
         4 . The method of  claim 1 , wherein the therapeutically effective amount of donepezil base is sufficient to achieve a plasma concentration of donepezil for up to a 7-day period that is bioequivalent to daily administration of donepezil hydrochloride orally at a dose of up to approximately 10 mg/day. 
     
     
         5 . The method of  claim 1 , wherein the transdermal composition further comprises a skin contact adhesive layer that does not comprise the hydrophilic solvent. 
     
     
         6 . The method of  claim 5 , wherein the hydrophilic solvent is selected from the group consisting of glycerol, propylene glycol, liquid polyethylene glycol, acetonitrile, 1-propanol, N,N-dimethylformamide and dimethyl sulfoxide. 
     
     
         7 . The method of  claim 5 , wherein the hydrophilic solvent in glycerol. 
     
     
         8 . The method of  claim 7 , wherein the donepezil salt is donepezil hydrochloride and the alkaline salt is sodium bicarbonate. 
     
     
         9 . A method for treating Alzheimer's disease in a human subject, comprising:
 applying to skin of the subject a transdermal composition comprising a drug reservoir comprising a donepezil salt and an alkaline salt, whereby, after said applying, donepezil base is generated (i) in the drug reservoir by reaction of the donepezil salt and the alkaline salt and (ii) in amount therapeutically effective for transdermal of Alzheimer's disease.   
     
     
         10 . The method of  claim 9 , wherein applying comprises applying once weekly. 
     
     
         11 . The method of  claim 9 , wherein the transdermal composition comprises an amount of the donepezil salt sufficient to deliver to the subject between 1-25 mg of donepezil base in 24 hours. 
     
     
         12 . The method of  claim 9 , wherein the donepezil salt is donepezil hydrochloride and the alkaline salt is sodium bicarbonate. 
     
     
         13 . The method of  claim 9 , wherein the transdermal composition comprises between about 10-30 wt % donepezil HCl and between about 0.5-10 wt % sodium bicarbonate. 
     
     
         14 . A composition, comprising:
 a drug reservoir comprising between about 10-30 wt % of a donepezil salt, between about 0.5-10 wt % of an alkaline salt, between about 2-20 wt % of a hydrophilic solvent selected from the group consisting of glycerol, propylene glycol, liquid polyethylene glycol, acetonitrile, 1-propanol, N,N-dimethylformamide and dimethyl sulfoxide, and an acrylate polymer adhesive matrix; and   a contact adhesive layer that does not comprise the hydrophilic solvent.   
     
     
         15 . The composition of  claim 14 , wherein the contact adhesive layer comprises a solvent selected from the group consisting of triethyl citrate, lauryl lactate and sorbitan monolaurate. 
     
     
         16 . The composition of  claim 15 , wherein the contact adhesive layer is comprised of an acrylic acid/vinyl acetate copolymer adhesive. 
     
     
         17 . The composition of  claim 16 , wherein the contact adhesive layer comprises triethyl citrate, lauryl lactate and sorbitan monolaurate 
     
     
         18 . The composition of  claim 17 , wherein the hydrophilic solvent is glycerol. 
     
     
         19 . The composition of  claim 14 , wherein donepezil salt is donepezil hydrochloride. 
     
     
         20 . The composition of  claim 15 , wherein the alkaline salt is sodium bicarbonate or potassium bicarbonate.