Method and devices for transdermal delivery of lithium

Abstract

A method and device for treating acute mania or bipolar disorder is disclosed, by transdermal delivery of Li + at substantially constant rate through the skin via a dermal patch.

What is claimed is:  
     
         1 . A method for administering lithium at a substantially constant rate without causing significant pain or tissue damage to a human patient in need thereof, which method comprises: 
 (a) providing a source of iontophoretically deliverable lithium; and    (b) iontophoretically delivering Li +  to said patient.    
     
     
         2 . The method of  claim 1 , further comprising monitoring the blood Li +  concentrations and adjusting the dose rate if necessary to provide and maintain blood Li +  concentrations of between about 0.6 and about 1.4 mEq/L.  
     
     
         3 . The method of  claim 1 , wherein the source of iontophoretically deliverable lithium is a dermal patch.  
     
     
         4 . The method of  claim 3 , wherein the dermal patch comprises a current distribution member capable of delivering current sufficient to iontophoretically deliver Li +  across a stratum corneum of an epidermis of said human.  
     
     
         5 . The method of  claim 4 , wherein said current is direct current.  
     
     
         6 . The method of  claim 5 , wherein said direct current is pulsed direct current.  
     
     
         7 . The method of  claim 4 , wherein said current is provided at a density in the range of from about 50 to about 350 μA/cm 2 .  
     
     
         8 . The method of  claim 7 , wherein the current density is between about 50 and about 200 μA/cm 2 .  
     
     
         9 . The method of  claim 6 , wherein the pulsed direct current has a pulse frequency between about 1 and about 10 kHz.  
     
     
         10 . The method of  claim 9 , wherein the pulse frequency is about 4 kHz.  
     
     
         11 . The method of  claim 9 , wherein patch has an on:off ratio duty cycle between about 1 and about 99%.  
     
     
         12 . The method of  claim 11 , wherein the on:off ratio duty cycle is about 75%.  
     
     
         13 . The method of  claim 4 , wherein the current distribution member does not cause or reduces skin irritation or discoloration or both.  
     
     
         14 . The method of  claim 13 , wherein the current distribution member is an Ag/AgCl mesh.  
     
     
         15 . A method of treating in humans acute mania or bipolar (manic/depressive) disorder comprising the steps of 
 (a) topically applying to the skin of a patient in need of such treatment a transdermal delivery system comprising a source of lithium, and    (b) delivering an effective amount of lithium ion to the patient's bloodstream.    
     
     
         16 . A dermal patch for administering lithium to a human patient at substantially constant rate without causing significant pain or tissue damage, which patch comprises: 
 a source of lithium for iontophoretic delivery;    a support for said lithium source;    a current distribution member for delivering a pulsed direct current sufficient to iontophoretically deliver lithium across a stratum corneum layer of the epidermis of said human, said current distribution member comprising an electrochemically active component in electrical connection with a battery, a voltage pulse generator and a precision resistor; and    a detoxification or neutralization effective amount of a complexing agent selected from EDTA or EGTA or pharmaceutically acceptable salts thereof;    wherein the lithium source is unbuffered; and    wherein the patch is substantially free of any skin permeability enhancers.    
     
     
         17 . A method of treating acute mania or bipolar (manic/depressive) disorder with lithium, by providing and maintaining blood Li +  concentrations of between about 0.6 and about 1.4 mEq/L in humans in need thereof, which method comprises the steps of 
 (a) providing a dermal patch for administering lithium to a patient at substantially constant rate;  
 (b) attaching the patch to the patient's skin;  
 (c) iontophoretically delivering Li +  from said patch to the patient.  
 
     
     
         18 . The method of  claim 17 , further comprising monitoring the blood Li +  concentrations and adjusting the dose rate if necessary to provide and maintain blood Li +  concentrations of between about 0.6 and about 1.4 mEq/L.  
     
     
         19 . The method of  claim 17 , wherein the dermal patch comprises: 
 a source of lithium for iontophoretic delivery;    a support for said lithium source;    a current distribution member for delivering a pulsed direct current sufficient to iontophoretically deliver lithium across a stratum corneum layer of the epidermis of said human, said current distribution member comprising an electrochemically active component in electrical connection with a battery, a voltage pulse generator and a precision resistor.    
     
     
         20 . The method of  claim 19 , wherein the electrochemically active component of the patch comprises an Ag/AgCl mesh.  
     
     
         21 . The method of  claim 19 , wherein the source of lithium is LiCl, lithium carbonate, or lithium nitrate, or combination thereof.  
     
     
         22 . The method of  claim 19 , wherein the support for lithium in the patch comprises a drug reservoir, a tamper-proof occlusive backing, a conductive gel, and a membrane permeable to Li +  suitable for contact with the epidermal layer of the skin.  
     
     
         23 . The method of  claim 22 , wherein the support further comprises an adhesive.  
     
     
         24 . The method of  claim 17 , wherein the lithium source is unbuffered.  
     
     
         25 . The method of  claim 17  further comprising detoxification or neutralization effective amount of a complexing agent selected from the group consisting of EDTA, EGTA, and pharmaceutically acceptable salts thereof.  
     
     
         26 . The method of  claim 17 , wherein the patch is substantially free of skin permeability enhancers.  
     
     
         27 . A method of treating acute mania or bipolar (manic/depressive) disorder with lithium, by providing and maintaining blood Li +  concentrations of between about 0.6 and about 1.4 mEq/L in humans in need thereof, which method comprises the steps of: 
 (a) providing a dermal patch for administering lithium to a patient at substantially constant rate without causing significant pain or tissue damage;  
 (b) attaching the patch to the patient's skin;  
 (c) iontophoretically delivering Li +  from said patch to the patient;  
 wherein the dermal patch for administering lithium to a patient at substantially constant rate comprises: 
 a source of lithium for iontophoretic delivery;  
 a support for said lithium source;  
 a current distribution member for delivering a pulsed direct current sufficient to iontophoretically deliver lithium across a stratum corneum layer of the epidermis of said human, said current distribution member comprising an electrochemically active component in electrical connection with a battery, a voltage pulse generator and a precision resistor; and  
 a detoxification or neutralization effective amount of a complexing agent selected from the group consisting of EDTA, EOTA, and pharmaceutically acceptable salts thereof;  
 
 wherein the patch lithium source is unbuffered, and  
 wherein the patch is substantially free of skin permeability enhancers.  
 
     
     
         28 . A dermal patch for administering lithium to a human patient at substantially constant rate without causing significant pain or tissue damage, which patch comprises: 
 a source of lithium for iontophoretic delivery;    a support for said lithium source;    a current distribution member for delivering a pulsed direct current sufficient to iontophoretically deliver lithium across a stratum corneum layer of the epidermis of said human, said current distribution member comprising an electrochemically active component in electrical connection with a battery, a voltage pulse generator and a precision resistor.    
     
     
         29 . The dermal patch of  claim 28 , wherein the electrochemically active component comprises an Ag/AgCl mesh.  
     
     
         30 . The dermal patch of  claim 28 , wherein the source of lithium is LiCl, lithium carbonate, or lithium nitrate, or combination thereof.  
     
     
         31 . The dermal patch of  claim 28 , wherein the support for said lithium source comprises a drug reservoir, a tamper-proof occlusive backing, a conductive gel, and a membrane permeable to Li +  suitable for contact with the epidermal layer of the skin.  
     
     
         32 . The dermal patch of  claim 31 , further comprising an adhesive.  
     
     
         33 . The dermal patch of  claim 28 , wherein the lithium source is unbuffered.  
     
     
         34 . The dermal patch of  claim 31 , further comprising a detoxification or neutralization effective amount of a complexing agent selected from the group consisting of EDTA or EGTA or pharmaceutically acceptable salts thereof.  
     
     
         35 . The dermal patch of  claim 28 , wherein the patch is substantially free of skin permeability enhancers.  
     
     
         36 . The dermal patch of  claim 28 , wherein the patch is substantially free of ethylene glycol.