Apparatus and method for in vivo delivery of therapeutic agents

Abstract

Electroporation electrodes are laminated to a permeable membrane to form an electrode membrane. Such an electrode membrane is useful for a continuous controlled delivery of a therapeutic agent through the skin or mucosa, when placed in direct contact with the skin or mucosa and by application of electric field pulses at specified intervals. An electrode membrane can be assembled such that it incorporates an iontophoretic electrode in the same device. This device can be jointly utilized for electroporation and iontophoretic drug delivery through the skin and mucosal membrane.

What is claimed is:  
     
         1 . A device for administering a therapeutic agent, including an agent permeable membrane having a pair of contact electrodes, such that when the device is contacted to a site of administration, the agent permeable membrane directly contacts the site of administration.  
     
     
         2 . The device of  claim 1  where the agent permeable membrane has pores with a diameter from about 0.01 μm to 10 μm.  
     
     
         3 . The device of  claim 2  where the agent permeable membrane has pores with a diameter from about 0.1 μm to 5 μm.  
     
     
         4 . The device of  claim 1  where the agent permeable membrane is made from one or more materials which have a permeability matched to permeation characteristics of the therapeutic agent.  
     
     
         5 . The device of  claim 1  where the agent permeable membrane is selected from the group consisting of: nylon, polyvinylidene fluoride, cellulose, nitro cellulose, polycarbonate, polysulfone, polyethylene, polypropylene, nonwoven fabric, gauze, woven fabric, paper, cotton, polyethylene foam, polypropylene foam, polyvinyl acetate foam, polyorefine foam, polyamide foam, and polyurethane foam.  
     
     
         6 . The device of  claim 1  where the contact electrodes are from about 10 μm to 1 cm apart.  
     
     
         7 . The device of  claim 6  where the contact electrodes are from about 50 μm to 5 mm apart.  
     
     
         8 . The device of  claim 7  where the contact electrodes are from about 100 μm to 2 mm apart.  
     
     
         9 . The device of  claim 1  where the contact electrodes are made from a metal or a semiconductor.  
     
     
         10 . The device of  claim 1  where the contact electrodes are made from carbon, silver, or silver chloride.  
     
     
         11 . The device of  claim 1  which further includes a casing attached to the agent permeable membrane.  
     
     
         12 . The device of  claim 11  where the casing is attached to the agent permeable membrane such that a reservoir is formed between the casing and the agent permeable membrane.  
     
     
         13 . The device of  claim 12  which is adapted for application to skin or mucosa.  
     
     
         14 . The device of  claim 12  where the casing is made from a material that is elastically deformable.  
     
     
         15 . The device of  claim 12  where the casing is made from a material that is water-resistant.  
     
     
         16 . The device of  claim 12  where the casing is made from a polymer or copolymer.  
     
     
         17 . The device of  claim 12  where the casing is made from at least one material selected from the group consisting of: polyvinylidene chloride, polyvinyl chloride, polyorefine, polyester, polystyrene, poly acryl, polyamide, polyoxymethylene, polyphenylenesulfuramide, polyamide, polyimide, polyacrylonitrile, polyetherketon, polyethersulfone, polysulfone, ehterimide, polybutadiene, and isoprene.  
     
     
         18 . The device of  claim 12  where the casing is from about 5 to 250 μm thick.  
     
     
         19 . The device of  claim 12  which further includes a pharmaceutical composition having a therapeutic agent where the pharmaceutical composition is contained in the reservoir.  
     
     
         20 . The device of  claim 19  where the pharmaceutical composition further includes one or more substances selected from the group consisting of: an electrolyte, an absorption accelerant, a stabilizer, a pH buffer, a thickener, a detergent, an emulsifier, an ion exchange resin, an ion exchange membrane, or a nonwoven fabric.  
     
     
         21 . The device of  claim 12  where the reservoir includes an iontophoretic electrode.  
     
     
         22 . The device of  claim 21  where the iontophoretic electrode is a polarized electrode made from a material selected from the group consisting of: carbon, platinum, gold, or titanium.  
     
     
         23 . The device of  claim 21  where the iontophoretic electrode is an unpolarized electrode.  
     
     
         24 . The device of  claim 23  where the iontophoretic electrode is an anode electrode which includes copper.  
     
     
         25 . The device of  claim 23  where the iontophoretic electrode is an anode electrode which includes silver.  
     
     
         26 . The device of  claim 23  where the iontophoretic electrode is a cathode electrode which includes copper chloride.  
     
     
         27 . The device of  claim 23  where the iontophoretic electrode is a cathode electrode which includes silver chloride.  
     
     
         28 . The device of  claim 1  where the therapeutic agent is one or more agents selected from the group consisting of: an analgesic, a peptide/protein, a tranquilizer, an antineoplastic drug, a cardiotonic, a hormone, a hypotensive drug, and a polynucleotide.  
     
     
         29 . The device of  claim 1  which further includes an adhesion layer upon the agent permeable membrane which contacts the site of administration.  
     
     
         30 . The device of  claim 12  where the casing is sealed to the agent permeable membrane using heat sealing.  
     
     
         31 . An electrode membrane device including: 
 (a) an adhesive layer,    (b) an agent permeable membrane attached to the adhesive layer,    (c) a first electrode affixed to the agent permeable membrane,    (d) a therapeutic agent,    (e) a pharmaceutical composition including one or more non-biologically active substances and the therapeutic agent,    (f) a casing which forms a reservoir between the agent permeable membrane and the casing where the reservoir contains the pharmaceutical composition, and    (g) a second electrode affixed to the casing.    
     
     
         32 . A method of in vivo administration of a therapeutic agent including the following steps: 
 (a) contacting a device which includes an agent permeable membrane having a pair of contact electrodes to a site of administration, such that the agent permeable membrane directly contacts the site of administration,    (b) applying a therapeutic agent to the agent permeable membrane, and    (c) applying an electric signal to the contact electrodes.    
     
     
         33 . The method of  claim 32  where the contact electrodes are for electroporation.  
     
     
         34 . The method of  claim 33  where the electric signal creates a voltage differential from about 10 to 2000 V/cm between the contact electrodes.  
     
     
         35 . The method of  claim 34  where the voltage differential is from about 50 to 1000 V/cm.  
     
     
         36 . The method of  claim 35  where the voltage differential is from about 50 to 500 V/cm.  
     
     
         37 . The method of  claim 33  where the electric signal is applied in a square wave form to the contact electrodes.  
     
     
         38 . The method of  claim 33  where the electric signal is applied in an exponential logarithmic wave form to the contact electrodes.  
     
     
         39 . A method of in vivo administration of a therapeutic agent including the following steps: 
 (a) contacting a device which includes an agent permeable membrane having a pair of contact electrodes to a site of administration such that the agent permeable membrane directly contacts the site of administration, a casing attached to the agent permeable membrane forming a reservoir, a pharmaceutical composition including the therapeutic agent where the pharmaceutical composition is contained in the reservoir, an iontophoretic electrode which is located in the reservoir;    (b) contacting a counter electrode to a second site;    (c) applying a first electric signal to the contact electrodes; and    (d) applying a second electric signal to the iontophoretic electrode.    
     
     
         40 . The method of  claim 39  where the second electric signal is a pulsed current signal from about 0.01 to 10 mA.  
     
     
         41 . The method of  claim 40  where the pulsed current signal is from about 0.01 to 5 mA.  
     
     
         42 . The method of  claim 39  where the second electric signal creates a voltage differential from about 0.1 to 50 V between the iontophoretic electrode and the counter electrode.  
     
     
         43 . The method of  claim 42  where the voltage differential is from about 1 to 30 V.  
     
     
         44 . The method of  claim 43  where the voltage differential is from about 3 to 15 V.  
     
     
         45 . The method of  claim 39  where the second electric signal is a pulse depolarization signal at a pulse frequency from about 100 Hz to 1000 KHz.  
     
     
         46 . The method of  claim 45  where the pulse frequency is from about 1 to 500 KHz.  
     
     
         47 . The method of  claim 46  where the pulse frequency is from about 10 KHz to 300 KHz.  
     
     
         48 . The method of  claim 39  where the second electric signal has a duty cycle with an ON/OFF ratio between about 1 and 99%.  
     
     
         49 . The method of  claim 48  where the duty cycle is between about 10 and 80%.  
     
     
         50 . The method of  claim 49  where the duty cycle is between about 15 and 50%.  
     
     
         51 . The device of  claim 19  where the therapeutic agent is one or more agents selected from the group consisting of: an analgesic, a peptide/protein, a tranquilizer, an antineoplastic drug, a cardiotonic, a hormone, a hypotensive drug, and a polynucleotide.  
     
     
         52 . The device of  claim 12  which further includes an adhesion layer upon the agent permeable membrane which contacts the site of administration.  
     
     
         53 . A device for administering a therapeutic agent, comprising: 
 an electrode cup, including an electrode and a rim; and    an electrode membrane attached to the rim of the electrode cup, including a permeable membrane and a pair of electrodes imprinted into the permeable membrane.    
     
     
         54 . The device of  claim 53  where the electrode in the electrode cup is connected to an iontophoretic generator.  
     
     
         55 . The device of  claim 53  where the electrodes in the electrode membrane are connected to an electroporation generator.