Abstract:
A portable iontophoresis apparatus for facilitating delivery of medication across the cutaneous membrane into adjacent underlying tissues and blood vessels. The apparatus employs a modular, detachable non-reusable medicament-containing applicator electrode which is adapted to attach to a base assembly. The apparatus is designed to be hand-held and includes a circumferential tactile electrode band on the base assembly which provides electrical connection between the skin of the user&#39;s hand and one pole of a bipolar power source housed within the base assembly. The opposing pole of the power source is connected to the applicator electrode. The user&#39;s body completes the electrical circuit between the applicator and tactile electrodes. A method for using the device for the treatment of Herpes simplex infection and related viral infections which produce similar cutaneous lesions is presented. The apparatus, when used in accordance with the method described herein, demonstrated &gt;90% treatment efficacy in clinical trials.

Description:
REFERENCE TO RELATED APPLICATIONS 
     This application is a divisional of allowed U.S. patent application Ser. No. 08/646,853 filed May 8, 1996, now U.S. Pat. No. 5,676,648, issued Oct. 14, 1997. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates generally to the transdermal electrokinetic mass transfer of medication into a diseased tissue, and, more specifically, to a portable apparatus for the iontophoretic delivery of medication across the skin and incorporation of the medication into diseased tissues and blood vessels adjacent to the delivery site. The apparatus provides a new method for treating and managing diseases presenting cutaneous lesions. 
     2. Prior Art 
     Iontophoresis has been employed for several centuries as a means for applying medication locally through a patient&#39;s skin and for delivering medicaments to the eyes and ears. The application of an electric field to the skin is known to greatly enhance the skin&#39;s permeability to various ionic agents. The use of iontophoretic transdermal delivery techniques has obviated the need for hypodermic injection for many medicaments, thereby eliminating the concomitant problems of trauma, pain and risk of infection to the patient. 
     Iontophoresis involves the application of an electromotive force to drive or repel oppositely charged ions through the dermal layers into a target tissue. Particularly suitable target tissue include tissues adjacent to the delivery site for localized treatment or tissues remote therefrom in which case the medicament enters into the circulatory system and is transported to a tissue by the blood. Positively charged ions are driven into the skin at an anode while negatively charged ions are driven into the skin at a cathode. Studies have shown increased skin penetration of drugs at anodic or cathodic electrodes regardless of the predominant molecular ionic charge on the drug. This effect is mediated by polarization and osmotic effects. 
     Regardless of the charge of the medicament to be administered, a iontophoretic delivery device employs two electrodes (an anode and a cathode) in conjunction with the patient&#39;s skin to form a closed circuit between one of the electrodes (referred to herein alternatively as a “working” or “application” or “applicator” electrode) which is positioned at the delivered site of drug delivery and a passive or “grounding” electrode affixed to a second site on the skin to enhance the rate of penetration of the medicament into the skin adjacent to the applicator electrode. 
     Recent interest in the use of iontophoresis for delivering drugs through a patient&#39;s skin to a desired treatment site has stimulated a redesign of many of such drugs with concomitant increased efficacy of the drugs when delivered transdermally. As iontophoretic delivery of medicaments become more widely used, the opportunity for a consumer/patient to iontophoretically administer a transdermal dosage of medicaments simply and safely at non-medical or non-professional facilities would be desirable and practical. Similarly, when a consumer/patient travels, it would be desirable to have a personal, easily transportable apparatus available which is operable for the iontophoretic transdermal delivery of a medication packaged in a single dosage applicator. The present invention provides a portable iontophoretic medicament delivery apparatus and a unit-dosage medicament-containing applicator electrode which is disposable and adapted for use with the apparatus for self-administering medicament. 
     SUMMARY OF THE INVENTION 
     The present invention discloses a portable iontophoretic transdermal or transmucoscal medicament delivery apparatus and a unit dosage medicament applicator electrode adapted for use with the apparatus for the self-administration of a unit dose of a medicament into the skin. The apparatus is particularly suited for the localized treatment of herpes infections. Recurrent herpetic infections (fever blisters or herpes labialis) are very common and usually involve the mucocutaneous juncture. The established treatment for recurrent herpetic lesions (oral or genital) has been primarily supportive; including local topical application of anesthesia. Severe cases have been treated with systemic Acyclovir® (Zovirax Burroughs-Wellcome). Some cases the condition is managed with prophylactic long-term dosing administration with a suitable anitviral agent at great expense. Systemic treatment of acute herpetic flare-ups may reduce the normal 10-12 day course of cutaneous symptoms into a 6-8 day episode. Topical treatment of lesions with Acyclovir® has not been as effective as in vitro studies would suggest. A compound which is not presently available to clinicians but has demonstrated significant anti herpetic activity is 5-iodo-2 deoxyuridine (IUDR). Both of those agents have shown limited clinical efficacy when applied topically to the herpetic lesion. It is the present inventor&#39;s contention that the limited efficacy of topical administration previously observed is, at least in part, due to the poor skin penetration of these medicaments when applied topically. The present invention provides improved transdermal delivery of these medicaments and demonstrates improved clinical results in the case of Herpes. 
     Oral Herpes (most commonly Herpes simplex I infection) as well as genital Herpes (usually Herpes Simplex II infection) afflict many people, cause discomfort, shame, and may contribute to more severe and costly illnesses such as cervical cancer, prostate cancer, and perinatal blindness from herpetic conjunctivitis. The present invention discloses a portable, user-friendly transdermal delivery device and a method for using the device with Acyclovir® [ 2 - hydroxyethoxy ( methyl ) guanine  (or similar antiviral agent) to greatly benefit these afflicted patients. The present inventor has constructed embodiments of this device and conducted human clinical trials which clearly demonstrate improved therapeutic efficacy using iontophoretically administered antiviral agents when compared to unassisted topical application of the agent. 
     It is an object of the present invention to provide an iontophoretic medicament delivery apparatus which is portable and operable for self-administration of medicament into the skin of a person. 
     It is another object of the present invention to provide an improved iontophoretic transdermal drub  drug delivery apparatus having a medicament-containing application electrode which disperses a single dosage and is disposable and non-reusable. 
     It is a feature of the present invention that the iontophoretic medicament delivery apparatus is easily maneuverable and operable when hand-held. 
     It is another feature of the present invention that the iontophoretic medicament delivery apparatus is battery powered and conveniently transported by a person. 
     It is a further feature of the present invention that the iontophoretic medicament delivery apparatus employs a tactile electrode which is in electrical contact with the skin of a user&#39;s hand when the apparatus is held in the user&#39;s hand, obviating the need for a separate grounding electrode connector or wire: 
     It is still another feature of the present invention that the iontophoretic medicament delivery apparatus is adapted to be operable with a disposable medicament containing applicator electrode which applicator electrode includes an absorbent, inert, non-corrosive portion containing a therapeutic agent. 
     It is yet another feature of the present invention to provide an embodiment of an iontophoretic transdermal delivery device wherein the disposable iontophoretic medicament-containing applicator electrode is adapted for releasable attachment to use with a hand-held base assembly housing a grounding electrode. 
     It is yet another feature of the present invention that the disposable iontophoretic medicament applicator electrode include indicator means operable for enabling a user to determine when the medicament within the removable applicator electrode has been released in delivery and/or depleted. 
     It is yet another feature of the present invention that the circuitry employed in the disposable iontophoretic medicament applicator include current limiting means operable for limiting the electrical current flowing between the surface of the applicator and the skin to less than about one milliampere per square centimeters of application electrode skin-contacting surface. 
     It is another advantage of the present invention that the iontophoretic medicament delivery apparatus employs a disposable application electrode which conducts the electrical current to the tissue through the solution in which the medicament is dissolved. 
     It is still another advantage of the present invention that the improved disposable iontophoretic medicament applicator is inexpensive, safe to use and greatly increases the therapeutic efficacy of a medicament administered thereby. 
     The apparatus in accordance with the present invention provides a means for topically administering medicament directly and with high efficiency into a diseased tissue thereby providing a novel method for treating clinical conditions presenting mucocutaneous symptoms and particularly mucocutaneous Herpes Simplex viral eruptions and sequelle associated therewith. 
     The above objects, features and advantages of the invention are realized by the improved monopolar iontophoretic medicament applicator which is easily transportable. The applicator employs a detachable medicament containing application electrode. The objects, features and advantages of the invention will become apparent upon consideration of the following detailed disclosure of the invention, especially when it is taken in conjunction with the accompanying drawings wherein: 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 is a side elevational plan view of the iontophoretic medicament delivery apparatus showing the circumferential tactile ground electrode on the outer surface of the base housing and a disposable iontophoretic application electrode; 
     FIG. 2 is a side elevational view of the disposable non-reusable iontophoretic application electrode with a portion broken away to view the medicament dose packet; 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENT 
     FIG. 1 shows, in side elevation, a preferred embodiment of the hand-held iontophoretic transdermal medicament delivery apparatus of the present invention. The apparatus, indicated generally by the numeral  10 , has an elongate base assembly  11  the major portion of which is preferably formed of plastic and shaped to conform to and comfortably fit within a users hand. An applicator electrode module  12 , containing a unit dose of medicament  23 , is releasably attached to a applicator electrode receptacle  14  on the distal end of the base assembly  11 . The application electrode  12  is preferably a “clip-on” type of electrode similar in configuration to an electrocardiogram electrode. In the drawing presented in FIGS. 1 and 2, electrically conductive elements such as wires and busses are presented as heavy lines. A wire  16  provides electrical connection between the applicator electrode receptacle  14  and wire  18  within the neck  15  of the base assembly  11 . Connecting wire  18 , in turn, provides electrical connection between the wire  16  and the current driver unit  19  housed within the base assembly  11 . A conductive tactile electrode  20  forms a portion of the exterior skin-contacting surface of the base assembly  11  preferably circumferentially enclosing a portion of the base housing or it may be interrupted or discontinuous on the outer surface. The tactile electrode  20  is in electrical communication with the cathode  24 C of battery  24  by means of a buss  17  and conductive urging spring  25  which secures the battery in position within the base assembly  11 . For the self-administration of medicament a user must have skin contact with the tactile electrode  20  for the unit to operate. Current driver  19  underlies the cathodic (ground) tactile electrode  20  and is electrically connected via wire  21  to a voltage multiplier  22 . The voltage multiplier  22  receives low voltage power from the anode  24 a of the battery power source  24  and increases the available voltage for presentation to the application electrode  12 . The battery  24 , a self- contained electrical power source,  is preferably a size AA or AAA. Battery  24  is held in place by an electrically conductive biasing spring  25  and ensures that electrical power is available at the application electrode  12  when the user grasps and holds the base housing  11  of the apparatus  10  thereby touching the cathodic tactile electrode  20 . The application electrode  12  and the tactile electrode  20  thus form a closed circuit in series with the user&#39;s skin. 
     When current flows across the user&#39;s skin to  from the application electrode in response to an applied voltage the current promotes and hastens the penetration of the medicament  23  contained in a reservoir  26  within the working electrode  12  into the skin. The polarity of the working electrode  12  is preferably unidirectional to promote the above described penetration without requiring a separate grounding electrode. The working application electrode  12  will be described in greater detail below. 
     The base assembly  11  of apparatus  10  serves as a housing to the aforesaid components as a handle. The portion of the base assembly  11 , exclusive of the tactile electrode, is preferably made of a plastic such as polyethylene, acrylonitrile, butadiene, styrene or similar durable plastic. The battery portion  24  is connected to a voltage multiplier  22  which steps up the voltage supplied by the battery  24  and applies the stepped up voltage to the current driver  19 . Current driver  19  presents a defined current and voltage output at the application electrode  12  the value of the current, which may be empirically determined being sufficient to drive the medicament through the porous, open-celled material  27  (FIG. 2) within the application electrode interposed between the skin contacting surface  13  and reservoir  26  containing the unit dose medicament and penetrate the patient&#39;s skin. The circuitry limits the maximum current available to the application electrode to preferably to less than about one milliampere per two square centimeters of the skin-contacting surface area  13  of the application electrode  12 . However, depending upon working electrode&#39;s  12  skin-contacting surface  13  configuration, the current level can vary from about 0.1 to about 1.2 milliamps. Currents ranging between 0.1 ma to 5 ma have been used clinically by the present inventor, but the higher currents caused the user minor discomfort and, with chronic use over time, may produce untoward effects. 
     FIG. 2 shows a preferred embodiment of the iontophoretic medicament-containing application electrode  12 . The application electrode  12  is preferably disposable and non-reusable and is suitable, for example, for transdermally delivering antiviral agents such as Acyclovir® for the treatment of cold sores or genital herpes. The size of the skin-contacting surface  13  of application electrode  12  may vary to accommodate specific clinical applications. The application electrode  12  is detachably housed within a recess within the receptacle  14  which recess presents an electrically conductive interior surface to complete the electrical flow path from the connecting wires  18  and  16  to a conductive element  29  within the application electrode. The electrical current from the current driver  19  is conducted through conductive inner surface of the application electrode receptacle  14  to the electrically conductive element  29  within the applicator electrode which element  29  is in electrical contact with the inner surface of the receptacle in contact therewith to drive the medicament  23  or treatment agent through the open-celled sponge-like like matrix material  27  and through the user&#39;s skin (not shown). The medicament or treatment agent  23  is contained within a rupturable polymer reservoir  26  until dispensed during treatment. A slight exertion of pressure or squeezing of the reservoir  26  against reservoir puncture means  28  releases the medicament or treatment agent into an open-celled sponge-like material  27  within the application electrode for iontophoretic delivery into the patient&#39;s skin. Medicament  23  release can occur at the time of application or upon peruse compression of the electrode  12 . Application electrode  12  can be advantageously designed to include a stripping portion adapted so that upon removal of the application electrode  12  from the electrode receptacle  14  a protruding stripping portion (not shown) scrapingly strips the conductive coating from the conductive support arm  29  to prevent reuse of the disposable electrode  12 . Application electrode  12  is intentionally packaged with a single dose packet or reservoir  26  of treatment agent or medicament  23 . In addition to the medicament, the reservoir  26  can include a coloring agent, such as iodine, which turns dark blue upon contact with starch in the open-celled material to visibly indicate that the unit dose encapsulation has been used. Other suitable coloring agents can include pH indicators, wet saturation indicators or oxidizable pigments. 
     The open-celled sponge-like material  27 , i.e., a substrate, surrounding reservoir  26  should be inert to the medicament or treatment agent being employed, as well as being non-corrosive and stable when in contact with the treatment agent. Suitable materials include plastic pads, such as polyethylene, paper or cotton, porous ceramics, open-celled porous polytetrafluoroethylene, polyurethane and other inert plastics, and open-celled silicone rubber, such as may be employed with vertically aligned medicament-containing tubes. A typical medicament that can be contained within the rupturable polymer reservoir  26  is xylocaine or similar topical anesthetic. The disposable electrode  12  possesses the advantages of preventing leaching or migration of the medicament from within the rupturable polymer reservoir, no attendant loss of efficacy, a long shelf life and little or no electrode corrosion. A suitable electrical control circuit for use in the iontophoretic medicament delivery apparatus  12  is shown in U.S. patent application, Ser. No. 07/579,799, filed Sep. 10, 1990, now U.S. Pat. No. 5,160,316 and hereby specifically incorporated by reference herein in pertinent part. 
     Experimental Clinical Trials 
     The inventor has conducted a clinical study using a prototype iontophoretic device in accordance with the present invention for the treatment of cold sores. The clinical response was promising. A second independent, qualified investigator, a board-certified Urologist, conducted a study using the present apparatus and method for treating male genital herpes lesions with encouraging results. Table 1 summarizes data (discussed below) supporting the claim to unexpected clinical benefits treating disease with this novel method. The method and medicament application device when used together for treating these common, embarrassing, and previously not easily-treatable ailments provide surprising advantages. 
     The embodiment of the device shown in FIG.  1  and described hereinabove is a improvement over the prototype used in the clinical study, which was a larger unit, not user friendly, which required physically connecting wires to the patient&#39;s body which created anxiety, and could not be used without attending personnel. Notwithstanding design, the apparatus used in the clinical study summarized in Table 1 employed electronics similar to the apparatus described herein and was used to optimize the clinical performance of the embodiment 12 of the device described herein. 
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 STAGE I TREATMENT RESULTS 
               
             
          
           
               
                   
                 RESPONSE 
                 IUDR 
                 ACYCLOVIR ® 
                 TOTALS 
               
               
                   
                   
               
             
          
           
               
                   
                 No response 
                 1 
                 1 
                 2 
               
               
                   
                 Some response 
                 1 
                 3 
                 4 
               
               
                   
                 Major response 
                 26 
                 42 
                 68 
               
               
                   
                   
               
             
          
         
       
     
     The study included a control situation wherein seven patients were found who had simultaneous concurrent herpes lesions at separate locations on their bodies. In each case one lesion was treated with iontophoretic application of antiviral agent (Acyclovir® or IUDR) and the other lesion was treated in the standard method employed in the prior art comprising repeated topical application of the same antiviral agent. The iontophoretically enhanced treated lesion received a single 10-15 minute treatment. All iontophoretically treated lesions demonstrated resolution in 24 hours and none of the unassisted topically treated lesions demonstrated a similar response. The results for the control group are summarized in Table 2. 
     
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 CONTROL GROUP RESULTS 
               
             
          
           
               
                   
                 No response 
                 Some resp. 
                 Major resp. 
               
               
                   
                   
               
             
          
           
               
                 IUDR 
                   
                   
                   
               
               
                 Treated lesion 
                 0 
                 0 
                 7 
               
               
                 Control lesion 
                 5 
                 2 
                 0 
               
               
                 ACYCLOVIR ® 
               
               
                 Treated lesion 
                 0 
                 0 
                 1 
               
               
                 Control lesion 
                 1 
                 0 
                 0 
               
               
                   
               
             
          
         
       
     
     The clinical studies included patient volunteers with full informed consent who suffered from recurrent cold sores. The study demonstrated greatest treatment efficacy if the herpes lesion received iontophoretic treatment within 36 hours of lesion onset. The treatment incorporated an electrode saturated with Acyclovir® ointment (ZOVIRAX®) or IUDR (STOXIL®) ophthalmic drops as supplied by the manufacturer. Thus mounted Anodic electrode of the prototype system was used for a 10-15 minute application directly to the lesion with the average current setting of 0.2 ma-0.6 ma which was well tolerated by all patients. 
     The lesion was evaluated in 24 hours. In 92% of the iontophoretically treated cases (&gt;70 lesions treated) a major response was noted. A major response was categorized by resolution of pain in &lt;6 hours and lesion crusted and healing within 24 hours. The normal course of cold sores involves an average period of 10-12 days before resolution and healing occurs. The present apparatus and clinical method for treatment of mucocutaneous Herpes Simplex (type I and Type II) eruptions presented herein have been described and performed with excellent results. This novel user friendly apparatus in combination with the disclosed clinical treatment method presents a very effective new treatment for Herpes Simplex eruptions. 
     While the invention has been described above with references to specific embodiments thereof, it is apparent that many changes, modifications and variations in the materials, arrangements of parts and steps can be made without departing from the inventive concept disclosed herein. For example, an impregnated conductive gel can also be used to as medicament containing medium to increase the physical stability and the tissue adhering characteristics of the electrode. Accordingly, the spirit and broad scope of the appended claims is intended to embrace all such changes, modifications and variations that may occur to one of skill in the art upon a reading of the disclosure. All patent applications, patents and other publication cited herein are incorporated by reference in their entirety.