CA1312247C - Method and apparatus for iontophoretic drug-delivery - Google Patents
Method and apparatus for iontophoretic drug-deliveryInfo
- Publication number
- CA1312247C CA1312247C CA000529451A CA529451A CA1312247C CA 1312247 C CA1312247 C CA 1312247C CA 000529451 A CA000529451 A CA 000529451A CA 529451 A CA529451 A CA 529451A CA 1312247 C CA1312247 C CA 1312247C
- Authority
- CA
- Canada
- Prior art keywords
- active ingredient
- electrode
- patient
- skin
- containment means
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/0404—Electrodes for external use
- A61N1/0408—Use-related aspects
- A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
- A61N1/0444—Membrane
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/0404—Electrodes for external use
- A61N1/0408—Use-related aspects
- A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
- A61N1/0448—Drug reservoir
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M2037/0007—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/0404—Electrodes for external use
- A61N1/0408—Use-related aspects
- A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
- A61N1/0432—Anode and cathode
- A61N1/0436—Material of the electrode
Abstract
Abstract of the Disclosure A device for iontophoretic delivery of active ingredient to a patient includes an electrode, a first cavity for holding a solution of active ingredient in at least partially ionized form to be delivered to a patient, a member for maintaining a solution in the first cavity while allowing passage of active ingredient from the first cavity, and an ion exchange member separating the electrode and the first cavity for inhibiting the flow of ions having a charge similar to the charge of the ionized form of the active ingredient from the electrode means to the first cavity is disclosed. Methods for iontophoretic delivery of active ingredients to a patient are also disclosed.
Description
.
~L31~2~7 METHOD AND APPARATUS FOR IONTOPHORETIC DRUG-DELIVERY
The present invention relates to a device for iontophoretic delivery of active ingredients-to a patientO The invention also relates to a method for iontophoretic delivery of active ingredients to a patient, and to a method for reducing the possibility of skin trauma caused by iontophoretic delivery of active ingredients to a patient.
Iontophoretic drug delivery is based on the principle that charged molecules will migrate in an electric field toward the electrode of opposite charge.
In practice, the process of iontophoretic drug delivery is performed by putting a solution of the drug, often contained in a piece of filter paper or in a gel or in some other device, onto intact skin. The solution is then covered by an electrode. A second electrode is placed elsewhere on the skin, and a direct current source is connected between the two electrodes in such a way that the electrode in contact with the drug solution assumes the same charge as the ionized drug. Under the influence of the electric field present, drug molecules migrate through the skin. A current flows between the electrodes, part of which is carried by the drug.
Although the prosess of iontophoretic drug delivery may be accomplished using very simple 13~22~7 electrodes, certain advantages accrue through the use of more sophisticated electrode configurations. For example, one side effect of the iontophoretic process is the possible formation of vesicles and bullae on the skin beneath the electrodes, as described by W.B. Shelley et al. in J. Invest. Dermatol., 11, pg. 275 (1948).
Minimizing this type of skin trauma has been the subject of several recent patents. Jacobsen et al. in U.S.
Patent No. 4~416,274 describe a segmented electrode which is designed to ensure uniform current flow, thereby minimizing skin trauma arising from high localized currents.
In~another series of patents, U.S. Patent Nos.
4,166,457, 4,250,878, and 4,4770971, ~acobsen et al.
describe electrodes to which a solution of a drug may be added just prior to the application of the iontophoretic treatment to the patient. The salient feature of these electrodes is that they have an empty chamber closed on the side which is to be attached to the skin by a microporous membrane, which allows the iontophoretic passage of ions but inhibits fluid flow under modest pressure differentials. These electrode designs contain self-sealing devices which allow addition of the drug solution, similar in function to the rubber seals commonly used in medical practice in the manipulation of parenteral solutions. These electrodes employ clothing snaps to provide electrical contact with the external circuit, a common practice also with the use of electrocardiographs and other medical devices which require electrical contact with the skin. One important ~actor in the use of these electrodes i5 to ensure that gas bubbles ~either from gas originally present in the electrode or ~rom that which is formed by the electrode reaction) do not interfere with the electrical contact between the drug solution and the clothing snap.
~3~2~7 Addition of the drug solution to the elec-trode at the time of application of iontophoretic treatment to the patie~t provides several advantages~
One electrode may be used for delivery of several different drugs. Further, since many o~ the drugs ~or which iontophoretic delivery is practical are available in paren-teral form, the parenteral form of the drug can often be used without modification.
None of these recent patents concerning the design and construction of iontophoretic electrodes identify or address the problem of pH control in the electrodes. Protons are produced at the anode and hydroxide ions are produced at the cathode by water electrolysis under the usual conditions employed in iontophoretic drug delivery. No~ only will this lead to a change in pH at the electrode; also the ion pro-duced in the drug solution has the same charge as the drug, and if the ion is allowed to accumulate in the solution it will begin to compete with the drug as the treatment proceeds. The pH-change is signifi-cant also because the maximum current density which may be passed through the skin appears to be pH-related. The maximum current is the maximum current density times the electrode area employed. The penalties for exceeding the maximum permissible current density are pain and burns. Molitar and Fernandez, Am. J. Med. Sci., 198, pg. 778 (1939) reported that the maximum permissible current density is dependent on the electrode area. We observe similar behavior.
For the better understanding of the invention a pr~ferred embodiment will be described in conjunction with Figs. 2 and 3 of the accompanying drawings, wherein: ;
FIG. 1 is a graph o~ experimental and calculated results as discussed above, wherein the experimental results are shown as points in circles . --" .
13122~7 -3a-and the calculated results are shown by a smooth curve;
FIG. 2 is a cross sectional view of a device made in accordance. with the present invention;
and FIG. 3 is a -top view of the device of FIG.
~L31~2~7 METHOD AND APPARATUS FOR IONTOPHORETIC DRUG-DELIVERY
The present invention relates to a device for iontophoretic delivery of active ingredients-to a patientO The invention also relates to a method for iontophoretic delivery of active ingredients to a patient, and to a method for reducing the possibility of skin trauma caused by iontophoretic delivery of active ingredients to a patient.
Iontophoretic drug delivery is based on the principle that charged molecules will migrate in an electric field toward the electrode of opposite charge.
In practice, the process of iontophoretic drug delivery is performed by putting a solution of the drug, often contained in a piece of filter paper or in a gel or in some other device, onto intact skin. The solution is then covered by an electrode. A second electrode is placed elsewhere on the skin, and a direct current source is connected between the two electrodes in such a way that the electrode in contact with the drug solution assumes the same charge as the ionized drug. Under the influence of the electric field present, drug molecules migrate through the skin. A current flows between the electrodes, part of which is carried by the drug.
Although the prosess of iontophoretic drug delivery may be accomplished using very simple 13~22~7 electrodes, certain advantages accrue through the use of more sophisticated electrode configurations. For example, one side effect of the iontophoretic process is the possible formation of vesicles and bullae on the skin beneath the electrodes, as described by W.B. Shelley et al. in J. Invest. Dermatol., 11, pg. 275 (1948).
Minimizing this type of skin trauma has been the subject of several recent patents. Jacobsen et al. in U.S.
Patent No. 4~416,274 describe a segmented electrode which is designed to ensure uniform current flow, thereby minimizing skin trauma arising from high localized currents.
In~another series of patents, U.S. Patent Nos.
4,166,457, 4,250,878, and 4,4770971, ~acobsen et al.
describe electrodes to which a solution of a drug may be added just prior to the application of the iontophoretic treatment to the patient. The salient feature of these electrodes is that they have an empty chamber closed on the side which is to be attached to the skin by a microporous membrane, which allows the iontophoretic passage of ions but inhibits fluid flow under modest pressure differentials. These electrode designs contain self-sealing devices which allow addition of the drug solution, similar in function to the rubber seals commonly used in medical practice in the manipulation of parenteral solutions. These electrodes employ clothing snaps to provide electrical contact with the external circuit, a common practice also with the use of electrocardiographs and other medical devices which require electrical contact with the skin. One important ~actor in the use of these electrodes i5 to ensure that gas bubbles ~either from gas originally present in the electrode or ~rom that which is formed by the electrode reaction) do not interfere with the electrical contact between the drug solution and the clothing snap.
~3~2~7 Addition of the drug solution to the elec-trode at the time of application of iontophoretic treatment to the patie~t provides several advantages~
One electrode may be used for delivery of several different drugs. Further, since many o~ the drugs ~or which iontophoretic delivery is practical are available in paren-teral form, the parenteral form of the drug can often be used without modification.
None of these recent patents concerning the design and construction of iontophoretic electrodes identify or address the problem of pH control in the electrodes. Protons are produced at the anode and hydroxide ions are produced at the cathode by water electrolysis under the usual conditions employed in iontophoretic drug delivery. No~ only will this lead to a change in pH at the electrode; also the ion pro-duced in the drug solution has the same charge as the drug, and if the ion is allowed to accumulate in the solution it will begin to compete with the drug as the treatment proceeds. The pH-change is signifi-cant also because the maximum current density which may be passed through the skin appears to be pH-related. The maximum current is the maximum current density times the electrode area employed. The penalties for exceeding the maximum permissible current density are pain and burns. Molitar and Fernandez, Am. J. Med. Sci., 198, pg. 778 (1939) reported that the maximum permissible current density is dependent on the electrode area. We observe similar behavior.
For the better understanding of the invention a pr~ferred embodiment will be described in conjunction with Figs. 2 and 3 of the accompanying drawings, wherein: ;
FIG. 1 is a graph o~ experimental and calculated results as discussed above, wherein the experimental results are shown as points in circles . --" .
13122~7 -3a-and the calculated results are shown by a smooth curve;
FIG. 2 is a cross sectional view of a device made in accordance. with the present invention;
and FIG. 3 is a -top view of the device of FIG.
2 with domed member not shown to expose the interior parts.
The data from Molitor and Fernandez, on the maximum current which can be applied from~an effectively unbuffered but relatively constant pH
electrode to the skin for fifteen minutes without causing pain, as a function of area, are shown in FIG. 1 of the accompanying drawings. The points are taken from the aforementioned reference. The l.ine of FIG. 1 was derived from a model ~3~L22~7 which says that the pain is derived from the buildup of a substance in the skin~ the generation of which is proportional to current and the dissipation of which is proportional to the concentration. The derivation of the equation for the line, designed to fit the endpoints of the data, i5 given below. The fit of the data appears to support this hypothésis.
Fick's first law of diffusion:
J = R(Cs - Co) J is 1ux (mass/area time) K is mass transfer ooefEicient (length/time) Cs is source concentration (mass/volume) Co is sink concentration Q = JA Q is total flow (mass/time) A is area thus Q = KA(Cs - Co) however~ Co is QJV where V is the fl~rate in the sink (volume time) thus Q = KACs - KAQ~V
and Q = hCsV
A + V/K
defining constants as follows F = i/Q (where i is maximwm current) L = C~VF
M - V/K
thus i = AL/(M~A) Using the endpoints of the Molitor et al. data (A = 25, Q = 10 and A = 500, Q = 26.5) yields a value for L
of 29.0 and for M of 47.55. Thus i = 29.0A(47.55 ~ A.) The Molitor et al. experimental values and those calculated from the above equation appear below for comparison and are plotted in FIG. 1 as noted above.
~31~
Area cm2 ~ en~al i~ Calculated 10.0 (10.0 14~0 14.9 17.0 17.8 100 19.0 19.6 125 20.5 21.0 150 21.5 2~.0 175 22.5 22.
200 23.0 23.4 225 23.~ 23.9 250 24.2 2~.4 275 24.7 24.7 3Q0 25.2 25.0 400 26.3 25.9 500 . 26.5 (26.5) Duration of treatment is also.a factor affecting the maximum permissible current density. In Table I beIow is presented the relationship between the maximum time for an iontophoretic experiment and current density as determined by the drop in skin resistance under a weakly buffered electrode. A significant drop in skin resistance is indicative of skin traumaO Also presented is the total charge passed~ which is related to the product of the current and the timeO
TABLE I
Maximum Time for Iontophoresis as a F~unction of Current Current Time Char~e 5.0 mA 36 min 10.8 coulombs 2.Q mA 72 min 8.6 coulombs 1.5 mA 110 min 9.9 coulombs Medium: physiological saline buffered with O.OlM
phosphate.
At a given curren~ an experiment could only be run for the specLfied length of time. The tlme increase~
~3~22~7 with decreasing current in such a way that the product of the two, the total charge, remained relatively constant. Molitor (Merck Report, January 22, 1943) hypothesizes that the factor which limits the current density is the buildup of protons or hydroxyl ions in the subcutaneous tissue as evidenced by a change in pH.
Molitor and Fernandez had shown that a change in subcutaneous pH of as much as 1.5pH units can occur after fifteen minutes of iontophoresis.
This hypothesis is also consistent with the data in Table I r if one assumes that the reason why the subcutaneous pH ~eneath an anode drops more or less linearly for fiftèen minutes is not that steady state between proton generation and dissipation is reached this slowly, but rather that increase in proton concentration in the subcutaneous tissue is due to increasing proton transport from the donor solution as the buffer capacity of the donor solution is strained by the continuous production of protons at the anode. For example, the data in Table I were generated using physiological saline buffered with 0 OlM phosphate. By using 0.5M phosphate as the electrolyte at both electrodes, operation at 2 mA
for at least two hours was possible without experiencing a drop in skin resistance. It appears, therefore, that pH control (achieved here with the more concentrated bufer), in addition to being a major factor in optimizing current efficiency, is also a major factor in enabling the use of high current densities and/or long iontophoretic durations without discomfort or skin trauma.
Accordingly, there is a continuing need for an efficient and safe iontophoretic drug deli~ery device that inhibits the curren~-carrying capacity of ions that compete with the active ingredient.
The present invention provides an electrode 13~22~7 device for iontophoretic delivery of active inyredient to a patient. The device is designed to increase the rate and efficiency of drug delivery to the patient, and also to reduce the possibility of skin trauma, including chemical burns caused by uncontrolled production of protons or hydroxide ions at the electrode during iontophoretic delivery of the drug, and electrical burns caused by the use of high currents.
A first aspect of this invention is a device for iontophoretic delivery of an at least partially ionized active ingredient through the skin of a patient, comprising:
- (a) a first containment means for containing an electrolyte;
(b) an electrode for said first containment means to contact electrolyte in said containment means;
tc~ a second containment means, adjacent to said first containment means, for containing said active ingredient;
(d) an ion-exchange membrane as an ion mobility inhibiting means, separating said first containment means from said second containment means, for inhibiting the flow of ions having a charge like that of the at least partially ionized active ingredient between said first and second containment means; and ~ e} maintaining means for maintaining the active ingredient in said second containment means while allowing passage of activè ingredient ions to the skin of the patient.
The term "electrode" herein is meant to denote a conductive component within the electrode device of the present invention at which, when in contact with electrolyte, oxidation or reduction takes place.
In a second aspect, this invention provides a ~ 3 ~
method of using such a device for iontophoretic delivery of active ingredient to a patient, which comprises the steps of applying such a device to the skin sur~ace of the patient, the device containing electrolyte in said first containment means and an effective amount of the active ingredient in said second containment means, applying to the skin surface of the patient a second electrode device spaced from the first device, and supplying current through the electrode devices to cause migration of an effective amount of the active ingredient into the patient.
In a further embodiment of this invention, the skin surface of the patient is iontophoretically pre-treated with an anionic surface active agent prior to administration of a cationic active ingredient, or with a cationic surface active agent prior to administration of an anionic active ingredient.
In a yet further embodient of the present invention, when the active ingredient i5 in basic form, it is associated with a pharmaceutically acceptable weak acid. Similarly, when the active ingredient is in acid form, it is associated wiht a pharmaceutically acceptable weak base. An electrode device may be provided which already contains such active ingredient, ready to use.
In another embodiment, there is provided a method for iontophoretic delivery of active ingredient to a patient comprising applying to the skin surface of the patient an electrode device that includes an electrode and an associated ionized activ~ ingredient, applying to the skin surface of the patie~t a second electrode device spaced rom the first device, and supplying current to the electrode devices to cause migration of a therapeutically effective amount of the active ingredient into the patient, said active ingredient being associated with buffering means. A ready-to-use electrode device '` 1312247 may be provided, containing active ingredient and bu~eri~y means.
FIG. 2 o~ the drawings illustrates a device including a generally conical or domed flanged molding 1, which is made of electrically nonconduc-tive material such as polyethylene or polypropylene.
The particular shape is not critical. The opening at the base of the molding may be covered by a micro-porous membrane 3 which is attached to the bottom of the molding and is made of electrically nonconduc-tive material, such as stretched polyeth~lene or polypropylene film. One specific example of such a material is a polypropylene film sold under the trademark Celgard 3501 by Celanese, Inc. ~he mem-brane can be coated with a sur~actant if necessary for the purpose of wettability. The microporous membrane 3 allows electrical migration of ions but inhibits leakage of fluid. The material of which the microporous memhrane is made can vary with the active ingredient used in the device. Alternatively, the active ingredient could be maintained in the electrode by providing it in the form of a self-supporting gel. The gel form and the microporous membranes thus are equivalent methods of maintaining the active ingredient in the electrode.
The molding 1 and the microporous membrane ~3~2~7 together define a chamber that is divided by an ion exchange membrane 4, discussed below/ into upper and lower cavities, 6 and 10 sespectively, each of which contains a different solution~ Thus upper cavity 6 is defined by the upper portion of molding 1 and the membrane 4, while the lower cavity 10 is defined by the lower portion of ~olding 1 and the ion exchange membrane 4 on top and the microporous membrane 3 on bottom. Good results have been obtained with a device having an active area of 15 cm2, wherein the upper cavity has a volume of 6 ml and the lower cavity a volume of 2 ml. An electrode 7 is provided through the exterior wall of the upper cavity 6 for eonnection to a current source. -Filling means/ typically an injection tube 2,is fitted through an opening in the center of the top of the molding 1, as shown in FIG. 2, so that the upper end of the tube is exposed to the outside of the molding to allow introduction therethrough of drug solution. The tube extends through membrane 4 so that the lower end of the tube is open to the lower cavity. The tube 2 is sealed to the molding at the point where it passes through, to prevent leakage of fluid out of the upper cavity. The tube 2 is conveniently made of electrically nonconductive material similar to the material of which the molding is made, althouyh the two may be made of different materials.
The upper end of the tube is sealed, preferably by a self-sealing means 5. In a preferred embodiment of the invention, the self-sealing means is a serum stopper which can be punctured by a hypodermic needle. When the needle is removed, the material of the sealing means closes about and obliterates the opening made by the needle. Such a self-sealing mean~ can also be located in the wall of lower cavity 19, so that the drug can be injected directly into the cavity without the need for an ~3~L2247 in~ection tube~
Lower cavity 10 contain~ an eleatrolytic ~olution o~ an at least partially ionlzed pharmaceutically ac~ive ingredient, and upper aavity 6 aontains an eleatrolyteO Between th~m is ths lon-exahange membrane 4, which will now be di~aus~ed.
Membrane 4 inhibit~ the passage oE the drug io~ and ions - of ~imilar aharge within the drug solution loca~ed in the lower cavity 10 into the upper cavity 6, and al50 the passage o~ lons of similar charge from the elea~rode into the drug solution, thus reducing competltion with the druy ions as current carriers. Membrane 4 thu~ 3eparates i . the drug soIution in lower cavi~y lO ~rom the electrode 7 which is in contact with the electrolyte i~ upper cavity i 6~ Suitable ion exchange membranes are those old under the designations AR103-QZL by Ionlcs~ Inc., and RaiporeTM
4010 and 4035 by RAI Research Corp. Generally, the membrane should have as high a selectivi~y a~ possible, keeping in mind practical considerations such as the~
. ~lexibility of the film (which is advantageous ~or the fabrication oE the el~ctrode) and th~ increase in electrical resistance with the thickness o the membrane. A selectivity o~ BO~, as determined through 0.5N KCl and l.ON KCl solutions on diferent sides o the membrane, is useful, al~hough the selectivlty may be higher or lower. A bufer, such as a phosphate buf~er or ion exchange resin particles, may be used wi~h the electrolyte if desired.
The electrode 7 conveniently can ~ake ~he form ~ o a clothing snap 7 mounted in the wall of the upper j~ ~olding so that the stud of the snap is exposed to the outer surface of the molding Eor connection to an electrical power source~ not shown~- The base of the snap i9 exposed to the electrolytic solution within the upper ;~ cavity 6, where said solution is preferably gelled and .
~3~L2~7 buffered. Th~ electrode could also simply comprise a wire passing through the molding into the electrolyte~
An electrode made of stainless steel is desirable if corrosion is a problem.
~ flange portion 11 of the molding can also he provided at the base of the device. The 1ange i5 coated on its underside with an adhesive layer 8. Any suitable adhesive material can be employed. The adhesive layer serves to secure the device to the skin of the patient during treatment.
A protective release layer 9 may be held on the underside of the flange portion 11 by the adhesive layer 8. The release layer 9 protects the mi-croporous membrane 3 from contamination and damage when the device is not being used. When the device is ready for use, the release layer 9 is peeled off to expose the adhesive layer 8 and the microporous membrane 3~
Any standard iontophoretic electrode device ~ay be used as the second electrode device, although the active area should be about the same as that of the first electrode device. Karaya gum is a useful electrolyte Eor the second electrode device, since it can also act as an adhesive and exhibits some buffering characteristics.
Additional buffering may be provided if desired.
It has been discovered that the rate of drug delivery generally drops by an order of magnitude when power is shut of, depending specifically on the passive delivery rate of the active ingredient. Thus, the present device may be used with a microprocessor and sensor capable of shutting off power when a given drug dose has been administered, particularly where there is a clear physiological indication, e~g. a given heart rate, when a certain amount has been administered.
It may be desirable to provide the solution of active ingredient with a buffer. The ion of the buffer 1 3 ~ 7 -~3-of like charge to the drug ion should have low ionic mobility. Tha limiting ionic mobility of this ion is preferably no greater than 1 x 10-4 cm2/volt-sec. The buffer can include large multiply-charged ions or weak anion exchange resin or weak cation exchange resin. The buffer ions should have a smaller charge-to-mass ratio than the active ingredient. The pK of the weak anion exchange resin should be in the range of about 4 to about 7, preferably about 6. The anionic exchange resin is especially useful at a pH of 0-7. One example of such a resin is Amberlite IRA-45 resin sold by Rohm and Haas.
The pK of the weak c~tion exchange resin should be in the range of about 6 to ab~ut 10, preferably about 9. The cationic exchange resin is especially useful at a pH of about 5-14. One example of such a resin is Amberlite CG-50 resin. This buffering method can be used with iontophoretic drug delivery electrode devices other than the specific one disclosed herein.
In accordance with another aspect of the present invention, the active ingredient to be ion~ophoretically administered to the patient is in the form of a weak acid or weak base salt, so that the competition of protons and hydroxide ions is reduced, thus advantageously improving the current efficiency of the active ingredient. Among such weak acids are included maleic, acetic and succinic acids, and an example of such a weak base is ammonia. This reduction of protons and hydroxide ions allows for delivery of an increased amount of active ingredient without the possibility of skin burns and trauma. ~hese aspects of the invention are useful for any ion~ophoretic drug delivery process and apparatus, not only the electrode device and accompanying method disclosed herein.
A wide variety of active ingredients may be used in the present invention. Virtually any active -~3:~2~
ingredient capable of assuming an ionized form is useful in the present invention, for the active ingredient must be at least partially in ionized form. However, the present invention is particularly useful for drugs of short duration of action, where frequent and lengthy application is required. Typical examples of such active ingredients include catecholamines such as dobutamine, anticholinesterase agents such as neostigmine, ergot alkaloids, opioids, opioid antagonists, salicylates and scopolamine. Particularly useful are the inotropic compounds disclosed in U.S. Patent No. 4,562,206. In one preferred embodiment of the present invention the quaternary ~mmonium salt forms of aminated active ingredients are used, since the quaternary form will not normally pass across the blood-brain barrier or the placental barrier, and additionally will not ionize to yield protons. The amount of active ingredient in the ionized form in solution is preferably from about 1 to about 5 mg. ionized active ingredient per ml solution.
The pH of the solution containing the active ingredient can be from about 3 to about 10.
In accordance with a preferred embodi~ent of the present invention, the skin surface of a patient i5 pre-treated iontophoretically with a solution of a pharmaceutically acceptable surface active agent having a charge opposite to the charge of the active ingredient.
This reduces competition rom the migration of body tissue ions outward through the skin, allowing for increased current efficiency of iontophoretic drug delivery, and avoiding discomfort and skin trauma to the patient. Pharmaceutically acceptable surface active agents for use in accordance with the present invention include, but are not limited to, sodium lauryl sulfate, sodium dodecylsarcosinate, cholesterol hemisuccinate, sodium cetyl sulfate, sodium dodecylbenzenesulfonate, :l3~.~2~7 sodium dioctylsulfosuccinate, and quaternary ammonium compounds such as cetyl trimethylammonium chloride. It is believed that the surface active agent functions ~o drive out similarly charged physiological ions, which can carry charge and thus decrease the efficiency of the iontophoretic drug delivery. The surface active agent does not exhibit ~he mobility of the physiological ions, and thus does not affect the current efficiency as the physiological ions do. This pretreatment also is useful for iontophoretic electrode devices other than that of the present invention~
In use, the release liner 9 is peeled off and the device i~ attached to the skin o.f the patient, with the adhesive layer 8 securely contacting the skin. A
syringe or other suitable drug delivery means is filled with a volume of drug solution somewhat larger than the volume of the lower cavity, and the needle of the syringe is forced through the serum stopper 5 into the tube 2.
The syringe plunger is drawn back to aspirate air from the lower chamber 10 and then the drug solution is forcibly transerred through the needle into the tube 2. This process of air aspiration and transfer of solution is repeated until the drug solution in the device completely fills lower cavity 10 and thus completely covers the bottom o~ the ion-exchange membrane 4. The device is then attached to any suitable power supply (preferably DC) by means of the electrode 7. Also attached to the power supply is a second electrode device that is applied to the skin surface of the patient spaced from the first device. The spacing between the first and second electrode devices can be relatively closey as long as the current is prevented from passing from one electrode device to the other without passing through the skin~ Th~ electrode devices provide an electric field by which the active ingredien~ migra~es through the 13122~7 microporous membrane 3 and through the skin into the body.
The present invention has been described in connection with a preferred embodiment as shown in Figures 2 and 3. It should be unders~oodt however, that such a device could have a wide variety of shapes or structures consistent with the aspec~s and embodiments of the present invention as hereinabove described. For instance the device could be of a generally flatter profile, in order to minimize size, and can be of any d~sired shape for application to a particular area of the skin. The two electrode devices can be incorporated into a unitary bQdy, provided that the above-discussed spacing requirements are met. Such an embodiment would then only require one apparatus to be affixed to the patient. As discussed above, the electrolyte of either cavity can be in the form of a liquid or a self supporting gel. Other embodiments might contain the electrolyte in a sponge member or other absorbent material such as filter paper. The term ~Icavity~ throughout this description is used in its broadest sense as any unfilled space within which the electrolytic media are contained. Such a cavity may in fact be defined by the electrolytic medium itself if it is in the orm of a self-supporting gel or sponge member. Therefore the term cavity is intended to encompass any suitable containment means.
The data from Molitor and Fernandez, on the maximum current which can be applied from~an effectively unbuffered but relatively constant pH
electrode to the skin for fifteen minutes without causing pain, as a function of area, are shown in FIG. 1 of the accompanying drawings. The points are taken from the aforementioned reference. The l.ine of FIG. 1 was derived from a model ~3~L22~7 which says that the pain is derived from the buildup of a substance in the skin~ the generation of which is proportional to current and the dissipation of which is proportional to the concentration. The derivation of the equation for the line, designed to fit the endpoints of the data, i5 given below. The fit of the data appears to support this hypothésis.
Fick's first law of diffusion:
J = R(Cs - Co) J is 1ux (mass/area time) K is mass transfer ooefEicient (length/time) Cs is source concentration (mass/volume) Co is sink concentration Q = JA Q is total flow (mass/time) A is area thus Q = KA(Cs - Co) however~ Co is QJV where V is the fl~rate in the sink (volume time) thus Q = KACs - KAQ~V
and Q = hCsV
A + V/K
defining constants as follows F = i/Q (where i is maximwm current) L = C~VF
M - V/K
thus i = AL/(M~A) Using the endpoints of the Molitor et al. data (A = 25, Q = 10 and A = 500, Q = 26.5) yields a value for L
of 29.0 and for M of 47.55. Thus i = 29.0A(47.55 ~ A.) The Molitor et al. experimental values and those calculated from the above equation appear below for comparison and are plotted in FIG. 1 as noted above.
~31~
Area cm2 ~ en~al i~ Calculated 10.0 (10.0 14~0 14.9 17.0 17.8 100 19.0 19.6 125 20.5 21.0 150 21.5 2~.0 175 22.5 22.
200 23.0 23.4 225 23.~ 23.9 250 24.2 2~.4 275 24.7 24.7 3Q0 25.2 25.0 400 26.3 25.9 500 . 26.5 (26.5) Duration of treatment is also.a factor affecting the maximum permissible current density. In Table I beIow is presented the relationship between the maximum time for an iontophoretic experiment and current density as determined by the drop in skin resistance under a weakly buffered electrode. A significant drop in skin resistance is indicative of skin traumaO Also presented is the total charge passed~ which is related to the product of the current and the timeO
TABLE I
Maximum Time for Iontophoresis as a F~unction of Current Current Time Char~e 5.0 mA 36 min 10.8 coulombs 2.Q mA 72 min 8.6 coulombs 1.5 mA 110 min 9.9 coulombs Medium: physiological saline buffered with O.OlM
phosphate.
At a given curren~ an experiment could only be run for the specLfied length of time. The tlme increase~
~3~22~7 with decreasing current in such a way that the product of the two, the total charge, remained relatively constant. Molitor (Merck Report, January 22, 1943) hypothesizes that the factor which limits the current density is the buildup of protons or hydroxyl ions in the subcutaneous tissue as evidenced by a change in pH.
Molitor and Fernandez had shown that a change in subcutaneous pH of as much as 1.5pH units can occur after fifteen minutes of iontophoresis.
This hypothesis is also consistent with the data in Table I r if one assumes that the reason why the subcutaneous pH ~eneath an anode drops more or less linearly for fiftèen minutes is not that steady state between proton generation and dissipation is reached this slowly, but rather that increase in proton concentration in the subcutaneous tissue is due to increasing proton transport from the donor solution as the buffer capacity of the donor solution is strained by the continuous production of protons at the anode. For example, the data in Table I were generated using physiological saline buffered with 0 OlM phosphate. By using 0.5M phosphate as the electrolyte at both electrodes, operation at 2 mA
for at least two hours was possible without experiencing a drop in skin resistance. It appears, therefore, that pH control (achieved here with the more concentrated bufer), in addition to being a major factor in optimizing current efficiency, is also a major factor in enabling the use of high current densities and/or long iontophoretic durations without discomfort or skin trauma.
Accordingly, there is a continuing need for an efficient and safe iontophoretic drug deli~ery device that inhibits the curren~-carrying capacity of ions that compete with the active ingredient.
The present invention provides an electrode 13~22~7 device for iontophoretic delivery of active inyredient to a patient. The device is designed to increase the rate and efficiency of drug delivery to the patient, and also to reduce the possibility of skin trauma, including chemical burns caused by uncontrolled production of protons or hydroxide ions at the electrode during iontophoretic delivery of the drug, and electrical burns caused by the use of high currents.
A first aspect of this invention is a device for iontophoretic delivery of an at least partially ionized active ingredient through the skin of a patient, comprising:
- (a) a first containment means for containing an electrolyte;
(b) an electrode for said first containment means to contact electrolyte in said containment means;
tc~ a second containment means, adjacent to said first containment means, for containing said active ingredient;
(d) an ion-exchange membrane as an ion mobility inhibiting means, separating said first containment means from said second containment means, for inhibiting the flow of ions having a charge like that of the at least partially ionized active ingredient between said first and second containment means; and ~ e} maintaining means for maintaining the active ingredient in said second containment means while allowing passage of activè ingredient ions to the skin of the patient.
The term "electrode" herein is meant to denote a conductive component within the electrode device of the present invention at which, when in contact with electrolyte, oxidation or reduction takes place.
In a second aspect, this invention provides a ~ 3 ~
method of using such a device for iontophoretic delivery of active ingredient to a patient, which comprises the steps of applying such a device to the skin sur~ace of the patient, the device containing electrolyte in said first containment means and an effective amount of the active ingredient in said second containment means, applying to the skin surface of the patient a second electrode device spaced from the first device, and supplying current through the electrode devices to cause migration of an effective amount of the active ingredient into the patient.
In a further embodiment of this invention, the skin surface of the patient is iontophoretically pre-treated with an anionic surface active agent prior to administration of a cationic active ingredient, or with a cationic surface active agent prior to administration of an anionic active ingredient.
In a yet further embodient of the present invention, when the active ingredient i5 in basic form, it is associated with a pharmaceutically acceptable weak acid. Similarly, when the active ingredient is in acid form, it is associated wiht a pharmaceutically acceptable weak base. An electrode device may be provided which already contains such active ingredient, ready to use.
In another embodiment, there is provided a method for iontophoretic delivery of active ingredient to a patient comprising applying to the skin surface of the patient an electrode device that includes an electrode and an associated ionized activ~ ingredient, applying to the skin surface of the patie~t a second electrode device spaced rom the first device, and supplying current to the electrode devices to cause migration of a therapeutically effective amount of the active ingredient into the patient, said active ingredient being associated with buffering means. A ready-to-use electrode device '` 1312247 may be provided, containing active ingredient and bu~eri~y means.
FIG. 2 o~ the drawings illustrates a device including a generally conical or domed flanged molding 1, which is made of electrically nonconduc-tive material such as polyethylene or polypropylene.
The particular shape is not critical. The opening at the base of the molding may be covered by a micro-porous membrane 3 which is attached to the bottom of the molding and is made of electrically nonconduc-tive material, such as stretched polyeth~lene or polypropylene film. One specific example of such a material is a polypropylene film sold under the trademark Celgard 3501 by Celanese, Inc. ~he mem-brane can be coated with a sur~actant if necessary for the purpose of wettability. The microporous membrane 3 allows electrical migration of ions but inhibits leakage of fluid. The material of which the microporous memhrane is made can vary with the active ingredient used in the device. Alternatively, the active ingredient could be maintained in the electrode by providing it in the form of a self-supporting gel. The gel form and the microporous membranes thus are equivalent methods of maintaining the active ingredient in the electrode.
The molding 1 and the microporous membrane ~3~2~7 together define a chamber that is divided by an ion exchange membrane 4, discussed below/ into upper and lower cavities, 6 and 10 sespectively, each of which contains a different solution~ Thus upper cavity 6 is defined by the upper portion of molding 1 and the membrane 4, while the lower cavity 10 is defined by the lower portion of ~olding 1 and the ion exchange membrane 4 on top and the microporous membrane 3 on bottom. Good results have been obtained with a device having an active area of 15 cm2, wherein the upper cavity has a volume of 6 ml and the lower cavity a volume of 2 ml. An electrode 7 is provided through the exterior wall of the upper cavity 6 for eonnection to a current source. -Filling means/ typically an injection tube 2,is fitted through an opening in the center of the top of the molding 1, as shown in FIG. 2, so that the upper end of the tube is exposed to the outside of the molding to allow introduction therethrough of drug solution. The tube extends through membrane 4 so that the lower end of the tube is open to the lower cavity. The tube 2 is sealed to the molding at the point where it passes through, to prevent leakage of fluid out of the upper cavity. The tube 2 is conveniently made of electrically nonconductive material similar to the material of which the molding is made, althouyh the two may be made of different materials.
The upper end of the tube is sealed, preferably by a self-sealing means 5. In a preferred embodiment of the invention, the self-sealing means is a serum stopper which can be punctured by a hypodermic needle. When the needle is removed, the material of the sealing means closes about and obliterates the opening made by the needle. Such a self-sealing mean~ can also be located in the wall of lower cavity 19, so that the drug can be injected directly into the cavity without the need for an ~3~L2247 in~ection tube~
Lower cavity 10 contain~ an eleatrolytic ~olution o~ an at least partially ionlzed pharmaceutically ac~ive ingredient, and upper aavity 6 aontains an eleatrolyteO Between th~m is ths lon-exahange membrane 4, which will now be di~aus~ed.
Membrane 4 inhibit~ the passage oE the drug io~ and ions - of ~imilar aharge within the drug solution loca~ed in the lower cavity 10 into the upper cavity 6, and al50 the passage o~ lons of similar charge from the elea~rode into the drug solution, thus reducing competltion with the druy ions as current carriers. Membrane 4 thu~ 3eparates i . the drug soIution in lower cavi~y lO ~rom the electrode 7 which is in contact with the electrolyte i~ upper cavity i 6~ Suitable ion exchange membranes are those old under the designations AR103-QZL by Ionlcs~ Inc., and RaiporeTM
4010 and 4035 by RAI Research Corp. Generally, the membrane should have as high a selectivi~y a~ possible, keeping in mind practical considerations such as the~
. ~lexibility of the film (which is advantageous ~or the fabrication oE the el~ctrode) and th~ increase in electrical resistance with the thickness o the membrane. A selectivity o~ BO~, as determined through 0.5N KCl and l.ON KCl solutions on diferent sides o the membrane, is useful, al~hough the selectivlty may be higher or lower. A bufer, such as a phosphate buf~er or ion exchange resin particles, may be used wi~h the electrolyte if desired.
The electrode 7 conveniently can ~ake ~he form ~ o a clothing snap 7 mounted in the wall of the upper j~ ~olding so that the stud of the snap is exposed to the outer surface of the molding Eor connection to an electrical power source~ not shown~- The base of the snap i9 exposed to the electrolytic solution within the upper ;~ cavity 6, where said solution is preferably gelled and .
~3~L2~7 buffered. Th~ electrode could also simply comprise a wire passing through the molding into the electrolyte~
An electrode made of stainless steel is desirable if corrosion is a problem.
~ flange portion 11 of the molding can also he provided at the base of the device. The 1ange i5 coated on its underside with an adhesive layer 8. Any suitable adhesive material can be employed. The adhesive layer serves to secure the device to the skin of the patient during treatment.
A protective release layer 9 may be held on the underside of the flange portion 11 by the adhesive layer 8. The release layer 9 protects the mi-croporous membrane 3 from contamination and damage when the device is not being used. When the device is ready for use, the release layer 9 is peeled off to expose the adhesive layer 8 and the microporous membrane 3~
Any standard iontophoretic electrode device ~ay be used as the second electrode device, although the active area should be about the same as that of the first electrode device. Karaya gum is a useful electrolyte Eor the second electrode device, since it can also act as an adhesive and exhibits some buffering characteristics.
Additional buffering may be provided if desired.
It has been discovered that the rate of drug delivery generally drops by an order of magnitude when power is shut of, depending specifically on the passive delivery rate of the active ingredient. Thus, the present device may be used with a microprocessor and sensor capable of shutting off power when a given drug dose has been administered, particularly where there is a clear physiological indication, e~g. a given heart rate, when a certain amount has been administered.
It may be desirable to provide the solution of active ingredient with a buffer. The ion of the buffer 1 3 ~ 7 -~3-of like charge to the drug ion should have low ionic mobility. Tha limiting ionic mobility of this ion is preferably no greater than 1 x 10-4 cm2/volt-sec. The buffer can include large multiply-charged ions or weak anion exchange resin or weak cation exchange resin. The buffer ions should have a smaller charge-to-mass ratio than the active ingredient. The pK of the weak anion exchange resin should be in the range of about 4 to about 7, preferably about 6. The anionic exchange resin is especially useful at a pH of 0-7. One example of such a resin is Amberlite IRA-45 resin sold by Rohm and Haas.
The pK of the weak c~tion exchange resin should be in the range of about 6 to ab~ut 10, preferably about 9. The cationic exchange resin is especially useful at a pH of about 5-14. One example of such a resin is Amberlite CG-50 resin. This buffering method can be used with iontophoretic drug delivery electrode devices other than the specific one disclosed herein.
In accordance with another aspect of the present invention, the active ingredient to be ion~ophoretically administered to the patient is in the form of a weak acid or weak base salt, so that the competition of protons and hydroxide ions is reduced, thus advantageously improving the current efficiency of the active ingredient. Among such weak acids are included maleic, acetic and succinic acids, and an example of such a weak base is ammonia. This reduction of protons and hydroxide ions allows for delivery of an increased amount of active ingredient without the possibility of skin burns and trauma. ~hese aspects of the invention are useful for any ion~ophoretic drug delivery process and apparatus, not only the electrode device and accompanying method disclosed herein.
A wide variety of active ingredients may be used in the present invention. Virtually any active -~3:~2~
ingredient capable of assuming an ionized form is useful in the present invention, for the active ingredient must be at least partially in ionized form. However, the present invention is particularly useful for drugs of short duration of action, where frequent and lengthy application is required. Typical examples of such active ingredients include catecholamines such as dobutamine, anticholinesterase agents such as neostigmine, ergot alkaloids, opioids, opioid antagonists, salicylates and scopolamine. Particularly useful are the inotropic compounds disclosed in U.S. Patent No. 4,562,206. In one preferred embodiment of the present invention the quaternary ~mmonium salt forms of aminated active ingredients are used, since the quaternary form will not normally pass across the blood-brain barrier or the placental barrier, and additionally will not ionize to yield protons. The amount of active ingredient in the ionized form in solution is preferably from about 1 to about 5 mg. ionized active ingredient per ml solution.
The pH of the solution containing the active ingredient can be from about 3 to about 10.
In accordance with a preferred embodi~ent of the present invention, the skin surface of a patient i5 pre-treated iontophoretically with a solution of a pharmaceutically acceptable surface active agent having a charge opposite to the charge of the active ingredient.
This reduces competition rom the migration of body tissue ions outward through the skin, allowing for increased current efficiency of iontophoretic drug delivery, and avoiding discomfort and skin trauma to the patient. Pharmaceutically acceptable surface active agents for use in accordance with the present invention include, but are not limited to, sodium lauryl sulfate, sodium dodecylsarcosinate, cholesterol hemisuccinate, sodium cetyl sulfate, sodium dodecylbenzenesulfonate, :l3~.~2~7 sodium dioctylsulfosuccinate, and quaternary ammonium compounds such as cetyl trimethylammonium chloride. It is believed that the surface active agent functions ~o drive out similarly charged physiological ions, which can carry charge and thus decrease the efficiency of the iontophoretic drug delivery. The surface active agent does not exhibit ~he mobility of the physiological ions, and thus does not affect the current efficiency as the physiological ions do. This pretreatment also is useful for iontophoretic electrode devices other than that of the present invention~
In use, the release liner 9 is peeled off and the device i~ attached to the skin o.f the patient, with the adhesive layer 8 securely contacting the skin. A
syringe or other suitable drug delivery means is filled with a volume of drug solution somewhat larger than the volume of the lower cavity, and the needle of the syringe is forced through the serum stopper 5 into the tube 2.
The syringe plunger is drawn back to aspirate air from the lower chamber 10 and then the drug solution is forcibly transerred through the needle into the tube 2. This process of air aspiration and transfer of solution is repeated until the drug solution in the device completely fills lower cavity 10 and thus completely covers the bottom o~ the ion-exchange membrane 4. The device is then attached to any suitable power supply (preferably DC) by means of the electrode 7. Also attached to the power supply is a second electrode device that is applied to the skin surface of the patient spaced from the first device. The spacing between the first and second electrode devices can be relatively closey as long as the current is prevented from passing from one electrode device to the other without passing through the skin~ Th~ electrode devices provide an electric field by which the active ingredien~ migra~es through the 13122~7 microporous membrane 3 and through the skin into the body.
The present invention has been described in connection with a preferred embodiment as shown in Figures 2 and 3. It should be unders~oodt however, that such a device could have a wide variety of shapes or structures consistent with the aspec~s and embodiments of the present invention as hereinabove described. For instance the device could be of a generally flatter profile, in order to minimize size, and can be of any d~sired shape for application to a particular area of the skin. The two electrode devices can be incorporated into a unitary bQdy, provided that the above-discussed spacing requirements are met. Such an embodiment would then only require one apparatus to be affixed to the patient. As discussed above, the electrolyte of either cavity can be in the form of a liquid or a self supporting gel. Other embodiments might contain the electrolyte in a sponge member or other absorbent material such as filter paper. The term ~Icavity~ throughout this description is used in its broadest sense as any unfilled space within which the electrolytic media are contained. Such a cavity may in fact be defined by the electrolytic medium itself if it is in the orm of a self-supporting gel or sponge member. Therefore the term cavity is intended to encompass any suitable containment means.
Claims (19)
1. An electrode device for iontophoretic deliv-ery of an at least partially ionized active ingredient through the skin of a patient, comprising:
(a) a first containment means defining a first chamber for containing an electrolyte;
(b) an electrical connection in electrical contact with said first chamber defined by said first containment means, for electrically contacting an electrolyte within said first chamber;
(c) a second containment means defining a second chamber for containing an active ingredient in at least partially ionized form and for iontophoreti-cally delivering said at least partially ionized ingre-dient into the skin of a patient, said second contain-ment means being separated from said first contain-ment means;
(d) an ion mobility inhibiting means sepa-rating said first and second containment means, capable of passing current from the first containment means to said second containment means while inhibiting the flow of electrolytic ions having a charge like that of the at least partially ionized active ingredient from said first containment means into said second containment means and allowing the flow from the second containment means to the first containment means of ions having a charge which is different from the charge of the at least partially ionized active ingredient, said ion mobility inhibiting means being spacially separated from said electrical contact, and (e) maintaining means for maintaining the unionized active ingredient within the second cavity, while allowing electrical current and said at least partially ionized active ingredient to pass from said second containment means into the skin of a patient during iontophoretic treatment.
(a) a first containment means defining a first chamber for containing an electrolyte;
(b) an electrical connection in electrical contact with said first chamber defined by said first containment means, for electrically contacting an electrolyte within said first chamber;
(c) a second containment means defining a second chamber for containing an active ingredient in at least partially ionized form and for iontophoreti-cally delivering said at least partially ionized ingre-dient into the skin of a patient, said second contain-ment means being separated from said first contain-ment means;
(d) an ion mobility inhibiting means sepa-rating said first and second containment means, capable of passing current from the first containment means to said second containment means while inhibiting the flow of electrolytic ions having a charge like that of the at least partially ionized active ingredient from said first containment means into said second containment means and allowing the flow from the second containment means to the first containment means of ions having a charge which is different from the charge of the at least partially ionized active ingredient, said ion mobility inhibiting means being spacially separated from said electrical contact, and (e) maintaining means for maintaining the unionized active ingredient within the second cavity, while allowing electrical current and said at least partially ionized active ingredient to pass from said second containment means into the skin of a patient during iontophoretic treatment.
2. The device of claim 1, wherein the ion mobility inhibiting means comprises an ion exchange membrane.
3. The device of claim 1 further comprising electrolyte in said first containment means, said electrolyte further comprising buffering means for neutralizing ions produced at said electrode.
4. The device of claim 1, wherein the electrode is an anode.
5. The device of claim 1, wherein the electrode is a cathode.
6. The device of claim 1, further comprising active ingredient in a solution in said second contain-ment means, said solution further comprising buffering means for the solution, wherein the ions of the buffering means of like charge to the active ingredient have a limited ionic mobility of less than 1 X 10-4 cm2/volt-sec.
7. The device of claim 3, wherein the electro-lyte means is in the form of a gel.
8. The device of claim 1, further comprising a filling means in communication with said second contain-ment means.
9. A device for iontophoretic delivery of an at least partially ionized active ingredient through the skin of a patient, comprising:
(a) a first containment means for containing an electrolyte;
(b) an electrode for said first containment means to contact electrolyte in said containment means;
(c) a second containment means, adjacent to said first containment means, for containing said active ingredient;
(d) an ion mobility inhibiting means, separating said first containment means from said second containment means, for inhibiting the flow of ions having a charge like that of the at least partially ionized active ingredient between said first and second containment means; and (e) maintaining means for maintaining the active ingredient in said second containment means while allowing passage of active ingredient ions to the skin of the patient.
(a) a first containment means for containing an electrolyte;
(b) an electrode for said first containment means to contact electrolyte in said containment means;
(c) a second containment means, adjacent to said first containment means, for containing said active ingredient;
(d) an ion mobility inhibiting means, separating said first containment means from said second containment means, for inhibiting the flow of ions having a charge like that of the at least partially ionized active ingredient between said first and second containment means; and (e) maintaining means for maintaining the active ingredient in said second containment means while allowing passage of active ingredient ions to the skin of the patient.
10. A device as claimed in claim 9, wherein the ion mobility inhibiting means comprises an ion exchange membrane.
11. An iontophoretic delivery device for delivering an active ingredient which is in either anionic or cationic form to a patient, comprising:
means for pretreating the skin of the patient by iontophoretically delivering a cationic or anionic surfactant into the skin of the patient;
a first electrode device that includes an electrode and an associated ionized active ingredient for application to the skin surface of the patient at the pretreatment skin site;
a second electrode device for application to the skin surface of the patient at a location spaced from said first electrode device; and a current source electrically connected to the first and second electrode devices for supplying current to the electrode devices to cause migration of an effective amount of the active ingredient into the patient.
means for pretreating the skin of the patient by iontophoretically delivering a cationic or anionic surfactant into the skin of the patient;
a first electrode device that includes an electrode and an associated ionized active ingredient for application to the skin surface of the patient at the pretreatment skin site;
a second electrode device for application to the skin surface of the patient at a location spaced from said first electrode device; and a current source electrically connected to the first and second electrode devices for supplying current to the electrode devices to cause migration of an effective amount of the active ingredient into the patient.
12. A device as claimed in claim 11, wherein the means for pretreating the skin iontophoretically delivers the surfactant in an amount sufficient to increase the iontophoretic drug delivery efficiency of the device.
13. A device as claimed in claim 11, wherein the surfactant ions have a charge opposite in sign to the charge of the active ingredient ions.
14. A device as claimed in claim 11, wherein the surfactant is selected from sodium lauryl sulfate, sodium dodecylsarcosinate, cholesterol hemisuccinate, sodium cetyl sulfate, sodium dodecylbenzene sulfonate, sodium dioctylsulfosuccinate and quatenary ammonium compounds.
15. An iontophoretic delivery device for delivering an active ingredient to a patient, comprising:
a first electrode device that includes an electrode and an associated ionized active ingredient for application to the skin surface of the patient;
a second electrode device for application to the skin surface of the patient at a location spaced from said first electrode device; and a current source electrically connected to the first and second electrode devices for supplying current to the electrode devices to cause migration of an effective amount of the active ingredient into the patient, characterized by said active ingredient being in basic form and being associated with a pharmaceutically acceptable weak acid.
a first electrode device that includes an electrode and an associated ionized active ingredient for application to the skin surface of the patient;
a second electrode device for application to the skin surface of the patient at a location spaced from said first electrode device; and a current source electrically connected to the first and second electrode devices for supplying current to the electrode devices to cause migration of an effective amount of the active ingredient into the patient, characterized by said active ingredient being in basic form and being associated with a pharmaceutically acceptable weak acid.
16. The device of claim 15, wherein the weak acid is selected from maleic acid, acetic acid and succinic acid.
17. An iontophoretic delivery device for deliverying an active ingredient to a patient, comprising:
a first electrode device that includes an electrode and an associated ionized active ingredient for application to the skin surface of the patient;
a second electrode device for application to the skin surface of the patient at a location spaced from said first electrode device; and a current source electrically connected to the first and second electrode devices for supplying current to the electrode devices to cause migration of an effective amount of the active ingredient into the patient, characterized by said active ingredient being in acidic form and being associated with a pharmaceutically acceptable weak base.
a first electrode device that includes an electrode and an associated ionized active ingredient for application to the skin surface of the patient;
a second electrode device for application to the skin surface of the patient at a location spaced from said first electrode device; and a current source electrically connected to the first and second electrode devices for supplying current to the electrode devices to cause migration of an effective amount of the active ingredient into the patient, characterized by said active ingredient being in acidic form and being associated with a pharmaceutically acceptable weak base.
18. The device of claim 17, wherein the weak base is ammonia.
19. A device for iontophoretic delivery of an active ingredient to a patient, comprising:
a first electrode device that includes an electrode and an associated at least partially ionized active ingredient for application to the skin surface of the patient, said active ingredient being associated with buffering means;
a second electrode device for application to the skin surface of the patient at a location spaced from said first electrode device;
a current source electrically connected to the first and second electrode devices for supplying current to the electrode devices to cause migration of a therapeutically effective amount of the active ingredient into the patient; characterized by the ions of said buffering means of like charge to the active ingredient having a limiting ionic mobility of less than 1 x 10-4cm2/volt-sec.
a first electrode device that includes an electrode and an associated at least partially ionized active ingredient for application to the skin surface of the patient, said active ingredient being associated with buffering means;
a second electrode device for application to the skin surface of the patient at a location spaced from said first electrode device;
a current source electrically connected to the first and second electrode devices for supplying current to the electrode devices to cause migration of a therapeutically effective amount of the active ingredient into the patient; characterized by the ions of said buffering means of like charge to the active ingredient having a limiting ionic mobility of less than 1 x 10-4cm2/volt-sec.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US828,794 | 1986-02-12 | ||
| US06/828,794 US4722726A (en) | 1986-02-12 | 1986-02-12 | Method and apparatus for iontophoretic drug delivery |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1312247C true CA1312247C (en) | 1993-01-05 |
Family
ID=25252772
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000529451A Expired - Lifetime CA1312247C (en) | 1986-02-12 | 1987-02-11 | Method and apparatus for iontophoretic drug-delivery |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US4722726A (en) |
| EP (1) | EP0258392B1 (en) |
| JP (1) | JP2636290B2 (en) |
| AU (1) | AU592860B2 (en) |
| CA (1) | CA1312247C (en) |
| DE (1) | DE3789642T2 (en) |
| DK (1) | DK175043B1 (en) |
| WO (1) | WO1987004936A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5135477A (en) * | 1984-10-29 | 1992-08-04 | Medtronic, Inc. | Iontophoretic drug delivery |
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| US4416274A (en) * | 1981-02-23 | 1983-11-22 | Motion Control, Inc. | Ion mobility limiting iontophoretic bioelectrode |
| US4406658A (en) * | 1981-03-06 | 1983-09-27 | Medtronic, Inc. | Iontophoretic device with reversible polarity |
| US4419092A (en) * | 1981-11-06 | 1983-12-06 | Motion Control, Inc. | Iontophoretic electrode structure |
| US4526176A (en) * | 1981-12-22 | 1985-07-02 | Frantz Medical Development Ltd. | Long-life biomedical application device, particularly electrode, and method of transferring electrical current |
| US4465074A (en) * | 1982-04-20 | 1984-08-14 | Gilbert Buchalter | Method of applying an electrode to the skin of a patient |
| US4557723A (en) * | 1983-08-18 | 1985-12-10 | Drug Delivery Systems Inc. | Applicator for the non-invasive transcutaneous delivery of medicament |
| CA1262564A (en) * | 1983-09-01 | 1989-10-31 | Minoru Sasaki | Iontophoresis device |
| CA1267937A (en) * | 1984-10-29 | 1990-04-17 | Joseph Bradley Phipps | Iontophoretic drug delivery |
-
1986
- 1986-02-12 US US06/828,794 patent/US4722726A/en not_active Expired - Lifetime
-
1987
- 1987-02-11 WO PCT/US1987/000250 patent/WO1987004936A1/en active IP Right Grant
- 1987-02-11 CA CA000529451A patent/CA1312247C/en not_active Expired - Lifetime
- 1987-02-11 JP JP62501450A patent/JP2636290B2/en not_active Expired - Lifetime
- 1987-02-11 DE DE3789642T patent/DE3789642T2/en not_active Expired - Lifetime
- 1987-02-11 EP EP87901834A patent/EP0258392B1/en not_active Expired - Lifetime
- 1987-02-11 AU AU70827/87A patent/AU592860B2/en not_active Expired
- 1987-10-12 DK DK198705325A patent/DK175043B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63502404A (en) | 1988-09-14 |
| DE3789642T2 (en) | 1994-11-03 |
| DE3789642D1 (en) | 1994-05-26 |
| AU592860B2 (en) | 1990-01-25 |
| DK532587D0 (en) | 1987-10-12 |
| WO1987004936A1 (en) | 1987-08-27 |
| US4722726A (en) | 1988-02-02 |
| EP0258392A1 (en) | 1988-03-09 |
| DK175043B1 (en) | 2004-05-10 |
| EP0258392B1 (en) | 1994-04-20 |
| AU7082787A (en) | 1987-09-09 |
| DK532587A (en) | 1987-10-12 |
| JP2636290B2 (en) | 1997-07-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |