CA2042994C - Iontophoretic delivery device - Google Patents
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- CA2042994C CA2042994C CA 2042994 CA2042994A CA2042994C CA 2042994 C CA2042994 C CA 2042994C CA 2042994 CA2042994 CA 2042994 CA 2042994 A CA2042994 A CA 2042994A CA 2042994 C CA2042994 C CA 2042994C
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Abstract
An iontophoretic agent delivery device adapted to transdermally deliver an ionic agent, and a method of using same, are provided. The device has first and second electrodes connected to a source of electrical power. The first electrode is associated with a first agent reservoir and the second electrode is associated with a second agent reservoir. The device is adapted to deliver an agent, the agent having an isoelectric point at a specified pH, from both of the agent reservoirs simultaneously. This is accomplished by adjusting the pH of the first reservoir to a level above the isoelectric point of the agent while adjusting the pH of the second agent reservoir to a level below the isoelectric point. The device and method are particularly useful in iontophoretically delivering amino acids, polypeptides and proteins.
Description
IONTOPHORETIC DELIVERY DEVICE
TECHNICAL FIELD
s This invent ion relates to a device for delivering an agent transdermally or transmucosally by iontophoresis. More particularly, this invention relates to an electrically powered iontophoretic delivery device which can deliver a drug from both the anodic and catholic electrodes simultaneously.
io BACKGROUND ART
Iontophoresis, according to Dorland°s Illustrated Medical Dictionary, is defined to be "the introduction, by means of is electric current, of ions of soluble salts into the tissues of the body for therapeutic purposes." Iontophoretic devices have been known since the early 1900's. British patent specification No.
410,009 (1934) describes an iontophoretic device which overcame one of the disadvantages of such early devices known to the art at zo that time, namely the requirement of a special low tension (low voltage) source of current which meant that the patient needed to be irr~nobilized near such source. The device of that British specification was made by forming a galvanic cell from the electrodes and the material containing the medicament or drug to zs be delivered transdermally. The galvanic cell produced the current necessary for iontophoretically delivering the medicament.
This ambulatory device thus permitted iontophoretic drug delivery with substantially less interference with the patient's daily activities.
ao More recently, a number of United States patents have issued in the iontophoresis field, indicating a renewed interest in this mode of drug delivery. For example, U.S. Patent No. 3,991,755 issued to Ilernon et al; U.S. Patent No. 4,141,359 issued to 35 Jacobsen et al; U.S. Patent No. 4,398,545 issued to Wilson; and U.S. Patent ~o. 4,250,878 issued to Jacobsen disclose examples of iontophoretic devices and some applications thereof. The iontophoresis process has been found to be useful in the transdermal administration of medicaments or drugs including s lidocaine hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate, insulin and many other drugs.
Perhaps the most common use of iontophoresis is in diagnosing cystic fibrosis by delivering pilocarpine salts iontophoretically.
The piiocarpine stimulates sweat production; the sweat is io collected and analyzed for its chloride content to detect the presence of the disease.
In presently known iontophoretic devices, at least two electrodes are used. Both of these electrodes are disposed so as is to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the ionic substance, medicament, drug precursor or drug is delivered into the body by iontophoresis.
The other electrode, called the counter or return electrode, zo serves to close the electrical circuit through the body. In conjunction with the patient's skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery. For example, if the ionic substance to be delivered into the body is positively 2s charged (i.e., a can on), then the anode will be the active electrode and the cathode will serve to complete the circuit. If the ionic substance to be delivered is negatively charged (i.e., an anion), then the cathode will be the active electrode and the anode will be the counter electrode.
It is also known that iontophoretic delivery devices can be used to deliver an uncharged drug or agent into the body. This is accomplished by a process called electroosmosis. Electroosmosis is the transdermal flux of a liquid solvent (e. g., the liquid 3s solvent containing the uncharged drug or agent) which is induced ~a4~~94 by the presence of an electric field imposed across the skin by the donor electrode. As used herein, the terms "iontophoresis"
and "iontophoretic" refer to (1) the delivery of charged drugs or agents by electromigration, (2) the delivery of uncharged drugs or s agents by the process of electroosmosis, (3) the delivery of charged drugs or agents by the combined processes of electromigration and electroosmosis, and/or (4) the delivery of a mixture of charged and uncharged drugs or agents by the combined processes of electromigration and electroosmosis.
Furthermore, existing iontophoresis devices generally require a reservoir or source of the beneficial agent (which is preferably an ionized or ionizable agent or a precursor of such agent) to be iontophoretically delivered into the body. Examples is of such reservoirs or sources of ionized or ionizable agents include a pouch as described in the previously mentioned Jacobsen U.S. Patent No. 4,250,878, or a pre-formed gel body as described in Webster U.S. Patent No. 4,383,529 and Ariura et al. U.S. Patent No. 4,474,570. Such drug reservoirs are electrically connected to zo the anode or the cathode of an iontophoresis device to provide a fixed or renewable source of one or more desired agents.
Most typically, the drug and electrolyte reservoir layers of iontophoretic delivery devices have been formed of hydrophilic 2s polymers. See for example, Ariura et al, U.S. Patent 4,474,570;
Webster U.S. Patent 4,383,529 and Sasaki U.S. Patent 4,764,164.
There are several reasons for using hydrophilic polymers. First, water is the preferred solvent for ionizing many drug salts.
Secondly, hydrophilic polymer components (i.e., the drug reservoir ao in the donor electrode and the electrolyte reservoir in the counter electrode) can be hydrated while attached to the body by absorbing water from the skin (i.e., through transepidermal water loss or sweat) or from a mucosal membrane (e. g., by absorbing saliva in the case of oral mucosal membranes). Once hydrated, the 35 device begins to deliver ionized agent to the body. This enables the drug reservoir to be manufactured in a dry state, giving the device a longer shelf life.
DISCLOSURE OF THE INVENTION
It is an object of this invention to provide an improved iontophoretic delivery device and method of using same.
It is another object of this invention to provide an io iontophoretic delivery device which can deliver the same agent from both electrodes simultaneously.
These and other objects are met by an electrically powered iontophoretic delivery device which is adapted for placement on a is body surface for iontophoretically delivering an agent therethrough. The device includes a first electrode, a means for electrically connecting the first electrode to a source of electrical power, and a first agent reservoir electrically connected to the first electrode. The first agent reservoir Zo contains a portion of the agent to be delivered through the body surface.
The device also includes a second electrode, means for electrically connecting the second electrode to the source of 2s electrical power, and a second agent reservoir electrically connected to the second electrode. The second agent reservoir contains a portion of the agent to be delivered through the body surface.
ao The agent delivered by the device has an isoelectric point at a specified pH. The first agent reservoir has a pH above the specified pH which renders at least a portion of the agent in the first agent reservoir negatively charged. The second agent reservoir has a pH below the specified pH which renders at least a 35 portion of the agent in the second agent reservoir positively charged.
In this way, a portion of the agent in the first agent reservoir has a net negative charge in solution and therefore is delivered from the first agent reservoir by electromigration. Simultaneously, a portion of the agent in 5 the second agent reservoir has a net positive charge in solution and likewise is delivered from the second agent reservoir by electromigration.
Also provided is a method of iontophoretically delivering an agent through a body surface from such a delivery device. The method includes the steps of:
adjusting the pH of the first agent reservoir to a pH above the specified pH;
adjusting the pH of the second agent reservoir to a pH below the specified pH; and placing the first and second agent reservoirs in agent transmitting relation to the body surface.
According to one aspect of the present invention, there is provided an iontophoretic delivery device adapted for placement on a body surface for iontophoretic delivery of an agent therethrough, the device comprising:
a first electrode, means for electrically connecting the first electrode to a source of electrical power, and a first agent reservoir electrically connected to the first electrode, the first agent reservoir containing a portion of the agent to be delivered through the body surface; and a second electrode, means for electrically 5a connecting the second electrode to the source of electrical power, and a second agent reservoir electrically connected to the second electrode, the second agent reservoir containing a portion of the agent to be delivered through the body surface, wherein the agent has an isoelectric point at a specified pH; the first agent reservoir has a pH above the specified pH and hence the agent in the first reservoir has a net negative charge in a solution; and the second agent reservoir has a pH below the specified pH, and hence the agent in the second reservoir has a net positive charge in a solution, whereby the agent can be delivered simultaneously from both the first and second agent reservoirs through the body surface by electromigration, and wherein at least about 10% of the agent in the first agent reservoir has a net negative charge in solution, and at least about 10% in the agent in the second agent reservoir has a net positive charge in solution.
According to another aspect of the present invention, there is provided a method of operating a delivery device having a first electrode electrically connected to a first agent reservoir containing an agent having an isoelectric point at a specified pH, and a second electrode electrically connected to a second agent reservoir containing the agent, the first and second electrodes being electrically connected to a source of electrical power, the delivery device being for iontophoretically delivering the agent through a body surface, the method comprising:
5b adjusting the pH of the first agent reservoir to a pH above the specified pH so that the agent in the first reservoir has a net negative charge in a solution;
adjusting the pH of the second agent reservoir to a pH below the specified pH so that the agent in the second reservoir has a net positive charge in a solution; and placing the first and second agent reservoirs in agent transmitting relation to the body surface, whereby the delivery device is caused to simultaneously deliver the agent from both the first and second agent reservoirs through the body surface by electromigration, wherein the pH of the first agent reservoir is adjusted to a pH wherein at least about 10% of the agent in the first agent reservoir has a net negative charge in solution and a pH of the second agent reservoir is adjusted to a pH wherein at least about 10% of the agent in the second agent reservoir has a net positive charge in solution.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a schematic view of an iontophoretic drug delivery device according to the present invention;
Figure 2 is a schematic view of another embodiment of an iontophoretic delivery device according to the present invention;
Figure 3 is a schematic view of another embodiment of an iontophoretic delivery device which is described in Example I; and 5c Figure 4 is a schematic view of another embodiment of an iontophoretic delivery device according to the present invention.
MODES FOR CARRYING OUT THE INVENTION
Figure 1 is a schematic view of an iontophoretic delivery device 10 for delivering a beneficial agent through a body surface s 22. Body surface 22 is typically intact skin or a mucosal membrane. Iontophoretic delivery device 10 includes a pair of electrodes 11 and 12 which are composed of dissimilar electrochemical couples and which therefore form a galvanic couple. Typical materials for delivering an agent into the body io include a zinc electrode 11 and a silver/silver chloride counter electrode 12. A Zn-Ag/AgCI galvanic couple provides an electrical potential of about 1 volt. The device also includes agent reservoirs 14 and 16 which contain the beneficial agent to be iontophoretically delivered by device 10. The reservoirs 14 and is 16 are separated by an insulator 18. Insulator 18 is comprised of a material which is impermeable to the passage of ions and electrical current. The device has a backing layer 13 made of an electrically insulating material of the type commonly used in transdermal delivery systems (e.g., ethylene vinyl acetate or zo polyethylene terephthalate). The device is adhered to the body surface 22 by means of a peripheral adhesive layer 15. Suitable adhesives include, without limitation, polyisobutylene/mineral oil and silicone adhesives. The device 10 normally includes a strippable release liner, not shown, which is removed before is placing the device on body surface 22.
Figure 2 illustrates a device 20 having an adhesive overlay 23 and a power source 17. The device 20 also has a strippable release liner 28 which is removed dust before placement of device so 20 on the body. Power source 17 is typically one or more batteries.
Figure 4 illustrates one example of a preferred iontophoretic delivery device 40. Device 40 has a top layer 41 ss which contains an electrical power supply (e.g., a battery or a 2~4~9~4 series of batteries) as well as optional control circuitry such as a current controller (e. g., a resistor or a transistor-based current control circuit), an on/off switch, and/or a microprocessor adapted to control the current output of the power s source over time.
Device 40 also includes electrode assembly 48 and electrode assembly 49. Electrode assemblies 48 and 49 are separated from one another by electrical insulator 18. Electrode 11 is io positioned adjacent drug reservoir 14 while electrode 12 is positioned adjacent drug reservoir 16. Electrodes 11 and 12 may be formed from metal foils (e. g., silver or zinc), or a polymer matrix loaded with metal powder, powdered graphite, carbon fibers, or any other suitable electrically conductive material. Most is preferably, the anodic electrode is comprised of an oxidizable metal such as silver or zinc and the cathodic electrode is comprised of a reducible material such as silver chloride.
Reservoirs 14 and 16 can be polymeric matrices or gel matrices.
Insulator 18 is composed of a non-electrical conducting and non-2o ion-conducting material which acts as a barrier to prevent short-circuiting of the device 40. Insulator 18 can be an air gap, a non-ion-conducting polymer or adhesive or other suitable barrier to ion flow. The device 40 is adhered to the skin by means of ion-conducting adhesive layers 45 and 46. The device 40 also 2s includes a strippable release liner 28 which is removed just prior to application to the skin.
Generally, the combined skin-contacting area of electrode assemblies 48 and 49 can range from about 1 cmZ to greater than ao Z00 cmz, but typically will range from about 5 to 50 cm2.
When the device 40 is in storage, no current flows because the device forms an open circuit. When the device 40 is placed on the skin or mucosal membrane of a patient and reservoirs 14 and 35 16, and layers 45 and 46, become sufficiently hydrated to allow conduction of ions therethrough, the circuit between the electrodes is closed and the power source begins to deliver current through the device and through the body of the patient.
Electrical current flowing through the conductive portions of the s device 40 (i.e., those portions used to connect the power source to the electrodes) is carried by electrons (electronic conduction), while current flowing through the hydrated portions of the device 40 (e.g., the agent reservoirs 14 and 16 and the ion-conducting adhesive layers 45 and 46) is carried by ions io (ionic conduction). In order for current to flow through the device, it is necessary for electrical charge to be transferred from the power source in layer 41 to chemical species in solution in reservoirs 14 and 16 by means of oxidation and reduction charge transfer reactions at the surface of the electrodes 11 and 12 as is is known in the art.
In accordance with the present invention, at least one of agent reservoirs 14 and 16 is formulated to have a pH above the isoelectric point of the agent while the other agent reservoir is 2o formulated to have a pH below the isoelectric point of the agent.
Specifically, the pH of the agent reservoir which is electrically connected to the catholic electrode should be kept at a pH above the isoelectric point for the agent while the pH of the agent reservoir which is electrically connected to the anodic electrade zs should be kept at a pH below the isoelectric point for the agent.
In this way, electromigration (i.e., delivery of charged agent ions through the action of an electrical field) is maximized.
The pH of agent reservoirs 14 and 16 can be ad3usted using ao techniques well known to those skilled in the art. For example, appropriate acids, bases and/or buffering agents may be added to reservoirs 14 and 16 in order to maintain the desired pH. Either inorganic acids or organic acids can be used to lower the pH in the anodic agent reservoir. Suitable organic acids include acetic ss acid and succinic acid. Suitable inorganic acids include 2~429~4 hydrochloric acid, sulfuric acid, and nitric acid. Of these, hydrochloric acid is most preferred. In general, only relatively small amounts of acid, usually less than 1 wt% of the agent reservoir (on a dry weight basis) are necessary to achieve the s desired low pH. For the cathodic agent reservoir, bases such as NaOH, LiOH, NaZC03, Na3AS04, sodium borate, disodium tartarate and Na3P04 are suitable to raise the pH level of the agent reservoir.
Of these, sodium hydroxide is most preferred to raise the pH to the desired level.
io In the most preferred embodiment, the agent in the anodic agent reservoir is a salt formed by reacting the agent with an acid, e.g., reacting the agent with hydrochloric acid to form the hydrochloride salt of the agent. Such a salt will naturally i5 buffer the pH of the anodic agent reservoir to a level below the isoelectric point of the agent. Similarly, the agent in the cathodic agent reservoir is most preferably a salt formed by reacting the agent with a base, e.g., reacting the agent with sodium hydroxide to form the sodium salt of the agent. Such a 2o salt will naturally buffer the pH of the cathodic agent reservoir to a level above the isoelectric point of the agent. In this embodiment, it is unnecessary to separately add an acid or base to the drug reservoir since the agent salt itself acts to modify the pH of the drug reservoir to the appropriate level.
In accordance with the present invention, the pH of the anodic agent reservoir is preferably adjusted to a point sufficiently above the isoelectric pH to insure that at least about 10%, more preferably at least about 25% and most preferably ao at least about 50% of the agent has a net negative charge.
Similarly, the pH in the cathodic agent reservoir is preferably adjusted to a pH sufficiently lower than the isoelectric pH to insure that at least about 10%, more preferably at least about 25%
and most preferably at least about 50% of the agent in the reservoir has a net positive charge. The actual reservoir pH
2~4~99~
level, as well as the difference between the reservoir pH and the isoelectric pH, will vary depending upon the particular agent being delivered. Those skilled in the art can easily determine the optimum pH for each reservoir using routine experimentation s starting with a pH of at least 1 pH unit, and preferably at least 2 pH units, removed from the isoelectric point.
As an alternative to the side-by-side alignment of the electrode assemblies 48 and 49, and the insulator 18 shown in to Figure 4, the electrode assemblies can be concentrically aligned with one electrode assembly positioned centrally and surrounded by the insulator 18 and the other electrode assembly. The concentric alignment of the electrode assemblies can be circular, elliptical, rectangular or any of a variety of geometric configurations.
The agent reservoirs 14 and 16 can be formed by blending the desired drug, acid or base, and other component(s), with the polymer by melt blending, solvent casting or extrusion, for example. The drug loading in the polymer matrix is generally 2o about 10 to 60 wtfo, although drug loadings outside this range may also be used.
Suitable polymers for use as the matrix of reservoirs 14 and 16 include, without limitation, hydrophobic polymers such as z5 polyethylene, polypropylene, polyisoprenes and polyalkenes, rubbers such as polyisobutylene, copolymers such as Kraton~, polyvinylacetate, ethylene vinyl acetate copolymers, polyamides including nylons, polyurethanes, polyvinylchloride, cellulose acetate, cellulose acetate butyrate, ethylcellulose, cellulose ao acetate, and blends thereof; and hydrophilic polymers such as hydrogels, polyvinylpyrrolidones, polyethylene oxides, Polyox~, Polyox~ blended with polyacrylic acid or Carbopol~, cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxyprapyl cellulose, pectin, starch, guar gum, ss locust bean gum, and the like, along with blends thereof.
2042~~4 The adhesive properties of the reservoirs 14 and 16 may be enhanced by adding a resinous tackifier. This is especially important when using a non-tacky polymeric matrix. Examples of suitable tackifiers include products sold under the trademarks s Staybelite Ester #5 and #10, Regal-Rez and Piccotac, all sold by Hercules, Inc. of Wilmington, DE. Additionally, the matrix may contain a rheological agent, suitable examples of which include mineral oil and silica.
io In addition to the drug, the reservoirs 14 and 16 may also contain other conventional materials such as buffers, dyes, pigments, inert fillers, and other excipients.
The electronic layer 41 of device 40 optionally includes a is control circuit. The control circuit may take the form of an on-off switch for "on-demand" drug delivery (e. g., on-demand delivery of an analgesic for pain control), a timer, a fixed or variable electrical resistor, a controller which automatically turns the device on and off at some desired periodicity to match the natural 20 or circadian patterns of the body, or other more sophisticated electronic control devices known in the art. For example, it may be desirable to deliver a predetermined constant level of current from device 40 since a constant current level ensures that the drug or agent is delivered through the skin at a constant rate.
Zs The current level can be controlled by a variety of known means, for example, a resistor or a field effect transistor or a current limiting diode. The control circuit may also include a microchip which can be programmed to control the dosage of beneficial agent, or even to respond to sensor signals in order to regulate the ao dosage to maintain a predetermined dosage regimen. A relatively simple controller or microprocessor can control the current as a function of time, and if desired, generate complex current waveforms such as pulses or sinusoidal waves. In addition, the control circuit may employ a bio-feedback system which monitors a 35 biosignal, provides an assessment of the therapy, and adjusts the 2~4~9~~
drug delivery accordingly. A typical example is the monitoring of the blood sugar level for controlled administration of insulin to a diabetic patient.
s As used herein, the expression "agent" can mean a drug or other beneficial therapeutic agent which can be delivered to a living organism to produce a desired, usually beneficial, effect and which has an isoelectric point. An agent having an isoelectric point can be made to carry (i) a net positive charge io when in solution at a pH below the isoelectric point of the agent, and (ii) a net negative charge when in solution at a pH above the isoelectric point of the agent. In general, this includes therapeutic agents in all of the major therapeutic areas including, but not limited to, anti-infectives including is antibiotics such as ampicillin, amoxicillin, vancomycin, benzylpenicillin novocaine salt, 6-aminopenicillin acid, penicillamine disulfide, sulfadiazine, sulfamerizine and amphotericin B, antiviral agents such as vidarabine, analgesics and analgesic combinations, anesthetics, anorexics, antiarthritics zo such as aminosulfonic acids, antiasthmatic agents, anticonvulsants, antidepressants such as aztreonam, antidiabetic agents such as insulin, antidiarrheals, antihistamines, anti-inflammatory agents such as baclofin, antimigraine preparations, antimotion sickness preparations, antinauseants, zs antineoplastics, antiparkinsonism drugs such as 1-dopa, antipruritics, antipsychotics such as benperidol, antipyretics, antispasmodics including gastrointestinal and urinary antispasmodics, anticholinergics, sympathomimetrics, xanthine derivatives, cardiovascular preparations including calcium channel so blockers and ACE inhibitors such as moexipril, beta-blockers, antiarrythmics, antihypertensives, diuretics, vasodilators including general, coronary, peripheral and cerebral vasodilators, central nervous system stimulants, cough and cold preparations, decongestants, diagnostics, hormones such as liothyronine and as thyroxine, hypnotics, immunosuppressives, muscle relaxants, 2~~~~~~
parasympatholytics, parasympathomimetrics, proteins, peptides, psychostimulants, sedatives and tranquilizers.
The invention is particularly useful in the controlled s delivery of amino acids, polypeptides and proteins. These macromolecular substances have isoelectric paints and typically have a molecular weight of at least about 300 daltons, and more typically a molecular weight in the range of about 300 to X0,000 daltons. Specific examples of amino acids, polypeptides and io proteins in this size range include, without limitation, adenosine, alcohol dehydrogenases, aprotinin, avidin, arginine, riboflavin, LHRH, LHRH analogs such as busere7in, gonadorelin, naphrelin and leuprolide, GHRH, insulin, insulin-like growth factors, heparin, calcitonin, calmodulin, carbonic anhydrases, is granulocyte colony stimulating factors, cytochrome C, endorphin, TRH, NT-36 (chemical name: N~[[(s)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide), liprecin, pituitary hormones (e. g., HGH, HMG, HCG, desmopressin acetate, etc.), follicle luteoids, aANF, growth factor releasing factor (GFRF), ~MSH, somatostatin, 2o bradykinin, somatotropin, platelet-derived growth factor, asparaginase, bleomycin sulfate, chymopapain, cholecystokinin, chorionic gonadotropin, corticotropin (ACTH), erythropoietin, epidermal growth factors, epoprostenol (platelet aggregation inhibitor), ferredoxin, glucagon, hyaluronidase, interferon, 2s interleukin-2, lactalbumin, lactoglobulin, lysozyme, menotropins (urofollitropin (FSH) and LH), myoglobin, myokinase, ovalbumin, oxytocin, pepsin, ribonuclease A, streptokinase, tissue plasminogen activator, urokinase, vasopressin, ACTH analogs, ANP, ANP clearance inhibitors, angiotensins, angiotensin II
ao antagonists, antidiuretic hormone agonists, antidiuretic hormone antagonists, bradykinin antagonists, CD4, ceredase, CSF's, enkephalins, FAB fragments, IgE peptide suppressors, IGF-1, neurotrophic factors, parathyroid hormone and agonists, parathyroid hormone antagonists, prostaglandin antagonists, 35 pentigetide, protein C, protein S, renin inhibitors, thymosin 2~4~~~~
alpha-1, thrombolytics, TNF, vaccines, vasopressin, vasopressin antagonist analogs, alpha-1 anti-trypsin (recombinant). It is most preferable to use a water soluble salt of the drug or agent to be delivered.
The invention is also useful in the controlled delivery of compounds having at least one positively charged function and at least one negatively charged function, such as amphoteric compounds and zwitter ionic compounds. Amino acids are one io example of zwitter ionic compounds. Amino acids have the general formula:
R-CH-COON.
is NHZ
The carboxylic acid function carries a negative charge at low pH's but carries no charge at high pH's. The amino group on the other hand carries a positive charge at high pH's and no charge at low 2o pH's. Depending upon the particular acid and base groups in the agent molecule, the agent is likely to have a pH range surrounding the isoelectric point, within which pH range the agent is substantially neutral, i.e., it carries no net charge in solution.
The pH of the agent reservoir is adjusted to be either above or 2s below this "neutral" range.
Other suitable agents are compounds which have both at least one acid function (which is negatively charged) and at least one base function (which is positively charged) in the molecule.
so Examples of suitable negatively charged functional groups include organic acids such as carboxylic acids, sulphates, phosphates, nitrates, phosphonates, sulphites, perchlorates and chlorates.
Most preferred are the organic acid functional groups. Examples of suitable organic acid groups include formic, acetic, citric, as succinic, malefic, lactic, butyric, propionic and valeric acid groups. Examples of suitable positively charged functional groups include amino groups, including primary, secondary, tertiary and quaternary amine groups, sulphonium groups and phosphines. Of these, the amines are clearly preferred.
Having thus generally described our invention, the following s examples will illustrate preferred embodiments thereof.
EXAMPLE I
An electrotransport device for transdermal delivery of 1-io dope (pI of about 6) has the configuration of device 30 illustrated in Figure 3 and is made of the following materials.
The first electrode reservoir 14 is a self-adhering karaya gum composition containing 1-dope formulated at a pH about 3.5 below the isoelectric point. The second electrode reservoir 16 is a is self-adhering karaya gum composition containing 1-dope formulated at a pH of about 7.5 above the isoelectric point. In this manner, both reservoirs 14 and 16 act as donors and deliver 1-dope to the body surface. To form a galvanic couple capable of supplying enough power to run the device, the electrode 11 is composed of Zn zo while the electrode 12 is composed of Ag/AgCI. Insulator 18 is composed of ethylene vinyl acetate having a vinyl acetate content of 40% (EYA 40) and backing member 13 is composed of polyethylene terephthalate/EVA.
An iontophoretic delivery device for delivering baclofin (pI
of about 6) from both the anodic and cathodic drug reservoirs has the configuration illustrated in Figure 4. The anodic electrode ao is a silver foil laminated to a polymeric drug reservoir containing baclofin. The anodic drug reservoir comprises on a dry weight basis: 20 wt~ of polyisobutylene (PIB) having a molecular weight of 1,200,000 (sold by Exxon Carp. of Irving, Texas), 20 wt~o of PIB having a molecular weight of 35,000 (sold by Exxon Corp. of as Irving, Texas), 25 wt~o of polyvinylpyrrolidone, (PVP-XL 10 sold by GAF Corp. of Wayne, New Jersey) having a degree of cross-linking of 10%, and 35 wtfo of baclofin HC1. Baclofin HCl is prepared by reacting baclofin with hydrochloric acid and subsequently drying the salt in accordance with known procedures. The pH of the s anodic drug reservoir is below the isoelectric point of baciofin.
The catholic electrode is comprised of a sheet of sintered silver chloride laminated to a polymeric drug reservoir containing baclofin. The catholic drug reservoir comprises on a dry weight i~ basis: 20 wt% PIB having a molecular weight of 1,200,000, 20 wt/o of PIB having a molecular weight of 35,000, 25fo wt% of PVP-XL 10, and 35 wt% of sadium baclofin. Sodium baclofin is prepared by reacting baclofin with sodium hydroxide and subsequently drying the salt in accordance with known procedures. The catholic drug is reservoir has a pH above the isoelectric point of baclofin.
The power source and control circuitry of the electronic layer produce a current density of 100 NA/cm2. The device operates to deliver baclofin from both the anodic drug reservoir zo and the catholic drug reservoir. The baclofin which is delivered from the anodic drug reservoir (low pH) is positively charged while the baclofin which is delivered from the catholic drug reservoir (high pH) is negatively charged.
2s EXAMPLE III
An iontophoretic delivery device for delivering insulin from both the anodic drug reservoir and the catholic drug reservoir has the configuration illustrated in Figure 4. The electrodes of the 3o device have the same composition as described in Example 2. The anodic drug reservoir comprises 25 wtfo PIB having a molecular weight of 1,200,000, 25 wt% PIB having a molecular weight of 35,000, 25 wt% PVP-XL 10, 24.7 wt% of insulin and 0.3 wt% succinic acid. The pH of the anodic drug reservoir is about 3Ø
The cathodic drug reservoir has the same composition as the anodic drug reservoir except in place of succinic acid, the cathodic drug reservoir contains 0.3 wt9~ Na3P04. The cathodic drug reservoir has a pH of about 10.
The device has a power source and control circuitry sufficient to produce a current density of 100 pA/cmz. The device operates to deliver insulin from both the anodic drug reservoir and the cathodic drug reservoir simultaneously. The insulin which io is delivered from the anodic drug reservoir (pH of about 3.0) is positively charged while the insulin which is delivered from the cathodic drug reservoir (pH of about 10) is negatively charged.
Having thus generally described our invention and described is in detail certain preferred embodiments thereof, it will be readily apparent that various modifications to the invention may be made by workers skilled in the art without departing from the scope of this invention and which is limited only by the following claims.
TECHNICAL FIELD
s This invent ion relates to a device for delivering an agent transdermally or transmucosally by iontophoresis. More particularly, this invention relates to an electrically powered iontophoretic delivery device which can deliver a drug from both the anodic and catholic electrodes simultaneously.
io BACKGROUND ART
Iontophoresis, according to Dorland°s Illustrated Medical Dictionary, is defined to be "the introduction, by means of is electric current, of ions of soluble salts into the tissues of the body for therapeutic purposes." Iontophoretic devices have been known since the early 1900's. British patent specification No.
410,009 (1934) describes an iontophoretic device which overcame one of the disadvantages of such early devices known to the art at zo that time, namely the requirement of a special low tension (low voltage) source of current which meant that the patient needed to be irr~nobilized near such source. The device of that British specification was made by forming a galvanic cell from the electrodes and the material containing the medicament or drug to zs be delivered transdermally. The galvanic cell produced the current necessary for iontophoretically delivering the medicament.
This ambulatory device thus permitted iontophoretic drug delivery with substantially less interference with the patient's daily activities.
ao More recently, a number of United States patents have issued in the iontophoresis field, indicating a renewed interest in this mode of drug delivery. For example, U.S. Patent No. 3,991,755 issued to Ilernon et al; U.S. Patent No. 4,141,359 issued to 35 Jacobsen et al; U.S. Patent No. 4,398,545 issued to Wilson; and U.S. Patent ~o. 4,250,878 issued to Jacobsen disclose examples of iontophoretic devices and some applications thereof. The iontophoresis process has been found to be useful in the transdermal administration of medicaments or drugs including s lidocaine hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate, insulin and many other drugs.
Perhaps the most common use of iontophoresis is in diagnosing cystic fibrosis by delivering pilocarpine salts iontophoretically.
The piiocarpine stimulates sweat production; the sweat is io collected and analyzed for its chloride content to detect the presence of the disease.
In presently known iontophoretic devices, at least two electrodes are used. Both of these electrodes are disposed so as is to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the ionic substance, medicament, drug precursor or drug is delivered into the body by iontophoresis.
The other electrode, called the counter or return electrode, zo serves to close the electrical circuit through the body. In conjunction with the patient's skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery. For example, if the ionic substance to be delivered into the body is positively 2s charged (i.e., a can on), then the anode will be the active electrode and the cathode will serve to complete the circuit. If the ionic substance to be delivered is negatively charged (i.e., an anion), then the cathode will be the active electrode and the anode will be the counter electrode.
It is also known that iontophoretic delivery devices can be used to deliver an uncharged drug or agent into the body. This is accomplished by a process called electroosmosis. Electroosmosis is the transdermal flux of a liquid solvent (e. g., the liquid 3s solvent containing the uncharged drug or agent) which is induced ~a4~~94 by the presence of an electric field imposed across the skin by the donor electrode. As used herein, the terms "iontophoresis"
and "iontophoretic" refer to (1) the delivery of charged drugs or agents by electromigration, (2) the delivery of uncharged drugs or s agents by the process of electroosmosis, (3) the delivery of charged drugs or agents by the combined processes of electromigration and electroosmosis, and/or (4) the delivery of a mixture of charged and uncharged drugs or agents by the combined processes of electromigration and electroosmosis.
Furthermore, existing iontophoresis devices generally require a reservoir or source of the beneficial agent (which is preferably an ionized or ionizable agent or a precursor of such agent) to be iontophoretically delivered into the body. Examples is of such reservoirs or sources of ionized or ionizable agents include a pouch as described in the previously mentioned Jacobsen U.S. Patent No. 4,250,878, or a pre-formed gel body as described in Webster U.S. Patent No. 4,383,529 and Ariura et al. U.S. Patent No. 4,474,570. Such drug reservoirs are electrically connected to zo the anode or the cathode of an iontophoresis device to provide a fixed or renewable source of one or more desired agents.
Most typically, the drug and electrolyte reservoir layers of iontophoretic delivery devices have been formed of hydrophilic 2s polymers. See for example, Ariura et al, U.S. Patent 4,474,570;
Webster U.S. Patent 4,383,529 and Sasaki U.S. Patent 4,764,164.
There are several reasons for using hydrophilic polymers. First, water is the preferred solvent for ionizing many drug salts.
Secondly, hydrophilic polymer components (i.e., the drug reservoir ao in the donor electrode and the electrolyte reservoir in the counter electrode) can be hydrated while attached to the body by absorbing water from the skin (i.e., through transepidermal water loss or sweat) or from a mucosal membrane (e. g., by absorbing saliva in the case of oral mucosal membranes). Once hydrated, the 35 device begins to deliver ionized agent to the body. This enables the drug reservoir to be manufactured in a dry state, giving the device a longer shelf life.
DISCLOSURE OF THE INVENTION
It is an object of this invention to provide an improved iontophoretic delivery device and method of using same.
It is another object of this invention to provide an io iontophoretic delivery device which can deliver the same agent from both electrodes simultaneously.
These and other objects are met by an electrically powered iontophoretic delivery device which is adapted for placement on a is body surface for iontophoretically delivering an agent therethrough. The device includes a first electrode, a means for electrically connecting the first electrode to a source of electrical power, and a first agent reservoir electrically connected to the first electrode. The first agent reservoir Zo contains a portion of the agent to be delivered through the body surface.
The device also includes a second electrode, means for electrically connecting the second electrode to the source of 2s electrical power, and a second agent reservoir electrically connected to the second electrode. The second agent reservoir contains a portion of the agent to be delivered through the body surface.
ao The agent delivered by the device has an isoelectric point at a specified pH. The first agent reservoir has a pH above the specified pH which renders at least a portion of the agent in the first agent reservoir negatively charged. The second agent reservoir has a pH below the specified pH which renders at least a 35 portion of the agent in the second agent reservoir positively charged.
In this way, a portion of the agent in the first agent reservoir has a net negative charge in solution and therefore is delivered from the first agent reservoir by electromigration. Simultaneously, a portion of the agent in 5 the second agent reservoir has a net positive charge in solution and likewise is delivered from the second agent reservoir by electromigration.
Also provided is a method of iontophoretically delivering an agent through a body surface from such a delivery device. The method includes the steps of:
adjusting the pH of the first agent reservoir to a pH above the specified pH;
adjusting the pH of the second agent reservoir to a pH below the specified pH; and placing the first and second agent reservoirs in agent transmitting relation to the body surface.
According to one aspect of the present invention, there is provided an iontophoretic delivery device adapted for placement on a body surface for iontophoretic delivery of an agent therethrough, the device comprising:
a first electrode, means for electrically connecting the first electrode to a source of electrical power, and a first agent reservoir electrically connected to the first electrode, the first agent reservoir containing a portion of the agent to be delivered through the body surface; and a second electrode, means for electrically 5a connecting the second electrode to the source of electrical power, and a second agent reservoir electrically connected to the second electrode, the second agent reservoir containing a portion of the agent to be delivered through the body surface, wherein the agent has an isoelectric point at a specified pH; the first agent reservoir has a pH above the specified pH and hence the agent in the first reservoir has a net negative charge in a solution; and the second agent reservoir has a pH below the specified pH, and hence the agent in the second reservoir has a net positive charge in a solution, whereby the agent can be delivered simultaneously from both the first and second agent reservoirs through the body surface by electromigration, and wherein at least about 10% of the agent in the first agent reservoir has a net negative charge in solution, and at least about 10% in the agent in the second agent reservoir has a net positive charge in solution.
According to another aspect of the present invention, there is provided a method of operating a delivery device having a first electrode electrically connected to a first agent reservoir containing an agent having an isoelectric point at a specified pH, and a second electrode electrically connected to a second agent reservoir containing the agent, the first and second electrodes being electrically connected to a source of electrical power, the delivery device being for iontophoretically delivering the agent through a body surface, the method comprising:
5b adjusting the pH of the first agent reservoir to a pH above the specified pH so that the agent in the first reservoir has a net negative charge in a solution;
adjusting the pH of the second agent reservoir to a pH below the specified pH so that the agent in the second reservoir has a net positive charge in a solution; and placing the first and second agent reservoirs in agent transmitting relation to the body surface, whereby the delivery device is caused to simultaneously deliver the agent from both the first and second agent reservoirs through the body surface by electromigration, wherein the pH of the first agent reservoir is adjusted to a pH wherein at least about 10% of the agent in the first agent reservoir has a net negative charge in solution and a pH of the second agent reservoir is adjusted to a pH wherein at least about 10% of the agent in the second agent reservoir has a net positive charge in solution.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a schematic view of an iontophoretic drug delivery device according to the present invention;
Figure 2 is a schematic view of another embodiment of an iontophoretic delivery device according to the present invention;
Figure 3 is a schematic view of another embodiment of an iontophoretic delivery device which is described in Example I; and 5c Figure 4 is a schematic view of another embodiment of an iontophoretic delivery device according to the present invention.
MODES FOR CARRYING OUT THE INVENTION
Figure 1 is a schematic view of an iontophoretic delivery device 10 for delivering a beneficial agent through a body surface s 22. Body surface 22 is typically intact skin or a mucosal membrane. Iontophoretic delivery device 10 includes a pair of electrodes 11 and 12 which are composed of dissimilar electrochemical couples and which therefore form a galvanic couple. Typical materials for delivering an agent into the body io include a zinc electrode 11 and a silver/silver chloride counter electrode 12. A Zn-Ag/AgCI galvanic couple provides an electrical potential of about 1 volt. The device also includes agent reservoirs 14 and 16 which contain the beneficial agent to be iontophoretically delivered by device 10. The reservoirs 14 and is 16 are separated by an insulator 18. Insulator 18 is comprised of a material which is impermeable to the passage of ions and electrical current. The device has a backing layer 13 made of an electrically insulating material of the type commonly used in transdermal delivery systems (e.g., ethylene vinyl acetate or zo polyethylene terephthalate). The device is adhered to the body surface 22 by means of a peripheral adhesive layer 15. Suitable adhesives include, without limitation, polyisobutylene/mineral oil and silicone adhesives. The device 10 normally includes a strippable release liner, not shown, which is removed before is placing the device on body surface 22.
Figure 2 illustrates a device 20 having an adhesive overlay 23 and a power source 17. The device 20 also has a strippable release liner 28 which is removed dust before placement of device so 20 on the body. Power source 17 is typically one or more batteries.
Figure 4 illustrates one example of a preferred iontophoretic delivery device 40. Device 40 has a top layer 41 ss which contains an electrical power supply (e.g., a battery or a 2~4~9~4 series of batteries) as well as optional control circuitry such as a current controller (e. g., a resistor or a transistor-based current control circuit), an on/off switch, and/or a microprocessor adapted to control the current output of the power s source over time.
Device 40 also includes electrode assembly 48 and electrode assembly 49. Electrode assemblies 48 and 49 are separated from one another by electrical insulator 18. Electrode 11 is io positioned adjacent drug reservoir 14 while electrode 12 is positioned adjacent drug reservoir 16. Electrodes 11 and 12 may be formed from metal foils (e. g., silver or zinc), or a polymer matrix loaded with metal powder, powdered graphite, carbon fibers, or any other suitable electrically conductive material. Most is preferably, the anodic electrode is comprised of an oxidizable metal such as silver or zinc and the cathodic electrode is comprised of a reducible material such as silver chloride.
Reservoirs 14 and 16 can be polymeric matrices or gel matrices.
Insulator 18 is composed of a non-electrical conducting and non-2o ion-conducting material which acts as a barrier to prevent short-circuiting of the device 40. Insulator 18 can be an air gap, a non-ion-conducting polymer or adhesive or other suitable barrier to ion flow. The device 40 is adhered to the skin by means of ion-conducting adhesive layers 45 and 46. The device 40 also 2s includes a strippable release liner 28 which is removed just prior to application to the skin.
Generally, the combined skin-contacting area of electrode assemblies 48 and 49 can range from about 1 cmZ to greater than ao Z00 cmz, but typically will range from about 5 to 50 cm2.
When the device 40 is in storage, no current flows because the device forms an open circuit. When the device 40 is placed on the skin or mucosal membrane of a patient and reservoirs 14 and 35 16, and layers 45 and 46, become sufficiently hydrated to allow conduction of ions therethrough, the circuit between the electrodes is closed and the power source begins to deliver current through the device and through the body of the patient.
Electrical current flowing through the conductive portions of the s device 40 (i.e., those portions used to connect the power source to the electrodes) is carried by electrons (electronic conduction), while current flowing through the hydrated portions of the device 40 (e.g., the agent reservoirs 14 and 16 and the ion-conducting adhesive layers 45 and 46) is carried by ions io (ionic conduction). In order for current to flow through the device, it is necessary for electrical charge to be transferred from the power source in layer 41 to chemical species in solution in reservoirs 14 and 16 by means of oxidation and reduction charge transfer reactions at the surface of the electrodes 11 and 12 as is is known in the art.
In accordance with the present invention, at least one of agent reservoirs 14 and 16 is formulated to have a pH above the isoelectric point of the agent while the other agent reservoir is 2o formulated to have a pH below the isoelectric point of the agent.
Specifically, the pH of the agent reservoir which is electrically connected to the catholic electrode should be kept at a pH above the isoelectric point for the agent while the pH of the agent reservoir which is electrically connected to the anodic electrade zs should be kept at a pH below the isoelectric point for the agent.
In this way, electromigration (i.e., delivery of charged agent ions through the action of an electrical field) is maximized.
The pH of agent reservoirs 14 and 16 can be ad3usted using ao techniques well known to those skilled in the art. For example, appropriate acids, bases and/or buffering agents may be added to reservoirs 14 and 16 in order to maintain the desired pH. Either inorganic acids or organic acids can be used to lower the pH in the anodic agent reservoir. Suitable organic acids include acetic ss acid and succinic acid. Suitable inorganic acids include 2~429~4 hydrochloric acid, sulfuric acid, and nitric acid. Of these, hydrochloric acid is most preferred. In general, only relatively small amounts of acid, usually less than 1 wt% of the agent reservoir (on a dry weight basis) are necessary to achieve the s desired low pH. For the cathodic agent reservoir, bases such as NaOH, LiOH, NaZC03, Na3AS04, sodium borate, disodium tartarate and Na3P04 are suitable to raise the pH level of the agent reservoir.
Of these, sodium hydroxide is most preferred to raise the pH to the desired level.
io In the most preferred embodiment, the agent in the anodic agent reservoir is a salt formed by reacting the agent with an acid, e.g., reacting the agent with hydrochloric acid to form the hydrochloride salt of the agent. Such a salt will naturally i5 buffer the pH of the anodic agent reservoir to a level below the isoelectric point of the agent. Similarly, the agent in the cathodic agent reservoir is most preferably a salt formed by reacting the agent with a base, e.g., reacting the agent with sodium hydroxide to form the sodium salt of the agent. Such a 2o salt will naturally buffer the pH of the cathodic agent reservoir to a level above the isoelectric point of the agent. In this embodiment, it is unnecessary to separately add an acid or base to the drug reservoir since the agent salt itself acts to modify the pH of the drug reservoir to the appropriate level.
In accordance with the present invention, the pH of the anodic agent reservoir is preferably adjusted to a point sufficiently above the isoelectric pH to insure that at least about 10%, more preferably at least about 25% and most preferably ao at least about 50% of the agent has a net negative charge.
Similarly, the pH in the cathodic agent reservoir is preferably adjusted to a pH sufficiently lower than the isoelectric pH to insure that at least about 10%, more preferably at least about 25%
and most preferably at least about 50% of the agent in the reservoir has a net positive charge. The actual reservoir pH
2~4~99~
level, as well as the difference between the reservoir pH and the isoelectric pH, will vary depending upon the particular agent being delivered. Those skilled in the art can easily determine the optimum pH for each reservoir using routine experimentation s starting with a pH of at least 1 pH unit, and preferably at least 2 pH units, removed from the isoelectric point.
As an alternative to the side-by-side alignment of the electrode assemblies 48 and 49, and the insulator 18 shown in to Figure 4, the electrode assemblies can be concentrically aligned with one electrode assembly positioned centrally and surrounded by the insulator 18 and the other electrode assembly. The concentric alignment of the electrode assemblies can be circular, elliptical, rectangular or any of a variety of geometric configurations.
The agent reservoirs 14 and 16 can be formed by blending the desired drug, acid or base, and other component(s), with the polymer by melt blending, solvent casting or extrusion, for example. The drug loading in the polymer matrix is generally 2o about 10 to 60 wtfo, although drug loadings outside this range may also be used.
Suitable polymers for use as the matrix of reservoirs 14 and 16 include, without limitation, hydrophobic polymers such as z5 polyethylene, polypropylene, polyisoprenes and polyalkenes, rubbers such as polyisobutylene, copolymers such as Kraton~, polyvinylacetate, ethylene vinyl acetate copolymers, polyamides including nylons, polyurethanes, polyvinylchloride, cellulose acetate, cellulose acetate butyrate, ethylcellulose, cellulose ao acetate, and blends thereof; and hydrophilic polymers such as hydrogels, polyvinylpyrrolidones, polyethylene oxides, Polyox~, Polyox~ blended with polyacrylic acid or Carbopol~, cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxyprapyl cellulose, pectin, starch, guar gum, ss locust bean gum, and the like, along with blends thereof.
2042~~4 The adhesive properties of the reservoirs 14 and 16 may be enhanced by adding a resinous tackifier. This is especially important when using a non-tacky polymeric matrix. Examples of suitable tackifiers include products sold under the trademarks s Staybelite Ester #5 and #10, Regal-Rez and Piccotac, all sold by Hercules, Inc. of Wilmington, DE. Additionally, the matrix may contain a rheological agent, suitable examples of which include mineral oil and silica.
io In addition to the drug, the reservoirs 14 and 16 may also contain other conventional materials such as buffers, dyes, pigments, inert fillers, and other excipients.
The electronic layer 41 of device 40 optionally includes a is control circuit. The control circuit may take the form of an on-off switch for "on-demand" drug delivery (e. g., on-demand delivery of an analgesic for pain control), a timer, a fixed or variable electrical resistor, a controller which automatically turns the device on and off at some desired periodicity to match the natural 20 or circadian patterns of the body, or other more sophisticated electronic control devices known in the art. For example, it may be desirable to deliver a predetermined constant level of current from device 40 since a constant current level ensures that the drug or agent is delivered through the skin at a constant rate.
Zs The current level can be controlled by a variety of known means, for example, a resistor or a field effect transistor or a current limiting diode. The control circuit may also include a microchip which can be programmed to control the dosage of beneficial agent, or even to respond to sensor signals in order to regulate the ao dosage to maintain a predetermined dosage regimen. A relatively simple controller or microprocessor can control the current as a function of time, and if desired, generate complex current waveforms such as pulses or sinusoidal waves. In addition, the control circuit may employ a bio-feedback system which monitors a 35 biosignal, provides an assessment of the therapy, and adjusts the 2~4~9~~
drug delivery accordingly. A typical example is the monitoring of the blood sugar level for controlled administration of insulin to a diabetic patient.
s As used herein, the expression "agent" can mean a drug or other beneficial therapeutic agent which can be delivered to a living organism to produce a desired, usually beneficial, effect and which has an isoelectric point. An agent having an isoelectric point can be made to carry (i) a net positive charge io when in solution at a pH below the isoelectric point of the agent, and (ii) a net negative charge when in solution at a pH above the isoelectric point of the agent. In general, this includes therapeutic agents in all of the major therapeutic areas including, but not limited to, anti-infectives including is antibiotics such as ampicillin, amoxicillin, vancomycin, benzylpenicillin novocaine salt, 6-aminopenicillin acid, penicillamine disulfide, sulfadiazine, sulfamerizine and amphotericin B, antiviral agents such as vidarabine, analgesics and analgesic combinations, anesthetics, anorexics, antiarthritics zo such as aminosulfonic acids, antiasthmatic agents, anticonvulsants, antidepressants such as aztreonam, antidiabetic agents such as insulin, antidiarrheals, antihistamines, anti-inflammatory agents such as baclofin, antimigraine preparations, antimotion sickness preparations, antinauseants, zs antineoplastics, antiparkinsonism drugs such as 1-dopa, antipruritics, antipsychotics such as benperidol, antipyretics, antispasmodics including gastrointestinal and urinary antispasmodics, anticholinergics, sympathomimetrics, xanthine derivatives, cardiovascular preparations including calcium channel so blockers and ACE inhibitors such as moexipril, beta-blockers, antiarrythmics, antihypertensives, diuretics, vasodilators including general, coronary, peripheral and cerebral vasodilators, central nervous system stimulants, cough and cold preparations, decongestants, diagnostics, hormones such as liothyronine and as thyroxine, hypnotics, immunosuppressives, muscle relaxants, 2~~~~~~
parasympatholytics, parasympathomimetrics, proteins, peptides, psychostimulants, sedatives and tranquilizers.
The invention is particularly useful in the controlled s delivery of amino acids, polypeptides and proteins. These macromolecular substances have isoelectric paints and typically have a molecular weight of at least about 300 daltons, and more typically a molecular weight in the range of about 300 to X0,000 daltons. Specific examples of amino acids, polypeptides and io proteins in this size range include, without limitation, adenosine, alcohol dehydrogenases, aprotinin, avidin, arginine, riboflavin, LHRH, LHRH analogs such as busere7in, gonadorelin, naphrelin and leuprolide, GHRH, insulin, insulin-like growth factors, heparin, calcitonin, calmodulin, carbonic anhydrases, is granulocyte colony stimulating factors, cytochrome C, endorphin, TRH, NT-36 (chemical name: N~[[(s)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide), liprecin, pituitary hormones (e. g., HGH, HMG, HCG, desmopressin acetate, etc.), follicle luteoids, aANF, growth factor releasing factor (GFRF), ~MSH, somatostatin, 2o bradykinin, somatotropin, platelet-derived growth factor, asparaginase, bleomycin sulfate, chymopapain, cholecystokinin, chorionic gonadotropin, corticotropin (ACTH), erythropoietin, epidermal growth factors, epoprostenol (platelet aggregation inhibitor), ferredoxin, glucagon, hyaluronidase, interferon, 2s interleukin-2, lactalbumin, lactoglobulin, lysozyme, menotropins (urofollitropin (FSH) and LH), myoglobin, myokinase, ovalbumin, oxytocin, pepsin, ribonuclease A, streptokinase, tissue plasminogen activator, urokinase, vasopressin, ACTH analogs, ANP, ANP clearance inhibitors, angiotensins, angiotensin II
ao antagonists, antidiuretic hormone agonists, antidiuretic hormone antagonists, bradykinin antagonists, CD4, ceredase, CSF's, enkephalins, FAB fragments, IgE peptide suppressors, IGF-1, neurotrophic factors, parathyroid hormone and agonists, parathyroid hormone antagonists, prostaglandin antagonists, 35 pentigetide, protein C, protein S, renin inhibitors, thymosin 2~4~~~~
alpha-1, thrombolytics, TNF, vaccines, vasopressin, vasopressin antagonist analogs, alpha-1 anti-trypsin (recombinant). It is most preferable to use a water soluble salt of the drug or agent to be delivered.
The invention is also useful in the controlled delivery of compounds having at least one positively charged function and at least one negatively charged function, such as amphoteric compounds and zwitter ionic compounds. Amino acids are one io example of zwitter ionic compounds. Amino acids have the general formula:
R-CH-COON.
is NHZ
The carboxylic acid function carries a negative charge at low pH's but carries no charge at high pH's. The amino group on the other hand carries a positive charge at high pH's and no charge at low 2o pH's. Depending upon the particular acid and base groups in the agent molecule, the agent is likely to have a pH range surrounding the isoelectric point, within which pH range the agent is substantially neutral, i.e., it carries no net charge in solution.
The pH of the agent reservoir is adjusted to be either above or 2s below this "neutral" range.
Other suitable agents are compounds which have both at least one acid function (which is negatively charged) and at least one base function (which is positively charged) in the molecule.
so Examples of suitable negatively charged functional groups include organic acids such as carboxylic acids, sulphates, phosphates, nitrates, phosphonates, sulphites, perchlorates and chlorates.
Most preferred are the organic acid functional groups. Examples of suitable organic acid groups include formic, acetic, citric, as succinic, malefic, lactic, butyric, propionic and valeric acid groups. Examples of suitable positively charged functional groups include amino groups, including primary, secondary, tertiary and quaternary amine groups, sulphonium groups and phosphines. Of these, the amines are clearly preferred.
Having thus generally described our invention, the following s examples will illustrate preferred embodiments thereof.
EXAMPLE I
An electrotransport device for transdermal delivery of 1-io dope (pI of about 6) has the configuration of device 30 illustrated in Figure 3 and is made of the following materials.
The first electrode reservoir 14 is a self-adhering karaya gum composition containing 1-dope formulated at a pH about 3.5 below the isoelectric point. The second electrode reservoir 16 is a is self-adhering karaya gum composition containing 1-dope formulated at a pH of about 7.5 above the isoelectric point. In this manner, both reservoirs 14 and 16 act as donors and deliver 1-dope to the body surface. To form a galvanic couple capable of supplying enough power to run the device, the electrode 11 is composed of Zn zo while the electrode 12 is composed of Ag/AgCI. Insulator 18 is composed of ethylene vinyl acetate having a vinyl acetate content of 40% (EYA 40) and backing member 13 is composed of polyethylene terephthalate/EVA.
An iontophoretic delivery device for delivering baclofin (pI
of about 6) from both the anodic and cathodic drug reservoirs has the configuration illustrated in Figure 4. The anodic electrode ao is a silver foil laminated to a polymeric drug reservoir containing baclofin. The anodic drug reservoir comprises on a dry weight basis: 20 wt~ of polyisobutylene (PIB) having a molecular weight of 1,200,000 (sold by Exxon Carp. of Irving, Texas), 20 wt~o of PIB having a molecular weight of 35,000 (sold by Exxon Corp. of as Irving, Texas), 25 wt~o of polyvinylpyrrolidone, (PVP-XL 10 sold by GAF Corp. of Wayne, New Jersey) having a degree of cross-linking of 10%, and 35 wtfo of baclofin HC1. Baclofin HCl is prepared by reacting baclofin with hydrochloric acid and subsequently drying the salt in accordance with known procedures. The pH of the s anodic drug reservoir is below the isoelectric point of baciofin.
The catholic electrode is comprised of a sheet of sintered silver chloride laminated to a polymeric drug reservoir containing baclofin. The catholic drug reservoir comprises on a dry weight i~ basis: 20 wt% PIB having a molecular weight of 1,200,000, 20 wt/o of PIB having a molecular weight of 35,000, 25fo wt% of PVP-XL 10, and 35 wt% of sadium baclofin. Sodium baclofin is prepared by reacting baclofin with sodium hydroxide and subsequently drying the salt in accordance with known procedures. The catholic drug is reservoir has a pH above the isoelectric point of baclofin.
The power source and control circuitry of the electronic layer produce a current density of 100 NA/cm2. The device operates to deliver baclofin from both the anodic drug reservoir zo and the catholic drug reservoir. The baclofin which is delivered from the anodic drug reservoir (low pH) is positively charged while the baclofin which is delivered from the catholic drug reservoir (high pH) is negatively charged.
2s EXAMPLE III
An iontophoretic delivery device for delivering insulin from both the anodic drug reservoir and the catholic drug reservoir has the configuration illustrated in Figure 4. The electrodes of the 3o device have the same composition as described in Example 2. The anodic drug reservoir comprises 25 wtfo PIB having a molecular weight of 1,200,000, 25 wt% PIB having a molecular weight of 35,000, 25 wt% PVP-XL 10, 24.7 wt% of insulin and 0.3 wt% succinic acid. The pH of the anodic drug reservoir is about 3Ø
The cathodic drug reservoir has the same composition as the anodic drug reservoir except in place of succinic acid, the cathodic drug reservoir contains 0.3 wt9~ Na3P04. The cathodic drug reservoir has a pH of about 10.
The device has a power source and control circuitry sufficient to produce a current density of 100 pA/cmz. The device operates to deliver insulin from both the anodic drug reservoir and the cathodic drug reservoir simultaneously. The insulin which io is delivered from the anodic drug reservoir (pH of about 3.0) is positively charged while the insulin which is delivered from the cathodic drug reservoir (pH of about 10) is negatively charged.
Having thus generally described our invention and described is in detail certain preferred embodiments thereof, it will be readily apparent that various modifications to the invention may be made by workers skilled in the art without departing from the scope of this invention and which is limited only by the following claims.
Claims (21)
1. An iontophoretic delivery device adapted for placement on a body surface for iontophoretic delivery of an agent therethrough, the device comprising:
a first electrode, means for electrically connecting the first electrode to a source of electrical power, and a first agent reservoir electrically connected to the first electrode, the first agent reservoir containing a portion of the agent to be delivered through the body surface; and a second electrode, means for electrically connecting the second electrode to the source of electrical power, and a second agent reservoir electrically connected to the second electrode, the second agent reservoir containing a portion of the agent to be delivered through the body surface, wherein the agent has an isoelectric point at a specified pH; the first agent reservoir has a pH above the specified pH and hence the agent in the first reservoir has a net negative charge in a solution; and the second agent reservoir has a pH below the specified pH, and hence the agent in the second reservoir has a net positive charge in a solution, whereby the agent can be delivered simultaneously from both the first and second agent reservoirs through the body surface by electromigration, and wherein at least about 10% of the agent in the first agent reservoir has a net negative charge in solution, and at least about 10% in the agent in the second agent reservoir has a net positive charge in solution.
a first electrode, means for electrically connecting the first electrode to a source of electrical power, and a first agent reservoir electrically connected to the first electrode, the first agent reservoir containing a portion of the agent to be delivered through the body surface; and a second electrode, means for electrically connecting the second electrode to the source of electrical power, and a second agent reservoir electrically connected to the second electrode, the second agent reservoir containing a portion of the agent to be delivered through the body surface, wherein the agent has an isoelectric point at a specified pH; the first agent reservoir has a pH above the specified pH and hence the agent in the first reservoir has a net negative charge in a solution; and the second agent reservoir has a pH below the specified pH, and hence the agent in the second reservoir has a net positive charge in a solution, whereby the agent can be delivered simultaneously from both the first and second agent reservoirs through the body surface by electromigration, and wherein at least about 10% of the agent in the first agent reservoir has a net negative charge in solution, and at least about 10% in the agent in the second agent reservoir has a net positive charge in solution.
2. The device of claim 1, wherein the agent is selected from the group consisting of amino acids, polypeptides and proteins.
3. The device of claim 1, wherein at least about 25%
of the agent in the first agent reservoir has a net negative charge in solution and at least about 25% of the agent in the second agent reservoir has a net positive charge in solution.
of the agent in the first agent reservoir has a net negative charge in solution and at least about 25% of the agent in the second agent reservoir has a net positive charge in solution.
4. The device of claim 1, wherein at least about 50%
of the agent in the first agent reservoir has a net negative charge in solution and at least about 50% of the agent in the second agent reservoir has a net positive charge in solution.
of the agent in the first agent reservoir has a net negative charge in solution and at least about 50% of the agent in the second agent reservoir has a net positive charge in solution.
5. The device of claim 1, 3 or 4, wherein the first electrode is a cathodic electrode and the second electrode is an anodic electrode.
6. The device of claim 1 or any one of claims 3 to 5, wherein the pH of the first agent reservoir is at least about 1.0 pH unit above the specified pH and the pH of the second agent reservoir is at least about 1.0 pH unit below the specified pH.
7. The device of claim 1 or any one of claims 3 to 5, wherein the pH of the first agent reservoir is at least about 3.5 pH units above the specified pH and the pH of the second agent reservoir is at least about 3.5 pH units below the specified pH.
8. The device of claim 1 or any one of claims 3 to 7, wherein the agent is water soluble.
9. The device of claim 1 or any one of claims 3 to 8, wherein the agent is a compound having at least one positively charged function and at least one negatively charged function.
10. The device of claim 9, wherein the positively charged function is selected from the group consisting of amino, sulfonium and phosphine groups.
11. The device of claim 9 or 10, wherein the negatively charged function is selected from the group consisting of organic acid groups, sulfates, phosphates, nitrates, sulphites, phosphonates, chlorates and perchlorates.
12. The device of claim 11, wherein the organic acid group comprises a carboxylic acid group.
13. The device of claim 12, wherein the carboxylic acid group is selected from the group consisting of formic, acetic, citric, succinic, maleic, lactic, butyric, propionic, and valeric acid groups.
14. The device of claim 1, 8 or 9, wherein the agent is reacted with an acid or a base to form a buffered salt.
15. A method of preparing iontophoretic reservoir formulations used in an iontophoretic delivery device having a first electrode electrically connected to a first agent reservoir containing an agent having an isoelectric point at a specified pH, and a second electrode electrically connected to a second agent reservoir containing the agent, the first and second electrodes being electrically connected to a source of electrical power, the method comprising:
adjusting the pH of the first agent reservoir to a pH above the specified pH so that the agent in the first reservoir has a net negative charge in a solution; and adjusting the pH of the second of agent reservoir to a pH below the specific pH so that the agent in the second reservoir has a net positive charge in a solution;
wherein the pH of the first agent reservoir is adjusted to a pH wherein at least about 10% of the agent in the first agent reservoir has a net negative charge in solution and a pH of the second agent reservoir is adjusted to a pH wherein at least about 10% of the agent in the second agent reservoir has a net positive charge in solution, and wherein the delivery device is so adapted as to simultaneously deliver the agent from both the first and second agent reservoirs through the body surface by electromigration, while the first and second agent reservoirs are placed in agent transmitting relation to the body surface.
adjusting the pH of the first agent reservoir to a pH above the specified pH so that the agent in the first reservoir has a net negative charge in a solution; and adjusting the pH of the second of agent reservoir to a pH below the specific pH so that the agent in the second reservoir has a net positive charge in a solution;
wherein the pH of the first agent reservoir is adjusted to a pH wherein at least about 10% of the agent in the first agent reservoir has a net negative charge in solution and a pH of the second agent reservoir is adjusted to a pH wherein at least about 10% of the agent in the second agent reservoir has a net positive charge in solution, and wherein the delivery device is so adapted as to simultaneously deliver the agent from both the first and second agent reservoirs through the body surface by electromigration, while the first and second agent reservoirs are placed in agent transmitting relation to the body surface.
16. The method of claim 15, wherein the pH of the first agent reservoir is adjusted to a pH wherein at least about 25% of the agent in the first agent reservoir has a net negative charge in solution and the pH of the second agent reservoir is adjusted to a pH wherein at least about 25% of the agent in the second agent reservoir has a net positive charge in solution.
17. The method of claim 15, wherein the pH of the first agent reservoir is adjusted to a pH wherein at least about 50% of the agent in the first agent reservoir has a net negative charge in solution and the pH of the second agent reservoir is adjusted to a pH wherein at least about 50% of the agent in the second agent reservoir has a net positive charge in solution.
18. The method of any one of claims 15 to 17, wherein the pH of the first agent reservoir is adjusted to a pH of at least about 1 pH unit above the specified pH and the pH
of the second agent reservoir is adjusted to a pH of at least about 1 pH unit below the specified pH.
of the second agent reservoir is adjusted to a pH of at least about 1 pH unit below the specified pH.
19. The method of any one of claims 15 to 17, wherein the pH of the first agent reservoir is adjusted to a pH of at least about 3.5 pH units above the specified pH and the pH of the second agent reservoir is adjusted to a pH of at least about 3.5 pH units below the specified pH.
20. The device of any one of claims 1 to 14, wherein the first and second electrodes are composed of electrochemically dissimilar materials so that they form a galvanic couple.
21. The device of claim 20, wherein one of the electrode is a zinc electrode and the other is a silver/silver chloride counter electrode.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60028490A | 1990-10-17 | 1990-10-17 | |
| US07/600,284 | 1990-10-17 | ||
| US70344291A | 1991-05-20 | 1991-05-20 | |
| US07/703,442 | 1991-05-20 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2042994A1 CA2042994A1 (en) | 1992-04-18 |
| CA2042994C true CA2042994C (en) | 2004-08-03 |
Family
ID=27083561
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2042994 Expired - Lifetime CA2042994C (en) | 1990-10-17 | 1991-05-21 | Iontophoretic delivery device |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2042994C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0643981B1 (en) | 1993-09-22 | 2002-01-09 | Hisamitsu Pharmaceutical Co., Inc. | A matrix for iontophoreses |
-
1991
- 1991-05-21 CA CA 2042994 patent/CA2042994C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA2042994A1 (en) | 1992-04-18 |
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