WO2001051120A1 - Selected drug delivery profiles using competing ions - Google Patents
Selected drug delivery profiles using competing ions Download PDFInfo
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- WO2001051120A1 WO2001051120A1 PCT/US2001/000744 US0100744W WO0151120A1 WO 2001051120 A1 WO2001051120 A1 WO 2001051120A1 US 0100744 W US0100744 W US 0100744W WO 0151120 A1 WO0151120 A1 WO 0151120A1
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- ions
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/20—Applying electric currents by contact electrodes continuous direct currents
- A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
Definitions
- the present invention relates to a non-invasive method and apparatus for pre selecting the drag delivery profile of a drag by controlling the concentration of ions added to or present in the reservoir containing the drug to be delivered, which ions would compete with the drug ions for the current.
- Iontophoretic drug delivery systems have, in recent years, become an increasingly important means of administering drags.
- transdermal drag delivery systems i.e., passive and iontophoretic.
- Passive patch systems deliver small and relatively lipophilic drugs through the skin of the patient by diffusion, an example of which would involve the application of the Duragesic® patch which releases the narcotic analgesic, fentanyl, to provide pain relief.
- Iontophoresis systems deliver drug through the skin of the patient through the application of an electromotive force
- Iontophoresis to drive ionizable substances (medicament/drug) into the skin so that they can be absorbed by adjacent tissues and blood vessels.
- Iontophoresis therefore, allows charged and hydrophilic drugs to be transported across the skin which are poorly deliverable through passive diffusion.
- Transdermal systems offer advantages clearly not achievable by other modes of administration, such as hypodermic injection which has the associated problem of pain, risk of infection and trauma to the patient.
- Iontophoresis also has advantages over oral administration in that continuous and prolonged delivery can be achieved. In addition inactivation of the medicament, food interactions, first pass hepatic metabolism and gastrointestinal side effects may be avoided.
- Conventional iontophoretic devices such as those described in U.S. Patent Nos.
- the flux of a drug across the skin from an iontophoretic device is proportional to current, thus, a way to obtain varied flux or drag delivery profiles would be to vary the current.
- a way to obtain varied flux or drag delivery profiles would be to vary the current.
- to vary the current adds complexities to the iontophoresis control circuit and it also increases the likelihood that the patient will feel sensation due to the changes in the current being administered.
- the method and apparatus of the present invention overcomes these shortcomings and provides a method and apparatus for pre-selecting or controlling the drug delivery of flux profile of a drug being iontophoretically delivered.
- One embodiment of the present invention provides a method for controlling the flux profile of drug delivered by iontophoresis by, prior to iontophoretic delivery, adding to or having present in the reservoir containing the drug, ions which would compete with the drug ions for current (hereinafter referred to as "competing ions").
- mixing ions ions which would compete with the drug ions for current
- Another embodiment of the present invention provides for an iontophoretic device for controlling the flux profile of drug delivered by iontophoresis by, prior to iontophoretic delivery, adding to or having present in the reservoir containing the drug, ions which would compete with the drug ions for current.
- the iontophoretic device has
- FIGURE 1 depicts an embodiment of the iontophoretic device of the present invention.
- FIGURE 2 depicts in vitro delivery with lOmg/mlOf a GPIIb/IIIa receptor antagonist and 154mM NaCl at 50 ⁇ A with 2 cm 2 .
- FIGURE 3 depicts Iontophoretic delivery across excised pig skin of a lOmg/mL positively charged ester drag (GPIIb/IIIa receptor antagonist) and 9mg/mL 15 NaCl to therapeutic flux levels (1-lOug/h).
- FIGURE 4 depicts plasma concentrations of the acid drug form during TV infusion of the acid drug form at a rate equivalent to lOug/h active component of the GPIIb/IIIa receptor antagonist in unanesthetized swine.
- FIGURE 5 depicts plasma concentration of the GPIIb/IIIa receptor antagonist acid drag form following iontophoretic delivery in an unanesthetized swine using a 2cm 2 patch with 20 mg/mlOf GPIIb/IIIa receptor antagonist and 154mM NaCl at 200 ⁇ A.
- FIGURE 6 compares the delivery rate profiles for the dual compartment patches at a current of 400 ⁇ A.
- FIGURE 7 depicts the delivery profile of dual compartment patches loaded with 50 mg/mL chloride salt and run at a current of lOO ⁇ A. and 200 ⁇ A.
- FIGURE 8 depicts the delivery rate profile of dual compartment patches loaded with ImM NaCl, 150mg/mL formulation and ran at a current of lOO ⁇ A. and loaded with 75mM NaCl, lOOmg/mL formulation and run at a current of 400 ⁇ A.
- FIGURE 9 A depicts the delivery rate profile of a dual compartment patch loaded with a 154 mM NaCl, 50 mg/mL formulation and run at a current of 250 ⁇ A.
- FIGURE 9B depicts the delivery rate profile of a dual compartment patch loaded with a 154 mM NaCl, 150 mg/mL formulation and run at a current of 250 ⁇ A.
- FIGURE 10A depicts the delivery rate profile of a dual compartment patch loaded with a 250 mM NaCl, 50 mg/mL formulation and ran at a current of 250 ⁇ A.
- FIGURE 10B depicts the delivery rate profile of a dual compartment patch loaded with a 250 mM NaCl, 150 mg/mL formulation and run at a current of 250 ⁇ A.
- FIGURE 11A depicts the delivery rate profile of a dual compartment patch loaded with a 87.5 mM NaCl, 50 mg/mL formulation and ran at a current of lOOuA.
- FIGURE 1 IB depicts the delivery rate profile of a dual compartment patch loaded with a 87.5 mM NaCl, 50 mg/mL formulation and run at a current of 400 ⁇ A.
- FIGURE 12A depicts the delivery rate profile of a dual compartment patch loaded with a 25 mM NaCl, 50 mg/mL formulation and run at a current of 250 ⁇ A.
- FIGURE 12B depicts the delivery rate profile of a dual compartment patch loaded with a 25 mM NaCl, 150 mg/mL formulation and run at a current of 250 ⁇ A.
- FIGURE 13A depicts the delivery rate profile of a dual compartment patch loaded with a 87.5 mM NaCl, 150 mg/mL formulation and ran at a current of lOO ⁇ A.
- FIGURE 13B depicts the delivery rate profile of a dual compartment patch loaded with a 87.5 mM NaCl, 150 mg/ml, formulation and ran at a current of 400 ⁇ A.
- FIGURE 14A depicts the delivery rate profile of a dual compartment patch loaded with a 154 mM NaCl, 30 mg/mL formulation and ran at a current of 150 ⁇ A.
- FIGURE 14B depicts the delivery rate profile of a dual compartment patch loaded with a 150 mM NaMeasylate, 30 mg/mL formulation and run at a current of 150 ⁇ A.
- FIGURE 15 A depicts the delivery rate profile of a dual compartment patch loaded with a 154 mM NaCl, 10 mg/mL formulation and ran at a current of 50 ⁇ A.
- FIGURE 15B depicts the delivery rate profile of a dual compartment patch loaded with a 154 mM NaCl, 50 mg/mL formulation and ran at a current of 50 ⁇ A.
- FIGURE 16A depicts the delivery rate profile of a dual compartment patch loaded with a 154 mM NaCl, 10 mg/mL formulation and ran at a current of 250 ⁇ A.
- FIGURE 16B depicts the delivery rate profile of a dual compartment patch loaded with a 154 mM NaCl, 50 mg/mL formulation and run at a current of 250 ⁇ A.
- FIGURE 17A depicts the delivery rate profile of a dual compartment patch loaded with a 154 mM NaCl, 20 mg/mL formulation and ran at a current of lOO ⁇ A.
- FIGURE 17B depicts the delivery rate profile of a dual compartment patch loaded with a 154 mM NaCl, 20 mg/mL formulation and ran at a current of lOO ⁇ A.
- One embodiment of the present invention provides a method for controlling the flux profile of drug delivered by iontophoresis by, prior to iontophoretic delivery, adding to or having present in the reservoir containing the drag, ions which would compete with the drag ions for current. To achieve various flux profiles for the drag being delivered, one may use constant current but vary the concentration of the competing ions.
- Another more specific embodiment provides for a method for controlling the flux profile of an iontophoretically delivered positively-charged ionic drag.
- a reservoir is formed containing the drug with a negatively-charged counter-ion and adding to the reservoir a concentration of cations which compete with the drug ions for carrying charge from the reservoir to the body surface of a patient.
- the concentration of cations is an amount sufficient for controlling the flux profile of the ionic drug.
- the concentration of cations is an amount greater than about 0.06% and less than 1.0% by weight of electrolyte in the reservoir.
- the concentration of cations is present in a range from about 0.146% (Example 9) to about 0.9% (Examples 6 and 12-14) by weight of electrolyte in the reservoir.
- An electrically conductive member is applied to the reservoir.
- the electrically conductive member is made up of a sacrificial material readily oxidizable when the conductive member is in contact with the reservoir and a positive voltage is applied to the conductive member. The material when oxidized readily combines with the counter-ion to form a compound which is substantially immobile within the reservoir during the application of the positive voltage .
- the reservoir containing the ionic drag is placed in drug transmitting relation to the body surface of the patient. While the reservoir is in drag transmitting relation to the body surface of the patient and the conductive member is applied to the reservoir, a positive voltage is applied to the conductive member to oxidize the material and to drive the ionic drag through the body surface of the patient. At this time the ionic drug is driven through the body surface in the presence of cations which can compete with the drag ions for carrying charge from the reservoir.
- Another more specific embodiment provides for a method for controlling the flux profile of an iontophoretically delivered negatively-charged ionic drag.
- a reservoir containing the drag with a positively-charged counter-ion is formed and a concentration of anions which compete with the drug ions for carrying charge from the reservoir to a body surface of a patient is added to the reservoir.
- the concentration of anions is an amount sufficient for controlling the flux profile of the ionic drug.
- the concentration of anions is an amount greater than 0.06% and less than 1.0% by weight of electrolyte in the reservoir.
- the concentration of anions is present in a range from about 0.146% (Example 9) to about 0.9% (Examples 6 and 12-14) by weight of electrolyte in the reservoir.
- An electrically conductive member is applied to the reservoir.
- the conductive member is made up of a sacrificial material readily reducible when the conductive member is in contact with the reservoir and a negative voltage is applied to the conductive member. The material when reduced is readily combined with the counter-ion to form a compound which is substantially immobile within the reservoir during the application of the negative voltage.
- the reservoir containing the ionic drug is placed in drug transmitting relation to the body surface of the patient. While the reservoir is in drug transmitting relation to the body surface of the patient and the conductive member is applied to the reservoir, a negative voltage is applied to the conductive member to reduce the material and to drive the ionic drug through the body surface of the patient. The ionic drug is driven through the body surface in the presence of anions which can compete with the drag ions for carrying charge from the reservoir. 5
- Another embodiment of the present invention provides for an iontophoretic device for controlling the flux profile of drag delivered by iontophoresis by, prior to iontophoretic delivery, adding to or having present in the reservoir containing the drag, ions which would compete with the drag ions for current.
- the iontophoretic device has (a) a current distributing member; 10. (b) an ionized substance reservoir containing an ionized or ionizable substance, in electrical communication with the current distributing member and adapted to be placed in ionic communication with the epithelial surface of a subject;
- the iontophoretic device of the present invention may by way of example and not limitation include the following component and materials.
- the Current Distributing Member (active electrode) active electrode
- the iontophoretic electrode of the invention includes a current distributing member which conveys electrical current into the iontophoretic reservoirs for the delivery of an ionized substance.
- the current distributing member is constructed of any of a large variety of electrically conductive materials, including both inert and sacrificial materials.
- Inert conductive materials are those electrically conductive materials which, when employed in the iontophoretic devices of the invention, do not themselves undergo or participate in electrochemical reactions. Thus, an inert material distributes current without being eroded or depleted due to the distribution of current, and conducts current through generating ions by either reduction or oxidation of water.
- Inert conductive materials typically 0 include, for example, stainless steel, platinum, gold, and carbon or graphite.
- the current distributing member may be constructed from a sacrificial conductive material.
- a material may be considered sacrificial if, when employed as an electrode in an iontophoretic device of the invention, the material is eroded or depleted due to its oxidation or reduction. Such erosion or depletion occurs when the materials and formulations used in the iontophoresis device enable a specific electrochemical reaction, such as when a silver electrode is used with a formulation containing chloride ions. In this situation, the current distributing member would not cause electrolysis of water, but would itself be oxidized or reduced.
- a sacrificial material would include an oxidizable metal such as silver, zinc, copper, etc.
- the ions electrochemically generated via a sacrificial material would include metal cations resulting from oxidation of the metal.
- Metal/metal salt anodes may also be employed. In such cases, the metal would oxidize to metal ions, which would then be precipitated as an insoluble salt.
- the current distributing member may be constracted from any electrically conductive material provided an appropriate electrolyte formulation is provided.
- the cathodic current distributing member may be constructed from a metal/metal salt material.
- a preferred cathodic material is a silver/silver halide material.
- a metal halide salt is preferably employed as the electrolyte.
- the device would electrochemically generate halide ions from the electrode as the metal halide salt is reduced.
- accompanying silver ions in a formulation would be reduced to silver metal and would deposit (plate) onto the electrode.
- the cathode material may be an intercalation material, an amalgam, or other material which can take electrolyte cations such as sodium out of solution, below the reduction potential Of water.
- other materials may be used which permit the plating out of a metal from the appropriate electrolyte solution.
- metals such as silver, copper, zinc, and nickel, and other materials, such as carbon, may be employed when an appropriate metal salt such as silver nitrate or zinc sulfate is in solution in the electrolyte reservoir. While such materials may develop increased resistivity as a metal plates out during use, they are not eroded or depleted during use as cathodic current distributing members. They are therefore not strictly "sacrificial" in this context.
- the current distributing member may take any form known in the art, such as the form of a plate, foil layer, screen, wire, or dispersion of conductive particles embedded in a conductive matrix.
- an electrolyte reservoir is arranged in electrical communication with a current distributing member.
- electrical communication requires that electrons from the current distributing member are exchanged with ions in the electrolyte reservoir upon the application of electrical current.
- Such electrical communication is preferably not impeded to any excessive degree by any intervening materials) used in the construction of the iontophoretic device.
- the resistivity of the interface is preferably low.
- the electrolyte reservoir comprises at least one electrolyte, i.e., an ionic or ionizable component which can act to conduct current toward or away from the current distributing member.
- the electrolyte comprises one or more mobile ions, the selection of which is dependent upon the desired application.
- suitable electrolytes include aqueous solutions of salts.
- a preferred electrolyte is an aqueous solution of NaCl, having concentration of less than 1 mole/liter ( ⁇ 1M), more preferably at about physiological concentration.
- Such other reservoir species include, without limitation, chelation agents (e.g., citrate ions, EDTA) surfactants (e.g., non-ionic, zwitterionic, cationic, or anionic), buffers, ionic excipients, osmolarity adjusters (e.g., alkanols), stabilizers, enzyme inhibitors, preservatives, thickening agents (e.g., acrylic acids, cellulosic resins, clays, polyoxyethylenes), and the like.
- chelation agents e.g., citrate ions, EDTA
- surfactants e.g., non-ionic, zwitterionic, cationic, or anionic
- buffers e.g., ionic excipients
- osmolarity adjusters e.g., alkanols
- enzyme inhibitors e.g., preservatives
- thickening agents e.g., acrylic acids, cellulos
- the electrolyte may comprise a material which is itself relatively immobile in the absence of an electric field, but which acts to deliver mobile ions in the presence of an electric field.
- the electrolyte may more properly be termed an "ion source.”
- ion sources include polyelectrolytes, ion exchange membranes and resins, non-ionic buffers which become ionic upon pH change, and other known ion sources.
- the electrolyte reservoir may contain counterions that form a soluble salt with an electrochemically generated ion.
- a suitable counterion might be acetate or nitrate.
- the electrolyte reservoir can provide at least one ion of the same charge as the electrochemically generated ion, to permit current to be conducted, and at least one oppositely charged ion.
- the reservoir structure of the iontophoretic apparatus of the invention further includes an ionized substance reservoir.
- the ionized substance reservoir must be in ionic communication with an epithelial surface.
- the construction of the ionized substance reservoir must be consistent with the requirements for ionic communication with the epithelial surface and electrical communication with the current distribution member. Accordingly, the structure of the ionized substance reservoir would vary, depending upon the desired application.
- the ionized substance reservoir may include a liquid, semi-liquid, semi-solid, or solid material.
- the ionized substance reservoir preferably further comprises means for at least substantially inhibiting the flow of the contents out of the reservoir. In such situations, the flow of the contents is desirably minimized when the device is in storage.
- a membrane may be deployed to surround the contents of the ionized substance reservoir. In certain situations the flow of the contents of the reservoir may be minimized while in storage, but increased in use.
- a surrounding membrane may increase in porosity, permeability, or conductivity upon the application of an electric field across the membrane.
- Examples of such membranes are disclosed in U.S. Patent Nos. 5,080,546; 5,169,382; and 5,232,428, the disclosures of which are incorporated by reference herein.
- the ionized substance reservoir is constracted to retain its physical integrity and to inherently resist migration and loss of the ionized substance.
- the ionized substance reservoir includes a solid or semi- solid material such as a gel or other polymeric material.
- the ionized substance reservoir includes a polymeric film in which the substance to be iontophoretically delivered is dispersed. The mobility of the substance to be delivered is substantially increased by the application of the electric field, permitting effective delivery across the target epithelial surface. Such a film need not contain any significant amount of hydrating material.
- a cross-linked hydrogel in the electrolyte reservoir because it inherently contains significant amounts of water, can serve as a water reservoir during iontophoresis.
- the ion of the buffer of like charge to the drug ion should have low ionic mobility.
- the limiting ionic mobility of this ion is preferably no greater than 1 x 10 " cm 2 /volt-sec.
- the ionized substance reservoir also contains an amount of an ion which will compete with the ionized or ionizable drag, the amount of the ion should be sufficient for controlling the flux profile of the ionized or ionizable drug being delivered.
- the concentration of ions is an amount greater than about 0.06% and less than 1.0% by weight of electrolyte in the reservoir. More preferably, the concentrations of ions is present in a range from about 0.146% (Example 9) to about 0.9%) (Examples 6 and 12-14) by weight of electrolyte in the reservoir.
- the Ionizable Substance (Drug) for Iontonhoretic Delivery An ionic drug can be delivered from either the anode, the cathode, or both simultaneously. For example, if the ionic substance to be driven into the body is positively charged, then the positive electrode or anode will be the active electrode and the negative electrode or cathode will serve to complete the electrochemical circuit. Alternatively, if the ionic substance to be delivered is negatively charged, then the negative electrode will be the active electrode and the positive electrode will be the indifferent electrode.
- the drug formulation may contain an amount of an ion which will compete with the ionized or ionizable drug, the amount of the ion should be sufficient for controlling the flux profile of the ionized or ionizable drug being delivered.
- the concentration of ions is an amount greater than about 0.06% and less than 1.0% by weight of electrolyte in the reservoir. More preferably, the concentrations of ions is present in a range from about 0.146% (Example 9) to about 0.9% (Examples 6 and 12-14) by weight of electrolyte in the reservoir.
- the iontophoretic apparatus of the invention may also include a suitable backing film positioned on top of the electrolyte reservoir.
- the backing film provides protection against contamination and damage to the current distributing member, if present, and the electrolyte reservoir of the apparatus.
- the iontophoretic apparatus of the invention optionally includes a release liner which may be fixed to the underside of the ionized substance reservoir by an adhesive.
- the release liner protects the surface of the ionized substance reservoir which contact the epithelial surface from contamination and damage when the device is not in use.
- the release liner may be peeled off to expose the epithelial contacting surface of the ionized reservoir for application of the device to a patient.
- Iontophoretic devices require at least two electrodes to provide a potential to drive drug ions into the skin of a patient. Both electrodes are disposed to be in intimate electrical contact with the skin thereby completing the electrochemical circuit formed by the anode pad and cathode pad of the iontophoretic device.
- the electrode pads may be further defined as an active electrode from which an ionic drag is delivered into the body.
- An indifferent or ground electrode serves to complete the electrochemical circuit.
- Various types of electrodes may be employed such as is described in United States application entitled Low-Cost Electrodes for Iontophoretic Device, by Reddy et al., Serial No. 08/536,029 filed September 29, 1995.
- an embodiment of the iontophoretic device of this invention 50 is configured as follows: an anode patch 10, having an anode electrode compartment 11 in ionic communication with a skin contacting compartment 13.
- the skin contacting compartment 13 and the anode electrode compartment 11 may be separated by a compartment separation means (membrane) 17.
- the anode electrode compartment 11 also contains an anode 14 and an electrolyte (anolyte) 15.
- the skin contacting compartment is attached to the patient's skin 36.
- the skin contacting compartment 23 and the cathode electrode compartment 21 may be separated by a compartment separation means (membrane) 27.
- the cathode electrode compartment 21 also contains a cathode 24 and an electrolyte (catholyte) 25.
- the skin contacting compartment is attached to the patient's skin 36.
- electrophoresis which includes the movement of particles in an electric field toward one or the other electric pole (anode or cathode), and electroosmosis, which includes the transport of uncharged compounds due to the bulk migration of water induced by an electric field.
- electrophoresis which includes the movement of particles in an electric field toward one or the other electric pole (anode or cathode)
- electroosmosis which includes the transport of uncharged compounds due to the bulk migration of water induced by an electric field.
- the patient or subject may include humans as well as animals.
- Example 1 In vitro Excised Skin Delivery Experiments Patch Designs: The two (2) compartment patch design includes an absorbent drag reservoir with 2 cm 2 skin-contacting area and volume of 0.30mL. The drug reservoir is separated from the electrode compartment with a 100 MWCO ultrafiltration membrane. The electrode compartment included a silver anode and cation exchange media in a hydrogel. A monolithic patch design was also used, consisting of a sandwich composed of a silver anode in the middle of 2 layers of absorbent material. The patches are assembled and loaded with the dosing solution just before applying to the skin.
- the receiver solution was an isotonic pH 7.4 buffered saline solution containing 10 mM HEPES, 100 mM NaCl, PEG400, and a surfactant, Pluronic P- 103.
- Iontophoresis current was provided by WIP power cells, and the applied currents and cell voltages were recorded with a Fluke databucket.
- Figure (2) demonstrates that iontophoresis is a capable means for delivering GPIIb/IIIa receptor antagonists to constant flux levels over a period of 24 hours.
- Figure 2 shows a steady drag flux of about 3.5 ⁇ /h/cm 2 during the 4 to 24 hour period after the beginning of iontophoretic delivery. The variability in delivery from skin to skin is also low.
- Figure (3) shows that the in-vitro delivery is proportional to current and that the flux is very constant over the 24 hours period. In these experiments the flux reaches steady state rapidly and it is also evident that flux levels drop rapidly on termination of the current.
- Figure 3 shows a steady drug flux during the 4 to 24 hour period after the beginning of iontophoretic delivery.
- Figures (4) and (5) show the comparison of the in-vivo delivery of the GPIIb/IIIa to pigs using constant iontophoresis and constant IV infusion. The results show that blood levels obtained from both delivery techniques is similar and the variability in plasma levels seen with the iontophoreses is low.
- Example 3 In vitro Iontophoretic delivery of GPIIb/IIIa antagonist, effect of Membrane Separator.
- the patch design can fall into one of three profiles: a) bolus or peaked profile: this is obtained by using a low or near zero saline concentration.
- Figure (6) compares the delivery rate profiles for the dual compartment patches at 400 ⁇ A. While the anion exchange membrane patch provided somewhat greater delivery, the two profiles are similar. These results fit the bolus or peaked profile, the flux starts high, and falls as electrolyte cations accumulate with time. In particular, as can be seen in Figure 6, the flux increases from 0 to 120 ⁇ g/h during the first four hours of iontophoretic delivery and steadily falls to 40 ⁇ g/h by the twenty-sixth hour of iontophoretic delivery.
- Example 4 In vitro Iontophoretic delivery of GPIIb/IIIa antagonist, effect of chloride salt.
- Patches A dual compartment 2cm 2 patch design, loaded with 50 mg/mL chloride salt.
- Results The delivery rate profiles for these runs are shown in Figure (7).
- the results at 100 ⁇ A show nearly flat delivery at 10-20 ⁇ g/h.
- the run at higher current (200 ⁇ A) also gave nearly constant delivery in the 20-35 ⁇ g/h range. These results fit the nearly flat profile and a steady flux is obtained during the 6 to 27 hour period after the beginning of iontophoretic delivery.
- Example 5 In vitro Iontophoretic delivery of GP Ilb/IIIa antagonist, effect of current, drug concentration, and salinity.
- Patches A dual compartment 2cm 2 patch design, loaded with either a ImM NaCl, 150mg/mL formulation, or a 75mM NaCl, lOOmg/mL formulation.
- Example 6 In vitro Iontophoretic delivery of GPIIb/IIIa antagonist, effect of chloride salt.
- Patches A dual compartment 2cm 2 patch design, loaded with 154 mM NaCl, 50mg/mL chloride salt and a dual compartment 2cm 2 patch design, loaded with 154 mM NaCl, 150mg/mL chloride salt.
- Figures 9A and 9B At a NaCl concentration of 154 mM, the results show a greater rate of delivery with the patch having the higher drag concentration of 150mg/mL chloride salt (Figure 9B) than with the patch having a drag concentration of 50mg/mL chloride salt (Figure 9A).
- Figure 9B shows a nearly flat delivery profile of 20-25 ug/h during the 4 to 24 hour period after the beginning of iontophoretic delivery
- Figure 9A shows a nearly flat delivery profile of 10 ug/h during the 4 to 24 hour period after the beginning of iontophoretic delivery.
- Example 7 In vitro Iontophoretic delivery of GPIIb/IIIa antagonist, effect of chloride salt at a high NaCl concentration.
- Patches A dual compartment 2cm 2 patch design, loaded with 250 mM NaCl, 50mg/mL chloride salt and a dual compartment 2cm 2 patch design, loaded with 250 mM NaCl, 150mg/mL chloride salt.
- Experimental Protocol See Example 1, current applied at 250 ⁇ A.
- Patches A dual compartment 2cm 2 patch design, loaded with 25 mM NaCl, 50mg/mL chloride salt and a dual compartment 2cm 2 patch design, loaded with 25 mM NaCl, 150mg/mL chloride salt.
- the delivery rate profiles for the dual compartment patches are shown in Figures 12A and 12B.
- the results show a greater rate of delivery at a drug concentration of 150mg/mL chloride salt (Figure 12B) than at a drag concentration of 50mg/mL chloride salt (Figure 12A).
- the rate of delivery shown in Figure 12B falls slowly from about 55 ug/h to about 45 ug/h during the 4 to 24 hour period after the beginning of iontophoretic delivery.
- the rate of delivery in Figure 12A falls slowly from about 32-33 ug/h to about 20 ug/h during the 4 to 24 hour period after the beginning of iontophoretic delivery.
- the drug delivery profiles shown in Figures 12A and 12B are not as smooth as the profiles shown in Figures 9A and 9B (154 mM NaCl concentration).
- Example 10 In vitro Iontophoretic delivery of GPIIb/IIIa antagonist, effect of current at a high drug concentration.
- Patches Dual compartment 2cm 2 patch designs, loaded with 87.5 mM NaCl, 150mg/mL chloride salt.
- the delivery rate profiles for the dual compartment patches are shown in Figures 13A and 13B.
- the results show a greater rate of drug delivery at a current of 400 ⁇ A (Figure 13B) than at a current of lOO ⁇ A ( Figure 13A).
- the rate of delivery shown in Figure 13B falls from about 54 ug/h to 40 ug/h, then is smooth and then rises to about 48 ug/h during the 4 to 24 hour period after the beginning of iontophoretic delivery.
- the rate of drug delivery shown in Figure 13 A rises slowly from about 10 ug/h to about 25 ug/h during the 4 to 24 hour period after the beginning of iontophoretic delivery.
- the profiles of the patches shown in Figures 13 A and 13B are not as smooth as the profiles of similar patches with a lower drag concentration, as shown in Figures 11 A and 1 IB.
- Example 11 In vitro Iontophoretic delivery of GPIIb/IIIa antagonist, effect of NaCl and NaMesylate at a low drug concentration.
- Patches A dual compartment 2cm 2 patch design, loaded with 154 mM NaCl, 30mg/mL chloride salt and a dual compartment 2cm 2 patch design, loaded with 150 mM NaMesylate, 30mg/mL chloride salt.
- Figures 14A and 14B show similar drug delivery profiles at a drag concentration of 154 mM NaCl, 30mg/mL chloride salt (Figure 14A) and 150 mM NaMesylate, 30mg/mL chloride salt ( Figure 14B).
- Figure 14A shows a nearly flat delivery profile of 5- 7 ug/h during the 4 to 24 hour period after the beginning of iontophoretic delivery
- Figure 14B shows a nearly flat delivery profile of 6-8 ug/h during the 4 to 24 hour period after the beginning of iontophoretic delivery. Accordingly, desirable results can be obtained using different salt solutions.
- Example 12 In vitro Iontophoretic delivery of GPIIb/IIIa antagonist, effect of drug concentration at a low current and a NaCl concentration of 154mM.
- Patches A dual compartment 2cm 2 patch design, loaded with 154 mM NaCl, lOmg/mL chloride salt and a dual compartment 2cm 2 patch design, loaded with 154 mM NaCl, 50mg/mL chloride salt.
- Example 13 In vitro Iontophoretic delivery of GPIIb/IIIa antagonist, effect of drug concentration at a current of 250 ⁇ A and a NaCl concentration of 154mM.
- Patches A dual compartment 2cm 2 patch design, loaded with 154 mM NaCl, lOmg/mL chloride salt and a dual compartment 2cm 2 patch design, loaded with 154 mM NaCl, 50mg/mL chloride salt.
- Figures 16A and 16B The results show a greater rate of drag delivery at a drag concentration of 50mg/mL chloride salt (Figure 16B) than at a drug concentration of lOmg/mL chloride salt (Figure 16A).
- the rate of drug delivery shown in Figure 16B falls slightly from about 13 ug/h to 12 ug/h, then is smooth and then rises to about 14 ug/h during the 4 to 24 hour period after the beginning of iontophoretic delivery.
- the rate of drug delivery shown in Figure 16A rises slowly from about 10 ug/h and then slowly falls to about 8 ug/h during the 4 to 24 hour period after the beginning of iontophoretic delivery.
- the results shown in Figures 16A and 16B both show a nearly flat drug delivery profile. Accordingly, desirable results can be obtained at low drag concentrations, a 154 mM NaCl concentration and at an intermediate current, such as 250 ⁇ A.
- Example 14 In vitro Iontophoretic delivery of GPIIb/IIIa antagonist, effect of a low drag concentration with a NaCl concentration of 154 mM and at a current of lOO ⁇ A.
- Patches Dual compartment 2cm 2 patch designs, loaded with 154 mM NaCl, 20mg/mL chloride salt.
- Experimental Protocol See Example 1, current applied at lOO ⁇ A.
- FIGS 17A and 17B The delivery rate profiles for the dual compartment patches are shown in Figures 17A and 17B.
- the results show similar drug delivery profiles, as expected, since both patches have identical drug and salt concentrations of 154 mM NaCl, 20mg/mL chloride salt.
- Figure 17A shows the rate of drug delivery falling from 9 ug/h to 7 ug/h during the 4 to 24 hour period after the beginning of iontophoretic delivery.
- Figure 17B shows a flat drug delivery rate of about 8 ug/h during the 4 to 24 hour period after the beginning of iontophoretic delivery. Accordingly, patches having a low drug concentration and a 154 mM NaCl concentration at a moderate to low current of lOO ⁇ A provide desirable results.
Abstract
Description
Claims
Priority Applications (5)
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EP01901935A EP1159029B1 (en) | 2000-01-10 | 2001-01-10 | Selected drug delivery profiles using competing ions |
JP2001551540A JP2003519541A (en) | 2000-01-10 | 2001-01-10 | Selective drug delivery profiles using competing ions |
DE60124340T DE60124340T2 (en) | 2000-01-10 | 2001-01-10 | SELECTED ADMINISTRATIVE PROFILES OF MEDICAMENTS USING COMPETITIVE IONS |
AU2001227786A AU2001227786A1 (en) | 2000-01-10 | 2001-01-10 | Selected drug delivery profiles using competing ions |
CA002359830A CA2359830A1 (en) | 2000-01-10 | 2001-01-10 | Selected drug delivery profiles using competing ions |
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US09/480,540 | 2000-01-10 | ||
US09/480,540 US6350259B1 (en) | 1996-09-30 | 2000-01-10 | Selected drug delivery profiles using competing ions |
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EP (1) | EP1159029B1 (en) |
JP (1) | JP2003519541A (en) |
AU (1) | AU2001227786A1 (en) |
CA (1) | CA2359830A1 (en) |
DE (1) | DE60124340T2 (en) |
WO (1) | WO2001051120A1 (en) |
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Also Published As
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EP1159029B1 (en) | 2006-11-08 |
CA2359830A1 (en) | 2001-07-19 |
US6350259B1 (en) | 2002-02-26 |
AU2001227786A1 (en) | 2001-07-24 |
DE60124340T2 (en) | 2007-10-11 |
DE60124340D1 (en) | 2006-12-21 |
JP2003519541A (en) | 2003-06-24 |
EP1159029A1 (en) | 2001-12-05 |
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