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WO2020037294A1 - Système et méthode d'administration iontophorétique transdermique biphasique de diclofénac et d'autres agents thérapeutiques - Google Patents

Système et méthode d'administration iontophorétique transdermique biphasique de diclofénac et d'autres agents thérapeutiques Download PDF

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Publication number
WO2020037294A1
WO2020037294A1 PCT/US2019/046955 US2019046955W WO2020037294A1 WO 2020037294 A1 WO2020037294 A1 WO 2020037294A1 US 2019046955 W US2019046955 W US 2019046955W WO 2020037294 A1 WO2020037294 A1 WO 2020037294A1
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WIPO (PCT)
Prior art keywords
diclophenac
delivery
patch
compound
period
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
PCT/US2019/046955
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English (en)
Inventor
Mir Imran
Mir Hashim
Sanjay Patel
Joel Harris
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Incube Laboratories LLC
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Incube Laboratories LLC
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Filing date
Publication date
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Publication of WO2020037294A1 publication Critical patent/WO2020037294A1/fr
Anticipated expiration legal-status Critical
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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
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/325—Applying electric currents by contact electrodes alternating or intermittent currents for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0412—Specially adapted for transcutaneous electroporation, e.g. including drug reservoirs

Definitions

  • the controller may correspond to an analogue controller known in the electrical control arts.
  • At least one of the current source or the controller is disposed or otherwise positioned in a housing coupled to the non-tissue contacting side of the patch.
  • the housing has sufficient flexibility such that when the housing is engaged with the patch to form the patch assembly and the patch is adhered to a target site on a patient's skin (e.g., the arm, knee or back), the patch assembly has sufficient flexibility to deform with movement of the patient's skin so as to remain sufficiently adhered to the patient's skin over an extended period of time to transdermally deliver the diclophenac compound.
  • the extended period may be, for example, 1, 2, 3 or 7 days or even longer.
  • the patch and/or patch assembly can be shaped or otherwise adapted to fit over or around a selected target tissue site and stay adhered to the site during movement of the patient's skin at the selected target tissue site.
  • the patch and/or patch assembly is adapted to fit over or around the patient's leg, knee, foot, arm, elbow, back, neck or lower back, with adjustments in size and shape of the patch being made for the patient's size as well as their degree and type of activity (e.g., walking, running, engaging in a sport and the like).
  • Fig. 3a is a schematic side view showing placement of an embodiment of a transdermal iontophoretic patch device on the surface of the skin, wherein the device comprises an active electrode assembly and a return electrode assembly.
  • Fig. 5a is a top down view showing an embodiment of an on demand user-activated transdermal delivery system including a patch assembly.
  • Figs. 5b, 5c and 5d are time sequence graphs illustrating an
  • Fig. 9 is a block diagram of a transfer function used to model an embodiment of the transdermal iontophoretic delivery system used in the example.
  • Figs. 10a and 10b are plots of delivered therapeutic agent versus time.
  • Fig 10a shows the cumulative input vs. the estimated system response based on an optimum cross-correlation FIR filter response of the measured system response;
  • Fig. 10b plot shows the density input vs. the estimated system response based on an optimum cross-correlation FIR filter response of the measured system response.
  • Figs. 13a-13c illustrate embodiments of a patch assembly configured for placement on a patient's knee to deliver an NSAID such as diclophenac or other therapeutic agent to the patient's knee.
  • Fig. 13a shows the placement of the patch assembly on the patient's knee;
  • Fig. 13b shows an embodiment of the knee patch assembly including at least one bending feature; and
  • Fig. 13c shows an embodiment of the knee patch assembly without any bending features.
  • Figs. 15a-15c illustrate embodiments of a patch assembly configured for placement on a patient's lower back to deliver an NSAID such as diclophenac or other therapeutic agent to the patient's lower back.
  • Fig 15a shows the placement of the patch assembly on the patient's lower back;
  • Fig. 15b shows an embodiment of the lower back patch assembly including at least one bending feature;
  • Fig. 15c shows an embodiment of the lower back patch assembly without any bending features.
  • Various embodiments of the invention described herein provide a device, system and method for the transdermal iontophoretic delivery of various drugs and other therapeutic agents. Many embodiments provide devices, systems and methods for the biphasic transdermal iontophoretic delivery of various drugs and other therapeutic agents. Many embodiments provide devices, systems and methods for the biphasic transdermal iontophoretic delivery of various drugs and other therapeutic agents. Many embodiments provide devices, systems and methods for the biphasic transdermal iontophoretic delivery of various drugs and other therapeutic agents. Many embodiments provide devices, systems and methods for the biphasic transdermal iontophoretic delivery of various drugs and other therapeutic agents. Many embodiments provide devices, systems and methods for the biphasic transdermal iontophoretic delivery of various drugs and other therapeutic agents. Many embodiments provide devices, systems and methods for the biphasic transdermal iontophoretic delivery of various drugs and other therapeutic agents. Many embodiments provide devices, systems and methods for the biphasic transdermal
  • substantially means within ⁇ 10% of a stated property or quality and where appropriate within a numerical value of a stated property or quality, more preferably, ⁇ 5% of the stated property or quality.
  • an embodiment of a system 5 for the transdermal iontophoretic delivery of a therapeutic agent 51 to a tissue site TS (such as the arm A) also referred to as a delivery site TS, on the skin S of patient, comprises at least two electrode assemblies 14 including an active electrode assembly 20 and a return electrode assembly 30 and a power supply 100.
  • Target tissue site TS may also correspond to one or more of the patients leg (including the knee), arm (including the elbow) neck, back (including the upper and lower back), particularly for embodiments containing or otherwise configured to deliver an NSAID such as diclophenac or other therapeutic agent 51p for the treatment of pain or inflammation.
  • an NSAID such as diclophenac or other therapeutic agent 51p for the treatment of pain or inflammation.
  • Tissue contacting portion 24 is also electrically conductive (herein conductive) so as to function as an active electrode 20 and/or return electrode 30. This can be achieved by fabricating tissue contacting portion 24 from conductive porous materials (e.g., conductive carbon or other conductive fibers) and/or by having it become wetted with a conductive solution 54 (the
  • Connector 26 can extend into or otherwise make electrical contact with tissue contacting portion 24 so to be electrically coupled to portion 24.
  • connector 26 can be coupled to a conductive element 28 positioned within the electrode assembly 14 and coupled to conductive porous portion 24.
  • lateral electrodes 40 can comprise various conductive materials including stainless steel, carbon, silver chloride (AgCI) or other conductive materials known in the art.
  • the size and configuration of adhesive portion 25 can be adapted for the particular skin location (e.g., arm vs. leg, amount of hair, etc.) and type of skin (e.g., pediatric vs. geriatric etc., amount of hair, etc.).
  • patch 15 also includes one or more pair of electrodes known as lateral electrodes 40.
  • Lateral electrodes 40 are desirably placed on either side of porous portion 24 at a selectable distance from the perimeter 24p of porous portion 24 as is shown in the embodiments of Figs. 3a- 3b and 4a-4b.
  • Lateral electrodes 40 can comprise various conductive materials including metals, graphite, silver chloride and other like materials.
  • all or a portion of lateral electrode 40 can include an insulative coating so as to be a capacitively coupled electrode that delivers current to the skin via capacitive coupling.
  • Lateral electrodes 40 are also desirably electrically isolated from electrodes 20 and 30 and will typically include their own wave form generator circuits.
  • the lateral electrodes 40 are desirably arranged with respect to porous portion 24 such that they result in a conductive pathway 104 which goes through the skin S underlying portion 24 and is substantially parallel to the skin.
  • Embodiments of patch 15 that employ lateral electrodes 40 with delivery electrodes 20, allow for the flow of two currents, a first current 60 and a second current 70.
  • First current, 60 flows between electrodes 20 and 30 and serves to provide an electromotive force which acts to drive the therapeutic agent 51 into and across the layers of the skin S.
  • the second current 70 known as sieving current 70, provides an electromotive force that acts on the therapeutic agent 51 in a direction parallel to the skin S so as to cause oscillation of therapeutic agent 51 in a direction parallel to skin S.
  • Figs 5a-5d various embodiments of the invention for use in on demand transdermal delivery of a therapeutic agent will now be described.
  • Such embodiments include systems 5' and methods for on demand delivery of therapeutic agents 51.
  • the term "on demand" refers to the ability of the patient or other person (e.g., a medical care provider) to initiate the delivery of therapeutic agent. This includes the initiation of a therapeutic agent delivery period and/or cycle of therapeutic agent delivery periods described below. The initiation of any of these can be a signal/input from a patient activation device such as a push button device and/or a signal received from a wireless device such as cell phone or other RF-enabled device.
  • on demand embodiments provide for one or more of the following : i) the ability for the patient, other user or a controller/machine to initiate the delivery of therapeutic agent 51 to the patient; and ii) the ability to stop or otherwise limit the passive diffusion of therapeutic agent 51 during periods of time when an iontophoretic current is not supplied to patch assembly 15cp.
  • on demand transdermal delivery can be implemented by use of a biphasic transdermal iontophoretic delivery system 5" (biphasic transdermal iontophoretic delivery is defined and further described below).
  • embodiments are particularly useful for the delivery of therapeutic agents 51p (herein after pain medication 51p) for the treatment of pain (e.g., pain reduction), such as an opioid-based pain medication (e.g., fentanyl and its analogues).
  • pain e.g., pain reduction
  • opioid-based pain medication e.g., fentanyl and its analogues
  • embodiments of such a system 5" can be used for the delivery of any therapeutic agent 51 described herein or known in the art for the treatment of any number of conditions.
  • activation device 91 is coupled to controller 93 (or other controller) so that signals 91s generated by device 91 provide an input to the controller for initiating a function such as initiation of a delivery period and/or delivery cycle of therapeutic agent 51.
  • activation device 91 may comprise an externally connected device such as a push-button device that is electrically connected to module 90 (e.g., by a wire) and positioned and configured for easy access by the patient (e.g., a device that is attached to the patient belt or may lie by the patients bed side).
  • Controller 93 keeps the delivery current 310 on for the delivery period 340 to deliver a selected dose of the therapeutic agent 51 into the skin as shown by the delivery curve 350 in Fig. 5d (the delivery period and delivery current can be stored in controller 93 and/or determined by program 93p for example using the transfer function and other modeling methods described in the appended example).
  • the controller stops the delivery current 310 and starts a non-delivery period 330 (also known as refractory period 330) by generating a holding current 320.
  • the magnitude of the current 320 can be proportionally or otherwise adjusted (e.g., geometrically) relative to the concentration of therapeutic agent 51 within solution 54.
  • the adjustment can be done at the factory, by the medical caregiver or via software within controller 93.
  • the adjustments can also be done dynamically over the course of a delivery cycle to account for changes in the changes of the concentration of agent 51 within solution 54.
  • a sensor may be employed to measure the concentration of agent 51 within solution 54 within output of the sensor being fed as an input to controller 93.
  • similar adjustments can be in the characteristics of current 310 relative to the
  • concentration of agent 51 in solution 54 or other property of solution 54 so as to assure that sufficient agent 51 is delivered out of reservoir 21 and into the patient's skin.
  • a system 500 for iontophoretic transdermal delivery of various pain medication 51p and/or other therapeutic agents can comprise a skin conformable patch 505 and an electronics assembly 550.
  • System 500 (also described herein as patch assembly 500) can be configured as an "on demand" transdermal delivery system 5' and/or biphasic transdermal iontophoretic delivery system 5" as described herein.
  • Patch 505 includes first and second electrode assemblies 510 and 512 which can correspond to one or more embodiments of electrode assemblies described herein.
  • the materials used to fabricate the electrode portions of the assemblies can include various corrosion resistant materials such as graphite further described in U.S Patent Nos.
  • electrode assemblies 510 and 512 can include a pair 520 of tissue contacting ring shaped electrodes 521 and 522 concentrically spaced or otherwise arranged to reduce edge effects as is further described in U.S. Patent Application Serial No. 8,433,401.
  • Electronics assembly 550 typically includes a housing 560 which engages patch 505 so as to form patch assembly 500.
  • Housing 560 includes a bottom and top surface 561 and 562 respectively, with the bottom surface 561 typically being the area of contact for engaging patch 505, though other arrangements are also contemplated.
  • the housing 560 can be configured to be detachably coupled to patch 505 via one or more detachment elements 600.
  • Contours 563 and 564 may: i) correspond to a standard contour for a particular target site TS; ii) may come in different sizes and shapes for different target tissue sites and sizes of patients; or iii) may be custom shaped for the particular patient and target tissue site.
  • the housing 560 can be conformable so as to at least partially conform to the contour C of the skin surface SS at the target tissue site TS where the patch 505 and housing 560 are placed (both when the patient is still and when they are moving resulting in bending movement and other
  • housing 560 can comprise various flexible polymers known in the art such as various elastomeric polymers, e.g., silicone and polyurethane. Other flexible polymers are also contemplated.
  • the flexibility/conformability of the housing can also be
  • the patch 505 and/or patch assembly 500 can be shaped and/or otherwise adapted to fit over or around a selected target tissue site TS and stay adhered to the site during movement of the patient's skin at the selected target tissue site.
  • the patch 505 an/or patch assembly 500 can be is adapted to fit over or around one or more of the patient's leg, knee, foot, arm, elbow, back, neck or lower back, with adjustments in size and shape of the patch 505 being made for the patient's size as well as their degree and type of activity (e.g., walking, running engaging in sport and the like).
  • Figs. 12a-12c illustrate embodiments of a patch assembly 500, 500E configured for placement on a patient's elbow E to deliver an NSAID such as diclophenac or other therapeutic agent to the patient's elbow to treat a condition of the elbow such as tennis elbow or tendinitis.
  • Fig. 12a shows the placement of the patch assembly 500E on the patient's elbow E.
  • Fig. 12b shows an NSAID
  • Figs. 14a-14c illustrate embodiments of a patch assembly 500, 500S configured for placement on a patient's shoulder/upper back SUB to deliver an NSAID such as diclophenac or other therapeutic agent to a patient's
  • an NSAID such as diclophenac or other therapeutic agent
  • FIG. 15a-15c illustrate embodiments of a patch assembly 500, 500LB configured for placement on a patient's lower back LB to deliver an NSAID such as diclophenac or other therapeutic agent to the patient's lower back to treat a condition in the area of the lower back such as a pulled/strained muscle, tendinitis or spinal stenosis.
  • Fig 15a shows the placement of the patch assembly 500LB on the patient's lower back LB.
  • Fig. 15b shows an embodiment of the lower back patch assembly 500LB including at least one bending feature 505b.
  • Fig. 15c shows an embodiment of the lower back patch assembly 500LB without any bending features.
  • the patch 505 may include at least one bending feature 505b configured to enhance flexibility of the patch 505 and/or assembly 500 with movement of the patient's skin such as may occur during walking or other activity (e.g., engaging in exercise or a sport). Bending feature 505b may correspond to a shaped opening placed 505o positioned along a perimeter (or edge) 505p of patch 505 or within an interior portion 505i of patch 505.
  • the housing 560 or patch 505 may include a pressures sensor 567, such as a solid state strain gauge which senses the amount of force applied by the user's clothes to the housing and/or patch and/or forces of the patch 505 being bent or deformed by the patient's position or movement. Input from the pressure sensor can then be used to modulate (either increase or decrease) current delivered to the patch relative to the applied force. The current can be modulated down to prevent the development of hot spots on the patch from excessive pressure or modulated up to account for any increase in the electrical impedance of the skin due to the applied pressure.
  • a pressures sensor 567 such as a solid state strain gauge which senses the amount of force applied by the user's clothes to the housing and/or patch and/or forces of the patch 505 being bent or deformed by the patient's position or movement. Input from the pressure sensor can then be used to modulate (either increase or decrease) current delivered to the patch relative to the applied force. The current can be modulated down to prevent the development of hot spots on the patch
  • Assembly 550 will typically include a power source 570 (also referred to herein as current source 570) and a controller 530 (e.g., a microprocessor or like device) for controlling one or more aspects of the iontophoretic delivery of the agent to the skin.
  • Controller 530 can also include an integrated or separate power controller 535 for controlling the delivery of current to the skin.
  • One or both of the controllers 530 and 535 can be coupled to an H-bridge or other current switching/limiting device 540 for limiting or otherwise controlling the delivery of current to the skin.
  • the housing will also typically include a cavity 580 for current source 570, such as a cylindrical shaped cavity which may be sized for standard size batteries such as AA or AAA batteries. Other shapes for cavity 580 are also contemplated.
  • Detachment elements 600 can be spring loaded and can be spring loaded.
  • detachment elements 600 may include or be mechanically coupled to one or more anchoring elements 601 such as a hook for anchoring into patch 505.
  • the anchoring elements 601 may also comprise adhesive areas placed on the housing bottom surface 561 which engage the patch surface 505S.
  • detachment elements 600 allow the user to attach and detach an electronics assembly 550 to a selected patch 505. This allows the electronics assembly 550 to be reused for multiple patches.
  • the user can obtain a particular patch 505, scan
  • the indicia 508 can comprise a symbol or marking 509 that becomes visible when the amount of therapeutic agent 51 has been delivered. Visibility of the marking can be due to depletion of therapeutic agent 51 within patch 505 and/or a chemical or electrochemical reaction within or on the patch.
  • the information contained in memory device 556 can be entered at the factory and/or by the doctor or pharmacist. Also information entry can be done directly or over a network such as the internet or cellular phone network or other like network.
  • Other indicia reading means for reading/detecting other indicia of information about patch 505 are also contemplated. Such indicia reading means can include, without limitation, use of various RFID chips known in the art.
  • System 500 including patch 505 and assembly 550 can be sized and shaped to be placed in any number of locations on the patient's skin including the arm, leg or abdomen, back or other location.
  • the particular material properties of the patch 505 and housing 560 e.g., thickness, modulus of elasticity, bendability, etc.
  • patch 505 and assembly 550 can be packaged together, for example, as a kit 500k (which can include instructions for use) wherein the assembly 550 is matched to patch 505 in terms of size, current source, programming mechanical properties etc.
  • a given assembly 550 can be calibrated for such a group of patches 505 or patches 505 from a particular lot number.
  • multiple patches 505 can be included with a particular assembly 550. In use, this allows the patient to obtain a complete supply of patches to meet the delivery requirements for a particular therapeutic agent 51 over a period of days, weeks, or months.
  • the assembly 550 can be programmed such that when the patient is near the end of his or supply of patches 505, that the assembly will give the patient a message to purchase more patches.
  • the assembly 550 can be configured to interface with the Internet, the Cloud and/or a mobile communication device such as cell phone, to send a message to the patient's pharmacy and/or doctor to do one or more of the following : i) renew the patient's prescription for a particular therapeutic agent patch 505; ii) have an order for a supply of the therapeutic agent patch 505 ready for the patient's pick up at his or her drug store; and/or iii) ship an order for the therapeutic agent patch 505 to the patient's house.
  • waveforms 800 or current output variations (over time) and their characteristics which can be used to promote delivery or retention of one or more therapeutic agents 51.
  • Embodiments of these waveforms can be used for embodiments of the invention having a single or two or more active electrodes 20.
  • Numerous embodiments described herein provide for waveforms 800 that vary between a given polarity and zero, wherein at that polarity, the current (e.g., current 310) causes the therapeutic agent 51 to be repelled into the skin.
  • the waveforms 800 alternate between positive and negative polarity such waveforms are referred to herein as waveforms 801.
  • the skin may be assumed to handle only a maximum amount of current in a given duration (maximum current delivery) (e.g. 80 milliamps per minute).
  • maximum current delivery e.g. 80 milliamps per minute
  • the duration of the output of an alternating power source may be set so as to not exceed the maximum current delivery.
  • the maximum current delivery (Ii) is assumed to be 80 milliamps for one minute. In such an implementation, the delivery duration is set for 20 seconds at a 4 milliamp output.
  • non-delivery duration 830 may coincide with no current output, rather than reverse current.
  • non-delivery duration 830 is achieved through the use of a current which has a polarity which is opposite to the charge of active agent 51 as described below in the
  • Fig. 8C illustrates another embodiment of the invention in which the alternating power signal outputs an asymmetrical wave 805 such as an asymmetrical square wave 806, in that the delivery duration 840 is different than the non-delivery duration 830.
  • the asymmetrical square wave 805 may include longer delivery durations (ti), followed by short(er) rest durations (t 2 ).
  • the rest durations may correspond to periods of no current, or as shown, reverse current (I 2 ).
  • the rest duration enables the skin layer to recuperate from the drug delivery in the prior duration (e.g., to dissipate any heat, concentration of ions, or other by products resulting from the delivery of current).
  • the rest period may follow a period where no current is applied to the skin layer, so as to enable the skin layer to recuperate from application of current.
  • Fig. 8D illustrates another embodiment in which the alternating power signal has a trapezoidal waveform 807, so as to include ramp-up and/or ramp-down periods 808 and 809.
  • Ii is the maximum current output generated from an alternating power source (e.g. power source 100).
  • the ramp- up period 808 extends for a duration t r , that is selected for reasons that include enabling the user to physically accustom to the application of current and/or delivery of therapeutic agent 51.
  • the ramp-up period 808 may be long, to enable the ramp-up duration to be effective.
  • a ramp-down period 809 may optionally be implemented.
  • Fig. 8E and Fig. 8F illustrate alternative waveform variations including compound waveforms 813 in which high-frequency oscillations 811 are superimposed on a low frequency base waveform 810.
  • the base waveform 810 may have a period Psio that lasts seconds or minutes, corresponding to output current to the electrode assemblies ranging from a maximum (e.g., 4 mA) to no current and/or reverse current.
  • the high-frequency oscillations reflect small variations in the current value at instances in the period.
  • the period Pen of the high-frequency oscillations 811 may be one or more magnitudes shorter than that of the base waveform.
  • the base waveform 800 may have a period Psio ranging from seconds to minutes, and the high-frequency oscillations of the waveform may have a period that ranges between milliseconds and seconds.
  • the effect of the high-frequency oscillations 811 is to reduce the effects of the capacitive charge in the skin layer in receiving the therapeutic agent 51.
  • the high frequency oscillations 811 may also be used to facilitate transport of the therapeutic agent through the skin including the stratum corneum by causing oscillations in the movement of the therapeutic agent as it travels through the skin so as to find pathways of least resistance through the skin.
  • the high frequency oscillations may be adjusted to enhance this effect through use of modeling (e.g., pharmacokinetic modeling) and/or the patient's age, skin type and skin location
  • the base waveform 810 may be selected for considerations such as described in prior embodiments.
  • the waveform 813 includes a ramp-up time period 808.
  • the waveform 800 has a delivery duration 840 that is switched to a non-delivery duration 830.
  • the embodiment of Fig. 8F illustrates that the high-frequency oscillations 811 may be generated to be present only during the delivery duration 840, in alternative embodiments, the high frequency oscillations during both the delivery and non delivery durations 840 and 830.
  • a diclophenac compound which may include diclophenac and/or its analogues and derivatives for the treatment of one or more medical conditions including pain and/or inflammation. Accordingly, a discussion will now be presented on diclophenac and the use of various embodiments of the invention for its transdermal delivery. Such embodiments can include various systems, patches and electrode assemblies described herein.
  • Diclofenac having the chemical formula of 2-(2,6-dichloro-anilino)-phenyl-acetic acid, is a type of non-steroidal anti-inflammatory drug (NSAID). NSAIDs have the therapeutic effect or reducing pain and inflammation.
  • COX cyclooxygenase
  • PGs prostaglandins
  • COX-1 makes PGs that protect the stomach and kidneys.
  • COX-2 produces PGs that cause pain and inflammation.
  • Diclofenac is a non-selective NSAID that inhibits both types of COX enzymesl and is thus able to treat both pain and inflammation.
  • diclophenac compounds which may be delivered by various embodiments of the invention include, without limitation, a free acid of diclofenac, an alkali metal salt such as a sodium or potassium salt, or an organic salt, particularly an amine salt, such as diethylamine.
  • a particular embodiment includes a combination of a diclofenac acid and diclofenac potassium.
  • aqueous solution 54 of a water soluble diclofenac salt (e.g., diclofenac sodium (diclofenac potassium and diclofenac diethylammonium) as well as its/their analogues or derivatives.
  • the aqueous solution 54 may be contained within or otherwise incorporated into a hydrophilic polymer matrix 21m (also referred to as matrix 21m) such as a hydrogel matrix, with other hydrophilic matrix materials considered as well.
  • matrix 21m may be contained in reservoir 21, tissue contacting layer 24 or other portion of an electrode/patch assembly such as assemblies 14 and 15cp and 500 described herein.
  • the hydrogel or other hydrophilic polymer matrix 21m containing or incorporating the diclophenac salt or other form of diclophenac be can suitably be made of any number of materials including a hydrophilic polymeric material, including those for example that are polar in nature so as to enhance the stability of the diclophenac compound or other NSAID or therapeutic agent.
  • Suitable polar polymers for the hydrogel matrix 21m comprise a variety of synthetic and naturally occurring polymeric materials.
  • the hydrogel formulation comprises a suitable hydrophilic polymer, a buffer, a humectant, a thickener, water and a water soluble diclophenac compound (e.g., a diclophenac salt).
  • suitable hydrophilic polymers for hydrophilic polymer matrix 21m may correspond to a polyvinyl alcohol such as a washed and fully hydrolyzed polyvinyl alcohol (PVOH).
  • the hydrophilic matrix 21m may contain a solubility enhancing agent 52se, (herein a solubility enhancer) which functions to enhance the solubility of a diclophenac salt or other form of diclophenac
  • Suitable solubility enhancing agents 52se include without limitation polyvinylpyrrolidone polymers,
  • polyethylene oxide polyacrylic acid, polyvinyl alcohol, silicone dioxide, silica, celluloses and cellulose derivatives such as hydroxymethyl cellulose,
  • the invention uses a soluble polyvinylpyrrolidone (PVP) as a matrix constituent.
  • PVP soluble polyvinylpyrrolidone
  • Soluble PVP is preferably present composition in an amount ranging from about 5% to about 20% and more preferably from about 10% to about 20% by weight of the total adhesive matrix composition.
  • the hydrogel or other hydrophilic polymer matrix 21m containing the diclophenac salt (or form of diclophenac) may also containing various agents, herein transport enhancing agents or transport enhancers 52te, to enhance the iontophoretic transport of a diclophenac compound or diclophenac analogue into the patient's skin and underlying tissue.
  • transport enhancers 52te may include various terpenes such as geraniol and l-menthol as well as their functional analogues and derivatives.
  • the solution/and or hydrophilic polymer matrix 21m (also described as a diclophenac solution) containing the diclophenac salt or other DC may include substantially no buffer ions and/or salt ions such as those derived from NaCI, KCI or other salt used in the pharmaceutical arts.
  • substantially no buffering ions or salt ions means less than 5% weight, molarity or volume, more preferably less than 2% and still more preferably less than 1%.
  • the enhanced transport of the DC is due to reduced completion from the buffer ion and/or salt ion.
  • the iontophoretic sale e.g., sodium diclophenac can be bound to an ion- exchange material such as ion exchange fibers). According to some
  • the ion exchange materials may be present in the solution containing the DC and/or in the hydrophilic matrix material containing the DC.
  • the diclophenac salt used for transport may include a counterion (i.e., the ion (cation) having the opposite charge as the ionized form diclophenac) includes a ring structure such as amine structure or other ring structure having hydrophilicity and polarity which contribute to the increased transport.
  • a counterion i.e., the ion (cation) having the opposite charge as the ionized form diclophenac
  • a ring structure such as amine structure or other ring structure having hydrophilicity and polarity which contribute to the increased transport.
  • Example daily dosage regimens and ranges for particular conditions include the following: osteoarthritis: 50 mg 2 to 3 times per day (i.e. 24 hours), 150mg maximum; ankylosing spondylitis: 25 mg 4 to 5 times per day, 125 mg maximum;
  • dysmenorrhea 50 mg 3 times per day, 150mg maximum; rheumatoid arthritis, 50 mg 3 to 4 times per day or 75 mg 2 to 3 times per day, 225 mg maximum.
  • the dosage of diclophenac can be in the range of about 50 to 75 mg per delivery period a dosage of bupvicaine can be in the range from 100 to 175 mg per dose with a maximum of 400 mg per day (i.e., 24 hours).
  • System Description One embodiment of a system that was tested for delivery of therapeutic agents comprised an active electrode, passive electrode, iontophoresis system and a programmer which are described below.
  • Active electrode This was constructed by using a DuPel Model #198809-001 (Empi, Inc., Clear Lake, SD, USA) electrode with the buffering agent removed and replaced with a teabag filled with two sheets of 3M gauze with 4.0 ml of solution.
  • the solution was prepared by dissolving 1.2g of FeCI2 (Sigma-Aldrich, St. Louis, MO, USA) and 300 mg of Poly-Ethylene Oxide (PEO, Mol wt. 100k) into 4 ml of DI water.
  • the active electrode area was 13.3 cm2.
  • Passive electrode This was constructed using a DuPel
  • Programmer This comprised a personal computer that was able to be interfaced to the iontophoresis system via a USB cable.
  • the application code used to program the device was written in TCL/TK.
  • This program was able to set the therapy pulse duration and current value along with the inhibit pulse duration and current value. It was also capable of specifying the total therapy duration.
  • the programmer was also able to retrieve the data stored in the unit for analysis.
  • the iontophoresis system was configured to provide a 6 hour therapy session.
  • the first hour of the therapy session consisted of the system in an inhibit mode with a current value of -3 mA.
  • the second hour of the therapy session was a drive mode with a current value of 3mA.
  • the system was in the inhibit mode with a current value of-3 mA.
  • the system was in a drive mode with a current value of 3mA
  • in hour 6 the system was in an inhibit mode with a current value of -3mA.

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Abstract

Dans divers modes de réalisation, l'invention concerne des méthodes et des systèmes d'administration transdermique iontophorétique d'agents thérapeutiques comprenant des AINS, par exemple, du diclofénac, à un site tissulaire cible (TTS), à l'aide d'au moins un ensemble d'électrodes qui est positionné de sorte à être en communication électrique avec la peau d'un patient au-dessus du TTS. Dans certains modes de réalisation, une dose de l'agent est administrée au TTS de manière passive à partir d'un ensemble pendant une première période, au moyen d'un premier courant présentant une certaine caractéristique, par exemple une polarité et/ou une amplitude, qui repousse l'agent hors de l'ensemble. Pendant une seconde période, un second courant présentant une caractéristique permettant d'attirer l'agent est utilisé pour retenir l'agent dans l'ensemble de sorte que l'administration de l'agent dans la peau est réduite au minimum. Des modes de réalisation sont particulièrement utiles pour l'administration d'agents qui provoquent des effets indésirables à partir d'une diffusion passive non souhaitée.
PCT/US2019/046955 2018-08-17 2019-08-16 Système et méthode d'administration iontophorétique transdermique biphasique de diclofénac et d'autres agents thérapeutiques Ceased WO2020037294A1 (fr)

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