HK1120451B - Transdermal systems for the delivery of therapeutic agents including granisetron using iontophoresis - Google Patents

Description

Transdermal delivery system for delivering therapeutic agents including granisetron using iontophoresis

Background of the invention

1. Field of the invention

The present invention relates generally to transdermal delivery of therapeutic agents through the use of an applied electromotive force (emf), commonly referred to as iontophoresis. More particularly, the present invention relates to the transdermal administration of agents such as the antiemetic granisetron (granisetron).

2. Correlation technique

LeDuc described iontophoresis in 1908, and since that time found commercial use in the administration of ionically charged therapeutic agent molecules such as pilocarpine, lidocaine, dexamethasone. In this method of administration, positively charged ions are driven through the skin at the site of the dielectric electrical system anode, while negatively charged ions are driven through the skin at the site of the dielectric system cathode.

Early and for quite some time, iontophoretic devices typically consisted of 2 electrodes attached to the patient with adhesive material, each electrode connected by wires to a remote power source, usually microprocessor-controlled electronics. In recent years, self-contained (self-contained) wearable iontophoretic systems have been developed. The advantage of these systems is that they are much smaller, without external wires. Examples of such systems can be found in a number of U.S. patents, including U.S. Pat. nos. 4,927,408; 5,358,483, respectively; 5,458,569, respectively; 5,466,217, respectively; 5,355,971, respectively; 5,605,536, respectively; 5,651,768, respectively; 5,685,837, respectively; 6,421,561; WO 00/12172; 6,653,014. These systems also comprise 2 electrodes fixed to the patient's skin by means of an adhesive material.

Unlike passive release patches, iontophoretic devices can exhibit the ability to modify the release rate by simply adjusting the magnitude of the current. This ability can be used to create a wearable system that allows the patient to self-regulate drug release as needed by the individual. Patent 6,171,294; 6,216,033, respectively; 6,452,892, respectively; and 6,745,071 describe that patients can self-regulate the pain therapeutic amount of fentanyl or sufentanil using iontophoretic devices that rapidly administer or modify sustained release rates as needed.

Two-stage iontophoretic devices have also been described which can initially produce a rapid burst effect with a high level of current followed by an automatic reduction of the current to a lower sustained level to provide a sustained dose over a long period of time. Patents 5,207,752 and 6,421,561 are examples that may be used to describe such a staged release pattern.

The present invention relates to the improved use of iontophoresis for the treatment of emesis. Emesis is a form of nausea and vomiting that commonly occurs after chemotherapy, after surgery with anesthetic agents, or possibly after exposure to biological agents and/or radiation in a military setting. It will be appreciated that oral dosage forms are convenient, but unreliable for emesis cases because patients cannot retain ingested medication.

Granisetron is a selective 5-hydroxytryptamine (5-HT3) receptor antagonist and is commercially available in either oral or injectable dosage forms. It is known to be an effective drug for the treatment of emesis, and has become a primary dose (primary dose) drug and a "rescue dose" drug. The term "rescue dose" is defined as an additional dose necessary to treat sudden exacerbation or recurrence of symptoms. For additional information, a summary of the clinical effectiveness of granisetron as a primary and rescue dose drug administration is provided in the "dose investigative study of granisetron in patients receiving high-dose cisplatin chemotherapy" by, for example, Riviere A (British journal of cancer (Br. J. cancer), 1994, 69: 967-.

As regards the mode of administration, the disadvantages of oral administration are evident, as mentioned above. A disadvantage of injectable administration forms is the invasive nature of the injections, since injections can be painful, require clinical skill, can cause infections and are therefore not suitable for self-administration in the field or at home.

Recognizing the drawbacks of oral and injectable formulations of granisetron, several companies describe methodologies for transdermal delivery methods. For transdermal drug delivery systems, these include passive patches, heated passive patches, passive patches applied to RF-treated skin and systems that spray on the skin, where the total amount applied is fixed, delivery is improved by co-formulated penetration enhancers.

One advantage of transdermal systems is the ability to provide sustained release of the drug over a period of time, which can provide a longer duration of action. However, a significant limitation and disadvantage of passive transdermal administration is the slow onset of disease-modifying action. Passive transdermal patches typically take several hours (3 hours or more than 3 hours) to reach therapeutic levels. With passive transdermal administration, the skin may act as a reservoir, and release to the bloodstream does not occur until the skin reservoir area is saturated. The slow onset of this effect creates two clinical limitations: (1) cannot replace existing oral or injectable dosage forms because patch application must be performed hours prior to chemotherapy or surgical procedures, (2) slow-acting transdermal patches have no reason to be a rescue medication form because patients prefer a fast-acting treatment. The second limitation is evident, for example, in that in many cases with high emetic therapies (e.g., high dose chemotherapeutic agents), a substantial percentage of patients do not adequately respond with the first, basal dose of dosage form alone.

More rapid action can occur with transdermal systems including iontophoresis. Granisetron in the form of its hydrochloride salt is positively charged and can be rapidly released from the positively charged anode pad. For example, in recent years, it has been reported that scientific abstract 1: the paper at 2003 AAPS conference at 10 months in 2003 "evaluation of transdermal penetration kinetics of granisetron by subcutaneous microdialysis technique" and scientific abstract 2: the 2004 paper at the 2004 AAPS conference at 10 months, "ivivivc using subcutaneous microdialysis for iontophoretic administration of granisetron", demonstrates that therapeutic dose can be achieved within about 2 hours with iontophoresis (hairless rat animal model).

However, the 2 hour system described in the above report may not provide additional benefit to emesis that may not occur until several days after exposure to the emetic procedure. In addition, even if therapeutic levels are reached in the 2 hour range, they are unacceptably long for patients and physicians waiting before applying an emetic therapy such as chemotherapy. Finally, known iontophoretic patches do not provide a second or rescue dose for emesis management in the event that the base dose in the patch is insufficient.

There is therefore a need for a simple and inexpensive transdermal dosage form that not only provides the benefits of transdermal delivery of drugs such as granisetron, but also provides very rapid treatment of an initial or basal dose and one or more follow-on self-administered rescue doses.

Summary of the invention

The present invention provides a transdermal iontophoresis device and method having the ability to rapidly administer large doses of a therapeutic agent (especially the therapeutic agent granisetron) using a disposable, disposable transdermal patch. With regard to granisetron, the patch of the present invention typically achieves therapeutic levels of action in less than 1 hour. In addition, at least one embodiment of the patch device enables a patient to quickly self-administer at least one other dose or rescue dose after the initial base dose.

In illustrating one embodiment of the invention, a disposable skin-worn patch device for the transdermal administration of multiple doses of a charged therapeutic substance, such as granisetron, by iontophoresis is presented. The device comprises: a reservoir (donor reservoir) capable of delivering a therapeutic agent to the body, the reservoir comprising an amount of the therapeutic agent to be transdermally administered by iontophoresis and one or more donor electrodes; a counter reservoir (counter reservoir) containing a counter electrode, the counter reservoir being capable of completing a circuit through the body; a power supply connected in a loop between the donor reservoir and the reverse reservoir; and a user operable control system for controlling the current in the circuit to administer a plurality of successive doses of the therapeutic agent from the donor reservoir. The multiple doses are controlled by switching and selectively connecting each of a plurality of donor electrodes designed to be oxidized or reduced during operation of the iontophoresis device circuit.

Those skilled in the art will recognize that a microprocessor or other electronic or electrical control circuitry may be used to adjust the rate of current flow and thus the rate of drug delivery. In an alternative embodiment, the current is controlled to produce a drug delivery device capable of providing a bolus (bolus) and/or an alternative waveform dose from a single donor electrode configuration (configuration).

By applying the patch to the skin of the patient, the first dose can be automatically provided by a predetermined switching device in the circuit. Optionally, a patch may also be used to provide a sustained, lower level delivery rate of granisetron after the first bolus. Such as the system illustrated and described in, for example, U.S. patent 6,421,051 assigned to the same assignee as the present application and which is deemed to be incorporated herein by reference for any purpose.

In another detailed embodiment, a disposable skin-worn patch is provided that embodies an activation system that automatically administers granisetron after a sensor triggers the system based on an alarm signal. The control system is designed to react to externally generated signals, such as radio frequency (radio frequency) signals, which may be applied to a variety of devices such as those worn by soldiers in a military. Switching means are provided in the circuit to prevent accidental activation of the reservoir patch.

While other substances may be delivered from the anode or cathode regions using the iontophoretic device of the present invention, as described above, one preferred therapeutic substance that may be delivered is granisetron. Granisetron is preferably contained in a hydrogel formulation and more preferably as a charged species that can only be successfully delivered in therapeutic amounts using effective iontophoresis techniques. Generally, granisetron and other therapeutically active substances contained in ionic or charged form, when used in a passive application system for iontophoresis, will migrate transdermally to a small extent. Such means may not deliver therapeutically effective levels of the drug. Hydrogels based on polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC), and polyethylene oxide are examples of hydrogels that can be co-formulated with granisetron.

Generally accepted therapeutic amounts of granisetron are between about 300 μ g and 1000 μ g. The patch made according to the present invention has the ability to administer or deliver a bolus of about 300 μ g to about 1000 μ g in less than about 1 hour. It was thus determined that this amount could be successfully delivered with an iontophoretic charge of between 20 and 60mAmin, thus requiring a current of 0.3-1.0mA for a 1 hour delivery period. Furthermore, it is known that the optimum current density range falls between 50 μ A and 250 μ A per square centimeter. Therefore, the contact area of the drug delivery pad needs to be large enough to obtain a desired current density range.

With respect to the successful and rapid administration of granisetron by iontophoresis, it has also been determined that the total granisetron content delivered in the donor reservoir or pad should significantly exceed the total intended dose. In general, two or even more coefficients can be found. Thus if the total amount to be administered is, for example, 2mg, then at least 4mg should be provided in the donor reservoir or pad. It is believed that if the total granisetron content of the patch is less than 2 times the total granisetron intended to be administered, the efficacy of administration in a second or rescue dose is significantly lacking.

Brief description of the drawings

In the drawings, like numbering represents like parts:

FIG. 1 is a schematic representation of one embodiment of the present invention of a transdermal patch capable of multiple dose delivery of a therapeutic agent;

FIG. 2 is a schematic representation of another embodiment of the present invention selectively designing a transdermal patch that can be activated by an external signal;

FIG. 3 is a schematic representation of another embodiment of the present invention capable of delivering multiple doses of a therapeutic agent with a single donor electrode;

fig. 4 is a diagram of an embodiment similar to fig. 2 including an element that prevents improper activation.

Detailed Description

The detailed description contained in the present specification is provided only for illustrating the principle of the invention, and the principle of the invention is not limited thereto. The present description provides a limited number of illustrative embodiments as examples, and it is anticipated that others will occur to those skilled in the art, within the scope of the inventive concept.

Figure 1 shows an iontophoretic patch device which automatically releases a dose of granisetron or other therapeutic agent when applied to the skin. The device is also capable of releasing a second dose upon activation of the switch device by the patient.

The embodiment of fig. 1 illustrates an iontophoretic self-powered adhesive patch device for application to the skin generally designated 10. The patch includes a cathode region or counter reservoir 12 containing a cathode or counter electrode 14, and an anode region or donor reservoir 16 containing a pair of anodes 18 and 20, the anodes 18 and 20 being spaced apart and electrically insulated from each other but in electrical communication with respective conductors 22 and 24 and the material in the donor reservoir 16. A two-contact switching element is shown at 26, and a pair of series connected power supplies, which may be conventional button cells, are shown at 28 and 30. 32. 34 and 36 are additional interconnecting conductor elements. Thus, the anode 18 or 20 can be selectively connected or patched into a circuit using the switch 26, and the circuit, as is known, is completed by applying the patch 10 to the skin of a patient.

By adjusting the amount of oxidizable material on each anode, the depletion of the oxidizable material or the separation of the connections as a result of which an open circuit condition occurs, followed by anode connection, the charge capacity, and thus the dose, associated with anode 18 or 20 can be further adjusted to any desired amount. This technique is illustrated and described in U.S. patent 6,653,014, assigned to the same assignee as the present application, which is hereby incorporated by reference for any purpose.

Although one and two anode arrangements are shown in the figures, it will be appreciated that additional anodes, conductors and switch contacts can be readily added as desired, if desired. The circuit may optionally include components to limit or control the current in a known manner to produce a lower dose at any switch contact that is sustained over time. For example, it may be desirable to administer a low steady dose of granisetron, perhaps about 40 μ g/hour, for an extended period of time after an initial bolus or first dose administration. Additional or other types of Direct Current (DC) power supplies and control systems may be used, optionally including program control as shown in fig. 3.

In operation, when the iontophoretic patch device of fig. 1 is adhered to the skin of a patient, a first circuit is completed which selectively includes anodes 18, 20, and the patch will immediately activate and begin delivery of a dose of granisetron or other therapeutic agent contained in the anode or donor reservoir in an amount corresponding to the amount of oxidizable material available in the circuit at the anode to which it is then connected. This is preferably preset by the position of the switch 26 mounted on the end of the product so that the initial bolus of granisetron, known as the initial therapeutic dose, is quickly released when the drug delivery device is applied to the skin of a patient. Thereafter, if a second or so-called rescue dose is required, the user can manipulate switch 26 to another position to connect the second or preliminary anode 18, 20 in the circuit to trigger such second or rescue dose to automatically administer a further dose of granisetron.

Another embodiment of figure 2 includes a similar self-energizing skin application patch 40 which includes a cathode region or counter reservoir 42 with a cathode or counter electrode 44, and an anode region or donor reservoir 46 with a single anode or donor electrode 48. A normally open switch or other activation element or device 50 is connected to a sensor 52 associated with receipt of an external activation signal and is placed in circuit between anode 48 and a pair of series connected power sources 54 and 56. 58. 60, 62 and 64 are connected conductive elements.

This embodiment is designed to be worn by a patient who may need to receive a dose of the therapeutic agent from the patch. In any event, an externally generated signal is received by sensor 52, which in turn triggers element 50, closes a switch or other function to complete a circuit, thereby regulating patch activation and drug release. Embodiment 40 has a single anode and is designed to deliver a single dose to the wearer.

It will be appreciated that the sensor 52 is designed to receive various types of signals (including radio frequency, audio, infrared, etc.), as occurs in troops that are typically engaged in military operations, with a single signal activating patches for many wearers. This embodiment provides a method for the transdermal administration of granisetron by automated iontophoresis in the military field, which may be desirable, for example, when the military is accidentally exposed to radiation and/or chemical and biological agents.

Fig. 4 depicts a sensor activation embodiment 40a that, similar to that shown in fig. 2, provides the user with an activated element to prevent unwanted activation of a patch (e.g., a patch stock). Thus, the embodiment of FIG. 4 provides a manually operated switch, as shown at 70, which is closed by the user prior to sensor-regulated activation. When switch 70 is in the open position, power is cut off on conductor 60 and power source 56 is not connected. Closure of switch 70 also activates sensor 52, otherwise sensor 52 is in an inactive mode. This embodiment shows a single power source 56, but as in the embodiment of fig. 2, additional power sources or other operating devices like those of fig. 3 may of course be used. The system can be automatically activated by sensor control once the user adjusts the switch 70 to the closed position.

Fig. 3 shows a further embodiment 10a in which an electronic control circuit or element 37 is connected by a conductor 38 to switch 26 and by a conductor 39 to power source 28. Electronic control circuit element 37 may include a microprocessor or a microprocessor-operated regulating device, which may be a well-known timing controller, controlled by element 37 and switch 26, operable in conjunction with a single donor electrode 20a to administer multiple doses transdermally from the patch. This is an alternative operating scheme to the scheme shown in figure 1 in which the electrode continues to be depleted. The control system may be used to provide sustained or steady-state low-level release of the therapeutic agent. For example, in the case of granisetron, it may be about 30 to about 50 μ g/hr, and more preferably about 40 μ g/hr.

Several examples of the detailed description show the administration of therapeutic agents where the donor pool is the anodic compartment. Of course, as previously noted, for example, one skilled in the art will recognize that oppositely charged materials may be imparted using the cathode region as the donor reservoir and the anode region as the counter reservoir. Other variations in the configuration and control of the device are also contemplated. These include circuit elements that control the delivery of power over a period of time, etc.

The present invention has been described in considerable detail in order to comply with the patent statutes and to provide those skilled in the art with the information necessary to apply the novel principles and to construct and use such specialized components as are required. It is to be understood that the invention can be carried out by specifically different equipment and devices, and that various changes can be made in the equipment and operating procedures and materials without departing from the scope of the invention itself.

Claims (19)

1. A disposable skin-worn device for transdermal delivery of a plurality of doses of a charged therapeutic substance by iontophoresis, comprising:

(a) a single donor reservoir containing an amount of a therapeutic substance to be delivered transdermally by iontophoresis, said donor reservoir further comprising a plurality of donor electrodes providing separate sources of selectively connectable reactive substances to provide a plurality of sequential doses of the therapeutic substance;

(b) a reverse library;

(c) a power supply connected in circuit between said donor reservoir and said reverse reservoir; and

(d) a user operable control system for controlling the current in said circuit to administer a plurality of successive doses of said therapeutic substance from said donor reservoir.

2. The device of claim 1, wherein the control system further comprises a switching device that selectively connects each of the plurality of donor electrodes into the loop.

3. The device of claim 1, wherein the circuit is completed and the first dose is automatically provided after the device is applied to the skin of the patient.

4. The device of claim 2, wherein the circuit is completed and the first dose is automatically provided after the device is applied to the skin of the patient.

5. The device of claim 1, wherein said control system further comprises a two-contact switch, said donor reservoir comprising two donor electrodes selectively connected in said circuit by said switch, whereby a first active donor electrode is connected to said circuit to provide a first dose of said therapeutic substance upon application of said dermally worn device, and a second active donor electrode is selectively connectable to provide a second dose of said therapeutic substance by manipulation of said switch.

6. A device according to any preceding claim, wherein the therapeutic substance is granisetron.

7. The device of claim 6, wherein the dose is between about 300 μ g and 1000 μ g.

8. The device of claim 7, wherein at least a first dose is released within about 1 hour.

9. A device as in claim 6 wherein the granisetron is contained in a hydrogel formulation.

10. A disposable skin-worn device for transdermal delivery of at least one dose of a charged therapeutic substance by iontophoresis, the device comprising:

(a) a donor reservoir containing an amount of a therapeutic substance to be delivered transdermally by iontophoresis, said donor reservoir further comprising a plurality of donor electrodes providing separate sources of selectively connectable reactive substances to provide a plurality of sequential doses of the therapeutic substance;

(b) a reverse library;

(c) a power supply connected in circuit between said donor reservoir and said reverse reservoir; and

(d) a control system for controlling the current in said circuit to transdermally administer at least one dose of said therapeutic substance by iontophoresis, wherein said control system comprises a control element including a sensor activated by an externally generated signal to cause a patch device pre-applied to the body of a user to release a dose of said therapeutic substance; and

(e) the therapeutic substance is granisetron.

11. A disposable skin-worn patch device for delivering granisetron by iontophoresis for providing multiple doses of granisetron to a body, comprising:

(a) a donor reservoir containing granisetron, said donor reservoir further comprising a plurality of donor electrodes providing separate sources of sequentially connectable reactive species for providing a plurality of successive doses of granisetron;

(b) a reverse library;

(c) a power supply connected in circuit between said donor reservoir and said reverse reservoir; and

(d) a control system for providing a first dose of about 300 μ g to about 1000 μ g of granisetron in a first loop controlled delivery of the drug in less than 2 hours after application of the patch to a body surface, and a user operable means for enabling a user to self-administer successive doses of about 300 μ g to about 1000 μ g of granisetron.

12. A disposable skin-worn patch device for delivering granisetron by iontophoresis, optionally providing multiple doses to a body, comprising:

(a) a donor reservoir containing granisetron, said donor reservoir further comprising a plurality of donor electrodes providing separate sources of reactive species to provide a plurality of successive doses of granisetron;

(b) a reverse library;

(c) a power supply connected in circuit between said donor reservoir and said reverse reservoir; and

(d) a control circuit for controlling the flow of electrical current, the control circuit providing a circuit including a first donor electrode in said donor reservoir for providing a first dose of about 300 μ g to about 1000 μ g of granisetron within 2 hours of patch application to a body surface, and a user manipulable device connected in circuit to a second donor electrode in said donor reservoir for enabling a user to self-administer successive doses of about 300 μ g to about 1000 μ g of granisetron.

13. A device as in claim 11 or 12 wherein the granisetron is contained in a hydrogel formulation.

14. A device as in claim 11 or 12 wherein said granisetron is in a dosage form administrable only by iontophoresis.

15. The device of claim 11 wherein said control system provides steady state low level administration of about 40 μ g/hr granisetron after said first initial dose.

16. The device of claim 11, wherein the donor reservoir comprises a single reactive species source.

17. The device of claim 16, wherein the control circuit electronically controls the administration of the dose.

18. A device as claimed in claim 11 or 12 wherein the supply of granisetron from the donor reservoir exceeds the total amount expected to be administered to the user by the device.

19. The device of claim 1,2 or 5, wherein the therapeutic substance is an antiemetic.