Title:  Method and devices for transdermal delivery of lithium

United States Patent:  6,375,990

Assignee:  Emory University (Atlanta, GA)

Filed:  May 24, 2000

PCT NO:  PCT/US98/21320

102(e) Date:  May 24, 2000

PCT PUB. Date:  April 22, 1999

A method and device for treating acute mania or bipolar disorder is disclosed, by transdermal delivery of Li⁺ at substantially constant rate through the skin via a dermal patch.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a dermal patch for administering lithium to a human patient at substantially constant rate without causing significant pain or tissue damage, which patch comprises:

a source of lithium for iontophoretic delivery;

a support for said lithium source;

a current distribution member for delivering a pulsed direct current sufficient to iontophoretically deliver lithium across a stratum corneum layer of the epidermis of said human, said current distribution member comprising an electrochemically active component in electrical connection with a battery, a voltage pulse generator and a precision resistor.

In one embodiment of the present invention, the electrochemically active component of the dermal patch comprises an Ag/AgCl mesh. This also helps to minimize skin irritation and/or discoloration.

In another embodiment of the dermal patch of the present invention, the source of lithium is LiCl, lithium carbonate, or lithium nitrate, or combination thereof

In another embodiment of the dermal patch of the present invention, the support for the lithium source comprises a drug reservoir, a tamper-proof occlusive backing, a conductive gel, and a membrane permeable to Li⁺ suitable for contact with the skin, and optionally an adhesive. The adhesive is suitable for reversibly attaching said patch to the epidermal layer of the skin of the patient.

In another embodiment of the dermal patch of the present invention, Li⁺ source is not buffered. This helps to avoid or reduce decreases in transdermal iontophoretic drug flux due to competing ions.

In another embodiment of the dermal patch of the present invention, a detoxification or neutralization effective amount of a complexing agent selected from the group consisting of EDTA, EGTA, and pharmaceutically acceptable salts thereof is included in the patch. This complexing agent is typically included in the occlusive backing, so that it detoxifies or neutralizes the lithium in the event that the backing is damaged or ruptured.

In another embodiment of the dermal patch of the present invention, the patch is substantially free of skin permeability enhancers, including organic solvents, such as ethylene glycol. However, while not necessary, skin permeability enhancers may be used if desired.

Another embodiment of the present invention is dermal patch for administering lithium to a human patient at substantially constant rate without causing significant pain or tissue damage, which patch comprises:

a source of lithium for iontophoretic delivery;

a support for said lithium source;

a current distribution member for delivering a pulsed direct current sufficient to iontophoretically deliver lithium across a stratum corneum layer of the epidermis of said human, said current distribution member comprising an electrochemically active component in electrical connection with a battery, a voltage pulse generator and a precision resistor; and

a detoxification or neutralization effective amount of a complexing agent selected from EDTA or EGTA or pharmaceutically acceptable salts thereof, wherein the lithium source is unbuffered; and

wherein the patch is substantially free of any skin permeability enhancers.

Another embodiment of the present invention is a method of treating acute mania or bipolar (manic/depressive) disorder with lithium, by providing and maintaining blood Li⁺ concentrations of between about 0.6 and about 1.4 mEq/L in humans in need thereof, which method comprises the steps of

(a) providing a dermal patch for administering lithium to a patient at substantially constant rate;

(b) attaching the patch to the patient's skin;

(c) iontophoretically delivering Li⁺ from said patch to the patient. This embodiment of the invention can further comprise monitoring the blood Li⁺ concentrations and adjusting the dose rate if necessary to provide and maintain blood Li⁺ concentrations of between about 0.6 and about 1.4 mEq/L.

This method can use the dermal patch described above for administering lithium to a patient at substantially constant rate without causing significant pain or tissue damage.

More particularly, the method of this embodiment of the present invention comprises providing and attaching a patch that comprises:

a source of lithium for iontophoretic delivery;

a support for said lithium source;

a current distribution member for delivering a pulsed direct current sufficient to iontophoretically deliver lithium across a stratum corneum layer of the epidermis of said human, said current distribution member comprising an electrochemically active component in electrical connection with a battery, a voltage pulse generator and a precision resistor.

In these embodiments of the method of the present invention:

the electrochemically active component of the patch can comprise an Ag/AgCl mesh, in order to minimize skin irritation and discoloration;

the source of lithium may be LiCl, lithium carbonate, or lithium nitrate, or a combination thereof;

the support for lithium in the patch may comprise a drug reservoir, a tamper-proof occlusive backing, a conductive gel, and a membrane permeable to Li⁺ suitable for contact with epidermal layer of the skin, and optionally an adhesive to reversibly attach said patch to the epidermal layer of the skin of the patient,

the lithium source may be unbuffered, in order to avoid or reduce decreases in transdermal iontophoretic drug flux resulting from competing ions;

a detoxification or neutralization effective amount of a complexing agent selected from the group consisting of EDTA, EGTA, and pharmaceutically acceptable salts thereof can be added, desirably to the occlusive backing; and

the Li⁺ composition may be substantially free of skin permeability enhancers, such as ethylene glycol.

Another embodiment of the present invention relates to a method of treating acute mania or bipolar (manic/depressive) disorder with lithium, by providing and maintaining blood Li⁺ concentrations of between about 0.6 and about 1.4 mEq/L in humans in need thereof, which method comprises the steps of:

(a) providing a dermal patch for administering lithium to a patient at substantially constant rate without causing significant pain or tissue damage;

(b) attaching the patch to the patient's skin;

(c) iontophoretically delivering Li⁺ from said patch to the patient;

wherein the dermal patch for administering lithium to a patient at substantially constant rate comprises:

a source of lithium for iontophoretic delivery;

a support for said lithium source;

a current distribution member for delivering a pulsed direct current sufficient to iontophoretically deliver lithium across a stratum corneum layer of the epidermis of said human, said current distribution member comprising an electrochermically active component in electrical connection with a battery, a voltage pulse generator and a precision resistor; and

a detoxification or neutralization effective amount of a complexing agent selected from the group consisting of EDTA, EGTA, and pharmaceutically acceptable salts thereof;

wherein the patch lithium source is unbuffered, and

wherein the patch is substantially free of skin permeability enhancers.

Another embodiment of the present invention relates to method of treating in humans acute mania or bipolar (manic/depressive) disorder comprising the steps of

(a) topically applying to the skin of a patient in need of such treatment a transdermal delivery system comprising a source of lithium, and

(b) delivering an effective amount of lithium ion to the patient's bloodstream.

Another embodiment of the present invention relates to a method for administering lithium at a substantially constant rate without causing significant pain or tissue damage to a human patient in need thereof, which method comprises:

(a) providing a source of iontophoretically deliverable lithium; and

(b) iontophoretically delivering Li⁺ to said patient.

This method may further comprise monitoring the blood Li⁺ concentrations and adjusting the dose rate if necessary to provide and maintain blood Li⁺ concentrations of between about 0.6 and about 1.4 mEq/L. The source of iontophoretically deliverable lithium used in this method may be a dermal patch. In particular, the dermal patch may comprise a current distribution member capable of delivering current sufficient to iontophoretically deliver Li⁺ across at least the stratum corneum layer of the human epidermis. This current may be direct current, and more particularly may be pulsed direct current. The current may have a density in the range of from about 50 to about 350 .mu.A/cm², desirably between about 50 and about 200 .mu.A/cm², and when pulsed may have a pulse frequency between about 1 and about 10 kHz, more particularly about 4 kHz. The dermal patch used in this embodiment of the present invention may have an on:off ratio duty cycle between about 1 and about 99%, more particularly about 75%.

Desirably, the method of this embodiment of the invention uses a patch wherein the current distribution member does not cause or reduces skin irritation or discoloration or both. This can be achieved using an Ag/AgCl mesh as the current distribution member.

Claim 1 of 36 Claims

What is claimed is:

1. A method for administering lithium at a substantially constant rate without causing significant pain or tissue damage to a human patient in need thereof, which method comprises:

(a) providing a source of iontophoretically deliverable lithium; and

(b) iontophoretically delivering Li⁺ to said patient.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.