Title:  Iontophoretic delivery of cell adhesion inhibitors

United States Patent:  5,935,598

Inventors:  Sage; Burton H. (Raleigh, NC); Bock; Carl Randolph (Durham, NC); Green; Philip G. (Cliffside Park, NJ)

Appl. No.:  877602

Filed:  June 18, 1997

This invention relates to novel methods and devices for iontophoretically administering therapeutic doses of cell adhesion receptor antagonists in a controlled manner through the skin. Such antagonist compounds include but are not limited to antagonists of the IIb/IIIa and ( .alpha.)_v (.beta.)₃ inter and related cell surface adhesive protein receptors. The present invention includes iontophoretic delivery devices comprising cell adhesion receptor antagonists. Such methods and devices are useful, alone or in combination with other therapeutic agents, for the treatment of thromboembolic disorders, angiogenic disorders, inflammation, bone degradation, cancer metastasis, diabetic retinopathy, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis.

Summary of the Invention

The present invention provides novel methods and devices for iontophoretically administering therapeutic doses of ( .alpha.)_v (.beta.)₃ antagonists in a controlled manner through the skin. The present invention includes iontophoretic delivery devices comprising ( .alpha.)_v (.beta.)₃ integrin antagonists.

In one embodiment, the invention is an iontophoretic device for non-invasively administering a therapeutic dose of a cell adhesion receptor antagonist to a mammal at a delivery rate of 0.5 .mu.g/h or greater, comprising:

(a) a current distributing member;

(b) an agent reservoir containing an ionized or ionizable substance, in electrical communication with the current distributing member and adapted to be placed in ionic communication with an epithelial surface, wherein the ionized or ionizable substance is a cell adhesion receptor antagonist; and

(c) an electrolyte reservoir containing an electrolyte, in electrical communication with an indifferent electrode and adapted to be placed in ionic communication with an epithelial surface;

(d) an electrical power source in current delivering connection with the current distribution member and the electrolyte reservoir.

Preferably, the cell adhesion receptor antagonist is an integrin antagonist, such as a glycoprotein IIb/IIIa antagonist, an (.alpha.)₆ (.beta.)₁  or  (.alpha.)₂(.beta.)₁ antagonist, or a glycoprotein Ic/IIa antagonist.

In the device, the agent reservoir can further comprise competing ions of a charge similar in sign to the charge on cell adhesion receptor in its ionized form.

In another embodiment, the invention is an iontophoresis device comprising an integrin inhibitor compound. Preferably, the integrin inhibitor compound is an inhibitor of the IIb/IIIa integrin.

The device preferably further comprises:

a cathode and an anode each disposed so as to be in electrical connection with a source of electrical energy and in intimate contact with skin of a subject, and a drug reservoir electrically connected to the cathode or the anode for containing the integrin inhibitor for delivery into the body of the subject.

In another embodiment, the invention is an iontophoresis device for non-invasively administering a therapeutic dose of a positively charged ester to a mammal, comprising:

(a) a current distributing member;

(b) an agent reservoir containing an ionized or ionizable substance, in electrical communication with a current distributing member and adapted to be placed in ionic communication with an epithelial surface, wherein the ionized or ionizable substance is a positively charged ester; and

(c) an electrolyte reservoir containing an electrolyte, in electrical communication with an indifferent electrode and adapted to be placed in ionic communication with an epithelial surface;

(d) an electrical power source in current delivering connection with the current distribution member and the electrolyte reservoir.

Preferably, the positively charged ester is a glycoprotein IIb/IIIa antagonist.

Also, the agent reservoir of the device can further comprise competing ions having a like charge to the positively charged ester.

The invention, therefore, further includes a method of administering an integrin inhibitor compound, the method comprising iontophoretically administering to a mammal a therapeutically effective amount of the integrin inhibitor using an iontophoresis device.

In another embodiment, the invention is method for the treatment of thrombosis, comprising administering to a mammal a therapeutically effective amount of an integrin inhibitor using an iontophoresis device.

In still another embodiment, the invention is a method of inhibiting the aggregation of blood platelets, comprising administering to a mammal a therapeutically effective amount of a IIb/IIIa inhibitor using an iontophoresis device.

In a further embodiment, the invention is a method of treating a thromboembolic disorder selected from thrombus or embolus formation, harmful platelet aggregation, reocclusion following thrombolysis, reperfusion injury, restenosis, atherosclerosis, stroke, myocardial infarction, and unstable angina, the method comprising administering to a mammal a therapeutically effective amount of an integrin inhibitor using an iontophoresis device.

In another embodiment, the invention is a method of non-invasively administering a therapeutic dose of a cell adhesion receptor antagonist to a mammal, comprising the step of iontophoretically driving the cell adhesion receptor antagonist through a predetermined area of skin of the mammal at a delivery rate of 0.5 .mu.g/h or greater.

Preferably, the cell adhesion receptor antagonist is an integrin antagonist, such as a glycoprotein IIb/IIIa antagonist, a glycoprotein Ic/IIa antagonist, or an (.alpha.)₆(.beta.)₁  or (.alpha.)₂(.beta.)₁  antagonist.

In the method, the iontophoretically driving step can comprise driving the cell adhesion receptor antagonist with competing ions thereto.

The method can include administering the cell adhesion receptor antagonist continuously at a current of from about 10 .mu.A to about 3 mA over a period of time up to about 24 hours, or discontinuously at a current of from about 10 .mu.A to about 3 mA over a period of time up to about 24 hours.

In still another embodiment, the invention is a method of non-invasively administering a therapeutic dose of a positively charged ester to a mammal, comprising the step of iontophoretically driving the positively charged ester through a predetermined area of skin of the mammal. An exemplary positively charged ester is a glycoprotein IIb/IIIa antagonist.

The iontophoretically driving step of the method can comprise driving the positively charged ester with competing ions thereto.

In another embodiment, the invention is an iontophoretic device for non-invasively administering to a mammal a therapeutic dose of a cell adhesion receptor antagonist, wherein the cell adhesion receptor antagonist is a peptide or peptidomimetic compound having a structure that binds to the RGD-binding domain of a cell adhesion receptor, provided that the cell adhesion receptor inhibitor is not a compound of Formula L: 

or a salt solvate or ester thereof, or a salt or solvate of such ester, in which X represents either CH₂ --CH₂ or CH=CH.

Such methods and devices are useful, alone or in combination with other therapeutic agents, for the treatment of thromboembolic disorders, angiogenic disorders, inflammation, bone degradation, cancer metastasis, diabetic retinopathy, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis.

These and other advantages of the present invention will be appreciated from the detailed description and examples which are set forth herein. The detailed description and examples enhance the understanding of the invention, but are not intended to limit the scope of the invention.

Claim 1 of 27 Claims

1. An iontophoretic device for non-invasively administering a therapeutic dose of a cell adhesion receptor antagonist to a mammal at a delivery rate of 0.5  .mu.g/h or greater, comprising:

(a) a current distributing member;

(b) an agent reservoir containing an ionized or ionizable substance, in electrical communication with the current distributing member and adapted to be placed in ionic communication with an epithelial surface, wherein the ionized or ionizable substance is a cell adhesion receptor antagonist; and

(c) an electrolyte reservoir containing an electrolyte, in electrical communication with an indifferent electrode and adapted to be placed in ionic communication with an epithelial surface;

(d) an electrical power source in current delivering connection with the current distribution member and the electrolyte reservoir.

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