Iontophoretic delivery of integrin inhibitors

Details Iontophoretic delivery of integrin inhibitors Iontophoretic delivery of integrin inhibitors

1997-06-18

2001-02-06

Weddington, Kevin E. (Department: 1614)

Surgery

Means for introducing or removing material from body for...

Infrared, visible light, ultraviolet, x-ray or electrical...

C604S028000, C424S449000, C514S374000, C514S378000

Reexamination Certificate

active

06185453

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel methods and devices for iontophoretically administering therapeutic doses of integrin receptor antagonists in a controlled manner through the skin. Such integrin receptor antagonists include but are not limited to antagonists of the IIb/IIa and &agr;
v
&bgr;
3
integrins and related cell surface adhesive protein receptors. The present invention includes iontophoretic delivery devices comprising integrin inhibitors. 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.
BACKGROUND OF THE INVENTION
A number of cell surface receptor proteins, referred to as integrins, have been identified which bind to extracellular matrix ligands or other cell adhesion protein ligands thereby mediating cell-cell and cell-matrix adhesion processes. The integrins are encoded by genes belonging to a gene superfamily and are composed of heterodimeric transmembrane glycoproteins containing &agr;- and &bgr;-subunits. Integrin subfamilies contain a common &bgr;-subunit combined with different &agr;-subunits to form adhesion protein receptors with different specificities. The genes for at least eight distinct &bgr;-subunits have been cloned and sequenced to date.
The integrin glycoprotein IIb/IIIa (GPIIb/IIIa or IIb/IIIa), also referred to as the fibrinogen receptor, is the membrane protein mediating platelet aggregation. IIb/IIIa in activated platelets is known to bind four soluble RGD-containing adhesive proteins, namely fibrinogen, von Willebrand factor, fibronectin, and vitronectin. “RGD” refers to the amino acid sequence Arg-Gly-Asp. The binding of fibrinogen and von Willebrand factor to IIb/IIIa causes platelets to aggregate. The binding of fibrinogen is mediated in part by the Arg-Gly-Asp (RGD) recognition sequence which is common to the adhesive proteins that bind IIb/IIIa. RGD-peptidomimetic IIb/IIIa antagonist compounds are known to block fibrinogen binding and prevent platelet aggregation and the formation of platelet thrombi. IIb/IIIa antagonists represent an important new approach for antiplatelet therapy for the treatment of thromboembolic disorders.
In addition to IIb/IIIa, a number of other integrin cell surface receptors have been identified. For example, members of the &bgr;1 subfamily, &agr;4&bgr;1 and &agr;5&bgr;1, have been implicated in various inflammatory processes, including rheumatoid arthritis. In addition, studies with monoclonal anti-&agr;4 antibodies provide evidence that &agr;4/&bgr;1 may additionally have a role in allergy, asthma, and autoimmune disorders. Anti-&agr;4 antibodies block the migration of leukocytes to the site of inflammation.
The &agr;
v
&bgr;
3
integrin, also referred to as the vitronectin receptor, is a heterodimer and is a member of the &bgr;
3
integrin subfamily. The &agr;
v
&bgr;
3
integrin is found on platelets, endothelial cells, melanoma cells, smooth muscle cells, and osteoclasts. Like the integrin IIb/IIIa, the &agr;
v
&bgr;
3
integrin binds a variety of RGD-containing adhesive proteins such as vitronectin, fibronectin, von Willebrand factor, fibrinogen, osteopontin, bone sialo protein II and thrombosponden in a manner mediated by the RGD sequence. Thus, &agr;
v
&bgr;
3
acts as the endothelial cell, fibroblast, and smooth muscle cell receptor for adhesive proteins including von Willebrand factor, fibrinogen (fibrin), vitronectin, thrombospondin, and osteopontin.
The integrin &agr;
v
&bgr;
3
allows endothelial cells to interact with a wide variety of extracellular matrix components. These adhesive interactions are considered to be important for angiogenesis since vascular cells must ultimately be capable of invading virtually all tissues. Integrin &agr;
v
&bgr;
3
is involved in bone resorption since a key event in bone resorption is the adhesion of osteoclasts to the matrix of bone. During endothelium injury, the basement membrane zones of blood vessels express several adhesive proteins, including von Willebrand factor, fibronectin, and fibrin. Additionally, several members of the integrin family of adhesion protein receptors are expressed on the surface of endothelial, smooth muscle and on other circulating cells. Among these integrins is &agr;
v
&bgr;
3
. These integrins initiate a calcium-dependent signaling pathway that can lead to endothelial cell, smooth muscle cell migration and, therefore, may play a fundamental role in vascular cell biology.
Inhibitors of &agr;
v
&bgr;
3
integrin have been shown to inhibit angiogenesis and are recognized as being useful as therapeutic agents for the treatment of human diseases such as cancer, restenosis, thromoembolic disorders, rheumatoid arthritis and ocular vasculopathies.
The use of iontophoresis, also referred to as electrotransport, in drug delivery is well known. The iontophoresis process has been found to be useful in the transdermal administration of therapeutic drugs including lidocaine hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate, insulin and other drugs. A common use of iontophoresis is in the diagnosis of cystic fibrosis by delivering pilocarpine salts iontophoretically, where the pilocarpine stimulates sweat production and the sweat is collected and analyzed for its chloride content to detect the presence of the disease.
SUMMARY OF THE INVENTION
The present invention provides novel methods and devices for iontophoretically administering therapeutic doses of integrin receptor antagonists in a controlled manner through the skin. Such integrin receptor antagonists include but are not limited to antagonists of the IIb/IIIa and &agr;
v
&bgr;
3
integrins and related cell surface adhesive protein receptors. The present invention includes iontophoretic delivery devices comprising integrin inhibitors. 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.


REFERENCES:
patent: 5334596 (1994-08-01), Hartman et al.
patent: 5607691 (1997-03-01), Hale et al.
patent: 5738647 (1998-04-01), Bernhard et al.
patent: 0748636 (1996-12-01), None
patent: 9514683 (1995-06-01), None
patent: 9637492 (1996-11-01), None

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