Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1993-04-05
2001-12-04
Kishore, Gollamudi S. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S423000, C424S484000, C424S486000, C514S012200, C514S056000, C514S423000, C604S890100, C604S891100
Reexamination Certificate
active
06326017
ABSTRACT:
TECHNICAL FIELD
The present invention is generally directed toward the localized delivery of agents to blood vessels, and more specifically to the localized delivery of agents, such as heparin, for which systemic distribution may be undesirable.
BACKGROUND OF THE INVENTION
Agents useful for the treatment of, or protection against, disorders of blood vessels may present a considerable risk to a patient when administered systemically. Heparin is a representative example of such an agent.
Heparin compounds are sulfated glycosaminoglycans that inhibit coagulation at several stages in the clotting sequence. The most prominent anticoagulant effect is related to potentiation of antithrombin III. Heparin, when administered subcutaneously, intra-muscularyly, or intravenously, can provide systemic anticoagulation. However, variability in protein binding, half-life, distribution and coagulation testing procedures complicate the accurate administration of heparin, which must be undertaken in the hospital setting. Optimal anticoagulation is frequently difficult to achieve and often requires continuous infusion.
Hemorrhage is the primary complication associated with heparin anticoagulation although thrombocytopenia, hypersensitivity reactions, lipolysis, and rebound hypercoagulability occur less frequently. Hemorrhage during heparin therapy is directly related to the degree of anticoagulation and the duration of therapy. Recent surgery, thrombocytopenia, peptic ulcers, uremia, and concurrent antiplatelet agents all increase the risk of hemorrhage during systemic anticoagulation with heparin and represent relative contraindications to its use. From 5% to 33% of patients receiving full heparin anticoagulation suffer hemorrhagic complications, many of which are fatal or disabling.
Heparin, in addition to its antithrombotic effect, suppresses late smooth muscle cell proliferation in arteries after endothelial damage. Proliferation of smooth muscle cells in blood vessels (“myointimal proliferation”) occurs in conditions such as atherosclerosis, hypertension and following various vascular surgical procedures. Despite the effectiveness of heparin as an anti-intimal proliferation agent when administered systemically, its use necessitates considerable risk, due to side effects such as those described above, and is frequently contraindicated after surgical procedures.
Due to the complications associated with systemic administration of agents useful for the treatment of, or protection against, vascular disorders, there is a need in the art for methods that provide for the localized delivery of such agents to blood vessel. The present invention fills this need, and further provides other related advantages.
SUMMARY OF THE INVENTION
Briefly stated, the present invention provides methods for the localized delivery of agents to a blood vessel. In one embodiment, the method comprises applying a carrier containing at least one agent to an external surface of a blood vessel and isolating the agent from adjacent tissue.
In another embodiment, the method comprises applying a carrier containing at least one agent to an external surface of a blood vessel, the carrier adapted to restrict the release of the agent into tissue adjacent to the blood vessel.
In yet another embodiment, the method comprises:
applying a carrier containing at least one agent to an external surface of a blood vessel; and
covering the carrier with a barrier adapted to restrict the release of the agent into tissue adjacent to the blood vessel.
Within preferred embodiments of the methods, the agent comprises at least one antithrombotic agent and/or at least one anti-intimal proliferation agent.
These and other aspects of the present invention will become evident upon reference to the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
As noted above, the present invention discloses methods for the localized delivery of agents to a blood vessel. The methods provide advantages over existing methods for treating, diagnosing, or preventing, vascular disorders. The advantages include: (1) substantially eliminating, or at least reducing, side effects of an agent that result from its systemic administration, (2) providing high concentrations of the agent at the site of action, and (3) supplanting procedures such as continuous intravenous infusion.
A variety of vascular disorders exist for which localized delivery of an agent for therapeutic, diagnostic or prophylactic purposes is desirable. A representative example of such a vascular disorder is thrombosis, which is a major cause of death and disability and affects arteries and veins in nearly all organ systems of the body. The methods of the present invention provide, by localized delivery of antithrombotic agents, for selective local antithrombosis without systemic anticoagulation. Suitable antithrombotic agents include heparin, antiplatelet agents such as aspirin, thrombolytic agents such as tissue plasminogen activator, or combinations of two or more agents. For example, heparin may be used alone or in combination with one or more other antithrombotic agents.
The methods of the present invention may be applied to a variety of surgical and nonsurgical clinical conditions. Surgical settings include endarterectomy, large vessel and microvascular anastomosis, cerebral and systemic venous procedures, arteriovenous shunts, angioplasty, and free flaps. Nonsurgical settings include deep-vein thrombosis, cardiac valvular disease, and arterial stenosis.
Another representative example of a vascular disorder for which localized delivery of an agent is desirable is the proliferation of vascular smooth muscle cells (“myointimal proliferation”). As noted above, hyperplasia of vascular smooth muscle cells has been related to the pathogenesis of atherosclerosis, hypertension, and arterial stenosis after experimental or surgical endothelial injury. The complex interaction between circulating blood elements and components of the vessel wall determine in part the nature and degree of the arteriopathic response. Endothelial injury initiates platelet adherence and aggregation, with release of the smooth muscle cell mitogen platelet-derived growth factor (PDGF). In addition, exposure of the media to normally excluded serum components after endothelial injury may initiate smooth muscle cell proliferation and migration. Myointimal proliferation may be diminished by systemic administration of an anti-intimal proliferation agent, for example, heparin. However, as noted above, systemic administration of heparin is associated with considerable risk of hemorrhage and its use is limited in clinical settings with increased potential risk for bleeding. The methods of the present invention provide, by localized delivery of anti-intimal proliferation agents, for selective local anti-intimal proliferation effects without significant systemic effects. Suitable anti-intimal proliferation agents include heparin, calcium antagonists such as diltiazem, inhibitors of angiotensin-converting enzyme such as cilazapril, or combinations of two or more agents. For example, heparin may be used alone or in combination with one or more other anti-intimal proliferation agents.
It may be advantageous in certain situations to use the methods of the present invention to deliver two or more different types of agents. For example, one or more antithrombotic agents may be used in combination with one or more anti-intimal proliferation agents.
Localized delivery of an agent to a blood vessel by the methods of the present invention is achieved by applying a carrier containing at least one agent to an external (“adventitial”) surface of a blood vessel and isolating the agent, or agents, from the adjacent tissue. An agent may act on a wall or the lumen of a blood vessel. The blood vessel to which an agent is applied may be an artery or a vein. A preferred blood vessel is an artery or vein undergoing anastomosis. A preferred artery is an artery undergoing endarterectomy, such as a carotid, aorta or femoral artery. The carrier may be appli
Kishore Gollamudi S.
Seed Intellectual Property Law Group PLLC
University of Washington
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