Patent Application
20080039362
The present invention relates to devices and methods to prevent the formation of scar tissue and/or adhesions following a surgical procedure, trauma, or wound. In one embodiment, the present invention relates to medical devices comprising antiproliferative drugs (i.e., for example, catheters or grafts). In another embodiment, the present invention relates to medical devices that prevent scar tissue and/or adhesion formation comprising a cytostatic antiproliferative drug in combination with other drugs including, but not limited to, antiplatelet drugs, antithrombotic drugs or anticoagulant drugs. The present invention also relates to devices and methods comprising sirolimus, tacrolimus and analogs of sirolimus to prevent the formation of scar tissue and/or adhesions following a surgical procedure. In one embodiment, the present invention relates to surgical wraps comprising sirolimus, tacrolimus and analogs of sirolimus that prevent scar tissue and/or adhesion formation following a surgical procedure.
The present invention contemplates compositions comprising antiproliferative drugs (i.e., for example, the rapamycins) and/or antithrombotic drugs (i.e., for example, antiplatelet, antithrombin, or anticoagulant) intended for local tissue delivery. Further, the present invention contemplates methods using these compositions to: i) prevent native and synthetic graft failure; ii) inhibit and/or reduce post-surgical adhesion formation; iii) inhibit and/or reduce fibrin sheath formation around a medical device, and iv) inhibit and/or reduce scar tissue formation. It is believed that these drug combinations have not been previously evaluated clinically. Current practice for maintaining patency of native or synthetic grafts involves utilization of thrombolytic agents (urokinase or tPA) or thrombolectomy. Ultimately, however, vascular complications require either graft replacement or graft relocation. Current practice for inhibiting post-surgical adhesion formation involves placing non-drug eluting barrier products (i.e., Seprafilm® or SurgiWrap®) in or around the surgical site. Current practice for inhibiting fibrin sheath formation involves a mechanical stripping of the sheath from the outside of the encapsulated medical device. Current practice to prevent post-stent implantation thrombosis involves chronic systemic antiplatelet drug administration (i.e., for example, aspirin and/or clopidogrel).
Excess scar tissue and/or adhesions production is a known morbidity consequence of healing from a number of types of wounds. Examples include, but are not limited to, hypertrophic burn scar tissue and/or adhesions, surgical adhesions (i.e., for example, abdominal, vascular, spinal, neurological, thoracic and cardiac), capsular contracture following breast implant surgery and excess scarring and/or adhesions following eye surgery and ear surgery.
In particular, adhesion formation following surgical procedures is very common. It is known that platelets and inflammatory cells promote fibrin deposition leading to adhesion formation. Reijnen et al., “Pathophysiology Of Intra-abdominal Adhesion And Abscess Formation, And The Effect Of Hyaluronan” Br J Surg. 90:533-541 (2003). Although it is not necessary to understand the mechanism of an invention it is believed that adhesion formation is an extravascular process promoted by blood and cells escaping from a surgical site, wound, or trauma. Adhesions can form very rapidly (i.e., for example, from within 7-14 days of injury) and result in severe complications for the patient, often slowing recovery or leading to additional surgical procedures. Thus, one embodiment of the present invention comprises an antiinflammatory and antithrombotic drug combination that may be very effective in reducing the incidence and severity of adhesion formation. Sirolimus (i.e., rapamycin) is a known antiproliferative agent, however, this drug also possesses antiinflammatory pharmacological activity. Francischi et al., “Reduction Of Sephadex-Induced Lung Inflammation And Bronchial Hyperreactivity By Rapamycin” Braz J Med Biol Res. 10:1105-1110 (1993). Therefore, the present invention contemplates a membrane barrier material comprising an antiinflammatory (i.e., for example sirolimus), an antiplatelet (i.e., for example, xemilofiban), an antithrombin (i.e., for example, bivalirudin), or an anticoagulant (i.e., for example, low molecular weight heparin) drug combination that has distinct advantages over current practice using non-drug eluting barrier materials. In one embodiment, the membrane barrier material is selected from the group comprising a polymeric sheet of material or a currently marketed barrier materials including, but not limited to, Seprafilm® or SurgiWrap®.
Drug combination therapy involving antiproliferatives and antiplatelets is known in the medical arts. Vasculoproliferative disease (i.e., neointimal hyperplasia) has been suggested to respond after administering extravascularly a rapamycin compound in combination with other antivasculoproliferative drugs. This drug combination administration is limited to impregnation into a bioresorbable matrix constructed of collagen, fibrin, or chitosan. Iyer et al., “Apparatus And Methods For Preventing Or Treating Failure Of Hemodialysis Vascular Access And Other Vascular Grafts” U.S. Pat. No. 6,726,923 (2004). Tissue graft and organ transplant rejection may be treated with systemically administered antiplatelet drugs (glycoprotein IIb/IIIa receptor antagonists) in combination with rapamycin, tacrolimus, anticoagulants and antithrombins. Porter et al., “Inhibition Of Platelet Aggregation” WO 03/090733 A1. Anticoagulant and antiplatelet drug combinations are known to treat conditions including acute coronary ischemic syndrome, thrombosis, thromboembolism, thrombic occlusion, restenosis, transient ischemic attack, and thrombotic stroke. Wong et al., “Synergy Between Low Molecular Weight Heparin And Platelet Aggregation Inhibitors, Providing A Combination Therapy For The Prevention And Treatment Of Various Thromboembolic Disorders” WO 00/53168; and El-Naggar et al., “Prevention And Treatment Of Thromboembolic Disorders Associated With Arterial & Venous Thrombosis” United States Patent Application Publ No: 2003/0199457A1. An implantable medical device (i.e., limited to, stents, artificial graft, vascular sutures) is disclosed as having a coating with a least one drug that inhibits smooth muscle cell migration to prevent restenosis after implantation into a bodily organs' lumen. The antirestenosis drugs include smooth muscle cell antiproliferatives (rapamycin and everolimus), antithrombotics, and antiinflammatory drugs. Rowland et al., “Drug Eluting Implantable Medical Device” United States Patent Application Publ No: 2004/0039441 A1. These therapies do not, however, solve the problem regarding scar tissue and/or adhesion formation either following surgery, trauma or wound. Further, these therapies do not teach one skilled in the art controlled drug release both during and after a catheter implantation such that fibrin sheath formation may be prevented. (i.e., for example, during long-term dialysis).
The present invention contemplates various embodiments wherein a medium comprising a cytostatic and antiproliferative drug (i.e., sirolimus, tacrolimus and analogs of sirolimus) is applied to a surgical site or the outside of an organ with a lumen (i.e., for example, extravascularly). In one embodiment, the drug reduces or prevents the formation of scar tissue and/or adhesions or tissue adhesions. The medium contemplated by this invention to deliver a specific drug, or a drug combination, to a surgical site or wound includes, but is not limited to, microparticles, gels, hydrogels, foams, bioadhesives, liquids, or xerogels. Particularly, these media are produced in various embodiments providing a controlled release of a drug such as sirolimus either singly or in a combination as according to the present invention.
Reductions in scar tissue and/or adhesion formation will be obtained if the cytostatic antiproliferative drug that is used is both cytostatic and anti-inflammatory. Improved reductions in scar tissue and/or adhesion formation will be obtained if the antiproliferative drug is combined with an antiplatelet and/or antithrombotic drug (i.e., for example, xemilofiban). Even better improved reductions in scar tissue and/or adhesion formation will be obtained if the antiproliferative-antiplatelet/antithromotic combination is further combined with an anticoagulant drug (i.e., heparin or low molecular weight heparin).
In one embodiment, this invention contemplates cytostatic antiproliferative drugs such as, but not limited to, sirolimus, tacrolimus and analogs of sirolimus. For example, these drug include, but are not limited to, sirolimus, tacrolimus, everolimus, CCI-779, ABT-578, 7-epi-rapamycin, 7-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy-rapamycin and 2-desmethyl-rapamycin. Other non-sirolimus related drugs may also be effective at reducing scar tissue and/or adhesion formation, including, but not limited to, antisense to c-myc and turnstatin.
Other derivatives of sirolimus comprising mono-esters and di-esters at positions 31 and 42 have been shown to be useful as antifungal agents and as water soluble prodrugs of rapamycin. Rakit S., “Acyl Derivatives Of Rapamycin” U.S. Pat. No. 4,316,885 (1982); and Stella et al., “Prodrugs Of Rapamycin” U.S. Pat. No. 4,650,803 (1987). A 30-demethoxy rapamycin has also been described in the literature. Vezina et al., “Rapamycin (AY-22,989), A New Antifungal Antibiotic. I. Taxonomy Of The Producing Streptomycete And Isolation Of The Active Principle” J. Antibiot. (Tokyo) 28:721-726 (1975); Sehgal et al., “Rapamycin (AY-22,989), A New Antifungal Antibiotic. II. Fermentation, Isolation And Characterization” J. Antibiot. (Tokyo) 28:727-732 (1975); Sehgal et al., “Demethoxyrapamycin (AY-24,668), A New Antifungal Antibiotic” J. Antibiot. (Tokyo) 36:351-354 (1983); and Paiva et al., “Incorporation Of Acetate, Propionate, And Methionine Into Rapamycin By Streptomycetes hygroscopicus” J. Nat Prod 54:167-177 (1991).
Numerous other chemical modifications of rapamycin have been attempted. These include the preparation of mono- and di-ester derivatives of rapamycin (WO 92/05179), 27-oximes of rapamycin (EP 467606); 42-oxo analog of rapamycin (Caufield et al., “Hydrogenated Rapamycin Derivatives” U.S. Pat. No. 5,023,262 (1991)(herein incorporated by reference)); bicyclic rapamycins (Kao et al., “Bicyclic Rapamycins” U.S. Pat. No. 5,120,725 (1992)(herein incorporated by reference)); rapamycin dimers (Kao et al., “Rapamycin Dimers” U.S. Pat. No. 5,120,727 (1992)(herein incorporated by reference)); silyl ethers of rapamycin (Failli et al., “Silyl Ethers Of Rapamycin” U.S. Pat. No. 5,120,842 (1992)(herein incorporated by reference)); and arylsulfonates and sulfamates (Failli et al., “Rapamycin 42-Sulfonates And 42-(N-carboalkoxy) Sulfamates Useful As Immunosuppressive Agents” U.S. Pat. No. 5,177,203 (1993)(herein incorporated by reference)). Rapamycin was recently synthesized in its naturally occurring enantiomeric form. Nicolaou et al., “Total Synthesis Of Rapamycin” J. Am. Chem. Soc. 115: 4419-4420 (1993); Romo et al, “Total Synthesis Of (−) Rapamycin Using An Evans-Tishchenko Fragment Coupling” J. Am. Chem. Soc. 115:7906-7907 (1993); Hayward et al, “Total Synthesis Of Rapamycin Via A Novel Titanium-Mediated Aldol Macrocyclization Reaction” J. Am. Chem. Soc., 115:9345-9346 (1993).
Cytotoxic drugs such as taxol, though they are anti-proliferative, are not nearly as efficient as cytostatic drugs such as sirolimus related drugs for reducing scar tissue and/or adhesion formation resulting from a surgical procedure. Although it is not necessary to understand the mechanism of an invention, it is believed that these cytotoxic drugs, such as taxols (i.e., for example, paclitaxel) act primarily by inhibiting microtubule stabilization, that is quite unlike the macrolide family (i.e., for example, rapamycins), which is believed to be cytostatic by binding with the mTOR protein.
Previous attempts to solve problematic post-surgical scarring and/or adhesions using cytostatic drug therapies have used these highly cytotoxic mitosis inhibitors such as anthracycline, daunomycin, mitomycin C and doxorubin. However, no mention is made of any cytostatic antiproliferative drug such as sirolimus or similar acting drugs. Kelleher P. J., “Methods And Compositions For The Modulation Of Cell Proliferation And Wound Healing”, U.S. Pat. No. 6,063,396 (2000)(herein incorporated by reference). Similarly, both systemic and targeted local administration of cytotoxic antiproliferative drugs (i.e., taxol) are reported to inhibit or reduce arterial restenosis. Kunz et al., “Therapeutic Inhibitor Of Vascular Smooth Muscle Cells”, U.S. Pat. No. 5,981,568 (1999)(herein incorporated by reference). Importantly, the most preferred antiproliferative agents of Kunz et al. (i.e., taxol and cytochalasin) are admitted to be cytotoxic during prolonged treatment. Kunz et al., however, fails to consider the drug sirolimus or any functional sirolimus analogs for extraluminal application to reduce cellular proliferation that can result in scar tissue and/or adhesion formation.
Other attempts to reduce scar tissue and/or adhesion formation include using beta-emitting radioisotopes placed onto a sheet of material that irradiates the local tissue. Fischell et al., “Radioisotope Impregnated Sheet Of Biocompatible Material For Preventing Scar Tissue Formation” U.S. Pat. No. 5,795,286 (1998)(herein incorporated by reference). Although radioisotopes may be effective at preventing cellular proliferation associated with adhesions, the limited shelf life and safety issues associated with radioisotopes make them less than ideal.
It is known that cellular proliferation and restenosis are reduced within angioplasty injured arteries when intraluminal vascular stents are coated with anti-proliferative drugs such as rapamycin (i.e., sirolimus), actinomycin-D or taxol. Falotico et al., “Drug/Drug Delivery Systems For The Prevention And Treatment Of Vascular Disease” U.S. Pat. Publ. No's. 2002/0007214 A1; 2002/0007215 A1; 2001/0005206 A1; 2001/007213 A1 & 2001/0029351 A1; and Morris et al., “Method Of Treating Hyperproliferative Vascular Diseases” U.S. Pat. No. 5,665,728 (all herein incorporated by reference). These disclosures are limited to treating hyperproliferative smooth muscle by rapamycin administration using an intraluminal device, such as a stent.
Platelet adherence followed by platelet aggregation is believed the first biological event to occur following any injury to a blood vessel (i.e., for example, a surgical incision, trauma or wound). Although it is not necessary to understand the mechanism of an invention it is believed that platelets maintain blood hemostasis and provide a phospholipid surface for coagulation reactions to occur, thereby stabilizing a developing thrombus. Further, white blood cells (i.e., leukocytes), in association with platelets, also promote coagulation reactions by expressing tissue factors that trigger the blood coagulation cascade resulting in fibrin formation and deposition. Leukocytes are also referred to in the art as inflammatory cells, thereby making the inflammatory process an integral aspect in thrombogenesis. Shebuski et al., “Role Of Inflammatory Mediators In Thrombogenesis: Perspectives in Pharmacology (PIP)” J. Pharmacol. Exp. Ther., 300:729-735 (2002).
Various embodiments of the present invention contemplate inhibiting thrombus formation. Thrombus formation inhibition may occur at various points in the blood coagulation cascade. It is generally known in the art that circulating blood platelets (3×109 cells/ml) are usually the initiating factor. Platelets may be the first to react by binding to a foreign surface or an injured tissue. Recently, GPIIb/IIIa fibrinogen receptor antagonists have been introduced as effective antiplatelet drugs. Alternatively, inhibiting fibrin formation and/or thrombus stabilization may be accomplished by administering antithrombins, heparin, low molecular weight heparin analogs or other anticoagulant drugs.
In one embodiment, the GPIIb/IIIa inhibitor is administered as a delayed release formulation, wherein the release of the inhibitor is delayed by approximately 1-3 days. Although it is not necessary to understand the mechanism of an invention, it is believed that GPIIb/IIIa acts upon a platelet receptor that activates fibrin formation.
Currently, three GPIIb/IIIa fibrinogen receptor antagonists are available commercially (Aggrastat®, Integrilin® and ReoPro®). These drugs are administered intravenously and currently prescribed to patients: i) having angioplasty with a high risk for complications; ii) undergoing emergent percutaneous coronary intervention (i.e., for example, balloon angioplasty, atherectomy, or stent placement) starting 18-24 hours before surgery and continuing for at least an hour after surgery; and iii) with refractory unstable angina.
As mentioned above, platelets and white blood cells respond to foreign substances in much the same way as an injured tissue (i.e., for example, a blood vessel). Although it is not necessary to understand the mechanism of an invention, it is believed that platelet adherence, followed by fibrin deposition and subsequent encapsulation, is involved in fibrin sheath formation. Fibrin sheaths are known to be responsible for intravascular catheter medical complications, in particular, when using central venous and intraperitoneal dialysis catheters. Santilli, J., “Fibrin Sheaths And Central Venous Catheter Occlusions: Diagnosis And Management” Tech. in Vascular and Interventional Radiology 5:89-94 (2002).
In one embodiment, the present invention contemplates a method to prolong catheter or vascular graft (i.e., for example, a synthetic vascular graft) function comprising coating the outside surface with a drug combination comprising a GPIIb/IIIa inhibitor (i.e., for example, xemilofiban) and an anticoagulant (i.e., for example, a low molecular weight heparin analog) thereby preventing fibrin sheath formation. In another embodiment, the present invention contemplates a method to prolong catheter or vascular graft (i.e., for example, a synthetic vascular graft) function comprising coating the inside surface with a drug combination comprising a GPIIb/IIIa inhibitor (i.e., for example, xemilofiban) and an anticoagulant (i.e., for example, a low molecular weight heparin analog) thereby preventing fibrin sheath formation.
In one embodiment, the present invention contemplates a method to prolong catheter function comprising coating the outside surface of an intravascular catheter or vascular graft (i.e., for example, a synthetic vascular graft) with a drug combination comprising antithrombins (i.e., for example, bivalirudin) and an anticoagulant (i.e., for example, a low molecular weight heparin analog). In another embodiment, the present invention contemplates a method to prolong catheter function comprising coating the inside surface of an intravascular catheter with a drug combination comprising antithrombins (i.e., for example, bivalirudin) and an anticoagulant (i.e., for example, a low molecular weight heparin analog).
Platelets are also known to release growth factors, in particular, platelet-derived growth factor (PGDF) which promote smooth muscle cell proliferation. Schwartz et al., “Common Mechanisms Of Proliferation Of Smooth Muscle In Atherosclerosis And Hypertension” Hum Pathol. 18:240-247 (1987). For example, following stent placement in patients with coronary lesions, platelets adhere to the injured blood vessel's intraluminal surface. Subsequently, the bound platelets release growth factors that result in restenosis. Restenosis is a condition where smooth muscle cells accumulate within an injured blood vessel such that vessel blockage occurs within 3-6 months (i.e., such as following an intravascular stent placement). Restenosis may be reduced with the use of drug-eluting stents, in particular with drugs such as rapamycin. Falotico et al., “Drug/Drug Delivery Systems For The Prevention And Treatment Of Vascular Disease” United States Patent Application Publ. No: 2002/0016625 A1 Filed: May 7, 2001. Published: Feb. 7, 2002. However, thrombus formation following stent placement is a problem. Jeremias et al., “Stent Thrombosis After Successful Sirolimus-Eluting Stent Implantation” Circulation 109(16):1930-1932 Epub Apr. 12 (2004). Stent technology is attempting to solve this problem using antiplatelet drug-eluting stents or grafts, but its efficacy is as yet unknown. Falotico, R., “Coated Medical Devices For The Prevention And Treatment Of Vascular Disease” United States Patent Application 2003/0216699 A1. Filed: May 7, 2003. Published; Nov. 20, 2003.
The present invention contemplates administering a drug combination comprising an antiproliferative, an antiplatelet, an antithrombin, or an anticoagulant at, or near, an intravascular stent placement.
Platelet-mediated thrombosis is also known to complicate successful native and synthetic graft implantation. Hemodialysis vascular access sites (infra) or an obstructed arterial vasculature (i.e., for example, in the vascular periphery or the heart) bypass utilize these grafts. Vascular neointimal formations are known to occur in native and synthetic grafts, particularly in the venous outflow tracts. Walles et al., “Functional Neointima Characterization Of Vascular Prostheses In Human” Ann Thorac Surg. 77:864-868 (2004).
Vascular neointimal formations (i.e., for example, lesions) are composed primarily of smooth muscle cells, and ultimately lead to a decreased blood flow within the grafts. Platelet-released growth factors may, in part, stimulate vascular neointimal formations. As a neointimal lesion develops, blood flow becomes more turbulent and further injury occurs, resulting in additional platelet recruitment. With additional platelet recruitment, fibrin deposition may result with complete graft failure as a probable consequence. Thus, a drug combination comprising an antiproliferative, an antiplatelet, an antithrombin, and an anticoagulant may have distinct advantages over an antiproliferative agent alone or an anticoagulant combined with just one other drug.
In one embodiment, the present invention contemplates devices and methods to administer a drug combination to a graft venous outflow tract. In one embodiment, a drug combination is administered using a controlled-release polymer-based medium or carrier. In one embodiment, the medium or carrier may be wrapped or draped around the exterior graft surface such that the drug combination diffuses to an intraluminal blood vessel surface (i.e., for example, the vaso vasorum). In one embodiment, the medium or carrier comprising at least one drug including, but not limited to, an antiproliferative drug (i.e., for example rapamycin), an antiplatelet drug (i.e., for example, xemilofiban), an antithrombin drug (i.e., for example, bivalirudin) or an anticoagulant (i.e., for example, heparin). One of skill in the art will recognize that a combination of two or more drugs is intended when describing a drug combination as contemplated by the present invention.
Specific embodiments of this invention comprise treatment methods combining at least one antiproliferative drug with one or more supplemental and/or complementary pharmaceutical drugs. In one embodiment, antiproliferative drug combinations comprise supplemental and/or complementary pharmaceutical drugs including, but are not limited to, “antithrombotics” commonly known in the art as antiplatelet drugs, antithrombins, and anticoagulants. Any drug combination may be delivered locally to the surgical site before, during, or after a surgical procedure. For example, an antithrombotic and heparin combination may be used to coat intravascular catheters, or other medical devices suited to the central venous system.
In one embodiment, an antiplatelet drug includes, but is not limited to, a glycoprotein IIb/IIIa (GPIIb/IIIa) fibrinogen receptor antagonist comprising xemilofiban, cromafiban, elarofiban, orbofiban, roxifiban, sibrafiban, RPR 109891, UR-4033, UR-3216, UR-2922, abciximab, tirofiban, or eptifibatide. Although it is not necessary to understand the mechanism of an invention, it is believed that xemilofiban is a potent antiplatelet GPIIb/IIIa fibrinogen receptor antagonist. Further, it is believed that xemilofiban hydrochloride (SC-54684A) is a prodrug (base) and undergoes rapid ester hydrolysis into a pharmacologically active acid metabolite (i.e., for example, SC-54701A). Further, one having skill in the art should realize that antiplatelet GPIIb/IIIa fibrinogen receptor antagonists are also known as platelet GPIIb/IIIa receptor antagonists.
In one embodiment, an antithrombin includes, but is not limited to, bivalirudin, ximelagatran, hirudin, hirulog, argatroban, inogatran, efegatran, or thrombomodulin.
In one embodiment, an anticoagulant comprises heparin. In one embodiment, an anticoagulant comprises a low molecular weight heparin (LMWH). In another embodiment, an anticoagulant comprises an unfractionated heparin (UFH). In another embodiment, an anticoagulant includes, but is not limited to, tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin or dalteparin. In one embodiment, an anticoagulant includes, but is not limited to, Factor Xa (FXa) inhibitors (i.e., for example, fondaparinux), Factor IXa (FIXa) inhibitors, Factor XIIIa (FXIIIa) inhibitors, and Factor VIIa (FVIIa) inhibitors.
Another embodiment of the present invention contemplates coating a medical device with a medium or carrier comprising sirolimus, tacrolimus or an analog of sirolimus. A medical device is “coated” when a medium comprising a cytostatic or antiproliferative drug (i.e., for example, sirolimus or an analog of sirolimus) becomes attached to the surface of the medical device. For example, such attachment includes, but is not limited to, surface adsorption, impregnation into the material of manufacture, covalent or ionic bonding and simple friction adherence to the surface of the medical device.
Carriers or mediums contemplated by this invention may comprise a polymer including, but not limited to, gelatin, collagen, cellulose esters, dextran sulfate, pentosan polysulfate, chitin, saccharides, albumin, fibrin sealants, synthetic polyvinyl pyrrolidone, polyethylene oxide, polypropylene oxide, block polymers of polyethylene oxide and polypropylene oxide, polyethylene glycol, acrylates, acrylamides, methacrylates including, but not limited to, 2-hydroxyethyl methacrylate, poly(ortho esters), cyanoacrylates, gelatin-resorcin-aldehyde type bioadhesives, polyacrylic acid and copolymers and block copolymers thereof; poly (L-lactide) (PLA), 75/25 poly(DL-lactide-co-E-caprolactone), 25/75 poly(DL-lactide-co-E-caprolactone), poly(ε-caprolactone) (PCL), collagen, polyactive, and polyglycolic acid (PGA); polytetrafluoroethylene, polyurethane, polyester, polypropylene, polyethylene, polydioxanone (PDO), and silicone. Other polymers may include, but are not limited to, cellulose acetate, cellulose nitrate, silicone, cross-linked polyvinyl alcohol (PVA) hydrogel, cross-linked PVA hydrogel foam, polyurethane, polyamide, styrene isobutylene-styrene block copolymer (Kraton), polyethylene teraphthalate, polyurethane, polyamide, polyester, polyorthoester, polyanhidride, polyether sulfone, polycarbonate, polypropylene, high molecular weight polyethylene, polytetrafluoroethylene, or other biocompatible polymeric material, or mixture of copolymers thereof; polyesters such as, polylactic acid, polyglycolic acid or copolymers thereof, a polyanhydride, polycaprolactone, polyhydroxybutyrate valerate or other biodegradable polymer, or mixtures or copolymers, extracellular matrix components, proteins, collagen, fibrin or other bioactive agent, or mixtures thereof.
The medium can be selected from a variety of polymers. However, the media should be biocompatible, biodegradable, bioerodible, non-toxic, bioabsorbable, and with a slow rate of degradation. Biocompatible media that can be used in the invention include, but are not limited to, poly(lactide-co-glycolide), polyesters such as polylactic acid, polyglycolic acid or copolymers thereof, polyanhydride, polycaprolactone, polyhydroxybutyrate valerate, and other biodegradable polymer, or mixtures or copolymers, and the like. In another embodiment, the naturally occurring polymeric materials can be selected from proteins such as collagen, fibrin, elastin, and extracellular matrix components, or other biologic agents or mixtures thereof.
Polymer media used with the coating of the invention such as poly(lactide-co-glycolide); poly-DL-lactide, poly-L-lactide, and/or mixtures thereof are of various inherent viscosities and molecular weights. For example, in one embodiment of the invention, poly(DL lactide-co-glycolide) (DLPLG, Birmingham Polymers Inc.) is used. Poly(DL-lactide-co-glycolide) is a bioabsorbable, biocompatible, biodegradable, non-toxic, bioerodible material, which is a vinylic monomer and serves as a polymeric colloidal drug carrier. The poly-DL-lactide material is in the form of homogeneous composition and when solubilized and dried, it forms a lattice of channels in which pharmaceutical substances can be trapped for delivery to the tissues.
The drug release kinetics of any coating on any device contemplated by some embodiments of the present invention can be controlled depending on the inherent viscosity of the polymer or copolymer used as the matrix and the amount of drug in the composition. The polymer or copolymer characteristics can vary depending on the inherent viscosity of the polymer or copolymer. For example, in one embodiment of the invention using poly(DL-lactide-co-glycolide), the inherent viscosity can range from about 0.55 to 0.75 (dL/g). Poly(DL-Lactide-co-Glycolide) can be added to the coating composition from about 50 to about 99% (w/w) of the polymeric composition. A poly(DL-lactide-co-glyc-olide) polymer coating amy deform without cracking, for example, when the coated medical device is subjected to stretch and/or elongation and undergoes plastic and/or elastic deformation. Therefore, polymers which can withstand plastic and elastic deformation such as poly(DL-lactide-co-glycolide) acid-based coats, have advantageous characteristics over known polymers. The rate of dissolution of the media can also be controlled by using polymers of various molecular weight. For example, for slower rate of release of the pharmaceutical substances, the polymer should be of higher molecular weight. By varying the molecular weight of the polymer or combinations thereof, a preferred rate of dissolution can be achieved for a specific drug. Alternatively, the rate of release of pharmaceutical substances can be controlled by applying a polymer layer to the medical device, followed by one or more than one layer of drugs, followed by one or more layers of the polymer. Additionally, polymer layers can be applied between drug layers to decrease the rate of release of the pharmaceutical substance from the coating.
Further, the malleability of the coating composition of some embodiments of the present invention can be further improved by varying the ratio of lactide to glycolide in the copolymer. That is, the ratio of components of the polymer can be adjusted to make the coating more malleable and to enhance the mechanical adherence of the coating to the surface of the medical device and aid in the release kinetics of the coating composition. In this embodiment of the invention, the polymer can vary in molecular weight depending on the rate of drug release desired. The ratio of lactide to glycolide can range, respectively, from about 50-85% to 50-15% in the composition. By adjusting the amount of lactide in the polymer, the rate of release of the drugs from the coating can also be controlled.
GPIIb/IIIa inhibitors may be attached to a medical device in a number of ways and utilizing any number of biocompatible materials (i.e., polymers). Different polymers are utilized for different medical devices. For example, a ethylene-co-vinylacetate and polybutylmethacrylate polymer is utilized with stainless steel. Falotico et al., United States Patent Application, 2002/0016625. Other polymers may be utilized more effectively with medical devices formed from other materials, including materials that exhibit superelastic properties such as alloys of nickel and titanium. In one embodiment, drugs such as, but not limited to, GPIIa/IIIb inhibitors, sirolimus, tacrolimus or analogs of sirolimus are directly incorporated into a polymeric medium and sprayed onto the outer surface of a catheter such that the polymeric spray becomes attached to said catheter. In another embodiment, said drug will then elute from the polymeric medium over time and enter the surrounding tissue. In one embodiment, said drug is expected to remain attached on the catheter for at least one day up to approximately six months. One of skill in the art will recognize that any drug may preferentially integrate with a polymer-based medium as either a base or acid formulation. In one embodiment, an antiplatelet drug (i.e., for example, xemilofiban) is converted to an acid formulation prior to integration into a polymer-based medium.
In one embodiment, the present invention contemplates a method of preventing post-operative surgical adhesions of tissue, protecting tissue and/or preventing tissue damage during surgery. In one embodiment, the method provides the tissue surfaces involved in the surgery with a wet coating of a physiologically acceptable aqueous solution of a hydrophilic polymeric material (i.e., for example, hyaluronic acid) prior to manipulation of the tissue during the surgery. Goldberg et al., “Method And Composition For Preventing Surgical Adhesions And Tissue Damage” U.S. Pat. No. 6,010,692 (2000)(herein incorporated by reference). Hyaluronic acid comprises a linear chain of about 2500 repeating disaccharide units in specific linkage, each composed of an N-acetylglucosamine residue linked to one glucuronic acid residue. In one embodiment, the hyaluronic acid polymeric material further comprises drugs including, but not limited to, antiproliferative drugs (i.e., for example, rapamycin), antiplatelet drugs (i.e., for example, xemilofiban), antithrombin drugs, anticoagulant drugs (i.e., for example, heparin) or antiinflammatory drugs. In one embodiment, the hydrophilic polymeric material comprises a commercially available product (i.e., for example, Seprafilm®).
Reducing postoperative adhesions is known when using a drapable, conformable adhesion barrier fabric constructed of a bioresorbable material, such as oxidized regenerated cellulose (ORC) knitted fabric. Linsky et al., “Heparin-Containing Adhesion Prevention Barrier And Process” U.S. Pat. No. 4,840,626 (1989)(herein incorporated by reference). In one embodiment, a membranous adhesion barrier comprises a fabric of oxidized regenerated cellulose impregnated with heparin and characterized by having a porosity as defined by open area of 12 to 20 percent and a density of from about 8 to 15 mg/cm2. Linsky et al., “Method And Material For Prevention Of Surgical Adhesions” U.S. Pat. No. 5,002,551 (1991)(herein incorporated by reference). In one embodiment, the membrane barrier is prepared from 60 denier, 18 filament bright rayon yarn knitted on a 32 gauge 2 bar warp knitting machine. In another embodiment, the membrane barrier is a commercially available product (i.e., for example, Interceed®, Johnson & Johnson). In another embodiment, the heparin-ORC membrane barrier further comprises a drug combination comprising antiproliferative drugs, antiplatelet drugs or antithrombin drugs. Other commercially available ORC products may also be coated with embodiments of the present invention (i.e., for example, Surgicel®). Although it is not necessary to understand the mechanism of an invention, it is believed that heparin acts as an adhesion-preventing medicament upon incorporation into the polymer coatings of the present invention.
In one embodiment, the present invention contemplates an improved anti-adhesion polymer membrane barrier wherein the polymer membrane barrier comprises a drug-eluting medium (i.e., for example, a controlled release medium). Polymer membrane barriers are currently commercially available that are compatible with the improvements described herein. (i.e., for example, SurgiWrap®). One of skill in the art will recognize that similar anti-adhesion polymer membrane barriers compatible with the improvements described herein may be constructed from other compositions comprising polymers including, but not limited to, gelatin-riboflavin polymers crosslinked in situ with ultraviolet light, poly(ethylene oxide-copropylene oxide) polymers, chitosan-poly(ethylene glycol) polymers, or pourable (i.e., for example, flowable) sodium alginate polymers.
In one embodiment, the present invention contemplates a method for administering a hydrogel-based bioadhesive to a surgical site, comprising: a) providing; i) a surgical site (i.e., for example, open or closed); ii) a twin-barrel syringe or catheter comprising; I) a first barrel containing a first aqueous medium comprising sirolimus and analogs of sirolimus and a functional polymer; and II) a second barrel containing a second aqueous medium comprising a small crosslinker molecule; b) contacting the first and second mediums onto a surgical site (i.e., for example, open or closed) under conditions such that the first and second aqueous mediums become mixed; and c) crosslinking the first and second mediums initiated by a self-polymerizing reaction to form a bioadhesive layer on the surgical site. In one embodiment, the first and second mediums are sprayed on the surgical site. In one embodiment, the first and second mediums are sequentially contacted with the surgical site. In another embodiment, the first and second mediums are mixed prior to contacting the surgical site. Preferably, the mixing occurs on a surface of a surgical site to form a crosslinked adhesive barrier; exemplary crosslinker molecules and functional polymers include, but are not limited to, components comprising DuraSeal™ or SprayGel™ (Confluent Surgical, Waltham, Mass.). Preul et al., “Toward Optimal Tissue Sealants For Neurosurgery: Use Of A Novel Hydrogel Sealant In A Canine Durotomy Repair Model”, Neurosurgery 53:1189-1199 (2003). In one embodiment, sirolimus and analogs of sirolimus are phase-separated in the first aqueous medium. In one embodiment, the first aqueous medium further comprises a supplemental or complementary drug selected from an antiplatelet drug, an antithrombin drug, an anticoagulant drug, or an antiinflammatory drug. In one embodiment, the phase separation comprises an oil-water mixture. In another embodiment, the phase separation comprises microparticles as described herein. In one embodiment, the crosslinked adhesive barrier forms a controlled release medium.
Another embodiment of the present invention contemplates a hydrogel-based bioadhesive comprising: i) a first medium comprising sirolimus and analogs of sirolimus and a functional polymer and ii) a second medium comprising a small crosslinker molecule. In one embodiment, the first medium further comprises a supplemental or complementary drug selected from an antiplatelet drug, an antithrombin drug, an anticoagulant drug, or an antiinflammatory drug. In one embodiment, the crosslinker molecule includes, but is not limited to, ethoxylated glycerols, inositols, trimethylolpropanes, succinates, glutarates, combinations of 2 or more esters (i.e., for example, glycolate/2-hydroxybutyrate or glycolate/4-hydroxyproline). In one embodiment, the functional polymer includes, but is not limited to, polyethylene oxide or polyethylene glycol. Preferably, this hydrogel-based bioadhesive forms a biocompatible crosslinked polymer from water soluble precursors having electrophilic and nucleophilic groups capable of reacting and crosslinking in situ. Pathak et al., “Biocompatible Crosslinked Polymers” U.S. Pat. No. 6,566,406 (herein incorporated by reference). In one embodiment, the crosslinked polymers are biodegradable or bioresorbable. Certain embodiments are contemplated that provide biodegradable crosslinkages that allow degradation or resorption within a predetermined period of time (i.e., for example, by chemically or enzymatically hydrolyzable crosslinkages). Examples of such chemically hydrolyzable linkages include, but are not limited to, polymers, copolymers and oligomers of glycolide, (dl)-lactide, (l)-lactide, caprolactone, dioxonone or trimethylene carbonate. Examples of such enzymatically hydrolyzable linkages include, but are not limited to, peptide linkages cleavable by metalloproteinases or collagenase. Over time, the hydrogel-based bioadhesive liquefies to form water-soluble materials that are absorbed and readily cleared from the body (i.e., for example, by renal action). The crosslinking reactions preferably occur in aqueous solution under physiological conditions. In one embodiment, the crosslinking reactions occur “in situ”, meaning they occur at local sites such as organs or tissues in a living animal or human body. In one embodiment, the crosslinking reactions do not release a substantial heat of polymerization. In one embodiment, the crosslinking reaction is completed within 10 minutes, preferably within 2 minutes, more preferably within one minute and most preferably within 30 seconds.
Anti-adhesion drug combination coatings contemplated by various embodiments of the present invention may comprise polymers having a covalent attachment to inner and outer surfaces of a medical device. In one embodiment, the coating provides versatile surface characteristics, such as lubricity, therapeutic loading and duration of therapeutic efflux. In another embodiment, the coating comprises characteristics including, but not limited to, lubricious, hydrophilic, flexible loading capabilities, controllable therapeutic release kinetics, an inner and outer lumen coating that does not significantly alter the diameter of the device, and is biocompatible. In one embodiment, a drug combination coating further comprises a silver-based antimicrobial composition effective against pathogenic bacteria (i.e., for example, Staphylococcus aureus and Pseudomonas).
In one embodiment, an anti-adhesion drug combination coating composition comprises a commercially available high-quality hydrophilic polymer that is covalently bonded to a polymeric invasive medical device (i.e., for example, Covalon Technologies Inc., Toronto Canada). Although it is not necessary to understand the mechanism of an invention it is believed that the coating results in improved biocompatibility and functionality by reducing the coefficient of static friction of a medical device polymer surface including, but not limited to, silicone, polyurethane, or polyvinyl chloride. Further, it is believed that the surface coating acts as a repository for a controlled efflux a drug combination composition at the site of device insertion or application. In one embodiment, an anti-adhesion drug combination is applied after coating the medical device. In one embodiment, coated medical devices include, but are not limited to, catheters, peritoneal dialysis catheters, hemodialysis catheters, wound drains, central venous lines, other tubular medical devices, and various wound dressings and skin coverings.
The present invention contemplates a method comprising dip-coating a medical device with a polymer-based drug combination medium and polymerizing the polymer-based drug combination by exposure to ultraviolet light. In one embodiment, the polymerization is a low-energy, surface modification process applicable to polymers including, but not limited to, silicone, polyurethane, or polyvinyl chlorides. Although it is not necessary to understand the mechanism of an invention, it is believed that when a polymer is activated by ultraviolet light, initiator reagents yield highly reactive intermediate molecules that remove a hydrogen atom from the polymer surface. Further, it is believed that the reactive polymer surface now allows monomers in solution to form carbon-carbon or carbon-nitrogen bonds with the polymer device surface by a chain reaction mechanism that also causes the monomers in solution to form a covalent polymer coating. In one embodiment, the initiator intermediates are highly reactive and facilitate creating covalently bound coatings. In another embodiment, the drug combination is integrated after polymer-based medium formation. In another embodiment, the drug combination polymer coating further comprises hydrated and dehydrated collagen. For example, these collagen-based polymer medium devices include, but are not limited to, topical and implantable surgical sheets of material (i.e., surgical wraps, sutures, gauzes etc.) or three-dimensional scaffolds useful for skin or tissue regeneration following trauma or burns.
One of skill in the art will recognize that polymers for coating medical devices (i.e., for example, vascular grafts and intravascular catheters) include, but are not limited to, polyvinyl pyrrolidone, poly(acrylic acid), poly(vinyl acetamide), poly(propylene glycol), poly(ethylene co-vinyl acetate), poly(n-butyl methacrylate) or poly(styrene-b-isobutylene-b-styrene).
One embodiment of this invention contemplates a composition that slowly releases drugs (i.e., for example, a cytostatic antiproliferative drug) in a controlled manner to reduce the formation of scar tissue and/or adhesions following a surgical procedure, trauma, or wound. In one embodiment, cytostatic drugs may be attached to medical devices comprising a surgical material and a medium, wherein said devices include, but are not limited to, catheters, grafts, meshes, wraps or closures. In another embodiment, the cytostatic drug may be combined with other drugs including, but not limited to, antiplatelet drugs, antithrombotic drugs, anticoagulant drugs or antiinflammatory drugs. In one embodiment, the antiplatelet drug comprises xemilofiban, cromafiban, elarofiban, orbofiban, roxifiban, sibrafiban, RPR 109891, UR-4033, UR-3216, UR-2922, abciximab, tirofiban, or eptifibatide. In another embodiment, the antiplatelet drug comprises SC-54701A, an acid xemilofiban metabolite. The medium may comprise polymers and/or copolymers that slowly elute drugs (for a time of at least one day) from the medical device onto which the medium is attached. In one embodiment, the medium provides a controlled release of cytostatic anti-proliferative drugs, such as sirolimus, tacrolimus and analogs of sirolimus. In another embodiment, other drugs including, but not limited to, antiplatelet drugs, antithrombotic drugs or anticoagulant drugs may also be released from the medium or device in a controlled manner. Alternatively, the drug may be attached directly to a device and subsequently released. Although it is not necessary to understand the mechanism of a successful invention, it is believed that sirolimus-like drugs interfere with the initiation of mitosis by means of interaction with the mTOR protein complex formation and cyclin signaling. Furthermore, it is believed that these drugs prevent the initiation of DNA replication by acting on cells in close proximity to the mesh from which the drug slowly elutes as very early cell cycle mitosis inhibitors that act at or before the S-phase of cellular mitosis.
The present invention contemplates a medium that has the capability of providing controlled release of drugs. For example, liposomes, microparticles, gels, hydrogels, xerogels, foams are known media having compositions compatible with controlled release characteristics. Specifically, liposomes and microparticles may provide controlled release of a drug by varying, for example, polymer composition, concentration, physical size or physical shape. Gels and hydrogels may comprise controlled release liposomes or microparticles. Alternatively, the polymer composition or concentration of a gel or hydrogel may result in the production of a micellular gel structure wherein the dissolution of the gel itself is responsible for the controlled release of the attached drug. Furthermore, foams may comprise liposomes or microparticles that allow the medium to provide controlled release characteristics.
In one embodiment, the present invention contemplates a sirolimus hydrogel polymer coating on a stainless steel medical device (i.e., for example, a permanent implant). Preferably, a stainless steel implant is brush coated with a styrene acrylic aqueous dispersion polymer (55% solids) and dried for 30 minutes at 85° C. Next, this polymer surface is overcoated with a controlled release hydrogel composition consisting of:
The coating is then dried for 25 hours at 85° C. prior to use. It is not intended that the present invention be limited by the above sirolimus concentration. One skilled in the art should realize that that various concentrations of sirolimus may be used such as, but not limited to, 0.001-10 mg/ml, preferably 0.1-5 mg/ml, and more preferably 0.001-1 mg/ml.
In another embodiment, a multiple layering of non-erodible polymers may be utilized in conjunction with sirolimus. Preferably, the polymeric medium comprises two layers; a inner base layer comprising a first polymer and the incorporated sirolimus and an outer second polymer layer acting as a diffusion barrier to prevent the sirolimus from eluting too quickly and entering the surrounding tissues. In one embodiment, the thickness of the outer layer or top coat determines the rate at which the sirolimus elutes from the medium. Preferably, the total thickness of the polymeric medium is in the range from about 1 micron to about 20 microns or greater. Another embodiment of the present invention contemplates spraying or dipping a polymer/sirolimus mixture onto a catheter.
In one embodiment, the present invention contemplates a composition comprising a di-amino acid polymer (i.e., for example, a poly(ester amide); PEA), an antiproliferative drug (i.e., for example, sirolimus, tacrolimus and analogs of sirolimus), and another drug including, but not limited to, antiplatelet drugs, antithrombotic drugs, or anticoagulant drugs. In one embodiment, the di-amino acid polymer comprises a family of biodegradable polymers composed of naturally occurring amino acids and other nontoxic building blocks.
Di-amino acid polymers may be prepared under mild solution polymerization conditions, are devoid of toxic catalysts, have reproducible molecular weights, and exhibit excellent blood and tissue compatibility. For example, PEA may be made by synthesizing monomers of two alpha-amino acids, (i.e., for example, L-leucine and L-lysine) with a diol (i.e., for example, hexanediol) and a diacid (e.g., i.e., for example, sebacic acid (1,8-octanedicarboxylic acid).
In vivo PEA biocompatibility was tested by implanting either PEA polymer-coated stents or bare metal stents into porcine coronary arteries. No differences in stent induced restenosis were seen. Specifically stenotic diameter, injury score, and stenotic area were not different between the two groups. This study suggests that the PEA polymers are suitable for implantation. Lee et al., “In-vivo biocompatibility evaluation of stents coated with a new biodegradable elastomeric and functional polymer” Coron Artery Dis. 13:237-41 (2002).
In one embodiment, the present invention contemplates a di-amino acid polymer comprising at least one carboxyl group. In one embodiment, a lysine amino acid comprises the carboxyl group. In one embodiment, the carboxyl group attaches a drug. In one embodiment, the drug may be selected from the group comprising sirolimus, tacrolimus, analogs of sirolimus, antiplatelet drugs, antithrombotic drugs, or anticoagulant drugs.
In one embodiment, the present invention contemplates a di-amino acid polymer comprising an antioxidant. In one embodiment, the antioxidant comprises tempamine (4-amino-2,2,6,6-tetramethylpiperidine-N-oxyl; also known as 4-amino TEMPO). In one embodiment, a PEA is conjugated to PEA-4-amino-TEMPO (i.e., for example, PEA-TEMPO).
Pharmaceutical grade biodegradable polymers (i.e., for example, polylactic acid and polyglycolic acid) are known in the medical arts, but have proven inadequate to provide sustained site-specific drug delivery applications due to their degradation characteristics. Specifically, these polymers degrade by hydrolysis, making them inherently unstable in biologic conditions. This degradation by water results in bulk erosion, resulting in grossly ineffective drug delivery capabilities. Consequently, medical devices containing these polymers provide an erratic release of pharmaceutical agents within the body, both in terms of the quantity of agent released, as well as the release horizon.
In one embodiment, the present invention contemplates a PEA polymer having no hydrolytic degradation, wherein an incorporated drug elutes from the polymer. In another embodiment, a PEA polymer contacting an enzymatic solution (i.e., for example, chymotrypsin or an esterase enzyme) degrades uniformly and linearly. Although it is not necessary to understand the mechanism of an invention, it is believed that a uniform and linear degradation profile will provide an effective and controlled drug delivery.
In one embodiment, the present invention contemplates a PEA copolymer capable of promoting a natural healing response. PEA polymer are biocompatible following exposure of human peripheral blood monocytes to PEA, PEA-TEMPO, 50:50 poly(D,L-lactide-co-glycolide) (PLGA), poly(n-butyl methacrylate) (PBMA) and tissue culture-treated polystyrene (TCPS). Also, human coronary artery endothelial cells (EC) were grown or human platelets were exposed to PEA, PEA-TEMPO and non-degradable polyethylene-co-vinyl acetate (PEVAc)/PBMA and showed no toxic effects.
PEA polymer surfaces modulate the morphology and quantity of adherent monocytes. For example, monocytes attached to PEA and/or PEA-TEMPO polymers differentiated into macrophages which fused to form multinucleated cells at an equivalent rate to a control, non-activating TCPS, and other polymers. For example, human monocytes may be seeded into wells. After a twenty-four hour incubation adhesion may be monitored by quantifying intracellular adenosine triphosphate levels.
Interleukin-6 (IL-6) is known to be secreted by activated monocytes and may induce secretion of additional pro-inflammatory cytokines. Monocytes attached to PEA and/or PEA-TEMPO secreted reduced levels of IL-6 when compared to PLGA and PBMA.
Human coronary artery endothelial cells may be attached to PEA and/or PEA-TEMPO to determine natural healing property promotion capability. Endothelial cell proliferation on PEA is known to be 4-fold higher than on PEVAc/PBMA.
Hemocompatibility can be determined by contacting PEA polymer with freshly isolated human platelets for 30 minutes. ATP release, a measure of activation, from platelets on PEA are known to be 2-fold lower than platelets on PEVAc/PBMA.
In vitro assessments of the tissue compatibility of biodegradable amino acid-based polymers (i.e., for example, PEA polymers) suggest that these polymers may promote the natural healing response by attenuating the pro-inflammatory reaction and promoting re-endothelialization. In addition, platelet activation suppression suggests that polymers comprising PEA are hemocompatible.
Poly(ester amide) (PEA) polymers have numerous advantages over other well-known biodegradable polymers including, but not limited to:
Although it is not necessary to understand the mechanism of an invention, it is believed that PEA and/or PEA-TEMPO polymers provide biodegradable polymers suitable for clinical cardiovascular therapies. It is also believed that: i) PEA polymers promote the natural healing response by attenuating the pro-inflammatory reaction and promoting re-endothelialization (i.e., for example, monocytes adhere to PEA surfaces but do not generate a pro-inflammatory response); ii) endothelial cells preferentially adhere and proliferate on PEA polymers as compared to smooth muscle cells; iii) PEA polymers suppress platelet adhesion, aggregation, and activation; and iv) an enzyme-driven, PEA surface erosion biodegradation may be controlled by enzymatic means.
In one embodiment, the present invention contemplates a PEA polymer that can be programmed for different drug delivery applications. In one embodiment, polymer programming comprises obtaining desired physical properties by selecting different components that make up the polymer backbone. Alternatively, different methods of making the PEA polymer are contemplated. For example, PEA materials can be combined with drugs by mechanical mixing that allows the release of the drug to be controlled by diffusion (i.e., for example, by non-covalent interactions). Alternatively, drugs can be conjugated to the polymers by covalent attachment and released by polymer biodegradation once they reach their targets.
Many drug delivery means are known in the art including, but not limited to, sheets of material, catheters, syringes, foams, gels, sprays etc. Fischell et al., United States Patent Publication No: 2004/0018228 A1 (herein incorporated by reference). The methods of the present invention are exemplified by the following description of various medical device embodiments. These illustrations are not intended to limit the scope of the invention but are only intended as examples.
One embodiment of the present invention comprises a method to reduce and/or prevent fibrin sheath formation on dialysis catheters. Another embodiment comprises a method to coat a catheter with a drug and/or drug combinations as contemplated herein.
In one embodiment, the present invention contemplates an improved dialysis/apheresis catheter comprising an anti-adhesion drug combination (i.e., for example, a GPIIb/IIIa inhibitor and an antiproliferative drug). Dialysis/apheresis and peritoneal dialysis catheters are used in both acute and chronic clinical applications. In one embodiment, a dialysis/apheresis catheter coating comprises a drug combination including an antiproliferative, antiplatelet, antithrombin or an anticoagulant that inhibits fibrin sheath formation. It is known that most dialysis/apheresis catheters comprise multilumens (3 or 4 lumen) that may be used simultaneously (i.e., thereby allowing a withdrawal and return of equal amounts of blood). In one embodiment, these lumens match flow resistance between a designated inflow lumen and a designated outflow lumen, and supports a high exchange flow rate for long-term placements. Loggie B. W., “Multi-Lumen Catheter System Used In A Blood Treatment Process” U.S. Pat. No. 6,126,631 (2000)(herein incorporated by reference).
In another embodiment, the present invention contemplates an improved dialysis catheter comprising an anti-adhesion drug combination coating. Martin et al., “Triple Lumen Catheter” U.S. Pat. No. 5,195,962 (1993)(herein incorporated by reference). Commercially available dialysis catheters include, but are not limited to, Vas-Cath® or Hickman® catheters (Bard Access Systems). One skilled in the art will recognize that these catheters are useful for acute and chronic conditions, provide optimal flow rates with a small insertion profile, are available in a variety of French sizes, single- or dual-lumen configurations, and have straight or precurved configurations. In one embodiment, a dialysis catheter coating comprises a drug combination including an antiproliferative, antiplatelet, antithrombin or an anticoagulant that inhibits fibrin sheath formation. In another embodiment, the dialysis catheter comprises a tissue in-growth cuff (i.e., for example, SureCuff®), that optionally, may comprise an antimicrobial cuff (i.e., for example, VitaCuff®), both of which are coated with an anti-adhesion drug combination.
In another embodiment, the present invention contemplates an improved peritoneal dialysis catheter (i.e., for example, Tenckhoff™, Bard Access Systems) comprising an anti-adhesion drug combination. In one embodiment, the peritoneal dialysis catheter comprises either one or two tissue in-growth cuffs (i.e., for example, SureCuff®) and/or an antimicrobial cuff (i.e., for example, VitaCuff®). Although it is not necessary to understand the mechanism of an invention, it is believed that peritoneal dialysis is a continuous flow technique which utilizes a certain amount of fluid (i.e., for example, a dialysate) which is constantly infused into the abdomen. Continuous flow peritoneal dialysis previously known in the art has utilized two single lumen peritoneal dialysis catheters or a modified large bore hemodialysis catheter. The inflow and uptake catheters enable the dialysate inflow and outflow to remain constant. However, high dialysate flow rates and re-circulation due to channeling or poor mixing inside the peritoneal cavity are problems associated with continuous flow peritoneal dialysis and may result in tissue injury or trauma. In one embodiment, the present invention contemplates an anti-adhesion drug composition attached to a continuous flow peritoneal dialysis catheter that effectively allows the dialysate to mix into the peritoneum while reducing trauma to the peritoneal walls. In the continuous flow peritoneal dialysis technique, the peritoneal dialysis solution is either utilized in a single pass or a re-circulation loop. Various re-circulation systems, such as sorbent cartridges or dialyzers, are also known. Work et al., “Catheter” U.S. Pat. No. 6,749,580 (2004)(herein incorporated by reference).
In another embodiment, the present invention contemplates an improved fixed split-tip dialysis catheter (i.e., for example, HemoSplit™, Bard Access Systems) comprising an anti-adhesion drug combination. Pourchez T., “Multilumen Catheter, Particularly For Hemodialysis” U.S. Pat. No. 6,001,079 (1999)(herein incorporated by reference). Although it is not necessary to understand the mechanism of an invention, it is believed that a fixed split-tip dialysis catheter reduces the risk of lumen damage from the tip being split too far apart during dialysate infusion that can lead to infection and bleeding.
Other dialysis catheters suitable for coatings with compositions described herein are also exemplified by: i) a Uldall Double Lumen Hemodialysis Catheter Tray (Cook Critical Care, Bloomington, Ind.)—these dialysis catheters are primarily used for vascular access during routine hemodialysis treatment; ii) a Femoral Hemodialysis Set (Cook Critical Care, Bloomington, Ind.)—these femoral catheters are used for blood withdrawal and infusion; and iii) a Spiral Acute Peritoneal Dialysis Catheter (Cook Critical Care, Bloomington, Ind.)—these peritoneal catheters have spiral side ports and are used for acute access to the peritoneal cavity and may be percutaneously inserted. A synthetic fiber cuff is affixed to the catheter to allow tissue ingrowth.
One embodiment of the present invention contemplates a composition comprising an anti-adhesion drug combination attached to an in vivo blood filter device comprising a dialysis membrane that is implanted within the superior vena cava. In one embodiment, the filter device includes a dialysate cavity which is exposed to the interior surface of the dialysis membrane, with the exterior dialysis membrane surface exposed to the patient's blood within the blood vessel. In another embodiment, the filter device is secured at the end of a multiple lumen catheter through which dialysate fluid is continually directed. Gorsuch R. G., “Apparatus And Method For In Vivo Hemodialysis” U.S. Pat. No. 6,561,996 (2003)(herein incorporated by reference).
PTFE vascular grafts are known that have a smooth PTFE luminal surface in an attempt to provide a non-adhesive surface for occlusive blood components. Brauker et al., “Vascular Graft With Improved Flow Surfaces” U.S. Pat. No. 6,517,571 (2003)(herein incorporated by reference). In one embodiment, the present invention contemplates an improved coating for a tubular intraluminal graft comprising a tubular, diametrically adjustable stent having an exterior surface, a luminal surface and a wall having a multiplicity of openings through the wall, and further having a tubular covering of porous expanded PTFE film affixed to the stent, said covering being less than about 0.10 mm thick. Myers D. J., “Intraluminal Stent Graft” U.S. Pat. No. 6,547,815 (2003)(herein incorporated by reference). In one embodiment, the intraluminal graft comprises an improved coating, wherein the coating comprises a drug combination selected from the group including, but not limited to, an antiproliferative, an antiplatelet, an antithrombotic or an anticoagulant.
In an alternative embodiment, the anti-adhesion drug combination coating is contemplated to improve a tubular intraluminal graft comprised of porous expanded PTFE film having a microstructure of nodes interconnected by fibrils, the fibrils being oriented in at least two directions which are substantially perpendicular to each other. Lewis et al., “Tubular Intraluminal Graft And Stent Combination” U.S. Pat. No. 5,993,489 (1999); and Campbell et al., “Thin-Wall Intraluminal Graft” U.S. Pat. No. 6,159,565 (2000)(both herein incorporated by reference). In one embodiment, the graft is bifurcated. Thornton et al., “Kink Resistant Bifurcated Prosthesis” U.S. Pat. No. 6,551,350 (2003)(herein incorporated by reference). In one embodiment, the anti-adhesion drug combination coating is contemplated to improve a thin-wall polyethylene tube. Campbell et al., “Thin-Wall Polytetrafluoroethylene Tube” U.S. Pat. No. 6,027,779 (2000)(herein incorporated by reference). One having skill in the art can realize that a device comprising a polyethylene tube coated with an anti-adhesion drug combination as contemplated herein, is useful to improve any graft or catheter.
In one embodiment, a drug delivery device is placed on the adventitial or periadventitial tissue (i.e., for example, the outside surface of a blood vessel and/or vascular graft) as a sheet of material. In one embodiment, these combinations are sheets of material as contemplated by the methods and devices described in U.S. Pat. No. 6,534,693 To Fischell et al. (herein incorporated by reference). The methods of the invention are achieved by coating a suitable sheet of material, a mesh, or other suitable matrix on one side or on both sides thereof, or impregnating into such material, mesh, or other suitable matrix with the desired combination of drugs and bringing the combination to the space external to the vascular structure to deliver the desired drugs and achieve the desired effect(s). The matrix can be biodegradable (or bioerodible) or nonbiodegradable (or biostable). The antiproliferative drug and the supplemental or complementary pharmaceutical drug can be mixed together and attached to a delivery device, or such drugs can be attached to a delivery device in discrete layers and/or locations of the device. In one embodiment, the present invention contemplates a composition comprising a sheet of material to which antiproliferative, antiplatelet, antithrombotic or anticoagulant drugs are attached either singly, or in any combination.
The present invention contemplates medical devices to reduce scar tissue and/or adhesion formation following surgical procedures, trauma or wounds. Most surgical procedures require tissue injury wherein the consequential healing process inevitably results in the formation of scar tissue and/or adhesions. Surgical tissue injury may be external or internal and may be performed using an open surgical site or a closed surgical site. The present invention contemplates prevention of scar tissue and/or adhesion formation by administering cytostatic antiproliferative drugs using medical devices both before, during and after surgical procedures that are performed, for example, using a traditional scalpel (i.e., an open surgical site) or using an endoscopic procedure (i.e., a closed surgical site). The present invention also contemplates prevention of fibrin sheaths, scar tissue and/or adhesion formation by administering a GPIIb/IIIa inhibitor. In one embodiment, the antiproliferative drugs are combined with antiplatelet and/or antithrombotic drugs. In another embodiment, the antiproliferative drugs, with or without the antiplatelet and/or antithrombotic drugs, are combined with anticoagulant drugs. In one embodiment, the present invention contemplates a patient having symptoms of end stage renal disease that requires frequent dialysis.
One embodiment of the present invention contemplates a device comprising a surgical material (i.e., for example, a mesh, wrap, sponge, or gauze) wherein a cytostatic antiproliferative drug is attached.
A mesh or surgical material comprising a medium wherein a cytostatic anti-proliferative drug is attached contemplated by the present invention may or may not be biodegradable as long as the mesh or surgical material is biocompatible. In one embodiment, the medium, mesh or surgical material gradually releases the cytostatic anti-proliferative drug into the surrounding surgically injured tissue over a period from as short as a day to as long as a few months, the rate of release being controlled by the type of material into which the drug is placed (supra). In one embodiment, a polymer coating is placed over the medium, mesh or surgical material to slow the eluting of the drug into the surrounding tissue. Such polymer materials are known in the field of controlled release formulations. Goldstein et al., “Compositions And Methods For Coating Medical Devices” U.S. Pat. No. 6,143,037 (2000)(herein incorporated by reference). Although it is not necessary to understand the mechanism of a successful invention, it is believed that the effect of the cytostatic anti-proliferative drug attached to at least part of the medium, mesh or surgical material decreases cellular proliferation and therefore decreases the formation of scar tissue and/or adhesions and/or adhesions. Preferably, the mesh 10 wrapped around a vascular anastomosis reduces the narrowing of that vessel which often occurs at the site of an anastomosis.
The '693 patent to Fischell et al. (supra) describes various means and methods to reduce scar tissue and/or adhesion formation resulting from a surgical procedure. However, Fischell et al. does not describe a cytostatic antiproliferative surgical wrap that is placed around biological tissue of a patient where there is a risk of formation of scar tissue and/or adhesions. Further, Fischell et. al. does not describe combining cytostatic antiproliferative drugs (i.e., for example, rapamycin) with either antiplatelet, antithrombotic or anticoagulant drugs. The present invention contemplates various means and methods including, but not limited to, surgical wraps that are placed around a biological vessel organ of a patient where there is a risk of scar tissue, adhesion and thrombus formation. Although several companies have developed products (such as biodegradable mesh, gels, foams and barrier membranes of various materials) that can be placed between these structures to reduce the tissue growth, none are entirely effective. In one embodiment, the present invention contemplates a composition comprising tissue barrier membranes to which antiproliferative, antiplatelet, antithrombotic or anticoagulant drugs are attached either singly, or in any combination.
One embodiment of the present invention contemplates a surgical wrap comprising a cytostatic antiproliferative drug (i.e., sirolimus, tacrolimus and analogs of sirolimus) wherein the drug reduces the narrowing of a body vessel, duct or lumen. In one embodiment, the present invention contemplates a composition comprising surgical wrap to which antiproliferative, antiplatelet, antithrombotic or anticoagulant drugs are attached either singly, or in any combination. In one embodiment, the surgical wrap is configured by wrapping to contact the external surface of the vessel, duct or lumen such that as the cytostatic antiproliferative drug is released from the surgical wrap, the drug is absorbed into the surrounding tissue. For example,
In one embodiment, the surgical wraps are configured by sliding to contact, or be near to, the external surface of the vessel, duct or lumen such that as the cytostatic antiproliferative drug is released from the surgical wrap, the drug is absorbed into the surrounding tissue. For example,
In the examples described above, both the surgical wrap 21 and the annular wrap 25 would each have attached an anti-proliferative drug as described herein to prevent the formation of scar tissue and/or adhesions when contacting, or being near to, biological tissues including, but not limited to, the blood vessel 41 or aorta 40. The anastomosis exemplified in
In one embodiment, an anastomosis creates a coronary bypass by joining two arteries, wherein the surgical wrap comprising a cytostatic antiproliferative drug is configured to contact the anastomosis site. For example,
One embodiment of the present invention contemplates a surgical closure (i.e., for example, a suture or a staple) to which a cytostatic antiproliferative drug is attached. Haynes et al., “Drug Releasing Surgical Implant Or Dressing Material” U.S. Pat. No. 5,660,854 (1997); and Keogh et al., “Method For Attachment Of Biomolecules To Medical Devices Surfaces” U.S. Pat. No. 5,925,552 (1999)(both herein incorporated by reference). In one embodiment, the present invention contemplates a composition comprising surgical closures to which antiproliferative, antiplatelet, antithrombotic or anticoagulant drugs are attached either singly, or in any combination. A drawing of a representative suture 45 and highly enlarged cross section of such a suture comprising an cytostatic antiproliferative drug is shown in
As with the other embodiments, when desired, the surgical wrap 21, annular wrap 25 or slit annular wrap 27 can be secured in place by a mechanical engagement between each wrap and a vessel, duct or lumen. One securing embodiment of the present invention contemplates the use of transluminally delivered staples which can take on the appearance of rivets. Preferably, these staples are made of an elastomeric material and are bioresorbable.
Surgical closures contemplated by this invention may be either soluble or insoluble. Methods of the present invention contemplate that by using a surgical closure to which a cytostatic anti-proliferative drug is attached, a surgeon can reduce scar tissue and/or adhesion formation on the surface of the skin or anywhere else where surgical closures are used. In one embodiment, placing surgical closures (i.e., for example, sutures) contemplated by this invention during eye or plastic surgery will reduce the expected scar tissue and/or adhesion formation which can compromise the result of a surgical procedure. In another embodiment, a cytostatic antiproliferative drug could be attached to any conventional surgical staple that is used to join together human tissue after a surgical procedure. It should also be understood to those skilled in the art that any of the surgical closures contemplated by the present invention (i.e., for example, sutures 22, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 46 as shown in
Surgical wraps are especially useful for surgical procedures comprising anastomoses. In one embodiment, an end-to-end arterial anastomosis comprises a surgical wrap 21 placed on the exterior surface of an artery, wherein two anastomoses sites allow the integration of a joining arterial section. The surgical wrap 21 may comprise a cytostatic antiproliferative drug that will reduce subsequent scarring and/or adhesions and vascular stenosis. (See
Although it is not necessary to understand the mechanism of a successful invention, it is believed that those skilled in the art would understand that surgical closures including, but not limited to, sutures or staples with a cytostatic anti-proliferative agent attached are useful for joining any biological tissue (i.e., for example, human tissue) resulting in a reduction of cellular proliferation, and consequently, formation of adhesions or scar tissue and/or adhesions.
For example, when cytostatic anti-proliferative sutures are used on the skin's surface, it should be understood that an ointment that includes a cytostatic anti-proliferative drug could be applied to the skin at the site of a surgical incision. Preferably, cytostatic anti-proliferative drugs contemplated the present invention comprise the group including sirolimus, anti-sense to c-myc (Resten-NG), tacrolimus (FK506), everolimus (SDZ-RAD), any other analog of sirolimus including, but not limited to, CCI-779, ABT-578, 7-epi-rapamycin, 7-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy-rapamycin or 2-desmethyl-rapamycin.
The present invention contemplates compositions and methods to reduce or inhibit the formation of adhesions. Adhesions is an unsolved medical problem to which current medical practice is largely ineffective.
The rate of adhesion formation after surgery is surprising given the relative lack of knowledge about adhesions within the medical community. Traffic accident victims who undergo surgery form adhesions in 67% of the cases. Weibel et al., Am J Surg. 126:345-353(1973). This number increases to 81% and 93% for patients with major and multiple procedures respectively. Similarly, 93% of patients who had undergone at least one previous abdominal operation had adhesions, compared with only 10.4% of patients who had never had a previous abdominal operation. Menzies et al., Ann R Coll Surg Engl. 72:60-63 (1990). Furthermore, 1% of all laparotomies develop obstructions due to adhesions within one year of surgery with 3% leading to obstruction at some time after surgery. Similarly, in regards to small bowel obstruction, 60-70% of cases involve adhesions. Following surgical treatment of adhesions causing intestinal obstruction, obstruction due to adhesion reformation occurs in 11 to 21% of cases. Between 55 and 100% of patients undergoing pelvic reconstructive surgery will form adhesions.
Adhesions are believed to cause pelvic pain by tethering down organs and tissues, causing traction (pulling) of nerves. Nerve endings may become entrapped within a developing adhesion. If the bowel becomes obstructed, distention will cause pain. Some patients in whom chronic pelvic pain has lasted more than six months may develop “Chronic Pelvic Pain Syndrome.” In addition to the chronic pain, emotional and behavioral changes appear due to the duration of the pain and its associated stress. According to the International Pelvic Pain Society:
Not all adhesions cause pain, and not all pain is caused by adhesions. In fact, the medical community is not in complete agreement that adhesions cause pain. Adhesions are not easy to observe non-invasively, for example with MRI or CT scans. However, it is clear that a medical relationship exists between pain and adhesions. Of patients reporting chronic pelvic pain, about 40% have adhesions only, and another 17% have endometriosis (with or without adhesions).
One embodiment of the present invention contemplates the treatment of patients exhibiting symptoms of a renal disease. In one embodiment, the present invention contemplates treatment of a renal disease comprising a medium to which antiproliferative, antiplatelet, antithrombotic or anticoagulant drugs are attached either singly, or in any combination. Renal diseases may include, but are not limited to, atherosclerosis of the renal artery, atherosclerotic nephropathy, fibromuscular dysplasia and end-stage renal disease.
The optimal treatment of patients with renal diseases is currently in debate. Management options include, but are not limited to, surgical or percutaneous procedures (i.e., for example, angioplasty and stenting). Generally, in patients with fibromuscular disease, the results of surgery and percutaneous approaches are successful. In patients with atherosclerotic diseases, however, the data is less promising.
Atherosclerotic renal stenosis is a rather frequent condition which, because of it's progressive nature, is becoming one of the leading causes of end-stage renal disease. For example, atherosclerotic renal artery stenosis accounts for 12-14% of new dialysis patients each year. Atherosclerotic renal artery stenosis may be associated with other clinical disease states including, but not limited to, coronary artery disease, atherosclerotic peripheral vascular disease, malignant hypertension and diabetes mellitus. Morganti et al., “Treatment Of Atherosclerotic Renal Artery Stenosis” J Am Soc Nephrol 13:S187-S189 (2002).
The clinical diagnosis of atherosclerotic renal artery stenosis may be determined by noninvasive imaging techniques known in the art. Three distinct clinical syndromes are known associated with atherosclerotic renal artery stenosis: i) renin-dependent hypertension, ii) essential hypertension and iii) ischemic nephropathy. Symptoms associated with atherosclerotic renal artery stenosis include, but are not limited to, abrupt onset or accelerated hypertension, unexplained or chronic azotemia, azotemia induced by angiotensin-converting enzyme inhibitors, asymmetric renal dimensions and congestive heart failure with normal ventricular function. Safian, R. D., “Atherosclerotic Renal Artery Stenosis” Curr Treat Options Cardiovasc Med., 5:91-101 (2003).
Type 2 diabetes mellitus patients may develop atherosclerotic nephropathy that is associated with renal artery stenosis. Subcritical (<65%) renal artery stenosis is known to occur during chronic kidney disease in patients with type 2 diabetes with uncontrolled hypertension and serum creatinine levels of 1.8 mg/dL or greater. The relative risk for progression to end-stage renal disease is greater in those patients having renal stenosis than those without the condition. Myers et al., “Renal Artery Stenosis By Three-Dimensional Magnetic Resonance Angiography In Type 2 Diabetics With Uncontrolled Hypertension And Chronic Renal Insufficiency: Prevalence And Effect On Renal Function” Am J Kidney Dis 41(2):351-359 (2003).
Surgical intervention, such as operative renal artery repair, is a known approach to alleviate symptoms of atherosclerotic renal diseases. Hypertension and parameters associated with renal function (i.e., for example, estimated glomerular filtration rates, creatinine levels etc.) are improved after surgical vascular reconstruction. Chem et al., “Surgical Management Of Atherosclerotic Renovascular Disease”, J Vasc Surg 35:236-245 (2002).
One embodiment of the present invention contemplates a method comprising a patient exhibiting at least one symptom of atherosclerotic renal artery stenosis, wherein a surgical material comprising sirolimus, tacrolimus and analogs of sirolimus is extravascularly placed within the patient during a surgical procedure. In another embodiment, the surgical material may further comprise a drug selected from the group comprising antiplatelet drugs, antithrombotic drugs, or anticoagulant drugs. In one embodiment, at least one symptom of the renal artery stenosis is reduced. In one embodiment, the surgical procedure comprises stenting. In another embodiment, the surgical procedure comprises renovascular reconstruction.
End-stage renal disease has various causes that requires mechanical removal of water, salt, electrolytes and waste products excreted by normal kidneys or their accumulation will result in death. Removal of these products can be variably achieved by either hemodialysis or peritoneal dialysis. The most common cause of end-stage renal disease in the US is diabetes mellitus. End-stage renal disease almost always follows chronic kidney failure which has persisted for 10 to 20 years or more. Symptoms of end-stage renal disease may include, but are not limited to, unexplained weight loss, nausea, vomiting, general ill feelings, fatigue, headache, frequent hiccups, generalized itching, little or no urine output, easy bruising or bleeding, bloody vomit or stools, decreased alertness, drowsiness, somnolence, lethargy, confusion, delirium, coma, muscle twitching or cramps, seizures, an increased skin pigmentation (i.e., for example, yellow or brown), nail abnormalities or decreased sensation in the hands, feet, or other areas.
The primary source of morbidity in adult patients subjected to long-term dialysis comprises complications related to vascular access. As with adults, pediatric patients having end-stage renal disease must rely on chronic hemodialysis upon failure of transplantation options. Long-term survival of arteriovenous fistulas and arteriovenous grafts in pediatric patients is even more important in children than adults due to the concomitant increase in treatment duration. Patency rates between arteriovenous fistulas and arteriovenous grafts do not show consistent differences in pediatric patients: one-year—74% v. 96%; three-year—59% v. 69%; and five-year—59% v. 40%. Furthermore, access patency does not correlate with a patient's weight or age at access creation. Access failure due to thrombosis, stenosis and infection occurred more frequently in arteriovenous grafts. Despite these complications, arteriovenous fistulae and arteriovenous grafts are preferable to facilitate long-term hemodialysis treatments. Sheth et al., “Permanent Hemodialysis Vascular Access Survival In Children And Adolescents With End-Stage Renal Disease” Kidney Int 62(5):1864-1869 (2002)
The practical difficulties in maintaining a patent entry for the connection of dialysis tubing has proved to be one of the most significant obstacles to successful long-term treatment. Several other complications that may develop during long-term dialysis of end-stage renal disease patients that include, but are not limited to, vascular calcification, cardiovascular disease, arterial damage, arterial stiffening and vascular stenosis.
Chronic hemodialysis requires reliable vascular access. Historically, double lumen catheters introduced into wide bore veins have replaced the traditional Scribner shunt intended as temporary access that reduced complications and morbidity. Cuffed tunneled internal jugular catheters and synthetic arteriovenous grafts usually made of polytetrafluoroethylene (PTFE) improved the vascular access armamentarium, but the arteriovenous fistula remains the life-line for chronic hemodialysis patient. Preferably, however, synthetic arteriovenous grafts are used in elderly and diabetic patients. Arteriovenous synthetic grafts have advantages including, but not limited to, a short maturation time and multiple potential access sites.
Venous stenosis and thrombotic episodes are responsible for approximately 80% of vascular access failures. Vascular access related morbidity accounts for almost 25% of all hospital stays for end-stage renal disease patients and may contribute to as much as 50% of all hospitalization costs. Monitoring and treatment of vascular access failure due to outflow stenosis may be measured by ultrasound dilution and duplex color flow Doppler technique. Conventional and digital subtraction angiography procedures, however, have the additional advantage of visualizing the total vasculature and blood flow. Current treatments to correct vascular access failure due to outflow stenosis include use of percutaneous transluminal angioplasty, stents and surgical correction. The various methods being used to prevent graft stenosis include use of dipyridamole and radiation. Pareek et al., “Angio-Access For Hemodialysis—Current Perspective” J Indian Med Assoc 99(7):382-384 (2001) The present invention contemplates a method to reduce vascular access morbidity and outflow stenosis by administration of a cytostatic antiproliferative drug such as, but not limited to, sirolimus, tacrolimus and analogs of sirolimus.
Patients with hemodialysis vascular access may be evaluated using radiological ultrasound procedures of the peripheral veins of the upper extremities for initial placement of a dialysis fistula and identification of stenosis and thrombosis in misfunctional dialysis fistulas. Preoperative screening enables the identification of a suitable vessel to create a hemodynamically-sound dialysis fistula. Thrombosed fistula and grafts can be declotted by purely mechanical methods or in combination with a lytic drug. Surlan et al., “The Role Of Interventional Radiology In Management Of Patients With End-Stage Renal Disease” Eur J Radiol 46(2):96-114 (2003).
If an arterio-venous fistula shunt is placed into the arm of a dialysis patient, then the same type of cytostatic anti-proliferative agent(s) as described above could be attached to that shunt device to increase the time during which the associated vein in the arm would remain patent. Ideally, the cytostatic anti-proliferative drug could be placed throughout the inner surface of the shunt or it could be placed near the ends where the shunt attaches to the vein or to the artery.
The advent of permanent hemodialysis access has made possible the use of chronic hemodialysis in patients with end-stage renal disease. Although autogenous arteriovenous fistulae remain the conduit of choice, their construction is not always feasible. Consequently, grafts are placed approximately 51% of the time while arteriovenous fistulas are placed only 26% of the time. Prosthetic grafts made of polytetrafluoroethylene (PTFE) are typically the second-line choice for hemoaccess. However, these grafts suffer from decreased rates of patency and an increased number of complications. Anderson et al., “Polytetrafluoroethylene Hemoaccess Site Infections” American Society for Artificial Internal Organs Journal 46(6):S18-21(2000). In one embodiment, the present invention contemplates the administration of a medium comprising sirolimus, tacrolimus or an analog of sirolimus to a patient having PTFE graft complication. In one embodiment, the medium comprises an antiproliferative, antiplatelet, antithrombotic or anticoagulant drugs, either singly, or in any combination. In one embodiment, the medium is sprayed onto the PTFE graft. In another embodiment, the medium is attached to a surgical wrap that encircles the PTFE graft. In one embodiment, the medium is attached to a surgical sleeve (i.e., a bandage or mesh that is tubular in nature) that is placed or draped onto the exterior surface of the vasculature during the PTFE graft procedure.
Stenosis, the most common vascular complication, occurs in 1-12% of transplanted renal arteries and represents a potentially curable cause of hypertension following transplantation and/or renal dysfunction. Treatment with percutaneous transluminal renal angioplasty with a stent has been technically successful in 82-92% of the cases, and graft salvage rate has ranged from 80 to 100%. Restenosis, however, occurs in up to 20% of cases. Surlan et al., “The Role Of Interventional Radiology In Management Of Patients With End-Stage Renal Disease” Eur J Radiol 46(2):96-114 (2003).
Central vein stenosis and occlusion is known to occur following upper extremity placement of peripherally inserted central venous catheters and venous ports. Catheter caliber is not believed to affect the development of these central vein abnormalities. Longer durations of catheter dwell times, however, is positively correlated with central vein stenosis or occlusion. In order to preserve vascular access for dialysis fistulae and grafts it is suggested that alternative venous access sites be considered for patients with chronic renal insufficiency and end-stage renal disease. Gonsalves et al., “Incidence Of Central Vein Stenosis And Occlusion Following Upper Extremity PICC And Port Placement” Cardiovasc Intervent Radiol 26(1) (2003)
Renal replacement therapy comprises a combination of dialysis and transplantation that is the only means of sustaining life for patients with end-stage renal disease. The present invention contemplates the administration of a cytostatic antiproliferative drug to reduce renal artery stenosis following a kidney transplant. In one embodiment, the reduction in stenosis is due to a diminished presence of atherosclerosis and fibrosis at the anastomosis. Although transplantation is the treatment of choice, the number of donor kidneys are limited and transplants may fail. Hence many patients require long-term or even life-long dialysis. Vale et al., “Continuous Ambulatory Peritoneal Dialysis (CAPD) Versus Hospital Or Home Hemodialysis For End-Stage Renal Disease In Adults” Cochrane Database Syst Rev (1):CD003963 (2003).
In one embodiment, the present invention contemplates a method to treat stenosis or restenosis comprising a medium comprising an antiproliferative, antiplatelet, antithrombotic or anticoagulant drug, either singly, or in any combination.
Cardiovascular complications are known to occur in patients having end-stage renal disease. The present invention contemplates the administration of a complementary pharmaceutical drug comprising a cytostatic antiproliferative drug under conditions such that cardiovascular complications related to end-stage renal disease are reduced. In one embodiment, the present invention contemplates a complementary antiproliferative pharmaceutical drug combination selected from the group comprising an antiplatelet, antithrombotic or anticoagulant drug.
Vascular calcification is common in patients with end-stage renal disease who are treated with regular dialysis, and is known to contribute to the very high mortality rate from cardiovascular causes in such patients. Arterial calcification in those with chronic renal failure can result from the deposition of mineral along the intimal layer of arteries in conjunction with atherosclerotic plaques or from calcium deposition in the medial wall of arteries that is due, at least in part, to disturbances in mineral metabolism. It appears that coronary artery calcification is common and often quite extensive in patients with end-stage renal disease and its appearance may be useful in predicting the risk of adverse cardiovascular events. Goodman W., “Vascular Calcification In End-Stage Renal Disease” J Nephrol 15(Suppl 6):S82-S85 (2002).
Large artery damage is a major contributory factor to the high cardiovascular morbidity of patients with end-stage renal disease. Arterial stiffness (i.e., for example, carotid distensibility) results from this tissue damage and measurements of this phenomenon may be important to assess cardiovascular risk reduction strategies. Aortic stiffness measurements could serve as an important tool in identifying end-stage renal disease patients having a higher risk of cardiovascular disease. Blacher et al., “Prognostic Significance Of Arterial Stiffness Measurements In End-Stage Renal Disease Patients” Curr Opin Nephrol Hypertens 11(6):629-34 (2002).
For any of the applications described herein, the systemic application of one or more of the cytostatic anti-proliferative agents that have been described could be used conjunctively to further minimize the creation of scar tissue and/or adhesions.
Although only the use of certain cytostatic anti-proliferative agents has been discussed herein, it should be understood that other medications could be added to the cytostatic anti-proliferative drugs to provide an improved outcome for the patients. Specifically, for applications on the skin, an antiseptic, and/or antibiotic, and/or analgesic, and/or antiinflammatory agent could be added to a cytostatic anti-proliferative ointment to prevent infection and/or to decrease pain. These other agents could also be applied for any other use of the cytostatic antiproliferative drugs that are described herein. It is further understood that any human patient in whom a cytostatic antiproliferative agent is used plus at least one of the other drugs listed above could also benefit from the systemic administration of one or more cytostatic anti-proliferative agent that has been listed herein.
Various other modifications, adaptations, and alternative designs are of course possible in light of the above teachings. Therefore, it should be understood at this time that within the scope of the appended claims, the invention can be practiced otherwise than as specifically described herein.
The following is merely intended as a representation of one embodiment of the present invention and is not intended to be limiting.
This example predicts the ability of one embodiment of a hydrogel-based bioadhesive comprising sirolimus and analogs of sirolimus, xemilofiban, and bivalirudin to prevent post-surgical adhesions and scarring. Eighteen female New Zeland White Rabbits, 3-4 kg in body weight will undergo a standardized pericardial abrasion protocol known in the art. Bennett et al., “Next-Generation HydroGel Films As Tissue Sealants And Adhesion Barriers”, J Card Surg 18:1-6 (2003); and Wiseman et al., “Fibrinolytic Drugs Prevent Pericardial Adhesions In The Rabbit” J Surg Res 53:362-368 (1992).
The rabbits will be sedated, placed in dorsal recumbency, intubated, and maintained under inhalation anesthesia. A median sternotomy is performed to expose the heart. The pericardial sac is opened and a standardized superficial abrasion with a dry gauze on the anterior (ventral) surface of the heart will create a “central strip” (CS) of roughened tissue. The rabbits are then randomized into a control group (N=6) that receives no further treatment, a first treatment group (N=6) where the hydrogel-based bioadhesive, as contemplated by the present invention, comprises sirolimus and analogs of sirolimus xemilofiban, and bivalirudin and is applied to the abraded anterior epicardium reaching a thickness of approximately 1-2 millimeters and a second treatment group (N=6) where the hydrogel-based bioadhesive is combined with the anticoagulant, heparin, and applied to the abraded anterior epicardium reaching a thickness of approximately 1-2 millimeters. In situ polymerization of the hydrogel occurs thereby generating a film. The tissue is then rinsed four times with 20 ml of buffered isotonic saline. Excess fluids are then suctioned off and the pericardium is left open. The sternum, however, is closed with interrupted sutures and the fascia and skin are closed in layers. During recovery, the rabbits are administered pain medication (i.e., for example, butorphanol 0.1-0.2 mg/kg S.C.) at 0, 6 and 12 hours after surgery.
Fourteen days post-surgery the rabbits will be sacrificed and a necropsy performed. A blind scoring protocol determines the extent, tenacity and density of adhesions resulting from the pericardial abrasions.
The results are expected to show that significantly more adhesions are present in the control group when compared to either the first treatment group or the second treatment group. The first treatment group (i.e., treated with a hydrogel-based bioadhesive comprising sirolimus and analogs of sirolimus xemilofiban, and bivalirudin) will show significantly less adhesions than the second treatment group (i.e., treated with hydrogel-based bioadhesive-heparin combination). Adhesion tenacity and density are also expected to decrease in the following order: control>second treatment group>first treatment group.
This example presents the basic materials that were used in the following Examples related to PEA efficacy, biocompatibility
Poly(ester amides) (PEA) were manufactured by MediVas, Inc. Poly(D,L-lactide-co-glycolides) (PLGA) were purchased from Boehringer-Ingelheim. Poly(n-butyl methacrylate) (PBMA) was purchased from Polysciences.
PEA is made in the presence of hexanediol and sebacic acid by synthesizing monomers of two alpha amino acids, L-Leucine and L-Lysine, with diols (x) and diacids (y). See
Human peripheral blood monocytes were isolated by density centrifugation and magnetic separation (Miltenyi). Human platelets were purchased from the San Diego Blood Bank. Human coronary artery endothelial cells and aortic smooth muscle cells were purchased from Cambrex. Tissue culture polystyrene plates (TCPS; Falcon) with or without fibronectin coating (1 mg/ml) were used as controls.
Phenotypic progression of monocytes-to-macrophages and contact-induced fusion to form multinucleated cells proceeded at a similar rate over three weeks of culture. PEA surfaces supported adhesion and differentiation of human monocytes, but, qualitatively, PEA surfaces do not appear to induce a hyper-activated state as judged by morphology and differentiation/fusion rates. See
Secretion of pro-inflammatory and anti-inflammatory mediators by monocytes and macrophages were measured by ELISA (R&D Systems) after 24 hours (shown) and 7 days (not shown) of incubation on the polymers.
Interleukin-6 is a pleiotropic pro-inflammatory cytokine that can increase macrophage cytotoxic activities. Monocytes secreted over 5-fold less IL-6 when on PEAs than on the other polymers (representative experiment of n=4). IL-6 secretion was less than 10 pg/ml on all polymers by day 7 of culture (not shown). See
Interleukin-1b is a potent pro-inflammatory cytokine that can increase the surface thrombogenicity of the endothelium. After 24 hours, monocytes on PEA secreted less IL-1b than on PLGA 73K and PBMA (representative experiment of n=4). IL-1b secretion was less than 10 pg/ml on all polymers by day 7 of culture (not shown). See
Interleukin-1 receptor antagonist is a naturally occurring inhibitor of IL-1b that competitively binds the receptors for IL-1 and block pro-inflammatory signaling. PEAs induced adherent monocytes to secrete a significant amount of this anti-inflammatory mediator (representative experiment of n=4). See
Platelet aggregation, used as a marker of polymer hemocompatibility, was visualized using human platelets that were exposed to PEA and a fibrinogen-coated surface for 30 minutes. Platelets did not readily adhere to or aggregate on PEA but aggregated as expected on fibrinogen. See
Human platelets were incubated with polymer-coated or protein-coated wells for 30 minutes at 37° C., and ATP release was measured by luminescence assay (Cambrex). Platelets were 2-fold less activated on PEA than on PEVAc/PBMA, and PEA was only about 2 times as activating to platelets as a heparin-coated surface, suggesting that PEA is highly hemocompatible. See
Human coronary artery endothelial cells (EC) and aortic smooth muscle cells (SMC) were incubated on the polymers for 72 hours. EC proliferation on PEA was 4-fold higher than on PEVAc/PBMA, and PEA supported EC growth more than SMC growth relative to the cells' growth on a gelatin-coated surface. See
Polymers were cast onto stainless steel disks and were incubated in enzyme or control buffers at 37° C. Solutions were changed every 48 hours, and the activity of the enzyme, α-chymotrypsin (CT) was confirmed by a fluorescent substrate assay. At the indicated time points, polymer samples were rinsed and dried to a constant weight. Weight loss was measured gravimetrically, and molecular weight was measured using gel permeation chromatography (GPC).
Both PEAs degraded enzymatically with significant weight loss over one month compared to no weight loss in a saline solution (PBS). PLGA, which is known to degrade via hydrolytic bulk erosion, does not degrade enzymatically as shown by the early time points. The samples eventually lose physical integrity, which increases the measurement error. No weight loss was observed for PBMA in buffer with or without enzyme (not shown). See
No significant MW change was observed for the PEAs in both PBS and chymotrypsin solutions. A significant MW change (87% decrease at 21 day) was observed for PLGA in both PBS and chymotrypsin solutions. At day 28, the MW of PLGA was too small to be determined by GPC. See
Taken together, these results support an enzymatically-driven, surface erosion mechanism for PEAs compared to the known bulk erosion of PLGAs.
