HK1176895B - Therapeutic agent delivery system and method for localized application of therapeutic substances to a biological lumen - Google Patents

Description

Therapeutic drug delivery system and method for local administration of therapeutic drugs to biological lumens

Technical Field

The present invention relates to systems, devices and methods for locally delivering therapeutic agents to treat a biological cavity wall, such as an animal cavity wall.

Background

Various techniques and instruments have been developed to remove or repair tissue within biological conduits, such as blood vessels and similar body passageways, but are not limited to these examples. A common goal of these techniques and instruments is to remove atherosclerotic plaque from a patient's artery. Atherosclerosis is characterized by the accumulation of fat deposits (atheroma) in the intimal layer (beneath the endothelium) of a patient's blood vessel. Over time, the initially soft, cholesterol-rich atheromatous material, when deposited, often hardens to form calcified atherosclerotic plaques. This atheroma restricts the flow of blood and is often referred to as a stenotic lesion or stenosis, and the occluding material is referred to as stenotic material. Such stenosis, if left untreated, can lead to angina, hypertension, myocardial infarction, stroke, leg pain, and the like.

Rotational atherectomy has become a common method of removing such stenotic material. Such rotational atherectomy is often used to open calcified lesions in coronary arteries. Rotational atherectomy is not usually used alone, but rather is followed by balloon angioplasty followed by placement of a stent to help maintain patency of the open artery. In the case of non-calcified lesions, balloon angioplasty alone is often used to open the artery and a stent is typically placed to maintain the patency of the open artery. However, studies have shown that a significant proportion of patients undergoing balloon angioplasty and having a stent placed in an artery have stent restenosis-i.e. over time, stent occlusion often occurs due to excessive growth of scar tissue within the stent. In this case, in order to remove excessive scar tissue on the stent, the preferred procedure is rotational atherectomy (balloon angioplasty is not effective inside the stent), thereby restoring patency to the artery.

Several rotational atherectomy devices have been developed to remove stenotic material. In one arrangement, as shown in U.S. patent 4,990,134 (Auth), a rotating tip covered with an abrasive material such as diamond particles is provided at the distal end of a flexible drive shaft. The rotating head rotates at high speed (typically at about 150,000 and 190,000 rpm) while advancing through the stenosis. However, when the rotational atherectomy head clears the stenotic tissue, it can also block blood flow. Once the atherectomy head has passed through the stenosis, the artery is dilated to a diameter equal to or only slightly greater than the maximum outer diameter of the atherectomy head. In order to open an artery to a desired diameter, it is often necessary to use a variety of gauge atherectomy heads.

U.S. patent No. 5,314,438 (Shturman) discloses another rotational atherectomy device having a drive shaft with a portion of the drive shaft having an enlarged diameter, at least a portion of the surface of the enlarged portion being coated with abrasive material to define an abrasive section of the drive shaft. When rotated at high speed, the abrasive segment is capable of clearing stenotic tissue of the artery. This rotational atherectomy device has certain advantages over the Auth device due to its flexibility, however, because the device is not eccentric in nature, the diameter of the expanded artery is only approximately equal to the diameter of the enlarged abrasive surface of the drive shaft.

U.S. Pat. No. 6,494,890 (Shturman) discloses a rotational atherectomy device having a drive shaft with an enlarged eccentric portion, wherein at least a portion of the surface of the enlarged portion is covered with abrasive material. When rotated at high speed, the abrasive segment is capable of clearing stenotic tissue of the artery. Due in part to the orbital rotational motion during high speed operation, such devices are capable of dilating an artery to a diameter greater than the resting diameter of the enlarged eccentric portion. Because the enlarged eccentric portion includes drive axes that are not bundled together, the enlarged eccentric portion of the drive shaft may bend when placed in a narrow space or during high speed operation. During high speed operation, this bending makes the expanded diameter larger, but the control of the actual abraded artery diameter is worse than expected. In addition, some stenotic tissue may completely occlude the passageway, thereby preventing the Shturman device from being placed through them. Since the Shturman device requires that the enlarged eccentric portion of the drive shaft be placed within the stenotic tissue to achieve abrasion, the effectiveness is reduced if the enlarged eccentric portion cannot move into the stenosis. The disclosure of U.S. Pat. No. 6,494,890 is incorporated by reference in its entirety.

U.S. patent No. 5,681,336 (element) provides an eccentric tissue-removing rotational abrasive tip having a coating of abrasive particles secured to a portion of the outer surface of the rotational abrasive tip by a suitable bonding material. However, as described by Clement at column 3, lines 53-55, "to compensate for heat or imbalance, the speed of such asymmetric abrasive tips is slower than high speed ablation devices," and thus, this configuration is limited. That is, due to the size and mass of such a robust rotational head, it cannot be rotated at high speeds during rotational atherectomy, i.e., at 20,000-. In fact, the offset of the center of mass with respect to the axis of rotation of the drive shaft will result in the formation of significant centrifugal forces, thereby exerting too much pressure on the artery wall, generating too much heat and forming oversized particles.

Another method of treating occluded blood vessels involves the use of stents. The stent may be placed at the stenotic site and expanded to widen the vessel and remain in place in the form of a vascular implant.

Regardless of the method used to open an occlusive catheter (e.g., a blood vessel) and restore its normal fluid flow, they present a problem: restenosis. After a period of time, portions of the treatment catheter and blood vessel will reocclude (restenosis); this occurs in proportions as high as 30-40%. When restenosis occurs, it may be necessary to repeat the original procedure or to use alternative methods to restore the flow of fluid (e.g., blood).

A related common denominator of the above treatments is that each may cause some damage to the catheter wall. Restenosis occurs as a result of several causes, each of which is associated with injury. Small clots may form on the arterial wall. Small tears in the wall can expose the blood to foreign bodies and proteins that are highly embolic. The formed clot may become progressively larger and may even contain growth hormone released by the platelets within the clot. In addition, growth hormone released by other cells, such as macrophages, can cause smooth muscle cells and fibroblasts in the affected area to multiply in an abnormal manner. With the above method, damage may occur to the vessel wall, resulting in inflammation, thereby causing new tissue growth.

It is well known that certain therapeutic agents have a positive effect on the prevention and/or inhibition of restenosis. There are several difficulties in administering therapeutic doses of these therapeutic agents to the affected area. For example, the area to be treated is very small and localized. The flow of fluid, such as blood, through the catheter is continuous and therefore the flow boundary along the catheter wall must be broken to allow the therapeutic agent in the dosage range that achieves the therapeutic effect to reach the local treatment area. These techniques do not satisfactorily provide a mechanism to break such flow boundaries to direct the region of interest; in contrast, the option of delivering therapeutic agents into the general flow of catheters by intravenous or intraluminal infusion is often much higher than therapeutic doses, since most therapeutic agents simply flow downstream, are absorbed systemically, or are eliminated as waste products. For example, intravenous medication is delivered systemically through blood vessels, or, alternatively, by intraluminal infusion to an area, which is not targeted to the target area. Such unnecessary systemic exposure can cause unknown and unnecessary side effects in areas, tissues and/or organs remote from the region of interest. Clearly, systemic administration and exposure are not well suited for treating diseases or disorders of a single luminal area of interest.

The potential use of topically administered therapeutic doses of therapeutic agents is not limited to treating coronary arteries. In addition to coronary delivery, other atherosclerotic sites, such as the renal, iliac, femoral, calf, and carotid arteries, as well as saphenous vein grafts, synthetic grafts, and arteriovenous shunts for hemodialysis, are biological conduits suitable for treatment with local therapeutic drug delivery methods and mechanisms. Potential applications are not limited to blood vessels; any biological conduit having a region of interest that facilitates treatment may benefit from this treatment method and mechanism.

The present invention overcomes these deficiencies.

Disclosure of Invention

The present invention provides a system and method for local administration of therapeutic agents to a biological lumen and lumen wall. In various embodiments, a biodegradable tubular prosthesis comprising a plurality of pores is disposed in a biological lumen. Following or concurrent with prosthesis deployment, a drug-eluting balloon comprising at least one therapeutic drug is inflated within the lumen of the tubular prosthesis, thereby releasing the drug from the balloon and delivering it into the prosthesis bore. The at least one therapeutic agent then diffuses through the pores and onto the lumen wall.

The figures and detailed description that follow more particularly exemplify these aspects and other embodiments of the invention.

Drawings

The present invention may be more completely understood in consideration of the following detailed description of various embodiments of the invention in connection with the accompanying drawings.

FIG. 1A is a side partial cross-sectional view of one embodiment of the present invention;

FIG. 1B is an end view of one embodiment of the present invention;

FIG. 2A is a side partial cross-sectional view of one embodiment of the present invention;

FIG. 2B is a side partial cross-sectional view of one embodiment of the present invention;

FIG. 3A is a side partial cross-sectional view of one embodiment of the present invention;

fig. 3B is a side partial cross-sectional view of one embodiment of the present invention.

Detailed Description

While the invention is amenable to various modifications and alternative forms, specifics thereof have been shown by way of example in the drawings and will be described in detail. It should be understood, however, that the intention is not to limit the invention to the particular embodiments described. On the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.

The following terms and definitions apply to the present invention:

"physical disorder" refers to any disorder that adversely affects the functioning of the body.

The term "treating" includes preventing, reducing, delaying, stabilizing and/or eliminating a bodily disorder, such as a vascular disease. In certain embodiments, treatment includes repairing damage, disorders, and/or interventions on the body, such as blood vessels, including but not limited to mechanical interventions.

"therapeutic agent" includes any substance capable of exerting an effect including, but not limited to, a therapeutic, prophylactic or diagnostic effect. Thus, therapeutic agents may include anti-inflammatory agents, anti-infective agents, analgesics, antiproliferative agents, and include, but are not limited to, anti-restenosis agents, and the like. The therapeutic agent further comprises mammalian stem cells. Therapeutic agents as used herein further include other drugs, genetic material and biological material. Genetic material refers to DNA or RNA, including but not limited to DNA/RNA encoding useful proteins, intended for insertion into the human body including viral and non-viral vectors. Viral vectors include adenovirus, entero-free adenovirus, adeno-associated virus, retrovirus, alphavirus, lentivirus, herpes simplex virus, modified cells from the body (e.g., stem cells, fibroblasts, myoblasts, satellite cells, pericytes, cardiomyocytes, skeletal muscle cells, macrophages), replication-competent virus, and hybrid viral vectors. Non-viral vectors include artificial chromosomes and minichromosomes with and without targeting sequences such as Protein Transduction Domains (PTDs), plasmid DNA vectors, cationic polymers, graft copolymers, neutral polymers PVP, SP1017, lipids or liposomes, nanoparticles and microparticles. Biological materials include cells, yeasts, bacteria, proteins, peptides, cytokines, and hormones. Examples of peptides and proteins include growth factors (FGF, FGF-1, FGF-2, VEGF, endothelial mitogen and epidermal growth factor, transforming growth factors alpha and beta, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor alpha, hepatocyte growth factor and insulin-like growth factor), transcription factors, protein kinases, CD inhibitors, thymidine kinases and bone morphogenic proteins. These dimeric proteins may be provided alone or with other molecules in the form of homodimers, heterodimers, or combinations thereof.

The therapeutic agent further comprises cells, either from the human body (autologous or allogeneic) or from the animal (xenogeneic), and if desired, from genetic engineering, to provide the protein of interest at the site of implantation. Cells that fall within the definition of therapeutic agents herein further include whole bone marrow, bone marrow-derived monocytes, progenitor cells (e.g., endothelial progenitor cells), stem cells (e.g., mesenchymal cells, hematopoietic cells, neuronal cells), pluripotent stem cells, fibroblasts, macrophages, and satellite cells.

Therapeutic agents also include non-genetic material such as: antithrombotic agents such as heparin, heparin derivatives and urokinase; antiproliferative drugs such as enoxaparin (enoxaprin), angiopeptin, or monoclonal antibodies capable of blocking smooth muscle cell proliferation, hirudin and acetylsalicylic acid, amlodipine (amlodipine) and doxazosin (doxazosin); anti-inflammatory drugs such as glucocorticoids, betamethasone (betamethasone), dexamethasone (dexamethasone), prednisolone (prednisolone), corticosterone, budesonide, estrogens, sulfasalazine, and mesalamine; antineoplastic/antiproliferative/anti-miotic drugs such as paclitaxel (paclitaxel), 5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones (epothilones), methotrexate (methotrexate), azathioprine (azathioprine), doxorubicin (adriamycin), and mitomycin; endostatin (endostatin), angiostatin (angiostatin), and thymidine kinase inhibitors, paclitaxel (taxol), and analogs or derivatives thereof; narcotics such as lidocaine (lidocaine), bupivacaine (bupivacaine) and ropivacaine (ropivacaine); anticoagulants, such as heparin, antithrombin compounds, platelet receptor antagonists, anticoagulant antibodies (anti-thrombin antibodies), antiplatelet receptor antibodies, aspirin, dipyridamole (dipyridamole), protamine (protamine), hirudin, prostaglandin inhibitors, platelet inhibitors, and tick anticoagulant peptides (tick anticoagulant peptides); vascular cell growth promoters such as growth factors, vascular endothelial growth factors, growth factor receptors, transcriptional activators and transcriptional promoters; vascular cell growth inhibitors such as antiproliferative drugs, growth factor inhibitors, growth factor receptor antagonists, transcription inhibitors, translation inhibitors, replication inhibitors, inhibitory antibodies, antibodies against growth factors, bifunctional molecules consisting of growth factors and cytotoxins, bifunctional molecules consisting of antibodies and cytotoxins; cholesterol lowering agents; a vasodilator; and drugs that intervene through endogenous vasoactive mechanisms; antioxidants, such as probucol (probucol); antibiotics, such as penicillin, cefoxitin (cefoxitin), oxacillin (oxacillin), tobramycin (tobramycin) angiogenic substances, such as acidic and basic fibroblast growth factors, estrogens (including estradiol (E2), estriol (E3), and 17-beta estradiol); and drugs for heart failure such as digoxin (digoxin), beta-blockers, angiotensin converting enzymes, inhibitors (including captopril (captopril) and enalapril (enalopril)). The bioactive material may be used with: biologically inactive materials, including solvents, carriers or excipients, such as sucrose acetate isobutyrate, ethanol, n-methyl pyrrolidone, dimethyl sulfoxide, benzyl benzoate and benzyl acetate.

Furthermore, and particularly in preferred methods of treatment of the present invention, "therapeutic agent" includes administration of at least one therapeutic agent to a mammalian blood vessel surgically traumatized by angioplasty or atherectomy to inhibit restenosis. The therapeutic agent is preferably a cytoskeletal inhibitor or a smooth muscle inhibitor, for example comprising paclitaxel and functional analogues, equivalents or derivatives thereof, such as docetaxel, paclitaxel, albumin-bound paclitaxel, coroxane or cytochalasin, such as cytochalasin B, C, A, D or analogues or derivatives thereof.

Specific examples of other "therapeutic agents" that may be administered to a body lumen using embodiments of the present invention include, but are not limited to:

l-arginine;

an adipocyte;

genetically modified cells, such as beta-autologous endothelial cell species transfected with galactosidase genes on the surface of injured arteries;

erythromycin;

penicillin:

heparin;

aspirin;

cortisol;

dexamethasone;

forskolin (Forskolin);

GP IIb-IIIa inhibitors;

cyclohexane;

a Rho kinase inhibitor;

rapamycin (Rapamycin);

histamine;

nitroglycerin;

a vitamin E;

vitamin C;

stem cells;

a growth hormone;

hirudin;

hirulog;

argatroban (Argatroban);

Vapirprost；

prostacyclin (Prostacyclin);

dextran (Dextran);

erythropoietin (erythropoetin);

endothelial growth factor;

an epidermal growth factor;

a core binding factor A;

vascular endothelial growth factor;

fibroblast growth factor;

thrombin;

a thrombin inhibitor;

glucosamine, and many other therapeutic agents.

The therapeutic drug delivery system of the present invention can be used to administer therapeutic drugs to any wall of a biological lumen into which a catheter is inserted. Such biological lumens include, inter alia, blood vessels, the urinary tract, coronary vessels (coronary), the esophagus, trachea, colon, and biliary tract.

A therapeutically effective, or effective dose refers to an amount of a therapeutic agent that alleviates and/or treats the symptoms or disease. As will be readily appreciated by those skilled in the art, efficacy and toxicity may be determined using standard pharmaceutical procedures in cell culture or using laboratory animals, e.g., by calculating ED₅₀(dose having therapeutic effect on 50% of the population) or LD₅₀(dose lethal to 50% of the population). Pharmaceutical formulations having a large therapeutic index are preferably used. Data from cell culture assays and animal studies are used to specify dosage ranges for human use. Preferred dosages contained in such formulations are in the range including ED₅₀And has little or no toxicity. The dosage will vary within this range depending upon the dosage form employed, the degree of sensitivity of the patient and the route of administration.

The exact dosage will be determined by the practitioner, depending on various factors related to the subject in need of treatment. By adjusting the dosage and administration, sufficient levels of active are provided or the desired effect is maintained. Factors that may be considered include the severity of the disease, the general health of the subject, age, weight, sex, time and frequency of administration, drug combination, degree of response sensitivity and response to treatment. Long acting pharmaceutical formulations may be administered once every 3-4 days, weekly, or biweekly, depending on the half-life and clearance of the particular formulation. The normal dose is about 0.1 μ g to 100,000 μ g, with a total dose of up to about 1g, and in some embodiments higher.

In addition, the dose diffusivity of the at least one therapeutic drug delivered and administered to the lumen wall varies depending on the application and the size of the patient. An acceptable dose spread rate of the at least one therapeutic agent is from about 0.01 mg/day to about 100 mg/day, more preferably from about 0.2 mg/day to about 20 mg/day, and more preferably from 1 mg/day to about 5 mg/day.

In some embodiments, the formulation contains at least 1% by weight drug. For example, the formulation contains at least 1%, at least 2%, at least 5%, at least 7%, at least 10%, at least 15%, at least 17%, at least 20%, at least 30%, at least 40%, at least 45%, at least 50%, at least 60%, or at least 70% by weight of the drug, such as 1-20%, 5-30%, 10-50%, 20-30%, or 20-50% by weight of the drug. In other embodiments, the formulation may contain less than 1% drug.

Turning now to fig. 1A and 1B, embodiments of the present invention include a tubular therapeutic drug delivery prosthesis 10 having a cylindrical profile including a lumen 12 for allowing passage of biological fluids (e.g., blood), a lumen cylindrical inner surface 14 and a cylindrical outer surface 16, a thin wall 20 defined by the cylindrical inner surface 14 and the cylindrical outer surface 16, and an open cell structure in which a plurality of pores 18 allow fluid communication between the lumen inner surface 14 and the outer surface 16.

The tubular prosthesis may comprise at least one biodegradable material. Such materials are well known in the art. For example, poly-L, D-lactic acid, poly-L-lactic acid, poly-D-lactic acid, polyglycolic acid, polylactic acid, polycaprolactone, polydioxanone, poly (lactic acid-ethylene oxide) copolymer, or combinations thereof are suitable for the present invention, but are not limited thereto. In addition, Vainionp et al, 1989, published in Polymer science development, Vol.14, pp.697 to 716, and U.S. Pat. No. 4,700,704, U.S. Pat. No. 4,653,497, U.S. Pat. No. 4,649,921, U.S. Pat. No. 4,599,945, U.S. Pat. No. 4,532,928, U.S. Pat. No. 4,605,730, U.S. Pat. No. 4,441,496, and U.S. Pat. No. 4,435,590, disclose various compounds that can make bioabsorbable stents. The above documents are incorporated by reference in the present application. These materials may further include aliphatic polyesters such as PLGA, PLAA, PLA, PDLLA, PDLA, PCL, PGA and PHB, polyanhydrides, aliphatic polycarbonates, POE, PDXO and the family of biodegradable polymers known as polyketals. As is well known in the art, in addition to being biodegradable, the material is also bioabsorbable. In addition, when the tubular prosthesis 10 is inserted into a biological lumen, a preferred time range for its degradation includes preferably about 1 week to about 6 months, more preferably about 2 weeks to about 6 months, and most preferably about 2 weeks to about 4 months.

The size of the pores 18 is one of the factors that should be considered to control the release rate of the at least one therapeutic agent from the insertion prosthesis 10. The pore size is preferably from 0.02 microns to 100 microns, more preferably from 5 microns to 100 microns. For larger molecules or stem cells, a larger pore size may be required.

Further, the pore size of the pores 18 may be graded from the inner surface 14 to the outer surface 16. The pore size gradient may be a smaller pore size at the inner surface 14 and a larger pore size at the outer surface 16, with a smooth step-wise increase in pore size from the inner surface 14 to the outer surface 16, depending on the therapeutic agent employed, the time frame, and various other factors known to those skilled in the art. This arrangement will allow the therapeutic agent to diffuse more rapidly to the lumen wall. Alternatively, the pore size gradient may be such that the pore size is larger at the inner surface 14 and smaller at the outer surface 16, with the pore size decreasing smoothly and progressively from the inner surface 14 to the outer surface 16. This latter pore size gradient configuration will slow the diffusion of the therapeutic agent from the pores 18 into the lumen wall. As will be readily appreciated by those skilled in the art, the manufacturing process may be modified to accommodate the particular therapeutic agent being delivered by the present invention.

As shown in fig. 2A and 2B, in certain embodiments, the tubular prosthesis 10 of the present invention is self-expanding. Thus, the materials in these embodiments may be deformed to a deformed configuration having a first diameter D1 and an expanded configuration having a second diameter D2, wherein the first diameter D1 is less than the second diameter D2. The tubular prosthesis 10 may thus be delivered to a deployment site within the patient's lumen L via a delivery sheath or catheter 22. The tubular prosthesis 10 in the deformed configuration is delivered from the distal end 23 of the sheath or catheter 22 through the delivery sheath or catheter 22, thereby causing the tubular prosthesis 10 to achieve an expanded configuration having a larger second diameter D2, as shown in fig. 2B. Deployment of the tubular prosthesis 10 is completed when the self-expanding tubular structure 10, and in particular the cylindrical outer surface 16 of the prosthesis 10, is pressed against the lumen wall.

In other embodiments, as shown in fig. 3A and 3B, the tubular prosthesis 10 of the present invention may be adhered (such adhesion is peelable) to the outer surface of an inflatable balloon 24, by which the prosthesis 10 is inflated, pressed against the lumen wall and disposed within the lumen L. The balloon 24 and the tubular prosthesis are moved axially distally through the delivery sheath or catheter 22 and ultimately out the distal end 23 of the delivery sheath or catheter 22 so that the balloon 24 can be inflated using methods well known in the art. In this manner, the outer surface 16 of the tubular prosthesis 10 expands against the lumen wall, thereby deploying the prosthesis 10. Inflation of the balloon 24 breaks the peelable adhesion between the tubular prosthesis 10 and the balloon outer surface 24, enabling removal of the balloon 24.

The present invention includes placing the tubular prosthesis within a lumen without preloading the bore 18 with any therapeutic drug. The tubular prosthetic material also does not include any therapeutic drugs, which are slowly released through the tubular prosthetic as the prosthetic material degrades, as is well known in the art. The present invention involves introducing a therapeutic agent into the opening, i.e., the hole 18, on the inner surface 14 of the tubular prosthesis 10 only after the lumen deployment is complete, with the agent slowly diffusing through the hole 18 on the outer surface 16 of the tubular prosthesis into the lumen wall.

As is well known in the art, at least one therapeutic drug may be introduced into the deployed tubular prosthesis by a drug eluting balloon. Thus, in some embodiments, the inflatable balloon 24 serves two purposes: the tubular prosthesis 10 is inflated and the prosthesis 10 is disposed within the lumen, and a therapeutic drug is delivered from the drug eluting balloon 24 through the aperture 18 or the like as is well known in the art into the aperture 18 of the tubular prosthesis 24. The drug may be delivered from the balloon 24 into the bore 18 of the prosthesis 10 in a manner well understood by those familiar with drug eluting balloons, such as inflation of the balloon 24 to facilitate delivery of the drug from a balloon reservoir. An alternative method of delivering the drug to the balloon 24, followed by draining or eluting from the balloon 24 and into the prosthesis bore 18 is disclosed in a commonly owned co-pending patent entitled "Devices and Methods for Low housing Local Delivery of therapeutic Agents to the Wall of Body of Lunen", filed on day 14, 2011, the entire contents of which are incorporated herein by reference.

If the tubular prosthesis 10 is self-expanding, i.e., transitioning from the first deformed configuration to the second expanded and deployed state, the expandable balloon 24 may be moved into the lumen 12 of the tubular prosthesis 10 and expanded, thereby releasing the therapeutic agent from the drug eluting balloon 24 and delivering the agent into the pores 18 of the tubular prosthesis 10.

In certain embodiments, the preferred tubular prosthetic material is a biodegradable open cell foam. Various methods of making such materials are known. For example, a composite of biodegradable polymer and gelatin microspheres may be manufactured. The thin-walled tubular structure, i.e., the tubular prosthesis, can then be compression molded at a temperature above the glass transition temperature of the polymer. The gelatin is then extracted from the composite using double distilled water, leaving an open-cell foam having a pore size, the foam morphology being defined by the size of the gelatin microspheres extracted from the composite. See U.S. patent US 5,866,155 to Thompson, the entire contents of which are incorporated herein by reference. Other methods of making open cell materials are disclosed in the following references, which are incorporated herein by reference. Mikos, U.S. patent No. US 5,699,175; US patent US 5,626,861 to Laurencin; U.S. patent US 6,281,256 to Harris.

The present invention should not be considered limited to the particular examples described above, but rather should be understood to cover all aspects of the invention. It will be apparent to those skilled in the art from this disclosure that various changes, equivalent processes, as well as numerous structures can be made which are within the scope of this invention.

Claims (6)

1. A system for inserting a cylindrical tubular prosthesis into a biological lumen and delivering an effective dose of at least one therapeutic agent to a wall of the lumen, comprising:

a cylindrical tubular prosthesis formed from a biodegradable material, comprising:

a cylindrical wall defined by a cylindrical inner surface and a cylindrical outer surface,

a lumen defined by a cylindrical wall,

a plurality of openings through which the cylindrical inner surface and the cylindrical outer surface are in fluid communication,

a smooth graded pore size between the cylindrical inner surface and the cylindrical outer surface in each of the plurality of openings, the graded pore size including a smaller pore size at the cylindrical inner surface and a larger pore size at the cylindrical outer surface, the pore size smoothly increasing in steps from the cylindrical inner surface to the cylindrical outer surface,

a first deformed configuration having a first diameter, wherein the plurality of apertures are open and do not contain at least one therapeutic agent therein;

a second expanded configuration having a second diameter, wherein the second diameter is greater than the first diameter;

a delivery sheath having a lumen therethrough and a distal end, wherein the tubular prosthesis is axially movable when in a first deformed configuration, the tubular prosthesis being released from the distal end, expanded to a second expanded configuration, and disposed against a lumen wall;

and

an expandable drug-eluting balloon axially movable into a lumen of a deployed expanded tubular prosthesis, the balloon including a reservoir therein containing an effective dose of at least one therapeutic drug for release into a plurality of openings, and further including an inflating means by which the balloon is inflated to deliver the effective dose of the at least one therapeutic drug from the reservoir in the balloon into the plurality of openings, the at least one therapeutic drug passing through the openings into the pore size gradient and through the pores to a wall of the lumen at a rate controlled by the pore size gradient.

2. The system of claim 1, further comprising a wire in operable and peelable connection with the tubular prosthesis in the first deformed configuration, the wire being arranged to pass the tubular prosthesis through the lumen of the delivery sheath and out of the distal end of the delivery sheath.

3. The system of claim 1, wherein the at least one therapeutic agent is selected from the group consisting of stem cells, anti-inflammatory agents, anti-infective agents, analgesics, and antiproliferative agents.

4. The system of claim 1, wherein the at least one therapeutic agent comprises a cytoskeletal inhibitor and/or a smooth muscle inhibitor.

5. The system of claim 4, wherein the at least one therapeutic drug comprises paclitaxel (taxol) and functional analogs, equivalents, or derivatives thereof.

6. The system of claim 4 or 5, wherein an effective dose of the drug is delivered to prevent restenosis following vascular injury caused by angioplasty or atherectomy.