WO2003041756A1 - Endoluminal devices coated with latrunculin to prevent ingrowth of cells - Google Patents

Endoluminal devices coated with latrunculin to prevent ingrowth of cells Download PDF

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WO2003041756A1
WO2003041756A1 PCT/BE2002/000165 BE0200165W WO03041756A1 WO 2003041756 A1 WO2003041756 A1 WO 2003041756A1 BE 0200165 W BE0200165 W BE 0200165W WO 03041756 A1 WO03041756 A1 WO 03041756A1
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latrunculin
stent
prothesis
coated
struts
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PCT/BE2002/000165
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French (fr)
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Ivan De Scheerder
Johan Bosmans
Koen Salu
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Dsb Invest Holding Sa
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • A61K31/427Thiazoles not condensed and containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L29/00Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/30Compounds of undetermined constitution extracted from natural sources, e.g. Aloe Vera
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus

Abstract

Delivery of Latrunculin A or B locally, particularly from an intraluminal prothesis such as a coronary stent, directly from the surface of the prothesis or from pores, micropores, or perforations in the stent body, mixed or bound to a polymer coating applied on the endoluminal prothesis, or mixed or bound toa glue applied to the endoluminal prothesis, to inhibit neointimal tissue proliferation and ingrowth of tissue, thereby facilitating the performance of the prothesis in inhibiting restenosis.

Description

ENDOLUMINAL DEVICES COATED WITH LATRUNCULIN TO PREVENT INGROWTH OF CELLS

Field of the Invention Delivery of a therapeutic agent locally, particularly from an intraluminal prothesis such as a coronary stent, directly from the surface of the prothesis or from pores, micropores, or perforations in the prothesis body, directly bounded on the prothesis or mixed or bound to a polymer coating applied on the prothesis, or mixed or bound to a glue applied to the prothesis, to inhibit neointimal tissue proliferation and thereby prevent restenosis. This invention also facilitates the performance of the prothesis in inhibiting restenosis. Furthermore prevention of tissue ingrowth into the prothesis and by this reducing their failure.

Background of the Invention:

Re-narrowing (restenosis) of an atherosclerotic coronary artery after percutaneous transluminal coronary angioplasty (PTCA) occurs in 10-50% of patients undergoing this procedure and subsequently requires either further angioplasty or coronary artery bypass graft. While the exact hormonal and cellular processes promoting restenosis are still being determined, our present understanding is that the process of PTCA, besides opening the atherosclerotically obstructed artery, also injures resident coronary arterial smooth muscle cells (SMC). In response to this injury, adhering platelets, infiltrating macrophages, leukocytes, or the smooth muscle cells (SMC) themselves release cell derived growth factors with subsequent proliferation and migration of medial SMC through the internal elastic lamina to the area of the vessel intima. Further proliferation and hyperplasia of intimal SMC and, most significantly, production of large amounts of extracellular matrix over a period of 3-6 months results in the filling in and narrowing of the vascular space sufficient to significantly obstruct coronary blood flow.

Several recent experimental approaches to preventing SMC proliferation have shown promise although the mechanisms for most agents employed are still unclear. Heparin is the best known and characterised agent causing inhibition of SMC proliferation both in vitro and in animal models of balloon angioplasty-mediated injury. The mechanism of SMC inhibition with heparin is still not known but may be due to any or all of the following: 1 ) reduced expression of the growth regulatory protooncogenes c-fos and c-myc, 2) reduced cellular production of tissue plasminogen activator, or 3) binding and dequestration of growth regulatory factors such as fibrovalent growth factor (FGF).

Other agents which have demonstrated the ability to reduce myointimal thickening in animal models of balloon vascular injury are angiopeptin (a somatostatin analog), calcium channel blockers, angiotensin converting enzyme inhibitors (captopril, cilazapril), cyclosporin A, trapidil (an antianginal, antiplatelet agent), terbinafine (antifungal), colchicine and taxol (antitubulin antiproliferatives), and c- myc and c-myb antinsense oligonucleotides. Additionally, a goat antibody to the SMC mitogen platelet derived growth factor (PDGF) has been shown to be effective in reducing myointimal thickening in a rat model of balloon angioplasty injury, thereby implicating PDGF directly in the etiology of restenosis. Thus, while no therapy has as yet proven successful clinically in preventing restenosis after angioplasty, the in vivo experimental success of several agents known to inhibit SMC growth suggests that these agents as a class have the capacity to prevent clinical restenosis and deserve careful evaluation in humans.

Coronary heart disease is the major cause of death in men over the age of 40 and in women over the age of fifty in the western world.

Most coronary artery-related deaths are due to atherosclerosis. Atherosclerotic lesions which limit or obstruct coronary blood flow are the major cause of ischemic heart disease related mortality and result in 500,000-600,000 deaths in the United States annually. To arrest the disease process and prevent the more advanced disease states in which the cardiac muscle itself is compromised, direct intervention has been employed via percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG). PTCA is a procedure in which a small balloon-tipped catheter is passed down a narrowed coronary artery and then expanded to re-open the artery. It is currently performed in approximately 250,000- 300,000 patients each year. The major advantage of this therapy is that patients in which the procedure is successful need not undergo the more invasive surgical procedure of coronary artery bypass graft. A major difficulty with PTCA is the problem of post-angioplasty closure of the vessel, both immediately after PTCA (acute reocclusion) and in the long term (restenosis).

The mechanism of acute reocclusion appears to involve several factors and may result from vascular recoil with resultant closure of the artery and/or deposition of blood platelets along the damaged length of the newly opened blood vessel followed by formation of a fibrin/red blood cell thrombus. Recently, intravascular stents have been examined as a means of preventing acute reclosure after PTCA. Restenosis (chronic reclosure) after angioplasty is a more gradual process than acute reocclusion: 30% of patients with subtotal lesions and 50% of patients with chronic total lesions will go on to restenosis after angioplasty. While the exact mechanism for restenosis is still under active investigation, the general aspects of the restenosis process have been identified:

In the normal arterial wall, smooth muscle cells (SMC) proliferate at a low rate (<0.1%/day). SMC in vessel wall exists in a 'contractile' phenotype characterised by 80-90% of the cell cytoplasmic volume occupied with the contractile apparatus. Endoplasmic reticulum, golgi bodies, and free ribosomes are few and located in the perinuclear region. Extracellular matrix surrounds SMC and is rich in heparin-like giycosylaminoglycans which are believed to be responsible for maintaining SMC in the contractile phenotypic state. Upon pressure expansion of an intracoronary balloon catheter during angioplasty, smooth muscle cells within the arterial wall become injured. Cell derived growth factors such as platelet derived growth factor (PDGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), etc. are released from platelets (i.e., PDGF) adhering to the damaged arterial luminal surface, invading macrophages and/or leukocytes, or directly from SMC (i.e., BFGF) provoke a proliferation and migratory response in medial SMC. These cells undergo a phenotypic change from the contractile phenotype to a 'synthetic' phenotype characterised by only few contractile filament bundles but extensive rough endoplasmic reticulum, golgi and free ribosomes. Proliferation/migration usually begins within 1-2 days post-injury and peaks at 2 days in the media, rapidly declining thereafter (Campbell et al., In: Vascular Smooth Muscle Cells in Culture, Campbell, J.H. and Campbell, G.R., Eds, CRC Press, Boca Ration, 1987, pp. 39-55) ; Clowes, A.W. and Schwartz,. S.M., Circ. Res. 56:139-145, 1985). Finally, daughter synthetic cells migrate to the intimal layer of arterial smooth muscle and continue to proliferate. Proliferation and migration continues until the damaged luminal endothelial layer regenerates at which time proliferation ceases within the intima, usually within 7-14 days post-injury. The remaining increase in intimal thickening which occurs over the next 3-6 months is due to an increase in extracellular matrix rather than cell number. Thus, SMC migration and proliferation is an acute response to vessel injury while intimal hyperplasia is a more chronic response. (Liu et al., Circulation, 79:1374- 1387, 1989).

Patients with symptomatic reocclusion require either repeat PTCA or CABG. Because 30-50% of patients undergoing PTCA will experience restenosis, restenosis has clearly limited the success of PTCA as a therapeutic approach to coronary artery disease. Because SMC proliferation and migration are intimately involved with the pathophysiological response to arterial injury, prevention of SMC proliferation and migration represents a target for pharmacological intervention in the prevention of restenosis.

Novel Features and Applications to Stent Technology

Currently, attempts to improve the clinical performance of endoluminal prothesis such as coronary stents have involved some variation of either searching for a more biocompatible metal alloy, optimising the stent surface, applying a coating to the metal, attaching a covering or membrane, or embedding material on the surface via ion bombardment. A stent designed to include reservoirs that can be filled up with therapeutic agents, influencing the restenosis process has also been proposed. Local Drug Delivery from an endoluminal prothesis such as a Stent to Inhibit Restenosis

In this application, a therapeutic agent is delivered to the site of arterial injury. The conventional approach has been to incorporate the therapeutic agent into a polymer material which is then coated on the stent. The ideal coating material must be able to adhere strongly to the metal stent both before and after expansion, be capable of retaining the drug at a sufficient load level to obtain the required dose, be able to release the drug in a controlled way over a period of several weeks, and be as thin as possible so as to minimize the increase in profile. In addition, the coating material should not contribute to any adverse response by the body and should be perfectly biocompatible (i.e., should be non-thrombogenic, non-inflammatory, etc.). To date, the ideal coating material has not been developed for this application. An alternative to this polymer/drug loading method is direct binding of the therapeutic agent to the metal surface. This method has the advantage to be perfectly biocompatible. Disadvantages are however the limited dose of drug that can be loaded on the stent and the (too) fast release of the drug. An other alternative is to use a drug impregnated biocompatible glue, in particular a biocompatible oil/solvent emulsion. Also with this method the drug release is quite fast, but combination with barrier coating could improve the release characteristics.

Another approach is to design a stent that contains reservoirs which could be loaded with the drug. A coating or membrane of biocompatable material could be applied over the reservoirs which would control the diffusion of the drug from the reservoirs to the arterial wall. The advantages of this system is that much more drug can be loaded and much longer drug release can be achieved. Pharmacologic attemps to prevent restenosis

Pharmacological attempts to prevent restenosis by pharmacologic means have thus far been unsuccessful and all involve systemic administration of the trial agents. Neither aspirin-dipyridamole, ticlopidine, acute heparin administration, chronic warfarin (6 months) nor methylprednisolone have been effective in preventing restenosis although platelet inhibitors have been effective in preventing acute reocclusion after angioplasty. The calcium antagonists have also been unsuccessful in preventing restenosis, although they are still under study. Other agents currently under study include thromboxane inhibitors, prostacyclin mimetics, platelet membrane receptor blockers, thrombin inhibitors and angiotensin converting enzyme inhibitors. These agents must be given systemically, however, and attainment of a therapeutically effective dose may not be possible; antiproliferative (or anti-restenosis) concentrations may exceed the known toxic concentrations of these agents so that levels sufficient to produce smooth muscle inhibition may not be reached (Lang et al., 42 Ann. Rev. Med., 127-132 (1991); Popma et al., 84 Circulation, 1426-1436 (1991)).

Additional clinical trials in which the effectiveness for preventing restenosis of dietary fish oil supplements, thromboxane receptor antagonists, cholesterol lowering agents, and serotonin antagonists has been examined have shown either conflicting or negative results so that no pharmacological agents are as yet clinically available to prevent post-angioplasty restenosis (Franklin, S.M. and Faxon, D.P., 4 Coronary Artery Disease, 232-242 (1993); Serruys, P.W. et al., 88 Circulation, (part 1 ) 1588-1601 , (1993).

Conversely, stents have proven useful in reducing restenosis. Stents, which when expanded within the lumen of an angioplastied coronary artery, provide structural support to the arterial wall, are helpful in maintaining an open path for blood flow. In two randomized clinical trials, stents were shown to increase angiographic success after PTCA, increased the stenosed blood vessel lumen and reduced the lesion recurrence at 6 months (Serruys et al., 331 New Eng Jour. Med, 495, (1994); Fischman et al., 331 New Eng Jour. Med, 496- 501 (1994). Additionally, in a preliminary trial, heparin coated stents appear to possess the same benefit of reduction in stenosis diameter at follow-up as was observed with non-heparin coated stents. Additionally, heparin coating appears to have the added benefit of producing a reduction in sub-acute thrombosis after stent implantation (Serruys et al., 93 Circulation, 412-422, (1996). Thus, 1) sustained mechanical expansion of a stenosed coronary artery has been shown to provide some measure of restenosis prevention, and 2) coating of stents with heparin has demonstrated both the feasibility and the clinical usefulness of delivering drugs to local, injured tissue off the surface of the stent. Numerous agents are being actively studied as antiproliferative agents for use in restenosis and have shown some activity in experimental animal models. These include: heparin and heparin fragments (Clowes and Karnovsky, 265 Nature, 25-626, (1977); Guyton, J.R. et al. 46 Circ. Res., 625-634, (1980); Clowes, A.W. and Clowes, M.M., 52 Lab. Invest., 611-616, (1985); Clowes, A.W. and Clowes, M.M., 58 Circ. Res., 839-845 (1986); Majesky et al., 61 Circ Res., 296-300, (1987); Snow et al., 137 Am. J. Pathol., 313-330 (1990); Okada, T. et al., 25 Neurosurgery, 92-898, (1989), colchicine (Currier, J.W. et al., 80 Circulation, 11-66, (1989), taxol (ref), angiotensin converting enzyme (ACE)inhibitors (Powell, J.S. et al., 245 Science, 186- 188 (1989), angiopeptin (Lundergan, C.F. et al., 17 Am. J. Cardiol. (Suppl. B); 132B-136B (1991), Cyclosporin A (Jonasson, L et. al., 85 Proc. Nati, Acad. Sci., 2303 (1988), goat-anti-rabbit PDGF antibody (Ferns, G.A.A., et al., 253 Science, 1129-1132 (1991 ), terbinafine (Nemecek, G.M. et al., 248 J. Pharmacol. Exp. Thera., 1167-11747 (1989), trapidil (Liu, M.W. et al., 81 Circulation, 1089-1093 (1990), interferon-gamma (Hansson, G.K. and Holm, 84 J. Circulation, 1266- 1272 (1991), steroids(Colburn, M.D. et al., 15 J. Vase. Surg., 510-518 (1992), see also Berk, B.C. et al., 17 J. Am. Coll. Cardiol., 111B-1 17B (1991), ionizing radiation , fusion toxins, antisense oligonucleotides, gene vectors , and rapamycin.

Summary of the Invention

Latrunculin A or B coated on an endoluminal prothesis to inhibit cell proliferation and neointimal hvperplasia

In accordance with the present invention, use is made of Latrunculin A or B to coat the endoluminal prothesis. Latrunculin A & B are architecturally novel marine compounds isolated from the Red Sea sponge Latrunculia magnifica. While the precise mechanism of action of the latrunculins is still under active investigation, they have been shown to disrupt the microfilament organization in different cell cultures (mouse neuroblastoma and fibroblast cells) by inhibition of the actin polymerisation (Spector et al., Science 214:493-495, (1983)). These in vitro effects were ten times more potent than for the cytochalasins, the best known group of actin-skeleton inhibitors (Spector et al., Cell Motil. Cytoskeleton 13:127-144, (1989)). Cytochalasins have shown there capability of inhibiting in vitro SMC proliferation (Numaguchi et al., Circ Res 85:5-11, (1999)) and migration, the latter also in vivo using peri- adventitial delivery in a rabbit carotid artery (Bruijns & Bult, Br J Pharmacol 134:473-483, (2001)). Moreover, cytochalasins inhibit in vitro the migration of inflammatory cells (also in vivo) and the activation of platelets (Casella et al., Nature 293:302-305, (1981); Anderson et al., J Cell Science 113:2737-2745, (2000); Bruijns & Bult, Br J Pharmacol 134:473-483, (2001)). Recently, latrunculins have shown to reduce SMC differentiation in vitro (Mack et al., J Biol Chem 276:341-347, (2001)). These observations clearly support the achievement of good results in the method according to the present invention although further fundamental and clinical research towards a role of latrunculins in the in vitro and in vivo inhibition of SMC proliferation and migration, as also towards their effect on inflammation, platelet aggregation and re- endothelisation, all important steps in the mechanism of post-angioplasty restenosis, is still required.

Although the ideal agent for restenosis inhibition has not yet been identified, latrunculins show some desired properties like inhibition and modulation of the neointimal hyperplasia cascade induced by arterial injury, including local inflammation, SMC dedifferentiation, SMC migration and proliferation at the site of angioplasty without serious systemic complications. Inasmuch as stents prevent at least a portion of the restenosis process, an agent which prevents inflammation and the proliferation of SMC combined with a stent may provide the most efficacious treatment for post-angioplasty restenosis.

Pre-clinical evaluation of the effect of Latrunculins

For the in vitro experiments, a proliferation assay on both SMC and endothelial cells (EC) were performed. After the isolation of rabbit aorta SMC and human umbilical vein endothelial cells (HUVEC), they were seeded on culture wells and latrunculin A or B was administrated to the wells (single-dose or prolonged administration) in several concentrations (varying from 0.0001 μM to 10000 μM), together with several specific growth factors to stimulate their growth. After several days (varying from 1 to 28 days), cells were counted (with Coulter Counter) and mitotic indexes were determined (using BrdU-ELISA's). Also platelet aggregation assays were performed to assess the influence of several concentrations of latrunculin A or B (varying from 0.0001 μM to 10000 μM) on this pathophysiological phenomenon. In vitro release curves from the stent (with all possible latrunculin A or B stent coatings claimed here, coating doses varying from 0.0001 μg to 10000 μg/mm2 stent) were assessed in serum or fysiological solution using HPLC. Also for the in vivo release curves, HPLC was used to assess the concentrations of latrunculin A or B that remain in the vessel tissue, on the stent and in the plasma on several time points (1 , 2, 6 and 24 hours, 2, 7, 14 and 28 days, 2, 3, 6 and 12 months) using the rabbit a.iliaca as vessel wherein a latrunculin A or B coated stent (with all possible latrunculin A or B stent coatings claimed here, coating doses varying from 0.0001 μg to 10000 μg/mm2 stent) were placed. These studies showed a significant effect on SMC proliferation and only a very miid inhibition of endothelial cell proliferation.

For the in vivo assessment of the effect of latrunculin A or B coated stents (with all possible latrunculin A or B stent coatings claimed here, coating doses varying from 0.0001 μg to 10000 μg/mm2 stent), a porcine coronary in-stent restenosis model was used. Two stents were randomly placed in one pig, one stent in the right coronary artery (RCA, stent size varying from 2.5 to 4.0 mm in diameter, and 13 to 23 mm in lengths) and one in the left coronary artery (LAD, stent size varying from 2.5 to 4.0 mm in diameter, and 13 to 23 mm in lengths). Coronary angiographies were taken before stent deployment, immediately afterwards and at follow-up (varying from 3 days to 12 months). These angiographies were quantified using the CAAS-ll-automated-QCA- system. Minimal lumen diameters were assessed and lumen late loss and percentage stenosis were calculated. At the follow-up time point, pigs were sacrificed and the stents were taken out; perfusion-fixation using 10% formolaldehyde were performed for 30 minutes at 80 mmHg. Then, the stents were fixated (for 24 hours or longer in formol) and dehydrated using several alcoholic solutions. Afterwards, they were polymerised (using Technovit 9100 or other commercially available polymer-kits) and cut into 2 to 5 μm slices using a fully motorised microtome and a Wolfram Tungsten Carbide knife. These 2 to 5 μm slices were afterwards stained for haematoxylin-eosin, elastin, toluidin blue, alpha-SMC-actin, von Willebrand Factor, CD-31 , Ki-67, PCNA, Brdu, TUNEL, macrophage-monocyte markers and all other stainings commercially available and of particular interest for our research. Finally, morphometrical and histopathological analysis was performed. Results showed that with a direct latrunculin A stent coating (total dose on stent ± 3 μg), intimal area could be significantly reduced in this porcine coronary in-stent restenosis model (Figure 1). Further studies, using higher total latrunculin dosages (up to 20μg/mm2) showed even more pronounced effects.

Indications: By coating of latrunculin onto an endoluminal prothesis, shunt or catheter and local drug delivery after implantation of the prothesis, catheter or shunt, inhibition of cell proliferation to prevent neointimal hyperplasia and restenosis, prevention of tumor expansion and ingrowth into the prothesis, and prevention of ingrowth of tissue into catheters and shunts inducing their failure.

Different potential delivery methods for latrunculins from an endovascular prothesis:

Local delivery of Latrunculins or analogs from an endovascular prothesis, for example a coronary stent, from the struts of a stent, from perforations in the struts of the stents, from channels in the strut of the stent, from a hollow wire forming the stent, from a stent graft, grafts, stent cover or sheath.

Involving direct binding of the drug to the stent strut metal backbone and to the perforations, channels in the struts; or involving a co-mixture with polymers (both degradable and nondegrading)or a biocompatible glue (in particular an oil or fat) to hold the drug to the stent or graft; or entrapping the drug into the metal of the stent or graft body which has been modified to contain micropores, channels or perforations; or including covalent binding of the drug to the stent via solution chemistry techniques or dry chemistry techniques (e.g. vapour deposition methods such as rf-plasma polymerization) and combinations thereof.

Catheter delivery intravascularly from a tandem balloon or a porous balloon for intramural uptake.

Extravascular delivery by the pericardial route.

Extravascular delivery by the advential application of sustained release formulations.

1. Direct drug coating on the metallic surface:

Stents are dipped in a solution of a Latrunculin in a solvent, for example ethanol, at final concentration range 0.001 to 50 weight %. Solvent is allowed to evaporate to leave a film of the Latrunculin on the stent.

2. Delivery from Polymer Matrix:

Solution of a Latrunculin, prepared in a solvent miscible with polymer carrier solution, is mixed with solution of polymer at final concentration range 0.001 weight % to 30 weight % of drug. Polymers are biocompatible (i.e., not elicit any negative tissue reaction or promote mural thrombus formation) and degradable, such as lactone-based polyesters or copolyesters, e.g., polylactide, polycaprolacton- glycolide.polyorthoesters, polyanhydrides; poly-aminoacids; polysaccharides; polyphosphazenes; poly(ether-ester) copolymers, e.g., PEO-PLLA, or blends thereof. Nonabsorbable biocompatible polymers are also suitable candidates. Polymers such as polydimethylsiloxane; poly(ethylene-vingylacetate); acrylate based polymers or copolymers, e.g., poly(hydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone; fluorinated polymers such as polytetrafluoroethylene; cellulose esters.

Polymer/drug mixture is applied to the surfaces of the stent by either dip-coating, or spray coating, or brush coating or dip/spin coating or combinations thereof, and the solvent allowed to evaporate to leave a film with entrapped Latrunculin.

3. Delivery from a biocompatible glue (oil/solvent emulsion).

Solution of a Latrunculin, mixed in an oil/solvent emulsion at final concentration range 0.001 weight % to 50 weight % of drug. The oil/solvent drug mixture is applied to the surface of the stent by either dip coating, or spray coating, or brush coating or dip/ spin coating or combinations thereof, and the solvent is allowed to evaporate to leave a film of oil or fat with entrapped Latrunculin.

4. Delivery from microporous depots, pores or perforations in stent backbone through either a Polymer Membrane Coating or oil/solvent emulsion drug coating:

A stent, whose body has been modified to contain micropores, pores, channels or perforations is dipped into a solution of Latrunculin A or B, range 0.001 wt% to saturated, in organic solvent such as acetone or methylene chloride, for sufficient time to allow solution to permeate into the pores. (The dipping solution can also be pressurised to improve the loading efficiency.) After the solvent has been allowed to evaporate, the stent is dipped briefly in fresh solvent to remove excess surface bound drug. Additionally a solution of polymer, chosen from any identified in the first experimental method, can be applied to the stent as detailed above. This outer layer of polymer will than act as release and diffusion-controller for release of drug.

5. Delivery via lysis of a Covalent Drug Tether

Latrunculin A or B is modified to contain a hydrolytically or enzymatically labile covalent bond for attaching to the surface of the stent which itself has been chemically derivatized to allow covalent immobilization. Covalent bonds such as ester, amides or anhydrides may be suitable for this.

6. Pericardial Delivery

A: Polymeric Sheet: Latrunculin A or B is combined at concentration range previously highlighted, with a degradable polymer such as poly(caprolactone-glycolide) or non-degradable polymer, e.g., polydimethylsiloxane, and mixture cast as a thin sheet, thickness range 10p to 10μm. The resulting sheet can be wrapped perivascularly on the target vessel. Preference would be for the absorbable polymer.

B: Conformal coating: Latrunculin A or B is combined with a polymer that has a melting temperature higher than 37°C, more particularly in the range of 40 to 45°C. Mixture is applied in a molten state to the external side of the target vessel. Upon cooling to body temperature the mixture solidifies conformally to the vessel wall. Both non-degradable and absorbable biocompatible polymers are suitable. These and other concepts are disclosed herein. It would be apparent to the reader that modifications are possible to the stent or the drug dosage applied. In any event, however, any obvious modifications should be perceived to fall within the scope of the invention which is to be realized from the attached claims and their equivalents.

Claims

1. A method for preventing cell proliferation and cell ingrowth into an endoluminal prothesis or catheter or in a shunt, wherein a Latrunculin, in particular Latrunculin A or B, or an analogue therapeutic compound is applied on and/or in the prothesis, catheter or shunt.
2. Use of a Latrunculin, in particular Latrunculin A or B, or an analogue therapeutic compound to manufacture a pharmaceutical composition for preventing cell proliferation and cell ingrowth into an endoluminal prothesis or catheter or in a shunt by applying the Latrunculin, in particular Latrunculin A or B, or the analogue therapeutic compound on and/or in the prothesis, catheter or shunt.
3. An endoluminal prothesis or catheter coated with Latrunculin, in particular Latrunculin A or B, or an analogue therapeutic compound to prevent cell proliferation and cell ingrowth into the endoluminal prothesis or catheter.
4. A Latrunculin coated endoluminal prothesis according to claim 3 wherein said prothesis is an endovascular stent, more preferably a coronary stent.
5. A Latrunculin coated stent according to claim 4, wherein the stent is made of a wire, optionally a hollow wire filled with Latrunculin or a Latrunculin comprising product.
6. A Latrunculin coated stent according to claim 4, wherein the stent comprises a generally thin walled cylinder, said cylinder containing a plurality of struts, said struts expandable depending on the amount of force applied to said strut, and said struts having a generally uniform thickness.
7. A Latrunculin coated stent according to claim 4, wherein the stent comprises a generally thin walled structure containing a plurality of struts, the struts expandable to assume the shape of a lumen into which the stent is placed, said struts having a thickness and are in particular provided with one or more perforations formed in at least one of said struts, said perforations having a closed perimeter on all sides and an open top and eventually an open bottom, and said perforation smaller in all dimensions than said strut, said perforation containing Latrunculin applied therein.
8. A Latrunculin coated stent according to claim 4, having Latrunculin coated on the stent by either direct coating on the stent surface, by impregnating the Latrunculin in a biocompatible oil emulsion, coated on the stent struts, or by embedding the Latrunculin in a biocompatible polymer, coated on the stent struts.
9. A Latrunculin coated stent according to claim 4, having one ore more perforations, filled with Latrunculin or a Latrunculin containing product, either by direct coating, impregnation of the Latrunculin in a biocompatible oil or fat emulsion, filling the perforations or impregnation of the Latrunculin in a biocompatible polymer, filling the perforations.
10. A Latrunculin coated prothesis according to claim 3, having a total Latrunculin coating dose within a range of 0.0001 μg/mm2 and 10 000 μg/mm2, more preferably 0.1 μg/mm2 to 10 μg/mm2, and most preferably 0.5 μg/mm2 to 5.0 μg/mm2.
PCT/BE2002/000165 2001-11-08 2002-11-07 Endoluminal devices coated with latrunculin to prevent ingrowth of cells WO2003041756A1 (en)

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