WO2005053767A1 - Cis-hydrogenated fatty acid coating of medical devices - Google Patents

Cis-hydrogenated fatty acid coating of medical devices Download PDF

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WO2005053767A1
WO2005053767A1 PCT/BE2003/000201 BE0300201W WO2005053767A1 WO 2005053767 A1 WO2005053767 A1 WO 2005053767A1 BE 0300201 W BE0300201 W BE 0300201W WO 2005053767 A1 WO2005053767 A1 WO 2005053767A1
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cis
medical device
coating
stent
oil
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PCT/BE2003/000201
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French (fr)
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Ivan De Scheerder
Pierre Jacobs
Johan Martens
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K.U. Leuven Research & Development
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    • 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
    • A61L2300/258Genetic materials, DNA, RNA, genes, vectors, e.g. plasmids
    • 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
    • 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
    • A61L2300/43Hormones, e.g. dexamethasone
    • 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
    • A61L2300/432Inhibitors, antagonists
    • A61L2300/434Inhibitors, antagonists of enzymes
    • 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
    • A61L2300/60Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/64Animal cells

Abstract

A coated implantable medical device is described, wherein the coating composition comprises or consists of at least 20% of one or more cis-hydrogenated fatty acids. The cis-hydrogenated fatty acids which are used for the coating of medical devices in the context of the present invention are, according to one embodiment selected from mono-, di-or triglycerides or esters thereof. Most particularly, they are made up of between 20% and 95% triglycerides. Preferably, they have been trans-free hydrogenated. According to a particular embodiment of the invention the cis-hydrogenated fatty acid is an omega-3-fatty acid, from fish oil or cod liver oil .

Description

CIS-HYDROGENATED FATTY ACID COATING OF MEDICAL DEVICES

Field of the invention This invention relates generally to compositions suitable for use for use in drug delivery and/or as .coatings for human and veterinary medical devices, especially devices which are to be introduced into or implanted in a human or animal body, especially such devices as will come into contact with circulating blood supply and more particularly to those devices which provide drug release, e.g. devices incorporating biologically active, therapeutic or similar agents in said coatings. The compositions are additionally suitable. The present invention also relates to methods of making these compositions and methods of applying such the coatings comprising the compositions of the invention to medical devices.

Background Artherosclerosis is one of the most important causes of deat in the Western world. Coronary artherosclerosis is the result of a progressive degeneration of the vessel wall which causes the occlusion of the arteries with different substances including lipids, cholesterol, calcium and different types of cells including smooth muscle cells and platelets. Classical treatments include medical therapies, balloon-dilatations optionally involving stent-implantation and coronary bypass surgery. Balloon-dilatations or percutaneous transluminal angioplasty (PTA) is being applied more and more and consists of breaking up and/or removing already formed deposits along arterial walls using a balloon attached to a catheter that is introduced to a patient percutaneously and threaded through the arteries to the occluded site, where the balloon is inflated. An important limitation of this technique however is the high risk of re-closing (restenosis) of the treated artery. Thus, balloon-angioplasty does not always lead to a permanently opened artery. Though systemic drug therapy has been developed to reduce this restenosis reaction it has not shown convincing results, mostly because of unwanted side effects in other parts of the body while the concentrations in the blood vessel wall at the site of occlusion were too low to be effective. In order to prevent the reclosing of the arteries, scaffolding devices called stents - have been developed which are introduced into the lumen of the artery to keep them open. Unlike the balloon-catheter, the stent remains in the body as a permanent prosthesis. Stents coatings have been developed for different purposes. Firstly, in order to reduce allergic or immunological reactions to the stent material, biocompatible polymers have been used to improve the biocompatibility of the stent. A coating substance may also add to the strength of the stent, or make its surface smoother, allowing easier introduction into the vessels. The use of stents to permanently maintain the opening in the lumen of arterial walls has not completely eliminated the problem of restenosis. Apparently, introduction of the stent itself often causes damage to the inner lining of the vessel wall, inducing a 'reparatory' reaction leading to platelet aggregation and the migration of vascular smooth muscle cells into the arterial lumen, where they accumulate and cause occlusion of the vessel. While the accumulated platelets can produce inflammatory mediators, the damaged endothelium recruits monocytes and leucocytes to the injury site, further contributing to neointimal hyperplasia (Rogers and Edeman, 1995, Circulation 91:2995- 3001). The problem of stent-induced restenosis has been addressed in different ways. Irradiation therapy has been suggested based on intravascular low-power red laser light (LPRLL) (De Scheerder et al. 2000, Catheter Cardiovasc Interv 49(4):468-471), using a liquid sodium 186Re perrhenate solution as beta emitter (Coussement P et al.; 2000, J Invasive Cardiol 12(4): 206-210), or potentially gamma radioactive stents made of platinum-iridium (Bhargava B. et al., 2000, Catheter Cardiovasc Interv 51(3):364-368). Use of radioactive materials in intimate contact with body tissue over long periods is not preferred. Alternatively, local drug delivery by the stents themselves has been suggested.

Bare metallic stents can be used as a platform to deliver drugs locally where the stents struts enter the vascular wall providing a high drug concentration around the stent struts. Though bare stents can be loaded with a drug without using a carrier interface, the amount of drug loaded this way is low and the release curve fast and not controllable (De Scheerder et al. 1996, Coron Arteery Dis 7(2): 161-166). Most drug eluting stents therefore use a drug carrying interface, e.g. a coating. Coated stents can be loaded with a larger amount of drug and drug release can be better modified to obtain a more optimal drug release profile resulting in more prolonged effective tissue drug levels. Moreover, this form of drug-delivery is not limited to restenosis-inhibiting compounds. A number of biocompatible materials suitable for the coating of implantable medical devices have been developed. More particularly, in the field of stent-coating several materials have been tested for drug delivery-characteristics either in animal models only or also in clinical trials, such as phosphorylcholine (PC)(Lewis A. et al., 2002, biomaterials 23(7): 1697-1706; Huang Y et al., 2003, Int J Cardiovasc Intervent 5(3): 166-171) polylactide or polylactide copolymers (Nguyen K. et al. 2003, Biomaterials 24(28):5191-5201) and fluorinated polymethacrylates PFM-P75 (Verweire et al. 2000, J Materials Science:Materials in Medicine 11(4):207-212; Huang Y et al. 2002, J Invasive Cardiol 14(9):505-513). More recently elastomeric poly (ester-amide) (coPEA) polymers (Lee-Seeung H. et al., 2002, Coron Artery Dis 13(4):237-241) and poly-bis-trifluorethoxy phosphazene (PTFEP) (Huang Y. et al., 2003 Coron Artery Dis 14(5):401-408) have been shown to have the required bio compatibility characteristics and have been suggested as a candidate for local drug delivery. Using stacked layers of polymer it was been demonstrated that the pharmacokinetics of the drugs could be manipulated (Finkelstein et al., 2003, Circulation 107(5):777-784). Different drugs have been tested using local delivery from stent coatings to reduce neointimal hyperplasia, including anti-proliferative, immunosuppressive, anti- thrombotic and anti-inflammatory drugs. Heparin has shown only limited benefits in clinical trials. Use of poly(organo)phosphazene coating impregnated with the corticosteroid methylprednisolone was shown to result in a significantly reduced neointimal thickening over the long term (6 weeks) after stenting of pig coronary arteries (De Scheerder et al. 1996, Coronary Artery Disease 7(2): 161-166). More recently, local delivery of a high dose of methylprednisolone from phosphatidyl choline-coated stents or PMF 75 spray- coated stents was found to effectively decrease inflammatory response and result in a significant reduction of neointimal hyperplasia (Huang Y et al., 2003, Int J Cardiovasc Intervent 5(3): 166-171; Huang Y et al. 2002, J Invasive Cardiol 14(9):505-513). Other new drugs also appear to be promising. Recent studies have evaluated these drugs as to their release kinetics, effective dosage, safety in clinical practice and benefit. These studies include trials on sirolimus or rapamycin (RAVEL, SIRIUS), Actinomycin D (ACTION), Tacrolimus (PRESENT), Placitaxel and derivatives (SCORE, ASPECT, ELUTE), dexamethason (EMPEROR), everolimus (FUTURE). Estrogen inhibits initimal proliferation and accellerates endothelial regeneration after angioplasty. 17Beta-estradiol-eluting phophorylcholine coated stents were found to be associated with reduced neointimal formation (New G. et al., 2002, Catheter Cardiovasc Interv 57(2):5266-271) Gene therapy on the vessel wall by local delivery of DNA has also been considered. Effective transfection of neointimal cells was demonstrated using plasmid DNA loaded Polylactic-polyglycolic acid (PLGA) as stent coating (Perlstein et al., 2003, Gene Ther. 10(17): 1420-1428). WO 03/035134 describes a stent coating composition comprising a biodegradable carrier and a bioactive component. The biodegradable carrier is either polymeric or non- polymeric and examples of non-polymeric carriers are vitamin E or derivatives thereof, peanut oil, cotton-seed oil, oleic acid or combinations thereof.

There is a general interest in compositions which achieve prolonged release of bioactive substances as they allow a reduction of the frequency of treatments and/or can minimize trauma to the treated animal. For sustained release, the compositions should not only have the desired drug-release characteristics but have a sufficiently high loading capacity of the therapeutic agent to be released. Oil solutions or suspensions have been used which can be injected intramuscularly, subcutaneously or otherwise. Typically, the oils are gelled with components such as pectin, gelatin or aluminum salts of fatty acids such as aluminum monostearate or distearate to obtain the appropriate consistency. Drug release patterns from 24 hours up to more than twenty days have been described (U.S. Pat. No. 2,491,537; U.S. Pat. No. 2,507,193; U.S. Pat. No. 2,964,448). Alternatively, oils have been used for the coating of microparticles or microcapsules to ensure the controlled release of an active agent present therein (EP 295,941).

Epidemiologic studies have shown an inverse correlation between consumption of fish or other sources of dietary omega-3 fatty acids and cardiovascular events. Trials with parenteral administration of omega-3 fatty acids for restenosis prevention after percutaneous transluminal coronary angioplasty have yielded conflicting results, but recent studies suggest a long term treatment before PTCA may decrease restenosis rate in a significant manner (Maresta et al., 2002, Am Heart J 143(6):E5).

Summary of the invention The present invention is based on the observation that cis-hydrogenated fatty acids are particularly biocompatible in that they elicit a very limited 'foreign-body' reaction when in close contact with animal or human tissues. Additionally, it has been observed that cis-hydrogenated fatty acid compositions can be used for the controlled delivery of therapeutic compounds. By influencing the hydrogenation of the fatty acids, the viscosity can be manipulated, so as to obtain optimal characteristics for drug release.

Hence, it is a particular aspect of the present invention to prepare a composition which can be used as a drug-delivery composition, more particularly as a drug-eluting coating material or a component of a coating for a human or veterinary medical device, especially a device which is to be introduced into or implanted in a human or animal body, especially such a device as will come into contact with circulating blood supply and more particularly to a device which provides drug release, e.g. a device incorporating biologically active, therapeutic or similar agents in the coating. Such a composition is provided, according to the present invention, by firstly providing a fat or oil with a melting point below 37°C and to trans-free hydrogenate such oil or fat to raise the melting point, e.g. to greater than 39°C and less than 50°C. Ideally, both for the coating of medical devices and for the microcarrier application, the fatty acid should not be molten at body temperature. It is particularly preferred if the material is in a thermoplastic state when introduced into the body and in contact with body tissue, i.e. at or near the blood temperature. In addition, drug loading may affect the thermomechanical properties of the composition, particularly when the drug is a lipophilic liquid. In accordance with a further aspect of the present invention trans-free incomplete hydrogenation of the starting material is so selected and controlled that the final drug- comprising composition is in a thermoplastic state at body temperature, e.g. in the range 32 to 43°C. An important application of the invention is the provision of compositions comprising cis-hydrogenated fatty acids for use in the drug delivery of biologically active agents. The invention is particularly suited for the delivery of biological agents to directly to body tissues (as opposed to delivery through the digestive tract), such as the skin, blood, muscle, nose and lung epithelial tissue. Thus, more particularly for the delivery of biological agents which can or need to be administered supra-dermally, intradermally, subcutaneously, intravenously or intra-arterially, intramuscularly, intranasally or by inhalation. The cis-hydrogenation of fatty acids ensure biocompatibility and a suitable viscosity of the composition of the present invention, which combined with the high loading capacity allows controlled, more particularly prolonged drug release. One object of the invention is the provision of compositions comprising cis- hydrogenated fatty acids for use in the coating of medical devices. It has been observed that the drug-release curves obtained correspond to therapeutic requirements. More particularly, with regard to the processes underlying the occurrence of restenosis after stent-implantation, an appropriate release of drugs could be obtained using stents coated with cis-hydrogenated fatty acids, e.g. as prepared by the above method. Thus, the present invention relates to the use of compounds comprising biocompatible fatty acids for the coating of implantable medical devices such as stents, more particularly for use in controlled drug-delivery. According to a first aspect, the invention relates to a coated implantable medical device, wherein the coating composition composition comprises or consists of at least 20% of one or more cis-hydrogenated fatty acids. The cis-hydrogenated fatty acids which are used for the coating of medical devices in the context of the present invention are, according to one embodiment selected from mono-, di- or triglycerides or esters thereof. Most particularly, they are made up of between 20% and 95% triglycerides. Preferably, they have been trans-free hydrogenated. According to a particular embodiment of the invention the cis-hydrogenated fatty acid is an omega-3 -fatty acid. Another aspect of the invention relates to an implantable medical device coated with a coating composition which consists for at least 20% of one or more cis- hydrogenated fatty acids, whereby the coating is a drug-eluting coating and comprises one or more biologically active or therapeutic agents. Moreover medical devices coated with two or more layers of the composition of the invention, optionally comprising different biologically active agents. Such different layers may differ in biochemical characteristics, ensuring different release rates. Biologically active agents can be selected over a wide range of drugs and are determined by the therapeutic target. A particular embodiment of the present invention relates to the coating of stents, more particularly, coronary artery stents. Thus, for this purpose, particularly suited therapeutic agents are biologically agents which reduce restenosis. According to a particular embodiment, the biologically active agent is selected from the group consisting of corticosteroids, drugs used to prevent transplant rejection, antiprohferative drugs and metalloprotease inhibitors. Particular non-limiting embodiments of the drugs envisaged in the context of the present invention are dexamethasone, methylprednisolone, cyclosporin, sirolimus, tacrolimus, everolimus, vincristine, doxyrubicine, paclitaxel, actinomycin, and batimastat. Alternatively, such a biologically active agent is a steroid, such as estradiol. According to another embodiment the biologically active agent is a composition comprising a nucleic acid encoding one or more biologically active agents, or cells, which are optionally genetically modified. Thus, a particular embodiment of the present invention relates to a drug-eluting medical device, particularly a drug-eluting stent, more particularly, a coronary artery drug eluting stent. Another aspect of the invention relates to a coated implantable medical device, wherein the coating composition has a melting temperature which is above body temperature, which ensures that the characteristics of the coating are maintained within the body. This is particularly relevant when drug-release from the coating is envisaged. A suitable temperature range for the melting point of the coating is above 39°C and below 50°C. Another aspect of the invention relates to the coating of an implantable medical device with the coating compositions described herein. This coating can be a complete coating or can relate to the filling of particular structures present on the external surface of the implantable device. These structures can be used as drug-reservoirs. Another aspect of the invention relates to a method of coating a stent which method comprises, providing a stent and coating it with a composition consisting for at least 20% of cis-hydrogenated fatty acids. Optionally, the coating further comprises a biologically active agent. A particular embodiment relates to the use of cis-hydrogenated fatty acids in the coating of stents for use in local drug release. Compositions comprising cis-hydrogenated fatty acids, more particularly compositions comprising high levels of cis-hydrogenated omega-3 fatty acids were found to be particularly suited for the delivery of lipophilic drugs, as these lipophilic drugs showed a high solubility in the cis- hydrogenated omega-3-fatty acid based coating. Another aspect of the invention relates to a method of treating restenosis, comprising providing a stent which is coated with a coating composition consisting for at least 20% of cis-hydrogenated fatty acids and deploying the coated stent into the vascular lumen of a patient. Other objects of the invention relate to the use of the compositions comprising cis-hydrogenated fatty acids in the formulation of tablets, capsules or microcapsules for sustained and/or controlled drug release.

Detailed Description The present invention relates to the use of compositions comprising cis- hydrogenated fats and oils as drug-releasing compositions and in the coating of medical devices, particularly to the use of this type of coating for local drug delivery. The term medical device as used herein refers to an implantable device such as stents, orthopedic devices, implants, or replacements. A stent as used herein refers to an implantable medical device used to support a structure within the human or animal body, such as but not limited to the esophagus, trachea, colon, biliary tract, urinary tract, vascular system or other location within a human or veterinary patient. A particular embodiment of the invention relates to a vascular stent, more particularly a stent for use in supporting coronary arteries. Different stents designs have been described in the art which are suitable for coating, optionally with drug-delivering compositions. Most commonly the stents are made out of metal or metal alloy, such as titanium, tantalum, stainless steel, or nitinol. Particularly suited in the context of the present invention are the stent designs described in US 6,562,065, which relates to pitted stents or stents comprising laser drilled holes for drug wells, and US 5,728,150 which relates to a microporous prosthesis. The cis- hydrogenated fats of the present invention can be applied to the whole stent and/or be used to fill the pits of the stent, optionally carrying particular therapeutic agents as described below. Other examples of suitable stents include but are not limited to those described in WO02/060351, WO03/082152, WO 03/079936, WO 03077802, WO 03072287, WO 03/063736, WO 03061528, WO 03/059207, WO 03/057078. These moreover include stents which are available commercially and/or have been tested in clinical trials including but not limited to the NTRx® stent (Bostn Scientific, Natick, Massachusetts), Cordis Bx Velocity®, Cook N-Flex plus®, S-Flex® and ChromoFlex® stent, Gianturco-Z®, Gianturco-Roche Z®, and Gianturco-Roubinll® stent. The term drug-delivery composition relates to a composition for use in the formulation of tablets, gelules, microcapsules (e.g. in sprays) or of a film such as a coating, which is biocompatible and non-toxic and ensures appropriate release of biologically active molecules. The term 'cis-hydrogenated fats' as used herein relates to fatty acid compounds which are essentially free of trans-unsaturated double bonds. Fatty acid compounds comprise esters, mono-, di- and triglycerides, phospholipids, glycolipids, diol esters of fatty acids waxes and sterol esters, more particularly oleic acid, stearic acid or any mixture thereof. Most suitable fatty acids are triglycerides having a length of 4 to 24h. The fatty acid can originate from vegetable oils, such as, particularly sesame seed and peanut oil, but also including sunflower seed, soybeen, cottonseed, corn, safflower, palm, rapeseed or animal oils, such as fish oils and mixtures of such oils. Oils of mineral origin or synthetic fats can also be employed as long as they are sufficiently biocompatible and/or non-toxic. According to a particular embodiment of the invention, the cis- hydrogenated fat can comprises one or more cis-hydrogenated omega-3 fatty acids, particularly, but not limited to cis-hydrogenated forms of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). According to a more particular embodiment of the invention, the fatty acid comprises a substantial amount of omega-3 fatty acids. Oils obtained from cold water fish are generally rich in omega-3 fatty acids. Cod liver oil comprises about 20% by weight of omega-3 fatty acids. Fatty acids with reduced level of trans-unsaturated double bonds can be obtained by influencing the hydrogenation conditions of oils to reduce the amount of trans-isomers formed (Puri P. J Am Oil Chem Soc 55(12):865-), by use of metal alloy catalysts or adding modifiers or ammonium compounds (US 4,307,026). In WO 98/54275, however, a process is described which enables the significant reduction or elimination of trans- unsaturated fatty acid compounds from a substrate containing cis and trans isomers by means of a zeolite material. As these cis-hydrogenated fats do not contain trans-unsaturated fatty acids, which have been demonstrated to be a potential health hazard, these fatty acids are particularly biocompatible, making them suitable for introduction into the body. Coatings essentially comprising fatty acids moreover have the advantage that they are less likely to crack during temperature changes and, for expandable structures such as stents, the coating will also be more resistant to expansion and contraction of the stent during fabrication and use. This also implies that no harmful fragments will be released from the coating in the body. Fatty acid coatings can result in a smooth layer, minimizing the chances of damage to the surrounding tissues in the body, e.g. the endothelium in the case of a vascular stent. Moreover it is demonstrated in the present invention that cis-hydrogenated fatty acids are particularly suited for (controlled/sustained) drug release. The physicochemical properties of fatty acids strongly depend on the chemical structure of the fatty acid residues and more particularly on their chain length and the amount of double bonds present. In particular, natural materials such as fats often have three states close to the melting point: a higher temperature state in which the material is molten a lower temperature state in which the material is recognisably solid and an intermediate or "thermoplastic" state in which it exhibits some solid and plastic properties.According to the present invention, the composition used for drug-delivery or for the coating of medical devices has a wax or gel-like (non-fluid) consistency, which is maintained within the body. Thus, the melting point of the fatty acid coating should be above body temperature, i.e. above 37°C, particularly between 38°C and 52°C, more particularly above 39°C and below 45°C, e.g. between 39.6°C and 42.6°C. By selecting the melting temperature of the composition to be just above body temperature, it is ensured that the wax-like properties of the material are maintained within the body. This is of importance not only with regard to the interaction of the coating composition of the medical device per se with its environment within the body, but is also necessary to maintain an even prolonged release of therapeutic agents. Hardening by dehydrogenation is a common process to increase the melting profile of fatty acids. Hydrogenation can be partial or result in complete saturation of all double bonds. One particular way of obtaining the appropriate properties of the compositions according to the present invention, is by incomplete hydrogenation, more particularly by cis-(or trans-free)hydrogenation as described in WO 98/54275. The hydrogenation process is well characterised and is demonstrated herein to be well suited to targeting the melting point range for the fatty acids of the present invention. Thus, in accordance with a particular embodiment of the present invention, the melting point of the fatty acid is raised to above body temperature by controlled incomplete trans-free hydrogenation. Additionally or alternatively, if the material is used as a drug delivery composition, the desired consistency of the compound with regard to the method of administration is taken into account. Incomplete hydrogenation is a well-described flexible process whereby the nature of the products is determined by the nature of the starting material, the extent of hydrogenation and the selectivity. The number of saturated bonds in the starting material will influence the level to which the melting temperature can be increased. The latter parameters are controlled by the process conditions and the nature of the catalyst used (Gunstone F. 1999, Chapter 4: "Processing of Fatty Acids and Lipids", in "Fatty Acid and Lipid Chemistry", Aspen Publishers Inc., Gaithersburg, Maryland). The reaction time of the hydrogenation is classically used to influence the degree of hydrogenation or viscosity desired. The process of hydrogenation can be monitored by tracking the amount of hydrogen consumed, by iodine value, the refractive index, by measuring the solid fatty acid content by NMR, measuring the solid fat index by dilatometry, determination of the slip melting point and/or gas chromatography of the methyl esters. With the hydrogenation processes used industrially, isomerization of the carbon- carbon double bonds in the fatty acid residues occurs, beside the saturation of double bonds by the addition of hydrogen. Thus, even if the starting material does not contain any trans-isomers (as is the case of fatty acids from most biological origins), hydrogenation by means of metal catalysts will inevitably result in cis/trans isomerization. However, using the method as described in WO 98/54275, hydrogenation can be carried out with selective adsorption of trans-isomers, ensuring an essentially trans-free cis-hydrogenated fatty acid composition. Hence, it is a particular aspect of the present invention to prepare a material for use as a drug delivery composition and/or as a coating material or a component of a coating material for a human or veterinary medical device, especially a device which is to be introduced into or implanted in a human or animal body. More particularly the present invention is suitable for use as a drug composition which is administered through a route which is immunosensitive and/or for the coating of a device which will come into contact with circulating blood supply and more particularly to a device which provides drug release, e.g. a device incorporating biologically active, therapeutic or similar agents in the coating. The method of the invention comprises the step of providing a fat or oil with a melting point below 37°C and to trans-free hydrogenate such oil or fat to raise the melting point, e.g. to greater than 39°C and less than 50°C. Ideally, the fatty acid composition should not be molten at body temperature. In addition, drug and excipient loadings may affect the thermomechanical properties of the composition, particularly when the drug is a lipophilic liquid. In accordance with a further aspect of the present invention trans-free incomplete hydrogenation of the starting material is so selected and controlled that the final drug/excipient coating material mixture is in a thermoplastic state at body temperature, e.g. in the range 32 to 43°C, i.e. not in a liquid state in this range. Further, it is a particular aspect of the present invention to control the thermomechanical properties of a fatty acid composition for use as drug delivery composition and/or for the coating of a drug eluting medical device, so as to determine, select or set a drug elution profile by trans-free hydrogenation of an oil or fat, especially a cis-hydrogenated fatty acid composition. Additionally or alternatively the desired consistency of the fatty acid composition can be influenced by the chain length of the fatty acids. The melting point of fatty acids increases with the number of carbon atoms (e.g. Butyric 7.9°C (4c), Laurie 44.2°C (12c), Stearic 69.6°C (18c), Behenic 79.7°C (22c)). Moreover odd chain fatty acids usually melt at a lower temperature than do the even chain acids containing one less carbon. Thus, by selecting the starting material to be cis-hydrogenated, the melting point can be influenced. The desired consistency of the fatty acid composition can also be obtained by mixing of different components. For instance, triglycerides, which correspond to a glycerol attached to three fatty acids by separate ester bonds) can have different combinations of different fatty acids. By combining fatty acids of different chain lengths and number of double bonds, the desired melting point can be obtained. In the fatty acid compositions of the present invention, the content of the cis- hydrogenated fats is not specifically limited, but is preferably 20-100% by weight, more preferably 70-100%. Other components can be added to the composition comprising the cis-hydrogenated fat of the invention, depending on the intended application, such as, but not limited to anti-oxidants (e.g. tocopherol), solvents (which are optionally removed before use) or emulsifiers. According to a more general application of the present invention, compounds comprising cis-hydrogenated fatty acids are used as a drug delivery composition, i.e. for the delivery of bioactive agents, in any formulation. The term bioactive (or biologically active) in the context of the present invention includes without limitation physiologically or pharmacologically active substances that act locally or systemically in a human body or an animal body. Representative bioactive agents or drugs that are envisaged include, without limitation, peptide drugs, protein drugs, desensitizing agents, antigens, vaccines, anti-infectives, antibiotics, antimicrobials, antineoplastics, antitumor, antiallergenics, steroidal anti-inflammatory agents, analgesics, decongestants, miotics, anticholinergics, sympathomimetics, sedatives, hypnotics, antipsychotics, psychic energizers, tranquilizers, contraceptives, androgenic steroids, estrogens, progestational agents, humoral agents, prostaglandins, analgesics, antispasmodics, antimalarials, antihistamines, cardioactive agents, non-steroidal anti-inflammatory agents, antiparkinsonian agents, antihypertensive agents, beta-adrenergic blocking agents, nutritional agents, antivirals, DNA fragments, nucleic acids, genetic material, oligonucleotides, radioisotopes, or combinations of these classes of compounds. Also, various forms of the drugs or biologically active agents may be used. These include, without limitation, forms such as uncharged molecules, molecular complexes, salts, ethers, esters, amides, and other chemically modified forms of the biologically active agent which are biologically activated when injected into a body. The different formulations envisaged include, but are not limited to tablets, beadlets, gelules, capsules, films and microcapsules. More particularly, the present invention provides a composition having the required physicochemical characteristics allowing the preparation of high-dose formulations without problems of dissolution of the bioactive ingredient(s) due to compression. Moreover, the provision of cis- hydrogenated fatty acid in combination with traditional drug-containing beads can function as a cushion, preventing the dissolution from the traditional beads upon compression of the table. According to a particular application of the present invention, compounds comprising cis-hydrogenated fats are used for the coating of implantable medical devices. The term coating as used herein can optionally refer to the application of a uniform layer over all or part of the medical device. Different methods of applying coatings are envisaged within the context of the invention, including dipcoating, inkjet printing, painting and spray-coating. According to a particular embodiment the cis- hydrogenated fats are mixed with a solvent, such as ethanol, whereafter the medical device is dipped into the oil/ethanol solution. The solvent is then evaporated under a heated airflow. Moreover, according to the present invention, different layers of cis- hydrogenated fats of the same or different composition can be applied, optionally separated by intermediate layers. This can be of interest for the sequential release of drugs (see below). Additionally or alternatively, coating of a medical device can refer to the filling up of particular structures in the structure of the medical device, for instance the filling up of pits or grooves on the exterior (i.e. the side in contact with the body structure to be supported) of the medical device.

One particular embodiment of a drug-delivery composition according to the present invention is the local drug-delivery through the coating of medical devices which are implanted into the animal or human body. A wide variety of drugs is envisaged for which local delivery by way of the coating of an implanted medical device would be beneficial. More particularly, in the context of implants, local delivery of anti- inflammatory and immuno-modulatory drugs has generally been demonstrated to be beneficial. It is presently demonstrated that a wide range of drugs can be impregnated and released by the cis-hydrogenated fat-based coating of a medical device. In the application of the invention to drug-eluting stents (also referred to as DES), the therapeutic agents envisaged suitable include but are not limited to corticosteroids such as dexamethasone and methylprednisolone, drugs used to prevent transplant rejection, such as cyclosporin, sirolimus, tacrolimus and everolimus, antiprohferative drugs such as vincristine, doxyrubicine, paclitaxel and actinomycin and metalloprotease inhibitors, such as batimastat. Other suitable therapeutic agents include sodium heparin, low molecular weight heparin, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone, dipyridamole, glycoprotein Ib/IIb/IIIa platelet membrane receptor antibody, recombinant hirudin, thrombin inhibitor, angiopeptin, angiotensin converting enzyme inhibitors, calcium channel blockers, colchicine, fibroblast growth factor antagonists, histamine antagonists, HMG-CoA reductase inhibitor, methotrexate, monoclonal antibodies, nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitor, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine, PDGF antagonists, alpha-interferon, genetically engineered epithelial cells, and combinations thereof. Alternatively, it the therapeutic agent for use in the context of the present invention can be a nucleic acid, encoding one or more therapeutic agents such as those described above or encoding a molecule which, when present in the cells of the tissues surrounding the implantable device, has a therapeutic effect. According to yet another embodiment of the present invention the therapeutic agent can be a composition comprising cells, such as (genetically modified) epithelial cells. According to the present invention the loading capacity of the cis-hydrogenated fat composition for the drugs will be dependent on the hydrophilicity characteristics of the drug. More specifically, it is demonstrated that lipophilic drags have a higher solubility in the cis-hydrogenated omega-3 -fatty acids and a higher maximal drug loading capacity than hydrophilic drugs in coronary vascular wall. The cis-hydrogenated fat-based coatings are shown to potentially release about 20% of a therapeutic agent within 24 hours, allowing a fast loading of the injured tissue surrounding the stent strut. Local tissue drug concentrations rise quickly, and reach effective tissue drug concentrations within 24 hours to prevent the pathologic reactions after stent implantation. The present application demonstrates that coating of a medical device with cis- hydrogenated fats can provide a drug release curve characterised by a 20% of total drug amount released within 24 hours, 50% within one week, and 80% within four weeks. These release characteristics are well correlated with the pathologic processes induced by stent implantation. In a porcine model, after stent implantation, acute pathologic reactions (thrombus formation, inflammation) happen within five days, and subacute reactions (smooth muscle cell proliferation) happen within four weeks. Thus, the drug release rate using the cis-hydrogenated fat-based stent coating is appropriate, from a therapeutic point of view. It is furthermore demonstrated that for some drugs a prolonged drug release rate over 6 weeks can be obtained. As demonstrated in the present application, the design of the release of the drug from the coating of the stent will also be influenced by the design of the stent. Thus, particular designs, such as stents provided with pits (such as described in WO 01/66036, WO 02/032347, US 2003/0105512 and US 6,562,065) or grooves (such as described in US 2003/015512). Moreover, the provision of several layers of coatings with cis- hydrogenated fats of the same or different compositions allows the modulation of the release of one or several drugs from the stent. In particular, the thermomechanical properties of each layer may be controlled, selected or determined by the degree of trans- free incomplete hydrogenation of the material of each layer so as to achieve a specific drug eluting profile for each layer. Alternatively, the coating with cis-hydrogenated fats of the present invention can be combined with other bio-degradable coatings to ensure different release rates of one or more drugs from the coating. The amount of therapeutic agent to be included in the coating of the stent will be determined by the therapeutic effect envisaged and the release curve of the therapeutic agent from the coating. Generally, for stents coated over their entire surface, the therapeutic agent will be present in the coating in an amount ranging from about 0.01 mg to about 10 mg and more preferably from about 0.1 mg to about 4 mg of the therapeutic agent per cm2 of the gross surface area of the stent. "Gross surface area" refers to the area calculated from the gross or overall extent of the structure, and not necessarily to the actual surface area of the particular shape or individual parts of the structure. In other terms, about 100 micrograms to about 300 micrograms of therapeutic agent per 0.002 cm of coating thickness may be contained on the stent surface.

BRIEF DESCRIPTION OF THE FIGURES

The following examples, not intended to limit the invention to specific embodiments described, may be understood in conjunction with the accompanying Figure, incorporated herein by reference, in which:

Figure 1 : Relation between oversizing and neointimal hyperplasia in coated stents Figure 2: Relation between oversizing and area stenosis in coated stents Figure 3 : Relation between inflammation score and area stenosis in coated stents Figure 4: Drug release curves for cytochalasin D, latranculin A and latranculin B over two weeks; -■- cytochalasin D; -A- latranculin A; -T- latranculin B

Figure 5: Drug release curve for different dosages of Paclitaxel over 6 weeks; -■- high dose (150 mg/ml); -A- medium dose (50 mg/ml); -▼- low dose (10 mg/ml) Figure 6: Release curves for methylprednisolone for different stent lenghts during 70 days; -■- 32 mm stent; -A- 16 mm stent Figure 7: Estradiol release curve for pitted and non-pitted stent (70 days); -■- pitted stent; -A- normal stent Figure 8: Ledertrexate release curve over a period of 4 weeks

Examples

Preparation of cys-hydrogenated fatty acids

Example 1 - cys-hydrogenation of soybean oil

Soy oil has an iodine value of 132. The hydrogenation reaction was done in a Parr- reactor at 100°C and 1000 rpm with a pressure of 60 bar H2. 50 g of soy oil and 1 g catalyst (125 Pt/Ba-ZSM-5, CBN 1502, ox 350, red 500) were used. First the mixture was flushed with H to remove the air. The reaction started when a temperature of 100°C was reached. When the reaction was stopped, the mixture was flushed with argon to remove the H2. All samples were centrifuged and filtered with a HPLC-filter of 0.45 μm to remove the catalyst. The samples were conserved in the freezer.

Different reaction times were applied. Samples were collected after 10, 15, 20, 40 min and 2 h reaction. This resulted in iodine values of respectively 117, 106,105, 79 and 62. The iodine value was determined by gas chromatography.

Example 2- cys-hydrogenation of Fish oil

Fish oil has an iodine value of I 313, reflecting the higher degree of saturation compared to soybean oil. A sample of fish oil triglycerides of Larodan Lipids was used. This oil has a composition of 30% EPA, Eicosapentaenoic Acid, and 20%) DHA, Docosahexaenoic Acid.

The reaction was carried out on the same way as described in Example 1. The characteristics of the products obtained after different reaction times are provided in Table 1

Figure imgf000019_0001

The iodine value was determined with H -NMR. On the basis of the surface of the peak from the cis-H-binding at 5.39 ppm and one peak which stays unchanged at the end (beginning) of the molecule at 0.98 ppm, the conversion can be calculated. Using a fish oil of a different composition, a smelttemperature of 40°C was obtained after a reaction time of 1 hour and 30 minutes

Testing of the in vivo biocompatibility and drug-elution profile of a cys-hydrogenated fatty acid sample. Example 3 - Biocompatibility of different coatings of a metal stent

Operative procedures and evaluation methods

Stent implantation in the right coronary artery, left anterior descending or left circumflex was performed according to the method described by De Scheerder et al. (1996, Coron Artery Dis 7(2): 161-166) The guiding catheter was used as a reference to obtain an oversizing from 10 to 20%. 4 or 6 weeks after implantation, control angiography of the stented vessels was performed to confirm the arterial patency after administration of 0.25mg of nitroglycerin. Pigs were sacrificed using an intravenous bolus of 20ml oversaturated potassium chloride. For these follow-up studies, the instrumentation of the pigs and angiographic technique were identical to those used during the implantation procedure.

Coronary segments were carefully dissected together with a 1cm minimum vessel segment both proximal and distal to the stent. The segments were fixed in a 10% formalin solution. Each segment was cut into a proximal, middle and distal stent segment for histomorphometric analysis. Tissue specimens were embedded in a cold- polymerizing resin (Technovit 7100, Heraus Kulzer GmbH, and Wehrheim, Germany). Sections, 5 microns thick, were cut with a rotary heavy duty microtome HM 360 (Microm, Walldorf, Germany) equipped with a hard metal knife and stained with hematoxylin-eosin, masson's trichrome, elastic stain and phosphotungstic acid hematoxylin stain. Light microscopic examination was performed by an experienced pathologist who was blinded to the type of stent used. Injury of the arterial wall due to stent deployment (and eventually inflammation induced by the polymer) was evaluated for each stent filament and graded as described by Schwartz et al. (1992 ,J Am Coll Cardiol. 19:267-274.). Grade 0=internal elastic membrane intact, media compressed but not lacerated; Grade 1= internal elastic membrane lacerated, media visibly lacerated; Grade 2=external elastic membrane compressed but intact; Grade 3=large laceration of the media extending through the external elastic membrane or stent filament residing in the adventitia. Inflammatory reaction at each stent filament was carefully examined, searching for inflammatory cells, and scored as followed: l=sparsely located histolymphocytes surrounding the stent filament; 2=more densely located histolymphocytes covering the stent filament, but no lymphogranuloma and/or giant cells formation found; 3=diffusely located histolymphocytes, lymphogranuloma and/or giant cells, also invading the media.

Mean score = sum of score for each filament/ number of filaments present. Morphometric analysis of the coronary segments harvested was performed using a computerized morphometry program (Leitz CBA 8000). Measurements of lumen area, lumen area inside the internal elastic lamina, and lumen inside the external elastic lamina were performed. Furthermore, area stenosis and neointimal hyperplasia area were calculated.

Stainless steel stents (n=10) of the type described in WO 01/66036 were used. Fish oil (cod liver) was hydrogenated using a procedure as described in Example 1 and 2 above, to obtain cis-hydrogenated fatty acid. Cod liver oil contains a high percentage of omega- 3 fatty acids. Cis-hydrogenated fatty acid (cis-HFA) coated stents were compared with commercially available coatings including spray-coated PFM-P75 stents(n=12), PTFEP dipcoated Coroflex stents (n=8), phosphorylcholine (PC) coated BiodivYsio stents (PC- 1, n=10; PC-2, n=ll) and PEA dipcoated Blue medical stents (n=16). Additionally stents were coated with a sample of unsaturated cod oil + Vitamin E. All stents were implanted in the coronary arteries of pigs. Pigs were sacrificed after 4 or 6 weeks to evaluate peri- strut inflammation and neointimal hyperplasia.

The results of the histological and morphometric analysis of the vessel segments obtained at 4 or 6 weeks follow-up are provided in Table 1. As can be seen from these data, the PFM-P75 coated stents induced a severe inflammatory response (2.34±0.73). Inflammation score graded as 3 was frequently observed. The PTFEP coated and PC coated stents (PC-1, PC-2) showed a mild to moderate inflammatory reaction. A minimal inflammatory response was observed with the cis-hydrogenated omega-3 FA coated stents. Especially in cis-hydrogenated omega-3 FA coated stents, a homogenous low inflammatory response was observed. Consistent with the decreased inflammatory response, the cis-hydrogenated omega-3 FA coated stents also showed decreased injury scores. The neointimal hyperplasia of PFM-P75 coated stents was high and the area stenosis was 76%. The lumen area of these stents was dramatically reduced. The neointimal hyperplasia of commercial PTFEP and PC coated stents was less than the PFM-P75 coated stents, but higher than other coated stent groups. The cis-HFA coated stents showed very low neointimal hyperplasia (0.88±0.21 mm2) and area stenosis (16±7%), even the ratio of Balloon-a/EEL-a was the highest. This result was significantly better than that obtained with the coating of unsaturated fatty acids tested.

Table 2: histopathology and morphometry of coated stents

Figure imgf000021_0001
LA= lumen area, NTH= neointimal hyperplasia , AS= area stenosis, Bal-a/IEL-a = balloon oversizing expressed as a ratio of size of balloon-artery/lumen area inside the internal elastic lamina, NIH/Bal-a/IEL-a = neointimal hyperplasia results matched for balloon oversizing; * Bal/artery

Thus, it can be deduced that cis-hydrogenated fatty acid based coatings are particularly biocompatible when used as stent coatings. When implanted in porcine coronary vessels no increased inflammatory reaction was observed and neointimal hyperplasia was lower compared to bare stents or compared to commercial coatings.

Example 4 - Correlation analysis of Balloon-a/JEL-a, injury, inflammation with neointimal hyperplasia and area stenosis (figures 1-3)

By linear regression analysis it was found that the oversizing (Balloon-a/IEL-a) did not show a correlation to neointimal hyperplasia, area stenosis as well as injury score. However, the inflammation score and arterial injury both showed a significant correction to neointimal hyperplasia and area stenosis.

The oversizing (Balloon-a/TEL-a) did not show a positive correlation to neointimal hyperplasia and area stenosis. It means that the mechanical force at oversizing around 10- 20% during stent implantation in coated stents is not as important as in bare metal stents to neointimal formation.

The inflammation and arterial injury induced by coated stents are important factors to both neointimal hyperplasia and area stenosis.

Example 5 - Drug loading capacity and in vitro-drug release using of cis- hydrogenated fatty acid based stent coatings.

The total drag amount that can be loaded in the cis-hydrogenated fatty acid based stent coating was investigated and an evaluation was made of the in- vitro drag release curves for several potential interesting drags. Again a hydrogenated fish oil sample was used. These drags included an anti-tumour agent (paclitaxel), anti-inflammatory agents (methylprednisolone and methotrexate), and other potential interesting compounds like estradiol, cytochalasin D and lantruculin. Balloon mounted bare stents (16mm long, 3.0 mm diameter, slotted tube stent) were dip- coated in the oil solution loaded with the maximal solubalisable amount of paclitaxel (paclitaxel, lOOmg/ml), cytochalasin D (cyto D, lOmg/ml), latranculin A or B (Lat A, 500μg/ml, or Lat B, 5mg/ml), ledertrexate (LDT, 50mg/ml), methylprednisolone (MP, 75mg/ml), estradiol (Estradiol, lOOmg/ml). Balloon mounted drag-loaded stents were carefully dislodged form the balloon by inflating and deflating the balloon and placed in a vial containing 1 ml 0.9% NACL at 37°C. The UV absorbance was monitored at the appropriate wavelength for the drug studied (Cary4E spectrophotometer, Varian Inc) at several time points for in total 2 weeks or longer. In general, a wavelength of 205nm to 222nm was used, depending on the drag characteristics. Most commonly, the wavelength used was 273nm. Within 24 hours, time points were lh, 2h, 3h, 4h, 6h, 8h, and 24h, afterwards Id, 2d, 3d, 4d, 5d, 6d, 7d, 14d, 21d, 28d, 35d, and 42d were set as time points. Some drags had different time points dependent on the endpoint. After each time point, the stent was replaced in a fresh vial. Using a calibration curve, the amount of drag in the vials at each time point was determined. The total amount of drug released was considered as the total loaded amount of the drug, and it was used to draw the release curve.

In vitro release curves are shown in Figures 4 to 8. Except where indicated, a wavelength of 273 nm was used.

As can be seen from the release curves, the drag release was fast in the first 24 hours with more than 20% of drag released within the first 24 hours. This means that using these oil-based coatings one can expect a fast loading of the injured tissue surrounding the stent strat. Local tissue drug concentrations will raise quickly, and reach effective tissue drag concentrations within 24 hours to prevent the pathologic reactions after stent implantation. Within two weeks a drag release of about 50% was generally observed.

A continuous drug release was observed during at least two weeks after implantation. Since most pathologic events resulting in neointimal hyperplasia start within one week, this drag release is sufficiently long to have a good effect on the neointimal hyperplasia cascade. After two weeks, drag release persisted, though the amount of release clearly decreased. Within 4 weeks about 80% of the drug has been released. These release curves demonstrate that the cis-hydrogenated fatty acid based stent coating is suitable as a biodegradable coating and can sustain a continuous drag release over 6 weeks at least. Furthermore for lipophilic agents it is expected that the drug remains in the vessel for a much longer time period.

For paclitaxel (Figure 5), different drag concentrations (100%, 33%), 7%) were used in the oil-based stent coating, resulting in different release curves. However, these release curves showed similar drag release characteristics demonstrating that the cis- hydrogenated fatty acid based stent coating result in a dose-dependent drag release.

For methyl prednisolone (Figure 6) different stent lengths were used, i.e. 16mm and 32 mm. A perfect relationship between the length of the stent and the total drag dose delivered was observed.

In Figure 7, a different drug release curve is observed for estradiol compared to the other drugs. The release of estradiol from the oil-based stent coating showed a prolonged drag release rate over 6 -10 weeks. This release curve demonstrates that for some drugs much more prolonged drug release can be obtained.

In Figure 8, a continuous drug release (Ledertrexate) was observed during at least two weeks after implantation. After the first week, drag release persisted at a sensibly constant rate up to 4 weeks.

Claims

Claims
1. The use of a composition consisting for at least 20% of cis-hydrogenated fatty acids as a drug delivery composition.
2. The use according to claim 1, wherein the drag delivery composition is used as a coating.
3. A coated implantable medical device, wherein the coating composition consists for at least 20% of cis-hydrogenated fatty acids.
4. The coated implantable medical device of claim 3, wherein said coating composition has a melting point which is above body temperature.
5. The coated implantable medical device of claim 3, wherein said coating composition further comprises one or more therapeutic agents.
6. The coated implantable medical device of any one of claims 3 to 5, which is a stent.
7. The coated implantable medical device of claim 6, wherein said stent is a coronary artery stent.
8. The coated implantable medical device of any one of claims 3 to 1, wherein said one or more therapeutic agents are selected from the group consisting of corticosteroids, drugs used to prevent transplant rejection, antiprohferative drugs and metalloprotease inhibitors.
9. The coated implantable medical device of claim 6, wherein said therapeutic agent is selected from the group consisting of dexamethasone, methylprednisolone, cyclosporin, sirolimus, tacrolimus, everolimus, vincristine, doxyrubicine, paclitaxel, actinomycin, and batimastat.
10. The coated implantable medical device of claim 6, wherein said therapeutic agent is estradiol.
11. The coated implantable medical device of any one of claims 3 to 7, wherein said therapeutic agent is a nucleic acid or a composition comprising cells.
12. The coated implantable medical device of any one of claims 3 to 11, wherein said cis-hydrogenated fatty acid comprises one or more of the fatty acids selected from mono-, di- or triglycerides or esters thereof.
13. The coated implantable medical device of any one of claims 3 to 11, wherein said cis-hydrogenated fatty acid is an omega-3 -fatty acid.
14. The coated implantable medical device of any one of claims 5 to 13, wherein the structure of said implantable medical device comprises grooves or pits on its external surface.
15. A method of coating a stent said method comprising a) Providing a stent b) Providing a coating composition consisting for at least 20% of cis-hydrogenated fatty acids. c) Applying the coating composition to the stent.
16. The method of claim 15, wherein said coating further comprises a therapeutic agent.
17. The method of claim 15, wherein said cis-hydrogenated fatty acid is a triglyceride.
18. The method of claim 15, wherein said coating has a melting point which is above body temperature.
19. The method of claim 13, wherein said cis-hydrogenated fatty acid is an omega-3 fatty acid.
20. A method of treating restenosis, comprising: a) providing a stent which is coated with a coating composition consisting for at least 20% of cis-hydrogenated fatty acids b) deploying said coated stent into the vascular lumen of a patient.
21. A method of preparing a drug release composition comprising: providing a fat or oil with a melting point below 37°C and trans-free hydrogenation of the oil or fat to raise the melting point of the fat or oil to greater than 39°C.
22. The method of claim 21, wherein the melting point of the hydrogenated fat or oil is less than 50°C.
23. The method of claim 21 or 22, wherein the drug-release composition is a coating composition for a medical device.
24. A method of applying coating materials to a medical device comprising: a) providing a first fat or oil with a melting point below 37°C and ensuring trans- free hydrogenation of the oil or fat to raise the melting point of the fat or oil to a first melting point greater than 39°C; b) providing a second fat or oil with a melting point below 37°C and ensuring trans-free hydrogenation of the oil or fat to raise the melting point of the fat or oil to a second melting point greater than 39°C; and c) applying the first and second hydrogenated fat or oil to the medical device in the form of a coating.
PCT/BE2003/000201 2003-11-11 2003-11-17 Cis-hydrogenated fatty acid coating of medical devices WO2005053767A1 (en)

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