Coating for Medical Devices

Europäisches Patentamt *EP001247537A1* (19) European Patent Office

Office européen des brevets (11) EP 1 247 537 A1

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.7: A61L 27/34, A61L 29/08, 09.10.2002 Bulletin 2002/41 A61L 31/10

(21) Application number: 01201259.7

(22) Date of filing: 04.04.2001

(84) Designated Contracting States: (72) Inventor: The designation of the inventor has not AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU yet been filed MC NL PT SE TR Designated Extension States: (74) Representative: Prins, Adrianus Willem et al AL LT LV MK RO SI Vereenigde, Nieuwe Parklaan 97 (71) Applicant: IsoTis B.V. 2587 BN Den Haag (NL) 3723 MB Bilthoven (NL)

(54) Coating for medical devices

(57) The invention relates to a coating for medical leased in vivo in a controlled manner, as the degrada- devices. The coating comprises a copolymer of a poly- bility of the coating may also be adjusted to a predeter- alkylene glycol terephtalate and an aromatic polyester mined rate. The invention further relates to a process of which the composition may be adjusted such as to for applying the coating to a surface and to a medical achieve an excellent adhesion to a wide range of sur- device comprising the coating. faces. The coating may further comprise an additive, such as a biologically active agent, which may be re- EP 1 247 537 A1

Printed by Jouve, 75001 PARIS (FR) 1 EP 1 247 537 A1 2

Description tude of variations that can be used to achieve an opti- mum property profile of a coating. These parameters do [0001] The invention relates to a coating for medical not only serve to adjust the adhesion of the coating. Oth- devices. The invention further relates to a process for er properties can be optimised as well. Examples of applying a coating to a surface, e.g. a surface of a med- 5 such properties include the degradability and swelling ical device, and to a medical device comprising said behaviour of the coating and mechanical properties, like coating. elasticity and tensile strength. Other properties and ad- [0002] Great effort has been put into studies of coat- vantages will become clear form the following, more de- ings for medical devices. Materials used for the manu- tailed description of the invention. facture of medical devices are not always chosen from 10 [0009] A coating according to the invention comprises a biocompatability point of view as often other consid- a copolymer of a polyalkylene glycol terephtalate and erations, e.g. with respect to strength or tensile and an aromatic polyester. Preferably, the copolymer com- stretching properties, prevail. prises 20-90 wt.%, more preferably 40-70 wt.% of the [0003] Coatings for medical devices are, however, not polyalkylene glycol terephtalate, and 80-10 wt.%, more only interesting for enhancing the biocompatibility of a 15 preferably 60-30 wt.% of the aromatic polyester. A pre- medical device. They also provide a possibility to pro- ferred type of copolymers according to the invention is vide a controlled release of biologically active agents, in formed by the group of block copolymers. which case it is necessary that the coating is also bio- [0010] The polyalkylene glycol may have a weight av- degradable. erage molecular weight of about 150 to about 10000. [0004] Problems encountered in the design of coat- 20 Preferably, the polyalkylene glycol has a weight average ings for medical devices are many. One of the bigger molecular weight of 200 to 4000. The aromatic polyester problems concerns the adhesion of the coating to the preferably has a weight average molecular weight of material of which the medical device is made. As many from 200 to 9000, more preferably from 250 to 4000. different materials, varying from metals to ceramics and The weight average molecular weight of the copolymer polymeric materials, are used for the manufacture of 25 preferably lies between 10,000 and 300,000, more pref- medical devices, it is important that a good coating ad- erably between 40,000 and 120,000. heres sufficiently to all sorts of materials. This is, how- [0011] The weight average molecular weight may ever, often not the case. suitably be determined by gel permeation chromatogra- [0005] Another problem concerns the conditions a phy (GPC). This technique, which is known per se, may medical device is subjected to during use. Certain med- 30 for instance be performed using chloroform, hexafluoro ical devices, such as catheters, are for instance subject- isopropanol or m-cresol as a solvent and polystyrene as ed to deformation in vivo. When the device expands, it external standard. Alternatively, a measure for the is important that the coating is capable of undergoing weight average molecular weight may be obtained by the same deformation without breaking or coming loose. using viscometry (see NEN-EN-ISO 1628-1). This tech- This would lead to exposure of the surface of the mate- 35 nique may for instance be performed at 25°C using chlo- rial of the medical device to the surrounding tissue in roform as a solvent. Preferably, the intrinsic viscosity of vivo. In the worst case, parts of the coating might detach the copolymer lies between 0.2 and 1.5 dL/g, which cor- from the device completely. responds to a weight average molecular weight be- [0006] Accordingly, there is a need for a coating ma- tween 10,000 and 300,000. Likewise, the more pre- terial for medical devices which may be used universally 40 ferred ranges for the weight average molecular weight for different sorts of medical devices of different materi- measured by GPC mentioned above can also be ex- als. pressed in terms of the intrinsic viscosity. [0007] The invention provides a coating that fulfils this [0012] In a preferred embodiment, the polyalkylene need. A specific copolymer has been found of which the glycol terephtalate component has units of the formula properties may be adjusted to the needs and require- 45 -OLO-CO-Q-CO-, wherein O represents oxygen, C rep- ments of application on a specific medical device of a resents carbon, L is a divalent organic radical remaining specific material. Accordingly, the invention relates to a after removal of terminal hydroxyl groups from a poly coating for a medical device comprising a copolymer of (oxyalkylene)glycol, and Q is a divalent organic radical. a polyalkylene glycol terephtalate and an aromatic pol- [0013] Preferred polyalkylene glycol terephtalates are yester. 50 chosen from the group of polyethylene glycol terephta- [0008] A coating according to the invention may be late, polypropylene glycol terephtalate, and polybuty- applied to a wide range of materials. It is one of the great lene glycol terephtalate and copolymers thereof, such advantages of the invention that the composition of the as poloxamers. A highly preferred polyalkylene glycol copolymer may be adjusted such as to achieve a good terephtalate is polyethylene glycol terephtalate. adhesion to nearly any type of material. The nature and 55 [0014] The terms alkylene and polyalkylene generally molecular weights of the monomers of the copolymer, refer to any isomeric structure, i.e. propylene comprises as well as the ratio of the two monomers and the mo- both 1,2-propylene and 1,3-propylene, butylene com- lecular weight of the copolymer itself, provide a multi- prises 1,2-butylene, 1,3-butylene, 2,3-butylene, 1,2-iso-

2 3 EP 1 247 537 A1 4 butylene, 1,3-isobutylene and 1,4-isobutylene (tetram- tive agents. In addition, depending on the chosen com- ethylene) and similarly for higher alkylene homologues. position of the copolymer, a certain swelling behaviour The polyalkylene glycol terephtalate component is pref- may be set. Swelling may serve as an additional tool to erably terminated with a dicarboxylic acid residue modulate release of active agents from the coating. -CO-Q-CO-, if necessary to provide a coupling to the 5 When the coating is used on certain types of medical polyester component. Group Q may be an aromatic devices, e.g. which are subject to deformation during group having the same definition as R, or may be an use in vivo, an elastic behaviour may be very useful. aliphatic group such as ethylene, propylene, butylene [0020] Examples of materials onto the surface of and the like. which a coating according to the invention may be ap- [0015] The polyester component preferably has units 10 plied include metals and alloys, ceramics, glasses, and -O-E-O-CO-R-CO-, wherein O represents oxygen, C polymers. More specific examples of metals include represents carbon, E is a substituted or unsubstituted stainless steel, titanium, nickel, cobalt, chrome, nio- alkylene or oxydialkylene radical having from 2 to 8 car- bium, molybdenum, zirconium, tantalum, and combina- bon atoms, and R is a substituted or unsubstituted di- tions thereof. Further, ceramic materials, such as alumi- valent aromatic radical. 15 na and zirconia, glasses such as bioactive glasses [0016] In a preferred embodiment, the polyester is made of CaO-SiO2-P2O5, and calcium phosphates, chosen from the group of polyethylene terephthalate, such as hydroxyapatite and tricalcium phosphate, may polypropylene terephthalate, and polybutylene tereph- be coated in accordance with the invention. The subject thalate. A highly preferred polyester is polybutylene coatings can further be applied to various polymers and terephthalate. 20 plastics, more preferably biocompatible or bioresorba- [0017] The preparation of the copolymer will now be ble ones like polylactic acid or polyglycolic acid, but also explained by way of example for a polyethylene glycol polyolefines, such as (ultra high molecular weight) pol- terephtalate/polybutylene terephthalate copolymer. yethylene and the like. Based on this description, the skilled person will be able [0021] The material of which a surface is coated may to prepare any desired copolymer within the above de- 25 be a flat, dense or a complex shaped body. It may have scribed class. An alternative manner for preparing poly- a porous, beaded or meshed ingrowth surface, all de- alkylene glycol terephtalate/polyester copolymers is dis- pending on the purpose of the body. closed in US-A-3,908,201. [0022] In a preferred embodiment, the coating is ap- [0018] A polyethylene glycol terephtalate/polybuty- plied to a medical device, which is to be used in vivo. lene terephthalate copolymer may be synthesized from 30 Examples of medical devices that may be coated ac- a mixture of dimethyl terephthalate, butanediol (in ex- cording to the invention include, but are not limited to, cess), polyethylene glycol, an antioxidant and a catalyst. catheters, fibres, non-woven fabrics, vascular grafts, The mixture is placed in a reaction vessel and heated porous metals for e.g. acetabulum revision, dental filling to about 180°C, and methanol is distilled as transester- materials, materials for approximation, adhesion of tis- ification proceeds. During the transesterification, the es- 35 sues, materials used in osteo-synthesis (e.g. pins or ter bond with methyl is replaced with an ester bond with bone screws), cardiac patches, sutures, soft and hard butylene and/or the polyethyene glycol. After transes- tissue scaffolds and fillers (e.g. collagen, calcium phos- terification, the temperature is raised slowly to about phate, bioglass), stents, bone void fillers intended for 245°C, and a vacuum (finally less than 0.1 mbar) is the repair of bone defects, intrauterine devices, root ca- achieved. The excess butanediol is distilled off and a 40 nal fillers, drug delivery pumps, implantable infusion prepolymer of butanediol terephthalate condenses with pumps, spacer devices, implants containing medicinal the polyethylene glycol to form a polyethylene/polybuty- products, and scaffolds for tissue engineering. lene terephthalate copolymer. A terephthalate moiety [0023] As has been mentioned, the composition of the connects the polyethylene glycol units to the polybuty- copolymer of which a coating according to the invention lene terephthalate units of the copolymer and thus such 45 is made, may be adjusted to provide optimal properties a copolymer also is sometimes referred to as a polyeth- for adhesion on various surfaces. In addition the com- ylene glycol terephthalate/polybutylene terephthalate position may be adjusted to achieve predetermined oth- copolymer (PEGT/PBT copolymer). er properties, such as swelling behaviour and biode- [0019] In principle, a coating according to the inven- gradability. This adjusting may be done as follows. tion of the above described copolymer may be applied 50 [0024] It envisaged that, under certain circumstances, to any type of surface. In fact, it is one of the great ad- two coatings are applied. For instance, in case the coat- vantages of the invention that the properties of the co- ing is to be applied to an inert surface (like a metal or polymer may be adjusted over a wide range so that a metal alloy surface), a first coating of the copolymer hav- good adhesion to all sorts of materials may be achieved. ing a relatively hydrophobic character, and a second At the same time, the properties of the copolymer may 55 coating of the copolymer having a different, less hydro- be set such as to provide a certain desired degradability phobic character, are applied. The first hydrophobic profile in vivo, which enables the use of the coating for coating may serve to promote adhesion to the substrate, controlled release of additives, such as biologically ac- whereas the second coating may assist in or be respon-

3 5 EP 1 247 537 A1 6 sible for release of a biologically active agent. Penicillins: ampicillin, nafcillin, amoxicillin, oxa- [0025] The rate of degradation of the coating may be cillin, azlocillin, penicillin G, carbenicillin, peni- set by the weight percentage poly(ethylene glycol) cillin V, dicloxacillin, phenethicillin, floxacillin, terephtalate in the copolymer. A higher relative amount piperacillin, mecillinam, sulbenicillin, methicil- of PEGT will generally result in a faster degradation. 5 lin, ticarcillin, mezlocillin [0026] The swelling behaviour of the coating can be Cephalosporins: cefaclor, cephalothin, ce- influenced by the length of the poly(ethylene glycol) fadroxil, cephapirin, cefamandole, cephradine, terephtalate segments and/or the weight percentage cefatrizine, cefsulodine, cefazolin, ceftazidim, poly(ethylene glycol) terephtalate in the copolymer. A ceforanide, ceftriaxon, cefoxitin, cefuroxime, higher amount of PEGT, or, more important, longer 10 cephacetrile, latamoxef, cephalexin PEGT segments, will generally increase the tendency Aminoglycosides: amikacin, neomycin, dibeka- of the coating to swell, as well as the extent of swelling. cyn, kanamycin, gentamycin, netilmycin, kan- [0027] The above mentioned additives that can be in- amycin, tobramycin corporated into the coating may vary widely in nature; Macrolides: amphotericin B, novobiocin, baci- in principle any type of additive may be incorporated as 15 tracin, nystatin, clindamycin, polymyxins, colis- long as its nature or used amount does not obstruct with tin, rovamycin, erythromycin, spectinomycin, the coating-forming capacity of the copolymer. Depend- lincomycin, vancomycin ing on the envisaged application of the surface onto Tetracyclines: chlortetracycline, oxytetracy- which the coating of the copolymer is applied, the addi- cline, demeclocycline, rolitetracycline, doxycy- tive may be chosen from the group of biologically active 20 cline, tetracycline, minocycline agents. As the copolymer is biodegradable in vivo, and Other antibiotics: chloramphenicol, rifamycin, allows diffusion of molecules, the additives will be re- rifampicin, thiamphenicol leased to the surroundings of the coating in a controlled 2.2 Chemotherapeutic agents manner. This behaviour of the copolymer has previously Sulfonamides: sulfadiazine, sulfamethizol, sul- been described in EP-A-0 830 859. These additives may 25 fadimethoxin, sulfamethoxazole, sulfadimidin, be added to the solution in amounts ranging from 0 to sulfamethoxypyridazine, sulfafurazole, sul- 50 wt.%, preferably from 1 to 20 wt.%. faphenazol, sulfalene, sulfisomidin, sulfamera- [0028] The term "biologically active agent", as used zine, sulfisoxazole, trimethoprim with sulfame- herein, means an agent which provides a therapeutic or thoxazole or sulfametrole prophylactic effect. Such agents include, but are not lim- 30 Urinary tract antiseptics: methanamine, qui- ited to, antimicrobial agents (including antibacterial and nolones(norfloxacin, cinoxacin), nalidixic acid, anti-fungal agents), anti-viral agents, anti-tumor agents, nitro-compounds (nitrofurantoine, nifurtoinol), hormones immunogenic agents, growth factors, lipids, oxolinic acid and lipopolysaccharides. Anaerobic infections: metronidazole [0029] Biologically active agents which may be incor- 35 porated include, but are not limited to, non-peptide, non- 3. Drugs for tuberculosis: aminosalicyclic acid, iso- protein small-sized drugs. They have a molecular niazide, cycloserine, rifampicine, ethambutol, tio- weight which in general is less than 1500, and in partic- carlide, ethionamide, viomycin ular less than 500. A second important group of biolog- 4. Drugs for leprosy: amithiozone, rifampicine, ically active agents are biologically active peptides and 40 clofazimine, sodium sulfoxone, diaminodiphenyl- proteins. sulfone (DDS, dapsone) [0030] Examples of non-peptide, non-protein small- 5. Antifungal agents: amphotericin B, ketoconazole, sized drugs which may be incorporated include, but are clotrimazole, miconazole, econazole, natamycin, not limited to, the following: flucytosine, nystatine, griseofulvin 45 6. Antiviral agents: aciclovir, idoxuridine, amanti- 1. Anti-tumor agents: altretamin, fluorouracil, amsa- dine, methisazone, cytarabine, vidarabine, ganci- crin, hydroxycarbamide, asparaginase, ifosfamid, clovir bleomycin, lomustin, busulfan, melphalan, chlo- 7. Chemotherapy of amebiasis: chloroquine, iodo- rambucil, mercaptopurin, chlormethin, methotrex- quinol, clioquinol, metronidazole, dehydroemetine, ate, cisplatin, mitomycin, cyclophosphamide, pro- 50 paromomycin, diloxanide, furoatetinidazole, emet- carbazin, cytarabin, teniposid, dacarbazin, thi- ine otepa, dactinomycin, tioguanin, daunorubicin, treo- 8. Anti-malarial agents: chloroquine, pyrimeth- sulphan, doxorubicin, tiophosphamide, estramucin, amine, hydroxychloroquine, quinine, mefloquine, vinblastine, etoglucide, vincristine, etoposid, sulfadoxine/pyrimethamine, pentamidine, sodium vindesin. 55 suramin, primaquine, trimethoprim, proguanil 2. Antimicrobial agents 9. Anti-helminthiasis agents: antimony potassium tartrate, niridazole, antimony sodium dimercapto- 2.1 Antibiotics succinate, oxamniquine, bephenium, piperazine,

4 7 EP 1 247 537 A1 8 dichlorophen, praziquantel, diethylcarbamazine, 16.3 Estrogens pyrantel parmoate, hycanthone, pyrivium pamoate, levamisole, stibophen, mebendazole, tetramisole, 16.3.1 Estrogenic steroids used in therapy: metrifonate, thiobendazole, niclosamide diethylstilbestrol, estradiol, estriol, ethi- 10. Anti-inflammatory agents: acetylsalicyclic acid, 5 nylestradiol, mestranol, quinestrol mefenamic acid, aclofenac, naproxen, azopro- panone, niflumic acid, benzydamine, oxyphenbuta- 16.3.2 Anti-estrogens: chlorotrianisene, zone, diclofenac, piroxicam, fenoprofen, pirprofen, clomiphene, ethamoxytriphetol, nafoxi- flurbiprofen, sodium salicyclate, ibuprofensulindac, dine, tamoxifen indomethacin, tiaprofenic acid, ketoprofen, tolmetin 10 11. Anti-gout agents: colchicine, allopurinol 16.4 Progestins: allylestrenol, desogestrel, 12. Centrally acting (opoid) analgesics: alfentanil, dimethisterone, dydrogesterone, ethi- methadone, bezitramide, morphine, buprenorfine, nylestrenol, ethisterone, ethynadiol diace- nicomorphine, butorfanol, pentazocine, codeine, tate, etynodiol, hydroxyprogesterone, lev- pethidine, dextromoramide, piritranide, dextropro- 15 onorgestrel, lynestrenol, medroxyproges- poxyphene, sufentanil, fentanyl terone, megestrol acetate, norethindrone, 13. Local anesthetics: articaine, mepivacaine, bupi- norethisterone, norethynodrel, norgestrel, vacaine, prilocaine, etidocaine, procaine, lidocaine, progesterone tetracaine 14. Drugs for Parkinson's disease: amantidine, 20 17. Thyroid drugs diphenhydramine, apomorphine, ethopropazine, benztropine mesylate, lergotril, biperiden, levo- 17.1 Thyroid drugs used in therapy: levothyro- dopa, bromocriptine, lisuride, carbidopa, metixen, nine, liothyronine chlorphenoxamine, orphenadrine, cycrimine, pro- 17.2 Anti-thyroid drugs used in therapy: carbi- cyclidine, dexetimide, trihexyphenidyl 25 mazole, methimazole, methylthiouracil, pro- 15. Centrally active muscle relaxants: baclofen, car- pylthiouracil isoprodol, chlormezanone, chlorzoxazone, cy- clobenzaprine, dantrolene, diazepam, febar- [0031] When a non-peptide, non-protein, small-sized bamate, mefenoxalone, mephenesin, metoxalone, drug, such as those described above, is to be incorpo- methocarbamol, tolperisone 30 rated, the polyalkylene glycol terephtalate component 16. Hormones and hormone antagonistics of the copolymer preferably has a molecular weight of from about 200 to 400. Also, the polyalkylene glycol 16.1 Corticosteroids terephtalate component is present in the copolymer in an amount of from 20 wt.% to 90 wt.% of the weight of 16.1.1 Mineralocorticosteroids: cortisol, 35 the copolymer, preferably from about 40 wt.% to about desoxycorticosterone, flurohydrocortisone 70 wt.% of the weight of the copolymer. In general, the 16.1.2 Glucocorticosteroids: beclometha- aromatic polyester is present in the copolymer in an sone, betamethasone, cortisone, dexame- amount of from 10 wt.% to 80 wt.% of the copolymer, thasone, fluocinolone, fluocinonide, fluo- preferably in an amount of from about 30 wt.% to about cortolone, fluorometholone, fluprednisolo- 40 60 wt.% of the copolymer. ne, flurandrenolide, halcinonide, hydrocor- [0032] When a hydrophobic small-sized drug, such tisone, medrysone, methylprednisolone, as, for example, a steroid hormone is incorporated, pref- paramethasone, prednisolone, pred- erably at least one hydrophobic antioxidant is present. nisone, triamcinolone (acetonide) Hydrophobic antioxidants which may be employed in- 45 clude, but are not limited to, tocopherols, such as α-to- 16.2 Androgens copherol, β-tocopherol, γ-tocopherol, δ-tocopherol, ε-tocopherol, ζ1-tocopherol, ζ2-tocopherol, and η-tocophe- 16.2.1 Androgenic steroids used in thera- rol; and 1-ascorbic acid 6-palmitate. Such hydrophobic py: danazole, fluoxymesterone, mesterolo- antioxidants retard the degradation of the copolymer ne, methyltestosterone, testosterone and 50 and retard the release of the biologically active agent. salts thereof Thus, the use of a hydrophobic or lipophilic antioxidant 16.2.2 Anabolic steroids used in therapy: is applicable particularly to the formation of matrices calusterone, nandrolone and salts thereof, which include drugs which tend to be released quickly dromostanolone, oxandrolone, ethylestre- from the coating, such as, for example, small drug mol- nol, oxymetholone, methandriol, stano- 55 ecules having a molecular weight less than 500. The at zolol methandrostenolone, testolactone least one hydrophobic antioxidant may be present in the 16.2.3 Antiandrogens: cyproterone ace- coating in an amount of from about 0.1 wt.% to about tate 10 wt.% of the total weight of the matrix, preferably from

5 9 EP 1 247 537 A1 10 about 0.5 wt.% to about 2 wt.%. bacterium leprae, Mycrobacterium tuberculosis, [0033] When the coating includes a hydrophilic small- Neisseria gonorrhoeae, Neisseria meningitidis, sized drug, such as an aminoglycoside, it may also in- Proteus species, Pseudomonas aeruginosa, Sal- clude, in addition to the hydrophobic antioxidant, a hy- monella species, Shigella species, Staphylococcus drophobic molecule such as cholesterol, ergosterol, 5 aureus, Streptococcus pyogenes, Vibrio cholera, lithocholic acid, cholic acid, dinosterol, betuline, or olea- Yersinia pestis nolic acid, which may be employed in order to retard the Surface antigens of parasites causing disease or release rate of the agent from the copolymer coating. portions of parasites: Plasmodium vivax - malaria, Such hydrophobic molecules prevent water penetration Plasmodium falciparum - malaria, Plasmodium into the coating, but do not compromise the degradabil- 10 ovale - malaria, Plasmodium malariae - malaria, ity of the coating. In addition, such molecules have melt- Leishmania tropica - leishmaniasis, Leishmania do- ing points from 150°Cto200°C or decreases the coating novani, leishmaniasis, Leishmania branziliensis - diffusion coefficient for the biologically active agent, leishmaniasis, Trypanosoma rhodescense - sleep- such as small drug molecule, to be released. Thus, such ing sickness, Trypanosoma gambiense - sleeping hydrophobic molecules provide for a more sustained re- 15 sickness, Trypanosoma cruzi - Chagas' disease, lease of a biologically active agent from the coating. The Schistosoma mansoni - schistosomiasis, Schisto- at least one hydrophobic molecule may be present in somoma haematobium - schistomiasis, Schisto- the coating in an amount of from about 0.1 wt.% to about soma japonicum - shichtomiasis, Trichinella spiralis 20 wt.%, preferably from 1.0 wt.% to 5.0 wt.%. - trichinosis, Stronglyloides duodenale - hookworm, [0034] If it is desired to increase the hydrophilicity of 20 Ancyclostoma duodenale - hookworm, Necator the polymer, and thereby increase the degradation rate americanus - hookworm, Wucheria bancrofti - and drug releasing rate of the copolymer, the copolymer filariasis, Brugia malaya - filariasis, Loa loa - filaria- may be modified by partially replacing the aromatic moi- sis, Dipetalonema perstaris - filariasis, Dracuncula ety with an aliphatic moiety such as succinate and/or by medinensis - filariasis, Onchocerca volvulus - replacing partially the alkylene with dioxyethylene. For 25 filariasis example, terephthalate can be replaced by succinate in Immunoglobulins: IgG, IgA, IgM, Antirabies immu- an amount of from about 0.1 mole% to about 20 mole%, noglobulin, Antivaccinia immunoglobulin Antitoxins: preferably from about 0.1 mole% to about 5 mole%, by Botulinum antitoxin, diphtheria antitoxin, gas gan- partially replacing dimethyl terephthalate as a starting grene antitoxin, tetanus antitoxin. component with dimethyl succinate. As another exam- 30 ple, butylene is replaced with oxydiethylene in an [0036] Other peptides or proteins which may be en- amount of from about 0.1 mole% to about 20 mole%, capsulated include, but are not limited to, antigens preferably from about 0.5 mole% to about 2 mole%, by which elicit an immune response against Foot and replacing 1,4-butanediol with dimethyleneglycol as a Mouth Disease, hormones and growth factors such as starting component. 35 follicle stimulating hormone, prolactin, angiogenin, epi- [0035] Examples of peptides or proteins which may dermal growth factor, calcitonin, erythropoietin, thyro- advantageously be contained in the coating include, but tropic releasing hormone, insulin, growth hormones, in- are not limited to, immunogenic peptides or immuno- sulin-like growth factors 1 and 2, skeletal growth factor, genic proteins, which include, but are not limited to, the human chorionic gonadotropin, luteinizing hormone, following: 40 nerve growth factor, adrenocorticotropic hormone (ACTH), luteinizing hormone releasing hormone Growth factors: bone morphogenetic proteins, (LHRH), parathyroid hormone (PTH), thyrotropin re- transforming growth factors, fibroblast growth fac- leasing hormone (TRH), vasopressin, cholecystokinin, tors, epidermal growth factors, etc. and corticotropin releasing hormone; cytokines, such as Toxins: diphtheria toxin, tetanus toxin 45 interferons, interleukins, colony stimulating factors, and Viral surface antigens or parts of viruses: adenovi- tumor necrosis factors: fibrinolytic enzymes, such as ruses, Epstein-Barr urokinase, kidney plasminogen activator; and clotting Virus, Hepatitis A Virus, Hepatitis B Virus, Herpes factors, such as Protein C, Factor VIII, Factor IX, Factor viruses, HIV-1, HIV-2, HTLV-III, Influenza viruses, VII and Antithrombin III. Examples of other proteins or Japanese encephalitis virus, Measles virus, Papil- 50 peptides which may be encapsulated include, but are loma viruses, Paramyxoviruses, Polio Virus, Ra- not limited to, albumin, atrial natriuretic factor, renin, su- bies, Virus, Rubella Virus, Vaccinia (Smallpox) vi- peroxide dismutase, α1-antitrypsin, lung surfactant pro- ruses, Yellow Fever Virus teins, bacitracin, bestatin, cydosporine, delta sleep-in- Bacterial surface antigens or parts of bacteria: Bor- ducing peptide (DSIP), endorphins, glucagon, gramici- detella pertussis, Helicobacter pylori, Clostridium 55 din, melanocyte inhibiting factors, neurotensin, oxytoc- tetani, Corynebacterium diphtheria, Escherichia co- in, somostatin, terprotide, serum thymide factor, thy- li, Haemophilus influenza, Klebsiella species, Le- mosin, DDAVP, dermorphin, Met-enkephalin, peptidog- gionella pneumophila, Mycobacterium bovis, Myco- lycan, satietin, thymopentin, fibrin degradation product,

6 11 EP 1 247 537 A1 12 des-enkephalin-α-endorphin, gonadotropin releasing to harm the stability and/or activity of the biologically ac- hormone, leuprolide, α-MSH, and metkephamid. It is to tive agent. be understood, however, that the scope of the present [0042] If it is desired that a porous coating is formed, invention is not limited to any specific peptides or pro- a pore-forming agent can be included in the solution or teins. 5 suspension of the copolymer from which the coating is [0037] Before applying the coating, the surface to formed. Pore-forming agents may include organic sol- which it is to be applied is preferably cleaned or treated vents, water, salts (sodium chloride, sodium citrate, and to remove any contaminants and to promote good ad- the like), sugars and water-soluble synthetic polymers. hesion of the coating. Various methods for cleaning may Using such pore-forming agents, pores can be created be employed. The metallic implants may be rinsed with 10 by leaching-out of the agent, or by phase separation. a degreaser, i.e. acetone, alkyl alcohols, etc. and then [0043] The thickness of the coatings of this invention thoroughly rinsed with pure water. may range from a few microns up to any desired thick- [0038] In order to improve coating adhesion, various ness (up to a few hundred microns). The thickness of surface treatments may be applied to metal implants. the coating may be adjusted by the viscosity of the co- Mechanical surface treatments, such as sand-blasting, 15 polymer solution that is used to prepare the coating. The scoring, polishing and grinding can increase surface viscosity of the copolymer solution may be adjusted by roughness of the implants and improve the bonding parameters like the molecular weight of the copolymer, strength between the coatings and metal substrate. For the copolymer concentration in the solution, the select- similar purposes, chemical surface treatments may be ed solvent, the temperature, etc. In case of spraying or also applied to metal substrates prior to coating. Among 20 brushing, spraying time and flow rate may also influence others chemical treatments available for metals, acid the thickness of the coating. etchings will be preferred by treating implantable devic- [0044] The invention will be further elucidated by the es with strong mineral acids, such as hydrofluoric, hy- following, non-restrictive example. drochloric, sulfuric, nitric and perchloric acids. It may also useful to treat the metal devices with oxidising agents 25 Example such as nitric acid, peroxyhalogen acids, hydroxyperox- ides, or hydrogen peroxide to form a fresh metal oxide [0045] A porous scaffold was produced as described layer. After the mechanical or chemical treatment, it is in example 1 of European patent application necessary to rinse the implants with pure water under 01200328.1, the contents of which are incorporated ultrasound for removal of surface contaminants. 30 herein by reference, from a copolymer of polyethylene [0039] A coating according to the invention may be glycol (PEG, MW = 300 g/mole) and polybutylene applied to a surface by methods known to those skilled terephthalate (PBT), wherein the weight percentage in the art, like by brushing, spraying, wiping, dipping, ex- PBT was 55 %. The porosity of the scaffold was approx- truding or injecting. The latter three methods are pre- imately 77 v/v%. About 400 mg of the scaffold to be coat- ferred when porous structures or fibrous meshes are to 35 ed was placed on a grid that was connected to a vacuum be coated. Use of these methods allows penetration of pump (see figure 1 for a schematic representation). the copolymer of which the coating is formed inside the [0046] The coating emulsion was prepared by mixing pores of the devices and a (uniform) coating of the total a protein solution (1.0 ml, 50 mg lysozyme per ml phos- surface area. Brushing and spraying are preferred in phate buffered saline (PBS), pH 7.4) with a polymer so- case of non-porous devices. 40 lution (6 ml chloroform, 1g copolymer of polyethylene [0040] If desired, organic solvents may be used to dis- glycol (PEG, MW = 1000 g/mole) and polybutylene solve the copolymer. Suitable solvents are chloroform, terephthalate (PBT), wherein the weight percentage dichloromethane, N-methyl-2-pyrrolidone, dimethyl sul- PBT was 30 %.) using ultra-turrax mixing (30 s at 19 foxide, acetone, hexafluoroisopropanol and the like. krpm, Ika Labortechnik T25). The resulting water-in-oil The selection of a suitable solvent will be dependent on 45 emulsion was poured on top of the scaffold, and a vac- the composition of the chosen copolymer. Alternatively, uum of 300 Torr was applied for 5 minutes. Thereafter, heat may be applied to process a copolymer of which a the scaffolds were dried overnight under vacuum at coating is to be formed. room temperature. [0041] A biologically active agent may be incorporat- [0047] To evaluate the release of lysozyme form the ed into the coating by dissolving it in the copolymer so- 50 coated scaffolds, pieces of approximately 75 mg were lution of which the coating is formed. Hence, a homoge- incubated in 1 ml PBS (pH 7.4). Vials were continuously neous solution is formed or a suspension is formed by shaken at 37°C and samples were taken at various time dispersion. Alternatively, a solution of a biologically ac- points. The protein concentration in the buffer solution tive agent may be mixed with the copolymer solution to was determined using a standard Coomassie Blue as- form a homogeneous mixture, or an emulsion. Also, a 55 say (Pierce). In figure 2, the release of lysozyme from biologically agent can be incorporated by physically mix- the coated scaffolds is presented. ing with the copolymer, for example by extrusion. Since in the latter case heat is applied, care must be taken not

7 13 EP 1 247 537 A1 14

Claims 13. A coating according to claim 12, wherein the surface is a surface of a medical device chosen from 1. A coating for a medical device comprising a copol- the group of catheters, stents, fibres, non-woven ymer of a polyalkylene glycol terephtalate and an fabrics, vascular grafts, porous metals for e.g. aromatic polyester. 5 acetabulum revision, and porous scaffolds for tissue engineering. 2. A coating according to claim 1, wherein the polyalkylene glycol is chosen from the group of polyeth- 14. A coating according to any of the preceding claim, ylene glycol terephtalate, polypropylene glycol which is porous. terephtalate, and polybutylene glycol terephtalate. 10 15. A method for applying a coating according to any of 3. A coating according to claim 2, wherein the poly- the preceding claims to a surface, comprising alkylene glycol is polyethylene glycol terephtalate. brushing, spraying, wiping, dipping, extruding or injecting. 4. A coating according to any of the preceding claims, 15 wherein the polyester is chosen from the group of 16. A method according to claim 15, wherein the sur- polyethylene terephthalate, polypropylene tereph- face is cleaned and/or subjected to a mechanical thalate, and polybutylene terephthalate. treatment prior to application of the coating.

5. A coating according to claim 4, wherein the polyes- 20 17. A method according to claim 15 or 16, wherein the ter is polybutylene terephthalate. coating is applied from a solution or suspension of the copolymer. 6. A coating according to any of the preceding claims, wherein the copolymer comprises 20-90 wt.%, pref- 18. A method according to claim 17, wherein a biolog- erably 40-70 wt.%, based on the weight of the co- 25 ically active agent is included in the solution or sus- polymer, of the polyalkylene glycol. pension.

7. A coating according to any of the preceding claims, 19. A method according to claim 17 or 18, wherein a wherein the weight average molecular weight of the pore-forming agent is included in the solution or polyalkylene glycol is from about 150 to about 4000, 30 suspension. preferably from about 200 to about 1500. 20. A medical device comprising a coating according to 8. A coating according to any of the preceding claims, any of the claims 1-13. wherein the weight average molecular weight of the copolymer lies between about 10,000 and about 35 21. A medical device according to claim 20 chosen from 300,000, preferably between about 40,000 and the group of catheters, fibres, non-woven fabrics, about 120,000. vascular grafts, porous metals for e.g. acetabulum revision, dental filling materials, materials for ap- 9. A coating according to any of the preceding claims proximation, adhesion of tissues, materials used in further comprising an additive. 40 osteo-synthesis (e.g. pins or bone screws), cardiac patches, sutures, soft and hard tissue scaffolds and 10. A coating according to claim 9, wherein the additive fillers (e.g. collagen, calcium phosphate, bioglass), is a biologically active agent chosen from the group stents, bone void fillers intended for the repair of of antimicrobial agents, such as antibacterial and bone defects, intrauterine devices, root canal fillers, anti-fungal agents, anti-viral agents, anti-tumor 45 drug delivery pumps, implantable infusion pumps, agents, immunogenic agents, lipids, lipopolysac- spacer devices, implants containing medicinal charides, hormones and growth factors. products, and scaffolds for tissue engineering.

11. A coating according to claim 9, wherein the additive is a biologically active agent is chosen from the 50 group of peptides, oligopeptides, polypeptides and proteins.

12. A coating according to any of the preceding claims, applied to a surface chosen from the group of met- 55 als, metal alloys, ceramics, glasses and polymeric materials.

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