GB2533762A - Novel method and products - Google Patents

Abstract

A method for preparing an elution delivery system for a reagent, the method comprising depositing a polymeric substance onto a substrate by a plasma polymerisation process in which a plasma is pulsed, so as produce a coating thereon. In one embodiment the substrate comprises said reagent, and in another embodiment the reagent is subsequently absorbed into the coating, provided that the reagent is other than an amino acid or peptide. Also claimed is the reagent delivery system obtained by the method, and a method of using this system for the controlled release of a reagent from the substrate. Preferably the substrate comprises a medical device such as a stent, and preferably the reagent is a therapeutic substance such as one useful in oncology. The polymeric substance is preferably polylactide, polyethylene oxide or polyurethane.

Description

Novel Method and Products The present invention relates to a method for preparing an elution type delivery system, in particular, a slow or sustained release drug delivery system or a elution delivery system used in chemical or biochemical reactions, and delivery systems obtained thereby.

Over the years, many drug delivery systems have been developed which aim to allow the therapeutic substance or drug to be released into the body of a patient over a prolonged period of time. The methods by which this is achieved varies widely. In some cases formulations in which drugs substances are encapsulated within for example polymeric microcapsules, the coating of which degrades slowly in the body are produced. Alternatively, devices intended for implantation in the body, such as implants, depot formulations, stents, catheters, balloons, filters, or grafts, where the drugs are held on the surface in conjunction with a biodegradable material, in particular a biodegradable polymer which slowly degrades allowing the drug to be released from the surface of the device into the body.

Elution delivery systems in which reagents are released into reaction after particular time periods or over a prolonged period of time, may also be useful in the context of some chemical and biochemical and biological reactions and assays. For example, it may be desired to release indicator dyes or other colour change reagents, PH indicators, binding agents in particular specific binding agents or the like to indicate the progress of a reaction, for example, the metabolic reactions of certain microorganisms such as yeasts, when subjected to different environmental conditions.

Conventional polymer synthesis tends to produce structures containing repeat units that bear a strong resemblance to the monomer species, whereas a polymer network generated using a plasma can be extremely complex due to extensive monomer fragmentation. The properties of the resultant coating can depend upon the nature of the substrate as well as the nature of the monomer used and conditions under which it is deposited.

Plasma deposition techniques have been quite widely used for the deposition of polymeric coatings onto a range of surfaces, and in particular onto fabric surfaces. This technique is recognised as being a clean, dry technique that generates little waste compared to conventional wet chemical methods. Using this method, plasmas are generated from organic molecules, which are subjected to an electrical field. When this is done in the presence of a substrate, the radicals of the compound in the plasma polymerise on the substrate. Conventional polymer synthesis tends to produce structures containing repeat units that bear a strong resemblance to the monomer species, whereas a polymer network generated using a plasma can be extremely complex. The properties of the resultant coating can depend upon the nature of the substrate as well as the nature of the monomer used and conditions under which it is deposited.

However, the fact that the substrate needs to be exposed to extreme reaction conditions within a plasma processor means that this method has not generally been used in the production of drug delivery systems, since the drug themselves tend to be relatively unstable compounds. Exposure to plasmas can therefore lead to partial or complete destruction or inactivation of the drug materials themselves. Although, as described by Kondyurin et al. J. Biomaterials Sci, (2004) 15, 2, p145-159, the destruction of drugs on a surface layer may be useful in some slow release formulations, this clearly represents a significant limitation in the way plasma polymerisation may be employed in the formation of drug delivery systems.

US Patent No 6,335,029 describes implantable devices such as stents or the like in which a composite layer of bioactive material and polymer material is formed and then a barrier layer applied over it using low energy plasma. Low energy plasma can be achieved suing a radio frequency energy source, and the negative effects of the plasma on the drug itself is minimised by keeping the exposure times very small.

US Patent Application No. 2005/0249777 describes the deposition of a plasma polymerised film layer on a stent, followed by the adhesion of compounds with charged amino acid groups such as amino acids or peptides thereto. The range of compounds which may be delivered in this way is therefore highly restricted.

The present inventors have found that by using specifically pulsed plasmas, the tolerance of a drug substrate may be enhanced, allowing the procedure to be used in the preparation of a wider variety of drug delivery systems.

According to the present invention there is provided a method for preparing a reagent delivery system comprising depositing a biocompatible polymeric substance onto a substrate by a plasma polymerisation process in which the plasma is pulsed, so as produce a coating thereon wherein either (a) the substrate comprises the said reagent or (b) the reagent is subsequently absorbed into the coating.

In particular the reagent is a therapeutic substance. The term "therapeutic substance" used herein refers to substance useful in therapy, prophylaxis or diagnosis of diseases or conditions of the human or animal body. Suitably the therapeutic substance is other than an amino acid or peptide.

The coating produced using the plasma polymerisation controls the release of said reagent as necessary, for example, in the case of a therapeutic substance, when in contact with or incorporated into a human or animal body.

The nature of the polymer coating applied should be such that 5 it delays the release of the reagent without impeding its activity. For example, where the reagent is a therapeutic substance, the polymer coating should be such that it does not cause any significant adverse reaction in the patient. It should therefore be biocompatible. It may be biodegradable, and preferably resorbable at a relatively slow rate. However, it is possible that in some cases the coating does not itself degrade, but the structure is such that the therapeutic substance slowly elutes from the coating.

Examples of suitable polymers of this nature are known in the art, but include for example polysiloxanes, polysilanes, polyurethanes, polyacrylates, polylactides, polyglycolid polyorthoesters, polyalkylenes, polyhydrofluorocarbons, polyesters in particular, polycarboxylic acids, polyamides, polyvinylalcohols, polypeptides, polyvinylpyrrolidone, maleic anhydride polymers, polyethylene oxides, and co-polymers of any of these.

Particularly suitable biocompatible polymers which may be deposited onto elution delivery systems in accordance with the invention include polyglycolic acid-polylactide copolymers, polyethyleneoxide, polyethyleneoxide-polybutylene terephthalate, polyethylene glycol, polydextrin, polyorthoester and 2-methacroyloyloxyethyl phosphorylcholine-b-butyl methacrylate copolymer.

The precise nature or composition in the case of the co-polymers will affect the rate at which the coating degrades when in use, for example in the body, or the time for the reagent such as the drug to elute, allowing the reagent such as the therapeutic substance to be released. Therefore, this can be controlled by ensuring that an appropriate monomer or mix of monomers is introduced into the plasma chamber.

In the method, in general, the substrate to be treated is placed within a plasma chamber together with one or more monomers, which are able to venerate the target polymeric substance, in an essentially gaseous state, a glow discharge is ignited within the chamber and a suitable pulsed voltage is applied.

As used herein, the expression "in an essentially gaseous state" refers to gases or vapours, either alone or in mixture, as well as aerosols.

The gas present within the plasma chamber may comprise a vapour of the monomeric compound alone, but it may be combined with a carrier gas, in particular, an inert gas such as helium or argon. In particular helium is a preferred carrier gas as this can minimise fragmentation of the monomer.

When used as a mixture, the relative amount of the monomer vapour to carrier gas is suitably determined in accordance with procedures that are conventional in the art. The amount of monomer added will depend to some extent on the nature of the particular monomer being used, the nature of the substrate being treated, the size of the plasma chamber etc. Generally, in the case of conventional chambers, monomer is delivered in an amount of from 50-250mg/min, for example at a rate of from 100-150mg/min. Carrier gas such as helium is suitably administered at a constant rate for example at a rate of from 5-90, for example from 15-30sccm. In some instances, the ratio of monomer to carrier gas will be in the range of from 100:0 to 1:100, for instance in the range of from 10:0 to 1:100, and in particular about 1:0 to 1:10. The precise ratio selected will be so as to ensure that the flow rate required by the process is achieved.

Using pulsed plasmas, in which low average powers can be achieved, a highly controllable surface covering can be obtained with minimal deterioration of the reagent, which is particularly important when this is a therapeutic substance or drug.

The applied fields are suitably of power of from 20 to 500W, suitably at about 100W peak power, applied as a pulsed field.

The pulses are applied in a sequence which yields very low average powers, for example in a sequence in which the ratio of the time on: time off is in the range of from 1:3 to 1:1500, depending upon the nature of the monomer gas employed. Alternatively the ratio of the time on: time off may be in the range of from 1:6 to 1:1500. Although for monomers which may be difficult to polymerise, time on: time off ranges may be at the lower end of this range, for example from 1:3 to 1:5, many polmerisations can take place with a time on:time off range of 1:500 to 1:1500. Particular examples of such sequence are sequences where power is on for 20-50ps, for example about 30ps, and off for from 1000ps to 30000v, in particular about 20000ps. Typical average powers obtained in this way are 0.01W.

The fields are suitably applied from 30 seconds to 90 minutes, preferably from 5 to 60 minutes, depending upon the nature of the monomer and the substrate, and the nature of the target coating required.

Suitable plasmas for use in the method of the invention include non-equilibrium plasmas such as those generated by radiofrequencies (Rf), microwaves or direct current (DC). They may operate at atmospheric or sub-atmospheric pressures as are known in the art. In particular however, they are generated by radiofrequencies (Rf).

Various forms of equipment may be used to generate gaseous plasmas. Generally these comprise containers or plasma chambers in which plasmas may be generated. Particular examples of such equipment are described for instance in W02005/089961 and W002/28548, but many other conventional plasma generating apparatus are available.

In all cases, a glow discharce is suitably ignited by applying a high frequency voltage, for example at 13.56MHz. This is applied using electrodes, which may be internal or external to the chamber, but in the case of larger chambers are internal.

Suitably the gas, vapour or cas mixture is supplied at a rate of at least 1 standard cubic centimetre per minute (sccm) and 15 preferably in the range of from 1 to 100sccm.

In the case of the monomer vapour, this is suitably supplied at a rate of from 80-300mg/minute, for example at about 120mg per minute depending upon the nature of the monomer, whilst the 20 pulsed voltage is applied.

Gases or vapours may be drawn or pumped into the plasma region. In particular, where a plasma chamber is used, gases or vapours may be drawn into the chamber as a result of a reduction in the pressure within the chamber, caused by use of an evacuating pump, or they may be pumped, sprayed, dripped, electrostatically ionised or injected into the chamber as is common in liquid handling.

Polymerisation is suitably effected using vapours of monomers which are maintained at pressures of from 0.1 to 400mtorr, suitably at about 10-100mtorr.

A particularly suitable apparatus and method for producing drug 35 delivery systems in accordance with the invention is described in W02005/089961, the content of which is hereby incorporated by reference.

Precise conditions under which the plasma polymerization takes place in an effective manner will vary depending upon factors such as the nature of the polymer being deposited, as well as the nature of the substrate and will be determined using routine methods and/or other techniques.

The dimensions of the chamber will be selected so as to accommodate the particular substrate or device being treated. The chamber may be a sealable container, to allow for batch processes, or it may comprise inlets and outlets for the substrates, to allow it to be utilised in a continuous process as an in-line system. In particular in the latter case, the pressure conditions necessary for creating a plasma discharge within the chamber are maintained using high volume pumps, as is conventional for example in a device with a "whistling leak". However it will also be possible to process drug delivery systems at atmospheric pressure, or close to, negating the need for "whistling leaks".

Substrates used in the method of the invention may comprise a therapeutic substance in a variety of forms. For instance, it may comprise the substance itself in for example powder or granule. During the plasma polymerisation, the monomer will flow around the powder and into any pores or crevices in the granules, and form a polymer layer thereon. This will lead to an essentially encapsulated substrate. In this case, it may he preferable to provide the plasma chamber with a fluidised bed to ensure that monomer access around the individual particles is achieved.

Alternatively, the substrate may comprise a medical device such as an implant, stent (such as a vascular stent), catheter, balloon, filter (such as a vena cava filter), heart valves or pacemakers, osteopathic implants (such as joint replacements, or bone support implants) or graft including coronary artery bypass grafts.

The device itself will generally be made of a biocompatible material, which may be biodegradable or bioresistant, depending upon the nature of the device as would be understood in the art. Biodegradable materials include polymers such as those listed above for the coating materials. Bioresistant materials include metals such as titanium and the like as well as nondegradable polymers such as polyamine-heparin, methacryloylphophorylcholine-laurylmethacrylate, some polyurethanes, silicone, polycaprolactone, polyethylene terphthalate as is understood in the art.

In this case, the therapeutic substance may be applied for example onto or adsorbed into the surface of the device, either alone or in combination with a biocompatible binding material, such as a polymeric material, prior to deposition of the coating layer. Suitable biocompatible binding materials include polyurethanes, polyacrylates, polylactides, polyglycolids, polyorthoesters, polyalkylenes, polyhydrofluorocarbons, polyesters in particular, polycarboxylic acids, polyamides, polyvinylalcohols, polypeptides, polyvinylpyrrolidone, maleic anhydride polymers, polyethylene oxides, and co-polymers or mixtures of any of these.

A particular blend of polyoxyethylene and polyurethane as a lubricious eluting polymer blend for use in providing a coating containing a therapeutic substance is described for example in W02007/016182, the content of which is incorporated herein by reference. A device coated with such a blend incorporating a therapeutic substance may be subsequently treated in accordance with the method of the invention, in order to further delay or control release of the therapeutic substance after the device is applied to the body.

Alternatively, the substrate itself may be coated using a pulsed plasma and the therapeutic substance then absorbed onto the resultant coating.

In some instances, such as certain implants, such as depot formulations, the therapeutic substance may be incorporated throughout the body of the device, which is entirely biodegradable, for instance is of a biodegradable polymer material. Such formulations tend to take the form of rod or boluses for implantation under the skin.

The thickness of the deposited polymer coating which is applied using the method of the invention will depend upon the nature of the product and how slow the release requirement is. Generally, the thickness of the coating may be uniform, so as to ensure that the drug is released at a similar rate from all parts of the device of from the entire formulation in the case of substrates which are powders or granules.

Factors which may be used to control thickness include the length of exposure to the plasma and the pattern of the pulsing, as well as the pressure, flow rate and nature of the monomer.

Generally, to produce a slow release formulation, a coating of a biocompatihle polymer which is up to 5000A thick, for example from 10-2000A is applied.

The nature of the therapeutic substance will vary depending upon the intended use of the device. However, the method of the invention will be generally applicable to a wide range of therapeutic substances which are generally to be delivered using a slow release dosage form. These will include anti-biotics, anti-inflammatory, anti-thrombotic, anti-coagulant, anti-allergy, contraceptive, oncology, cholesterol lowering drugs, immunosuppressants, steroids, radiological therapeutic agents, and anti-stenosis or anti-restenosis drugs.

Particular examples of anti-inflammatory drugs include aminoglycosides such as Gentamicin, Kanamycin and Neomycin, Amphenicols such as Choramphenicol, Ansamycins such as rifamycin, P-lactams such as carbacephems (including Loracarbef), carbapenems (including Biopenem, Ertapenem, Frompenen), cephalosporins (including Cefprozil), Cephamycins, monobactams, oxacephems (including Noxalactam), penicillins (cinluding amoxicillin, ampicillin, carbenicillin, oxacillin, penmecillin, Penicillin G, Penicillin V, Pivampicillin, and Sulbenicillin), Lincosamides, macrolides (including Erythromycin and derivatives), Polypeptides (including Vancomycin), Tetracylines (including oxytetracyline), antibacterial 2,4-diaminopyrimidines and nitrofurans, oxazolidones, antibactierial quinlones and analogues, sulphonamides (including Chloramine, Sulfabenzamide), antibacterial sulphones (cinludine Suloxone sodium and Thioazolsulfone).

Examples of anti-inflammatory substances include non-steroidal anti-inflammatories such as aminoarylcarboxylic acid derivatives (including Nefenamic acid, Ethofenamate), arylacetic acid derivatives (including dichlorfenac, oxametacine and Zomepirac), arylbutyric acid derivatives (including Fenbufen), aryl carboxylic acids (including Ketorolac), arylpropionic acid derivatives (including Ibuprofen, Fenoprofen, Oxaprozin and Sulfofen), pyrazoles (including Difenamizole), pyrazolones (including phenylbutazone), Salicylic acid derivatives (including aspirin, fendosal, Salacetamide), thiazinecarboxamindes (including Ampiroxicam), and steroidal anti-inflammatories such as Glucocoricoids (including Prednisolone and derivatives, cortisone, and corticosterone).

Anti-thrombotic substances which may be used in the invention include heparin, Abciximab, Ardeparin, Argatroban, 3eraprost, Bivalirudin, Cilostazol, Clinprost, Clopidogrel, Chloricromen, Dalteparin, daltroban, danaparoid, defibrotide, dipyridamole, enoxaparin, eptifibatide, fondaparinux, iloprost, indobufen, ishogrel, lamifiban, lotrafiban, melagatran, nadroparin, ozagrel, pamicogrel, picoitamide, plafibride, reviparin sodium, ridogrel, satigrel, sulfinpyrazone, taprosiene, ticlopidine, tifacogin, tinzaparin, tirofiban, trifusal and Xemilofiban.

Anti-coagulants include Acenocoumarol, ancrod, anisindione, bromindione, clorindione, coumetarol, cyclocumarol, dextran sulphate sodium, dicumarol, diphenadione, ethyl biscoumacetate, ethylidene disoumarol, fluindione, heparin, hirudin, lyapolate sodium, pentosan polysulfate, phenindione, phenprocoumon, phosvitin, picotamide, tionclomarol and warfarin.

Therapeutic substances with anti-allergy properties include amlexanox, cromolyn, fenpiprane, ibudilast, lodoxamide, nedocromil, olizumab, oxatomide, pemirolast, pentigetide, picumast, ramatroban, repirinast, suplatast tosylate, tazanolast, tranilast and traxanox as well as antihistamines such as alkylamine derivatives (including Chlorpheniramine and Metron S), aminoalkyl ethers (including Diphenylhydramine and Setastine), ethylenediamine derivatives (including Chloropyramine) piperazines (including Cetrizine and Hydroxyzine) tricylics such as phenothiazines (including Etymemazine) and chlobenzepam, and antazoline, astemizole, azelastine, bepotastine, cetoxime, clemizole, clobenztropine, ebastine, emedastine, epinastine, fexoenadine, levocabastine, mebhydroline, mizolastine, phenindamine, terfenadine and tritogualine.

Contraceptives which may be implanted in accordance with the invention include Etonogestrel.

Suitable oncology drugs in particular are Antineoplastics such alkaloids (including etopside, vinbalstine and paclitaxel (TaxorN), alkylating agents such as alkyl sulfonates (including busulfan, improsulfan and piposulfan), aziridines (including carboquone and uredepa), ethylenimines and methylmeamines (including atretamine and treiethylenethiophophoamide), nitrogen mustards (including chlorambucil, ifosamide, prednimustine and uracil mustard), nitrosoureas (including carmustine, chlorozotocin and minustine), dacarbazine, mannomustine, mitrobronitol, mitolactol pipbroman and temozolomide, antineoplastic antibiotics and analogues (including daunorubicin, anthramycin, doxorubicin, tubercidin, zinostatin and zorubicin), antimetabolites such as folic acid analogues and antagonists (including methotrexate, nolatrexed), purine analogues (including cladribine, thioguanine) pyrimidine analogues (including azacitidine, decitabine, fluorouracil) enzymes (including L-asparaginase and ranpirnase), immunomodulators (including bropirimine, interferon-a, interferon-y, interleukin-2), immunotoxins (including denileukin diftitox), monoclonal antibodies (including edrecolomab, tiruximan, and tositumomab), platinum complexes (including cisplatin, carboplatin), amsacrine, arsenic trixoxide, bisantrene, defosfamide, demecolcine, diaziquone, effornithine, elliptinium acetate, etoglucid, fenretinide, flavopiridol, galliun nitrate, hydroxyurea, imatinib, liarozole, lonidamine, miltefosine, mitoguazone, mitoxantrone, mopidamol, nitracrine, pentostatin, phenamet, podophylinic acid 2-ethylhydrazide, procarbazine, razoxane, sobuzoxane, spirogernamium, tenuazonic acid, tirapazamine, triaziquone, urethan, hormonal antineoplastic agents such as androgens (including calusterone, epitiostanol and testolactone), antiadrenals (including aminoglutethimide, mitostane and trilostane), antiandrogens (includint bicalutamide, flutamide and nilutamide), antiestrogens (cinluding droloxifene, idoxifene, tamoxifen and toremifene), antiprogestins (including onatpristone), aromatase inhibitors (including aminoglutethimde, anastrozole, formestane, letrozole and votrozole), estrogens (including diethylstilbestrol, hexestrol and polyestradiol phosphate), LH-RH analogues (including buserelin, cetrorelix, goserelin, leuprolide and triptorelin), progestogens (including medroxyprogesterone, megestrol acetate), retinoids and analogues (including alitretinoin, bexarotene, mofarotene) and somatostatin analogues (including lanreotide.

Cholesterol lowering drugs include bile acid sequesterants (including cholestyramine resin, coleservelam hydrochloride, colestipol, polidexide) fibrates (including bexafibrate, binifibrate, ciprofibrate, cerivastatin, fluvastatin, lovastatin, pravastatin sodium, simvastatin) nicotinic acid derivatives (including acipimox, aluminium nicotinate, niceritrol, nicoclonate, nicomol, oxiniacic acid) thyroid hormone/analogs (including dextrothyroxine, etiroxate, thyropropic acid) and acrifan, benfluorex, 0-benzalbutyramide, carnitine, chonodroitin sulphate, clomestrone, dextaxtran, dextran sulphate sodium, eicosapentaenoic acid, eritadenine, ezetimibe, furazabol, meglutol, melinamide, y-oryzanol, pantethine, pentaerythritol tetracetate, cy-phenylbutyramide, pirozadil, probucol, p-sitosterol, sultosilic acid, tiadenol, triparanol and xenbucin.

Suitable immunosuppressants include alemtuzumab, azathioprine, basiliximab, brequinar, cyclosporins, daclizumab, gusperimus, 6-mercaptopurine, mizoribine, muromonab CD3, pimecrolimus, rapamycin and tacrolimus.

Radiological agents include radioactive implants, such as radioactive iodine implants, used for example in the treatment of thyroid or other conditions.

Anti-stenosis or anti-restenosis drugs include many of the substances defined above and would be well understood by the skilled person.

Other examples would be apparent, for example from The Merck Index.

In a particular embodiment, the device produced using the method of the invention is a stent and the reagent is a therapeutic substance which is an antirestenosis or antineoplastic compound such as paclitaxel, an antibiotic/immunosuppressant such as rapamycin or antithromobotic such as heparin.

Delivery systems, and in particular drug delivery systems which 20 have been treated in accordance with the method as described above form a further aspect of the invention.

Thus in particular, the invention provides a device such as a medical device, for example a stent, which has a reagent, and in particular a therapeutic substance coated thereon, for example in conjunction with a polymer binding mixture, and where a barrier layer such as a biocompatible barrier layer, obtained using a pulsed plasma polymerisation process, is provided over some or all of the surface of the device.

In a further aspect, the invention provides a method for controlling the release of a reagent from a substrate, said method comprising using device or substrate treated in accordance with the method described above. In particular the reagent is a therapeutic substance and the substrate is a substrate or device implanted in the human or animal body.

Example 1 -Elution layer A stent, which has been pre-coated with the drug Taxorm, optionally in combination with a binding substance, using conventional coating methodology, is placed inside the appropriate sized vacuum chamber and evacuated to low pressure -5 x mtorr. On reaching base pressure and ensuring the out-gassing rate is satisfactory a chemical monomer such as lactic acid or ethylene oxide and gas mix are introduced to a pressure of 80 mtorr. On reaching the required operating pressure a pulsed plasma is struck using a radio frequency source at 60W peak power at a pulse on-time of 50 ms and an off time of 250 ms and the deposition of a well adhered, thin plasma polymer ensues. The deposition process runs for 20 mins after which the RE, monomer and gases are turned off and the system is evacuated to base pressure. The resulting stent with drug and permeable elution layer, for example of biocompatible polylactide or polyethylene oxide, is then removed Example 2 -Absorbent coating A stent is placed inside the appropriate sized vacuum chamber and evacuated to low pressure -5 x mtorr. On reaching base pressure and ensuring the out-gassing rate is satisfactory, a chemical monomer which forms an absorbent polymer, such as urethane, and gas mix are introduced to a pressure of 80 mtorr. On reaching the required operating pressure a pulsed plasma is struck using a radio frequency source at 60W peak power at a pulse on-time of 50 ms and an off time of 250 ms and the deposition of a well adhered, thin plasma polymer ensues. The deposition process runs for 20 mins after which the RF, monomer and gases are turned off and the system is evacuated to base pressure. The resulting stent with a desirable absorbent layer can now be dipped into the required drug solution to 'charge' the polymer layer. The stent will then be left to air dry.

Claims (20)

1. Claims 1. A method for preparing an elution delivery system for a reagent comprising depositing a polymeric substance onto a substrate by a plasma polymerisation process in which a plasma is pulsed, so as produce a coating thereon wherein either (a) the substrate comprises said reagent or (b) the reagent is subsequently absorbed into the coating, provided that in the case of (b), the reagent is other than an amino acid or peptide.
2. 2. A method according to claim 1 wherein the substrate comprises the reagent before the polymeric substance is deposited thereon.
3. 3. A method according to claim 1 or claim 2 wherein the reagent is a therapeutic substance, and said polymeric substance is a biocompatible polymeric substance.
4. 4. A method according to claim 3 wherein the biocompatible polymeric substance is biodecradable and resorbable.
5. 5. A method according to claim 4 wherein the biocompatible polymeric substance is a polysiloxanes, polysilanes, polyurethanes, polyacrylates, polylactides, polyglycolid polyorthoesters, polyalkylenes, polyhydrofluorocarbons, polyesters in particular, polycarboxylic acids, polyamides, polyvinylaloohols, polypeptides, polyvinylpyrrolidone, maleic anhydride polymers, polyethylene oxides, or co-polymers of any of these.
6. 6. A method according to any one of claims 3 to 5 wherein the substrate comprises a medical device.
7. 7. A method according to claim wherein the medical device is an implant, stent, catheter, balloon, filter, heart valve, pacemaker, osteopathic implant or graft.
8. 8. A method according to claim 6 or claim 7 wherein therapeutic substance may be applied onto or adsorbed into the surface of the device, either alone or in combination with a biocompatible binding material.
9. 9. A method according to claim 8 wherein the biocompatible binding materials is a polyurethanes, polyacrylates, polylactides, polyglycolid polyorthoesters, polyalkylenes, polyhydrofluorocarbons, polyesters in particular, polycarboxylic acids, polyamides, polyvinylalcohols, polypeptides, polyvinylpyrrolidone, maleic anhydride polymers, polyethylene oxides, and co-polymers or mixtures of any of these.
10. 10. A method according to any one of claims 3 to 5 wherein 20 the substrate is an implant, wherein the therapeutic substance is incorporated throughout the body of the substrate.
11. 11. A method according to any one of claims 3 to 10 wherein the substance substance useful in therapy, prophylaxis or diagnosis is an antibiotic, anti-inflammatory, anti-thrombotic, anti-coagulant, anti-allergy, contraceptive, oncology, cholesterol lowering, immunosuppressants, steroid, radiological therapeutic agent, or anti-stenosis or anti-restenosis drug.
12. 12. A method according to any one of the preceding claims wherein the deposited polymer coating is up to 5000A thick.
13. 13. A method according to any one of the preceding claims wherein the substrate to be treated is placed within a plasma 35 chamber together with one or more monomers, which are able to generate the target polymeric substance, in an essentially gaseous state, a glow discharge is ignited within the chamber and a suitable pulsed voltage is applied.
14. 14. A method according to any one of the preceding claims 5 wherein pulses are applied in a sequence in which the ratio of the time on: time off is in the range of from 1:3 to 1:1500.
15. 15. A method according to any one of claims 1 to 13 wherein pulses are applied in a sequence in which the ratio of the time on: time off is in the range of 1:6 to 1:1500.
16. 16. A method according to any one of the preceding claims wherein pulses are applied in a sequence in which the ratio of the time on: time off is in the range of 1:500 to 1:1500.
17. 17.

    A reagent delivery system obtainable using a method according to any one of the preceding claims.
18. 18. A reagent delivery system according to claim 17 which is a drug delivery system. 20
19. 19. A reagent delivery system according to claim 14 which comprises a device having the said reagent coated thereon, and where a barrier layer, obtained using a pulsed plasma polymerisation process, is provided over some or all of the surface of the device.
20. 20. A method for controlling the release of a reagent from a substrate or device, said method comprising using device or substrate treated in accordance with the method according to 30 any one of claims 1 to 16.