WO2014177221A1

WO2014177221A1 - Balloon surface coating

Info

Publication number: WO2014177221A1
Application number: PCT/EP2013/059191
Authority: WO
Inventors: Michael Orlowski
Original assignee: Cardionovum Gmbh
Priority date: 2013-05-02
Filing date: 2013-05-02
Publication date: 2014-11-06

Abstract

The present invention relates to balloon catheter coated with an active agent and a shellac alkali salt, preferably shellac ammonium salt. Moreover the present invention relates to a method for coating catheter balloons with a pharmacological active agent and an aqueous solution of shellac.

Description

Balloon Surface Coating

Description

Implantation of vessel grafts such as stents has become a well-established surgical intervention for the treatment of stenosis. In this context, so-called restenosis (recurrent stenosis), i.e. the reocclusion of the vessel is a frequently occurring complication. There's no exact definition of the term restenosis to be found in literature. The most frequently used morphological definition of restenosis defines restenosis as a reduction of the vessel diameter to less than 50% of the normal value subsequent to successful PTA (percutaneous transluminal angioplasty). Said definition describes an empirically determined value and its hemodynamic meaning and association with clinical symptoms lack scientific background. In practice, clinical deterioration in a patient is often considered a sign for the occurrence of restenosis in the previously treated vessel section.

To avoid such problems, a so-called "biological stenting" may be performed using only a coated catheter balloon without any stent, i.e. the vessels are dilated at a constricted site by the dilatation of a coated catheter balloon, wherein, while the catheter balloon is dilated for a short period of time, a sufficient amount of pharmacological agent is transferred to the vessel wall to avoid re-constriction or reocclusion of the vessel due to the dilatation of the vessel and the delivery of active agents.

Nowadays, it is known that active agents can be applied to a balloon catheter with various matrix-substances, including substances such as the terpenoid shellolic acid. The active agents are released during the balloon inflation at the stenosis, in order to penetrate the arterial wall segment, in order to evolve their antiproliferative and antiinflammatory effects on the smooth muscle cells and to suppress proliferation in the vessel lumen. Suppression of cellular reactions is mainly accomplished during the first days and weeks by means of preferably antiproliferative, immunosuppressive and/or antiphlogistic agents and their likewise active derivatives /analogues and metabolites. The international patent application WO 2004/028582 A1 discloses multifold balloons which are coated, especially within the folds, with a composition of a pharmacological agent and a contrast medium. A method for spray coating catheter balloons is described in WO 2004/006976 A1 . WO 2008/046641 discloses coatings for implants, not mentioning catheter or catheter balloons comprising a combination of shellac and paclitaxel. Thereby WO 2008/046641 refers to stents in particular showing in vitro release kinetics of stents coated with 1 .0% / 0.5% shellac composite. It was shown that stents coated with rapamycin only released the drug more efficiently in contrast to shellac and rapamycin coated stents, which released the drug much slower. Shellac was deemed to be useful to modulate the release kinetics of an implant-based, e.g. stent- based compound to slow the release kinetic (more than 60 days). Such a retardation of drug release is not favourable for a catheter balloon, where it is the main goal, in contrast to a stent, to release as much of the coated drug in a time frame as short as possible.

EP2421572 discloses coating method of a catheter balloon using a solution of paclitaxel together with shellac in a suitable organic solvent such as acetone, ethyl acetate, ethanol, methanol, DMSO, THF, chloroform, methylene chloride.

The authors of a publication in Circulation 2004, Vol. 1 10, 810 - 814 demonstrated that catheter balloons coated with pure Paclitaxel did not show any therapeutic effect. A therapeutic effect was only achieved when the Paclitaxel was combined with the contrast agent solution ULTRAVIST^® ULTRAVIST^® is a solution of the contrast agent iopromide. The same observation was made by Cremers et al., Clin. Res. Cardiol., 2008, 97 - Suppl.1 .

Therefore, it is an objective of the present invention to apply an active agent, especially preferred the active agent paclitaxel or sirolimus, onto a catheter balloon in such a manner that a coating is created which is homogenously detached from the balloon and can be effectively transferred to the vessel wall so that an optimal bioavailability of the active agent and a therapeutic effect concerning reduction of restenosis can be achieved. Said objective is solved by the technical teaching of the independent claims. Further advantageous embodiments of the invention result from the dependent claims, the description, the figures and the examples. Surprisingly it has been found that a catheter balloon comprising a coating with an active agent and a shellac alkali salt, preferred a shellac ammonium salt, is suited for resolving said objective.

Thus the present invention relates to a catheter balloon comprising a coating with an active agent and a shellac alkali salt. The preferred alkali salt of shellac is shellac ammonium salt.

The term "alkali salts" or "alkali" as used herein refer to a basic, ionic salt of an alkali metal or alkaline earth metal element. The shellac alkali salt may be a potassium salt, an ammonium salt, a basic amino acid salt and/or a mixture thereof.

Shellac is the general term for the refined form of lac, a natural polyester resin secreted by insects. Lac insects belong to the order of Hemiptera, superfamily Coccoidea such as Metatachardia, Laccifer, Tachordiella, and others, however, members of two families— Lacciferidae and Tachardinidae are more prominent in lac secretion. The one that is commercially cultured is Kerria lacca, which is also known by such synonyms as Laccifer lacca Ker, Tachardia lacca, and Carteria lacca. Kerria lacca is an Indian scale insect, which infests branches of numerous trees from the East Indies, such as Butea frondos Rosch, Acacia arabica Willd and Ficus religiosa Linn. Broken branches are sold as stick lac and, after grounding and washing with water to eliminate wood and red pigments (lac dye), seed lac is obtained. Raw material shellac consists of 70-80% resin, 4-8% dye, 6-7% hard and high gloss finished wax, 3% water, up to 9% vegetable and animal impurities and aroma substances. Purification of seed lac gives the more homogeneous product known as shellac. The major components of shellac are aleuritic, jalaric and shellolic acids, as well as butolic and kerrolic acids. Seed lac and orange shellac contain approximately 5-6% wax and two coloring components, the water soluble laccaic acid and the water insoluble erythrolaccin. A possibility for chemical description of resin molecule is a structure model where in each case 4 molecules jalaric or laccijalaric acid and aleuritic acid are connected by ester bonding alternately.

jalaric acid (I) laccijalaric acid (II)

Its chemical composition is almost constant, although the amount of some components changes depending on the nature of host trees on which the insects grows. By Cannizzaro-type disproportionation under alkaline hydrolysis will be synthesized from these acids shellolic acid (IV) and derivate compounds. Purified shellac consists of two main components. These components are 9,10,16- trihydroxypalmitic acid (aleuritic acid) CAS [53-387-9] and shellolic acid (IV).

aleuritic acid (III) shellolic acid (IV) Under the general name shellac, many types or grades of shellac are commercially available. Their properties and color depend on the raw material (seedlac), the method for refining, and the processing parameters. Three very different processes are used for refining the seed lac to shellac (bleaching, melting, and solvent extraction), resulting in products with different characteristics and properties.

By the bleaching process refined bleached or white shellac is obtained by dissolving seed lac in an aqueous alkaline solution, which is then filtered, dewaxed, and bleached with sodium hypochlorite to completely remove the color. However, changes in the molecular structure and the addition of chlorine substituents may lead to self-crossl inking and polymerization.

After melting the seed lac, the highly viscous molten lac is pressed through a filter and drawn to a thin film. Once cooled, the film breaks into thin flakes. The shellac wax is not removed by this process and the color depends on the type of seed lac used.

Solvent extraction is a very gentle process for refining shellac. The seed lac is dissolved in ethanol, and wax and impurities are removed by filtration. Activated carbon is used to produce light-colored grades. After a further filtration step and the removal of ethanol, the resin is drawn to a thin film, which breaks into flakes after cooling. The properties of the final product depend on the type of seed lac used and are influenced by the processing parameters and the grade of activated carbon.

Followings are the commercial grades of shellac:

- Seedlac

- Hand Made Shellac

- Machine Made Shellac

- PhEur 7 European Pharmacopoeia Edition 7 specifies: Bleached shellac,

Bleached Dewaxed Shellac, Wax-containing Shellac, and Dewaxed Shellac

- The United States Pharmacopeia and The National Formulary (USP-NF) specifies. Regular bleached shellac, Refined bleached shellac, Orange shellac, and Dewaxed orange shellac.

Shellac is widely used as a moisture barrier coating for tablets and pellets due to its low water vapor and oxygen permeability. Shellac has been used for pharmaceutical and controlled release coatings for a long time. It has usually been applied in the form of alcoholic solutions (pharmaceutical glazes) or solutions using other organic solvents.

Shellac, like other polymers with carboxyl groups, is not soluble in water. It is soluble in ethanol, methanol and partially soluble in ether, ethyl acetate and chloroform. However, it is possible to prepare aqueous shellac solutions of alkali salts. The selection of the base and the method for dissolving will influence the properties of the film, in regard to the present invention ammonium is preferable. Therefore ammonium carbonate was chosen as a preferred base. The preferred shellac alkali salt in regard to the present invention is shellac ammonium salt having CAS number [68308-35-0].

There are several disadvantages associated with the use of organic solvents in general:

1 . They are flammable and toxic 2. Their vapor causes hazards to the coating equipment operator

3. High cost of solvent

4. Solvent residue in formulation Alcoholic solutions of shellac or in general shellac solution in an organic solvent have the disadvantage that during the process of coating a certain degree of active agent evaporates too, which makes it more difficult to ensure a uniform amount of active agent in the coating. Furthermore the repeatability is worse. It has been found that aqueous alkali shellac solutions, preferably ammonium shellac solutions, based on dewaxed orange shellac, do not show problems exhibited by alcoholic shellac solutions and have very stable release characteristics even after extended storage times. Furthermore, they can be formulated in combination with other water soluble polymers such as HPMC, CMC, alginates, or modified starch eventually together with plasticizers.

The invention is also directed to coating methods of the following type which are especially suited for manufacturing a balloon catheter with a coated balloon according to the present invention.

One method of the invention for loading or coating balloon catheter comprises the following steps:

I) providing an uncoated balloon catheter;

and

IIA) providing an aqueous solution of an active agent and shellac;

or

MB) providing a solution of an active agent and providing an aqueous solution of shellac;

and

IMA) coating the surface of the balloon of the balloon catheter with the aqueous solution of the active agent and shellac;

or

1MB) coating the surface of the balloon of the balloon catheter with the solution of the active agent and subsequently with the aqueous solution of shellac or coating the surface of the balloon of the balloon catheter with the aqueous solution of shellac and subsequently with the solution of the active agent;

IV) drying the coated catheter balloon. Thereby it is preferred that the aqueous solution of shellac or the aqueous solution of the active agent and shellac are prepared using a solution of an alkali salt, more preferably an ammonium salt. The term "uncoated" as used herein refers to a catheter balloon with a smooth or structured or roughened surface without any drug coating, i.e. the balloon surface does not comprise a pharmaceutically active agent and especially no anti-proliferative, anti-angiogenic or anti-restenosis drug and no coating containing an anti-proliferative, anti-angiogenic or anti-restenosis drug. Of course the coating steps IMA) and 1MB) respectively, may be repeated several times, with or without a drying step in between.

It is further preferred that said method comprises further a step D' after step D):

D') applying the aqueous solution of shellac again

Of course drying steps can follow after each coating step so a more detailed method reads as follows:

A) providing an uncoated balloon catheter;

and

B) providing an solution of an active agent and providing an aqueous solution of shellac;

and

C) coating the surface of the balloon of the catheter balloon with the aqueous solution of shellac and drying the coated balloon surface;

and

D) applying the solution of the active agent and drying the coated balloon surface

and subsequently

E) drying the coated catheter balloon.

Thereby it is preferred that the solution of an active agent is an aqueous solution, too. The application of aqueous shellac solutions, does not only avoid the problems with organic solvent systems but also reproves the performance of the obtained coating by stable dissolution or respectively release characteristics, especially after extended storage time and result in improved mechanical properties compared to coatings from alcoholic shellac solutions.

One aspect of the method according to the invention comprises that a catheter balloon and preferably an uncoated catheter balloon or a catheter balloon without any releasable active agent in its surface is provided. Than a solution of an active agent and an aqueous shellac solution is prepared and applied sequentially using conventional coating methods such as spray coating, dip coating etc. in order to obtain after the drying step a solid coating on the surface of the catheter balloon. Another aspect of the inventive method comprises that one aqueous solution containing an active agent and shellac is prepared. Subsequently, this solution is applied on the surface of a catheter balloon and preferably an uncoated catheter balloon or a catheter balloon without any releasable active agent in its surface using conventional coating methods like the one mentioned above. Shellac contains carboxyl groups. It is not soluble in water, but it can dissolve at higher pH, so it is possible to prepare aqueous shellac solutions of alkali salts. Therefore the term "aqueous solution of shellac" as used herein refers always to shellac dissolved in aqueous solution of inorganic alkalis so that a shellac alkali salt originates. By the physical drying of the aqueous solution of shellac a film of the shellac alkali salt forms wherein at least one active agent is incorporated. Aqueous solutions are easy to handle and allow the production of films that lack the aging instability of films made using organic solvents. Therefore using aqueous shellac solutions the performance of the resulting polymer film is improved by stable dissolution characteristics even after extended storage time. A suitable alkali salt in regard to this invention may be selected from the group consisting of sodium bicarbonate, sodium carbonate, calcium hydroxide, calcium bicarbonate and calcium carbonate, potassium bicarbonate, potassium carbonate, ammonia, ammonium carbonate, and ammonium bicarbonate. Preferably the salt is a solution of an alkali salt is a solution of ammonia, ammonium carbonate, or ammonium bicarbonate. The solutions may be prepared by dissolved shellac directly in the alkali solution. For example shellac is directly dissolved in ammonium carbonate solution and the excess ammonia evaporates as NH₃. Alternatively a ready to use aqueous shellac solution may be used like AQUALACCA 25^® distributed by Chemacon GmbH. It is preferred that the aqueous solution of shellac alkali salt, preferably shellac ammonium salt, contains 10 - 30% solids, more preferably 20 - 25% solids and has a pH of 7 - 7.5. The viscosity of the coating solution containing the shellac alkali salt according to DIN cup 4mm is preferably < 25 sec.

In one coating method according to the present invention step D is carried out in a way that the solution of the active agent penetrates the layer of shellac alkali salt. Thereby a concentration gradient originates. Preferably the layer of shellac alkali salt should not soak the solution of the active agent till the surface of the catheter balloon. This means directly on the surface of the catheter balloon stays a base coat or a zone in the layer of shellac alkali salt which is free of the active agent. Hence, preferably the catheter balloon has a base coat which consists of shellac alkali salt only. The concentration of the active agent preferably increases from zero, or nearly zero, to the maximum with increasing distance from the balloon surface. Within the coating of the catheter balloon there could be one zone or layer consisting of pure active agent on top of the coating.

The drying step E) or IV) can be performed at room temperature or at elevated temperatures up to 50°C and at atmospheric pressure or under reduced pressure to high vacuum. The drying step is also possible after the surface of the catheter balloon has been coated firstly with the aqueous solution of shellac and after the layer of the active agent has been applied. Thereby the first drying steps are preferably conducted at room temperature and atmospheric pressure, while preferably after the last coating step of the method the drying step is more intensive, i.e. longer or with vacuum or with elevated temperature.

One preferred method of the invention for loading or coating dilatable catheter balloons comprises the following steps:

IA) providing an uncoated balloon catheter;

and

I IA) providing an aqueous solution of an active agent and shellac;

and

IMA) coating the surface of the catheter balloon with the aqueous solution of the active agent and shellac;

and

IV) drying the coated catheter balloon,

wherein the aqueous solution of shellac is prepared using a solution of an alkali salt, more preferably an ammonium salt.

The present invention includes further a method for loading or coating dilatable catheter balloons comprising the following steps:

IA) providing an uncoated catheter balloon; and

MB) providing a solution of an active agent and an aqueous solution of shellac; and

1MB) coating the surface of the catheter balloon with the solution of the active agent and subsequently with the aqueous solution of shellac or coating the surface of the catheter balloon with the aqueous solution of shellac and subsequently with the solution of the active agent;

IV) drying the coated catheter balloon.

wherein the aqueous solution of the active agent and shellac is prepared using a solution of an alkali salt, more preferably an ammonium salt. An inventive coating method can optionally further comprise step V):

V) Sterilization of the active agent and shellac alkali salt coated catheter balloons.

The sterilization is most preferably performed with ethylene oxide.

The invention is furthermore directed to a catheter balloon comprising a coating with an active agent and shellac alkali salt and optionally a base coat, and/or a top coat. The term "base coat" as used herein refers to a layer of the coating of a catheter balloon which is immediately on the surface of the catheter balloon. This layer is a first layer which directly overlays the material of the catheter balloon. The term "top layer" or "topcoat" as used herein refers to a layer of the coating free of an active agent which overlays the active agent containing layer.

Another embodiment of the present invention relates to a catheter balloon comprising a coating with an active agent and a shellac alkali salt, wherein the coating comprises a concentration gradient of the active agent. Thereby the concentration gradient of the active agent is in the layer of shellac alkali salt as a matrix substance. This concentration gradient is referred herein as radial or vertical concentration gradient, because the concentration of the active agent increases from the surface of the balloon to the top or the surface of the coating or in other words the concentration of the active agent decreases from the top of the coating where the concentration is preferably between 90% by weight to 100% by weight to the surface of the catheter balloon where the concentration of the active agent is preferably between 0% by weight and 10% be weight.

In addition to this vertical concentration gradient a longitudinal or horizontal concentration gradient can be present so that the concentration of the active agent decreases from the middle of the catheter balloon to the distal end and proximal end of the catheter balloon. Thus the term "vertical concentration gradient" or "radial concentration gradient" as used herein refers to a decreasing concentration of the active agent and especially of paditaxel from the top of the coating in direction to the balloon surface. The term "gradient" as used herein refers to is a concentration gradient. This means that in the coating of the catheter balloon according to the invention is a gradual difference in the concentration of the active agent, preferably of paditaxel or sirolimus, in the matrix of shellac alkali salt between two regions. It is preferred that this regions are located radial or vertical to the catheter balloon that the lowest concentration of the active agent, like paclitaxel or sirolimus is directly on the surface of the catheter balloon (on the base material the balloon is made of) and the highest concentration is on top of the coating, which means on the end which comes in contact to the tissue. Exceptions are the embodiments which comprise a top coat of pure active agent. There it is preferred that the highest concentration is on top of the active agent containing layer, which means directly below the top coat. Further preferred is that the catheter balloon of the invention has more than one gradient, which means that there are gradual differences in the concentration of the active agent, preferably of paclitaxel, in shellac between four regions. Thereby the direction of said gradients should differ. It is especially preferred that beside the radial gradient described a longitudinal or horizontal gradient is present in the balloon coating, which means that the longitudinal or horizontal is an additional concentration gradient to the radial gradient. Here the regions are located longitudinal to the catheter balloon, so that for example the lowest concentration of the active agent, like paclitaxel is directly at one or both ends of the catheter balloon (where the balloon ends and the catheter or the catheter tip starts) and the highest concentration is in the middle of the balloon.

The term "longitudinal concentration gradient" or "horizontal concentration gradient" as used herein refers to a decreasing concentration of the active agent and especially of paclitaxel from the middle or middle part of the balloon surface to the proximal end as well as the distal end of the catheter balloon.

Preferably the coating of the catheter balloon comprises further a base coat of shellac as a first layer under the active agent layer. Also preferred is a catheter balloon, wherein the coating comprises further a top coat of shellac.

Preferred is a catheter balloon, wherein the active agent is an antiproliferative, immunosuppressive, anti-angiogenic, anti-inflammatory, and/or anti-thrombotic agent. It is preferred if the active agent is selected from the group consisting of or comprising:

abciximab, acemetacin, acetylvismione B, aclarubicin, ademetionine, adriamycin, aescin, afromosone, akagerine, aldesleukin, amidorone, aminoglutethimide, amsacrine, anakinra, anastrozole, anemonin, anopterine, antimycotics antithrombotics, apocymarin, argatroban, aristolactam-AII, aristolochic acid, ascomycin, asparaginase, aspirin, atorvastatin, auranofin, azathioprine, azithromycin, baccatin, bafilomycin, basiliximab, bendamustine, benzocaine, berberine, betulin, betulinic acid, bilobol, bisparthenolidine, bleomycin, combrestatin, Boswellic acids and derivatives thereof, bruceanol A, B and C, bryophyllin A, busulfan, antithrombin, bivalirudin, cadherins, camptothecin, capecitabine, o-carbamoyl-phenoxyacetic acid, carboplatin, carmustine, celecoxib, cepharanthin, cerivastatin, CETP inhibitors, chlorambucil, chloroquine phosphate, cicutoxin, ciprofloxacin, cisplatin, cladribine, clarithromycin, colchicine, concanamycin, Coumadin, C-type natriuretic peptide (CNP), cudraisoflavone A, curcumin, cyclophosphamide, ciclosporin A, cytarabine, dacarbazine, daclizumab, dactinomycin, dapsone, daunorubicin, diclofenac, 1 ,1 1 - dimethoxycanthin-6-one, docetaxel, doxorubicin, daunamycin, epirubicin, erythromycin, estramustine, etoposide, everolimus, filgrastim, fluroblastin, fluvastatin, fludarabine, fludarabine-5'-dihydrogen phosphate, fluorouracil, folimycin, fosfestrol, gemcitabine, ghalakinoside, ginkgol, ginkgolic acid, glycoside 1 a, 4-hydroxyoxycyclo phosphamide, idarubicin, ifosfamide, josamycin, lapachol, lomustine, lovastatin, melphalan, midecamycin, mitoxantrone, nimustine, pitavastatin, pravastatin, procarbazine, mitomycin, methotrexate, mercaptopurine, thioguanine, oxaliplatin, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, pegaspargase, exemestane, letrozole, formestane, mycophenolate mofetil, β-lapachone, podophyllotoxin, podophyllic acid-2-ethyl hydrazide, molgramostim (rhuGM-CSF), peginterferon a-2b, lenograstim (r-HuG-CSF), macrogol, selectin (cytokine antagonist), cytokinin inhibitors, COX-2 inhibitor, angiopeptin, monoclonal antibodies inhibiting muscle cell proliferation, bFGF antagonists, probucol, prostaglandins, 1 - hydroxy-1 1 -methoxycanthin-6-one, scopoletin, NO donors, pentaerythrityl tetranitrate and sydnoimines, S-nitroso derivatives, tamoxifen, staurosporine, β-estradiol, a- estradiol, estriol, estrone, ethinyl estradiol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, kamebakaurin and other terpenoids used in cancer therapy, verapamil, tyrosine kinase inhibitors (tyrphostins), paclitaxel and derivatives thereof, 6-a-hydroxy-paclitaxel, taxoteres, paclitaxel bound to albumin, like nap-paclitaxel, mofebutazone, lonazolac, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, penicillamine, hydroxychloroquine, sodium aurothiomalate, oxaceprol, β-sitosterol, myrtecaine, polidocanol, nonivamide, levomenthol, ellipticine, D-24851 (Calbiochem), colcemid, cytochalasin A-E, indanocine, nocodazole, bacitracin, vitronectin receptor antagonists, azelastine, guanidyl cyclase stimulator, tissue inhibitor of metal proteinase-1 and -2, free nucleic acids, nucleic acids incorporated into virus transmitters, DNA and RNA fragments, plasminogen activator inhibitor 1 , plasminogen activator inhibitor 2, antisense oligonucleotides, VEGF inhibitors, IGF-1 , active agents from the group of antibiotics, cefadroxil, cefazolin, cefaclor, cefoxitin, tobramycin, gentamicin, penicillins, dicloxacillin, oxacillin, sulfonamides, metronidazole, enoxaparin, heparin, hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators, dipyramidole, trapidil, nitroprussides, PDGF antagonists, triazolopyrimidine, seramin, ACE inhibitors, captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin, vapiprost, interferon α, β and γ, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators, halofuginone, nifedipine, tocopherol, tranilast, molsidomine, tea polyphenols, epicatechin gallate, epigallocatechin gallate, leflunomide, etanercept, sulfasalazine, tetracycline, triamcinolone, mutamycin, procainimide, retinoic acid, quinidine, disopyrimide, flecainide, propafenone, sotalol, natural and synthetically obtained steroids such as bryophyllin A, inotodiol, maquiroside A, ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, non-steroidal substances (NSAIDS), fenoprofen, ibuprofen, indomethacin, naproxen, phenylbutazone, antiviral agents, acyclovir, ganciclovir zidovudine, clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine, antiprotozoal agents, chloroquine, mefloquine, quinine, natural terpenoids, hippocaesculin, barringtogenol-C21 -angelate, 14- dehydroagrostistachin, agroskerin, agrostistachin, 17-hydroxyagrostistachin, ovatodiolids, 4,7-oxycycloanisomelic acid baccharinoids B1 , B2, B3 and B7, tubeimoside, bruceantinoside C, yadanziosides N and P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A,B C and D, ursolic acid, hyptatic acid A, iso- iridogermanal, maytenfoliol, effusantin A, excisanin A and B, longikaurin B, sculponeatin C, kamebaunin, leukamenin A and B, 13,18-dehydro-6-alpha- senecioyloxychaparrin, taxamairin A and B, regenilol, triptolide, cymarin, hydroxyanopterine, protoanemonin, cheliburin chloride, sinococuline A and B, dihydronitidine, nitidine chloride, 12- -hydroxypregnadien-3,20-dione, helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol, podophyllotoxin, justicidin A and B, larreatin, malloterin, mallotochromanol, isobutyrylmallotochromanol, marchantin A, maytansin, lycoridicin, margetine, pancratistatin, liriodenine, oxoushinsunine, periplocoside A, deoxypsorospermin, psychorubin, ricin A, sanguinarine, manwu wheat acid, methylsorbifolin, chromones of spathelia, stizophyllin, dihydrousambaraensine, hydroxyusambarine, strychnopentamine, strychnophylline, usambarine, usambarensine, liriodenine, daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, sirolimus (rapamycin), rapamycin derivatives, biolimus A9, pimecrolimus, everolimus, zotarolimus, tacrolimus, sirolimus bound to albumin, like nap-sirolimus fasudil, epothilones, somatostatin, roxithromycin, troleandomycin, simvastatin, rosuvastatin, vinblastine, vincristine, vindesine, teniposide, vinorelbine, trofosfamide, treosulfan, temozolomide, thiotepa, tretinoin, spiramycin, umbelliferone, desacetylvismione A, vismione A and B, zeorin. Basically any active agent as well as combination of active agents can be used, wherein, however, paclitaxel and paclitaxel derivatives, taxanes, docetaxel, paclitaxel bound to albumin, like nap-paclitaxel, as well as sirolimus and rapamycin derivatives as e.g. biolimus A9, pimecrolimus, everolimus, zotarolimus, tacrolimus, sirolimus bound to albumin, like nap-sirolimus fasudil and epothilones are preferred and particularly preferred are paclitaxel and sirolimus. The use of sirolimus is preferred since in contrast to paclitaxel, siromlimus, a hydrophilic macrolid antibiotic, is highly water soluble. Thus all ranges and values given herein and all embodiments disclosed herein are especially in regard to paclitaxel or sirolimus and should be first of all interpreted in this way.

Therefore the present invention relates to a balloon catheter comprising a coating with paclitaxel and a shellac alkali salt, preferably shellac ammonium salt. Another embodiment of the present invention relates to a balloon catheter comprising a coating with sirolimus and a shellac alkali salt, preferably shellac ammonium salt.

It was surprisingly found that an active agent - shellac alkali salt - coating, like paclitaxel or sirolimus in a matrix of shellac ammonium salt, is therapeutically highly useful in keeping blood vessels open, in reducing the late lumen loss and in reducing restenosis. The film which results from the aqueous shellac solution after drying is more elastic or less friable compared to the coatings obtained with alcoholic solutions so that an optimized transfer of the active agent to the lesion site is obtained. Furthermore this causes that the risk of thrombosis is reduced. An active agent, especially sirolimus or paclitaxel, itself is no warrant for an optimal prophylaxis of restenosis. The active agent-eluting catheter balloon has to meet the requirements in its entirety. Besides the determination of dosing the active agent elution has to be effective during the short time of dilatation (around 30 sec). The active agent elution does not depend only on the physical and chemical properties of the active agent but depends also on the properties of the utilized matrix and the interactions of the matrix and the active agent.

The inventive balloon coating ensures that the at least one an antiproliferative, immunosuppressive, anti-angiogenic, anti-inflammatory, and/or anti-thrombotic agent, preferably sirolimus or paclitaxel, is released directly and clearly to the vessel wall during balloon inflation because the active agent in the coating is approximate to the surface of the coating. The active agent is immediately and clearly purer and highly concentrated when brought into contact to the vessel wall, i.e. without large proportion of shellac.

The clinical benefit is the purer drug delivery, leading to a significantly higher bioavailability in arterial tissues having less unwanted side effects. The inventive coating is compared to the coating made from alcoholic solutions less sticky so that the transfer to the vessel wall is more uniform having less residuals on the balloon after dilatation. The use of an aqueous shellac solution enables manufacture of a more homogenous coating which causes a homogenous transfer and a homogenous release of the active agent to the area of the lesion site. This higher drug concentration in the tissue of the vessel wall provides increased effectiveness against migration and proliferation of vascular muscle cells towards the lumen of the artery at the site of the treated stenosis (lesion site). Neointimal hyperplasia is more effectively suppressed.

Materials used for the balloon catheter are all common materials, wherein the following polymers are particularly preferred: polyamides, block copolymers of polyamide, polyether and polyester, polyurethanes, polyesters and polyolefins.

The catheter balloon of the inventive catheter can be dilatable or expandable and is most preferably an angioplasty catheter balloon which could be used without crimped stent or with a crimpled stent. As stent, all kinds of common stents, such as self- expandable stents, not self-expandable stents, metal stents, polymer stents, biodegradable stents, bifurcation stents, uncoated (bare) stents, polymer coated stents, drug release coated stents, stents with a pure active agent coating etc. can be used.

Moreover, the stent can be crimped on the catheter balloon before the inventive coating procedure is carried out so that catheter balloon and stent are coated together with a shellac alkali salt-active agent coating. However, it is preferred to use the coated balloon catheter of the present invention without stent.

The provided balloon catheter contains normally a multifold catheter balloon which will also be coated under or within the folds. Moreover it is possible to selectively coat or fill the folds. The coating within or under the folds has the advantage that during insertion of the balloon catheter the coating and thus the active agent is protected against being washed off by the blood stream.

Furthermore, the catheter balloon of the inventive balloon catheter can be coated in its expanded (inflated) or deflated state. Any commercially available dilatable catheter balloon may be used as catheter balloon. Preferably, so called multifold balloons are used, as described for example in the international patent application WO 94/23787 A1 by David H. Rammler, Labintelligence, USA; or the international patent application WO 03/059430 A1 by Scimed Life Sciences, Inc., USA; or the international patent application WO 2004/028582 A1 by Prof. Dr. Ulrich Speck or the European Patent No. EP 0519063 B1 by Medtronic Inc., USA. Such balloons are provided with folds or wings forming essentially closed cavities when the balloon is in its compressed state but bending outward during dilatation and being capable of releasing substances contained in the folds or respectively of pressing said substances against the vessel wall.

Such balloons are advantageous since the substances enclosed in the folds or respectively active agent enclosed in the folds is protected from being detached too soon during the insertion of the catheter.

The catheter balloons according to the invention were coated with alkali salts of different commercial grades of shellac as well as with varying batches, which differed in the Lac insects, and host tree types used as well as in the time of harvest. There were no differences in release of the active agents observable in various coated catheter balloons.

Regardless of the source of shellac, alkali salts, preferably ammonium salts, of all kinds of shellac types obtained from various locations or from different insects were able to achieve the inventive results so that any kind or sort of shellac can be used in the present invention. Preferably an alkali salt of dewaxed orange shellac is used. Even more preferred an ammonium salt of dewaxed orange shellac is included in the coating on the balloon catheter.

Generally, an amount of 0.1 g to 30 g of the used active agent per mm² of the surface of the balloon catheter to be coated can be applied onto the surface of the balloon catheter, while an amount of 0.5 g/mm² to 12 g/mm² of paclitaxel and 1 .0 - 15.0 g/mm² of sirolimus is sufficient in order to achieve the desired effect on restenosis prophylaxis. The surface load of the active agent, and preferably of paclitaxel or sirolimus, on the catheter balloon is between 0.1 g/mm² and 30 g/mm². Preferably the amount of the active agent present on the coated balloon surface is between 1 g/mm² and 15 g/mm² balloon surface, more preferably between 2 g/mm² and 10 g/mm² and most preferably between 2.5 g and 5 g active agent per mm² balloon surface ( g/mm²). Preferred is also a total amount of 10 to 1000 g of an active agent, preferably paclitaxel or sirolimus, per catheter balloon and most preferably 20 to 400 g per catheter balloon. The surface load of the shellac alkali salt, preferably of shellac ammonium salt, on the catheter balloon is between 1 g/mm² and 25 g/mm². Preferably the amount of shellac alkali salt, preferably of shellac ammonium salt, present on the coated balloon surface is between 2.5 g/mm² and 15 g/mm² balloon surface.

The surface of the catheter balloon may be textured, smooth, rough, harsh, provided with cavities or provided with channels open towards the outside of the balloon. In the case, a textured surface of the catheter balloon is desired, the surface of the catheter balloon can be textured mechanically, chemically, electronically and/or by means of radiation to allow for an improved adhesion of the active agent and to assist the precipitation or crystallization of the active agent.

The content of the active agent in the active agent containing solution or in the solution of the aqueous solution of the active agent and shellac is between 1 g to 1 mg of the active agent per ml solution, preferably between 10 g to 500 g of the active agent per 1 ml solution, more preferably between 30 g to 300 g of the active agent per 1 ml solution, and most preferably between 50 g to 100 g of the active agent per 1 ml solution. The content of the shellac in the aqueous shellac solution of an alkali salt is between 1 g to 10 mg of the solution, preferably between 10 g to 500 g of shellac per 1 ml solution.

In another embodiment the catheter balloon is coated with an active agent and shellac alkali salt, wherein the weight ratio of the active agent to shellac alkali salt is from 100 : 1 to 1 : 100, preferably 95:1 to 1 :95, more preferable 90:1 to 1 :90, more preferable 85:1 to 1 :85, further preferable 80:1 to 1 :80, more preferable 75:1 to 1 :75, more preferably 70:1 to 1 :70, more preferable 65:1 to 1 :65, more preferable 60:1 to 1 :60, more preferable 55:1 to 1 :55, more preferable 50:1 to 1 :50, more preferable 45:1 to 1 :45, more preferable 40:1 to 1 :40, more preferable 35:1 to 1 :35, more preferable 30:1 to 1 :30, more preferable 25:1 to 1 :25, more preferable 20:1 to 1 :20, even more preferable 15:1 to 1 :15, further preferable 10:1 to 1 :10 and most preferable 5:1 to 1 :5.

According to the invention, the balloon catheter does not have to be completely coated. Partial coating of the catheter balloon or partial loading of certain texture elements onto the surface of the catheter balloon may be sufficient. A special catheter balloon including micro-needles or micro-pores or micro-chambers is disclosed in the international patent application no. WO 02/043796 A2 issued to Scimed Life Systems, Inc., USA, wherein inflatable and textured areas are present on the balloon surface. In said embodiment, loading or inflating certain portions of the balloon surface would be sufficient to achieve the desired therapeutic success, wherein it is also possible, evidently, that the whole surface is coated.

A especially preferred embodiment of the present invention is directed to a balloon catheter coated with shellac alkali salt, preferably shellac ammonium salt and an active agent wherein the coating comprises a concentration gradient of the active agent in direction to the balloon surface so that on top of the coating almost 100% by weight active agent is present and directly on the surface of the balloon almost 100% by weight shellac alkali salt is present while the concentration of the active agent in the shellac alkali salt decreases from 100% by weight from the top of the coating to 0% by weight directly on the surface of the balloon.

In addition to this vertical concentration gradient which is perpendicular to the longitudinal axis of the catheter balloon, a horizontal concentration gradient could be present in a further preferred embodiment. Such a horizontal concentration gradient means that in the middle of the catheter balloon the highest concentration of the active agent is present and this concentration of the active agent will decrease in proximal and also in distal direction so that the lowest active agent concentration is present at the proximal and distal ends of the catheter balloon. Another preferred embodiment of the present invention is directed to a balloon catheter having a balloon which is completely coated with a shellac alkali salt, preferably with shellac ammonium salt, but which is coated with active agent only partially, i.e. certain sections of the catheter balloon. Since the active agent-shellac alkali salt coating is hard to characterize, the present invention relates also to coated balloon catheters obtained according to the inventive coating methods disclosed herein as well as to balloon catheter and dilatation catheter comprising an active agent-shellac alkali salt coated catheter balloon. In comparison to coatings prepared using alcoholic solutions of shellac the stability of the release kinetics from this coating is increased and the polymeric film on the balloon catheter has better mechanical properties. For example it is less sticky.

Such balloon catheters or catheter balloons which are coated according to the invention are preferably used for treating constricted vessel segments, particularly of blood vessels and for the treatment and prophylaxis of stenosis, restenosis, arteriosclerosis and fibrotic vessel constriction. Furthermore the coated balloon catheters of the present invention are suitable for dilatation in patients (for example patients on hemodialysis) with failing arteriovenous fistulas (AV-shunts). Balloon catheter or catheter balloons which are coated according to the invention are preferably suited for the treatment and prophylaxis of in-stent restenosis, i.e. a reoccurring vessel constriction within an already implanted stent. Furthermore, the catheter balloons coated according to the invention are particularly suited for the treatment of small vessels, like coronary arteries, preferably such vessels having a vessel diameter of less than 2.5 mm. But also treatment of larger vessels with a vessel diameter up to 8 mm, like the treatment of femoro or popliteal artery lesions, is possible. The balloon catheters coated according to the invention are preferably used in the cardiovascular area, but the catheter balloons coated according to the invention are also suited for the treatment of peripheral blood vessels, vessel constrictions of biliary tracts, esophagus, urinary tracts, pancreas, renal tracts, pulmonary tracts, trachea, small intestine and large intestine.

Furthermore, a second active agent may be added to the active agent containing solution. Said further active agent can be selected from the following group comprising or consisting of:

abciximab, acemetacin, acetylvismione B, aclarubicin, ademetionine, adriamycin, aescin, afromosone, akagerine, aldesleukin, amidorone, aminoglutethimide, amsacrine, anakinra, anastrozole, anemonin, anopterine, antimycotics antithrombotics, apocymarin, argatroban, aristolactam-AII, aristolochic acid, ascomycin, asparaginase, aspirin, atorvastatin, auranofin, azathioprine, azithromycin, baccatin, bafilomycin, basiliximab, bendamustine, benzocaine, berberine, betulin, betulinic acid, bilobol, bisparthenolidine, bleomycin, combrestatin, Boswellic acids and derivatives thereof, bruceanol A, B and C, bryophyllin A, busulfan, antithrombin, bivalirudin, cadherins, camptothecin, capecitabine, o-carbamoyl-phenoxyacetic acid, carboplatin, carmustine, celecoxib, cepharanthin, cerivastatin, CETP inhibitors, chlorambucil, chloroquine phosphate, cicutoxin, ciprofloxacin, cisplatin, cladribine, clarithromycin, colchicine, concanamycin, Coumadin, C-type natriuretic peptide (CNP), cudraisoflavone A, curcumin, cyclophosphamide, ciclosporin A, cytarabine, dacarbazine, daclizumab, dactinomycin, dapsone, daunorubicin, diclofenac, 1 ,1 1 - dimethoxycanthin-6-one, docetaxel, doxorubicin, daunamycin, epirubicin, erythromycin, estramustine, etoposide, everolimus, filgrastim, fluroblastin, fluvastatin, fludarabine, fludarabine-5'-dihydrogen phosphate, fluorouracil, folimycin, fosfestrol, gemcitabine, ghalakinoside, ginkgol, ginkgolic acid, glycoside 1 a, 4-hydroxyoxycyclo phosphamide, idarubicin, ifosfamide, josamycin, lapachol, lomustine, lovastatin, melphalan, midecamycin, mitoxantrone, nimustine, pitavastatin, pravastatin, procarbazine, mitomycin, methotrexate, mercaptopurine, thioguanine, oxaliplatin, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, pegaspargase, exemestane, letrozole, formestane, mycophenolate mofetil, β-lapachone, podophyllotoxin, podophyllic acid-2-ethyl hydrazide, molgramostinn (rhuGM-CSF), peg interferon a-2b, lenograstim (r-HuG-CSF), macrogol, selectin (cytokine antagonist), cytokinin inhibitors, COX-2 inhibitor, angiopeptin, monoclonal antibodies inhibiting muscle cell proliferation, bFGF antagonists, probucol, prostaglandins, 1 - hydroxy-1 1 -methoxycanthin-6-one, scopoletin, NO donors, pentaerythrityl tetranitrate and sydnoimines, S-nitroso derivatives, tamoxifen, staurosporine, β-estradiol, a- estradiol, estriol, estrone, ethinyl estradiol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, kamebakaurin and other terpenoids used in cancer therapy, verapamil, tyrosine kinase inhibitors (tyrphostins), paclitaxel and derivatives thereof, 6-a-hydroxy-paclitaxel, taxoteres, mofebutazone, lonazolac, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, penicillamine, hydroxychloroquine, sodium aurothiomalate, oxaceprol, β-sitosterol, myrtecaine, polidocanol, nonivamide, levomenthol, ellipticine, D-24851 (Calbiochem), colcemid, cytochalasin A-E, indanocine, nocodazole, bacitracin, vitronectin receptor antagonists, azelastine, guanidyl cyclase stimulator, tissue inhibitor of metal proteinase-1 and -2, free nucleic acids, nucleic acids incorporated into virus transmitters, DNA and RNA fragments, plasminogen activator inhibitor 1 , plasminogen activator inhibitor 2, antisense oligonucleotides, VEGF inhibitors, IGF-1 , active agents from the group of antibiotics, cefadroxil, cefazolin, cefaclor, cefoxitin, tobramycin, gentamicin, penicillins, dicloxacillin, oxacillin, sulfonamides, metronidazole, enoxaparin, heparin, hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators, dipyramidole, trapidil, nitroprussides, PDGF antagonists, triazolopyrimidine, seramin, ACE inhibitors, captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin, vapiprost, interferon α, β and γ, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators, halofuginone, nifedipine, tocopherol, tranilast, molsidomine, tea polyphenols, epicatechin gallate, epigallocatechin gallate, leflunomide, etanercept, sulfasalazine, tetracycline, triamcinolone, mutamycin, procainimide, retinoic acid, quinidine, disopyrimide, flecainide, propafenone, sotalol, natural and synthetically obtained steroids such as bryophyllin A, inotodiol, maquiroside A, ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, nonsteroidal substances (NSAIDS), fenoprofen, ibuprofen, indomethacin, naproxen, phenylbutazone, antiviral agents, acyclovir, ganciclovir zidovudine, clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine, antiprotozoal agents, chloroquine, mefloquine, quinine, natural terpenoids, hippocaesculin, barringtogenol-C21 -angelate, 14-dehydroagrostistachin, agroskerin, agrostistachin, 17-hydroxyagrostistachin, ovatodiolids, 4,7-oxycycloanisomelic acid baccharinoids B1 , B2, B3 and B7, tubeimoside, bruceantinoside C, yadanziosides N and P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A,B C and D, ursolic acid, hyptatic acid A, iso-iridogermanal, maytenfoliol, effusantin A, excisanin A and B, longikaurin B, sculponeatin C, kamebaunin, leukamenin A and B, 13,18- dehydro-6-alpha-senecioyloxychaparrin, taxamairin A and B, regenilol, triptolide, cymarin, hydroxyanopterine, protoanemonin, cheliburin chloride, sinococuline A and B, dihydronitidine, nitidine chloride, 12- -hydroxypregnadien-3,20-dione, helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol, podophyllotoxin, justicidin A and B, larreatin, malloterin, mallotochromanol, isobutyrylmallotochromanol, marchantin A, maytansin, lycoridicin, margetine, pancratistatin, liriodenine, oxoushinsunine, periplocoside A, deoxypsorospermin, psychorubin, ricin A, sanguinarine, manwu wheat acid, methylsorbifolin, chromones of spathelia, stizophyllin, dihydrousambaraensine, hydroxyusambarine, strychnopentamine, strychnophylline, usambarine, usambarensine, liriodenine, daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, sirolimus (rapamycin), rapamycin derivatives, biolimus A9, pimecrolimus, everolimus, zotarolimus, tacrolimus, fasudil, epothilones, somatostatin, roxithromycin, troleandomycin, simvastatin, rosuvastatin, vinblastine, vincristine, vindesine, teniposide, vinorelbine, trofosfamide, treosulfan, temozolomide, thiotepa, tretinoin, spiramycin, umbelliferone, desacetylvismione A, vismione A and B, zeorin.

Due to the inventive coating method, the active agent-shellac alkali salt composite dried at the surface of the catheter balloon has a special consistence, which is hard to characterize but seems to be essential for the optimized drug release and local transfer into the cell wall of the lesion segment and the incorporation, especially into the smooth muscle cells. Thus the improved structure of the coating prepared using an aqueous solution of shellac has direct impact of the antiproliferative effect of the balloon catheter coated according to the solution. Another aspect of the present invention are balloon catheter comprising a coating with an active agent and shellac alkali salt, preferably shellac ammonium salt wherein the coating comprises further a water soluble polymer and/or a plasticizer.

Basically water soluble polymers are highly hydrophilic as a result of the presence of oxygen and nitrogen atoms: hydroxyl, carboxylic acid, sulfonate, phosphate, amino, imino groups etc.. Water soluble polymers as herein are preferably macromolecules such as naturally occurring biopolymers such as polysaccharides and polypeptides as well as semi-synthetic derivatives thereof but also completely synthetically prepared compounds. Thereby it is preferred that the water soluble polymer is selected from the group comprising cellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), polyvinylpyrrolidone (PVP), starch, hydroxyl ethyl starch, polyacrylic acid, polyethyleneimine, dextran, agar, carrageenan, alginate, copolymers and/or mixtures of these substances. Addition of sodium alginate, hydroxypropyl methylcellulose and polyvinylpyrrolidine result in increased solubility of the obtained coatings. The term "plasticizers" as used herein refers to substances added to a coating or coating solution in order to modify their physical properties, like imparting viscosity, flexibility, or softness. Their uses include also preventing dried coatings from becoming too brittle. Thereby it is preferred that the plasticizers are chosen from the group consisting of glycerine, propylene glycol, mineral oil, triacetin, polyethylene glycol, glyceryl monostearate, acetylated monoglyceride, polysorbate, oleic acid, butyryl-tri- hexylcitrat (BTHC), and glyceryl tricaprylate/caprate. The following examples illustrate potential embodiments of the invention without limiting the scope of the invention to said precise examples.

Examples

Example 1 Coating of a catheter balloon with paclitaxel and shellac ammonium salt Firstly, 120 mg paclitaxel are solved in 800 μΙ_ ethanol and mixed with 800 μΙ_ of a ready to use aqueous solution of shellac ammonium salt, AQUALACCA 25 by stirring for 24 h at room temperature. The shellac ammonium salt solution is applied to the surface of a fold balloon which is rotatably mounted by a pipetting device. Then the fold balloon is dried under slow rotation at room temperature. The paclitaxel solution is then sprayed on the balloon catheter in a way that 3.0 g/mm² paclitaxel are applied. Then the balloon is dried without rotation at room temperature. Finally, the shellac ammonium salt solution is applied as a separate topcoat by a pipetting device on the active agent layer. 1 g/mm² shellac is applied. Subsequently, the catheter balloon is thoroughly dried for 30 minutes at 50 °C. The presence of a stent or drug-eluting stent crimped on the balloon does not interfere with the coating process. Example 2 Coating of a catheter balloon with rapamycin and shellac salt

A commercially available dilatation catheter with expandable balloon made of a polyamide is provided. The balloon surface is textured but without channels or cavities. Ground shellac was dissolved in 2.5% (w/w) ammonium bicarbonate solution at 40°C under continuous mechanical stirring to produce a final concentration of 20% (w/w). The solution was heated up to 70°C for 30 minutes under continuous stirring, to evaporate excessive ammonium in order to reach the optimum pH 7.3. Then water was added to achieve the concentration of 20% (w/w).

Subsequently this solution was applied onto the horizontal area of the surface of the catheter balloon by brushing. A solution of 140 g of rapamycin in 2.0 ml_ of water is prepared and the catheter balloon is immersed into said solution. Subsequently, the catheter balloon is thoroughly dried and sterilized with ethylene oxide.

Example 3 Coating of a catheter balloon with sirolimus, gum arabic and shellac alkali salt

A balloon of a balloon catheter suitable for expansion vessel dilatation is degreased with acetone and ethanol in an ultrasonic bath for 10 minutes and the balloon catheter is then dried at 100 °C. Solution of gum arabic was prepared by adding the spray-dried powder to 1 % (w/w) ammonium bicarbonate solution in demineralised water at 50°C and stirring mechanically until the gum was dissolved completely. Ammonium bicarbonate was added until increase of the pH of the gum solution to above 7. Subsequently this solution was mixed with shellac so that 18% w/w solutions were prepared. 120 mg sirolimus are solved in 1 ml_ aqueous shellac solution and is applied to the catheter balloon by spraying. The coated catheter balloon is dried within 13 hours at 70 °C.

Example 4 Coating of a catheter balloon with paclitaxel, a plasticizer and shellac salt Firstly, 120 mg paclitaxel are solved in 800 μΙ_ ethanol and 190 g shellac and 9 g glycerol are solved in 1000 ml_ 2.5% (w/w) ammonium bicarbonate solution stirring for 24 h at 40°C. After this 100 μΙ_ of the solution of paclitaxel is mixed with 900 μΙ_ of the shellac ammonium salt solution and pipetted on a catheter balloon. The coated catheter balloon was dried over night at 70 °C.

Example 5 Coating of a catheter balloon with sirolimus and shellac salt using a gradient mixer

A solution of rapamycin and shellac salt were prepared as described in Example 2. After this 100 μΙ_ of the solution of sirolimus is mixed with 900 μΙ_ of the shellac salt solution.

The pure shellac salt solution is applied to the surface of a fold balloon which is rotatably mounted by a spraying device. Then the fold balloon is dried under slow rotation at room temperature. The base coat contained 1 μg/mm² shellac salt on the balloon surface.

The solution containing sirolimus and shellac is poured in the first chamber of a gradient mixer and the pure sirolimus solution is poured in the second, posterior chamber. The outlet of the gradient mixer is connected to a spray gun. The solution out of the gradient mixer is then sprayed on the balloon catheter with the base coat in a way that increasing sirolimus concentration is applied. A total of 3.0 μg/mm² sirolimus is applied. Then the balloon is dried under slow rotation at room temperature.

Example 6 Coating of a catheter balloon with sirolimus and shellac sodium salt A commercially available dilatation catheter with expandable balloon made of a polyamide is provided. The balloon surface is textured but without channels or cavities. Ground shellac was dissolved in 2.5% (w/w) sodium bicarbonate solution at 40°C under continuous mechanical stirring water was added to achieve the concentration of 20% (w/w). Subsequently this solution was applied onto the horizontal area of the surface of the catheter balloon by brushing. A solution of 140 g of rapamycin in 2.0 mL of water is prepared and the catheter balloon is immersed into said solution. Subsequently, the catheter balloon is thoroughly dried and sterilized with ethylene oxide.

Example 7 Coating of a catheter balloon with sirolimus and shellac ammonium salt Firstly, 100 mg sirolimus are solved in 1 mL of a ready to use aqueous solution of shellac ammonium salt, AQUALACCA 25.

The shellac ammonium salt solution containing sirolimus is applied to the surface of a fold balloon which is rotatably mounted by spraying. Then the fold balloon is dried under slow rotation at room temperature. Thereafter a second layer of the same coating solution is sprayed as described before. Subsequently, the catheter balloon is thoroughly dried for 2 hours at 50 °C. Finally, 5.0 g/mm² balloon surface sirolimus were applied.

Claims

A balloon catheter comprising a coating with an active agent and shellac alkali salt.

Balloon catheter according to claim 1 , wherein the shellac alkali salt is a shellac ammonium salt.

Balloon catheter according to claim 1 or 2, wherein the coating comprises a concentration gradient of the active agent

Balloon catheter according to anyone of claim 1 - 3, wherein the concentration gradient of the active agent is in the layer of shellac alkali salt as a matrix substance.

Balloon catheter according to anyone of claim 1 - 4, wherein the active agent is an antiproliferative, immunosuppressive, anti-angiogenic, antiinflammatory, and/or anti-thrombotic agent.

Balloon catheter according to anyone of claim 1 - 5, wherein the active agent is selected from the group consisting of:

abciximab, acemetacin, acetylvismione B, aclarubicin, ademetionine, adriamycin, aescin, afromosone, akagerine, aldesleukin, amidorone, aminoglutethimide, amsacrine, anakinra, anastrozole, anemonin, anopterine, antimycotics antithrombotics, apocymarin, argatroban, aristolactam-AII, aristolochic acid, ascomycin, asparaginase, aspirin, atorvastatin, auranofin, azathioprine, azithromycin, baccatin, bafilomycin, basiliximab, bendamustine, benzocaine, berberine, betulin, betulinic acid, bilobol, bisparthenolidine, bleomycin, combrestatin, Boswellic acids and derivatives thereof, bruceanol A, B and C, bryophyllin A, busulfan, antithrombin, bivalirudin, cadherins, camptothecin, capecitabine, o-carbamoyl-phenoxyacetic acid, carboplatin, carmustine, celecoxib, cepharanthin, cerivastatin, CETP inhibitors, chlorambucil, chloroquine phosphate, cicutoxin, ciprofloxacin, cisplatin, cladribine, clarithromycin, colchicine, concanamycin, Coumadin, C-type natriuretic peptide (CNP), cudraisoflavone A, curcumin, cyclophosphamide, ciclosporin A, cytarabine, dacarbazine, daclizumab, dactinomycin, dapsone, daunorubicin, diclofenac, 1 ,1 1 -dimethoxycanthin-6-one, docetaxel, doxorubicin, daunamycin, epirubicin, erythromycin, estramustine, etoposide, everolimus, filgrastim, fluroblastin, fluvastatin, fludarabine, fludarabine-5'-dihydrogen phosphate, fluorouracil, folimycin, fosfestrol, gemcitabine, ghalakinoside, ginkgol, ginkgolic acid, glycoside 1 a, 4-hydroxyoxycyclo phosphamide, idarubicin, ifosfamide, josamycin, lapachol, lomustine, lovastatin, melphalan, midecamycin, mitoxantrone, nimustine, pitavastatin, pravastatin, procarbazine, mitomycin, methotrexate, mercaptopurine, thioguanine, oxaliplatin, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, pegaspargase, exemestane, letrozole, formestane, mycophenolate mofetil, β-lapachone, podophyllotoxin, podophyllic acid-2-ethyl hydrazide, molgramostim (rhuGM-CSF), peginterferon a- 2b, lenograstim (r-HuG-CSF), macrogol, selectin (cytokine antagonist), cytokinin inhibitors, COX-2 inhibitor, angiopeptin, monoclonal antibodies inhibiting muscle cell proliferation, bFGF antagonists, probucol, prostaglandins, 1 -hydroxy-1 1 - methoxycanthin-6-one, scopoletin, NO donors, pentaerythrityl tetranitrate and sydnoimines, S-nitroso derivatives, tamoxifen, staurosporine, β-estradiol, a- estradiol, estriol, estrone, ethinyl estradiol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, kamebakaurin and other terpenoids used in cancer therapy, verapamil, tyrosine kinase inhibitors (tyrphostins), paclitaxel and derivatives thereof, 6-a-hydroxy-paclitaxel, taxoteres, paclitaxel bound to albumin, like nap-paclitaxel, mofebutazone, lonazolac, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, penicillamine, hydroxychloroquine, sodium aurothiomalate, oxaceprol, β-sitosterol, myrtecaine, polidocanol, nonivamide, levomenthol, ellipticine, D-24851 (Calbiochem), colcemid, cytochalasin A-E, indanocine, nocodazole, bacitracin, vitronectin receptor antagonists, azelastine, guanidyl cyclase stimulator, tissue inhibitor of metal proteinase-1 and -2, free nucleic acids, nucleic acids incorporated into virus transmitters, DNA and RNA fragments, plasminogen activator inhibitor 1 , plasminogen activator inhibitor 2, antisense oligonucleotides, VEGF inhibitors, IGF-1 , active agents from the group of antibiotics, cefadroxil, cefazolin, cefaclor, cefoxitin, tobramycin, gentamicin, penicillins, dicloxacillin, oxacillin, sulfonamides, metronidazole, enoxaparin, heparin, hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators, dipyramidole, trapidil, nitroprussides, PDGF antagonists, triazolopyrimidine, seramin, ACE inhibitors, captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin, vapiprost, interferon α, β and γ, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators, halofuginone, nifedipine, tocopherol, tranilast, molsidomine, tea polyphenols, epicatechin gallate, epigallocatechin gallate, leflunomide, etanercept, sulfasalazine, tetracycline, triamcinolone, mutamycin, procainimide, retinoic acid, quinidine, disopyrimide, flecainide, propafenone, sotalol, natural and synthetically obtained steroids such as bryophyllin A, inotodiol, maquiroside A, ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, non-steroidal substances (NSAIDS), fenoprofen, ibuprofen, indomethacin, naproxen, phenylbutazone, antiviral agents, acyclovir, ganciclovir zidovudine, clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine, antiprotozoal agents, chloroquine, mefloquine, quinine, natural terpenoids, hippocaesculin, barringtogenol-C21 -angelate, 14-dehydroagrostistachin, agroskerin, agrostistachin, 17-hydroxyagrostistachin, ovatodiolids, 4,7- oxycycloanisomelic acid baccharinoids B1 , B2, B3 and B7, tubeimoside, bruceantinoside C, yadanziosides N and P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A,B C and D, ursolic acid, hyptatic acid A, iso-iridogermanal, maytenfoliol, effusantin A, excisanin A and B, longikaurin B, sculponeatin C, kamebaunin, leukamenin A and B, 13,18-dehydro-6-alpha- senecioyloxychaparrin, taxamairin A and B, regenilol, triptolide, cymarin, hydroxyanopterine, protoanemonin, cheliburin chloride, sinococuline A and B, dihydronitidine, nitidine chloride, 12- -hydroxypregnadien-3,20-dione, helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol, podophyllotoxin, justicidin A and B, larreatin, malloterin, mallotochromanol, isobutyrylmallotochromanol, marchantin A, maytansin, lycoridicin, margetine, pancratistatin, liriodenine, oxoushinsunine, periplocoside A, deoxypsorospermin, psychorubin, ricin A, sanguinarine, manwu wheat acid, methylsorbifolin, chromones of spathelia, stizophyllin, dihydrousambaraensine, hydroxyusambarine, strychnopentamine, strychnophylline, usambarine, usambarensine, liriodenine, daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, sirolimus (rapamycin), rapamycin derivatives, biolimus A9, pimecrolimus, everolimus, zotarolimus, tacrolimus, sirolimus bound to albumin, like nap- sirolimus, fasudil, epothilones, somatostatin, roxithromycin, troleandomycin, simvastatin, rosuvastatin, vinblastine, vincristine, vindesine, teniposide, vinorelbine, trofosfamide, treosulfan, temozolomide, thiotepa, tretinoin, spiramycin, umbelliferone, desacetylvismione A, vismione A and B, zeorin.

Balloon catheter according to claim 6, wherein the active agent is selected from the group consisting of:

paclitaxel and paclitaxel derivatives, taxanes, docetaxel, paclitaxel bound to albumin, like nap-paclitaxel, sirolimus, biolimus A9, pimecrolimus, everolimus, zotarolimus, tacrolimus, sirolimus bound to albumin, like nap- sirolimus, fasudil and epothilones.

8. Balloon catheter according to claim 7, wherein the active agent is sirolimus.

9. Balloon catheter according to anyone of claim 1 - 4, wherein the coating comprises further a water soluble polymer and/or a plasticizer.

10. Balloon catheter according to claim 9, wherein the water soluble polymer is selected from the group comprising cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, starch, hydroxyl ethyl starch, polyacrylic acid, polyethyleneimine, dextran, agar, carrageenan, alginate, copolymers and/or mixtures of these substances.

1 1 . Method for coating a balloon catheter according to claim 1 comprising the following steps:

IA) providing an uncoated balloon catheter;

and

I IA) providing an aqueous solution of an active agent and shellac;

or

MB) providing a solution of the active agent and providing an aqueous solution of shellac;

and

or

1MB) coating the surface of the balloon of the balloon catheter with the solution of the active agent and subsequently with the aqueous solution of shellac or coating the surface of the balloon of the balloon catheter with the aqueous solution of shellac and subsequently with the solution of active agent;

IV) drying the coated balloon,

wherein the aqueous solution of shellac or the aqueous solution of the active agent and shellac are prepared using a solution of an alkali salt.

12. Method according to claim 1 1 , wherein the solutions of an alkali salt is a solution of ammonia, ammonium carbonate, or ammonium bicarbonate.

13. Method according to claim 1 1 or 12, wherein the active agent is sirolimus.

14. Method according to any one of claims 1 1 to 13, wherein the active agent containing solution is applied by means of spray coating, brush coating, vapour deposition or pipetting. 15. Coated balloon catheter which can be obtained by the method according to any one of claims 1 1 to 14.