EP2701756A1

EP2701756A1 - Catheter balloon coated with rapamycin and shellac

Info

Publication number: EP2701756A1
Application number: EP12724297.2A
Authority: EP
Inventors: Rembert Pogge Von Strandmann
Original assignee: Eurocor GmbH
Current assignee: Eurocor GmbH
Priority date: 2011-04-26
Filing date: 2012-04-26
Publication date: 2014-03-05
Also published as: DE102011100122A1; CN103561790A; WO2012146681A1; JP2014512238A; US20140107574A1; BR112013027414A2

Abstract

The present invention relates to a catheter balloon having a coating comprising rapamycin and shellac, and to a method for coating catheter balloons, preferably structured catheter balloons, with the active pharmacological ingredient rapamycin, shellac and optionally further constituents. In addition, the present invention also relates to the use of such coated catheter balloons for the release of the active pharmaceutical ingredient rapamycin for prophylaxis and treatment of restenosis, preferably of restenosis caused by angioplasty. The coated catheter balloons can be used alone or in combination with a coated or uncoated stent which is crimped onto the catheter balloon before or after coating with shellac and rapamycin.

Description

Catheter balloon coated with rapamycin and shellac

description

The present invention relates to a catheter balloon with a coating containing rapamycin and shellac and to a method for coating catheter balloons, preferably structured catheter balloons, with the pharmacologically active substance rapamycin, shellac and optionally further constituents. Moreover, the present invention also relates to the use of such coated catheter balloon for the release of the pharmaceutical agent rapamycin for the prophylaxis and treatment of restenosis, preferably restenosis caused by angioplasty. The coated catheter balloons may be used alone or in combination with a coated or uncoated stent that is crimped onto the catheter balloon before or after coating with shellac and rapamycin.

Today, the implantation of vascular prostheses such as stents for the treatment of stenosis has become a well established surgical intervention. In this context, the so-called restenosis (recurrent stenosis), i. the reocclusion of the vessel, a common complication. There is no exact definition of the term restenosis in the literature. The most commonly used morphological definition for restenosis defines restenosis as a reduction in vessel diameter to less than 50% of normal following successful PTA (percutaneous transluminal angioplasty). The said definition describes an empirically determined value, and its hemodynamic significance and association with clinical symptoms lack the scientific background. In practice, the clinical deterioration of a patient is often considered a sign of the occurrence of restenosis in the previously treated vascular section.

Restenosis after stenting is one of the main reasons for further hospitalizations. Vascular injury caused by stent placement causes inflammatory reactions that play a significant role in the healing process during the first seven days. In the recent past it has also been found that stents provided with a drug-eluting layer could cause late thrombosis, ie, in addition to Restenosis, the stent could also lead to a long-term problem such as late thrombosis.

Concerns have been expressed that the biostable or bioresorbable polymeric matrix of the stent in which the drug is embedded could trigger persistent inflammation with increased neointimal proliferation. In addition, the drug concentration achieved is not homogeneous in the tissue: it is highest near the stent struts and lowest between the stent struts; this causes uneven inhibition of vascular smooth muscle cell proliferation and may result in delayed and inhomogeneous re-endothelialization in various stent segments. Significant involvement in late thrombosis and in stent restenosis was discussed for both mechanisms. The problem of late thrombosis caused by drug-eluting stents such as paclitaxel or rapamycin-releasing stents has been described as a serious problem that can cause the death of a patient. Compared to drug-eluting stents that release the drug over a period of time, drug-coated catheter balloons must release the drug immediately because dilatation of a catheter balloon must not take longer than 60 seconds to avoid any harm to the patient, and two- can be repeated up to three times. However, even repeating the dilation to obtain a total dilation time of three or four or five minutes continues to be a short-term release of the drug compared to stents releasing the drug over days, weeks or months.

In order to avoid such problems, a so-called "biological stenting" can be carried out, in which only a coated catheter balloon, without a stent, is used. The vessels are dilated at a restricted site by the dilatation of the coated catheter balloon, the catheter balloon being dilated for a short time and a sufficient amount of the pharmacologically active agent transferred to the vessel wall to re-narrow or re-occlude the vessel as a result of dilation to avoid the vessel.

Such coated catheter balloons are already known from WO 2005/089855 A1, and international patent application WO 2004/028582 A1 discloses folded balloons coated with a composition of a pharmacological agent and a contrast agent, preferably under the folds. A method for spray-coating catheter balloons is described in WO 2004/006976 A1. WO 2008/046641 discloses coated implants with respect to stents, particularly demonstrating the in vitro release kinetics of stents coated with 1.0% rapamycin without shellac mix and 1.0% rapamycin / 0.5% shellac mix. Shellac had a profound effect on stent-based rapamycin through long-term delay in drug release. Uncoated stents with rapamycin released the drug more efficiently, unlike shellac and rapamycin coated stents, which released the drug much more slowly. Shellac was considered useful to control the release kinetics of an implant-based, e.g. A stent-based compound to slow down (more than 60 days) the release kinetics needed to prevent in-stent restenosis after 6-9 months in the course.

Such a slowdown in drug release is actually not favorable for a catheter balloon. Unlike a stent, with a catheter balloon, so much of the coated drug should be released within as short a time as possible to reduce the inflation time to an absolute minimum. Therefore, it is surprising and unexpected that a catheter balloon coated with rapamycin and shellac results in an improvement in drug release as compared to a catheter balloon that is not coated with shellac. WO 2008/046641 rather implies that shellac, combined with an active ingredient, results in a stable formulation that releases the drug very slowly over a long period of time (months) and would not be suitable for rapid release of drug by balloon catheter. Bruno Scheller and Ulrich Speck et al., Circulation 2004, 1 10, 810-814 have shown that coated with pure drug catheter balloons showed no therapeutic effect. A therapeutic effect was only achieved if paclitaxel was combined with the contrast agent solution ULTRAVIST ^® . Ultravist ^® is iopromide a solution of the contrast agent.

By virtue of the fact that the active substance rapamycin has proven to be particularly useful for the prevention of restenosis, whereas coated stents are detrimental to the late thrombosis described above, it is the object of the present invention to apply the active ingredient of the type to a catheter balloon a coating is formed that is easily detached from the balloon and can be effectively transferred to the vessel wall so that a therapeutic effect in reducing restenosis can be achieved. Said object is achieved by the technical teaching of the independent claims. Further advantageous embodiments will become apparent from the dependent claims, the description, the figures and the examples. Surprisingly, it has been found that a coating method of the following type is particularly suitable for solving said object.

Said method for loading or coating of dilatable catheter balloons comprises the following steps:

I) providing an uncoated catheter balloon;

and

IIA) providing a solution of rapamycin and shellac;

or

IIB) providing a solution of rapamycin and providing a solution of shellac;

and

INA) coating the surface of the catheter balloon with the solution of rapamycin and shellac;

or

HIB) coating the surface of the catheter balloon with the solution of rapamycin and then with the solution of shellac or coating the surface of the catheter balloon with the solution of shellac and then with the solution of rapamycin;

IV) drying the coated catheter balloon.

In addition, the invention is directed to a catheter balloon characterized by a coating comprising rapamycin and shellac. The term "uncoated" as used herein refers to a catheter balloon having a smooth or textured or roughened surface without any drug coating, ie, the balloon surface does not contain any pharmaceutically active agents and particularly no antiproliferative, anti-angiogenic or antirestenotic agent and coating It has been surprisingly found that such a rapamycin shellac coating is therapeutically highly useful for keeping blood vessels open to reduce late lumen loss and restenosis a balloon catheter comprising a catheter balloon coated with a combination of rapamycin and shellac which, even after a short period of dilatation, is therapeutically highly effective in keeping blood vessels open and reducing vascular constriction and restenosis. Compared to drug eluting stents, where about 85% of the stented plaque surface is not covered by struts, rapamycin and shellac coated catheter balloons allow a homogeneous distribution of an antiproliferative compound to be administered across the area. In addition, this uniformity of release to the vessel wall enhances the efficacy of the drug. The concentration of active substance within the vessel is highest at the time of injury due to dilation of the vessel, although the inflammatory and proliferative processes are most severe.

In one embodiment, the rapamycin and shellac-coated balloon catheter is further characterized in that after balloon infiltration for> 30 s, preferably> 25% of the rapamycin is released from the balloon surface, more preferably> 30%, more preferably> 40%, even more preferably> 50 %, even more preferably> 60%, most preferably> 70%. Consequently, a dilation time of <30 seconds is preferred for a single dilatation. Moreover, a total dilation time of <60 seconds is preferred, which means that the single dilatation of <30 seconds is repeated once.

In another embodiment, the catheter balloon coated with rapamycin and shellac is further characterized in that after a balloon inflation time of 30 seconds in the dilated segment, 45 minutes after dilation, a rapamycin tissue concentration of preferably> 10 μΜ / L, more preferably> 30 μΜ / L, even more preferably> 50 μΜ / L, more preferably> 80 μΜ / L, even more preferably> 100 μΜ / L, more preferably> 120 μΜ / L, most preferably> 140 μΜ / L can be achieved.

In a further preferred embodiment, the catheter balloon coated with rapamycin and shellac is characterized in that after a balloon infiltration time of 15 seconds in the dilated segment 45 minutes after dilation, a rapamycin tissue concentration of preferably> 1 μΜ / L, more preferably> 3 μΜ / L, even more preferably> 5 μΜ / L, more preferably> 8 μΜ / L, even more preferably> 10 μΜ / L, more preferably> 15 μΜ / L, most preferably> 20 μΜ / L can be achieved. In another embodiment, the catheter balloon is coated with rapamycin and shellac wherein the weight ratio of rapamycin to shellac is from 100: 1 to 1: 100, preferably 95: 1 to 1:95, more preferably 90: 1 to 1:90, more preferably 85: 1 to 1: 85, more preferably 80: 1 to 1:80, more preferably 75: 1 to 1:75, more preferably 70: 1 to 1:70, more preferably 65: 1 to 1:65, more preferably 60: 1 to 1:60, more preferably 55: 1 to 1:55, more preferably 50: 1 to 1:50, more preferably 45: 1 to 1:45, more preferably 40: 1 to 1:40, more preferably From 35: 1 to 1:35, more preferably from 30: 1 to 1:30, more preferably from 25: 1 to 1:25, more preferably from 20: 1 to 1:20, even more preferably from 15: 1 to 1:15 preferably 10: 1 to 1:10 and most preferably 5: 1 to 1: 5.

Any commercially available dilatable catheter balloon can be used as a catheter balloon in the context of the invention. So-called multi-fold balloons (Mu / f / fo / c / balloons) can be used as described, for example, in International Patent Application WO 94/23787 A1 by David H. Rammler, Labintelligence, USA; or in the international patent application of Scimed Life Sciences, Inc., USA; or international patent application WO 2004/028582 A1 to Prof. Dr. med. Ulrich Speck, European Patent No. EP 0519063 B1 to Medtronic Inc., USA.

Such balloons are provided with wrinkles or wings which form closed cavities in the western, when the balloon is in its deflated state, but flex outward during dilatation and are capable of releasing the substances contained in the wrinkles or the said substances against the vessel wall to press.

Such balloons are advantageous in that the substances enclosed by the folds, or the rapamycin enclosed by the folds, are protected against premature detachment during insertion through the catheter.

In order to protect the active ingredient rapamycin from early detachment from the catheter balloon, rapamycin may also be incorporated, incorporated or embedded in one or more carrier substances, preferably a polymeric carrier. Shellac is the most preferred biodegradable polymeric carrier. Regardless of the source of shellac, all types of shellac types obtained from different locations or from different insects have been able to achieve the results of the invention so that any type or variety of shellac can be used with the present invention , Therefore, there are no limits to shellac. Shellac is a natural resin made from the glandular secretions of several lacquer-producing insects. Lacquer insects belong to the genus Hemiptera, Superfoil Coccoidea such as Metatachardia, Laccifer, Tachordiella and others; however, members of two families - Lacciferidae and Tachardinidae - are particularly important for lacquer production. A commercially-kept blue-throated louse is Kerria lacca, also known by the synonyms Laccifer lacca Ker, Tachardia lacca, and Carteria lacca. Kerria lacca is an Indian scale insect that infests the branches of numerous trees such as Butea frondos Rosh, Acacia arabica Willd and Ficus religiosa Linn in Southeast Asia. Shellac is the only commercially used natural resin of animal origin and is very different from all other natural resins. Recently, as a new awareness of the environment and the toxicity of chemical raw materials is becoming apparent everywhere, shellac and modified shellac resins are gaining in importance because of their interesting and unique characteristics. Broken branches are sold as stick paint. After milling and washing with water to remove wood and red pigments (paint dye), you get grain varnish. Purification of the grain varnish results in a more homogeneous product, known as shellac. Its use began in Europe towards the end of the 16th century mainly as a varnish (mainly known as "French polish") for wooden objects, musical instrument and gilding, as protection for vinyl windows and murals, as an insulating material for early radios and other electric tools and as an adhesive for the restoration of pottery Unprocessed shellac material consists of 70-80% resin, 4-8% dye, 6-7% hard and high gloss wax, 3% water, up to 9% vegetable and animal impurities and flavors is a complex mixture of aliphatic (60%) and sesquiterpene acids (32%) and their esters, sesquiterpene acids are jalaric acid and lacci-jalaric acid (structures I and II), and aliphatic acids are aleuritic acid (III) and butyric acid.

One possibility for the chemical description of the resin molecule is a structural model in which at least 4 molecules of jalaric acid or lacci-jalaric acid and aleuritic acid are connected in an alternating manner via ester bonds.

Jalaric Acid (I) Lacci-Jalaric Acid (II)

Its chemical composition is approximately constant, although the amount of some constituents varies depending on the type of host tree on which the insects live. From these acids, schellolic acid (IV) and derived compounds are synthesized by Cannizzaro-like disproportionation under alkaline hydrolysis. These compounds are 9,10,16-

Trihydroxypalmitic acid (aleuritic acid) CAS [53-387-9] and schellolic acid (IV)

Aleuritic acid (III) Schellolic acid (IV) Modification with other natural or synthetic resins or copolymerization with various monomers is possible to crosslink shellac, modified shellac resins and shellac copolymers with urea, melamine, formaldehyde, isocyanides; other chemical processes such as polymerization, hydroxylation, exposure are also possible.

Shellac has the following grades:

- Grain varnish

- Handgewonner shellac

- Machine shellac

- Disappeared shellac

- Degraded and bleached shellac

- Aleuritic acid The most important properties of shellac are:

- Shellac is a tough natural resin

- Shellac has good resistance to solvents

- Shellac is based on hydrocarbons

- Shellac is not toxic

- Shellac is thermoplastic

- Shellac is physiologically harmless

- Shellac is approved for various applications in the food industry

- Shellac is not UV-resistant

- Shellac is soluble in low alcohols

- Shellac has excellent dielectric properties, high dielectric strength, low dielectric constant, good tracking resistance, etc.

- Shellac has a low melting point (65-85 ° C).

- Shellac is water-soluble in aqueous-alkaline solutions

- Coatings do not change their electrical properties under UV irradiation

Shellac has excellent film-forming properties

- Schallack has a low thermal conductivity, and a low expansion coefficient forms smooth, high-gloss films and surfaces

- Shellac coating has good adhesion to many coatings and can be polished

- Shellac can be cross-linked to modify other natural / synthetic resins

Examples of industrial applications are:

- Coating of pills and tablets

- coating of fruits

- cosmetics

- French polish for surface coating, sealing

- Optical frames

The catheter balloons according to the invention were coated both with shellac of different commercial classes and with different batches, which differed in the lacquer insects and types of the host tree as well as the harvest time. There were no differences in the observed rapamycin release for the different rapamycin shellac-coated catheter balloons. To apply said carrier shellac or other additional carriers to the catheter balloon surface, the carrier may be added to the rapamycin solution or may be applied as a second solution with or without rapamycin. Such solutions containing rapamycin and / or shellac and optionally further carrier substances are then applied to the catheter balloon surface by means of conventional coating methods, in particular spraying, spraying or dipping methods. Suitable additional carriers are those substances which are also used as balloon material, in particular polymeric and polymerizable substances as listed below.

The rapamycin is embedded or stored in shellac, with up to 30% of the total being prematurely released during the introduction of the catheter balloon, but there is still a sufficiently high and therapeutically effective amount of rapamycin present on the balloon once it has reached its target position ,

Therefore, it is preferred to protect the active ingredient rapamycin from premature detachment by embedding it in the shellac on the surface of the catheter balloon and optionally under the folds of the balloon

But even in those cases where the coating, i. E. If the rapamycin is not protected by the folds of a multi-fold balloon (Mu / f / 7ö / c / balloon), or where the rapamycin is not embedded in a large excess of shellac, a correspondingly higher amount of the active ingredient rapamycin may be applied to the catheter balloon so that an effective dose is released at the target site.

In general, an amount of 0.1 g to 30 g of rapamycin per mm ^{2 can be} applied to the surface of the balloon catheter to be coated, while a rapamycin amount of 0.5 g / mm ² to 6 g / mm ^{2 is} sufficient to produce the desired Effect on the restenosis prophylaxis. Preferably, the amount of rapamycin per mm ² surface of the balloon between 1 g / mm ² and 5 g / mm ^2, more preferably between 1, 5 g / mm ² and 4.5 g / mm ^2, even more preferably between 2.0 g / mm ² and 4.0 g / mm ^2, and most preferably between 2.5 g / mm ² and 3.5 g / mm ² .

Also preferred is a total amount of rapamycin of from 10 to 1000 g per catheter balloon, and most preferably from 20 μ to 400 g per catheter balloon. Rapamycin is commercially available from several manufacturers, such as Sigma-Alderich, Merck, Seileck and Cayman. Rapamycin is also known under the trade name Rapamune ^® and is also synonymous with different names referred to as:

Sirolimus, sirolimusum, D02.540.505.760, D04.345.349.760 and SRL.

Its chemical structure is as follows:

IUPAC nomenclature is as follows:

[(3S, 6R, 7E, 9R, 10R, 12R, 14S, 15E, 17E, 19E, 21S, 23S, 26R, 27R, 34aS) - 9, 10, 12, 13, 14, 21, 22, 23 24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3- [(1R) -2 - [(1S, 3R, 4R) -4-hydroxy-3- methoxycyclohexyl] -1-methylethyl] -10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido [2,1-c] [1,4] - oxaazacyclohentriacontine-1, 5.1, 28.29 (4 / - /, 6H, 31H) -pentones.

Rapamycin is an immunosuppressant with a macrolide structure (31-membered) and can be obtained as a metabolic end product from streptomycete Streptomyces hygroscopicus. Rapamycin inhibits a number of cytokine-mediated signal transduction pathways by complexing with the mammalian target of rapamycin (mTOR) protein. This ultimately leads to the inhibition of the cell cycle and thus cell division. Rapamycin is highly soluble in dimethyl sulfoxide (DMSO) and methanol as well as in anhydrous ethanol, but it is comparatively poorly soluble in water (2.6 μg / ml). As the solvent for rapamycin, dimethylsulfoxide (DMSO), acetone, chloroform, ethyl acetate, ethanol and methanol are used.

The coating process according to the invention can be carried out in two alternative ways. A catheter balloon, and preferably an uncoated catheter balloon or catheter balloon without any releasable drug on its surface, is provided. Then, a solution of rapamycin together with shellac is prepared in a suitable solvent such as acetone, ethyl acetate, ethanol, methanol, DMSO, THF, chloroform, methylene chloride, or a mixture thereof and applied by conventional coating methods such as spray coating, dip coating, etc., after a drying step to obtain a solid rapamycin shellac coating on the surface of the catheter balloon (steps I + IIA + INA + IV).

Alternatively, one can prepare a rapamycin solution and a separate shellac solution, and apply both solutions simultaneously or subsequently, to obtain a solid rapamycin shellac coating on the surface of the catheter balloon after the drying step (steps I + IIB + HIB + IV).

The coating steps INA) and IV) or HIB) and IV) can be repeated several times in the inventive coating methods. Typically, the coating procedure is repeated once, twice or three times, but said repetition is not mandatory. Also, a coating procedure may be sufficient to obtain the required amount of rapamycin and shellac on the catheter balloon.

The drying step IV) can be carried out at room temperature or elevated temperatures up to 50 ° C and at atmospheric pressure or under reduced pressure to high vacuum. If the coating step III) [INA] or HIB)] is repeated, the drying steps IV) are preferably carried out at room temperature and atmospheric pressure, while preferably after the last coating step of the cycle, the drying step is more intense, i. longer or under vacuum or at elevated temperature.

The catheter balloon is dilatable or expandable, and is preferably an angioplasty catheter balloon, without a crimped stent or with a crimped one Stent can be used. The stent may be any of the types of conventional stents, such as self-expandable stents, non-self-expandable stents, metal stents, polymer stents, biodegradable stents, bifurcated stents, bare stents, polymer coated stents, drug-eluting stents, pure drug-coating stents, etc.

In addition, the stent may be crimped onto the catheter balloon prior to performing the inventive coating method so that the balloon catheter and stent are coated together with a shellac rapamycin coating. If the catheter balloon is first coated and the stent is then crimped onto the balloon, a rapamycin coated stent or a rapamycin shellac coated stent having the same or a different concentration of rapamycin and / or shellac on the surface could be used.

However, it is preferred to use the coated catheter balloon of the present invention without a stent.

The catheter catheter provided is usually a multi-fold catheter balloon (Mu / f / fo / d catheter balloon) which is also 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 the introduction of the catheter balloon, the coating and therefore the drug rapamycin is protected against washing by the bloodstream.

In addition, the catheter balloon may be coated in its expanded (inflated) or deflated state.

The preferred solvents for shellac and rapamycin are volatile, readily removable solvents such as acetone, ethyl acetate, ethanol, methanol, DMSO (dimethylsulfoxide), THF (tetrahydrofuran), chloroform and methylene chloride.

The total surface load of the catheter balloon with rapamycin and shellac is between 1 g / mm ² and 12 g / mm ² . Preferably, the amount of rapamycin and shellac on the coated balloon surface is between 2 g / mm ² and 10 g / mm ² balloon surface, more preferably between 3 g / mm ² and 9 g / mm ² , even more preferably between 4 g / mm ² and 8 g / mm ² , more preferably between 5 g / mm ² and 7 g / mm ² , and most preferably between 5.5 g / mm ² and 6.5 rapamycin and shellac per mm ² balloon surface area (g / mm ² ). The inventive coating method may optionally further comprise step V):

V) Sterilization of rapamycin and shellac coated catheter balloons.

The sterilization is preferably carried out with ethylene oxide.

In addition, the inventive coating method may optionally further comprise step IB):

IB) Protect the parts of the balloon catheter that are not to be coated with a removable protective cover.

Since the catheter balloon is only part of a balloon catheter, the surfaces of the balloon catheter that are not to be coated with the rapamycin shellac composition can be protected by a removable protective cover such as a plastic bag or plastic film and only the catheter balloon remains freely accessible that only the exposed part can be coated. After the coating process is completed, the protective cover is removed.

The inventive coating method may optionally further comprise step VI):

VI) Protecting the coated catheter balloon with a removable protective cover.

The removable protective cover is useful to protect the finished coated catheter balloon, and more particularly, the coating on the catheter balloon from damage, e.g. during transport or storage. As described in detail below, the surface of the catheter balloon is structured, smooth, uneven, rough, holed, or provided with channels open to the outside of the balloon.

In addition to shellac, the rapamycin-containing coating solution may optionally contain at least one further carrier substance. Said at least one further carrier substance is selected from the group consisting of or comprising:

Parylene C, Parylene D, Parylene N, Parylene F, polyvalerolactone, poly-ε-decalactone, polylactic acid, polyglycolic acid, polylactides, polyglycolides, copolymers polylactides and polyglycolides, poly-s-caprolactone, polyhydroxybutyrylic acid, polyhydroxybutyrates, polyhydroxyvalerates, polyhydroxybutyrate-co-valerate, poly (1,4-dioxane-2,3-dione), poly (1,3-dioxane-2-one) , Poly-para-dioxanone, polyanhydrides, polymaleic anhydride, polyhydroxymethacrylates, fibrin, polycyanoacrylates, polycaprolactone-dimethylacrylates, poly-.beta.-maleic acid, polycaprolactone-butyl acrylates, multiblock polymers of oligocaprolactonediols and oligodioxanonediols, polyetherester multiblock polymers of PEG and polybutylene terephthalates, polypivotolactones, polyglycolic acid trimethylcarbonates , Polycaprolactone glycolide, poly (Y-ethylglutamate), poly (DTH-iminocarbonate), poly (DTE-co-DT-carbonate), poly (bisphenol A-iminocarbonate), polyorthoester, polyglycolic acid-trimethylcarbonate, polytrimethylcarbonate, polyiminocarbonate, poly (N-) vinyl) -pyrrolidone, polyvinyl alcohols, polyester amides, glycosylated polyesters, polyphosphoesters, polyphosphazenes, poly [p-carboxyphenoxy) propane],

Polyhydroxypentanoic acid, polyanhydrides, polyethylene oxides, propylene oxides, soft polyurethanes, polyurethanes with amino acid residues in the main chain, polyether esters, polyethylene oxides, polyalkene oxalates, polyorthoesters and copolymers thereof, lipids, carrageenans, fibrinogen, starch, collagen, protein-based polymer, polyamino acids, synthetic polyamino acids, zein , Polyhydroxyalkanoates, pectic acid, actinic acid, carboxymethyl sulfates, albumin, hyaluronic acid, chitosan and its derivatives, heparan sulfates and their derivatives, heparins, chondroitin sulfates, dextran, β-cyclodextrins, copolymers with PEG and polypropylene glycol, gum arabic, guar, gelatin, collagen N-hydroxysuccinimide , Phospholipids, polyacrylic acid, polyacrylates,

Polymethyl methacrylates, polybutyl methacrylates, polyacrylamides, polyacrylonitriles, polyamides, polyetheramides, polyethyleneamines, polyimides, polycarbonates, polycarbourethanes, polyvinyl ketones, polyvinyl halides, polyvinylidene halides, polyvinyl ethers, polyisobutylene, polyvinylaromatics, polyvinylesters, polyvinylpyrrolidone, polyoxymethylene, polytetramethyleneoxide, polyethylene, polypropylene, polytetrafluoroethylene, polyurethanes, polyetherurethanes, Silicone polyether urethanes, silicone polyurethanes, silicone polycarbonate urethanes, polyolefin elastomers, EPDM rubbers, fluorosilicones, carboxymethyl chitosans, polyaryletheretherketones, polyetheretherketones, polyethylene terephthalates, polyvalerates, carboxymethylcellulose, cellulose, viscose, viscetriacetates, cellulose nitrates, cellulose acetates, hydroxyethylcellulose, cellulose butyrates, cellulose acetate butyrates, ethylvinylacetate copolymers, polysulfones, epoxy resins , ABS resins, silicones, polysiloxanes, polydimethylsiloxanes, polyvinylhalogens and copolymers, C cellulose ethers, cellulose triacetates, chitosans and copolymers and / or mixtures of the aforementioned polymers. If a structured surface of the catheter balloon is desired, the surface of the catheter balloon may be structured mechanically, chemically, electronically, and / or by irradiation to allow for improved attachment of rapamycin and promote the deposition or crystallization of the rapamycin.

When structuring the surface of the catheter balloon, the surface of the catheter balloon must be modified in the range of nanometers to micrometers, i. a kind of micro-level surface structure must be provided. Surface structuring is preferably applied to the entire surface of the catheter balloon to be coated and may result in organized or random structures.

The catheter balloon may consist of the following materials:

Parylene C, Parylene D, Parylene N, Parylene F, polyvalerolactones, poly-ε-decalactones, polylactic acid, polyglycolic acids, polylactides, polyglycolides, copolymers of polylactides and polyglycolides, poly-s-caprolactones, polyhydroxybutyrylic acid, polyhydroxybutyrates, polyhydroxyvalerates,

Polyhydroxybutyrate-co-valerate, poly (1,4-dioxane-2,3-diones), poly (1,3-dioxanes-2-ones), poly-para-dioxanones, polyanhydrides, polymaleic anhydride,

Polyhydroxymethacrylates, fibrin, polycyanoacrylates, polycaprolactone dimethyl acrylates, poly-β-maleic acid, polycaprolactone-butyl acrylates,

Multiblock polymers of oligocaprolactone diols and oligodioxanonediols, polyetherester multiblock polymers of PEG and polybutylene terephthalates, polypivolactones, polyglycolic acid trimethylcarbonates, polycaprolactone glycolides, poly (Y-ethylglutamate), poly (DTH-iminocarbonate), poly (DTE-co-DT-carbonate), poly (bisphenol A-iminocarbonates), polyorthoesters, polyglycolic acid trimethylcarbonates, polytrimethylcarbonates, polyiminocarbonates, poly (N-vinyl) pyrrolidones, polyvinyl alcohols, polyesteramides, glycosylated polyesters, polyphosphoesters, polyphosphazenes, poly [p-carboxyphenoxy) propanes], polyhydroxypentanoic acid, polyanhydrides, polyethylene oxides, Propylene oxides, polyurethanes, polyurethanes with amino acid residues in the main chain, polyether esters, polyethylene oxides, polyalkene oxalates, polyorthoesters and their copolymers, lipids, carrageenans, fibrinogen, starch, collagen, protein-based polymer, polyamino acids, synthetic polyamino acids, zein, polyhydroxyalkanoates, pectic acid, Actinic acid, carboxymethyl sulfates, albumin, hyaluronic acid, chitosan and its derivatives, heparan sulfates and their derivatives, heparins, chondroitin sulfates, dextran, β-cyclodextrins, copolymers with PEG and polypropylene glycol, gum arabic, guar, gelatin, collagen N- Hydroxysuccinimide, phospholipids, polyacrylic acid, polyacrylates,

Polymethyl methacrylates, polybutyl methacrylates, polyacrylamides, polyacrylonitriles, polyamides, polyetheramides, polyethyleneamine, polyimides, polycarbonates, polycarbourethanes, polyvinyl ketones, polyvinyl halides, polyvinylidene halides, polyvinyl ethers, polyisobutylenes, polyvinylaromatics, polyvinylesters, polyvinylpyrrolidones, polyoxymethylene, polytetramethyleneoxide, polyethylene, polypropylene, polytetrafluoroethylene, polyurethanes, polyetherurethanes, Silicone polyether urethanes, silicone polyurethanes, silicone polycarbonate urethanes, polyolefin elastomers, EPDM rubbers, fluorosilicones, carboxymethyl chitosans, polyaryletheretherketones, polyetheretherketones, polyethylene terephthalates, polyvalerates, carboxymethylcellulose, cellulose, viscose, viscetriacetates, cellulose nitrates, cellulose acetates, hydroxyethylcellulose, cellulose butyrates, cellulose acetate butyrates, ethylvinylacetate copolymers, polysulfones, epoxy resins , ABS resins, silicones, polysiloxanes, polydimethylsiloxanes, polyvinylhalogens and copolymers, Cellulose ethers, cellulose triacetates, chitosans and copolymers and / or mixtures of the aforementioned polymers.

Polyamides, block copolymers of polyamide-polyether-polyester, polyurethanes, polyesters and polyolefins are preferred.

It is important to avoid any damage to the catheter balloons while the balloon surface is structured and to ensure that their ability to expand is not adversely affected. Thus, the balloon surface microstructuring techniques must not result in the formation of holes, micropores, or cracks in the balloon material. Ideally, only the outer surface of the balloon, i. up to a maximum depth of 1 mm, structured.

The dilatable catheter balloon may be mechanically structured by the use of a file-like device, a file, or a solid particle jet method, such as a sandblasting method.

In a chemical-mechanical process, a suspension or dispersion of solid particles in a solvent, especially in water, is used. Such methods are also referred to as chemical polishing processes. By rubbing such compositions on the surface of the balloon material, the material is roughened without creating deep cracks or holes.

In a purely chemical structuring method, the surface of the balloon material becomes attacking acids, bases, etching chemicals and / or oxidizing agents Used chemicals. However, such chemicals must be used with caution as the balloon material could be damaged if the exposure time is too long or the chemicals are too concentrated. When an electrical or electronic method is used to pattern the surface of the dilatable catheter balloon, patterning is accomplished by means of conductors that are heated by electrical current flow. For example, a fine, warm, hot or glowing needle can be used to melt the surface of the balloon material, whereby certain patterns can be created on the surface, especially when the needle is moved along the surface of the catheter balloon.

An elegant method for creating organized structures, especially in the form of microwells or microchannels, may be the use of a laser or generally highly focused radiation. Said radiation means are very accurate and can be used especially for the creation of defined structures such as grids, spirals or lines.

The patterned or micronized to nanomodated surface of the catheter balloon as well as the unstructured catheter balloons may be wetted prior to application of the coating solution by any conventional means to increase the adherence of the coating to the balloon surface.

Any type of common coating method such as spray coating, brush coating, dip coating, vapor deposition, pipetting and the like can be used to apply the rapamycin shellac solution or the rapamycin solution and shellac solution to the balloon surface.

The content of rapamycin in the rapamycin-containing coating solution is between 1 g to 1 mg rapamycin per ml solution, preferably between 10 g to 500 g rapamycin per 1 ml solution, more preferably between 30 g to 300 g rapamycin per 1 ml solution and most preferably between 50 g to 100 g of rapamycin per 1 ml of solution. For example, the solution of rapamycin in ethanol, acetone, ethyl acetate or DMSO may be applied to the balloon surface via syringing, dipping, plasma deposition, brushing or spraying. While normally the entire surface of the catheter balloon is coated by a dipping method or plasma deposition method, in particular, spray, brush and spray methods may be used to coat only a portion of the balloon surface. According to the invention, the catheter balloon does not have to be completely coated. Partial coating of the catheter balloon or partial loading of certain structural elements on the surface of the catheter balloon may be sufficient. A particular catheter balloon, including microneedles or micropores or microcompartments, is disclosed in International Patent Application No. WO 02/043796 A2, Scimed Life Systems, Inc., USA, in which inflatable and structured surfaces are present on the balloon surface. In said embodiment, loading or inflation of certain parts of the balloon surface would be sufficient to achieve the desired therapeutic success, although it is obviously also possible for the entire surface to be coated.

An example in which it is desirable to only partially coat the catheter balloon is valvuloplasty. Balloon ovuloplasty is a procedure in which a narrowed heart valve is distended via a procedure that does not require open heart surgery. Balloon ovuloplasty is performed to improve valve function and blood flow by enlarging the valve opening. It is a treatment for aortic, mitral and pulmonary stenosis. In balloon vivuloplasty, a thin catheter balloon is inserted through the skin in the groin into a blood vessel and then advanced to the opening of the narrowed heart valve. The balloon is inflated to stretch the flap and release the valve obstruction. The prevention of restenosis is also a concern; however, catheter balloons coated over the entire surface are not suitable because only a small portion in the center of the catheter balloon comes into contact with the valve, the remainder of the catheter balloon being in the chamber and the atria of the heart. After inflation of the balloon, the walls in the ventricle and the atria come into contact with the catheter balloon. Drug release on these healthy tissues is undesirable and could lead to serious side effects. A balloon catheter according to the invention for balloon avulsoplasty is coated only in the region which comes into direct contact with the valve, where inhibition of restenosis is desired. Therefore, a preferred embodiment of the present invention is a shellac and rapamycin coated balloon catheter for balloon avulsoplasty in which only that portion of the catheter balloon which comes in contact with the heart valve is coated. Another preferred embodiment of the present invention is directed to a catheter balloon which is completely coated with shellac but which is coated with rapamycin only on the portion of the surface of the catheter balloon which comes into contact with the heart valve. In addition, there is a possibility in a partial coating of the catheter balloon, ie certain sections of the catheter balloon and successively additional surfaces until a, if desired, completely coated catheter balloon is obtained.

Since the rapamycin shellac coating is difficult to characterize, the present invention also relates to rapamycin shellac coated catheter balloons obtainable by the inventive inventive disclosed coating method and balloon catheters and dilatation catheters comprising said rapamycin shellac coated catheter balloon.

In addition, another active ingredient may be added to the rapamycin-containing solution. Said additional active ingredient may 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, Anopterin, Antimycotica, Antithrombotica, Apocymarin, Argatroban, Aristolactam-All, Aristolochinic Acid, Ascomycin , Asparaginase, aspirin, atorvastatin, auranofin, azathioprine, azithromycin, baccatin, bafilomycin, basiliximab, bendamustine, benzocaine, berberine, betulin, betulinic acid, bilobol, bisparthenolidine, bleomycin, combrestatin, boswellic acid and its derivatives, bruceanol A, B and C, bryophyllin A, busulfan, antithrombin, bivalirudin, cadherins, camptothecin, capecitabine, o-carbamoylphenoxyacetic acid, carboplatin, carmustine, celecoxib, cepharanthine, cerivastatin, CETP inhibitors, chlorambucil, chloroquine phosphate, cicutoxin, ciprofloxacin, cisplatin, cladribine, clarithromycin, colchicine, Concanamycin, coumadin, C-type natriuretic peptide (CNP), cudraisoflavones A, curcumin, cyclo phosphamid, ciclosporin A, cytarabine, dacarbazine, daclizumab, dactinomycin, dapsone, daunorubicin, diclofenac, 1,1,1-dimethoxycanthin-6-one, docetaxel, doxorubicin, daunamycin, epirubicin, epothilone A and B, erythromycin, estramustine, etoposide, everolimus , Filgrastim, fluroblastin, fluvastatin, fludarabine, fludarabine-5'-dihydrogenphosphate, fluorouracil, folimycin, fosfestrol, gemcitabine, ghalacinosides, ginkgol, ginkgolic acid, glycoside 1 a, 4-hydroxyoxycyclophosphamide, 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, beta-lapachone, Podophyllotoxin, podophyllinic acid 2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferon a-2b, lenograstim (r- HuG-CSF), macrogol, selectin (cytokine antagonist), cytokinin inhibitors, COX-2 inhibitor, angiopeptin, muscle cell proliferation-inhibiting monoclonal antibodies, bFGF antagonists, probucol, prostaglandins, 1-hydroxy-1 1 -methoxycanthin-6-one, scopoletin , NO donors, pentaerythrityl tetranitrate and sydnoimines, S-nitrosoderivatives, tamoxifen, staurosporines, β-estradiol, α-estradiol, estriol, estrone, ethinyl estradiol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, camebakaurin and other terpenoids used in cancer therapy, verapamil, Tyrosine kinase inhibitors (tyrphostins), rapamycin and its derivatives, 6-a-hydroxy-rapamycin, taxotere, mofebutazone, lonazolac, ildocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, penicillamine, hydroxychloroquine, sodium aurothiomalate, oxaceprol, beta-sitosterol, myrtcaine, polidocanol, Nonivamide, levomenthol, ellipticine, D-24851 (Calbiochem), colcemid, cytochalasin AE, indanocine, nocodazole, bacitracin,

Vitronectin receptor antagonists, azelastins, guanidyl cyclase stimulators, metalloproteinase-1 and -2 tissue inhibitors, free nucleic acids, nucleic acids incorporated into virus carriers, DNA and RNA fragments, plasminogen activator inhibitor 1, plasminogen activator inhibitor 2, antisense oligonucleotides, VEGF inhibitors, IGF-1 , Drugs from the group of antibiotics, cefadroxil, cefazolin, cefaclor, cefoxitin, tobramycin, gentamicin, penicillin, dicloxacillin, oxacillin, sulfonamides, metronidazole, enoxaparin, heparin, hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators, Dipyramidole, trapidil, nitroprusside, PDGF antagonists, triazolopyrimidine, seramin, ACE inhibitors, captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin, vapiprost, interferon α, ß and γ, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators, halofuginones , Nifedipine, tocopherol, tranilast, molsi domine, teepolyphenols, epicatechingallate, epigallocatechin gallate, leflunomide, etanercept, sulfasalazine, dicloxacillin, tetracycline, triamcinolone, mutamycin, procainimide, retinoic acid, quinidine, disopyrimide, flecainide, propafenone, sotalol, natural and artificially derived steroids such as bryophyllin A, inotodiol, maquiroside A, Ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, nonsteroidal substances (NSAIDS) such as fenoprofen, 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-dehydroagrostistachine, agroskin, agrostistachin, 17-hydroxyagrostistachine, ovatodiolids, 4,7-

Oxycycloanisomelic acid baccharinoids B1, B2, B3 and B7, tubeimoside, bruceantinosides C, yadanziosides N and P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A, BC and D, ursolic acid, hyptatic acid A, iso-iridogermanal, maytenfoliol, effusantin A, excisanin A and B, longikauhn B, sculponeate C, kamebaunin, leukemain A and B, 13,18-dehydro-6 -a-senecioyloxychaparhn, taxamairin A and B, Regenilol, triptolide, cymarin, hydroxyanopterin, protoanemonin, cheliburine chloride, sinococulins A and B, dihydronitidine, nitidine chloride, 12-.beta.-hydroxypregnadiene-3,20-dione, helenaline, indicine, indicine-N oxide, lasiocarpine, inotodiol, podophyllotoxin, Justicidin A and B, Larreatin, Malloterin, Mallotochromanol, Isobutyrylmallotochronnanol, Marchantin A, Maytansin, Lycoridicin, Margetine, Pancratistatin, Liriodenine, Oxoushinsunin, Periplocoside A, Deoxypypsorospermine, Psychorubin, Ricin A, Sanguinarine, Acid from manwu wheat, methylsorbifoline, chromosomes from spathelia, stizophyllin, dihydrousambaraensine, hydroxyusbarine, strychnopentamine, strychnophyllin, usambarin, usambarensin, liriodenins, daphnoretin, lariciresinol, methoxylariciresinol, Sy ringaresinol, sirolimus (rapamycin), somatostatin, tacrolimus, roxithromycin, troleandomycin, simvastatin, rosuvastatin, vinblastine, vincristine, vindesine, teniposide, vinorelbine, trofosfamide, treosulfan, temozolomide, thiotepa, tretinoin, spiramycin, umbelliferone, deacetylvismion A, vismions A and B , Zeorin.

Moreover, the present invention relates to dilatable and expandable catheter balloons and more particularly to multi-pleated balloons for catheters coated according to the method of the invention.

The catheter balloons are preferably coated except with shellac substantially with pure rapamycin. Therefore, the catheter balloons preferably carry a layer consisting of an active ingredient in the form of incorporated in the biopolymer shellac rapamycin, wherein in said layer only traces of solvent are present. Optionally, another active ingredient and / or an additional carrier may be present in the same or a different amount, such as rapamycin or shellac.

Due to the inventive coating method, the rapamycin-shellac composition dried on the surface of the catheter balloon has a particular nature that is difficult to characterize, but seems to be critical for transfer to the cell wall and incorporation, especially in the vascular smooth muscle cells.

In the case of multi-folded balloons, a portion of a coat containing rapamycin shellac is provided under the folds if the balloon is in its compressed, ie deflated condition. The said amount is sufficient to achieve the desired therapeutic effect, even if the remaining uncoated balloon surface is not coated with the drug rapamycin. Therefore, the present invention also relates to balloon catheters comprising a catheter balloon according to the invention coated with rapamycin and shellac and optionally with a further active ingredient and / or optionally with a further carrier substance or matrix substance. Such catheters are preferably used for the treatment of stenotic vessel sections, especially blood vessels, and for the treatment and prophylaxis of stenosis, restenosis, arteriosclerosis and fibrotic vessel narrowing. In addition, the catheter balloons coated according to the invention are suitable for the treatment and / or prophylaxis of in-stent restenoses, ie a recurrent vasoconstriction within a stent already used. In such cases, the placement of an additional stent proves to be very problematic or even impracticable from a medical point of view. Such in-stent restenoses can be treated effectively and without an additional stent by administering paclitaxel with the aid of the catheter balloon coated according to the invention or a catheter whose balloon is coated according to the invention. In addition, the catheter balloons coated according to the invention are particularly suitable for the treatment of small vessels, preferably those vessels having a vessel diameter of less than 2.25 mm.

The catheter balloons coated according to the invention are preferably used in the cardiovascular area, but the catheter balloons coated according to the invention are also suitable for the treatment of vascular constrictions of the bile ducts, esophagus, urinary tract, pancreas, renal, pulmonary, trachea, small intestine and large intestine. The following examples illustrate possible embodiments of the invention without limiting the scope of the invention to the particular examples given. Examples

Example 1a

A commercially available balloon catheter for angiogenesis is provided.

50 g of rapamycin are dissolved in acetone together with 100 g of shellac per ml of acetone.

The solution of rapamycin and shellac is sprayed onto the catheter balloon and then dried. This process is repeated a further three times after drying the coated balloon surface. The drying step is carried out at room temperature and atmospheric pressure.

After the last coating step, the catheter balloon is sterilized with ethylene oxide. Then the coated balloon surface is provided with a protective cover and packed.

Example 1 b

A commercially available balloon catheter for angiogenesis with expandable polyamide balloon is provided.

Rapamycin is dissolved together with shellac in a concentration of 50 g of rapamycin and 100 g of shellac per ml of ethanol in ethanol.

The solution of rapamycin and shellac in ethanol is applied to the catheter balloon with a micropipette.

After the coating step, the catheter balloon is dried under reduced pressure and sterilized with ethylene oxide. Then the coated balloon surface is protected with a protective cover and packaged for shipping or storage.

Example 1c

A commercially available dilatation catheter with expandable polyamide balloon is provided.

Rapamycin is dissolved together with shellac in a concentration of 50 g of rapamycin and 100 g of shellac per ml of ethanol in ethanol. The solution of rapamycin and shellac in ethanol is applied to the catheter balloon by immersing the catheter balloon on the catheter balloon for 10 seconds (dip coating). This process is repeated twice more.

After each coating step, the catheter balloon is dried and additionally sterilized with ethylene oxide after the last step. Then the coated balloon surface is protected with a protective cover and packaged for shipping or storage.

Example 2

A multi-folded balloon such as described in WO 2004/028582 A1, WO 94/23787 A1 or WO 03/059430 A1 is provided. The multi-folded balloon is provided with a total of 5 folds, enclosing a cavity when the balloon is in a compressed state, and outwardly curved when in an expanded state so that the balloon in its expanded state has a substantially tubular shape ,

The multi-folded balloon is expanded and then the surface is roughened by a so-called "chemical polishing process" using a suspension of fine particles, preferably in the micron range, in said process and rubbing said suspension over the surface of the expanded catheter balloon. A solution of 80 g of rapamycin in 1.0 mL of ethyl acetate and a solution of 100 g of shellac in THF is provided The roughened, expanded balloon is dipped several times in said solution of rapamycin in ethyl acetate and at The shellac solution in THF is then filled into a pipette and applied to the dry rapamycin coating on the balloon surface.

The total rapamycin loading on the balloon surface is between 1 g to 5 g rapamycin per mm ² coated balloon surface.

After sterilization, the balloon is provided with a protective cover with the intention of protecting the active agent on the coated, dilatable catheter balloon during transport and storage, the sleeve being removed by the cardiologist prior to insertion of the catheter.

Claims

claims

Catheter balloon characterized by a coating containing rapamycin and shellac.

The catheter balloon of claim 1, wherein the weight ratio of rapamycin to shellac is between 10: 1 and 1:10.

The catheter balloon according to one of claims 1 or 2, wherein the total surface loading of the catheter balloon with rapamycin and shellac is between 1 g / mm ² and 12 g / mm ² and / or wherein the total surface loading of the catheter balloon with rapamycin is between 0.5 g / mm ² and is 6 g / mm ^2.

A method of coating a catheter balloon according to any one of the preceding claims, comprising the following steps:

I) providing an uncoated catheter balloon;

and

IIA) providing a solution of rapamycin and shellac; or

IIB) providing a solution of rapamycin and providing a solution of shellac;

and

or

IV) drying the coated catheter balloon.

A process according to claim 4, wherein the solution of rapamycin and the solution of shellac or the solution of rapamycin and shellac are prepared in acetone, ethyl acetate, ethanol, methanol, DMSO, THF, chloroform, methylene chloride or mixtures of the aforementioned solvents.

A method according to claim 4, wherein the method further comprises step IB):

A method according to claim 4 or 6, wherein the method further comprises step VI):

VI) Protecting the coated catheter balloon with a removable protective cover.

A method according to claims 4-7, wherein at least one vehicle is added to the coating solution containing rapamycin. 9. A method according to claim 8, wherein the at least one carrier substance is selected from the group consisting of:

Parylene C, Parylene D, Parylene N, Parylene F, polyvalerolactones, poly-ε-decalactones, polylactic acid, polyglycolic acid, polylactides, polyglycolides, copolymers of polylactides and polyglycolides, poly-s-caprolactones, polyhydroxybutyrylic acid, polyhydroxybutyrates, polyhydroxyvalerates, polyhydroxybutyrate-co- valerate, poly (1,4-dioxane-2,3-dione), poly (1,3-dioxane-2-one), poly-para-dioxanone, polyanhydride, polymaleic anhydride, polyhydroxymethacrylate, fibrin, polycyanoacrylate, polycaprolactone dimethylacrylate, Poly-β-maleic acid, polycaprolactone-butyl acrylate, multiblock polymers of oligocaprolactone diols and oligodioxanonediols, polyetherester multiblock polymers of PEG and polybutylene terephthalates, polypivolactones, polyglycolic acid trimethylcarbonates, polycaprolactone glycolides, poly (Y-ethylglutamate), poly (DTH-iminocarbonate), poly (DTE) co-DT-carbonate), poly (bisphenol A-iminocarbonate), polyorthoester, polyglycolic acid trimethyl carbonate, polytrimethyl carbonate, polyimino carbonates, poly (N-vinyl) pyrrolidones, polyvinyl alcohols, polyester amides, glycated polyesters, polyphosphoesters, polyphosphazenes, poly [p-carboxyphenoxy) propanes], polyhydroxypentanoic acid, polyanhydrides, polyethylene oxides, propylene oxides, soft polyurethanes, polyurethanes having amino acid residues in the backbone, polyether esters , Polyethylene oxides, polyalkene oxalates, polyorthoesters and also their copolymers, lipids, carrageenans, fibrinogen, starch, collagen, protein-based polymer, polyamino acids, synthetic polyamino acids, zein, polyhydroxyalkanoates, pectinic acid, actinic acid, carboxymethyl sulfates, albumin, hyaluronic acid, chitosan and its derivatives, heparan sulfates and their derivatives, heparins, chondroitin sulfates, dextran, β-cyclodextrins, copolymers with PEG and polypropylene glycol, gum arabic, guar, gelatin, collagen N-hydroxysuccinimide, phospholipids, polyacrylic acid, polyacrylates, polymethyl methacrylates, polybutyl methacrylates, polyacrylamides, polyacrylonitriles, Pol yamides, polyetheramides, polyethyleneamine, polyimides, polycarbonates, Oolycarbourethanes, polyvinyl ketones, polyvinyl halides,

Polyvinylidene halides, polyvinyl ethers, polyisobutylenes, polyvinylaromatics, polyvinyl esters, polyvinylpyrrolidones, polyoxymethylene, polytetramethylene oxide, polyethylene, polypropylene, polytetrafluoroethylene, polyurethanes, polyether urethanes, silicone polyether urethanes, silicone polyurethanes,

Silicone polycarbonate urethanes, polyolefin elastomers, EPDM gums, fluorosilicones, carboxymethyl chitosans, polyaryletheretherketones,

Polyetheretherketones, polyethylene terephthalates, polyvalerates,

Carboxymethyl cellulose, cellulose, viscose, viscose triacetates, cellulose nitrates, cellulose acetates, hydroxyethyl cellulose, cellulose butyrates,

Cellulose acetate butyrates, ethyl vinyl acetate copolymers, polysulfones, epoxy resins, ABS resins, silicones, polysiloxanes, polydimethylsiloxanes, polyvinyl halides and copolymers, cellulose ethers, cellulose triacetates, chitosans and copolymers and / or mixtures of the aforementioned polymers.

A method according to claims 4-9, wherein an additional active agent is added to the solution containing rapamycin and / or shellac and wherein said additional active agent is selected from the group consisting of: abciximab, acemetacin, acetylvismione B, aclarubicin, ademetionine, adriamycin , Aescin, Afromosone, Akagerine, Aldesleukin, Amidoron, Aminoglutethimide, Amsacrine, Anakinra, Anastrozole, Anemonin, Anopterin, Antimycotica, Antithrombotica, Apocymarin, Argatroban, Aristolactam-All, Aristolochinic Acid, Ascomycin, Asparaginase, Aspirin, Atorvastatin, Auranofin, Azathioprine, Azithromycin , Baccatin, bafilomycin, basiliximab, bendamustine, benzocaine, berberine, betulin, betulinic acid, bilobol, bisparthenolidine, bleomycin, combrestatin, boswellic acid and its derivatives, bruceanol A, B and C, bryophyllin A, busulfan, antithrombin, bivalirudin, cadherins, camptothecin, Capecitabine, o-carbamoyl-phenoxyacetic acid, carboplatin, carmustine, celecoxib, cepharanthine , 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, epothilone A and B, erythromycin, estramustine, etoposide, everolimus, filgrastim, fluroblastin, fluvastatin, fludarabine, Fludarabine-5'-dihydrogen phosphate, fluorouracil, folimycin, fosfestrol, gemcitabine, ghalacinosides, ginkgol, ginkgolic acid, glycoside 1 a, 4-hydroxyoxycyclophosphamide, 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, beta -Lapachone, podophyllotoxin, podophyllic acid-2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferon a-2b, lenograstim (r -HuG-CSF), macrogol, selectin (cytokine antagonist), cytokinin inhibitors, COX-2 inhibitor, angiopeptin, muscle cell proliferation inhibiting monoclonal antibodies, bFGF antagonists, probucol, prostaglandins, 1-hydroxy-1 1 -methoxycanthin-6-one, scopoletin, NO donors, pentaerythrityl tetranitrate and sydnoimines, S-nitrosoderivatives, tamoxifen, staurosporines, β-estradiol, α- Estradiol, estriol, estrone, ethinylestradiol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, kamebakaurin and other terpenes used in cancer therapy oide, verapamil, tyrosine kinase inhibitors (tyrphostins), rapamycin and its derivatives, 6-a-hydroxy rapamycin, taxotere, mofebutazone, lonazolac, ildocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, penicillamine, hydroxychloroquine, sodium aurothiomalate, oxaceprol, β-sitosterol, Myrtecaine, Polidocanol, Nonivamide, Levomenthol, Ellipticine, D-24851 (Calbiochem), Colcemid, Cytochalasin AE, Indanocine, Nocodazole, Bacitracin, Vitronectin Receptor Antagonists, Azelastins,

Guanidyl cyclase stimulators, tissue inhibitor of metalloproteinases-1 and -2, free nucleic acids, nucleic acids incorporated in virus carriers, DNA and RNA fragments, plasminogen activator inhibitor 1, plasminogen activator inhibitor 2, antisense oligonucleotides, VEGF inhibitors, IGF-1, drugs of the Antibiotics group, cefadroxil, cefazolin, cefaclor, cefoxitin, tobramycin, gentamicin, penicillin, dicloxacillin, oxacillin, sulfonamides, metronidazole, enoxaparin, heparin, hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators, dipyramidol, 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, halofuginones, nifedipine, tocopherol , Tranilast, Molsidomine, Teepolyphenole, Epicatechingallat,

Epigallocatechin gallate, leflunomide, etanercept, sulfasalazine, tetracycline, triamcinolone, mutamycin, procainimide, retinoic acid, quinidine, disopyrimide, flecainide, propafenone, sotalol, natural and artificially derived 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-dehydroagrostistachine, agro-skin, agrostistachin, 17-Hydroxyagrostistachin, Ovatodiolides, 4,7-

Oxycycloanisomelic acid baccha- ninoids B1, B2, B3 and B7, tube imo- side, bruceantinosides C, yadanziosides N and P, isodeoxyelephantopin, tomenphantopin A and B, coronarine A, BC 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-senecioyloxychaparin, Taxamairin A and B, Regenilol, Triptolide, Cymarin, Hydroxyanopterin, Protoanemonin, Cheliburin chloride, Sinococulins A and B , Dihydronitidine, nitidinium chloride, 12-.beta.-hydroxypregnadiene-3,20-dione, helenaline, indicine, indicine-N-oxide, lasiocarpine, inotodiol, podophyllotoxin, justicidin A and B, larreatine, malloterine, mallotochromanol, isobutyrylmallotochromanol, Marchantin A, maytansine , Lycoridicin, Margetine, Pancratistatin, Liriodenine, Oxoushinsunin, Periplocoside A, Deoxypypsorospermine, Psychorubin, Ricin A, Sanguinarine, Acid from Manwu Wheat, Methylsorbifoline, Chromosomes from Spathelia, Stizophyllin, Dihydrousam baraensin, hydroxyusambarin, strychnopentamine, strychnophyllin, usambarin, usambarensin, liriodenine, daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, sirolimus (rapamycin), somatostatin, tacrolimus, roxithromycin, troleandomycin, simvastatin, rosuvastatin, vinblastine, vincristine, vindesine, teniposide, vinorelbine, trofosfamide , Treosulfan, Temozolomide, Thiotepa, Tretinoin, Spiramycin, Umbelliferone, Desacetylvismion A, Vismions A and B, Zeorin.