Limus deposition formulation on balloon catheters

Abstract

Balloon catheter for angioplasty with a polymer-free coating on the balloon surface having at least one unencapsulated crystalline Limus substance, wherein the unencapsulated crystalline Limus substance is applied directly from a solvent mixture of at least one polar organic solvent and at least one nonpolar organic solvent.

Description

Limus deposition formulation on balloon catheters Within a few weeks or months after the reopening of narrowed or closed arteries and other procedures in the body using various mechanical or thermal techniques, a new narrowing often occurs due to excessive tissue proliferation. This process and its prevention have been studied particularly meticulously in the coronary arteries. Since approximately 2002, drug-eluting stents have been implanted. These stents maintain the coronary artery lumen open after enlargement to its original diameter not only through sufficient radial force but also through the continuous release of proliferative drugs that limit the growth of vascular wall components through the stent struts into the lumen. Two classes of substances were originally used successfully for stent coating: macrolidolactones such as rapamycin (= sirolimus), everolimus, biolimus, and zotarolimus, which bind to mTOR (mammalian target of rapamycin) and thereby inhibit cell division; and the taxane paclitaxel, which stabilizes microtubules and also inhibits cell division. Since then, macrolidolactones, also known as Limus substances, have become the standard for stent coating. Drug-coated balloon catheters have since become available as a complement to coronary stents and as an alternative to treating other arteries. As with stents, the drug serves to prevent the re-narrowing of vessels widened by balloon angioplasty. However, the drug is released from the balloon only during the brief period of balloon expansion (from less than 1 minute to a maximum of 5 minutes in peripheral vessels). Unlike stents, paclitaxel is the dominant active ingredient. Limus substances have been studied multiple times in animal experiments for years, but to date with unsatisfactory, contradictory or difficult to reproduce results (Cremers B, Toner JL, Schwartz LB, von Oepen R, Speck U, Kaufels N, Clever YP, Mahnkopf D, Bohm M, Scheller B. Inhibition of Neointimal Hyperplasia with a Novel Zotarolimus Coated Balloon Catheter.Clin Res Cardiol. 2012; 101: 469-76; document US20100331816; Takimura CK, Galon MZ, Sojitra P, Doshi M, Aiello V, Gutierrez PS, Carvalho J, Ferreira SK, Chaves MJF, Laurindo FRM, Lemos PA. Excipient Dose-Drug Study: Evaluation of Neointimal Hyperplasia by Optical Coherence Tomography and Histopathology in Porcine Coronary Arteries after Use of Sirolimus-Eluting Balloon. Rev Bras Cardiol Invasiva. 2012;20 (2) :133-9; Schmehl J, von der Ruhr J, Dobratz M, Kehlbach R, Braun I, Greiner TO, Claussen CD, Behnisch B. Rapamine Balloon Coating Using a Local Coating Device. Cardiovasc Intervent Radiol 2013; 36:756-763; Granada JF, Milewski K, Zhao H, Stankus JJ, Tellez A, Aboodi MS, BS; Kaluza GL, Krueger CG, Virmani R, MD; Schwartz LB, Nikanorov A. Vascular Response to Zotarolimus-Strained Balloons in Superficial Femoral Arteries Injured by Familial Hypercholesterolemic Swine. Circ Cardiovasc Interv. 2011; 4:447-455).To date, there is no clinical evidence of effectiveness in inhibiting restenosis. The reason for the reduced effectiveness of sirolimus substances on balloon catheters is considered to be the reduced transfer of the pharmaceuticals to the vascular wall and the fact that the levels of active ingredient in the vascular wall are not maintained long enough to produce the desired effect (Gray WA, Granada JF. Drug-coated balloons for the prevention of vascular restenosis. Circulation. June 22, 2010; 121 (24):2672-2680, see pages 2673-2674, figure 1; Tellez A, Buszman P, Afari M, Palmieri T, Cheng Y, Rate W, Stone S, Conditt G, Keng YF, Bingham B, Baumbach W, Sherman D, Kaluza G, Granada J. Acute Delivery and Long Term Retention of Sirolimus Nanoparticles Using a Novel Porous Angioplasty Balloon in the Porcine Coronary Model. JACC 2012; 60 / 17 / Suppl B: B173) . Compared to paclitaxel, similar concentrations of active ingredient have been achieved initially in the arterial wall, but the concentration of active ingredient decreases essentially faster, so that the concentrations are subsequently substantially lower. Limus substances, as well as many other pharmaceutical products, are known in both amorphous (e.g., documents WO2006039237 A1, WO2010129328 A1) and crystalline forms. Both forms have certain advantages and disadvantages depending on the application. For example, US patent 2013 / 053947 A1 shows that crystals of active pharmaceutical ingredients, especially those of limestone, dissolve more slowly than the amoria substance. This has been exploited to delay the release of rapamycin from endoprosthesis surfaces. A complex procedure for coating endoprostheses with suitable rapamycin crystals has been described (Farah S, Khan W, Domb AJ. Crystalline coating of rapamycin onto a stent: Process development and characterization. Int J Pharmaceutics 2013;445:20-28). Studies conducted on stent coatings cannot be easily transferred to the coating of angioplasty balloons. The stent is inserted into the artery and remains there. The coating material can slowly detach, especially in the case of stents with a stable surface composed of multiple crystal layers. In contrast, the balloon only comes into contact with the vascular wall for a very brief time. Therefore, the necessary dose must be delivered to the vascular wall. Whenever the active ingredient is not already dissolved, the dissolution of individual particles or crystals takes place, which are accessible from all sides to the solvent. The use of crystals for coating balloon catheters is controversial due to the risk of embolism and is partly rejected. Amorphous coatings are preferred (document WO 2011 / 147408, p. 4, lines 14-24). The objective of the present invention is to coat balloon catheters with Limus substances in such a way that the coating adheres sufficiently to avoid being lost en route to the narrowed arterial segment, detaches almost completely during balloon expansion, transfers a sufficient percentage to the vascular wall, and remains there long enough to be continuously effective. The means to achieve these objectives are, on the one hand, properties similar to those of clinically effective paclitaxel coatings and, on the other hand, high concentrations of the active ingredient that remain in the tissue significantly longer than those known to date for macrolide-lactones, particularly Limus substances. The objective is achieved with an angioplasty balloon catheter according to claim 1 as well as with coating procedures according to claim 9. Additional preferred embodiments are obtained from the dependent claims. In other words, the objective is achieved with balloon catheters having a coating on the balloon surface that contains at least one unencapsulated crystalline Limus substance. In this regard, the unencapsulated crystalline Limus substance is intended to be applied directly from a solvent mixture of at least one polar organic solvent and at least one nonpolar organic solvent. The term "balloon catheters" means, in its usual sense, balloon catheters for angioplasty, that is, balloon catheters for percutaneous transluminal angioplasty for widening or reopening narrowed or blocked blood vessels (most often arteries, less frequently veins) by balloon inflation. The coatings for balloon catheters must adhere to the balloon as it travels to the narrowed or blocked segment of a blood vessel—that is, while being guided through a hemostatic valve, as well as through a blood-filled sheath or guiding catheter and through proximal sections of the blood vessel—and then rapidly deliver the active ingredient to the vascular wall during balloon inflation. Unlike an implant such as an endoprosthesis or a permanent implantable catheter, the balloon catheter does not remain in the body after the operation."At least one lime substance" means that mixtures of several lime substances are also included. Preferably, a single lime substance is used. Limus substances (synonymous with limus pharmaceuticals) are preferably selected from sirolimus, everolimus, zotarolimus, biolimus, temsirolimus, miolimus, novolimus, ridaphorolimus, as well as tacrolimus and pimecrolimus. The sirolimus, everolimus, zotarolimus, biolimus, and temsirolimus group is most preferred. The especially preferred group consists of sirolimus and everolimus. Everolimus is most preferably used as the limus substance. Alternatively, sirolimus is most preferred. The aforementioned objectives are achieved according to the invention in a remarkably effective, complete, reproducible, and economical manner: the Limus pharmaceutical products are crystallized in a known way using suitable solvents. To achieve sufficient dosage on the flask surfaces, solvent mixtures of at least one polar organic solvent and at least one nonpolar organic solvent are used. The nonpolar and polar organic solvents preferably have a difference in their logKow of at least 1 (Kow: octanol / water partition coefficient). By polar organic solvent, we mean in particular an organic solvent with a logKow between -1.0 and +2.0, preferably between -0.5 and +1.8. By nonpolar solvent, we mean in particular organic solvents with a logKow of 3, preferably between 3 and 6.5.Polar organic solvents are also referred to simply as polar solvents, and the same applies to nonpolar organic solvents. In at least one of the solvents, preferably the polar organic solvent, the Limus substance must have a solubility of > 10 mg / ml, preferably > 30 mg / ml. Examples include volatile organic solvents such as alcohols, acetone, ethyl acetate, and chloroform. Alcohols are specifically defined as mono- or polyvalent alkanols, most preferably monovalent C1-C3 alkanols, and most preferably methanol and / or ethanol. Additional polar organic solvents include tetrahydrofuran, acetonitrile, and diethyl ether. In the other solvent or one of the other solvents, preferably in the nonpolar organic solvent, the lime substance should be only slightly soluble, for example, with < 1 mg / ml (from 0.001 to 0.999 mg / ml).Examples of organic solvents with low solubility for lime substances were mentioned in US patent 20110009618 A1; these are in particular highly nonpolar solvents such as aliphatic C6-C10 hydrocarbons, for example, cyclohexane, hexane, heptane, octane, etc. The solvents or solvent mixtures may contain water, as explained in further detail below. The preferred solutions for crystallization or direct coating contain 20-80% by volume of a polar solvent and 80-20% by volume of a nonpolar solvent; mixtures of 30-70% by volume of one of said polar solvents and 65-35% by volume of one of said nonpolar solvents are especially preferred. The term "nonpolar or polar organic solvent" also includes mixtures of several solvents from one and / or both categories; however, preferably one solvent per category is used in each case. A preferred pair of polar and nonpolar organic solvents is, for example, ethyl acetate / heptane. The lime substance can first be dissolved in a polar organic solvent, for example, ethanol or other alcohols, acetone, ethyl acetate, tetrahydrofuran, acetonitrile, diethyl ether, etc. (step a). The solution can then be mixed with the nonpolar solvent, so that either a supersaturated solution is generated or the true solubility is maintained (step b). In the case of a supersaturated solution, crystallization of the lime substance can be induced by suitable measures, for example, by rubbing glass on glass or by introducing crystallization germs (step d), or the supersaturated or true solution, without the presence of crystals, is applied to the flask and crystallizes therein (step c). If crystallization is already taking place in the solution, the suspension can be applied to the surface of the flask and further crystallize and / or dry therein (step d1). There are different possibilities depending on the invention for reproducibly coating surfaces of a balloon catheter balloon with Limus crystals: a) The lime crystals are suspended in a solvent or a mixture of solvents in which the crystals do not dissolve. For this purpose, the nonpolar organic solvents mentioned above are preferably used as solvents / suspending agents. This suspension is then applied to the balloon in the therapeutic dose. (b) The Limus crystals are applied as described in (a), but at a very low, subtherapeutic dose, for example, between 0.001 and 0.5 g of Limus substance / mm² of balloon surface, preferably between 0.001 and 0.1 g of Limus substance / mm², to deposit seed crystals onto the balloon. Immediately afterward, or after the seed crystals have dried, the balloon is coated with a mostly or completely saturated or supersaturated Limus solution until a therapeutically effective dose is reached. In other words, an additional dose of at least one Limus substance is applied in the form of a solution that is at least saturated, corresponding to a dose of between 1 and 10 g of Limus substance / mm² of balloon surface (in the final dry state).Saturated or supersaturated solutions can be produced in a wide variety of solvents. Mixtures of a polar solvent (ethyl acetate, acetone, isopropanol) and a nonpolar solvent (e.g., cyclohexane, hexane, heptane, octane) are preferred, sometimes with the addition of water. Crystallization, crystal size, and aggregation can be controlled through drying conditions, particularly temperature and air movement. According to the invention, these are free, unencapsulated microcrystals, also partially unencapsulated (unlike Micell Technologies, documents US2012015442, WO2013059509). The (free) microcrystals may be found in a matrix on the surface of the balloon, promoting either the matrix's adhesion to the balloon surface or the release of the active ingredient crystals during balloon expansion, but not the release of the active ingredient from the capsule after passing into the tissue. The therapeutically effective dosage range, i.e., those that inhibit neointimal proliferation or are otherwise effective, is preferably between 1 and 10 jg of Limus substance / mm2 of balloon surface. More than 30% by weight of the lime substance must be in the form of crystals on the surface of the flask, preferably more than 50% by weight and especially more than 70% by weight. The individual crystals, called microcrystals, are preferably rhombic in shape and of variable size, with a substantial proportion of the crystals (relative to mass), i.e., >30% by weight, ranging from 1 to 300 µm in maximum length, preferably >50% by weight, and more preferably >80% by weight. Aggregates are formed from individual crystals upon drying, and these aggregates may be larger. The melting point of the crystals is in the range of 171 to 188°C. The residence time of the Limus substances delivered from the balloons to the tissue is significantly longer than that of known preparations. The mean half-life (elimination half-life) in pig coronary arteries is > 1 week, preferably > 2 weeks. In other words, the balloon catheter with a coating on the balloon surface containing at least one Limus substance in crystalline form is characterized by the fact that the crystals, after delivery via a balloon catheter to pig coronary arteries, have an elimination half-life of > 1 week, preferably > 2 weeks, within a period of 4 weeks after treatment. The coating may contain exclusively the lime substance, or in the case of solvate crystals. Various excipients and / or additives may be added to the coating; polymer-free coatings are preferred. Suitable excipients / additives include, among others, antioxidants, preferably ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, nordihydroguaiaretic acid, robucol, propyl gallate, and resveratrol, with butylated hydroxytoluene and / or resveratrol being particularly preferable, and resveratrol being the most preferable. In addition, other high and low molecular weight substances used for coating drug-releasing balloon catheters are suitable, such as those mentioned, for example, in documents USP 8,439,686, US2010324648, US 2008 / 0118544, USP 20130123695 or usual pharmaceutical excipients.In other words, in a preferred embodiment, the coating consists solely of the Limus substance, optionally also in solvate crystals, and additionally, optionally, of excipients and / or additives, such as antioxidants. It need not contain polymers, for example, carrier polymers; that is, the coating is preferably polymer-free. In another embodiment, coatings containing only the Limus substance in crystalline form, optionally as solvate crystals, are preferred. In other words, in this other preferred embodiment, the coating on the surface of the flask consists of at least one Limus substance in crystalline form, optionally as solvate crystals; that is, after drying / removal of all solvents, no additional substances are present.In this other preferred embodiment and this other additional preferred embodiment there is also no polymer in particular, for example, carrier polymer. These coatings can also be sufficiently stable at room temperature without the addition of antioxidants for more than one year; that is, the active ingredient content decreases by less than 5% by weight during this time. Furthermore, different excipients can positively influence the adhesion of the active ingredient to the balloon material, its release during balloon expansion, its penetration into the vascular wall, and its efficacy and compatibility.Preferred excipients are antioxidants, preferably in percentages of > 5% by weight of the lime substance, hydrophilic substances such as X-ray contrast agents, sugars and sugar alcohols, glycerin, urea preferably in weight percentages of 5-100% by weight of the lime substance, in addition amphiphilic substances in very low percentages, preferably < 1% by weight of the lime substance, and lipophilic substances such as fatty acid salts, preferably in the range of 0.5 to 50% by weight of the lime substance. Pharmaceutically effective substances can be used as additives. Excipients or additives, excluding polymers as previously mentioned, may be used individually or in mixtures. When used in mixtures, the quantity data applies to the sum of the excipients or additives. Excipients / additives may be added to the coating solution or, preferably, applied to the surface of the balloon in advance, or more preferably, applied afterward, i.e., after drying is complete, so as not to alter the crystalline structure of the lime substances. If the excipients / additives are applied afterward, solvents and conditions that prevent detachment of the lime crystals should be chosen, for example, solvents in which the lime substance is sparingly soluble, highly volatile solvents, spray coating, and low temperatures. Preferably, at least one additional layer of an additive or excipient is applied in a final stage.Preferably, it is applied in such a way that the lime crystals cannot transform into an amorphous form. Alternatively, it can be said that in a further final step (e) at least one additional layer of an additive / excipient is applied without using an agent that releases the lime substance. In each of the production variants according to the invention, work is preferably done without polymers and consequently a polymer-free coating is generated. For the coating of the balls, all the usual methods are possible: dipping, spraying, printing, spreading, microdosing procedures, etc., although microdosing procedures are preferred. All dimensionally stable and extensible materials that can be used are taken into account as a ball membrane, in particular polyamides / nylon, PEBAX, polyethylene, polyurethane, silicone, latex, Chronoprene; ball membranes can be further reinforced by structures contained within the membranes (threads, strips, wires) or surrounded on the outside by such structures, as is the case, for example, in "marking" or "cutting" balls. The balloons may also contain pre-assembled balloon-expandable or self-expanding endoprostheses, which are preferably uncoated. The coating of the balloons preferably takes place before the endoprostheses are assembled, but it can also be done additionally or individually afterward. The invention is further explained below by means of, but not limited to, examples. Examples Example 1 100 mg of everolimus were dissolved in 1 ml of ethyl acetate. Then 2 ml of heptane were added. The resulting crystal suspension was treated with ultrasound and was then available for coating balloon catheters. The coating of the balloons can be carried out in detail as described above or as illustrated in the following examples. Example 2 45 mg of sirolimus and 6 mg of butylhydroxytoluene were dissolved in 0.5 ml of ethyl acetate; then 0.5 ml of heptane was added; sirolimus crystallization was induced; a mixture of sirolimus crystal suspension in saturated sirolimus solution was generated; the suspension was treated with ultrasound for 30 min; then the suspension was applied to expanded balloons of percutaneous transluminal coronary angioplasty catheters (Sequent®, B. Braun) using a microsyringe. After coating, the balloons were folded and sterilized by electrophoresis. Analysis: 6.8 |jg of sirolimus / mm2 of balloon surface, X-ray diffraction and differential thermoanalysis demonstrate the crystalline structure of the active ingredient. Example 3 The coronary arteries of young domestic pigs (approximately 25 kg body weight) were treated with balloon catheters as described in Example 2. Two animals (6 treated vessels) were sacrificed approximately 10 minutes after treatment, and an additional 11 animals (11 treated vessels) were sacrificed after 4 weeks. In all animals, the treated vessel segments were removed. The sirolimus content of the arteries was determined and compared with the sirolimus content of arteries from the same animals that had been treated with balloons of the same construction, coating composition, and dose (45 mg sirolimus + 6 mg butylated hydroxytoluene, 7 g sirolimus / mm²), in which, however, the sirolimus was in amorphous form. The results are shown in Table 1.The crystalline preparation surprisingly shows a very long residence time in the tissue: while the amount of active ingredient in the tissue in the case of the amorphous preparation and identical test conditions within 4 weeks decreased by a factor of 80, the amount of active ingredient in the case of the crystalline coated balloons decreased by a factor of < 3. Table 2 shows that the formulation according to the invention, compared to the prior art, leads to extraordinarily increased levels of the active ingredient in the vascular walls. Such continuously high levels in the tissue are considered crucial for efficacy in restenosis prophylaxis. Table 1 Transfer and residence of sirolimus in the vascular wall after insufflation of coated angioplasty balloons for 1 min into the coronary arteries of pigs. Table 2 Comparison with published data: sirolimus concentration in pig coronary arteries (ng / mg of tissue = mg / g of tissue) after treatment with sirolimus-coated balloon catheter Example 4 Coronary arteries in the animals of Example 3 were treated simultaneously with uncoated catheters of the same type, with treatment of the arteries randomized with respect to catheter order and artery type. Immediately after treatment, the luminal diameter of the slightly overextended coronary vessel segments was measured, and the measurement was repeated after 4 weeks. The decrease in luminal diameter during the 4 weeks is termed late lumen loss (LLL) and characterizes the unwanted narrowing of the vessels due to neointimal proliferation. The results are shown in Table 3. Table 3 Influence of sirolimus coating of balloon catheters on narrowing of porcine coronary arteries after extension / injury of the vascular wall. Dose = sirolimus per mm2 of balloon surface; RFD = reference artery diameter (without treatment); MLD post. = minimum luminal diameter after overextension; MLD FU = minimum luminal diameter after 4 weeks; *) p<0.02 vs. uncoated control. Vessels treated with crystalline sirolimus show, 4 weeks after treatment, the largest luminal diameter, the least luminal loss, and the least diameter stenosis. Example 5 Fifty milligrams of sirolimus were dissolved in 0.5 mL of ethyl acetate, followed by the addition of 0.5 mL of heptane. After 24 h at room temperature, crystals had formed. The sample was treated with ultrasound for 30 min, then the suspension was centrifuged, the pellet was washed once with 1 mL of heptane, and dried. Five and a half milligrams of crystals were suspended in 1 mL of heptane. Round-bottom flasks (2.5–20 mm) were coated with 10 µl of the crystallization suspension and then immediately coated with 43 µl of a solution of 15 mg of sirolimus in 1 mL of ethyl acetate-heptane (1:1, v / v). After a short drying time, the flasks were homogeneously coated with white. The sirolimus was found mainly in crystalline form. The coated balloon catheters were fitted with endoprostheses and studied in the coronary arteries of young pigs, as described in Examples 3 and 4, for the inhibition of vascular narrowing due to neointimal proliferation. Catheters with uncoated balloons, as well as the coating described in Example 2 at different dosages, were used for comparison. Table 4 Influence of sirolimus coating of balloon catheters on narrowing of porcine coronary arteries after extension / injury of the vascular wall; comparison of different dosages and coating methods Dose = sirolimus per mm2 of balloon surface; RFD = reference artery diameter (without treatment); MLD post. = minimum luminal diameter after overextension; MLD FU = minimum luminal diameter after 4 weeks; *) p<0.02 vs. uncoated control. Vessels treated with crystalline sirolimus show, 4 weeks after treatment, a larger luminal diameter, less luminal loss, and less diameter stenosis than vessels treated with uncoated balloon. Crystalline sirolimus applied to balloon catheters reproducibly inhibits coronary artery narrowing in pigs following vascular wall injury. This effect is also achieved with a significantly lower dose than that used in Example 4. Example 6 PTCA catheter balloons (2.5–20 mm) were coated, as in Example 5, with a reduced dose of sirolimus seed crystals, then with the sirolimus solution in ethyl heptane acetate, and after drying with 15 ml of a 15 mg probucol / ml diethyl ether solution. The sirolimus crystalline structure was preserved.

Claims

1. Angioplasty balloon catheter with a polymer-free coating on the balloon surface comprising at least one unencapsulated crystalline Limus substance, wherein the unencapsulated crystalline Limus substance is applied directly from a solvent mixture of at least one polar organic solvent and at least one nonpolar organic solvent.

2. Angioplasty balloon catheter with a polymer-free coating on the balloon surface comprising at least one unencapsulated crystalline Limus substance according to claim 1, characterized in that the nonpolar organic solvent has a logKow^3 and the polar organic solvent has a logKow between -1.0 and +2.

0. 3.A balloon catheter for angioplasty with a polymer-free coating on the balloon surface comprising at least one non-encapsulated crystalline substance of Limus according to claim 2, characterized in that the nonpolar organic solvent is selected from cyclohexane, hexane, heptane, octane, and the polar organic solvent is selected from methanol, ethanol, acetone, ethyl acetate, chloroform.

4. A balloon catheter for angioplasty with a polymer-free coating on the balloon surface comprising at least one non-encapsulated crystalline substance of Limus according to claim 3, characterized in that the nonpolar organic solvent is heptane and the polar organic solvent is ethyl acetate.

5. A balloon catheter for angioplasty according to one or more of claims 1 to 4, characterized in that the coating comprises additional excipients and / or additives, excluding polymers. 6.Balloon catheter for angioplasty according to one or more of claims 1 to 4, characterized in that an additional layer is applied comprising additional excipients and / or additives, excluding polymers.

7. Balloon catheter for angioplasty according to claim 5, characterized in that the excipients are antioxidants in percentages of > 5% by weight of the Limus substance.

8. Balloon catheter for angioplasty according to claim 5, characterized in that the excipients are fatty acid salts in the range of 0.5 to 50% by weight of the Limus substance. 9.A method for the polymer-free coating of balloon surfaces, in particular angioplasty balloon catheters, with crystalline Limus substances comprising the following steps: a) dissolving at least one Limus substance in a polar organic solvent, b) mixing the solution from a) with a nonpolar organic solvent, so that either a supersaturated solution is generated, or the true solubility is maintained, then either c) applying the supersaturated solution or the true solution to the balloon surface and crystallizing, or d) in the case of a supersaturated solution, inducing the crystallization of said at least one Limus substance, so that a suspension containing crystals is obtained, and d1) applying the suspension to the balloon surface and further crystallizing and / or drying. 10.Method for polymer-free coating of balloon surfaces, in particular of angioplasty balloon catheters with crystalline lime substances according to claim 9, characterized in that in an additional final step e) at least one additional layer of an additive / excipient is applied, excluding polymers as additives / excipients.