Pharmaceutical products for delivery of drugs with enhanced efficacy

Abstract

The present invention relates to medical devices, such as stents or balloon catheters, that are in at least regular contact with diseased blood vessels, as well as to a method for coating them with a defined solution. According to the present invention, the restenosis inhibitor is 4 μg / mm 2 on the exterior surface at an active agent concentration greater than

Description

[Technical Field]

[0001] The present invention relates to the selection of a product for more effectively inhibiting restenosis of arteries or other conduits in the body after mechanical opening or dilation of each lumen. [Background technology]

[0002] Over the past 20 years, the problem of restenosis of arteries damaged by procedures such as angioplasty, atherectomy, or stent implantation has been greatly reduced using locally applied drugs. Notable examples include drug-eluting stents (DES) and paclitaxel-coated balloon angioplasty catheters (drug-coated balloons, DCBs) for use in coronary arteries.

[0003] DES (Dysplasia Streptococci) contain very small doses of drugs that are delivered slowly over a long period of time and inhibit cell proliferation that occurs after damage to the arterial wall due to forced dilation of arteries narrowed, for example, arteriosclerotically constricted arteries. Excessive cell proliferation leads to thickening of the arterial wall and narrowing of the arterial lumen, thus reducing blood flow. A drawback of currently available DES is that they are permanent implants, permanently altering the structure and flexibility of the treated arterial segment, making subsequent interventions more difficult. Permanent implants are associated with a clinical event of 0.4% to 2.0% per year during the life expectancy after implantation, according to current knowledge. Preferred drugs for stents belong to the class of immunosuppressive macrolides, also known as limus substances, with rapamycin (sirolimus) being a known example. Limus substance-coated stents are currently used in most cases of coronary artery stenosis. As an alternative, and in difficult cases, bypass surgery and DCBs are also available, especially in cases of stenosis in vessels already stented. In selected cases where stenting should be avoided, DCBs may also be used as an alternative to stents for the initial treatment of coronary artery stenosis or occlusion. For peripheral arteries, balloon catheters are preferred; stents should only be used if satisfactory outcomes cannot be obtained with balloons.

[0004] DCBs also include active substances that inhibit cell proliferation, most preferably paclitaxel, which are known from tumor treatment. The advantage of DCBs is that they deliver drugs to the blood vessel wall, but the catheter itself remains in the blood vessel for only a few seconds to a few minutes, and is then removed as a whole at the end of the short treatment period. Only a portion of the drug that was originally on the angioplasty balloon remains in the blood vessel wall. The blood vessel retains its original structure and flexibility, its function can be restored, and future interventions do not become more difficult. The disadvantage of DCBs over stent implantation is, among other things, the lack of stabilization of the cross-section of the blood vessel. While elastic restenosis of the blood vessel lumen is not uncommon after the expansion of the blood vessel lumen by balloon and the release and removal of pressure inside the balloon, stents largely prevent the blood vessel wall from undergoing elastic contraction.

[0005] Coated balloon catheters and stents with growth inhibitors significantly reduce the frequency of restenosis of the lumen of treated vascular segments; however, the clinical outcomes obtained to date, particularly in peripheral arteries, have not been entirely satisfactory. Some treatments do not achieve the desired outcome, i.e., within 6–12 months, despite treatment with drug-coated products, the vascular lumen constricts again to the extent that further treatment is required. The frequency of this therapy failure is 5–10% on average. This means that the treated vascular segments often do not remain permanently open, but rather, two or three years or more after initial treatment success, new constrictions or occlusions lead to further symptoms, thereby requiring repeated interventions in the best-case scenario, and in the more unfortunate case, they can no longer be removed.

[0006] Currently, macrocyclic immunosuppressants (also known as limus substances, e.g., sirolimus such as rapamycin, everolimus, etc.) are primarily used on coronary stents; paclitaxel is used on balloons. It is clear that there is a need to study more effective active substances. For this purpose, experiments with stents have been conducted in the past (Muni NI et al. 2005; Liistro and Bolognese, 2003). Similarly, cell proliferation inhibitors that may be far more effective than paclitaxel have been tested on balloons of balloon catheters, but without success (Speck U et al., J Cardiovasc Surg 2016;57:3-11).

[0007] Multiple balloon catheters coated with proliferation inhibitors underwent clinical trials, and on average, vascular lumen stenosis was reduced in all treated patients. However, none of the coatings were effective in all patients or in all treated vascular portions (Anantha-Narayanan M et al. Catheter Cardiovasc Interv. 2019 Jul 1;94(1):139-148). This claim was made at a point 6–12 months post-treatment. The desired effect of the coating diminished after this point.

[0008] To date, none of the DCBs described have met the necessary requirements for efficacy in as many patients as possible and over the long term. A more effective drug for coated balloon catheters has yet to be discovered.

[0009] In this regard, improvements in the effectiveness of current minimally invasive local therapies for vasoconstriction or occlusion are important and are the objectives of this invention. The improvements aim to reduce the proportion of patients who require new treatment prematurely after mechanical dilation or restoration of the vascular lumen, or who lose the initial success of treatment several years later.

[0010] Therefore, an object of the present invention is to obtain more reliable, enhanced, and / or longer-lasting opening of constricted blood vessels in a single treatment, particularly by using the preferred active substance paclitaxel. The concentration or amount of the active substance (paclitaxel) in the blood vessel wall immediately after treatment is observed and measured as an essential condition for achieving this object and as an experimentally readily measurable factor. [Overview of the project]

[0011] This objective is achieved by a medical device having the features of an independent claim and by coating thereof with a coating solution. In this regard, in a first embodiment, the present invention relates to a medical device that comes into at least periodic contact with an affected blood vessel, comprising a long, hollow body having an external surface, wherein an active substance or mixture of active substances containing a restenosis inhibitor that is specific to delivery onto the blood vessel wall is disposed on the external surface. According to the present invention, the active substance or mixture of active substances is 4 μg / mm³ in at least a plurality of regions. 2 Ultra-high, especially 5 μg / mm³ 2 Ultra-high, especially 6 μg / mm³ 2 It exists on the surface with the above loading (or surface density). [Modes for carrying out the invention]

[0012] In the following text, the term “external surface” should be understood to mean the surface of a hollow body that faces outward from the inner diameter or internal lumen of the hollow body, or that faces the inner wall of a blood vessel during its intended use. Because the size of the area containing the drug or coating varies, the loading on the pharmaceutical product is μg / mm². 2 The total amount of drug on a pharmaceutical product is given as "dosage / pharmaceutical product" (= "loading density"). Dosages in experimental or clinical use may be increased by using two or more of these products.

[0013] The subject matter of the present invention relates to a selection invention. Drug-coated balloon catheters for the inhibition of restenosis after endovascular dilation using mechanical methods were first studied approximately 20 years ago and have been clinically proven since approximately 2003. There is no doubt about the desired inhibition of restenosis in the treated arterial segments of the coronary arteries and some peripheral blood vessels, but it must be recognized that the effect is not observed in all patients and all treated arteries, nor does it last for a long time. Despite testing various active substances, coating compositions, and coating methods, nothing has changed in this regard.

[0014] Obvious ways to improve efficacy or the duration of efficacy, such as increasing the dosage, have not been pursued, partly due to concerns about compatibility and partly due to difficulties in adhesion and the thickness of the layer on the surface of the suitable pharmaceutical product.

[0015] Possible variables have been known for a long time, but suitable selections necessary to achieve the objective have not yet been made available.

[0016] Therefore, currently actually known products consistently have lower dosages than those currently claimed in the present invention due to the above-mentioned reasons, namely concerns about compatibility and coating ability (sufficient adhesion, layer thickness, and thus suitability for use). Furthermore, there are no examples in the patent literature or in clinical use in the literature of dosages exceeding 3.5 μg / mm of the active substance. In contrast, considering animal experiments, manufacturers have introduced dosages lower than the originally selected and tested dosage of 3 μg / mm. 2 For example, there is no example in the patent literature or in clinical use in the literature of dosages exceeding 3.5 μg / mm of the active substance. In contrast, considering animal experiments, manufacturers have introduced dosages lower than the originally selected and tested dosage of 3 μg / mm. 2 than the originally selected and tested dosage of 3 μg / mm.

[0017] Many publications have issued warnings about paclitaxel and actually teach the opposite of the teachings of the present invention regarding increased coatings and higher dosages with the preferred active substance paclitaxel, which has been found to be possible and useful.

[0018] Surprisingly, it has been shown that the action of DCB can approach the goal of a reliable and permanent effect by a suitable selection of balloon material and coating. In this regard, compared to the standard, an active substance density exceeding 4 μg / mm 2 , especially exceeding 5 μg / mm 2 , results in a significantly higher migration rate when the contact time with the vessel wall is the same, and thus it is easy to evaluate that it results in a higher concentration of the active substance in the vessel wall.

[0019] To achieve this goal, the use of a higher dosage must result in a larger amount of drug at the target site, and an increase in the amount of the active substance introduced into the target tissue results in a higher effect. In particular, for an increase in dosage, it is necessary that the drug tolerance is good.

[0020] Of course, a long balloon with a large diameter for the treatment of a long segment of a larger blood vessel requires more active substance than a small segment of a blood vessel with a small lumen, so the normal dosage on the balloon is based on the balloon surface area. The originally introduced dosage of paclitaxel at 3 μg / 1 mm of balloon surface 2 was the maximum loading possible for a smooth balloon membrane that was manufacturable at that time. Products available to date have quite low dosages, often only 2 μg / 1 mm of balloon surface of the active substance paclitaxel 2 and contain only that. The product with the highest dosage administered was 3.5 μg of paclitaxel / mm 2 . Publications indicate concerns regarding the compatibility of the active substance paclitaxel on the balloon compared to sirolimus, which is used less frequently (Wessely et al. 2006), or point out the risk of embolism due to paclitaxel, which is washed away distally and has low solubility in water (Gongora et al., 2017). Recently, a study was published suggesting an increase in mortality after the use of pharmaceutical products coated with paclitaxel and also suggesting a warning to keep the dosage of paclitaxel low.

[0021] A high dose means a dose sufficient to reduce the percentage of treated vessels that rapidly narrow again and to extend the period during which the treated vascular segments remain open, relative to the total number of treated vessels. In the case of paclitaxel and sirolimus, this dose corresponds to 1 mm of the surface of the pharmaceutical product. 2 5 μg or more per unit, preferably 6 μg / mm³ 2 The above is particularly preferably 10 μg / mm³ 2 That's all.

[0022] It is advised in all cases that a significant increase in the loading of conventional balloon catheters due to paclitaxel would impair their fit, and that a significant increase in the loading of conventional balloon catheters due to any active substance would make these catheters difficult to use in patients due to numerous technical, drug, and physiological problems.

[0023] Increasing the dose on the balloon surface assumes that the increased amount of drug adheres well enough and is not lost during the necessary balloon fold-down.

[0024] Furthermore, while a higher dose on the balloon should deliver a higher amount / concentration of the active substance into the arterial wall, this is not clear because the increased amount of active substance may not adhere very well to the balloon surface and may be lost during transport to the treatment site, and because the take-up capacity of the vascular wall during the short period of balloon inflation may be limited with respect to that drug.

[0025] Nevertheless, the aforementioned objectives are achieved by novel combinations of balloon coating components and methods, which are themselves publicly known.

[0026] The active substances or drugs that may be considered are highly lipophilic, substantially water-insoluble, highly potent drugs that bind to any tissue component. A drug is described as lipophilic if its partition coefficient in an aqueous buffer at butanol:pH7 is 0.5, preferably 1, particularly preferably 5, or if its partition coefficient in an aqueous buffer at octanol:pH7 is 1, preferably 10, particularly preferably greater than 50. Alternatively, or additionally, the drug must bind to cellular components reversibly and / or irreversibly in amounts greater than 10%, preferably greater than 50%, particularly preferably greater than 80%. Preferred substances are those that inhibit cell proliferation or further inhibit inflammatory processes, or antioxidants, such as paclitaxel and other taxanes, rapamycin and related substances, tacrolimus and related substances, corticoids, sex hormones (estrogen, estradiol, antiandrogens) and related substances, statins, epothilone, probucol, prostacyclin, and angiogenesis-inducing factors. The substance is preferably in the form of a dry solid or as an oil on the surface of various pharmaceutical products. The smallest possible particle size is preferred (mostly less than 5 μm, preferably less than 1 μm, and particularly preferably less than 0.1 μm). A crystalline structure is particularly preferred.

[0027] The dosage is determined to achieve the desired effect and efficacy of the drug being used. It is as high as 6 μg / mm³. 2 It can go up to this point, but this does not constitute an upper limit. The coating according to the present invention uses a wire, such as one used to guide a catheter; a needle and catheter or a portion of a catheter are assumed to be pressed against the affected tissue at least for a short period of time using pressure. The length and diameter of the area of ​​the catheter or balloon intended for drug therapy are not very important for application, because the dosage is μg of active substance / 1 mm of surface 2This is because it is calculated as follows. For example, coronary artery dilation balloons typically have a diameter in the range of 2-4 mm and a length of 1.0-4.0 cm. For other blood vessels, balloons with diameters up to over 20 mm and lengths up to over 20 cm may be used. The surface to be coated can be smooth (i.e., without specific structures to receive the active substance), rough, or have any kind of structure; a special surface structure is not essential for the adhesion of the active substance, but it does not inhibit adhesion. The adhesion of the active substance to the balloon surface is brought about solely by the selection of a suitable solvent and, where appropriate, additives that affect adhesion. Surprisingly, it adheres firmly even to very and completely smooth balloon surfaces.

[0028] All surfaces may be further coated with a substance that improves the glide properties of the product, without releasing the materials used in the coating into the environment, and without the coating substantially limiting the delivery of active substances for the treatment of target tissue, thereby preventing blood clotting on the surface or improving other properties of the pharmaceutical product and thus improving its effectiveness.

[0029] Therefore, in one embodiment of the present invention, the medical device preferably further has auxiliary substances on its external surface.

[0030] Improved tissue uptake and good adhesion to the surface of catheters, needles, or wires are achieved by incorporating highly lipophilic, low-water-solubility active substances into a readily water-soluble matrix material. Suitable matrix materials are low-molecular-weight (molecular weight less than 5000D, preferably less than 2000D) hydrophilic substances such as contrast agents used in vivo and dyes for various diagnostic methods in medicine, sugars and sugar alcohols, biocompatible organic and inorganic salts such as low-molecular-weight polyethylene glycol and benzoates, and salts and other derivatives of salicylic acid. Iodine-based radiographic contrast agents and paramagnetic chelates are examples of contrast agents; examples of dyes are indocyanine green, fluorescein, and methylene blue. Auxiliary substances may also be used for quality control, to improve the shelf life of the product, to provide supplemental pharmacological effects, or to enhance quality control.

[0031] Therefore, the surface of the apparatus according to the present invention may conveniently contain or consist of organically bound iodine, preferably iopamidol, iomeprole, iopromide, and / or iohexol, as well as auxiliary substances including urea, magnesium salts, particularly magnesium stearate, dexpanthenol, lipophilic antioxidants, particularly nordihydroguaiaretic acid, resveratrol, and / or propyl gallate, or combinations thereof.

[0032] In a particularly preferred embodiment of the present invention, organically bonded iodine is present in at least one region at a concentration of 0.1 μg / mm³. 2 From 0.8 μg / mm³ 2 Preferably 0.1 μg / mm 2 From 0.5 μg / mm³ 2 It is located on the external surface at a loading density in the range of 4-6 μg of active material per mm² of surface area. 2 For active substances in the range of approximately 0.2 μg / mm³ 2 From 1.6 μg / mm³ 2 Alternatively, this corresponds to the loading density of iodine-containing organic materials with an iodine content of approximately 2% to 20%.

[0033] It has been shown that a reduced loading density of auxiliary substances compared to standard amounts leads to improved transport of active substances over the blood vessel wall.

[0034] In further embodiments, the pharmaceutically active substance may be adsorbed onto particles or coated onto the surface of a suitable pharmaceutical product together with a low molecular weight matrix. Again, suitable particles are known biocompatibility diagnostic compounds, such as ferrites and various contrast agents for ultrasound.

[0035] Balloon catheters are formed by expanding segments from a very thin plastic tube to lengths ranging from 1 to over 20 cm. The expanded, very thin-walled balloon membrane is then arranged in multiple folds aligned longitudinally with respect to the catheter axis and tightly wound around the catheter axis in its folded state, such that the area to be subsequently unfolded has a diameter only minimally larger than that of a normal catheter. The tight folds of the balloon sheath are essential for the balloon catheter to pass through the loading connector, guide catheter, and, for example, significantly narrowed areas of the blood vessel without problems.

[0036] In a preferred embodiment of the present invention, the outer surface is an inelastic compression-resistant membrane in at least a plurality of portions, and the membrane is preferably the balloon of the balloon catheter described above.

[0037] Preferred catheter materials include polyamides, polyamide blends and copolymers, polyethylene terephthalate, polyethylene and copolymers.

[0038] In a particularly preferred embodiment, the membrane, i.e., the catheter material, comprises or consists of polyamide, polyether block amide (PEBAX, vestamid), polyethylene, polyethylene terephthalate, or copolymers and / or blends thereof.

[0039] In a preferred embodiment, the balloon can be inflated to more than 15 bar, and particularly to more than 30 bar. This can be achieved, in particular, with the materials described above.

[0040] In a further embodiment, the present invention relates to the use of a solution for coating medical devices for the treatment of diseased blood vessels, and in particular for the manufacture of devices according to the present invention. The solution used in this regard comprises a solvent, a restenosis-inhibiting active substance, and an auxiliary substance comprising organically bound iodine that forms a matrix for the active substance. According to the present invention, the auxiliary substance contains organically bound iodine in an amount ranging from 1.2% to 12.5% ​​by weight, preferably 2.5% to 12.5% ​​by weight, relative to the active substance in the solution. If the loading density of the active substance is 4, this is conveniently 0.1 μg / mm³. 2 From 0.75 μg / mm³ 2 Preferably 0.1 μg / mm 2 This results in an iodine loading density on the external surface ranging from 0.5 to 0.5.

[0041] Medical devices coated with the solution according to the present invention, particularly balloon catheters, have been shown to deliver more active substances to the blood vessel wall over the same period of time than known coated devices of the prior art.

[0042] Conveniently, organically bound iodine exists in solution as iopromide, iopamidol, and / or iomeprole.

[0043] In a preferred embodiment of the present invention, the solution contains an active substance, particularly paclitaxel or sirolimus, at a concentration ranging from 100 mg to 200 mg in 5 mL of solution.

[0044] Examples of suitable solvents include methanol, ethanol, isopropanol, ethyl acetate, diethyl ether, acetone, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, water, or mixtures thereof. The choice of solvent is made as a function of the solubility of the active substance and additives, as well as the wetting of the surface to be coated, the effect on the surface of the coating left after evaporation of the solvent and particles, its adhesion to the surface, and the transfer of the active substance into the structure over a very short contact time.

[0045] Particularly convenient, the solution contains acetone, water, and / or ethanol as solvents, and the solvent mixture contains 3% to 25% by volume, especially 5% to 15% by volume of water.

[0046] The starting point for the experiment is preferably the formulation according to International Publication No. 2004 / 028582, Example 7, preferably Solution B. Unlike the cited example, the ratio of Ultravist 370 was reduced from 100 μL / 5 mL of coating solution to 5–50 μL / 5 mL of solution mixture; the reduced volume of Ultravist resulted in 3.8–38.45 mg of iopromide / 150 mg of paclitaxel or 1.85–18.5 mg of organically bound iodine / 150 mg of paclitaxel, particularly preferably 5–20 μL of Ultravist 370 / 5 mL of solution mixture. 100 μL of Ultravist 370 contains 76.9 mg of radiographic contrast agent iopromide, which corresponds to 37 mg of organically bound iodine.

[0047] In the solvents of paclitaxel and Ultravist, the proportion of water increased from less than 1.3 vol% to 3-25 vol%, particularly preferably 5-15 vol%, compared to Example 7 of International Publication No. 2004 / 028582 having Solution B. Instead of the radiographic contrast agent Ultravist 370, an aqueous solution of the contrast agent iopromide contained in Ultravist may be used. Similarly, other equivalent contrast agents may be used, such as Isovue® 370 with iopamidol as the contrast agent, or Iomeron 400 with iomeprole as the contrast agent, or other equivalent products at available concentrations.

[0048] The coating may be carried out, for example, by immersion, coating, application using volumetric measuring devices, or spraying, at different temperatures, and, where appropriate, by vapor saturation of the solvent in the atmosphere. The procedure may be repeated multiple times, with different solvents and auxiliary substances, where appropriate.

[0049] In a particularly preferred embodiment, the balloon is coated, in particular together with the cannula, in an inflated state with a defined volume of active substance solution. After drying and folding, the balloon may be treated with a dry lubricant, such as magnesium stearate powder, or immersed for a very short time in an aqueous suspension of magnesium stearate or a suspension or solution of another biocompatible lubricant that is biodegradable in human metabolism and excretable by humans, or sprayed with this type of suspension or solution, or wetted in some other way. After this step, the balloon is dried again, given a protective sleeve, and sterilized using EO. The final product is a sterile, properly packaged, high-dose paclitaxel-coated balloon catheter suitable and approved for human use.

[0050] The drug or multiple drug support is a conventional balloon catheter of a size suitable for treating all types of arteries, e.g., arteries in the heart, skull, limbs, or other parts of the body. It comprises a proximal handle, a catheter shaft having a wire lumen and a liquid lumen, a proximal handle having a syringe connector and a guidewire insertion port, and a distal balloon having a smooth or structured surface made from a thin, inelastic or virtually elastic compression-resistant membrane manufactured from polyamide, e.g., polyether block amide (e.g., PEBAX or vestamid), polyamide blends and copolymers, polyethylene, polyethylene terephthalate. “Compression-resistant” means the balloon can be inflated to over 4–30 bar without rupturing. The balloon may contain elements made from other materials, e.g., metal or plastic, that provide further compressive strength to the balloon membrane, alter the shape of the inflated balloon, and exert an effect on the tissue it contacts during inflation, for example, that it may damage, cut, or affect the tissue by thermal or electrical pulses.

[0051] For coating, the active substance, and, where appropriate, auxiliary substances and additives as well, are dissolved or suspended in an organic solvent with or without the addition of water. Preferred solvent mixtures include acetone, ethanol, and water. Preferred additives are radiographic contrast agents such as iopamidol, iopromide, or iohexol, but also other conventional auxiliary substances for coating balloon catheters, such as urea, magnesium salts in a ratio of 20% by weight or less of the active substance, which positively influence their adhesion to the surface of the pharmaceutical product and their release at the target site, and / or facilitate the movement of the active substance into the tissue. Additives of active or auxiliary substances that alleviate the inflammatory response of tissue and / or accelerate healing are particularly preferred; examples are dexpanthenol and corticoids.

[0052] The efficacy of a drug on a pharmaceutical product can be enhanced without increasing the dosage by improving its delivery to the tissue being treated. This is particularly important for pharmaceutical products that remain at the target site for only a short period of time. An example of this is a balloon catheter that inflates in a blood vessel, but the inflation completely blocks blood flow, and therefore, in the coronary arteries, for example, or in arteries supplying the central nervous system, they deflate and are removed after a very short period of time. According to the initial report by Scheller et al., 2004, the delivery of drug from the balloon of a balloon catheter to the coronary artery wall was, on average, 8.7 ± 4.9% of the total dose on the balloon, either without or as long as a stent was not implanted. In a more recent study (Speck et al., 2018), the delivery was given to be 7.8 ± 3.4% of the dose in the coronary arteries and 7.1 ± 6.1% of the dose in the arteries of a pig's leg.

[0053] Increasing the proportion of active material delivered to the treated tissue is an objective in the development of novel DCBs. For this purpose, the composition and coating method of the coating have been varied in many ways with various films, but no significant improvement in efficacy has been evident (Anantha-Narayanan M et al. Catheter Cardiovasc Interv. 2019 Jul 1;94(1):139-148; Meredith IT, TCT2019). Clinically, balloon catheter handling has improved in that the treated vascular segment is carefully prepared in advance and the balloon inflation period is extended where possible.

[0054] Quite surprisingly, drug-tissue transport was found to be improved by selecting a suitable balloon membrane in combination with a chosen coating formulation and coating mode, resulting in reproducible and high drug transport into the arterial wall. For example, this applies to combinations of polyether block amide membranes, particularly those marketed under trade names PEBX or vestamid, with formulations containing lipophilic antioxidants such as NDGA (nordihydroguaiaretic acid) and propyl gallate. On the other hand, in the case of transport of active substances into the arterial wall, other formulations (with or without auxiliary substances) did not show any difference between PEBAX and, for example, nylon membranes (Example 3, Table 3).

[0055] The membranes of balloon catheters have different levels of stability when the pressure inside the balloon is increased. There are elastic membranes made from elastic materials such as latex or polyurethane that inflate at low pressure and conform to the shape or diameter of the blood vessel or body cavity. A further group consists of balloons conventionally used in angioplasty, for example, used to dilate narrowed arteries, with generally dimensionally stable membranes made from nylon or PEBAX (non-compliant or semi-compliant) that can withstand pressures of approximately 15, up to 20 bar. Finally, in very solid vascular stenosis, for example in highly calcified vessels or in arteriovenous shunts for dialysis in patients with insufficient renal function, balloon catheters with balloons that can withstand significantly higher pressures are used. In cases of stenosis where dilation requires high pressure, these can be dilated with a high-pressure balloon (suitable for pressures up to approximately 20-40 bar) in a "vessel preparation" situation, and then subsequent treatment with a DCB can prevent excessive scarring irritated by the wound to the blood vessel. Using DCB reduces restenosis of the lumen. Furthermore, the treatment's longevity is often poor (Steiner K, Endovascular Today June 2016; Karnabatidis TCT 2013).

[0056] Previous studies have shown that inflation pressure during drug movement into the vascular wall (Bienek et al., Catheter Cardiovasc Interv. 2020 Feb;95:319-328) and its effect (Cremers et al., Clin Res Cardiol. 2012;101:385-91) does not have a significant impact. Animal studies showed that low inflation pressure (2 bar) for DCBs inhibited luminal stenosis similarly to that achieved with higher inflation pressure (12 bar). With a different balloon, even at very low pressures (less than 2 bar), 13.9 ± 6.4% of the administered dose moved from the balloon into the vascular wall.

[0057] Experiments using covered high-pressure balloons yielded the opposite results. A significant increase in drug movement into the treated arterial wall was observed compared to conventional DCBs inflated to approximately 10 bar. Since there was no substantial difference in drug effect between very low and high inflation pressures, and between balloons inflated to approximately 2 bar and those inflated to approximately 12 bar, the observed increase in drug movement into the vascular wall after using balloons inflated to very high pressures was surprising. Increased drug movement into tissues would mean that significant inhibition of restenosis can be expected even in vascular stenosis that is difficult to treat and cannot be widened without great force, such as in calcified arteries.

[0058] In its preferred application, balloon catheters function to dilate narrowed or occluded arteries. To prevent restenosis caused by excessive cell proliferation immediately after dilation of the arterial lumen, balloon catheters have been coated with drugs. The properties and therapeutic outcomes of the first such drug-coated balloon catheters were published in 2004 (experimental, Scheller et al.) and 2007 (clinical, Scheller et al.). At that time, only 8.7 ± 4.9% of the administered dose traveled from the balloon into the arterial tissue with the coating (Scheller et al., 2004). This intra-arterial wall delivery is decisive in terms of efficacy and can be significantly higher, even compared to B. Braun's current commercially available products. [Examples]

[0059] [Example 1] Increased paclitaxel (Ptx) migration from coated EO sterile balloons into treated arterial tissue due to coating modifications (Column 6): reduced auxiliary substances (Column 4), increased water content of coating solution (Column 3), and coating the balloon in an expanded state (Column 2). The total balloon contains approximately 3 μg of paclitaxel per 1 mm of balloon surface. 2 It has the following characteristics. Method: Experiments in the coronary arteries of pigs; for details of the method, see Scheller et al. 2004, Speck et al. 2018.

[0060] [Table 1]

[0061] With balloon catheters coated according to Example 7B of German Patent Application Publication No. 10244847, an average of 8.7% of the active substance paclitaxel was transported into the arterial wall, and the selected new coating resulted in a significantly higher rate of administration within the vascular wall (19.1–29.9%). However, the version without the adjuvant (Group A) was not considered here, because the previous balloon coating with paclitaxel but without the adjuvant had been found to be less effective in patients considering the desired inhibition of restenosis.

[0062] [Example 2] Increased dose on the balloon Acotec balloon catheters with balloon dimensions of 4×40 to 7×40 mm were coated with paclitaxel using a composition containing 10 vol% water and 10 wt% iopromide relative to the active substance in solution, and inflated for 1 minute in the internal iliac artery or femoral artery of farmed pigs (see Scheller et al. 2004, Speck et al. 2018 for the method).

[0063] Column (1): Since balloons have or may have different lengths and (for uses other than those specified herein) different diameters for the treatment of different arteries and parts of arteries, μg / balloon surface area per 1 mm 2 Paclitaxel (Ptx) in the following locations. Columns 2-4: Paclitaxel in the treated arterial wall 10-40 minutes after balloon deflation (segments of the internal iliac or femoral artery of domesticated pigs, approximately 3 months old, approximately 25 kg body weight); Column 5: Ratio of the original paclitaxel dose observed on the balloon after removal from the animal (see Column 1). Line 4, Column 1: Number of balloon catheters measured; Columns 2-4: Number of arteries investigated; Column 5: Number of balloons used. Line 5, Columns 2-5: 3 μg / mm³ in each artery. 2 The balloon, coated with paclitaxel on its surface, was inflated for one minute, then deflated and removed. Line 6, Columns 2-5: In each artery, two balloons coated with the same type of paclitaxel as in Line 5 were inflated sequentially within the same arterial segment to move more of the drug into the arterial wall. Line 7: Similar to Line 5, only one coated balloon was inflated within each arterial segment, but this was coated with twice the amount of paclitaxel.

[0064] [Table 2]

[0065] Results and conclusions: 3 μg / 1 mm of balloon surface 2 The expected value of this type of coating for drug transfer into tissues and the small amount remaining on the balloon at the end were measured at the given dosage. The use of two identical catheters inflated within the exact same segment of the blood vessel resulted in nearly twice the amount of drug entering the artery. Doubling the balloon dosage had at least the same effect; at least twice the amount of drug moved into the arterial wall. This should be understood as an indication of increased efficacy.

[0066] [Example 3] The effect of balloon membrane and coating composition on the migration of paclitaxel and sirolimus onto the arterial wall of pigs. The balloon of the balloon catheter was covered in an expanded state with a paclitaxel-containing (Ptx) or sirolimus-containing formulation as described above, folded, and sterilized with ethylene oxide; the decrease in the active substance was measured by the residence time in the blood (line 5) for 1 minute while passing through a hemostatic valve and a guide catheter (1 m in length) filled with blood, and lines 6-8 show the results of experiments in the coronary arteries of pigs; see Example (1) for the method. PTCA = percutaneous coronary intervention, Pebax = polyether block amide, NDGA = nordihydroguaiaretic acid, BHT = butylhydroxytoluene.

[0067] [Table 3]

[0068] Results and conclusions: The balloons were made of nylon or Pebax and were indistinguishable in transparency and smoothness. The balloon membrane had a substantially homogeneous coating of approximately 2 to 5 μg / mm³. 2 The results were obtained within the specified range. On average across all experiments, approximately 10% of the dose was lost due to residence time in the blood as it passed through the hemostatic valve and blood-filled guide catheter. The migration of paclitaxel from formulations containing the antioxidant NDGA and propyl gallate was significantly higher with balloons containing the pebax membrane, approximately 30% of the dose, both in direct comparison with balloons made from nylon membranes (6.0±3.4%) and in comparison with data from the literature (Scheller et al., 2004: 7.9±2.6%, Speck et al. 2018: 7.8±3.4%). This resulted in high paclitaxel concentrations in the tissue (line 8). The significantly improved migration of the active substance paclitaxel (combined with antioxidants and the pebax balloon) into the observed arterial tissue is remarkable and represents the enhanced efficacy of this balloon catheter. The ratio of residual dose on the balloon (line 9) did not differ significantly between pebax and nylon balloons, but it was much smaller when propyl gallate was used as the antioxidant.

[0069] [Example 4] Coating composition and optimization according to Example 7 of International Publication No. 2004 / 028582: 5 mL of coating solution contains 81.1% by volume acetone, 8.8% by volume ethanol, 0.4% by volume Ultravist 370, 9.7% by volume water, and 150 mg of paclitaxel.

Claims

1. A medical device for more effectively preventing restenosis of an artery or other blood vessel in the body by mechanical opening or dilatation of each lumen, said medical device comprising an elongated hollow body having an outer surface, said outer surface having disposed thereon an active substance for delivery onto a blood vessel wall, said active substance being paclitaxel, and said active substance being paclitaxel, and having disposed on said outer surface in at least a plurality of regions thereof a concentration of 6 μg / mm ２ a loading density of 0.1 μg / mm 2 to 0.5 μg / mm 2 in at least a plurality of regions on the outer surface of the medical device, the medical device being a balloon catheter, and further comprising an excipient selected from the group consisting of organically bound iodine disposed on the outer surface of the medical device;

2. 10. The medical device of claim 1, wherein at least portions of the exterior surface comprise a non-stretchable, pressure-resistant membrane.

3. 3. The medical device of claim 2, wherein the membrane comprises or consists of polyamide, polyether block amide, polyethylene, polyethylene terephthalate, or copolymers and / or blends thereof.

4. 4. The medical device according to claim 2 or claim 3, characterized in that the balloon can be inflated to more than 15 bar.

5. Use of a solution for coating a medical device as described in any one of claims 1 to 4, characterized in that the solution comprises a solvent, paclitaxel as a restenosis-inhibiting active substance at a concentration ranging from 100 mg to 200 mg per 5 mL of the solution, and an excipient containing organically bound iodine for forming a matrix for the active substance, wherein the excipient containing organically bound iodine is present at a concentration ranging from 1.2% to 12.5% ​​by weight relative to the active substance in the solution, and the organically bound iodine is present as iopromide, iopamidol, and / or iomeprol.

6. 6. Use of the solution according to claim 5, characterized in that the solution comprises acetone, water and / or ethanol as the solvent, the solvent comprising 3% to 25% by volume of water.

7. A method for coating a medical device according to any one of claims 1 to 4, comprising: a. preparing a solution according to claim 5 or 6; b. applying the solution to at least a plurality of areas of the exterior surface of the medical device by dipping, spraying, or wetting with a volumetric measuring device; c. drying the medical device; A method that includes, in order.

8. 8. The method of claim 7, wherein the medical device has an inflatable balloon, and in step (b), the outer surface of the balloon is coated in at least a plurality of regions in an inflated state.

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