EP4093452A1 - Medicinal product for enhanced-effect drug release - Google Patents

Abstract

The invention relates to a medicinal device for at least temporarily contacting diseased vessels, such as for example a stent or a balloon catheter, and to a method for coating such a device with a defined solution. According to the solution, a restenosis inhibitor with an active ingredient concentration of more than 4µg/mm² is present on an outer surface.

Description

MEDICAL DEVICE FOR DRUG DELIVERY WITH ENHANCED EFFECT

The invention relates to a selection of products for the more effective prevention of re-narrowing of arteries or other passages in the body after mechanical opening or widening of the respective lumens.

In the past 20 years the problem of re-narrowing of arteries injured by angioplasty, atherectomy or stent implantation, for example, has been significantly reduced by means of locally applied drugs. Outstanding examples are the drug-eluting stents (DES) intended for use in coronary arteries and the paclitaxel-coated balloons of angioplasty catheters (drug-coated balloons, DCBs).

The DES contain a very small dose of drug that is slowly released over a long period of time and inhibits the cell proliferation caused by, for example, violent expansion of arteriosclerotically narrowed arteries after the vessel wall has been damaged. Excessive cell proliferation leads to a thickening of the arterial wall and a narrowing of the arterial lumen and thus to a reduction in blood flow. The DES available today has the disadvantage that they are permanent implants that change the structure and mobility of the treated artery segment forever and make future interventions more difficult. Clinical events are associated with the permanent implant at a frequency of 0.4 to 2.0% annually after implantation, and lifelong according to the current state of knowledge. Preferred drugs on stents belong to the class of immunosuppressive macrolides, also known as limus substances, with the well-known representative rapamycin (sirolimus). Stents coated with Limus substances are currently used in most cases for constriction of coronary arteries. Alternatively and in difficult cases, bypass operations and, in particular, DCBs are available for constrictions in vessels that have already been supplied with stents. If stents are to be avoided, DCBs can also be used in selected cases instead of stents for the initial treatment of constrictions or occlusions of coronary arteries. Balloon catheters are preferred in peripheral arteries, stents only if the balloon does not produce a sufficient result.

The DCBs also contain an active ingredient that inhibits the proliferation of cells, most preferably paclitaxel known from tumor therapy. The advantage of DCBs is that they release the drug to the vessel wall, but the catheters themselves only remain in the vessel for seconds to a few minutes and are completely removed again at the end of the brief treatment. Only part of the drug originally located on the angioplasty balloon remains in the vessel wall. The vessel retains its original Structure and mobility, function can recover and future interventions are not hindered. The main disadvantage of the DCB compared to stent implantation is the lack of stabilization of the vessel cross-section. After the vascular lumen has been expanded with a balloon and the pressure in the balloon released and removed, it is not uncommon for the vascular lumen to narrow again elastically, while the stent largely prevents the vascular wall from elastic recovery.

While the coating of balloon catheters and the coating of stents with proliferation-inhibiting drugs clearly reduces the frequency of re-narrowing of the lumina of the treated vascular segments, the results clinically achieved so far are not entirely satisfactory, especially in peripheral arteries. Some of the treatments do not have the desired effect, i.e. the vascular lumens, despite treatment with the drug-coated products, narrow again within 6 - 12 months to such an extent that a new treatment is necessary. The frequency of these therapy failures is high with an average of 5 - 10%. In addition, the treated vascular segments often do not remain permanently open; 2, 3 or more years after an initially successful treatment of a constriction or an occlusion, symptoms arise again, which in the best case make it necessary to repeat the procedure, in the worst case not more are to be eliminated.

At present, macrocyclic immunosuppressants (also known as Limus substances, e.g. sirolimus such as rapamycin, everolimus etc.) are mainly used on stents for coronary arteries and paclitaxel on balloons. The obvious thing to do is to look for more effective active ingredients. To this end, experiments with stents have been carried out in the past (Muni NI et al. 2005; Liistro and Bolognese, 2003). Very different cytostatic substances, some of them much more effective than paclitaxel, were also tested without success on balloons of balloon catheters (Speck U et al., J Cardiovasc Surg 2016; 57: 3-11).

Several balloon catheters coated with proliferation-inhibiting drugs have been clinically tested and have mostly reduced a narrowing of the vascular lumen on average over all treated patients, but none of the coatings worked in all patients and all treated vascular sections (Anantha-Narayanan M et al. Catheter Cardiovasc Interv. 2019 Jul 1; 94 (1): 139-148). The statement refers to a point in time 6-12 months after the treatment. This desired effect of the coating diminishes after this point in time. None of the DCBs described so far meets the requirement for an effect in as many patients as possible and over many years. More effective drugs for coating balloon catheters have not yet been found.

To this extent, an improvement in the effect of the current approaches for the minimally invasive local therapy of vascular constrictions or occlusions is important and the aim of the present invention. The aim of the improvement is to reduce the proportion of patients who, after mechanical expansion or restoration of the vascular lumen, require renewed treatment at an early stage, or for whom the initial success of the treatment is lost after a few years.

The object of the invention is to achieve a more reliable, stronger and / or longer-lasting openness of the constricted vessel, in particular using the preferred active ingredient paclitaxel, with a single treatment. The active ingredient (paclitaxel) concentration or the active ingredient (paclitaxel) amount in the vascular wall immediately after treatment is viewed and measured as a prerequisite and experimentally measurable variable for achieving this goal.

This object is achieved by a medical device and its coating with a coating solution having the features of the independent claims. Thus, a first aspect of the invention relates to a medical device for at least temporarily contacting diseased vessels, having an elongated hollow body with an outer surface, with an active substance or active substance mixture intended for delivery to the vessel wall having a restenosis inhibitor being arranged on the outer surface. According to the invention, it is provided that the active ingredient or the active ingredient mixture at least regionally in a loading or. Surface density) of more than 4 pg / mm ^2, in particular of more than 5 pg / mm ^2, in particular of> 6 pg / mm ^2, is present on the surface.

In the following text, under 'outer surface' is one of the inner diameter or

To understand the inner lumen of the hollow body facing away from or, when used as intended, a surface of the hollow body facing an inner wall of the vessel.

The loading of the medical products is given in pg / mm ² surface area (=

'Loading density'), the total amount of drug on a medical device as a 'dose / medical device'. The dose for experimental or clinical use may increase with the use of more than one of these products. The subject matter of the invention is a selection invention.

Balloon catheters coated with medicaments for the inhibition of vasoconstriction after lumen enlargement with mechanical methods were tested for the first time about 20 years ago and have been clinically tested since about 2003. While the desired inhibition of a re-narrowing of the treated arterial sections of the arteries of the heart and some peripheral vessels has been proven beyond doubt, one must accept that an effect does not occur in all patients and all treated arteries or does not last for a long time. Despite the testing of various active ingredients, compositions of the coatings and the coating methods, nothing has changed.

Obvious measures to improve the effectiveness or duration of effectiveness, such as an increase in the dose, were not taken, partly out of concern about compatibility, partly because of the difficulty with the adhesion and the layer thickness on the surfaces of suitable medical products.

The possible variables have been known for a long time; a suitable selection necessary to achieve the goal is not yet available.

For the reasons mentioned above, compatibility concerns and coatability (adequate adhesion, layer thickness and thus suitability for use), the products actually known to date consistently contain a lower dose than claimed according to the invention. There are also no examples of dosages above 3.5 pg active ingredient / mm ² in the patent literature or clinical use in the literature. On the contrary, under the influence of animal experiments, manufacturers have introduced lower dosages than those originally selected and tested ^{with 3pg / mm 2.}

Numerous publications warn against paclitaxel and to this extent teach the opposite of the inventive teaching with regard to the higher coating and dose with the preferred active ingredient paclitaxel found to be possible and useful.

Surprisingly, it has been shown that the effect of DCBs comes close to the goal of a more reliable and lasting effect through a suitable selection of the balloon material and the coating. In this context, it is easy to measure that increased compared with the standard drug density of more than 4PG / mm ^2, in particular more than 5pg / mm ² with the same duration of contact with a vessel wall leads to a significantly increased transmission rate and thus a higher concentration of active substance in the vessel wall.

In order to achieve the goal, the use of a higher dose must lead to an increased amount of drug at the site of action, and the increase in the active ingredient input into the target tissue must lead to more effect. An increase in the dose requires, among other things, that the drug is well tolerated.

The usual dosages on balloons are based on the balloon surface, since long balloons with a large diameter for the treatment of long segments of large vessels naturally require more active ingredient than short segments of small-lumen vessels. The originally introduced dose of 3 pg paclitaxel / mm ^{2 of} the balloon surface was the maximum feasible loading of the smooth balloon membranes at that time. The products available on the market up to now contain rather lower doses, for the active ingredient paclitaxel in many cases only 2 pg / mm ² balloon surface, the highest dosed product 3.5 pg paclitaxel / mm ² . Publications point to concerns about the tolerability of the active ingredient paclitaxel compared to the sirolimus, which has so far been rarely used on balloons (Wessely et al. 2006) or to the risk of embolism due to distally washed-off paclitaxel that is poorly soluble in water (Gongora et al. 2017). A paper was recently published that suggests an increased mortality rate after the use of paclitaxel-coated medical devices, also an indication that the dose of paclitaxel should be kept low.

A high dose means a dose which is sufficient to reduce the proportion of vessels that rapidly narrow again after treatment in relation to the total number of treated vessels and to lengthen the duration for which the treated vessel segments remain open. In the case of paclitaxel and sirolimus, this dose is> 5 pg / mm ² surface area of the medical product, preferably> 6 pg / mm ² and particularly preferably> 10 pg / mm ² .

A substantial increase in the loading of conventional balloon catheters with paclitaxel is opposed to the universally expressed reservations about tolerability; a substantial increase in the loading of conventional balloon catheters with any active ingredients is difficult because of a large number of technical, pharmaceutical and physiological problems if these catheters are to be used for the benefit of the patient . An increase in the dose on a balloon surface requires that the increased amount of medicinal substance adheres sufficiently well and is not lost when the balloon is folded.

Furthermore, the higher dose on the balloon must lead to a higher amount / concentration of the active ingredient in the arterial wall, which is not a matter of course because an increased amount of active ingredient adheres poorly to the balloon surface, can be lost on the way to the treatment site and the absorption capacity of the Vessel wall for the drug can be limited during the short period of balloon insufflation.

Nevertheless, the goals defined above were achieved with the novel combination of known components and methods of balloon coating.

As active ingredients or drugs, highly lipophilic, largely water-insoluble, highly effective drugs that bind to any tissue constituents are possible. Pharmaceuticals are referred to as lipophilic whose partition coefficient is butanol: aqueous buffer pH 7 = 0.5, preferably = 1 and particularly preferably = 5, or octanol: aqueous buffer pH 7 = 1, preferably = 10, particularly preferably> 50. Alternatively or additionally, the medicinal substances should bind> 10%, preferably> 50%, particularly preferably> 80% reversibly and / or irreversibly to cell components. Preference is given to substances for inhibiting cell proliferation or inflammatory processes or antioxidants, such as paclitaxel and other taxanes, rapamycin and related substances, tacrolimus and related substances, corticoids, sex hormones (estrogens, estradiol, antiandrogens) and related substances, statins, epothilones, probucol, Prostacyclines, angiogenesis inducers, etc. The substances are preferably present as a dry solid substance or as an oil on the surfaces of the various medical products. Particles of the smallest size are preferred (the majority <5 pm, preferably <1 pm, particularly preferably <0.1 pm), and crystalline structures are particularly preferred.

The dosage depends on the desired effect and the effectiveness of the medicinal substance used. It can reach up to 6pg / mm ² , although this is not an upper limit.

According to the invention, wires such as those used to guide catheters, needles and catheters or parts of catheters which are pressed against diseased tissue with pressure at least for a short time are provided for coating. The length and the diameter of the areas of the catheters or balloons intended for pharmacotherapy are not of decisive importance for the application, since the dosage is ^{calculated in pg active ingredient / mm 2} surface. For example, balloons in the range of <2-4 are used for coronary dilatations mm in diameter and from 1.0 to 4.0 cm in length. Balloons up to> 20 mm in diameter and lengths up to> 20 cm can also be used for other vessels. The surfaces to be coated can be smooth (ie without a special structure for taking up the active ingredients), roughened or provided with structures in any way, with special surface structures not being a prerequisite for the adhesion of the active ingredients, but also not hindering the adhesion. The adhesion of the active ingredients to the balloon surfaces is brought about exclusively by the choice of suitable solvents and, if necessary, additives that influence adhesion. It is surprisingly firm even on balloon surfaces that are completely smooth on the outside.

All surfaces can also have been or will be coated with substances that improve the sliding properties of the products, prevent the coagulation of blood on the surface or improve other properties of the medical products, without the materials used for the coating having to be released into the environment and without the coating significantly restricts the release of the active ingredients for treating the target tissue and thus the effectiveness.

In an embodiment of the invention, it is therefore preferred that the medical device also has auxiliary materials on the outer surface.

Good adhesion to the surfaces of the catheter, needles or wires with improved absorption into the tissue is achieved by embedding highly lipophilic, poorly water-soluble active ingredients in a readily water-soluble matrix substance. The matrix substances are low molecular weight (molecular weight <5000 D, preferably <2000 D) hydrophilic substances such as contrast media and dyes used in vivo for various diagnostic methods in medicine, sugars and related substances such as sugar alcohols, low molecular weight polyethylene glycols, biocompatible organic and inorganic salts such. B. benzoates, salts and other derivatives of salicylic acid, etc. are suitable. As contrast media, reference is made to the iodized X-ray contrast media and the paramagnetic chelates, examples of dyes are indocyanine green, fluorescein and methylene blue. Auxiliaries can also serve to improve the shelf life of the products, cause special supplementary pharmacological effects or serve for quality control.

Thus, the surface of the device according to the invention advantageously has auxiliaries that contain organically bound iodine, preferably lopamidol, lomeprol, lopromide and / or lohexol, as well as urea, magnesium salts, in particular stearate, dexpanthenol, lipophilic Antioxidants, in particular nordihydroguajaretic acid, resveratrol and / or propyl gallate or combinations of these comprise or consist of these.

In a particularly preferred embodiment of the invention it is provided that an organically bound iodine in a loading density in the range from 0.1 pg / mm ² to 0.8 pg / mm ^2, preferably 0.1 pg / mm ² to 0.5 pg / mm ^{2 is arranged} on the outer surface. This corresponds to a loading density of iodine-containing organic substance of approx. 0.2 pg / mm ² to 1.6 pg / mm ² or approx. 2 to 20% iodine based on the active ingredient in the range 4-6pg active ingredient / mm ² surface.

It was found that the reduced loading density of the excipient compared to the standard leads to an improved transfer of the active substance to the vessel wall.

In a further embodiment, the active pharmaceutical ingredients can be adsorbed on particles or applied with a low molecular weight matrix to the surfaces of suitable medical products. Diagnostics known as biocompatible, such as ferrites and various contrast media for sonography, are again suitable as particles.

Balloon catheters are formed from very thin plastic tubes by expanding a segment from 1 to> 20 cm in length. The expanded, very thin-walled balloon membrane is then placed in several folds arranged longitudinally to the catheter axis and wrapped tightly around the catheter axis so that the later expanded area in the folded state only has a slightly larger diameter than the rest of the catheter. The tight folding of the balloon envelope is a prerequisite for the problem-free passage of the balloon catheter through introductory sheaths, guide catheters and, for example, severely narrowed sections of blood vessels.

In a preferred embodiment of the invention it is provided that the outer surface, at least in sections, is a non-stretchable, pressure-resistant membrane, the membrane preferably being the balloon of a balloon catheter described above.

Preferred catheter materials are polyamides, polyamide mixtures and copolymers, polyethylene terephthalate, polyethylene and copolymers.

In a particularly preferred embodiment, it is provided that the membrane, i.e. the catheter material, polyamide, polyether block amides (PEBAX, Vestamid), polyethylene, Comprises polyethylene terephthalate or their copolymers and / or mixtures or consists of such.

A preferred embodiment provides that the balloon can be inflated to more than 15 bar, in particular more than 30 bar. This can be achieved in particular by means of the aforementioned materials.

Another aspect of the invention is the use of a solution for coating a medical device for treating diseased vessels, in particular for producing the device according to the invention. The solution used here comprises a solvent, a restenosis-inhibiting active ingredient and an adjuvant containing organically bound iodine which forms a matrix for the active ingredient. According to the invention it is provided that the adjuvant with organically bound iodine contain in the range from 1.2 to 12.5% by weight, preferably 2.5% by weight to 12.5% by weight, based on the active ingredient in the solution is. With a loading density of the active ingredient of 4, this advantageously leads to a loading density of the iodine in the range from 0.1 pg / mm ² to 0.75 pg / mm ² , preferably from 0.1 pg / mm ² to 0.5 on the outer surface .

It was found that a medical device coated with the solution according to the invention, in particular a balloon catheter, releases more active substance to the vessel wall at the same time than the coated devices known in the prior art.

The organically bound iodine is advantageously present in the solution as lopromide, lopamidol and / or lomeprol.

In a preferred embodiment of the invention, it is provided that the solution contains the active ingredient, in particular paclitaxel or sirolimus, in a concentration in the range from 100 mg to 200 mg per 5 ml of solution.

Suitable solvents are, for example, methanol, ethanol, isopropanol, ethyl acetate, diethyl ether, acetone, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, water or mixtures thereof. The choice of solvents depends on the solubility of the active ingredients and additives as well as the wetting of the surfaces to be coated and the effect on the structure of the coating and particles remaining after evaporation of the solvent, their adhesion to the surface and the active ingredient transfer into the tissue during very short contact times . The solution particularly advantageously contains acetone, water and / or ethanol as solvent, the solvent mixture containing 3 to 25% by volume, in particular 5 to 15% by volume, of water.

The starting point for the investigations is preferably formulations according to WO2004028582A1, Example 7, Solution B. Compared to the example mentioned, the proportion of Ultravist-370 is reduced from 100 μl / 5 ml of coating solution to 5-50 ml / 5 ml of solution mixture, the reduced volume of Ultravist results in 3.8-38.45 mg of iopromide / 150 mg of paclitaxel or 1.85 -18.5 mg organically bound iodine / 150 mg paclitaxel, particularly preferred are 5-20 ml Ultravist 370/5 ml mixed solution. 100 ml of Ultravist -370 contain 76.9 mg of the X-ray contrast agent lopromide, equivalent to 37 mg of organically bound iodine.

In the solvent for Paclitaxel and Ultravist, the proportion of water was increased from <1.3% by volume to 3-25% by volume, particularly preferably 5-15% by volume, compared with Example 7 of WO2004028582A1 with solution B. Instead of the X-ray contrast agent Ultravist 370, an aqueous solution of the contrast agent Iopromid contained in the Ultravist can be used. Other comparable contrast media can also be used, such as Isovue ™ 370 with lopamidol as a contrast medium or lomeron 400 with lomeprol as a contrast medium or other comparable products in available concentrations.

The application can take place, for example, by dipping, brushing, application by means of volume measuring devices or spraying, in each case at different temperatures and, if necessary, with vapor saturations of the solvents in the atmosphere. The process can be repeated several times, if necessary using different solvents and auxiliaries.

In a particularly preferred embodiment, the balloons are coated in the insufflated state, in particular with a cannula with a defined volume of the active substance solution. After drying and folding, the balloons can be cleaned with dry lubricant, e.g. B. magnesium stearate powder treated or immersed for a very short time in an aqueous suspension of magnesium stearate or a suspension or solution of another biocompatible, metabolically degradable or human excretable lubricant or sprayed or otherwise wetted with such a suspension or solution . After this step, the balloons are dried again, fitted with a protective tube and sterilized by means of EO. The end product is a sterile, properly packaged, approved and approved for human use, high-dose paclitaxel-coated balloon catheter. Conventional balloon catheters with a proximal handle, a catheter shaft with a wire and a fluid lumen, a proximal handle with a connection for a syringe and an insertion nozzle for a guide wire and a distal balloon with a smooth or structured surface made of a thin one serve as a carrier for the medicinal substance (s) , non-stretchable or little stretchable pressure-resistant membrane made of z. B. polyamide, a polyether block amide (e.g. PEBAX or Vestamid), polyamide mixtures and copolymers, polyethylenes, polyethylene terephthalate in sizes that are suitable for the treatment of arteries of all kinds, e.g. B. in the fierce, in the skull, in the extremities or elsewhere in the body. Pressure-resistant means that the balloons can be inflated to 4 -> 30 bar without bursting. The balloons can contain elements made of other materials, e.g. B. contain metals or plastics that give the balloon membrane additional compressive strength, change the shape of the inflated balloon, or exert an effect on the tissue adjacent to inflation, z. B. scratch, cut or influence the tissue via heat or electrical impulses.

For the coating, the active ingredients and, if necessary, the auxiliaries and additives are dissolved or suspended in organic solvents with or without an addition of water. Preferred solvent mixtures contain acetone, ethanol and water, preferred additives are X-ray contrast media such as lopamidol, lopromid or lohexol, but also other common auxiliaries for the coating of balloon catheters such as urea, magnesium salts, which in proportions of <20 percent by weight of the active ingredients make their adhesion to the surfaces of the Favorably influence medical devices and their release at the site of action and / or promote the transfer of the active ingredients into the tissue. Additions of active substances or auxiliary substances which reduce inflammatory reactions of the tissue and / or accelerate healing are particularly preferred; Dexpanthenol and corticoids are examples.

The effectiveness of drugs on medical devices can be increased without increasing the dose by improving the transfer into the tissue to be treated. This is particularly important for medical devices that only remain at the site of action for a short period of time. An example of this are balloon catheters that are inflated in a vessel, completely interrupting the blood flow during the inflation and are therefore deflated and removed again after a very short time, for example in coronary arteries or arteries supplying the central nervous system. According to the first publication (Scheller et al., 2004), the transfer of the drug from a balloon of a balloon catheter into the vessel wall of the coronary arteries averaged 8.7 ± 4.9% of the total dose on the balloon if no stent was or has been implanted. In a more recent study (Speck et al., 2018) the transmission was given as 7.8 ± 3.4% for coronary arteries and 7.1 ± 6.1% of the dose for leg arteries of the pig.

One of the goals of developing new DCBs is to increase the proportion of the active ingredient released into the tissue to be treated. For this purpose, the composition of the coating and the method of coating were changed in many ways and by different companies, but apparently without any substantial improvement in effectiveness (Anantha-Narayanan M et al. Catheter Cardiovasc Interv. 2019 Jul 1; 94 (1): 139-148; Meredith IT, TCT2019) On the clinical side, the handling of the balloon catheter has been improved by carefully preparing the vessel segments to be treated in advance and extending the inflation time of the balloons where possible.

Quite surprisingly, it was found that the transfer of the drug into the tissue through the choice of a suitable balloon membrane in combination with selected coating formulations and coating methods leads to a reproducibly high transfer of drugs into the arterial wall. This applies, for example, to polyether block amide membranes, in particular those sold under the brand names PEBAX or Vestamid in connection with formulations with lipophilic antioxidants such as NDGA (north dihydroguajaretic acid) and propyl gallate, while other formulations (without or with other auxiliary substances) make no difference between PEBAX and nylon membranes, for example show during the transfer of the active ingredients into the arterial wall (Example 3, Tab. 3).

The membranes of balloon catheters have different levels of stability when the pressure in the balloon increases. There are stretchable membranes made of elastic materials such as latex or polyurethane, which are inflated at low pressure and adapt to the shape or diameter of vessels or body cavities. Another group are the balloons commonly used for angioplasty with largely dimensionally stable membranes, e.g. made of nylon or PEBAX (non-compliant or semi-compliant), which are used to widen narrowed arteries and can withstand pressures of up to approx. 15, maximum 20 bar . Finally, for very tight vascular constrictions, for example in heavily calcified vessels or in arterio-venous shunts for dialysis in patients with insufficient kidney function, balloon catheters whose balloons can withstand much higher pressures are available. In the case of stenoses, the expansion of which requires high pressures, these can be expanded using a high pressure balloon (suitable for pressure up to approx. 20-40 bar) in the sense of a 'vessel preparation' and then excessive scarring stimulated by the vascular injury can be counteracted by subsequent treatment with a DCB. Using the DCB will reduce re-narrowing of the lumen. However, in many cases the durability of the treatment is not good (Steiner K, Endovascular Today June 2016; Karnabatidis TCT 2013).

Earlier work indicates that inflationary pressure in the transfer of the drug 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) has no significant influence. With a low inflation pressure (2 bar) of a DCB a similar inhibition of the lumen constriction was found in animal experiments as with the higher inflation pressure (12 bar). With another balloon, 13.9 ± 6.4% of the dose was transferred from the balloon into the vessel wall even at very low (<2 bar) pressures.

Tests with coated high-pressure balloons showed the opposite. A significant increase in drug transfer into the treated arterial wall compared to the common DCBs inflated at about 10 bar was observed. Since no significant difference was found between the drug transfer at very low inflationary pressure and higher inflationary pressure and the effect of the drug when the balloons were inflated at approx. 2 bar and at approx. 12 bar, the observed increase in drug transfer into the vessel wall was after the use of balloons surprising given very high inflationary pressures. The increased drug transfer into the tissue makes it possible to expect a stronger inhibition of re-narrowing, especially in vascular constrictions that are difficult to treat and that only dilate with great force, e.g. calcified arteries.

In a preferred application, balloon catheters serve to expand narrowed or closed arteries. Balloon catheters were coated with drugs to prevent the re-narrowing (restenosis) caused by excessive cell proliferation soon after the arterial lumen was enlarged. The properties and treatment success of the first such drug-coated balloon catheters were published in 2004 (experimental, Scheller et al.) And 2007 (clinical, Scheller et al.). With the coating at that time, only 8.7 ± 4.9% of the dose from the balloon reached the arterial tissue (Scheller et al. 2004). This entry into the arterial wall, which is decisive for the effect, could be significantly increased, also compared to the commercial product currently manufactured by B. Braun.

Example 1 Increase in the paclitaxel (Ptx) transfer from the coated, EO-sterilized balloon into the treated arterial tissue (column 6) by changing the coating: reduction of the auxiliary substance (column 4), increase in the water content of the coating solution (column 3) and Coating of the balloons in the expanded state (column 2). All balloons with approx. 3 pg paclitaxel / mm ² balloon surface. Methods: Investigations on coronary arteries of pigs, methodology see Scheller et al. 2004, Speck et al. 2018. The balloon catheters coated in accordance with Example 7B of DE 10244847 transferred an average of 8.7% of the active ingredient paclitaxel into the arterial wall; the new coatings selected led to a significantly higher proportion of the dose in the vascular wall (19.1-29.9%) , whereby the version without an adjuvant (group A) is not taken into account, since balloon coatings with paclitaxel without an adjuvant have proven to be ineffective in patients with regard to the desired inhibition of restenoses.

Example 2 Increasing the dose on the balloon

Balloon catheters from Acotec, balloon sizes 4 x 40 to 7 x 40 mm, were coated with paclitaxel corresponding to a composition with 10% by volume of water and 10% by weight of lopromide based on the active ingredient in the solution and in the internal iliac artery or the A. femoralis of domestic pigs inflated for 1 min (methodology see Scheller et al. 2004, Speck et al. 2018).

Column (1): Paclitaxel (Ptx) in pg / mm ² balloon surface, in relation to the balloon surface, because the balloons for the treatment of different arteries and artery sections are of different lengths and (for other applications than described here) have or can have a different diameter . Columns 2 - 4: Paclitaxel in the treated arterial wall (segment of the internal iliac artery or femoral artery of domestic pigs, approx. 3 months old, weighing approx. 25 kg) 10-40 min after balloon deflation; Column 5: On the balloon after removal Proportion of the original paclitaxel dose recovered from the animal on the balloon (see column 1).

Row 4, Column 1: Number of balloon catheters measured, Columns 2-4: Number of arteries examined, Column 5: Number of balloons used Row 5, Columns 2-5: A paclitaxel-coated balloon was placed in each artery at 3 pg / mm ² Balloon surface inflated for 1 min, then deflated and removed.

Row 6, columns 2-5: In each artery, two paclitaxel-coated balloons of the same type as in row 5 were inflated one after the other in exactly the same arterial segment in order to transfer more drug into the arterial wall. Line 7: As in line 5, only one coated balloon was inflated per arterial segment, but this was coated with twice the amount of paclitaxel.

Result and conclusion: With the dose of 3 mg / mm ² balloon surface, the expected values for this type of coating with regard to drug transfer into the tissue and finally the small amount remaining on the balloon were measured. The use of 2 identical catheters with the inflation in exactly the same vessel segment resulted in approximately twice the amount of drug in the artery. Doubling the dose on the balloon had at least the same effect.-It was at least twice the amount Transfer of drug into the arterial wall. This is to be understood as an indication of increased effectiveness.

Example 3 Influence of the balloon membrane and the composition of the coating on the transfer of paclitaxel and sirolimus to the arterial wall of pigs

Balloons of balloon catheters were coated in the expanded state as indicated with paclitaxel (Ptx) or sirolimus-containing formulations, folded and sterilized by means of ethylene oxide; the loss of active ingredient was measured on passage through a hemostatic valve, a blood-filled guide catheter (length 1 m) and 1 min stay in blood (line 5), lines 6-8 show results of the examinations on coronary arteries of pigs, methodology see example (1). PTCA = percutaneous transluminal coronary angioplasty, Pebax = polyether block amides, NDGA = nordihydroguajaretic acid, BHT = butylhydroxytoluene

Result and conclusion: The balloons consisted of nylon or Pebax, indistinguishable transparent and smooth. A largely homogeneous coating of the balloon membranes was achieved in the range of approx. 2 to 5 pg / mm ² . On average over all experiments, approx. 10% of the dose was lost on the way through a hemostatic valve, a guide catheter filled with blood and the amount of time remaining in the blood. The transfer of paclitaxel from formulations with the antioxidants NDGA and propyl gallate was unusually high at about 30% of the dose for the balloons with Pebax membranes, both in direct comparison with balloons made of nylon membranes (6.0 ± 3.4%) and compared to literature data (Scheller et al., 2004: 7.9 ± 2.6%, Speck et al. 2018: 7.8 ± 3.4%). This led to high concentrations of paclitaxel in the tissue (line 8). The significantly improved transfer of the active ingredient paclitaxel into the arterial tissue (observed in the combination of antioxidant and Pebax balloon) is surprising and indicates that these balloon catheters are more effective. The proportion of the dose remaining on the balloons (line 9) was not very different between Pebax and nylon balloons, but was significantly lower when propyl gallate was used as an antioxidant.

Example 4 Composition of a coating according to WO2004028582A1, example 7, optimized:

81.1 vol% acetone, 8.8 vol% ethanol, 0.4 vol% Ultravist-370, 9.7 vol% water, 150 mg paclitaxel on 5 ml coating solution.

Claims

Claims 1. Medical device for at least temporary contact with diseased vessels, having a longitudinally elongated hollow body with an outer surface, with an active substance or active substance mixture intended for delivery to the vessel wall having a restenosis inhibitor being arranged on the outer surface, characterized in that the active substance or the active substance mixture at least in some areas with a proportion of more than 4 pg / mm ² , in particular more than 5 pg / mm ² and particularly preferably> 6 pg / mm ² on the surface. 2. Medical device according to claim 1, characterized in that the medical device is a balloon catheter and / or stent for coronary use. 3. Medical device according to one of the preceding claims, wherein the active ingredient contains sirolimus or paclitaxel or consists of one of these. 4. Medical device according to one of the preceding claims, characterized in that auxiliaries are also arranged on the outer surface, in particular to be selected from organically bound iodine, preferably lopamidol, lopromide, lomeprol and / or lohexol, as well as urea, magnesium salts, in particular magnesium stearate, dexpanthenol , lipophilic antioxidants, in particular nordihydroguajaretic acid, resveratrol and / or propyl gallate or combinations of these. 5. Medical device according to one of the preceding claims, characterized in that an organically bound iodine in a loading density in the range from 0.1 pg / mm ² to 0.5 pg / mm ^{2 is also arranged} on the outer surface at least in some areas. 6. Medical device according to one of the preceding claims, characterized in that the outer surface is at least partially a non-stretchable, pressure-resistant membrane, the membrane preferably being designed as a balloon of the device designed as a balloon catheter. 7. Medical device according to claim 6, characterized in that the membrane Polyamide, polyether block amide, polyethylene, polyethylene terephthalate or their copolymers and / or mixtures or consists of such. 8. Medical device according to claim 6 or 7, characterized in that the balloon can be inflated to more than 15 bar, in particular more than 30 bar. 9. Use of a solution for coating a medical device for the treatment of diseased vessels comprising a solvent, a restenosis-inhibiting active ingredient and an organically bound iodine having a matrix for the active ingredient, characterized in that the excipient with organically bound iodine in a concentration in the range from 1.2% by weight to 12.5% by weight, preferably 2.5% by weight to 12.5% by weight, based on the active ingredient in the solution. 10. Use according to claim 9, characterized in that the organically bound iodine is present as lopromide, lopamidol, lohexol and / or lomeprol. 11. Use of a solution according to one of claims 9 or 10, characterized in that the solution contains the active ingredient, in particular paclitaxel or sirolimus, in a concentration in the range from 100 mg to 200 mg per 5 ml of solution. 12. Use of a solution according to one of claims 9 to 11, characterized in that the solution contains acetone, water and / or ethanol as solvent, the solvent containing 3 to 25% by volume, in particular 5 to 15% by volume, of water . 13. A method for coating a medical device for treating diseased vessels, comprising the following steps in the order given: a. Production of a solution according to one of Claims 9 to 12 b. Application of the solution at least in areas to an outer surface of the device, preferably according to one of Claims 1 to 8, by dipping, spraying or wetting with a volume measuring device c. Drying the device 4. The method according to claim 13, characterized in that the device has an inflatable balloon and in step (b) an outer surface of the balloon in the inflated state is at least partially coated.