Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/95—Instruments specially adapted for placement or removal of stents or stent-grafts
  • A61F2/958—Inflatable balloons for placing stents or stent-grafts
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L31/16—Biologically active materials, e.g. therapeutic substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
  • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
  • A61L2300/606—Coatings

Definitions

• 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.
• 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.
• bypass operations and, in particular, DCBs are available for constrictions in vessels that have already been supplied with stents.
• 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.
• 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.
• macrocyclic immunosuppressants also known as Limus substances, e.g. sirolimus such as rapamycin, everolimus etc.
• Limus substances e.g. sirolimus such as rapamycin, everolimus etc.
• stents for coronary arteries and paclitaxel on balloons.
• the obvious thing to do is to look for more effective active ingredients.
• 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).
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• the medicinal substances should bind> 10%, preferably> 50%, particularly preferably> 80% reversibly and / or irreversibly to cell components.
• 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.
• 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.
• 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.
• the medical device also has auxiliary materials on the outer surface.
• 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.
• 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.
• 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.
• 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.
• 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.
• the active pharmaceutical ingredients can be adsorbed on particles or applied with a low molecular weight matrix to the surfaces of suitable medical products.
• 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.
• the outer surface 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.
• 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.
• 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.
• the organically bound iodine is advantageously present in the solution as lopromide, lopamidol and / or lomeprol.
• 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.
• the proportion of Ultravist-370 is reduced from 100 ⁇ l / 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.
• 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.
• 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 TM 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.
• the balloons are coated in the insufflated state, in particular with a cannula with a defined volume of the active substance solution.
• 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 .
• 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 .
• 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.
• 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.
• 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.
• 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.
• 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.
• 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)
• 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.
• the membranes of balloon catheters have different levels of stability when the pressure in the balloon increases.
• 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.
• 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 .
• 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.
• 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.
• 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).
• 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
• 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.
• Example 4 Composition of a coating according to WO2004028582A1, example 7, optimized:

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