EP2701756A1 - Ballonnet de cathéter revêtu de rapamycine et de gomme-laque - Google Patents

Ballonnet de cathéter revêtu de rapamycine et de gomme-laque

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Publication number
EP2701756A1
EP2701756A1 EP12724297.2A EP12724297A EP2701756A1 EP 2701756 A1 EP2701756 A1 EP 2701756A1 EP 12724297 A EP12724297 A EP 12724297A EP 2701756 A1 EP2701756 A1 EP 2701756A1
Authority
EP
European Patent Office
Prior art keywords
rapamycin
shellac
acid
balloon
catheter balloon
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12724297.2A
Other languages
German (de)
English (en)
Inventor
Rembert Pogge Von Strandmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eurocor GmbH
Original Assignee
Eurocor GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eurocor GmbH filed Critical Eurocor GmbH
Publication of EP2701756A1 publication Critical patent/EP2701756A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/005—Ingredients of undetermined constitution or reaction products thereof
    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • 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
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/02—Methods for coating medical devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M2025/1043—Balloon catheters with special features or adapted for special applications
    • A61M2025/105—Balloon catheters with special features or adapted for special applications having a balloon suitable for drug delivery, e.g. by using holes for delivery, drug coating or membranes

Definitions

  • the present invention relates to a catheter balloon with a coating containing rapamycin and shellac and to a method for coating catheter balloons, preferably structured catheter balloons, with the pharmacologically active substance rapamycin, shellac and optionally further constituents. Moreover, the present invention also relates to the use of such coated catheter balloon for the release of the pharmaceutical agent rapamycin for the prophylaxis and treatment of restenosis, preferably restenosis caused by angioplasty.
  • the coated catheter balloons may be used alone or in combination with a coated or uncoated stent that is crimped onto the catheter balloon before or after coating with shellac and rapamycin.
  • restenosis recurrent stenosis
  • PTA percutaneous transluminal angioplasty
  • the biostable or bioresorbable polymeric matrix of the stent in which the drug is embedded could trigger persistent inflammation with increased neointimal proliferation.
  • the drug concentration achieved is not homogeneous in the tissue: it is highest near the stent struts and lowest between the stent struts; this causes uneven inhibition of vascular smooth muscle cell proliferation and may result in delayed and inhomogeneous re-endothelialization in various stent segments.
  • Significant involvement in late thrombosis and in stent restenosis was discussed for both mechanisms.
  • a so-called “biological stenting” can be carried out, in which only a coated catheter balloon, without a stent, is used.
  • the vessels are dilated at a restricted site by the dilatation of the coated catheter balloon, the catheter balloon being dilated for a short time and a sufficient amount of the pharmacologically active agent transferred to the vessel wall to re-narrow or re-occlude the vessel as a result of dilation to avoid the vessel.
  • Such coated catheter balloons are already known from WO 2005/089855 A1, and international patent application WO 2004/028582 A1 discloses folded balloons coated with a composition of a pharmacological agent and a contrast agent, preferably under the folds.
  • a method for spray-coating catheter balloons is described in WO 2004/006976 A1.
  • WO 2008/046641 discloses coated implants with respect to stents, particularly demonstrating the in vitro release kinetics of stents coated with 1.0% rapamycin without shellac mix and 1.0% rapamycin / 0.5% shellac mix. Shellac had a profound effect on stent-based rapamycin through long-term delay in drug release.
  • Uncoated stents with rapamycin released the drug more efficiently, unlike shellac and rapamycin coated stents, which released the drug much more slowly.
  • Shellac was considered useful to control the release kinetics of an implant-based, e.g. A stent-based compound to slow down (more than 60 days) the release kinetics needed to prevent in-stent restenosis after 6-9 months in the course.
  • Said method for loading or coating of dilatable catheter balloons comprises the following steps:
  • INA coating the surface of the catheter balloon with the solution of rapamycin and shellac
  • the invention is directed to a catheter balloon characterized by a coating comprising rapamycin and shellac.
  • the term "uncoated” as used herein refers to a catheter balloon having a smooth or textured or roughened surface without any drug coating, ie, the balloon surface does not contain any pharmaceutically active agents and particularly no antiproliferative, anti-angiogenic or antirestenotic agent and coating It has been surprisingly found that such a rapamycin shellac coating is therapeutically highly useful for keeping blood vessels open to reduce late lumen loss and restenosis a balloon catheter comprising a catheter balloon coated with a combination of rapamycin and shellac which, even after a short period of dilatation, is therapeutically highly effective in keeping blood vessels open and reducing vascular constriction and restenosis.
  • rapamycin and shellac coated catheter balloons allow a homogeneous distribution of an antiproliferative compound to be administered across the area.
  • this uniformity of release to the vessel wall enhances the efficacy of the drug.
  • the concentration of active substance within the vessel is highest at the time of injury due to dilation of the vessel, although the inflammatory and proliferative processes are most severe.
  • the rapamycin and shellac-coated balloon catheter is further characterized in that after balloon infiltration for> 30 s, preferably> 25% of the rapamycin is released from the balloon surface, more preferably> 30%, more preferably> 40%, even more preferably> 50 %, even more preferably> 60%, most preferably> 70%. Consequently, a dilation time of ⁇ 30 seconds is preferred for a single dilatation. Moreover, a total dilation time of ⁇ 60 seconds is preferred, which means that the single dilatation of ⁇ 30 seconds is repeated once.
  • the catheter balloon coated with rapamycin and shellac is further characterized in that after a balloon inflation time of 30 seconds in the dilated segment, 45 minutes after dilation, a rapamycin tissue concentration of preferably> 10 ⁇ / L, more preferably> 30 ⁇ / L, even more preferably> 50 ⁇ / L, more preferably> 80 ⁇ / L, even more preferably> 100 ⁇ / L, more preferably> 120 ⁇ / L, most preferably> 140 ⁇ / L can be achieved.
  • the catheter balloon coated with rapamycin and shellac is characterized in that after a balloon infiltration time of 15 seconds in the dilated segment 45 minutes after dilation, a rapamycin tissue concentration of preferably> 1 ⁇ / L, more preferably> 3 ⁇ / L, even more preferably> 5 ⁇ / L, more preferably> 8 ⁇ / L, even more preferably> 10 ⁇ / L, more preferably> 15 ⁇ / L, most preferably> 20 ⁇ / L can be achieved.
  • the catheter balloon is coated with rapamycin and shellac wherein the weight ratio of rapamycin to shellac is from 100: 1 to 1: 100, preferably 95: 1 to 1:95, more preferably 90: 1 to 1:90, more preferably 85: 1 to 1: 85, more preferably 80: 1 to 1:80, more preferably 75: 1 to 1:75, more preferably 70: 1 to 1:70, more preferably 65: 1 to 1:65, more preferably 60: 1 to 1:60, more preferably 55: 1 to 1:55, more preferably 50: 1 to 1:50, more preferably 45: 1 to 1:45, more preferably 40: 1 to 1:40, more preferably From 35: 1 to 1:35, more preferably from 30: 1 to 1:30, more preferably from 25: 1 to 1:25, more preferably from 20: 1 to 1:20, even more preferably from 15: 1 to 1:15 preferably 10: 1 to 1:10 and most preferably 5: 1 to 1: 5.
  • any commercially available dilatable catheter balloon can be used as a catheter balloon in the context of the invention.
  • So-called multi-fold balloons can be used as described, for example, in International Patent Application WO 94/23787 A1 by David H. Rammler, Labintelligence, USA; or in the international patent application of Scimed Life Sciences, Inc., USA; or international patent application WO 2004/028582 A1 to Prof. Dr. med. Ulrich Speck, European Patent No. EP 0519063 B1 to Medtronic Inc., USA.
  • Such balloons are provided with wrinkles or wings which form closed cavities in the western, when the balloon is in its deflated state, but flex outward during dilatation and are capable of releasing the substances contained in the wrinkles or the said substances against the vessel wall to press.
  • Such balloons are advantageous in that the substances enclosed by the folds, or the rapamycin enclosed by the folds, are protected against premature detachment during insertion through the catheter.
  • rapamycin may also be incorporated, incorporated or embedded in one or more carrier substances, preferably a polymeric carrier.
  • a carrier substances preferably a polymeric carrier.
  • Shellac is the most preferred biodegradable polymeric carrier. Regardless of the source of shellac, all types of shellac types obtained from different locations or from different insects have been able to achieve the results of the invention so that any type or variety of shellac can be used with the present invention , Therefore, there are no limits to shellac.
  • Shellac is a natural resin made from the glandular secretions of several lacquer-producing insects.
  • Lacquer insects belong to the genus Hemiptera, Superfoil Coccoidea such as Metatachardia, Laccifer, Tachordiella and others; however, members of two families - Lacciferidae and Tachardinidae - are particularly important for lacquer production.
  • a commercially-kept blue-throated louse is Kerria lacca, also known by the synonyms Laccifer lacca Ker, Tachardia lacca, and Carteria lacca.
  • Kerria lacca is an Indian scale insect that infests the branches of numerous trees such as Butea frondos Rosh, Acacia arabica Willd and Ficus religiosa Linn in Southeast Asia.
  • Shellac is the only commercially used natural resin of animal origin and is very different from all other natural resins. Recently, as a new awareness of the environment and the toxicity of chemical raw materials is becoming apparent everywhere, shellac and modified shellac resins are gaining in importance because of their interesting and unique characteristics. Broken branches are sold as stick paint. After milling and washing with water to remove wood and red pigments (paint dye), you get grain varnish. Purification of the grain varnish results in a more homogeneous product, known as shellac.
  • Unprocessed shellac material consists of 70-80% resin, 4-8% dye, 6-7% hard and high gloss wax, 3% water, up to 9% vegetable and animal impurities and flavors is a complex mixture of aliphatic (60%) and sesquiterpene acids (32%) and their esters, sesquiterpene acids are jalaric acid and lacci-jalaric acid (structures I and II), and aliphatic acids are aleuritic acid (III) and butyric acid.
  • One possibility for the chemical description of the resin molecule is a structural model in which at least 4 molecules of jalaric acid or lacci-jalaric acid and aleuritic acid are connected in an alternating manner via ester bonds.
  • Trihydroxypalmitic acid (aleuritic acid) CAS [53-387-9] and schellolic acid (IV)
  • Shellac has the following grades:
  • - Shellac has excellent dielectric properties, high dielectric strength, low dielectric constant, good tracking resistance, etc.
  • - Shellac has a low melting point (65-85 ° C).
  • Shellac has excellent film-forming properties
  • the catheter balloons according to the invention were coated both with shellac of different commercial classes and with different batches, which differed in the lacquer insects and types of the host tree as well as the harvest time. There were no differences in the observed rapamycin release for the different rapamycin shellac-coated catheter balloons.
  • the carrier may be added to the rapamycin solution or may be applied as a second solution with or without rapamycin.
  • Such solutions containing rapamycin and / or shellac and optionally further carrier substances are then applied to the catheter balloon surface by means of conventional coating methods, in particular spraying, spraying or dipping methods.
  • Suitable additional carriers are those substances which are also used as balloon material, in particular polymeric and polymerizable substances as listed below.
  • the rapamycin is embedded or stored in shellac, with up to 30% of the total being prematurely released during the introduction of the catheter balloon, but there is still a sufficiently high and therapeutically effective amount of rapamycin present on the balloon once it has reached its target position ,
  • the active ingredient rapamycin from premature detachment by embedding it in the shellac on the surface of the catheter balloon and optionally under the folds of the balloon
  • rapamycin is not protected by the folds of a multi-fold balloon (Mu / f / 7ö / c / balloon), or where the rapamycin is not embedded in a large excess of shellac, a correspondingly higher amount of the active ingredient rapamycin may be applied to the catheter balloon so that an effective dose is released at the target site.
  • an amount of 0.1 g to 30 g of rapamycin per mm 2 can be applied to the surface of the balloon catheter to be coated, while a rapamycin amount of 0.5 g / mm 2 to 6 g / mm 2 is sufficient to produce the desired Effect on the restenosis prophylaxis.
  • the amount of rapamycin per mm 2 surface of the balloon between 1 g / mm 2 and 5 g / mm 2, more preferably between 1, 5 g / mm 2 and 4.5 g / mm 2, even more preferably between 2.0 g / mm 2 and 4.0 g / mm 2, and most preferably between 2.5 g / mm 2 and 3.5 g / mm 2 .
  • rapamycin is also preferred.
  • a total amount of rapamycin of from 10 to 1000 g per catheter balloon, and most preferably from 20 ⁇ to 400 g per catheter balloon.
  • Rapamycin is commercially available from several manufacturers, such as Sigma-Alderich, Merck, Seileck and Cayman. Rapamycin is also known under the trade name Rapamune ® and is also synonymous with different names referred to as:
  • Rapamycin is an immunosuppressant with a macrolide structure (31-membered) and can be obtained as a metabolic end product from streptomycete Streptomyces hygroscopicus. Rapamycin inhibits a number of cytokine-mediated signal transduction pathways by complexing with the mammalian target of rapamycin (mTOR) protein. This ultimately leads to the inhibition of the cell cycle and thus cell division. Rapamycin is highly soluble in dimethyl sulfoxide (DMSO) and methanol as well as in anhydrous ethanol, but it is comparatively poorly soluble in water (2.6 ⁇ g / ml). As the solvent for rapamycin, dimethylsulfoxide (DMSO), acetone, chloroform, ethyl acetate, ethanol and methanol are used.
  • DMSO dimethylsulfoxide
  • acetone chloroform
  • chloroform chloroform
  • ethyl acetate ethanol
  • methanol m
  • the coating process according to the invention can be carried out in two alternative ways.
  • a catheter balloon and preferably an uncoated catheter balloon or catheter balloon without any releasable drug on its surface, is provided.
  • a solution of rapamycin together with shellac is prepared in a suitable solvent such as acetone, ethyl acetate, ethanol, methanol, DMSO, THF, chloroform, methylene chloride, or a mixture thereof and applied by conventional coating methods such as spray coating, dip coating, etc., after a drying step to obtain a solid rapamycin shellac coating on the surface of the catheter balloon (steps I + IIA + INA + IV).
  • rapamycin solution and a separate shellac solution, and apply both solutions simultaneously or subsequently, to obtain a solid rapamycin shellac coating on the surface of the catheter balloon after the drying step (steps I + IIB + HIB + IV).
  • the coating steps INA) and IV) or HIB) and IV) can be repeated several times in the inventive coating methods. Typically, the coating procedure is repeated once, twice or three times, but said repetition is not mandatory. Also, a coating procedure may be sufficient to obtain the required amount of rapamycin and shellac on the catheter balloon.
  • the drying step IV) can be carried out at room temperature or elevated temperatures up to 50 ° C and at atmospheric pressure or under reduced pressure to high vacuum. If the coating step III) [INA] or HIB)] is repeated, the drying steps IV) are preferably carried out at room temperature and atmospheric pressure, while preferably after the last coating step of the cycle, the drying step is more intense, i. longer or under vacuum or at elevated temperature.
  • the catheter balloon is dilatable or expandable, and is preferably an angioplasty catheter balloon, without a crimped stent or with a crimped one Stent can be used.
  • the stent may be any of the types of conventional stents, such as self-expandable stents, non-self-expandable stents, metal stents, polymer stents, biodegradable stents, bifurcated stents, bare stents, polymer coated stents, drug-eluting stents, pure drug-coating stents, etc.
  • the stent may be crimped onto the catheter balloon prior to performing the inventive coating method so that the balloon catheter and stent are coated together with a shellac rapamycin coating. If the catheter balloon is first coated and the stent is then crimped onto the balloon, a rapamycin coated stent or a rapamycin shellac coated stent having the same or a different concentration of rapamycin and / or shellac on the surface could be used.
  • coated catheter balloon of the present invention without a stent.
  • the catheter catheter provided is usually a multi-fold catheter balloon (Mu / f / fo / d catheter balloon) which is also coated under or within the folds. Moreover, it is possible to selectively coat or fill the folds.
  • the coating within or under the folds has the advantage that during the introduction of the catheter balloon, the coating and therefore the drug rapamycin is protected against washing by the bloodstream.
  • catheter balloon may be coated in its expanded (inflated) or deflated state.
  • the preferred solvents for shellac and rapamycin are volatile, readily removable solvents such as acetone, ethyl acetate, ethanol, methanol, DMSO (dimethylsulfoxide), THF (tetrahydrofuran), chloroform and methylene chloride.
  • the total surface load of the catheter balloon with rapamycin and shellac is between 1 g / mm 2 and 12 g / mm 2 .
  • the amount of rapamycin and shellac on the coated balloon surface is between 2 g / mm 2 and 10 g / mm 2 balloon surface, more preferably between 3 g / mm 2 and 9 g / mm 2 , even more preferably between 4 g / mm 2 and 8 g / mm 2 , more preferably between 5 g / mm 2 and 7 g / mm 2 , and most preferably between 5.5 g / mm 2 and 6.5 rapamycin and shellac per mm 2 balloon surface area (g / mm 2 ).
  • the inventive coating method may optionally further comprise step V):
  • the sterilization is preferably carried out with ethylene oxide.
  • inventive coating method may optionally further comprise step IB):
  • the catheter balloon is only part of a balloon catheter, the surfaces of the balloon catheter that are not to be coated with the rapamycin shellac composition can be protected by a removable protective cover such as a plastic bag or plastic film and only the catheter balloon remains freely accessible that only the exposed part can be coated. After the coating process is completed, the protective cover is removed.
  • inventive coating method may optionally further comprise step VI):
  • the removable protective cover is useful to protect the finished coated catheter balloon, and more particularly, the coating on the catheter balloon from damage, e.g. during transport or storage.
  • the surface of the catheter balloon is structured, smooth, uneven, rough, holed, or provided with channels open to the outside of the balloon.
  • the rapamycin-containing coating solution may optionally contain at least one further carrier substance.
  • Said at least one further carrier substance is selected from the group consisting of or comprising:
  • Polyhydroxypentanoic acid Polyanhydrides, polyethylene oxides, propylene oxides, soft polyurethanes, polyurethanes with amino acid residues in the main chain, polyether esters, polyethylene oxides, polyalkene oxalates, polyorthoesters and copolymers thereof, lipids, carrageenans, fibrinogen, starch, collagen, protein-based polymer, polyamino acids, synthetic polyamino acids, zein , Polyhydroxyalkanoates, pectic acid, actinic acid, carboxymethyl sulfates, albumin, hyaluronic acid, chitosan and its derivatives, heparan sulfates and their derivatives, heparins, chondroitin sulfates, dextran, ⁇ -cyclodextrins, copolymers with PEG and polypropylene glycol, gum arabic, guar, gelatin, collagen N-hydroxysuccinimide , Phospholipid
  • the surface of the catheter balloon may be structured mechanically, chemically, electronically, and / or by irradiation to allow for improved attachment of rapamycin and promote the deposition or crystallization of the rapamycin.
  • the surface of the catheter balloon When structuring the surface of the catheter balloon, the surface of the catheter balloon must be modified in the range of nanometers to micrometers, i. a kind of micro-level surface structure must be provided. Surface structuring is preferably applied to the entire surface of the catheter balloon to be coated and may result in organized or random structures.
  • the catheter balloon may consist of the following materials:
  • Polyhydroxybutyrate-co-valerate poly (1,4-dioxane-2,3-diones), poly (1,3-dioxanes-2-ones), poly-para-dioxanones, polyanhydrides, polymaleic anhydride,
  • Polyamides block copolymers of polyamide-polyether-polyester, polyurethanes, polyesters and polyolefins are preferred.
  • the balloon surface microstructuring techniques must not result in the formation of holes, micropores, or cracks in the balloon material. Ideally, only the outer surface of the balloon, i. up to a maximum depth of 1 mm, structured.
  • the dilatable catheter balloon may be mechanically structured by the use of a file-like device, a file, or a solid particle jet method, such as a sandblasting method.
  • the surface of the balloon material becomes attacking acids, bases, etching chemicals and / or oxidizing agents Used chemicals.
  • such chemicals must be used with caution as the balloon material could be damaged if the exposure time is too long or the chemicals are too concentrated.
  • an electrical or electronic method is used to pattern the surface of the dilatable catheter balloon, patterning is accomplished by means of conductors that are heated by electrical current flow. For example, a fine, warm, hot or glowing needle can be used to melt the surface of the balloon material, whereby certain patterns can be created on the surface, especially when the needle is moved along the surface of the catheter balloon.
  • An elegant method for creating organized structures may be the use of a laser or generally highly focused radiation.
  • Said radiation means are very accurate and can be used especially for the creation of defined structures such as grids, spirals or lines.
  • the patterned or micronized to nanomodated surface of the catheter balloon as well as the unstructured catheter balloons may be wetted prior to application of the coating solution by any conventional means to increase the adherence of the coating to the balloon surface.
  • Any type of common coating method such as spray coating, brush coating, dip coating, vapor deposition, pipetting and the like can be used to apply the rapamycin shellac solution or the rapamycin solution and shellac solution to the balloon surface.
  • the content of rapamycin in the rapamycin-containing coating solution is between 1 g to 1 mg rapamycin per ml solution, preferably between 10 g to 500 g rapamycin per 1 ml solution, more preferably between 30 g to 300 g rapamycin per 1 ml solution and most preferably between 50 g to 100 g of rapamycin per 1 ml of solution.
  • the solution of rapamycin in ethanol, acetone, ethyl acetate or DMSO may be applied to the balloon surface via syringing, dipping, plasma deposition, brushing or spraying.
  • a particular catheter balloon, including microneedles or micropores or microcompartments, is disclosed in International Patent Application No. WO 02/043796 A2, Scimed Life Systems, Inc., USA, in which inflatable and structured surfaces are present on the balloon surface. In said embodiment, loading or inflation of certain parts of the balloon surface would be sufficient to achieve the desired therapeutic success, although it is obviously also possible for the entire surface to be coated.
  • Balloon ovuloplasty is a procedure in which a narrowed heart valve is distended via a procedure that does not require open heart surgery. Balloon ovuloplasty is performed to improve valve function and blood flow by enlarging the valve opening. It is a treatment for aortic, mitral and pulmonary stenosis.
  • balloon vivuloplasty a thin catheter balloon is inserted through the skin in the groin into a blood vessel and then advanced to the opening of the narrowed heart valve. The balloon is inflated to stretch the flap and release the valve obstruction.
  • a balloon catheter according to the invention for balloon avulsoplasty is coated only in the region which comes into direct contact with the valve, where inhibition of restenosis is desired.
  • a preferred embodiment of the present invention is a shellac and rapamycin coated balloon catheter for balloon avulsoplasty in which only that portion of the catheter balloon which comes in contact with the heart valve is coated.
  • Another preferred embodiment of the present invention is directed to a catheter balloon which is completely coated with shellac but which is coated with rapamycin only on the portion of the surface of the catheter balloon which comes into contact with the heart valve.
  • there is a possibility in a partial coating of the catheter balloon ie certain sections of the catheter balloon and successively additional surfaces until a, if desired, completely coated catheter balloon is obtained.
  • the present invention also relates to rapamycin shellac coated catheter balloons obtainable by the inventive inventive disclosed coating method and balloon catheters and dilatation catheters comprising said rapamycin shellac coated catheter balloon.
  • Another active ingredient may be added to the rapamycin-containing solution.
  • Said additional active ingredient may be selected from the following group, comprising or consisting of:
  • Abciximab Acemetacin, Acetylvismione B, Aclarubicin, Ademetionine, Adriamycin, Aescin, Afromosone, Akagerine, Aldesleukin, Amidorone, Aminoglutethimide, Amsacrine, Anakinra, Anastrozole, Anemonin, Anopterin, Antimycotica, Antithrombotica, Apocymarin, Argatroban, Aristolactam-All, Aristolochinic Acid, Ascomycin , Asparaginase, aspirin, atorvastatin, auranofin, azathioprine, azithromycin, baccatin, bafilomycin, basiliximab, bendamustine, benzocaine, berberine, betulin, betulinic acid, bilobol, bisparthenolidine, bleomycin, combrestatin, boswellic acid and its derivatives, bruceanol A, B and C,
  • Vitronectin receptor antagonists azelastins, guanidyl cyclase stimulators, metalloproteinase-1 and -2 tissue inhibitors, free nucleic acids, nucleic acids incorporated into virus carriers, DNA and RNA fragments, plasminogen activator inhibitor 1, plasminogen activator inhibitor 2, antisense oligonucleotides, VEGF inhibitors, IGF-1 , Drugs from the group of antibiotics, cefadroxil, cefazolin, cefaclor, cefoxitin, tobramycin, gentamicin, penicillin, dicloxacillin, oxacillin, sulfonamides, metronidazole, enoxaparin, heparin, hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators, Dipyramidole, trapidil, nitro
  • the present invention relates to dilatable and expandable catheter balloons and more particularly to multi-pleated balloons for catheters coated according to the method of the invention.
  • the catheter balloons are preferably coated except with shellac substantially with pure rapamycin. Therefore, the catheter balloons preferably carry a layer consisting of an active ingredient in the form of incorporated in the biopolymer shellac rapamycin, wherein in said layer only traces of solvent are present.
  • another active ingredient and / or an additional carrier may be present in the same or a different amount, such as rapamycin or shellac.
  • the rapamycin-shellac composition dried on the surface of the catheter balloon has a particular nature that is difficult to characterize, but seems to be critical for transfer to the cell wall and incorporation, especially in the vascular smooth muscle cells.
  • the present invention also relates to balloon catheters comprising a catheter balloon according to the invention coated with rapamycin and shellac and optionally with a further active ingredient and / or optionally with a further carrier substance or matrix substance.
  • catheters are preferably used for the treatment of stenotic vessel sections, especially blood vessels, and for the treatment and prophylaxis of stenosis, restenosis, arteriosclerosis and fibrotic vessel narrowing.
  • catheter balloons coated according to the invention are suitable for the treatment and / or prophylaxis of in-stent restenoses, ie a recurrent vasoconstriction within a stent already used. In such cases, the placement of an additional stent proves to be very problematic or even impracticable from a medical point of view.
  • Such in-stent restenoses can be treated effectively and without an additional stent by administering paclitaxel with the aid of the catheter balloon coated according to the invention or a catheter whose balloon is coated according to the invention.
  • the catheter balloons coated according to the invention are particularly suitable for the treatment of small vessels, preferably those vessels having a vessel diameter of less than 2.25 mm.
  • the catheter balloons coated according to the invention are preferably used in the cardiovascular area, but the catheter balloons coated according to the invention are also suitable for the treatment of vascular constrictions of the bile ducts, esophagus, urinary tract, pancreas, renal, pulmonary, trachea, small intestine and large intestine.
  • the following examples illustrate possible embodiments of the invention without limiting the scope of the invention to the particular examples given. Examples
  • a commercially available balloon catheter for angiogenesis is provided.
  • rapamycin 50 g are dissolved in acetone together with 100 g of shellac per ml of acetone.
  • the solution of rapamycin and shellac is sprayed onto the catheter balloon and then dried. This process is repeated a further three times after drying the coated balloon surface.
  • the drying step is carried out at room temperature and atmospheric pressure.
  • the catheter balloon is sterilized with ethylene oxide. Then the coated balloon surface is provided with a protective cover and packed.
  • a commercially available balloon catheter for angiogenesis with expandable polyamide balloon is provided.
  • Rapamycin is dissolved together with shellac in a concentration of 50 g of rapamycin and 100 g of shellac per ml of ethanol in ethanol.
  • the catheter balloon is dried under reduced pressure and sterilized with ethylene oxide. Then the coated balloon surface is protected with a protective cover and packaged for shipping or storage.
  • a commercially available dilatation catheter with expandable polyamide balloon is provided.
  • Rapamycin is dissolved together with shellac in a concentration of 50 g of rapamycin and 100 g of shellac per ml of ethanol in ethanol.
  • the solution of rapamycin and shellac in ethanol is applied to the catheter balloon by immersing the catheter balloon on the catheter balloon for 10 seconds (dip coating). This process is repeated twice more.
  • the catheter balloon is dried and additionally sterilized with ethylene oxide after the last step. Then the coated balloon surface is protected with a protective cover and packaged for shipping or storage.
  • a multi-folded balloon such as described in WO 2004/028582 A1, WO 94/23787 A1 or WO 03/059430 A1 is provided.
  • the multi-folded balloon is provided with a total of 5 folds, enclosing a cavity when the balloon is in a compressed state, and outwardly curved when in an expanded state so that the balloon in its expanded state has a substantially tubular shape ,
  • the multi-folded balloon is expanded and then the surface is roughened by a so-called "chemical polishing process" using a suspension of fine particles, preferably in the micron range, in said process and rubbing said suspension over the surface of the expanded catheter balloon.
  • a solution of 80 g of rapamycin in 1.0 mL of ethyl acetate and a solution of 100 g of shellac in THF is provided
  • the roughened, expanded balloon is dipped several times in said solution of rapamycin in ethyl acetate and at The shellac solution in THF is then filled into a pipette and applied to the dry rapamycin coating on the balloon surface.
  • the total rapamycin loading on the balloon surface is between 1 g to 5 g rapamycin per mm 2 coated balloon surface.
  • the balloon After sterilization, the balloon is provided with a protective cover with the intention of protecting the active agent on the coated, dilatable catheter balloon during transport and storage, the sleeve being removed by the cardiologist prior to insertion of the catheter.

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Abstract

La présente invention concerne un ballonnet de cathéter pourvu d'un revêtement contenant de la rapamycine et de la gomme-laque et un procédé pour revêtir des ballonnets de cathéter, de préférence des ballonnets de cathéter structurés, avec le principe actif pharmacologique rapamycine, de la gomme-laque et en option d'autres ingrédients. La présente invention concerne en outre l'utilisation de tels ballonnets de cathéter ainsi revêtus pour la libération du principe actif pharmaceutique rapamycine à titre prophylactique et pour le traitement de resténoses, de préférence de resténoses provoquées par angioplastie. Les ballonnets de cathéter revêtus peuvent être utilisés seuls ou en combinaison avec un stent revêtu ou non revêtu qui est serti sur le ballonnet de cathéter avant ou après le revêtement à la gomme-laque et à la rapamycine.
EP12724297.2A 2011-04-26 2012-04-26 Ballonnet de cathéter revêtu de rapamycine et de gomme-laque Withdrawn EP2701756A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102011100122A DE102011100122A1 (de) 2011-04-26 2011-04-26 Katheterballon beschichtet mit Rapamycin und Schellack
PCT/EP2012/057698 WO2012146681A1 (fr) 2011-04-26 2012-04-26 Ballonnet de cathéter revêtu de rapamycine et de gomme-laque

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EP2701756A1 true EP2701756A1 (fr) 2014-03-05

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US (1) US20140107574A1 (fr)
EP (1) EP2701756A1 (fr)
JP (1) JP2014512238A (fr)
CN (1) CN103561790A (fr)
BR (1) BR112013027414A2 (fr)
DE (1) DE102011100122A1 (fr)
WO (1) WO2012146681A1 (fr)

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Publication number Publication date
WO2012146681A1 (fr) 2012-11-01
US20140107574A1 (en) 2014-04-17
CN103561790A (zh) 2014-02-05
JP2014512238A (ja) 2014-05-22
DE102011100122A1 (de) 2012-10-31
BR112013027414A2 (pt) 2019-09-24

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