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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• • 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
• • 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
  • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution

Definitions

• the present invention concerns medical products, which come into contact with the organism, such as short-term implants and long-term implants, coated with at least one layer, containing a molecular-disperse distributed or dissolved active substance in at least one carrier and optionally one or more adjuvants, wherein the at least one layer forms a stably spreadable solution, methods for making this coating of stably spreadable solutions and use of the medical products coated with the stably spreadable solution.
• EP 0 383 429 A discloses, for instance, a balloon catheter with tiny holes, whereby during dilatation heparin solution is delivered.
• the strong lipophil and water-insoluble chemotherapeutic agent paclitaxel which is used in form of an emulsion as injection solution or infusion solution.
• the solvent used is ethanol (with approximately 50 volume percent) and a mixture of macrogolricinoleate (Cremophor EL) as emulgator, thereby improving the solubility in the aqueous blood system. It is a proven fact that the addition of Cremophor EL is responsible for diverse, partially serious acceptance problems (New Engl J of Medicine, Vol 332 No 15, 1995:1004).
• Cremophor is a necessary and therefore often used additive to enhance the solubility of water-insoluble active substances, such as paclitaxel, cyclosporine, vitamin K, propofol, diazepam etc.
• paclitaxel derivatives were manufactured e.g. by covalent binding of water-soluble polymers, thereby trying to enhance the availability without loss of effectiveness in the vessel system of the organism (U.S. Pat. No. 5,648,506A; U.S. Pat. No. 6,262,107B1, U.S. Pat. No. 6,441,025B2); however with no success.
• the antiproliferative active substances paclitaxel and rapamycin were not only effective in antitumor therapy but proved to be generally effective against excessive cell growth.
• the active substances are brought into direct contact with the area to be treated, either systemically or with the aid of a medical product without a polymer matrix or embedded in a solid and preferably polymer matrix.
• the advantage of a non-systemic application is apparent, given that by means of a medical product, the applicated active substance concentrations are so low, that toxic side effects, as known from systemic administrations, do not occur and no further stress is placed on the organism.
• Active substances such as paclitaxel and rapamycin proved to be especially suitable against hyperproliferative cells. Exactly these highly effective active substances show the above described disadvantages concerning the particle release during dilatation and insolubility in water. Therefore, among other things the applicant was faced with the task to apply effective substances on a catheter ballon resulting in a hydrophil coating, which detaches easily from the balloon during dilatation of the vessel, releases the active substance in colloidal or solubilized form and above all, transfers to the vessel wall without formation of particles.
• the present invention is directed to medical devices, wherein the surface of the device is coated completely or partially with a stably spreadable solution containing at least one active substance and at least one carrier.
• the medical products or medical devices, as described herein, which come into contact with the organism, are implants, which remain permanently in the body, such as stents and vessel prosthesis and therefore are termed herein as long-term implants, but also removable, for a limited time period implanted devices, such as catheters, e.g. bladder catheters, ventilation tubes, venous catheter, balloon catheter, dilatation catheter, PTCA- and PTA-catheter, embolectomy catheter, valvuloplasty catheter and cannulas.
• catheters e.g. bladder catheters, ventilation tubes, venous catheter, balloon catheter, dilatation catheter, PTCA- and PTA-catheter, embolectomy catheter, valvuloplasty catheter and cannulas.
• the balloon, the catheter balloon or the dilatable area of the catheter is provided with a coating in form of a stably spreadable solution.
• coatings that are not a suspension and are not a solid dispersion, since solid dispersions are too fragile and flake with high probability during implantation or introduction of the catheter balloon.
• Particular severe risks come off fragile or brittle coatings, applied to expandable medical devices. This is in particular harmful for implants in hollow organs (stents, balloon catheters), since the fragments can cause an occlusion.
• coating fragments must be prevented, because in the increasingly smaller vessels, already the smallest fragments bring the danger of stenosis and of acute injury of the respective tissue, even up to a heart infarct.
• These fragments can be crystalline particles of the active substance or particles of the solid coating, which detach during introduction of the catheter and/or during dilatation of the catheter balloon.
• solid dispersion describes systems in a solid state, containing at least one active substance in an inert carrier.
• the generic term solid dispersion covers solid suspensions as well as solid solutions.
• the active substance is contained in particulate form in the carrier.
• the active substance is molecular-disperse distributed, i.e. it is dissolved in the basis structure of the carrier.
• a carrier in the solid state functions as solid solvent for the active substance molecules.
• the active substance is either integrated in the crystal lattice or is located in the space between the lattice molecules of the carrier. If the carrier with the dissolved active substance molecules is amorphous, these are known as glass-like solid solutions.
• stably spreadable solution describes a system of at least one active substance, molecular-disperse distributed in a viscous carrier, which is not a solid but a liquid. As with any liquid, the active substance molecules are dissolved in the carrier. The stably spreadable solution, as defined herein, is no longer capable of flowing.
• molecular-disperse as used herein, implies that the active substance is contained in the carrier as single molecules, dispersed in the carrier, i.e. the particle size of the active substance is on the level of single active substance molecules.
• the stably spreadable solution or rather the coating on the medical device, the stent, the catheter balloon without a stent or the catheter balloon with a stent has preferably a dynamic viscosity between 105 mPa ⁇ s and 1018 mPa ⁇ s, further preferred between 1,5 ⁇ 105 mPa ⁇ s and 1013 mPa ⁇ s, more preferred between 2,5 ⁇ 105 mPa ⁇ s and 1012 mPa ⁇ s and in particular preferred between 106 mPa ⁇ s and 109 mPa ⁇ s.
• the stably spreadable solution or the coating of the inventive device has preferably a viscosity >250 Pa ⁇ s and more preferred >1000 Pa ⁇ s. All herein mentioned values refer to a viscosity at 20° C.
• the viscosity is a measure for the thickness of a liquid or a gas.
• the reciprocal value of viscosity is fluidity, which is a measure for the flowability of a liquid or a solution. The higher the viscosity, the thicker (less capable of flowing) is the liquid; the lower the viscosity, the thinner (more capable of flowing) is the liquid.
• viscosity is associated with shearing viscosity however it is also possible to measure the extensional viscosity. It is known to the skilled artisan that several types of viscometers, measuring devices for measurement of tenacity (viscosity) exist, wherein usage of them is common knowledge to the skilled artisan.
• Solids are in a solid state of matter.
• a particular characteristic of solids is the stability of order of its components (amorphous or crystalline).
• a liquid is matter in the liquid state of matter.
• a liquid is a substance, wherein a dimensional change (i.e. a deformation or change in shape) is not resisted, while a change of volume is greatly resisted.
• a dimensional change i.e. a deformation or change in shape
• a change of volume is greatly resisted.
• liquids are volume-retaining, variable in shape and are liable to a constant Brownian movement.
• stably spreadable solution preferably also comprises melts and in particular undercooled melts.
• An undercooled melt is a state, wherein the substance remains in a state of matter, which usually should not exist under the transition point.
• An undercooled melt or liquid has a lower temperature at a given pressure, than would be adequate for its state of matter.
• the molecular mobility of the undercooled melt is reduced so far at the glass transition, that further lowering of temperature cannot establish a state of equilibrium of the undercooled melt as fast as thermal energy is withdrawn from the system.
• the molecules of the undercooled liquid become kinetic frozen at glass transition and therefore have a similar random distribution pattern as in the liquid state.
• the molecular mobility in the glass-like state is significantly reduced.
• the state of the undercooled melt (rubberelastic state) and the glass-like state of a substance are separated by the glass transition temperature T g . Above this temperature the substance is in the state of undercooled melt and below in a glass-like solid state, which is characterized by a viscosity greater than 10 12 Pa ⁇ s.
• the inventive coatings in form of an undercooled melt have a glass transition temperature T g preferably below 30° C., further preferred below 20° C., even further preferred below 10° C. and in particular preferred below 0° C. Furthermore, it is to be noted, that it is not crucial, whether the temperature falls below the glass transition temperature T g during storage of the inventive coated medical device or the inventive coated catheter balloon or the inventive coated stent. It is important that during introduction or implantation of the inventive coated medical device or the inventive coated catheter balloon or the inventive coated stent, the temperature is above of T g . Since the body temperature is usually 37° C., T g must be below 37° C., preferably below 30° C., further preferred under 20° C., even further preferred below 10° C. and in particular preferred below 0° C.
• stably spreadable solutions for coating of a medical device containing at least one active substance are in particular suitable to achieve a successful local application of an active substance and especially of hydrophobic active substances. Because of their structure (low degree of order), solutions show the advantage that there is no occurrence of strong lattice forces that would oppose a fast dissolution of the carrier and the release of the active substance. Stably spreadable solutions with strongly reduced flowing capabilities or strongly increased viscosity additionally show the property to remain on the medical device even during introduction through a distance of more than one meter of blood vessel. Furthermore, it could be shown that this is also true for implantation processes or during introduction by means of a catheter.
• the stably spreadable solution as defined herein, can also be described as a solution with a rubber-like, gel-like, viscous, semisolid, thickly viscose or highly viscose consistency. This means, without disturbances, stably spreadable coatings are in a solid-like state, but they begin to deform and to flow under the influence of external forces. The pressure, building up during dilatation, can be seen as such an external force, which deforms the coating which is in form of a stably spreadable solution.
• the active substance is molecular-disperse distributed in a carrier, so that it is already dissolved when coming into contact with the solvent (such as blood or other body liquids).
• the rate at which the active substance is released is solely determined by the dissolution rate of the carrier. The active substance is released more rapidly than any of its crystalline or colloidal forms during the dissolution procedure, because of the omission of the melting enthalpy.
• Stably spreadable solutions can prevent recrystallization, which occurs frequently during storage of pure amorphous active substances. Recrystallization is hindered by dissolution of the active substance in the carrier, whereby the molecules are mainly separated from each other.
• the proportion of the at least one active substance and the at least one carrier ranges from 90% by weight of the active substance to 10% by weight of the carrier to 10% by weight of the active substance to 90% by weight of the carrier.
• antirestenotic effective substances and active substances for treatment and prophylaxis of disorders of the blood and the blood-building organs in particular antithrombotic and anticoagulating active substances.
• antiproliferative, antimicrotubuli, antimitotic and cytostatic active substances are particularly preferred.
• the at least one active substance is selected from the group comprising or consisting of:
• Taxanes such as paclitaxel, docetaxel, limus-compounds such as rapamycin (sirolimus), biolimus A9, zotarolimus, everolimus, myolimus, novolimus, pimecrolimus, tacrolimus, ridaforolimus, temsirolimus, lapachon, vitamin K, vitamin D, propofol, diazepam.
• limus-compounds such as rapamycin (sirolimus), biolimus A9, zotarolimus, everolimus, myolimus, novolimus, pimecrolimus, tacrolimus, ridaforolimus, temsirolimus, lapachon, vitamin K, vitamin D, propofol, diazepam.
• taxanes and rapamycin and their derivatives are taxanes and rapamycin and their derivatives (limus-compounds), cumarin, cumarin-derivatives, heparin, heparin-derivatives, dabigatran, fondaparinux, hirudin, lepirudin, rivaroxaban and calcium-complexing agents.
• taxanes such as paclitaxel
• docetaxel also the limus-compounds such as rapamycin (sirolimus), biolimus A9, zotarolimus, everolimus, myolimus, novolimus, pimecrolimus, tacrolimus, ridaforolimus and temsirolimus.
• rapamycin sirolimus
• biolimus A9 zotarolimus
• everolimus everolimus
• myolimus novolimus
• pimecrolimus tacrolimus
• ridaforolimus ridaforolimus and temsirolimus.
• Suitable carriers are substances, in which the at least one active substance is soluble. Suitable carriers are furthermore compounds, which are able to prevent or impede crystallization in an undercooled melt or in a solution, because due to their great number of hydrogen bonds and at the same time allow a heating up to the melting temperature without degradation.
• An essential requirement for a suitable carrier is the miscibility of active substance and carrier in molten state, provided a stably spreadable solution shall be manufactured by melting method.
• the active substance and the carrier have to be soluble in the same solvent or solvent mixture, provided a stably spreadable solution shall be manufactured by solution method.
• a suitable pure carrier can be solid as well as liquid at room temperature. It is common knowledge to every chemical lab technician, how to determine, which active substance is soluble in which carrier and/or solvent. If adjuvants are used, they should or they also have to be soluble in the carrier or solvent. Suitable systems of active substance, carrier and optionally adjuvant and/or optionally solvent or solvent mixture can be found with simple standard solubility experiments, which belong to the common repertoire of the skilled artisan and even of any lab technician.
• the at least one carrier is selected from the group comprising or consisting of polyether, polylactonic acid, polyethylene glycol (PEG), poly(N-vinyl) pyrrolidone, N-dodecyl pyrrolidone, N-decyl pyrrolidone, N-octyl pyrrolidone, polyvinyl alcohols, derivatives of polyvinyl alcohols, glycolated polyesters, polyphosphoesters, polyethylene oxide propylene oxide, polyethylene oxide, hyaluronic acid, copolymers with PEG and polypropylene glycol, lipids, phospholipids, polyacrylic acid, polyacrylates, carboxymethyl chitosane, vanillin, farnesol, sorbitol, gelatine, derivatives of gelatine, fatty acid partial glycerides with a monocontent of 50 to 95% by weight, cellulose, derivatives of cellulose, hydroxypropyl cellulose,
• the at least one carrier is selected from the group comprising or consisting of: poly(N-vinyl) pyrrolidone, derivatives of polyvinyl alcohols, glycolated polyesters, polyacrylic acid, polyacrylates, sorbitol, gelatin, starch, derivatives of starch, cholic acid, lithocholic acid and polycarbonate urethanes.
• the at least one carrier is selected from the group comprising or consisting of dexpanthenol, hyaluronic acid, vanillin, carboxymethyl chitosane or polyethylene glycol.
• Oils, fats or waxes are not preferred or are not used for the manufacture of an inventive coating in form of a stably spreadable solution.
• n number of the monomer units
• polyethelene glycol an average molecular mass of 1.000 to 10.000 g/mol is preferred. This paragraph is valid for all herein disclosed embodiments and not only for the aforementioned one.
• a further embodiment concerns the use of a crystallization inhibitor as adjuvant in the coating of the inventive medical devices.
• the orderly aggregation of the drug molecules to a subnucleus and the crystallization or recrystallization is prevented by a crystallization inhibitor due to specific interactions with the active substance molecules.
• the viscosity of the coating can be increased by addition of an adjuvant, if the distribution of the adjuvant in the carrier lowers the mobility of the active substance in the system.
• the present embodiments are therefore also directed to medical devices, wherein the surface of the device is coated completely or partially with a stably spreadable solution containing at least one molecular-disperse distributed active substance, at least one carrier and at least one adjuvant. It is preferred, if a maximum of 15 percent by weight, further preferred a maximum of 10 percent by weight, even further preferred a maximum of 5 percent by weight or especially preferred a maximum of 1 percent by weight of the adjuvant is contained in the inventive coating.
• the herein made details to the percentages by weight of the adjuvant are made with reference to the total weight of the composition for coating of the inventive devices or in other words to the total weight of the inventive coating.
• the adjuvants are preferably able to significantly reduce the molecular mobility of the drug molecules in the stably spreadable solution or to prevent the orderly aggregation of drug molecules to a crystal by interaction with the active substance.
• solvent residues are contained in the coating, these solvent residues make less than 5 percent by weight with reference to the total weight of the inventive coating.
• the embodiments concern amongst others medical devices, in particular stents as well as catheter balloons with or without stent, wherein the surface of the device is coated completely or partially or at least partly with a stably spreadable solution containing at least one active substance and one carrier and the stably spreadable solution on the surface of the device can contain in addition optionally an adjuvant.
• the adjuvant is preferably a crystallization inhibitor selected from the group comprising or consisting of:
• sugar alcohols such as: glucose, mannitol, isomalt (palatinitol), lactitiol and maltitol, phenols amd biphenoles, urea, oleic acid, fatty acids, lecithin, soja lecithin, alkyl glycosides, glycerine, poly(N-vinyl) pyrrolidone, N-dodecyl pyrrolidone, N-decyl pyrrolidone, N-octyl pyrrolidone, sorbitan tristearate, sucrose esters and polyglycerine ester of fatty acids, carbamide acid esters, highly disperse silicon oxide, x-ray contrast agents.
• sugar alcohols such as: glucose, mannitol, isomalt (palatinitol), lactitiol and maltitol, phenols amd biphenoles, urea, oleic acid, fatty acids, lecit
• Further preferred adjuvants are thickeners, gelling agents or binders.
• Thickeners are used to lower the molecular mobility. There are also higher molecular crystallization inhibitors that can be classified as adjuvants for increasing viscosity. Hence, in the following it is only referred to adjuvants in general. Thickeners can be able to bind water. As a result viscosity is increased or they can also be used to preserve the high viscosity especially during storage by binding e.g. condensed water.
• thickeners are linear or branched macro molecules (e.g. polysaccharides or proteins) able to interact with each other through intermolecular interactions such as hydrogen bonds, hydrophobic interactions or ion relations.
• thickeners are plant gums. Plant gums are polysaccharides of natural origin able to increase the viscosity of a solution even at low concentrations drastically. The food industry uses them as thickeners, gelling agents and stabilizers.
• embodiments are also directed to medical devices, wherein the adjuvant is preferably a thickener selected from the group comprising or consisting of: agar, alginic acid, alginate, chicle, dammar, althaea extract, gellan gum (E 418), guar gum (E 412), gum Arabic (E 414), gum from plantago, gum from spruce juice, locust bean gum (E 410), karaya (E 416), konjac flour (E 425), mastix, pectin, tara gum (E 417), tragacanth (E 413), xanthan (E 415), carrageenan, cellulose, cellulose ether, gelatin, sago and starch.
• a thickener selected from the group comprising or consisting of: agar, alginic acid, alginate, chicle, dammar, althaea extract, gellan gum (E 418), guar gum (E 412), gum Arabic (E 414), gum from
• the stably spreadable solution can be prepared by melt-embedding, co-precipitation, evaporation of a solvent or condensing of a solution or a combination of these methods.
• the preparation of stably spreadable solutions by melt-embedding consists of a mixture of carrier, active substance and eventually adjuvants in molten state. This mixture has preferably either a melting point below the body temperature and also below the storage temperature or remains in the region of an undercooled melt.
• a solution of an active substance and a carrier, eventually in combination with an adjuvant in a volatile solvent is applied for the coating. While the solvent evaporates, an extremely high viscous, homogenous solution of the carrier, eventually an adjuvant and the active substance remains, containing the active substance in molecular-disperse form without any crystals or particles of the active substance.
• the mixture of carrier and active substance thereby form a stably spreadable solution.
• solvents with a high vapour pressure are preferred, i.e. solvents that are gaseous at low temperatures (e.g. 50° C.) or are highly volatile at room temperature.
• the boiling range of the solvent lies preferably between 0 and 150° C. and further preferred between 10° C. and 100° C. and particular preferred between 20° C. and 50° C.
• Suitable organic solvents are acetonitrile, dimethylsulfoxide, ethers such as dioxane, tetrahydrofurane (THF), light petroleum, diethyl ether, methyl-tert.-butyl ether (MTDC), ketones such as acetone, butanone or pentanone, alcohols such as methanol, ethanol, propanol, isopropanol, carboxylic acids such as formic acid, acetic acid, propionic acid, amides such as dimethylformamide (DMF) or dimethylacetamide, aromatic solvents such as toluene, benzene, xylene, pure hydrocarbon solvents such as pentane, hexane, cyclohexane, halogenated solvents such as chloroforme, methylene chloride, carbon tetrachloride, as well as carboxylic acid esters such as acetic acid ethyl ester.
• ethers such
• Suitable methods for rapid undercooling of a melt are melt-solidification, spray-solidification and hot-spin-melting.
• a general prerequisite for the preparation of stably spreadable solutions by melt-solidification is the miscibility of the carrier, active substance and adjuvants in the molten state.
• the molecular-disperse distribution which is necessary for the development of a stably spreadable solution, can only be achieved by dissolving the active substance in the molten carrier.
• An active substance is immiscible, if it is not miscible with the melt of a carrier in a concentration of ⁇ 1%. The execution of such melting experiments is well within the competence of the skilled artisan and even any chemical lab technician.
• the method for coating a catheter balloon comprises the following steps:
• Embodiments also include coated medical devices obtainable according to above method.
• the surface can be provided with an additional hemocompatible layer as base coat by applying semisynthetic heparin derivatives, such as desulfated reacetylated heparin or chitosane derivatives such as N-carboxy methylated, partially N-acetylated chitosane through covalent immobilization.
• semisynthetic heparin derivatives such as desulfated reacetylated heparin or chitosane derivatives such as N-carboxy methylated, partially N-acetylated chitosane through covalent immobilization.
• the coating After introduction or implantation of the inventive medical device into the body, the coating is pressed against the surrounding tissue, adheres there due to its high viscosity and releases the active substance in molecular-disperse, dissolved and/or in micro crystalline form to the tissue. In the latter case, the formation of microcrystals is triggered by contact with the aqueous system blood or the aqueous system extracellular liquid, because there are no crystals in the coating.
• Suspensions appear milky and cloudy, because similar to an emulsion, an inclusion of droplets of the lower concentrated phase occurs in the carrier.
• a crystalline active substance in a carrier shows macroscopic clouding of the transparent carrier. The only exception is, when the refraction indices of the active substance phase and the phase of the carrier are not different.
• the occurrence of clouding or a milky appearance is either a sign for a (re)crystallization of the active substance or for a suspension.
• stably spreadable solutions appear preferably clear or transparent. This does not exclude that they are colored or also glass colored but nonetheless clear or transparent. For a better quality control, it can be advantageous, to introduce a small amount of a coloring agent into the coating.
• Phase transitions of first order are phase transitions that are associated with an absorption or emission of latent heat. Plotting enthalpy H against the temperature then shows a step at the transformation temperature. Phase transitions of second order proceed without absorption or emission of latent heat. The enthalpy shows here a kink at the transformation temperature and the heat capacity shows a step when plotted against the temperature.
• a distinction between a solid solution, an undercooled melt, or a highly viscose solution, can be made by differential scanning calorimetry (DSC).
• DSC differential scanning calorimetry
• sample and reference are located on a thermoconductive disc with a good thermal conductivity, under which temperature sensors are affixed. The difference between the heat flows of sample and reference are measured. If sample and reference are equal, the heat flow difference is zero. A difference in the heat flow arises, if one sample changes during the measurement, e.g. by phase transformation, melting, or evaporation.
• Melting processes are characterized by a positive heat flow and crystallization processes by a negative heat flow.
• the transition of an amorphous substance from glass-like state to the region of undercooled melt is characterized by a sudden increase of heat capacity, however, without the occurrence of an additional heat transfer. Therefore, during a DSC, an elevated differential heat flow to the sample can be measured, after the glass transition temperature Tg is exceeded.
• the characterization of the coatings can also be done by means of release studies, i.e. the way of distribution of an active substance in the carrier can be determined.
• the medical device is therefore placed in a release-medium (adapted to the corresponding, the implant surrounding liquid, such as a physiological saline solution or blood) so that the coating can dissolve or rather release the active substance.
• a release-medium adapted to the corresponding, the implant surrounding liquid, such as a physiological saline solution or blood
• the active substance dissolved in the carrier substance
• the carrier dissolves quickly, occurrence of a temporary oversaturation of active substance in the release-medium is possible. From the extent of oversaturation and the rate of release of active substance in the release-medium, conclusions about the bioavailability can be made.
• the present embodiments are directed preferably to cathether balloons with or without a stent, wherein the surface of the catheter balloon as well as the surface of the stent is coated completely or partially with a stably spreadable solution containing at least one active substance. It is preferred, if the active substance is anti-restenotic and water insoluble or rather poorly water soluble.
• substances with already proven anti-restenotic efficacy on stents as the taxanes such as paclitaxel, docetaxel as well as the limus-compounds such as rapamycin (sirolimus), biolimus A9, zotarolimus, everolimus, myolimus, novolimus, pimecrolimus, tacrolimus, ridaforolimus and temsirolimus.
• the choice of active substances is not restricted to these two groups. In principal, any given active substance, able to hinder the development of restenosis, can be used, such as antiproliferative, antiangiogenic or antimigrative substances.
• catheter balloons can be used as catheter balloons.
• bifurcation balloons and folding balloons or special balloons such as the slit balloon or the scoring balloon.
• a solution of an active substance and a carrier, eventually in combination with an adjuvant in a volatile solvent is applied for coating. While the solvent evaporates, an extremely high viscous, homogenous solution of the carrier, eventually an adjuvant and the active substance remains, containing the active substance in molecular-disperse form without any crystals or particles of the active substance.
• the carrier and the at least one active substance thereby form a stably spreadable solution.
• the coating is pressed against the vessel wall, adheres there due to its high viscosity and releases the active substance in molecular-disperse, dissolved and/or in micro crystalline form to the vessel wall.
• the formation of micro crystals is triggered by contact with the aqueous system blood, after the coating in form of a stably spreadable solution is transferred to the vessel wall, because the inventive coating contains no active substance crystals or active substance particles.
• the whole balloon surface is coated evenly with a stably spreadable solution containing the active substance, this includes the areas under the folds as well as the surfaces not covered by the folds of the catheter balloon. Further it is preferred, if the at least one active substance is evenly distributed on the balloon surface. In the case of valvuloplasty balloon, a coating of the middle third of the balloon is preferred as only this area of the balloon comes into contact with the heart valve. The distal and ventral end of the catheter ballon remains preferably uncoated, in order to save active substance and to minimize the active substance exposure to the patient.
• the inventive coated catheter balloons are used without a stent, however, use with a biostable or biodegradable stent is also possible.
• This stent can either be uncoated or can be coated together with the catheter balloon or can already be coated before attachment, i.e. before crimping the stent on the catheter balloon either with the same or with another active substance as well as either with the same or with another carrier.
• the complete surface of the catheter balloon or only the folds of the balloon as well as the surface of the stent can be coated completely or partially with a stably spreadable solution containing at least one anti-restenotic active substance and one carrier.
• the stent can also be provided with another coating of choice.
• the release kinetic of the anti-restenotic active substance on the stent can be different from the release kinetic of the active substance on the catheter balloon. Therefore, the inventive expandable system also provides a combination of catheter balloon with a stent.
• the stent can also be provided only with a hemocompatible coating, with or without an active substance.
• the catheter balloon with a crimped stent can be coated simultaneously or the catheter balloon and the stent can be coated separately and afterwards the coated stent is crimped on the coated catheter balloon.
• coating shall not only comprise a coating of the surface of the catheter balloon but also a filling or coating of folds, cavities, pores, microneedles or other fillable spaces on or between or in the balloon material.
• the inventive coating is characterized by the absence of solids or solid particles. Therefore, it can be necessary to add as much crystallization inhibitor to the active substance, so that after evaporation or removal of the solvent of the coating solution the active substance does not crystallize or solid active substance particles are not formed in the carrier.
• crystal growth inhibitor describes a substance that prevents or decreases the formation of crystals after addition to an active substance in a stably spreadable solution.
• Carriers are termed as “hydrophil” if the partition coefficient between n-octanol and water is T OW ⁇ 6.30 (log T OW ⁇ 0.80), preferably T OW ⁇ 1.80 (log T OW ⁇ 0.26), more preferred T OW ⁇ 0.63 (log T OW ⁇ 0.20) and further preferred T OW ⁇ 0.40 (log T OW ⁇ 0.40).
• Anti-restenotic active substances are termed as “hydrophobic” or “lipophilic” if the partition coefficient between n-butanol and water is ⁇ 0.5, preferably ⁇ 0.7, more preferred ⁇ 0.9 and in particular preferred ⁇ 1.1.
• stably spreadable solutions are in particular suitable for a coating containing active substances and preferably hydrophobic, anti-restenotic active substances and impart the following properties for successful local application:
• the method for coating a catheter balloon comprises the following steps:
• dilatable catheter balloons are coated by this method.
• the coating solution is applied to all surfaces to be coated. This includes the surface of the catheter balloon as well as the surface of the catheter balloon and the stent.
• the catheter balloon can also be coated only partially.
• the catheter balloon can be coated in its folded or comprimated (deflated) state as well as in its dilated or expanded (inflated) state, whereby after applying the coating the balloon is then refolded.
• the catheter balloon can be coated without a stent and also with a stent crimped thereon, i.e. a crimped stent, so that the abluminal surface of the stent and also the balloon surface, in particular between the stent struts is coated with the stably spreadable, viscous solution containing at least one anti-restenotic active substance and at least one carrier.
• An uncoated stent or an already coated stent can be used with the catheter balloon.
• the stent surface can be provided with an additional hemocompatible layer as basic coating, by application of semisynthetic heparin derivatives through covalent immobilization, such as desulfated reacetylated heparin or chitosane derivatives such as N-carboxy methylated and partially N-acetylated chitosane on the stent surface.
• semisynthetic heparin derivatives through covalent immobilization, such as desulfated reacetylated heparin or chitosane derivatives such as N-carboxy methylated and partially N-acetylated chitosane on the stent surface.
• a coating of a stably spreadable solution containing an anti-restenotic active substance in a carrier, optionally with an adjuvant is obtained after evaporating or removing the solvent at elevated temperature and/or under reduced pressure.
• the anti-restenotic active substance is thereby molecular-disperse distributed in the solidified or highly viscous carrier. In this way, usability of hydrophobic active substances is extended to hydrophil systems without changes to the structure of the active substance.
• the coating can also be dried actively by heating or by applying a vacuum or in a gas flow. Use of temperatures between 50° C. and 100° C. is preferred.
• anti-restenotic effective hydrophobic substances such as paclitaxel, docetaxel, rapamycin (sirolimus), biolimus A9, zotarolimus, everolimus, myolimus, novolimus, pimecrolimus, tacrolimus, ridaforolimus, temsirolimus, cyclosporines, vitamin K, propofol, and diazepam.
• rapamycin rapamycin
• biolimus A9 zotarolimus
• everolimus everolimus
• myolimus novolimus
• pimecrolimus tacrolimus
• ridaforolimus temsirolimus
• cyclosporines vitamin K, propofol, and diazepam
• vitamin K propofol
• diazepam particularly preferred are taxanes and rapamycin and its derivatives (limus-compounds).
• taxane is used in the application as generic term for paclitaxel, paclitaxel derivatives and paclitaxel analogs.
• limus-compounds stand for sirolimus (rapamycin) and its derivatives and analogs.
• derivative denotes a derived substance of similar structure to a corresponding basic structure.
• Derivatives are substances, which molecules have in place of an H-atom or a functional group another atom or another functional group, whereby one or more atoms/functional groups are removed and/or added and/or exchanged.
• a catheter balloon wherein the at least one taxane is preferably paclitaxel or the at least one limus-compound is rapamycin.
• the active substances paclitaxel or rapamycin are thereby provided in combination with a suitable carrier in the coating of the catheter balloon.
• the active substance releasing coating on the catheter balloon and/or the stent can contain the following substances: polyether, polylactonic acid, polyethylene glycol (PEG), poly(N-vinyl) pyrrolidone, N-dodecyl pyrrolidone, N-decyl pyrrolidone, N-octyl pyrrolidone, polyvinyl alcohols, derivatives of polyvinyl alcohols, glycolated polyester, polyphosphoester, polyethylene oxide propylene oxide, polyethylene oxide, hyaluronic acid, copolymers with PEG and polypropylene glycol, lipids, phospholipids, polyacrylic acid, polyacrylates, carboxymethyl chitosane, lanolin, vanillin, sorbitol, gelatine, derivatives of gelatine, fatty acid partial glycerides with a monocontent of 50 to 95 w.-%, highly disperse silicion oxide, cellulose, derivatives of cellulose,
• carrier particularly preferred as carrier are dexpanthenol, hyaluronic acid, carboxymethyl chitosane, vanillin and PEG and especially dexpanthenol.
• Dexpanthenol is known under the trademark Bepanthen® and the synonyms panthothenol, D-panthenol or panthenol and the IUPAC name (+)-(R)-2,4-dihydroxy-N-(3-hydroxypropyl)-3,3-dimethyl butyramide.
• an amount of 0.5 ⁇ g to 50 ⁇ g active substance is applied to the surface of the balloon per mm2 surface of the balloon catheter to be coated and preferably an amount of 1 ⁇ g to 20 ⁇ g active substance per mm2 surface of the balloon catheter to be coated.
• Per catheter balloon preferably 10 to 1000 ⁇ g active substance and particularly preferred 20 ⁇ g to 400 ⁇ g active substance are applied on the balloon.
• Chloroform, ethanol, methanol, tetrahydrofuran, acetone, methyl acetate, ethyl acetate, methylene chloride or its mixtures, such as methanol/ethanol-mixtures or ethanol/water-mixtures can be used as solvent for the mixture of active substance and carrier.
• a suitable solvent dissolves the required amount of active substance and carrier and does not or only slightly damages the material of the catheter balloon.
• Particularly preferred are acetone, ethanol and ethyl acetate.
• the chosen solvent preferably 0.1 mg-600 mg, further preferred 1 mg to 500 mg and particularly preferred 10 mg-250 mg active substance are dissolved. Furthermore, in one mL of the chosen solvent preferably 0.1 mg-600 mg, more preferred 1 mg to 250 mg and particularly preferred 10 mg-250 mg carrier are dissolved.
• a catheter balloon with a coating exhibiting a proportion of anti-restenotic active substance and carrier of 90 percent by weight anti-restenotic active substance to 10 percent by weight carrier to 10 percent by weight anti-restenotic active substance to 90 percent by weight carrier.
• a catheter balloon with a coating exhibiting a molar ratio of active substance to carrier of 90% active substance to 10% carrier to 10% active substance to 90% carrier. Further preferred are mixtures of 1:5 to 5:1 and even more preferred of 1:2 to 2:1.
• a further adjuvant e.g. as crystallization inhibitor in the active substance solution.
• suitable adjuvants are for example biologically acceptable organic substances that improve the coating properties and increase the uptake of active substances in the vessel such as amino acids, vitamins, benzoic acid benzyl ester, triethyl- and dimethyl phthalate, fatty acids esters such as isopropyl myristate and -palmitate, triacetin and the like. Mixtures of these different substances also proved to be suitable.
• the mixture of the polysaccharide carrageenan, lecithin and glycerine showed to be a suitable active substance carrier system.
• physiological acceptable salts can be used as adjuvants for incorporation of the active substance.
• a further preferred embodiment comprises a coated catheter balloon with a crimped stent.
• the stent can be uncoated or have the same inventive coating as the catheter balloon.
• the catheter balloon with or without a stent is coated completely or partially with a glass-like solid solution of anti-restenotic active substance in a carrier by spraying, brushing, squirting, dragging, rolling or pipetting method or electrospinning, wherein a further adjuvant such as a crystallization inhibitor can be added to the coating solution.
• the catheter balloon can be coated partially or completely in the expanded or in the folded state or together with a stent crimped thereon. Moreover, the coating can be applied exclusively to the folds or exclusively outside of the folds.
• the coating can be realized by spraying, dipping, brushing, squirting, dragging, thread dragging, rolling or pipetting method.
• the pipetting, dragging, rolling or squirting method is especially suitable for use on a folded catheter balloon or a catheter balloon with folds, because with these methods it is possible to apply substances directly in the folds or under the folds. Drying of the coated balloon catheters with or without a stent can be done by rotation-drying.
• the coating methods are described in detail in WO2008086794A.
• active substance containing composition or “coating solution” as used herein is to be understood as the mixture of at least one active substance, a carrier and a solvent or solvent mixture, thus, an actual solution of an active substance, a carrier and at least one further component selected from the solvents mentioned herein.
• An adjuvant can be added to the coating. This can be a crystallization inhibitor or a substance that further accelerates the dissolving of the coating during dilatation, fatty acid esters, amino acids, vitamins, salts and/or membrane-forming or membrane-disruptive substances.
• solution shall further clarify that a liquid mixture is concerned, which can have a rubber-like, gel-like, thick or paste-like (thickly viscous or highly viscous) consistency.
• the coating solution is not necessarily a stably spreadable solution. These can be obtained by use of a coating solution, only after application and after removal of the solvent e.g. by drying.
• stably spreadable solutions can mostly only be obtained by rapid cooling or shock-freezing of the melt of active substance and carrier. It is also possible to coat the balloon catheter by applying a melt of at least one anti-restenotic active substance and a carrier. In this case no further solvent is present.
• inventive coated catheter balloons without a crimped stent are in particular suitable for treatment of small vessels, preferably small blood vessels.
• Small vessels are those with a vessel diameter smaller than 2.5 mm, preferably smaller than 2.2 mm.
• inventive coated catheter balloons without crimped stent are in particular suitable for treatment of periphery blood vessels, where the implantation of a stent is problematic.
• paclitaxel (Sigma-Aldrich Chemie GmbH, Germany) is dissolved in acetone.
• dexpanthenol (Cal Roth GmbH, Germany) is dissolved in 500 ⁇ l ethanol. Afterwards both solutions are combined.
• 100 mg paclitaxel and 200 mg PEG A and 200 mg PEG B are dissolved in 1000 ⁇ l acetone.
• PEG A is PEG 400 (Sigma-Aldrich Chemie GmbH, Germany) and has a molecular mass between 380 and 420 and an average molecular mass M n of 400.
• PEG B is a polyethylene glycol (Sigma-Aldrich Chemie GmbH, Germany) with a molecular mass between 950 and 1050.
• sirolimus (Merck4Biosciences, Germany) is dissolved in ethyl acetate and 200 mg PEG A and 200 mg PEG B are dissolved in 1000 ⁇ l absolute ethanol. Both solutions are combined.
• the folding balloon is held in a horizontal position on a revolvable axis and sprayed with active substance containing solution.
• the solvent is evaporated afterwards in a drying chamber at 70° C. for 30 min.
• a coated or uncoated (bare stent) stent can be crimped thereon.
• a hemocompatible coated stent with the coating of choice by pipetting method or spray method, while it is crimped on the already coated balloon catheter.
• the folding balloon is held in a horizontal position on a revolvable axis, such that the fold to be filled always comes to rest on the upper side.
• Each fold is then filled step by step with the viscous active substance containing solution of example 1 by filling each fold slowly from the beginning of the fold to the end of the fold with a Teflon cannula as extension to a needle tip and subsequent drying in a drying chamber at 70° C. for 30 min.
• the result is a folding balloon, wherein exclusively the folds are coated with a transparent, stably spreadable solution. This can be seen particularly well after dilatation. For a better quality control, a small amount of a couloring agent such as curcumin can be introduced.
• a coated or uncoated (bare stent) stent can be crimped thereon.
• a hemocompatible coated stent with the coating of choice by pipetting method or spray method, while it is crimped on the already coated balloon catheter.
• the stent is crimped on a folding balloon.
• the folding balloon with stent is held in a horizontal position on a revolvable axis and sprayed with active substance containing solution.
• the solvent is evaporated afterwards in a drying chamber at 80° C. for 30 min.
• rapamycin is dissolved in 500 ⁇ L ethanol and 500 ⁇ L glycerine is added. Therein 5 mg carrageenans are added.
• the folding balloon is held in a horizontal position on a revolvable axis and is slightly delated and then brushed with the active substance containing solution.
• the solvent is evaporated afterwards in a drying chamber at 60° C. for 20 min. After that the balloon is again folded. Subsequently, if desired, a coated or uncoated stent can be crimped thereon.
• paclitaxel is dissolved in 1000 ⁇ L ethanol. This solution is mixed with 8 mg of molten chios-mastix (Sigma-Aldrich Chemie GmbH, Germany) (heated to approximately 80° C.). Likewise 20 mg Carbopol is dissolved in 500 ⁇ l water. Afterwards both solutions are combined.
• the folding balloon is held in a horizontal position on a revolvable axis and sprayed with the active substance containing solution according to example 9.
• the solvent is evaporated afterwards in a drying chamber at 70° C. for 30 min.
• a coated or uncoated (bare stent) stent can be crimped thereon.
• a hemocompatible coated stent with the coating of choice by pipetting method or spray method, while it is crimped on the already coated balloon catheter.
• paclitaxel is dissolved in 1000 ⁇ L acetone.
• 30 mg dexpanthenol is dissolved in 500 ⁇ L ethanol. Afterwards both solutions are combined and 10 mg ricinoleic acid is added.
• the folding balloon is held in a horizontal position on a revolvable axis, such that the fold to be filled always comes to rest on the upper side.
• Each fold is then filled step by step with the viscous active substance containing solution of example 11 by filling each fold slowly from the beginning of the fold to the end of the fold with a Teflon cannula as extension to a needle tip and subsequent drying in a drying chamber at 70° C. for 30 min.
• a coated or uncoated (bare stent) stent can be crimped thereon.
• a hemocompatible coated stent with the coating of choice by pipetting method or spray method, while it is crimped on the already coated balloon catheter.
• paclitaxel is dissolved in 800 ⁇ L ethanol and 2 mg resorcin is added (Merck4Biosciences, Germany).
• 200 mg PEG B is dissolved in 1000 ⁇ L acetone. Afterwards both solutions are combined.
• the balloon catheter is pinned through an adapter to the drive shaft of a rotation motor and is fixated in such a way that it comes to rest in the horizontal plane without being bended.
• the whole balloon surface is coated with the solution by painting the balloon with a set number of paintings.
• a drop of the solution is dragged over the rotating balloon, until the solvent is evaporated so far that a stably spreadable solution is formed.
• the catheter is taken from the machine and dried at 60° C. and further rotation over night.
• a coated or uncoated (bare stent) stent can be crimped thereon.
• a hemocompatible coated stent with the coating of choice by pipetting method or spray method, while it is crimped on the already coated balloon catheter.
• rapamycin (Merck4Biosciences, Germany) is dissolved in 1000 ⁇ l ethyle acetate. Likewise 60 mg dexpanthenol is dissolved in 500 ⁇ L ethanol. Afterwards both solutions are combined and 5 mg isomalt (Carl Roth GmbH, Germany) is added.
• a first layer of the coating solution from example 15 is sprayed on the stent. After drying this layer at room temperature, a second layer of the coating solution from example 15 is sprayed on the stent and then the stent is dried in a drying chamber at 70° for 30 min.
• a coated or uncoated (bare stent) stent can be crimped thereon.
• a hemocompatible coated stent with the coating of choice by pipetting method or spray method, while it is crimped on the already coated balloon catheter.
• a blood vessel is extracted from a pig and stored in physiological saline solution, which shall also perfuse through the vessel. Subsequently, the balloon catheter is expanded in the vessel and the amount of coating adhered to as well as remaining on the balloon catheter is determined. This test showed that all catheter balloons, which were manufactured according to the examples, only had small amounts ( ⁇ 15%) of the coating remaining on the balloon surface.
• cleaned stents made of medical stainless steel LVM 316 were dipped for 5 minutes in a 2% solution of 3 aminopropyltriethoxysilane in a mixture of ethanol/water (50/50: (v/v)) and dried afterwards. Subsequently, the stents were washed over night with demineralized water.

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