US20050176678A1 - Compounds and method for coating surfaces in a haemocompatibe manner - Google Patents

Compounds and method for coating surfaces in a haemocompatibe manner Download PDF

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US20050176678A1
US20050176678A1 US10/513,982 US51398204A US2005176678A1 US 20050176678 A1 US20050176678 A1 US 20050176678A1 US 51398204 A US51398204 A US 51398204A US 2005176678 A1 US2005176678 A1 US 2005176678A1
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acid
layer
hemocompatible
heparin
active agent
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Roland Horres
Marita Linssen
Michael Hoffmann
Erika Hoffmann
Donato Di Baise
Volker Faust
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Hemoteq AG
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Assigned to HEMOTEQ GMBH reassignment HEMOTEQ GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HORRES, ROLAND, DI BIASE, DONATO, FAUST, VOLKER, HOFFMANN, ERIKA, HOFFMANN, MICHAEL, LINSSEN, MARITA KATARINA
Publication of US20050176678A1 publication Critical patent/US20050176678A1/en
Priority to US12/827,710 priority patent/US8784862B2/en
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    • A—HUMAN NECESSITIES
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    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
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    • 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
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/06—Use of macromolecular materials
    • A61L33/08—Polysaccharides
    • A—HUMAN NECESSITIES
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    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/10—Heparin; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D105/00—Coating compositions based on polysaccharides or on their derivatives, not provided for in groups C09D101/00 or C09D103/00
    • C09D105/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the use of oligo- and/or polysaccharides containing the sugar building block N-acylglucosamine and/or N-acylgalactosamine for the preparation of hemocompatible surfaces, methods for the hemocompatible coating of surfaces with said oligo- and/or polysaccharides as well as the use of the hemocompatibly coated surfaces.
  • non-thrombogenic, hemocompatible materials such as protheses, organ spareparts, membranes, cannulae, tubes, blood containers, stents etc. which do not activate the coagulation system in case of blood contact and do not cause coagulation of the blood.
  • EP-B-0 333 730 describes a method for preparation of hemocompatible substrates by incorporation, adhesion and/or modification and attachment of non-thrombogenic endothelial cell surface polysaccharide (HS-I).
  • HS-I non-thrombogenic endothelial cell surface polysaccharide
  • the immobilization of this specific endothelial cell surface proteoheparan sulphate HS I on biological or artificial surfaces causes that suchlike coated surfaces become blood compatible and suitable for the permanent blood contact.
  • said process for the generation of HS I requires the cultivation of endothelial cells, so that the economical usability of said process is very limited because the cultivation of endothelial cells is time consuming, and relatively large amounts of cultivated endothelial cells are only available at a considerably high cost.
  • the object of the present invention to provide medical products, which allow a continuous controlled ingrowth of the medical product—on the one hand by suppression of the cellular reactions during the first days and weeks after the implantation by means of the chosen active agents and active agent combinations and on the other hand by providing an atrombogeneous resp. inert resp. biocompatible surface, which guarantees, that with decreasing of the active agent influence no reactions on the present alien surface occur anymore, which also can lead to complications on the long-term.
  • the present invention discloses polysaccharides of the general formula Ia as well as structurally very similar polysaccharides of the general formula Ib
  • the polysaccharides according to formula Ia have molecular weights from 2 kD to 400 kD, preferably from 5 kD to 150 kD, more preferably from 10 kD to 100 kD, and particularly preferably from 30 kD to 80 kD.
  • the polysaccharides according to formula Ib have molecular weights from 2 kD to 15 kD, preferably from 4 kD to 13 kD, more preferably from 6 kD to 12 kD, and particularly preferably from 8 kD to 11 kD.
  • the variable n is an integer ranging from 4 to 1050.
  • n is an integer from 9 to 400, more preferably from 14 to 260, and particularly preferably an integer between 19 and 210.
  • the general formulas Ia and Ib represent a disaccharide, which is to be seen as a basic unit of the polysaccharide according to invention and forms the polysaccharide by stringing together said basic unit n times. Said basic unit comprising two sugar molecules does not intend to suggest that the general formulas Ia and Ib only relate to polysaccharides having an even number of sugar molecules. Of course, the general formula Ia and the formula Ib also comprise polysaccharides having an odd number of sugar units. Hydroxy groups are present as terminal groups of the oligosaccharides and polysaccharides, respectively.
  • the groups Y and Z independently of each other, represent the following chemical acyl or carboxyalkyl groups: —CHO, —COCH 3 , —COC 2 H 5 , —COC 3 H 7 , —COC 4 H 9 , —COC 5 H 11 , —COCH(CH 3 ) 2 , —COCH 2 CH(CH 3 ) 2 , —COCH(CH 3 )C 2 H 5 , —COC(CH 3 ) 3 , —CH 2 COO ⁇ , —C 2 H 4 COO ⁇ , —C 3 H 6 COO ⁇ , —C 4 H 8 COO — .
  • the group Y represents an acyl group
  • the group Z represents a carboxyalkyl group. It is more preferred if Y is a group —COCH 3 , —COC 2 H 5 or —COC 3 H 7 and in particular —COCH 3 .
  • Z is a carboxyethyl or carboxymethyl group, the carboxymethyl group being particularly preferred.
  • the disaccharide basic unit shown by formula Ia comprises each a substituent Y and a further group Z.
  • the polysaccharide of the invention comprises two different groups, namely Y and Z.
  • the general formula Ia should not only comprise polysaccharides containing the groups Y and Z in a strictly alternating sequence, which would result from stringing together the disaccharide basic units, but also polysaccharides carrying the groups Y and Z in a completely random sequence at the amino groups. Further, the general formula Ia should also comprise polysaccharides containing the groups Y and Z in different numbers.
  • the ratios of the number of Y groups to the number of X groups can be between 70%:30%, preferably between 60%:40%, and particularly preferably between 45%:55%.
  • polysaccharides of the general formula Ia carrying on substantially half of the amino groups the Y residue and on the other half of the amino groups the Z residue in a merely random distribution.
  • substantially half means exactly 50% in the most suitable case but should also comprise the range from 45% to 55% and especially from 48% to 52% as well.
  • Y is one of the following groups: —CHO, —COCH 3 , —COC 2 H 5 or —COC 3 H 7 .
  • Y is one of the following groups: —CHO, —COCH 3 , —COC 2 H 5 or —COC 3 H 7 .
  • the compounds of the general formula Ib contain only a minor amount of free amino groups. As with the ninhydrine test free amino groups could not be detected anymore, it can be concluded due to the sensitivity of this test, that less than 2%, preferred less than 1% and especially preferred less than 0.5% of all of the —NH—Y groups are present as free amino groups, i.e. at this low percentage of the groups —NH—Y that Y represents hydrogen.
  • the general formulas Ia and Ib also comprise alkali and alkaline earth metal salts of the respective polysaccharides.
  • alkali metal salts such as the sodium salt, potassium salt, lithium salt or alkaline earth metal salts such as the magnesium salt or calcium salt can be mentioned.
  • ammonia primary, secondary, tertiary and quaternary amines, pyridine and pyridine derivatives, ammonium salts, preferably alkyl ammonium salts and pyridinium salts, can be formed.
  • the bases forming salts with the polysaccharides include inorganic and organic bases such as NaOH, KOH, LiOH, CaCO 3 , Fe(OH) 3 , NH 4 OH, tetraalkyl ammonium hydroxides and similar compounds.
  • Heparan sulphates are ubiquitous on cell surfaces of mammals. Depending on the cell type, they are very different with respect to molecular weight, degree of acetylation and degree of sulfation. Liver heparan sulphate, for example, has a degree of acetylation of approximately 50%, whereas the heparan sulphate from the glycocalyx of endothelial cells can show a degree of acetylation of up to 90% and more. Heparin only shows a very small degree of acetylation of up to 5%.
  • liver heparan sulphate and heparin The degree of sulfation of liver heparan sulphate and heparin is ⁇ 2 per disaccharide unit, of endothelial cell heparan sulphate nearly 0, and of heparan sulphates from other cell types between 0 and 2 per disaccharide unit.
  • All heparan sulphates have the process of biosynthesis in common with heparin.
  • the core protein with the xylose-containing bond region is built up. It consists of the xylose and two galactose residues connected therewith.
  • glucuronic acid and galactosamine are then alternately bonded to each other until the respective chain length is achieved.
  • Heparin is built up alternately from D-glucosamine and D-glucuronic acid resp. L-iduronic acid, wherein D-glucosamine and D-glucuronic acid are linked in a ⁇ -1,4-glycosidic manner (resp. L-iduronic acid in an ⁇ -1,4-glycosidic manner) to the disaccharide, which forms the heparin subunits. These subunits, in turn, are linked to each other in a ⁇ -1,4-glycosidic manner and lead to the heparin. The position of the sulfonyl groups can change.
  • a tetrasaccharide unit contains an average of 4 to 5 sulfuric acid groups.
  • Heparan sulphate also referred to as heparitin sulphate, contains, with the exception of liver heparan sulphate, less N— and O-bonded sulfonyl groups than heparin, but more N-acetyl groups.
  • the compounds of the general formula Ia (see FIG. 3 c as example) and the compounds of the general formula Ib (see FIG. 3 b as example) are structurally very similar to the natural heparan sulphate of endothelial cells, but prevent the initially described disadvantages in using endothelial cell heparan sulphates.
  • a special pentasaccharide unit is made responsible which can be found in commercial heparin preparatives in about every 3rd molecule.
  • Heparin preparations of different antithrombotic activity can be produced by special separation techniques.
  • highly active for example by antithrombin-III-affinitychromatography obtained preparations (“High-affinity”-heparin) this active sequence is found in every heparin molecule, while in “No-affinity”-preparations no characteristical pentasaccharide sequences and thus no active inhibition of coagulation can be detected.
  • the amino groups of the heparin are mostly N-sulphated or N-acetylated.
  • the most important O-sulphation positions are the C2 in the iduronic acid as well as the C6 and the C3 in the glucosamine.
  • the sulphate group on C6 is made responsible, in smaller proportion also the other functional groups.
  • heparin or heparansulphates Surfaces of medicinal implants coated with heparin or heparansulphates are and remain only conditionally hemocompatible by the coating.
  • the heparin or heparansulphate which is added onto the artificial surface loses partially in a drastic measure its antithrombotic activity which is related to a restricted interaction due to steric hindrence of the mentioned pentasaccharide units with antithrombin III.
  • heparansulphate still show the hemocompatible properties of heparin and additionally during the immobilisation of the compounds of the general formulas Ia and Ib no noteworthy depositions of plasma proteins which represent an initial step in the activation of the coagulation cascade could be observed.
  • the hemocopatible properties of the compounds according to invention still remain also after their immobilisation on artificial surfaces.
  • the sulphate groups of the heparin resp. the heparansulphates are necessary for the interaction with antithrombin III and impart thereby the heparin resp. the heparansulphate the anticoagulatory effect.
  • the inventive compounds according to formula Ib as well as the compounds according to formula Ia are not actively coagulation suppressive, i.e. anticoagulative, due to an almost complete desulphation the sulphate groups of the compounds of the general formulas Ib are removed up to a low amount of below 0.2 sulphate groups per disaccharide unit.
  • the compounds of the invention according to the general formula Ib can be made from heparin or heparan sulphates by first substantially entirely desulfating and then substantially entirely N-acylating the polysaccharide.
  • substantially entirely desulphated refers to a degree of desulfation of more than 90%, preferred more than 95%, and particularly preferred more than 98%.
  • the degree of desulfation can be determined according the so-called ninhydrine test, which detects free amino groups. Desulfation is effected to such an extent that a color reaction is no longer obtained with DMMB (dimethylmethylene blue). This color test is suitable for detecting sulphated polysaccharides; however, the detection limit thereof is not known in the literature of the art.
  • the desulfation can, for example, be carried out by heating the pyridinium salt in a solvent mixture. In particular, a mixture of DMSO, 1,4-dioxane and methanol proved to be suitable.
  • Heparansulphates as well as heparin were desulphated via total hydrolysis and subsequently reacylated. Thereafter the number of sulphate groups per disaccharide unit (S/D) was determined by 13C-NMR.
  • the following table 1 shows these results on the example of heparin and desulphated, reacetylated heparin (Ac-heparin).
  • the compounds of the general formulas Ia and Ib have a content of sulphate groups per disaccharide unit of less than 0.2, preferred less than 0.07, more preferred less than 0.05 and especially preferred less than 0.03 sulphate groups per disaccharide unit.
  • substantially entirely N-acylated refers to an N-acylating degree of more than 94%, preferably more than 97%, and particularly preferably more than 98%.
  • the acylation is effected in such a complete manner that the ninhydrine detection of free amino groups does no longer show any color reaction.
  • acylation agents carboxylic acid chlorides, bromides or anhydrides are used preferably.
  • Acetic acid anhydride, propionic acid anhydride, butyric acid anhydride, acetic acid chloride, propionic acid chloride or butyric acid chloride, for example, are suitable for preparing the compounds according to the invention.
  • Carboxylic acid anhydrides are particularly suitable as acylation agents.
  • deionized water is used, preferably together with a cosolvent, which is added in an amount of 10 to 30 volume percent.
  • cosolvents methanol, ethanol, DMSO, DMF, acetone, dioxane, THF, acetic acid ethyl ester and other polar solvents are suitable. If carboxylic acid halides are used, polar water-free solvents such as DMSO or DMF are preferably used.
  • solvent deionized water preferably together with a cosolvent, which is added in an amount of 10 to 30 volume percent.
  • cosolvents methanol, ethanol, DMSO, DMF, acetone, dioxane, THF, acetic acid ethyl ester and other polar solvents are suitable.
  • the compounds of the invention according to the general formula Ia have a carboxylate group on half of the sugar molecules, and a N-acyl group on the other half.
  • Such compounds can also be made from the polysaccharides hyaluronic acid, dermatan sulphate, chondroitin sulphate. Differencies to heparin and heparansulphate result from the connection of the monosaccharides, which are here not present in a 1,4-glycosidic but 1,3-glycosidic connection. The disaccharides are again connected to each other 1,4-glycosidically. In the case of the also in the blood coagulation antithrombotically active dermatan sulphates [Biochem.
  • chondroitin sulphate and dermatan sulphate are chondroitin sulphate and dermatan sulphate. Typical for this group ist the ⁇ -1,3-glycosidic bonding of the uronic acid to the galactosamine. Galactosamine is bound on its part ⁇ -1,4-glycosidically to the next uronic acid. Dermatan sulphate differs from chondroitin sulphate by a high amount of another also in heparin and heparan sulphate occurring uronic acid, the L-iduronic acid. The sulphation degree of chondroitin sulphate is at 0.1 to 1.3 sulphate groups per disaccharide.
  • Dermatan sulphate has with 1.0 to 3.0 sulphate groups per disaccharide an averagely higher sulphation degree as chondroitin sulphate and thereby reaches heparin like values.
  • the amino groups are N-acetylated.
  • Heparin and heparan sulphate are solely ⁇ -1,4-bound, whilst in hyaluronan, which is also accounted to this type, the monosaccharids D-glucuronic acid and D-glucosamine are ⁇ -1,3-bound monosaccharids.
  • This polysaccharide has as only polysaccharide no sulphate groups and is N-acetylated. The molecular weight reaches in comparison to heparin and heparan sulphate maximum values up to 8000 kD. The reduction of the chain length and the maintaining of the acetyl groups resp. the N-reacetylation leads to a structure, which is distinguishable from the formula Ib only by the ⁇ -1,3-glycosidic connection of the monosaccharids.
  • Chitin is a nitrogen-containing polysaccharide, the monomer units of which consist of N-acetyl-D-glucosamine, which are linked in a ⁇ -1,4-glycosidic manner. This results in linear polymers consisting of about 2,000 sugar units and having a molecular weight of about 400,000 g/mol. Chitin shows a very poor solubility and is almost insoluble in water, organic solvents and dilute acids or dilute bases. Mixing with strong acids leads to hydrolysis, where D-glucosamine and acetic acid are produced. The treatment with strong bases, however, leads to chitosan and acetate.
  • Chitosan can easily be produced by the saponification of chitin.
  • Chitosan consists of ⁇ -1,4-glycosidically linked glucosamine (2-amino-2-deoxy-D-glucose).
  • Chitosan is known for its film forming properties, and is further used as a basic material for ion exchangers and as an agent for reducing the cholesterol level in the blood serum and for weight reduction.
  • the substances according to the invention of the general formula Ia can be made from chitin by partially deacetylating chitin by means of strong bases and then monocarboxyalkylating the free amino groups (see FIG. 1 ).
  • the deacetylation degree i.e. the amount of demasked primary amino groups, can be determined volumetrically.
  • the quantitative detection of the free amino groups is effected by means of the ninhydrine reaction.
  • deacetylation degrees of 20 to 80% can be obtained.
  • Deacetylation degrees of 40 to 60% are preferred, 45 to 55% are particularly preferred.
  • polysaccharides can be obtained the sugar units of which contain either an N-acetyl group or an N-carboxyalkyl group in a merely random distribution.
  • Chitosan which is easily accessible by the basic hydrolysis of the N-acetyl groups of the chitin (see FIG. 1 ), equally serves as a starting material for the synthesis of the polysaccharides according to formula Ia.
  • the compounds according to the invention can, on the one hand, be obtained by carboxyalkyating substantially the half of the free amino groups in a first step, and then acylating the remaining free amino groups, or by first carrying out the acylation and then reacting the remaining free amino groups with a suitable carboxyalkylation agent. It is preferred if substantially the half of the amino groups is acylated and the remaining half is carboxyalkylated.
  • Partially N-acylated chitosan refers to an N-acylation degree of 30-70%, preferably of 40-60%, and particularly preferably of 45-55%. Particularly preferred are chitosan derivates carrying the Y residue on substantially the half of the amino groups, and on the other half of the amino groups the Z residue in a merely random distribution. The term “substantially the half” means exactly 50% in the most suitable case, but should also include the range of 45% to 55%.
  • the carboxyalkylation and acylation degrees can be determined by means of 13C-NMR, for example (deviation tolerance ⁇ 3%).
  • the present invention describes the use of the compounds of the general formulas Ia and/or Ib as well as salts of said compounds for the coating, in particular a hemocompatible coating of natural and/or artificial surfaces.
  • Hemocompatible refers to the property of the compounds according to the invention, which means not to interact with the substances of the blood coagulation system or the blood platelets and thus not to trigger the blood coagulation cascade.
  • the invention discloses oligosaccharides and/or polysaccharides for the hemocompatible coating of surfaces.
  • Preferred are polysaccharides within the molecular weight limits mentioned above.
  • One of the remarkable features of the oligosaccharides and/or polysaccharides used is, that they contain large amounts of the sugar unit N-acylglucosamine or N-acylgalactosamine. This means that 40-60%, preferred 45-55% and especially preferred 48-52% of the sugar units are N-acylglucosamine or N-acylgalactosamine, and substantially the remaining sugar units each have a carboxyl group.
  • usually more than 95%, preferably more than 98%, of the oligosaccharides and/or polysaccharides consist of only two sugar units, one sugar unit carrying a carboxyl group and the other one an N-acyl group.
  • One sugar unit of the oligosaccharides and/or polysaccharides is N-acylglucosamine resp. N-acylgalactosamine, preferably N-acetylglucosamine resp. N-acetylgalactosamine, and the other one is uronic acid, preferably glucuronic acid and iduronic acid.
  • oligosaccharides and/or polysaccharides substantially consisting of the sugar glucosamine resp. galactosamine, substantially the half of the sugar units carrying an N-acyl group, preferably an N-acetyl group, and the other half of the glucosamine units carrying a carboxyl group directly bonded via the amino group or bonded via one or more methylenyl groups.
  • carboxylic acid groups bonded to the amino group are preferably carboxymethyl or carboxyethyl groups.
  • preferred oligosaccharides and/or polysaccharides wherein substantially the half, i.e. 48-52%, preferred 49-51% and especially preferred 49.5-50.5%, consists of N-acyl glucosamine resp.
  • N-acyl galactosamine preferably of N-acetyl glucosamine or N-acetyl galactosamine, and substantially the other half thereof consists of an uronic acid, preferably glucuronic acid and iduronic acid.
  • oligosaccharides and/or polysaccharides showing a substantially alternating sequence (i.e. despite of the statistic deviation ratio in the case of the alternating connection) of the two sugar units.
  • the ratio of the deviated connections should be under 1%, preferred under 0.1%.
  • a process for the hemocompatible coating of surfaces is disclosed, which are intended for direct blood contact.
  • a natural and/or artificial surface is provided, and the oligosaccharides and/or polysaccharides described above are immobilized on said surface.
  • the immobilisation of the oligosaccharides and/or polysaccharides on these surfaces can be achieved via hydrophobic interactions, van der Waals forces, electrostatic interactions, hydrogen bonds, ionic interactions, cross-linking of the oligosaccharides and/or polysaccharides and/or by covalent bonding onto the surface.
  • Preferred is the covalent linkage of the oligosaccharides and/or polysaccharides (side-on bonding), more preferred the covalent single-point linkage (side-on bonding) and especially preferred the covalent end-point linkage (end-on bonding).
  • any natural and/or artificial surfaces of medical products can be used here such as surfaces of prostheses, organs, vessels, aortas, cardiac valves, tubes, organ replacement parts, implants, fibers, hollow fibers, stents, hypodermic needles, syringes, membranes, conserves, blood containers, titer plates, pacemakers, adsorber media, chromatography media, chromatography columns, dialyzers, connection parts, sensors, ventiles, centrifuge chambers, heat exchangers, endoscopes, filters, pump chambers as well as other surfaces, which should have hemocompatible properties.
  • the term “medical products” is to be understood widely and refers especially to the surfaces of such products, which come into contact with blood shortly (e.g. endoscopes) or permanently (e.g. stents).
  • Biological and/or artificial surfaces of medical devices can be provided with a hemocompatible coating by means of the following method:
  • Deposition shall refer to at least partial coating of a surface with the corresponding compounds, wherein the compounds are deposited and/or introduced and/or immobilized or anyhow anchored on and/or in the subjacent surface.
  • non-hemocompatible surfaces shall refer to such surfaces that can activate the blood coagulatory system, thus are more or less thrombogeneous.
  • the last-mentioned embodiment makes sure, even in the case of mechanical damage of the polymeric layer and therewith also of the exterior hemocompatible layer, e.g. due to inappropriate transport or complicated conditions during the implantation, that the surface coating does not lose its characteristic of being blood compatible.
  • biological and artificial surface is the combination of an artificial medical device with an artificial part to be understood, e.g. a pork heart with an artificial heart valve.
  • the single layers are deposited preferably by dipping or spraying methods, whereas one can deposit at the same time with the deposition of one layer also another or more active agents onto the medical device surface, which is then implemented in the respective layer covalently and/or adhesively bound. In this way one or more active agents can be deposited at the same time with the deposition of a hemocompatible layer onto the medical device.
  • the active agents as well as the substances, which can be used for a biostable or biodegradable layer, are itemized more below.
  • an active agent layer of one or more active agents it is then possible in an additional non compulsory step c) to deposit an active agent layer of one or more active agents.
  • the active agent or agents are bound covalently on the subjacent layer.
  • the active agent is preferably deposited by dipping or spraying methods.
  • an additional step d) can follow, which comprises the deposition of at least one biodegradable layer and/or at least one biostable layer onto the hemocompatible layer resp. the active agent layer.
  • a step d′) can follow, which comprises the deposition or immobilisation of at least one oligosaccharide and/or polysaccharide according to invention according to formula Ia or Ib and/or at least one oligosaccharide and/or polysaccharide, which contains between 40% and 60% the sugar unit N-acyl glucosamine or N-acyl galactosamine and the remaining sugar units substantially contain one carboxyl group per sugar unit, as hemocompatible layer.
  • the step d′) follows.
  • step d) resp. d′) the deposition of another active agent layer of one or more active agents can take place into or onto the subjacent biodegradable and/or biostable layer or the hemocompatible layer.
  • biostable, biodegradable and/or hemocompatible layers can contain further active agents, which were deposited together with the biostable and/or biodegradable substances or the hemocompatible oligosaccharides and/or polysaccharides on the medical device and are contained in the respective layers.
  • the biostable layer is covalently and/or adhesively bound on the surface of the medical device and completely or incompletely covered with a hemocompatible layer, which (preferably covalently) is bound to the biostable layer.
  • the hemocompatible layer comprises heparin of native origin of regioselectively synthesized derivatives of different sulphation coefficients (sulphation degrees) and acylation coefficients (acylation degrees) in the molecular weight range of the pentasaccharide which is responsible for the antithrombotic activity, up to the standard molecular weight of the purchasable heparin of 13 kD, heparansulphate and its derivatives, oligo- and polysaccharides of the erythrocytic glycocalix, desulphated and N-reacetylated heparin, N-carboxymethylated and/or partially N-acetylated chitosan as well as mixtures of these substances.
  • sulphation degrees sulphation coefficients
  • acylation degrees acylation degrees
  • Subject of the invention are also medical devices, which are hemocompatibly coated according to one of the herein mentioned methods.
  • the surface of the medical devices is covered directly or via at least one interjacent biostable and/or biodegradable layer and/or active agent layer with a hemocompatible layer, which consists of at least one oligosaccharide and/or polysaccharide, which contains between 40% and 60% the sugar unit N-acyl glucosamine or N-acyl galactosamine and the remaining sugar units substantially contain one carboxyl group per sugar unit.
  • a hemocompatible layer which consists of at least one oligosaccharide and/or polysaccharide, which contains between 40% and 60% the sugar unit N-acyl glucosamine or N-acyl galactosamine and the remaining sugar units substantially contain one carboxyl group per sugar unit.
  • hemocompatible layer of the afore-mentioned oligosaccharides and/or polysaccharides is at least one biostable layer present, which is additionally preferred covalently bound to the surface of the medical device.
  • At least one biostable and/or at least one biodegradable layer is present, which covers the hemocompatible layer completely or incompletely.
  • a biodegradable layer which covers the hemocompatible layer.
  • a further preferred embodiment contains between the biostable lower layer and the subjacent hemocompatible layer an active agent layer of at least one antiproliferative, antiinflammatory and/or antithrombotic active agent, which is bound covalently and/or adhesively to the hemocompatible layer.
  • an active agent layer of at least one antiproliferative, antiinflammatory and/or antithrombotic active agent, which is bound covalently and/or adhesively to the hemocompatible layer.
  • the lower biostable and/or upper hemocompatible layer can contain further active agents, which are deposited preferably together with the deposition of the respective layer.
  • every layer i.e. a biostable layer, a biodegradable layer and a hemocompatible layer can contain one or more antiproliferative, antiinflammatory and/or antithrombotic active agents and moreover between the afore-mentioned layers active agent layers of one or more active agents can be present.
  • an active agent layer of one or more active agents is present.
  • three-layer systems which consist of a biostable, biodegradable and hemocompatible layer. Thereby preferably the lowest layer is a biostable layer.
  • one or two active agent layers are possible. It is also possible to deposit two active agent layers directly above each other. In a further preferred embodiment at least one active agent is bound covalently on or in a layer.
  • active agents are tacrolimus, pimecrolimus, PI88, thymosin ⁇ -1, PETN (pentaerythritol tetranitrate), baccatin and its derivatives, docetaxel, colchicin, paclitaxel and its derivatives, trapidil, ⁇ - and ⁇ -estradiol, dermicidin, tialin (2-methylthiazolidine-2,4-dicarboxylic acid), tialin-sodium (sodium salt of tialin), simvastatine, macrocyclic suboxide (MCS) and its derivatives, sirolimus, tyrphostines, D24851, colchicin, fumaric acid and fumaric acid esters, activated protein C (aPC), interleucine-1 ⁇ inhibitors, and melanocyte-stimulating hormone ( ⁇ -MSH) as well as mixtures of these active agents.
  • tacrolimus pimecrolimus
  • PI88 thymosin
  • the natural and/or artificial surfaces of the medical devices which are coated according to the herein described methods with a hemocompatible layer of the inventive oligosaccharide and/or polysaccharide resp. the oligosaccharides and/or polysaccharides which contain between 40% and 60% the sugar unit N-acyl glucosamine or N-acyl galactosamine and the remaining sugar units substantially contain one carboxyl group per sugar unit, are especially suitable as implants and organ replacement parts, respectively, which are in direct contact with the blood circuit and the blood.
  • the medical devices coated according to invention are especially suitable, but not only, for the direct and permanent blood contact, but show surprisingly also the characteristic to reduce or even to prevent the adhesion of proteins onto suchlike coated surfaces.
  • the deposition of the inventive coating prevents or at least reduces for example the unspecific adhesion of proteins on micro-titer plates or other support mediums which are used for diagnostic detection methods, that disturb the generally sensitive test reactions and can lead to a falsification of the analysis result.
  • the coating according to invention on adsorption media or chromatography media the unspecific adhesion of proteins is also prevented or reduced, whereby better separations can be achieved and products of greater purity can be generated.
  • stents are coated according to the inventive methods.
  • the implantation of stents using balloon dilatation of occluded vessels increasingly established in the last years. Although stents decrease the risk of a renewed vessel occlusion they are until now not capable of preventing such restenoses completely.
  • restenosis cannot be found in the technical literature.
  • the most commonly used morphologic definition of the restenosis is the one which defines the restenosis after a successful PTA (percutaneous transluminal angioplasty) as a reduction of the vessel diameter to less than 50% of the normal one.
  • PTA percutaneous transluminal angioplasty
  • This is an empirically defined value of which the hemodynamic relevance and its relation to clinical pathology lacks of a massive scientific basis.
  • the clinical aggravation of a patient is often viewed as a sign for a restenosis of the formerly treated vessel segment.
  • U.S. Pat. No. 5,891,108 discloses for example a hollow moulded stent, which can contain pharmaceutical active agents in its interior, that can be released throughout a various number of outlets in the stent.
  • EP-A-1 127 582 describes a stent that shows ditches of 0.1-1 mm depth and 7-15 mm length on its surface which are suitable for the implementation of an active agent. These active agent reservoirs release similarly to the outlets in the hollow stent the contained pharmaceutically active agent in a punctually high concentration and over a relatively long period of time which however leads to the fact that the smooth muscle cells are not anymore or only very delayed capable of enclosing the stent.
  • phosphorylcholine a component of the erythrocyte cell membrane, shall create a non thrombogeneous surface as a component of the coated non biodegradable polymer layer on the stent.
  • Dependent of its molecular weight, thereby the active agent is absorbed by the polymer containing phosphorylcholine layer or adsorbed on the surface.
  • the stents according to invention are coated with a hemocompatible layer and feature one or more additional layers which at least comprise an antiproliferative and/or antiinflammatory and if needed an antithrombotic active agent.
  • the hemocompatible coating of a stent provides the required blood compatibility and the active agent (or active agent combination) which is distributed homogeneously over the total surface of the stent provides that the covering of the stent surface with cells especially smooth muscle and endothelial cells takes place in a controlled way.
  • the covering of the stent surface with cells especially smooth muscle and endothelial cells takes place in a controlled way.
  • the incorporation of active agents guarantees that the active agent or the active agent combination which is bound covalently and/or adhesively to the subjacent layer and/or implemented covalently and/or adhesively into the layer is released continuously and in small doses so that the population of the stent surface by cells is not inhibited however an overgrowth is prevented.
  • This combination of both effects awards the ability to the inventive stent to grow rapidly into the vessel wall and reduces both the risk of restenosis and the risk of thrombosis.
  • the release of one or more active agents spans over a period from 1 to 12 months, preferably 1 to 3 months after implantation.
  • Antiproliferative substances are used as active agents.
  • cytostatics, macrolide antibiotics and/or statins are used as antiproliferative active agents.
  • Applyable antiproliferative active agents are sirolimus (rapamycin), everolimus, pimecrolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin, ascomycin, bafilomycin, erythromycin, midecamycin, josamycin, concanamycin, clarithromycin, troleandomycin, folimycin, cerivastatin, simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin, pravastatin, pitavastatin, vinblastine, vincristine, vindesine, vinorelbine, etoposide, teniposide, nimustine, carmustine, lomustine, cyclophosphamide, 4-hydroxycycl
  • cefadroxil cefazolin, cefaclor, cefotixin, tobramycin, gentamycin are used.
  • Positive influence on the postoperative phase have also the penicillins such as dicloxacillin, oxacillin, sulfonamides, metronidazol, antithrombotics such as argatroban, aspirin, abciximab, synthetic antithrombin, bivalirudin, coumadin, dermicidin, enoxaparin, hemoparin, tissue plasminogen activator, GpIIb/IIIa platelet membrane receptor, factor X a inhibitor, activated protein C, dermicidin, antibodies, heparin, hirudin, r-hirudin, PPACK, protamin, prourokinase, streptokinase, warfarin, urokinase, vasodilators such as dipyramidole, trapid
  • Further active agents are steroids (hydrocortisone, betamethasone, dexamethasone), non-steroidal substances (NSAIDS) such as fenoprofen, ibuprofen, indomethacin, naproxen, phenylbutazone and others.
  • NSAIDS non-steroidal substances
  • Antiviral agents such as acyclovir, ganciclovir and zidovudine are also applyable. Different antimycotics are used in this area. Examples are clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine.
  • Antiprozoal agents such as chloroquine, mefloquine, quinine are effective active agents in equal measure, moreover natural terpenoids such as hippocaesculin, barringtogenol-C21-angelate, 14-dehydroagrostistachin, agroskerin, agrostistachin, 17-hydroxyagrostistachin, ovatodiolids, 4,7-oxycycloanisomelic acid, baccharinoids B1, B2, B3, tubeimoside, bruceanol A, B, C, bruceantinoside C, yadanziosides N and P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A, B, C and D, ursolic acid, hyptatic acid A, zeorin, iso-iridogermanal, maytenfoliol, effusantin A, excisanin A and B, longikaurin B, sculponeatin C, kamebau
  • the active agents are used separately or combined in the same or a different concentration. Especially preferred are active agents which feature also immunosuppressive properties besides their antiproliferative effect. Suchlike active agents are erythromycin, midecamycin, tacrolimus, sirolimus, paclitaxel and josamycin. Furthermore preferred is a combination of several antiproliferatively acting substances or of antiproliferative active agents with immunosuppressive active agents.
  • Preferred for the present invention are tacrolimus, pimecrolimus, PI88, thymosin ⁇ -1, PETN (pentaerythritol tetranitrate), baccatin and its derivatives, docetaxel, colchicin, paclitaxel and its derivatives, trapidil, ⁇ - and ⁇ -estradiol, dermicidin, simvastatine, macrocyclic suboxide (MCS) and its derivatives, sirolimus, tyrphostines, D24851, colchicin, fumaric acid and fumaric acid esters, activated protein C (aPC), interleucine-1 ⁇ inhibitors and melanocyte-stimulating hormone ( ⁇ -MSH) and tialin (2-methylthiazolidine-2,4-dicarboxylic acid) as well as tialin-Na (sodium salt of tialin).
  • aPC activated protein C
  • ⁇ -MSH melanocyte-stimulating hormone
  • the active agent is preferably contained in a pharmaceutical active concentration from 0.001-10 mg per cm 2 stent surface and per active agent layer or active agent containing layer. Additional active agents can be contained in a similar concentration in the same or in other layers.
  • the medical devices coated according to invention especially the stents coated according to invention, can release the active agent or the active agents continuously and controlled and are suitable for the prevention or reduction of restenosis (see FIG. 6 ).
  • the hemocompatible layer which covers directly the stent preferably comprises heparin of native origin as well as synthetically obtained derivatives with different sulphation coefficients (sulphation degrees) and acylation coefficients (acylation degrees) in the molecular weight range of the pentasaccharide which is responsible for the antithrombotic activity up to the standard molecular weight of the purchasable heparin, as well as heparan sulphates and derivatives thereof, oligo- and polysaccharides of the erythrocyte glycocalix, which imitate in a perfect way the athrombogeneous surface of the erythrocytes, since contrary to phosphorylcholine, here the actual contact between blood and erythrocyte surface takes place, completely desulphated and N-reacetylated heparin, desulphated and N-reacetylated heparin, N-carboxymethylated and/or partially N-acetylated chitosan, chitosan and/or mixtures
  • These stents with a hemocompatible coating are prepared by providing conventional normally non coated stents and by preferably covalent deposition of a hemocompatible layer which permanently masks the surface of the implant after the release of the active agent and thus, after the decay of the active agent's influence and the degradation of the matrix.
  • the conventional stents which can be coated according to the inventive methods consist of stainless steel, nitinol or other metals and alloys or of synthetic polymers.
  • Another preferred embodiment of the stents according to invention shows a coating which consists of at least two layers. Multiple layer systems are used as well. In such multiple layer systems the layer which is directly deposited on the stent is labelled first layer. Labelled second layer is that layer which is deposited on the first layer, etc.
  • the first layer consists of a hemocompatible layer which is substantially covered completely by a biodegradable layer which comprises at least an antiproliferative, antiphlogistic and/or antithrombotic active agent bound covalently and/or adhesively. Also applied are active agent combinations which mutually facilitate and replenish themselves.
  • biodegradable substances for the external layer can be used: polyvalerolactones, poly- ⁇ -decalactones, polylactonic acid, polyglycolic acid, polylactides, polyglycolides, copolymers of the polylactides and polyglycolides, poly- ⁇ -caprolactone, polyhydroxybutanoic acid, polyhydroxybutyrates, polyhydroxyvalerates, polyhydroxybutyrate-co-valerates, poly(1,4-dioxane-2,3-diones), poly(1,3-dioxane-2-ones), poly-p-dioxanones, polyanhydrides such as polymaleic anhydrides, polyhydroxymethacrylates, fibrin, polycyanoacrylates, polycaprolactonedimethylacrylates, poly-b-maleic acid, polycaprolactonebutyl-acrylates, multiblock polymers such as from oligocaprolactonedioles and oligodioxanonedioles
  • the layer and layers respectively which contain the active agent is slowly degradated by components of the blood such that the active agent is released of the external layer according to the degradation velocity or resolves itself from the matrix according to its elution behavior.
  • the first hemocompatible layer guarantees the required blood compatibility of the stent once the biodegradable layer is degradated. This biological degradation of the external layer and the corresponding release of the active agent reduces strongly an ongrowth of cells only for a certain period of time and an aimed controlled adhesion is enabled where the external layer has been already widely degradated.
  • the biological degradation of the external layer spans advantageously from 1 to 36 months, preferably from 1 to 6 months, especially preferred from 1 to 2 months. It was shown that suchlike stents prevent or at least very strongly reduce restenosis. In this period of time the important healing processes take place.
  • the hemocompatible layer remains as athrombogeneous surface and masks the foreign surface in such a way that no life-threatening reaction can occur anymore.
  • the amounts of polymer deposited on the surfaces of the medical devices, preferably stents, are between 0.01 mg to 3 mg/layer, preferred between 0.20 mg to 1 mg/layer and especially preferred between 0.2 mg to 0.5 mg/layer.
  • Suchlike stents are preparable via a method for the hemocompatible coating of stents the basis of which is formed by the following principle:
  • the principle of coating offers a big range of variation concerning the contrived requirements for the active agent and is separable into different coating types, which can be combined also among themselves.
  • Another advantageous embodiment is represented by a stent with an at least three layered coating, whereas the first layer covers the surface of the stent with the hemocompatible layer, the second layer contains the active agent and is not biodegradable and is covered by a third hemocompatible layer.
  • the external layer provides the stent herein the necessary blood compatibility and the second layer serves as an active agent reservoir.
  • the active agent which is if needed covalently bound to the matrix via a hydrolysis-weak bonding and/or added in a solvent dissolved matrix which is required for the coating method, is thus released from the second layer continuously and in small concentrations and diffuses uninhibited through the external hemocompatible layer.
  • This layer assembly also yields the result that the population of the stent surface with cells is not prevented but is reduced to an ideal degree.
  • the first layer offers a risk minimization for eventually occurring damages of the coated stent surface during the implantation e.g. by abrasions through the present plaque or during the prearrangement e.g. during the crimping.
  • a second security guarantee results from the fact that even a bio-stable polymer is degradated in the body over a more or less long period of time which at least partially uncovers the stent surface. Combinations especially with biodegradable material as described in the coating principles are possible, too.
  • Suchlike stents can be prepared by providing a conventional stent, depositing a hemocompatible first layer on its surface, depositing a non biodegradable layer which at least comprises one active agent as well as combinations with other active agents from other groups bound covalently and/or adhesively and coating of this layer substantially completely with another hemocompatible layer.
  • polyacrylic acid and polyacrylates such as polymethylmethacrylate, polybutyl methacrylate, polyacrylamide, polyacrylonitriles, polyamides, polyetheramides, polyethylenamine, polyimides, polycarbonates, polycarbourethanes, polyvinylketones, polyvinylhalogenides, polyvinylidenhalogenides, polyvinyl ethers, polyvinylaromates, polyvinyl esters, polyvinylpyrrolidones, polyoxymethylenes, polyethylene, polypropylene, polytetrafluoroethylene, polyurethanes, polyolefin elastomers, polyisobutylenes, EPDM gums, fluorosilicones, carboxymethyl chitosan, polyethylenterephthalate, polyvalerates, carboxymethylcellulose, cellulose, rayon, rayon tri
  • the newly deposited layer covers the subjacent layer substantially completely.
  • substantially means in this context, that at least the stent surface, which comes into contact with the vessel wall, is covered completely resp. at least 90%, preferred 95% and especially preferred at least 98% of the stent surface are covered.
  • the stents according to invention solve both the problem of acute thrombosis and the problem of neointima hyperplasia after a stent implantation.
  • the stents according to invention are well suitable due to their coating whether as single layer or as multi layer system especially for the continuous release of one or more antiproliferative and/or immunosuppressive active agents. Due to this feature of aimed continuous active agent release in a required amount the coated stents according to invention prevent almost completely the danger of restenosis.
  • any plastic surfaces can be coated with a hemocompatible layer of the oligosaccharides and/or polysaccharides.
  • synthetic polymers as well as biopolymers are suitable, comprising, for example, the monomers ethene, vinyl acetate, methacrylic acid, vinylcarbazole, trifluoroethylene, propene, butene, methylpentene, isobutene, styrene, chlorostyrene, aminostyrene, acrylonitrile, butadiene, acrylic ester, divinylbenzene, isoprene, vinyl chloride, vinyl alcohol, vinylpyridine, vinylpyrrolidone, tetrafluoroethylene, trifluorochloroethene, vinyl fluoride, hexafluoroisobutene, acrylic acid, acrolein, acrylamide, methacrylamide, maleic acid, hydroxymethyl methacrylic acid, methyl methacrylic acid
  • polymers can be considered: silicones, cellulose and cellulose derivatives, oils, polycarbonates, polyurethane, agarose, polysaccharides, dextranes, starch, chitin, glycosamino glycans, gelatin, collagen I-XII and other proteins.
  • FIG. 1 shows a disaccharide structure fragment of chitin which can be transformed into chitosan by basic hydrolysis, or into the compounds of the general formula Ia by partial deacetylation and subsequent N-carboxyalkylation.
  • FIG. 2 shows a disaccharide structure fragment of chitosan, which can be transformed into the compounds of the general formula Ia by partial N-acylation and subsequent N-carboxyalkylation or by partial N-carboxyalkylation and subsequent N-acylation.
  • FIG. 3 shows a tetrasaccharide unit of a heparin or heparan sulphate with a random distribution of the sulphate groups and a degree of sulfation of 2 per disaccharide unit as typical for heparin ( FIG. 3 a ).
  • FIG. 3 b shows an example of a compound according to the general formula Ib
  • FIG. 3 c shows a section with a typical structure for a N-carboxymethylated, partially N-acetylated chitosan.
  • FIG. 4 shows the influence of an into a PVC-tube expanded, surface modified stainless steel coronary stent on the platelet loss (PLT-loss).
  • An uncoated stainless steel coronary stent was measured (uncoated) as reference. As zero value the level of the platelet loss in case of the PVC-tube without stainless steel coronary stent was set.
  • SH1 is a with heparin covalently coated stent
  • SH2 is a with chondroitinsulphate coated stent
  • SH3 is a stent coated with polysaccharides gained from the erythrocytic glycocalix
  • SH4 is a with Ac-heparin covalently coated stainless steel coronary stent.
  • FIG. 5 shows a schematic presentation of the restenosis rate of with completely desulphated and N-reacetylated heparin (Ac-heparin) covalently coated stents and with oligo- and polysaccharides of the erythrocytic glycocalix coated stents in comparison to the uncoated stent and with polyacrylic acid (PAS) coated stents after 4 weeks of implantation time in pork.
  • Ac-heparin N-reacetylated heparin
  • FIG. 6 Quantitative coronary angiography:
  • FIG. 7 Elution plot of paclitaxel from the stent (without support medium).
  • FIG. 8 Elution diagram of paclitaxel embedded into PLGA-matrix.
  • FIG. 9 Elution diagram of paclitaxel embedded into PLGA-matrix and of a layer of undiluted paclitaxel which covers the basis coating completely.
  • FIG. 10 Elution diagram of a hydrophilic active agent embedded into the matrix and of a suprajacent active agent free polymer (topcoat) which covers the basis coating completely for diffusion control.
  • FIG. 11 Elution diagram of colchicine from PLGA-matrix.
  • FIG. 12 Elution diagram of simvastatin from PLGA-matrix.
  • FIG. 13 Elution diagram of a statin from the matrix with polystyrene which completely covers the basis coating as diffusion controlling layer.
  • FIG. 14 Comparison of the thrombocyte number (platelet number) in the blood after Chandler loop between coated (coat.) and non coated (unco.) stent as regards the empty tube (control), the platelet number of freshly extracted blood (donor) and after the storage of 60 min in the syringe (syringe 60).
  • FIG. 15 Comparison of the platelet factor 4 concentration in the freshly extracted blood (donor), in the empty tube (control) after 60 minutes and non coated stents (unco.) with coated (coat.) stent.
  • FIG. 16 Comparing diagram to the activated complement factor C5a in the freshly extracted blood (donor), in the empty tube (control) after 60 minutes and non coated (unco.) stents with coated (coat.) stent.
  • FIG. 17 Schematic presentation of the %-diameter restenosis rate of with completely desulphated and N-reacetylated heparin (Ac-heparin) covalently coated stents and with a 2 nd layer of poly(D,L-lactide-co-glycolide) in comparison to the uncoated stent (after 12 weeks of implantation time in the pork).
  • the chronological progression of the stenosis formation in the case of PLGA is shown, whereas “%-diameter restenosis rate” represents the diameter of the vessel related percentually to the initial state directly after implantation of the stent (post).
  • the vessel diameter was measured before (pre) and after the implantation of the stent (Post) via intravascular ultrasound (IVUS).
  • IVUS intravascular ultrasound
  • the stented areas were examined respectively via coronary angiography and with intravascular ultrasound (IVUS).
  • the obtained data show an unexpected remarkably positive effect, which is due to the coating beyond doubt.
  • the values of stenosis after three months hardly differ for the uncoated stent and for the coated stent, the reaction of the vessel wall towards the PLGA-coated stent is substantially smoother.
  • the stenosis value lies with 6% significantly below the value of the uncoated implants with 10.4%.
  • the masking of the metal surface results after four weeks even with 10% (an increase of 33%) in a more than factor two lower stenosis rate than the uncoated stent, which reaches after this period of time its maximum value of 22.6% (an increase of 54%).
  • the coated stent shows a maximum after six weeks with only 12.33%. After 12 weeks the values of both systems equal each other with approx. 11%.
  • FIG. 18 Pictures of the quantitative coronary angiography of the animal experiments respectively to FIG. 17 after 1 week, 4 weeks, 6 weeks and 3 months of hemocompatibly supplied PLGA-coated stents in the pig.
  • heparin pyridinium salt 0.9 g were added to 90 ml of a 6/3/1 mixture of DMSO/1,4-dioxane/methanol (v/v/v) in a round bottomed flask with reflux cooler and heated to 90° C. for 24 hours. Then, 823 mg of pyridinium chloride were added and heating to 90° C. was effected for further 70 hours. Subsequently, dilution was carried out with 100 ml of water, and titration to pH 9 with dilute soda lye was effected. The desulphated heparin was dialyzed against water and freeze-dried.
  • N-carboxymethylated, Partially N-acetylated chitosan N-carboxymethylated, Partially N-acetylated chitosan:
  • heparin-pyridinium-salt 0.9 g heparin-pyridinium-salt were added in a round flask with a reflux condenser with 90 ml of a 6/3/1 mixture of DMSO/1,4-dioxan/methanol (v/v/v) and heated for 24 hours to 90° C. Then 823 mg pyridiniumchloride were added and heated additional 70 hours to 90° C. Afterwards it was diluted with 100 ml of water and titrated with dilute sodium hydroxide to pH 9. The desulphated heparin was dialyzed contra water and freeze-dried.
  • N-carboxymethylated, Partially N-propionylated chitosan N-carboxymethylated, Partially N-propionylated chitosan:
  • the chamber is composed of four building parts plus conical nipples and threaded joints and is manufactured of polymethylmethacrylate and allows the parallel investigation of two modified membranes, so that in every run already a statistic coverage is included.
  • the construction of this chamber permits quasi_laminar perfusion conditions.
  • the membranes After 5 minutes of perfusion at 37° C. the membranes are extracted and after fixation of the adherent platelets the platelet occupancy is measured. The respective results are set into relation to the highly thrombogeneous subendothelial matrix as negative standard with a 100% platelet occupancy.
  • the adhesion of the platelets takes place secondary before the formation of the plasma protein layer on the foreign material.
  • the plasma protein fibrinogen acts as cofactor of the platelet aggregation.
  • the such induced activation of the platelets results in the bonding of several coagulation associated plasma proteins, such as vitronectin, fibronectin and von Willebrand-factor on the platelet surface. By their influence finally the irreversible aggregation of the platelets occurs.
  • the platelet occupancy presents because of the described interactions an accepted quantum for the thrombogenity of surfaces in case of the foreign surface contact of blood. From this fact the consequence arises: the lower the platelet occupancy is on the perfunded surface the higher is the hemocompatibility of the examined surface to be judged.
  • heparin as an antithrombotic is not transferable to covalently immobilised heparin. In the systemic application in dissolved form it can fully unfold its properties. But if heparin is not covalently immobilised, its antithrombotic properties, if at all, is only short-lived. Different is the Ac-heparin (“No-affinity”-heparin), that due to the desulphation and N-reacetylation in fact totally loses the active antithrombotic properties of the initial molecule, but acquires in return distinctive athrombogeneous properties, that are demonstrably founded in the passivity versus antithrombin III and the missing affinity towards coagulation initiating processes and remain after covalent bonding.
  • the recess holes of the syringes were closed by pushing the glass tubes over them and the tube was clamp taut into a dialysis pump.
  • the blood was pumped for 10 minutes with a flow rate of 150 ml/min.
  • the platelet content of the blood was measured before and after the perfusion with a Coulter counter.
  • the stent covered surface which solely accounts for about 0.84% of the total test surface, causes a significant and reproducable effect on the platelet content.
  • the analysis of the polished, chemically not surface coated stent yields an additional average platelet loss of 22.7%. Therewith causes this compared to the PVC empty tube less than 1% measurable foreign surface an approximately comparable platelet loss.
  • the medicinal stainless steel 316 LVM used as stent material induces an about 100 times stronger platelet damage compared to a medical grade PVC surface, although this test surface only accounts for 0.84% of the total surface.
  • Not expanded stents of medicinal stainless steel LVM 316 were degreased in the ultrasonic bath for 15 minutes with acetone and ethanol and dried at 100° C. in the drying closet. Then they were dipped for 5 minutes into a 2% solution of 3_aminopropyltriethoxysilane in a mixture of ethanol/water (50/50:(v/v)) and then dried for 5 minutes at 100° C. Afterwards the stents were washed with demineralised water over night.
  • the coated stents are given in small hydrolysis tubes and are abandoned with 3 ml 3 M HCl for exactly one minute at room temperature.
  • the metal probes are removed and the tubes are incubated after sealing for 16 hours in the drying closet at 100° C. Then they are allowed to cool down, evaporated three times until dryness and taken up in 1 ml degassed and filtered water and measured contra an also hydrolysated standard in the HPLC: desulphat. + desulphat. + desulphat. + reacet. reacet. reacet. reacet.
  • sample heparin area heparin heparin stent area [g/sample] [cm 2 ] [g/cm 2 ] [pmol/cm 2 ] 1 129.021 2.70647E ⁇ 07 0.74 3.65739E ⁇ 07 41.92 2 125.615 2.63502E ⁇ 07 0.74 3.56084E ⁇ 07 40.82 3 98.244 1.93072E ⁇ 07 0.74 2.60908E ⁇ 07 29.91 4 105.455 2.07243E ⁇ 07 0.74 2.80058E ⁇ 07 32.10 5 119.061 2.33982E ⁇ 07 0.74 3.16192E ⁇ 07 36.24 6 129.202 2.53911E ⁇ 07 0.74 3.43124E ⁇ 07 39.33 7 125.766 2.53957E ⁇ 07 0.74 3.43185E ⁇ 07 39.34
  • the difference between the uncoated control stent and the Ac-heparin coated stent is unambiguous.
  • the generation of a distinct neointima layer is in case of the uncoated control stent very well observable.
  • the proliferation promotional effect of the uncoated stent surface on the surrounding tissue occurs in such a degree, that ultimately the danger of the vessel occlusion in the stent area is given.
  • Donor blood is taken up into 1.5 U/ml of heparin.
  • the 4 tubes (K3-K6) and two empty tubes (L1, L2) are filled in each case with 7.5 ml isotonic sodium chloride solution and rotated for 15 minutes at 5 r/min at 37° C. in the Chandler loop.
  • the completely emptied tubes are filled carefully with heparinated donor blood (7.5 ml) and rotated for 60 min at 5 r/min. Accordingly to the anticoagulants samples are taken in monovettes and sample jars respectively (PF4-CTAD, C5a-EDTA, BB-EDTA) and processed.
  • the determination of the platelet number shows no significant difference between the empty control tubes, the coated and non coated stents.
  • the released PF4 is in case of the coated and non coated tubes at the same level.
  • the determination of the activated complement factor 5 (C5a) shows in case of the coated stents a smaller activation as in case of the non coated stents.
  • the aim of the experiments was primarily to evaluate the influence of the PLGA-coating towards the stent induced vessel reaction.
  • 28 six to nine month old domestic porks were used.
  • the stented areas were examined after one week (1 WoFUP), one month (4 WoFUP), six weeks (6 WoFUP) and after three months (12 WoFUP).
  • the obtained data show an unexpected incredibly positive effect, which is due to the the presence of PLGA 50/50 beyond doubt.
  • the values of stenosis after three months hardly differ for the uncoated stent and for the coated stent, the reaction of the vessel wall towards the PLGA-coated stent is substantially smoother.
  • the stenosis value lies with 6% significantly below the value of the uncoated implants with 10.4%.
  • the masking of the metal surface results after four weeks even with 10% (an increase of 33%) in a more than factor two lower stenosis rate than the uncoated stent, which reaches after this period of time its maximum value of 22.6% (an increase of 54%).
  • the coated stent shows a maximum after six weeks with only 12.33%. After 12 weeks the values of both systems equal each other with approx. 11% ( FIG. 16 ).
  • the data for the restenotic processes were determined via quantitative coronary angiography (QCA) and intravascular ultra sound examinations (IVUS).
  • the stent is weighed out on the analytical balance and the weight is noted.
  • a small hydrolysis tube 0.5 g polylactide are dissolved in 2 ml of CHCl 3 . Therefore, it is heated to 65° C. in the water bath. The solution is cooled down in the freezing compartment. Thereto are added 200 ⁇ g toluidine blue in 200 ⁇ l of CHCl 3 .
  • the stent is dipped into this solution. After a couple of minutes the stent is taken out of the solution with tweezers and moved within the fume hood until the solvent evaporates. Then the stent is dipped in for a second time. After air drying the stent is freeze dried for about 10 min. After the drying the stent is balanced again. The amount of the immobilized polylactide with toluidine blue is measured from the weight difference (sample 1).
  • sample 3 the dipping solution (1.93 ml) which results from experiment 1 (sample 1) and experiment 2 (sample 2) is mixed with 0.825 mg toluidine blue in 0.825 ml of CHCl 3 and 250 mg polylactide. The polylactide is dissolved during heating. Then a stent is dipped into it two times as described above.
  • the untreated stents had a weight of 176.0 mg and 180.9 mg. After dipping into the polylactide solution the stents balanced 200.9 and 205.2 mg.
  • the dipping solution contains 500 mg polylactide and 200 ⁇ g toluidine blue.
  • the bound amount of toluidine blue can be measured for the samples 1 and 2 from this ratio.
  • sample 3 2.755 ml solution contain 1 mg toluidine blue and 638.6 mg polylactide (initial weight-consumption sample 1+2; approx. 50 mg).
  • two stents are given into one preparation to obtain higher absorptions.
  • As the dipping solution was very viscous which yielded a very thick coating it was diluted from 2.625 ml with chloroform to 4 ml.
  • a stent is hung into a beaker with 25 ml of physiological sodium chloride solution in a phosphate buffer pH 7.4 (14.24 g NaH 2 PO 4 , 2.72 g K 2 HPO 4 and 9 g NaCl) and stirred gently at room temperature. After 0.5, 1, 2, 3, 6, 24, 48 and 120 hours, each time a sample of 3 ml is taken, measured spectroscopically and given back into the preparation. c c c c time/ (ng/ (ng/ (ng/ (ng/ (ng/ (ng/ h abs. s1 ml) abs. s2 ml) abs. s3 ml) abs.
  • the dipping solution may not be too thick and should be cooled so that the chloroform cannot evaporate too fast during the extraction as else the thickness of the coating becomes too large and inhomogeneous.
  • the polylactide concentration in sample 4 (134 mg/ml) seems to be sufficient, above all in case of higher concentrations the solution becomes extremely viscous and the polylactide is only very difficult to dissolve.
  • the stents are fixed in such way, that the interior of the stents does not touch the bar.
  • the stent is sprayed with the respective spray solution. After the drying (about 15 minutes) at room temperature and proximately in the fume hood over night it is balanced again.
  • the stents are sprayed in each case with 3 ml of the spraying solution, balanced before and after the spraying and the yielding layer thickness is determined by measuring under the microscope 100-times magnified.
  • layer stent No. before coating after coating weight of coating thickness 0.0193 g 0.0205 g 1.2 mg 10.4 ⁇ m 2 0.0193 g 0.0205 g 1.2 mg 10.4 ⁇ m 3 0.0204 g 0.0216 g 1.2 mg 10.4 ⁇ m 4 0.0206 g 0.0217 g 1.1 mg 10.4 ⁇ m
  • the stents are balanced before and after the spraying. stent No. before coating after coating weight of coating 1 0.0194 g 0.0197 g 0.30 mg
  • Spray solution Polylactide RG502/taxol—solution is replenished from 145.2 mg polylactide and 48.4 mg taxol to 22 g with chloroform.
  • Basis coat 19.8 mg polylactide and 6.6. mg taxol are replenished with chloroform to 3 g.
  • Topcoat 8.8 mg taxol are replenished with chloroform to 2 g. weight weight weight of active layer spray before weight of active agent thick- stent solution (g) after (g) coating agent ⁇ g/mm 2 ness 1 0.85 ml 0.0235 0.0238 0.30 mg 131 ⁇ g 1.56 9.7 ⁇ m 2 0.85 ml 0.0260 0.0264 0.40 mg 175 ⁇ g 2.09 10.1 ⁇ m
  • Basis coating 22 mg polylactide and 22 mg hydrophilic active agent are balanced and replenished with chloroform to 5 g.
  • Topcoat 22 mg polylactide and 22 mg polystyrene are balanced and replenished with chloroform to 5 g. weight of weight of spray solution before coating after coating coating active agent 0.85 ml 0.0135 g 0.0143 g 0.8 mg 200 ⁇ g

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