CA2218103A1 - Coating for biomaterial which can be introduced into the bloodstream or into the tissue of the human body - Google Patents

Coating for biomaterial which can be introduced into the bloodstream or into the tissue of the human body

Info

Publication number
CA2218103A1
CA2218103A1 CA 2218103 CA2218103A CA2218103A1 CA 2218103 A1 CA2218103 A1 CA 2218103A1 CA 2218103 CA2218103 CA 2218103 CA 2218103 A CA2218103 A CA 2218103A CA 2218103 A1 CA2218103 A1 CA 2218103A1
Authority
CA
Canada
Prior art keywords
coating
up
carbon atoms
medicinal substance
preferably
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA 2218103
Other languages
French (fr)
Inventor
Martin Reers
Werner Stuber
Axel Stemberger
Eckhard Alt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hoechst AG
Original Assignee
Behringwerke Aktiengesellschaft
Martin Reers
Werner Stuber
Axel Stemberger
Eckhard Alt
Hoechst Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to DE1995114104 priority Critical patent/DE19514104C2/en
Priority to DE19514104.0 priority
Application filed by Behringwerke Aktiengesellschaft, Martin Reers, Werner Stuber, Axel Stemberger, Eckhard Alt, Hoechst Aktiengesellschaft filed Critical Behringwerke Aktiengesellschaft
Publication of CA2218103A1 publication Critical patent/CA2218103A1/en
Application status is Abandoned legal-status Critical

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L33/00Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/0005Use of materials characterised by their function or physical properties
    • A61L33/0011Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
    • A61L33/0041Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate characterised by the choice of an antithrombatic agent other than heparin

Abstract

The coating consists of a composition, the components of which are soluble in a solvent, preferably chloroform. In detail, they are a medicament carrier like poly-D, L-lactide, serine protease inhibitors, advantageously thrombin inhibitors and prostaglandines or prostacyclines or derivatives thereof. With such a coating, coated bio-material in the tissue or in the bloodstream are continuously slowly decomposed and the formation of thromboses is prevented.

Description

CA 022l8l03 lgg7-lO-lO

Coating for biomaterial which can be introduced into the bloodstream or into the tissue of the human body The invention relates to a coating for biomaterial which can be introduced into the bloodstream or into the tissue of the human body. This term is used to designate, for example, infusion catheters, cardiac catheters, balloon catheters, electrodes, suture mate-rials for vessel anastomoses, oxygenators, vessel pros-theses or supports for vessels, called stents, etc.,which remain for a short time or else for a long time directly in arteries and velns and in body tissue or come into contact with blood. The hazards for the patients, for example due to thrombosis formation and inflammations, are known and have to be considered with regard to the success of therapy and severity of the disorder.

EP-A1-0578998 discloses the production of such bio-material with a covering of a biodegradable material,for example poly-D,L-lactide, with medicaments then also being incorporated into this biodegradable mate-rial and, on degradation of the biomaterial in the implanted state, being gradually released at, prefer-ably, a constant rate to the patient. Heparin is men-tioned, for example, as medicament which, incorporated in dispersed form, then specifically reaches the blood circulation and speeds up the action of plasmatic inhibitors such as antithrombin III and heparin cofactor II as catalyst thereof.

It has furthermore been proposed, in German Patent Applications P 43 34 272.8 and P 44 35 652.8, to coat biomaterial with a biodegradable material, with the coating being very thin with layer thicknesses of less than 100 micrometers so that only the primary structure of the biomaterial is covered. If, for example, the REPT~Cr ~NT SHEET (RULE 26) primary structure is a network structure as is the case with said vessel prostheses or stents, only the indi-vidual strands of the prosthesis are coated; in no case is the prosthesis enveloped by a complete casing. It has emerged with a paint-like coating of this type that an antithrombogenic effect is achieved merely by the slow biological microdegradation of the coating mate-rial. The coating material used in this case comprises biodegradable synthetic polymers such as polyglycols and polylactides, and corresponding copolymers or mix-tures etc., which are dissolved in an organic solvent, preferably chloroform, which evaporates after applica-tion to the biomaterial.

It is also proposed in these patent applications to incorporate medicinal substances into the coating mate-rial, using as medicinal substances both anticoagulant and antiinflammatory medicinal substances. The incorpo-ration of antibiotics is also possible. However, in contrast to the abovementioned process, these medicinal substances are intended not to be released to a large extent into the bloodstream but to act essentially locally.

It has emerged from experiments that the formation of thrombi can be prevented to a large extent with a paint-like coating of this type, where appropriate in combination with incorporated medicinal substances, so that the surgical risks which are always a worry other-wise can be greatly reduced.

The invention is based on the object of indicating acoating material in which the advantageous effects can be further increased.
This object is achieved according to the invention by the features of claim 1.

REPT-~M~T SHEET (RULE 26) According to this, at least one inhibitor of serine proteases which, just like the medicinal substance car-rier itself, is it itself able to dissolve in the organic solvent necessary for preparation of the coat-ing material, preferably chloroform, is used. Thlsresults in a homogeneous solution, which is applied to the biomaterial, after which the solvent is subse-quently evaporated off so that a dissolved homogeneous mixture is then present as coating on the biomaterial.
The inhibitor is a directly acting thrombin inhibitor, i.e. acts without the involvement of an endogenous cofactor or the like.

Another homogeneously dissolved medicament which can also be present is a prostaglandin or prostacycline, it additionally being possible to incorporate fast-acting antithrombogenic agents such as hirudin.

The medicinal substance carrier preferably used is a poly-D,L-lactide which can be bought as R203 from Boehringer, Ingelheim; the antithrombin preferably used is an amidinophenylalanine derivative as claimed in claims 9 and 10, which is marketed by Behring-Werken AG
under the name CRC220 and is described in detail in EP-A1-0513543.

The provision of a coating material according to the present invention was based on the idea that endothe-lial cells have, as inner linings of blood vessels, mechanisms which prevent adhesion of cells and plasma proteins. In this connection, released substances such as prostaglandins in particular prevent the deposition of blood plateletsi in addition, substances which coun-teract thrombin formation are produced on the surface.
It has now emerged from the experiments for the present invention that so-called self-cleaning surfaces, i.e.
permanently biodegradable materials, in combination REPT-~M~NT SHEET (RULE 26) with homogeneously dispersed inhibitors of thrombin and serine proteases, and, where appropriate, prostaglan-dins or prostacycline derivatives or appropriate analogs, which are incorporated in dissolved form into the coating materials, have an endothelium-like action.
The result of this is, while there is only low systemic availability of the incorporated dissolved medicaments, by combination with the self-cleaning surface coating there is prevention of deposition, of activation of plasma coagulation and of blood platelet aggregation.
The coating material can be referred to, as it were, as long-term depot, the aim being to keep the release of the medicaments, in particular of the antithrombins, as low as possible in order not to result in the known disadvantages of systemic dosage.

A so-called triple combination consisting of thrombin inhibitors such as hirudin and said CRC220 with a syn-thetic prostaglandin derivative (iloprost) has proven useful on introduction into the blood circulation of implants or prostheses which are associated with a par-ticularly high risk of activating coagulation. In this case, the hirudin acts as thrombin inhibitor which is rapidly available directly in the surgical phase and by which the complication of the surgical intervention is reduced. The inhibitors which are also homogeneously dispersed in the medicinal substance carrier then bring about the necessary long-term compatibility.

The coating material according to the invention is pro-duced by initially preparing a basic solution of a medicinal substance carrier, preferably poly-D,L-lactide, and a solvent, preferably chloroform. For the solution, 50 to 300 milligrams, preferably 150 to 160 milligrams, of a medicinal substance carrier are dissolved in one milliliter of solvent, preferably chloroform.

REPT-~C~M~T SHEET (RULE 26) Said antithrombin CRC220 is dissolved in this basic solution to result in a content of between 0.5 and about 20% by weight, preferably up to 10% by weight, in the final mixture based on the medicinal substance carrier. Furthermore, said prostaglandin derivative Iloprost is also dissolved in a content between 0.5 and 7% by weight, preferably 1 to 5% by weight, and finally hirudin is added in a content between 2 and 10% by weight of the complete solution, preferably about 5% by weight.

After application of this solution to biomaterial, the chloroform evaporates so that a homogeneous mixture of medicinal substance carrier and added medicaments is then present as coating.

REPT-~M~NT SHEET (RULE 26)

Claims (12)

1. A coating for biomaterial which can be introduced into the bloodstream or into the tissue of the human body, such as infusion, cardiac or balloon catheters, electrodes for heart pacemakers and defibrillators, suture material, oxygenators, support constructions for vessels (stents) or the like, this coating preventing in particular blood coagulating on the biomaterial due to adhesion of plasmatic or cellular constituents, and the coating having a blood- and tissue-compatible medicinal substance carrier which is dissolved in an organic solvent, and in which at least one medicament is incorporated and which, after application to the biomaterial and evaporation of the solvent, is permanently biodegraded in the body, wherein an inhibitor of serine proteases is present in homogeneously dispersed dissolved form in the medicinal substance carrier, this inhibitor being soluble together with the medicinal substance carrier in the same organic solvent, so that application to the biomaterial and evaporation of the solvent result in a homogeneous coating which is composed of medicinal substance carrier and inhibitor and has a function comparable to that of endothelium.
2. A coating as claimed in claim 1, wherein the inhibitor is a directly acting thrombin inhibitor.
3. A coating as claimed in claim 2, wherein the thrombin inhibitor suppresses contact activation of blood coagulation.
4. A coating as claimed in any of the preceding claims, wherein, to achieve an endothelium-like action, furthermore a prostaglandin or prosta-cycline or a corresponding derivative is added together with the medicinal substance carrier and the inhibitor to the solvent and is contained in dissolved form in the medicinal substance carrier.
5. A coating as claimed in any of the preceding claims, wherein additionally an antithrombin which can be rapidly released, such as hirudin, is incorporated into the medicinal substance carrier.
6. A coating as claimed in any of the preceding claims, wherein a poly-D,L-lactide is used as medicinal substance carrier.
7. A coating as claimed in any of the preceding claims, wherein the individual components of the coating are dissolved in chloroform.
8. A coating as claimed in any of the preceding claims, wherein the coating forms on the biomaterial a paint-like adhesive layer with layer thicknesses of less than 100 micrometers, preferably less than 50 micrometers or 10 micrometers.
9. A coating as claimed in any of the preceding claims, wherein a compound of the following structure is used as soluble antithrombin:

in which R' is a naphthalene ring which is bonded in the alpha or beta position and is optionally derivatized with alkyl groups which contain up to 3 carbon atoms, and/or alkoxy groups with in each case up to 3 carbon atoms, or is a tetralin ring or indane ring which is bonded in the alpha or beta position and which is optionally derivatized with alkyl groups which comprise up to 3 carbon atoms, and/or else alkoxy groups with in each case up to 3 carbon atoms, or is a phenyl ring which is optionally derivatized with alkyl groups which contain up to 4 carbon atoms, and/or with up to three groups of the structure O-X in which O is oxygen and X is hydrogen, methyl, ethyl, n-propyl, i-propyl or tert-butyl, and/or with a group of the structure -COOY in which Y is hydrogen, methyl, ethyl, n-propyl, i-propyl, tert-butyl, i-butyl, i-pentyl or neo-pentyl, or is a chroman system which is preferably derivatized with up to 5 alkyl groups which contain up to 3 carbon atoms, is a qroup of the structure A-B where A = -(CH2) n- and n = 1-4 and B is an acid functionality selected from the group consisting of carboxyl functionality which can optionally be esterified or be in an amide form, where the esters contain an alcohol with up to 17 carbon atoms, sulfonic acid functionality, a functionality of a phosphorus acid, a boronic acid functionality and tetrazole group, or R1 is a group of the structure A-B-C
where A has the above meaning, B is carbonyl or sulfonyl, and the group C is derived from an N-bonded alpha, beta, gamma or delta amino acid or from the group of N-glycosidically linked uronic acids, and R2 and R3 can be identical or different and are alkyl groups with up to 4 carbon atoms or together form a heterocyclic ring which has up to 8 ring members and can be derivatized with a hydroxyl group or a hydroxyalkyl group with up to 3 carbon atoms, and this hydroxyl group is optionally in esterified form, where the corresponding acids are carboxylic acids which contain up to 17 carbon atoms, and in which the carbon atom labeled with * has the R or S structure, but preferably the R structure (CRC220).
10. A coating as claimed in claim 9, wherein R' is 4-methoxy-2,3,6-trimethylphenyl, R1 is -CH2-COOX
with X equal to hydrogen and R2 and R3 together are piperidine.
11. A coating as claimed in any of the preceding claims, wherein the components of the coating are present dissolved in a solvent, preferably chloroform, where the contents of the individual components per milliliter of the solvent have the following values:

100 to 300, preferably 150 to 160, milligrams of medicinal substance carrier;

0.5 to 20% by weight, preferably up to 10% by weight, of a directly acting antithrombin (CRC220);

0.3 to 2% by weight, preferably 0.5-1% by weight, of a prostaglandin derivative or of a corresponding analog;

0.5 to 10% hirudin.
12. A coating as claimed in claim 10, wherein the mixture preferably comprises 5% by weight of each individual substance.
CA 2218103 1995-04-13 1996-02-06 Coating for biomaterial which can be introduced into the bloodstream or into the tissue of the human body Abandoned CA2218103A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DE1995114104 DE19514104C2 (en) 1995-04-13 1995-04-13 Coating for can be introduced into the bloodstream or into the tissue of the human body biomaterial
DE19514104.0 1995-04-13

Publications (1)

Publication Number Publication Date
CA2218103A1 true CA2218103A1 (en) 1996-10-17

Family

ID=7759689

Family Applications (1)

Application Number Title Priority Date Filing Date
CA 2218103 Abandoned CA2218103A1 (en) 1995-04-13 1996-02-06 Coating for biomaterial which can be introduced into the bloodstream or into the tissue of the human body

Country Status (8)

Country Link
EP (1) EP0820316B1 (en)
JP (1) JP2000503555A (en)
KR (1) KR19980703832A (en)
AT (1) AT218897T (en)
AU (1) AU4787496A (en)
CA (1) CA2218103A1 (en)
DE (1) DE19514104C2 (en)
WO (1) WO1996032143A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
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US8257305B2 (en) 2002-09-20 2012-09-04 Bayer Pharma Aktiengesellschaft Medical device for dispensing medicaments
US8389043B2 (en) 2001-03-26 2013-03-05 Bayer Pharma Aktiengesellschaft Preparation for restenosis prevention

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DE19508772C2 (en) 1995-03-01 1998-01-29 Schering Ag Methods and compounds for the detection of analytes by means of remanence and their use
TW499412B (en) 1996-11-26 2002-08-21 Dimensional Pharm Inc Aminoguanidines and alkoxyguanidines as protease inhibitors
DE19718339A1 (en) * 1997-04-30 1998-11-12 Schering Ag Polymer coated stents, methods for their preparation and their use for the prophylaxis of restenosis
US6344486B1 (en) 1998-04-03 2002-02-05 3-Dimensional Pharmaceuticals, Inc. Benzamide and sulfonamide substituted aminoguanidines and alkoxyguanidines as protease inhibitors
CA2329929A1 (en) 1998-04-24 1999-11-04 3-Dimensional Pharmaceuticals, Inc. Amino acid amidinohydrazones, alkoxyguanidines and aminoguanidines as protease inhibitors
CA2334679C (en) 1998-06-11 2012-10-23 3-Dimensional Pharmaceuticals, Inc. Pyrazinone protease inhibitors
DE59903490D1 (en) 1998-09-11 2003-01-02 Schmidmaier Gerhard Biologically active implants
JP2003501352A (en) 1999-05-27 2003-01-14 3−ディメンショナル ファーマシューティカルズ, インコーポレイテッド Okisaza heterocyclic ring as a protease inhibitor
WO2001004117A1 (en) 1999-07-09 2001-01-18 3-Dimensional Pharmaceuticals, Inc. Heteroaryl protease inhibitors and diagnostic imaging agents
US8496699B2 (en) 2000-03-01 2013-07-30 Medinol Ltd. Longitudinally flexible stent
US7141062B1 (en) 2000-03-01 2006-11-28 Medinol, Ltd. Longitudinally flexible stent
US8920487B1 (en) 2000-03-01 2014-12-30 Medinol Ltd. Longitudinally flexible stent
US8202312B2 (en) 2000-03-01 2012-06-19 Medinol Ltd. Longitudinally flexible stent
US7592017B2 (en) 2000-03-10 2009-09-22 Mast Biosurgery Ag Resorbable thin membranes
CA2415932A1 (en) 2000-07-17 2002-01-24 3-Dimensional Pharmaceuticals, Inc. Cyclic oxyguanidine pyrazinones as protease inhibitors
WO2002012207A1 (en) 2000-08-04 2002-02-14 3-Dimensional Pharmaceuticals, Inc. Cyclic oxyguanidine protease inhibitors
EP3251722A1 (en) * 2001-04-20 2017-12-06 ALZA Corporation Microprojection array having a beneficial agent containing coating and method of forming the coating thereon
WO2002085447A2 (en) 2001-04-20 2002-10-31 Alza Corporation Microprojection array having a beneficial agent containing coating
DE10146814A1 (en) * 2001-09-18 2003-04-03 Uronova Gmbh Medical sutures
AU2003259684C1 (en) 2002-07-31 2009-03-26 Mast Biosurgery Ag Apparatus and method for preventing adhesions between an implant and surrounding tissues
US8048444B2 (en) 2002-07-31 2011-11-01 Mast Biosurgery Ag Apparatus and method for preventing adhesions between an implant and surrounding tissues
US7704520B1 (en) 2002-09-10 2010-04-27 Mast Biosurgery Ag Methods of promoting enhanced healing of tissues after cardiac surgery
CA2556785A1 (en) * 2003-02-20 2004-09-02 Hamilton Civic Hospitals Research Development Inc. Coating composition for polymeric surfaces comprising serpin or serpin derivatives
WO2004091613A2 (en) 2003-04-10 2004-10-28 3-Dimensional Pharmaceuticals, Inc. Substituted phenyl acetamides and their use as protease inhibitors
DE10330900B4 (en) * 2003-07-01 2006-09-14 Leibniz-Institut Für Polymerforschung Dresden E.V. Biomaterial with a modular coating system for use in direct blood contact medical devices
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CN102727989B (en) * 2011-04-12 2014-07-09 上海林静医疗器械有限公司 Environmental-friendly and energy-saving degradable disposable vagina dilator and preparation method thereof

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8389043B2 (en) 2001-03-26 2013-03-05 Bayer Pharma Aktiengesellschaft Preparation for restenosis prevention
US9066990B2 (en) 2001-03-26 2015-06-30 Bayer Intellectual Property Gmbh Preparation for restenosis prevention
US8257305B2 (en) 2002-09-20 2012-09-04 Bayer Pharma Aktiengesellschaft Medical device for dispensing medicaments
US8439868B2 (en) 2002-09-20 2013-05-14 Bayer Pharma AG Medical device for dispersing medicaments
US9649476B2 (en) 2002-09-20 2017-05-16 Bayer Intellectual Property Gmbh Medical device for dispersing medicaments

Also Published As

Publication number Publication date
DE19514104C2 (en) 1997-05-28
DE19514104A1 (en) 1996-11-28
KR19980703832A (en) 1998-12-05
WO1996032143A1 (en) 1996-10-17
EP0820316B1 (en) 2002-06-12
AU4787496A (en) 1996-10-30
AT218897T (en) 2002-06-15
JP2000503555A (en) 2000-03-28
EP0820316A1 (en) 1998-01-28

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