AU625391B2 - Articles exhibiting a blood-compatible surface layer and process for providing articles with such a surface layer - Google Patents

Description

DECLARED at moinciai this 18th day of December ASTR MFnTTPF AfTFRni A.

A.D. 1989 AUSTRALIA (51)

PATENT

(43) MIg-A-M317 8 PCT WORLD INTELLECTUAL PROPERTY ORGANIZATION InternationiaLBi

W.

INTERNATIONAL APPLICATIZ U H Ui Re PAI NT COOPERATION TREATY (PCT) (51) International Patent Classification 4: International Publication Number: WO 89/ 01791 A61L 31/00 A l (43) International Publication Date: 9 March 1989 (09.03.89) (21) International Application Number: PCT/SE88/00421 (74) Agents: MIKSCHE, Gerhard et al.; AB Astra, Patent and Trademark Department, S-151 85 S6dertAlje (22) International Filing Date: 18 Aigust 1988 (18.08.88) (SE).

(31) Priority Application Number: 8703310-6 (81) Designated States: AT (European patent), AU, BE (European patent), CH (European patent), DE (Euro- (32) Priority Date: 26 August 1987 (26.08.87) pean patent), DK, FI, FR (European patent), GB (European patent), IT (European patent), JP, LU (33) Priority Country: SE (European patent), NL (European patent), NO, SE (European patent), US.

(71) Applicant (for all designated States except US): ASTRA MEDITEC AKT!EBOLAG [SE/SE]; Box 14, S-431 Published 21 M1lndal With international search report.

(72) Inventors; and Inventors/Applicants (for US only) NYGREN, Bo, Hakan [SE/SE]; Valebergsvigen 4C, S-427 00 Billdal STENBERG, Johan, Emanuel [SE/SE]; Hedelungsvigen 5, S-41.7 43 G6teborg A.O. J.P. 1 1 MAY 189

AUSTRALIAN

3 1 MAR 1989 PATENT OFFICE (54)Title: ARTICLES EXHIBITING A BLOOD-COMPATIBLE SURFACE LAYER AND PROCESS FOR PROVID- ING ARTICLES WITH SUCH A SURFACE LAYER (57) Abstract Article exhibiting at least one surface of glass, metal or hydrophobic polymer coated with blood-compatible surface layer, in which the biocompatible surface layer consists of an adsorbed hydrophobized water-soluble polymer. Process for providing said articles by adsorption of hydrophobized water-soluble polymer. Use of such a substrate material coated with said surface layer for manufacture of medical articles having a blood-compatible surface.

WO 89/01791 PCT/SE88/00421 Articles exhibiting a blood-compatible surface layer and process for providing articles with such a surface layer Field of the invention The present invention relates to articles exhibiting a blood-compatible surface layer and methods for providing such articles with such a surface layer and in particular for providing articles useful within medicine.

More particularly, the invention relates to articles exhibiting at least one surface of glass, metal or a hydrophobic polymer coated with a blood-compatible surface layer and processes for providing articles exhibiting at least one surface of glass, metal or a hydrophobic polymer with a coating of a blood-compatible surface layer, as well as tl-. use of substrate material of glass, rretal or hydrophobic polymer, coated with the surface layer of an adsorbed hydrophobized water-soluble polymer preferably a non-protein for manufacture of a medical article having a blood-compatible surface.

Background of the invention Prior art technique to provide articles useful in medicine with a blood-compatible surface layer often comprises an alteration in the surface energy of the material. An improvement in the properties of various materials has been obtained by modifying the surface layers either to a more hydrophobic character or to a more hydrophilic character. Hydrophobization of the surface layer, for instance by the methylization of a glass surface, results in a decrease in the effectiveness of the surface activated coagulation system of the blood. However, proteins such as fibrinogen are bound comparatively firmly to such surface and to this protein layer certain cells, the thrombocytes, can be bound and activated whereafter coagulation is started even though it proceeds slowly. Hydrophilic surfaces, e.g. hydrolysed nylon or oxidized aluminium, have presented reduced binding of cells but the surface activated coagulation system is not prevented at these surfaces. The use of these surfaces in contact with blood thus implies the addition of anti-coagulants, for instance heparin to the blood.

WO 89/01791 2 PCT/SE88/00421 Another prior art surface treatment technique for preventing coagulation comprises binding of anticoagulants into the surface layer. Heparin has primarily been used with this technique. Heparin is a hexoseaminehexuronic acd polysaccharide which is sulphatized and has acid properties, i.e. heparin is an organic acid. According to DE-A-21 54 542 articles of an organic thermoplastic resin is first impregnated with an amino-silane coupling agent and the article thus treated is then reacted with an acid solution of heparin salt to the binding of heparin in the surface layer by means of ionic bonds. Surfaces thus treated with heparin have proved to reduce the coagulation reaction.

A considerable disadvantage of these surfaces, however, is that the heparin treatment does not prevent the adherence of thrombocytes, which is a great problem in, for instance, heart-lung machines.

On the 10th Annual Meeting of the Society for Biomaterials (Washington D.C. April 27,1984) was described that polyethylenglycol surfaces on quartz minimize protein adsorption. Procedures for covalent binding of polyethylenglycol to surfaces have previously been described, e.g. in W086/02087. Polyion complexes formed between a cationic and an anionic cellulose derivative have also been found to have good blood-compatibilities (Ito, H. et.al., J. Appl. Polym. Sci.,Vol. 32 (1986) 3413). Methods of covalent binding of water-soluble polymers to surfaces have also been described, e.g. in EP 166 998.

It is known that water-binding gels, for instance polyhydroxyalkylmethacrylate, reduce the adsorption of proteins and present a low adhesiveness to cells (Hoffman et al., Ann. N.Y. Acad. Sci., Vol. 283 (1977) 372). These properties are considered to be due to the fact that gels containing water give a low surface energy in the interface to the blood. The prior art technique for manufacturing of water-binding gels, however, is impaired by disadvantages such as complicated preparation technique and incomplete polymerization, which results in leakage of toxic monomers. A gel-like mixture of sacccharose and glucose included in a matrix of the polysaccharide dextran or dextrin is used in accordance with previously known technique as a tube for the connection of blood-vessels. This mixture should have the effect that no toxicity to the patient occurs that the implantate is dissolved in the blood after some

IAXL-X-

WO 89/01791 PCT/SE88/00421 time. It is known that the neutral polysaccharide dextran is miscble with blood without provoking any coagulation reaction. Dextran has been used as a surface coating on glass, aluminium and silicon rubber, and has been shown to reduce blood coagulation during blood contact with these surfaces as described in W083/03977.

The adhesion of blood components to surfaces in contact with blood could be decreased by preadsorption of albumin to hydrophobic surfaces (Mosher, D.F in: Interaction of blood with natural and artificial surfaces, Ed. Salzman, E.W, Dekker Inc 1981). The adsorbed albumin does not form a stable coating, but is desorbed during contact with blood and coagulation is induced although at a lower rate.

Disclosure of the invention The object of the present invention is to provide articles useful within medidcne with a blood-compatible surface layer. This means, for articles 15 intended for use in contact with blood, that the article which is alien to the blood is treated in such a way that it does not induce coagulation or "iformation of thromboses.

The present invention affords technique for the surface treatment of :..material important for medical technology, such as glass, metal and 20 hydrophobic polymers polytetrafluoroethylene (PTFE)).

The article according to the invention which exhibits at least one surface of glass, metal or hydrophobic polymer coated with a blood-compatible surface layer, is characterized in that the blood-compatible surface layer consists of an adsorbed alkylhydroxyalkylcellulose having a flocculation temperature of about 35-40 0

C.

The process according to the invention for providing articles exhibiting at least one surfzce of glass, metal or hydrophobic polymer coated with blood-compatible surface layer, is characterized in that said substrate pun( surface of the article, after hydrophobization when required, is exposed to S4 a solution of an alkylhydroxyalkylcellulose having a flocculation temperature of about 35-40 0 at a temperature below flocculation.

WO 89/01791 4 PCT/SE88/00421 The substrate surface has to be hydrophobic before coating. For metals or metal oxides this can be achieved by methylization with silanes.

The polymers used in the present invention are hydrophobized derivatives of water-soluble polymers. This means that the polymers used are limited soluble in water depending on the degree of hydrophobization. Examples of possible polymers that could be hydrophobized and used as surface coating polymers are mentioned below, however, only those identified above are claimed herein: Natural water-soluble polymers 1) Starches, especially derivatives such as ethers 2) Celluloses, especially cellulose ethers 3) Other polysaccharides alginic add, gum arabic, gum guar, gum tragacanth, tannin, tamarind and lignin 15 Synthetic water-soluble polymers 1) PVA polyvinyl alcohol 2) Polyethylene oxides polyethylene oxide, polyethylene glycol S 20 3) Acrylates sodium polyacrylate 4) Maleic anhydride polymers Smethyl vinyl ether-maleic anhydride copolymers Phtalates polyhydroxy ethyl phtalates 6) Water-soluble polyesters polydimethylol propionate 7) Ketone aldehyde resins methyl isopropyl ketone formaldehyde resin 8) Acrylamides /9 y\ polyacrylamide WO 89/01791 PCT/SE88/00421 9) Polyvinyl pyrrolidone

PVP

water-soluble nylon The water-soluble polymer used in this invention is a hydrophobized derivative of one of these polymers and it is characterized by the property of the ability to adsorb at hydrophobic surfaces. The hydrophobization of the polymer can be performed by binding of hydrocarbons to the polymer backbone. Examples of such hydrocarbons are alkyl-groups, benzyl-groups or alkenyl-groups. The hydrophobization renders the polymer partly insoluble in water with a flocculation temperature as specified above.

The substrate surface is exposed to a solution of the polymer at a temperature below flocculation and at a salt concentration below flocculation. The hydrophobized polymers adsorbs strongly to 15 hydrophobic surfaces, the specified polymers having a flocculation temperature of about 35-40 0 C. as indicated above.

The treated surface proves biologically inert and surfaces treated in this way give reduced adsorption of proteins, adherence of cells and coagulation.The adsorbed polymer is not exchanged by plasma proteins.

20 The process according to the present invention can'be applied within many fields. Thus, in heart-lung machines there are used many details which are made of aluminum which can easily be treated by methyl-silane to get a hydrophobic surface.

The process according to the present invention is ideilly suited for treatment of venous catheters. These are often manufactured in PTFE and this material is normally not blood compatible. For this material it is also difficult to find appropriate processes for covalent coupling of hydrophilic polymers.

0pLc~ 4-1 SWO 89/01791 6 PCT/SE88/00421 The invention may also be applied in other connections, for instance, for treatment of articles of hydrophobic plastics for sampling and/or storage of blood.

The invention will in the following be illustrated by a working example but is not limited thereto and hence modifications are of course conceivable within the limits of the claims.

Working example Coating procedure a) The polymer is purified and isolated by repeated heat flocculation and centrifugation.

b) A polytetraflouroethylene-tube (teflon), diameter 3 mm, and a i polyurethane-tube, diameter 3 mm, were immersed in a solution of Sethyl-hydroxyethyl-cellulose (EHEC, 1 g/l, prepared according to US 3,926,951) in distilled water for 20 hours in room temperature.The tubes were rinsed in saline for 1 minute.

Experimental tests Two different tests were performed. Incubation with a solution of fibrinogen at high concentration was performed in order to detect exchange reactions between the polymer and plasma protein. Incubation Swith whole blood followed by measurement of released thromboglobulin was used to measure the stability of the polymer coating and the activation of platelets at the surface.

s Fibrinogen adsorption a) Coated and non-coated tubes were incubated in a solution of human fibrinogen (1 g/l in saline for 30 minutes at room temperature.

b) The tubes were rinsed in saline for 10 seconds.

WO 89/01791 PCT/SE88/00421 c) Incubation in anti-fibrinogen antiserum diluted 1:1000 for 1 hour at room temperature.

d) Incubation with peroxidase-conjugated anti-antibodies for minutes.

e) Incubation in a solution of orthophenylenediamine (0.5 g/1 and 0.01 H202 in 0.1 M citrate buffer, f) Addition of 2 M H 2 S0 4 and reading of absorbance at =450 nm.

Blood-compatibility test a) Venous blood (18 ml) was tapped from a healthy donor into 2.0 ml of a solution of hirudin in saline (500 IE /ml) (Hirudin is a thrombin inactivator b) The blood was filled into coated and non-coated tubes and allowed to incubate for 2 hours at room temperature.

c) 1 ml of blood was drawn into a syringe containing 0.2 ml diatube® and the mixture was centrifugated at 5000 g for 30 minutes at +3 0

C.

d) The supernatant was collected and the amount of B-thromboglobuline using a commercial kit Diagnostica Stago).

Results The results of the tests above are presented in table I and II. Table I shows that the amount of fibrinogen adsorbed to the tubes is reduced by the coating with ethyl-hydroxyethyl-ellulose. Table II shows that the amount of 9-thromboglobuline released from the platelets during incubation with blood is also reduced by the coating with ethyl-hydroxyethyl-cellulose.

WO 89/01791 WO 9/0791PCT/SE88/00421 TABLE I Amount of surface adsorbed fibrinogen as measured by the ELISA teflon poly- poly- latex poly- silicone polyurethane propene rubber vinyl rubber styrene uncoated 0.953 0.868 0.406 0.220 0.439 0.794 0.634

EI-IEC

0.242 0.188 0.304 0.110 0.268 0.246 0.005

EHEMC

0.969 0.420 0.308 0.153 0.274 0.560 0.016 KIucelTM 1.042 0.922 0.434 0.131 0.203 0.722 Footnotes: *flocculation temperature of the polymer in distilled water.

**propyl-hydroxypropyl cellulose TABLE rI Amount of f9-thrombogzlobuline released as measured by the EUSA teflon polyurethane uncoated 1.38 1.67

EHEC

0 C) 0.44 0.85

Claims (12)

1. Article exhibiting at least one hydrophobic surface of glass, metal or a hydrophobic polymer coated with a blood-c onpatible surface layer, characterized in that the blood-compatible surface layer consists of an adsorbed alkylhydroxyalkylcellulose having a flocculation temperature of about 35-40"C.

2. Article according to claim 1 characterized in that the alkylhydroxy- alkylcellulose is ethylhydroxyethylcellulose.

3. Article according to claim 1 or 2, characterized in that the hydrophobic 10 polymer surface is polytetrafluoroethylene.

4. Article according to any one of claims 1-3, characterized in that it is a catheter, tube, or a device for sampling and/or storage of blood.

5. Article according to any one of claims 1-3, characterized in that it is a heart-lung machine exhibiting at least one hydrophobic aluminium surface S"1s with a coating of a blood-ccmpatible surface layer. S.

6. Process for providing articles exhibiting at least one hydrophobic surface of glass, metal or a hydrophobic polymer with a coating of a blood- ccmpatible surface layer, characterized in that said surface of the article, after hydrophobization when required, is exposed to a solution of an alkyl- hydroxyalkylcellulose having a flocculation temperature of about 35-40°C, at ;a a temperature below flocculation.

7. Process according to claim 6 wherein the hydrophobic surface is polytetrafluoroethylene which is exposed to a solution of ethylhydroxy- ethylcellulose. I I MMM1Mr_____

8. Use of a substrate material of glass, metal or hydrophobic polymer coated with a surface layer consisting of an adsorbed alkylhydroxyalkyl- cellulose having a flocculation temperature of about 35-40°C for manufacture of a medical article having a blood-compatible surface.

9. Use according to claim 8 whe:ein the substrate is polytetrafluoro- ethylene coated with a surface layer consisting of an adsorbed ethylhydroxy- ethylcellulose. Articles obtained by the process or use according to any one of claims 6 to 9, respectively.

DATED this 14th day of April, 1992 ASTRA MEDITEC AKTIEBOLAG, By its Patent Attorneys, E. F. WELLINGTON CO., S. Wellingto S. Wellington) C i\L INTERNATIONAL SEARCH REPORT International Application No PCT /SE 88/OtJ42 1 1. CLASSIFICATION nF SUBJECT MATTER lif several classificotion Symbolsi apply, indicate all) According to International Patent Classification (IPC) or to both National Classification and PC ~4 A 61 L 31/00

11. FIELDS SEARCHE1 Minimum Documentation Searched Classification System IClassification Symbols IPC 4A 61 L, A 61 F Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included In the Fields Searched G SE, NO, DK, FI classes as above Ill. DOCUMENTS CONSIDERED TO BE RELEVANT' category j Citation of Document, 11 with Indication, where appropriate, of the relevant passages

12 Relevant to Claim No. X CA, A, 1 208 557 (G B MARKS et al.) 1-12 29 July 1986 see page X Chemical Abstracts, Vol. 102(1985), abstract No. 1-12 67 368, Kenkya Hokoku-Seni Kobunshi Zairyo Kenkyusho, 1982, (131), 11-22 (Jap) X Dertuent's Abstract No. 87-239975/'34 I 1-4 JP, A, 62164468 (DAICLE CHEM IND KK) 21 July 1987 X Deruient's Abstract No. 87-105705/15 1-2 JP, A, 620536660 (MITSUBISHI RAYON KK) 9 March 1987 X Deruient's Abstract No. 86-282129/43 1-2 JP, A, 61206452 (NIPPON ZEON KK) 12 September 1986 X Derwent's Abstract No. 85-293554/47 1-2 JP, A, 60202702 (SHOWA DENKO KK) 14 October 1985 *Special categories of cited documents: If T Itter document published after the international filing date document defining the general state of the oil which Is not or priority date and not in conflict with the application but cosdrdt eo priua eeac cited to undiiratand the principle or theory underlying the consdere tobe o paticuar elevnceInvention E'1 earier document but published on or otter the International document of particular relevance: the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority clm(s) or Involve an Inventive etop which is cited to establish the publication date 14 another documnent of particular relevance; the claimed Itivention ciation or other special reason (as specified) cannot be considered to Involve an inventlive step when the document referring to an oral disclosure, ue, exhibition or document ie combined with one or more other such docu- other means ments, auch combination being obvloui, to a person skilled do-ument published prior to the International filing date bukt In tOe art. leter than the priority date claimed document member of the eam* patent family IV. CERT1FICATIOi4Dt fMiigo haInentoa erhRpr Date of the Actual Completion of the International '-',arch

1988-10-26 Internat~onal Searching Authority Swedish Patent Office Form PCTIISA/210 (second eheet (January 111111) 4WB -11 1 1 Has~ -n IL International Application No. PCT/SEBB/00421 Ill. DOCUMENTS CONSIDERED TO BE RELEVANT (CONTIIIUED FR Dll THE SECOND SHEET) Catagory j Citationi of Domesnt, with ind~ction, w""r appropinate, of te relevant passage$ Relevant to Claim No P US, A, 4 708 951 INAGAKI et al.) 1-4 24 Novjember 1987 The whole document A US, A, 4 553 973 EDGREN) 1-12 19 Novjember 1995 The whole document A Journal of Bioengineering, Viol. 2, p. 241-249, 1978 1-12 J.M. Courtney et 21.: "Polymer Modification and Blood Compatibility". The whole document Form" PCTISA/21O (extra sheet) (Januany