SU764742A1 - Coating method - Google Patents

Description

one

The invention relates to medical technology and concerns the application of openings to vascular prostheses, artificial heart parts and other products that come in contact with bulk blood, which must have antithrombogenic properties and biological inertness.

To reduce blood clotting, the walls of the vascular prostheses and blood-contacting materials are coated with various substances of both natural and synthetic origin. .

. .. 15A well-known method for producing a coating is that a prosthesis of a knitted fabric material is loaded into a solution of an acrylic monomer, which is then polymerized G. 20 The monomer is chosen so that the polymer formed reversibly swollen upon contact with blood and gave thus the rogel ... Hydrogel covers the material, the prosthesis i fills the holes in it and 25

1yo1yy. A chemical bond arises between the prosthesis polymer material and the polymer. The hydrogel consists of glycol monoacrylate. With one olefin bond and less than 2% 30

6 tons of total weight of diacrylate or methacrylate with two olefinic bonds.

However, this method is suitable, dl. tubular knitwear, no. Suitable for monolithic products because of possible deposits of hydrogel. In addition, it is a great difficulty to control the GEL POINTS, since gelation must occur after the product has been boiled. Children taken out of the bath. And the main thing is that the f 1 coating does not have specific anti-thrombogenic properties.

The closest in technical essence to the present invention is a method of applying a coating of a polyelectrolyte complex based on strong electrolytes, which means that the surface of the product is treated with a liquid adhesive, yes; tee the product is pressed into the powder of the polyelectrolyte complex, then the product is treated with a solution of polyollectrolyte complex screen a solvent, ternary solvent, after which the solvent is removed 2.

The disadvantages of this method are the need to choose an adhesive that is suitable for both material, cure, and the product is made for. ...

lyelektrolitnogo complex, yeobs vigilance to have a liquid adhesive, the difficulty of ayyuysrvyvani powder (especially in the case of product profiles).

In addition, the disadvantages of this coating are its high cost, complexity in the synthesis and processing, undesirable biological activity, contamination with inorganic salts, and insufficient anthropomorphic impurity of the implantable products and the possibility of their prolonged nausea and a living organism. due to the destruction of the material, not enough Lees,) of CI of trace elements on Wednesday.

The aim of the invention is the simplification of the method and the improvement of thromboresthesis: the properties of the obtained pokryti

The goal is determined by the fact that in the method of treating the coating on the polymer surface, which includes pretreatment of the polymer surface, its treatment with a solution of a polyethylene polymer complex and the removal of the solvent, the preliminary treatment is carried out by grafting poly (meth) acrylic acid, and then the polyethylene polymer is injected. based on the indicated Acid in a mixture with a crosslinked agent — polyvinylminr or polyethylenimine, taken in an amount of 1-50 mol%; and after removal of the solvent, a thermal sample is carried out treatment at crosslinking temperatures, agent with poly-. electrolyte complex.

Before coating the polyelectrolyte complex, the polymer is grafted with a polycarboxylic acid: polyacrylic, polymeric sci, which is one of the components of the polyelectrolyte complex. This makes it possible to coat a polyelectrolyte complex on various polymeric surfaces, for example, from polyolefins, rafluoroethylene, polyethylene terephthalate, nitrocellulose, silicone, etc.,. The other component of the complex is Polyheat V. 6d {Schwanie, containing a polyurethane complex. chains (napyr Schlietilenpiperazin, 1,2-polyethylenepiperidine, 1,4-polyethylenepiperidine).

Inoculation polyKieLyOUSchUS: Іl -yu raslichymyyyyododamy, in particular radiation or thermo-oxidative. The radiation is applied in the liquid phase, both by direct irradiation with Co / rays and by co-equilibrization with a preliminary irradiation. In the corresponding section, the radiation dose for the direct method ranges from 0.25 to 1 mrad (optimally selected for each polymer material), and for postpolymerization with pre-irradiation in air from 2 to 10 mrad. Concentrator7 (54742

for monomeric acids (acrylic, methacrylic) in a solution of dioxane or water during grafting: it was not less than 10%, and for some polymeric materials (up to 40%). To prevent the homopolymerization process from proceeding, SlO with Mohr salt is added to the solution. These methods reach 10 wt.% Of the vaccination. For good adhesion of the polycomplex to the polymer surface, 2–5 wt.% Of the privy acidic acid is sufficient.

. After the polyacid is grafted, the polymer surface is washed with water to remove the monomer and homopolymer and the polycomplex is immersed in the solution.

5 sa containing polymeric crosslinkers agent.

The polycomplex solvent is a water solution of a low molecular weight, weak, volatile electrolyte (anthrax and acetic acid, acid, triethylamine T).

Then the polymer surface is dried and subjected to heat treatment at a temperature above. The time and temperature of heat treatment are selected individually for each polymeric material in order to avoid its melting or destruction. To create a coating of different composition men; the ratio of components

0 polik slab to polyso-base (calculated on the basis of mol) in a polycomplex solution from 1: 1 to 10: 1. The thickness of the coating is controlled both by the concentration of the solution and by the repetition of the steps of immersing the solution and drying.

Example 1. A vial loads non-fatty polyethylene terephthalate Hyo film (0.3 g thickness 50 μm) l is heated .5 min at 110 ° C in air, after cheto it is poured with methacrylic acid and absorbed for 72 hours at 70 ° C in argon current. After vaccination, I wash the film with water from the monomer and homopolymer. The degree of vaccination 4%. The film is immersed in 10 ml of a solution of a polyelectrolyte complex of composition:

Solvent A mixture of water and ethyl alcohol (73 by volume) containing 1% ammonium aka.

., Polymeth Acrylic

acid, g 0,86 1,2-Polyethylenepiperidine, g 1,11

five

. Polyvinylamine, oh, 043. Pleyku is removed from the solution, dried, subjected to heat treatment for 1 hour at 135 ° C. It is a durable, transparent, low-density coating 25 µm thick. .

Example 2. Low-fat poly-ethylene film 0.1 g is placed in an ampoule and irradiated with γ rays in air with a dose of 10 mrad, a dose rate of 0.765 mrad / h. Then pour

10% acrylic acid solution S dioxane, vacuum to a pressure of 10 mm Hg. and polymerized 8 hours. At 75 ° C. Then the ampoule is opened, the film is washed in water from the monomer and homopolymer and immersed in 10 ml of a solution of a polyelectrolyte complex of composition:

Solvent A mixture of water and ethyl alcohol 17: 3 by volume) containing 3% triethylamine.

Polyacryl

acid, 0.72 g

1,4-Polyethylenepiperidine, g 1,11

Polyethyleneimine

linear, g 0,043

The film is removed from the solution, dried and subjected to heat treatment at 110 ° C for 30 minutes. A clear, durable, non-extruded coating with a thickness of 25 μm is obtained.

Etc. and me r 3. A defatted polyethylene terephthalate film of 0.3 g, 50 µm thick, 15 ml of an aqueous solution of methacrylic acid and the Mora salt with concentrations of 40% and 5-10 mol, respectively, is loaded into the ampoule. The vacuum is vacuumized to a pressure of ... / 10 mm Hg, sealed and irradiated with Y-rays with a dose of 0.5 mrad. With a dose of 0.765 mrad / h. Then the film is washed with water. The degree of grafting, 5%.

The film is immersed in 10 W: a solution of a poly-electrolyte complex composition. va:

 Solvent 50% water

acetic acid solution.

Polymethacrylic. acid, g, 0.86

Polyethylene piperazine, 0.56

Polyvinylamine, g 0.043 The film is dried and heat treated at 125 ° C for 40 minutes. Get a transparent, durable, non-lining coating thickness of 25 microns.

Example4. In the ampoule load degreased plastic film. 0., 1 and 15 ml of a 10% -gr acrylic acid solution in dioxane. The ampule is evacuated to a pressure of 10 mm Hg. Soldered and irradiated: ay-rays from Co. dose of 1 mrad dose rate of 0.765 mrad / h. Then the film is washed with water from the monomer and homopolymer. The degree of vaccination 1%.

The film is immersed in 10 ml of a solution of a polyelectrolyte complex of composition:

Solvent 50% water

solution of formic acid Polyacrylic acid, g 0.72

Polyethylene piperazine, 0.56

Polyethylenimine, g 0.043 The film is dried and subjected to “heat treatment at 110 ° C for 30 minutes. - Get a transparent, durable, non-lining coating thickness of 25 microns.

Thromboresistant properties of coatings on polyethylene film are given in Table 1 /.

Q Example5. Five degreased silicone tubes 25 cm long and 5 mm in diameter are loaded into a special vessel, where 150 ml of an aqueous solution of acrylic acid and Mohr's salt with a concentration of 10% and 5 510 mol, respectively, are placed and irradiated j; -rays With a dose of 0.25 mrad, a dose rate of 0.25 mrad / h.

After vaccination, the tubes are washed with water from the monomer and homopolymer. The degree of vaccination is 3%.

The tubes are immersed in solutions that differ from each other in the composition of the polyelectrolyte complex (PEC) in order to obtain a coating of different composition 5. Solvent is everywhere 50% formic acid water solution.

Solution No. 1 Solvent 10 ml Polyacrylic acid 0.72 g Q Polyethylene piperazine 0.56 g Polyethylene im g

Solution No. 2 Solvent 10 ml; Polyacrylic acid 1.44 g 5 Jolietilenpiperazin 0.56 g Polyethylenimine 0.043 g

Solution No. 3 Solvent 15 ml Polyacrylic acid 2.16 g 0 Polyethylene piperEin 0.56 g Polyethylene imine 0.043 g

Solution number 4. . Solvent 20 ml. Polyacrylic acid 3.6 g 5 Polyethylene piperazine 0.56 g Polyethyleneimine 0.043 g

Solution No. 5 Solvent 10 ml Polyacrylic acid 3.6 g 0 Polyethylene piperazine 0.28 g Polyethyleneimine. 0.0215 g

The tubes are dried and heat treated at 135 ° C for 30 minutes. Get a Strong coating composition of polyacrylo-5 wa acid / polyethylene piperazine 1/1; 2/1; 3/1; 5/1; .10 / 1.coating is opaque in the case of solutions No. 2,3,4.

Thromboresistant properties of coatings are presented in table. 2

0 PRI me R 6. 12 degreased

tubes of polyallomere block copolymer of polyethylene and polypropylene) is loaded into a special ampoule, where I pour 20 ml of 40% solution

5.-acrylic acid in 5-10 molar.

water solution of salt Mora. The ampoule is evacuated to a pressure of Hg. and irradiated in γ-rays with a dose of 1 mrad with a dose rate of 0.25 mrad / h.

Then the tubes are washed in water from the monomer and homopolymer. Degree of priming 4%,

Two tubes each are immersed in solutions of the polyacrylic acid – polyethylene complex пр prlylethlenpy-11 рρ11ІG $ 1ShtoshstavG as in example 5. After drying, heat treatment at 125 ° C for 1 h is followed. The thromboresistant properties of the coatings are presented in Table 3, which shows the citric acid thromboelastogram of citrate ;: ( 1: 4), incubated for 1 h in test tubes. . ..: ..... For example 7. 12 test tubes made from nitrocellulose can be processed in the same way as in example b; Only privevKu lead in a 30% solution of acidic acid. The degree of vaccination 7%. The thromboresistant properties of pbc | rytyy are presented in Table 4, in which the thrombus of the elastogram of the platelet blood plasma of citrate (1: 4), incubated for 1 h in a test tube, is given.

Apply p.8. Into a special ampoule are loaded with 1-ethylene terephthalate prostheses of blood vessels with a diameter of 6 and 8 mm and a length of 30 cm, 150 ml of a solution of polyacrylic acid in dioxane, evacuated to mercury, sealed and irradiated with rays of a dose of 0.5 mrad with a dose of 0.765 mrad / h Then the prostheses are washed with water from the monomer and homopolymer. The degree of vaccination 2%. The prosthesis is immersed in a 50 ml solution of a polyelectrolyte complex in 50% (water) formic acid with 6CTasa, r

Polyacrylic acid 4.32 Prolyethenylpiperazn 2.24 Polyethylenimine 0.172

Then the prosthetic blood vessel is dried and subjected to heat treatment at 130 ° C for 1 hour, .. --- ... - ...-.-. - .----- The thromboresistant properties of polyethylene terephthalate vascular prostheses coated with polyelectrolyte kleprakami on the basis of weak prleelectrolytes investigated in an experiment in vivo. The experiments were carried out on purebred dogs weighing 15 to 25 kg. The vessels of the vessels 6–8 mm in diameter and 30–40 mm long are fed to seven dogs in the abdominal aiopTy. The prosthesis is sewn at the end of the neck with a continuous suture (silk four zero). Incorporation of the prosthesis into the bloodstream is performed by removing the distal clamp, then gradually, removing the proximal clamp. The frosts of the prostheses are insignificant and reprosthetic hematomas are not observed; - .-. . : -.

Intraoperatively, the period before and after vessel prosthetics are the following hemodynamic studies:

measurement of aortic and arterial pressure in the femoral artery; aortic flowmetry prior to prosthetics and after prosthetics; as well as blood tests: a) citrate (1: 4) thromboelastogram, platelet plasma, platelet-free plasma; b) blood count in the Chandler apparatus, Kvik time, fibrinogen amount, free heparin amount, amount of sample, sample, sample, fibrinogen, amount of free heparin, amount of platelet sample. . Aorta angiography is performed. The animals were slaughtered at 2, 4, 6, 7, 15 days, 4.5 months.

As a result of the research, prostheses function normally and imitate natural hemodynamic parameters, and morphological and microscopic studies of these prostheses show that they are completely passable. On the surface of the prostheses there are no detected blood cells. A pronounced eudotelization of the inner surface is observed, and from the outer one - the development of a connective tissue layer.

PRI me R 9. A connecting heart of an artificial heart, an implantable calf consisting of a lavsan-fluoron corrugated tube with a diameter of 26 mm, a length of 200 mm, and two silicone tubes, are treated in the same way as in Example 8 and hemmed calf

Normally used mylar vascular prostheses as the connecting arteries of an artificial heart do not differ in optimal thromboresistance and mechanical properties. In such vascular prostheses, near-wall and even obstructive thrombi are often formed.

Lavsan-fluorinated vascular prostheses coated with polyelectrolyte complexes according to the invention are used. The distal end of the vascular prosthesis, the end of the end of the vein to the ascending aorta and pulmonary artery. The proximal end of the vascular prosthesis is fixed on the output section of the left and right artificial ventricles of the heart. The results of experiments on the implantation of the connecting line to the artificial heart of bodies there weighing 80-100 kg show that the elimination of vascular prostheses paved with a polyelectrolyte complex meets the requirements of Mj made from the point of view of thromboresistance and mechanical properties. This is expressed by the 5 mercury absence of blood clots during long-term experiments and optimum blood permeability. .

Thus, coatings of polyelectrolyte complexes based on the proposed polyelectrolytes are characterized by pronounced thromboree-resistant properties. In addition, biological compatibility with body tissues is characteristic of GGbliye electrolyte complexes. Through these Coatings, metabolic processes are actively carried out. This is indicated by a well-developed vascular graft. Apparently, coatings of polyelectrolyte complexes based on weak polyelectrolytes promote activation of the regenerator. processes after prosthetic blood vessels.

The proposed method of applying a coating of a polyelectrolyte complex based on weak polyelectrolytes has advantages over a method of applying a hydrogel and a polyelectrolyte complex based on strong polyelectrolytes, namely, it is relatively inexpensive, affordable, simple in technology, and the coating itself is biologically inbrate, has optimal microthromborethylene properties .; The use of a polyelectrolyte complex based on weak polyelectrolytes as antithrombogenic coatings will provide an opportunity to obtain biologically inert antithrombogenic, chemically pure, Soviet-made products and designs of an artificial heart, secondary blood circulation, vascular prostheses, catheters and implant them into a living organism for a long period without various complications and undesirable effects, which will eliminate the cost of developing and improving anti-thrombogenic substances. The final result will give savings in the national economy and significant results in experimental and practical medicine, improvement of medical care.

Experimental batches of artificial

sert, Prosthetics, vessels, connective blood arteries, thrombolus, membrane n, catheters, covered with a polyelectrolyte complex based on weak polyelectrolytes,

which were tested in animals and in vitro.

Table 1

The blood coagulation time in Linholm cells, with

The adhesion index of platelets as the amount of fibrinogen, mg% 376.5 + 2.1 280.2 + 33.3

one

899.3 + 85.8

392.6 + 17.1 640.8 ± 14.1 0.001

177.8 + 20.5

0.001

0.02

eleven

764742

Heparin free

Number of thrombo497 + 26, 825 304 + 6 cytes, thou.

Notes

rafte of chandler

Note; P - reliability pr. Compared with silicone.

12 .. Continuation of the table, 1

483,571 + 33,429 0.05 0.001

Table 3 e; R. - dignity compared to glass; surface; - P, reliability compared to polyethylene. Table 2

Polyeshlomar PEK PAK-Pepp Stl 2 min 5 s + 5 o 1 min 5 s ±, 2 e Note.

-. .;.: - .V ..:.-L, „- .-,: / f in l. h at 4

The thromooelastograms of plasma trobocytoma of Cdwi C wastes (1 | 4) were incubated with 1-H in a microtube of test tubes coated with full electrolysis of weak polyelectrolytes. . Nitrotsvlulova PEK PAK-Pepp Itl ZkinZo + 30s

Iitrocellhshoaa i-PEK PAK-PEPP Sti

Prodo Geneve & Ow.

28min + iMiffi44,

65.5 + 2.5

The memory + 17th

Dinos

0.1

0.1 0.001 0.05 0.001 0.001. Reliability of P tib compared with glass surface and P "polyallomere; PEC - polyelectrolyte complex, PAA-polyacrylic acid, PEPP-polyethylene teraeen. 43mn45b + 1min15s 70 0.001. 0.1

Glass (control)

Zmin7s ± 1 mnnbs

Nitrocellulose a (control)

4min15s ± 15s Notes

Claims (2)

1. US patent number 3862452, cl. 3-1, publ. 01.27.75. 2. US patent number 3582386, cl. 117-21, published, 01,06.71fnpOTototype). The reliability of P is compared with the glass surface and the Pj cellulose cellulose. PEC - polyelectrolyte complex, PAK-polyacrylic acid. PEPP - polyet Lenpiperats.