RU2686747C1 - METHOD OF PRODUCING BIODEGRADABLE POLYMER COATING BASED ON POLYLACTIDE ON TiNbTaZr WIRE - Google Patents

Abstract

FIELD: technological processes.

SUBSTANCE: invention relates to a method of producing a biodegradable polylactide-based polymer coating on TiNbTaZr wire for cava filters used in endovascular prevention of pulmonary artery thromboembolia. Method involves dissolving polylactide in chloroform, adding a drug, dipping the wire into the obtained solution and drying the coating. Coating is applied on TiNbTaZr alloy wire, poly-D,L-lactide with molecular weight from 45 to 180 kDa is used for dissolution in amount of 2 to 10 g per 200 ml of chloroform, heparin is used as medicinal agent with concentration of 1 to 5 % weight, drying is carried out for 2 days in air at 37 °C in thermostat.

EFFECT: invention enables to obtain a coating with given thickness and controlled biodegradation.

1 cl, 2 ex

Description

The invention relates to medicine, in particular to the production of biodegradable polymer coatings on TiNbTaZr wire for cava filters used in the endovascular prophylaxis of pulmonary embolism.

Pulmonary artery thromboembolism (PE) is the third leading cause of sudden death after strokes and heart attacks. When a thrombus is separated from the wall of the vein, it enters the pulmonary artery, which can cause thromboembolism - a complication that often leads to the death of the patient. For the prevention of pulmonary embolism, medical devices “kava-filter” are widely used, which is implanted into the lumen of the inferior vena cava to catch blood clots carrying blood. However, implantation of kava-filter medical devices has a number of postoperative risks, such as the risk of infectious complications, allergic reactions, and blood vessel damage, for which further modification of the kava filters is necessary.

Currently, in the medical practice, operations with the use of a “kava-filter” are widespread and active development of new products continues, since, in addition to their merits, they all have significant drawbacks. The latter are largely due to the properties used for their production of classical materials, as well as limitations in product design. Complications can occur during the operation itself: bleeding, pneumothorax, perforation of the vein or artery, infection, incorrect position during the installation, and during the rehabilitation period. The longer the cava filter is in the body, the more at risk the patient is: cava filter thromboembolism with the development of occlusion of the inferior vena cava, pulmonary embolism, renal and peripheral vein thrombosis, perforation of the vein walls, movement of the cava filter into the right ventricle of the heart, fragmentation filter, allergic reactions of the body.

As in all areas of modern human activity, in medicine, in connection with the increasing demands on man-made products, there is a need to create more and more complex functional materials of a structure that unite and improve the performance characteristics previously considered incompatible. This trend is clearly expressed in the creation and production of medical devices implanted into the human body - a complex, sensitive and aggressive environment. The development of new materials for medical purposes requires not only short-term tasks, but also compliance with a wide range of operational constraints: minimal invasiveness of introducing the product into the human body, no negative impact of the material on living systems, maximum service life of the product, possibility of using several products at once. therapeutic tasks. Such a wide range of physicochemical properties, high biocompatibility, durability, a variety of shapes and sizes of a medical device can be provided by a complex multicomponent structure of the material. So, in the Institute of Mathematics and Mathematics RAS earlier (patent No. 2656626 dated 05.15.2017) wire from Ti-Nb-Ta-Zr alloy was obtained with minimized formation of titanium oxides and tantalum, which provided the material with increased strength, ductility and improved performance characteristics.

In addition to the main areas of improvement of the cava filters mentioned above, the application of a coating consisting of biocompatible, biodegradable (absorbable) or biostable materials, which can also serve as carriers of active substances that perform an additional therapeutic effect, turned out to be promising.

One of the possible solutions may be the formation of bioactive and bioinert coatings based on derivatives of natural biopolymers (for example: polylactide, different molecular weight) on a medical device in order to optimize the implant biointegration process. Possessing high biocompatibility, capable of full biodegradation, polylactide is used in many areas of medicine. Due to the gradual biodegradation, polylactide is capable of releasing the drug for a given period of time. These active medicinal substances are supposed to stop the thrombosis process by entering the body for a desired period of time and in the required concentration. Gradually controlled by changing the molecular weight and thickness of the layer biodegradation of polylactide provides a prolonged local release of the drug, reducing the likely risk of postoperative complications and providing a therapeutic effect.

In patent B2 7,682,387 US. A61F 2/82. Drug-delivery endovascular stent and method for treating restenosis / J.E. Shulze, R.E. Betts, D.R. Savage (Biosensors International Group, Ltd). - №382,426; Claims 05.03.2003 describes a coating with a thickness of 3-30 μm, consisting of poly-DL-lactic acid (25-50% by weight) and an antirheating agent (50-75% by weight), having the following form (1).

where R is H or CH 2 -X-OH, and X is CH 2. This compound is known as everolimus. The coating was carried out on a metal stent or on a pre-applied plasma deposition sublayer parylene. The underlayer was used to promote adhesion of the coating containing the biologically active agent and / or to stabilize the polymer coating on the stent (especially with a high concentration of the active agent: 40-80% by weight). The polymer solution with the active agent was fed through a movable capillary with a step of 0.2 mm to the stent, which was rotated with a step of 0.5 degrees. Thus, a uniform coating was obtained, but only on the external and lateral sides. To cover the inside, it was necessary to reduce the viscosity of the solution by increasing the amount of solvent. The study of the rate of release of the bioactive agent occurred in a solution of 25% ethanol, which varied from 48 to 320 hours depending on the concentration of everolimus and the presence of a sublayer, in a real environment, the authors note, the yield will be longer. The dependence of the mass of the released active substance on time had an exponential character, which may be a minus for the long term use of the stent, since there will be a decrease in the concentration of the bioactive agent. Studies on pigs showed that the area of stenosis after 28 days after surgery was 0.72% when using a conventional uncoated metal stent and 0.45% when a stent was implanted using the proposed method. Closest to the claimed is a method for coating in patent A2 1505930 EP. A61F 2/06. Drug-delivery endovascular stent and method for treating restenosis / J.E. Shulze, R.E. Betts, D.R. Savage (Sun Biomedical LTD, BM). - No. EP 20030747310 20030424; Claims February 16, 2005. The coating has a thickness of 3-15 microns and consists of 20-60% of the mass of poly-DL-lactide and 40-80% of the mass. of antirestenotic agent having the formula (2),

where R represents H or CH 2 -X-OH, and X represents a linear or branched alkyl group containing from 1 to 7 carbon atoms, R'means H or at least one of the radicals R or R 'has the form (3 ),

where m means an integer from 1 to 3, R1 and R2 represent a hydrogen atom or an alkyl radical of from 1 to 3 carbon atoms. There is also a sublayer of parylene with a thickness of 1-5 microns. The application was carried out through the capillary. The release time of the antirheating agent is up to 4 weeks.

The use of antirheumatic preparations for administration to the coating is aimed at preventing possible re-restenosis, which does not solve the problem of thrombus formation.

The objective of the invention is to provide a method for producing a biodegradable polymeric coating based on polylactide on a TiNbTaZr wire for cava filters used in endovascular prophylaxis of pulmonary embolism.

The technical result is a given coating thickness and controlled biodegradation of the coating.

The technical result is achieved by the fact that the method of obtaining a biodegradable polymer coating based on polylactide on a TiNbTaZr wire for cava filters includes:

1) Dissolving the polymer (weight from 2 to 10 g) in a solvent (volume 200 ml), adding a drug, dipping a wire of Ti-Nb-Ta-Zr into the resulting solution and drying;

2) Use as a polymer Poly-D, L-lactide molecular weight from 45 to 180 kDa, and as a solvent - chloroform;

3) Use as a drug of heparin with a concentration of from 1 to 5% by weight.

Summary of Invention

The biodegradable polymeric coating must be able to maintain the required level of the drug in the implantation zone for a required time, despite the blood flow, which can be ensured by controlled biodegradation of the coating.

Poly-D, L-lactide of various molecular weights are used as starting components for the coating. Polylactide is an aliphatic polyester whose monomer is lactic acid. It is biodegradable, biocompatible and thermoplastic. An obvious advantage is the fact that the raw material for the production of polylactide are renewable resources, namely silage crops.

Polylactide is already used in medicine for the manufacture of surgical sutures and the processing of pins. The polymer in the body decompose to the safest compounds - carbon dioxide and water. Using polylactide of different molecular weight, one can vary the rates of biodegradation.

Polylactide can encapsulate molecules of almost any size. Using variable molecular weights, various concentrations of polymer solutions, it is possible to obtain a wide range of coatings with different properties with a further choice of the required characteristics.

A solution of polylactide in chloroform is prepared at the rate of from 2 to 10 g per 200 ml of chloroform, which contributes to obtaining a homogeneous polymer layer with a thickness of from 30 to 300 μm. For the further creation of an optimal cava filter, a mass of 2 g is chosen, which contributes to the formation of a thickness of 30–35 μm. Heparin from 1 to 5% is used as a filler layer. By changing the thickness of the coating and the concentration of heparin, the volume of the drug release per unit of time is controlled. By varying the molecular weight used to obtain a polymer coating from 45 kDa to 180 kDa, the rate of biodegradation can be varied from 150 to 360 days. With a different composition and thickness of the coating, it is possible to obtain different biodegradation of coatings depending on the required application.

Example 1

A heparin-introduced polylactide was coated on a TiNbTaZr wire.

To create coatings, we prepared a sample of Poly-D, L-lactide (45 kDa) weighing 2 (± 0.01) g.

Chloroform with a volume of 200 ml was placed in a flask with a volume of 500 ml and heated to 80 ° C on a magnetic stirrer.

Next, the resulting weights of the polymers were dissolved to a homogeneous state in chloroform at 80 ° C for 1 hour with constant stirring using an electronic overhead stirrer.

Heparin was injected into the resulting homogeneous solution in an amount necessary to obtain a 2% weight. coatings. Mixing was performed using a mechanical paddle stirrer, at a solution temperature of 30 ° C. The mixing speed is 200 rpm, the mixing time is 30 minutes.

The resulting homogeneous solution was applied to the wire from TiNbTaZr.

Drying was carried out for 2 days in air at 37 ° C in a thermostat.

The result was a coating with a thickness of 42 μm and a degree of biodegradation of 5.4% on day 30.

Example 2

A heparin-introduced polylactide was coated on a TiNbTaZr wire.

To create coatings, we prepared a sample of Poly-D, L-lactide (180 kDa) weighing 10 (± 0.01) g.

Chloroform with a volume of 200 ml was placed in a flask with a volume of 500 ml and heated to 80 ° C on a magnetic stirrer.

Next, the resulting weights of the polymers were dissolved to a homogeneous state in chloroform at 80 ° C for 1 hour with constant stirring using an electronic overhead stirrer.

Heparin was injected into the resulting homogeneous solution in an amount necessary to obtain 3% weight. coatings. Mixing was performed using a mechanical paddle stirrer, at a solution temperature of 30 ° C. The mixing speed is 200 rpm, the mixing time is 30 minutes.

The resulting homogeneous solution was applied to the wire from TiNbTaZr.

Drying was carried out for 2 days in air at 37 ° C in a thermostat.

As a result, a coating was obtained with a thickness of 152 μm and a degree of biodegradation of 7.4% on day 30.

Claims (1)

A method of obtaining a biodegradable polymeric coating based on polylactide on a TiNbTaZr wire for cava filters used in endovascular prophylaxis of pulmonary embolism, including dissolving polylactide in chloroform, adding a drug, dipping the wire into the resulting solution and drying the coating, which is different in themes, in a chloroform, coating, covering the coating with the resulting solution and drying the coating, which is different in that chloroform TiNbTaZr alloy wire, used for dissolution Poly-D, L-lactide with a molecular weight of 45 to 180 kDa at the rate of 2 to 10 g per 200 ml of chloroform, as a drug Twain means used heparin at a concentration of from 1 to 5 wt.%, drying is carried out for 2 days in air at 37 ° C in an incubator.