RU2737827C1 - Method of producing biocompatible composite material with nanostructure titanium nickelide base and biodegradable drug-containing polylactide with heparin - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to the technology of producing a biocompatible composite material with a base of nanostructured titanium nickelide and a biodegradable drug layer of polylactide with heparin. Method of producing includes preparation of polymer solution, addition of medicinal agent. Coating is applied on a corrosion-resistant base of nanostructured nickelide of titanium in two layers with difference of 10 seconds. To prepare the solution, polylactide with molecular weight of 45 kDa is used, chloroform is used as a solvent. Polylactide weight is 2 g in chloroform of 200 ml. Dissolution takes place at temperature of 80 °C, then obtained solution is cooled to 30 °C and adding a drug substance, namely heparin, a direct anticoagulant in amount of 1 to 3 percent of the weight of the polymer. Then one performs stirring during 30 minutes for uniform distribution in polymer matrix. Drying is carried out for 24 hours in air at 30 °C in thermostat.

EFFECT: technical result consists in producing composite material with corrosion-resistant hypo-allergenic base of nanostructured titanium nickelide and homogeneous drug coating, which provides prolonged controlled exposure to medicinal agent for more than 30 days.

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Description

The invention relates to medicine, in particular to a technology for producing a composite biomedical composite material with a corrosion-resistant base of biocompatible nano-structural titanium nickelide and a biodegradable drug coating (polylactide with heparin).

Today, most serious diseases are associated with obstruction, blockage of sections of the transport systems of the human body. Such diseases need to be diagnosed at an early stage, which, unfortunately, does not occur in most cases. When it is impossible to cure a patient in a conservative way, medical devices such as "stent", "cava-filter", etc. are used. They are installed endovascularly, without surgery, and the area of catheter insertion is anesthetized with a local anesthetic.

At the same time, these interventions can lead to unfavorable consequences, there is a risk of complications during implantation, in the postoperative period, during the removal of the device or in the long term. Complications of implantation are recorded in 4-15% of cases. Complications associated with prolonged stay of the implant include thrombosis, restenosis, displacement, fragmentation (from 3% to 69%) and others, which can even lead to death. Ways to finally eliminate these problems are still being sought.

The first generations of implants were made of pure metal. They drastically reduced the risk of developing the disease, but restenosis occurred within six months. Scientists have long worked on the problem of preventing restenosis. The solution was found - drug coatings were applied.

High requirements are imposed on cava filters, stents and other similar medical devices for endovascular surgery: high flexibility (for easy movement through the circulatory system to the installation site), high plasticity (to ensure safe deployment), high strength, rigidity (to ensure radial stability during operation), high radiopacity (for good visibility in an angiograph and X-ray tomograph), biocompatibility with the body (to prevent possible reactions of product rejection).

Currently, for these and other similar medical devices, either polymeric materials or metals are used as the base material. The metals used are mainly stainless steel, tantalum, cobalt-chromium alloys, titanium, titanium nickelide.

Titanium nickelide has mechanical characteristics similar to the behavior of living tissues (superelasticity, lag law), is a self-passivating material, that is, it forms a surface oxide layer (in this case, TiO2), which protects the material from corrosion. The behavior of titanium nickelide is largely determined by the composition and structure that determine the production process (residual surface stress and defects, impurities, content and ratio of nickel and titanium on the surface, porosity, etc.), as well as by the processing method.

However, in the course of many observations devoted to the problem of the body's allergic reaction to metal implants, which manifests itself in the form of aseptic inflammation, it was found that most often allergic manifestations in the body occur on chromium, molybdenum, nickel.

Corrosive properties are the most important indicators of the biochemical compatibility of all materials that have found application in medicine. It was found that the yield of nickel from the investigated nanostructured titanium nickelide is lower in comparison with microstructured titanium nickelide in a solution with any acidity. Mechanical treatment allows to increase its corrosion resistance by another 2-3 times. The highest concentration of metals is observed in the most acidic solution, lower in saline, dissolution does not occur in an alkaline medium.

However, the use of bare metal devices is associated with a risk of thrombosis in the first 30 days and requires dual antiplatelet therapy for 1 month, as well as a 20-30% risk of restenosis (re-narrowing of the vessel) within 6-9 months after implantation. To reduce thrombosis and restenosis, it has been proposed to coat with drug-containing coatings. The coating material must meet the requirements for biomaterials introduced into the human body: non-toxicity, antibacteriality, biocompatibility, optimal mechanical properties.

Imported manufacturers are beginning to create cava filters and stents using partially or even completely biodegradable polymers. The coating dissolves completely, the required dose of the drug component has been released and the treatment is completed. This reduces the incidence of thrombosis compared to previous generations.

As a drug in our studies, we used a coating with heparin, the presence of which will provide a controlled local delivery of this drug to the site of the cava filter, which will eliminate the risk of re-clotting.

Biodegradable polymers used in medicine, upon contact with biological media of a living organism, can dissolve in these media without changing the molecular weight or undergo biodegradation. Therefore, these polymers are promising as drug carriers in controlled release systems.

Biodegradable synthetic biomaterials based on polymers of organic acids, for example, lactic acid (PLA, polylactate) and glycolic (PGA, polyglycolide), were among the first in tissue engineering to use. Chitosan and alginate occupy a special place among the materials for biomatrix carriers. Alginate is a polysaccharide from seaweed. Chitosan is a nitrogen-containing polysaccharide obtained from the chitinous shells of crustaceans and molluscs. In contrast to chitin, chitosan obtained during its deacetylation dissolves even in dilute organic acids, for example, in an aqueous solution of acetic acid. At the same time, for solutions of chitosan, like other polymers, a significant dependence of viscosity on concentration is characteristic (with an increase in the concentration of a solution of chitosan in a 1-2% solution of acetic acid from 2 to 4%, the viscosity of the solution increases by about 30 times). The high viscosity of the solution complicates the process of introducing and evenly distributing the drug over the volume of the polymer, which complicates the process of applying to the product, and the effect of ultrasound contributes to the destruction of the polymer.

Therefore, the most popular biopolymer will remain polylactide (PLA - Poly Lactide), which is a product of lactic acid polymerization. The most important feature of polylactide is its safe destruction under the influence of the environment. Decomposition products are naturally occurring metabolites that can be safely processed, and the rate is also temperature dependent.

Polylactic acid is known in three isomeric forms: D (-), L (+) and their racemic mixture (D, L), depending on which racemate it was synthesized from. The type of isomer determines many of the properties of this polymer, in particular the crystallinity and conditions of dissolution in organic solvents.

Materials made of polylactic acid are characterized by volumetric destruction, however, the action of some active substances or an increase in the ionic strength of the medium makes it possible to achieve an increase in the proportion of the surface component, i.e. helps to increase the reproducibility of release.

In US Pat. Nos. 6,702,850 and 7,129,224, antithrombotic agents such as heparin are bound with a non-absorbable polymer prior to use in a coating composition. The overall hydrophobicity is controlled by the addition of hydrophobic octadecylamine, which is a long hydrocarbon chain amine. This method has several disadvantages, namely: after metabolism of heparin in vivo, toxic polyacrylic acid remains, the addition of a hydrophobic amine also increases the problems of tissue compatibility and repeated displacement reactions at each stage, and the remaining components of the coating are not biodegradable.

Patent RUS 2472529 describes a material intended to be applied to a part of the surface of an article or to be inserted into an article. A bioabsorbable polymer, the structure of which includes an antithrombotic composition, and an anti-restenotic agent may be contained in the polymer matrix, however, the agents in the matrix will not be evenly distributed without stirring, which is very important for a correct controlled yield.

In US Patent Application No. US 2012/0071566 A1, poly (p-dioxanone) is mixed with polylactide or lactide-glycolide copolymer. However, the addition of poly (p-dioxanone) decreases the stiffness of the mixture.

In US Pat. Nos. 6,559,132 and 6,767,405, a carrier molecule such as chitosan is conjugated to an activated surface of a metal device. Thereafter, heparin is covalently linked to the intermediate molecule. The disadvantage is the complexity of the process.

In US 20040034409 A1, polylactide was applied to a stent to prevent restenosis.

The closest is the patent US 5837313, which describes a method of obtaining a heparin coating composition. However, this composition has a disadvantage: in addition to heparin, it contains anti-restenosis agents, and heparin, due to its hydrophilic nature, will interfere with their elution profile.

A common disadvantage of the above patents is the lack of data on the kinetics of the release of drug delivery substances, however, specific studies of this have not been carried out, there is no data on the controllability of the release of drugs. Also, the base metal is not indicated, and for the safety of the patient's health, biocompatibility, non-toxicity and hypoallergenicity of the base material on which the coating is applied is very important.

The objective of this invention is to obtain a biocompatible composite material with a corrosion-resistant base of nanostructured titanium nickelide, which simultaneously provides both high biological and excellent mechanical properties that ensure the reliability of the design and safety of the device for the patient, and the surface biodegradable drug layer (polylactide with heparin) provides the possibility of controlled delivery of a medicinal agent within a given time.

The technical result consists in obtaining a composite material with a corrosion-resistant hypoallergenic base of nanostructured titanium nickelide and a homogeneous homogeneous drug coating, which provides a prolonged controlled effect of the drug for a period of more than 30 days.

The technical result is achieved by the fact that the production method includes the following stages:

1) Preparation of a polylactide solution at 80 ° C, cooling to 30 ° C, adding a medicinal substance, namely heparin, a direct anticoagulant, in an amount from 1% to 3% of the polymer mass, and then stirring for 30 minutes for uniform distribution in the polymer matrix ...

2) Application of a two-layer uniform homogeneous coating on nanostructured titanium nickelide with a solution of polylactide with a drug, where the polymer concentration is chosen 2 g, in chloroform with a volume of 200 milliliters.

3) Fixation of the coating based on nanostructured titanium nickelide is carried out by drying in a thermostat at 30 ° C for 24 hours.

The essence of the invention

The surface layer is represented by a matrix of a biodegradable polymer polylactide with a drug evenly distributed throughout the volume, and a more intense release is provided during the first three days, for enhanced exposure in the initial postoperative period with further prolonged maintenance of a certain drug level, which is achieved by a controlled uniform release of the drug from homogeneous surface polymer layer at a given rate.

The following reagents were used as starting materials: Poly-D, L-lactide, Chloroform (high purity grade), wire of nanostructured titanium nickelide with a diameter of 280 μm after annealing and polishing.

Polylactide solutions are prepared on the basis of highly pure chloroform in an amount of 200 milliliters. It was found that this amount of chloroform does not affect the properties of the resulting polymer coatings. The composite material was created using 2 grams of polymer. This concentration is selected as optimal and contributes to the formation of a thickness of 50-100 microns. An anticoagulant (heparin) is used as a filler, which was introduced into a cooled (+ 30 ° C) polylactide solution at a concentration of 1, 2 and 3% of the polymer weight. Upon evaporation of chloroform, the polymer and drug form a bond with a uniform distribution of the drug.

In the first few days, the release of heparin from the polymer layer occurs most intensively, the average rate of release of heparin is in the range of 0.008-0.027 g / day. In the subsequent time of observation, the rate decreases, the characteristic rate lies in the range 0.001-0.005 g / day. By day 30, at least 50% of heparin remains. By varying the composition and thickness of the polymer layer, it is possible to achieve different biodegradation and select it for a specific application.

Example 1.

The composite material was obtained by applying a surface layer of polylactide with an injected drug (heparin) on a wire of nanostructured titanium nickelide.

Polylactide solutions are prepared on the basis of highly pure chloroform with a volume of 200 milliliters, which was poured into a flask with a volume of 300 milliliters and heated to 80 ° C on a magnetic stirrer. After heating, a polymer (polylactide 45 kDa) with a weight of 2 grams (± 0.001 g) was placed in the flask. To achieve a homogeneous state, the polymer solution is stirred for 1 hour on an electronic overhead stirrer at a temperature of 80 ° C. Then the resulting homogeneous solution was allowed to cool to 30 ° C and a drug (heparin) was introduced into it in an amount of 1% by weight of the polymer (30.303 mg - 1% of the drug is added to the solution with 3000 mg of polymer). Achievement of homogeneity is carried out using a dispersant at 5000 rpm for 10 minutes.

Degreased nickel-titanium wire is dipped twice with a solution of polylactide with a drug with an interval of 10 seconds. Then the material is removed from the solution and dried at a temperature of 30 ° C for 24 hours.

Figure 1 shows the kinetics of the release of the drug into the solution from the polylactide layer containing 1% heparin, where it can be seen that in the first few days the release of heparin from the polymer layer occurs most intensively, by 30 days at least 50% of heparin remains, which is confirmed by the technical result.

Example 2.

The composite material was obtained by applying a surface layer of polylactide with an injected drug (heparin) on a wire of nanostructured titanium nickelide.

Polylactide solutions are prepared on the basis of highly pure chloroform with a volume of 200 milliliters, which was poured into a flask with a volume of 300 milliliters and heated to 80 ° C on a magnetic stirrer. After heating, a polymer (polylactide 45 kDa) with a weight of 2 grams (± 0.001 g) was placed in the flask. To achieve a homogeneous state, the polymer solution is stirred for 1 hour on an electronic overhead stirrer at a temperature of 80 ° C. Then the resulting homogeneous solution was allowed to cool to 30 ° C and a drug (heparin) was introduced into it in an amount of 2% by weight of the polymer (60.606 mg - 2% of the drug is added to the solution with 3000 mg of polymer). Achievement of homogeneity is carried out using a dispersant at 5000 rpm for 10 minutes.

Degreased nickel-titanium wire is dipped twice with a solution of polylactide with a drug with an interval of 10 seconds. Then the material is removed from the solution and dried at a temperature of 30 ° C for 24 hours.

Figure 2 shows the kinetics of the release of the drug into the solution from the polylactide layer containing 2% heparin, where it can be seen that in the first few days the release of heparin from the polymer layer occurs most intensively, by 30 days at least 62% of heparin remains, which is confirmed by the technical result.

Example 3.

The composite material was obtained by applying a surface layer of polylactide with an injected drug (heparin) on a wire of nanostructured titanium nickelide.

Polylactide solutions are prepared on the basis of highly pure chloroform with a volume of 200 milliliters, which was poured into a flask with a volume of 300 milliliters and heated to 80 ° C on a magnetic stirrer. After heating, a polymer (polylactide 45 kDa) with a weight of 2 grams (± 0.001 g) was placed in the flask. To achieve a homogeneous state, the polymer solution is stirred for 1 hour on an electronic overhead stirrer at a temperature of 80 ° C. Then the resulting homogeneous solution was allowed to cool to 30 ° C and a drug (heparin) was introduced into it in an amount of 3% by weight of the polymer (92.784 mg - 3% of the drug is added to the solution with 3000 mg of polymer). Achievement of homogeneity is carried out using a dispersant at 5000 rpm for 10 minutes.

Degreased nickel-titanium wire is dipped twice with a solution of polylactide with a drug with an interval of 10 seconds. Then the material is removed from the solution and dried at a temperature of 30 ° C for 24 hours.

Figure 3 shows the kinetics of the release of the drug into the solution from the polylactide layer containing 3% heparin, where it can be seen that in the first few days the release of heparin from the polymer layer occurs most intensively, by 30 days at least 75% of heparin remains, which is confirmed by the technical result.

Claims (1)

A method of obtaining a biocompatible composite material with a base of nanostructured titanium nickelide and a biodegradable drug layer of polylactide with heparin, including preparing a polymer solution, adding a drug, characterized in that the coating is applied to a corrosion-resistant base of nanostructured titanium nickelide in two layers with a difference of 10 seconds, for the solution is prepared using polylactide with a molecular weight of 45 kDa, chloroform is used as a solvent, the mass of polylactide is 2 g in chloroform with a volume of 200 milliliters, dissolution occurs at a temperature of 80 ° C, then the resulting solution is cooled to 30 ° C and the drug is added, namely heparin, a direct anticoagulant, in an amount of 1 to 3 percent of the polymer weight, and then stirring occurs for 30 minutes for uniform distribution in the polymer matrix, drying is carried out for 24 hours in air at 30 ° C in a thermostat.

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