RU2723588C1 - Method of producing biomedical titanium-polylactide nickelide material with possibility of controlled drug delivery - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention relates to the technology of producing a composite biomedical material of titanium-polylactide nickelide with the possibility of controlled drug delivery. Proposed method of producing biomedical material of titanium-polylactide nickelides involves preparing polylactide solution with molecular weight of 180 kDa in chloroform. Cooled down to 30 °C polylactide solution is added with a drug gentamycin, cefotaxime or lincomycin in concentration of 1 % to 8 % by weight. Titanium nickelide (TiNi) wire is dipped in a polylactide solution cooled down to 30 °C and kept for 5 minutes. Obtained material is extracted and dried at room temperature 20–22 °C for 24 hours.EFFECT: invention enables to obtain homogenous film-like polylactide with a drug with the possibility of controlled drug delivery for a certain period of time sufficient to prevent tissue implant rejection.1 cl, 3 dwg, 3 ex

Description

The invention relates to medicine, in particular to a technology for producing composite biomedical material titanium nickelide - polylactide with the possibility of controlled drug delivery.

In recent years, medical devices such as stents of various configurations, usually consisting of cylinders made of several interwoven wires or thin rolled plates with many holes and used to expand narrowed or completely blocked body cavities (vessels, gastrointestinal tract, etc.), have been increasingly used.

Most often, stents are installed when atherosclerotic plaques block a blood vessel. These plaques are composed of cholesterol and other substances that attach to the walls of the vessel and glow there. Clogging can lead to myocardial infarction or apoplexy. In addition to blood vessels, stents can open any of the following passages: bile ducts that carry bile, bronchi, which are small airways in the lungs, ureters that carry urine from the kidneys to the bladder, and others. Near or inside these passages, a neoplasm may appear, which will lead to a narrowing or blockage of the lumen.

Due to the constant contact of the implants with the tissues of a living human body, the material for their manufacture must have a number of physicochemical properties that would ensure the biocompatibility of the product. About 30 years ago, for use in medicine, a new class of materials was first introduced - superelastic alloys with shape memory. The basis for them was titanium nickelide, as well as its alloys. The new material possessed the necessary physical and mechanical properties similar to body tissues.

But a medical implant of the “stent” type, like a foreign body, in contact with blood can cause the development of repeated narrowing of the lumen (restenosis). There are three different causes of implant restenosis:

a) During the first few days after implantation, the surface of the stent is in direct contact with the blood, which can lead to acute thrombosis, which again closes the lumen due to the external surface present.

b) Stent implantation can cause vascular damage that will cause inflammatory reactions within the first seven days, in addition to the aforementioned thrombosis.

c) After a couple of weeks, the stent can begin to grow into the tissue of the blood vessel. This means that the stent will be completely surrounded by smooth muscle cells and will not have contact with the blood. This effect can lead not only to the coating of the stent surface, but also to the occlusion of the entire internal space of the stent.

Now, stents are used, which differ in various design designs, manufacturing materials, as well as in appearance (self-expanding, expandable with an air spray; soluble and not; with or without a drug coating), but none of them can completely solve the problem (restenosis).

The solution consists in applying a polymer layer (polylactide) to a “stent” type medical device, which has biocompatibility, relative inertness, good mechanical properties, biodegradation, and it is also able to retain a dissolved substance (drug) in its structure, and thereby deliver drugs locally in the right concentration for a certain time for additional drug exposure and to prevent inflammatory reactions and get rid of restenosis. Polylactide, i.e. polylactic acid, which is usually obtained from a lactic acid dimer, i.e. lactide has been used for many years for medical purposes, for example, in the manufacture of surgical sutures, for degradable sutures and for the controlled release of drugs.

In patent CN 10405629 7A, polylactide films were prepared by dissolving 10% polymer in dichloromethane, stirring it in a magnetic stirrer for 24 hours to obtain a homogeneous system. In a special device, fibrous membranes were obtained and dried at 40 ° C for 12 hours. This method requires a sufficiently long amount of film production time.

In the patent US 611792 8A, the mechanical properties of polylactide films were improved by adding glycerol to the polymer with ether plasticizers, but these plasticizers lead to rapid hydrolysis and cause problems with adhesion. Also, the mechanical properties of the films are sufficient for use as a surface layer on the stent, so the addition of plasticizers is not necessary.

In US 20040034409 A1, polylactide, with a molecular weight of more than 200 kDa, was applied to a stent to prevent restenosis. It was found that the use of high molecular weight polylactide leads to a decrease in inflammatory processes. The patent mentions that it is possible to introduce drugs into the polymer and deliver them locally to the lesion site, but no specific studies have been conducted.

In US Patent No. 20050060028 A1, which is closest, stents are coated with one or more surface layers that contain an antiproliferative and / or anti-inflammatory and, if necessary, an antithrombotic active agent. A hemocompatible coating of the stent provides the required blood compatibility, and the active agent (or a combination of active agents ), which is evenly distributed over the entire surface of the stent, provides coverage of the stent surface with cells. Thus, there is no rapid population or excessive cell growth on the stent surface, which can lead to restenosis, however, coating the stent surface with cells can increase the risk of thrombosis.

The objective of this invention is to obtain a composite biomedical material titanium nickelide-polylactide for the manufacture of a stent-type medical device with the possibility of controlled delivery of drugs for a certain time, sufficient to prevent implant rejection by tissues.

The technical result consists in obtaining a composite material and studying the surface layer, namely, in obtaining uniform polylactide films with a drug and controlling the release rate of the drug over a period of time.

Achieving the technical result includes the following steps:

1) Preparation of a homogeneous polymer solution (polylactide), the addition of a drug, the application of a polymer with a drug to the wire by dipping and further drying.

2) Used polylactide with different molecular weights (45 kDa, 90 kDa, 180 kDa)

3) Chloroform in the amount of 100, 150 and 200 milliliters is used as a solvent for the preparation of solutions.

4) Medicinal substances, namely gentamicin, cefotaxime and lincomycin, are added in an amount of from 1 to 8% by weight.

5) Fixation of the polymer is achieved by drying at room temperature (20 ° C - 22 ° C)

SUMMARY OF THE INVENTION

Maintaining a certain level of the drug, despite the blood flow, is achieved by controlled biodegradation and the release of the drug from the surface polymer layer.

The following reagents were used as starting materials: Poly-D, L-lactide (45 kDa, LLC MEDIN-N, Russia), Poly-D, L-lactide (90 kDa, LLC MEDIN-N, Russia), Poly- D, L-lactide (180 kDa, MEDIN-N LLC, Russia), Chloroform (OCh, supplier of Component-Reagent LLC, Russia), TiNi wire with a diameter of 280 microns after annealing and polishing (IMET RAS).

Polylactide solutions are prepared on the basis of highly pure chloroform in an amount of from 100 to 200 milliliters. It was found that the amount of chloroform, in this range, does not affect the properties of the obtained polymer films, therefore, 100 milliliters of solvent was used to obtain films with the drug. A polylactide with various molecular weights (45, 90, and 180 kDa) was used and it was found that polylactide with a molecular weight of 180 kD possesses the optimal strength and plastic properties for use as a surface layer on a stent. Polymer films were created using 1, 3 and 5 grams of polymer. The optimal concentration of 3 grams was selected, which contributes to the formation of a thickness of 82-125 microns. As a filler, antibiotics (lincomycin, cefotoxime, gentamicin) are used, which were introduced into a cooled (+ 30 ° C) polylactide solution at a concentration of 1, 3, 5 and 8% by weight. During the evaporation of chloroform, the polymer with the drug form a bond with a uniform distribution of the drug. The rate of biodegradation of a polymer film from polylactide depends on the environment and type of antibiotic and ranges from 180 to 358 days, and the release rate of the drug depends on the antibiotic and its concentration from 1 to 8% weight. By varying the composition and thickness of the polymer layer, various biodegradation can be achieved and selected for a specific application.

Example 1

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

Polylactide solutions are prepared on the basis of highly pure chloroform with a volume of 100 milliliters, which was poured into a flask with a volume of 300 milliliters and heated to 50 ° C on a magnetic stirrer. After heating, a polymer (polylactide 180 kDa) was weighed into a flask with a weight of 3 grams (± 0.001 g). To achieve a homogeneous state, the polymer solution is mixed for 1 hour on an electronic overhead stirrer at a temperature of 50 ° C. Then, the resulting homogeneous solution was allowed to cool to 30 ° C and a drug (gentamicin) was introduced into it in an amount of 1, 3, 5, 8% by weight of the polymer (30.303 mg - 1%, 92.784 mg - 3 are added to the solution with 3000 mg of polymer %, 157.895 mg - 5% or 260.870 mg - 8% of the drug). Grinding the drug in solution and achieving homogeneity is carried out using a dispersant at a speed of 5000 rpm for 10 minutes.

Fat-free TiNi wire is dipped in a cooled (+ 30 ° C) solution of polylactide with a drug and aged for 5 minutes. Then, the material is extracted from the solution and dried at room temperature (20-22 ° C) for 24 hours.

In Figure 1, one can observe the kinetics of the release of gentamicin from the polymer layer into solutions simulating extracellular body fluids (Fig. 1a, pH 5.3; Fig. 1b, pH 7.4; Fig. 1c, pH 9.0). It can be seen that after 1 day an abrupt appearance of the antibiotic was observed, and then its uniform output. An increase in the concentration of the antibiotic led to a greater amount of drug release in 1 day.

Example 2

The composite material was obtained by applying a polylactide surface layer with an injected drug (cefotaxime) onto a titanium nickelide wire.

Polylactide solutions are prepared on the basis of highly pure chloroform with a volume of 100 milliliters, which was poured into a flask with a volume of 300 milliliters and heated to 50 ° C on a magnetic stirrer. After heating, a polymer (polylactide 180 kDa) was weighed into a flask with a weight of 3 grams (± 0.001 g). To achieve a homogeneous state, the polymer solution is mixed for 1 hour on an electronic overhead stirrer at a temperature of 50 ° C. Then, the resulting homogeneous solution was allowed to cool to 30 ° C and a drug (cefotaxime) was introduced into it in an amount of 1, 3, 5, 8% by weight of the polymer (30.303 mg - 1%, 92.784 mg - 3 are added to the solution with 3000 mg of polymer %, 157.895 mg - 5% or 260.870 mg - 8% of the drug). Grinding the drug in solution and achieving homogeneity is carried out using a dispersant at a speed of 5000 rpm for 10 minutes.

Fat-free TiNi wire is dipped in a cooled (+ 30 ° C) solution of polylactide with a drug and aged for 5 minutes. Then, the material is extracted from the solution and dried at room temperature (20-22 ° C) for 24 hours.

In Fig. 2, one can observe the kinetics of the release of cefotaxime from the polymer layer into solutions simulating extracellular body fluids (Fig. 2a, pH 5.3; Fig. 2b, pH 7.4; Fig. 2c, pH 9.0). It can be seen that after 1 day an abrupt appearance of the antibiotic was observed, and then its uniform output. An increase in the concentration of the antibiotic led to a greater amount of drug release in 1 day.

Example 3

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

Polylactide solutions are prepared on the basis of highly pure chloroform with a volume of 100 milliliters, which was poured into a flask with a volume of 300 milliliters and heated to 50 ° C on a magnetic stirrer. After heating, a polymer (polylactide 180 kDa) was weighed into a flask with a weight of 3 grams (± 0.001 g). To achieve a homogeneous state, the polymer solution is mixed for 1 hour on an electronic overhead stirrer at a temperature of 50 ° C. Then, the resulting homogeneous solution was allowed to cool to 30 ° C and a drug (lincomycin) was introduced into it in an amount of 1, 3, 5, 8% by weight of the polymer (30.303 mg - 1%, 92.784 mg - 3 are added to the solution with 3000 mg of polymer %, 157.895 mg - 5% or 260.870 mg - 8% of the drug). Grinding the drug in solution and achieving homogeneity is carried out using a dispersant at a speed of 5000 rpm for 10 minutes.

Fat-free TiNi wire is dipped in a cooled (+ 30 ° C) solution of polylactide with a drug and aged for 5 minutes. Then, the material is extracted from the solution and dried at room temperature (20-22 ° C) for 24 hours.

In Figure 3, one can observe the kinetics of the release of lincomycin from the polymer layer into solutions simulating extracellular body fluids (Fig. 3a, pH 5.3; Fig. 3b, pH 7.4; Fig. 3c, pH 9.0). It can be seen that after 1 day an abrupt appearance of the antibiotic was observed, and then its uniform output. An increase in the concentration of the antibiotic led to a greater amount of drug release in 1 day.

Claims (1)

A method of obtaining a biomedical material titanium nickelide-polylactide with the possibility of controlled drug delivery, comprising dissolving polylactide in chloroform, adding a drug, dipping the wire into a solution of polylactide with a drug, aging and further drying, characterized in that a polylactide solution with a molecular weight of 180 is obtained kDa, gentamicin, cefotaxime or lincomycin is added to the polylactide solution cooled to 30 ° C in a concentration of 1% to 8% by weight, dip a titanium nickelide (TiNi) wire into the polylactide solution cooled to 30 ° C, incubated within 5 min, the resulting material is removed and dried at room temperature 20-22 ° C for 24 hours

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