RU2733708C1 - Method of producing titanium-polylactide nickelide composite biomedical material with possibility of controlled drug delivery - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to a method of producing titanium nickelide - polylactide composite biomedical material with the possibility of controlled drug delivery. Polylactide with molecular weight of 45 kDa is dissolved in chloroform in amount of 3 g of polymer in 100 ml of chloroform at temperature of 80 °C for 1 hour while stirring. Then polylactide solution cooled down to 30 °C is added with a drug presented by Gentamycin, Cefotaxime, Lincomycin with concentration of 1 to 8 wt. %. Drug milling and mixing in solution is performed by means of disperser at speed of 1000 rpm for 30 minutes. Then homogeneous solution is applied onto TiNi wire by dipping, holding for 1 minute and extraction with subsequent drying for 2 days in air under drawing at room temperature of 22 °C.

EFFECT: technical result is obtaining coating of specified thickness and controlled biodegradation of polymer layer.

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Description

The invention relates to medicine, in particular to the production of a composite biomedical material titanium nickelide - polylactide with the possibility of controlled delivery of drugs.

Currently, the need for the use of stents is hundreds of thousands of operations annually. But all the products that exist now have both advantages and significant disadvantages. After stent implantation into the human body, there is a possibility of re-narrowing (restenosis), the formation of blood clots, and the development of inflammatory reactions at the site of the medical device. The solution to this problem is to apply a biocompatible and biodegradable polymer coating to the stent. As such a polymer, a polymer layer of natural origin was chosen - polylactide, into which a drug can be added. Due to the biodegradation of polylactide, the drug is delivered locally, in the required concentration to prevent negative tissue reactions to the implant.

Shape memory alloys are the best candidates for creating stents that are plastically deformable in the cold state to an extremely compact state that facilitates easier and less traumatic delivery to the desired site of the body, and takes a functional shape under specified operating conditions without additional impact. The most famous medical material of this class is TiNi (titanium nickelide), which is also endowed with mechanical characteristics similar to the behavior of living tissues, which helps it adapt to physiological stress, providing the necessary operating conditions.

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 site of injury, but no specific studies have been carried out on this.

Close to the claimed one is a Method for producing a biodegradable polymer coating based on polylactide on a TiNbTaZr wire (patent No. RU 2686747 C1, Appl. 08.11.2018). The coating is made of 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; heparin with a concentration of 1 to 5% by weight is used as a drug. The application was carried out by the dipping method. The use of poly-D, L-lactide in combination with heparin provides long-term local drug delivery, however, depending on the specific case, other drugs may be required and, accordingly, different release kinetics.

In US 20050060028 A1, which is the closest, stents are covered with one or more surface layers that contain an antiproliferative and / or antiinflammatory and optionally antithrombotic active agent. The hemocompatible coating of the stent provides the required compatibility with blood, and the active agent (or a combination of active agents), which is evenly distributed over the entire surface of the stent, ensures the coverage of the stent surface with cells. Thus, there is no rapid population and overgrowth of cells on the surface of the stent, which can lead to restenosis, however, covering the surface of the stent with cells can increase the risk of thrombosis.

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

The technical result is a predetermined coating thickness and controlled biodegradation of the polymer layer.

Achieving a technical result includes the following steps:

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

2) A polylactide with a molecular weight of 45 kDa is used.

3) Chloroform in an amount of 100 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 1 to 8% by weight.

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

The essence of the invention

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

The following reagents were used as starting materials: Poly-D, L-lactide (45 kDa, OOO MEDIN-N, Russia), Chloroform (high purity grade, supplier OOO Komponent-Reaktiv, Russia), TiNi wire with a diameter of 280 μm.

Polylactide solutions are prepared on the basis of highly pure chloroform in an amount of 100 milliliters. A polylactide with a molecular weight of 45 kDa was used. Polymer films were created using 1, 3 and 5 grams of polymer. The optimum concentration is 3 grams, which contributes to the formation of a thickness of 95-135 microns. As a filler, antibiotics are used (lincomycin, cefotoxime, gentamicin), which were introduced into a cooled (+ 30 ° C) polylactide solution at a concentration of 1, 3, 5 and 8 wt%. Upon evaporation of chloroform, the polymer and drug form a bond with a uniform distribution of the drug. The rate of biodegradation of the polymer film from polylactide depends on the medium and the type of antibiotic and ranges from 180 to 358 days, and the rate of release of the drug depends on the antibiotic and its concentration from 1 to 8 wt%. 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 (gentamicin) on a wire of titanium nickelide.

To create a composite material, a sample of Polylactide (45 kDa) weighing 3 (± 0.01) g was prepared.

Chloroform with a volume of 100 ml was placed in a 200 ml flask and heated to 80 ° С on a magnetic stirrer.

Then the obtained weighed portions of polymers were dissolved to a homogeneous state in chloroform at 80 ° C for 1 hour with constant stirring using an electronic overhead stirrer.

In the resulting cooled (+ 30 ° C) homogeneous solution, a drug (Gentamycin) was injected in an amount of 1, 3, 5, 8% of the polymer weight (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 and mixing the drug in solution and achieving homogeneity is carried out using a dispersant at a speed of 1000 rpm for 30 minutes.

The resulting homogeneous solution was applied to the TiNi wire by dipping, holding for 1 minute and extracting.

Drying was carried out for 2 days in air under a hood at a room temperature of 22 ° C.

As a result, a coating with a thickness of 95-132 microns was obtained, depending on the concentration of the drug.

Figure 1 shows the kinetics of gentamicin release from the polymer layer into solutions simulating extracellular body fluids with a pH of 7.4. You can see that after 3 days there was an abrupt appearance of the antibiotic, and then its uniform release. Increasing the concentration of the antibiotic resulted in more drug release in the first 3 days.

Example 2.

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

To create a composite material, a sample of Polylactide (45 kDa) weighing 3 (± 0.01) g was prepared.

Chloroform with a volume of 100 ml was placed in a 200 ml flask and heated to 80 ° С on a magnetic stirrer.

Then the obtained weighed portions of polymers were dissolved to a homogeneous state in chloroform at 80 ° C for 1 hour with constant stirring using an electronic overhead stirrer.

A drug (Cefotaxime) was injected into the resulting cooled (+ 30 ° C) homogeneous solution in an amount of 1, 3, 5, 8% of the polymer weight (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 and mixing the drug in solution and achieving homogeneity is carried out using a dispersant at a speed of 1000 rpm for 30 minutes.

The resulting homogeneous solution was applied to the TiNi wire by dipping, holding for 1 minute and extracting.

Drying was carried out for 2 days in air under a hood at a room temperature of 22 ° C.

As a result, a coating with a thickness of 116-135 μm was obtained, depending on the concentration of the drug.

Figure 2 shows the kinetics of cefotaxime release from the polymer layer into solutions simulating extracellular body fluids with a pH of 7.4. You can see that after 3 days there was an abrupt appearance of the antibiotic, and then its uniform release. At an antibiotic concentration of 3 to 8%, the same drug yield was observed in the first 30 days.

Example 3.

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

To create a composite material, a sample of Polylactide (45 kDa) weighing 3 (± 0.01) g was prepared.

Chloroform with a volume of 100 ml was placed in a 200 ml flask and heated to 80 ° С on a magnetic stirrer.

Then the obtained weighed portions of polymers were dissolved to a homogeneous state in chloroform at 80 ° C for 1 hour with constant stirring using an electronic overhead stirrer.

A drug (Lincomycin) was injected into the resulting cooled (+ 30 ° C) homogeneous solution in an amount of 1, 3, 5, 8% of the polymer weight (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 and mixing the drug in solution and achieving homogeneity is carried out using a dispersant at a speed of 1000 rpm for 30 minutes.

The resulting homogeneous solution was applied to the TiNi wire by dipping, holding for 1 minute and extracting.

Drying was carried out for 2 days in air under a hood at a room temperature of 22 ° C.

As a result, a coating with a thickness of 113-128 μm was obtained, depending on the concentration of the drug.

Figure 3 shows the kinetics of lincomycin release from the polymer layer into solutions simulating extracellular body fluids with pH 7.4 (Fig. 1). You can see that after 3 days there was an abrupt appearance of the antibiotic, and then its uniform release. Increasing the concentration of the antibiotic resulted in more drug release in the first 3 days.

Claims (1)

A method of obtaining a composite biomedical material titanium nickelide-polylactide with the possibility of controlled delivery of drugs includes dissolving polylactide with a molecular weight of 45 kDa in chloroform at the rate of 3 grams of polymer in 100 ml of chloroform at a temperature of 80 ° C for 1 hour with stirring, adding into a solution of the drug polylactide cooled to 30 ° C, which is Gentamicin, Cefotaxime, Lincomycin with a concentration of 1 to 8% by weight, grinding and mixing the drug in the solution using a dispersant at a speed of 1000 rpm for 30 minutes , applying a homogeneous solution to a TiNi wire by dipping, holding for 1 minute and extracting, followed by drying for 2 days in air under a hood at a room temperature of 22 ° C.

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