RU2585576C1 - Method of producing biodegradable polymer coating with controlled output of drug for minimally invasive surgery - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method of producing biodegradable polymer coating for controlled drug release involves dissolving chitosan in acids, addition of medicinal agent, dipping of titanium nickelide wire to obtained solution, fixation of coating and drying. For chitosan dissolution in solvent phosphoric, hydrochloric, glutamic or acetic acid with concentration from 1 to 4 wt% is used. As medicinal agent lincomycin, gentamicin or cefotaxime with concentration from 0.9 to 7 wt% is used. Fixation of coating is performed in alcoholic ammonia solution in ratio of 1:2, followed by drying at temperature of 40-45°C for 24 hours.

EFFECT: invention ensures uniform thickness of coating and controlled drug release rate depending on thickness of coating.

1 cl, 3 dwg, 1 tbl, 3 ex

Description

The invention relates to medicine, in particular to the production of biodegradable polymer coatings for minimally invasive surgery.

Pathological changes in the lumens of blood vessels and other tubular organs can lead to their narrowing and complete clogging. Atherosclerosis, like acute thrombosis, is often the cause of conditions such as myocardial infarction or apoplexy.

Another common danger to which the lumens of blood vessels and other tubular organs are exposed is the growth of malignant and benign neoplasms. As a result of intense uncontrolled cell division of a tumor located near or inside a tubular organ, the lumens of the tubular organs affected by the process narrow or clog. Examples of such conditions include stomach cancer, intestinal cancer, lung cancer, kidney cancer, blockage (occlusion) of the bile ducts, pancreatic ducts and urethra.

Over the past two decades, the use of stents has proven itself in many cases for topical treatment of narrowing of blood vessels. After expanding the affected area of the vessel with a balloon catheter - or even after removing the narrowed area - a stent is installed in this area, which, when opened, expands the wall of the tubular organ, restoring the diameter of the lumen to a normal value, and maintains the patency of the tubular organ in the future. In particular, an important circumstance is that the stent in contact with blood can cause, as a foreign body, the development of repeated narrowing (restenosis) of the lumen. Efforts to improve stents are aimed at increasing the biocompatibility of materials for stents, increasing the elasticity and resilience of materials in combination with decreasing the tendency of materials to fatigue, as well as reducing the surface area of contact with foreign material, thereby reducing the risk of restenosis caused by stent implantation.

In addition to the mentioned main directions of stent improvement, a promising direction was the application of a coating on the stent surface, consisting of biocompatible, biodegradable (absorbable) or biostable materials, which can also serve as carriers of active substances that counteract restenosis.

One of the possible solutions to this problem may be the formation of bioactive and bioinert coatings based on derivatives of natural biopolymers (for example, chitosan of various molecular weights) on a medical device in order to optimize the implant bio-integration process. With its high biocompatibility, antibacterial effect, capable of complete biodegradation, chitosan is used in many fields of medicine. Due to the large number of hydrogen bonds that chitosan can form, it is able to retain a solvent and a dissolved substance in its structure, making it possible to introduce a drug to improve the anti-inflammatory properties of the coating. These active substances are supposed to stop the process of restenosis, entering the body for a desired period of time and in the required concentration. The gradual biodegradation of chitosan, controlled by changes in the molecular weight and layer thickness, provides a sustained local release of the drug, reducing the likely risk of postoperative complications.

In WO 2004112863 A1, a porous chitosan coating is prepared using a plasticizer, preferably polyethylene oxide (PEO). Chitosan was dissolved in a 0.1 M solution of acetic acid (2% by weight) overnight and filtered. PEO was dissolved in glacial acetic acid and added to a 70/30 ratio of chitosan solution. The mixture was stirred for 4 hours, degassed and applied by casting, after which it was dried and washed 1 N. NaOH solution. The introduction of heparin has also been proposed to improve the thrombogenic properties of the coating. However, with the porous structure of the coating, the yield of the drug agent is uneven, and the proposed control of the rate of biodegradation of the coating due to a change in thickness is ineffective due to the loss of the required mechanical properties.

Closest to the claimed is a method for producing a biodegradable chitosan coating with a drug, described in patent WO 2012138184 A2. Chitosan was dissolved in 0.2 M acetic acid and mixed with a solution of dexamethasone. The application to the stent was carried out by dipping and subsequent drying for one hour at a temperature of 100 ° C. When using drying to fix the coating, its thickness is not uniform, which leads to uneven biodegradation and the release of the drug.

The objective of the invention is to provide a method for producing a biodegradable polymer coating for minimally invasive surgery.

The technical result is a uniform coating thickness and a controlled release rate of the drug.

The technical result is achieved in that a method for producing a biodegradable polymer coating with a controlled drug release for minimally invasive surgery includes:

1) dissolving chitosan in acids, adding a drug, dipping a titanium nickelide wire into the resulting solution, fixing the coating with an ammonia solution and drying;

2) the use as a solvent of phosphoric, or hydrochloric, or glutamic, or acetic acid with a concentration of from 1 to 4% by weight .;

3) the use of lincomycin or gentamicin or cefotoxime as a medicine with a concentration of from 0.9 to 7% by weight .;

4) fixing the coating in an alcoholic ammonia solution in a ratio of 1: 2, followed by drying at a temperature of 40-450 ° C for 24 hours.

SUMMARY OF THE INVENTION

The biodegradable polymer coating should be able to maintain the required level of the drug in the implantation area for a long and stationary period for the required time despite the blood flow, which can be ensured by a uniform controlled release of the drug from the coating.

Chitosan (a linear biodegradable polysaccharide known for its non-toxicity, non-immunogenicity, wound healing and antimicrobial properties is used as the starting components for coating; the structure of chitosan contains active amino and hydroxyl functional groups suitable for fixing and gradual release of drugs directly at the treatment site) high molecular weight (500 kDa) and medium molecular weight (500 kDa).

Chitosan solutions are prepared on the basis of acetic, hydrochloric, phosphoric and glutamic acids with a concentration of 1 to 4%, which contributes to the homogeneity of the polymer layer with a thickness of 4 to 70 microns. Table 1 shows the dependence of the coating thickness on the type and concentration of solvent. The optimum acid concentration of 3% was selected, which contributes to the formation of a thickness of 15-30 μm with the best mechanical characteristics and biodegradation. Antibiotics are used as a filler layer. The rate of biodegradation of the coating at a pH of 5.8 to 9.2 depending on chitosan (high molecular or medium molecular weight) and the type of antibiotic (lincomycin, cefotoxime, gentamicin) is from 4 to 358 days. Depending on the antibiotic administered and its concentration from 0.9 to 7%, a change in the release rate from 100% is observed during the first days before the start of the release, only on the 10th day. With a different composition and thickness of the coating, various biodegradation of the coatings can be obtained depending on the required application.

Example 1

Received a coating of chitosan with introduced lincomycin on a titanium nickelide wire.

Preparation of 3% solutions of high molecular weight chitosan (500 kDa, supplier Aldrich) in 3% solutions of acids (per 100 grams of distilled water, 3.2 grams of chitosan and 3.2 grams of acid) was carried out by stirring to a homogeneous state for one and a half hours using an overhead stirrer at a solution temperature of 40 ° C. Glutamic acid was used as the starting acid. A drug (lincomycin) was introduced into the obtained homogeneous solution in the amount necessary to obtain 3.2% solutions (2 g of antibiotic powder was added to 50 ml of solution). Mixing is carried out in a glass beaker using a mechanical paddle mixer. The stirring speed is 200 rpm, the mixing time is 30 minutes

The titanium nickelide wire is dipped in a chilled (+ 5 ° C) solution of chitosan with drugs, after which it is transferred to a fixing solution (prepared by mixing 2 to 1 ammonia water and ethyl alcohol) and aged. Then carry out drying at a temperature of 40-45 ° C for 24 hours. Samples are washed in a fixing solution to neutralize and remove acids for 5 hours at room temperature, followed by washing in distilled water and then in ethanol. The resulting titanium nickelide coating was dried at 40 ° C. for 24 hours.

The dynamics of the release of lincomycin from the coating into solutions simulating extracellular body fluids is shown in Fig. 1, from which it is seen that a uniform yield of lincomycin is achieved on the 6th day.

Example 2

Received a coating of chitosan with introduced cefotoxime on a wire of titanium nickelide.

Preparation of 3% solutions of high molecular weight chitosan (500 kDa, supplier Aldrich) in 3% solutions of acids (per 100 grams of distilled water, 3.2 grams of chitosan and 3.2 grams of acid) was carried out by stirring to a homogeneous state for one and a half hours using an overhead stirrer at a solution temperature of 40 ° C. Glutamic acid was used as the starting acid. A drug (cefotoxime) was introduced into the obtained homogeneous solution in the amount necessary to obtain 3.2% solutions (2 g of antibiotic powder was added to 50 ml of solution). Mixing is carried out in a glass beaker using a mechanical paddle mixer. The stirring speed is 200 rpm, the mixing time is 30 minutes

The titanium nickelide wire is dipped in a chilled (+ 5 ° C) solution of chitosan with drugs, after which it is transferred to a fixing solution (prepared by mixing 2 to 1 ammonia water and ethyl alcohol) and aged. Then carry out drying at a temperature of 40-45 ° C for 24 hours. Samples are washed in a fixing solution to neutralize and remove acids for 5 hours at room temperature, followed by washing in distilled water and then in ethanol. The resulting titanium nickelide coating was dried at 40 ° C. for 24 hours.

The dynamics of the release of cefotoxime from the coating into solutions simulating extracellular body fluids is shown in Fig. 2, from which it is seen that a uniform yield of cefotoxime is achieved on the 1st day.

Example 3

A coating of chitosan with gentamicin introduced on a titanium nickelide wire was obtained.

Preparation of 3% solutions of high molecular weight chitosan (500 kDa, supplier Aldrich) in 3% solutions of acids (per 100 grams of distilled water, 3.2 grams of chitosan and 3.2 grams of acid) was carried out by stirring to a homogeneous state for one and a half hours using an overhead stirrer at a solution temperature of 40 ° C. Glutamic acid was used as the starting acid. A drug (gentamicin) was introduced into the obtained homogeneous solution in the amount necessary to obtain 3.2% solutions (2 g of antibiotic powder was added to 50 ml of solution). Mixing is carried out in a glass beaker using a mechanical paddle mixer. The stirring speed is 200 rpm, the mixing time is 30 minutes

The titanium nickelide wire is dipped in a chilled (+ 5 ° C) solution of chitosan with drugs, after which it is transferred to a fixing solution (prepared by mixing 2 to 1 ammonia water and ethyl alcohol) and aged. Then carry out drying at a temperature of 40-45 ° C for 24 hours. Samples are washed in a fixing solution to neutralize and remove acids for 5 hours at room temperature, followed by washing in distilled water and then in ethanol. The resulting titanium nickelide coating was dried at 40 ° C. for 24 hours.

The dynamics of the release of gentamicin from the coating into solutions simulating extracellular body fluids is shown in Fig. 3, from which it is seen that a uniform yield of gentamicin is achieved on the 7th day.

Claims (1)

A method of producing a biodegradable polymer coating with a controlled drug release for minimally invasive surgery, including dissolving chitosan in acids, adding a drug, dipping titanium nickelide wire into the resulting solution, fixing the coating and drying, characterized in that phosphoric is used as a solvent to dissolve chitosan , or hydrochloric, or glutamic, or acetic acid with a concentration of from 1 to 4% by weight, lincomycin is used as a medicine ., Either gentamicin or tsefotoksim a concentration of from 0.9 to 7% by weight, the coating fixing takes place in an alcoholic ammonia solution in the ratio 1: 2, followed by drying at a temperature of 40-45 ° C for 24 hours.

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