RU2828587C1 - Polymer composition of antibacterial surgical bone cement - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention relates to a polymer composition of antibacterial surgical bone cement and can be used in medicine, mainly in traumatology, orthopedics in plastic reconstruction of injured bone tissues, endoprosthesis replacement, fixation of bone fragments, replacement of absent bone tissue, as well as in maxillofacial surgery, plastic surgery and dentistry. Polymer composition of the antibacterial surgical bone cement contains a liquid component and a powder component, with the following ratio of components, wt.pts.: liquid component: methyl methacrylate—100, polymerisation accelerator N,N-dimethyl-n-toluidine—0.31–0.41, hydroquinone—22 ppm, powdered component: polymethyl methacrylate—100, barium sulphate—11.4, benzoyl peroxide—2.7, chromium oxide III—0.57–1.14, cefazolin—11.4, with the ratio between the powder component and the liquid component of 2:1.

EFFECT: development of a polymer composition of an antibacterial surgical bone cement having high antibacterial activity and providing local application of antibiotics with prolonged release without significant change in physical and mechanical properties.

1 cl, 2 tbl, 8 ex

Description

The invention relates to medicine, primarily to traumatology, orthopedics, and can be used to obtain polymer cement with antibacterial properties, used in plastic reconstruction of damaged bone tissue, endoprosthetics, fixation of bone fragments, replacement of missing bone tissue, as well as in maxillofacial surgery, plastic surgery and dentistry.

An important place among surgical methods of treatment is occupied by the use of a binding fixation material in the "implant - fixation material - bone tissue" system, as well as the use of fixation material in the treatment of osteosynthesis and in plastic surgery. This material can be a polymer composition based on derivatives of acrylic and methacrylic monomers, known as bone cement.

The basis of all types of known polymer compositions intended for use as bone cements is a powdered polymer and a liquid monomer.

The powder polymer is a pre-polymerized polymethyl methacrylate obtained by suspension polymerization. The powder fraction may also contain mineral fillers: barium sulfate as a radiopaque substance, modified quartz, etc.

The liquid fraction consists of a mixture of monomer: methyl methacrylate (MMA), inhibitor (hydroquinone), polymerization activator, usually a tertiary amine (e.g. N,N-dimethyl-para-toluidine).

The powder fraction is mixed with the monomer liquid in a ratio of approximately 2:1 by weight.

When mixing the cement components, swelling and dissolution of the powder in the monomer, as well as partial polymerization of the monomer, occur. This process takes 2-6 minutes and corresponds to the adhesive state of the cement mass. The beginning of the working stage, determined by the surgeon organoleptically (when the cement mass stops sticking to the finger in the glove), is considered to be the formation of a plastic dough, convenient for use both with a syringe and manually. The working stage of the cement lasts from 3 to 7 minutes and is accompanied by an increase in the polymerization rate, while the viscosity of the cement mass increases, and its plasticity and adhesion to the implant and bone tissue gradually decrease.

However, the polymer composition must have constant plasticity, good adhesion to the implant and bone tissue during the working phase (5-8 min). During this time, the surgeon must have time to deliver the cement (often in several portions) to the appropriate place, introduce and fix the elements of the endoprosthesis, before a noticeable decrease in the plasticity of the first portions of the introduced cement mass begins. Then the cement should harden within 2-3 minutes.

A composite material is known (patent US 4910259), which is a two-phase system of powder and liquid. The liquid fraction is based on, in wt. parts:

Methyl methacrylate - 100

Polymerization accelerator N,N-dimethyl-p-toluidine - 0.83

Hydroquinone - 22 ppm

The basis of the powder component consists of, wt. parts:

Polymethyl methacrylate - 90.6

Barium sulfate - 9.4

Benzoyl peroxide - 2.8

The ratio between liquid-phase and solid-phase components is 0.5:1.

The disadvantages of this material include shortened setting times. This cement does not have sufficient plasticity for the period of working time, during which the cement paste loses its mobility and during which the hardening mass can be worked with and shaped. A noticeable decrease in the plasticity of this composition occurs in 2.5-3 minutes. After implantation, the polymerization reaction proceeds by a radical mechanism.

Lengthening the working phase and reducing the viscosity of the cement mass is possible in various ways: by increasing the percentage content of the monomer component in the composition (patent GB 2156824) or using special additives (patent US 4758612), for example glycolic or citric acids, compounds containing at least one phosphorus-carbon or phosphorus-boron covalent bond.

It is known that during the polymerization of methyl methacrylate, significant heating of the cement mass and surrounding bone tissue occurs. The maximum temperature in the cement layer depends on the "powder: liquid" ratio in the cement mass, the composition of the monomer liquid, and the ratio between the initiator and activator.

It is known that decreasing the concentration of the polymerization activator can reduce the polymerization rate, which in turn will reduce the internal energy of the system due to an increase in the heat given off to the environment.

In addition, standard bone cement compositions are mostly white in color, which, when replacing worn-out prostheses, does not allow surgeons to visually assess the degree of completeness of removal of the old layer of cement from the surface of the patient's bone.

The polymer composition of surgical bone cement, made from domestic materials and described in the application for invention No. 2023106020 dated 03/13/2023 (decision to issue a patent on 09/05/2023), allows to obtain a material with an extended working phase (up to 5 minutes) and a comfortable polymerization temperature, while maintaining the plasticity of the cement mass throughout the working phase, and also has the color necessary for visualizing the manipulations performed.

However, the disadvantages of this material include the risk of postoperative infections; often, operations involving the installation of implants are accompanied by an increased risk of developing infectious complications.

The introduction of antibiotics into bone cement is a traditional method of reducing the risk of postoperative infections. Research results have shown that antibiotic-containing bone cements have advantages in preventing postoperative infections compared to conventional bone cement. Antibiotic-containing bone cements are designed to provide high local concentrations of the drug at the surgical site, while the overall concentration of the antibiotic in the body remains low.

A method for producing polymer cement is known, which includes mixing a prescribed amount of powdered polymer, liquid monomer with the addition of the antibiotic gentamicin hydrochloride or gentamicin sulfate. The resulting polymer cement is intended for the formation of bone-like structures of artificial origin and the simultaneous prevention of the development of an infectious process in the contact zone due to the presence of an antibiotic in the composition of the product (patent US 4059684).

A method for producing polymer cement is known, which includes mixing a powdered polymer and a liquid monomer with the addition of the antibiotic gentamicin hydrochloride in an amount of 0.5-1.0 wt.% of the total amount of components of the composition (patent RU 2195320).

The disadvantages of these methods include low antibacterial properties associated with the presence of the antibiotic gentamicin hydrochloride or gentamicin sulfate in the polymer cement, which in modern conditions may be ineffective due to a number of factors, including the emission of the antibiotic into the surrounding tissues, the resistance of microorganisms to a specific antibiotic, and the possibility of toxic side effects.

The objective of the present invention is to reduce the risk of postoperative infections and provide prolonged antimicrobial action at the implantation site, increasing the spectrum of antibacterial agents used by creating a polymer composition of antibacterial surgical bone cement with increased antibacterial properties and a sufficient duration of the working stage, having high adhesion and an acceptable polymerization temperature.

The specified result is achieved by the proposed composition of the polymer composition of surgical bone cement, containing a liquid component of methyl methacrylate, a polymerization accelerator of N,N-dimethyl-p-toluidine, hydroquinone and a powder component of polymethyl methacrylate, barium sulfate, benzoyl peroxide, and chromium (III) oxide in the following ratio of components, wt. parts:

The liquid component contains:

Methyl methacrylate - 100;

Polymerization accelerator N,N-cymethyl-p-toluidine - (0.31-0.41);

Hydroquinone - 22 ppm;

The powder component contains:

Polymethyl methacrylate - 100;

Barium sulfate - 11.4;

Benzoyl peroxide - 2.7;

Chromium(III) oxide - (0.57-1.14),

Cefazolin - 11.4

at a ratio between the powder component and the liquid component of 2:1.

The novelty and essence of the invention lies in the fact that in order to solve the set tasks, it is proposed to introduce the antibiotic Cefazolin, which has a broad spectrum of antimicrobial action, into the composition of bone cement.

Cefazolin is a first-generation cephalosporin semi-synthetic antibiotic, acts bactericidally, disrupting the synthesis of the cell wall of microorganisms, is used in infectious and inflammatory diseases: skin and soft tissues; bones and joints; burn and postoperative infections; as well as for the prevention of surgical infections in the pre- and postoperative period.

The technical result of solving the set problem is the development of a polymer composition of antibacterial surgical bone cement, which has increased antibacterial activity and ensures local application of antibiotics with prolonged release, without significant changes in physical and mechanical properties, which is confirmed by the results of experiments.

The proposed polymer composition of surgical bone cement provides prolonged antimicrobial action - sustained release of antibiotics for 6 weeks and allows to exclude the development of infection and the growth of new multiresistant bacterial strains. At the same time, the proposed material has an extended working phase (up to 5 minutes) and a comfortable polymerization temperature (39-40 ° C), while maintaining the plasticity of the cement mass throughout the working phase, and the material has the necessary color for the effective removal of bone cement residues from the surface of the patient's bone. In addition, the proposed polymer composition is made of domestic materials and can be used in medical practice.

Below are specific examples confirming the possibility of implementing the invention to obtain the above technical result.

Example 1

The proposed composition in the liquid component contains, in parts by weight:

Methyl methacrylate - 100;

Polymerization accelerator N,N-dimethyl-p-toluidine - 0.41;

Hydroquinone - 22 ppm;

The powder component contains, in mass parts:

Polymethyl methacrylate - 100;

Barium sulfate - 11.4;

Benzoyl peroxide - 2.7;

Cefazolin - 2.85.

The ratio between the solid-phase and liquid-phase components is 2:1.

Example 2.

The proposed composition in the liquid component contains, in parts by weight:

Methyl methacrylate - 100;

Polymerization accelerator N,N-dimethyl-p-toluidine - 0.41;

Hydroquinone - 22 ppm;

The powder component contains, in mass parts:

Polymethyl methacrylate - 100;

Barium sulfate - 11.4;

Benzoyl peroxide - 2.7;

Cefazolin - 5.7.

The ratio between the solid-phase and liquid-phase components is 2:1.

Example 3

The proposed composition in the liquid component contains, in parts by weight:

Methyl methacrylate - 100;

Polymerization accelerator N,N-dimethyl-p-toluidine - 0.41;

Hydroquinone - 22 ppm;

The powder component contains, in parts by weight:

Polymethyl methacrylate - 100;

Barium sulfate - 11.4;

Benzoyl peroxide - 2.7;

Cefazolin - 11.4.

The ratio between the solid-phase and liquid-phase components is 2:1.

Example 4

The proposed composition in the liquid component contains, in parts by weight:

Methyl methacrylate - 100;

Polymerization accelerator N,N-dimethyl-p-toluidine - 0.41;

Hydroquinone - 22 ppm;

The powder component contains, in mass parts:

Polymethyl methacrylate - 100;

Barium sulfate - 11.4;

Benzoyl peroxide - 2.7;

Cefazolin - 17.1.

The ratio between the solid-phase and liquid-phase components is 2:1.

Example 5

The proposed composition in the liquid component contains, in parts by weight:

Methyl methacrylate - 100;

Polymerization accelerator N,N-dimethyl-p-toluidine - 0.41;

Hydroquinone - 22 ppm;

The powder component contains, in mass parts:

Polymethyl methacrylate - 100;

Barium sulfate - 11.4;

Benzoyl peroxide - 2.7;

Chromium (III) oxide - 0.85;

Cefazolin - 2.85.

The ratio between the solid-phase and liquid-phase components is 2:1.

Example 6

The proposed composition in the liquid component contains, in parts by weight:

Methyl methacrylate - 100;

Polymerization accelerator N,N-dimethyl-p-toluidine - 0.41;

Hydroquinone - 22 ppm;

The powder component contains, in mass parts:

Polymethyl methacrylate - 100;

Barium sulfate - 11.4;

Benzoyl peroxide - 2.7;

Chromium (III) oxide - 0.85;

Cefazolin - 5.7.

The ratio between the solid-phase and liquid-phase components is 2:1.

Example 7

The proposed composition in the liquid component contains, in parts by weight:

Methyl methacrylate - 100;

Polymerization accelerator N,N-dimethyl-p-toluidine - 0.41;

Hydroquinone - 22 ppm;

The powder component contains, in mass parts:

Polymethyl methacrylate - 100;

Barium sulfate - 11.4;

Benzoyl peroxide - 2.7;

Chromium (III) oxide - 0.85;

Cefazolin - 11.4.

The ratio between the solid-phase and liquid-phase components is 2:1.

Example 8

The proposed composition in the liquid component contains, in parts by weight:

Methyl methacrylate - 100;

Polymerization accelerator N,N-dimethyl-p-toluidine - 0.41;

Hydroquinone - 22 ppm;

The powder component contains, in mass parts:

Polymethyl methacrylate - 100;

Barium sulfate - 11.4;

Benzoyl peroxide - 2.7;

Chromium (III) oxide - 0.85;

Cefazolin - 17.1

The ratio between the solid-phase and liquid-phase components is 2:1.

The obtained characteristics according to the recipe of the presented compositions (Examples 1-8) are presented in Tables 1, 2.

Table 1 presents data on the inhibition zone and release time of antibiotics in accordance with the formulation of Examples 1-8 under consideration.

Table 2 presents the obtained technical characteristics in accordance with the formulation of the compositions of Examples 1-8, confirming that the polymer composition proposed for obtaining surgical bone cement has antibacterial properties while maintaining the working characteristics of the composition.

Thus, the given Examples clearly illustrate the advantage of the claimed composition of the polymer composition of surgical bone cement, which can be used in medical practice.

The technical characteristics of the studied cement compositions were determined as follows.

To determine the duration of the working phase of the cement mass, a bottle with liquid was opened and the contents of the bottle were poured into a polyethylene cup. The corner of the polyethylene bag was cut off and the powder from the bag was poured into the liquid. The timer was turned on and the powder and liquid were mixed with a spatula for 30-40 seconds until a homogeneous mass was obtained.

The readiness of the cement for work (beginning of the working phase) was determined in accordance with ISO 5833.1992(E) (Appendix B) as follows: the surface of the cement was touched with a finger in a wet surgical glove. The cement was ready for work if it did not stick to the glove. This time was recorded with a timer. The end of the working phase of the cement was determined organoleptically as follows: a portion of cement from a cup in the amount of 10-15 g was stretched with fingers in a glove. The cement was not suitable for work if it did not stretch, but broke without forming threads. The end of the working phase was recorded with a timer. The working phase was determined at an air temperature of 23 degrees Celsius.

To confirm the prolonged action of the antibiotic, the obtained samples in the form of rods 3 cm long and 4 mm in diameter were each introduced into 20 ml of physiological solution and kept in this solution at a temperature of 37°C for 6 days. Samples were taken daily. Each time after taking samples, the volume of the medium was restored by adding fresh physiological solution.

The release of the antibiotic was confirmed by the agar diffusion method using Bacillus subtilis ATCC 6633 as the test microorganism. The diameter of the inhibition zone was measured with a conventional scanner.

Claims (6)

A polymer composition of antibacterial surgical bone cement containing a liquid component of methyl methacrylate, a polymerization accelerator of N,N-dimethyl-n-toluidine, hydroquinone and a powder component of polymethyl methacrylate, barium sulfate, benzoyl peroxide, characterized in that the powder component additionally contains chromium III oxide and cefazolin in the following ratio of components, parts by weight: liquid component: Methyl methacrylate 100 Polymerization accelerator N,N-dimethyl-n-toluidine 0.31-0.41 Hydroquinone 22 ppm, powder component: Polymethyl methacrylate 100 Barium sulfate 11.4 Benzoyl peroxide 2.7 Chromium III oxide 0.57-1.14 Cefazolin 11.4, at a ratio between the powder component and the liquid component of 2:1.