LT6227B - Biocompatible polyacrylamide hydrogel and method for production thereof - Google Patents

Abstract

The invention relates to the medical field, namely - reconstructive, restorative, plastic surgery and is related to obtaining a polyacrylamide gel that can be used for medical and/or biological purposes, as well as the graft or cells carrier.

Description

The present invention relates to the field of medicine, in particular to reconstructive, restorative, plastic surgery and relates to the production of a biocompatible polyacrylamide hydrogel which can be used for medical and / or biological purposes.

A Ukrainian patent "Biocompatible Polyacrylamide Hydrogel" (UA64849, published March 15, 2004, Bulletin No. 3) containing a polyacrylamide coupled with N.N'-methylene-bis-acrylamide as an isotonic solution is known in the art ( used as a dispersion medium) using 0.85% sodium chloride solution, 0.5% glucose solution, Ringer-Lock solution, Erl solution, Hanks solution, borate or phosphate buffers, and additionally using a plasticizer such as polyoxyethylene, methylcellulose, gelatin, polyvinylpyrrolidone , polyvinyl spirit.

The main disadvantage of said hydrogel is that it uses methylcellulose and gelatin, which form the medium for the growth and spread of the pathogenic microflora. The pathogenic microflora in the polyacrylamide hydrogel increases the likelihood of postoperative complications and other adverse reactions, especially in the body at a temperature of 36.6 ° C.

Also known in the art is the patent RU 2067873 (published October 20, 1996) entitled "Biocompatible hydrogel" consisting of 3.5 to 9.0% by weight of a crosslinked copolymer - acrylamide with a coupling agent methylene bisacrylamide and , 5-99.0% w / w water. The hydrogel is obtained by reacting the copolymerization of acrylamide with methylene bisacrylamide in aqueous medium using peroxide polymerization initiators and keeping the mixture at room temperature for 20 minutes. The polymerization process is carried out in one step using ammonium persulfate and tetramethylethylenediamine as peroxide initiators. Because the resulting gel has an insufficient degree of bonding due to the low temperature copolymerization process and the use of a single polymerization step, volume stability cannot be achieved.

The closest technical and achievable result is patent RU 2236872, "Polyfunctional Biocompatible Hydrogel and Methods for Its Preparation" (Published September 27, 2004). The hydrogel contains polyacrylamide and water, and the polyacrylamide in turn consists of an acrylamide copolymer, methacrylamide, 2-hydroxyethyl methacrylate and N, N'-methylene-bis-acrylamide. The copolymerization is carried out in three steps, the first step at 20-30 ° C and lasting 12-24 hours. The second stage is γ-irradiation at a radius of 0.4-1.0 megarads and the third stage takes place for 20-40 minutes at 100-130 ° C and 0-1.2 bar. After the first stage, the hydrogel is washed with water at 70-110 ° C at a ratio of 1: 8-10 hydrogel for at least 3 hours at a pressure of 0-1.2 atm. Hydrogen peroxide and / or ammonium persulfate are used as initiators of the copolymerization. Double-distilled pyrogen water is used as the aqueous medium. The disadvantage of this gel is low resistance to resorption in the internal medium of the body.

It is an object of the invention to provide a biocompatible polyacrylamide hydrogel that addresses deficiencies and performs the function of a biological tissue by selecting a combination of its components that provides maximum therapeutic effect.

Another object of the invention is to provide a biocompatible polyacrylamide hydrogel for use as a graft.

The technical result of the invention is to provide a biocompatible, stable structure polyacrylamide hydrogel, to use it as a graft to eliminate the drawbacks.

The essence of the invention is that the qualitative and quantitative composition of the biocompatible polyacrylamide hydrogel as well as the copolymerization conditions have been selected. Meanwhile, the bioactive properties of the biocompatible polyacrylamide hydrogel depend largely on the structure of the crosslinked polymer. The structure of the cross-linked polymer, in turn, depends on the synthesis conditions, namely the qualitative and quantitative composition of the starting reagents, including the coupling agent and the polymerization initiator, as well as the polymerization conditions and mode.

The following tasks are solved in the following way.

The biocompatible polyacrylamide hydrogel contains a solution of polyacrylamide and 0.9% sodium chloride. A polyacrylamide used is an acrylamide copolymer with N, N'-methylene-bis-acrylamide.

The polymerization reaction proceeds by the free radical mechanism and requires free acrylamide radicals. As the initiators of the polymerization reaction, free radicals are formed which react with acrylamide molecules to initiate polymerization. Ammonium persulfate is the most widely used initiator of the polymerization process. Because the polymerization reaction of acrylamide is a slow process, N, N, N ', N'-tetramethylethylenediamide is used as a catalyst to accelerate the polymerization process. The biocompatible polyacrylamide hydrogel contains the ratio of these components,% (w / w)

acrylamide 1.9-9.0; N, N'-methylene-bis-acrylamide 0.006-0.1; N, N, N ', N'-tetramethylethylenediamide 0.004-0.5; ammonium persulfate 0.02-0.2; sodium chloride solution 0,9% the remaining part

To ensure structure and volume stability of the biocompatible polyacrylamide hydrogel and to give it better biocompatibility with human tissues, a 0.9% sodium chloride solution is prepared on the basis of structured (derived from melted ice) water.

The process for preparing the biocompatible polyacrylamide hydrogel comprises the following steps: induce copolymerization of acrylamide with N, N-methylene-bis-acrylamide in a dispersion medium, with ammonium persulfate and N, N, N ', N'-tetramethylethylenediamide, then wash the resulting gel with 0.9% sodium chloride solution, based on structured (derived from melted ice) water, maintained until homogeneous, homogenized and sterilized.

The dispersion medium used is a 0.9% sodium chloride solution, which is based on structured (derived from melted ice) water. Component Ratio,% (w / w) Acrylamide 1.9-9.0;

N, N'-methylene-bis-acrylamide 0.006 - 0.1;

N, N, Ν ', N' - tetramethylethylenediamide 0.004-0.5;

ammonium persulfate 0.02-0.2;

sodium chloride solution 0.9% remaining.

The biocompatible polyacrylamide hydrogel is prepared as follows:

First, copolymerization is induced at 20-28 ° C for 3060 min. The resulting gel is washed with a 0.9% sodium chloride solution prepared on a structured (derived from melted ice) water. Wash the hydrogel for 3 hours in 6 steps, replacing each step with 0.9% sodium chloride solution. It is then allowed to swell for 18 hours at 20-30 ° C, with a swelling factor of 1,631,73, followed by homogenization for 5 to 15 minutes. It is then sterilized at 80-90 ° C for 5-10 minutes. Allow to stand for two hours and sterilize a second time at 118-135 ° C for 1.5 to 2.5 bar for 15-45 minutes.

The use of a 0.9% sodium chloride solution in water based on structured (derived from melted ice) ensures the structure and volume stability of the biocompatible polyacrylamide hydrogel and gives the hydrogel greater biocompatibility with human tissues.

The method described for the preparation of a biocompatible polyacrylamide hydrogel allows the reduction of the number of unbound amino groups, free NH 2 radicals and unsaturated double bonds. The degree of hydrogel bonding is also increased. This allows to reduce the patient's tissue response to biocompatible polyacrylamide hydrogel transplantation, to ensure shape stability after implantation due to patient compliance and decrease in resorption rate, to reduce its potential for contamination by microorganisms, including from the recipient, and to prevent their proliferation.

Example of embodiment of the invention. To obtain a biocompatible polyacrylamide hydrogel, we take:

acrylamide 62.7 g; N, N'-methylene-bis-acrylamide 0.9 g; N, N, Ν ′, N ′ - tetramethylethylenediamide 0.68 g; of ammonium persulfate 3.0 g; sodium chloride solution 0.9% 1580.72 g

The hydrogel is prepared according to the method described in the biocompatible method for obtaining a polyacrylamide hydrogel.

The acrylamide is first copolymerized with N, N-methylene-bis-acrylamide. The resulting gel is washed with a 0.9% sodium chloride solution prepared on a structured (derived from melted ice) water. Wash the hydrogel for 3 hours in 6 steps, replacing each step with 0.9% sodium chloride solution. It is then allowed to swell for 18 hours at 20-30 ° C and then homogenized for 515 minutes. The sterilization step is carried out in two stages - initial sterilization is carried out at 80-90 ° C for 5-10 minutes, then the hydrogel is maintained for two hours and sterilized again at 118-135 ° C at a pressure of 1.5-2.5 bar, 15 to 45 bar. minutes.

Method of administration - subcutaneous injection.

Indications for use.

- stimulation of the immune system;

- liver disease;

- diseases of the nervous system;

- cardiovascular disease.

70 patients with angina pectoris due to coronary artery stenosis were followed (follow-up period 2.5-3 years). Ischemic heart disease was diagnosed in most patients after coronographic examination. The observation protocol assessed the severity of angina, which was determined by exercise tolerance by a veloergometric test. Lipid spectra of blood serum were investigated by enzymatic method using standard reagents.

The substance was administered subcutaneously by a single injection into the anterior abdominal wall, at 4-5 points, in accordance with all aseptic and antiseptic rules.

Patients who received the first dose were divided into 3 groups. The first group consisted of 14 people who had a 9-12 month post-transplant benefit. At the end of this period, patients had an increase in the number of angina attacks per day, a corresponding increase in medication use, and worsening of exercise.

In the second group of patients (34 subjects), the condition deteriorated 12 to 18 months after transplantation. The third group included 22 patients whose health status was stable for up to 36 months, with no worsening. There were no deaths in the 70 patient group over three years.

Repeat transplantation fully replicates the results of the first transplant and can be used as an alternative to a treatment complex consisting of cholesterol-lowering and angina medications. Another way to use a graft based on a biocompatible polyacrylamide hydrogel is to look at the example of a burn center. We use the resulting biocompatible polyacrylamide hydrogel.

Twenty-two people were selected for the study in the experimental and control groups. Composition by age: 8 children from 1 to 12 years with 2-3 ab degree burns, burn area from 1.5 to 25%, and 14 people from 16 to 67 years with 3 ab degree burns, burn area from 1.5 to 25% 25%. Subcutaneous injection of a biocompatible polyacrylamide hydrogel around a 2-3 ab grade burn site from 2-3 ml of graft within the first three days indicated that the open wound had become closed, helping to reduce electrolyte and protein loss. This, in turn, is important in the early treatment of patients with acute burns. In the control group, the open wound healed on day 11-12. One of the features of the use of a biocompatible polyacrylamide hydrogel is that there is no likelihood of mechanical damage to the granules, drying of the damaged surface, and secondary necrosis. We also note that the epithelization time of the damaged surface is significantly reduced.

Thus, the use of biocompatible polyacrylamide hydrogel provides new opportunities for the development of other materials that can be used to repair cartilage and bone tissue by promoting wound healing and tissue regeneration in burn therapy.

Claims (5)

A biocompatible polyacrylamide hydrogel containing a solution of polyacrylamide and 0.9% sodium chloride, wherein the polyacrylamide is an acrylamide copolymer with N, N'-methylene-bis-acrylamide, which is characterized by the addition of ammonium persulfate and N, N, N'-tetramethylethylenediamide, with a component ratio (% by weight) DEFINITION OF INVENTION acrylamide 1.9-9.0; N, N'-methylene-bis-acrylamide 0.006-0.1; N, N, N ', N'-tetramethylethylenediamide 0.004-0.5; ammonium persulfate 0.02-0.2; sodium chloride solution 0,9% the remaining part Biocompatible polyacrylamide hydrogel according to claim 1, characterized in that the 0.9% sodium chloride solution is prepared on the basis of structured water (obtained from melted ice). A process for the preparation of a biocompatible polyacrylamide hydrogel comprising the steps of: copolymerizing acrylamide with N, N'-methylene-bis-acrylamide in a dispersion medium, with ammonium persulfate and N, N, N'-tetralmethylenediamide, washing the resulting gel to homogeneous state followed by homogenization and sterilization; The method is characterized in that the obtained gel is washed in 6 steps over 3 hours, allowed to swell for 18 hours at 20-30 ° C, using 0.9% w / w sodium chloride solution as the dispersion medium, as follows: acrylamide 1.9-9.0; 0.006-0.1; 0.004-0.5; 0.02-0.2; N, N'-methylene-bis-acrylamide N, N, Ν ', N' - tetramethylethylenediamide ammonium persulphate sodium chloride solution 0,9% residue. A process for preparing a biocompatible polyacrylamide hydrogel according to claim 3, characterized in that the copolymerization is carried out at 20-28 ° C for 30-60 minutes, washing with 0.9% sodium chloride solution, homogenization for 5-15 minutes, sterilization with 80- 90 ° C for 5-10 minutes, maintained for two hours and then sterilized a second time at 118-135 ° C at 1.5-2.5 bar for 15-45 minutes. Process for the preparation of a biocompatible polyacrylamide hydrogel according to claims 3 and 4, characterized in that the 0.9% sodium chloride solution is based on structured water (obtained from melted ice).