Bioresorbable hydrogel polymer composition with biologically active substances (versions)

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a bioresorbable hydrogel polymer composition for cardiovascular surgery in the form of a film prepared by a reaction of natural polymers, biologically active substances, a solvent and a softening agent wherein the polymers are presented by cross-linked bioresorbable polymers - gelatin, chitosan or a mixture of chitosan and gelatin, chitosan and polyhydroxybutyrate; the biologically active substance or mixtures thereof are presented by the antioxidant L-carnosine, the anticoagulant heparin, the antiaggregant dipyridamole, acetylsalicylic acid, the non-steroid anti-inflammatory preparation acetylsalicylic acid, the antimicrobial preparations - ciprofloxacin, metronidazole; mechanical strength of the film is not less than 1.2 MPa, the relative elongation is no more than 160%, and the elasticity modulus is 0.4-5 MPa.

EFFECT: there are used hydrogel polymer compositions with the control bioresorption period, prolonged length of biologically active substance release, having biocompatible and thrombus-resistant properties and improved mechanical characteristics - higher softness and elasticity.

7 cl, 12 dwg, 2 tbl, 4 ex

 

The invention relates to medicine, namely to the use of surgical interventions, including cardiovascular surgery, where bioresorbable hydrogel polymer compositions can be used alone in the form of films as biophysical barrier to reduce the formation of adhesions after cardiac operations for systems with controlled allocation of biologically active agents as a coating for an implantable vascular prosthesis, cardiac patches, cuffs for artificial heart valves and others (A.D. Myasnikov, V. VA TO the question of modern principles of prevention of postoperative adhesions in the abdominal cavity. Contemporary approaches to the science and practice of surgery: proceedings of the international conference dedicated to the 70th anniversary of the honored worker of science of the Russian Federation, Professor Viyalizina.: The compilation. Voronezh, 2002. - S-157; Whakatataka, Mavashev, Iusurance Postoperative adhesions in surgery: problems and solutions. // Pathology of circulatory and cardiac surgery. - 2011. No. 1. - P.100-104; Scars O.Y the Prevention of adhesions in the abdominal cavity when peritonitis (an experimental study). Abstract. Diss. MD, Saransk.- 2005).

Known polymeric compositions to prevent adhesions, consisting of cross-linked collagen "Cova-CARD"), and not bioresorbable composition of polytetrafluoroethylene - PTFE ("Preclude®") in the form of films, which were compared between themselves and with autologous pericardium (Alain Bela, Massimo Riccic, Julie Piquetc, Patrick Brunevald Prevention of postcardiopulmonary bypass pericardial adhesions by a new resorbable collagen membrane // Interact. CardioVasc. Thorac. Surg. 2012. - 14(4). - P.469-473; Hiroyuki Tsukihara, Shinichi Takamoto, Kazuo Kitahori, Kazuhisa Matsuda, Arata Murakami, Richard J. Novick, Yoshihiro Suematsu. Prevention of Postoperative Pericardial Adhesions With a Novel Regenerative Collagen Sheet // Ann. Thorac. Surg. 2006. No. 81. - R-657). In animal experiments after 4 months it is shown that the minimum formation was observed after application of collagen composition "Cova-CARD", which during this period was completely resorbables.

The disadvantage of the proposed compositions is the absence in their composition of biologically active substances, which could strengthen a positive effect.

Known application of polymeric compositions comprising cross-linked collagen with the addition of at least one cellular component, such as cells, fibroblasts, vascular smooth muscle cells, with the addition of glycoproteins and proteoglycans (US No. 2004018175 (A1)publication date 29.01.2004,) that is used to reduce adhesions in the form of an implantable anti-adhesive patches.

The disadvantage of the proposed compositions is the technological complexity of their receipt, the difficulty of practical implementation and the lack of biologically Akti the different substances.

Known polymeric compositions based on crosslinked gelatin films for reduction of adhesions after surgery (Kei Sakuma, Atsushi Iguchi, Yoshito Ikada, Koichi Tabayashi Closure of the Pericardium Using Synthetic Bioabsorbable Polymers Ann. Thorac. Surg. - 2005. No. 80. - P.1835-1840; Goki Matsumura, Toshiharu Shin'ei oka, Yoshito Ikada, Takahiko Sakamoto, Hiromi Kurosawa's way (Kurosawa. Novel Anti-Adhesive Pericardial Substitute for Multistage Cardiac. Surgery. // Asian. Cardiovasc. Thorac. Ann. - 2008. No. 16. - P.309-312) and compositions comprising gelatin in combination with polyglycolic acid (Ichiro Yoshioka, Yoshikatsu Saiki, Kei Sakuma, Atsushi Iguchi, Takuya Moriya, Yoshito Ikada, Koichi Tabayashi. Bioabsorbable Gelatin Sheets Latticed With Polyglycolic Acid Can Eliminate Pericardial Adhesion. // Ann. Thorac. Surg. - 2007. - No. 84. - R-870).

The disadvantage of these compositions is that no biologically active substances that do not provide anticoagulant, anti-inflammatory, antibacterial and other effects.

Known polymer composition consisting of hyaluronic acid and carboxymethylcellulose "Seprafilm"used to prevent postoperative adhesions and made in the form of membranes (Yuji Naito, Toshiharu Shin'ei oka, Narutoshi Hibino, MD, PhD, Goki Matsumura, Hiromi Kurosawa's way (Kurosawa. A novel method to reduce pericardial adhesion: A combination technique with hyaluronic acid biocompatible membrane // J. Thorac. Cardiovasc. Surg. - 2008. No. 135. - R-856).

Also known polymer composition consisting of various ether derivatives of hyaluronic acid, in the form of films, gels, grids, woven and non-woven cloth on the basis of these paintings is adnych hyaluronic acid and not at bioresorbable polymers (polytetrafluoroethylene - PTFE, polyethylene, polypropylene, polyester - Dacron (RU # 2177332 (A1)publication date 27.12.2001,).

The disadvantages of the compositions is that the hyaluronic acid itself is characterized by a very fast adsorption in the body, which is not comparable with the time of saving necessary to prevent adhesions, it also contains low molecular weight oligomers, which may affect its biocompatibility. In addition, hyaluronic acid is technologically difficult processing, in order to create a polymer composition in the form of a film (membrane). These technologies multistage, complex. Limited set of deposited biologically active substances was introduced only heparin.

All of the above compositions, the use of which is associated with attempts to reduce the formation of adhesions after surgery, concerned individual application of any one species of a natural polymer, in addition, has not been used for a complex of biologically active substances, which could also have an impact on the prevention of adhesions.

Known polymeric compositions used as coatings for implantable vascular prostheses and cardiac patches, consisting of bioresorbable polymer is purified gelatin, antimicrobial drug preparato is broad-spectrum and drugs anticoagulant and antiplatelet actions (artificial blood vessels and cardiac patches with thromboresistance, antimicrobial properties and zero surgical porosity. Bokeria L.A., S. p. Novikov // Bulletin of the Bakulev them. Avicula RAMS "cardiovascular disease". - 2008. - V.9. No. 4. - P.5-20).

The disadvantage of these compositions is that when used as coatings for synthetic textile implantable medical devices - artificial blood vessels "BASEX", cardiovascular patches, in the composition as a main component is used only gelatin and a limited range entered into the composition of biologically active substances, which is not enough provides a regulated bioresorption compositions and prolongation of extraction of biologically active substances.

The closest technical solution, taken as a prototype, is a biologically active medical polymer composition (RU # 2447902 (C2), publication date 20.04.2012,) consisting of a copolymer of 3-hydroxybutyrate and 3-hydroxyvalerate (3-FCB/3-IV) and at least one biologically active substance selected from the group of antibiotics (gentamicin, Tienam, rifampicin and vancomycin) or from the group of nonsteroidal anti-inflammatory drugs, consisting of meloxicam, diclofenac, ibuprofen and indomethacin, and as the solvent used dichloromethane or chloroform at next autosizecomponents, wt.%: 3-FCB/3-PHV - 1-6; biologically active substance 1-5; solvent - rest. Also in the composition of the used surfactant is polyvinyl alcohol or polyoxyethylene-20-sorbitan monooleate, polyethylene glycol (1-20) and gelatin (1-6). The composition is made in the form of microparticles, films or membranes. The composition is intended for the Deposit and delivery of medicines, as coatings for medical devices, independent film products (as protivospaechnyj tool as a barrier), matrix for cell culture.

Disadvantages song:

1) FCB and its copolymers slowly rezorbiruetsa in the body, so one of them is difficult to obtain a film composition with the set, including short deadlines resorption and long stay foreign material in the body is not desirable.

2) the Hydrophobicity of this song, despite the hydrophilic additive components, prevents the selection of drugs, the release rate of drugs is too low, because of this composition with antimicrobial drugs have little antimicrobial activity zone of lysis - 2-8 mm

3) FCB - vysokokritichnyh polymer, and therefore the film based on it hard, the elasticity is very low, which reduces the technological capabilities when used.

4) as bio is automatic active substances used drugs narrow spectrum assignment - only antibiotics or anti-inflammatory agents, no anticoagulants, antioxidants, antiplatelet agents, anti-adhesive substances.

5) the Ability FCB and its copolymers dissolve only in organic solvents leads to the use of multiple chemicals at different technological stages (dichloromethane or chloroform, hexane or isopropanol), which complicates the cleanup phase.

6) Polymer compositions on the basis of FCB have poor adhesion to substrates, such as polymers, which greatly complicates the use of these compositions.

The technical result of the invention is the creation of bioresorbable hydrogel polymer compositions with biologically active substances, with adjustable time bioresorption, prolonged periods of extraction of biologically active substances, biocompatible and thromboresistant properties, increased antimicrobially, improved mechanical characteristics, increased softness and elasticity.

The technical result is achieved by the fact that:

in bioresorbable hydrogel polymer compositions, including natural polymers, biologically active substances, solvent and plasticizer, as crosslinked polymers are used bioresorbable polymers or their mixtures, as which is used proteins gelatin, polysaccharides, chitosan and its derivatives, polyether - polyhydroxybutyrate, and as biologically active substances or their mixtures are used antioxidants, and/or anticoagulants and/or antiplatelet agents, and/or nonsteroidal anti-inflammatory agents and/or antimicrobial drugs, and the use of antioxidants peptides - L-carnosine as an anti - heparin, antiplatelet agents - dipyridamole, acetylsalicylic acid, as a non-steroidal anti-inflammatory substances - acetylsalicylic acid as an antimicrobial drugs - ciprofloxacin, metronidazole;

- number of biologically active substances in the proposed compositions are the following: for compositions on the basis of gelatin: 1-2 wt.%, for compositions based on chitosan: 4-8 wt.%, for compositions based on chitosan and gelatin: 4-8 wt.%, for compositions based on chitosan and polyhydroxybutyrate: 4-8 wt.%;

- the total number of polymers or their mixtures with biologically active substances should be such that the mechanical strength of the film was not less than 1.2 MPa, the elongation is not more than 160%, the modulus of elasticity is - 0.4 to 5 MPa;

- when sharing chitosan and gelatin gelatin in the composition should be at least 20%;

- when sharing chitosan and polyhydric is ibotirama polyhydroxybutyrate in the composition should be no more than 30%;

as a cross-linking agent can be used natural crosslinking agent from the class of glycosides genipin;

- to obtain compositions, when used together, chitosan and gelatin, in the solvent used water. Obtaining polymer compositions is as follows.

1. Prepare solutions of polymers

A solution of gelatin: 5-10 wt.% a solution of gelatin with a molecular weight of 60-80 kDa in distilled water.

A solution of chitosan: 3-6 wt.% a solution of chitosan with molecular weight of 200-300 kDa in 1-3 wt.% acetic acid.

The mixture solutions of chitosan and gelatin: 3-6 wt.% a solution of chitosan with molecular weight of 200-300 kDa in 1-3 wt.% acetic acid is added gelatin of at least 20% by weight of chitosan.

The mixture of chitosan solutions and polyhydroxybutyrate: 3-6 wt.% a solution of chitosan with molecular weight of 200-300 kDa in 1-3 wt.% acetic acid is added 0.5 to 1.5 wt.% R-R FCB in chloroform.

Compositions with a combination of polymers of gelatin and polyhydroxybutyrate not considered, because the preparation of a mixture of their fluids associated with technological difficulties. In the preparation of a mixture of solutions of gelatin and polyhydroxybutyrate there is a strong foaming, if gelatin in the mixture is present in more than 60-70 wt.%, in the polymer composition in the form of a film obtained fragile. If gelatin in the mixture m is her 50-60%, foaming is minimal, but the film composition is hard, time hydrolytic degradation will be very long.

2. Polymer compositions produced by the method of irrigation solutions on different substrate (polyethylene, polypropylene, glass).

3. Dried polymeric composition at a temperature not exceeding 30°C for 3-5 days.

4. For translation in a water-insoluble state polymeric composition is treated with a solution of a crosslinking agent (glutaraldehyde or genipin) or subjected to heat treatment.

5. Biologically active substances in the composition are introduced, or at the stage of preparation of a solution of the polymer or after transfer to the polymer composition in water-insoluble state by chemisorption.

6. In the polymer composition type plasticizer is glycerin.

Polymer compositions based on gelatin possess elasticity, softness with adequate hydrogel structures strength, variable speed hydrolytic degradation, which is determined by the film thickness, composition and number of biologically active substances, the degree of crosslinking. Natural cross - linking agent genipin less toxic than synthetic - glutaric aldehyde. Gelatin has the ability to form thermo-labile jellies that allows you to apply the composition on its fundamentals is as a coating for textile fundamentals of artificial blood vessels, cardiac patches.

Polymer compositions based on chitosan stronger than compositions based on gelatin, but less elastic. Joining is carried out by heat treatment, without the use of chemical reagents. Biologically active substances injected in the polymer solution, and chemisorption in the finished film. Chitosan possesses bacteriostatic properties is not a breeding ground for pathogens. Chitosan composition less susceptible to hydrolytic degradation, swelling in 3 times less selection of biologically active substances is slower than that of the films of gelatin.

Chitosan and gelatin belong to different classes of polymers and have different structure, chitosan is a polysaccharide, gelatin protein. The combination of these polymers has allowed to strengthen the positive properties of each: to increase the deposition of biologically active substances and the period of bioresorption by adding to the composition of chitosan, to increase the hydrophilicity and compatibility with various biologically active substances, to improve the mechanical properties (softness, elasticity) by adding the gelatin composition.

In case of use of the compositions as coating textile fundamentals of artificial blood vessels, cardiac patches, gelatin in the composition should byline less than 20 wt.%, as at smaller content of gelatin studiobased properties of the composition are violated.

The combination of chitosan and gelatin was allowed to translate compositions of water-insoluble state by heat treatment, i.e. without the use of chemical cross-linking reagents.

Polymer compositions based on poly-3-peroxyborate (FCB) in the form of films obtained from solutions in chloroform. They are hard because of the high degree of crystallinity, to introduce biologically active substances only in the original polymer solution. FCB is hydrophobic, weakly swelling the polymer and has a reduced release rate of drugs that provides them the selection to long-term. The selection of biologically active substances from the composition based on polyhydroxybutyrate very slow, not provided therapeutically significant concentrations of biologically active substances. Speed bioresorption very low, so the polymer as a foreign material in the body is long.

The combination of the polyester is poly-3-hydroxybutyrate (FCB) with the polysaccharide chitosan is allowed if necessary to provide increased deposition of biologically active substances (compared to chitosan compositions). Swelling hydrogel layer of chitosan provides the allocation of the necessary initial therapeutic the ski quantities of biologically active substances with greater speed at the initial time, and the introduction of polyhydroxybutyrate in the composition is allowed to increase the time of extraction of biologically active substances in 1.5 times. The content of polyhydroxybutyrate in the composition should not exceed 30 wt.%, due to the compatibility of the polymers in the composition. As polyhydroxybutyrate is a hydrophobic polymer and chitosan is hydrophilic, it is a significant phase separation of the composition is observed when the content of polyhydroxybutyrate more than 30 wt.% and this negatively affects the mechanical properties of the composition. The invention is illustrated by illustrations.

Figure 1. The change in the activity of neutrophil elastase (ne) after contact with film songs

(V blood = 2 ml, S sample = 1 cm2h (film thickness) = 60-90 microns; the time of contact with blood = 60 min, control-medical track)

* Abbreviations:
Polymers:Biologically active substances:
W - gelatine;AC - acetylsalicylic-TA;
HT - chitosan;GP - heparin;
FCB - polyhydroxybutyrate;Dr. dipyridamole;/td>
K - L-carnosine;
C - ciprofloxacin.

Figure 2. Blood counts after contact with the composition (V blood = 2 ml, S sample = 1 cm2h (film thickness) = 60-90 microns;

The time of contact with blood=60 min)

Figure 3. Compositions in the form of films based on chitosan without biologically active substances after 1 week after implantation (A), 2 weeks (B). Stained with hematoxilin and eosin, magnification 200.

Figure 4. Compositions in the form of films based on chitosan with biologically active substances (K, D, C, SE) after 1 week after implantation (A), an increase of 200, 2 weeks (B), magnification 400. Stained with hematoxilin and eosin.

Figure 5. Mylar medical cloth with a coating of gelatinous compositions of biologically active substances (AC, K, D, C, SE) 1 week after implantation. Stained with hematoxilin and eosin, magnification 200.

6. Mylar medical cloth with a coating of gelatinous compositions of biologically active substances (AC, K, D, C, SE) 2 weeks after implantation. Stained with hematoxilin and eosin, magnification 200.

7. Mylar medical cloth with a coating of chitosan-gelatin compositions of biologically active substances (K, D, C, SE), 1 week after impla is to be treated. Stained with hematoxilin and eosin, magnification 200.

Fig. Mylar medical cloth with a coating of chitosan-gelatin compositions of biologically active substances (K, D, C, SE) 2 weeks after implantation. Stained with hematoxilin and eosin, magnification 200.

Fig.9. Compositions in the form of films based on polyhydroxybutyrate (AC, K, D, C, SE), 3 months after implantation. Stained with hematoxilin and eosin, magnification 400.

Figure 10. Mylar medical cloth with a coating of chitosan-polyhydroxybutyrate compositions of biologically active substances (K, D, C, SE) 2 weeks after implantation. Stained with hematoxilin and eosin, magnification 400.

11. Antimicrobial properties of polymer compositions in the form of films

And a Strain of Escherichia coli,

B - Staphylococcus aureas.

4 - Gelatin+AC+SE+K+D+C;

10 - XT+K+D+C+SE;

K - XT without biologically active substances;

Fig. Antimicrobial properties of the modified polymer compositions medical paintings

And a strain of Escherichia coli,

B - Staphylococcus aureas.

1 - Gelatin+AC+SE+K+D+C;

2 - HT+K+D+C+SE;

3 - Chitosan+Gelatin+SE+K+D+C;

4 - Chitosan+FCB+K+D+C+SE;

The original canvas.

1. Biocompatibility, thromboresistant confirmed in vitro (1, 2).

Defined the main parameters of blood in contact with the compositions, the degree of hemolysis, the effect is as proteins and formed elements of the blood (the change in the number of platelets and the extent of ADP-induced platelet aggregation), proteins of the acute phase - albumin, C - reactive protein - CRP, a protein), the parameters of the coagulation system (activated partial thromboplastin time - APTT, prothrombin time - Pt), fibrinolytic system (change the content of fibrinogen, plasminogen activity of anti-thrombin III) and the complement system (immunoglobulins G, M).

Determined the impact of the developed compositions on the neutrophilic elastase (ne), which is an indicator of the activation of neutrophils. Ne is one of the main indicators of biocompatibility and thromboresistance foreign material in contact with blood.

Samples of polymer compositions with an area of 1 cm2incubated in blood, plasma or serum volume = 2 ml in static conditions at 37°C, the studied parameters was evaluated at 30, 60 minutes of contact.

Blood counts were determined by standard methods using the following equipment: automatic hematological analyzer "Nihon Konden"; analyzer platelet aggregation "Solar" AR 2110; biochemical analyzer "Synchron 7"; immunochemical analyzer "Array"; automatic coagulometer ACL - 2000; Hematology analyzer "Kultur". Change blood counts were expressed in % of baseline values in intact samples of blood, plasma, serum, taking the values of the source is of pokazateli for 100%. Hemolysis - all designed composition did not cause hemolysis. Activation of neutrophil elastase (Fig 1.) - developed compositions do not increase the activity of ne compared with intact blood, which indicates the biocompatibility and thromboresistance. The blood in contact with the compositions (figure 2) is designed compositions do not affect the content and the ratio of protein fractions, SLO. Slightly increases the activity of plasminogen and reduced the extent of ADP-induced platelet aggregation compared with intact blood, indicating that hemocompatible samples.

2. Biocompatibility and terms of biodegradation in vivo (figure 3-10).

In experiments on small laboratory animals (rats) underwent subcutaneous implantation of polymeric compositions in the form of films based on chitosan, polyhydroxybutyrate, gelatin and polyester medical paintings based coating compositions of chitosan, chitosan+gelatin, chitosan+FCB. The follow-up period from 1 week to 3 months. After removing the animals from the experiment a sample of the implant with the surrounding tissue was fixed in formalin. Sections 4-5 microns thick were stained with hematoxylin and eosin. Evaluated the reaction of the surrounding tissue, the thickness and composition of the fibrous capsule, the degree of resorption of songs.

Figa. Composition VI is e films based on chitosan without biologically active substances after 1 week of implantation was partially fragmentirovana, observed infiltration into the capsule macrophages, fibroblasts, lymphocytes.

Figb. Chitosan composition without biologically active substances after 2 weeks of implantation is significant resorption by macrophages. The integrity of the film composition is completely broken, there are individual multinucleated giant cells of foreign body (GSKIT).

Figa. The composition in the form of films based on chitosan with biologically active substances (acetylsalicylic acid (AC), L-carnosine (K), dipyridamole (L), ciprofloxacin (C), heparin (SE)) after 1 week of implantation homogeneous, not fragmented. Around her formed connective woven capsule without infiltrate.

Figb. Film chitosan composition containing biologically active substances, such as L-carnosine (K), dipyridamole (L), ciprofloxacin (C), heparin (SE)), after 2 weeks of implantation to preserve integrity and surrounded by a thin connective-woven capsule.

All implanted film composition on the basis of chitosan time 1-2 weeks did not cause a significant inflammatory response. The introduction of the complex of biologically active substances helped minimize the inflammatory reaction, the formation of a more delicate connective-woven capsules.

Figure 5. Composition based gelatin with biologically active substances in the form of ocrite textile fabrics (term implantation 1 week). In implantirovannomu medical canvas contains a single small fragments of the coating. The pores of the fabric partly couched connective tissue, many GMTIT. The capsule consists of immature connective tissue.

6. Composition based gelatin with biologically active substances in the form of a coating textile fabrics (term implantation 2 weeks). Canvas couched connective-woven walls, visible single GMTIT. The gelatinous composition was completely resorbables.

7. Composition based on chitosan in combination with gelatin and biologically active substances in the form of a coating of woven fabric (term implantation 1 week). Medical canvas contains significant portions of the coating - chitosan-gelatin compositions. See numerous GMTIT. Connection-woven thin capsule.

Fig. Composition based on chitosan in combination with gelatin and biologically active substances in the form of a coating of woven fabric (term implantation 2 weeks). Medical fabric coated largely sprouted connective tissue, chitosan - gelatin composition is observed in very small quantities. The capsule is very thin.

Compositions based on a combination of two polymers chitosan and gelatin were bioresorbables faster than compositions based on chitosan. Inflammatory R. the action on the coating on time 1-2 weeks minimum. Capsules slim.

Fig.9. Film composition on the basis of polyhydroxybutyrate (term implantation, 3 months). Even in the period of 3 months signs of bioresorbable film composition (thickness 70 μm) based on polyhydroxybutyrate not observed. Connection-woven capsule of dense, relatively thick, Mature, contains fibroblasts and macrophages.

Figure 10. Composition based on chitosan in combination with polyhydroxybutyrate and biologically active substances in the form of a coating on a medical canvas (term implantation 2 weeks). Polymer composition was significantly resorbables, on both sides of the medical fabric formed of a thin connective-woven capsule.

The combination of polymeric compositions of chitosan with polyhydroxybutyrate significantly shortens bioresorption compared to a composition based only polyhydroxybutyrate. The introduction of biologically active substances in the composition containing polyhydroxybutyrate, can reduce the thickness of the capsule more than twice.

Thus, all the investigated compositions are biocompatible, have a minimal inflammatory response characteristic of foreign material. The faster resorption occurs at compositions on the basis of gelatin, a little slower - compositions based on chitosan, the slow - compositions on the basis of p is digidroksiprolina. Composition based on chitosan in combination with gelatin lengthens the time bioresorption compared with composition-based gelatin. Composition based on chitosan in combination with polyhydroxybutyrate exposed bioresorption faster compared to a composition based on polyhydroxybutyrate.

3. Hydrogel properties (swelling of the compositions are given in table 1.

Hydrogel properties water absorption was evaluated by the degree of equilibrium swelling compositions gravimetrically after incubation of the sample composition in physiological solution at 37°.

The equilibrium degree of swelling of the gelatin, the highest - 500-600%, compared to compositions based on chitosan - 140-170% and chitosan in combination with gelatin - 320-350%, chitosan in combination with polyhydroxybutyrate - 100-120%.

4. The amount of deposited polymer compositions of biologically active substances and their prolonged selection is summarized in table 1.

The amount deposited into the composition of biologically active substances and their desorption was determined gravimetrically and spectrophotometrically on a spectrophotometer Shimadzu UV1240 in physiological solution at 37°C.

Number of biologically active substances (BAS) in the proposed compositions are the following:

the song is based gelatin: 1-2 wt.%
for compositions based on chitosan:4-8 wt.%
for compositions based on chitosan and gelatin:4-8 wt.%
for compositions based on chitosan and polyhydroxybutyrate:4-8 wt.%

The total number of selected active substances and polymers (or their mixtures) allow to obtain polymer compositions with desired physical and mechanical properties: mechanical strength is not less than 1.2 MPa, elongation is not more than 160%, the modulus of elasticity is - 0.4 to 5 MPa. Fewer BAS compositions will not provide the desired properties of the composition biocompatibility, thromboresistance, antimicrobiol specified time bioresorption, extended and adjustable selection of BAS. A large number will not provide the specified mechanical properties (elasticity, strength, softness), the timing of hydrolytic degradation (bioresource).

Features songs based on the proposed polymers or their mixtures allow you to adjust the timing for release of the biologically active substances.

5. Terms of hydrolytic degradation in vitro is shown in table 1. Degradation of the polymer compositions was investigated in model media (sterile item is kislany saline) at 37°.

Terms of hydrolytic degradation for compositions in the form of films with a thickness of 80=±10 μm: for gelatin - 35-50 days, for chitosan - 65-75 days, chitosan+gelatin - 50-55 days, chitosan+polyhydroxybutyrate - 75-85 days.

6. Antimicrobial activity of polymer compositions are given in table 2, 11-12.

Antimicrobial activity of samples of compositions on the basis of gelatin, chitosan and polyhydroxybutyrate with biologically active substances was determined disco-diffusion method ("Methods for the determination of sensitivity to antimicrobial drugs, guidelines MUK 4.2.1890-04.). Used reference strains of 4 species of pathogenic bacteria: Streptococcus aureas, Klebsiella pneumoniae, Escherichia coli, and Enterococcus. On agar medium cultures were placed samples of size 1×1 see the Zone of growth inhibition of microorganisms (zone of lysis) were evaluated at 1, 2, 3, 5 days. Antibiotic activity was expressed in millimeters of the diameter of the zone of lysis. The zone of lysis must be at least 15 mm of the Composition on the basis of gelatin, chitosan and polyhydroxybutyrate with biologically active substances had a zone of lysis within 20-31 mm

7. Physico-mechanical properties of the compositions shown in table 1.

Deformation-strength properties of the polymer compositions were determined on a universal testing machine ZWICK/ROELL Z 2,5/TN1S software Text Expert in terms of ml is osnago stretching, the force sensor 500kn, speed tests 10 mm/min, the test was carried out at room temperature of 25°C. At a deformation curve is the expected value of the maximum strength at break, elongation (elasticity), young's modulus (soft). To obtain statistically reliable results were testing not less than 10 samples.

Selected compounds of the proposed compositions - a combination of natural polymers, cross-linking agents, biologically active substances, these quantities allow to obtain polymer compositions with desired physico-mechanical properties: tensile strength is not less than 1.2 MPa, the elongation is not more than 160%, the modulus of elasticity is - 0.4 to 5 MPa.

Obtaining the claimed compositions is illustrated by the following variants of the examples.

Example 1

Obtaining polymer compositions of gelatin, gelatin with biologically active substances (BAS):

Cook 5-10 wt.% a solution of gelatin with a molecular weight of 60-80 kDa in distilled water. The solution is heated to a temperature of 40°C. until the gelatin has dissolved.

Then the solution was poured on a substrate of polypropylene, polyethylene. The drying of the composition is carried out at a temperature not exceeding 30°C for 3-5 days. For translation in a water-insoluble state polymer compositions for treatment is up 0.05 to 0.1 wt.% solutions of cross-linking agents - glutaraldehyde or genipin at room temperature. The polymer composition is washed with distilled water to remove unreacted residue of a crosslinking agent. Control of residues linking agent in the wash water was assessed spectrophotometrically for glutaraldehyde at a wavelength of 263 nm and 321 nm; for genipin - 240 nm and 640 nm. For plastifitsirovanie polymer compositions them immersed in a solution of the plasticizer with a concentration of 7-10 wt.%. The compositions have in the form of films.

To obtain a composition of gelatin with biologically active substances cook 5-10 wt.% a solution of gelatin with a molecular weight of 60-80 kDa in distilled water. The solution is heated to a temperature of 40°C. until the gelatin has dissolved, then pour out on a substrate of polypropylene, polyethylene. The drying of the composition is carried out at a temperature not exceeding 30°C for 3-5 days. For translation in a water-insoluble state polymeric composition is treated with 0.05 to 0.1 wt.% solutions of cross-linking agent is glutaraldehyde or genipin at room temperature. The polymer composition is washed with distilled water to remove unreacted residue of a crosslinking agent (control of wash water - spectrophotometric). Introduction to polymer composition BAS - acetylsalicylic acid, GE is Arina, of dipyridamole, L-carnosine, ciprofloxacin, metronidazole was carried out by chemisorption. The polymer composition was immersed in a solution of biologically active substances with a concentration of 0.05 to 1.0 wt.%. For plastifitsirovanie polymer compositions immerse them in the solution of plasticizer concentration - 7-10 wt.%. The compositions have in the form of films. The mixture composition, physico-chemical and physico-mechanical properties of the compositions shown in table 1 (examples 1-6), medico-biological properties of the compositions are presented in table 2 and illustrated by figure 1, 2, 5,6,11,12.

Example 2

Obtaining polymer compositions of chitosan and chitosan with biologically active substances:

To obtain compositions based on chitosan prepared 2-5 wt.% a solution of chitosan with molecular weight of 200-300 kDa in 1-3 wt.% acetic acid. The solution is kept over night at room temperature for complete dissolution of chitosan, then the solution is poured on the substrate (polypropylene, glass) and dried at a temperature not exceeding 30°C for 3-5 days. Translation of chitosan compositions of the water-insoluble state is carried out by heat treatment at 95-100°C - 2-1,5 hours Then the composition is washed with 0.25 wt.% the soda solution to neutralize the residue of acetic acid, then with distilled water. For plastifitsirovanie polymer compositions them immersed in a solution of the plasticizer with concentric the her - 10-20 wt.%.

To obtain compositions based on chitosan with biologically active substances prepared 2-5 wt.% a solution of chitosan with molecular weight of 200-300 kDa in 1-3 wt.% acetic acid. The solution is kept over night at room temperature for complete dissolution of chitosan. In a ready solution of chitosan is administered biologically active substances - dipyridamole, ciprof-loxacin, L-carnosine, metronidazole. The concentration of biologically active substances in the solution of the chitosan - 4-8 wt.% from the polymer. The polymer solution with biologically active substances are thoroughly mixed until complete dissolution of biologically active substances, then poured on a substrate (polypropylene, glass) and dried at a temperature not exceeding 30°C for 3-5 days. Translation of chitosan compositions of the water-insoluble state is carried out by heat treatment at 95-100°C - 2-1,5 hours Then the composition is washed with 0.25 wt.% the soda solution to neutralize the residue of acetic acid, then with distilled water. By chemisorption additionally, the composition is administered heparin and a plasticizer, for which the polymer composition is immersed in a heparin solution with a concentration of 50-100 IU/ml and plasticizer is glycerol concentration of 10-20 wt.%. The compositions have in the form of films.

The mixture composition, physico-chemical and physico-mechanical properties of the compositions, not only the us in table 1 (examples 7-9), biomedical properties of the compositions are presented in table 2 and illustrated by figure 1-4, 11, 12.

Example 3

Obtaining polymer compositions of chitosan and gelatin and biologically active substances:

Prepare a solution: 2-5 wt.% a solution of chitosan with molecular weight of 200-300 kDa in 1-3 wt.% acetic acid (as in option 2), it adds a gelatin with a molecular weight of 60-80 kDa, at least 20 wt.% by weight of chitosan. The solution is heated to a temperature of 40°C for 1-2 hours and then put aside for a day at room temperature until complete dissolution of the polymers, and then thoroughly stirred with a magnetic stirrer. In a ready solution of chitosan and gelatin introduce biologically active substances - dipyridamole, ciprofloxacin, L-carnosine, metronidazole. The concentration of biologically active substances - 4-8 wt.% from the polymer. The polymer solution with biologically active substances are thoroughly mixed until complete dissolution of biologically active substances, then poured on a substrate (polypropylene, polyethylene) and dried at a temperature not exceeding 30°C for 3-5 days. Translation of the compositions in water-insoluble state is carried out by heat treatment at 95-100°C - 2-1,5 hours Then the composition is washed with 0.25 wt.% the soda solution to neutralize the residue of acetic acid, then with distilled water. By chemisorption Supplement is Ino the composition is administered heparin and a plasticizer, to which the polymer composition is immersed in a heparin solution with a concentration of 50-100 IU/ml and plasticizer is glycerol concentration of 10-20 wt.%. The compositions have in the form of films. The mixture composition, physico-chemical and physico-mechanical properties of the compositions shown in table 1 (examples 10, 11), medico-biological properties of the compositions are presented in table 2 and illustrated by figure 1, 2, 7, 8, 11, 12.

Example 4

Obtaining polymer compositions of chitosan with poly-3-hydroxybutyrate and biologically active substances:

Prepare 2-5 wt.% a solution of chitosan with biologically active substances (as in option 2). Prepare 0.5 to 1.5 wt.% a solution of poly-3-hydroxybutyrate with a molecular weight of 300-600 kDa in chloroform, mix thoroughly with a magnetic stirrer until complete homogenization, it is administered biologically active substance dipyridamole, ciprofloxacin, L-carnosine in the number of 4-8 wt.% from polymers, thoroughly mixed with a magnetic stirrer. Solutions of chitosan and poly-3-hydroxybutyrate are mixed and then thoroughly stirred with a magnetic stirrer to obtain a stable emulsion. Then pour on a substrate (polypropylene, glass) and dried at a temperature not exceeding 30°C for 3-5 days. Translation of the compositions in water-insoluble state is carried out by heat treatment at 95-100° - 2-1,5 hours and Then the composition was washed with 0.25 m is S.% solution of soda and water to neutralize the residue of acetic acid. By chemisorption additionally, the composition is administered heparin and a plasticizer, for which the polymer composition is immersed in a heparin solution with a concentration of 50-100 IU/ml and plasticizer is glycerol concentration is 10-20 wt.%.

The compositions have films

The mixture composition, physico-chemical and physico-mechanical properties of the compositions shown in table 1 (examples 12, 13), medico-biological properties of the compositions are presented in table 2 and illustrated by figure 1, 2, 10-12.

Option 5

Obtaining polymer compositions based on chitosan and gelatin with biologically active substances as coatings for medical textile fabrics.

Prepare a solution: 2-5 wt.% a solution of chitosan with molecular weight of 200-300 kDa in 1-3 wt.% acetic acid, add gelatin with a molecular weight of 60-80 kDa, at least 20 wt.% by weight of chitosan (as in option 3). The solution is heated to a temperature of 40°C for 1-2 hours and then put aside for a day at room temperature until complete dissolution of the polymers, and then thoroughly stirred with a magnetic stirrer. In a ready solution of chitosan and gelatin introduce biologically active substances - dipyridamole, ciprofloxacin, L-carnosine, metronidazole. The concentration of biologically active substances - 4-8 wt.% from the polymer. The solution of polymer with a biologically active substance is matalino stirred until complete dissolution of biologically active substances, then applied on a polyester medical cloth and dried at a temperature not above 30°C during the day. The translation of the composition in the form of a coating in a water-insoluble state is carried out by heat treatment at 95-100°C for 1 h Then washed with 0.25 wt.% the soda solution to neutralize the residue of acetic acid, then with distilled water. By chemisorption additionally, the coating is injected heparin and a plasticizer, for which the cloth is coated is dipped in the heparin solution with a concentration of 50-100 IU/ml and plasticizer is glycerol concentration of 10-20 wt.%.

The compositions have in the form of a coating on a medical textile canvas.

The composition in the form of a coating:

the total number of polymers - 2-5 wt.%,

the total number of biologically active substances (BAS) - 4-8 wt.% from polymers

the coating thickness of 50±10 μm,

the duration of excretion of BAS 40 days,

the term hydrolytic degradation of the composition in the form of a coating - 45 days.

Biomedical properties of the compositions illustrated in Fig.7, 8, 12.

Thus, the combination of selected natural polymers and a combination of selected biologically active substances to obtain a bioresorbable polymer compositions allowed to obtain compositions with specified medical-biological, physico-chemical and physico-mechanical properties of the I.

The proposed compositions are:

- biocompatible,

- thromboresistance,

- with hydrogel properties

- with set deadlines bioresorption,

- slow and controlled allocation of BAS,

with the advanced complex of biologically active substances: antioxidants, anticoagulants, antiplatelet agents, anti-microbial, anti-adhesive and anti-inflammatory drugs,

with the optimum mechanical properties (elasticity, strength, softness).

Declare bioresorbable hydrogel polymer compositions with biologically active substances are:

for coating implantable devices and devices intended to come into contact with blood (cuff for artificial heart valves, cardiac patches, artificial blood vessels and other);

for use as a biophysical barrier to prevent adhesive processes after surgical intervention;

- to create systems with controlled release of biologically active and medicinal substances.

Table 1
COMPOSITION, PHYSICO-CHEMICAL AND PHYSICO-MECHANICAL properties of the COMPOSITIONS
№ p/p The COMPOSITIONPHYSICO-CHEMICAL PROPERTIESPHYSICO-MECHANICAL PROPERTIES
The composition of the polymer baseBASThe total amount of polymer wt. %The total number of BAS, Mas. % (relative to polymer)Thickness, micronsThe equilibrium degree of swelling, %The duration of the allocation, the BAD, the dayThe time of destruction, daysStrength, MPaElongation, %The modulus of elasticity, MPa
HeparinL-carnosineDipyridamoleAcetylsalicylic theCiprofloxacinMetronidazol
1Gelatin----- -5-10-80±10500-501,41000,6
2Gelatin++-+-+1,080±1055025451,41000,6
3Gelatin+++--+1,580±1055030401,51050,5
4Gelatin+ +-++-1,180±1055025351,3850,7
5Gelatin+++-+-1,280±1055030351.3900,6
6Gelatin+++++-2,080±1060030351,71200,5
Chitosan------2-5-80±10170-754,0604,0
8Chitosan+++-+-8,080±1014050652,8753,0
9Chitosan+++--+6,080±1017050 652,5753,0
10Chitosan + Gelatin (80:20)------2-5-80±10350-553,51002,0
11Chitosan + Gelatin (80:20)+++-+-8,080±1032040502,41101,5
12Chitosan + FCB (70:30)----- -2-5-80±10100-856,0505,0
13Chitosan + FCB (70:30)+++-+-8,080±1012070755,060the 3.8

Chitosan + FCB + BAS
Table 2
ANTIMICROBIAL ACTIVITY of POLYMER COMPOSITIONS WITH BIOLOGICALLY ACTIVE SUBSTANCES (BAS)
Type of microorganismZones of growth inhibition of microorganisms mm
Gelatin + BASChitosan + BASChitosan + Gelatin + BASThe control gelatin composition without BAS
1 day2nd dayThe day 35 days1 day2nd dayThe day 35 days1 day2nd dayThe day 35 days1 day2nd dayThe day 35 days1-5 day
Enterococcus232222202725242225232220252322200
Staphylococcus aureas22 2221212626252524242323232323230
Klebsiella pneumoniae252524243131303024242323262625240
Escherichia coli2626252427272524252524 24232322220

1. Bioresorbable hydrogel polymer composition for cardiovascular surgery in the form of a film obtained by the interaction of natural polymers, biologically active substances, solvent and plasticizer, characterized in that the crosslinked polymers are used bioresorbable polymers are gelatin, chitosan, or a mixture of the chitosan and gelatin, chitosan and polyhydroxybutyrate, as biologically active substances or their mixtures are used antioxidant L-carnosine, anticoagulant - heparin, anti-platelet agent - dipyridamole, acetylsalicylic acid, nonsteroidal anti-inflammatory agent is acetylsalicylic acid, antimicrobial drugs - ciprofloxacin, metronidazole, while the mechanical strength of the film is not less than 1.2 MPa, the elongation is not more than 160%, the modulus of elasticity is - 0.4 to 5 MPa.

2. The composition according to claim 1, characterized in that the joint use of chitosan and gelatin gelatin in the composition should be at least 20%, of biologically active substances 4-8 wt.%.

3. The composition according to claim 1, characterized in that the joint use of chitosan and polyhydroxybutyrate polyhydroxybutyrate in the composition should be no b is over 30%, biologically active substances 4-8 wt.%.

4. The composition according to claim 1, characterized in that the number of biologically active substances in the composition based on the gelatin is 1-2 wt.%.

5. The composition according to claim 1, characterized in that the number of biologically active substances in the composition based on chitosan is 4-8 wt.%.

6. The composition according to claim 1, characterized in that the crosslinking polymer - gelatin use natural cross-linking agent from the class of glycosides genipin.

7. The composition according to claim 1, characterized in that the crosslinking polymer is chitosan, chitosan and gelatin, chitosan with polyhydroxybutyrate use heat treatment.



 

Same patents:

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FIELD: medicine.

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FIELD: medicine.

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FIELD: medicine.

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36 cl, 1 tbl, 5 ex, 2 dwg

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FIELD: medicine.

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EFFECT: group of inventions allows making the blood compatible irregular products made of polytetrafluorethylene.

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FIELD: medicine.

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EFFECT: use of the invention enables forming a coating with antiseptic and service effective properties on the surface of the devices made of organosilicon polymers of molecular weight 2·105-6·105.

2 cl, 3 ex

FIELD: medicine.

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2 cl, 1 ex

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