RU2429022C1 - Method of producing chitosan-based films for medical purposes (versions) - Google Patents

Abstract

FIELD: chemistry. ^ SUBSTANCE: described is a method of producing chitosan-based films, involving preparation of a moulding solution from an air-dried weighed portion of chitosan and a solution of organic acid, depositing the obtained solution onto a substrate and then holding the solution on the substrate until obtaining a film structure, wherein the moulding solution contains chitosan in form a salt of acetic or amber acid. After holding, the film structure is treated water vapour or vapour of 0.5 N hydrochloric acid solution until achieving film swelling index of 70-190%. The elongation at rupture of the film is not less than 20%. Described also is a method in which the film is put into distilled water or a physiological solution (0.9% NaCl) until achieving film swelling index of not less than 90%. The elongation at rupture of the film is not less than 30%. ^ EFFECT: highly elastic, non-toxic, biocompatible and biodegradable film made from chitosan, having curative effect when healing various wounds, during mechanical or thermal tissue injury in animals or humans. ^ 2 cl, 10 tbl, 77 ex

Description

The group of inventions relates to chemical and biochemical technology, in particular to methods for producing highly elastic films and film materials based on chitosan, and can be used in medicine, pharmacology, biology, research practice, as well as in the cosmetic and food industries.

Currently, one of the relevant areas of combustiology is the creation of effective applications for wounds and burns. From the whole variety of wound coverings, according to literature and patent data, the following forms are distinguished for this purpose: sponges, gel-forming film coatings from biocompatible natural, artificial and synthetic polymers, as well as their compositions.

A modern wound cover must meet a number of requirements and, therefore, have the desired physicochemical and biological properties satisfying it: therapeutic, protective, sorption, transport and technological. In addition, it should be transparent, sufficiently strong and elastic, resistant to sterilization, convenient to use for the patient and medical staff, as well as biodegradable [Shapovalov SG Modern wound coverings in combustiology // FAR Mindeks-Practician. 2008. No8. S.38-46].

It is known that the chitosan copolymer (ChTZ) is obtained from the chitin biopolymer, which is part of the shell crustacean shell, squid skeletal plate, micellar and higher fungi biomass. This animal polysaccharide combines a wide range of physicochemical and biological properties. Chitosan is non-toxic, biocompatible with tissues of living organisms, has biocidal properties, is a highly effective sorbent, complexing agent, a promising base for sponges, gels, films with valuable properties [Chitin and chitosan: Production, properties and application / Under. ed. Skryabin K.G., Vikhoreva G.A., Varlamova V.P. M .: Science. 2002. 368 p.]. An important feature of chitosan is the preservation, and in some cases, the improvement of these useful qualities in solutions, gels, films.

In recent years, preparations based on chitosan and its compositions with other polymers are used in powdered form in regenerative medicine [RF Patent No. 2086247; Alekseev A.A., Feofilova E.P., Tereshina V.M., Memorskaya A.S., Evtushenkova V.P., Ivanovskaya A.G. Mikoran - a new drug for the treatment of burns // Combustiology. 2002. No4. ] and gel-like dermatoprotective agents [RF Patent No. 2258515, Application for invention of the Russian Federation No. 2003103087], perforated film coatings for treating wounds [RF Patent No. 2219954], biological compositions [RF Patent No. 2108114], hydrogel dressings [RF Patent No. 2270646] and etc.

, степени деацетилирования СД полимера), состава формовочного раствора и др. Так, величины разрывного напряжения (σ) и относительного удлинения при разрыве (ε) чувствительны к изменению

[Федосеева Е.Н., Алексеева М.Ф., Смирнова А.Л. // Вестник Нижегородск. ун-та. 2008. №5. С.58-62; Федосеева Е.Н., Алексеева М.Ф., Нистратов В.П., Смирнова А.Л. // Заводская лаборатория. Диагностика материалов. 2009. Т.75. №7. С.42-46]. При этом пленки из всего ряда исследуемых образцов являются хрупкими, что затрудняет их применение в регенеративной медицине и снижает лечебный эффект.It is known that the deformation-strength properties of chitosan films and film materials based on it depend on molecular characteristics (molecular weight

, the degree of deacetylation of the DM polymer), the composition of the molding solution, etc. Thus, the values of tensile stress (σ) and elongation at break (ε) are sensitive to changes

[Fedoseeva E.N., Alekseeva M.F., Smirnova A.L. // Bulletin of Nizhny Novgorod. un-that. 2008. No5. S.58-62; Fedoseeva E.N., Alekseeva M.F., Nistratov V.P., Smirnova A.L. // Factory laboratory. Diagnostics of materials. 2009.V. 75. Number 7. S.42-46]. At the same time, films from the entire range of the studied samples are fragile, which complicates their use in regenerative medicine and reduces the therapeutic effect.

An increase in the concentration of chitosan in the film-forming solution (at a fixed (2%) concentration of acetic acid in the solvent) also leads to a decrease in σ and little effect on ε [Illarionova E.L., Kalinina T.N., Chufarovskaya T.I. and others // Chem. fiber. 1995. No. 6. S.18-22]. The authors of the same work, unlike other authors, found that the nature of the substrate has little effect on these properties of the films.

Hardening of films of chitosan from organic acids by 35-45% was observed as a result of their thermal modification at 120 ° C for 3 hours. Moreover, the tensile elongation changed slightly and did not exceed 10% [Zotkin MA, Vikhoreva GA, Kechekyan A.S. // High. conn. B. 2004.V. 46. No. 2. S. Z59-363; Zotkin M.A., Vikhoreva G.A., Albulov A.I. et al. // Sat. doc. int. Symposium “Composites of the 21st Century”. Saratov: Publishing House of Saratov. state tech. un-that. 2004. S.172-175].

In this regard, new approaches to the creation of modern therapeutic highly elastic films from chitosan are relevant.

The solution to this problem is carried out in different ways.

It is known that improving the mechanical properties of chitosan films can be achieved by introducing a second polymer. For example, the highest values of strength (σ = 1.2 N / cm ² ) and elongation at break (ε = 30%) were observed for films from a mixture of chitosan and polyethylene oxide in a component ratio of 80:20 wt.%, Respectively [V. Alekseev ., Kelberg E.A., Bronikov SV. etc. \\ High Molecule. conn. B. 2001.V. 43. No. 10. S.1856-1860].

To improve the physicomechanical properties of films based on chitosan or water-soluble derivatives of chitosan, polyvinyl alcohol was used [G. Gabrielyan, A. Chernukhina. // Sat doc. int. symp "Composites of the XXI century." Saratov: Publishing House of Saratov. state tech. un-that. 2004. S.145-147; Kulish E.N., Chernova V.V., Kolesov SV. // Bulletin of Bashkirsk. un-that. 2007.V. 12. Number 3. S.23-25; Nikolaev A.F., Prokopov A.A., Shulgina E.S. et al. // Plastich. masses. 1987. No. 11. S.40-41].

In addition, polyacrylonitrile was used for this purpose [Sidorovich A.V., Sazanov Yu.N., Praslova O.E. et al. // Journal. butt, chemistry. 2006.V. 79. Number 8. S.1341-1344].

Improved physical and mechanical properties (σ = 42.1 MN / m ² , ε = 70%) were observed for films of grafted copolymers of chitosan and vinylpyrrolidone (chitosan-vinylpyrrolidone) of different compositions compared to films of pure chitosan [Mochalova A.E. Synthesis and properties of grafted block copolymers and mixtures of homopolymers of N-vinylpyrrolidone and acrylamide with chitosan. Abstract. thesis for a job. student Art. Cand. Chem. sciences. 2006.29 p.].

Thus, to date, the problem of manufacturing highly elastic films of chitosan has not been sufficiently solved, which affects the quality of treatment and limits the use of film materials in medical practice.

A known method of producing a dressing agent consisting of a polymer film with a layer of polymer hydrogel deposited on its surface [RF Patent No. 2270646]. The polymer film is made of a biocompatible optically transparent polymer (polyethylene terephthalate, carboxymethyl cellulose, polyimide, polycarbonate) with through holes with a diameter of D = 0.01-3.0 μm and the number of holes N = 10 ³ -10 ⁹ pcs / cm ² . As a polymer hydrogel, a hydrogel based on chitosan with a concentration of C _xtz = 1-25 wt.% _{Is used} . The hydrogel is obtained by mixing an aqueous solution of chitosan and a polyhydric alcohol or a mixture of polyhydric alcohols (C = 20-50 wt.%). In addition, the hydrogel can be multicomponent and include not only chitosan, but also polyvinylpyrrolidone (C = 5-50 wt.%), Gelatin or collagen (C = 1-20 wt.%), As well as antiseptics, antibiotics, antioxidants, etc. .

The disadvantage of this method is the multi-stage production of dressings, its multicomponent and high cost. The goal - improving the elastic properties of the dressing - was not set.

Known dressing for the treatment of wounds in the form of a film with perforation, which includes chitosan in the form of a salt of acetic, succinic or glycolic acid, glutaraldehyde, dietary supplement and polyvinyl alcohol [RF Patent No. 2219954].

A disadvantage of the known solution is the complex composition of the dressing, the inclusion of toxic glutaraldehyde, low elastic properties due to the increased crosslinking between glutaraldehyde, chitosan and polyvinyl alcohol.

A known method for producing a medical dressing containing cellulose, chitosan and a complex of enzymes from hepatopancreas crab [RF Patent No. 2323748]. The method involves the interaction of modified cellulose with proteolytic enzymes in an aqueous buffer solution. In this case, partially oxidized cellulose with an aldehyde group content of 0.01-2.5 mgEq / g is used as modified cellulose, the reaction is carried out at pH = 5.0-8.5, temperature 15-25 ° C for 0.5-1.0 hours at an initial concentration of the complex 0.1-0.5 mg / ml and bath module 7-10. As a result of applying this method, a medical dressing is made of chemically modified cellulose with enzymes and with immobilized chitosan.

The disadvantage of this method is its high sensitivity to temperature and concentration conditions, the pH of the medium and the high cost of medical dressings. The goal - obtaining an elastic bandage - was not set.

The closest solution to the proposed method is a method for producing chitosan films, including evaporation of the solvent from 1-5% by weight of acetic acid polymer solutions deposited on a polyethylene substrate at room temperature for 2-3 days [Ageev EP , Vikhoreva G.A., Matushkina N.N. and others // Vysokomol. conn. A. 2000.V. 42. No. 2. S.333-339]. To prepare the molding solution, a portion of air-dry chitosan is poured with a solution of acetic acid with a concentration of C _to = 1-90% and left for a day, periodically shaking. To transfer the film from the salt (C-) form to the base (O-) form, it is treated with sodium hydroxide solution for 24 hours, washed with distilled water until neutral and dried at room temperature on a polyethylene substrate in a fixed state.

и СД=83 мольн.% и времени набухания пленок 15 суток). Существенным недостатком способа является дополнительное высушивание пленок в O-форме при их закреплении, что приводит к ухудшению эластических свойств.The disadvantage of this method is the use of an aggressive solvent (concentrations of acetic acid close to glacial acetic acid), the duration (24 hours) of the process of transferring the film from C- to O-form. In addition, an increase in the concentration of acetic acid in molding solutions from 1 to 90%, as well as the degree of swelling of the films (140-630 wt.%) In the vapor of a solution of acetic acid of a fixed concentration, leads to a decrease in σ and practically does not affect ε (for films from a sample with a molecular weight

and SD = 83 mol.% and the swelling time of the films 15 days). A significant disadvantage of this method is the additional drying of the films in the O-form when they are fixed, which leads to a deterioration in elastic properties.

The objective of the proposed solution is to increase the elasticity of the films and simplify the technology for their manufacture.

The problem is solved in that in a method for producing a medical film based on chitosan, comprising preparing a molding solution from an air-dry sample of chitosan and an organic acid solution, applying the resulting solution to a substrate, followed by keeping the solution on the substrate until the film structure is reached, while forming the solution includes chitosan in the form of a salt of acetic or succinic acid, according to the technical solution, after aging, the film structure is treated with water vapor and whether an aqueous solution of 0.5 N hydrochloric acid to a degree of film swelling of 70-190%, while providing a value of the relative elongation of the film at break not less than 20%. A method variant is also claimed, including preparing a molding solution from an air-dry sample of chitosan and an organic acid solution, applying the resulting solution to a substrate, followed by maintaining the solution on a substrate until a film structure is achieved, the molding solution comprising chitosan in the form of an acetic or succinic acid salt, processing the obtained film with an alkaline reagent for 1 hour, followed by washing with distilled water until a neutral pH is achieved, according to the technical mu after washing solution film is placed in distilled water or saline (0.9% NaCl) to a degree of swelling of the film is not less than 90%, thus providing an elongation at break of the film is not less than 30%. Both methods are also characterized in that in the preparation of the molding solution, chitosan with a molecular weight of 80-700 kDa is used, and to obtain a film with a thickness of 50-70 μm, the molding solution is applied to the substrate in a volume of 0.20-0.25 ml / cm ² .

The method is as follows.

1. Preparation of the molding solution. An air-dry sample of chitosan is dissolved in acetic or succinic acid for 1 day, periodically shaking. To homogenize the solution at the last stage, use stirring on a magnetic stirrer.

2. Obtaining a film. The resulting molding solution is transferred to an inert plastic substrate and the solvent is evaporated at room temperature (T≅22 ± 2 ° C) and normal atmospheric pressure for 2-3 days. The complete evaporation of the solvent is fixed visually by detaching the finished film from the substrate. The polymer in the freshly formed films is in salt (C-) form.

3. Chemical modification of the polymer. To transfer the polymer from the C-form to the main (O-) form, the chitosan films are kept in a solution of triethanolamine or sodium hydroxide (C _NaOH = 1 H) for 1 hour (bath modulus 1:10). Then the films in the O-form are washed with distilled water to a neutral pH = 7.0-7.5.

4. Physicochemical modification of chitosan films in C-form. The films are treated with water vapor or an aqueous solution of hydrochloric acid (С _к = 0.5 H) in a hermetically sealed vessel, 1/25 part filled with liquid sorbate, at T≅22 ± 2 ° C and normal atmospheric pressure.

5. Physicochemical modification of chitosan films in O-form. Films are kept in a liquid medium - distilled water or isotonic solution (0.9% NaCl).

The swelling process was characterized by the degree of sorption (C _s , wt.%), Which was calculated by the formula: C _c = (mm ₀ ) · 100% / m ₀ , where m and m ₀ are the masses of dry and swollen ChTZ films, respectively.

The film thickness (d) was measured with a micrometer with a division value of 10 μm. The measurements were carried out several times in different parts of the film, then the average thickness was calculated. It was experimentally established that the molecular weight of the chitosan samples did not significantly affect the film thickness (Table 1).

Table 1

СД=80.8 мольн.%The thickness of the films of chitosan in the C - and O-forms obtained from different acids. Chitosan Characteristic:

SD = 80.8 mol% Chitosan Solvent for Film The chemical form of chitosan in the film Alkaline reagent Film thickness d, microns Name of acid The concentration of acid With _to , wt.% Vinegar 2 C - 50-60 O Sodium hydroxide 105-115 O Triethanolamine 90-105 Amber 1.5 C - 60-70 O Sodium hydroxide 120-130 0 Triethanolamine 100-110

The elastic-plastic properties of chitosan films were determined according to GOST No. 14236-81 [Polymer films. Tensile test method] on a Tira Test 28005 uniaxial tensile tensile testing machine with a load cell of 100 H. The breaking load and elongation were determined at break. Breaking stress (σ) was determined taking into account the cross-sectional area of the sample taken for testing, and expressed in MPa. The elongation at break (ε) was calculated taking into account the initial length of the film sample taken for testing, and expressed as a percentage.

, СД=83.6 мольн.% (табл.2).Examples 1, 2. Obtaining films of chitosan in salt form from solutions of different carboxylic acids on the example of sample c

, SD = 83.6 mol.% (Table 2).

The values of elongation at break (ε) and tensile stress (σ) are the arithmetic mean of 3 parallel measurements.

table 2

, СД=83.6 мольн.%Physico-mechanical characteristics of C-form chitosan films obtained from 2% polymer solutions in acetic and succinic acids. Chitosan Characteristic:

, SD = 83.6 mol.% Example No. Name of acid The concentration of acid With _to , wt.% Film thickness d, microns Breaking stress σ, MPa Elongation at break ε,% one Vinegar 2 fifty 53.4 1.4 2 Amber 1.5 70 37.6 3.7

Example 1. A portion of chitosan 2 g is dissolved in 100 ml of a 2% solution of acetic acid. 20 ml of the obtained molding solution is transferred to a polyethylene substrate and the solvent is evaporated for 2-3 days at room temperature under static conditions. The formed film sample is subjected to uniaxial tension on a tensile testing machine. The elongation was ε = 1.4% at a breaking stress of σ = 53.4 MPa.

Example 2 is carried out analogously to example 1. Instead of acetic acid, succinic acid is used. The elongation was ε = 3.7% at a breaking stress of σ = 37.6 mPa.

From table 2 it is seen that the films of chitosan obtained from a solution of acetic or succinic acid are characterized by low elasticity.

, СД=83 мольн.% (табл.3).The group of examples 3-11. Reproducibility of the elastic-plastic characteristics of C-form chitosan films before and after treatment with water vapor and a vapor of a medium formed by a 0.5 N hydrochloric acid solution, using as an example a sample with

, SD = 83 mol.% (Table 3).

Table 3

, СД=83 мольн.%Elastic-plastic characteristics of C-form chitosan films obtained from 2% polymer solutions in 2% acetic acid, before and after treatment with water and hydrochloric acid vapors. Chitosan Characteristic:

, SD = 83 mol.% Example No. Sorption medium Sorption degree _C, wt.% Breaking stress σ, MPa Elongation at break ε,% 3 - - 78.5 15.1 four 110 12.0 66.4 5 H ₂ O 107 14.5 60.6 6 111 16.5 69.2 7 120 12.1 61.0 8 70 10.7 57.1 9 HCl + H ₂ O 70 12.0 56.9 10 (C _to = 0.5 N) 70 12.2 51.3 eleven 72 11.8 63.8

, СД=83 мольн.%.Example 3 is performed analogously to example 1 using a film of chitosan with

, SD = 83 mol.%.

Example 4. A film of chitosan is obtained analogously to example 3. The resulting film is kept in water vapor to a degree of sorption With _c = 110 wt.%. The formed film sample in the C-form is subjected to uniaxial tension on a tensile testing machine. The elongation was ε = 66.4% at a breaking stress σ = 12 MPa.

Examples 5-7 are performed analogously to example 4.

Example 8 was performed analogously to example 4, but the film was kept in pairs of a solution of 0.5 N hydrochloric acid to a sorption degree of C _c = 70 wt.%. The elongation was ε = 57.1% at a tensile stress of σ = 10.7 mPa.

Examples 9-11 are performed analogously to example 8.

From table 3 follows a good reproducibility of the physico-mechanical parameters ε and σ of film samples after treatment with water vapor and an aqueous acid solution.

, СД=80.8 мольн.%. (табл.4).Group of examples 12-23. Influence of the degree of sorption by films of chitosan in the C-form of water vapor and the vapor of a medium formed by a 0.5 H hydrochloric acid solution on the elastic-plastic properties of films on the example of a sample with

, SD = 80.8 mol%. (table 4).

Table 4

, СД=80.8 мольн.%Elastic-plastic characteristics of C-form chitosan films obtained from 2% polymer solutions in 2% acetic acid before and during treatment with water and hydrochloric acid vapors. Chitosan Characteristic:

, SD = 80.8 mol.% Example No. Sorption medium Sorption degree _C, wt.% Breaking stress σ, MPa Elongation at break ε,% 12 - - 47.0 14.8 13 70 10.9 25.7 fourteen 70 9.5 26.0 fifteen H ₂ O 99 12.0 46.7 16 150 6.3 50.8 17 161 2.9 68.6 eighteen 64 10.7 41.8 19 70 13.5 52.4 twenty HCl + H ₂ O 81 10.2 39.0 21 (C _to = 0.5 H) 97 9.6 40.8 22 174 1.2 78.8 23 179 0.75 91.6

, СД=80.8 мольн.%.Example 12 is performed analogously to example 1, the difference was in the use of chitosan with

, SD = 80.8 mol%.

Examples 13-23. A chitosan film is obtained analogously to example 12. Examples 13-17 are made similarly to examples 4-7, examples 18-23 are made similarly to examples 8-11.

It follows from the Table 4 that the increase in the degree of sorption of C _with chitosan films to water vapor and vapors 160% aqueous acidic medium to about 180% increases the elasticity of the film samples. Further aging of the films in sorbate vapors is impractical because it leads to gel formation and dissolution.

, СД=83.6 мольн.% (табл.5).A group of examples 24-33. Influence of the degree of sorption by chitosan films in the C-form of water vapor and the vapor of a medium formed by a 0.5 N hydrochloric acid solution on the elastoplastic properties of the films by the example of a sample with

, SD = 83.6 mol.% (Table 5).

Table 5

, СД=83.6 мольн.%The elastic-plastic characteristics of C-form chitosan films obtained from 2% polymer solutions in 2% acetic acid before and during treatment with water and hydrochloric acid vapors. Chitosan Characteristic:

, SD = 83.6 mol.% Example No. Sorption medium Sorption degree _C, wt.% Breaking stress σ, MPa Elongation at break ε,% 24 - 55.7 1.6 25 74 8 24.8 26 80 8.8 27.9 27 H ₂ O 99 8.75 25.9 28 117 4.4 28.7 29th 185 1.6 30.7 thirty 26 9.7 42.9 31 HCl + H ₂ O 84 9.5 23.4 32 (C _to = 0.5 H) 114 10.3 30.4 33 130 11.5 38.0

Example 24 is performed analogously to example 1.

Examples 25-33. A chitosan film is obtained analogously to example 24. Examples 25-29 are made similarly to examples 13-17, examples 30-33 are made similarly to examples 18-23.

It follows from Table 5 that the increase in the degree of sorption of C _with chitosan films to water vapor and vapors 190% aqueous acidic medium to 130% increases the elasticity of the film samples. Further aging of the films in sorbate vapors is impractical because it leads to gel formation and dissolution.

хитозана на упругопластические характеристики пленочных образцов, полученных из растворов полимера в 2%-ной уксусной кислоте и подвергнутых физико-химической модификации в парах дистиллированной воды и в парах среды, образованной 0.5 H раствором соляной кислоты (табл.6).The group of examples 34-41. The influence of molecular weight

chitosan on the elastoplastic characteristics of film samples obtained from polymer solutions in 2% acetic acid and subjected to physico-chemical modification in vapors of distilled water and in vapors of a medium formed by a 0.5 H hydrochloric acid solution (Table 6).

Table 6 Elastic-plastic characteristics of modified C-form chitosan films obtained from 2% polymer solutions in 2% acetic acid after treatment with water and hydrochloric acid vapors to the degree of C vapor absorption _with ≈100 wt.% Example No.

, кДаMolecular weight of chitosan

kDa Sorption medium Breaking stress σ, MPa Elongation at break ε,% 34 640 H ₂ O 14.3 64.3 35 HCl + H ₂ O 12.0 57.3 36 480 H ₂ O 6.6 57.4 37 HCl + H ₂ O 11.5 53.1 38 270 H ₂ O 12.0 46.7 39 HCl + H ₂ O 9.6 40.8 40 87 H ₂ O 8.8 25.9 41 HCl + H ₂ O 10.3 30.4

Example 34. A film of chitosan is obtained analogously to example 3. The resulting film is kept in vapors of distilled water to a degree of sorption C _with ≈100 wt.%. The formed film sample is subjected to uniaxial tension on a tensile testing machine. The elongation was ε = 64.3% at a breaking stress σ = 14.3 MPa.

Example 35 was carried out analogously to example 34. The difference was in the use of a HCl + H ₂ O vapor medium. The elongation was ε = 57.3% at a breaking stress σ = 12.0 MPa.

образца хитозана.Examples 36-41. Examples 36, 38, 40 were carried out analogously to example 34, examples 37, 39, 41 were carried out analogously to example 35. The difference was the change

sample of chitosan.

According to Table 6, film samples obtained from high molecular weight samples have higher elasticity, regardless of the vapor medium.

, СД=83 мольн.% (табл.7).Group of examples 42-44. The effect of water vapor and water-acid medium vapor on the physicomechanical characteristics of chitosan succinate films by the example of sample c

, SD = 83 mol.% (Table 7).

Table 7

, СД=83 мольн.%Physico-mechanical characteristics of C-form chitosan films obtained from 2% polymer solutions in 1.5% succinic acid, before and after treatment with water and hydrochloric acid vapors. Chitosan Characteristic:

, SD = 83 mol.% Example No. Sorption medium Sorption degree _C, wt.% Breaking stress σ, MPa Elongation at break ε,% 42 - - 106 6.8 43 H ₂ O 104 0.65 60.6 44 HCl + H ₂ O 108 0.22 56.5

Example 42 is performed analogously to example 3. Example 43 is performed analogously to example 4 to achieve a degree of sorption With _c = 104 wt.%. Example 44 is carried out analogously to example 8 to achieve With _c = 108 wt.%. The difference between Examples 42-44 from Examples 3, 4, 8 was that 1.5% succinic acid was used as the solvent of chitosan.

According to Table 7, films from chitosan succinate treated with water vapor or with a pair of aqueous acidic medium are highly elastic. The elongation at break of the modified films is ~ 10 times higher than the value of e of the original film.

The group of examples 45-53. The effect of chemical modification of chitosan under the influence of an alkaline reagent on the mechanical properties of the films (Table 8).

Table 8 Physico-mechanical characteristics of modified O-form chitosan films obtained from 2% polymer solutions in carboxylic acids Example No. Carbolic acid

, кДа

kDa Alkaline reagent Sorption liquid _C, wt.% Characteristics σ, MPa ε,% 45 Acetic, C _to = 2% 480 Triethanolamine H ₂ O 96 2.65 34.5 46 NaOH H ₂ O 94 0.95 50.8 47 280 Triethanolamine H ₂ O 97 3.7 52.4 48 NaOH H ₂ O 102 2.25 28.1 49 87 Triethanolamine H ₂ O 93 1.87 22.3 fifty NaOH H ₂ O 114 3.45 44.6 51 NaOH NaCl + H ₂ O 185 5.3 120 52 Amber, C _to = 1.5% 640 NaOH H ₂ O 179 2.5 one hundred 53 87 NaOH NaCl + H ₂ O 180 2.2 58.5

, СД=79.1 мольн.%. Пленку ацетата хитозана в C-форме выдерживают в растворе триэтаноламина (модуль ванны 1:10) в течение 1 ч. Модифицированную пленку в O-форме промывают дистиллированной водой до pH=7.0-7.5 и помещают в дистиллированную воду на 10 мин. Степень сорбции С_с=96%, разрывное напряжение σ=2.65 мПа, относительное удлинение при разрыве ε=34.5%.Example 45. A film of chitosan is obtained analogously to example 1 using a polymer with

, SD = 79.1 mol.%. A film of chitosan acetate in the C form is kept in a solution of triethanolamine (bath modulus 1:10) for 1 h. The modified film in the O form is washed with distilled water to pH = 7.0-7.5 and placed in distilled water for 10 min. The degree of sorption С _с = 96%, the breaking stress σ = 2.65 MPa, the elongation at break ε = 34.5%.

Example 46 was carried out analogously to example 45. The difference was that 1 H sodium hydroxide solution (NaOH) was used as the alkaline reagent. Breaking stress σ = 0.95 MPa, elongation ε = 50.8%.

Examples 47-50. Examples 47, 49 are made analogously to example 45. Examples 48, 50 are made analogously to example 46. The difference was the use of chitosan samples with other molecular weights.

Example 51 was carried out analogously to example 50. The difference was that the sorption medium was an isotonic solution (0.9% NaCl). The degree of sorption С _с = 185%, breaking stress σ = 5.3 MPa, elongation ε = 120%.

, СД=83 мольн.%, в качестве растворителя использовали 1.5%-ную янтарную кислоту. Степень сорбции С_с=179%, разрывное напряжение σ=2.5 мПа, относительное удлинение при разрыве ε=100%.Example 52 was performed analogously to example 46. The difference was that they used a sample of chitosan with

, CD = 83 mol.%, 1.5% succinic acid was used as a solvent. The degree of sorption С _с = 179%, breaking stress σ = 2.5 MPa, elongation at break ε = 100%.

Example 53 was performed analogously to example 51. The difference was the use of a film of chitosan succinate. The degree of sorption C _c = 180%, the breaking stress σ = 2.2 MPa, the elongation at break ε = 58.5%.

From table 8 it follows that all the studied films of chitosan in the main form, regardless of the molecular weight of the polymer and the chemical structure of the carboxylic acid, after being kept in distilled water or physiological saline (0.9% NaCl) are more elastic than the original films of chitosan in saline form (comparison with table 2).

, СД=80.8 мольн.% (табл.9).Group of examples 54-65. The effect of the concentration of polymer in the molding solution and the concentration of acetic acid used to dissolve chitosan on the elastoplastic characteristics of the starting and modified films of chitosan of different chemical forms using a sample with

, SD = 80.8 mol.% (Table 9).

Table 9 Elastic-plastic characteristics of chitosan films of various chemical forms obtained from 1-5% polymer solutions in 1-10% acetic acid Example No. The concentration of polymer With _htz , wt.% The concentration of acetic acid With _to ,% The chemical form of chitosan in the film Sorption medium Sorption degree _C, wt.% Characteristics σ, MPa ε,% 54 C - - 32 twenty 55 one C H ₂ O 96 8 62 56 C H ₂ O 180 four 92 57 one C - - 26 17 58 10 C H ₂ O 104 12 58 59 O H ₂ O 185 3.5 49 60 C - - 69 8 61 one C H ₂ O 101 eighteen 56 62 5 O H ₂ O 178 12 48 63 C - - 58 7.5 64 10 C H ₂ O 98 21 41 65 O H ₂ O 184 6 46

Examples 54, 57, 60, 63 are made analogously to example 12 (the original film of chitosan in C-form). The difference consisted in a different ratio of polymer and acid concentrations in the molding solution to obtain film samples and corresponded to the minimum and maximum concentrations of chitosan (from the range of 1-5 wt.%) And acetic acid (from the range of 1-10%).

Examples 55, 58, 61, 64 are made analogously to example 13 (the original film of chitosan in the C-form, swollen in water vapor). The difference consisted in a different ratio of polymer and acid concentrations in the molding solution. The results for the boundary concentrations of chitosan (from the range of 1-5 wt.%) And acetic acid (from the range of 1-10%) are presented.

Examples 56, 59, 62, 65 are made analogously to example 48 (chemically modified films of chitosan in O-form). The difference consisted in a different ratio of polymer and acid concentrations in the molding solution and corresponded to the boundary concentrations of the components.

From table 9 it is seen that the chemical and physico-chemical modification of chitosan films obtained from molding solutions of different composition (chitosan + water + acetic acid) increases their elasticity under the accepted conditions. Moreover, an increase in both the concentration of chitosan in the molding solution and the concentration of acetic acid weakly affects the ε value of the modified samples.

, СД=80.8 мольн.% (табл.10).The group of examples 66-77. The effect of the concentration of polymer in solution and the concentration of succinic acid used to dissolve chitosan on the elastoplastic characteristics of the starting and modified films of chitosan of different chemical forms using a sample with

, SD = 80.8 mol.% (Table 10).

Table 10 Elastic-plastic characteristics of chitosan films of various chemical forms obtained from 1-5% polymer solutions in 1-2% succinic acid Example No. The concentration of polymer With _htz, wt.% The concentration of succinic acid With _to ,% The chemical form of chitosan in the film Sorption medium Sorption degree _C, wt.% Characteristics σ, MPa ε,% 66 C - - 48 4.5 67 one C H ₂ O one hundred 8.7 80 68 O H ₂ O 120 2.7 160 69 one C - - - fragile 70 2 C H ₂ O 80-190 - fragile 71 O H ₂ O 80-190 - fragile 72 C - - 60 3.7 73 one C H ₂ O 110 5.4 66 74 O H ₂ O 120 3.9 120 75 5 C - - - fragile 76 2 C H ₂ O 90-190 - fragile 77 O H ₂ O 90-190 - fragile

Examples 66, 69, 72, 75 are made analogously to example 42. The difference consisted in a different ratio of polymer and acid concentrations in the molding solution to obtain film samples and corresponded to the minimum and maximum concentrations of chitosan (from the range of 1-5 wt.%) And succinic acid ( from the range of 1-2%).

Examples 67, 70, 73, 76 are made analogously to example 43. The difference consisted in a different ratio of polymer and acid concentrations in the molding solution.

Examples 68, 71, 74, 77 are made analogously to example 52. The difference consisted in a different ratio of polymer and acid concentrations in the molding solution.

From table 10 it is seen that the chemical and physico-chemical modification of chitosan films obtained from molding solutions of different composition (chitosan + water + succinic acid), under the accepted conditions, increases their elasticity (examples 66-68 and 72-74).

Moreover, an increase in the concentration of succinic acid up to 2% leads to a significant deterioration in the elasticity of the modified samples. An increase in the concentration of chitosan in the molding solution weakly affects the ε value of the modified samples.

From the analysis of Table 1-10, the following optimal parameters follow for the production of highly elastic films and film materials based on biomedical chitosan.

1. The concentration of chitosan With _xtz = 1-5 wt.% (Regardless of the chemical structure of the carboxylic acid). Thin films are formed from solutions with C _xtz = 1 wt.%, Which complicates their use in the treatment of wounds. It is economically disadvantageous to use chitosan solutions with C _xtz = 5 wt.% To obtain films for medical use, since it increases the cost of obtaining the finished product.

полимера). Использование уксусной кислоты С_к=1 мас.% увеличивает время растворения полимера, С_к=10 мас.% экологически небезопасно. В обоих последних случаях увеличивается себестоимость получения пленок.2. The concentration of acetic acid With _to = 1-10 wt.% (Depending on

polymer). The use of acetic acid With _to = 1 wt.% Increases the dissolution time of the polymer, With _to = 10 wt.% Environmentally unsafe. In both latter cases, the cost of producing films increases.

3. The optimal degree of swelling of the film in C-form during physico-chemical modification in a vapor medium With _c = 70-190 wt.%. The absorption of vapors of the sorption medium by the polymer to C _with <70 wt.% Did not increase the elasticity of the film.

The absorption of vapors by the polymer to C _with > 190 wt.% Initially led to the formation of a gel, and then to the dissolution of the film sample.

4. The optimal degree of swelling of the film in OH-form during physico-chemical modification in a liquid medium With _c = 90-190 wt.%. The lower limit C _c = 90 wt.% Is due to the residual moisture of the film after washing it in distilled water. The absorption of liquid sorbate by the polymer to C _c > 190 wt.% Is impractical, since it practically does not change the relative elongation achieved at C _c = 90-190 wt.% When the film sample ruptures.

The proposed method allows to obtain highly elastic water-soluble (salt form) and insoluble films (basic form) with sufficient strength for use in medical practice, simple to perform, environmentally friendly and economically feasible. As a result of the application of the proposed method, a highly elastic (easily modeling surface with complex relief) non-toxic biocompatible and biodegradable film of chitosan is obtained, which has a therapeutic effect in the healing of wounds of various nature, in particular, with mechanical and / or thermal damage to dermal tissues of animals or humans.

Claims (6)

1. A method of producing a medical film based on chitosan, comprising preparing a molding solution from an air-dry sample of chitosan and an organic acid solution, applying the resulting solution to a substrate, followed by keeping the solution on the substrate until the film structure is reached, while the molding solution includes chitosan in the form salts of acetic or succinic acid, characterized in that after aging the film structure is treated with water vapor or an aqueous solution of 0.5 N hydrochloric acid to a degree nor film swelling of 70-190%, while providing a value of the relative elongation of the film at break of at least 20%. 2. The method of producing a film according to claim 1, characterized in that when preparing the molding solution, chitosan with a molecular weight of 80-700 kDa is used. 3. The method of producing a film according to claim 1, characterized in that to obtain a film with a thickness of 50-70 μm, the molding solution is applied to the substrate in a volume of 0.20-0.25 ml / cm ² . 4. A method of producing a medical film based on chitosan, comprising preparing a molding solution from an air-dry sample of chitosan and an organic acid solution, applying the resulting solution to a substrate, followed by keeping the solution on the substrate until the film structure is reached, while the molding solution comprises chitosan in the form salts of acetic or succinic acid, treatment of the obtained film with an alkaline reagent for 1 h, followed by washing with distilled water until neutral values of pH, characterized in that after washing the film was placed in distilled water or saline solution (0,9% NaCl) to a degree of swelling of the film is not less than 90%, thus providing an elongation at break of the film is not less than 30%. 5. The method of producing a film according to claim 4, characterized in that when preparing the molding solution, chitosan with a molecular weight of 80-700 kDa is used. 6. The method of producing a film according to claim 4, characterized in that to obtain a film with a thickness of 50-70 μm, the molding solution is applied to the substrate in a volume of 0.20-0.25 ml / cm ² .