Polymer composition and method for producing same

Abstract

The present invention relates to a method for dissolving an anionic polymer and a cationic polymer in an aqueous solution without aggregation / suspension phenomenon, and producing a composition in a form and for use in various fields from the mixed aqueous solution, the method comprising: (1) adding an electrolyte to a mixed aqueous solution containing an anionic polymer and a cationic polymer, the ionic strength (I) value of the electrolyte in the aqueous solution being such that [16.5 × (the number of moles of the least used polymer out of the anionic polymer and the cationic polymer) × (NIG 2 ]≦ionic strength≦(30×molar number of anionic polymer); or (2) adding an electrolyte to a mixed aqueous solution containing an anionic polymer and a cationic polymer such that the ionic strength (I) of the electrolyte in the aqueous solution satisfies the condition of 0.001<ionic strength<[16.5×(molar number of the anionic polymer and the cationic polymer that is used the least)×(NIG) 2 and adjusting the pH to 7.0 to 8.3.

Description

[Technical field]

[0001] The present invention relates to a polymer composition comprising an anionic polymer, a cationic polymer and an electrolyte, and a method for producing the same. [Background technology]

[0002] Biodegradable polymers have been developed in three forms, namely, "bioresorbable medical materials," "biodegradable plastics," and "bio-based materials," depending on their applications. The first biodegradable polymers developed were bioabsorbable medical materials, and in the late 1970s, dissolving surgical threads using polyglycolic acid were put to practical use. In this field, the importance of biodegradable polymers has become even greater in the field of regenerative medicine. Over the past two centuries, much development has been done to apply biodegradable polymer materials to biomedical applications. Biodegradable polymer materials are excellent representative materials for developing therapeutic tools. Representative examples include temporary artificial organs, three-dimensional porous materials for creating supports for tissue engineering, and drug delivery means for controlled / sustained release. To be applied in these applications, materials with specific physical, chemical, biological, biomedical, and degradable properties are required. Various natural and synthetic polymers that are degraded by hydrolysis or enzymatic action have been considered. Most biodegradable polymers currently available on the market are natural polymers such as collagen, and synthetic polymers such as poly(α-esters). The successful development of biodegradable polymer implants depends on how to design and modify conventional biomaterials to achieve appropriate biocompatibility, biodegradability and physical properties. A paradigm shift is occurring, moving from biostable biomaterials to biodegradable biomaterials. In the current trend, it seems that most of the permanent prosthetic materials for temporary treatment will be replaced by biodegradable tools that heal and regenerate damaged cells. The biomedical use of natural polymeric substances that are degraded by enzymes, such as collagen, has been around for thousands of years, but biodegradable synthetic polymers have only been used since the late 1960s. Especially in the last 20 years, groundbreaking developments have been made. The emergence of new biomedical technologies has played the role of a driving force. This is because biodegradable base materials are required in fields such as tissue engineering, regenerative medicine, gene therapy, drug delivery control, and bionanotechnology. Excellent biocompatibility is a prerequisite for the application of polymeric materials to living organisms. Biodegradable materials must be gradually decomposed by themselves and, as a result, converted into substances that are harmless to living organisms. Otherwise, various foreign body reactions such as inflammatory and fibrotic reactions will occur in the body.Therefore, it is very important that the materials are decomposed and discharged. Biodegradable materials are being widely used in the fields of medicine and pharmacy, and their applications are expected to expand further with the development of micro- and nano-technology. Polymeric materials are versatile and can replace other materials such as metals, alloys, and ceramics that have traditionally been used as biomaterials.

[0003] The cosmetics market is growing rapidly every year, and this growth is based on the dramatic development of cosmetics technology. Conventional approaches aimed at beauty are expanding, and the market for functional cosmetics that exhibit various functions such as high functionality, whitening, wrinkle improvement, UV protection, anti-inflammatory, and obesity suppression, which have been introduced with the concept of disease prevention and treatment, is also growing rapidly in recent years. In line with such changes and developments in the cosmetics industry, new concepts of cosmetics are constantly appearing on the market through the development of new materials and new technologies, and technological fusion with other industries. It can be said that the development of Korean cosmetics technology began in the 1960s. At that time, cosmetics technology was mostly focused on the manufacture of cosmetics, and in particular, interface research related to emulsification was the main focus. In the early days, research was mainly conducted on increasing the dispersion stability of products using emulsifiers, research on manufacturing process control, and research on improving the feel of use. In the 1980s, interest in skin aging and whitening increased greatly, and many studies were conducted to solve this problem. Products that introduced encapsulation technology such as liposomes to develop effective materials using biological methods and deliver them efficiently to the skin were released. In the 1990s, more efficacy-oriented products were released, and in addition to moisturizing and protective functions, efficacies such as whitening and wrinkle prevention were emphasized. In order to impart such efficacies, various materials including vitamins and natural extracts were developed, and much effort was focused on developing manufacturing techniques that could stabilize such ingredients within the product and effectively absorb them into the skin. In the 21st century, in the field of dermatology, research on anti-aging, inhibition of melanin production, and relief of hair loss, acne, skin irritation, etc. is actively being conducted in the field of materials, while the search for natural ingredients with such efficacies and the synthesis of new substances and derivatives with new efficacies are actively being conducted. Currently, herbal plant extracts obtained from toki and ginseng, and plant extracts obtained from chamomile and rose are widely used, and biomolecules such as ceramide, which is a component of intercellular lipids, are also being commercialized. In addition, the drug delivery technology for the absorption of the active ingredients through the skin, the technology for stabilizing unstable active substances, and the formulation technology for solubilizing poorly soluble active substances are being developed in combination with fluid and nanotechnology and are being used in products.

[0004] Thus, the advantages of biocompatible polymers are expected to be utilized in various fields. However, when polymers having opposite charges are mixed, precipitation or turbidity occurs, making it impossible to prepare a solution with an accurate content, and the properties of functional polymers using positive or negative charges are lost or reduced, so there is a need for a solution to these problems.

[0005] U.S. Patent No. 9220761, Materials 2020,13,5309, Biomaterials.2004 Aug;25(17):3583-92, Canadian Patent Publication No. 2739499, etc., describe the process of mixing poly-L-lysine with a counterion polymer. In such conventional techniques, the pH is adjusted in the reaction conditions to avoid the formation of precipitation, and pH adjustment is essential in setting the reaction conditions. When the pH is adjusted, the ionization tendency due to the pKa value of the ionic polymer is adjusted, so it is possible to avoid the formation of precipitation. However, when the charge characteristics of the ionic polymer are used, for example, poly-L-lysine exhibits antimicrobial or bacteriostatic functions due to its positive charge characteristics, but if the ionization tendency is reduced or suppressed, such functions disappear, which does not meet the initial purpose of using poly-L-lysine. Therefore, there is a need to develop a technique for mixing ionic polymers having opposite charges in a homogeneous state while maintaining the functionality obtained from the charge characteristics of the ionic polymer. Summary of the Invention [Problem to be solved by the invention]

[0006] The object of the present invention is to solve the above-mentioned problems in the development of polymer composite materials, and to provide a method for producing a polymer composition that can prevent precipitation or suspension that can occur when polymers having opposite charges are mixed, prepare a solution with an accurate content, and thereby maintain the properties of functional polymers that use positive or negative charges, and a polymer composition produced by such a method.

[0007] Another object of the present invention is to provide said polymer composition in liquid or dry form including foams, pads, films, sticks, sponges, threads, powders, etc., for use in wound dressings, hemostats, sutures, cosmetics, feminine hygiene products, etc. [Means for solving the problem]

[0008] The means for solving the above technical problems in the present invention are as follows.

[0009] 1. A method for producing a polymer composition comprising an anionic polymer and a cationic polymer, comprising: (1) The electrolyte is dissolved in a mixed aqueous solution containing an anionic polymer and a cationic polymer, and the ionic strength (I) of the electrolyte in the aqueous solution is [16.5 × (the number of moles of the least used polymer out of the anionic polymer and the cationic polymer) × (NIG)]. 2 ]≦ionic strength (I)≦(30×moles of anionic polymer); or (2) For a mixed aqueous solution containing an anionic polymer and a cationic polymer, the ionic strength (I) of the electrolyte in the aqueous solution is 0.001 < ionic strength (I) < [16.5 x (the molar number of the least used polymer out of the anionic polymer and cationic polymer) x (NIG)] 2 and adjusting the pH to 7.0 to 8.3; A method for producing a polymer composition, wherein in (1) and (2) above, the number of moles of polymer is a value calculated by weight of polymer / mass of polymer repeating unit, and NIG indicates the larger of the number of charged groups in the repeating unit of the anionic polymer and the cationic polymer.

[0010] 2. A method for producing the polymer composition described in 1 above, comprising preparing an aqueous anionic polymer solution, adding an electrolyte thereto so as to satisfy the above condition (1) or (2), and then adding a cationic polymer or an aqueous solution of a cationic polymer.

[0011] 3. The method for producing a polymer composition according to 1 above, wherein the anionic polymer and the cationic polymer are mixed in a molar ratio of 1.5:0.001-0.01:2.4 based on the number of moles of polymer repeat units.

[0012] 4. The method for producing a polymer composition described in 1 above, wherein the anionic polymer is selected from the group consisting of hyaluronic acid, alginic acid, polyglutamic acid, carboxymethylcellulose, sodium carboxymethyldextran, sodium carboxymethyl β-glucan and sodium carboxymethylstarch.

[0013] 5. The method for producing a polymer composition according to claim 1, wherein the cationic polymer is selected from the group consisting of polylysine, chitosan, protamine, polyarginine, poly(ethyleneimine) and poly(2-dimethyl(aminoethyl)methacrylate).

[0014] 6. The method for producing a polymer composition described in 1 above, wherein the electrolyte is an organic or inorganic salt selected from the group consisting of sodium chloride, potassium chloride, sodium citrate, sodium ascorbyl phosphate, sodium gluconate, sodium glucuronate, sodium malate, sodium borate, sodium acetate, sodium aspartate, sodium phosphate, calcium chloride, calcium carbonate, calcium hydroxide, calcium phosphate, calcium gluconate, calcium oxalate, calcium oxide, magnesium ascorbyl phosphate, magnesium aspartate, magnesium chloride, magnesium sulfate and magnesium stearate.

[0015] 7. The method for producing a polymer composition according to 1 above, wherein the anionic polymer or cationic polymer has a number average molecular weight of 1,000 Da to 3,000,000 Da.

[0016] 8. A polymer composition comprising an anionic polymer, a cationic polymer and an electrolyte, the polymer composition being produced by the method according to any one of 1 to 7 above.

[0017] 9. The polymer composition according to 8 above, wherein the mixing ratio of the anionic polymer to the cationic polymer is a molar ratio of 1.5:0.001-0.01:2.4 based on the number of moles of polymer repeating units.

[0018] 10. The polymer composition according to claim 8, provided in liquid form, or in dry form such as foams, pads, films, sticks, sponges, threads or powders.

[0019] 11. The polymer composition according to claim 10, which is used in wound dressings, hemostats, sutures, cosmetics or feminine hygiene products. Effect of the Invention

[0020] By preparing a mixed aqueous solution of an anionic polymer and a cationic polymer and providing the dried product thereof according to the present invention, it is possible to avoid the suspension phenomenon caused by precipitation or partial aggregation when mixing polymers having opposite charges to prepare a dried product of the composite component, and therefore it is possible to prepare a composite aqueous solution suited to the purpose and provide a liquid composition or a dried product in various forms such as foam, pad, film, stick, sponge, thread, powder, etc.

[0021] The liquid compositions provided by the present invention, or dry products such as foams, pads, films, sticks, sponges, threads, powders, etc., can be applied to wound dressings, hemostats, sutures, cosmetics, feminine hygiene products, etc. [Brief description of the drawings]

[0022] [Figure 1a] FIG. 1a is a high-resolution scanning electron microscope (transmission electron microscope, SEM) photograph of a pad produced in Example 1 of the present invention (FIG. 1a: Example 1). [Figure 1b] FIG. 1b is a high-resolution scanning electron microscope (transmission electron microscope, SEM) photograph of a pad produced in Example 5 of the present invention (FIG. 1b: Example 5). [Figure 1c] FIG. 1c is a high-resolution scanning electron microscope (transmission electron microscope, SEM) photograph of a pad produced in Example 7 of the present invention (FIG. 1c: Example 7). [Figure 1d] FIG. 1d is a high-resolution scanning electron microscope (transmission electron microscope, SEM) photograph of a pad produced in Example 13 of the present invention (FIG. 1d: Example 13). [Figure 1e] FIG. 1e is a high-resolution scanning electron microscope (transmission electron microscope, SEM) photograph of a pad produced in Example 15 of the present invention (FIG. 1e: Example 15). [Figure 1f] FIG. 1f is a high-resolution scanning electron microscope (transmission electron microscope, SEM) photograph of the pad produced in Comparative Example 1 (FIG. 1f: Comparative Example 1). [Figure 2a]FIG. 2a is a photograph of the mixed aqueous solution of hyaluronic acid and polylysine prepared in Example 1 of the present invention (FIG. 2a: Example 1). [Figure 2b] FIG. 2b is a photograph of the mixed aqueous solution of hyaluronic acid and polylysine prepared in Comparative Example 1 of the present invention (FIG. 2b: Comparative Example 1). [Figure 3a] FIG. 3a shows the results of comparing the antimicrobial effects of pads produced in Example 1 of the present invention and Comparative Example 1 (FIG. 3a: Example 1, FIG. 3b: Comparative Example 1). [Figure 3b] FIG. 3b shows the results of comparing the antimicrobial effects of pads produced in Example 1 of the present invention and Comparative Example 1 (FIG. 3a: Example 1, FIG. 3b: Comparative Example 1). [Figure 4] FIG. 4 is a photograph showing the appearance of the pad-like dried material produced in Example 1 of the present invention. [Diagram 5] FIG. 5 is a photograph showing the appearance of the film-like dried product produced in Example 1 of the present invention. [Figure 6] FIG. 6 is a photograph showing the appearance of the rod-shaped dried product produced in Example 1 of the present invention. [Figure 7] FIG. 7 is a photograph of the tablet-shaped dried product prepared in Example 1 of the present invention packaged in a blister pack. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The present invention relates to a method for mixing and dissolving an anionic polymer and a cationic polymer in an aqueous solution without aggregation or suspension, and producing a polymer composition from the mixed aqueous solution in a form and for use in various fields, the method comprising the steps of: (1) The electrolyte is dissolved in a mixed aqueous solution containing an anionic polymer and a cationic polymer, and the ionic strength (I) of the electrolyte in the aqueous solution is [16.5 × (the number of moles of the least used polymer out of the anionic polymer and the cationic polymer) × (NIG)]. 2 ]≦ionic strength (I)≦[30×moles of anionic polymer]; or (2) For a mixed aqueous solution containing an anionic polymer and a cationic polymer, the ionic strength (I) of the electrolyte in the aqueous solution is 0.001 < ionic strength (I) < [16.5 x (the molar number of the least used polymer out of the anionic polymer and cationic polymer) x (NIG)] 2 and adjusting the pH to 7.0 to 8.3; In the above (1) and (2), the number of moles of polymer is a value calculated by weight of polymer / mass of polymer repeat unit, and NIG indicates the larger number of the number of charge groups in the repeat unit of the anionic polymer and the cationic polymer. Therefore, when the number of charge groups in the repeat unit of the anionic polymer and the cationic polymer is all 1, NIG is 1, and when the number of charge groups in the repeat unit of one of the anionic polymer and the cationic polymer is 1 and the number of charge groups in the repeat unit of the other is 2, or when the number of charge groups in the repeat unit of the anionic polymer and the cationic polymer is all 2, NIG is 2.

[0024] The ionic strength (I) of the electrolyte is a value calculated by the following formula 1:

[0025]

number

[0026] In the formula, n is the number of electrolyte ions in the solution, i is a specific ion of the electrolyte, Ci is the number of moles of the electrolyte ions in the solution, and Zi is the valence of the electrolyte ions.

[0027] In the present invention, under the condition (1), the ionic strength value of the electrolyte calculated by the above formula 1 for the mixed polymer aqueous solution is 16.5 × (the molar number of the least used polymer out of the anionic polymer and the cationic polymer) × (NIG). 2The electrolyte is added in an amount that is 30 times or less the number of moles of the anionic polymer. In the present invention, the ionic strength value of the electrolyte is 16.5 × (the number of moles of the least used polymer out of the anionic polymer and the cationic polymer) × (NIG). 2 By adding the electrolyte in an amount equal to or greater than this amount, a mixed aqueous solution of ionic polymers having opposite charges can be prepared without precipitation or suspension. If the electrolyte is added in an amount that results in a lower ionic strength value, it is not preferable because it becomes difficult to ensure the stability of the mixed aqueous solution, as precipitation occurs even with slight changes in pH, temperature, concentration, etc. during the preparation of the mixed aqueous solution. The anionic polymer determines the viscosity of the mixed aqueous solution and has tension during freeze-drying. Therefore, in order to maintain the tension and prevent the dried product of the mixed aqueous solution from breaking, it is preferable to limit the amount of electrolyte added so that the ionic strength value does not exceed 30 times the number of moles of the anionic polymer.

[0028] In the present invention, under the condition (2), the ionic strength value of the electrolyte is greater than 0.001, and 16.5×(molar number of polymer)×(NIG) 2 The electrolyte is added in an amount less than the pH of the aqueous solution to adjust the pH of the aqueous solution to 7.0 to 8.3. This is because, even if a smaller amount of electrolyte is added than in the above condition (1), the same effect as in the condition (1) can be obtained by adjusting the pH of the aqueous solution to 7.0 to 8.3.

[0029] In the present invention, the anionic polymer may be selected from the group consisting of hyaluronic acid, alginic acid, polyglutamic acid, carboxymethylcellulose, sodium carboxymethyl dextran, sodium carboxymethyl β-glucan and sodium carboxymethyl starch, but is not limited thereto, and any polymer having one or more negatively charged groups in the repeating unit may be used.

[0030] In the present invention, the cationic polymer may be selected from the group consisting of polylysine, chitosan, protamine, polyarginine, poly(ethyleneimine) and poly(2-dimethyl(aminoethyl)methacrylate), but is not limited thereto, and any cationic polymer having one or more positively charged groups in the repeating unit may be used.

[0031] In one embodiment of the polymer composition according to the present invention, an anionic polymer aqueous solution is first prepared, an electrolyte is added thereto so as to satisfy the above-mentioned condition (1) or (2), and then a cationic polymer or an aqueous solution of a cationic polymer is added to obtain a mixed aqueous solution. At this time, the mixing ratio of the anionic polymer and the cationic polymer is 1.5:0.001-0.01:2.4, preferably 1.0:0.002-0.1:2.0, more preferably 0.5:0.01-0.01:1.0, and most preferably 0.1:0.003-0.01:0.01, based on the repeating unit of the polymer. In the present invention, by mixing the anionic polymer and the cationic polymer at such a ratio, the viscosity of the mixed aqueous solution, and the tension, anti-inflammatory and moisturizing properties of the dried product after freeze-drying can be secured from the anionic polymer, and the bacteriostatic activity can be secured from the cationic polymer.

[0032] In the present invention, the electrolyte may be an organic salt or an inorganic salt selected from the group consisting of sodium chloride, potassium chloride, sodium citrate, sodium ascorbyl phosphate, sodium gluconate, sodium glucuronate, sodium malate, sodium borate, sodium acetate, sodium aspartate, sodium phosphate, calcium chloride, calcium carbonate, calcium hydroxide, calcium phosphate, calcium gluconate, calcium oxalate, calcium oxide, magnesium ascorbyl phosphate, magnesium aspartate, magnesium chloride, magnesium sulfate, and magnesium stearate, but is not limited thereto.

[0033] Hyaluronic acid (hereinafter, also referred to as "HA") is a long linear polysaccharide in which β-D-glucuronic acid and β-DN-acetylglucosamine form mutual beta bonds, and is a biodegradable and biocompatible natural polymer that is widely present in natural systems with a wide distribution of molecular weights from 1,000 Da to 10,000,000 Da.

[0034] The following chemical formula 1 shows the repeating unit structure of hyaluronic acid, and the number of charged groups (anionic groups) in the repeating unit is one.

[0035] [ka]

[0036] Hyaluronic acid is found in large amounts in the vitreous body of the eye, synovial fluid, cartilage and skin in a gel state with high viscosity, combining with a large amount of water. It is known to play a role in joint lubrication, imparting flexibility to the skin and protecting it from bacterial penetration into the skin due to its high viscosity. Therefore, it has been used in many fields such as degenerative arthritis, cataracts, wrinkle improvement, drug delivery, stem cell support and cosmetic moisturizing. It is also found in large amounts in the extracellular matrix of tissues, and has been reported to regulate cell differentiation and proliferation, and to have a wound healing effect (Erika Nyman et al., J. Plasr Surg Hand Surg. 2013; 47; 89-92) and a wound healing mechanism (Richard D Price et al., Am J Clin Dermatol; 2005; 6 (6) 393-402).

[0037] Recent studies have also reported that low molecular weight hyaluronic acid induces vascular regeneration around damaged tissues, thereby effectively repairing wounds. Based on these properties, hyaluronic acid is widely used in wound healing agents, arthritis treatment agents, drug delivery systems, and tissue engineering fields. In addition, it is sometimes used as an adhesion inhibitor due to its excellent biocompatibility, biodegradability, and ability to prevent tissue adhesion. However, conventional hyaluronic acid provided in the form of sodium salt is known to have no hemostatic effect.

[0038] Poly-gamma-glutamic acid (γ-PGA) is a safe and edible biomaterial naturally produced by Bacillus subtilis. γ-PGA is an anionic polypeptide with a structure in which D- or L-glutamate is polymerized with γ-amide linkages. Three different types of γ-PGA have been discovered so far: homopolymers composed of D-glutamate, homopolymers composed of L-glutamate, and copolymers in which D-glutamate and L-glutamate are randomly arranged. Among these, Natto and Chungkookjang are representative strains of Bacillus subtilis with a copolymer structure. γ-PGA with a molecular weight of 10 to 10,000 kDa has been produced using Bacillus subtilis isolated from nuts, and recently, γ-PGA with a high molecular weight of over 1,000 kDa has been produced using Bacillus subtilis extracted from the traditional Korean dish Cheonggukjang. γ-PGA is used in a variety of food, industrial, environmental, and pharmaceutical fields, including health foods for preventing osteoporosis, food stabilizers, chelating agents for wastewater treatment, new bio materials, moisturizers, cosmetics, liquid crystal display (LCD) materials, drug deliverers, and gene vectors.

[0039] Alginic acid is a natural polymer extracted from brown algae such as wakame and kombu, and is used in various biomedical engineering applications. Alginic acid has the advantages of excellent biocompatibility, low toxicity, and low cost. It also binds with divalent cations (e.g., Ca2+) and relatively easily forms hydrogels. In particular, the molecular structure of alginic acid is in the form of a block copolymer of D-mannuronic acid and L-guluronic acid, and the L-guluronic acid block binds with divalent cations to form hydrogels, so the length of the L-guluronic acid block is an important factor that determines the physical properties of alginate hydrogels.

[0040] Chemical formula 2 below shows the structure of the repeating unit of alginic acid, and the number of charged groups (anionic groups) in the repeating unit is two.

[0041] [ka]

[0042] Alginic acid has been used as a medical material in various fields, including tissue engineering, and is known to have excellent biocompatibility and low toxicity in vitro and in vivo. In the case of commercially available alginic acid, it has been reported that it has low toxicity and hardly induces an immune response in animal experiments. Alginic acid is known to be non-degradable under physiological conditions, and the gel can be broken down and dissolved by releasing divalent cations that act as crosslinkers in alginic acid hydrogels through an exchange reaction with monovalent cations (e.g., Na+) present in the body. However, commercially available alginic acid has a large molecular weight, so after dissolving, it passes through the kidney and is difficult to be excreted from the body. A typical method for imparting degradability to alginic acid is partial oxidation. If alginic acid is partially oxidized and an aldehyde group is introduced into the main chain, it can be decomposed in physiological saline. The biodegradation rate of partially oxidized alginic acid can be adjusted by the degree of oxidation, pH, and temperature.

[0043] Polylysine (ε-poly-L-lysine, hereinafter also referred to as “PLL”) is a molecule in which 25 to 35 L-lysines, a strongly basic amino acid, are bonded together, and is positively (+) charged.

[0044] The following chemical formula 3 shows the repeating unit structure of polylysine, and the number of charged groups (cation groups capable of forming salts by ionic bonds with carboxylic acid) in the repeating unit is one.

[0045] [ka]

[0046] Thus, the positively charged polylysine ionically bonds with the cell membrane of a microorganism that is negatively (-) charged, thereby exhibiting antibacterial power that inhibits the proliferation of the microorganism. Due to such characteristics, PLL is widely used as a natural antibacterial agent (natural preservative) or food preservative. Polylysine has a wide antibacterial spectrum, exhibits antibacterial properties against all bacteria (gram-positive, gram-negative, fungi), is stable against pH changes, and maintains antibacterial activity without significant changes in the minimum inhibitory concentration (MIC) in the weakly acidic to neutral range (pH 4.0 to 8.0). It is also stable against heat, and there is no decrease in antibacterial power due to heat. In addition, polylysine is known to induce platelet aggregation, and its platelet aggregation-inducing ability varies depending on the molecular size.

[0047] Chitin is a linear polysaccharide in which N-acetyl-D-glucosamine (GlcNAc) is linked by a β-1,4 bond, and is a mucopolysaccharide with a chemical structure and crystalline structure similar to that of cellulose. Although chitin is a low-toxicity substance that is biodigestible, biocompatible, and stimulates epidermal cell growth factors, it is rarely used and only remains in its position as an intermediate substance for chitosan because it is difficult to process because it is insoluble in general solvents. Chitosan refers to deacetylated chitin, and while it is insoluble in water and bases, it is soluble in weak acids such as lactic acid, citric acid, and acetic acid, and is decomposed by the action of enzymes and easily absorbed. The most ideal one is 100% deacetylated, which shows a decisive difference in efficacy. Generally, chitosan is called chitosan when it is more than 60% deacetylated.

[0048] The following chemical formula 4 shows the structure of the repeating unit of chitosan, and the number of charge groups (cation groups that can form salts by ionic bonds with carboxylic acids) in the repeating unit (dimer) of chitosan is two.

[0049] [ka]

[0050] In addition, in the case of polymers such as alginic acid, in which the relative charge density of the anionic groups (carboxylic acid groups) in the repeating unit is large, ionic strength should be taken into consideration as well as valence. However, the number of anionic groups (charged groups) in the repeating unit (dimer) of alginic acid is two, while the number of anionic groups (charged groups) in the repeating unit (dimer) of hyaluronic acid is one.

[0051] Therefore, if we consider this to be the same concept as ionic strength, if the molar concentration of the polymer in the solution is equal to 0.01M, then the ionic strength of the carboxylic acid group in the hyaluronic acid repeat unit = 0.01M x (-1) 2 and the ionic strength of the carboxylic acid group of the alginic acid repeating unit = 0.01 M × (-2) 2 Therefore, the amount of electrolyte required for alginic acid is about four times that required for HA. In other words, for example, in the case of hyaluronic acid, if the ratio of the ionic strength of sodium citrate to the PLL concentration is 17:1, the alginic acid and PLL mixed solution requires sodium citrate at a concentration equivalent to about 68 times the ionic strength, which is four times 17. The same applies to other anionic or cationic polymers.

[0052] In addition, when adding a salt containing a monovalent ion such as sodium chloride or sodium citrate, and a salt containing a divalent ion such as magnesium ascorbyl phosphate, magnesium aspartate, magnesium chloride, etc., if the ionic strength of the electrolyte in the solution is less than 16.5 times the molar concentration of the cationic polymer, for example, 15 to 1 times, the same result can be obtained by mixing the aqueous solutions of the anionic polymer and cationic polymer in the above-mentioned ratio after adjusting the pH to 7.0 to 8.3. Such adjustment of the acidity takes into account the pKa of the cationic polymer, and since it has a sufficient charge to exhibit activity, it is possible to produce an aqueous solution that matches the purpose of blending.

[0053] In the present invention, the amount of electrolyte to be added is determined based on the ionic strength, so that aggregation due to the interaction between opposite charges of the polymers in the mixed aqueous solution is suppressed. As a result, when the mixture is mixed to satisfy the above condition (1) or (2), a uniform mixed aqueous solution can be obtained without aggregation or suspension phenomenon, regardless of the type of electrolyte used.

[0054] In the present invention, the anionic polymer or cationic polymer used has a number average molecular weight of 1,000 Da to 3,000,000 Da, preferably 3,000 Da to 2,000,000 Da, and more preferably 4,000 Da to 1,000,000 Da.

[0055] In the present invention, as described above, the mixed aqueous solutions of various polymers are used to provide dried products in various shapes for use in various fields.

[0056] Thus, the present invention relates to a polymeric composition comprising an anionic polymer, a cationic polymer and an electrolyte, and produced by the method described above.

[0057] In one embodiment of the present invention, the polymer composition prepared by the above-mentioned method can be used as it is in a liquid state, or can be dried by a method well known in the field of the present invention such as freeze drying, vacuum drying, spray drying, etc., and provided in the form of porous dry foam, pad, film, stick, sponge, thread, powder, tablet, etc. depending on the field of application, and can be used for applications such as wound dressing, hemostatic material, suture, cosmetics, feminine hygiene products, etc. EXAMPLES

[0058] Working Example The present invention will be described in more detail below with reference to examples. However, the examples presented below are merely examples for carrying out the present invention, and the scope of the present invention is not limited to the scope of these examples.

[0059] Examples 1 to 6: Production of a dried mixture of hyaluronic acid and polylysine 4g to 40g of hyaluronic acid (molecular weight 1,000KDa) was added to 1,000ml of purified water and stirred for 12 hours. Sodium citrate or magnesium chloride was mixed with this as an electrolyte at various ionic strengths, and an aqueous solution of polylysine (molecular weight 4,500Da) was added as a cationic polymer and dissolved, resulting in a mixed aqueous solution without any precipitation or suspension.

[0060] The mixed aqueous solution without precipitation or suspension was dispensed into a mold according to the shape of the dried product, and dried by freeze drying, vacuum drying or spray drying to produce dried products in the shape of porous dry pad, film, stick or tablet.

[0061] 1a and 1b are high-resolution scanning electron microscope (transmission electron microscope, SEM) photographs of pads produced in Examples 1 and 5 of the present invention (FIG. 1a: Example 1, FIG. 1b: Example 5).

[0062] 4 to 7 are photographs showing the external appearance of the pad-, film-, stick- and tablet-shaped dried products produced in Example 1 of the present invention, respectively.

[0063] The HA content (molar concentration), electrolyte addition amount and ionic strength, PLL content (molar concentration), and ratio of electrolyte ionic strength to polymer molar concentration in the mixed aqueous solution are shown in Table 1 below.

[0064] [Table 1]

[0065] Examples 7 to 12: Production of dried alginate-polylysine mixture 3.98 g of alginic acid (molecular weight 800 kDa) was added to 1,000 ml of purified water as an anionic polymer and stirred for 12 hours. Sodium citrate or magnesium ascorbyl phosphate (MAP) was mixed into this as shown in Table 2, and an aqueous solution of polylysine (molecular weight 4,500 Da) was added and dissolved as a cationic polymer, resulting in a mixed aqueous solution without any precipitation or suspension.

[0066] The aqueous solution, which did not cause precipitation or suspension, was dispensed into a mold according to the shape of the dried product, and freeze-dried to produce a porous dry pad or a film-like dried product. Figure 1c is a high-resolution scanning electron microscope (transmission electron microscope, SEM) photograph of the dry pad produced in Example 7 of the present invention.

[0067] The alginic acid content (molar concentration), electrolyte addition amount and ionic strength, PLL content (molar concentration), and ratio of electrolyte ionic strength to polymer molar concentration in the mixed aqueous solution are shown in Table 2 below.

[0068] [Table 2]

[0069] Examples 13-14: Production of hyaluronic acid-chitosan mixed dry product 4 g of hyaluronic acid hyaluronic acid (molecular weight 1,000 KDa) was added to 1,000 ml of purified water as an anionic polymer and stirred for 12 hours. Sodium citrate or magnesium ascorbyl phosphate (MAP) was mixed with this at various ionic strengths, and chitosan (molecular weight 300 KDa) was dissolved as a cationic polymer as shown in Table 3, and the pH was adjusted to 4.0 or less to check for the presence or absence of precipitation. Since chitosan has a different solubility depending on the pH, after dissolving chitosan in water, the pH was adjusted to 3.0, and the pH of the anionic polymer and electrolyte solution were adjusted as above before mixing.

[0070] The aqueous solution in which no precipitation or suspension occurred was dispensed into a mold according to the shape of the dried product, and freeze-dried or dried under reduced pressure in the same manner as in Examples 1 to 6 to produce pad-, film-, rod-, and tablet-shaped dried products. Figure 1d is a high-resolution scanning electron microscope (transmission electron microscope, SEM) photograph of the dried pad produced in Example 13 of the present invention.

[0071] The HA content (molar concentration), electrolyte addition amount and ionic strength, chitosan content (molar concentration), and ratio of electrolyte ionic strength to polymer molar concentration in the mixed aqueous solution are shown in Table 3 below.

[0072] [Table 3]

[0073] Examples 15 and 16: Preparation of a dried mixture of hyaluronic acid and polylysine 4 g of hyaluronic acid (molecular weight 1,000 KDa) as an anionic polymer was added to 1,000 ml of purified water and stirred for 12 hours. Sodium citrate and magnesium ascorbyl phosphate (MAP) were mixed as shown in Table 4, and the pH was adjusted to 8.0 and 8.3. Next, 0.5 g of polylysine (molecular weight 4,500 Da) as a cationic polymer was dissolved, and the presence or absence of precipitation was confirmed. The aqueous solution in which no precipitation or suspension phenomenon occurred was dispensed into a mold according to the shape of the dried product, and freeze-dried or dried under reduced pressure in the same manner as in Examples 1 to 6 to produce pad-shaped, film-shaped, rod-shaped, and tablet-shaped dried products. Figure 1e is a high-resolution scanning electron microscope (transmission electron microscope, SEM) photograph of the dried pad produced in Example 15 of the present invention.

[0074] The HA content (molar concentration) in the mixed aqueous solution, the amount of electrolyte added, ionic strength, aqueous solution pH, PLL content (molar concentration), and ratio of electrolyte ionic strength to polymer molar concentration are shown in Table 4 below.

[0075] [Table 4]

[0076] Comparative Examples 1 and 2: Preparation of Precipitated Hyaluronic Acid-Polylysine Mixed Aqueous Solution 4 g of hyaluronic acid (molecular weight 1,000 KDa) as an anionic polymer was added to 1,000 ml of purified water and stirred for 12 hours. Sodium citrate and magnesium chloride were mixed as shown in Table 5, and 0.5 g of polylysine as a cationic polymer was dissolved, and the presence or absence of precipitation was confirmed. Even when precipitation occurred and polylysine (molecular weight 4,500 Da) was further added until the concentration was the same as that of hyaluronic acid, the precipitation reaction continued. The precipitate was poured into a pad-shaped mold and freeze-dried.

[0077] Figure 1f is a high-resolution scanning electron microscope (transmission electron microscope, SEM) photograph of the freeze-dried pad prepared in Comparative Example 1. As can be seen from Figures 1a to 1e, the freeze-dried pad prepared from the mixed aqueous solution in which no precipitation occurs during mixing as in the embodiment of the present invention has a porous matrix structure, whereas Figure 1f shows that the freeze-dried pad prepared from the mixed aqueous solution in which precipitation occurs during mixing does not have a porous structure.

[0078] Fig. 2b is a photograph of the mixed aqueous solution of hyaluronic acid and polylysine prepared in Comparative Example 1. As can be seen from Fig. 2a, the mixed aqueous solution prepared in Example 1 did not cause precipitation or become cloudy, but as can be seen from Fig. 2b, the mixed aqueous solution prepared in Comparative Example 1 was cloudy and caused precipitation.

[0079] [Table 5]

[0080] Experimental Example 1: Antibacterial Activity Test ASTM E 2315-16 The weights of the freeze-dried pads prepared in Examples 1 and 2 and Comparative Examples 1 and 2 were measured, and bacterial culture fluid was added to the pads in an amount of about 10 times the weights, and the pads were used for the test. The culture temperature was 37°C, and tryptic soy media was used as the medium. The test strains were ATCC 6538 Staphylococcus aureus, ATCC 4352 Klebsiella peumoniae, ATCC 8739 Escherichia coli, and ATCC 10145 Pseudomonas aeruginosa.

[0081] 3a and 3b are photographs comparing the antimicrobial effects of the freeze-dried pads produced in Example 1 of the present invention and Comparative Example 1 against Staphylococcus aureus (FIG. 3a: Example 1, FIG. 3b: Comparative Example 1). FIG. 3a shows that in the freeze-dried pad produced in Example 1, PLL having bacteriostatic and antibacterial properties does not precipitate in the mixed aqueous solution, and the antibacterial activity against Staphylococcus aureus is maintained, and as a result, no microbial growth is observed. However, FIG. 3b shows that in the freeze-dried pad produced in Comparative Example 1, the antibacterial activity against Staphylococcus aureus is reduced due to the precipitation of PLL in the mixed aqueous solution, and as a result, microbial growth is observed.

[0082] Table 6 below shows the results of antibacterial activity tests on the freeze-dried pads produced in Examples 1 and 2 of the present invention and Comparative Examples 1 and 2. As can be seen from Table 6, the freeze-dried pads produced in Examples 1 and 2 exhibited antibacterial activity, but the freeze-dried pads produced in Comparative Examples 1 and 2 exhibited weak or no antibacterial activity.

[0083] [Table 6]

[0084] Experimental Example 2: Anti-adhesion test A rat cecum / abdominal wall abrasion model was used to evaluate the adhesion prevention performance of the pad-like dry material prepared in the examples. Seven-week-old male Sparague-Dawley mice were used as experimental animals, five per group. To induce adhesion, the experimental animals were anesthetized by intraperitoneal injection of Ketamin HCL (0.1 ml / 100 g), the abdominal hair was removed, disinfected with 70% ethanol, and the abdomen was opened along the center line at about 4 to 5 cm. The cecum was removed, and an injury was made to the intestinal membrane with a size of 1.2 cm x 1.2 cm using sterile gauze to the extent that bleeding occurred, and an injury of the same size was made to the opposing peritoneal membrane. Two sites 1 cm away from the friction injury site were fixed with 5-0 nylon sutures so that the injured surfaces faced each other to promote adhesion formation.

[0085] For the negative control group, saline was applied to the injury site, and for the experimental groups, pad-shaped dried materials prepared in Examples 1, 2, 7, and 13 were cut to a size of 1 cm x 1 cm and attached to the injury site, and then the abdominal cavity and skin were sutured. After the surgery, the animals were provided with sufficient water and food, and were allowed to grow for one week before being sacrificed. The scores were added up using an adhesion evaluation system to obtain an average value. The results are shown in Table 7 below. All results are shown as the mean ± standard error of each experimental group, and the significance of each group was tested at the p<0.05 level.

[0086] The degree of adhesion was graded from 0 to 5 according to the following criteria: 0: no adhesion, 1: one thin film-like adhesion, 2: two or more thin film-like adhesions, 3: dot-like centralized thick adhesions, 4: plate-like centralized adhesions, 5: very thick adhesions with vascularization or one or more plate-like thick adhesions.

[0087] The strength of adhesion was evaluated from 1 to 4 according to a standard (1: adhesion like a film that can be peeled off with very little force, 2: adhesion that requires moderate force, 3: adhesion that can be peeled off with considerable pressure, 4: adhesion that is very strong and difficult to peel off or requires very large pressure).

[0088] [Table 7]

[0089] As shown in Table 7, in the groups to which the pad-shaped dried materials prepared in Examples 1, 2, 7 and 13 were applied, the tissue adhesion area was significantly reduced compared to the negative control group.

[0090] Experimental Example 3: Infection-Prevention Test Using Infected Wound Model Male Sprague-Dawley mice (n = 10) weighing 280 g were anesthetized with isoflurane and incised on both sides of the back at least 2 cm apart, approximately 1 cm in length. E. coli solution (0.2 ml, 1 × 10 8 CFU / ml) was injected subcutaneously into the incision. For polylysine group (PLL), the pad prepared in Example 2 was inserted and the wound was sutured. As a negative control group, a hyaluronic acid pad (manufactured by the applicant only with hyaluronic acid) was used and sutured. The animals were transferred to individual cages with free access to food and water, and their weight, body temperature and behavioral changes were observed every day. The animals were sacrificed 4 days after implantation, and tissue specimens were dissected at two sites for microbiological examination.

[0091] [Table 8]

[0092] As can be seen from Table 8, the pads produced in the examples of the present invention were confirmed to be effective in preventing infection even in an artificial infection model.

[0093] As described above, it is understood by those skilled in the art that the present invention can be implemented in various modified forms. Therefore, the above-described embodiments should be understood as illustrative in all respects. The scope of the present invention is defined by the claims below rather than the detailed description, and all modifications and variations derived from the meaning and scope of the claims and equivalent concepts should be understood to be included in the scope of the present invention.

Claims

1. A method for producing a polymer composition containing an anionic polymer, a cationic polymer, and an electrolyte, comprising: step 1 producing an aqueous solution of an anionic polymer; step 2 adding an electrolyte to the aqueous solution obtained in step 1 so as to satisfy the following condition (1) or (2); and step 3 adding a cationic polymer or an aqueous solution of a cationic polymer to the aqueous solution obtained in step 2, (1) The electrolyte is dissolved in a mixed aqueous solution containing an anionic polymer and a cationic polymer, and the ionic strength (I) of the electrolyte in the aqueous solution is [16.5 × (the number of moles of the least used polymer out of the anionic polymer and the cationic polymer) × (NIG)]. ２ ]≦ionic strength (I)≦[19.3×(molar number of the anionic polymer and cationic polymer used less)×(NIG) 2 ], without adjusting the pH of the aqueous solution obtained in step 2; or (2) The electrolyte is dissolved in a mixed aqueous solution containing an anionic polymer and a cationic polymer, and the ionic strength (I) of the electrolyte in the aqueous solution is 0.001 < ionic strength (I) < [16.5 x (the molar number of the least used polymer out of the anionic polymer and the cationic polymer) x (NIG)]. ２ and adjusting the pH of the aqueous solution obtained in step 2 to 8.0 to 8.3; In the above (1) and (2), the number of moles of the polymer is a value calculated by weight of the polymer per unit volume / mass of the polymer repeating unit, and NIG represents the larger number of the number of charge groups in the repeating unit of the anionic polymer and the cationic polymer, the anionic polymer is selected from hyaluronic acid and alginic acid; The method for producing a polymer composition, wherein the cationic polymer is selected from polylysine and chitosan.

2. The method for producing a polymer composition according to claim 1, wherein the anionic polymer and the cationic polymer are mixed in a molar ratio of 1.5:0.001-0.01:2.4 based on the number of moles of polymer repeat units.

3. 2. The method of claim 1, wherein the electrolyte is an organic or inorganic salt selected from the group consisting of sodium chloride, potassium chloride, sodium citrate, sodium ascorbyl phosphate, sodium gluconate, sodium glucuronate, sodium malate, sodium borate, sodium acetate, sodium aspartate, sodium phosphate, calcium chloride, calcium carbonate, calcium hydroxide, calcium phosphate, calcium gluconate, calcium oxalate, calcium oxide, magnesium ascorbyl phosphate, magnesium aspartate, magnesium chloride, magnesium sulfate, and magnesium stearate.

4. The method for producing a polymer composition according to claim 1, wherein the anionic or cationic polymer has a number average molecular weight of 1,000 Da to 3,000,000 Da.

5. 5. A polymer composition comprising an anionic polymer, a cationic polymer and an electrolyte, produced by the method of any one of claims 1 to 4, said composition comprising: (1) The electrolyte is contained in an amount such that the ionic strength (I) value of the electrolyte in a mixed aqueous solution containing an anionic polymer and a cationic polymer satisfies the condition of [16.5 x (the molar number of the anionic polymer and the cationic polymer used less) x (NIG) 2 ] ≦ ionic strength (I) ≦ [19.3 x (the molar number of the anionic polymer and the cationic polymer used less) x (NIG) 2 ], and the pH of the aqueous solution of the anionic polymer and the electrolyte is not adjusted in the mixed aqueous solution; or (2) The electrolyte is contained in an amount such that the ionic strength (I) value of the electrolyte in the mixed aqueous solution containing the anionic polymer and the cationic polymer satisfies the condition of 0.001<ionic strength (I)<[16.5×(the molar number of the least used polymer out of the anionic polymer and the cationic polymer)×(NIG) 2 ], and in the mixed aqueous solution, the pH of the aqueous solution of the anionic polymer and the electrolyte is in the range of 8.0 to 8.3; In the above (1) and (2), the number of moles of the polymer is a value calculated by weight of the polymer per unit volume / mass of the polymer repeating unit, and NIG represents the larger number of the number of charge groups in the repeating unit of the anionic polymer and the cationic polymer, the anionic polymer is selected from hyaluronic acid and alginic acid; The polymer composition, wherein the cationic polymer is selected from polylysine and chitosan.

6. 6. The polymer composition according to claim 5, wherein the mixing ratio of the anionic polymer to the cationic polymer is a molar ratio of 1.5:0.001-0.01:2.4 based on the number of moles of polymer repeat units.

7. 6. The polymer composition of claim 5 provided in liquid form or dry form in the form of a foam, pad, film, stick, sponge, thread or powder.

8. 8. The polymer composition of claim 7, which is used in wound dressings, hemostats, sutures, cosmetics, or feminine hygiene products.

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