Hydrogel comprising hyaluronic acid derivative polymer

Abstract

The present invention relates to an anti-adhesion agent and a preparation method, the agent synthesizing and using gallic acid-conjugated hyaluronic acid (HA-gallol, HA-GA) in order to overcome the problem of downward flow from a surgical site, which is a disadvantage of a conventional liquid-type anti-adhesion agent, and, more specifically, to synthesis of hyaluronic acid-gallic acid, analysis of self-healing / injectability / fixation / stability properties thereof, a method for preparing an anti-adhesion agent by using same, and an anti-adhesion effect thereof.

Description

Hydrogel containing hyaluronic acid derivative polymer

[0001] The present invention relates to a hydrogel containing a hyaluronic acid derivative polymer for effective adhesion prevention.

[0002]

[0003] Postoperative adhesions of organs or tissues are a natural part of the healing process that occurs as damaged tissue regenerates. They occur in 67-93% of cases after open surgery. While some may resolve spontaneously, most remain adherent, causing various complications. These adhesions can cause pain, inflammation, organ dysfunction, and inconvenience in daily life, and can be life-threatening. Severe postoperative adhesions may require reoperation to remove the adhesions, making effective anti-adhesive agents essential. Currently, adhesions are prevented through 1) precision surgical techniques, 2) chemical methods, and 3) physical methods. Precision surgical techniques minimize tissue damage during surgery, minimize the use of foreign materials, and minimize the need for delicate surgery and unnecessary resections. However, other variables may exist. Chemical methods are significant because they employ methods that suppress adhesion between organs or tissues through drugs or systemic effects, based on the mechanisms of adhesion formation. Physical methods utilize anti-adhesion barriers to physically block contact with surrounding tissues, thereby inhibiting adhesions that may occur during tissue healing.

[0004]

[0005] One object of the present invention is to provide an anti-adhesion composition comprising gallic acid-conjugated hyaluronic acid (HA-GA) as an active ingredient.

[0006] Another object of the present invention is to provide an anti-adhesion agent comprising gallic acid-conjugated hyaluronic acid (HA-GA) as an active ingredient.

[0007] Another object of the present invention is to provide a method for producing an anti-adhesion composition, which comprises synthesizing hyaluronic acid (HA) together with an adipic acid dihydrazide (ADH) linker and gallic acid through a one-pot process.

[0008] Another object of the present invention is to provide a method for producing an anti-adhesion agent by synthesizing hyaluronic acid (HA) together with an adipic acid dihydrazide (ADH) linker and gallic acid through a one-pot process.

[0009]

[0010] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

[0011]

[0012] Various embodiments of the present invention are described with reference to the drawings. In the following description, various specific details, such as specific configurations, compositions, and processes, are set forth to provide a thorough understanding of the present invention. However, certain embodiments may be practiced without one or more of these specific details, or in conjunction with other known methods and configurations. In other instances, well-known processes and manufacturing techniques are not described in specific detail so as not to unnecessarily obscure the present invention. Reference throughout this specification to an embodiment means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in one or more embodiments of the present invention. Thus, the appearance of an embodiment in various places throughout this specification does not necessarily indicate the same embodiment of the present invention. Additionally, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.

[0013]

[0014] Currently, adhesions are prevented through 1) precision surgical methods, 2) chemical methods, and 3) physical methods. Among the three adhesion prevention methods, adhesion prevention membranes that form a physical barrier to prevent adhesions have the highest utilization rate, and the most products have been developed. For adhesion prevention, solution types such as Adept, Ringer's latate solution, Dextran 70, CMC solution, gel types such as Flowgel, Intergel, Guardix, films, and membrane types such as Separafilm, Interceed, Surgiwrap have been developed. However, there is no product with an excellent adhesion prevention effect, and when solution and gel types of adhesion prevention agents are applied to the surgical site, they do not fix to the surgical site but move or flow away (Malposition), which reduces the effectiveness of adhesion prevention. That is, due to the low elastic modulus of adhesion inhibitors (higher liquid properties than solid properties), they often flow down to organs or tissues other than the surgical site, or their in vivo retention period is insufficient, so they do not exist at the surgical site for sufficient time to complete the initial tissue healing process. Therefore, there is a need to develop an adhesion inhibitor that is in an injectable formulation that fits the minimally invasive trend, yet remains fixed to the surgical site or target tissue and remains there throughout the initial tissue healing process.

[0015] In the present invention, we synthesized hyaluronic acid-gallic acid and developed an anti-adhesion agent composition based on it. In addition, through analysis of the characteristics of hyaluronic acid-gallic acid, we demonstrated its potential as an anti-adhesion agent. Above all, when the hyaluronic acid-gallic acid / hyaluronic acid anti-adhesion agent was injected onto tissue, it was confirmed that it was well fixed on the target tissue without running off, unlike existing solution-type anti-adhesion agents. This hyaluronic acid-gallic acid-based anti-adhesion agent is fixed to the surgical site and can effectively prevent tissue or organ adhesion that may occur after surgery, and is therefore expected to have potential applications in various biomedical engineering fields.

[0016] In addition, the hyaluronic acid-gallic acid or the adhesion-preventing agent or adhesion-preventing composition containing hyaluronic acid-gallic acid provided by the present invention can be utilized for various diseases requiring adhesion prevention, and it is expected to have very high utilization in obstetrics and gynecology that directly performs cesarean section or surgery that resects human organs (i.e., colorectal surgery). For example, after performing a cesarean section, the adhesion-preventing agent containing the hyaluronic acid-gallic acid can be applied to the incision site, or after removing the cancer after surgery for colon or rectal cancer. In addition, the hyaluronic acid-gallic acid can be utilized in drug delivery, tissue engineering, and regenerative medicine due to various advantages such as biocompatibility and biodegradability. For example, it is possible to develop a hydrogel that can encapsulate and inject various drugs, so that patients can be treated by selectively delivering a drug suitable for the disease. Furthermore, it is believed that cell therapy will become possible by developing an injectable carrier capable of cell therapy through mixing with cells. Therefore, the technology developed through the present invention is expected to have diverse applications and applications in biomedical fields such as drug delivery and tissue engineering.

[0017]

[0018] The present invention provides an anti-adhesion composition comprising only hyaluronic acid-gallic acid and an anti-adhesion composition comprising hyaluronic acid-gallic acid and a biocompatible polymer. The biocompatible polymer comprises hyaluronic acid, collagen, gelatin, chitosan, a thermosensitive polymer (poloxamer 407, poloxamer 188, etc.), etc. As an example in which hyaluronic acid is used as the biocompatible polymer, an anti-adhesion composition comprising a hyaluronic acid-gallic acid and a hyaluronic acid mixture represented by the following chemical formula 2 is provided. In this case, the weight ratio of hyaluronic acid-gallic acid and hyaluronic acid is 1:9 to 9:1, and a sample denoted as HA-GA / HA below has a weight ratio of hyaluronic acid-gallic acid and hyaluronic acid of 1:9. As an example of using a thermosensitive polymer as the biocompatible polymer, an anti-adhesion composition comprising a mixture of hyaluronic acid-gallic acid and poloxamer is provided. In this case, the weight ratio of the hyaluronic acid, gallic acid, and thermosensitive polymer is 1:2 to 1:200.

[0019] [Chemical Formula 2]

[0020]

[0021] The term “polymer” as used herein refers to a synthetic or natural polymer compound in which monomers of the same or different types are continuously bonded. Accordingly, polymers include homopolymers (polymers polymerized from one type of monomer) and copolymers prepared by polymerizing at least two different types of monomers, while copolymers include copolymers (polymers prepared from two different types of monomers) and polymers prepared from more than two different types of monomers.

[0022] In this specification, the term “biocompatibility” means a property of not causing short-term or long-term side effects when administered into a living body and coming into contact with cells, tissues or body fluids of an organ, and specifically, it includes tissue compatibility and blood compatibility that do not cause necrosis of tissue or coagulation of blood when coming into contact with living tissue or blood, as well as biodegradability that disappears after a certain period of time after administration to the body.

[0023] 본 발명에서 사용 가능한 생체적합성 고분자는 폴록사머 (poloxamer), PCL[poly(caprolactone)], HEMA[poly(2-hydroxyethyl metacrylate)], PVA(polyvinylalcohol, PEO(Polyethyleneoxide), phospholipid, collagen, alipatic polyether, PLA[poly(lactide)], PGA[poly(glycolide)], PDO[poly(dioxanone)]), PBL[poly(butyrolactone)], PVL[poly(valerolactone)], PLGA[poly(lactide-co-glycolide)], PU(polyurethane), fibronectin, vitronectin, poly(L-lysin), poly(L-glutamic acid), Poly(aspartic acid), carboxymethyl cellulose, cellulose sulfate, agarose, alginate, carrangeenan, hyaluronic acid, dextran, chitosan, poly(hydroxybutyric acid), poly(alkylene succinate), polyamide, poly(anhydride), poly(ortho-ester), poly(cyano acrylates), polyphosphazene, poly(hydroxyethyl metacrylate), poly(methyl metacrylate), poly(tetrafluoroethylene), poly(dimethylsiloxane), poly(ethyleneoxide-β-propyleneoxide), Poly(vinylmethylether), Poly(N-alkylacrylamide), decelluarized matrix (dECM) 및 이들의 조합을 포함하나, 이에 제한되는 것은 아니다.More specifically, the biocompatible polymer used in the present invention is an aliphatic polyester, PLA [poly(lactide)], PGA [poly(glycolide)], PDO [poly(dioxanone)]), PBL [poly(butyrolactone)], PVL [poly(valerolactone)], PLGA [poly(lactide-co-glycolide)], PCL [poly(caprolactone)], or a combination thereof.

[0024] In the present invention, “poloxamer” is a nonionic triblock copolymer in which hydrophilic ethylene oxide is bonded to both ends of a hydrophobic propylene oxide, and has the characteristic of being temperature sensitive, so that it can be converted into a sol and a gel depending on the concentration and temperature, and the properties of the poloxamer change depending on the ratio of polyoxypropylene and polyoxyethylene. In addition to being a surfactant, poloxamer is also used as an emulsifier, stabilizer, and solubilizer.

[0025] In the present invention, the poloxamer may have an average molecular weight of 100 to 20,000 Da.

[0026] The above poloxamer is poloxamer 101, poloxamer 105, poloxamer 105 benzoate, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 182 dibenzoate, poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217, poloxamer 231, poloxamer 234, poloxamer 235, poloxamer 237, poloxamer 238, poloxamer 282, poloxamer 284, poloxamer 288, It may be selected from the group consisting of poloxamer 331, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 401, poloxamer 402, poloxamer 403 and poloxamer 407, and in one embodiment of the present invention, includes, but is not limited to, poloxamer 407 and poloxamer 188.

[0027] In the case of the generic term "poloxamer", these copolymers are often designated by the letter P (for poloxamer) followed by a three-digit number: the first two digits multiplied by 100 give an approximation of the molecular mass of the polyoxypropylene core, and the last digit multiplied by 10 gives the percentage polyoxyethylene content (e.g. P407 = poloxamer with a polyoxypropylene molecular mass of 4000 g / mol and a polyoxyethylene content of 70%). See Schmolka IR. Poloxamers in the pharmaceutical industry. In: Tarcha PJ, ed. Polymers for Controlled Drug Delivery, CRC Press, Boca Raton, FL 1991, pp 189-214.

[0028] Poloxamer 407 (poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)) is a specific nonionic polyoxyethylene-polyoxypropylene block copolymer having a polyoxypropylene portion having a molecular weight of about 4,000 daltons, a polyoxyethylene content of about 70%, and a total molecular weight of about 9,840 daltons to about 14,600 daltons, but is not limited thereto.

[0029]

[0030] 1. An anti-adhesion composition comprising gallic acid-conjugated hyaluronic acid (HA-GA) as an active ingredient.

[0031] In one embodiment of the present invention, an anti-adhesion composition is provided, which comprises gallic acid-conjugated hyaluronic acid (HA-GA) as an active ingredient.

[0032] In the present invention, the “polymer” or “polymer” is a molecule formed into a long chain with regular repeating units through a chemical reaction of monomer molecules. It is a compound word of the Greek words polus (many) and meros (parts), and is also called macromolecule.

[0033] In the present invention, the "hydrogel" or "hydrogel" is also called a hydrogel, and refers to a material that does not dissolve in an aqueous environment and can contain a significant amount of water, as a network structure in which water-soluble polymers form three-dimensional cross-links through physical (hydrogen bonds, van der Waals forces, hydrophobic interactions, or polymer crystals) or chemical (covalent bonds) bonds. Hydrogels can be made from various water-soluble polymers and therefore have various chemical compositions and properties. Furthermore, they are easy to process and can be transformed into various shapes depending on the application. As can be seen from their successful applications in the peritoneum and various other parts of the body, hydrogels have high biocompatibility due to their high water content and physicochemical similarity to the extracellular matrix. Due to these characteristics, hydrogels have attracted attention as one of the most attractive materials for medical and pharmacological applications.

[0034] The above “gallic acid” or “Gallic acid” or “GA” is a substance whose molecular formula is C7H6O5 and whose chemical formula is C6H2(OH)3COOH, and is represented by the following chemical formula 5.

[0035] [Chemical Formula 5]

[0036]

[0037] The above gallic acid is 3,4,5-trihydroxybenzoic acid, a type of phenolic acid found in extracts from various plants including Galla Rhois, Orostachys japonica, Damnacanthus major, and Acanthopanax koreanum.

[0038] In the present invention, the term "gallic acid derivative" or "gallic acid derivative" refers to a derivative having three hydroxyl groups as a basic structure and capable of including a functional group capable of bonding with a carboxyl group or a linker. The gallic acid derivative can exhibit the effect of the adhesion inhibitor provided in the present invention by having three hydroxyl groups present in the meta and para positions. Non-limiting examples of the gallic acid derivative are as follows.

[0039]

[0040] The above-mentioned "hyaluronic acid" or "HA" is a biosynthetic natural substance found abundantly in the skin of animals and other species. Because it contains many hydroxyl groups (-OH), it is a hydrophilic substance and plays a moisturizing role in the skin of animals and other species. It is also found in human skin, and is known to be particularly abundant in the skin of earthworms. Because of its moisturizing properties, it is widely used in cosmetics and other products. It is known to regulate various physiological functions by reacting with the CD44 protein expressed in various epithelial cells, and is a substance represented by the following chemical formula 6.

[0041] [Chemical Formula 6]

[0042]

[0043]

[0044] In the present invention, examples of the “hyaluronic acid” or “hyaluronic acid” may include, but are not limited to, substances including salts such as sodium hyaluronate, potassium hyaluronate, ammonium hyaluronate, calcium hyaluronate, magnesium hyaluronate, and tetrabutylammonium hyaluronate.

[0045]

[0046] In the present invention, the term “hyaluronic acid derivative” or “hyaluronic acid derivative” refers to a chemical derivative of hyaluronic acid in which some chemical functional groups of hyaluronic acid are replaced with other functional groups, or are combined with gallic acid or a gallic acid derivative through a chemical bond with the chemical functional group, or are combined with various linkers in the bond between hyaluronic acid and gallic acid or a gallic acid derivative, but is not limited thereto.

[0047]

[0048] The above “hyaluronic acid introduced with gallic acid” or “Gallic acid-conjugated hyaluronic acid, HA-GA” refers to a material or polymer material in which gallic acid and hyaluronic acid are connected by a chemical bond, typically a covalent bond, and the chemical bond introducing gallic acid into hyaluronic acid includes not only a covalent bond but also various chemical bonds known in the art.

[0049]

[0050] In another embodiment of the present invention, an anti-adhesion composition is provided, wherein the gallic acid is introduced into a carboxyl group of hyaluronic acid.

[0051] The above "carboxyl group" or "carboxyl group" is a functional group composed of carbon, oxygen, and hydrogen, and is represented by the functional group of carboxylic acid, -COOH. Furthermore, the name carboxyl group is derived from the combination of the two elements it contains: a carbonyl group and a hydroxyl group. The structure of a carboxyl group consists of a central carbon atom, with one oxygen atom double bonded to it, and one hydroxyl group single bonded to it. In molecular formula terms, a carboxyl group has a hydroxyl group attached to a carbonyl group in the form of -C=O-. Due to the difference in electronegativity between oxygen and carbon, the carbon atom carries a partial positive charge. Therefore, the carboxyl carbon atom is susceptible to nucleophilic attack. The hydroxyl portion of the carboxyl group is relatively acidic, and the proton is readily donated to a suitable partner. The increased acidity (acid strength) compared to alcohols is due to the resonance stabilization of the corresponding base, which is a negatively charged carboxylate anion. In the carboxylate anion (-COO-), the two oxygen atoms are equivalent, meaning that the negative charge is distributed across both oxygen atoms and both CO bonds have the characteristics of a partial double bond.

[0052] That is, the carboxyl group of hyaluronic acid and the carboxylic acid of gallic acid chemically bond, and gallic acid can be introduced to the carboxyl group of hyaluronic acid. However, the location where the hyaluronic acid and gallic acid chemically bond is not necessarily limited to the carboxyl group of hyaluronic acid or gallic acid.

[0053]

[0054] In another embodiment of the present invention, an anti-adhesion composition is provided, which further comprises a linker between the carboxyl group of the hyaluronic acid and gallic acid.

[0055] The above “linker” may be composed of peptides, polyethylene glycol, fatty acids, sugars, high molecular polymers, low molecular compounds, nucleotides, and combinations thereof, and may be any chemical bond such as a non-covalent chemical bond or a covalent chemical bond, without limitation. However, it may preferably be an adipic acid dihydrazide (ADH) linker, and both ends of the ADH linker may be connected to the carboxyl groups of hyaluronic acid and gallic acid through a dehydration bond, but is not limited thereto.

[0056] The above “adipic acid dihydrazide linker” or “adipic acid dihydrazide, ADH” is a linker mainly used for the conjugation of polysaccharides and transport proteins, and both ends are composed of a dual functional group of hydrazide, and the six carbons constituting the ADH linker exhibit hydrophobic properties due to their physicochemical properties.

[0057]

[0058] In another embodiment of the present invention, an anti-adhesion composition is provided, wherein the composition is represented by the following chemical formula 7.

[0059] [Chemical Formula 7]

[0060]

[0061] In the above chemical formula 1, x:y is 1:99 to 50:50, preferably x:y is 1:99 to 15:85, and more preferably x:y is 3:99 to 10:90 in the above chemical formula 1, but is not limited thereto.

[0062]

[0063] In another embodiment of the present invention, an anti-adhesion composition is provided, which further comprises hyaluronic acid in the composition.

[0064]

[0065] In another embodiment of the present invention, an anti-adhesion composition is provided, wherein the composition ratio of hyaluronic acid to which gallic acid is introduced and hyaluronic acid is 1:9 to 9:1 by weight.

[0066] The above “weight ratio” is also called “weight ratio,” and a person skilled in the art can accurately understand and reproduce the meaning of the word. In addition, the weight ratio of the hyaluronic acid to which gallic acid has been introduced and the hyaluronic acid is preferably 1:9 to 9:1, more preferably 1:9 to 9:2, and even more preferably 1:9 to 1:3, but is not limited thereto. When mixed at such a weight ratio, the viscosity, adhesiveness, and applicability as an anti-adhesion agent were excellent.

[0067] Flowing can be controlled by mixing hyaluronic acid and hyaluronic acid with the above gallic acid, and a viscosity control agent can be added to control viscosity.

[0068] If the above viscosity modifier has been confirmed to be safe and has no side effects when injected into the human body, there is no problem in using it.

[0069] The viscosity modifier may be glucomannan, guar gum, locust bean gum, xanthan gum, glucose, carboxymethylated starch, mannose, galactose, arabinose, fucose, ribose, fructose, or the like.

[0070]

[0071] In another embodiment of the present invention, an anti-adhesion composition is provided, wherein the anti-adhesion composition is used by injection.

[0072] In the present invention, the unit of the injection is indicated as “gauge (G)” according to the standard of the injection needle designated by the International Organization for Standardization (ISO), and a larger number means a thinner needle. Generally, a 22G diameter needle is used for a butterfly needle, 20G for a peripheral venous line, 18G for an operating room venous line, 18G for CT contrast media, 16G for blood donation / blood transfusion, and 25G or 26G for infants and young children; however, this may vary depending on the patient’s vascular condition, etc.

[0073] In addition, the hyaluronic acid-gallic acid or hyaluronic acid-gallic acid / hyaluronic acid adhesion prevention composition or adhesion prevention agent according to the present invention has an appropriate viscosity that allows easy injection even with a 26G diameter needle, which is the smallest needle used for infants and toddlers, and thus has the advantage of being convenient to use in actual medical settings.

[0074]

[0075] 2. Anti-adhesion agent containing gallic acid-conjugated hyaluronic acid (HA-GA) as an active ingredient

[0076] In one embodiment of the present invention, an anti-adhesion agent is provided that includes gallic acid-conjugated hyaluronic acid (HA-GA) as an active ingredient.

[0077] In the present invention, the above “adhesion” refers to a phenomenon in which tissues or organs of the human body that should be separated from each other form fibrous tissue due to a wound and do not separate from each other (Kwon YH, et al., 2004), and may occur when fibrous tissue is excessively created or blood leaks and coagulates during the healing process of wounds such as those caused by inflammation, wounds, friction, surgery, etc.

[0078] Furthermore, the term "adhesion" can refer to a phenomenon in which separate skin or membranes stick together. When tissue damage occurs after surgery, inflammation, foreign bodies, bleeding, infection, wounds, friction, or chemical treatments, blood leaks out and coagulates during the wound healing process, resulting in abnormal adhesions with surrounding tissues. These adhesions occur particularly frequently after surgery, and when adhesions occur in the pelvis, they can cause chronic pain and sexual dysfunction. Furthermore, when scar tissue forms after thyroid removal, adhesions can cause side effects such as chest pain and decreased swallowing ability. When spinal surgery causes adhesions, they compress nerves, causing severe pain. Furthermore, uterine adhesions are known to cause infertility, amenorrhea, and recurrent miscarriage.

[0079] The above hyaluronic acid is a straight chain natural acidic mucopolysaccharide in which β-DN-acetylglucosamine and β-D-glucuronic acid are alternately bonded at β-1, 3 and β-1, 4, and it is a high molecular weight compound with a molecular weight ranging from 50,000 to 800,000 depending on the regulation method. It has no species or organ specificity and has excellent biocompatibility and very high viscoelasticity even when transplanted or injected into the body. Due to these characteristics, hyaluronic acid can be used in various applications such as implants for the treatment of arthritis, gels / films for preventing adhesion, drug delivery vehicles, and plastic surgery aids.

[0080] When hyaluronic acid is used alone as the above-mentioned anti-adhesion agent, the retention time in the body is relatively short due to the excellent biocompatibility and biodegradability of hyaluronic acid, resulting in a weak anti-adhesion effect. In addition, due to its high water solubility, it diffuses and flows away from the wound surface in a short period of time. The anti-adhesion agent of the present invention, which comprises hyaluronic acid with gallic acid as an active ingredient, solves the above-mentioned problems and exhibits excellent biocompatibility and tissue regeneration properties.

[0081] The formulations of the above anti-adhesion agent can be divided into solution formulations, gel formulations, and film formulations.

[0082] When the above solution preparation is used by spraying, it is preferable to have a particle size of less than 200㎛ to enable spraying, and when simple application is used, it is preferable to have particles of less than 1,000㎛.

[0083] The above film formulation frequently requires removal and re-application after application. Therefore, when formulated as a film formulation, it is desirable for the anti-adhesion agent to have both excellent initial and re-adhesive properties. The scope of the present invention is not limited to this, and can be applied to various formulations.

[0084]

[0085] In another embodiment of the present invention, an anti-adhesion agent is provided, wherein the gallic acid is introduced into a carboxyl group of hyaluronic acid.

[0086] In another embodiment of the present invention, an anti-adhesion agent is provided, which further comprises a linker between the carboxyl group of the hyaluronic acid and gallic acid.

[0087] In another embodiment of the present invention, the composition provides an anti-adhesion agent represented by the following chemical formula 8.

[0088] [Chemical Formula 8]

[0089]

[0090] In the above chemical formula 1, x:y is 1:99 to 50:50, preferably x:y is 1:99 to 15:85, and more preferably x:y is 3:99 to 10:90 in the above chemical formula 1, but is not limited thereto.

[0091] In another embodiment of the present invention, an anti-adhesion agent is provided, which further comprises hyaluronic acid in the composition.

[0092] In another embodiment of the present invention, an anti-adhesion agent is provided in which the composition ratio of the hyaluronic acid to which the gallic acid is introduced and the hyaluronic acid is 1:9 to 9:1 by weight.

[0093] The above “weight ratio” is also called “weight ratio,” and a person skilled in the art can accurately understand and reproduce the meaning of the word. In addition, the weight ratio of the hyaluronic acid to which gallic acid has been introduced and the hyaluronic acid is preferably 1:9 to 9:1, more preferably 1:9 to 9:2, and even more preferably 1:9 to 1:3, but is not limited thereto. When mixed at such a weight ratio, the viscosity, adhesiveness, and applicability as an anti-adhesion agent were excellent.

[0094] In another embodiment of the present invention, an anti-adhesion agent is provided, wherein the anti-adhesion agent is used by injection.

[0095]

[0096] Since the hyaluronic acid, gallic acid, and injection used in the present invention have already been described above, their description is omitted to avoid excessive duplication.

[0097]

[0098] 3. A method for producing an anti-adhesion composition, wherein hyaluronic acid (HA) is synthesized through a one-pot process together with an adipic acid dihydrazide (ADH) linker and gallic acid.

[0099] In one embodiment of the present invention, a method for producing an anti-adhesion composition is provided, wherein hyaluronic acid (HA) is synthesized together with an adipic acid dihydrazide (ADH) linker and gallic acid through a one-pot process.

[0100] The "one-pot" process, as used herein, refers to a process in which two or more chemical transformations are performed starting from a substrate in a single reactor unit, without the isolation or separation of any reaction intermediates. This one-pot process eliminates the need for a separate process, thereby simplifying the process, increasing yield, and reducing costs.

[0101] In another embodiment of the present invention, a method for producing an anti-adhesion composition is provided, wherein the one-pot process is performed in a chlorine-based organic solvent.

[0102] As a non-limiting example of the above chlorinated organic solvent, one or a mixture of two or more selected from the group consisting of chloroform, methylene chloride, carbon tetrachloride, carbon dichloride, trichloroethane, vinyl chloride, ethylene dichloride, trichloroethylene, and tetrachloroethylene may be used, and preferably, ethylene dichloride (EDC) solvent may be used.

[0103] In another embodiment of the present invention, a method for preparing an anti-adhesion composition is provided, wherein the hyaluronic acid is represented by the following chemical formula 9:

[0104] [Chemical Formula 9]

[0105]

[0106] In the above chemical formula 2, n = an integer from 13 to 13,200, preferably n = an integer from 100 to 5,300, more preferably n = an integer from 260 to 4,000, but is not limited thereto.

[0107] Since hyaluronic acid, gallic acid, etc. used in the present invention have already been described above, their description is omitted to avoid excessive duplication.

[0108]

[0109] 4. A method for manufacturing an anti-adhesion agent, which comprises synthesizing hyaluronic acid (HA) together with an adipic acid dihydrazide (ADH) linker and gallic acid through a one-pot process.

[0110] In one embodiment of the present invention, a method for producing an anti-adhesion agent is provided, wherein hyaluronic acid (HA) is synthesized together with an adipic acid dihydrazide (ADH) linker and gallic acid through a one-pot process.

[0111] In another embodiment of the present invention, a method for producing an anti-adhesion agent is provided, wherein the one-pot process is performed in a chlorine-based organic solvent.

[0112] In another embodiment of the present invention, a method for producing an anti-adhesion agent is provided, wherein the chlorinated organic solvent is one or a mixture of two or more selected from the group consisting of chloroform, methylene chloride, carbon tetrachloride, carbon dichloride, trichloroethane, vinyl chloride, ethylene dichloride, trichloroethylene, and tetrachlorethylene.

[0113] In another embodiment of the present invention, a method for producing an anti-adhesion agent is provided, wherein the hyaluronic acid is represented by the following chemical formula 9:

[0114] [Chemical Formula 9]

[0115]

[0116] In the above chemical formula 2, n = an integer from 13 to 13,200, preferably n = an integer from 100 to 5,300, more preferably n = an integer from 260 to 4,000, but is not limited thereto.

[0117] Since hyaluronic acid, gallic acid, etc. used in the present invention have already been described above, their description is omitted to avoid excessive duplication.

[0118]

[0119] In the present invention, adipic acid dihydrazide (ADH) and gallic acid were introduced into hyaluronic acid (HA) through a one-pot process to synthesize hyaluronic acid-adipic acid dihydrazide-gallic acid (HA-GA), and its characteristics were analyzed. The hyaluronic acid-gallic acid hydrogel not only forms a hydrogel and maintains stability under biological conditions, but also has self-healing and shear-thinning properties, so that an injectable hydrogel is formed with a low elastic modulus (G') before and after injection. In addition, when the hyaluronic acid-gallic acid hydrogel was injected onto the tissue, it was confirmed that it was well fixed onto the target tissue without running off, unlike existing solution-type adhesion preventive agents. This hyaluronic acid-gallic acid-based adhesion inhibitor is fixed to the surgical site and can effectively prevent tissue or organ adhesion that may occur after surgery, so it is expected to be utilized in various biomedical engineering fields.

[0120]

[0121] Figure 1 is a nuclear magnetic resonance spectrum of hyaluronic acid-gallic acid (HA-GA) manufactured in Manufacturing Example 1. 1 (H-NMR spectrum) is shown.

[0122] Figure 2a shows the UV-Vis spectra of hyaluronic acid-gallic acid (HA-GA), and Figure 2b shows the UV-Vis spectra of gallic acid (GA) according to concentration.

[0123] Figure 3a shows the rheological properties of hyaluronic acid, and Figure 3b shows the rheological properties of hyaluronic acid-gallic acid (HA-GA).

[0124] Figure 4 shows the results of step-strain measurements of hyaluronic acid-gallic acid (HA-GA).

[0125] Figure 5 shows the results of frequency sweep measurements of hyaluronic acid-gallic acid (HA-GA) synthesized in various batches.

[0126] Figure 6 shows the results of analyzing the injectability characteristics of hyaluronic acid-gallic acid (HA-GA) using syringe needles with various diameters.

[0127] Figure 7 shows the results of analysis of the injectable duration of hyaluronic acid-gallic acid (HA-GA) using a 26 gauge syringe needle.

[0128] Figure 8 shows the results of analyzing the shear-thinning property of hyaluronic acid-gallic acid (HA-GA).

[0129] Figure 9 shows the results of analyzing the shear-thinning property of hyaluronic acid-gallic acid / hyaluronic acid (HA-GA / HA).

[0130] Figure 10 shows the results of analyzing the in vitro stability of hyaluronic acid, hyaluronic acid-gallic acid, and hyaluronic acid-gallic acid / hyaluronic acid (HA-GA / HA).

[0131] Figure 11 illustrates a method for analyzing target tissue fixation of hyaluronic acid (HA) and hyaluronic acid-gallic acid / hyaluronic acid (HA-GA / HA).

[0132] Figure 12 shows the results of analyzing the target tissue fixation of hyaluronic acid (HA) and hyaluronic acid-gallic acid / hyaluronic acid (HA-GA / HA).

[0133] Figure 13 shows the results of analyzing the tissue adhesive properties of hyaluronic acid, hyaluronic acid-gallic acid, and hyaluronic acid-gallic acid / hyaluronic acid (HA-GA / HA).

[0134] Figure 14 is a diagram summarizing the rheological properties of hyaluronic acid-gallic acid / poloxamer 407 (HA-GA / po).

[0135] Figure 15a shows the viscosity coefficient of hyaluronic acid-gallic acid / poloxamer 407 (HA-GA / po) at 25°C.

[0136] Figure 15b shows the rheological properties of hyaluronic acid-gallic acid / poloxamer 407 (HA-GA / Po) at 37°C.

[0137] Figure 16 shows the gelation point profile of hyaluronic acid-gallic acid / poloxamer 407 (HA-GA / Po).

[0138]

[0139] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples, in accordance with the gist of the present invention.

[0140]

[0141] Manufacturing example

[0142] Manufacturing Example 1. Manufacturing of hyaluronic acid-gallic acid (HA-GA)

[0143] In the present invention, in order to introduce gallic acid into a hyaluronic acid polymer, an adipic acid dihydrazide (ADH) linker was utilized, and hyaluronic acid-gallic acid was synthesized through a one-pot process that simultaneously combines hyaluronic acid, adipic acid dihydrazide, and gallic acid.

[0144] Specifically, through the above method, the present invention produced hyaluronic acid-gallic acid represented by the following chemical formula 10.

[0145] The molecular weights of hyaluronic acid-gallic acid manufactured through the above method were 200 kDa, 700 kDa, and 1 MDa, respectively. Specifically, when the molecular weight of hyaluronic acid-gallic acid is 200 kDa, n = 527.7, x = 503.3, y = 26.4; when the molecular weight of hyaluronic acid-gallic acid is 700 kDa, n = 1,847.0, x = 1,754.6, y = 92.4; and when the molecular weight of hyaluronic acid-gallic acid is 1 MDa, n = 2,638.5, x = 2,506.6, y = 131.9.

[0146] [Chemical Formula 10]

[0147]

[0148] In the above formula, n = an integer from 13 to 13,200, preferably n = an integer from 100 to 5,300, and more preferably n = an integer from 260 to 4,000. In the above formula, x : y = 1 : 99 to 50 : 50, more preferably x : y = 1 : 99 to 15 : 85, and even more preferably x : y = 3 : 99 to 10 : 90.

[0149]

[0150] Based on the hyaluronic acid-gallic acid polymer synthesized in Manufacturing Example 1, its spectroscopic properties, rheological properties, self-healing properties, flowability analysis, injectability properties, shear-thinning properties, and in vitro degradability properties were analyzed in the following examples. In addition, in order to utilize it as an anti-adhesion agent, hyaluronic acid and hyaluronic acid-gallic acid materials were mixed to ultimately develop it into the form of an anti-adhesion agent.

[0151]

[0152] Manufacturing Example 2. Specific manufacturing method of hyaluronic acid-gallic acid (HA-GA)

[0153] 500 mg of hyaluronic acid was dissolved in 100 mL of distilled and deionized water (DDW), 434 mg of adipic acid dihydrazide (ADH) and 212 mg of gallic acid (GA) were added, and the pH was maintained at 4.5-4.7 for 4 hours. 478 mg of 1-ethyl-3-(3-dimethylamino propyl) carbodiimide (EDC) was added and the reaction was continued for 6 hours. The pH was maintained at 4.5-4.7 during the reaction. The synthesized hyaluronic acid-gallic acid was purified using a dialysis membrane (Dialysis membrane, MWCO = 3.5 kDa or 12-14 kDa), and was processed for 3 days in a 100 mM NaCl solution at pH 2.5-3.0, for 2 days in distilled water at pH 2.5-3.0, and additionally for 4-6 hours in distilled water. Finally, the purified hyaluronic acid-gallic acid was freeze-dried and stored.

[0154]

[0155] Manufacturing Example 3. Confirmation of Synthesis of Hyaluronic Acid-Galic Acid (HA-GA)

[0156] It was confirmed that hyaluronic acid-gallic acid (HA-GA) synthesis was properly performed in Manufacturing Example 1 using nuclear magnetic resonance spectrum and ultraviolet-visible spectra (UV-Vis spectra).

[0157]

[0158] As a result, as shown in Fig. 1, the introduction of gallic acid into the hyaluronic acid polymer in hyaluronic acid-gallic acid (HA-GA) was analyzed using the nuclear magnetic resonance spectrum, and the proton of the aromatic ring of galol was found at 6.8-7.0 ppm, confirming the synthesis of the hyaluronic acid-gallol material. In addition, as shown in Fig. 2, the introduction of gallic acid (GA) into the hyaluronic acid polymer in hyaluronic acid-gallic acid (HA-GA) was analyzed using the UV-Vis spectra, and the degree of gallic acid substitution in the hyaluronic acid polymer was determined through the standard curve of gallic acid according to the concentration.

[0159]

[0160] Example

[0161] Example 1. Rheological properties of hyaluronic acid-gallic acid (HA-GA) - verification of hydrogel formation

[0162] Frequency sweep measurements were performed to analyze the characteristics of the hyaluronic acid-gallic acid (HA-GA) manufactured in the previous manufacturing example, which can be stably fixed on the surface by forming a hydrogel with an elastic modulus above a certain level. In general, the elastic modulus (G', Pa), which shows the rheological properties of a material, is known to represent the solid properties of the material, and the viscous modulus (G'', Pa), which shows the liquid properties of the material.

[0163]

[0164] As a result, as shown in Fig. 3, in the case of hyaluronic acid, the liquid properties were higher than the solid properties, whereas in the case of hyaluronic acid-gallic acid (HA-GA), the solid properties were higher than the liquid properties, confirming that a hydrogel was formed. As a result of analyzing the elastic modulus at a frequency of 1 Hz, it was confirmed to be 1.9 ± 0.3 kP.

[0165]

[0166] Example 2. Analysis of self-healing properties of hyaluronic acid-gallic acid (HA-GA)

[0167] To analyze the self-healing properties of the hyaluronic acid-gallic acid (HA-GA) prepared in the previous manufacturing example, step-strain measurement was performed. To this end, the elastic modulus and viscous modulus of the hyaluronic acid-gallol hydrogel were analyzed by applying strains of 0.5%, 1,000%, 0.5%, 1,000%, and 0.5% for 120 seconds each.

[0168]

[0169] As a result, as shown in Fig. 4, when a strain of 1,000% was applied to the hyaluronic acid-gallic acid (HA-GA) hydrogel, the elastic modulus decreased rapidly, and then recovered when a strain of 0.5% was applied again. This shows that hyaluronic acid-gallic acid (HA-GA) has self-healing properties, so that when injected using a syringe, it has a low elastic modulus, but after injection, the elastic modulus recovers.

[0170]

[0171] Example 3. Rheological property analysis of hyaluronic acid-gallic acid (HA-GA) by batch

[0172] The elastic modulus, which is an important indicator for the reproducibility of the synthesis of hyaluronic acid-gallic acid (HA-GA) manufactured in the previous manufacturing example, was compared and analyzed. In particular, in this example, several batches of hyaluronic acid-gallic acid (HA-GA) were synthesized, and the rheological properties were analyzed through frequency sweep measurements, and the changes in the elastic modulus were observed.

[0173]

[0174] As a result, as shown in Fig. 5, it was confirmed that there was no significant difference between each batch. Ultimately, it was confirmed that the hyaluronic acid-gallic acid (HA-GA) according to the present invention can form a hydrogel and the elastic modulus is restored even when synthesized in various batches.

[0175]

[0176] Example 4. Analysis of the possibility of injection of hyaluronic acid-gallic acid (HA-GA)

[0177] In order to analyze the injectability of the hyaluronic acid-gallic acid (HA-GA) manufactured in the manufacturing example above, the diameter (inner diameter) of the syringe needle through which the hyaluronic acid-gallic acid (HA-GA) hydrogel passes and the injectable time were analyzed.

[0178]

[0179] As a result, as shown in Fig. 6, it was confirmed that hyaluronic acid-gallic acid (HA-GA) was easily injected not only with an 18-gauge needle, which is generally used when injecting hydrogels, but also with a 26-gauge needle, and that continuous injection was possible without the needle becoming clogged. In other words, it was confirmed that the hyaluronic acid-gallic acid (HA-GA) according to the present invention had gel properties at an appropriate level to enable injection even with a thin needle.

[0180]

[0181] Example 5. Analysis of the injectable duration of hyaluronic acid-gallic acid (HA-GA)

[0182] In the injection of hyaluronic acid-gallic acid (HA-GA) manufactured in the previous manufacturing example, the injection duration was analyzed using a 26 gauge syringe needle.

[0183]

[0184] As a result, as shown in Fig. 7, it was confirmed that injection was possible using a 26-gauge syringe needle, and that continuous injection was possible for more than 10 minutes. In other words, it was confirmed that the hyaluronic acid-gallic acid (HA-GA) according to the present invention possesses an appropriate level of gel properties to enable injection even with a thin needle and continuous injection for more than 10 minutes.

[0185]

[0186] Example 6. Analysis of shear-thinning properties of hyaluronic acid-gallic acid (HA-GA)

[0187] In general, materials with shear-thinning properties have a characteristic of decreasing viscosity (Pa.s) as the shear rate increases. In the case of hyaluronic acid-gallic acid (HA-GA), it is expected to have shear-thinning properties because hydrogen bonding is possible through the hydroxyl (-OH) group in the galol group. As a result of observing the viscosity according to the shear rate through the viscometry mode using a rheometer, it was found that the viscosity (Pa.s) decreases as the shear rate increases.

[0188]

[0189] Therefore, as shown in Fig. 8, in the case of hyaluronic acid-gallic acid (HA-GA) manufactured in the previous manufacturing example, it was confirmed that it had shear-thinning properties as a result of hydrogen bonding through the hydroxyl (-OH) group in the galrol group.

[0190]

[0191] Example 7. Analysis of shear-thinning properties of hyaluronic acid-gallic acid / hyaluronic acid (HA-GA / HA)

[0192] As discussed in Examples 1 to 6, the hyaluronic acid-gallic acid (HA-GA) hydrogel was demonstrated to be injectable and possess self-healing properties. Therefore, it is clear that the hyaluronic acid-gallic acid (HA-GA) hydrogel alone exhibits superior efficacy compared to existing anti-adhesion agents.

[0193] However, as a result of observing the viscosity according to the shear rate, the viscosity was relatively high, so research was conducted to improve this and develop a more effective anti-adhesion agent. As a result, the composition of the improved anti-adhesion agent was analyzed by changing the mass ratio using hyaluronic acid and a hyaluronic acid-gallic acid mixture.

[0194]

[0195] As a result, as shown in Fig. 9, in the case of hyaluronic acid-gallic acid / hyaluronic acid (1:9 w / w), not only was injection successful even with a 26 gauge needle, but the viscosity was also significantly lower than when only hyaluronic acid-gallic acid was used.

[0196]

[0197] Example 8. In vitro stability analysis of hyaluronic acid-gallic acid and hyaluronic acid-gallic acid / hyaluronic acid (HA-GA / HA)

[0198] In order to analyze the in vitro stability of hyaluronic acid-gallic acid (HA-GA) and hyaluronic acid-gallic acid / hyaluronic acid (HA-GA / HA) manufactured in the previous manufacturing example, 0.5 mL of pH 7.4 PBS was added to 0.5 mL of hyaluronic acid-gallic acid (HA-GA) hydrogel, and the weight of chitosan-gallol remaining over time was measured.

[0199]

[0200] As a result, as shown in Fig. 10, hyaluronic acid was found to completely disappear within a few hours, and in the case of hyaluronic acid-gallol, it was observed that more than 30% remained after 7 days. In addition, in the case of hyaluronic acid-gallic acid / hyaluronic acid (1:9 w / w), it was observed to persist for approximately 3 days and then disappear, confirming its advantageous application as an adhesion inhibitor.

[0201]

[0202] Example 9. Analysis of target tissue fixation of hyaluronic acid (HA) and hyaluronic acid-gallic acid / hyaluronic acid (HA-GA / HA)

[0203] In order to analyze the target tissue fixation of the hyaluronic acid-gallic acid / hyaluronic acid (HA-GA / HA) anti-adhesion material manufactured in the manufacturing example above, as shown in Fig. 11, the same concentration of hyaluronic acid and hyaluronic acid-gallic acid / hyaluronic acid (HA-GA / HA) were applied onto the intestine of a fresh pig, and the degree of flow in the direction of gravity over time was analyzed.

[0204]

[0205] As a result, as shown in Fig. 12, it can be confirmed that while hyaluronic acid flows out within a few minutes, the hyaluronic acid-gallic acid / hyaluronic acid (HA-GA / HA) anti-adhesion material does not flow but is fixed to the target tissue. As seen in Example 6, etc., it was confirmed that not only can it be injected well even with a thin needle such as a 26 gauge needle, but it also has the unpredictable effect of being well fixed to the target tissue.

[0206]

[0207] Example 10. Analysis of tissue adhesive properties of hyaluronic acid (HA), hyaluronic acid-gallic acid, and hyaluronic acid-gallic acid / hyaluronic acid (HA-GA / HA).

[0208] The adhesive strength of the hyaluronic acid-gallic acid and hyaluronic acid-gallic acid / hyaluronic acid (HA-GA / HA) manufactured in the manufacturing example above was analyzed under various conditions using porcine intestinal tissue. As shown in Fig. 13, the hyaluronic acid, hyaluronic acid-gallol, and hyaluronic acid-gallic acid / hyaluronic acid (HA-GA / HA) compositions were found to exhibit low tissue adhesive properties, and there was no significant difference between each group. That is, it was confirmed that the present invention manufactured in the manufacturing example can effectively prevent adhesion of organs or tissues by being well fixed to the target tissue but not adhering to the tissue.

[0209]

[0210] Example 11. Rheological properties and gel point determination of hyaluronic acid-gallic acid / poloxamer 407 (HA-GA / Po)

[0211] As discussed in Examples 1 to 6, the hyaluronic acid-gallic acid (HA-GA) hydrogel was demonstrated to be injectable and possess self-healing properties. Therefore, it is clear that the hyaluronic acid-gallic acid (HA-GA) hydrogel alone exhibits superior efficacy compared to existing anti-adhesion agents.

[0212] However, in order to improve the user convenience, research was conducted to develop a more effective anti-adhesion agent. As a result, the composition of the improved anti-adhesion agent was analyzed by varying the mass ratio using a mixture of hyaluronic acid-gallic acid and poloxamer 407.

[0213] As shown in Figs. 14, 15a, and b, hyaluronic acid-gallic acid / poloxamer (HA-GA / Po) has a low viscosity coefficient at 25°C, which is the working environment, making it easier to inject using a syringe than hyaluronic acid-gallic acid. In addition, hyaluronic acid-gallic acid / poloxamer (HA-GA / Po) has a high elastic modulus at 37°C, which is the same temperature as human body temperature. Therefore, it has gel properties at human body temperature and has sufficient fixation properties.

[0214] In addition, as shown in Fig. 16, hyaluronic acid-gallic acid / poloxamer (HA-GA / Po) has the property of being gelled above a certain temperature due to poloxamer, which is a temperature-sensitive substance. At this time, the gelation point of hyaluronic acid-gallic acid / poloxamer (HA-GA / Po) can be controlled by controlling the mixed concentration of hyaluronic acid-gallic acid (HA-GA) / poloxamer (HA-GA / Po).

[0215]

[0216] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the art that these specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. Hydrogel containing a hyaluronic acid derivative polymer.

2. In paragraph 1, A hydrogel characterized in that the hyaluronic acid derivative is selected from the group consisting of sodium hyaluronate, potassium hyaluronate, ammonium hyaluronate, calcium hyaluronate, magnesium hyaluronate, and tetrabutylammonium hyaluronate.

3. In paragraph 2, The above hyaluronic acid derivative is a hydrogel represented by the following chemical formula 1: [Chemical Formula 1] In the above chemical formula 1, R1 is selected from the group consisting of a hydroxyl group, a carbonyl group, a carboxyl group, a hydroperoxy group, a carboxamide group, a primary amine group, and a secondary amine group.

4. In paragraph 3, A linker is chemically bonded to the R1 group of the hyaluronic acid derivative, A hydrogel wherein gallic acid or a gallic acid derivative is additionally chemically bonded to the above linker.

5. In paragraph 4, The above gallic acid derivative is a hydrogel represented by the following chemical formula 2: [Chemical Formula 2] In the above chemical formula 2, R2 is selected from the group consisting of a hydroxyl group, a carbonyl group, a carboxyl group, a hydroperoxy group, a carboxamide group, a primary amine group, and a secondary amine group.

6. In paragraph 5, The above polymer is a hydrogel represented by the following chemical formula 3: [Chemical Formula 3] A hydrogel in which the ratio of x:y in the above chemical formula 3 is 99:1 to 50:

50.

7. In paragraph 6, A hydrogel in which the ratio of x:y in the above chemical formula 3 is 99:1 to 85:

15.

8. In paragraph 7, A hydrogel in which the ratio of x:y in the above chemical formula 3 is 99:3 to 90:

10.

9. In paragraph 8, A hydrogel further comprising hyaluronic acid in the above polymer.

10. In paragraph 9, A hydrogel in which the composition ratio of the above polymer and hyaluronic acid is 1:9 to 9:1 by weight.

11. In paragraph 8, A hydrogel further comprising a biocompatible polymer in the above polymer.

12. In paragraph 11, The above biocompatible polymer is a thermosensitive polymer, a hydrogel.

13. In paragraph 11, The biocompatible polymers include poloxamer, hyaluronic acid (HA), carboxymethyl cellulose (CMC), alginic acid, pectin, carrageenan, chondroitin (sulfate), dextran (sulfate), chitosan, polylysine, collagen, gelatin, carboxymethyl chitin, fibrin, agarose, pullulan, polylactide, polyglycolide (PGA), polylactide-glycolide copolymer (PLGA), polyanhydride, polyorthoester, polyetherester, polycaprolactone, polyesteramide, poly(butyric acid), poly(valeric acid), polyurethane, polyacrylate, A hydrogel comprising at least one selected from the group consisting of ethylene-vinylacetate polymers, acrylic substituted cellulose acetate, non-degradable polyurethanes, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonate polyolefins, polyethylene oxide, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylates, hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), hydroxypropylcellulose (HPC), cyclodextrins and copolymers of monomers forming these polymers, and cellulose.

14. In paragraph 13, The above poloxamer is poloxamer 101, poloxamer 105, poloxamer 105 benzoate, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 182 dibenzoate, poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217, poloxamer 231, poloxamer 234, poloxamer 235, poloxamer 237, poloxamer 238, poloxamer 282, poloxamer 284, poloxamer 288, A hydrogel comprising at least one selected from the group consisting of poloxamer 331, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 401, poloxamer 402, poloxamer 403, and poloxamer 407.

15. In paragraph 12, A hydrogel in which the composition ratio of the above polymer and the thermosensitive polymer is 1:2 to 1:200 by weight.

16. In paragraph 10, The above hydrogel is a hydrogel used by injection.

17. An anti-adhesion agent comprising the hydrogel of claims 1 to 15.

18. A method for manufacturing a hydrogel, which is synthesized through a one-pot process using hyaluronic acid, a linker, and gallic acid.

19. In paragraph 18, A manufacturing method characterized in that the hyaluronic acid is selected from the group consisting of sodium hyaluronate, potassium hyaluronate, ammonium hyaluronate, calcium hyaluronate, magnesium hyaluronate, and tetrabutylammonium hyaluronate.

20. In paragraph 19, The above gallic acid is manufactured by the following chemical formula 2: [Chemical Formula 2] In the above chemical formula 2, R2 is selected from the group consisting of a hydroxyl group, a carbonyl group, a carboxyl group, a hydroperoxy group, a carboxamide group, a primary amine group, and a secondary amine group.

21. In paragraph 20, A manufacturing method wherein the above linker is an adipic acid dihydrazide (ADH) linker.

22. In paragraph 21, A manufacturing method wherein the above one-pot process is carried out in a chlorine-based organic solvent.

23. In paragraph 22, A manufacturing method, wherein the above chlorinated organic solvent is one or a mixture of two or more selected from the group consisting of chloroform, methylene chloride, carbon tetrachloride, carbon dichloride, trichloroethane, vinyl chloride, ethylene dichloride, trichloroethylene, and tetrachlorethylene.

24. In paragraph 23, The above hyaluronic acid is represented by the following chemical formula 2, manufacturing method: [Chemical Formula 4] In the above chemical formula 4, n = an integer from 13 to 13,200.

25. In paragraph 24, A manufacturing method wherein n in the above chemical formula 4 is an integer from 100 to 5,300.

26. In paragraph 25, A manufacturing method wherein n in the above chemical formula 2 is an integer from 260 to 4,000.

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