KR101327083B1 - Method for preparing water non-soluble gels and water non-soluble gels prepared by same method - Google Patents

Method for preparing water non-soluble gels and water non-soluble gels prepared by same method Download PDF

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KR101327083B1
KR101327083B1 KR1020100043161A KR20100043161A KR101327083B1 KR 101327083 B1 KR101327083 B1 KR 101327083B1 KR 1020100043161 A KR1020100043161 A KR 1020100043161A KR 20100043161 A KR20100043161 A KR 20100043161A KR 101327083 B1 KR101327083 B1 KR 101327083B1
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South Korea
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water
composition
soluble polymer
insoluble gel
diglycidyl ether
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KR1020100043161A
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Korean (ko)
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KR20110123602A (en
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아영창
이진희
정주아
배준호
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(주)아모레퍼시픽
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Priority to KR1020100043161A priority Critical patent/KR101327083B1/en
Priority to PCT/KR2011/003357 priority patent/WO2011139103A2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/042—Gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/24—Materials or treatment for tissue regeneration for joint reconstruction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction

Abstract

The present invention comprises the steps of preparing a composition by adding water, a dispersion aid, a water-soluble polymer, a pH adjusting agent and a crosslinking agent; And it discloses a method of producing a water-insoluble gel composition comprising the step of removing the dispersion aid from the composition prepared in the step. Through this method it is possible to efficiently prepare a good quality water insoluble gel composition. The present invention also discloses a water insoluble gel composition prepared by the above method of producing a water insoluble gel composition.

Description

Method for preparing water-insoluble gel composition and water-insoluble gel produced by the same {Method for preparing water non-soluble gels and water non-soluble gels prepared by same method}

The present invention relates to a water insoluble gel composition and a method for producing the same.

Water-soluble polymers classified into natural polymers, semi-synthetic polymers, and synthetic polymers have various functions such as thickening, gelling, moisturizing, and film forming, and thus are widely used in cosmetics, pharmaceuticals, detergents, paints, textiles, civil engineering, construction, etc. It is widely used in the field. In particular, the gelation of the water-soluble polymer has a wide range of applications have been studied for producing a water-soluble polymer as a water-insoluble gel.

The present invention seeks to provide an excellent method for preparing a water insoluble gel composition. It is also an object to provide a water insoluble gel composition having excellent quality and economy prepared by the above method.

One aspect of the present invention comprises the steps of preparing a composition by adding water, a dispersion aid, a water-soluble polymer, a pH adjusting agent and a crosslinking agent; And it provides a method of producing a water-insoluble gel composition comprising the step of removing the dispersion aid from the composition prepared in the step.

Another aspect of the present invention provides a water insoluble gel composition prepared by the method of producing a water insoluble gel composition.

The water-insoluble gel composition manufacturing method according to an aspect of the present invention can easily and efficiently solve the non-uniformity of the composition frequently appeared in the solution preparation step for bonding between the water-soluble polymer in the conventional gel composition manufacturing method, the same crosslinking agent Even if the amount is added, the gel can be obtained in a higher yield than the conventional method. In addition, by adjusting the pH of the water, the functional group capable of selectively binding the water-soluble polymer can be involved in the coupling reaction between the water-soluble polymers.

The water-insoluble gel composition prepared by the above production method has physical properties and appearance such as excellent density, strength and the like. In addition, it is stable to autoclave sterilization which must go through when inserting into the human body, and it is also excellent in economy and quality.

Previously, a method of preparing a water-insoluble gel composition by combining a water-soluble polymer is performed in a solution state in which the water-soluble polymer is dissolved in water, and in order to increase the binding efficiency, the concentration of the water-soluble polymer, the amount or type of crosslinking agent is adjusted, or the temperature, pH and the like were adjusted.

When water-insoluble gel is prepared from a water-soluble polymer using an epoxy-based or divinyl sulfone-based crosslinking agent, a solution containing a high concentration of the water-soluble polymer should be prepared to increase reaction efficiency and gel yield. However, when a high concentration of water-soluble polymer solution is prepared, the viscosity of the solution is so high that it is very difficult to uniform the concentration of the polymer in the solution. In addition, the crosslinking agent introduced for the reaction may also not be uniformly mixed in a high viscosity high concentration polymer solution. Due to this concentration non-uniformity, a very high concentration of crosslinking agent and polymer are present locally, and in this case, the external reaction of the intended main reaction increases rapidly, so that the water-soluble polymer is decomposed to degrade the physical properties of the water-insoluble gel or Discoloration occurs, resulting in poor quality and yield of the water insoluble gel.

In order to overcome the above disadvantages, a method of using excessive physical force or increasing the concentration of the water-soluble polymer only locally has been proposed, but it is still not possible to obtain a uniform solution. Then, there is still a problem that the crosslinking agent cannot be dissolved uniformly. On the other hand, even when the crosslinking agent and the water-soluble polymer are added to the water at the same time, in order to obtain a high concentration of uniform polymer solution, it is necessary to stir vigorously for a considerable time. When the crosslinking agent of epoxy or divinyl sulfone is in contact with water It has the property of rapidly decreasing activity.

In addition to controlling the concentration of the water-soluble polymer, a frequently used method is an ice method of increasing the amount of crosslinking agent or changing the type thereof. If the input amount of the crosslinking agent is increased to increase the binding density without considering the efficiency compared to the input amount of the crosslinking agent, there is an effect of increasing the reaction density, but a washing process for removing a large amount of unreacted crosslinking agent is added, and the water-insoluble gel The yield of is also lowered, and the phenomenon in which the crosslinking agent is locally concentrated is further intensified.

On the other hand, in addition to the above method in order to increase the binding rate between the water-soluble polymers to maintain a high pH or raise the temperature during the reaction for a long time. However, in this case, since the polysaccharide polymer such as hyaluronic acid is decomposed, the strength of the finally obtained gel composition is weakened or excessively swollen.

Accordingly, the present inventors prepare a water-insoluble gel composition using a water-soluble polymer and a crosslinking agent, but using a dispersion aid, the water-soluble polymer and water ratio, the dispersion aid and water ratio, the dosage of the dispersion aid, water, dispersion aid, water-soluble polymer and By adjusting the order of the crosslinking agent, to prepare a composition in which the water-soluble polymer is insoluble, and then to remove the dispersion aid to provide a method for efficiently producing a water-insoluble gel composition of a good quality.

Hereinafter, the present invention will be described in detail.

One aspect of the present invention comprises the steps of preparing a composition by adding water, a dispersion aid, a water-soluble polymer, a pH adjusting agent and a crosslinking agent; And it provides a method of producing a water-insoluble gel composition comprising the step of removing the dispersion aid from the composition prepared in the step.

As used herein, the water-soluble polymer has a property of dissolving in water, and refers to a large molecule having a molecular weight of 5000 Daltons (Da) or more. It is usually in the form of a polymer.

In one aspect of the invention, the water-soluble polymer may have a molecular weight of 5000 Daltons to 10 million Daltons for a suitable physical strength. It is not limited to this.

In one aspect of the invention, the water soluble polymer is converted to a gel to act as the main component of the gel composition.

In one aspect of the invention, the water-soluble polymer comprises at least one of a carboxyl (-COOH) group or carboxyl salt and a hydroxy (-OH) group or hydroxy salt. In another aspect of the invention, the water-soluble polymer is poly-g-glutamic acid or salts thereof, hyaluronic acid or salts thereof, agar (algar), alginic acid (alginic acid) or alginate alginate, carrageenan, percellaran, pectin, arabic gum, karaya gum, tragacanth gum, gatitti gum ), Guar gum, locust bean gum, psyllium seed gum, gelatin, chitin, dextran, xanthane gum, Chitosan, chondroitin-4-sulfate, chondroitin-6-sulfate, starch, polyvinylalcohol, polyacrylicacid and It includes at least one selected from the group consisting of polyacrylates.

In one aspect of the invention, the water-soluble polymer may be in the form of particles (particle). In another aspect of the invention, the water-soluble polymer may have an average particle diameter of 1㎛ to 5mm. This is because when the particle size of the water-soluble polymer is too large, the uniformity of the composition may be lowered, thereby lowering the quality and yield of the gel composition.

In one aspect of the present invention, the water is added to at least 150% by weight relative to the weight of the water-soluble polymer. If the amount of water added is too small, the water-soluble polymer is not converted to the solution even after the dispersing aid is removed.

In another aspect of the present invention, the water is added to less than 100% by weight based on the weight of the dispersion aid. If water is added over the above range, the water-soluble polymer may be converted into a solution state before removing the dispersion aid. When the water-soluble polymer is converted to a solution state other than the solid state in the composition in which the dispersion aid and the water are mixed, the viscosity of the composition is sharply increased. Increasing the viscosity, in turn, lowers the uniformity of the composition, which can drastically increase the side reactions other than the intended main reaction, discoloration of the gel may occur due to the side reactions, and the water-soluble polymers are decomposed to deteriorate the physical properties of the final gel composition. And the yield of the gel is also lowered.

In one aspect of the present invention, the dispersing aid includes a solvent having a boiling point lower than that of water and having a compatibility with water and not dissolving a water-soluble polymer. As used herein, "compatibility" refers to the property of forming a homogeneous mixture even in solution or solid when mixing two or more materials.

In another aspect of the present invention, the dispersing aid is acetone, tetrahydrofuran, methanol, ethanol, propanol, isopropanol, butanol, pentane And one or more selected from the group consisting of pentanol and hexanol.

In one aspect of the invention, the dispersion aid may be added in more than 100% by weight and less than 1900% by weight relative to the weight of water. When the dispersion aid is added below 100% by weight of water, the water-soluble polymer may be converted into a solution state before removing the dispersion aid. When the dispersion aid is added more than 1900% by weight based on the weight of water, the water-soluble polymer may not be converted into a solution even after the dispersion aid is removed.

As used herein, the term "crosslinking agent" may refer to a material that acts as a bridge between chains of a chain-like polymer. In one aspect of the invention, the crosslinking agent may act to bind to and combine them with a water-soluble polymer. In another aspect of the present invention, the crosslinking agent may include a functional group capable of forming a bond with at least one of a carboxyl group (-COOH) or a carboxyl salt of a water-soluble polymer and a hydroxy group (-OH) or a hydroxy salt. In another aspect of the invention, the bond comprises a covalent bond.

In one aspect of the invention, the crosslinking agent may be an epoxy-based or divinyl sulfone-based crosslinking agent. In another aspect of the invention, the cross-linking agent is divinyl sulfone, epichlorohydrin, epibromohydrin, butanediol diglycidyl ether (1,4-butandiol diglycidyl ether) Ethylene glycol diglycidyl ether, hexanediol diglycidyl ether, propylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether Polyethylenyl glycol diglycidyl ether, Polypropylene glycol diglycidyl ether, Polytetramethylene glycol diglycidyl ether, Neopentyl glycol diglycidyl ether neopentyl glycol diglycidyl ether, polyglycerol polyglycidyl ether, diglycerol polyglycidyl ether, Glycerol polyglycidyl ether, trimethlypropane polyglycidyl ether, bisepoxypropoxyethylene (1,2- (bis (2,3-epoxypropoxy) ethylene), pentae It includes at least one selected from the group consisting of rititolol glycidyl ether (pentaerythritol polyglycidyl ether) and sorbitol polyglycidyl ether (sorbitol polyglycidyl ether).

In one aspect of the invention, the crosslinking agent may be added above the gel point (the gel point) theoretically calculated. In another aspect of the present invention, the crosslinking agent may be added so that the bond formation rate of the water-soluble polymer with the carboxyl group (-COOH) or carboxyl salt and the hydroxy group (-OH) or hydroxy salt is 0.2 to 400%. The crosslinker bond formation rate may be calculated by Equation 1 below. If the crosslinker bond formation rate is less than 0.2%, sufficient gel may not be obtained. When the crosslinking agent bond formation rate is 400% or more, a large amount of unreacted crosslinking agent remains in the final gel composition, and the water yielded polymer may be changed to low molecular weight due to side reaction by the remaining crosslinking agent, thereby lowering the gel yield.

[Equation 1]

Crosslinker bond formation ratio (%) = [(Number of crosslinkable functional groups in crosslinker molecule ⅹ Crosslinker input amount (g) / Crosslinker molecular weight (g / mol)) / (Number of carboxyl groups and hydroxyl groups bondable in water soluble polymer repeat unit ⅹ Water soluble polymer weight ( g) / water soluble polymer repeating unit molecular weight (g / mol)) ⅹ 100

In one aspect of the invention, the pH adjusting agent in the step of preparing the composition by adding the water, the dispersion aid, the water-soluble polymer, the pH adjusting agent and the crosslinking agent is generally capable of adjusting the pH, mixed with water and acid or base strength And to prepare a buffer solution. At this time, the pH adjustment may be made using various types of pH adjusting agent depending on what purpose the composition prepared according to the production method according to an embodiment of the present invention.

In one aspect of the present invention, the functional group of the water-soluble polymer to which the crosslinker is bound may vary depending on the pH of the water. In one aspect of the present invention, when the pH of the water is basic, for example 9 or more, and the crosslinking agent is epoxy-based, the crosslinking agent may form a bond with a hydroxy group (-OH) or a hydroxy salt of the water-soluble polymer. have. At this time, the crosslinking agent and the hydroxy group (-OH) or the hydroxy salt may form an ether bond. In another aspect of the invention, when the pH of the water is acidic, for example 5 or less, and the crosslinking agent is epoxy-based, the crosslinking agent may form a bond with the carboxyl group (-COOH) or carboxyl salt of the water-soluble polymer. Can be. At this time, the crosslinking agent and the carboxyl group (-COOH) or the carboxyl salt may form an ester bond. In another aspect of the invention, when the pH of the water is neutral, for example 6 to 8, and the crosslinking agent is epoxy-based, the crosslinking agent is a carboxyl group (-COOH) or carboxyl salt and hydroxyl group (-COOH) of the water-soluble polymer ( -OH) or a hydroxy salt. At this time, the carboxyl group or salt thereof and the hydroxy group or salt thereof react at the same time to form a double bond. Therefore, by adjusting the pH of the water it is possible to selectively participate in the coupling reaction of the bondable functional group present in the water-soluble polymer.

In one aspect of the present invention, the step of preparing the composition by adding the water, the dispersion aid, the water-soluble polymer, the pH adjusting agent and the crosslinking agent may be carried out by first adding water and the dispersion aid, and then adding the water-soluble polymer and the crosslinking agent. In another aspect of the present invention, the dispersing aid and the water-soluble polymer may be added first, and then water and a crosslinking agent may be added. However, when the dispersion assistant and the water-soluble polymer are added first, it is necessary to vigorously stir the composition into which the dispersion assistant and the water-soluble polymer are added while introducing water very slowly. Otherwise, the water-soluble polymer may be locally in solution.

In one aspect of the invention, the step of removing the dispersion aid in the composition may be carried out by one or more methods selected from the group consisting of a pressure method, a pressure reduction method, a heating method, a cooling method and a membrane permeation method. This may be chosen depending on the nature of the dispersing aid. In this step, the dispersing aid is removed and the water-soluble polymer is dissolved in the remaining water and is slowly converted into a solution state. In this solution state, the water-soluble polymer and the crosslinking agent react to prepare a water-insoluble gel.

In one aspect of the invention, the step of removing the dispersing aid from the composition may utilize a rotary distillation apparatus or similar equipment. In order for the binding reaction of the water-soluble polymer to proceed smoothly, it is necessary to continuously maintain the agitation to uniform the concentration during the removal of the dispersing aid. Rotary distillers or similar equipment may be useful to remove dispersion aids while maintaining constant stirring.

 In one aspect of the invention, the temperature of the step of removing the dispersion aid is determined according to the vapor pressure curve of the dispersion aid. In another aspect of the invention, the step may be carried out at a temperature of less than 100 ℃. In another aspect of the invention, the step may be carried out at a temperature of less than 60 ℃. In another aspect of the invention, the step may proceed at room temperature.

When the water-soluble polymer is converted into a clear solution, the process for removing the dispersing aid is stopped.

In one aspect of the invention, after removing the dispersing aid from the composition, it may further comprise the step of leaving the composition. In another aspect of the invention, the step of leaving the composition may be performed for a temperature and time selected according to the properties of the water-soluble polymer and the crosslinking agent. In another aspect of the invention, the step of leaving the composition may be performed for 1 to 72 hours at room temperature. Through the step of leaving the composition can be sufficiently made a reaction between the additional water-soluble polymer.

In one aspect of the invention, after removing the dispersing aid from the composition, it may further comprise the step of drying the composition. In another aspect of the present invention, the drying of the composition may be performed under reduced pressure. The remaining water may be removed through the drying of the composition to promote the water-soluble polymer-coupling reaction.

One aspect of the present invention provides a water-insoluble gel composition prepared by the method of producing a water-insoluble gel composition. In another aspect of the present invention, the water-insoluble gel composition has physical properties and appearance such as excellent density, strength and the like. In addition, it is stable even under pressure sterilization which must go through when inserting into the human body, and maintains low swelling degree, and is also excellent in economy and quality.

On the other hand, while the water-insoluble gel compositions prepared by the previous method is transparent when suspended in an aqueous solution, the water-insoluble gel composition according to an aspect of the present invention has a characteristic of showing a translucent to opaque milky white when suspended in an aqueous solution.

The water-insoluble gel composition according to one aspect of the present invention is a composition for injection drug carrier, mucosal and transdermal absorption drug carrier composition, oral drug carrier composition, biological tissue repair composition, postoperative biotissue adhesion prevention composition, for molding Filling composition, composition for joint insertion, composition for patch wound treatment dressing, composition for treating osteoarthritis, composition for ophthalmic surgery injection, composition for treating dry eye, composition for injection of wrinkles, composition for gum treatment, composition for treating perforation of tympanic membrane It can be used as a health food composition or cosmetic composition.

Hereinafter, the configuration and effects of the present invention will be described in more detail with reference to Examples, Comparative Examples and Experimental Examples. However, these Examples, Comparative Examples and Experimental Examples are provided only for the purpose of illustration in order to facilitate understanding of the present invention, and the scope and scope of the present invention is not limited by the following Examples, Comparative Examples and Experimental Examples.

[Comparative Examples 1 to 11] Preparation of Conventional Water Insoluble Gel Composition

A water insoluble gel composition was prepared according to conventional methods. The specific process is as follows. First, a mixture of hyaluronic acid (HA) with sodium hydroxide (NaOH) is mixed with a suitable distilled water to make a 10% aqueous solution, and a crosslinking agent butanediol diglycidyl ether (BDDE) is added as shown in Table 1 below, and then 50 ° C. The crosslinking reaction was carried out by storage at 2 hours. After the crosslinking reaction, the HA gel was cut into a size of 0.5 cm or less and placed in 500 ml, followed by primary washing by stirring for 24 hours. During the first wash with distilled water, titrated with 0.1N hydrochloric acid solution to finally pH 6.5 ~ 7.5. After the first wash, the water-insoluble gel was separated by centrifugation (3000 rpm, 20 min). 500 ml of distilled water was further added to the separated gel, followed by further washing by stirring for 24 hours. Additional washes were performed twice. After three washes were completed, the gel yield was calculated by measuring the weight of the water-insoluble gel obtained by vacuum drying.

HA (g) Acetone (g) NaOH
Aqueous solution BDDE (g) Crosslinking agent bond formation ratio (%) Gel yield (%) Comparative Example 1 One 0 0N 9g 0.1 20 0 Comparative Example 2 One 0 10 -5 N 9 g 0.1 20 0 Comparative Example 3 One 0 10 -4 N 9 g 0.1 20 0 Comparative Example 4 One 0 10 -3 N 9 g 0.1 20 0 Comparative Example 5 One 0 10 -2 N 9g 0.1 20 0 Comparative Example 6 One 0 10 -1 N 9g 0.1 20 Not measurable Comparative Example 7 One 0 10 -1 N 9g 0.001 0.2 0 Comparative Example 8 One 0 10 -1 N 9g 0.025 0.5 0 Comparative Example 9 One 0 10 -1 N 9g 0.05 10 Not measurable Comparative Example 10 One 0 10 -1 N 9g 0.25 50 Not measurable Comparative Example 11 One 0 10 -1 N 9g 0.5 100 75

* Crosslinker bond formation rate (%) = [(Number of functional groups capable of binding in BDDE molecules ⅹ BDDE input (g) / BDDE molecular weight (g / mol)) / (Number of carboxyl groups and hydroxyl groups that can be bonded in HA repeat units ⅹ HA weight (g ) / HA repeating molecular weight (g / mol))] ⅹ 100

* Number of functional groups that can be bound in BDDE molecule: 2

BDDE Molecular Weight: 202 g / mol

Carboxyl and hydroxy number that can be bound to HA repeat unit: 2

HA repeat unit molecular weight: 401 g / mol

As can be seen from the results of Table 1, when preparing a water-insoluble gel composition by preparing a hyaluronic acid solution in a conventional manner, the concentration of sodium hydroxide is 0.1N (pH 13), the crosslinking agent is 100% cross-linking bond formation rate It is possible to obtain a water-insoluble gel composition capable of measuring the yield only in a limited area to be injected into.

Test Example 1 Evaluation of Mixing Ratio of Water and Dispersion Aids

A composition containing acetone, ethanol or tetrahydrofuran as water and a dispersing aid was prepared as shown in Table 2 below. The ratio of water in Table 2 is the value calculated as [water weight / (water weight + weight of dispersion aid)] ⅹ 100. 0.1 g of hyaluronic acid was added to the composition, and it was observed whether it was converted into a solution. The results are shown in Table 2 below.

% Of water 10 20 30 40 50 60 70 80 90 Acetone O O O △ △ X X X X ethanol O O O O △ X X X X THF O O O O O X X X X

THF: Tetrahydrofuran

O: There is no big change in viscosity after hyaluronic acid is charged, and the particle state of hyaluronic acid is maintained.

△: no significant change in viscosity after hyaluronic acid is added, but hyaluronic acid is aggregated

X: The viscosity increases after hyaluronic acid addition, and hyaluronic acid is converted into a solution.

As can be seen in Table 2, when the weight of water to the weight of the dispersing aid is more than 100% by weight, the viscosity of the composition increases after hyaluronic acid is added and the hyaluronic acid is converted into a solution. Increasing the viscosity lowers the mixing uniformity of the composition, it can be seen that in order to obtain a uniform gel composition, the weight of water should be 100% by weight or less relative to the weight of the dispersion aid.

Experimental Example 2 Evaluation of Proper Mixing Ratio of Water and Dispersion Aids

Sodium hyaluronate (Mn = 1.4 million Da, HA) particles were added to a 500 ml flask mounted in a rotary distillation apparatus, followed by acetone, which is distilled water and a dispersing aid, as shown in Table 3 below, followed by stirring with a magnetic stirrer. Was added, butanediol diglycidyl ether (1,4-butandiol diglycidyl ether, BDDE) was added as a crosslinking agent. After the crosslinking agent was added, the flask was mounted on a rotary distillation apparatus, and the acetone used as the dispersion aid was distilled off while the flask was immersed in a water bath controlled at 25 ° C. At this time, distillation was continued until the composition in plaque became completely transparent, being careful not to generate bubbles due to rapid distillation. When the composition in the flask became completely transparent, distillation was terminated, and the flask containing the composition containing HA was placed in a vacuum oven and dried under reduced pressure. After the vacuum drying was completed, 400 ml of distilled water was added to the flask, followed by washing three times with a magnetic stirrer for 24 hours. Each time one wash was finished, an insoluble gel was obtained using a filter paper, and the gels obtained after drying three times were dried in a vacuum oven to prepare Examples 1 to 4 and Comparative Example 12. The gel yield was calculated by measuring the weight of the dried gel.

HA (g) Acetone (g) Distilled water (g) BDDE (g) % Crosslinker bond formation Gel yield (%) Example 1 One 18 2 0.01 2 82.8 Example 2 One 14 6 0.01 2 94.6 Example 3 One 12 8 0.01 2 95.7 Example 4 One 10 10 0.01 2 82.1 Comparative Example 12 One 19 One 0.01 2 62.8
(Solution conversion failure)

As can be seen in Table 3, when the weight ratio of acetone: distilled water is 19: 1, it failed to finally convert the hyaluronic acid to the solution phase. That is, it can be seen that in order to prepare an insoluble gel composition, the dispersing aid should be added below 1900 wt% based on the weight of water.

Test Example 3 Evaluation of Proper Crosslinker Bond Formation Rate

In Examples 4 to 10 and Comparative Example 13 were prepared using the same method as in Examples 1 to 4 with the composition of Table 4, the gel yield was calculated. The gel yield comparison results according to the crosslinker bond formation rate are shown in Table 4 below.

HA (g) Acetone (g) Distilled water (g) BDDE (g) Crosslinking agent bond formation ratio (%) Gel yield (%) Example 5 One 16 4 0.001 0.2 35.4 Example 6 One 16 4 0.005 One 54.9 Example 7 One 16 4 0.01 2 87.7 Example 8 One 16 4 0.5 100 95.4 Example 9 One 16 4 One 200 82.8 Example 10 One 16 4 2 400 26.4 Comparative Example 13 One 16 4 0.0005 0.1 7.5

As can be seen in Table 4, when the crosslinker bond formation rate was lower than 0.2%, the gel yield decreased significantly. That is, it can be seen that excellent gel yield can be obtained when the bond formation ratio of the carboxyl group (-COOH) or the carboxyl salt of the hyaluronic acid and the hydroxyl group (-OH) or the hydroxy salt and the crosslinking agent is 0.2 to 400%. .

Test Example 4 Appropriate pH Evaluation

Examples 11 to 17 were prepared using the same method as Examples 1 to 4 with the compositions shown in Table 5 below, and gel yields were calculated. The gel yield comparison results according to the pH of the water are shown in Table 5 below. The pH of water was titrated using 4 g of water and sodium hydroxide or phosphoric acid.

HA (g) Acetone (g) pH BDDE (g) Crosslinker bond formation rate (%) Gel yield (%) Example 11 One 16 9 0.1 20 94.8 Example 12 One 16 10 0.1 20 93.5 Example 13 One 16 11 0.1 20 95.7 Example 14 One 16 12 0.1 20 97.9 Example 15 One 16 13 0.1 20 98.1 Example 16 One 16 One 0.1 20 92.7 Example 17 One 16 3 0.1 20 89.1

As can be seen in Table 5, butanediol diglycidyl ether (BDDE), which is a hyaluronic acid and an epoxy-based crosslinking agent, can be confirmed to exhibit excellent gel yield regardless of the pH range.

Test Example 5 Evaluation of Swelling Degree and Gel Yield

The hyaluronic acid water insoluble gels of Example 14 and Comparative Example 13 were evaluated for swelling degree and gel yield (%) before and after autoclaving.

Swelling measurement before autoclaving was performed using phosphate buffer (phosphate buffer solution, pH 7.4, NaCl 0.9%, PBS). 1 g of each of the water-insoluble gels of Example 14 and Comparative Example 13 was placed in 200 ml of PBS, stored with stirring in a flat plate stirrer until there was no more weight change, and then the weight of the gel when no further weight change appeared was found. It was set to, and the fully swollen gel was placed in 400 ml of distilled water and stirred in a flat plate stirrer for 24 hours to remove salt added for the production of PBS. The salt-free gel was dried in vacuo to measure the dry weight.

Swelling degree after autoclaving was also performed similarly to swelling degree measurement before autoclaving. However, the sample used for autoclaving was sterilized at 121 ° C. for 15 minutes after reaching full swelling state on PBS before autoclaving, and was put back into PBS and stored until there was no weight change. Swelling degree is calculated by the following equation (2). The measured values and the calculated degree of swelling are shown in Table 6 below.

&Quot; (2) "

Swelling Degree = Full Swell Weight / Dry Weight

Gel yield (%) Before autoclaving After autoclaving Swelling weight (g) Dry weight (g) Swelling degree Swelling weight (g) Dry weight (g) Swelling degree Example 14 98.1 1.24 0.073 17 1.84 0.092 20 Comparative Example 13 75 2.4 0.032 76 1.94 0.013 152

As can be seen in Table 6, Example 14 showed a higher degree of gel yield than Comparative Example 13 and showed a low degree of swelling despite the use of a small amount of crosslinking agent. In Comparative Example 13, the swelling degree was sharply increased after autoclaving, whereas Example 14 showed little change in the swelling degree after autoclaving. Through this, it can be confirmed that the water-insoluble gel composition of Example 14 is stable even under pressure sterilization which must pass through when used as an insert in the human body, and has excellent economic efficiency.

Claims (15)

Preparing a composition by adding water, a dispersing aid, a water-soluble polymer, a pH adjusting agent, and a crosslinking agent; And
Removing the dispersing aid from the composition prepared in the step;
In the step of preparing the composition, water and a dispersion aid are added first and then water-soluble polymer is added,
The water is added to 150 parts by weight or more based on 100 parts by weight of water-soluble polymer, and 100 parts by weight or less based on 100 parts by weight of the dispersing aid,
The dispersion aid is added to 100 parts by weight or more and less than 1900 parts by weight relative to 100 parts by weight of water. The method of claim 1,
The water-soluble polymer is a method of producing a water-insoluble gel composition comprising at least one of a carboxyl group (-COOH) or carboxyl salt and a hydroxy group (-OH) or hydroxy salt. The method of claim 1,
The water-soluble polymer is a method of producing a water-insoluble gel composition having an average particle diameter of 1㎛ 5mm. delete The method of claim 1,
The dispersing aid is a solvent having a compatibility with water, a solvent that does not dissolve the water-soluble polymer. The method of claim 1,
The dispersing aid is acetone, tetrahydrofuran, methanol, ethanol, propanol, isopropanol, butanol, butanol, pentanol and hexanol hexanol) water-insoluble gel composition production method comprising one or more selected from the group consisting of. delete 3. The method of claim 2,
And the crosslinking agent forms a bond with at least one of a carboxyl group (-COOH) or a carboxyl salt of a water-soluble polymer and a hydroxy group (-OH) or a hydroxy salt. The method of claim 8,
The cross-linking agent is a water-insoluble gel composition production method is added so that the bond formation ratio of the water-soluble polymer carboxyl group (-COOH) or carboxyl salt and hydroxy group (-OH) or hydroxy salt is 0.2 to 400%. The method of claim 1,
The crosslinking agent is divinyl sulfone, epichlorohydrin, epibromohydrin, butanediol diglycidyl ether (1,4-butandiol diglycidyl ether), ethylene glycol diglycidyl ether (ethylene glycol diglycidyl ether), hexanediol diglycidyl ether (1,6-hexanediol diglycidyl ether), propylene glycol diglycidyl ether, polyethyleneglycol diglycidyl ether ), Polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, neoopentyl glycol diglycidyl ether, polyglycerol Polyglycerol polyglycidyl ether, diglycerol polyglycidyl ether, glycerol polyglycidyl ether glycerol polyglycidyl ether, trimethlypropane polyglycidyl ether, bisepoxypropoxy ethylene (1,2- (bis (2,3-epoxypropoxy) ethylene), pentaerythritol polyglycidyl ether ( A method for producing a water-insoluble gel composition comprising at least one selected from the group consisting of pentaerythritol polyglycidyl ether) and sorbitol polyglycidyl ether. The method of claim 1,
Removing the dispersion aid from the composition is a method of producing a water-insoluble gel composition is carried out by one or more methods selected from the group consisting of a pressure method, a pressure reduction method, a heating method, a cooling method and a membrane permeation method. The method of claim 1,
After the step of removing the dispersion aid in the composition, further comprising the step of drying the water-insoluble gel composition. A water-insoluble gel composition prepared by the method of producing a water-insoluble gel composition according to any one of claims 1 to 3, 5 to 6, and 8 to 12. The method of claim 13,
The water-insoluble gel composition is a composition for injection drug carriers, mucosal and transdermal absorption drug carrier composition, oral drug carrier composition, biological tissue repair composition, postoperative biotissue adhesion prevention composition, molding filling composition or joint insertion A water insoluble gel composition which is a composition. The method of claim 13,
Wherein said composition exhibits a translucent to opaque milky white when suspended in an aqueous solution.
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