WO2018124474A1 - 가교된 히알루론산겔의 정제 방법 - Google Patents

가교된 히알루론산겔의 정제 방법 Download PDF

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WO2018124474A1
WO2018124474A1 PCT/KR2017/013162 KR2017013162W WO2018124474A1 WO 2018124474 A1 WO2018124474 A1 WO 2018124474A1 KR 2017013162 W KR2017013162 W KR 2017013162W WO 2018124474 A1 WO2018124474 A1 WO 2018124474A1
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hyaluronic acid
gel
washing
crosslinked hyaluronic
crosslinking agent
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PCT/KR2017/013162
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English (en)
French (fr)
Korean (ko)
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김정주
송성원
조완진
박광록
장무현
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주식회사 유영제약
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Priority to CN201780081222.2A priority Critical patent/CN110114373B/zh
Publication of WO2018124474A1 publication Critical patent/WO2018124474A1/ko

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0003—General processes for their isolation or fractionation, e.g. purification or extraction from biomass
    • 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
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates

Definitions

  • the present invention relates to a method for producing a crosslinked hyaluronic acid gel. Specifically, the present invention relates to a method for efficiently purifying an unreacted crosslinking agent after obtaining a crosslinked hyaluronic acid gel.
  • Hyaluronic acid is used as a raw material for fillers, joint injections, anti-adhesion agents, ophthalmic medicines or cosmetics.
  • hyaluronic acid itself is rapidly decomposed by enzymes and free radicals and discharged from the body, there is a limit that the duration of the target effect after the injection is not satisfactory, and a method for extending the decomposition time in the body has been sought. Attempts have been made to chemically crosslink hyaluronic acid.
  • the crosslinking agent component of the hyaluronic acid crosslinked product may be recognized as a foreign substance in vitro and may cause an inflammatory response.
  • the hyaluronic acid crosslinked preparation process thus involves the purification of the unreacted crosslinker component.
  • Korean Patent Laid-Open Publication No. 10-2015-0029578 dissolves a high concentration of at least 10 w / w% hyaluronic acid in an aqueous alkali solution to form a long chain, and then adds 0.5 to 1.0 w / w% to the linearized hyaluronic acid.
  • the hydrogel formed of the high density network was cut into a size of 1mm * 1mm to 20mm * 20mm, and the cut hydrogel was buffered at a pH of 6.8 or less. The process of swelling while removing residual crosslinking agent is initiated.
  • Korean Patent Publication No. 10-2013-0010973 discloses a method of crosslinking hyaluronic acid by adding a small amount of a crosslinking agent.
  • this method is only a small amount of the crosslinking agent used, not a method that can completely remove the residual crosslinking agent, did not prove that the amount of the residual crosslinking agent is reduced.
  • WO 2010/015901 discloses a process for cleaning a gel using a dialysis membrane, but this method also has a very difficult process of filling and cleaning a gel in a dialysis membrane and is difficult to apply to large-scale production. There is.
  • the above-mentioned Korean Patent Publication No. 10-2016-0125332 proposes a washing apparatus for washing the crosslinked hyaluronic acid gel, but controls whether the residual crosslinking agent is effectively washed and the content of hyaluronic acid contained in the crosslinked hyaluronic acid gel. There is no suggestion of how.
  • the inventors of the present invention aimed to develop a purification process capable of effectively removing the unreacted crosslinking agent in a manner that the viscoelasticity of the crosslinked hyaluronic acid is not impaired, thereby leading to the completion of the present invention.
  • the present invention has solved the above problems through the following means.
  • washing solution is an isotonic solution, for example a PBS buffer solution, so that the crosslinker can be purified through diffusion.
  • the hyaluronic acid content of the cross-linked hyaluronic acid according to any one of 3 to 6, to physically inhibit the swelling of the cross-linked hyaluronic acid to prevent the lowering of the content of hyaluronic acid to maintain 10 to 50 mg / mL after washing Purification method characterized in that.
  • the present invention it is possible to purify the unreacted crosslinking agent in the crosslinked hyaluronic acid obtained by the crosslinking reaction without degrading viscoelasticity. Specifically, according to the present invention, unlike the purification process according to the conventional simple swelling, it is possible to prevent swelling of the gel during the purification process and to prevent a decrease in the content of hyaluronic acid in the crosslinked hyaluronic acid.
  • Figure 1 shows a plan view of one embodiment of a washing vessel according to the present invention.
  • FIG. 2 shows a side view of one embodiment of a washing vessel according to the invention.
  • Figure 3 shows the real thing of one embodiment of a washing vessel according to the present invention.
  • Figure 5 illustrates a state filled with cross-linked hyaluronic acid gel in one embodiment of the washing vessel according to the present invention.
  • FIG. 6 illustrates a purification process for purifying an unreacted crosslinker using one embodiment of a washing vessel according to the present invention.
  • Figure 7 shows the results of sterility resistance test.
  • FIG. 8 shows the residual 2,2'-sulfonyldiethanol chromatogram of Example 3.
  • FIG. 9 shows the residual 2,2'-sulfonyldiethanol chromatogram of Example 4.
  • FIG. 10 shows the residual 2,2'-sulfonyldiethanol chromatogram of Comparative Example 1.
  • hyaluronic acid refers to all of the known hyaluronic acid raw materials alone or mixtures, such as hyaluronic acid, salts thereof, or precursors thereof.
  • Hyaluronic acid is a natural polymer material that is widely used in various fields such as cosmetic or medical purposes because of excellent biocompatibility. Natural hyaluronic acid is mainly present in the extracellular matrix, and mixes with fiber and collagen to form a matrix solution to stabilize tissue structure. It is a substance found in all vertebrate tissues. It is not immunogenic and is an ideal chemical to be used as a component for tissue repair purposes.
  • Crosslinked hyaluronic acid is a tangled gel in which a matrix is formed by connecting a polysaccharide polymer or the like with a crosslinking agent.
  • the three-dimensional structure of the cross-linked hyaluronic acid enables free movement of nutrients, oxygen, and hormones when injected into the body, thereby exerting general tissue functions.By crosslinking, the hyaluronic acid can extend the tissue residence time of the hyaluronic acid to about 12 months. Can be.
  • Crosslinked hyaluronic acid is degraded in the body at a much slower rate compared to a product based on uncrosslinked hyaluronic acid and still retains its absorption into the body.
  • the cross-linked hyaluronic acid gel having such properties may be administered subcutaneously or intradermally to improve wrinkles, or may be injected into the joint cavity of arthritis patients with cartilage loss to relieve joint pain through buffering. .
  • the preparation of the crosslinked hyaluronic acid gel proceeds as follows.
  • Pulverizing crosslinked hyaluronic acid gel having completed swelling to form a desired size (grinding process);
  • Sterilized by filling the ground gel in a container suitable for the purpose (sterilization process).
  • the crosslinked hyaluronic acid gel prepared through the above steps should maintain high biocompatibility so as not to cause side effects when used for the purpose of administration in the body.
  • the crosslinking agent used in the reaction process remains in the gel by a certain amount without participating in the crosslinking reaction with hyaluronic acid due to the nature of the chemical reaction.
  • the remaining crosslinking agent may cause side effects such as an inflammatory reaction when administered in the body, and the manufacturer of the crosslinked hyaluronic acid gel should design a manufacturing process capable of completely removing the remaining crosslinking agent.
  • Removal of the residual crosslinking agent is carried out in a purification process, and a general purification process is performed by supporting the crosslinked hyaluronic acid gel in an aqueous solution for washing.
  • the aqueous solution for washing uses saline or buffered solution. Since the crosslinked hyaluronic acid gel injected onto the aqueous solution has a matrix structure capable of mass exchange, the crosslinking agent remaining in the gel can escape to the outside of the gel through simple diffusion. Therefore, the residual crosslinker can be completely removed by immersing the crosslinked hyaluronic acid gel in an aqueous solution for washing for a sufficient time.
  • the crosslinked hyaluronic acid gel has a strong absorption (Water), when it is added to the aqueous solution it has the property of absorbing water and swelling. As the gel swells, it contains an increasing amount of water, so that the content of hyaluronic acid in the gel gradually dilutes and decreases.
  • the inventors have found that the hyaluronic acid content of the crosslinked hyaluronic acid gel is an important factor in determining the firmness of the matrix constituting the gel.
  • the content of hyaluronic acid contained in the crosslinked hyaluronic acid gel is 10 to 50 mg / mL, preferably 15 to 25 mg / mL after the purification process.
  • the cross-linked hyaluronic acid gel containing 10 mg / mL or more of hyaluronic acid still maintains strong absorption due to the high concentration of hyaluronic acid, and is added to an aqueous solution without a special device as in the conventional purification process of the simple swelling method described above.
  • the content of hyaluronic acid may already be very low before it swells at high speed and the washing of the residual crosslinking agent is complete.
  • the cross-linked hyaluronic acid having a lower content of hyaluronic acid after purification may reduce the inflammatory reaction due to the unreacted crosslinking agent when administered in the body, but the desired performance cannot be satisfactorily achieved through the injection of hyaluronic acid.
  • the content of hyaluronic acid 10 mg / mL or more could be preserved.
  • the washing container of the present invention is characterized in that it is embodied in a size capable of physically inhibiting swelling of the cross-linked hyaluronic acid gel and allowing the washing aqueous solution to pass freely.
  • the crosslinked hyaluronic acid gel purified by the purification method using the washing container according to the present invention is completely removed from the residual crosslinking agent, the resulting crosslinked hyaluronic acid gel will have a high purity and biocompatibility, the hyaluronic acid content is in the desired range Can be maintained. That is, after the purification process using the washing container according to the present invention, there is no significant change in physical properties such as viscoelasticity of the crosslinked hyaluronic acid gel before and after the purification process. This is a remarkable effect compared to the conventional purification method.
  • the washing container used in the present invention must satisfy the following conditions.
  • the size of the pores formed in the cleaning container should be such that the gel does not spill out of the cleaning container.
  • the pores of the cleaning vessel should be able to make contact with the gel with sufficient area.
  • the internal volume of the wash vessel should not be greater than the swelling target volume of the crosslinked hyaluronic acid gel.
  • the washing container according to the present invention that satisfies the conditions described above can prevent the crosslinked hyaluronic acid gel from swelling beyond a desired volume, thereby preventing the content of hyaluronic acid from lowering below the target content, and the crosslinked hyaluronic acid gel is purified. Even after the process, the deterioration of basic physical properties such as viscoelasticity may not appear.
  • (A) and (B) are the forces which suppress the swelling of the crosslinked hyaluronic acid gel
  • (C) and (D) are the forces which promote the swelling of the crosslinked hyaluronic acid.
  • (A + B)> (C + D) the gel's water is released into the aqueous solution, and the volume of the gel shrinks.
  • (A + B) ⁇ (C + D) the water in the aqueous solution is absorbed by the gel. The volume of the gel will expand.
  • the washing process of the residual crosslinking agent of the crosslinked hyaluronic acid gel proceeds regardless of the gel matrix, osmotic pressure, and hyaluronic acid absorption.
  • the residual crosslinking agent passes through the matrix and flows out from the inside of the gel to the outside by diffusion according to the concentration gradient of the free crosslinking agent between the aqueous solution for washing and the crosslinked hyaluronic acid gel.
  • the shape or size of the pores of the washing vessel for washing the crosslinked hyaluronic acid gel according to the present invention is not limited, but should be smaller than the size of the gel so that the crosslinked hyaluronic acid gel does not leave the washing vessel during the purification process.
  • the size of each pulverized gel is appropriately 10 to 50 mm
  • the size of the pores of the washing vessel is preferably 1 to 10 mm in length or diameter smaller than the size of the gel. Structures in the form of a network having the same inner diameter rather than pores are also suitable for realizing the present invention.
  • the material of the cleaning vessel should be capable of providing a tension that can physically inhibit the swelling of the crosslinked hyaluronic acid, which is suitable for plastic or metal materials.
  • chemically stable, high strength polypropylene, polyethylene, polytetrafluoroethyl, or equivalent materials are suitable as plastics, and chemically stable, high strength SUS 301, SUS 302, SUS 303, Suitable materials are SUS 30 3SE, SUS 304, SUS 304L, SUS 316, SUS 316H, SUS 316 L, SUS 316N, SUS 316Ti or equivalent.
  • the process for obtaining the crosslinked hyaluronic acid gel using the washing vessel according to the present invention is as follows.
  • the crosslinking reaction of the crosslinking agent and hyaluronic acid is performed.
  • the crosslinking agent can be adopted without limitation, for example, 1,3-butadiene diepoxide, 1,2,7,8-diepoxyoctane, 1,5-hexadiene diepoxide, ethylene glycol diglycidyl Ether, bisphenol A diglycidyl ether, divinylsulfone, epichlorohydrin, 1,4-butanediol diglycidyl ether (BDDE), 1,4-bis (2,3-epoxypropoxy) butane From 1,4-bisglycidyloxybutane, 1,2-bis (2,3-epoxypropoxy) ethylene and 1- (2,3-epoxypropyl) -2,3-epoxycyclohexane You can choose.
  • the molecular weight, crosslinking degree, etc. of hyaluronic acid can be suitably determined according to the properties of the desired product.
  • the crosslinked hyaluronic acid obtained is then cleaved and the cleaved crosslinked hyaluronic acid is filled into a washing vessel according to the present invention and washed with a washing solution.
  • a washing solution a well-known buffer solution may be selected, and salts such as NaOH, KOA, NaHCO 3 or LiOH may be added so as to have a pH of about 6.5 to 8.0 as necessary.
  • isotonic solutions such as phosphate buffer (PBS) may be used as the washing solution.
  • the degree of swelling of the crosslinked hyaluronic acid gel during the wash may also be desirable to check the degree of swelling of the crosslinked hyaluronic acid gel during the wash.
  • the degree of swelling may be checked by measuring the volume of the crosslinked hyaluronic acid gel being washed in units of 1-4 hours.
  • the washing is preferably carried out for a time sufficient to allow the unreacted crosslinker to be removed through diffusion. For example, there is no limit, but you can try 10-48 hours. Washings less than 10 hours may vary from case to case, but may be insufficient for sufficient purification of the unreacted crosslinker.
  • the present invention focuses on the improvement of the purification process, and thus, even if the technology is not disclosed in the present specification, the hyaluronic acid cross-linking production method other than the purification apparatus and the process may be used as a raw material, In all aspects, such as the content and method, known ones may be used without limitation.
  • cross-linked hyaluronic acid gel 5 g of sodium hyaluronate was dissolved in 50 mL of 0.5 M sodium hydroxide solution, and 0.3 mL of divinylsulfone was added to the solution. After aging at 37 ° C. for 2 hours, the gelled elastic cross-linked hyaluronic acid gel was cut to a size of about 10 mm in width, about 10 mm in length, and about 10 mm in height as shown in [Fig. 4].
  • Example 2 The resultant of Example 2 was weighed by about 4.8 mL and placed in the washing vessel of Example 1 as shown in [Fig. 5]. The lid of the washing vessel was closed, and a washing vessel filled with a cross-linked hyaluronic acid gel in 500 mL of pH 6.9 PBS buffer solution was added as shown in [Fig. 6]. After 24 hours, the wash container was taken out of the buffer solution and the gel filled in the wash container was recovered.
  • Example 2 The resultant of Example 2 was weighed by about 4.8 mL and filled into the washing vessel of Example 1.
  • the washing vessel was capped and a washing vessel filled with a cross-linked hyaluronic acid gel was added to 500 mL of pH 6.9 PBS buffer solution. After 48 hours the wash vessel was removed from the buffer solution and the gel filled in the wash vessel was recovered.
  • Example 3 The resultant of Example 3 was filled into a glass syringe and sterilized for 20 minutes at a temperature of 121 ° C.
  • Example 4 The resultant of Example 4 was filled into a glass syringe and sterilized for 20 minutes at a temperature of 121 ° C.
  • Example 2 The resultant of Example 2 was weighed by about 4.8 mL and added to 500 mL of pH 6.9 PBS buffer solution to measure the volume of the swollen gel every hour, and the gel from the buffer solution when the gel was swollen by 24 mL after 5 hours. Was recovered.
  • Example 2 The resultant of Example 2 was weighed by about 4.8 mL and added to 500 mL of pH 6.9 PBS buffer solution, and after 48 hours the gel was recovered from the buffer solution.
  • Example 3 The resultant of Example 3 was filled into a glass syringe and sterilized for 20 minutes at a temperature of 121 ° C.
  • Example 4 The resultant of Example 4 was filled into a glass syringe and sterilized for 20 minutes at a temperature of 121 ° C.
  • Hyaluronic acid content evaluation was performed about the crosslinked hyaluronic acid gel corresponding to Example 3, Example 4, Comparative Example 1, and Comparative Example 2.
  • Hyaluronic acid of each cross-linked hyaluronic acid gel was used as a sample solution by completely dissolving an amount corresponding to 3 mg in 5 mL of borax / sulfuric acid solution as a sample solution, according to the Assay of Hyaluronic Acid Ophthalmic Injection Solution in the Korean Pharmacopoeia General Test Method. Tested. The analysis results are shown in [Table 1].
  • Example 3 sample Sodium hyaluronate content
  • Example 4 19.9 mg / mL Comparative Example 1 20.2 mg / mL Comparative Example 2 8.8 mg / mL
  • the cross-linked hyaluronic acid gels filled in the washing vessels as in Example 3 and Example 4 were swollen for 5 hours despite being supported on the buffer solution for 24 hours and 48 hours, respectively. It was confirmed that sodium hyaluronate content of about 20 mg / mL was maintained on an equal basis with the crosslinked hyaluronic acid gel of 1. As shown in Comparative Example 2, the cross-linked hyaluronic acid gel that was added to the buffer solution for 48 hours without using the washing vessel was swollen in excess, indicating that the sodium hyaluronate content was very low.
  • the cross-linked hyaluronic acid gel which was filled in the washing container as in Example 3 and Example 4, was swollen for 5 hours, even though they were added to the buffer solution for 24 hours and 48 hours, respectively.
  • the crosslinked hyaluronic acid gel of 1 it was confirmed to exhibit an equivalent storage elasticity of about 700 Pa. Accordingly, it was confirmed that the swelling was physically inhibited for a long time through the crosslinked hyaluronic acid gel purified by the conventional purification method and the washing vessel of the present invention, and the purified crosslinked hyaluronic acid gel exhibited the same physical properties.
  • the crosslinked hyaluronic acid gel of Comparative Example 2 which was excessively swollen for 48 hours without a washing container, had a low storage elasticity of about 2 times or more, thereby deteriorating physical performance.
  • Example 3 As a non-sterile crosslinked hyaluronic acid gel, the storage elasticity of Example 3, Example 4, Comparative Example 1 and Comparative Example 2, and as a sterilized crosslinked hyaluronic acid gel filled in a glass syringe were used.
  • the storage elasticity of 3 and Comparative Example 4 was compared to test the sterilization resistance according to the purification conditions.
  • the evaluation of storage elasticity was carried out using a Rheometer MCR 302 (Anton Paar) instrument, and the analysis results are shown in [Table 3] and [Fig. 7].
  • Example 4 Evaluation of the residual crosslinking agent with respect to the crosslinked hyaluronic acid gel which concerns on Example 3, Example 4, and the comparative example 1 was performed. Each resultant was sieved through a 35 mesh sieve, diluted 100-fold in purified water, and sonicated for 24 hours. After the ultrasonic shaking was completed, the liquid was centrifuged. Concentration analysis of 2,2'-sulfonyldiethanol, a derivative of divinyl sulfone, on the centrifuged supernatant was performed using a UHPLC 1290-Agilnet 6490 QQQ LC / MS (Agilent) instrument. The analytical results of 2,2'-sulfonyldiethanol for Example 3, Example 4, Comparative Example 1 and Comparative Example 2 are shown in Table 4.

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PCT/KR2017/013162 2016-12-28 2017-11-20 가교된 히알루론산겔의 정제 방법 WO2018124474A1 (ko)

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KR102549875B1 (ko) 2020-09-22 2023-07-03 주식회사 필코리아 필러 정제용 장치
KR102640893B1 (ko) 2021-11-12 2024-02-27 주식회사 유영제약 히알루론산 가교물을 포함하는 조성물의 제조방법

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